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Tailoring psoriasis therapy: Towards a safer and more effective systemic treatment

Menting, S.P.

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Citation for published version (APA):Menting, S. P. (2016). Tailoring psoriasis therapy: Towards a safer and more effective systemic treatment.

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Tailoring psoriasis therapy:

Towards a safer and more effective systemic treatment

Stefanus Petrus Menting

Cover design: Pieter Versluis, [email protected]

Layout and printing: Off Page, Amsterdam, www.offpage.nl

© Copyright 2016 by Stefanus Petrus Menting, all rights reserved.

ISBN: 978-94-6182-742-5

This thesis was financially supported by:

Abbvie, BAP Medical, Beiersdorf-Eucerin, Celgene, Conva Tec, Fagron, Galderma, Huidstichting Chanfleury van IJsselsteijn, Leo Pharma, Pfizer, Pierre-Fabre Dermatologie/Mediq, Shire

Tailoring psoriasis therapy:

Towards a safer and more effective systemic treatment

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad van doctor

aan de Universiteit van Amsterdam

op gezag van de Rector Magnificus

prof. dr. ir. K.I.J. Maex

ten overstaan van een door het College voor Promoties ingestelde commissie,

in het openbaar te verdedigen in de Aula der Universiteit

op vrijdag 16 december te 13.00 uur

door

Stefanus Petrus Menting

geboren te Riethoven

PROMOTIECOMMISSIE

Promotores Prof. dr. P.I. Spuls Universiteit van Amsterdam

Prof. dr. M.A. de Rie Universiteit van Amsterdam

Copromotor Dr. L. Hooft Universiteit Utrecht

Overige leden Prof. dr. J. Lambert Universiteit Gent

Prof. dr. P.C.M. van de Kerkhof Radboud Universiteit Nijmegen

Dr. G.J. Wolbink Sanquin research

Prof. dr. G.R.A.M. D’ Haens Universiteit van Amsterdam

Prof. dr. P.M.M. Bossuyt Universiteit van Amsterdam

Dr. J.R. Mekkes Universiteit van Amsterdam

Faculteit Geneeskunde

TablE Of COnTEnTS

Chapter 1 GENERAL INTRODUCTION AND OUTLINE OF THIS THESIS 9

Chapter 2 SAFETY AND EFFECTIVENESS OF BIOLOGICAL AND METHOTREXATE TREATMENT 33

Chapter 2A Drug survival is not significantly different between biologics in patients with psoriasis vulgaris: a single-centre database analysis 35

Chapter 2B An increased risk of non-melanoma skin cancer during TNF inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors 53

Chapter 2C PIIINP measurements for the detection of liver fibrosis in methotrexate treated psoriasis patients: Daily practice use and clinical implications 71

Chapter 3 PERSONALIZING AND IMPROVING METHOTREXATE AND BIOLOGICAL TREATMENT 89

Chapter 3A Methotrexate dosing regimen for plaque-type psoriasis: a systematic review of the use of test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and folic acid supplementation 91

Chapter 3B Extent and Consequences of Antibody Formation Against Adalimumab in Patients With Psoriasis: One-Year Follow-up 113

Chapter 3C Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment 129

Chapter 3D Optimising adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol of a pragmatic, single-blinded, investigator-initiated randomized controlled trial 145

Chapter 3E The correlation of clinical efficacy, serum trough levels and antidrug-antibodies in ustekinumab treated psoriasis patients in a clinical practice setting 159

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Chapter 4 GENERAL DISCUSSION 173

Chapter 5 SUMMARY AND CONCLUSIONS/ SAMENVATTING VOOR NIET INGEWIJDEN 187

Addendum List of contributing authors 205

PhD portfolio 207

Bibliografie 211

Curriculum vitae 213

Dankwoord 215

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CHAPTER 1

GENERAL INTRODUCTION AND OUTLINE OF THIS THESIS

General introduction and outline of this thesis

1

InTROduCTIOn

History of psoriasisPsoriasis already dates back to the “father of medicine” Hippocrates (460-370 BC), who treated the disease with the still used topical treatment tar. In the early days, no distinction was made between psoriasis and other diseases such as leprosy. It wasn’t until Robert Willan (1757-1812, the founder of dermatology as a medical specialty), and Thomas Bateman (1778-1821, dermatologist) recognized psoriasis as a separate entity. Because no distinction was made between psoriasis and leprosy, psoriasis patients were treated as outcasts for centuries and had to announce their arrival with a clapper. In 1841 a Viennese dermatologist, Ferdinand Ritter von Hebra, named the disease psoriasis, after the Greek word “psora” meaning itch.

Epidemiology and comorbiditiesPsoriasis is a common chronic inflammatory skin disorder, with prevalence in Europe ranging from 0.7% to 2.9%. It is less common in Asia and very rarely seen in Africa (1). The prevalence in children is 0.6-1.4% (2) and the incidence shows two peaks; between 15 and 30 years of age and between 50 to 60 years (1, 3).

Besides the skin, psoriasis may affect the nails (psoriasis unguium) as well as the joints (psoriatic arthritis). Seven to 48% of psoriasis patients suffer from psoriatic arthritis (4), which some consider as a separate disease entity with a distinct therapeutic spectrum (5). Having psoriasis unguium is positively associated with having psoriatic arthritis (6). Sometimes psoriatic arthritis precedes skin psoriasis but in most cases it coincides with or follows the development of this skin disease.

Comorbidities such as Crohn’s disease, colitis ulcerosa (7) and metabolic syndrome (8) are associated with psoriasis. It has been argued whether psoriasis is an independent risk factor for cardiovascular disease (9, 10).

Forms of psoriasisPlaque type psoriasis, the focus of this thesis, is by far the most common clinical form of psoriasis with 80% of psoriasis patients suffering from it (11). Plaque type psoriasis, also known as psoriasis vulgaris, can occur everywhere on the skin and is characterized by well-defined, indurated erythematous scaly plaques. It mostly occurs at preferred body sites (elbows, knees, scalp, lumbosacral region, umbillicus). Other forms of psoriasis are e.g. guttate, inverse, erythrodermic and pustular. Guttate psoriasis is characterized by an acute eruption of small (<1 cm) papules of psoriasis, which are often thought to appear after a streptococcal throat infection. Inverse psoriasis (also known as flexural or intertriginous psoriasis) is a form of psoriasis in which lesions are located in the flexural body areas such as the groin, axilla, genital and natal cleft. Pustular psoriasis is characterized by

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noninfectious pustules in the skin and can (amongst other types of psoriasis) be triggered by e.g. medicine. It can be subdivided in a localized form (palmoplantar pustulosis and acrodermatitis continua of Hallopeau) and a generalized form (Von Zumbusch). Finally, erythrodermic psoriasis is characterized by widespread reddening and scaling of the total bodyskin.

Impact on quality of lifeIt is very well known that living with psoriasis has a great impact on quality of life (12) inducing a negative self-image, impaired emotional functioning and limitations in social contacts, daily activities and work. This can lead to stigmatization, psychological comorbidities (e.g. depression) and social isolation. Disease severity has been observed to negatively impact the financial status of psoriasis patients (13) and quality of life impairment of psoriasis has been shown to be comparable to that of other chronic diseases such as diabetes and cardiovascular disease (14).

Pathogenesis At first, psoriasis was thought only to be a keratinocytic disorder. Keratinocytes in psoriatic lesions were shown to have abnormally high proliferation and abnormal differentiation (15, 16). When cyclosporin, an agent used in transplant patients, was observed to have improved psoriasis lesions, the immune system was first appreciated as playing an important role in the pathogenesis of the disease (17). T-cells were later found to be one of the key players of the immune cells involved in psoriasis (18). Later it was observed that psoriasis lesions in a patient with inflammatory bowel disease dramatically decreased by the use of anti-tumor necrosis factor alpha (TNF-alpha) monoclonal antibodies (19). Nowadays, it is known that an elevated level of activated T-cells and dendritic cells is present in psoriatic skin, together with the increased production of cytokines, specifically tumor necrosis factor (TNF)-α and interleukin (IL)-23. These cytokines promote the development of T helper (Th) 1 and Th 17 cells, secreting TNF-α, IL-6, IL-12, IL-17, IL-22 and IL-23. This leads to inflammatory skin changes and epidermal hyperplasia (keratinocyte activation and proliferation), leading to more cytokine production (20).

Psoriasis seems to affect genetically predisposed individuals more often than those who are not genetically pre-disposed. Respectively, 4%, 28% and 65% is the lifetime risk of getting psoriasis if no parent, one parent or both parents are affected (21). Further, the risk of psoriasis is higher in monozygotic twins compared with dizygotic twins (22). HLA-Cw6 is consistently identified as the major histocompatibility locus antigen cluster (23), although its penetrance is low at about 10%, suggesting that other genetic and environmental factors (e.g. stress, medication, infections, microbiome (24)) are involved.

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Topical-, photo- and systemic treatments of psoriasis from a historical perspective For more than a century, the only treatments for psoriasis, besides sunlight, were topical treatments: coal tar, dithranol, salicylic acid, Dead Sea salts and emollients.

Dioscorides, an ancient Roman physician of Greek descent, described the use of coal tar for dermatological treatments around 2000 years ago. It is still used for treating psoriasis and atopic dermatitis. For the latter the mode of action has been unraveled (25). However, adherence is a problem as the tar preparations tend to stain and are malodorous. It may be used in combination with ultraviolet light B (UVB) phototherapy (Goeckermann regimen). In 1953 dithranol was added to this regimen, known as the Ingram method (26).

Dithranol was discovered in 1876. It was used mistakenly to treat psoriasis, which was diagnosed as a fungal infection, where dithranol was normally used for. It was first synthesized in 1916 (27), and is nowadays often used in a daycare setting due to staining of cloths and furniture (28).

Salicylic acid (a precursor of aspirin) is a natural product found in willow tree bark and has been used as a systemic treatment for centuries to relieve fever and pain. For psoriasis, it is applied topically to reduce keratinocyte proliferation.

In the 1950s, topical steroids came into use (29) and have proven to be a valuable psoriasis treatment ever since (30). Different strengths of topical therapies are available (in most countries divided in classes I to IV, the latter being the most potent), coming in different vehicles. The strength and vehicle may be selected based on the severity and the location of psoriasis. Long term excessive use of topical corticosteroids can lead to skin atrophy, teleangiectasia and may very rarely lead to adrenal suppression (31). Many patients are aware of these potential side effects. However, the fear for the use of corticosteroids leading to low adherence to therapy (corticophobia) should be avoided by good instructions beforehand (32). To reduce steroid use, they may be administered in combination with tar, dithranol, salicylic acid or with vitamin D analogues (33) or as intermittent monotherapy (for example two weeks daily followed by four sequential days of treatment and three days without topical corticosteroids). Topical corticosteroids can be applied under occlusion of an occlusive bandage to improve efficacy.

From the second half of the 20th century, systemic treatments became available for psoriasis treatment.

Methotrexate has been widely used and prescribed as a systemic treatment for psoriasis since Gubner first described the efficacy of folic acid antagonists in psoriasis treatment in 1951. It is the oldest systemic treatment used, approved by the Food and Drug Association (FDA) in 1971 before randomized clinical trials (RCTs) were used to judge the safety and efficacy of a drug (34). There is a wide variety of dosing regimens (35) and guidelines for methotrexate dosing are partially

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based on expert opinions (36, 37). It can be administered orally or per subcutaneous or intramuscular injection. Under regular monitoring (when stable dosing, every 3 months) methotrexate can be used for years and is therefore very suitable for treating psoriasis. Methotrexate is often administered in a start dose ranging from 7.5 mg to 15 mg per week together with folic acid the day after to prevent side effects. Side effects include gastro-intestinal complaints, myelosuppression, and pulmonary fibrosis. The most prominent long term side effect is hepatotoxicity (36). Methotrexate has been compared to many other treatments in RCTs, for example, its efficacy was shown to be equal to cyclosporin and fumaric acid (38, 39), though inferior to adalimumab and infliximab (40, 41). The RCT comparing methotrexate to adalimumab was commented though because methotrexate was dosed too low (42). Because of the teratogenic effect, men and woman should not conceive for three months after using methotrexate.

In 1959, a German chemist Schweckendiek discovered the effect of fumaric acid as a systemic treatment for psoriasis while treating himself for the disease (43). After developing gastric ulcerations due to the acidic nature of fumarates, he chemically modified the compounds into non-acidic ester derivates. Despite the treatment successfully clearing his skin, it was not until 1984 when Schafer (also a psoriasis patient) brought fumarates to attention again. Fumaric acid is administered orally and the dose is slowly increased to a maximum and then tapered to the minimal dose with which sufficient effectiveness is attained. Many patients develop gastro-intestinal complaints like nausea or diarrhea around one month of treatment, though this fades away. Nugteren-Huying et al (44) published about their effects in a randomized double-blind placebo controlled study in 1990. From then on, the use of fumarates became more widespread and eventually the treatment was incorporated in the European guidelines on psoriasis (37). However, fumarates remain an unregistered treatment in the Netherlands. Woman should not conceive during and up to two weeks after treatment with fumaric acid.

After the development of the first topical and systemic treatments for psoriasis, the effectiveness of psoralens’ addition to UVA therapy was discovered in the 1970’s (PUVA) (45). It has its roots in ancient Egypt (46). Photosensitizing psoralens can be administered orally and topically (bath or cream) and together with UVA this is highly effective in treating psoriasis. Because of the risk of skin cancer (47) it is advised to limit the UVA-dose to 1000 J/cm2 (150-200 treatments) (Dutch Guideline Psoriasis 2011) (48).

At the moment, several phototherapy modalities are used for treating psoriasis. UV light induces immunosuppression in the skin, which leads to suppression of psoriasis disease activity (49). Because it shows less side effects, narrow-band UVB is more commonly used than PUVA, narrow-band (emission peak at 311 nm) being more effective than broad-band (280-320 nm) (37). The UVB dose has to be increased gradually. Therapy is administered 2 or 3 times a week for an average

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period of three months. Patients can come to the hospital for treatment or patients can get a UVB cabin at home.

Both UVB and PUVA can be combined with retinoids (re-UVB and re-PUVA) to increase efficacy (50).

Development of new treatments for psoriasis continued. In 1971, cyclosporin was isolated from the fungus Tolypocladium inflatum. It was first investigated as anti-fungal antibiotic, though the spectrum was too narrow for this. It was discovered to cause a selective immunoregulation of T-cells in 1979 and is widely investigated for treating psoriasis (17). Cyclosporin is administered orally in a dose of 3-5 mg/kg/day divided in two doses. It is seen as a fast acting drug. Because of its nephrotoxicity and possible increases in blood pressure, it is advised to only use it for a 2-4 month period, up to a maximum of 1-2 years (37). For woman it is advised not to conceive during the use of cyclosporin.

In 1972, retinoids (to be administered orally) were first synthesized (etretinate) for treating skin cancer. Its effect on psoriasis was soon established. Because of etretinate’s long elimination half-life (making it hard to dose) and its high teratogenic effect, it was replaced by its active metabolite, acitretin, in 1988. Acitretin is thought to have the same effect, though with a shorter half-life. It is administered orally in a start dose of 0.3-0.5 mg/kg/day and in case of lack of efficacy the dose is increased up to a maximum of 1 mg/kg/day. Acitretin often causes dryness of skin and mucosa. Despite its shorter half-life, the teratogenic effect of acitretin is not shorter compared to etretinate and therefore women should avoid pregnancy for up to three years after termination of the treatment (37).

In the 90s, topical Vitamin D derivatives were added to the arsenal as calcipotriol and calcitriol. Calcipotriol (a synthetic derivative of calcitriol) was registered in the 90s, though it was withdrawn from the market as monotherapy about a decennium later because of economic reasons. Calcipotriol is now only available as combination therapy in the Netherlands (with topical betamethasone). It is available in a gel based vehicle, which makes it suitable for treating psoriasis of the scalp. In other countries (e.g. Germany, US) it is available as monotherapy. Currently, calcitriol is available as monotherapy in the Netherlands. It was registered in 2005. Irritation of the skin is the most commonly observed side effect.

Topical calcineurin inhibitors (tacrolimus ointment and pimecrolimus cream) are approved for the treatment of atopic dermatitis only (tacrolimus being registered in 2003), though some report on its effect on psoriasis (facial, genital and other inversa locations) (51). It has never been approved for the treatment of psoriasis.

An addition to the treatment spectrum: biologicalsIn the last two decades the increased understanding of the immunopathogenesis of psoriasis has led to the development of biologicals. A biological is a medicinal product manufactured in, extracted from, or semisynthesized from biological

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sources. They are proteins produced involving recombinant DNA technology. Biologics specifically target cytokines or signaling-molecules in the immune system to prevent the hyperproliferation of keratinocytes.

The first biological therapy to appear for psoriasis treatment was alefacept, an anti-T-cell treatment (2001) (52). This drug however, has never been registered for the treatment of psoriasis in most of Europe and has already been withdrawn from the market.

In 2004 the European Medicines Agency (EMA) approved efalizumab (an IgG1 kappa immunoglobulin interfering with T-cell activation) for the European market. In 2009 it was withdrawn because of reports about the development of progressive multifocal leukoencephalopathy (53).

In Europe, etanercept, infliximab, adalimumab, ustekinumab, secukinumab and ixekizumab are registered biologicals for treating psoriasis. Their efficacy assessed in existing RCTs is superior to that of other systemic treatments (54). Mainly due to the high cost (55) biological therapy is only started when patients suffer from severe psoriasis and when other therapies like UVB and methotrexate have failed.

Etanercept was approved for the treatment of psoriasis by EMA in 2004. It is a genetically engineered protein, which inhibits the biological activity of TNF- α (37) by binding to the single trimer form of TNF- α, resulting in a complex of etanercept and TNF- α in a 1:1 ratio. Etanercept is administered as a weekly (50 mg), or twice weekly (25 or 50 mg), subcutaneous injection. It is also used for treating e.g. rheumatoid arthritis, psoriatic arthritis and pediatric psoriasis. Etanecept has proven its efficacy in placebo controlled RCTs (56, 57). The addition of methotrexate or acitretin to the treatment of etanercept has proven to be well tolerated and has shown improved efficacy over etanercept monotherapy (58, 59). Sparse head-to-head trials comparing etanercept to other biologicals are available. One RCT compared etanercept (2x50mg/week) to ustekinumab (45 mg or 90 mg, administered at week 0 and 4). At week 12, ustekinumab (in both the low and high dose) showed superiority (measured by PASI) over etanercept (2x50mg/week) (60). In one RCT, etanercept (2x50mg/week for 12 weeks, then 1x50mg/week) was compared to secukinumab, the latter proved to be superior (61). Some patients form antibodies against etanercept, though all antibodies seem to be non-neutralizing and because of that they don`t influence the clinical response.

Infliximab was approved by EMA for the treatment of psoriasis in 2005. It is a chimeric (mouse-human) antibody administered intravenously every two months per IV at a dose of 5 mg/kg after a loading dose at week 0, 2 and 6. It binds with high affinity to TNF-α. Infliximab forms large complexes of soluble TNF molecules linked by anti-TNF monoclonal antibodies (62). Besides psoriasis, infliximab is also registered for the treatment of e.g. rheumatoid arthritis, Crohn`s disease and psoriatic arthritis. The efficacy of infliximab has been proven in placebo controlled RCTs (63, 64). In one RCT its superiority to methotrexate was shown (41). RCTs

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comparing infliximab to other biologicals are lacking though one study comparing it to etanercept is currently being performed (Netherlands Trial Registry number NTR1559). It is reported that up to 43.6% of patients develop neutralizing antibodies to infliximab (65), which are associated with a lower serum level of the drug and thereby loss of response (66).

Adalimumab, approved by EMA for the treatment of psoriasis in 2007, is a fully human antibody administered as a subcutaneous injection of 40 mg every two weeks from week 1, after an initial dose of 80 mg at week 0. Just like infliximab, it binds to TNF- α. Adalimumab was shown to be superior to placebo and to methotrexate (40) though it is commented that methotrexate was administered in a sub-optimal dose (42). Neutralizing antibodies to adalimumab may be formed in up to 45% of patients (65), leading to lower serum levels and thereby loss of response (67). Adalimumab is also registered for the treatment of other diseases like rheumatoid arthritis, Crohn`s disease, hidradenitis suppurativa and psoriatic arthritis.

Ustekinumab, a fully human antibody, is administered as a subcutaneous injection of 45 mg every three months, after an initial injection at week 0 and 4. In case of inefficacy the dose can be increased to 90 mg every three months in patients >100 kg. It binds specifically to the p40 subunit of IL-12 and IL-23. Ustekinumab was approved by EMA for the treatment of psoriasis in 2009 and is also registered for the treatment of psoriatic arthritis. The efficacy of ustekinumab has been demonstrated in placebo-controlled trials (68, 69). In one previously mentioned trial ustekinumab has been shown to be superior to etanercept (60). Antibodies to ustekinumab have been reported, though to a lesser extend compared to adalimumab and infliximab. Antibodies to ustekinumab have been reported to negatively impact response (65).

Secukinumab is the first IL-17 targeting human monoclonal antibody and was approved by EMA for the treatment of psoriasis in 2015. It is administered as subcutaneous injection, initiated with four injections of 300 mg, each one taken a week apart, followed by regular injections once a month (70). Efficacy has shown to be superior to etanercept and ustekinumab (60, 61). It is registered for treating psoriatic arthritis and spondylitis ankylopoetica (71).

Ixekizumab, an IL-17 targeting agent is the most recently approved biological. It is administered as a subcutaneous injection of 80 mg. At week 0, 2 injections are administered. From week 2-12, one injection is administered every other week. From week 12, one injection every four weeks is administered. It was shown to have superior efficacy over etanercept (72).

Recently the small molecule apremilast (a phosphodiesterase 4 blocking agent) was approved for the European market. Small molecules are low molecular-weight organic compounds that help to regulate a biological process. Apremilast has been shown to decrease psoriasis disease activity (73), although RCTs comparing its efficacy to another active substance are lacking.

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The future will bring new therapies for treating psoriasis, for example other small molecules like tofacitinib (a Janus kinase inhibitor).

While patents of some biologicals are expiring, the development of biosimilars (a copy of the original product) has started. Biosimilars for infliximab and etanercept are already approved for the European market. The biosimilars are cheaper than the original product, which makes the use more appealing. However, effectiveness and safety data from daily practice needs to establish its use.

Measuring biological serum levelsEnzyme-Linked Immuno Sorbent Assays (ELISA), commercially available for adalimumab, infliximab, etanercept and ustekinumab (Sanquin Diagnostic Services, Amsterdam), can be used for measuring biological serum concentrations. These assays are used in several studies (also presented in this thesis). For secukinumab an ELISA is expected to be available in 2016. The serum for measuring serum concentration is often drawn just before the next injection, the so-called “trough level”. Several factors influence the serum level like concomitant medication, inflammation (disease activity, in other words, the amount of target), and properties of the drug (dose, half-life, way of administration), but as mentioned above, also antibody formation against the drug (anti-drug antibodies, ADA). ADAs bind to the drug, at the locus where otherwise the inflammatory protein binds, for example TNF. ADAs are formed by the body as a reaction to the penetration of foreign body protein (the biological). Since ADAs often bind to the biological at the site where otherwise the inflammatory protein binds, the inflammatory protein can no longer be bound by the biological (the biological is neutralized). An ELISA measures only “free” biological; biological to which no ADA are bound. Dried Blood Spot Assays (DBA) are being developed, with which patients might be able to measure serum concentrations at home.

ADA can also be measured; this is done by means of a radioimmunoassay. Because ADA bind to the drug, serum for measuring ADA should be drawn at trough level. Measuring ADA in serum drawn at time points other than through level increases the risk of a false negative result.

Measuring disease activityMany tools have been developed for measuring psoriasis disease activity (74). The most commonly used are the Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA) and Physicians Global Assessment (PGA) (74). PASI takes into account the body surface area affected together with the appearance of lesions (erythema, induration and desquamation), with a score ranging from 0 to 72. It is the most extensively studied and most thoroughly validated outcome system (75). The efficacy of psoriasis therapies is often measured by PASI. For example, PASI 50 means that the PASI declined with 50% at the time of sampling compared to

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baseline and a patient with PASI 75 is seen as a good responder (76). BSA refers to the percentage of skin covered by a disease. The PGA is a score of which several variants are available with an ordinal scale typically ranging from 5-7 points, designating clear to very severe disease activity. The PGA has been found to correlate well with PASI (74).

Quality of life can be measured with several tools. Both dermatology specific tools like the Dermatology Life Quality Index (DLQI) and the Skindex-29 and disease specific tools like the Psoriasis Disability Index (PDI) are available. The DLQI and Skindex-29 are based on the patients’ opinion of his or her condition in terms of its symptoms, psychological impact and effects on daily activity (77, 78). The DLQI consists of ten items, with an overall sum score ranging from 0-30. It is the most commonly used tool for measuring impact on quality of life in dermatology research (79). The Skindex-29 (range 0-100) is a multi-dimensional instrument, consisting of 29 items covering three domains: symptoms, emotions and functioning. Several reviews suggest Skindex-29 is the instrument of choice for measuring the impact of a skin disease on quality of life (80, 81).

Treatment of psoriasis in daily practice (82)Treatment of psoriasis usually starts with topical treatment. Topical treatment consists of emollients and corticosteroids, sometimes combined with tar, dithranol, salicylic acid but most often with vitamin D analogues. Psoriasis of the scalp (psoriasis capitis) is often treated with tar based shampoos in combination with a lotion or emollient based topical corticosteroid, or with calcipotriol/betamethasone in a gel based vehicle, calcitriol and tacrolimus are often used for treating inverse psoriasis. If topical therapy is insufficient and psoriasis lesions are not limited to a few plaques but located on different body parts, UVB is added to the treatment regimen (most often narrow-band UVB). Because of the chronic nature of psoriasis, patients often have to continue topical therapy after stopping UVB to control disease activity. If the disease flares, another course of UVB therapy can be applied. Because of side effects (e.g. skin cancer), not all centers apply PUVA therapy, despite it being a highly effective treatment. If UVB and/or PUVA therapy are not sufficient in controlling disease activity, systemic therapies can be applied; methotrexate, fumaric acid, cyclosporin or sometimes acitretin. Methotrexate and fumaric acid and methotrexate and cyclosporin seem to be comparable in efficacy in RCTs (38, 39), though few head-to-head trials have been performed. Every systemic treatment has specific side effects and not all therapies can therefore be applied in every patient (83). With starting systemic treatment, the prescriber has to precisely investigate the patients’ co-morbidities and start a treatment, which is suitable for that specific patient. In patients in whom even systemic treatments fail, biologicals are the next treatment option. There is no treatment algorithm for choosing the biological to start with. Efficacy can be one of the factors on which

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the treating physician decides. Head to head trials comparing one biological to the other are sparse, as mentioned above only etanercept has been compared to infliximab, ustekinumab and secukinumab. In a systematic review analyzing data from 23 RCTs, PASI 75 at week 10-30 for etanercept 25 mg 2x/week was 38%, it was 52% for etanercept 50 mg 2x/week, 59% for adalimumab, 75% for ustekinumab 45 mg, 69% for ustekinumab 90 mg and 80% for infliximab (84). In a systematic review analyzing data observed in daily practice, PASI 75 at week 12-16 ranged from 12–66% for etanercept, 35–68% for adalimumab, 63–80% for ustekinumab and 38–53% for infliximab (85). Infliximab and ustekinumab seem to have a faster onset of action compared to etanercept and adalimumab (86). All biologicals seem to be effective in decreasing disease activity of psoriatic arthritis and the reported side effects are comparable. Also the costs or the ease of use can be of importance to decide upon which biological to start with. Biologicals are sometimes combined with e.g. UVB, acitretin, methotrexate (87). The result of a retrospective cohort study showed that the combination of methotrexate with adalimumab decreased the formation of antibodies against adalimumab in a dose-dependent manner (the more methotrexate, the less antibodies) in patients with rheumatoid arthritis (88).

Both national and international guidelines have been developed for guiding clinicians in treating psoriasis (36, 37). In the Netherlands, the Dutch Guideline Psoriasis (48) has been developed in 2011 and is currently being updated. All guidelines state contraindications, side effects and interactions. Also all guidelines state that monitoring of systemic and biological treatment is obligatory before and during treatment. For each systemic therapy monitoring is slightly different, depending on the side effects of the therapy. Blood count, hepatotoxicity and kidney function is included. Prior to initiation of methotrexate and biological treatment hepatitis screening is performed. Before initiating a biologic, patients are screened for tuberculosis and in cyclosporin treated patients blood pressure is always measured.

RegistriesTo register a drug for market access, classical RCTs are used to prove its efficacy and safety. Therefore most data available on efficacy and safety of biological treatment comes from RCTs in which the biological is compared to a placebo, a systemic treatment and in some RCTs another biological. For RCTs, patients are selected by strict in-and exclusion criteria. They are randomized into a treatment group to minimize the risk of differences in baseline characteristics between the groups and time of follow-up is limited. Often neither patient nor physician is aware of the treatment administered (double-blind). In daily practice, patients with all kinds of comorbidity, co-medication and all age groups are treated with a certain drug for a longer period of time (89). Unfortunately, the duration of

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many RCTs is too short to detect side effects that require a longer treatment episode to develop, like liver fibrosis in methotrexate treated patients (36) or squamous cell carcinoma in PUVA treated patients (47). Also, RCTs often are underpowered to detect rare side effects. In addition, some side effects might only show in patients of a certain age, or in patients with certain co-medication. Those patients are often excluded from RCTs. The difference between patient population in RCTs and daily practice and the difference between treatment environment in RCTs and daily practice can lead to a difference in drug safety and efficacy between these settings (90, 91). Therefore, it is important to observe safety and effectiveness of different treatments in daily practice; in observational cohort or registry studies (92). In a registry study, data is obtained from all treated patients. Data from registries can be analyzed to provide information on how for example elderly or patients with several co-morbidities respond to the drug. With these data, treatment can better be tailored per patient. It is essential to register all factors that could potentially influence treatment choice or patient outcome or other outcomes (e.g. adverse events), like key demographic factors (e.g. age, lifestyle, severity of disease), co-medication and drug dosage or duration, so the influence of these factors on the treatment outcome can be analyzed. Data from several registries has been published showing drug survival analyses. Drug survival is defined as the time a patient is treated with a certain drug. One would think that the longer the drug survival, the better. Though, drug discontinuation can be due to several factors e.g. treatment failure, side effects and also in some cases treatment success. Studies available on data from registries show conflicting results. Infliximab has shown better drug survival compared to etanercept and adalimumab (93), others report better drug survival to adalimumab and etanercept compared to infliximab (94). Also better drug survival to etanercept compared to adalimumab and infliximab is reported (95). At the Department of Dermatology of the Academic Medical Center in Amsterdam, a registry was initialized in January 2005, including all consecutive patients treated with anti-TNF-α agents (etanercept, adalimumab, infliximab), ustekinumab, secukinumab and apremilast. Newly registered systemic treatments for psoriasis will also be included in the future. For patients included in the registry, baseline characteristics are recorded. During every outpatient clinic visit, dosing, PASI (scored by a PASI-trained physician), Skindex-29 and adverse events are recorded.

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OuTlInE Of ThIS ThESIS

This thesis will focus on the treatment of plaque type psoriasis with methotrexate and biologicals. The goal is to optimize these treatments:

Tailoring psoriasis therapy: towards a safer and more effective systemic treatment.

The first part of this thesis (chapter 2) focuses on the safety and effectiveness of biological and methotrexate treatment of psoriasis in a daily practice setting.

Daily practice data of patients treated with biologicals registered in our local registry were analyzed and results are presented in chapter 2a:

Drug survival is not significantly different between biologicals in patients with psoriasis vulgaris: a single-center database analysis

The incidence of non-melanoma skin cancer (a term some argue should be replaced by keratinocyte carcinoma (96)) is rising (97). Non-melanoma skin cancer includes basal cell carcinoma and squamous cell carcinoma. In daily practice, specific concerns exist about non-melanoma skin cancer in anti-TNF-α treated patients (37, 98). Data from registries of the Department of Dermatology of the Academic Medical Center in Amsterdam and the Departments of Dermatology and Rheumatology of the Radboudumc in Nijmegen were analyzed regarding the incidence of non-melanoma skin cancer in patients treated with anti-TNF- α in chapter 2b:

The increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis

patients probably relates to disease-related factors

Methotrexate treatment may lead to hepatotoxicity resulting in liverfibrosis in some patients (99). Amino terminal type III procollagen peptide (PIIINP) is a non-invasive marker used as prescreening for detecting liver fibrosis. It is the screening method advised in the current European guideline (37). However PIIINP carries the risk for false positive outcomes (100). We describe the results of PIIINP monitoring in psoriasis patients treated with methotrexate in daily practice in chapter 2c:

PIIINP measurements for the detection of liver fibrosis in methotrexate treated psoriasis patients: Daily practice use and clinical implications

In the second part of this thesis (chapter 3) the focus is more on personalized medicine and trying to improve existing treatments with methotrexate and biologicals. There is a wide variation in treatment response between patients. This raised the question why this is the case and whether treatments can be tailored.

The first focus is on the optimization of methotrexate treatment. We provide an up-to-date overview of RCTs using oral methotrexate monotherapy in adults for the

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treatment of psoriasis and we summarize evidence from these RCTs regarding the methotrexate dosing regimen. Also, recommendations from aggregated evidence (guidelines and expert meetings) are summarized. Based on this review, initial suggestions for adjusting methotrexate dosing per subgroup of patients are given in chapter 3a:

Optimizing methotrexate treatment: a systematic review of the use of test-dose, start-dose, dosing scheme, dose adjustments, maximum dose

and folic acid supplementation

As described above, biologicals have been introduced in the treatment of psoriasis for more then a decade. Costs of biological therapy are considerably higher compared to conventional systemic therapies (55), which makes rational treatment even more relevant. An inter-patient treatment response is observed in biological treated patients. For adalimumab a low serum concentration is associated with non-response or a loss of response in a group of 29 patients followed for 24 weeks (67).

We investigated whether the correlation between adalimumab trough level concentration, adalimumab antibody concentration and clinical response persists until week 52 of treatment in a larger group of patients (n=80) in chapter 3b:

Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up

The next step towards the personalized treatment of adalimumab was taken in chapter 3C, a therapeutic range was developed for adalimumab trough levels:

Developing a therapeutic range of adalimumab serum concentrations in management of psoriasis: a step toward personalized treatment

In chapter 3d the study protocol of a randomized controlled trial is presented. This trial investigates the effect on efficacy and safety of the addition of methotrexate to adalimumab treatment:

Optimizing adalimumab treatment in psoriasis with concomitant methotrexate (OPTIMAP): study protocol for a pragmatic, single-

blinded, investigator-initiated randomized controlled trial

To investigate whether a therapeutic range could also be developed for ustekinumab treatment, the correlation between ustekinumab trough level, ustekinumab antibody concentration and clinical response was investigated in chapter 3e:

The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis

in a clinical-practice setting

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96. Karimkhani C, Boyers LN, Dellavalle RP, Weinstock MA. It’s time for “keratinocyte carcinoma” to replace the term “nonmelanoma skin cancer”. Journal of the American Academy of Dermatology. 2015;72(1):186-7.

97. Lomas A, Leonardi-Bee J, Bath-Hextall F. A systematic review of worldwide incidence of nonmelanoma skin cancer. The British journal of dermatology. 2012;166(5):1069-80.

98. van Lumig PP, Driessen RJ, Berends MA, Boezeman JB, van de Kerkhof PC, de Jong EM. Safety of treatment with biologics for

psoriasis in daily practice: 5-year data. Journal of the European Academy of Dermatology and Venereology : JEADV. 2012;26(3):283-91.

99. Berends MA, Snoek J, de Jong EM, van de Kerkhof PC, van Oijen MG, van Krieken JH, et al. Liver injury in long-term methotrexate treatment in psoriasis is relatively infrequent. Alimentary phar macology & therapeut ic s . 2006;24(5):805-11.

100. Driessen RJ, van de Kerkhof PC, de Jong EM. Daily practice assessment of liver injury in patients with psoriasis on methotrexate. The British journal of dermatology. 2010;162(1):211-3.

30

CHAPTER 2

SAFETY AND EFFECTIVENESS OF BIOLOGICAL AND

METHOTREXATE TREATMENT

2ADRUG SURVIVAL IS NOT

SIGNIFICANTLY DIFFERENT BETWEEN BIOLOGICS IN

PATIENTS WITH PSORIASIS VULGARIS: A SINGLE-CENTRE

DATABASE ANALYSIS

Chapter 2

2A

abSTRaCT

BACKGROUND: Drug survival depends on several factors such as dosing, effectiveness, quality-of-life improvement and safety, and could be seen as an overall marker for treatment success. Such data for biologics in psoriasis treatment are sparse.OBJECTIVES: To determine differences in drug survival between different biologics for psoriasis.METHODS: Drug survival, dosing, Psoriasis Area and Severity Index (PASI) and Skindex-29 at weeks 12 and 52, and adverse events of patients with psoriasis treated with a biologic registered in the local database of the Academic Medical Center, Amsterdam, were analysed. Patients were divided into those naive or non-naive for treatment episodes with biologics.RESULTS: Drug survival did not differ significantly for naive treatment episodes between the biologics (etanercept 85% to 64%, adalimumab 77% to 77%, infliximab 75% to 75% for year 1–4), or for non-naive treatment episodes (etanercept 86% to 42%, adalimumab 84% to 56%, infliximab 68% to 43% for year 1–4; ustekinumab 84% to 57% for year 1–3). The naive group showed better drug survival and PASI 75 response at week 12, although the difference was not significant. A similar improvement of mean PASI and mean Skindex-29 was observed at weeks 12 and 52 for all biologics for both groups, although no significant difference was seen between groups. Treatment termination was due mainly to nonresponse for all biologics.CONCLUSIONS: There was no significant difference in drug survival, mean PASI or Skindex-29 response at weeks 12 or 52 between the biologics or between the naive and non-naive groups. Treatment termination was due mostly to nonresponse. Sequential treatment with the available biologics can be effective.

S.P. Menting, A.S. Sitaram, H.M. Bonnerjee-van der Stok, M.A. de Rie, L. Hooft and Ph.I. Spuls

Br J Dermatol. 2014 Oct;171(4):875-83.

36

SAFETY AND EFFECTIVENESS OF BIOLOGICAL AND METHOTREXATE TREATMENT

2A

InTROduCTIOn

Biologics are used for long-term treatment of moderate-to-severe psoriasis if conventional systemic treatments fail or are contraindicated. Several randomized clinical trials (RCTs) have established the efficacy of these treatments.1–3 However, long-term clinical practice data are sparse.4–9 These data are important because they show the result of biological treatments in daily practice, which might differ from RCT results because non-RCT patients are often less healthy, and might have comorbidities and relative contraindications for treatment with a biologic.10 In the Netherlands, treatment with a biologic is reimbursed if several criteria are met: disease severity [Psoriasis Area and Severity Index (PASI)] > 10, or > 8 combined with a Skindex-29 [quality of life (QoL) parameter] > 35, together with unresponsiveness and/or intolerance for ultraviolet B or psoralen–ultraviolet A, and failure or contraindications to conventional systemic therapy (methotrexate and/or ciclosporin). Drug survival and the factors contributing to it (e.g. effectiveness, safety) can be considered as markers for treatment success. The results of earlier publications on drug survival of antitumour necrosis factor (anti-TNF)-a agents seem to differ between three daily clinical practice studies.11–13 Also, no comparison of the effectiveness of biologics in terms of improvement of QoL in daily clinical practice has yet been published.14 This study aims to compare drug survival and effectiveness (PASI and QoL) between four biologics (etanercept, infliximab, adalimumab and ustekinumab) for naive treatment episodes (NTEs) and non-naive treatment episodes (NNTEs). Reason for withdrawal from treatment will be evaluated, together with safety [adverse events (AEs)] and treatment strategies used in patients treated with biologics for psoriasis.

PaTIEnTS and METhOdS

Patient selectionAt the Academic Medical Center, Amsterdam, the Netherlands, a prospective database was instigated in January 2005, including all consecutive patients treated with anti-TNF-a agents (etanercept, adalimumab, infliximab) and an interleukin-12/23 monoclonal antibody (ustekinumab). Included were baseline characteristics (see data collection and management below), and at every outpatient visit dosing, PASI (scored by a PASI-trained physician), Skindex-2915 and AEs were recorded. At treatment termination the reason and total duration were noted. Patients gave written informed consent for enrolment.

Data collection and managementIn July 2013 data of individual treatment episodes for each biologic were extracted from the database. The baseline characteristics extracted were patient identification number, sex, age, body mass index, duration of psoriasis, presence of psoriatic

37

Chapter 2

2A

arthritis (PsA) and previous and concomitant systemic therapies. For efficacy and safety data the following were extracted: dosing, PASI and Skindex-29 score at baseline, week 12 and week 52; duration of treatment episodes and whether the treatment was still active; reason for treatment termination and AEs.

From the PASI scores, responder status at weeks 12 and 52 was calculated (nonresponders defined as < 50% PASI improvement from baseline, moderate responders PASI 50–74% and good responders PASI ≥ 75%).16 Cut-off scores of 25, 32 and 44 were used for defining very little, mild, moderate or severe impairment of QoL, respectively (measured by Skindex-29, range 0–100).17 In case of lack of effectiveness, it was determined whether this was primary nonresponse (inability to achieve PASI ≥ 50%) or secondary nonresponse [loss of response in patients previously responding (PASI ≥ 50%) and termination of treatment due to decline of effectiveness]. AEs were recorded (not categorized for severity/relatedness). Some of the patients included participated in the PIECE study (an investigator-initiated study comparing infliximab with etanercept – visit frequency according to clinical practice). Because the inclusion and exclusion criteria required conforming to the eligibility criteria for treatment with a biologic in daily practice, and visit frequency was according to daily practice, these patients were not excluded from analyses. The database was monitored by one research nurse (H.M.B.).

Statistical analysisAnalyses were performed in SPSS (version 20.0; IBM, Armonk, NY, U.S.A.) and consisted of two parts, one for NTEs and one for NNTEs. An individual patient could be included multiple times in the NNTE group, each time for treatment with a different biologic or with the same biologic if a second treatment episode with this biologic was initiated. A treatment episode was defined as the period during which a patient was treated with a biologic until discontinuation of treatment. A temporary interruption of treatment ≤ 3 months was not considered treatment discontinuation. Differences in baseline characteristics between the four biologics were compared using the one-way ANOVA test. For dichotomous variables, the v2-test was used.

Dosing was evaluated by years, and the number of patients who underwent dose adjustments within 1 year was calculated. A dose escalation was defined as a dose increase or interval reduction. A dose decrease was defined as lowering of the dose or interval lengthening. Drug survival was analysed by the Kaplan–Meier method. Time to event was defined as the number of months during which a patient was on a biologic until termination of treatment due to inefficacy or AEs. Other reasons and patients still on treatment at the time of analysis were censored (event not occurred). Drug survival between the biologics was compared using the log-rank test. Patients on a biologic for a minimum of 3 months were included. Patients in the PIECE study were excluded for drug survival analyses if treatment was discontinued per protocol.

38


2A

Missing PASI scores at baseline were replaced with the PASI score of the last visit previous to baseline if < 3 months prior to baseline. Other missing PASI baseline values were calculated by imputation of the mean. Missing PASI and Skindex-29 values at week 12 and week 52 were replaced if available within the following windows. Etanercept and adalimumab: week 12 between weeks 10 and 14, and week 52 between weeks 44 and 60. Infliximab: week 12 between weeks 14 and 22 and week 52 between weeks 44 and 60. For ustekinumab, week 16 values replaced week 12, as ustekinumab is administered at the outpatient clinic then. For week 52, weeks 40–64 were used. If not available within these windows, the values were noted as missing. The v2-test was used to compare dichotomous variables, and Bonferroni correction was applied for multiple comparisons.

Mean changes in PASI at weeks 12 and 52 were compared using the one-way ANOVA method. The same analysis was performed for Skindex-29 improvement.

The reason for treatment discontinuation and occurrence of AEs was described using a frequency table. Patients were excluded if insufficient data were available (e.g. single PASI available).

RESulTS

In total 226 patients were included in the analyses; five had been excluded (Fig. 1) because of insufficient data. Fifteen had a missing PASI baseline score. Missing PASI and Skindex-29 scores at weeks 12 and 52 were replaced 29 times.

Naive treatment episodes

Patient characteristics

Overall 167 treatment episodes were included (167 patients; Table 1). For baseline characteristics, Skindex-29 and the percentage of patients with PsA in the etanercept-treated group were higher (both P < 0.05). Ustekinumab was not analysed further due to the small number (n = 1) of patients in this group.

Treatment strategies

The treatment strategies are summarized in Figure 2a. Etanercept was initiated with the labelled dose 2 x 50, 2 x 25 or 1 x 50 mg in 86.4%, 9.3% or 4.2% of cases, respectively. Adalimumab was initiated per label with a start dose of 2 x 40 mg and the week thereafter 40 mg per 2 weeks in 100% of NTEs. Infliximab was started in 94.7% of cases at 5 mg/kg per 8 weeks, with an introduction phase of administration at weeks 0, 2 and 6. Within 1 year, a dose increase had taken place in 11 (9.3%) treatment episodes of patients on etanercept, two (7%) treatment episodes on adalimumab and two (11%) treatment episodes on infliximab, whereas in 17 (14.4%) treatment episodes of NTEs on etanercept and one (5%) treatment

39

Chapter 2

2A

Figure 1 Flowchart patient subdivision

np, number of patients; nnte, number of naive treatment episodes; nn_nte, number of non-naive treatment episodes; nte, number of treatment episodes; total t.e., total treatment episodes; ETA, etanercept; ADA, adalimumab; IFX, infliximab; UST, ustekinumab. A single patient can be represented more than once in the number n = 96. If a patient has been treated with the first biologic and subsequently with a second and a third, both the second and the third treatment episodes are included in n = 96.

fig 1. flowchart of patient subdivision. np, number of patients; nnte, number of naive treatment episodes; nn nte, number of non-naive treatment episodes; nte, number of treatment episodes; total t.e., total treatment episodes; ETA, etanercept; ADA, adalimumab; IFX, infliximab; UST, ustekinumab. aA single patient can be represented more than once in the number n = 96. If a patient has been treated with the first biologic and subsequently with a second and a third, both the second and the third treatment episodes are included in n = 96.

Fig 2. Administered dosages in patient-years in (a) naive- and (b) non-naive treatment episodes. wks, weeks.

fig 2. administered dosages in patient-years in (a) naive- and (b) non-naive treatment episodes. wks, weeks.








40


2A

Tab

le 1

. B

asel

ine

char

acte

ristic

s na

ive

pat

ient

s an

d n

on-

naiv

e tr

eatm

ent

epis

od

es

1a. N

aive

pat

ient

s1b

. No

n-na

ive

trea

tmen

t ep

iso

des

ETA

(n=

118

)A

DA

(n=

29)

INF

(n=

19)

UST

(n=

1)To

tal

(n=

167

)p

-val

ueE

TA(n

= 5

5)A

DA

(n=

58)

INF

(n=

21)

UST

(n=

21)

Tota

l(n

= 1

55)a

p-v

alue

Mal

es/f

emal

es, n

72/4

619

/10

11/8

0/1

102/

65p

= 0

.595

35/2

040

/18

15/6

16/5

106/

49p

= 0

.738

Ag

e (y

ears

), b

46 (4

3-48

)45

(40-

50)

45 (3

8-52

)53

46 (4

4-48

)p

= 0

.936

47 (4

3-50

)48

(44-

51)

47 (4

3-52

)50

(46-

55)

48 (4

6-50

)p

= 0

.724

BM

I, m

ean

b27

.8(2

6.7-

28.8

)

28.0

(25.

3-30

.6)

29.3

(25.

6-33

.0)

25.3

28.0

(27.

0-28

.9)

p=

0.7

6120

.2(1

7.2-

23.2

)

29.8

(27.

9-31

.8)

28.4

(25.

2-31

.5)

29.8

(27.

0-32

.6)

30.0

(28.

7-31

.0)

p=

0.6

91

Psor

iasi

s d

urat

ion

(yea

rs),

b20

(17-

22)

20 (1

6-24

)17

(11-

23)

519

(18-

21)

p=

0.48

920

(17-

23)

23 (2

0-26

)22

(17-

26)

24 (1

9-28

)22

(20-

24)

p=

0.45

8

PASI

bas

elin

e, b

13.8

(12.

7-14

.9)

13.1

(10.

8-15

.5)

14.7

(10.

7-18

.8)

20.0

13.8

(12.

9-14

.8)

p=

0.6

4813

.9(1

2.2-

15.6

)

11.4

(9.8

-13.

1)15

.1(1

1.2-

19.1

)

12.1

(8.2

-16.

1)12

.8(1

1.7-

13.9

)

p=

0.1

15

Skin

dex

-29

bas

elin

e, b

62.5

(59.

0-66

.0)

51.8

(43.

4-60

.2)

49.4

(37.

1-61

.7)

-60

.0(5

6.8-

63.2

)

p=

0.0

1052

.7(4

6.4-

59.0

)

49.1

(43.

0-55

.2)

64.6

(50.

9-78

.2)

48.8

(37.

0-60

.6)

51.7

(47.

9-55

.6)

p=

0.1

64

Pres

ence

of P

sA,

n (%

)33

(28.

4)2

(6.9

)1

(5.9

)0

(0)

36 (2

2.1)

p=

0.0

2316

(29.

1)10

(17.

2)5

(23.

8)0

(0.0

)31

(20.

0)p

= 0

.036

Con

com

itant

MTX

, n

(%)

26 (2

2.0)

2 (6

.9)

1 (5

.3)

0 (0

)27

(17.

4)p

= 0

.104

13 (2

3.5)

10 (1

7.2)

1 (4

.8)

2 (9

.5)

26 (1

6.8)

p=

0.1

85

Prev

ious

tre

atm

ent

epis

odes

, bn.

v.t.

n.v.

t.n.

v.t.

n.v.

t.n.

v.t.

n.v.

t.1.

1 (1

.1-1

.2)

1.3

(1.2

-1.4

)1.

6 (1

.2-2

.0)

1.8

(1.5

-2.2

)1.

3 (1

.3-1

.5)

P= 0

.000

ETA

, eta

nerc

ept;

AD

A, a

dal

imum

ab; I

NF,

infli

xim

ab; U

ST, u

stek

inum

ab; B

MI,

bo

dy

mas

s in

dex

; PA

SI, P

sori

asis

Are

a an

d S

ever

ity

Ind

ex; P

sA, p

sori

atic

art

hrit

is; M

TX,

met

hotr

exat

e; N

A, n

ot

app

licab

le.

aEig

ht t

reat

men

t ep

iso

des

wer

e no

t in

clud

ed i

n th

e b

asel

ine

char

acte

rist

ics;

the

se w

ere

trea

tmen

t ep

iso

des

of

non-

naiv

e p

atie

nts

wit

h th

e us

e o

f th

e sa

me

bio

log

ic m

ore

tha

n o

nce.

bVa

lues

are

mea

n (9

5% c

onfi

den

ce in

terv

al).

41

Chapter 2

2A

episode of infliximab a dose decrease had taken place. Concomitant methotrexate was used in 22% (etanercept), 7% (adalimumab) and 5% (infliximab) of cases.

Drug survival

The drug survival for etanercept (n = 115, treatment administered mostly as 2 x 50 mg), adalimumab (n = 29) and infliximab (n = 13) decreased over time (Fig. 3) and there was no significant difference between the biologics. The drug survival of etanercept decreased from 85% to 64% at year 1–4. For adalimumab and infliximab drug survival at year one, respectively 77% and 75%, remained stable until at least year four (number at risk at year four were 8 patients for adalimumab and 4 patients for infliximab) (see Fig. 3).

Fig 3. Drug survival of naive treatment episodes. Log-rank P = 0.831, Breslow P = 0.909, Tarone–Ware P = 0.891. Patients in whom treatment with a biologic was stopped per protocol (Table 2) were not included in the drug survival analyses. ETA, etanercept; ADA, adalimumab; IFX, infliximab.

fig 3. drug survival of naive treatment episodes. Log-rank P = 0.831, Breslow P = 0.909, Tarone–Ware P = 0.891. Patients in whom treatment with a biologic was stopped per protocol (Table 2) were not included in the drug survival analyses. ETA, etanercept; ADA, adalimumab; IFX, infliximab.




42


2A

Fig 4. Drug survival of non-naive treatment episodes. Log rank P = 0.498, Breslow P = 0.568, Tarone-Ware P = 0.573. Patients in whom treatment with a biologic was stopped per protocol (table 2) were not included in the drug survival analyses.

fig 4. drug survival of non-naive treatment episodes. Log rank P = 0.498, Breslow P = 0.568, Tarone-Ware P = 0.573. Patients in whom treatment with a biologic was stopped per protocol (table 2) were not included in the drug survival analyses

Psoriasis area and severity index at weeks 12 and 52

The overall mean PASI at baseline was 13.8. The overall mean PASI at week 12 was 9.0, and PASI had decreased at week 52 by 10.6 compared with baseline. At week 12, infliximab showed the greatest mean PASI (10.4) and at week 52 adalimumab (13.3). The mean PASI scores between the three biologics were not significantly different at weeks 12 or 52. The responder status is shown in Figure 5a. Adalimumab showed the greatest PASI 75 response at weeks 12 and 52 and the greatest PASI 90 response at weeks 12 and 52 (42.9% and 43.5%, respectively). For etanercept and infliximab, the PASI 90 response rates at week 12 were 9.9% and 35.3%, respectively. At week 52 these were 13 3% and 18 2%.

Skindex-29 scores at weeks 12 and 52

The overall mean baseline Skindex-29 score was 61.0, decreasing to 27.4 at week 12 and 31.0 at week 52. Etanercept and adalimumab showed the greatest mean Skindex-29 at week 12 (both 28.2), and etanercept at week 52 (32.4). There was no significant difference in mean Skindex-29 between the three biologics at weeks 12 or 52. Skindex-29 severity is presented in Figure 6a, and it decreased in each group at weeks 12 and 52 compared with week 0.



43

Chapter 2

2A

Fig 5. Responder status at weeks 12 and 52 of (a) naive and (b) non-naive treatment episodes. ETA, etanercept; ADA, adalimumab; IFX, infliximab; UST, ustekinumab.

fig 5. Responder status at weeks 12 and 52 of (a) naive and (b) non-naive treatment episodes. ETA, etanercept; ADA, adalimumab; IFX, infliximab; UST, ustekinumab.

fig 6. Skindex-29 scores at weeks 0, 12 and 52 in (a) naive and (b) non-naive treatment episodes. wk, week; ETA, etanercept; ADA, adalimumab; IFX, infliximab; UST, ustekinumab.



Fig 6. Skindex-29 scores at weeks 0, 12 and 52 in (a) naive and (b) non-naive treatment episodes. wk, week; ETA, etanercept; ADA, adalimumab; IFX, infliximab; UST, ustekinumab.



44


2A

Treatment withdrawal

In total 86 (51.5%) NTEs were discontinued. In 37% of cases this was due to lack of effectiveness, mostly secondary nonresponse (69%) and AEs (23%; Table 2). Other reasons for discontinuation of treatment included an unspecified/ unknown category (32%; e.g. pregnancy, death, discontinuation of treatment due to patient choice). One patient on infliximab discontinued due to treatment success.

Adverse events

In 140 of 166 NTEs, at least one AE occurred. In 101 (85.6%) NTEs of etanercept at least one AE was recorded. For adalimumab this was the case in 23 NTEs (79%) and for infliximab 16 NTEs (84%). No significant difference between the biologics was found in the number of NTEs with at least one AE. The most frequently reported AEs in the whole group were upper respiratory tract infections, muscle pain, joint complaints and gastrointestinal complaints (reported by ≥ 18% of patients).

Non-naive treatment episodes

Patient characteristics

In total 163 NNTEs were included in the analyses (155 patients; Table 1). The presence of PsA was significantly higher with etanercept, and there were significantly more previous treatments with biologics in the ustekinumab group (both P < 0.05).

Treatment strategies

The treatment strategies are shown in Figure 2b. In the induction phase of etanercept the percentages of NNTEs with 2 x 50, 2 x 25 or 1 x 50 mg were 83.3%, 11.7% and 5.0%, respectively. Adalimumab was started with the labelled dose in 100% of cases. Infliximab was started per label in 85.7%. Ustekinumab was started per label in 85.7% (in patients < 100 kg body mass with 45 mg and patients > 100 kg with 90 mg per 12 weeks, with administration at weeks 0 and 4 and every 12 weeks thereafter). Within 1 year, a dose increase had taken place in six treatment episodes with etanercept (10%), three (5%) with adalimumab, two (10%) with infliximab and nine (43%) with ustekinumab. In five treatment episodes with etanercept (8%) and two (10%) with ustekinumab, a dose decrease had taken place. Concomitant methotrexate was used in 24% (etanercept), 17% (adalimumab), 5% (infliximab) and 10% (ustekinumab) of the episodes.

Drug survival

The drug survival of each biologic decreased over time (Fig. 4). After 1 year, drug survival for etanercept (n = 59, treatment administered mostly as 2 x 50 mg) was 86%, adalimumab (n = 61) 84%, infliximab (n = 20) 68% and ustekinumab (n = 21) 84%. After 4 years, drug survival decreased for etanercept to 42%, for adalimumab

45

Chapter 2

2ATa

ble

2.

Trea

tmen

t w

ithd

raw

al a

nd r

easo

n fo

r st

op

of t

reat

men

t in

nai

ve p

atie

nts

and

no

n-na

ive

trea

tmen

t ep

iso

des

2a. N

aive

pat

ient

s2b

. No

n-na

ive

trea

tmen

t ep

iso

des

With

dra

wal

from

tre

atm

ent,

n

(%)

ETA

65

/118

(55.

1)A

DA

9/29

(31.

0)IN

F12

/19

(63.

2)To

tal a

86

/167

(51.

5)ET

A44

/60

(73.

3)A

DA

28/6

1 (4

5.9)

INF

11/2

1 (5

2.4)

UST

7/

21 (3

3.3)

Tota

l 90

/163

(55.

2)

Lack

of e

ffica

cy, n

(%)

PN, n

(%)

SN, n

(%)

26 (4

0.0)

8 (3

0.8)

18 (6

9.2)

4 (4

4.4)

1 (2

5.0)

3 (7

5.0)

2 (1

6.7)

1 (5

0.0)

1 (5

0.0)

32 (3

7.2)

10 (3

1.2)

22 (6

8.7)

19 (4

3.2)

2 (1

0.5)

17 (8

9.5)

10 (3

5.7)

6 (6

0.0)

3 (3

0.0)

7 (6

3.6)

0 (0

.0)

6 (8

5.7)

5 (7

1.4)

3 (6

0.0)

2 (4

0.0)

41 (4

5.6)

11 (2

6.8)

28 (6

8.3)

Ad

vers

e ev

ents

, n (%

)17

(26.

2)2

(22.

2)1

(8.3

)20

(23.

3)13

(29.

5)8

(28.

6)2

(18.

2)2

(28.

6)25

(27.

8)

Oth

er, n

(%)

Prot

ocol

Non

-com

plia

nce

Tran

sfer

to

othe

r ho

spita

lU

nsp

ecifi

ed

21 (3

2.3)

3 (1

4.3)

5 (2

3.8)

7 (3

3.3)

6 (2

8.6)

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46


2A

to 56% and for infliximab to 43%. For ustekinumab it decreased to 57% at year 3. No significant difference was found between the four biologics.

Psoriasis area and severity index at weeks 12 and 52

The overall mean PASI at baseline was 12.9. The overall mean ΔPASI at week 12 was 6.8, and PASI had decreased at week 52 by 8.9 from baseline. Infliximab showed the greatest mean ΔPASI at week 12 (9.8). At week 52 the greatest mean ΔPASI was achieved with etanercept (10.3). The mean ΔPASI between the four biologics was not significantly different at weeks 12 or 52. The responder status of NNTEs is represented in Figure 5b. The largest PASI 75 responses at weeks 12 and 52 were attained with infliximab and etanercept, respectively.

The greatest PASI 90 response at week 12 was with adalimumab (18%). For etanercept, infliximab and ustekinumab the rates were 4%, 12% and 10%, respectively. The PASI 90 rates at weeks 52 for etanercept, adalimumab, infliximab and ustekinumab were 13%, 8%, 14% and 6%, respectively.

Skindex-29 scores at weeks 12 and 52

The overall mean baseline Skindex-29 score was 52.2, which decreased to 14.7 at week 12 and 24.3 at week 52. The greatest mean Skindex-29 scores at weeks 12 and 52 were for infliximab (20.2 and 33.6, respectively); however, the differences were not significant between the four biologics. Figure 6b shows the Skindex-29 scores. The percentages of patients with a severe impact on QoL according to Skindex-29 for each biologic decreased at weeks 12 and 52 compared with week 0.

Treatment withdrawal

In total 90 (55.2%) treatment episodes were discontinued, due mainly to lack of effectiveness (46%), most of which was secondary nonresponse (68%) or AEs (28%; Table 2).

Adverse events

In 127 of 163 treatment episodes at least one AE occurred. These occurred in 77% of NNTEs with etanercept, 75% with adalimumab, 86% with infliximab and 81% with ustekinumab. There was no significant difference between the biologics in the number of patients who experienced at least one AE. Common AEs were mainly upper respiratory tract infections and musculoskeletal diseases/complaints.

Treatment episodes in naive vs. non-naive patientsDrug survival was better for NTEs, although this did not differ significantly from NNTEs.

The mean PASI was found to show slightly better improvement in NTEs at weeks 12 and 52 compared with NNTEs. However, this difference was not significant.

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Looking at PASI 75 response, a treatment goal defined by Mrowietz et al.,16 a difference was observed between naive and non-naive patients at week 12. For etanercept the response rates were 32% and 12%, respectively, for adalimumab 54% and 26% and for infliximab 53% and 38% (Fig. 5).

There was no significant difference in mean Skindex-29 at weeks 12 and 52. Also no significant difference was found between the numbers of patients who experienced at least one AE.

dISCuSSIOn

No significant difference was found in drug survival, mean PASI, Skindex-29 response or patients experiencing at least one AE between the different biologics, or between the NTEs and NNTEs. It was found that the overall drug survival of the four biologics decreased over time, and treatment discontinuation was due mostly to lack of effectiveness, mainly secondary nonresponse and not due to AEs. Secondary nonresponse leading to treatment discontinuation is also reported in the study of Esposito et al.,11 and for adalimumab and infliximab this might be explained partially by the development of antidrug antibodies.18–20

The nonsignificant difference in drug survival between the biologics for NTEs is partially in contrast with other studies. The study by Esposito et al.11 showed that etanercept showed a significantly higher survival rate than adalimumab or infliximab. Gniadecki et al.12 found that infliximab had a significantly higher drug survival than etanercept and adalimumab. Esposito et al. describe etanercept being administered as 1 x 50 or 2 x 25 mg after an induction phase of 2 x 50 mg for the first 12 weeks. Gniadecki et al. do not describe the dosing regimen used. In our cohort, etanercept is administered as a continuous treatment, mostly as 2 x 50 mg per week (74% of treatment-years in the NTEs), and despite this high dosage regimen no superior drug survival was found. Of the 26 patients in whom etanercept was initiated as 2 x 25 or 1 x 50 mg per week, the dose was increased based on inefficacy in 70% of patients. The Dutch guideline states that treatment should be initiated with 2 x 25 or 1 x 50 mg per week. A dose of 2 x 50 mg is an option if the effectiveness has not been sufficient in the induction phase. This guideline was published in 2011, and administration of 2 x 50 mg was based on RCT data.21 If the guideline had been followed more strictly, etanercept would probably have shown less favourable results.21 Overall, it can be said that effectiveness obtained in clinical practice is less than that in RCTs. A systematic review with meta-analyses showed a PASI 75 response of 31% for etanercept 2 x 25 or 1 x 50 mg and 43.5% for etanercept 2 x 50 mg (both at week 12), 63% for adalimumab at week 16, 75.7% for infliximab at week 10, and 66.5% or 70.1% for ustekinumab 45 or 90 mg, respectively, at week 12.22 In our cohort the PASI 75

48


2A

response rates were 32%, 54% and 53% for the naive etanercept, adalimumab and infliximab groups, respectively, and 10% for the non-naive ustekinumab group.

Gniadecki et al.12 found that lack of efficacy of one or more anti-TNF-a agents negatively influences adherence to another anti-TNF-a agent. In line with this, the anti-TNF-a agents for NNTEs showed worse drug survival compared with NTEs. The worse drug survival of NNTEs compared with NTEs was not significant, and a decline was observed in disease severity expressed in terms of both PASI and Skindex-29 for all biologics in the NNTE group. This supports findings from previous studies that switching is worth a try, also between two anti-TNF-a agents,23,24 although worse drug survival can be expected.

Ustekinumab showed the worst responder status at week 12, with 10% being good responders, 24% moderate responders, 62% nonresponders and 4% having already terminated treatment, but drug survival was similar to that with anti-TNF-a agents in NNTEs. Patients in the ustekinumab group had a significantly higher number of previous treatments (mean 1.8, P < 0.05). This might indicate that patients in the ustekinumab group were rather treatment resistant, and if the number of previous treatments had been equal to that of anti-TNF-a agents in the NNTE group, ustekinumab might have shown more favourable results.

The high percentage of drug survival for ustekinumab (84%) is in contrast with the responder status. This contrast can possibly be explained by the fact that for this group of patients ustekinumab is the final treatment option, and less effectiveness is accepted. A study by Clemmensen et al.25 showed no difference in adherence to ustekinumab in NTEs vs. NNTEs, although several clinical trials have shown that previous failure to one or more anti-TNF-a agent does influence treatment response.1,26

From this study, we present single-centre, prospective daily-practice data from 8 years of biological treatment for psoriasis. The combination of drug survival analysis, effectiveness data (by PASI), influence on QoL (by Skindex-29), AE reporting and treatment strategies gives a very extensive view on the biological treatment of psoriasis. Due to the constant monitoring of the database by one single research nurse, data integrity is secured. The treating physicians have scored PASI. However, there could be interobserver variability. The ustekinumab group was relatively small, and these data should be interpreted with caution, although they are considered valuable because limited ustekinumab data are available. Possible selection bias might have occurred by not randomizing patients into a treatment. Ideally the size of treatment groups and the percentage of patients treated with concomitant methotrexate (no significant difference between the groups) would have been equally distributed among the treatment groups. These factors might lead to a bias in the results, although this is inherent in the study set-up.

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REfEREnCES

1. Papp KA, Griffiths CE, Gordon K et al. Long-term safety of ustekinumab in patients with moderate-to-severe psoriasis: final results from 5 years of follow-up. Br J Dermatol 2013; 168:844–54.

2. Papp KA. The long-term efficacy and safety of new biological therapies for psoriasis. Arch Dermatol Res 2006; 298:7–15.

3. Rustin MH. Long-term safety of biologics in the treatment of moderate-to-severe plaque psoriasis: review of current data. Br J Dermatol 2012; 167(Suppl. 3):3–11.

4. Brunasso AM, Puntoni M, Salvini C et al. Tolerability and safety of biological therapies for psoriasis in daily clinical practice: a study of 103 Italian patients. Acta Derm Venereol 2011; 91:44–9.

5. van Lumig PP, Driessen RJ, Berends MA et al. Safety of treatment with biologics for psoriasis in daily practice: 5-year data. J Eur Acad Dermatol Venereol 2012; 26:283–91.

6. van Lumig PP, Driessen RJ, Boezeman JB et al. Long-term efficacy of etanercept for psoriasis in daily practice. Br J Dermatol 2012; 166:445–7.

7. van Lumig PP, van de Kerkhof PC, Boezeman JB et al. Adalimumab therapy for psoriasis in real-world practice: efficacy, safety and results in biologic-naıve vs. non-naıve patients. J Eur Acad Dermatol Venereol 2013; 27:593–600.

8. Fernandez-Torres RM, Paradela S, Fonseca E. Long-term response to etanercept monotherapy in moderate to severe psoriasis: assess ment in daily practice by the maintenance of low values of PASI and BSA. J Dermatolog Treat 2013; 25:54–6.

9. Antoniou C, Stefanaki I, Stratigos A et al. Infliximab for the treatment of psoriasis in Greece: 4 years of clinical experience at a sin-gle centre. Br J Dermatol 2010; 162:1117–23.

10. de Groot M, Appelman M, Spuls PI et al. Initial experience with routine administration of etanercept in psoriasis. Br J Dermatol 2006; 155:808–14.

11. Esposito M, Gisondi P, Cassano N et al. Survival rate of anti-TNF-a treatments for psoriasis in routine dermatological practice: a multi-centre observational study. Br J Dermatol 2013; 169:666–72.

12. Gniadecki R, Kragballe K, Dam TN, Skov L. Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol 2011; 164:1091–6.

13. Brunasso AM, Puntoni M, Massone C. Drug survival rates of bio-logic treatments in patients with psoriasis vulgaris. Br J Dermatol 2012; 166:447–9.

14. Basra MK, Hussain S. Application of the dermatology life quality index in clinical trials of biologics for psoriasis. Chin J Integr Med 2012; 18:179–85.

15. Both H, Essink-Bot ML, Busschbach J, Nijsten T. Critical review of generic and dermatology-specific health-related quality of life instruments. J Invest Dermatol 2007; 127:2726–39.

16. Mrowietz U, Kragballe K, Reich K et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res 2011; 303:1–10.

17. Prinsen CA, Lindeboom R, de Korte J. Interpretation of Skindex-29 scores: cutoffs for mild, moderate, and severe impairment of health-related quality of life. J Invest Dermatol 2011; 131:1945–7.

18. Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Plasma trough levels of adalimumab and infliximab in terms of clinical efficacy during the treatment of psoriasis. J Dermatol 2013; 40:39–42.

19. Menting SP, van Lumig PP, de Vries AC et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. JAMA Dermatol 2014; 150:130–6.

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20. Bito T, Nishikawa R, Hatakeyama M et al. Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis. Br J Dermatol 2014; 170:922–9.

21. Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349:2014–22.

22. Puig L, L_opez A, Vilarrasa E, Garc_ıa I. Efficacy of biologics in the treatment of moderate-to-severe plaque psoriasis: a systematic review and meta-analysis of randomized controlled trials with dif ferent time points. J Eur Acad Dermatol Venereol 2013; doi: 10.1111/jdv.12238 [Epub ahead of print].

23. van Lumig PP, Lecluse LL, Driessen RJ et al. Switching from etaner-cept to

adalimumab is effective and safe: results in 30 patients with psoriasis with primary failure, secondary failure or intoler-ance to etanercept. Br J Dermatol 2010; 163:838–46.

24. Lecluse LL, de Groot M, Bos JD, Spuls PI. Experience with biologics for psoriasis in daily practice: switching is worth a try. Br J Dermatol 2009; 161:948–51.

25. Clemmensen A, Spon M, Skov L et al. Responses to ustekinumab in the anti-TNF agent-naıve vs. anti-TNF agent-exposed patients with psoriasis vulgaris. J Eur Acad Dermatol Venereol 2011; 25:1037–40.

26. Griffiths CE, Strober BE, van de Kerkhof P et al. Comparison of ustekinumab and etanercept for moderate-to-severe psoriasis. N Engl J Med 2010; 362:118–28.

51

2BAN INCREASED RISK OF NON-

MELANOMA SKIN CANCER DURING TNF INHIBITOR

TREATMENT IN PSORIASIS PATIENTS COMPARED TO RHEUMATOID ARTHRITIS

PATIENTS PROBABLY RELATES TO DISEASE-RELATED FACTORS

Chapter 2

2B

abSTRaCT

BACKGROUND: Concerns exist about a risk of non-melanoma skin cancer (NMSC) in psoriasis patients and rheumatoid arthritis (RA) patients treated with TNF-inhibitors. However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that these NMSC can be explained by previous therapies instead of by TNF-inhibitor therapy.OBJECTIVE: To investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and RA patients on TNF-inhibitors.METHODS: Time until first NMSC and the rate of NMSC were compared between psoriasis and RA patients from the same region treated with TNF-inhibitors and followed up for at least one year in prospective cohort studies, by using Cox regression and Poisson regression. Both analyses were corrected for confounders (age, gender, disease duration, prior NMSC, duration of anti-TNF and other systemic therapies).RESULTS: The NMSC risk was significantly higher in the psoriasis group [fully adjusted HR 6.0 (1.6–22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to RA. By Poisson regression, psoriasis patients had a 5.5 (2.2–13.4 95%CI) higher rate of NMSC.CONCLUSION: The time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in psoriasis compared with RA. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

P.P.M. van Lumig*, S.P. Menting*, J.M.P.A. van den Reek, Ph.I. Spuls, P.L.C.M. van Riel, P.C.M. van de Kerkhof, J. Fransen, W. Kievit, E.M.G.J. de Jong

* both authors contributed equally to this work

J Eur Acad Dermatol Venereol. 2015 Apr;29(4):752-60. Translation published: Ned Tijdschr Geneeskd. 2015;159:A8865

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InTROduCTIOn

Concerns exist about a possible increased risk of malignancies, including non-melanoma skin cancer (NMSC), in psoriasis and rheumatoid arthritis (RA) patients treated with TNF-inhibitors.1–3 However, current data also show that in some psoriasis patients, NMSC is diagnosed relatively short after the start of TNF-inhibitors, which suggests that previous therapies may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.2

To investigate this hypothesis and to investigate to what extent other factors than TNF-inhibitors are relevant in the induction of NMSC in anti-TNF-treated patients, a group of psoriasis patients and a group of RA patients treated with similar anti-TNF regimens were compared. The aim of the present analysis was to find out whether a significant difference exists between psoriasis and RA patients with respect to the duration of TNF-inhibitor therapy until the first NMSC and the rate of NMSC.

METhOdS

PatientsFirst, all available patients with plaque psoriasis initiated on etanercept, adalimumab and/or infliximab at the department of Dermatology of the Radboud university medical center (Radboudumc) and the department of Dermatology of the Academic Medical Center (AMC) of the University of Amsterdam between February 2005 and November 2011 with a follow-up of at least 1 year after the start of anti-TNF-a therapy and enrolled in their respective registries, were selected.4,5

Second, all RA patients initiated on the same TNF-inhibitors at the department of Rheumatic Diseases of the Radboudumc with a follow-up of at least 1 year between 2001 and November 2011 were selected.6 The number of available RA patients was higher than the number of available psoriasis patients, but all RA patients were selected for analysis (instead of a random selection). As the number of NMSC in the RA population was expected to be lower than in the psoriasis cohort, selecting all available RA patients would improve the power of the study.

The three registries cover the same time period and contain prospectively collected data about patient characteristics, exposure to biologic therapies and prior (systemic) therapies, concomitant therapies, adverse events and effectiveness.4–6 As the psoriasis group as well as the RA group cover the Netherlands and the same time period, the background degree of sun exposure related to latitude and skin cancer trends were expected to be the same for both groups. Although only patients with a follow-up of 1 year after the start of anti-TNF-a therapy were selected, they were not always treated with TNF-inhibitors

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for at least 1 year due to possible interruptions of therapy. Effects of etanercept, adalimumab and infliximab were analysed, as these agents are prescribed for psoriasis as well as RA. Exposure to TNF-inhibitors in other contexts (participation in trials or treatment in non-academic hospitals) before enrolment in the registries was corrected for as well.

Information about NMSC and histology data was obtained from PALGA, the Dutch national histo-and cytopathology data-base and verified with data from the registries and (electronic) patient records.7 This study focused on the most common types of NMSC, i.e. basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) of the skin. Keratoacanthomas were considered as SCCs. Only primary skin tumours were included for analysis.

Corrections are carried out for differences in previous treatments and demographic characteristics, which are described in more detail below. The protocol of the prospective study performed at the department of Dermatology and Rheumatic Diseases of the Radboudumc was presented to the institutional review board (IRB). A formal IRB procedure and obtaining informed consent was considered unnecessary by the board because of the non-interventional character of the studies. The prospective study performed at the AMC was approved by the IRB of the AMC and patients registered in this database gave informed consent for registration.

Statistical analysisThe primary analysis was a Cox proportional hazard regression analysis with time until occurrence of first NMSC after the start of anti-TNF-a therapy as dependent variable and ‘disease’ (psoriasis or RA) as independent variable. For patients who were not diagnosed with NMSC after the start of anti-TNF therapy, follow-up ended at November 2011 or the date of loss of follow-up or death, whichever was first (censoring date). As anti-TNF therapy may continue to influence the risk of NMSC after its cessation, follow-up time in patients who discontinued anti-TNF-a treatment before November 2011 was included in the analysis until November 2011 or another censoring date, if applicable. This is further named the ‘ever exposed to anti-TNF analysis’ and was considered the main analysis of this study. In the Cox regression analysis, only the first NMSC diagnosed after the start of TNF-inhibitor therapy contributes to the results. Time until first NMSC is presented by Kaplan–Meier survival curves.

The secondary analysis is a Poisson regression analysis with the rate of NMSC (number of events of NMSC divided by observation time in patient-years) as dependent variable and ‘disease’ as independent variable. This analysis was done to support the results of the Cox regression analysis. A rate ratio (RR) was calculated by dividing the rate of NMSC in the psoriasis group by the rate of NMSC in the RA group. For this analysis, observation time started at the time of initiation of the

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first anti-TNF agent and ended at November 2011 or another censoring date, if applicable. In the Poisson regression analysis, all NMSC diagnosed after the start of TNF-inhibitor therapy contribute to the results. This Poisson regression model was built using the Generalized Linear Models procedure with a binominal distribution and a logit link function.

It was foreseen that the psoriasis and RA patients would differ at important prognostic factors for getting NMSC, like for instance a difference in ciclosporin use. Both analyses were corrected for those possible confounders: age, gender, disease duration (as an intermediate variable for severity of the disease), history of NMSC before the start of anti-TNF-a therapy, cumulative duration of anti-TNF therapy, cumulative duration of MTX, ciclosporin and prednisone therapy and the cumulative duration of treatment with biologics with a mechanism of action other than TNF-blockade. Correction was planned for those immunosuppressive therapies which have in some studies been shown to increase the risk of developing NMSC.8–14 Correction for the duration of azathioprine therapy was not possible due to the low number of psoriasis patients that had used azathioprine. This means that after statistical corrections, an important difference between the psoriasis and the RA group, is the fact that the psoriasis patients have received phototherapy (UVB and/or PUVA), whereas the RA patients have not received phototherapy. The number of UVB and PUVA treatments per psoriasis patient was calculated. In case only the start date and stop date of UVB or PUVA were known, UVB and PUVA were expected to be applied 3 times a week.

As our hypothesis was based on the assumption of equal duration of exposure to anti-TNF therapy and because follow-up time was longer than the duration of exposure to anti-TNF in the ‘ever exposed to anti-TNF analysis’, ‘cumulative duration of anti-TNF therapy’ was included in this analysis independent of the presence of a significant difference in the univariate analysis. The other candidate confounding variables were tested univariately between the psoriasis and RA groups with the unpaired student’s t-test, Mann–Whitney U-test, chi-square test or Fisher’s exact test. Variables with a p-value < 0.1 were all included in the multivariate analysis.

In addition to the ‘ever exposed to anti-TNF analysis’, a sensitivity analysis was done to support the results of this analysis, analysing time until occurrence of first NMSC (Cox regression) and rates of NMSC (Poisson regression) between the start date of the first anti-TNF agent and the discontinuation date of the last anti-TNF agent (‘on drug analysis’). All analyses as described above were repeated for the ‘on drug analysis’. Analyses were done using SPSS Statistics 20.0 (IBM, Armonk, NY, USA).

As NMSC prior to the start of TNF-inhibitor therapy was a strong predicting factor for being diagnosed with NMSC after the start of TNF-inhibitor therapy, a second sensitivity analysis excluding patients with prior NMSC was performed.

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RESulTS

Patients

Demographics and treatment characteristics

Two hundred and eighty psoriasis patients and 448 RA patients were included in the ‘ever exposed to anti-TNF analysis’ (Table 1). One patient with psoriasis was excluded because of insufficient information about the treatment history.

The median follow-up of the psoriasis patients in the ‘ever exposed to anti-TNF analysis’ was 4.8 (range 1.0–9.3) years. In the RA patients, this was 6.6 (range 1.0–14.9) years. The median follow-up in the ‘on drug analysis’ was 4.5 (range 1.0–9.3) years in de psoriasis group and 5.3 (range 1.0–14.9) years in the RA group. In the psoriasis cohort, 27 patients (9.6%) were lost to follow-up. In the RA group, this concerned 14 patients (3.1%).

The median exposure (censored) to anti-TNF in the psoriasis group was 3.7 (range 0.2–8.1) years. In the RA group, this was 4.1 (range 0.1–14.9) years.

The two groups differed significantly at important demographic characteristics, but were representative of a group of psoriasis patients or RA treated with biologic agents (Table 1).6,15 The psoriasis group contained a significantly higher proportion of males. In the psoriasis group, the mean age and disease duration at the start of anti-TNF-a therapy was significantly lower, respectively longer. Ninety-nine per cent of the psoriasis patients had been treated with phototherapy (UVB and/or PUVA). For the RA patients, information about phototherapy was lacking. However, when only considering psoriasis as an indication for phototherapy, the percentage of RA patients that had been treated with phototherapy was expected to be low, as only 5.6% of the RA patients had a history of psoriasis. Twenty-eight per cent of the psoriasis patients had psoriatic arthritis and none had a concomitant diagnosis of RA.

For 154 psoriasis patients, the number of UVB treatments was known and for 76 psoriasis patients, the number of PUVA treatments was known. In these patients, the median number of UVB treatments (censored) was 75 (range 2–490) and the median number of PUVA treatments (censored) was 65 (range 4–936). The proportion of RA patients that had ever used prednisone or azathioprine was significantly higher and the duration of these therapies (censored) was significantly longer than in the psoriasis group (Table 1). In contrast, the proportion of patients that had ever used ciclosporin and the duration of ciclosporin therapy (censored) were significantly higher respectively longer in the psoriasis group. The dose of ciclosporin in the psoriasis patients was been between 2.5 and 3 mg/kg per day, according to Dutch guidelines. The proportion of patients that had used methotrexate did not differ significantly. The duration of methotrexate therapy (censored) was significantly longer in the RA group.

In the psoriasis group, 249 patients (89%) were treated with etanercept, 132 with adalimumab (47%) and 10 with infliximab (4%). In the RA group, 228 patients

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(51%) were treated with etanercept, 226 (50%) with adalimumab and 188 (42%) with infliximab.

Skin malignancies

Ever exposed to anti-TNF analysis

In the group of psoriasis patients, 11 patients (3.9%) were diagnosed with at least one NMSC after the start of TNF-inhibitor therapy (Table 2). In the group of RA patients, this concerned 12 patients (2.7%) (Table 3). The total number of NMSC was 38 (16 BCCs and 22 SCCs) in the psoriasis group and 27 (20 BCCs en 7 SCCs) in the RA group. One case of BCC in the psoriasis group showed locally transition to a basosquamous carcinoma, which was considered as a BCC. No forms of NMSC other than BCC and SCC were diagnosed.

Table 1. Demographics and treatment characteristics.

Psoriasisn = 280

Rheumatoid arthritisn = 448 p-value

Male gender, n (%) 181 (65) 144 (32) <0.001

Age, years, mean ± SD 46.8 ± 11.9 56.3 ± (12.9) <0.001

Disease duration, years, median (range) 19.7 (1.1 – 64.4) 9.7 (0 – 51.3) <0.001

Psoriatic arthritis, n (%) 77 (28) 0 (0) N.A.

NMSC prior to anti-TNF therapy, n (%) 6 (2.1) 5 (1.1) 0.4

Phototherapy (unspecified), % (n)a 99% (275/279)c UNK N.A.

UVB, % (n)a 92% (254/276)d UNK N.A.

PUVA, % (n)a 58% (160/275)e UNK N.A.

Methotrexate use, n (%)a 270 (96) 439 (98) 0.2

Duration of methotrexate use, years, median (range)b 1.3 (0 – 27.3) 4.4 (0 – 28.6) <0.001

Ciclosporin use, n (%)a 217 (78) 23 (5) <0.001

Duration of ciclosporin use, years, median (range)b 0.5 (0 – 10.2) 0 (0 – 2.1) <0.001

Prednisone use, n (%)a 25 (9) 270 (60) <0.001

Duration of prednisone use, years, median (range)b 0 (0 – 2.7) 0.5 (0 – 33.4) <0.001

Azathioprine use, n (%)a 3 (1) 160 (36) <0.001

Duration of azathioprine use, years, median (range)b 0 (0 – 0.6) 0 (0 – 30.4) <0.001

Duration of anti-TNF therapyb, years, median (range) 3.7 (0.2 – 8.1) 4.1 (0.1 – 14.9) 0.3

Duration of non anti-TNF biological therapyb, years, median (range)

0 (0 – 3.7) 0 (0 – 4.3) 0.009

aNumber and percentages represent patients ever exposed to the respective therapy.bDuration of use until date of first diagnosis of NMSC, November 2011 or the date of loss of follow-up or death (‘ever exposed to anti-TNF analysis’).N.A.; not applicable. UNK; unknown.c1 missing, d4 missing,e5 missing

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In the psoriasis group, six patients (2.1%) had a history of NMSC before the start of anti-TNF-a therapy (Table 1). In the RA group, this concerned five patients (1.1%). Of the 11 psoriasis patients who were diagnosed with NMSC after the start of anti-TNF-a therapy, 36% (4/11) received this diagnosis within

Table 2. Patients with psoriasis diagnosed with NMSC after the initiation of TNF-inhibitor therapy.

Pta NMSC

Total duration of anti-TNFα,

(unadjusted, months)b

N° of NMSCduring

anti-TNFαc

N° of NMSCafter

anti-TNFαd

Time to event (months) during

anti-TNFαe

Time to event(months) after

anti-TNFαe

Treatments, duration

(censored, years)f

Skin cancerhistoryg

1 SCC ETNh (101) 1 0 94 N.A. UVB (0.5), MTXi (1.4), CsAj (0.01), ETN (3.1)

-

2 SCCBCC

ETN (12) 32

13

2, 6, 105, 5

1614, 14, 16

UVB, PUVA (>2.5), MTX (3), ETN (0.2)

4 BCC2 KAm

3 BCC ETN, ADAk (17) 2 0 7, 7 N.A. UVB 7 courses, MTX (5.6), CsA (0.6), ETN (0.4), ADA (0.2)

-

4 BCC ETN, ADA (80) 1 0 78 N.A. UVB 213 J, PUVA 2 courses, MTX (0.4), ETN (3.7), ADA (2.6)

-

5 SCC ETN (39) 1 1 38 51 UVB (0.5), PUVA (>0.9), MTX (5.6), CsA (1.9), ETN (1.4)

-

6 BCC ETN (70) 5 0 2, 2, 4, 30, 33 N.A. UVB 138 J/cm2, PUVA 1982 J/cm2, MTX, CsA (1.5), AZAl (0.5), ETN (0.2)

-

7 BCC ETN (63) 1 0 3 N.A. PUVA, MTX (0.3), CsA (0.4), ETN (0.3)

-

8 SCC ETN, ADA (81) 1 0 17 N.A. UVB, MTX (1.2), CsA (0.4), alefacept (0.2), ETN (0.7)

-

9 BCC ETN (67) 1 0 45 N.A. UVB >74 J/cm2, PUVA, MTX (5.8), CsA (0.1),ETN (3.5)

-

10 BCC ETN (73) 1 0 21 N.A. UVB, PUVA, MTX (1), ETN (1.6)

-

11 SCC ETN, ADA (76) 14 0 19, 31, 31, 40, 45, 49, 50, 50, 50, 59, 69, 69, 74, 74

N.A. UVB, PUVA (12 courses), MTX (5.3), CsA (10.2), ETN (1.4)

5 BCC4 SCC1 KAm

1 melanoma in situ

aPt; patient.bDuration of therapy expressed as time (months) between the date of initiation of the first TNF-inhibitor and the date of discontinuation of the last TNF-inhibitor.cNMSC diagnosed between the date of initiation of the first TNF-inhibitor and the date of discontinuation of the last TNF-inhibitor. dNMSC diagnosed after the cessation of TNF-inhibitor therapy until November 2011 or the date of loss of follow up or death, whichever was first.

eTime (months) between the date of initiation of TNF-inhibitor therapy and NMSC diagnosis. fDuration of treatment until the date of the first diagnosis of NMSC.gSkin cancer history before the initiation of TNF-inhibitor therapy.hETN; etanercept, iMTX; methotrexate, jCsA; ciclosporin A, kADA; adalimumab; lAZA; azathioprinemKA; keratoacanthoma.

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Table 2. Patients with psoriasis diagnosed with NMSC after the initiation of TNF-inhibitor therapy.

Pta NMSC



N° of NMSCduring

anti-TNFαc

N° of NMSCafter

anti-TNFαd


anti-TNFαe


anti-TNFαe

Treatments, duration

(censored, years)f

Skin cancerhistoryg

1 SCC ETNh (101) 1 0 94 N.A. UVB (0.5), MTXi (1.4), CsAj (0.01), ETN (3.1)

-

2 SCCBCC

ETN (12) 32

13

2, 6, 105, 5

1614, 14, 16

UVB, PUVA (>2.5), MTX (3), ETN (0.2)

4 BCC2 KAm

3 BCC ETN, ADAk (17) 2 0 7, 7 N.A. UVB 7 courses, MTX (5.6), CsA (0.6), ETN (0.4), ADA (0.2)

-

4 BCC ETN, ADA (80) 1 0 78 N.A. UVB 213 J, PUVA 2 courses, MTX (0.4), ETN (3.7), ADA (2.6)

-

5 SCC ETN (39) 1 1 38 51 UVB (0.5), PUVA (>0.9), MTX (5.6), CsA (1.9), ETN (1.4)

-

6 BCC ETN (70) 5 0 2, 2, 4, 30, 33 N.A. UVB 138 J/cm2, PUVA 1982 J/cm2, MTX, CsA (1.5), AZAl (0.5), ETN (0.2)

-

7 BCC ETN (63) 1 0 3 N.A. PUVA, MTX (0.3), CsA (0.4), ETN (0.3)

-

8 SCC ETN, ADA (81) 1 0 17 N.A. UVB, MTX (1.2), CsA (0.4), alefacept (0.2), ETN (0.7)

-

9 BCC ETN (67) 1 0 45 N.A. UVB >74 J/cm2, PUVA, MTX (5.8), CsA (0.1),ETN (3.5)

-

10 BCC ETN (73) 1 0 21 N.A. UVB, PUVA, MTX (1), ETN (1.6)

-

11 SCC ETN, ADA (76) 14 0 19, 31, 31, 40, 45, 49, 50, 50, 50, 59, 69, 69, 74, 74

N.A. UVB, PUVA (12 courses), MTX (5.3), CsA (10.2), ETN (1.4)

5 BCC4 SCC1 KAm

1 melanoma in situ


eTime (months) between the date of initiation of TNF-inhibitor therapy and NMSC diagnosis. fDuration of treatment until the date of the first diagnosis of NMSC.gSkin cancer history before the initiation of TNF-inhibitor therapy.hETN; etanercept, iMTX; methotrexate, jCsA; ciclosporin A, kADA; adalimumab; lAZA; azathioprinemKA; keratoacanthoma.

the first year after the start of anti-TNF therapy and 18% (2/11) had a history of NMSC before the start of TNF-inhibitor therapy. In the RA group, 17% (2/12) received a NMSC diagnosis within the first year and 17% (2/12) had a history of NMSC.

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Table 3. Patients with RA diagnosed with NMSC after the initiation of TNF-inhibitor therapy.

Pta NMSC



N° of NMSCduring

anti-TNFαc

N°of NMSCafter

anti-TNFαd


anti-TNFαe


anti-TNFαe Treatments, duration (censored, years)f

Skin cancerhistoryg

1 BCC INFh (6) 0 3 N.A. 21, 53, 126 MTXi (2.2), CsAj (1), prednisone (8), AZAk (2), INF (0.5) 3 BCCs

2 BCC INF, ETNl, ADAm (113) 1 0 28 N.A. MTX (4.3), prednisone (5), INF (2.3) -

3 SCC

BCC

ETN (107) 6

1

0

0

5, 32, 58,67, 70, 8245

N.A.

N.A.

MTX (2.3), prednisone (9), AZA (6), ETN (0.4)

-

4 BCC ADA (10) 0 3 N.A. 31, 31, 56 MTX (0.7), prednisone (13), AZA (1), ADA (0.9) -

5 BCC ADA (69) 1 0 64 N.A. MTX (0.1), prednisone (17), AZA (5), ADA (5.3) -

6 SCC ADA (16) 0 1 N.A. 86 MTX (11.3), prednisone (10), ADA (1.1)

-

7 BCC INF, ETN, (11) 0 1 N.A. 66 MTX (1.8),prednisone (6), AZA (1)INF (0.6), ETN (0.3), rituximab (0.2)

-

8 BCC INF (16) 0 2 N.A. 59, 61 MTX (28.6), prednisone (22), AZA (5), INF (1.3)abatacept (0.7)

-

9 BCC ETN, ADA (49) 0 1 N.A. 49 MTX (1.6), ETN (2.0), ADA (0.5) -

10 BCC INF, ETN, ADA (94) 1 0 44 N.A. MTX (4.0), prednisone (2), AZA (1), INF (0.7), ETN (2.8),

6 BCCs

11 BCC INF (96) 1 0 71 N.A. MTX (10.8), prednisone (1), AZA (9), INF (6.0) -

12 BCC ETN (12) 5 0 3, 3, 3, 3, 3 N.A. MTX (0.1), prednisone (0.1), ETN (0.2)

-


eTime (months) between the date of initiation of TNF-inhibitor therapy and NMSC diagnosis. fDuration of treatment until the date of the first diagnosis of NMSC.gSkin cancer history before the initiation of TNF-inhibitor therapy.hINF; infliximab, iMTX; methotrexate, jCsA; ciclosporin A, kAZA; azathioprine, lETN; etanercept, mADA; adalimumab.

Apart from an SCC, patient 1 from the psoriasis group was also diagnosed with a superficial spreading melanoma (Breslow thickness 0.3 mm, Clark level 3) after 101 months of TNF-inhibitor therapy.

The BCC:SCC ratio in the psoriasis group was 0.7:1 (16:22). In the RA group, this was 2.9:1 (20:7). After excluding patient 11 of the psoriasis group who had multiple SCCs, the BCC:SCC ratio was 2:1 (16:8).

Cox regression analysisFigures 1 and 2 show the time until first NMSC after the start of anti-TNF-a therapy in all patients and in patients with an event only, respectively. The estimated mean time until first NMSC in all patients was 8.8 years in the psoriasis group and 12.9

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Table 3. Patients with RA diagnosed with NMSC after the initiation of TNF-inhibitor therapy.

Pta NMSC



N° of NMSCduring

anti-TNFαc

N°of NMSCafter

anti-TNFαd


anti-TNFαe


anti-TNFαe Treatments, duration (censored, years)f

Skin cancerhistoryg

1 BCC INFh (6) 0 3 N.A. 21, 53, 126 MTXi (2.2), CsAj (1), prednisone (8), AZAk (2), INF (0.5) 3 BCCs

2 BCC INF, ETNl, ADAm (113) 1 0 28 N.A. MTX (4.3), prednisone (5), INF (2.3) -

3 SCC

BCC

ETN (107) 6

1

0

0

5, 32, 58,67, 70, 8245

N.A.

N.A.

MTX (2.3), prednisone (9), AZA (6), ETN (0.4)

-

4 BCC ADA (10) 0 3 N.A. 31, 31, 56 MTX (0.7), prednisone (13), AZA (1), ADA (0.9) -

5 BCC ADA (69) 1 0 64 N.A. MTX (0.1), prednisone (17), AZA (5), ADA (5.3) -

6 SCC ADA (16) 0 1 N.A. 86 MTX (11.3), prednisone (10), ADA (1.1)

-

7 BCC INF, ETN, (11) 0 1 N.A. 66 MTX (1.8),prednisone (6), AZA (1)INF (0.6), ETN (0.3), rituximab (0.2)

-

8 BCC INF (16) 0 2 N.A. 59, 61 MTX (28.6), prednisone (22), AZA (5), INF (1.3)abatacept (0.7)

-

9 BCC ETN, ADA (49) 0 1 N.A. 49 MTX (1.6), ETN (2.0), ADA (0.5) -

10 BCC INF, ETN, ADA (94) 1 0 44 N.A. MTX (4.0), prednisone (2), AZA (1), INF (0.7), ETN (2.8),

6 BCCs

11 BCC INF (96) 1 0 71 N.A. MTX (10.8), prednisone (1), AZA (9), INF (6.0) -

12 BCC ETN (12) 5 0 3, 3, 3, 3, 3 N.A. MTX (0.1), prednisone (0.1), ETN (0.2)

-


eTime (months) between the date of initiation of TNF-inhibitor therapy and NMSC diagnosis. fDuration of treatment until the date of the first diagnosis of NMSC.gSkin cancer history before the initiation of TNF-inhibitor therapy.hINF; infliximab, iMTX; methotrexate, jCsA; ciclosporin A, kAZA; azathioprine, lETN; etanercept, mADA; adalimumab.

years in the RA group. In patients with an event only, the median time until event was 1.6 years in the psoriasis patients and 3.7 years in the RA patients. The unadjusted hazard ratio (HR) of developing NMSC in the psoriasis group compared with the RA group was 2.0 (0.9–4.7 95%CI) (raw model, Table 4). The fully adjusted HR was 6.0 (1.6–22.4 95%CI) (corrected model). The sensitivity analysis with exclusion of patients with NMSC prior to the start of TNF-inhibitor therapy showed an unadjusted HR of 2.1 (0.8–5.4 95%CI) and an adjusted HR of 13.4 (2.9–63.0 95%CI).

Poisson regression analysis In the psoriasis patients a total number of 38 NMSC was reported in 1306 patient-years, resulting in an event rate of 2.9 (2.1–4.0 95%CI) per 100 patient-years; in the

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figure 1. Time until first nMSC in all psoriasis and Ra patients

RA patients the event rate was 0.9 (0.6–1.3 95%CI) per 100 patient-years (27 events in 2863 patient-years). By Poisson regression, this resulted in an unadjusted rate ratio of 4.1 (2.3– 7.0 95%CI). Corrected for confounders, by Poisson regression, psoriasis patients had a 5.5 (2.2–13.4 95%CI) higher rate of NMSC compared to RA patients. The model fit statistics showed that the Poisson model fitted the data well. The sensitivity analysis with exclusion of patients with NMSC prior to the start of TNF-inhibitor therapy showed an unadjusted rate ratio of 2.1 (1.0–4.1 95%CI) and an adjusted rate ratio of 7.0 (2.3–21.5 95%CI).

On drug analysis

For this analysis, 397 RA patients and 279 psoriasis patients could be included. In the ‘on drug’ analysis, 11 psoriasis patients (3.9%) and 6 RA patients (1.5%) were diagnosed with NMSC (Tables 2–3). The total number of NMSC was 33 (13 BCCs and 20 SCCs) in the psoriasis group and 16 (10 BCCs and 6 SCCs) in the RA group.

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figure 2. Time until first nMSC in psoriasis and Ra patients with an event

Table 4. Results of the Cox regression analysis (‘every exposed to anti-TNF analysis’)

Variable B HR (exp B) 95% CI

Raw model

Diagnosis 0.689 1.992 0.853-4.656

Corrected model

Diagnosis 1.788 5.977 1.596-22.385

Age 0.053 1.054 1.011-1.099

Gender 0.381 1.464 0.586-3.660

Disease duration 0.010 1.010 0.997-1.023

NMSC prior to anti-TNF therapy 1.843 6.316 1.698-23.499

Duration of anti-TNF therapy -0.013 0.988 0.982-0.993

Duration of non anti-TNF biological therapy -1.324 0.266 0.037-1.907

Duration of ciclosporin therapy 0.029 1.030 0.794-1.336

Duration of prednison therapy 0.034 1.035 0.956-1.120

Duration of methotrexate therapy -0.058 0.944 0.862-1.034

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Cox regression analysisThe unadjusted HR of developing NMSC in the psoriasis group compared with the RA group was 6.8 (2.1–22.1 95%CI) (raw model, see Table 5) and the fully adjusted HR was 7.5 (1.7–33.6 95%CI) (corrected model).

Poisson regression analysisBy Poisson regression, the unadjusted rate ratio was 5.9 (2.8–12.3 95%CI). Corrected for con-founders, psoriasis patients had a 3.0 (1.1–8.4 95%CI) higher rate of NMSC compared to RA patients. The model fit statistics showed that the Poisson model fitted the data well.

Table 5. Results of the Cox regression analysis (‘on drug analysis’)

Variable B HR (exp B) 95% CI

Raw model

Diagnosis 1.910 6.752 2.064-22.094

Corrected model

Diagnosis 2.021 7.544 1.692-33.633

Age 0.091 1.095 1.041-1.151

Gender 0.803 2.233 0.736-6.776

Disease duration 0.013 1.013 0.993-1.033

NMSC prior to anti-TNF therapy 2.561 12.943 2.696-62.138

Duration of non anti-TNF biological therapy -4.197 0.015 0.000-48.898

Duration of ciclosporin therapy 0.072 1.074 0.810-1.426

Duration of prednison therapy 0.005 1.005 0.895-1.129

Duration of methotrexate therapy -0.126 0.882 0.768-1.012

dISCuSSIOn

In this study, the time till occurrence of the first NMSC after the initiation of TNF-inhibitors was shorter and the rate of NMSC was higher in psoriasis patients compared to RA patients. In the ‘ever exposed to anti-TNF analysis’, which was the main analysis of this study, the adjusted hazard ratio of developing NMSC was significantly higher in the psoriasis group with a shorter time until first NMSC [HR 6.0 (1.6–22.4 95%CI)], after correction for differences in previous systemic treatments and demographic characteristics. In addition, the total event rate was 5.5 (2.2–13.4 95%CI) times higher in the psoriasis group.

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It is therefore possible that disease-related factors like previous phototherapy play an important role in the occurrence of NMSC in psoriasis patients treated with TNF-inhibitors. This is supported by the finding that the proportion of patients diagnosed with NMSC within the first year after the start of anti-TNF-a therapy was higher in psoriasis (36%) compared with RA (17%). The low BCC:SCC ratio found in the psoriasis group points towards the role of phototherapy. In the general population, BCC:SCC ratios of 4:1 are reported.16–18 As it is known that the incidence of SCC may be more affected by phototherapy than BCC, the low BCC:SCC ratio found in this study supports an influence of phototherapy.18,19

It would be of great interest to compare the current psoriasis group to a group of psoriasis patients who had received photo-therapy and conventional systemic anti-psoriatic therapies but no anti-TNF-a therapy, to investigate the influence of TNF-inhibitors on the development of NMSC. However, this group of patients was not available. A comparison with data from the literature has many limitations due to differences in study procedures, different time periods covered and differences in the degree of sun exposure with latitude.

NMSC prior to the start of TNF-inhibitor therapy was shown to be a strong predicting factor for being diagnosed with NMSC after the start of TNF-inhibitor therapy. We corrected for this confounder (history of NMSC before the start of anti-TNF-a therapy) in the regression analyses. In addition, a sensitivity analysis excluding patients with prior NMSC was performed, which showed similar results.

A limitation is the fact that the absolute number of NMSC was small. However, despite the small number of NMSC, statistically significant differences between the psoriasis and the RA group were detected. In addition, the fact that the number of NMSC was small, is reassuring with respect to the risk of NMSC associated with treatment with TNF-antagonists.

Without the ambition to be complete, several factors besides phototherapy may be hypothesized to have a potential role in the induction of NMSC in psoriasis patients like skin type, sun exposure, detection bias, acitretin treatment and the presence of psoriatic arthritis.

Correction for important risk factors for developing NMSC such as skin type and sun exposure was not possible, as skin type information was only available for a part of the psoriasis patients and not for the RA patients. Information on sun exposure was not available. However, as both groups cover the Netherlands and the same time period, the degree of sun exposure related to latitude and skin cancer trends were expected to be the same for both groups. Nevertheless, psoriasis patients could have higher recreational sun exposure as this often improves their psoriasis.

Detection bias may have played a role in the psoriasis group due to more regular skin assessments by dermatologists. In addition, the actual number of NMSC may have been higher due to treatment of in particular superficial BCCs without taking

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a biopsy. However, as both groups were treated in academic hospitals where is common practice to take a biopsy before initiating treatment, this influence is expected to be small.

Acitretin treatment in combination with immunosuppressive treatments in renal transplant recipients may be protecting against NMSC.20,21 In psoriasis, concomitant acitretin may have the same effect. In this study, 150 psoriasis patients (54%) had ever used acitretin but only 16 patients (5.7%) used acitretin concomitantly with TNF-inhibitors. The influence of actitretin is therefore expected to be small. Twenty-eight per cent of the patients also had psoriatic arthritis, which theoretically should be analysed as a separate group with its own NMSC risk. In addition, the difference in the rate of NMSC found, could be influenced by the specific disease, i.e. having psoriasis or RA.

In conclusion, the time until first NMSC was significantly shorter and the rate of NMSC was significantly higher in the psoriasis group compared with the RA group. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

REfEREnCES

1. Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23(Suppl 2): 1–70.

2. van Lumig PP, Driessen RJ, Berends MA, Boezeman JB, van de Kerkhof PC, de Jong EM. Safety of treatment with biologics for psoriasis in daily practice: 5-year data. J Eur Acad Dermatol Venereol 2012; 26: 283–291.

3. Smith CH, Anstey AV, Barker JN et al. British Association of Dermatologists’ guidelines for biologic interventions for psoriasis 2009. Br J Derma-tol 2009; 161:987–1019.

4. Lecluse LL, de Groot M, Bos JD, Spuls PI. Experience with biologics for psoriasis in daily practice: switching is worth a try. Br J Dermatol 2009; 161: 948–951.

5. Driessen RJ, Boezeman JB, van de Kerkhof PC, de Jong EM. Three-year

6. registry data on biological treatment for psoriasis: the influence of patient

characteristics on treatment outcome. Br J Dermatol 2009; 160: 670–675.

7. Kievit W, Fransen J, Adang EM et al. Long-term effectiveness and safety of TNF-blocking agents in daily clinical practice: results from the Dutch Rheumatoid Arthritis Monitoring register. Rheumatology (Oxford) 2011; 50: 196–203.

8. Casparie M, Tiebosch AT, Burger G et al. Pathology databanking and biobanking in The Netherlands, a central role for PALGA, the nationwide histopathology and cytopathology data network and archive. Cell Oncol. 2007; 29: 19–24.

9. Bailin PL, Tindall JP, Roenigk HH Jr, Hogan MD. Is methotrexate therapy for psoriasis carcinogenic? A modified retrospective-prospective analysis. JAMA 1975; 232: 359–362.

10. Chakravarty EF, Michaud K, Wolfe F. Skin cancer, rheumatoid arthritis, and tumor necrosis factor inhibitors. J Rheumatol 2005; 32: 2130–2135.

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11. Jensen P, Moller B, Hansen S. Skin cancer in kidney and heart transplant recipients and dif ferent long-term immunosuppressive therapy regimens. J Am Acad Dermatol 2000; 42: 307.

12. Karagas MR, Cushing GL Jr, Greenberg ER, Mott LA, Spencer SK, Nierenberg DW. Non-melanoma skin cancers and glucocorticoid therapy. Br J Cancer 2001; 85: 683–686.

13. Stern RS, Laird N. The carcinogenic risk of treatments for severe psoriasis. Photochemotherapy Follow-up Study. Cancer 1994; 73: 2759–2764.

14. Stern RS, Zier ler S, Parr ish JA. Methotrexate used for psoriasis and the risk of noncutaneous or cutaneous malignancy. Cancer 1982; 50: 869– 872.

15. Setshedi M, Epstein D, Winter TA, Myer L, Watermeyer G, Hift R. Use of thiopurines in the treatment of inflammatory bowel disease is associated with an increased risk of non-melanoma skin cancer in an at-risk population: a cohort study. J Gastroenterol Hepatol 2012; 27: 385–389.

16. van Lumig PP, Driessen RJ, Kievit W, Boezeman JB, van de Kerkhof PC, de Jong EM. Results of three analytical approaches on long-term efficacy of etanercept for psoriasis in daily practice. J Am Acad Dermatol 2013; 68: 57–63.

17. Lim JL, Stern RS. High levels of ultraviolet B exposure increase the risk of non-melanoma skin cancer in psoralen and ultraviolet A-treated patients. J Invest Dermatol. 2005; 124: 505–513.

18. Ridky TW. Nonmelanoma skin cancer. J Am Acad Dermatol 2007; 57: 484–501.

19. Stern RS. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet A therapy: a 30-year prospective study. J Am Acad Dermatol 2012; 66: 553–562.

20. Stern RS, Liebman EJ, Vakeva L. Oral psoralen and ultraviolet-A light (PUVA) treatment of psoriasis and persistent risk of nonmelanoma skin cancer. PUVA Follow-up Study. J Natl Cancer Inst 1998; 90: 1278–1284.

21. Bavinck JN, Tieben LM, Van der Woude FJ et al. Prevention of skin cancer and reduction of keratotic skin lesions during acitretin therapy in renal transplant recipients: a double-blind, placebo-controlled study. J Clin Oncol 1995; 13: 1933–1938.

22. de Sevaux RG, Smit JV, de Jong EM, van de Kerkhof PC, Hoitsma AJ. Acitretin treatment of premalignant and malignant skin disorders in renal transplant recipients: clinical effects of a randomized trial comparing two doses of acitretin. J Am Acad Dermatol 2003; 49: 407–412.

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2CPIIINP MEASUREMENTS FOR

THE DETECTION OF LIVER FIBROSIS IN METHOTREXATE

TREATED PSORIASIS PATIENTS: Daily pracTicE usE aND

cliNical implicaTiONs

Chapter 2

2C

abSTRaCT

BACKGROUND: Methotrexate is an important antipsoriatic drug but associated with liver fibrosis. Procollagen-3 N-terminal peptide (PIIINP) is a non-invasive serum marker for detecting liver fibrosis. OBJECTIVES: To describe the results of serial PIIINP monitoring in psoriasis patients treated with methotrexate in daily practice by answering: (1) what percentage of patients had normal resp. abnormal PIIINP series, (2) did patient or treatment characteristics differ between groups, (3) what were results of additional liver fibrosis tests, and (4) did PIIINP and liver enzymes correlate?METHODS: Data collected from three Dutch hospitals were described. Correlations were calculated and expressed as Pearson correlation coefficients.RESULTS: We included 183 patients with 952 patient-years on methotrexate. Normal serial PIIINP concentrations were found in 142 patients (78%); 41 patients (22%) had elevated series. The average cumulative methotrexate dose did not differ between groups. Patients with elevated PIIINP concentrations were older with longer disease duration and higher BMI than patients with normal PIIINP. Twenty patients (49%) with elevated serial PIIINP concentrations had further diagnostics; one patient had significant fibrosis detected by liver biopsy, 2 patients had possible liver fibrosis on FibroScan and 14 patients showed signs of hepatic steatosis on ultrasound/biopsy. PIIINP concentrations showed low correlations with liver enzymes (ALT, γ-GT).DISCUSSION: When looking solely at PIIINP, 78% of patients were not expected to have liver fibrosis. Although not all patients underwent further diagnostics, the number of patients with liver fibrosis was low. Guidelines regarding PIIINP were differently applied. Many patients showed signs of hepatic steatosis which may be an underestimated risk factor for liver disease in psoriasis patients using methotrexate.

J.M.P.A. van den Reek, S.P. Menting (second first author), W.W.L. Janssen, R Dhaliwal, AC Heijboer, AE van Herwaarden, FCGJ Sweep, LM de Jong,

ET Tjwa, ME Otero, Ph.I. Spuls, EMGJ de Jong

Under review

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InTROduCTIOn

From the 1970s to 90s, some studies reported moderate to high (range 9-46%) proportions of psoriasis patients developing liver fibrosis and cirrhosis during methotrexate (MTX) treatment.(1-5) More recent reports show lower numbers of patients developing liver fibrosis, and a low or absent risk attributable to MTX.(6-12) Besides, it is shown that psoriasis patients are at risk for obesity, diabetes, metabolic syndrome and alcohol use, which might influence liver function.(13-16) Determination of serum procollagen-3 N-terminal peptide (PIIINP) is the screening method advised in the current European guideline during MTX treatment for psoriasis.(17) The development of non-invasive markers for fibrosis such as PIIINP intend to lower the amount of potential harmful liver biopsies.(18-21) Current European and Dutch guidelines advise to monitor PIIINP concentrations.(17, 22) Dutch guidelines advise to monitor every three months and refer the patient to a hepatologist when the test is serially elevated (3 consecutive PIIINP measures >4.2 mcg/l, or at least 2 consecutive measures ≥8 mcg/l or one >10mcg/l) (Figure 1).(22) PIIINP is a serum marker for collagen turnover, and related to fibrogenesis.(23, 24) Therefore, we need to be aware of the fact that PIIINP can be confounded by several factors such as active arthritis, recent myocardial infarction, recent bone fracture or young age, resulting in false positive outcomes.(19, 25-30) However, in a recent meta-analysis, PIIINP showed the best levels of diagnostic accuracy compared with other non-invasive tests (liver function tests, ultrasound, Fibroscan, radionuclide scans).(31) Though, ascertainment bias may have played a role in the included studies and low likelihood ratios for PIIINP were reported.(31) Other studies show that, when a normal serial PIIINP is measured, the risk of missing significant liver fibrosis seems very low.(24, 32, 33)

More studies are needed to assess the validity of non-invasive tests for detecting liver fibrosis.(31) As serum PIIINP concentration is the screening tool in guidelines and daily practice nowadays, it is meaningful to investigate the actual results of PIIINP monitoring in psoriasis patients treated with MTX in daily practice. For that purpose, we collected clinical data of patients with PIIINP measurements from three large dermatology centres in the Netherlands. The following research questions were answered: (1) What percentage of patients had normal resp. abnormal PIIINP concentrations, (2) did patient or treatment characteristics differ between these groups, (3) what were the results of tests for additional liver fibrosis detection and (4) what was the correlation of PIIINP with liver enzymes (ALT, γ-GT).

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METhOdS

Population, patient and treatment characteristicsPIIINP measurements from patients of the departments of dermatology of the Radboudumc Nijmegen, the Academic Medical Centre (AMC) Amsterdam and hospital the Gelderse Vallei Ede (GV), that were performed from 2006 until 2012, were collected. From the Radboudumc, all patients with PIIINPs included in the prospective ongoing MTX registry (Continuous Assessment of Psoriasis Treatment Use REgistry with Methotrexate – MTX CAPTURE) were selected. In the AMC and GV, psoriasis patients with PIIINP measurements were traced and their medical charts were investigated retrospectively. The following data was collected: age, sex, disease duration, MTX use (dosage and duration), body mass index (BMI), alcohol use, history of diabetes and hepatic diseases (e.g. viral hepatitis, hepatic steatosis), outcomes of liver biopsies and other hepatic investigations (e.g. Fibroscan, ultrasound), reason for referral to hepatologist, and corresponding measurements of alanine transaminase (ALT), aspartate transaminase (AST), gamma-glutamyl transferase (γ-GT), total bilirubin, and albumin.

PIIINP before initiation of MTX

>8.0 ug/L ≤8.0 ug/L

≤4.2 ug/L

>4.2 ug/L for 3

consecutive times/yr

>8 ug/L for 2

consecutive times/yr

>10 ug/L once

Consult gastroenterologist

before starting MTX

Initiate MTX, measure P3NP every 3 months

Consult gastroenterologistContinue MTX

Consult gastroenterologist, quit

MTX

figure 1. PIIInP protocol derived from the dutch Psoriasis Guideline.(34) MTX, methotrexate; yr, year.

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Patients were excluded when they had factors confounding PIIINP: this was the case when they were younger than 18 years or when they had an active malignancy, recent myocardial infarction, scleroderma, a recent bone fracture, and/or a diagnosis of psoriatic arthritis (or other inflammatory arthritis).(25-27, 29, 35) If the confounding factor played a role in a single PIIINP evaluation only, the other serial PIIINP evaluations were included for analysis. If successive measurements were not exactly performed every three months, the measurement closest to that time point was selected with a minimum window of 2.5 months in between. If patients had ≤2 PIIINP measurements, they were excluded unless these ≤2 measurements were already reason for referral (if PIIINP was once >10 mcg/l or twice >8 mcg/l) based on the current guideline.

Laboratory measurementsIn all centers, PIIINP concentrations were measured by UniQ radio-immuno assay from Orion Diagnostica, Espoo, Finland.

Data analysisAll data of patients until the moment of data lock (2012) were taken into account, even if patients had stopped using MTX in 2012. Patient and treatment characteristics were assessed. The proportion of patients with normal and elevated PIIINP series was assessed. Characteristics were compared between patients with and without elevated serial PIIINP concentrations and tested using an unpaired t-test, Pearson’s Chi-squared test or a non-parametric alternative.

The follow up of the patients was described: all diagnostic procedures providing information on the liver were extracted from the registry and/or medical charts. Different diagnostic procedures like liver biopsies, ultrasounds, and Fibroscans were taken into account. The percentage of patients with important liver injury was calculated per group. For liver biopsies, Roenigk score ≥3b was considered as significant liver fibrosis; for Fibroscans F-scores ≥2 were considered as a sign of significant liver fibrosis.(36-38)

The first and last PIIINP measurements per patient were correlated to their corresponding ALT and γ-GT measurements by Pearson correlation statistics. We chose ALT and γ-GT measurements because (1) they are frequently measured in clinical practice, (2) ALT is a sensitive test to monitor liver damage, and (3) γ-GT correlated with PIIINP in a previous study.(39, 40)

For statistical analyses, data were analysed with SPSS Statistics v20.0 (IBM, Armonk, NY, U.S.A.).

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RESulTS

PopulationFigure 2 shows the flow of the study population. Data of 183 patients with PIIINP measurements from 3 departments of Dermatology in the Netherlands were analysed: 98 (54%) patients from the Radboudumc; 40 (22%) from the AMC; and 45 (25%) from the GV. A substantial number of patients (n=59) were excluded due to the presence of confounders for PIIINP; in most cases this concerned having a diagnosis of psoriatic arthritis.

N=395MTX treated

psoriasis patients with

PIIINP

N=183Included

N=212Excluded:

-N=153 insufficient PIIIINPs*-N=59 confounders (e.g. psoriatic arthritis)

N=142Normal serial

PIIINP

N=41Elevated

serial PIIINP

N=121No

diagnostics/referral

N=21Diagnostics/

referral

N=20Diagnostics/

referral

N=21No

diagnostics/referral

* No serial PIIINP measurement, only 1 or 2 measurements; MTX, methotrexate.

figure 2: flow chart of study population.

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Patient and treatment characteristicsIn total 183, patients with 952.3 patient-years on MTX were present in the cohort. PIIINP measurements were available for 546 patient years. One-hundred forty-two patients (78%) had at least 3 PIIINP measurements without serial elevations. Of these patients, 41 (22%) had serially elevated PIIINPs that were reason for referral to a hepatologist according to current guidelines.(41) Table 1 shows baseline and treatment characteristic of the present cohort. Patients with elevated PIIINPs had a significantly higher age, higher BMI, used a lower mean weekly MTX dose, had a longer disease duration, and, more often, a pre-existing diagnosis with hepatic steatosis. The median cumulative dose and duration of MTX, baseline ALT and γ-GT were equal between patients with and without elevated PIIINPs. Diabetes was not significantly more prevalent in the patients with PIIINP elevation (8% versus 12%, p=0.369). More patients in the elevated PIIINP group stated not to drink any alcohol (46.3% vs. 29.6%). However, when comparing patients with and without alcohol use, no differences between groups was found (p=0.212). No patients with elevated PIIINP had a history of viral hepatitis. Six patients without elevated series had a history of hepatitis (A or B). One of them had an active hepatitis B infection with a low viral load.

Diagnostic procedures in patients with serial elevated PIIINPsIn the 41 patients with serially elevated PIIINP series, only 20 (49%) were referred to a hepatologist and/or underwent further diagnostics (table 2). As is shown in this table, some patients underwent more than one diagnostic procedure. Six patients showed no liver abnormalities. Relevant liver problems consisted of Roenigk 3b (n=1) and Roenigk 3a (n=1) detected by liver biopsy, and high liver stiffness score detected with Fibroscan (n=2). In 14 patients, signs of hepatic steatosis on ultrasound and/or in liver biopsy were present.

The patient with liver fibrosis (Roenigk 3b) detected with liver biopsy had a high PIIINP (11 mcg/l) at baseline, significantly elevated liver enzymes, known hepatic steatosis and an unknown BMI. One of the patients with liver fibrosis on Fibroscan (F3) had high but stable PIIINPs (5-6 mcg/l), mildly elevated liver enzymes (ALT), a BMI of 30.5, and steatosis at time of Fibroscan. The other patient with liver fibrosis on Fibroscan (F3) had high PIIINP from start (7 mcg/l, increasing to 12 mcg/l). This patient was obese (gastric belt), did not have significantly elevated liver function tests and had hepatic steatosis diagnosed at time of Fibroscan. All 3 patients reported to drink alcohol (unknown amounts), and no patient had diabetes.

Twenty-one (51%) patients were not referred to a hepatologist and/or did not undergo further diagnostics, while having elevated PIIINP series. One of these patients already stopped MTX, while in another patient, the physician waited and PIIINP normalized in time. In 2 patients, confounding factors were assumed to be of influence, one of them was referred to a rheumatologist to rule out arthritis. In the last patient, a malignancy became manifest and further liver diagnostics was renounced. In most cases however, the reason for non-referral was unknown.

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Table 1. Patient and treatment characteristics in patients with and without relevantly elevated PIIINP series mean ±sD, median [range], n (%)

Elevated PIIINPseries (n=41)

No elevated PIIINP series

(n=142) p-value

Patient characteristicsAge Sex (male) Disease durationBMI

55.9 ±16.521 (51.2)25.8 [1.5-59.7]27.8 [19.5-40.4]

48.3± 15.881 (57.0)16.4 [0-52.6]26.1 [18.3-62.5]

0.008c

0.508d

0.008e

0.047e

Alcohol use -No -Yes, 0-20 units a week -Yes, >21 units a week -Yes, amount unknownBaseline LFTPIIINP ALT γ-GTLFT at moment of (serial) elevated PIIINPPIIINP ALT γ-GT

19b (46.3)13b (31.7)-4b (9.8)

4.8 [2.1-11.0]31.0 [11.0-63.0]26.5 [9.0-84.0]

5.9 [4.3-18.0]38.0±20.230.0 [10-84]

42a (29.6)53a (37.3)3a (2.1)5a (3.5)

3.1 [1.4-7.8]27.0 [8.0-145.0]26.0 [6.0-193.0]

---

0.212df

<0.001 e

0.095 e

0.730 e

History of liver disease NAFLDLiver biopsy (past)γ No anomalies Roenigk 1 Roenigk 1-2 Roenigk 2 Roenigk 3aHepatitis B (active)Hepatitis B (non-active)Hepatitis C (non-active)Hepatitis A (non-active)Other (episode of icterus, hepatitis e.c.i.)History of other comorbidities Malignancies in past Diabetes in pastTreatment characteristicsDuration of MTX use (yrs)*Cumulative dose of MTX (mg)*Time Average dose (MTX/week)*

8 (19.5)

-1 (2.4)-2 (4.9)2 (4.9)-----

4 (9.8)5 (12.2)g

3.7 [0.7-33.2]2.747 [0.330-24.253]11.8±3.3

8 (5.6)

1 (0.7)7 (4.9)1 (0.7)3 (2.1)-1 (0.7)3 (2.1)-2 (1.4)1 (0.7)

7 (4.9)11 (7.7)g

3.3 [0.5-36.7]2.270 [0.280-20.180]13.9±3.5

0.015d

0.252d

0.369dg

0.265e

0.870e

0.001c

lFT, liver function tests; NaFlD, non-alcoholic fatty liver disease. γ highest roenigk score, a data of 103patients available, b data of 36 patients available, c independent t-test, d pearson’s chi-squared test, e mann-Whitney u test. f tested for alcohol use (yes) versus no alcohol use at all. g 2 patients in the non-elevated piiiNp group, and 1 patient in the elevated piiiNp group did have diabetes, but it was not known whether this was before or after piiiNp measurements. These patients were not included in this table, nor in the statistical analysis. *refers to the minimal (cumulative) dose and duration, no imputation for missing data was used.

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Table 2. Diagnostic procedures in patients with elevated PIIINP during PIIINP measurements (n=41)

PatientYear Liver

biopsyOutcome Liver

biopsyYear

UltrasoundOutcome

UltrasoundYear

FibroscanOutcome Fibroscan

1 2012 Roenigk 1, S+ 2012 Normal

2 2012 Roenigk 1, S-

3 2012 Roenigk 1, S+


5 2010 Roenigk 2, S+ 2010 Hepatic steatosis


2011 Hepatic steatosis

2012 Hepatic steatosis

7 2009 Roenigk 3b, S+ 2009 Hepatic steatosis


2011 Roenigk 3a, S+


2011 Roenigk 2, S+ 2011 Hepatic steatosis


2011 Roenigk 1, S+ 2011 Normal

11 2008 Hepatic steatosis

12 2012 Hepatic steatosis 2012 15,6 kpa/F3

13 2010 Hepatic steatosis 2010 14,3 kpa/F3



16 2012 Normal


18 2012 6.1 kpa/F0-F1

19 2012 5.5 kpa/F0-F1

20 2012 5,2 kpa/F0-F1

Reason for no diagnostical procedures after elevated PIIINP (n=21)

Referred to hepatologist, liver biopsy failed and was not repeated due to occurrence of a malignancy N=1

Patient was referred to a rheumatologist to rule out PsA first, PIIINP normalized in meantime N=1

Physician waited and repeated PIIINP, which normalized N=1

Patient stopped using methotrexate and was therefore not referred N=1

PIIINP was thought to be influenced by confounding factors (lymfadenopathy, angina pectoris) and therefore patient was not referred. N=1

Not referred to a hepatologist, reason unknown N=16

interpretation results liver biopsy: roenigk 1/2 = no fibrosis, roenigk 3a = mild fibrosis (fibrosis extending into acini), roenigk 3b = moderate or severe fibrosis. s+= signs of steatosis, s-=no signs of steatosis. Outcome fibroscan <7.1 kilopascal (kpa): no fibrosis (F0-F1), ≥7.1 kpa-<9.5kpa: moderate fibrosis (F2), ≤ 9.5 kpa: severe fibrosis (F3). as Fibroscan is not validated for this disease, results are provided in kilopascal as well.

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Diagnostic procedures in patients without serial elevated PIIINPsTwenty-one out of 142 patients who never had relevantly elevated PIIINP concentrations underwent diagnostic procedures for other reasons, such as a high cumulative dose of MTX or liver function test abnormalities (table 3). Eighteen patients (13%) underwent a liver biopsy. The highest score was Roenigk 2-3a (n=1) and Roenigk 2 (n=1), all others had Roenigk 1 (n=16). One patient in this group had a Fibroscan performed which was staged F2. Of note, this patient also had a liver biopsy showing Roenigk 1. Signs of hepatic steatosis were detected in ten patients undergoing ultrasounds or liver biopsies.

Correlation PIIINP with ALT and γ-GTWe tested whether correlations existed between PIIINP and ALT, and PIIINP and γ-GT. All first and all last PIIINP measurements were correlated to the liver enzymes. Low Pearson correlation coefficients (PCC) were found between first PIIINP and first ALT measurement (PCC 0.1, p=0.05, n=326), first PIIINP and first γ-GT measurement (PCC 0.06, p=0.3, n=312), last PIIINP and last ALT measurement (PCC 0.2, p=0.006, n=331), and last PIIINP and last γ-GT measurement (PCC 0.22, p<0.001, n=336).

dISCuSSIOn

Serum PIIINP is a non-invasive screening marker used to detect MTX-related liver fibrosis in psoriasis patients. The goal of introducing non-invasive markers is to prevent unnecessary and harmful liver biopsies. As serum PIIINP concentration is the screening tool in guidelines and daily practice nowadays, we investigated the actual results of PIIINP monitoring in psoriasis patients treated with MTX in daily practice. In the present study, 78% (n=142) of 183 patients had normal serial PIIINPs. Based on current PIIINP guidelines, no further diagnostics (liver biopsy) had to be performed in this subgroup when looking solely at PIIINP (four patients without elevated PIIINP were referred to a hepatologist because of elevated liver function tests, see table 3). The other 41 patients (22%) had elevated PIIINP series and should have been referred to a hepatologist and/or further diagnostics should have taken place according to the guidelines. However, this was only performed in 21 patients. The reason for non-referral was mostly unknown.

We found that patients with elevated PIIINP series had different characteristics than the non-elevated group: a higher BMI, age, disease duration, and more frequently a pre-existent diagnosis with hepatic steatosis. Strikingly, this subgroup used a lower weekly dose of MTX and the same cumulative dose as patients without elevated PIIINP concentrations. The fact that patients with elevated PIIINP concentrations had the same cumulative dose of MTX as patients with normal PIIINP concentrations, indicates that MTX may not be the only explaining factor for high PIIINP concentrations.

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Table 3. Diagnostic procedures in patients without elevated PIIINP during PIIINP measurements (n=142)

PatientYear Liver

biopsyOutcome Liver

biopsyYear

UltrasoundOutcome

UltrasoundYear

FibroscanOutcome Fibroscan

1 2006 Roenigk 1, S+ 2006 7.1 kPa/F2

2 2009 Roenigk 1, S- 2008 Normal




2012 Roenigk 1, S+



2010 Roenigk 1, S- 2010 Hepatic steatosis


9 2012 Roenigk 2-3a, S+



12 2006 Roenigk 1, S+ 2009 Non-interpretable

2009 Roenigk 1, S+

13 2008 Roenigk 1, S-






19 2009 Normal

20 2009 Normal


Reason for liver diagnostics or referral to hepatologist without an elevated PIIINP

-No diagnostics/referral-Cumulative dose-Liver function test elevated-Other reason for ultrasound, incidental finding

N=121N=16N=4N=1

interpretation results liver biopsy: roenigk 1/2 = no fibrosis, roenigk 3a = mild fibrosis (fibrosis extending into acini), roenigk 3b = moderate or severe fibrosis. s+= signs of steatosis, s-=no signs of steatosis. Outcome fibroscan <7.1 kilopascal (kpa): no fibrosis (F0-F1), ≥7.1 kpa-<9.5kpa: moderate fibrosis (F2), ≤ 9.5 kpa: severe fibrosis (F3). as Fibroscan is not validated for this disease, results are provided in kilopascal as well.

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Guidelines on PIIINP seemed difficult to adapt in daily practice. Only a part of the patients had further investigations for liver fibrosis when PIIINP indicated this. In this subgroup with investigations, the low incidence of relevant liver fibrosis (1 case confirmed by liver biopsy, 2 suspected cases based on Fibroscan) in psoriasis patients using MTX is consistent with other studies.(6, 7) A different, but relevant, problem identified in the present cohort is the high prevalence of hepatic steatosis, which could lead to an increased risk of liver fibrosis. A recent study of Van der Voort et al. found that psoriasis was an independent predictor in patients ≥55 years of age on developing NAFLD; these patients were 70% more likely to develop this disease as compared to a normal population.(42) Patient cohorts with severe psoriasis have a high mean BMI and other risk factors for fatty liver disease such as diabetes mellitus or increased alcohol intake.(7, 13, 14, 42-49) In our present cohort, obesity was correlated with elevated serial PIIINP concentrations. Therefore, the way to liver fibrosis in patients with severe psoriasis may also occur via the development of NAFLD caused by metabolic syndrome combined with severe psoriasis.

We found that correlations between PIIINP concentrations and ALT or γ-GT measurements were low. It must be noted that ALT is a marker for hepatocyte damage, while PIIINP measures fibrosis and are thus completely different markers. Maybury et al. found that liver function tests had a lower sensitivity (38%) than single PIIINP concentrations to detect liver fibrosis in psoriasis patients treated with MTX.(31) They added that serial PIIINP concentrations were superior to detect liver fibrosis as compared to other non-invasive tests such as liver enzymes and Fibroscan.(31) In the American psoriasis guidelines however, liver function tests are advised for routine monitoring and liver biopsies are advised to consider after a cumulative 3.5-4 gram of MTX ór when liver enzymes deviate.(50) PIIINP assays are generally not available in the US; other non-invasive methods are only advised when liver biopsy is technically difficult or contraindicated.(50)

The most important limitation of this study is that not all patients had a liver biopsy, the gold standard, performed as routine liver biopsy is expelled from current guidelines. Moreover, Fibroscan is not calibrated for detecting liver fibrosis in psoriasis patients but only in patients with liver fibrosis after hepatitis B/C infection.(51) As already mentioned, the number of MTX-treated psoriasis patients with liver fibrosis based on liver biopsies in a Dutch cohort, partly overlapping ours, was low.(7, 28) The number of ‘missed’ liver fibrosis is therefore expected to be limited in the present study as well. Based on earlier studies, the risk of missing significant liver fibrosis seems very low in the group with normal serial PIIINP.(24, 32, 33) Another limitation of this study is that PIIINP levels were not always determined on a regular basis. In total, not all patients using MTX may have been screened using PIIINP assays, however, we do not expect this led to selection bias as missings were supposedly at random. Many patients were excluded from this study due to

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confounding factors (psoriatic arthritis, malignancy etc). These patients should be monitored according to current guidelines.

To conclude, in 78% of patients normal PIIINP series were present and no further diagnostics for liver fibrosis were needed when following PIIINP guidelines. Patients with elevated PIIINPs had a significantly higher age, higher BMI, lower mean weekly MTX doses, a longer disease duration, and a pre-existing diagnosis with steatosis hepatis more often. Cumulative dosages of MTX did not differ between the groups. Although only part of the patients had further investigations, the number of patients detected with liver fibrosis in the present cohort using PIIINP was low. Correlations between PIIINP values and ALT and γ-GT measures were low.

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28. Driessen RJ, van de Kerkhof PC, de Jong EM. Daily practice assessment of liver injury in patients with psoriasis on methotrexate. The British journal of dermatology. 2010;162(1):211-3.

29. Bath LF, Crofton PM, Evans AE, Ranke MB, Elmlinger MW, Kelnar CJ, et al. Bone Turnover and Growth during and after Chemotherapy in Children with Solid Tumors. Pediatric research. 2004;55(2):224-30.

30. Lindsay K, Fraser AD, Layton A, Goodfield M, Gruss H, Gough A. Liver fibrosis in patients with psoriasis and psoriatic arthritis on long-term, high cumulative dose methotrexate therapy. Rheumatology. 2009;48(5):569-72.

31. Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. Diagnostic accuracy of noninvasive markers of liver fibrosis in patients with psoriasis taking methotrexate: a systematic review and meta-analysis. The British journal of dermatology. 2014;170(6):1237-47.

32. Maurice PD, Maddox AJ, Green CA, Tatnall F, Schofield JK, Stott DJ. Monitoring patients on methotrexate: hepatic fibrosis not seen in patients with normal serum assays of aminoterminal peptide of type III procollagen. The British journal of dermatology. 2005;152(3):451-8.

33. Boffa MJ, Smith A, Chalmers RJ, Mitchell DM, Rowan B, Warnes TW, et al. Serum type III procollagen aminopeptide for assessing liver damage in methotrexate-treated psoriatic patients. The British journal of dermatology. 1996;135(4):538-44.

34. Zweegers J, de Jong EM, Nijsten TE, de Bes J, te Booij M, Borgonjen RJ, et al. Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology. Dermatol Online J. 2014;20(3).

35. Nagy Z, Czirjak L. Increased levels of amino terminal propeptide of type III procollagen are an unfavourable predictor of survival in systemic sclerosis. Clinical and experimental rheumatology. 2005;23(2):165-72.

36. Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology. 2005;128(2):343-50.

37. Berends MA, Snoek J, de Jong EM, Van Krieken JH, de Knegt RJ, van Oijen MG, et al. Biochemical and biophysical assessment of MTX-induced liver fibrosis in psoriasis patients: Fibrotest predicts the presence and Fibroscan predicts the absence of significant liver fibrosis. Liver international : official journal of the International Association for the Study of the Liver. 2007;27(5):639-45.

38. Berends MA, van Oijen MG, Snoek J, van de Kerkhof PC, Drenth JP, Han van Krieken J, et al. Reliability of the Roenigk classification of liver damage after methotrexate treatment for psoriasis: a clinicopathologic study of 160 liver biopsy specimens. Archives of dermatology. 2007;143(12):1515-9.

39. Gabrielli GB, Faccioli G, Casaril M, Capra F, Bonazzi L, Falezza G, et al. Procollagen III peptide and fibronectin in alcohol-related chronic liver disease: correlations with morphological features and biochemical tests. Clinica chimica acta; international journal of clinical chemistry. 1989;179(3):315-22.

40. Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. The New England journal of medicine. 2000;342(17):1266-71.

41. Zweegers J, de Jong EM, Nijsten TE, de Bes J, te Booij M, Bogonjen RJ, et al. Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dermatology online journal. 2014;20(3).

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42. van der Voort EA, Koehler EM, Dowlatshahi EA, Hofman A, Stricker BH, Janssen HL, et al. Psoriasis is independently associated with nonalcoholic fatty liver disease in patients 55 years old or older: Results from a population-based study. Journal of the American Academy of Dermatology. 2014;70(3):517-24.

43. Wakkee M, Meijer W, Neumann HA, Herings RM, Nijsten T. Psoriasis may not be an independent predictor for the use of cardiovascular and anti-diabetic drugs: a 5-year prevalence study. Acta dermato-venereologica. 2009;89(5):476-83.

44. Danielsen K, Wilsgaard T, Olsen AO, Eggen AE, Olsen K, Cassano PA, et al. Elevated odds of metabolic syndrome in psoriasis - A population-based study of age and gender differences. The British journal of dermatology. 2014.

45. Nijsten T, Wakkee M. Complexity of the association between psoriasis and comorbidities. The Journal of investigative dermatology. 2009;129(7):1601-3.

46. Wakkee M, Herings RM, Nijsten T. Psoriasis may not be an independent risk factor for acute ischemic heart disease hospitalizations: results of a large population-based Dutch cohort. The Journal of investigative dermatology. 2010;130(4):962-7.

47. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, et al. Changes

in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2011;9(6):524-30 e1; quiz e60.

48. Dietrich P, Hellerbrand C. Non-alcoholic fatty liver disease, obesity and the metabolic syndrome. Best Pract Res Clin Gastroenterol. 2014;28(4):637-53.

49. Koppe SW. Obesity and the liver: nonalcoholic fatty liver disease. Transl Res. 2014;164(4):312-22.

50. Menter A, Korman NJ, Elmets CA, Feldman SR, Gelfand JM, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: section 4. Guidelines of care for the management and treatment of psoriasis with traditional systemic agents. Journal of the American Academy of Dermatology. 2009;61(3):451-85.

51. Afdhal NH, Bacon BR, Patel K, Lawitz EJ, Gordon SC, Nelson DR, et al. Accuracy of fibroscan, compared with histology, in analysis of liver fibrosis in patients with hepatitis B or C: a United States multicenter study. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2015;13(4):772-9 e1-3.

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PERSONALIZING AND IMPROVING METHOTREXATE AND BIOLOGICAL

TREATMENT

3AMETHOTREXATE DOSING

REGIMEN FOR PLAQUE-TYPE PSORIASIS: A SYSTEMATIC

REVIEW OF THE USE OF TEST-DOSE, START-DOSE, DOSING

SCHEME, DOSE ADJUSTMENTS, MAXIMUM DOSE AND FOLIC

ACID SUPPLEMENTATION

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abSTRaCT

There is a range of methotrexate dosing regimens for psoriasis. This review summarizes the evidence for test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and use of folic acid.

A literature search for randomized controlled trials and guidelines was performed.

Twenty-three randomized controlled trials (29 treatment groups) and 10 guidelines were included. Two treatment groups used a test-dose, 5 guidelines recommend it. The methotrexate start-dose in randomized controlled trials varied from 5 to 25 mg/week, most commonly being either 7.5 mg or 15 mg. Guidelines vary from 5 to 15 mg/ week. Methotrexate was administered as a single dose or in a Weinstein schedule in 15 and 11 treatment groups, respectively; both recommended equally in guidelines. A fixed dose (n = 18), predefined dose (n = 3), or dose adjusted on clinical improvement (n = 8) was used, the last also being recommended in guidelines. Ten treatment groups used folic acid; in 2 it was allowed, in 14 not mentioned, and in 3 no folic acid was used. Most guidelines recommend the use of folic acid.

Authors’ suggestions for methotrexate dosing are given.

S.P. Menting, P.M. Dekker, J. Limpens, L. Hooft and Ph.I. Spuls

Acta Derm Venereol. 2016 Jan 20;96(1):23-8.

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InTROduCTIOn

If topical medication and phototherapy are insufficient in controlling chronic plaque-type psoriasis (termed psoriasis in this article) the next step in the therapeutic strategy is systemic therapy, with methotrexate (MTX) frequently being used1.

However, MTX has potentially serious side-effects, including myelosuppression, pulmonary fibrosis and gastro-intestinal disorders. The most prominent long-term side-effect is hepatotoxicity 2,3. Folic acid (FA) is administered to prevent side-effects; however, this may reduce the efficacy of MTX 4,5.

The US Food and Drug Administration (FDA) approved the use of MTX for the treatment of psoriasis in 1972 6 before high-quality studies were accepted as the standard by which to judge efficacy and safety.

Guidelines regarding the dosing regimen for MTX are partially based on expert opinions 2 and vary in their recommendations. In daily clinical practice there is a wide variety of dosing regimens 7 and patients with psoriasis are often undertreated 8. Barker et al. 9 have identified a number of key questions about MTX therapy for psoriasis and have emphasized the need for appropriate studies to determine optimal dosing with regard to efficacy and safety. A survey of dermatologists worldwide identified that the clinical use of MTX in psoriasis is not uniform and is not in full agreement with clinical guidelines 7.

The aim of this systematic review is to provide an up-to-date overview of randomized controlled trials (RCTs) using oral MTX monotherapy in adults for the treatment of psoriasis and to summarize evidence from these RCTs for the MTX dosing regimen regarding a test-dose, start-dose, dosing scheme, dose adjustments, maximum dose, and the use of FA. Also, recommendations from aggregated evidence (AgEv; guidelines and expert meetings) were summarized. Based on this review, initial suggestions for MTX dosing are given for future consensus and guidance in daily practice.

METhOdS

Search strategyThis systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines 10.

A search for RCTs and AgEv in the following databases was performed by an expert librarian (JL) from inception till 26 September 2013: MEDLINE (OVID), EMBASE (OVID) (both with a methodological filter to identify RCTs adapted from Cochrane 11, the Cochrane Library complemented with a search of PubMed. TRIP and National Guideline Clearinghouse (NGC) were searched additionally for AgEv, complemented by AgEv known to the authors. The meta- register of controlled trials and clinicaltrials.gov were screened for ongoing trials. The search consisted

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of Subject Headings (if applicable), keywords and words in title and abstract for psoriasis and MTX. Reference Manager® software (version 12.0) was used to manage references.

Selection of articlesTwo authors (SM and PD) independently selected all articles for eligibility, based on title, abstract and full-text. In cases of disagreement, a third author (PhS) was consulted. RCTs had to fulfill the following inclusion criteria; reporting on efficacy; oral MTX monotherapy (topical therapy allowed); ≥ 10 adult patients treated with MTX (≥ 18 years of age); only including psoriasis patients (with ≥ 75% of patients having chronic plaque-type psoriasis).

AgEv was included if it contained clear recommendations regarding MTX dosing.

Risk of bias assessment RCTsThe risk of bias was assessed in duplicate by SM and PD independently using the Cochrane RoB tool ( Table I).

In case of clinical homogeneity, a meta-analysis was performed according to the applicable methodology.

Data from AgEv are summarized in Table II.

Table I. Risk of Bias of included RCT’s:

Study Risk of bias

Seq

uenc

e g

ener

atio

n

Allo

cati

on

conc

ealm

ent

Pat

ient

Out

com

e as

sess

or

Inco

mp

lete

o

utco

me

dat

a

Sele

ctiv

e o

utco

me

rep

ort

ing

Oth

er s

our

ces

of

bia

s

Blinding

Chladek 200214

Chladek 200513

Dogra 201215

Radmanesh 201112

Bhuiyan 201142

Yan 201143

Ali 200939

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Table I. Risk of Bias of included RCT’s:

Study Risk of bias

Seq

uenc

e g

ener

atio

n

Allo

cati

on

conc

ealm

ent

Pat

ient

Out

com

e as

sess

or

Inco

mp

lete

o

utco

me

dat

a

Sele

ctiv

e o

utco

me

rep

ort

ing

Oth

er s

our

ces

of

bia

s

Blinding

Malik 201044

Shehzad 200437

Gupta 200540

Gupta 200745

El-Eishi 201230

Arani 201116

Gümüşel 201146

Akhyani 201041

Saurat 201135

Reich 201134

Flytström 200817

Ho 200948

Barker 201133

Ranjan 200738

Heydendael 200332

Sandhu 200331

The quality varied strongly amongst included studies from low RoB, to high RoB. Half of the studies reported an adequate randomization process, the rest did not report the randomization process or inadequately. In general, most of the studies did not report on concealment of allocation and blinding of patients or outcome assessor. Reporting of incomplete outcome data was variable. Selective outcome reporting and other sources of bias were not thought to create a substantial risk of bias for most studies. Not having PASI as primary outcome was seen as a potential other source of bias.

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Table II. Aggregated evidence

BSR/BHPR18

(Great Britain, 2008)

NICE22


Update S3 guideline21

(Germany, 2012)

European S3 guideline20

(EU, 2009)

Guideline psoriasis27

(The Netherlands, 2011)

AAD guideline2

(US, 2009)

Guideline MTX in psoriasis19

(Spain, 2010)

SR Treatment

modalities3

Consensus conference

NPF 20096

Consensus report

TTP 201328

Test-dose Not mentioned

Not mentioned Not mentioned 2.5 mg in elderly patients

2.5-5 mg can be considered(no consensus)

2.5-5 mg is recommended

Recommended in patients with a relative contraindication and elderly patients

Not mentioned 5-15 mg Mandatory in patients with decreased glomerular filtration rate or risks for hematologic toxicity

Not mentioned

Start-dose 5-10 mg/wk 5-10 mg/wk 7.5-15 mg/wk 5-10 mg/wk 5-10 mg/wk Not mentioned Not mentioned 5-10 mg/wk 7.5-15 mg/wk 5-15 mg/wk

Single/Weinstein

Single Not mentioned Weinstein (no clear evidence)

Single or Weinstein (no evidence)


Single Single or Weinstein (no evidence)

Not mentioned Single or Weinstein Single or Weinstein (no evidence)

Dose increments

2.5-5 mg increments every 2-6 weeks until stable disease

Gradually increase up to an effective dose. Assessment after 3 months on target dose.

Increase up to 22.5 mg/wk depending on treatment response

Not mentioned Depending on response increment up to 15 mg/wk, perhaps to 22.5 mg/wk

Dose increase until optimal response. Effect of dose increasement noticeable after 4 weeks.

Lower the dose when treatment goal is reached

Rapid dose increase over 4 weeks to reach a target therapeutic dose between 15-25 mg/wk

Dose ↑↓ to obtain adequate control. It can take 4-8 weeks to see the result of a dose change

In case of low SD, rapid ↑ to 15 mg/wk at wk 3 and if necessary and possible to 20 mg/wk at wk 8

Max dose 25 mg/wk 25 mg/wk 22.5 mg/wk 30 mg/wk 30 mg/wk 25 mg/wk 30 mg/wk 25 mg/wk 25 mg/wk Not mentioned

FA 5 mg the day after MTX

The effect of FA on efficacy and AEs is unclear.

1-5 mg on non-MTX days with max of 20 mg/week. Perhaps no FA during induction phase

There is evidence that FA might reduce AEs without affecting efficacy

1 mg/day except on MTX days till 5-10 mg/week 24 h after MTX administration. (In RA: MTX<15 mg: 5 mg FA, MTX≥15 mg: 10 mg FA.)

1-5 mg/day except on the day of MTX administration

FA only in patient with FA deficiency or high need patients (infectious disease, use of certain antibiotics)

5 mg/day for 1-3 days to be taken 48 h after MTX dose

Adding FA to MTX treatment is beneficial. An options is 1 mg daily

Often recommended though there is little evidence about its effect on tolerability of MTX

MTX: methotrexate; FA: folic acid; AE: adverse event; AAD: American Association of Dermatologists; SR: systematic review; NPF: National Psoriasis Foundation; TTP: Transitioning Therapies Program; BSR/BHPR: British Society for Rheumatology/British Health Professionals in Rheumatology; NICE: National Institute for Health and Care Excellence; RA: rheumatoid arthritis.

In the discussion, evidence-based suggestions are made regarding MTX dosing regimen. Suggestions were primarily based on results from the RCTs, with AgEv used to support these.

RESulTS

RCT search result and study characteristics

Data extraction

Two authors performed data extraction independently (SM and PD). Study characteristics (author, country and year of publication, intervention, the number of patients in the MTX-treated group, duration of treatment and dosage regimen

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Table II. Aggregated evidence

BSR/BHPR18


NICE22


Update S3 guideline21

(Germany, 2012)

European S3 guideline20

(EU, 2009)

Guideline psoriasis27

(The Netherlands, 2011)

AAD guideline2

(US, 2009)

Guideline MTX in psoriasis19

(Spain, 2010)

SR Treatment

modalities3

Consensus conference

NPF 20096

Consensus report

TTP 201328

Test-dose Not mentioned

Not mentioned Not mentioned 2.5 mg in elderly patients

2.5-5 mg can be considered(no consensus)

2.5-5 mg is recommended

Recommended in patients with a relative contraindication and elderly patients

Not mentioned 5-15 mg Mandatory in patients with decreased glomerular filtration rate or risks for hematologic toxicity

Not mentioned

Start-dose 5-10 mg/wk 5-10 mg/wk 7.5-15 mg/wk 5-10 mg/wk 5-10 mg/wk Not mentioned Not mentioned 5-10 mg/wk 7.5-15 mg/wk 5-15 mg/wk

Single/Weinstein

Single Not mentioned Weinstein (no clear evidence)



Single Single or Weinstein (no evidence)

Not mentioned Single or Weinstein Single or Weinstein (no evidence)

Dose increments

2.5-5 mg increments every 2-6 weeks until stable disease

Gradually increase up to an effective dose. Assessment after 3 months on target dose.

Increase up to 22.5 mg/wk depending on treatment response

Not mentioned Depending on response increment up to 15 mg/wk, perhaps to 22.5 mg/wk

Dose increase until optimal response. Effect of dose increasement noticeable after 4 weeks.

Lower the dose when treatment goal is reached

Rapid dose increase over 4 weeks to reach a target therapeutic dose between 15-25 mg/wk

Dose ↑↓ to obtain adequate control. It can take 4-8 weeks to see the result of a dose change

In case of low SD, rapid ↑ to 15 mg/wk at wk 3 and if necessary and possible to 20 mg/wk at wk 8

Max dose 25 mg/wk 25 mg/wk 22.5 mg/wk 30 mg/wk 30 mg/wk 25 mg/wk 30 mg/wk 25 mg/wk 25 mg/wk Not mentioned

FA 5 mg the day after MTX

The effect of FA on efficacy and AEs is unclear.

1-5 mg on non-MTX days with max of 20 mg/week. Perhaps no FA during induction phase

There is evidence that FA might reduce AEs without affecting efficacy

1 mg/day except on MTX days till 5-10 mg/week 24 h after MTX administration. (In RA: MTX<15 mg: 5 mg FA, MTX≥15 mg: 10 mg FA.)

1-5 mg/day except on the day of MTX administration

FA only in patient with FA deficiency or high need patients (infectious disease, use of certain antibiotics)

5 mg/day for 1-3 days to be taken 48 h after MTX dose

Adding FA to MTX treatment is beneficial. An options is 1 mg daily

Often recommended though there is little evidence about its effect on tolerability of MTX

MTX: methotrexate; FA: folic acid; AE: adverse event; AAD: American Association of Dermatologists; SR: systematic review; NPF: National Psoriasis Foundation; TTP: Transitioning Therapies Program; BSR/BHPR: British Society for Rheumatology/British Health Professionals in Rheumatology; NICE: National Institute for Health and Care Excellence; RA: rheumatoid arthritis.

(including use of test-dose, start-dose, dosing scheme (daily, once weekly or in a Weinstein schedule (each weekly dose administered in 3 equally divided portions, given once a week, 12 h apart from each other)), dose adjustments, maximum dose and the use and dose/ frequency of FA) and efficacy and safety data from MTX treatment groups were extracted from RCTs. The use of concomitant topical therapy was not further noted in this systematic review.

The number of patients who had a dose adjustment due to inefficacy (defined by individual study protocols) or side-effects was reported. For adverse event (AE) reporting, only the percentage of patients who had to stop MTX treatment due to (serious) side-effects was reported.

If outcomes were reported in a graph, data were extracted from these graphs.From the AgEv, recommendations on MTX regimens were extracted.

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Data reportingFor RCTs, study characteristics were summarized (Table III). Secondly, all efficacy outcome of RCTs making a head to head comparison of 2 or more MTX dosing regimens were reported (Table IV). Thirdly, the most frequently reported outcome was identified to be used to compare results from RCTs comparing MTX with another active drug or placebo.

The search identified 870 hits. A total of 847 hits did not meet the inclusion criteria. In total, 23 eligible studies with 29 treatment groups were included (Fig. 1). The risk of bias of the included studies is reported in Table I.

The included studies randomized 1,352 patients, of whom 1,206 were included in the final analysis. The loss to follow -up was mainly attributable to one study, in which 305 patients were randomized but only 202 patients were analysed 12.

Table III. Summarized study characteristics of included RCTs. In numbers of treatment groups

Test-dose Start-dose Dosing scheme Dose adjustments Folic acid

Yes: 2 (2.5-5 mg)16, 48 5 mg: 2 16, 34 Single: 1513, 15, 30, 31,

33-35, 42-46, 48Fixed dose: 1812-15,

30, 37, 39, 40, 42-455 mg daily: 148

Not mentioned: 27 7.5 mg: 913, 14, 17, 35,

38, 39, 41-43Two portions: 237, 38 Predefined dosing

regimen: 316, 41, 465 mg daily except on MTX day: 417,

30, 42, 46

10 mg: 415, 37, 44, 48 Weinstein: 1112-14,

16, 17, 32, 39-41Dose based upon clinical improvement: 817,

31-35, 38, 48

1 mg/day except on MTX day: 141

15 mg: 1112-14, 32, 33,

40, 45, 46 (1: 2.5 mg for 6 days/wk12)

Six portions: 112 5 mg the day before and after MTX day: 215

25 mg: 115 5 mg the day after MTX day: 234, 35

Weight based: 2 (0.330 and 0.531 mg/kg/wk)

Allowed: 233, 38

Not used: 312, 32

Not mentioned: 14

Four studies compared 2 or more different MTX dosing regimens within a single study 12–15 (representing 10 treatment groups), 19 studies compared MTX with an-other active treatment (representing 19 treatment groups, 2 studies also used an additional placebo arm). The number of patients in each group ranged from 7 to 215. Summarized study characteristics are shown in Table III.

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3A

Efficacy outcome of included RCTs

rcTs making a head to head comparison between 2 or more mTX dosing regimens.

Of the included RCTs, 4 compared 2 or more (fixed) different MTX dosing regimens within a single study (Table IV).

In 2002, Chladek et al. 14 found no significant difference between 7.5 mg MTXWeinstein/week (n=12) and 15 mg MTX Weinstein/week (n = 12). In 2005, Chladek 13 compared 4 different MTX dosing regimens and did not report whether there was a significant difference in efficacy between these 4 groups. Both studies included a relatively small number of patients.

Dogra et al 15 found no significant difference (p > 0.05) in patients achieving Psoriasis Area and Severity Index 75 (PASI75; meaning 75% improvement of PASI compared with baseline) with 10 mg/week MTX (n = 30, 25 analysed) vs. 25 mg/week MTX (n = 30, 26 analysed), though the time to reach PASI75 was significantly shorter in the 25 mg/week MTX group.

fig. 1. Prisma flow chart RCT: randomized controlled trial; MTX: methotrexate

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Table IV. Randomized controlled trials (RCTs) making a head to head comparison between 2 or more methotrexate (MTX) dosing regimens

Author yearCountry

MTXgroups

N: Number of patients

TD: MTX test-dose FA: Use of folic acid

D: Duration of therapyDA: dose adjustment

Number of patients stopped

results

Week 12 or 13 Week 16 Other time point

Chladek 200214

Czech republicGroup1: MTXWeinstein 7.5mg/wk N: 12 TD: not mentioned

FA: not mentionedD: 13 weeks

No DA: fixed doseNo stopped patients mentioned

PASI50: 66.7%Mean ΔPASI:33.26%

Group 2: MTXWeinstein 15mg/wk N: 12 PASI50: 75%Mean ΔPASI 27.46%

Chladek 200513

Czech republicGroup1: MTXWeinstein 7.5 mg/wk N=12 TD: not mentioned



Mean ΔPASI: 55%

Group 2: MTXWeinstein 15 mg/wk N=12 Mean ΔPASI: 62%

Group 3: MTX 7.5 mg/wk N=7 Mean ΔPASI: 42%

Group 4: MTX 15 mg/wk N=10 Mean ΔPASI: 58%

Dogra 201215

IndiaGroup 1: MTX 10 mg N:30 (25

analyzed)TD: not mentionedFA: 5 mg the day before and after MTX administrationD: 12 weeks

No DA: fixed dose3% (n=1) stopped due to AE

PASI75: 72%PASI100: 30%

Median time to achieve PASI75 (mean ± SD): 66,29 ± 16.03

Group 2: MTX 25 mg N: 30 (26 analyzed)


PASI75: 92%PASI100: 69%

Median time to achieve PASI75 (mean ± SD): 55.44 days ± 13.37

Radmanesh 201112

BangladeshGroup 1: MTXWeinstein 15 mg/wk N: 147 (101

analyzed)TD: not mentionedFA: no folic acid allowedD: 4 months

No DA: fixed dose6% (9/147) stopped due to AE

PASI25: 94%PASI75: 80%

Group 2: MTX 2.5 mg 6 days/wk N: 158 (101 analyzed)

No DA: fixed dose3.5% (4/158) stopped due to AE

PASI25: 78%PASI75: 61%

I: intervention; N: number of patients in MTX-treated group; D: duration of therapy; TD: MTX test-dose; FA: use of folic acid; SD: standard deviation; ↑↓: increments; DA: dose adjustment.

The fourth study, published by Radmanesh et al. in 2011 12, found no significant difference in mean ΔPASI comparing 15 mg MTXWeinstein/week (group 1, n = 147, 101 analysed) with 2.5 mg MTX 6 days per week (group 2, n = 158, 101 analysed) (p = 0.0001).

Outcome of rcTs comparing mTX with another active substance.

To be able to compare results from RCTs comparing MTX with another active drug or placebo the most frequent reported outcome was identified. The PASI75 was identified as the most frequently reported outcome. In Table V the results of different PASI75 obtained with different MTX dosing regimens are shown.

In 13 studies (with 15 MTX treatment groups) the percentage of patients attaining PASI75 ranged from 24% 16, 17 to 92% 15 at week 12 (results shown in Table IV and Table V).

Meta-analysesBecause of clinical, methodological and statistical heterogeneity, illustrated by the many dosing regimens encountered (differences in start-dose, dosing scheme, dose

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Table IV. Randomized controlled trials (RCTs) making a head to head comparison between 2 or more methotrexate (MTX) dosing regimens

Author yearCountry

MTXgroups

N: Number of patients

TD: MTX test-dose FA: Use of folic acid

D: Duration of therapyDA: dose adjustment

Number of patients stopped

results

Week 12 or 13 Week 16 Other time point

Chladek 200214

Czech republicGroup1: MTXWeinstein 7.5mg/wk N: 12 TD: not mentioned



PASI50: 66.7%Mean ΔPASI:33.26%

Group 2: MTXWeinstein 15mg/wk N: 12 PASI50: 75%Mean ΔPASI 27.46%

Chladek 200513

Czech republicGroup1: MTXWeinstein 7.5 mg/wk N=12 TD: not mentioned



Mean ΔPASI: 55%

Group 2: MTXWeinstein 15 mg/wk N=12 Mean ΔPASI: 62%

Group 3: MTX 7.5 mg/wk N=7 Mean ΔPASI: 42%

Group 4: MTX 15 mg/wk N=10 Mean ΔPASI: 58%

Dogra 201215

IndiaGroup 1: MTX 10 mg N:30 (25

analyzed)TD: not mentionedFA: 5 mg the day before and after MTX administrationD: 12 weeks


PASI75: 72%PASI100: 30%

Median time to achieve PASI75 (mean ± SD): 66,29 ± 16.03

Group 2: MTX 25 mg N: 30 (26 analyzed)


PASI75: 92%PASI100: 69%

Median time to achieve PASI75 (mean ± SD): 55.44 days ± 13.37

Radmanesh 201112

BangladeshGroup 1: MTXWeinstein 15 mg/wk N: 147 (101

analyzed)TD: not mentionedFA: no folic acid allowedD: 4 months

No DA: fixed dose6% (9/147) stopped due to AE

PASI25: 94%PASI75: 80%

Group 2: MTX 2.5 mg 6 days/wk N: 158 (101 analyzed)

No DA: fixed dose3.5% (4/158) stopped due to AE

PASI25: 78%PASI75: 61%

I: intervention; N: number of patients in MTX-treated group; D: duration of therapy; TD: MTX test-dose; FA: use of folic acid; SD: standard deviation; ↑↓: increments; DA: dose adjustment.

adjustment, use of and dose of FA) and the diversity in outcome reporting (PASI in many ways and at different time-points), no data was pooled in a meta-analysis.

Aggregated evidence search resultsThe search included 9 guidelines 2, 18–25, 1 systematic review 3 and 1 consensus conference 6 (previous conferences leading to this conference were not included 26). One guideline and one consensus conference were known to the authors and did not result from the search 27, 28. Three guidelines did not contain clear recommendations regarding MTX dosing for inclusion in this review 23–25.

Summary of aggregated evidence (AgEv) (Table II)Test-dose. Five out of 10 AgEv mention the use of a test-dose, and in 5 a test-dose is not mentioned. One recommends the use of a test-dose 29. One states that a test-dose can be considered, though there is no consensus in the guideline committee 27. Three recommend a test-dose in specific cases; for example, for elderly patients or patients with impaired kidney function 6, 19, 20. If a test-dose is recommended, the dose mentioned is 2.5–15 mg.

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Table V. Randomized controlled trials (RCTs) comparing methotrexate (MTX) with another active substance

Author (year),

country

I: InterventionN: Number of patients in

MTX treated groupD: Duration of therapy

TD: MTX test-doseFA: Use of folic acidSD: MTX start-dose↑↓: Increments

DA: dose adjustmentNumber of patients stopped PASI75

Gupta 40

(2005), IndiaI: MTXWeinstein vs hydroxyureaN: 20D: 12 weeks

TD: not mentionedFA: not mentionedSD: MTXWeinstein 15 mg/wk (fixed dose)

No DA: fixed dose No stopped patients mentioned

75% at week 12

Akhyani41

(2010), IranI: MTX Weinstein vs mycophenolate mofetilN: 18 (15 analyzed)D: 12 weeks

TD: not mentionedFA: 1 mg/day except on the day of MTX administrationSD: 7.5mg/wk Weinstein , then wk 1: 15mg/wk, wk 4: 20mg/wk

86.7% (13/15 pt) failed to increase/needed to lower the dose due to AE.13.3% (2/15) reached 20 mg/wkNo stopped patients due to AE

73.3% at week 12

Ranjan38

(2007), IndiaI: MTX vs hydroxycarbamideN: 17 (15 analyzed)D: 12 weeks

TD: not mentionedFA: 5mg/day allowedSD: wk 0-4: 7.5mg 2dd/wk (15 mg/wk)↑↓: wk4 < PASI25: 20mg (in “divided dosage”)

DA: 40% (6/15) had a dose increase from 15 to 20 mg/wk.No stopped patients due to AE

66.7% at week 12

Ho 48

(2009), ChinaI: MTX vs traditional Chinese Medicine vs placeboN: 20 (19 analyzed)D:24 weeks

TD: 2.5-5mg/wk FA:5mg/daySD: 10mg/wk↑↓: 2.5mg until “good clinical response”Max: 30mg/wk

DA unclear5% (N=1) stopped due to AE

63% at week 24

Heydendael32

(2003), The Netherlands

I: MTX Weinstein vs CyclosporinN: 43D: 16 weeks

TD: not mentionedFA: not usedSD: week 0-4: 15mg/wk Weinstein

↑↓: if <PASI25 at wk 4:22.5mg/wkWeinstein,, tapering from week 12

DA: 9.3% (n=4) dose increase at wk 4 27.9% (n=12) stopped due to AE

60% at week 16

Barker33

(2011), Europe and Canada

I: MTX vs infliximabN: 215D: 16 weeks

TD: not mentionedFA: recommended, dose not mentionedSD:15 mg/wk↑↓: 5 mg if <PASI-25 at week 6

DA: 25% (n=54) had at least one dose increase between week 6 and 16.4% (n=8) stopped due to AE

27.0% at week 1039.5% at week 1441.9% at week 16

Reich34


I: MTX vs briakinumabN: 163D: 52 weeks

TD: not mentionedFA: 5 mg/wkSD: 5 mg/wk at wk 0, 10 mg/wk at wk 1, 15 mg/wk from wk 2-9↑↓: increment of 5 mg/wk at wk 10 and 16 if PASI< 75% or 6 point PGA≠ 0 or 1

DA: 10.4% (n=17) dose increase at week 10 to 20 mg/wk. 61.3% (n=100) dose increase at week 16 to 25 mg/wk. 6.1% (n=10) stopped due to AE (5 out of 10 were an SAE)

36.2% at week 1239.9% at week 24

Saurat (CHAMPION) (2011)35, Europe and Canada

I: MTX vs Adalimumab vs placeboN: 110D: 16 weeks

TD: not mentionedFA: 5mg/wkSD: Week 0-1: 7.5mg/wk, week 2-3: 10mg/wk, week 4-7: 15mg/wk↑↓: 5mg if <PASI50 at wk 8 or wk 12

DA: 36.4% (n=40) no dose increase. 20% (n=22) Dose increase at wk 8. 29.3% (n=41) Dose increase at wk 8 and wk 125.5% (n=6) stopped due to AE


Yan43

(2011), ChinaI: MTX vs rhLFA3-IgFPN: 105 (92 analyzed)D: 12 weeks

TD: not mentionedFA: not mentionedSD: 7.5 mg/wk (fixed dose)

DA: No dose increase: fixed dose2.9% (3/105) stopped due to AE

31.5% at week 12

Flytström17

(2008), Sweden

I: MTX Weinstein vs CyclosporinN: 41 (37 analyzed)D: 12 weeks

TD: not mentionedFA: 5 mg/day except on the day of MTX administrationSD: 7.5mg/wk↑↓: if <PASI50 increment, max: 15mg/wk

DA unclearNo stopped patients due to AE

24% at week 12

Arani16


I: MTX Weinstein vs fumaratesN: 30 (25 analyzed)D:12 weeks

TD: 5 mg/wkFA: not mentionedSD: from TD 5mg/wk gradually to 15mg/wk Weinstein at week 12, then ↓ to 12.5 to 10 to 5 t2.5 mg/wk at week 13, 14, 15 and 16 respectively.

DA: Standard dose increase based on study protocol 16% (4/25) stopped due to AE

24% at week 12

I: intervention; N: number of patients in MTX-treated group; D: duration of therapy; TD: MTX test-dose; FA: use of folic acid; SD: MTX start-dose; ↑↓: increments; DA: dose adjustment; AE: adverse event; PASI75: Psoriasis Area and Severity Index 75; SAE: serious adverse event

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Table V. Randomized controlled trials (RCTs) comparing methotrexate (MTX) with another active substance

Author (year),

country

I: InterventionN: Number of patients in

MTX treated groupD: Duration of therapy

TD: MTX test-doseFA: Use of folic acidSD: MTX start-dose↑↓: Increments

DA: dose adjustmentNumber of patients stopped PASI75

Gupta 40

(2005), IndiaI: MTXWeinstein vs hydroxyureaN: 20D: 12 weeks

TD: not mentionedFA: not mentionedSD: MTXWeinstein 15 mg/wk (fixed dose)

No DA: fixed dose No stopped patients mentioned

75% at week 12

Akhyani41

(2010), IranI: MTX Weinstein vs mycophenolate mofetilN: 18 (15 analyzed)D: 12 weeks

TD: not mentionedFA: 1 mg/day except on the day of MTX administrationSD: 7.5mg/wk Weinstein , then wk 1: 15mg/wk, wk 4: 20mg/wk

86.7% (13/15 pt) failed to increase/needed to lower the dose due to AE.13.3% (2/15) reached 20 mg/wkNo stopped patients due to AE

73.3% at week 12

Ranjan38

(2007), IndiaI: MTX vs hydroxycarbamideN: 17 (15 analyzed)D: 12 weeks

TD: not mentionedFA: 5mg/day allowedSD: wk 0-4: 7.5mg 2dd/wk (15 mg/wk)↑↓: wk4 < PASI25: 20mg (in “divided dosage”)

DA: 40% (6/15) had a dose increase from 15 to 20 mg/wk.No stopped patients due to AE

66.7% at week 12

Ho 48

(2009), ChinaI: MTX vs traditional Chinese Medicine vs placeboN: 20 (19 analyzed)D:24 weeks

TD: 2.5-5mg/wk FA:5mg/daySD: 10mg/wk↑↓: 2.5mg until “good clinical response”Max: 30mg/wk

DA unclear5% (N=1) stopped due to AE

63% at week 24

Heydendael32


I: MTX Weinstein vs CyclosporinN: 43D: 16 weeks

TD: not mentionedFA: not usedSD: week 0-4: 15mg/wk Weinstein

↑↓: if <PASI25 at wk 4:22.5mg/wkWeinstein,, tapering from week 12

DA: 9.3% (n=4) dose increase at wk 4 27.9% (n=12) stopped due to AE

60% at week 16

Barker33


I: MTX vs infliximabN: 215D: 16 weeks

TD: not mentionedFA: recommended, dose not mentionedSD:15 mg/wk↑↓: 5 mg if <PASI-25 at week 6

DA: 25% (n=54) had at least one dose increase between week 6 and 16.4% (n=8) stopped due to AE


Reich34


I: MTX vs briakinumabN: 163D: 52 weeks

TD: not mentionedFA: 5 mg/wkSD: 5 mg/wk at wk 0, 10 mg/wk at wk 1, 15 mg/wk from wk 2-9↑↓: increment of 5 mg/wk at wk 10 and 16 if PASI< 75% or 6 point PGA≠ 0 or 1

DA: 10.4% (n=17) dose increase at week 10 to 20 mg/wk. 61.3% (n=100) dose increase at week 16 to 25 mg/wk. 6.1% (n=10) stopped due to AE (5 out of 10 were an SAE)

36.2% at week 1239.9% at week 24

Saurat (CHAMPION) (2011)35, Europe and Canada

I: MTX vs Adalimumab vs placeboN: 110D: 16 weeks

TD: not mentionedFA: 5mg/wkSD: Week 0-1: 7.5mg/wk, week 2-3: 10mg/wk, week 4-7: 15mg/wk↑↓: 5mg if <PASI50 at wk 8 or wk 12

DA: 36.4% (n=40) no dose increase. 20% (n=22) Dose increase at wk 8. 29.3% (n=41) Dose increase at wk 8 and wk 125.5% (n=6) stopped due to AE


Yan43

(2011), ChinaI: MTX vs rhLFA3-IgFPN: 105 (92 analyzed)D: 12 weeks

TD: not mentionedFA: not mentionedSD: 7.5 mg/wk (fixed dose)

DA: No dose increase: fixed dose2.9% (3/105) stopped due to AE

31.5% at week 12

Flytström17

(2008), Sweden

I: MTX Weinstein vs CyclosporinN: 41 (37 analyzed)D: 12 weeks

TD: not mentionedFA: 5 mg/day except on the day of MTX administrationSD: 7.5mg/wk↑↓: if <PASI50 increment, max: 15mg/wk

DA unclearNo stopped patients due to AE

24% at week 12

Arani16


I: MTX Weinstein vs fumaratesN: 30 (25 analyzed)D:12 weeks

TD: 5 mg/wkFA: not mentionedSD: from TD 5mg/wk gradually to 15mg/wk Weinstein at week 12, then ↓ to 12.5 to 10 to 5 t2.5 mg/wk at week 13, 14, 15 and 16 respectively.

DA: Standard dose increase based on study protocol 16% (4/25) stopped due to AE

24% at week 12

I: intervention; N: number of patients in MTX-treated group; D: duration of therapy; TD: MTX test-dose; FA: use of folic acid; SD: MTX start-dose; ↑↓: increments; DA: dose adjustment; AE: adverse event; PASI75: Psoriasis Area and Severity Index 75; SAE: serious adverse event

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start-dose. Eight out of 10 AgEv indicate what the start-dose should be, varying from 5 to 15 mg MTX 3, 6, 18, 20–22, 27, 28.

Dosing scheme. Two AgEv recommend administration in a single dose 18, 29, 5 state that a single dose or a Weinstein schedule can be considered 6, 19, 20, 27, 28 and 1 states a Weinstein schedule 21. Most state that there is no high-quality evidence for either (single or Weinstein schedule).

Dose adjustments and maximum dose. Almost all AgEv advise increasing or decreasing the dose based on efficacy. The maximum dose varies from 22.5 21 to 30 mg 20, 27 MTX.

Folic acid. Seven out of 10 AgEv recommend the use of FA 3, 6, 18, 21, 27, 29, although its effect on reducing AEs remains unclear 22, 28. The FA dosing advised varies from 1 to 5 mg/day except on the day of MTX administration 2, 6, 21 to 5 mg the day after MTX administration 18.

dISCuSSIOn

This systematic review further highlights the wide heterogeneity in MTX dosing regimens in several aspects, such as the use of a test-dose, start-dose, dosing scheme, dose adjustment, maximum dose and FA. A great diversity in outcome reporting was found, thus it was not possible to pool the RCT data and no meta-analyses were performed.

Several aspects of MTX dosing regimens are discussed below and initial suggestions regarding the MTX dosing regimen for treating psoriasis are made based on the evidence available.

Test-doseA test-dose was used in 2 out of 29 treatment groups and recommended (sometimes only in frail patients) in 5 out of 10 included manuscripts presenting aggregated evidence. A test-dose is administered to detect any unusual predisposition to toxic effects, such as myelosuppression, which usually occurs within 7–10 days 26. In AgEv a test-dose and laboratory control after one week is often suggested only for frail patients (for example elderly people or patients with impaired kidney function) 2, 6, 19, 20.

Start-doseAmongst the included RCTs, start-dose varied from 5 to 25 mg/week MTX (Table III) and the best PASI75 response was obtained in a study using a start-dose of 25 mg/week MTX 15. Two studies based the start-dose on weight 30, 31. In the AgEv it is suggested to start MTX treatment with a dose ranging from 5 to 15 mg/week MTX 3, 18, 20–22, 27, 28. RCTs show that starting with 15 mg/week MTX 32, 33 or increasing rapidly to 15 mg/week MTX 34 leads to a better PASI75 improvement compared with

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starting with 5 16 or 7.5 mg/week MTX 35 and slow increases, or with a fixed dose of 7.5 mg/week MTX 17. The safety of the 15 mg/week MTX start-dose is illustrated by data from Barker et al. 33, where only 4% (n = 8) of patients stopped due to AEs (Table V). In AgEv, it is suggested that start -dose may vary depending on severity of disease, age, kidney function and other co-morbidities 18, 21 . MTX dose ≥ 15 mg/week MTX is suggested to have a more rapid onset of action compared with < 15 mg/week 36. The Psoriasis International Network survey has shown that 7.5 mg/week MTX is the most frequently used start-dose, and 15 mg/week MTX the second most frequently used start-dose 7.

Guideline recommendations on the subject of safety monitoring state that pre-treatment laboratory control is obligatory and advise laboratory control within one week after a test- or start-dose and every 2 weeks during the first 1–2 months. When at a stable dose of MTX or after 2–3 months of treatment, guidelines advise control every 2–3 months.

Dosing schemeFour different methods of MTX dosing were encountered in the included RCTs (Table III). Daily low dosing 12 (high risk of bias, never suggested in AgEv), weekly dosing with each dose divided in 2 equal dosages 37, 38 (small studies with an intermediate/high risk of bias and never suggested in AgEv), dosing in a Weinstein schedule 12–14, 16, 32, 39–41, or a single weekly dose 13, 15, 17, 30, 31, 33, 34, 42–48, the last 2 most frequently used in clinical practice and suggested in AgEv1. The Weinstein schedule is thought to decreases AEs 6, 20, 21, although this could not be concluded from included RCTs due to high risk of bias and small numbers of a study comparing single dose with Weinstein dosing 13. AgEv recommend the administration of MTX in a Weinstein schedule and in single dose, though there is little high-quality evidence supporting the use of one regimen over the other 6, 19–21, 27, 28.

Dose adjustmentsA fixed dose was used in 18 treatment groups, in 3 a predefined dosing regimen was used and in 8 the dose was adjusted based on clinical improvement (Table III). It is generally accepted that MTX dose should be adjusted to clinical response, individualized per patient 6, 21, 28. Comparing 3 different studies (all low risk of bias, similar inclusion criteria) included in this systematic review 33–35, shows that starting with 15 mg/week MTX and adjusting the dose based on clinical efficacy at week 6 or rapidly increasing the dose to 15 mg/week MTX at week 2 with adjustment based on clinical efficacy at week 10 leads to a greater improvement and similar treatment termination due to AEs compared with slowly increasing the dose from 7.5 mg at week 0 to 15 mg at week 4 (Table V). Due to the diversity in dose adjustments used in RCTs, no conclusion based on evidence from RCTs can be drawn regarding this topic. In AgEv, adjustment of the dose, based on efficacy or on AEs is advised. It

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has been suggested that, if an insufficient response is seen at week 8, the dose can be increased to 20 mg/week MTX 28. If with this dosing regimen, patients remain non-responders at weeks 12 35 to 24 34, the value of further dose escalation is unclear. Response to dose adjustments may take 4–8 weeks 6.

Maximum doseThe maximum dose of MTX allowed in one included RCT was 30 mg/week 48. In this RCT, it is unclear if 30 mg was actually administered. In another study, it was observed that increasing the dose from 20 to 25 mg/week provided little additional benefit; mean % change in PASI went from 16% to 25% in patients who had not previously obtained 50% improvement in PASI. The effect of increasing MTX to 25 mg/week in patients who have obtained 50% PASI improvement was not investigated 35. In AgEv maximum dose varied from 22.5 21 to 30 mg per week 19, 20, 27.

Use of folic acidThe use of FA was mentioned explicitly in 10 treatment groups, in 2 it was allowed, in 14 it was not mentioned, and in 3 it was mentioned explicitly that no FA was used (Table III). Most aggregated evidence recommends the use of FA, although in a variety of dosing regimens. Comparing 2 studies with similar MTX dosing, where in the first no FA was used 32 and in the second 5 mg/ week of FA was used 34, the use of FA seems to lead to less treatment termination. FA is thought to decrease the risk of AEs 49 and the (negative) influence on efficacy is debatable 5, 50. A meta-analysis performed in rheumatoid arthritis showed that administration of FA reduced the risk of gastro-intestinal side-effects, elevated liver enzymes or withdrawal from MTX for any reason. It did not appear to have a significant effect on efficacy, although only studies in which ≤7 mg/week FA was used were included in the analyses 51. The use of FA is recommended by an expert meeting to reduce the risk of hepatotoxicity, although there is no consensus on the optimal dosing regimen for FA 9.

Authors’ suggestionsWe have made suggestions below for several aspects of the MTX dosing regimen, based on this review (Table VI).

Test -dose. We suggest a test -dose with laboratory control after one week, only for frail patients (for example elderly people or patients with impaired kidney function). This suggestion is based on AgEv (Table II) and could not be based on RCTs.

start-dose. Based on RCTs 33 we suggest a start-dose of 15 mg/week MTX with laboratory control after one week in healthy patients. It is known that the population included in RCTs is generally more healthy compared with the daily practise population. Therefore we suggest a start-dose of 5–7.5 mg/week MTX in frail patients (e.g. elderly people or patients with impaired kidney function) as suggested in AgEv 18, 21 (Table II).

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Table VI. Authors’ suggestions for methotrexate dosing regimen

• Test dose: recommended for elderly or frail patients, for example patients with impaired kidney function.

• Start dose: 5–7.5 mg/week in elderly or frail patients and 15 mg/week in healthy patients.

• Administration as single dose. Use of the Weinstein schedule if gastrointestinal complaints occur.

• Dose increase at week 8–20 mg/week if an insufficient response is seen.

• Maximum dose of 25 mg/week.

• Folic acid is recommended, though in what dosing and frequency remains unclear.

Dosing scheme. Based on the fact that there is no high-quality evidence supporting increased efficacy or reduction in AEs by administration of MTX in a Weinstein schedule and administration in a single dose will probably increase drug compliance, we suggest administration of MTX in a single dose. If gastro-intestinal complaints occur, a Weinstein schedule could be applied, though one should be aware that little high-quality evidence is available to support the schedule.

Dose adjustments. We suggest increasing the dose by 5 mg/week MTX at week 8 if an insufficient response is observed and no substantial AEs are observed. This is based on a recommendation from a consensus report 28. A further increase in the dose by 5 mg/week MTX is possible if 4–8 weeks after the dose increase the response is still insufficient. In good-responders dose reductions should be considered.

maximum dose. We suggest a maximum dose of 25 mg/week MTX because the effect of a dose increase to 30 mg remains unclear and increase to 25 mg/week MTX has shown at least little benefit in patients who had not obtained 50% improvement in PASI 35. A maximum dose of 25 mg/week MTX is also most often recommended in AgEv (Table II).

Folic acid. We suggest the use of FA, though the dosing and frequency is debatable, varying from 1 to 5 mg/day (except on the day of MTX administration) to 5 or 10 mg/week, 24 or 48 h after MTX. This is based on data from RCTs 32, 34 and AgEv (Table II).

Strengths and weaknessesBy summarizing the dosing regimens and the efficacy obtained in RCTs of the treatment of psoriasis with oral MTX, and by systematically summarizing the MTX dosage regimens suggested in AgEv, this review creates evidence- based, initial suggestions regarding the MTX dosing regimen, which are more detailed than the existing recommendations in guidelines and consensus conferences. In a future consensus meeting or Delphi procedure, these data could form the basis for further recommendations attained amongst dermatologists worldwide. As mentioned before, more direct high-quality studies comparing the different aspects of MTX dosing regimens are needed.

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There are many factors related to MTX dosing, but this review focused on certain aspects. Due to the exclusion of patients under the age of 18 years and the exclusion of non-oral MTX administration no conclusions can be drawn regarding the treatment of children or the intramuscular/subcutaneous administration of MTX. Also, beyond the scope of this review are combination therapies with MTX (e.g. with etanercept 52) and whether the optimal dose of MTX depends on factors such as body weight or kidney function. Results from RCTs are extrapolated for use in daily practise; however, it is known that the population included in RCTs is generally different from the population treated in daily practice. The RCT results included are relatively short term (maximum treatment time 52 weeks), but MTX side-effects, such as hepatotoxicity, often develop after years of treatment.

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33. Barker J, Hoffmann M, Wozel G Ortonne JP, Zheng H, van Hoogstraten H, et al. Efficacy and safety of infliximab vs. methotrexate in patients with moderate-to-severe plaque psoriasis: results of an open-label, active-controlled, randomized trial (RESTORE1). Br J Dermatol 2011; 165: 1109–1117.

34. Reich K, Langley RG, Papp KA, Ortonne JP, Unnebrink K, Kaul M, et al. A 52-week tr ial comparing briakinumab with methotrexate in patients with psoriasis. N Engl J Med 2011; 365: 1586–1596.

35. Saurat JH, Langley RG, Reich K, Unnebrink K, Sasso EH, Kampman W. Relationship between methotrexate dosing and clinical response in patients with moderate to severe psoriasis: subanalysis of the CHAMPION study. Br J Dermatol 2011; 165: 399–406.

36. Nast A, Sporbeck B, Rosumeck S, Pathirana D, Jacobs A, Werner RN, et al.

Which antipsoriatic drug has the fastest onset of action? – Systematic review on the rapidity of the onset of action. J Invest Dermatol 2013; 133: 1963–1970.

37. Shehzad T, Dar NR, Zakria M. Efficacy of concomitant use of PUVA and methotrexate in disease clearance time in plaque type psoriasis. J Pak Med Assoc 2004; 54: 453–455.

38. Ranjan N, Sharma NL, Shanker V, Mahajan VK, Tegta GR. Methotrexate versus hydroxycarbamide (hydroxyurea) as a weekly dose to treat moderate-to-severe chronic plaque psoriasis: a comparative study. J Dermatolog Treat 2007; 18: 295–300.

39. Ali ME, Rahman GMM, Akhtar N, Wahab MA, Rashid MM, Islam AZMM. Efficacy and safety of leflunomide in the treatment of plaque type psoriasis. J Pakistan Association of Dermatologists 2009; 19: 18–22.

40. Gupta SK, Dogra A, Kaur G. Comparative efficacy of methotrexate and hydroxyurea in treatment of psoriasis. J Pakistan Association of Dermatologists 2005; 15: 247–251.

41. Akhyani M, Chams-Davatchi C, Hemami MR, Fateh S. Efficacy and safety of mycophenolate mofetil vs. methotrexate for the treatment of chronic plaque psoriasis. J Eur Acad Dermatol Venereol 2010; 24: 1447–1451.

42. Bhuiyan MSI, Sikder M, Rashid MM, Rabin F. Role of oral colchicine in plaque type psoriasis. A randomized clinical trial comparing with oral methotrexate. J Pakistan Association of Dermatologists 2010; 20: 146–151.

43. Yan H, Tang M, You Y, Yu JB, Zhang JA, Li XH, et al. Treatment of psoriasis with recombinant human LFA3-antibody fusion protein: a multi-center, randomized, double-blind trial in a Chinese population. Eur J Dermatol 2011; 21: 737–743.

44. Malik T, Ejaz A. Comparison of methotrexate and azathioprine in the

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treatment of psoriasis: A randomized controlled trial. J Pakistan Association of Dermatologists 2010; 20: 152–157.

45. Gupta R, Gupta S. Methotrexate-betamethasone weekly oral pulse in psoriasis. J Dermatolog Treat 2007; 18: 291–294.

46. Gumusel M, Ozdemir M, Mevlitoglu I, Bodur S. Evaluation of the efficacy of methotrexate and cyclosporine therapies on psoriatic nails: a one-blind, randomized study. J Eur Acad Dermatol Venereol 2011; 25: 1080–1084.

47. Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol 2008; 158: 558–566.

48. Ho SG, Yeung CK, Chan HH. Methotrexate versus traditional Chinese medicine in psoriasis: a randomized, placebo-controlled trial to determine efficacy, safety and quality of life. Clin Exp Dermatol 2010; 35: 717–722.

49. Al-Dabagh A, Davis SA, Kinney MA, Huang K, Feldman SR. The effect of folate supplementation on methotrexate efficacy and toxicity in psoriasis patients and folic acid use by dermatologists in the USA. Am J Clin Dermatol 2013; 14: 155–161.

50. Prey S, Paul C. Effect of folic or folinic acid supplementation on methotrexate-associated safety and ef ficacy in inflammatory disease: a systematic review. Br J Dermatol 2009; 160: 622–628.

51. Shea B, Swinden MV, Tanjong GE, Ortiz Z, Katchamart W, Rader T, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev 2013; 5: CD000951.

52. Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol 2012; 167: 649–657

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OF ANTIBODY FORMATION AGAINST ADALIMUMAB IN PATIENTS WITH PSORIASIS:

ONE-YEAR FOLLOW-UP

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abSTRaCT

IMPORTANCE: In a previously reported cohort of 29 patients with plaque-type psoriasis followed up for 24 weeks, clinically relevant antidrug antibody (ADA) to adalimumab was frequently found. Long-term data were lacking. We now present the extension of this study: 80 patients followed up for 1 year.OBJECTIVES: To assess the extent of ADA and its clinical consequences after 24 weeks of adalimumab treatment for psoriasis in a cohort of 80 patients.DESIGN, SETTING AND PARTICIPANTS: A multicenter cohort study, performed in the outpatient dermatology clinic of 2 academic hospitals, included 80 sequential patients receiving adalimumab therapy for plaque-type psoriasis and had a follow-up of 1 year. Outcome assessors were not aware of the presence of antibodies to adalimumab or the adalimumab serum concentration when assessing patients’ Psoriasis Area and Severity Index (PASI), and personnel analyzing serum samples were blinded to patients’ PASI.INTERVENTIONS: For 80 patients treated with adalimumab for psoriasis, disease severity (PASI) was assessed, blood samples were collected, and adalimumab and ADA concentrations was determined at baseline and at weeks 12, 24, and 52.MAIN OUTCOMES AND MEASURE: Patient PASI and adalimumab and ADA concentrations.RESULTS: Antidrug antibodies formed in 49% of patients, before week 24 in 90% of them. Adalimumab and ADA concentrations, clinical response and ADA concentration, and adalimumab concentration and clinical response had correlations of −0.872, −0.606, and 0.519, respectively. The adalimumab dose interval was shortened because of lack of efficacy in 15 patients, 7 with and 8 without ADA; improvement in responder status occurred in 1 of 7 and 4 of 8, respectively.CONCLUSIONS AND RELEVANCE: Patients with no ADA formation in the first 24 weeks of treatment have little chance of it in the following 24 weeks. The presence of ADA is strongly correlated with adalimumab concentration and greatly influences clinical response. If ADA is present, dose interval shortening is less useful.

S.P. Menting; P.P.M. van Lümig; A.C.Q. de Vries; J.M.P.A. van den Reek; D. van der Kleij; E.M.G.J. de Jong; P.I. Spuls; L.L.A. Lecluse

JAMA Dermatol. 2014 Feb 1;150(2):130-6.

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InTROduCTIOn

Adalimumab is a human monoclonal immunoglobulin G1 antibody and tumor necrosis factor antagonist that is a valuable treatment option for patients with moderate to severe psoriasis seen in clinical practice. As has been shown for patients with Crohn disease and rheumatologic conditions, antibodies against adalimumab are associated with nonresponse and loss of initial response to adalimumab in a substantial proportion of patients.1-8 This effect has also been shown for patients with psoriasis. In a cohort study of 29 patients evaluated for up to 24 weeks of treatment, antidrug antibody (ADA) to adalimumab formed in 45%.9 This cohort has been extended to 80 patients (including the original 29), and here we present 1-year follow-up data. The purpose of this study is to assess whether ADAs develop, persist, or reduce after 24 weeks of adalimumab treatment and to determine the clinical consequences.

METhOdS

Detailed methods and study design have been reported elsewhere9 and have not changed. Briefly, approached for this prospective observational cohort study were all consecutive patients with psoriasis who were naive to adalimumab and starting treatment with adalimumab for psoriasis at the Academic Medical Center, Amsterdam, and the Radboud University Nijmegen Medical Centre, Nijmegen (both in the Netherlands), between September 1, 2008, and July 12, 2012. The study was approved by the ethical committee of the participating hospitals and conducted according to Declaration of Helsinki principles. Patients gave written informed consent before initiation.

Certain baseline characteristics were collected. At the time of evaluation for this report, 80 patients were enrolled. Patients were treated with adalimumab according to the manurcturer’s recommendations, with an initial dose of 80 mg subcutaneously followed by 40 mg subcutaneously every other week, starting 1 week after the initial dose. Patients could be treated concomitantly with methotrexate from the start of the study. In patients with inadequate response to adalimumab, concomitant methotrexate could be started or the dose interval for adalimumab could be reduced to every 7 or 10 days (referred to hereafter as dose interval shortening). Treatment could be terminated because of nonresponse or adverse events. The reason for termination of treatment was registered. Decisions were made by the treating dermatologist and did not deviate from daily practice. The treating dermatologist was masked to the antibody status of the patient.

Disease severity was assessed by the treating physician at baseline and at weeks 12, 24, and 52 using the Psoriasis Area and Severity Index (PASI). Improvement was measured as the percentage of improvement compared with baseline PASI.

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Non-responders were defined as patients achieving less than 50% improvement compared with baseline PASI, moderate responders as those achieving 50% to less than 75% improvement, and good responders as those achieving at least 75% improvement.10 In case patients switched to adalimumab therapy from a previous biologic therapy without a washout period, the PASI before this biologic therapy was used as the baseline PASI. This was done because otherwise these patients would seem to be nonresponders despite a good response to adalimumab therapy.

Blood samples were obtained before initiation of adalimumab treatment and at adalimumab serum trough levels at baseline and at weeks 12, 24, and 52 (just before administration of adalimumab, patients received a letter notifying them of trough level sampling so this could be timed in relation to adalimumab administration). The adalimumab levels were measured by means of enzyme-linked immunosorbent assay, and the ADAs were detected with a radioimmunoassay2 (both performed at the Laboratory for Monoclonal Therapeutics, Sanquin Diagnostic Services). The radioimmunoassay does not detect ADA bound to adalimumab and might therefore underestimate ADA formation.11,12

The antibody test results were considered positive when the antibody concentration exceeded 12 AU/mL. Concentrations between 12 and 100 AU/mL were considered low ADA titers and those above 100 AU/mL were considered high ADA titers. If no detectable ADAs were present (<12 AU/mL) this result was categorized as “no ADA.”

The methods of statistical analysis are explained in the earlier report.9 In addition, we used the Spearman rank test to calculate the correlation coefficients between the clinical response (expressed as ΔPASI), the level of antibodies against adalimumab, and the adalimumab trough level. To replace missing baseline PASI values, imputation of the mean was used. For missing visits, missing adalimumab levels, and missing antibody titers, the last observation carried forward method was used.

RESulTS

Patient CharacteristicsThis cohort included 80 patients, 52 male and 28 female, with a mean age of 46 years (range, 24-73 years). The mean disease duration of psoriasis was 23 years (range, 7-51 years), and the mean PASI at baseline was 12 (range, 1.5-27). Three patients had low baseline PASI (1.5, 1.7, and 3.8) because they had to switch directly from efalizumab to adalimumab when efalizumab was withdrawn from the market. One patient had a baseline PASI of only 3 because she had switched from etanercept, to which her psoriasis responded but her arthritis did not. For these 4 patients, the baseline PASI from prior biologic therapy (9.6, 8.6, 18.8, and 11.7) was used as the baseline PASI for this study, as described in the Methods section.

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Sixty-five percent of patients had a PASI of at least 10.0 (excluding the 4 patients just mentioned with replaced PASI values). Sixty-nine percent had used at least 4 previous systemic treatments for psoriasis; the most frequently used previous treatments were methotrexate and UV-B (in 95% and 94% of patients, respectively). The mean body mass index (calculated as weight in kilograms divided by height in meters squared) was 29.4, and 25% of patients had a diagnosis of psoriatic arthritis. See the Table for patient characteristics.

Table. Patient Characteristics

Characteristics Total (n=80)Patients with

ADA n=39 (49%)Patients without ADA n=41 (51%)

Mean age y (SD) 46 (13) 46 (12) 46 (13)

Male sex no (%) 52 (65) 26 (67) 26 (63)

Mean disease duration y (SD) 23 (11) 22 (11) 25 (12)

Mean PASI baseline (SD) 13(5) 13 (6) 12 (5)

BMI (SD) 29 (6) 30 (5) 29 (7)

PsA no (%) 20 (25) 10 (26) 10 (24)

Concomitant MTX from week 0 no (%) 8 (10) 3 (8) 5 (12)

Previous systemic therapies no (%)

Methotrexate 76 (95) 37 (95) 39 (95)

Cyclosporine 55 (69) 29 (74) 26 (63)

Fumaric acid 23 (29) 13 (33) 10 (24)

UVB 75 (94) 36 (92) 39 (95)

PUVA 45 (56) 23 (59) 22 (54)

Etanercept 54 (68) 29 (74) 25 (61)

Infliximab 3 (3.8) 1 (3) 2 (5)

Efalizumab 16 (20) 11 (28) 5 (12)

Adalimumab 0 (0) 0 (0) 0 (0)

Ustekinumab 0 (0) 0 (0) 0 (0)

Mean no of previous treatments (SD) 4 (1) 5 (1) 4 (1)

Clinical ResponseAll patients reached the week 12 visit, at which point 38 patients (48%) were nonresponders, 16 (20%) were moderate responders, and 26 (32%) were good responders. Of 71 patients who reached the week 24 visit, 24 (30%) were non-responders, 22 (28%) were moderate responders, and 25 (31%) were good responders. Of the 9 patients who stopped treatment between the week 12 and 24 visits, 5 discontinued treatment early because of nonresponse and 3 because of an

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adverse event (herpes zoster, pneumonia, and abscess formation in the adalimumab injection site). One patient stopped treatment because of nonresponse together with an adverse event (psoriasis palmoplantaris). Fifty-nine patients (74%) reached the week 52 visit. Fifteen (19%) were nonresponders, 12 (15%) were moderate responders, and 32 were good responders (40%). Between the week 24 and 52 visits, 12 patients (15%) discontinued treatment; 3 were lost to follow-up, 8 stopped treatment with adalimumab because of nonresponse, and 1 stopped treatment because of nonresponse together with an adverse event. Termination of treatment for nonresponse occurred after a mean duration of 7.8 months. In total, 21 patients (26%) did not complete 1 year of treatment with adalimumab.

Of the 38 patients who were nonresponders at the week 12 visit, 18 and 9, respectively, remained nonresponders at weeks 24 and 52. Treatment was terminated early because of nonresponse in 6 nonresponders between weeks 12 and 24 and in 11 between weeks 24 and 52. Of the 26 patients who were good responders at the week 12 visit, 18 and 19, respectively, remained so at weeks 24 and 52. Treatment was terminated early (before week 52) in 6 good responders: in 1 because of an adverse event, in 3 because of loss of effectiveness over time, and in 2 because of loss to follow-up.

Clinical Response and Adalimumab Trough LevelsAt the study termination (at week 52 or the early termination [ET] visit), the adalimumab level varied significantly between nonresponders and moderate responders and between nonresponders and good responders (p < 0.05). There was no significant difference between moderate responders and good responders.

Adalimumab trough levels ranged from 0.0 to 20.9 mg/L for nonresponders, 1.1 to 16.5 mg/L for moderate responders, and 0.1 to 29.2 mg/L for good responders (Figure 1). The Spearman rank correlation coefficient was calculated and showed a moderately strong correlation coefficient of 0.519.

Concentrations of Antibodies to AdalimumabDuring 52 weeks of follow-up, ADAs were detected in 39 of 80 patients (49%). Antidrug antibody formation occurred for the first time before week 12 in 18 patients, between weeks 12 and 24 in 17, and between weeks 24 and 52 in 4. At the week 12 visit, 8 patients had a low ADA titer (13-34 AU/mL), 10 had a high ADA titer (195-7300 AU/mL), 53 had no ADA, and 9 had a missing value. In 16 of the 18 patients with ADA, the ADA titer at week 24 or ET had risen. At the week 24 visit, 20 patients had a low ADA titer (13-96 AU/mL), 9 had a high titer (1220-55700 AU/ mL), 37 had no ADA, and 5 had a missing value. In 5 patients with ADA at week 24 (range, 14-35 AU/mL), ADA had disappeared at week 52 (no explanation found). In the remaining patients with ADA at week 24, ADA had increased or remained the same or patients had undergone ET. At the week 52 visit, 19 had a low ADA

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titer (13-96 AU/mL), 1 had a high ADA titer (68 333 AU/mL), 37 had no ADA, and 2 had a missing value (Figure 2).

All 18 patients with ADA at week 12 had ADA at week 24 or underwent ET before week 24. All patients with low ADA titers continued to have low or high ADA titers at week 24. Of the 31 patients with ADA at the week 24 visit, 4 showed no ADA at week 52 (all had low ADA titers at week 24; range, 14-35 AU/ mL). The remaining 27 patients still showed ADA at week 52 or underwent ET.

Adalimumab Trough Level and Antibodies to AdalimumabAdalimumab trough level ranged from undetectable to 31 mg/L. At week 12, the median adalimumab level in patients receiving 40 mg of adalimumab every other week was 8 mg/L (range, 0-20). At weeks 24 and 52, the median (range) levels were 5 (0-31) and 7 (0-19) mg/L, respectively. Figure 2 shows different median adalimumab trough levels by ADA status and week. For weeks 12, 24, and 52, respectively, 9, 5, and 2 patients had no serum samples obtained. At week 52, in 5 patients it was not certain that serum samples were obtained at a trough level; these 5 measurements were excluded from analysis.

Figure 1 Adalimumab Trough Level at Study Termination Categorized by Responder Status Adalimumab trough levels are shown by responder status at study termination (week 52 or early termination visit). Responses were assessed according to the Psoriasis Area and Severity Index (PASI). Nonresponders were defined as patients achieving less than 50% improvement compared with baseline, moderate responders as those achieving 50% to less than 75% improvement, and good responders as those achieving at least 75% improvement. Outliers were included in the analyses. Nonresponders attained significantly lower adalimumab trough levels than good responders.

Figure 1. Adalimumab Trough Level at Study Termination Categorized by Responder StatusAdalimumab trough levels are shown by responder status at study termination (week 52 or early termination visit). Responses were assessed according to the Psoriasis Area and Severity Index (PASI). Nonresponders were defined as patients achieving less than 50% improvement compared with baseline, moderate responders as those achieving 50% to less than 75% improvement, and good responders as those achieving at least 75% improvement. Outliers were included in the analyses. Nonresponders attained significantly lower adalimumab trough levels than good responders.

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At termination of the study (week 52 or the ET visit), the adalimumab level did vary significantly among patients with no, low, and high ADA, with a median (range) of 10.5 (2.0-29.2), 2.0 (0.1-6.5), and 0.0 (0.0-0.1) mg/L, respectively (Figure 2). The Spearman rank correlation coefficient was calculated and showed a very strong negative correlation coefficient of −0.872 between adalimumab level and ADA concentration.

Adalimumab Dose Interval ShorteningTwo patients had the dosing interval shortened at week 12, both because of nonresponse. One patient had no ADA and changed into a good responder. One patient was receiving oral predni-sone for asthma together with a shortened dose interval. This patient had high ADA (474 AU/mL) at week 12 and changed into a moderate responder, with low ADA (25 AU/mL) at week 52. Seven patients had the dosing interval shortened between weeks 12 and 24, because of nonresponse in 5 and moderate response in 2. Three of the nonresponders had high ADA titers before dose interval shortening and remained nonresponders. Two patients without ADA before dose interval shortening improved in responder status, and 2 without ADA remained at the same level of responder status. Six patients had the

Figure 2 Median Adalimumab Trough Level per Antidrug Antibody (ADA) Status The 3 lines represent adalimumab trough levels by ADA group at weeks 12, 24, and 52. Antidrug antibody titers less than 12 AU/mL are considered no ADA; titers between 12 and 100 AU/mL, low ADA; and titers above 100 AU/mL, high ADA. Patients with low ADA titers or no ADA attained detectable adalimumab trough levels, but patients with high ADA titers did not.

figure 2. Median adalimumab Trough level per antidrug antibody (ada) Status.The 3 lines represent adalimumab trough levels by ADA group at weeks 12, 24, and 52. Antidrug antibody titers less than 12 AU/mL are considered no ADA; titers between 12 and 100 AU/mL, low ADA; and titers above 100 AU/mL, high ADA. Patients with low ADA titers or no ADA attained detectable adalimumab trough levels, but patients with high ADA titers did not.

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Figure 3 Flowchart of Patients with Adalimumab Dose Interval Shortening. The flowchart shows the patients receiving dose interval shortening and the effect on clinical

response. ADA status seems to be of influence on dose interval shortening, in other words,

dose interval shortening seems to be less useful if ADA are present.

figure 3. flowchart of Patients With adalimumab dose Interval Shortening. This flowchart shows patients in whom the adalimumab dose interval was shortened and the effect on clinical response. The antidrug antibody status seems to influence the effect of dose interval shortening; in other words, dose interval shortening seems less useful if antidrug antibodies to adalimumab are present.

dosing interval shortened between weeks 24 and 52, because of nonresponse and moderate response in 3 each. Three of the patients had ADA before dose interval shortening and did not improve responder status. Three of the patients had no ADA; responder status did not improve in 2 and did improve in 1 (Figure 3). There was no significant difference in adalimumab trough level between patients who underwent dose interval shortening and those who did not.

Concomitant Use of MethotrexateEight patients received concomitant methotrexate therapy from week 0. Among these 8 patients, (low) ADA developed in 3 (at weeks 12, 24, and 52). No methotrexate-treated patients had high ADA titers, and 5 had no ADA formation. Methotrexate dosage ranged from 2.5 to 20 mg/wk. Methotrexate therapy was initiated in 1 patient at week 12. Responder status improved in this patient who did not have ADA formation. At week 24, methotrexate therapy was initiated in 3 patients. Responder status improved in 2. In 1 of 2 patients who had ADA before concomitant methotrexate therapy, ADA titers went from high to low.

In 2 patients, the dose interval was shortened during the same time interval methotrexate was added. One patient remained a moderate responder, but ADA titers went from 2950 to 87 AU/mL; the other patient had no ADA and went from being a nonresponder to a good responder. There was no significant difference in adalimumab trough level between patients who were concomitantly treated with methotrexate and who were not.

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Clinical Response and Concentrations of Antibodies to AdalimumabAmong the 32 good responders at the week 52 visit, 27 had no ADA, 5 had low ADA (range 16-73 AU/mL), and none had high ADA. Among the 13 moderate responders, 7 had no ADA, 6 had low ADA (range 13-96 AU/mL), and none had high ADA. Among the 14 nonresponders, 4 had no ADA, 9 had low ADA titers (range 13-62 AU/mL), and 1 had a high ADA titer (68 333 AU/ mL). In total, 14 patients underwent ET because of nonresponse, 5 between week 12 and 24 and 9 between week 24 and 52. Two of them had no ADA, 3 had low ADA, and 9 had high ADA. Figure 4 shows the responder status by ADA titer at the termination of the study (week 52 or ET visit, whichever came first). All patients with high ADA at week 12, 24, or 52 or ET were nonresponders at that time. Not all nonresponders had high ADA. At the termination of the study (at week 52 or ET visit, whichever came first), the ADA concentration varied significantly between nonresponders and moderate responders and between nonresponders and good responders (p < 0.05). There was no significant difference between moderate responders and good responders.

Figure 4 Responder Status by Antidrug Antibody (ADA) to Adalimumab Titer at Study Termination Antidrug antibody titers less than 12 AU/mL are considered no ADA; titers between 12 and 100 AU/mL, low ADA; and titers above 100 AU/mL, high ADA. Responder status was based on improvement in the Psoriasis Area and Severity Index, relative to baseline (see Methods). This figure shows that patients with high ADA titers are always nonresponders. (Study termination was at week 52 or the early termination visit.)

figure 4. Responder Status by antidrug antibody (ada) to adalimumab Titer at Study Termination. Antidrug antibody titers less than 12 AU/mL are considered no ADA; titers between 12 and 100 AU/mL, low ADA; and titers above 100 AU/mL, high ADA. Responder status was based on improvement in the Psoriasis Area and Severity Index, relative to baseline (see Methods). This figure shows that patients with high ADA titers are always nonresponders. (Study termination was at week 52 or the early termination visit.)

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The median (range) in AU/mL was 0 (0-73), 0 (0-31), and 39 (0-68333) for good, moderate, and nonresponders, respectively. The Spearman rank correlation coefficient was calculated and showed a moderately strong negative correlation coefficient of −0.606.

dISCuSSIOn

The purpose of our study was to assess whether the extent of antibody formation against adalimumab in the treatment of psoriasis vulgaris increases, persists, or decreases after 24 weeks of adalimumab treatment and to determine the clinical consequences of such changes. In conclusion, our findings show that the biggest chance of first-time ADA development is in the first 24 weeks of treatment (35 vs 4 patients) and further support the notion that the presence of ADA is strongly correlated with adalimumab level (correlation coefficient −0.872) and greatly influences clinical response (correlation coefficient −0.606), also after 24 weeks of treatment. Dose interval shortening might be useful if no ADAs are present, but it seems less useful if they are present.

In the previous study, 13 of 29 patients (45%) had ADA formation,9 compared with 39 of 80 (49%) in the current study. In studies performed in patients with rheumatoid arthritis treated with adalimumab, these percentages are lower. Bartelds et al13 showed in a 3-year follow-up study that 28% of patients had ADA formation. Many patients (74%) in that study used concomitant methotrexate, but patients with ADA formation less often had concomitant MTX. Moreover, in other studies, the concomitant use of immunosuppressants reduces the frequency of antibody formation in response to biologic therapy,14,15 and a favorable effect of concomitant methotrexate on reducing antibody formation has been postulated. In a letter by Krieckaert et al,16 it was reported that methotrexate seems to reduce ADA formation efficiently and in a dose-dependent manner.

Methotrexate treatment did not reduce ADA formation in our study; 3 of 8 patients (38%) who received methotrexate had (low) ADA. This might be due to the low dose of methotrexate used by these 3 patients (2.5, 10, and 10 mg/wk). The number of patients using concomitant methotrexate in our study was limited, so these data should be interpreted with caution. Of the patients in our cohort not receiving concomitant methotrexate, 50% (36 of 72 patients) had ADA formation. Bartelds et al13 found the same, with ADA formation in 50% of patients (35 of 70) not receiving concomitant methotrexate. Of their patients receiving concomitant methotrexate, only 20% (41 of 202) had ADA formation, which further supports the role of methotrexate in reducing immunogenicity, instead of, for example, disease (psoriasis)–related factors. The treatment dose of adalimumab is similar for psoriasis and rheumatoid arthritis. A study by Karmiris et al17 included patients treated with adalimumab for Crohn disease; only 9.2% had ADA formation. This

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finding may be explained by disease-related factors or the fact that most of these patients (75% of 168) were treated with an initial dose of 160 mg for the first week and 80 mg for the next, instead of 80 mg as an initial dose and 40 mg for the next week, which is common practice in psoriasis treatment.

Obtaining a sufficient adalimumab trough level does not imply good clinical improvement. In our cohort, some patients obtained a good adalimumab trough level but no sufficient clinical improvement. Is it is not clear what factors other than antibody formation may impair treatment. A hypothesis could be that tumor necrosis factor may not be the leading inflammatory agent in these patients.

Adalimumab was administered every other week, and dose interval shortening to every 7 or 10 days could be applied in case of nonefficacy. As shown by our results, dose interval shortening might be useful if no ADAs are present. This might be explained by the fact that ADAs result in functional neutralization of adalimumab.12 However, given the limited size of this specific population within this study, these data should be interpreted with caution. Leonardi et al18 observed that patients weighing 102 kg or less or with a disease duration of less than 8.3 years were most likely to benefit from dose escalation. In the 15 patients with dose escalation presented here, we did not observe this.

In the group of patients with ADA, 90% had ADA formation for the first time before week 24. This is in line with the findings by Bartelds et al,13 in which 67% of patients had ADA formation during the first 28 weeks. This implies that most patients who have ADA formation will do so during the first 24 weeks of treatment.

As reported in the previous study, the response rate in the current study is surprisingly lower than those reported in 3 phase 3 trials,19-21 with PASI improvement of at least 75% at week 12 or 16 in 53%, 71%, and 80% of patients. In our current study, 33% of patients showed at least 75% improvement relative to baseline, in accordance with a study by van Lümig et al,22 in which 34% of patients showed at least 75% improvement at week 12; both of these studies present “real-world data,” which might explain the difference in response rates compared with the phase 3 trials.

Nine patients continued adalimumab treatment until at least week 52 despite remaining nonresponders. Six of them had PASI improvement of 32% to 43% at week 52 and were content with this result. Eight of 9 patients had been previously treated with etanercept. In these cases, treatment with adalimumab may also be continued because of lack of other treatment options. Infliximab would have to be administered intravenously in a daycare setting, and experience with ustekinumab was still small.

In this study, we have also further endorsed the strong negative correlation between ADA formation and adalimumab serum trough levels, with a correlation coefficient of −0.872. The higher the ADA titer, the lower the adalimumab trough level. In a different study,12 it was shown that virtually all ADAs are neutralizing

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and that the ADAs are highly specific for adalimumab, forming small immune complexes, in this way neutralizing the drug. It has been suggested that ADA may lead to thromboembolic events23 or a type III hypersensitivity reaction,12 which has not been observed in this cohort.

This study has some limitations. Because of the limited number of patients experiencing dose interval shortening and the limited number using concomitant methotrexate, the influence of these interventions on antibody formation and effectiveness should be further investigated in a larger cohort.

The last observation carried forward method was used to replace missing values for adalimumab levels and antibody titers. This may have led to underestimation of ADA formation and overestimation of drug levels.

The antibody assay used in this study (a radioimmunoassay) is the same used in the studies by Bartelds et al1,2,13 and Krieckaert et al16 but different from the bridging enzyme-linked immunosorbent assay used by Vermeire et al15 and Karmiris et al.17 The latter is more sensitive to drug interference and does not detect immunoglobulin G4 ADA,11 making comparison between these studies less reliable. The influence of methotrexate on ADA formation needs further research, as well as the influence of dose interval shortening in ADA-positive and ADA-negative patients.

REfEREnCES

1. Bartelds GM, Wolbink GJ, Stapel S, et al. High levels of human anti-human antibodies to adalimumab in a patient not responding to adalimumab treatment. ann rheum Dis. 2006;65(9):1249-1250.

2. Bar te lds GM, Wi jb randt s CA , Nurmohamed MT, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum adalimumab concentrations in rheumatoid arthritis. ann rheum Dis. 2007;66(7):921-926.

3. West RL, Zelinkova Z, Wolbink GJ, Kuipers EJ, Stokkers PC, van der Woude CJ. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. aliment pharmacol Ther. 2008;28(9):1122-1126.

4. Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. arthritis rheum. 2006;54(3):711-715.

5. de Vries MK, Brouwer E, van der Horst-Bruinsma IE, et al. Decreased clinical response to adalimumab in ankylosing spondylitis is associated with antibody formation. ann rheum Dis. 2009;68(11):1787-1788.

6. Radstake TR, Svenson M, Eijsbouts AM, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. ann rheum Dis. 2009;68(11):1739-1745.

7. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and c l in ic a l re levance. curr Opin rheumatol.2009;21(3):211-215.

8. Mok CC, van der Kleij D, Wolbink GJ. Drug levels, anti-drug antibodies, and clinical efficacy of the anti-TNFα biologics in rheumatic diseases. clin rheumatol. 2013;32(10):1429-1435.

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9. Lecluse LL, Driessen RJ, Spuls PI, et al. Extent and clinical consequences of antibody formation against adalimumab in patients with plaque psoriasis. arch Dermatol. 2010;146(2):127-132.

10. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. arch Dermatol res. 2011;303(1):1-10.

11. Hart MH, de Vrieze H, Wouters D, et al. Differential effect of drug interference in immunogenicity assays. J immunol methods. 2011;372(1-2):196-203.

12. van Schouwenburg PA, van de Stadt LA, de Jong RN, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. ann rheum Dis. 2013;72(1):104-109.

13. Ba r te ld s GM, K r ieckae r t CL , Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. Jama . 2011;305(14):1460-1468.

14. K r ieckae r t CL , Ba r te ld s GM, Lems WF, Wolbink GJ. The ef fect of immunomodulator s on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review. arthritis res Ther. 2010;12(5):217. doi:10.1186/ar3147.

15. Vermeire S, Noman M, Van Assche G, Baert F, D’Haens G, Rutgeerts P. Effectiveness of concomitant immunosuppressive therapy in suppressing the formation of antibodies to infliximab in Crohn’s disease. Gut. 2007;56(9):1226-1231.

16. Krieckaer t CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis patients in a dose dependent manner. ann rheum Dis. 2012;71(11):1914-1915.

17. Karmiris K, Paintaud G, Noman M, et al. Influence of trough serum levels and immunogenicity on long-term outcome of adalimumab therapy in Crohn’s disease. Gastroenterology. 2009;137(5):1628-1640.

18. Leonardi C, Sobell JM, Crowley JJ, et al. Efficacy, safety and medication cost implications of adalimumab 40 mg weekly dosing in patients with psoriasis with suboptimal response to 40 mg every other week dosing: results from an open-label study. Br J Dermatol. 2012;167(3):658-667.

19. Gordon KB, Langley RG, Leonardi C, et al. Clinical response to adalimumab treatment in patients with moderate to severe psoriasis: double-blind, randomized controlled trial and open-label extension study. J am acad Dermatol. 2006;55(4):598-606.

20. Menter A, Tyring SK, Gordon K, et al. Adalimumab therapy for moderate to severe psoriasis: a randomized, controlled phase III trial. J am acad Dermatol. 2008;58(1):106-115.

21. Saurat JH, Stingl G, Dubertret L, et al; CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558-566.

22. van Lümig PP, van de Kerkhof PC, Boezeman JB, Driessen RJ, de Jong EM. Adalimumab therapy for psoriasis in real-world practice: efficacy, safety and results in biologic-naive vs. non-naive patients. J Eur acad Dermatol Venereol. 2013;27(5):593-600.

23. Korswagen LA, Bartelds GM, Krieckaert CL et al. Venous and arterial thromboembolic events in adalimumab-treated patients with antiadalimumab antibodies: a case series and cohort study. arthritis rheum. 2011;63(4):877-883.

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3CDEVELOPING A THERAPEUTIC

RANGE OF ADALIMUMAB SERUM CONCENTRATIONS

IN MANAGEMENT OF PSORIASIS: A STEP TOWARD PERSONALIZED TREATMENT

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abSTRaCT

IMPORTANCE: Adalimumab has proven to be effective in suppressing psoriasis disease activity and is administered in a standard dose.OBJECTIVE: To establish a therapeutic range for adalimumab trough levels in the treatment of plaque-type psoriasis, leading to a more personalized treatment.DESIGN, SETTING AND PARTICIPANTS: A multicenter, prospective, observational, daily practice cohort study conducted at an academic hospital with affiliated secondary care hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2). Both cohorts included adult patients treated with adalimumab for plaque-type psoriasis. Cohort 1 comprised 73 patients who were being treated with adalimumab for more than 24 weeks until 401 weeks. In cohort 2 (n = 62), serum samples were obtained between weeks 24 and 52 of treatment.INTERVENTIONS: Before the start of adalimumab therapy and at time of serum sampling, Psoriasis Area and Severity Index (PASI) scores were determined.MAIN OUTCOMES AND MEASURES: Adalimumab trough level and PASI score at the time of serum sampling to determine the receiver-operator characteristics analyses and concentration effect curve.RESULTS: By means of receiver-operator characteristics analyses with an area under the curve of 0.756 (SD, 0.046; 95% CI, 0.666-0.847) and a sensitivity of 78% and a specificity of 70%, 3.51 mg/L was established as the lower margin for the therapeutic range. By means of a concentration effect curve, 7 mg/L was established as the upper margin. One-third of patients had an adalimumab trough concentration exceeding 7 mg/L.CONCLUSIONS AND RELEVANCE: A therapeutic range of adalimumab trough levels of 3.51 mg/L to 7.00 mg/L, which corresponds to an optimal clinical effect, was identified. In one-third of patients, it was observed that trough concentrations exceeded the therapeutic window. Based on the established range, a therapeutic algorithm for adalimumab treatment for patients with psoriasis can be developed and validated in a prospective patient cohort. By identifying this range, a step has been taken toward a more rational use of biological therapy in psoriasis. Developing a therapeutic algorithm may lead to less overtreatment of patients and cost savings.

S.P. Menting*; E. Coussens*; M.F. Pouw; J.M.P.A. van den Reek; L. Temmerman; H. Boonen; E.M.G.J. de Jong; Ph.I. Spuls**; J. Lambert**

* both authors contributed equally to this work** both authors contributed equally to this work

JAMA Dermatol. 2015 Jun;151(6):616-22.

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InTROduCTIOn

During the past 2 decades, a more profound insight in the pathogenesis of psoriasis has led to the development of biological treamtents, These large protein molecules exert their function by targeting crucial immunologic mediators in the pathogenesis of psoriasis, such as tumor necrosis factor (TNF).1

There are several biological treatments available for psoriasis. Adalimumab is a TNF-inhibitor that has proven to be highly effective in suppressing psoriasis disease activity, both in randomized clinical trials2,3 and daily practice.4,5 Aside from moderate to severe psoriasis, this biological agent is also a valuable treatment option for other immune-mediated inflammatory diseases (IMIDs) such as rheumatoid arthritis (RA) and Crohn disease. No relevant end-organ damage has yet been reported for TNF inhibitors.3,6 Adalimumab, like other biological agents, is isolated from mammalian cells by recombinant DNA technology.7 At present, all psoriatic patients are being treated with adalimumab according to a standardized dosing schedule. The European Medicines Agency and the US Food and Drug Administration approved adalimumab (40 mg) to be administered every other week from week 1 after an initial dose of 80 mg at week 0. With this fixed-dosing regimen, a wide variety in clinical response and adalimumab trough levels was observed in a daily practice cohort,8 with significantly higher serum drug concentrations in good-responding patients compared with nonresponders and moderate responders. Analogous to recent findings in RA, this possibly implies that a substantial part of psoriatic patients are under- or overtreated.9 Furthermore, some patients develop antidrug antibodies to adalimumab (ADAs), resulting in diminished adalimumab trough levels and reduced clinical response. Despite this extensive interindividual variation in pharmacokinetics, adalimumab serum levels and ADAs are not measured in daily practice and a therapeutic window of serum adalimumab trough concentrations has not yet been determined in psoriasis. In RA, such a range has been established,9 and personalized treatment by means of a therapeutic algorithm using trough levels has not only proven to be cost-effective,10 but quality-adjusted life-years were also gained through rational clinical decisions early in the treatment course.

Therefore, the main goal of this study was to establish a therapeutic range for adalimumab trough levels, corresponding with adequate clinical response. Determination of these values is necessary to compose a therapeutic algorithm for chronic plaque-type psoriasis, in which the dosing schedule can be adjusted according to serum trough levels of adalimumab and ADAs. A secondary objective of this study was to further detect and quantify ADAs and to correlate them with adalimumab trough levels and clinical response in a real-life setting in a larger cohort of patients with psoriasis.

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METhOdS

DesignThis multicenter cohort study consists of 135 patients. Ghent University Hospital (UZ Gent), in cooperation with affiliated dermatology clinics, collected samples from 73 patients, recruitment started in January 2014 (cohort 1). The Academic Medical Center (AMC Hospital) in collaboration with Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands, provided 62 suitable samples for this study from a previously described cohort (cohort 2).8 Approval was obtained from the medical ethics committees of all participating hospitals. All patients gave their written informed consent.

Patients and SamplesThe study population included patients aged 18 years or older with chronic plaque-type psoriasis diagnosed by a dermatologist, who were being treated with subcutaneous adalimumab (40 mg) every other week for at least 24 weeks from week 1 after an initial dose of 80 mg at week 0. A minimum treatment duration of 24 weeks was chosen because in RA it has been shown that adalimumab steady-state concentration is reached after 24 weeks of treatment,11 and in patients with psoriasis, ADAs (negatively impacting trough levels) mostly occur for the first time before 24 weeks of treatment.5 Cohort 1 consists of serum samples at random time points in treatment (after 24 weeks of treatment), whereas samples in cohort 2 were collected between 24 and 52 weeks of treatment. Patients who interrupted their treatment schedule during the 24 weeks prior to blood sampling were excluded. Samples of patients who were treated with adalimumab for any other inflammatory disease and later developed psoriasis were also excluded.

The blood samples, obtained within 24 hours before adalimumab administration, were each centrifuged during 10 minutes at 1500 rpm. Serum samples from cohort 1 were pre-served at −80°, whereas cohort 2 samples were kept at −20°, until they were sent batchwise to the Laboratory for Monoclonal Therapeutics, Sanquin Diagnostic Services, Amsterdam, the Netherlands. Adalimumab trough concentrations were determined by means of enzyme-linked immunosorbent assay (ELISA). This assay is based on the principle that adalimumab is captured through its ability to bind TNF. Results were reported in milligrams per liter. Levels of ADAs were detected using a radioimmunoassay, which measures specific high avidity IgG antibodies against adalimumab by an antigen binding test. These results were converted into arbitrary units (AU) per milliliter, with a cutoff value set at 12 AU/mL. The radioimmunoassay does not detect ADAs bound to adalimumab and therefore may underestimate ADA formation.12,13 For this reason, samples were obtained at trough level. In December 2013, the procedure for measuring adalimumab trough levels was

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altered, with both methods showing a correlation 0.97.14 To obtain comparable data for both patient cohorts, sample results from cohort 2 were converted by means of a correction factor.

Clinical ResponseDisease severity was measured by use of the Psoriasis Area and Severity Index (PASI) (the most extensively studied psoriasis clinical severity score and the most thoroughly validated15). In this way, clinical status was assessed by the treating dermatologist right before the start of adalimumab treatment (PASI baseline) and prior to serum sample collection (PASI sampling). In case patients switched to adalimumab therapy from a previous biological therapy without a washout period, the PASI before this biological therapy was used as the PASI baseline to avoid unfair classification of patients as nonresponders. Percentage of PASI improvement compared with baseline (ΔPASI) represents clinical response. Patients were classified as nonresponders (ΔPASI <50.00), moderate responders (ΔPASI 50.00-74.99), or good responders (ΔPASI 75.00-100.00).16

Statistical Analyses

Adalimumab Trough Levels, ADAs, and Clinical Response

To perform statistical data analysis, SPSS Statistics 22 (IBM Corp) was used. For continuous variables, Shapiro-Wilk normality tests were performed. Correlation coefficients between adalimumab, ADA concentrations, and clinical response (ΔPASI) were calculated by means of the nonparametric Spearman rank test. For comparison of mean values between groups, the independent-samples t test, Mann-Whitney test, or χ2 test was performed, as appropriate. For each test, the threshold for significance was set at p < 0.05.

Receiver-Operator Characteristics Analyses

To determine a representative cutoff value for adalimumab trough levels between the group of nonresponders and moderate responders and good responders, a receiver-operator characteristics curve was created. A trade-off was made between sensitivity and specificity to establish an adequate lower margin of the therapeutic adalimumab range.

Concentration Effect Curve

A concentration effect curve (CEC) was established to identify the upper margin of adequate adalimumab trough levels corresponding with maximal clinical efficacy. First, patients were stratified according to ascending adalimumab trough concentrations, with correlating ΔPASI scores. Data were then divided in equal-sized groups, each represented by a mean adalimumab trough level and a median ΔPASI score (with associated interquartile range). In this way, the interindividual

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variability between patients is reduced, and the relationship between adalimumab serum trough concentrations and clinical response is better represented.

RESulTS

Patient SelectionIn cohort 1, 82 patients were enrolled. Nine of them were excluded because adalimumab was not strictly administered every 2 weeks, resulting in 73 suitable samples. From the cohort previously described by Menting et al8 (cohort 2), 80 patients were enrolled, of which 18 were excluded because adalimumab was not administered every other week or because treatment was terminated prior to week 24. Thus, samples from 62 patients from cohort 2 were included.

Patient CharacteristicsThe total study population comprised 135 patients with a psoriasis (102 male [75.6%]), with a mean age of 45 years at the start of adalimumab treatment. Of the 135 patients enrolled in this study, 38 (28.8%) also had psoriatic arthritis. Only 11 patients were concomitantly being treated with methotrexate (dose range, 7.5-20 mg/wk), 6 of whom were classified as good responders. After at least 24 weeks of treatment, 46 patients (34%) did not reach a 75% improvement in treatment response (measured using the PASI). Treatment duration in cohort 1 varied between 24 and 401 weeks, with a mean value of 157 weeks. The mean (SD) PASI score at the time of sampling was 2.4 (0.4). In cohort 2, samples were collected between 24 and 52 weeks of treatment, resulting in a mean treatment duration of 45 weeks. The mean (SD) PASI score at the time of sampling was 5.17 (0.75). Except for this significant discrepancy, there were no relevant methodological differences concerning data collection or significant differences at baseline between both study cohorts. A separate concentration effect curve was established to investigate whether treatment duration was of any influence on the upper margin of the therapeutic range. Both Belgium and the Netherlands apply similar reimbursement criteria for adalimumab; therefore, previous systemic psoriasis treatments are comparable between cohorts. No significant differences were observed between good responders vs nonresponders and moderate responders (Table 1).

Adalimumab Trough LevelsAdalimumab trough levels ranged from 0.00 to 16.38 mg/L, with a mean serum concentration of 5.02 mg/L. By means of a Spearman rank correlation coefficient (ρ = 0.418), a significantly positive but weak correlation between adalimumab serum trough levels and clinical response (ΔPASI) was shown (p < 0.001). With a mean adalimumab serum trough concentration of 2.99 mg/L in nonresponders and moderate responders compared with 6.07 mg/L in good responders, patients who did not

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reach ΔPASI 75.00 had significantly lower adalimumab trough levels compared with patients obtaining a 75% improvement in treatment response (p < 0.001) (Figure 1). Antidrug antibodies to adalimumab were detected in 31.9% of the study cohort, with a significantly higher percentage (56.5%) of antibody formation in the group of nonresponders and moderate responders vs good responders (19.1%) (p < 0.001) (table 2). Patients with a positive ADA titer had a significantly lower mean adalimumab trough concentration of 1.35 mg/L compared with patients with a negative ADA titer, who had a mean adalimumab level of 6.74 mg/L (p < 0.001). With a correlation coefficient of ρ = −0.220, a significantly negative but weak correlation between body mass index and adalimumab trough level was shown (p = 0.01). However, no significant correlation (ρ = −0.079) between BMI and clinical response was found (p = 0.37).

Receiver-Operator Characteristics AnalysesWith an area under the curve of 0.756 (SD, 0.046; 95% CI, 0.666-0.847), these data demonstrate that determining the adalimumab serum trough level is a useful test to distinguish good responders from nonresponders and moderate responders (p < 0.001). The adalimumab cutoff value corresponding to the most optimal trade-off between sensitivity and specificity was 3.51 mg/L. With a sensitivity of 78% and a specificity of 70%, this demarcation point has a positive predictive value of 83% to obtain a 75% improvement in treatment response (Figure 2).

Table 1. Baseline characteristics

CharacteristicTotal

(n=135)

Good Responders

(n=89)

Non- and moderate responders

(n=46)

Age, mean (SD), y 45 (11) 46 (10) 43 (12)

Male sex, No. (%) 102 (75.6) 69 (77.5) 33 (71.7)

Disease duration, mean (SD), y 24 (10) 25 (9) 23 (11)

Treatment duration, mean (SD),w 105 (89) 127 (91) 64 (67)

PASI baseline, mean (SD) 15.5 (6.4) 16.5 (6.1) 13.4 (6.6)

BMI, mean (SD) 28.4 (5.2) 28.1 (5.0) 28.8 (5.5)

PsA, No. (%) 38 (28.8) 25 (29.1) 13 (28.3)

Concomitant methotrexate, No. (%) 11 (8.3) 6 (6.9) 5 (10.9)

Previous biologic treatment, No. (%) 74 (55.2) 39 (44.3) 35 (76.1)

Etanercept 71 (53) 38 (43.2) 33 (71.7)

Infliximab 6 (4.5) 3 (3.4) 3 (6.5)

Efalizumab 14 (10.4) 5 (5.7) 9 (19.6)

Adalimumab 1 (0.7) 1 (1.1) 0

Ustekinumab 1 (0.7) 1 (1.1) 0

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3Cfigure 1. Mean difference in adalimumab Trough level for nonresponders and Moderate vs Good Responders. Boxes represent standard deviations; error bars, interquartile ranges; and the circle, an outlier that was included in the analyses.

Table 2. Adalimumab trough levels, ADA’s and clinical response

CharacteristicTotal

(N=135)

Good Responders

(n=89)

Non- and moderate responders

(n=46)

Adalimumab Serum Level (mg/L)

Mean (SD) 5.02 (3,57) 6.07 (3.34) 2.99 (3.13)

Median 4.70 6,40 2.15

Range [0.00 – 16.38] [0.00 – 16.38] [0.00 – 10.37]

Clinical Response (ΔPASI)

Mean (SD) 73.03 (31.61) 90.49 (7.93) 39.24 (32.90)

Median 83.60 91.07 47.37

Range [-60.90 – 100] [75 – 100] [-60.90 – 74.14]

ADA positive, No. (%) 43 (31.9) 17 (19.1) 26 (56.5)

Concentration Effect CurveThe CEC of the total study cohort contains 135 patients (Figure 3). To obtain this graphic result, all 135 patients were stratified in ascending order of their adalimumab trough concentrations, with correlating ΔPASI score. Consequently, patients were divided in 10 groups of 11, 13, 14, or 15 patients (1, 3, 5, and 1 groups, respectively). Each open circle represents the mean adalimumab concentration with correlating median ΔPASI score for 1 group. Alongside each ΔPASI score, the equivalent interquartile range

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figure 2. Receiver-Operator Characteristics analyses. With an area under the curve of 0.756, determining the adalimumab serum trough level is a useful test to distinguish good responders from nonresponders and moderate responders. The adalimumab cutoff value corresponding with the most optimal trade-off between sensitivity and specificity is 3.51 mg/L (arrowhead).

is also depicted. As adalimumab trough levels increase, higher ΔPASI scores can be observed, with a maximal therapeutic response (ΔPASI 86.49) in the subgroup of patients with a mean trough level of 7 mg/L. Adalimumab concentrations exceeding 7 mg/L have no additional value to the therapeutic response.

Figure 3. Concentration Effect Curve for Total Study CohortAdalimumab concentrations exceeding 7 mg/L (vertical line) had no additional value to the therapeutic response. The dashed vertical line represents the adalimumab cutoff value of 3.51 mg/L. Each open circle in the curve represents the mean adalimumab concentration, with correlating median ΔPASI score, for one group. Alongside each ΔPASI score, the equivalent interquartile range (IQR) is depicted.

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figure 4. Concentration Effect Curves for Patients Treated for More Than 52 Weeks vs Patients Treated for 52 Weeks or lessB Patients treated for ≥52 weeksC Patients treaded for ≥24 weeks to ≤52 weeksFor patients treated for more than 52 weeks and patients treated for 24 weeks or more to 52 weeks or less, adalimumab concentrations exceeding 7 mg/L (solid vertical lines) had no additional value to the therapeutic response. A, Concentration effect curve for patients treated with adalimumab for more than 52 weeks and 24 weeks or more to 52 weeks or less. B, Concentration effect curve for patients treated with adalimumab for 52 weeks or more. C, Concentration effect curve for patients treated with adalimumab for 24 weeks or more to 52 weeks or less. The dashed vertical lines represent the adalimumab cutoff value of 3.51 mg/L. IQR indicates interquartile range.

The relationship between adalimumab trough levels and clinical response is shown separately for patients treated with adalimumab for more than 52 weeks (Figure 4A and B), and for 52 weeks or less (Figure 4A and C). Sixty patients were included for the CEC that included samples obtained at more than 52 weeks

B C

A

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of treatment and were sorted according to ascending adalimumab levels with correlating ΔPASI scores. These data were stratified in 7 groups of 8 or 9 patients (3 and 4 groups, respectively). The same was done for the CEC that included 74 samples obtained at 52 weeks or less of treatment. These data were stratified in 9 groups of 7, 8, or 9 patients (1, 5, and 3 groups, respectively). Both CECs flattened around the same adalimumab trough concentration point of 7 mg/L. Therefore, it was considered appropriate to determine 1 adalimumab trough level range for both groups of patients with a treatment duration under and over 52 weeks (Figure 4A). These separate curves also depicted that serum levels up to 7 mg/L show a positive association with ΔPASI and that concentrations exceeding 7 mg/L had no further clinical value. One patient, from whom the treatment duration was unknown, could not be taken into account for the CEC curve of treatment more than 52 weeks or 52 weeks or less of treatment but was included in the analyses for the CEC of the total study cohort.

dISCuSSIOn

Based on serum sample collection from 135 patients with psoriasis who were treated with adalimumab every other week for at least 24 consecutive weeks, a therapeutic range for adalimumab trough levels that corresponds with a good clinical response (ΔPASI 75.00) was defined (3.51-7.00 mg/L). With an area under the curve of 0.769, these data demonstrate that determining adalimumab serum trough level is a useful measurement to distinguish good responders from nonresponders to moderate responders. The lower margin was demarcated at 3.51 mg/L because this value correlated with the most optimal trade-off between sensitivity (78%) and specificity (70%).

Takahashi et al17 measured a mean adalimumab trough level of 7.62 μg/mL in 32 patients with psoriasis who were treated according to the standard dosing schedule. A cutoff value for obtaining good clinical response (ΔPASI 75.00) was established at 7.84 μg/mL. This cohort differs from our cohort in several ways. Our cohort consisted of 135 white patients with psoriasis patients vs 32 patients of Asian descent in the cohort described by Takahashi et al.17 The sample size of the latter cohort may be too limited to establish a cutoff in adalimumab trough level for obtaining good clinical response. Although Edson-Heredia et al18 stated that it is unlikely that race or ethnicity influence response rates of ΔPASI 75.00, we hypothesize that the mean body mass index, which according to Menter et al19 has a negative impact on adalimumab treatment response, is lower in the Japanese cohort compared with our cohort. Body mass index was not re-ported in the study by Takahashi et al.17

The upper margin of the therapeutic adalimumab range was determined by means of a CEC. By reducing intervariability between patients, an uncluttered

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image of the adalimumab clinical response correlation is generated. In the CEC curve of the total study cohort (Figure 3), as well as in both separate CEC curves according treatment duration subcategory (Figure 4), a deflection of the curve upward of 7 mg/L adalimumab can be observed. This trough level corresponded with a maximal improvement in treatment response (ΔPASI 86.46). Adalimumab levels exceeding 7 mg/L had no further beneficial effect on treatment response. In good responders, adalimumab trough concentrations up to 16.38 mg/L were observed, and 44 patients in this cohort (32.6%) had an adalimumab level higher than 7 mg/L. In these patients, adalimumab dosing interval might be lengthened, leading to adalimumab trough concentrations within the therapeutic range without losing clinical efficacy and saving costs. Therefore, these data support the hypothesis that, with the current standard dosing regimen, an important percentage of patients with psoriasis are being overtreated. Besides trough concentrations above the upper margin, trough concentrations below the lower margin were also observed in good responders. In 20 patients, an adalimumab trough concentration below the lower margin of 3.51 mg/L was measured, and in 13 of these patients, trough concentration was even below half of the lower margin (1.75 mg/L). Because a meaningful clinical effect of these trough concentrations is not expected based up the therapeutic adalimumab range established herein, we hypothesize that disease activity in some of these patients is low. In these cases, one could envisage to stop adalimumab treatment under further careful clinical monitoring.

Pouw et al9 determined a therapeutic range of adalimumab (5.0-8.0 μg/mL), corresponding with good clinical response in RA. The proposed therapeutic window is higher than the range determined in our cohort. Psoriasis and RA are 2 different IMIDs, which might explain a difference in therapeutic values. The lower therapeutic adalimumab levels observed in patients with psoriasis might also be attributable to the fact that concomitant methotrexate use is not routine practice in dermatology. Concomitant methotrexate use, which leads to significantly higher functional adalimumab levels, is much more frequently practiced in patients with RA than in those with psoriasis and can be a possible explanation for the observation that lower adalimumab levels are measured in psoriasis than in RA.9 In our cohort, 11 patients were also treated with methotrexate, without a significant impact on adalimumab trough levels (p = 0.92). This is, however, not a meaningful observation because these numbers are very small, and it is hypothesized that methotrexate treatment should be initiated before the start of adalimumab treatment to exert its preventive effect on ADA formation. With this study we were able to confirm, at random time points in adalimumab treatment, that serum adalimumab trough levels correlate with clinical response (p < .001). We also confirmed that patients positive for ADAs have significantly lower adalimumab trough levels (p < 0.001), and a worse clinical response status (p < 0.001). These results are consistent with

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those of Menting et al,8 from which serum samples were also included for cohort 2 presented herein). Thus, our data support the use of therapeutic drug monitoring in routine clinical practice.

This study has some limitations. As previously mentioned, only few patients were using concomitant methotrexate, and no subanalyses could be performed for this group of patients. Another limitation is that PASI baseline and the PASI at time of sampling were not always assessed by the same dermatologist, and interobserver variability might have been present. This study did not take into account other factors influencing response to treatment (genetic and nongenetic).20 Furthermore, we want to emphasize that before using the therapeutic range developed in this study in daily practice, this study requires validation with a confirmation cohort. A therapeutic algorithm based on these data needs to be confirmed in a prospective patient cohort.

COnCluSIOnS

More rational use of biological therapy is a growing necessity in psoriasis, as in other IMIDs. On the one hand, dermatologists need guidelines to make informed decisions about an optimal (efficacious and safe) treatment regimen for an individual patient. On the other hand, increasing socioeconomic pressure aims to reduce the elevated costs of biological agents. In this study, we identified a therapeutic window of adalimumab trough levels (3.51-7.00 mg/L), which corresponds to an optimal clinical effect (ΔPASI 75.00). In one-third of patients it was observed that trough concentrations exceeded the therapeutic window. Based on the established range, a therapeutic algorithm for patients with psoriasis can be developed and validated in a prospective patient cohort.

REfEREnCES

1. Nestle FO, Kaplan DH, Barker J. Psoriasis. N Engl J med. 2009;361(5):496-509.

2. Saurat JH, Stingl G, Dubertret L, et al; CHAMPION Study Investigators. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558-566.

3. Gordon K, Papp K, Poulin Y, Gu Y, Rozzo S, Sasso EH. Long-term efficacy and safety of adalimumab in patients with moderate to severe psoriasis treated continuously over 3 years: results from an

open-label extension study for patients from REVEAL. J am acad Dermatol. 2012;66(2): 241-251.

4. Gniadecki R, Kragballe K, Dam TN, Skov L. Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. Br J Dermatol. 2011;164(5):1091-1096.

5. Menting SP, Sitaram AS, Bonnerjee-van der Stok HM, de Rie MA, Hooft L, Spuls PI. Drug survival is not significantly different between biologics in patients with psoriasis vulgaris: a single-centre

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database analysis. Br J Dermatol. 2014;171(4): 875-883.

6. van Lümig PP, van de Kerkhof PC, Boezeman JB, Driessen RJ, de Jong EM. Adalimumab therapy for psoriasis in real-world practice: efficacy, safety and results in biologic-naïve vs non-naïve patients. J Eur acad Dermatol Venereol. 2013;27(5):593-600.

7. Vena GA, Cassano N. Drug focus: adalimumab in the treatment of moderate to severe psoriasis. Biologics. 2007;1(2):93-103.

8. Menting SP, van Lümig PP, de Vries AC, et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. Jama Dermatol. 2014;150(2): 130-136.

9. Pouw MF, Krieckaert CL, Nurmohamed MT, et al. Key findings towards optimising adalimumab treatment: the concentration-effect curve. ann rheum Dis. 2015;74(3):513-518.

10. Krieckaert CL, Nair SC, Nurmohamed MT, et al. Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects. ann rheum Dis. 2015;74(2):361-368.

11. Ba r te ld s GM, K r ieckae r t CL , Nurmohamed MT, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. Jama . 2011;305(14):1460-1468.

12. Hart MH, de Vrieze H, Wouters D, et al. Differential effect of drug interference in immunogenicity assays. J immunol methods. 2011; 372(1-2):196-203.

13. van Schouwenburg PA, van de Stadt LA, de Jong RN, et al. Adalimumab elicits

a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. ann rheum Dis. 2013;72(1):104-109.

14. Rispens T, van der Kleij D. Reply to Ruiz-Argüello et al: comparison study of two commercially available methods for the determination of infliximab, adalimumab, etanercept and anti-drug antibody levels. clin chem lab med. 2013;51(12):e291-e292.

15. Puzenat E, Bronsard V, Prey S, et al. What are the best outcome measures for assessing plaque psoriasis severity? a systematic review of the literature. J Eur acad Dermatol Venereol. 2010;24 (suppl 2):10-16.

16. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. arch Dermatol res. 2011;303(1):1-10.

17. Takahashi H, Tsuji H, Ishida-Yamamoto A, Iizuka H. Plasma trough levels of adalimumab and infliximab in terms of clinical efficacy during the treatment of psoriasis. J Dermatol. 2013;40(1): 39-42.

18. Edson-Heredia E, Sterling KL, Alatorre CI, et al. Heterogeneity of response to biologic treatment: perspective for psoriasis. J invest Dermatol. 2014; 134(1):18-23.

19. Menter A, Gordon KB, Leonardi CL, Gu Y, Goldblum OM. Efficacy and safety of adalimumab across subgroups of patients with moderate to severe psoriasis. J am acad Dermatol. 2010;63(3): 448-456.

20. Karczewski J, Poniedziałek B, Rzymski P, Adamski Z. Factors affecting response to biologic treatment in psoriasis. Dermatol Ther. 2014;27(6): 323-330.

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3DOPTIMISING ADALIMUMAB

TREATMENT IN PSORIASIS WITH CONCOMITANT METHOTREXATE

(OPTIMAP): STUDY PROTOCOL OF A PRAGMATIC, SINGLE-

BLINDED, INVESTIGATOR-INITIATED RANDOMIZED

CONTROLLED TRIAL

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abSTRaCT

BACKGROUND: The introduction of anti-TNFs has revolutionized the treatment of psoriasis with achievement of treatment goals (PASI 75, remission) that are not usually met with conventional systemics. Nevertheless, some patients continue to experience persistent disease activity or treatment failure over time. Strategies to optimize treatment outcomes include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory disease such as rheumatoid arthritis. METHODS: This study is an investigator-initiated, multi-center randomized controlled trial (RCT) designed to compare combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. Primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened. In our experience the main limitation for recruitment is prior adalimumab therapy and intolerability and / or toxicity of methotrexate in the past. DISCUSSION: OPTIMAP is the first RCT to examine combination therapy with adalimumab and methotrexate in a psoriasis population. With data derived from this study we expect to provide valuable data on long-term treatment outcomes. These data will be supported by assessment of the impact of concomitant methotrexate on adalimumab pharmacokinetics. Furthermore, the influence of several single nucleotide polymorphisms on adalimumab response will be analysed in order to support the development of a more personalized approach for this targeted therapy. TRIAL REGISTRATION: NTR4499. Date of registration 7 April 2014.

C.I.M. Busard, S.P. Menting, J.S. van Bezooijen, J.M. van den Reek, B.A. Hutten, E.P. Prens, E.M.G.J. de Jong, M.B. van Doorn, Ph.I. Spuls

Submitted

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baCkGROund

Adalimumab has shown to be highly valued by psoriasis patients due to profound improvements on disease severity and a favorable safety profile.(1, 2) Although its introduction (together with other anti-TNFs) has majorly advanced psoriasis care, some patients experience persistent disease activity (primary non-responders), treatment failure over time (secondary non-responders) or side effects.(3-5) Several factors have been identified to play a role in primary and secondary non-response to anti-TNFs, including interindividual variation in serum drug concentrations. This can partly partially be explained by due to variation in disease activity, however, it is suggested that single nucleotide polymorphisms (SNPs) affecting drug metabolization substantially contribute.(6, 7)

Another important factor associated with primary and secondary non-response to adalimumab includes the formation of anti-drug antibodies (immunogenicity). Multiple studies observed an association between the formation of anti-adalimumab antibodies, reduced serum levels and diminished clinical response (3, 8-11). When anti-drug antibodies are formed in patients treated with an anti-TNF, clearance of the biologic can, to a certain extent, be accelerated depending on the concentration of the anti-drug antibodies.(12) Moreover, antidrug antibodies can be functionally neutralizing, thereby directly affecting treatment efficacy.(13) Concomitant use of methotrexate (MTX) has demonstrated to decrease immunogenicity and significantly reduce clearance of adalimumab in patients with other inflammatory diseases, resulting in higher systemic exposure and enhanced clinical efficacy. (9, 14, 15)

In addition, combination therapy may enable dose reductions of individual agents, thereby decreasing toxicity and improving tolerability and compliance.(16) Moreover, by targeting unregulated increased cytokine levels associated with inflammatory comorbid conditions, it is hypothesized that combination therapy may also provide a broader benefit to the patient by reducing the risk of, for example, cardiovascular events.(17)

Based on currently available data, no profound differences in safety profiles have been demonstrated for combination therapy compared to monotherapy, (18) although a recent paper demonstrated an increased risk for tuberculosis reactivation when anti-TNFs are combined with immunosuppressive agents.(19) As the disposition of adalimumab and MTX do not compete for elimination pathways, direct pharmacokinetic drug-drug interactions between adalimumab and MTX are not expected.(12) However, both agents may suppress the immune system; thus combination therapy may theoretically convey an increased risk for serious infections and malignancies. .

Combination therapy with biologic agents has been widely used in the treatment of rheumatoid arthritis and psoriatic arthritis, but only a few small-scale,

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randomized, controlled trials have been undertaken in psoriasis.(16) Evidence exists for the superior efficacy of etanercept with methotrexate compared to etanercept monotherapy.(20, 21) As these beneficial effects will be mainly based on additive benefits (combined pharmacological activities) rather than synergistic benefits (increased systemic exposure due to decreased immunogenicity and decreased clearance), treatment outcomes might even improve when adalimumab is being combined with methotrexate. However, randomized controlled trial (RCT) data are lacking.(22)

To support the development of effective treatment strategies to address unmet medical needs, long-term RCT data on the use of anti-TNFs in combination with MTX in psoriasis populations are needed.(24;26;27) Additionally, in order to support personalized medicine with the development of biomarkers to predict response in individual psoriasis patients, it will be valuable to detect genetic factors associated with response and non-response to anti-TNF therapy.

Aims & objectives• To gain long-term RCT data on the efficacy and safety of adalimumab combined

with MTX compared to adalimumab monotherapy • To assess the impact of concomitant MTX on adalimumab immunogenicity and

serum concentrations • To test appropriate candidate genes and correlate genotypes with trial

outcomes

METhOdS

The trial was granted ethics approval by the Academic Medical Center research ethics committee (METC 2013_346). All participants will sign informed consent before participation. The study is being conducted according to the principles of the Declaration of Helsinki and in accordance with the Medical Research Involving Human Subjects Act (WMO) and other relevant guidelines, regulations and acts.

Participants Patients will be recruited from the outpatient clinics of the Departments of Dermatology of the Academic Medical Center (AMC) Amsterdam, Erasmus University Medical Center (EMC) Rotterdam and the Radboud university medical center (RUMC) Nijmegen. Moreover, other dermatologists will be contacted to recruit and refer eligible patients to the participating centers. Participants must meet inclusion criteria (Table 1) in order to participate. These will be assessed at the screening visit. Potential participants who are deemed ineligible at screening will be allowed a second screening visit if the reason for ineligibility is a temporary status (e.g. latent tuberculosis).

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3DInterventionsAll patients receive adalimumab 40 mg subcutaneously every other week starting one week after a loading dose of 80 mg and will be randomized 1:1 to receive either oral MTX 10 mg weekly (combination group) or no addition of MTX (monotherapy group). MTX therapy will be initiated two weeks prior to baseline and administration will be followed by folic acid 5 mg 24 hours after MTX intake (see flowchart; Figure 1).

In case of MTX toxicity (e.g. liver toxicity or leukopenia) or intolerability, titration can be paused (for a maximum of two weeks up to four times during the entire study) or the dose can be adjusted to 7.5 mg. Moreover, patients are allowed to switch from oral to subcutaneous administration. In case of adalimumab toxicity or intolerability, titration can be paused (for a maximum of 2 weeks up to 4 times during each study year).

Throughout the study, no systemic anti-psoriatic drugs are allowed for treatment other than study medication (Table 2/ Table 3). If medically necessary, (i.e. to control intolerable psoriasis activity), rescue treatment with topical corticosteroids, vitamin D derivates (calcipotriol/betamethasone or calcitriol) or calcineurin inhibitors may be provided to study patients at the discretion of the investigator after baseline and through week 145 (end of study).

Randomization and blinding Consecutive patients will be prospectively enrolled and randomly assigned if eligible to either the intervention (adalimumab with MTX) or control (adalimumab monotherapy) group after obtaining informed consent. Each consecutive patient will be assigned a randomization number according to a computer-generated randomization list (ALEA) using random block sizes of 2, 4, 6, and 8 to ensure allocation concealment. Randomization is stratified for TNFα-blocker exposure status to achieve balance with regard to prior TNFα-blocker exposure in the study population.

Table 1. Eligibility criteria

Inclusion Exclusion

• ≥18 years• Diagnosis of moderate to

severe plaque psoriasis (PASI ≥8)

• Adalimumab naïve • Candidate for biologic

therapy • Willing and able to use

adequate contraceptives during the study

• History of significant MTX toxicity, intolerability or contraindication• Known liver or kidney malfunction• Alcohol abuse• Bone marrow hypoplasia, leukocytopenia, thrombocytopenia or

significant anaemia• Known severe or chronic infections like tuberculosis or HIV• Ulcers in the oral cavity or known active ulcers in digestive tract• Pregnant or nursing women• Need for live vaccinations• Use of other immunosuppressive medication (e.g. prednisone,

mycophenolatemofetyl (Cellcept), ciclosporine (Neoral), sirolimus (Rapamune), systemic tacrolimus (Prograft))

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Figure 1. Optimizing adalimumab treatment in plaque psoriasis with concomitant methotrexate; (‘OPTIMAP’) study flow diagram.

figure 1. Optimizing adalimumab treatment in plaque psoriasis with concomitant methotrexate; (‘OPTIMaP’) study flow diagram.

Table 2. Wash out-periods

Therapy Wash-out period

Topical therapy 2 weeks

Phototherapy 2 weeks

Conventional systemic therapy / etanercept 4 weeks

Infliximab/ ustekinumab 6 weeks

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This is an observer-blinded study. The observer (outcome assessor) will perform clinical outcome assessments of disease severity (PASI and investigator global assessment (IGA)) at each study visit. Both clinician and participant know their treatment allocation, as such no special measures are required to allow for breaking of treatment codes. However, treatment allocation will not be revealed to the recruiting physician until participants’ details and key stratification variables have been irrevocably entered onto the web-based randomization site.

Endpoints Primary outcomes: • Adalimumab drug survival at week 49Secondary outcomes: • Adalimumab drug survival at week 145 • Proportion of patients that reach treatment goals* at week 13, week 25, week

49 and week 145 • Proportion of patients achieving PASI 75 at weeks 49 and 145• Proportion of patients achieving IGA clear or almost clear at weeks 49 and 145• Mean improvement in PASI at weeks 49 and 145• Proportion of patients with PGA clear or almost clear at weeks 49 and 145 • Mean improvement in DLQI and Skindex at weeks 49 and 145 • Proportion of patients with (serious) adverse events at weeks 49 and 145• Proportion of patients with changes in laboratory assessments at weeks 49

and 145• Proportion of patients with antibody formation at weeks 49 and 145• Median adalimumab trough concentrations (mg/L) at week 49 and 145 • Correlation between genetic polymorphisms and adalimumab response *Treatment goals will be achieved if patients reach PASI ≥75 or PASI ≥ 50 in combination with DLQI≤5. Treatment goals will not be achieved in case PASI<50 or PASI ≥50<75 in combination with DLQI≥5. (23)

Procedures and Assessments Patients will visit the outpatient clinic at screening, baseline, week 5, week 13 and every 12 weeks thereafter until study completion (weeks 25, 37, 49, 61, 73, 85, 97, 109, 121, 133 145) (Figure 1).

Table 3. Allowed escape medication

Scalp/palms/soles Low or high potency corticosteroids, calcitriol/ calcipotriol or a combination

Face and body Low potency corticosteroids, calcitriol/ calcipotriol or topical tacrolimus 0.1% or 0.03%

Psoriasis inverse component

Topical tacrolimus 0.1% or 0.03%

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A variety of parameters will be collected during each visit to assess efficacy, including physician (PASI/ IGA (static; scale 0-4 (24)) and patient reported (patient reported global assessment (PGA static; scale 0-4)) outcomes. Quality of life assessment will be performed using Skindex and DLQI questionnaires. Safety will be assessed by evaluating the incidence of (serious) adverse events, obtaining a detailed medical history, thorough physical examination, vital signs, clinical laboratory testing and urinalysis (including pregnancy tests females of childbearing potential at screening). Concomitant medication and medical procedures will be collected from obtainment of informed consent up to end of study. Patients will receive a diary in which they will register the administration dates of adalimumab (and MTX in the intervention group), any changes in their health status and/or changes in concomitant medication used. The local investigator reviews the diary to determine drug adherence and the incidence and type of adverse events. An independent Data Safety Monitoring Board (DSMB) has been established to review efficacy and safety data periodically in an unblinded fashion.

Laboratory testingBlood samples will be collected at each visit to monitor drug safety, to determine immunogenicity against adalimumab and to measure adalimumab serum through levels. Additionally, a single blood sample will be collected at screening from which DNA will be collected and stored at -80 Celsius. In psoriasis, several associations between single nucleotide polymorphisms (e.g. TNFR1B, TNFAIP3, IL12B/IL23R) and response to anti-TNFα drugs have been suggested.(6, 25) However, results have not been specified for different anti-TNFα drugs. In rheumatoid arthritis (RA) and crohn’s disease (CD), potential polymorphisms (e.g. FcGR and ATG16L1) as a predictor for adalimumab efficacy have been identified.(26, 27) RA and CD share pathogenic mechanisms with psoriasis, and a genetic association between RA or CD and psoriasis has been suggested.(6) Therefore, it would be valuable to test potential SNPs that have been associated with response to adalimumab treatment in patients with RA or CD. As scientific interest in this field is currently increasing, DNA analysis will be performed based upon accumulating data acquired from (ongoing) pharmacokinetic studies.

Justification of sample size A total of 84 patients (randomised 1:1 to concomitant MTX or no MTX) will give the study at least 80% power at a 0.05 two-sided significance level using a two-sample Chi-square test to detect a difference of 28% in drug survival at week 49. We aim to enroll 93 patients to allow for an approximate 10% loss to follow-up. These calculations were performed using Nquery 6.0.2. The expected clinically relevant difference in drug survival between both treatment groups was

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hypothesized based on studies performed in rheumatoid arthritis patients due to the lack of data in a psoriasis population. The prevalence of (clinically relevant) anti-drug antibody formation is estimated to be 45% in patients on adalimumab monotherapy (a similar percentage is found in psoriasis patients (28)) and around 17% in patients on adalimumab with low dose (5-10mg) MTX after 49 weeks.(29) A clear correlation between antibody formation and treatment failure (with subsequent treatment discontinuation) in patients on adalimumab has been demonstrated.(28) Based on these data, drug survival is estimated to be 83% (100 minus 17) for the experimental group and 55% (100 minus 45) for the control group after 49 weeks of follow up.

Statistical analysis The primary analysis will be conducted on the intention-to-treat population, including all randomized participants in the groups to which they were randomized. A per protocol population (excluding major protocol violations) will be used to check the robustness of the primary analyses. The safety population will consist of all patients receiving at least one dose of the study drug.

Adverse events will be coded according to the Med-DRA adverse event dictionary. The overall incidence of serious adverse events and adverse events and number and proportion of patients reporting such events will be summarized by treatment group.

Differences in dichotomous outcomes among the two study groups will be analyzed using the chi-square test or Fisher’s exact test when the expected cell frequencies fell below five. We will express differences in drug survival as absolute differences and relative risks, with associated 95% confidence intervals, with the group on adalimumab monotherapy as the reference. One-way analysis-of-variance statistics will be calculated to compare continuous outcome measures.

There are no formal planned interim analyses, but progress reports on all data issues are presented to the Data Safety Monitoring Board (DSMB).

Trial status Patient recruitment started in March 2014 and is currently ongoing. Based on our experience so far, recruitment is limited by two main factors; prior use of adalimumab and intolerability or toxicity for MTX in the past.

Moreover, disease activity in patients that are transitioned from another biologic is often suppressed (< PASI 8). To enlarge the geographical area in which patients can participate to the study and to enhance patient recruitment three additional hospitals have been activated for patient recruitment (Amphia Hospital, Breda, The Netherlands and Ghent University Hospital, Ghent, Belgium, Derma Team Clinic, Bergen op Zoom, the Netherlands).

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dISCuSSIOn

Although combination treatment with anti-TNFs and methotrexate are being prescribed in clinical practice, currently available evidence and guidance on the use of combination treatment is limited. No consensus about certain treatment aspect such as MTX dosing and timing of initiation of MTX (prior to anti-TNF or during anti-TNF therapy) exists. Therefore, we would like to emphasize on the choice of dosing and initiation of comedication for the current RCT.

Initiation of MTX prior to adalimumab therapy Concomitant use of MTX has demonstrated to significantly reduce the clearance of adalimumab, resulting in higher adalimumab trough levels in patients with RA. (30, 31) However, it takes time for MTX to exert a full effect on the pharmacokinetics of adalimumab.(31) The slow onset of drug action of MTX can be attributed to an intracellular accumulation process.(32, 33) After MTX uptake into cells, it is converted to MTX-polyglutamates, active metabolites which are believed to exert the anti-inflammatory actions of MTX. The current product label for adalimumab indicates that methotrexate decreases the apparent clearance of adalimumab after single and multiple doses by 29% and 44%, respectively.(31) In order to ensure maximal potential for MTX to exert a beneficial effect on adalimumab pharmacokinetics from the start on, MTX therapy is initiated two weeks before administration of adalimumab (at baseline) in the experimental treatment group.

Choice of MTX dosing The dose of MTX as monotherapy can range from 7.5 to 25 mg/week, depending on national guidelines and patient / physician’s preference. A systematic literature review of MTX monotherapy has recommended initial treatment with 10–15 mg orally with dose increases to 20mg/week if needed and tolerated.(34) Available evidence suggests that MTX toxicity is dose-dependent and low dose MTX monotherapy treatment can be effective. However, no RCTs have explored the minimally effective dose of MTX in a group of patients when used in combination with an TNFα inhibitor. This dose may differ from minimally effective monotherapy doses.

In a prospective cohort study (n=272) in RA patients a substantial decrease in immunogenicity against adalimumab was demonstrated with low-dose MTX (5-10mg/week).(35) In the treatment of psoriasis, methotrexate 10 mg per week is an accepted dose for treating psoriasis according to (inter)national guidelines.32 In order to avoid an increased risk of side effects like hepatotoxicity and subsequent early study termination a dosage of 10 mg MTX/week is chosen over a higher dose.

Over the last years new data on the pharmacokinetic impact of concomitant MTX in adalimumab therapy have emerged (mostly based on RA patients) and support our strategy.

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A large RCT in 395 patients with rheumatoid arthritis indicates a (non-significant) increase in adalimumab serum concentrations with higher doses of MTX (10-20mg) compared to low-dose MTX (2.5-5mg). However, a dose of 5mg of concomittant MTX seems already sufficient to maintain serum concentrations within the therapeutic range.

Although these data are helpful to guide the use of anti-TNF in combination with MTX, data on psoriasis populations are needed as patient characteristics and outcomes may differ (e.g. comorbidities, previous treatment regimens).

With this RCT we aim to improve the body of evidence for combination treatment in psoriasis and to optimize currently available treatment strategies. Moreover, with the analysis of pharmacogenetic data, we hope to support personalized medicine and more accurate prediction of treatment response.

Trial statusThis RTC is ongoing.

REfEREnCES

1. Saurat JH, Stingl G, Dubertret L, Papp K, Langley RG, Ortonne JP, et al. Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br J Dermatol. 2008;158(3):558-66.

2. van den Reek JM, van Luumig PP, Otero ME, Zweegers J, van de Kerkhof PC, Ossenkoppele PM, et al. Satisfaction of treatment with biologics is high in psoriasis: results from the Bio-CAPTURE network. The British journal of dermatology. 2014;170(5):1158-65.

3. Menting SP, van Lumig PP, de Vries AC, van den Reek JM, van der Kleij D, de Jong EM, et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up. JAMA dermatology. 2014;150(2):130-6.

4. Warren RB, Smith CH, Yiu ZZ, Ashcroft DM, Barker JN, Burden AD, et al. Differential Drug Survival of Biologic Therapies for the Treatment of Psoriasis: A Prospective Observational Cohort Study from the British Association of

Dermatologists Biologic Interventions Register (BADBIR). J Invest Dermatol. 2015;135(11):2632-40.

5. Bito T, Nishikawa R, Hatakeyama M, Kikusawa A, Kanki H, Nagai H, et al. Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis. Br J Dermatol. 2014;170(4):922-9.

6. Prieto-Perez R, Cabaleiro T, Dauden E, Abad-Santos F. Gene polymorphisms that can predict response to anti-TNF therapy in patients with psoriasis and related autoimmune diseases. Pharmacogenomics J. 2013;13(4):297-305.

7. Coto-Segura P, Batalla A, Gonzalez-Fernandez D, Gomez J, Santos-Juanes J, Queiro R, et al. CDKAL1 gene variants affect the anti-TNF response among Psoriasis patients. Int Immunopharmacol. 2015;29(2):947-9.

8. Ba r te ld s GM, K r ieckae r t CL , Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity

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and treatment failure during long-term follow-up. Jama. 2011;305(14):1460-8.

9. Bar te lds GM, Wi jb randt s CA , Nurmohamed MT, Stapel S, Lems WF, Aarden L, et al. Clinical response to adalimumab: relationship to anti-adalimumab antibodies and serum ada l imumab concent r a t ions in rheumatoid arthritis. Ann Rheum Dis. 2007;66(7):921-6.

10. Radstake TR, Svenson M, Eijsbouts AM, van den Hoogen FH, Enevold C, van Riel PL, et al. Formation of antibodies against infliximab and adalimumab strongly correlates with functional drug levels and clinical responses in rheumatoid arthritis. Ann Rheum Dis. 2009;68(11):1739-45.

11. West RL, Zelinkova Z, Wolbink GJ, Kuipers EJ, Stokkers PC, van der Woude CJ. Immunogenicity negatively influences the outcome of adalimumab treatment in Crohn’s disease. Aliment Pharmacol Ther. 2008;28(9):1122-6.

12. Xu Z, Davis HM, Zhou H. Clinical impact of concomitant immunomodulators on biologic therapy: Pharmacokinetics, immunogenicity, efficacy and safety. J Clin Pharmacol. 2015;55 Suppl 3:S60-74.

13. van Schouwenburg PA, van de Stadt LA, de Jong RN, van Buren EE, Kruithof S, de Groot E, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. Ann Rheum Dis. 2013;72(1):104-9.

14. Pouw MF, Krieckaert CL, Nurmohamed MT, van der Kleij D, Aarden L, Rispens T, et al. Key findings towards optimising adalimumab treatment: the concentration-effect curve. Annals of the rheumatic diseases. 2015;74(3):513-8.

15. Kuriya B, Arkema EV, Bykerk VP, Keystone EC. Efficacy of initial methotrexate monotherapy versus combination therapy with a biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission. Ann Rheum Dis. 2010;69(7):1298-304.

16. Busard C, Zweegers J, Limpens J, Langendam M, Spuls PI. Combined use of systemic agents for psoriasis: a systematic review. JAMA Dermatol. 2014;150(11):1213-20.

17. Hugh J, Van Voorhees AS, Nijhawan RI, Bagel J, Lebwohl M, Blauvelt A, et al. From the Medical Board of the National Psoriasis Foundation: The risk of cardiovascular disease in individuals with psoriasis and the potential impact of current therapies. J Am Acad Dermatol. 2014;70(1):168-77.

18. Weisman MH, Moreland LW, Furst DE, Weinblatt ME, Keystone EC, Paulus HE, et al. Efficacy, pharmacokinetic, and safety assessment of adalimumab, a fully human anti-tumor necrosis factor-alpha monoclonal antibody, in adults with rheumatoid ar thritis receiving concomitant methotrexate: a pilot study. Clin Ther. 2003;25(6):1700-21.

19. Lorenzetti R, Zullo A, Ridola L, Diamanti AP, Lagana B, Gatta L, et al. Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a sys tematic review of randomized controlled trials. Ann Med. 2014;46(7):547-54.

20. Gottlieb AB, Langley RG, Strober BE, Papp KA, Klekotka P, Creamer K, et al. A randomized, double-blind, placebo-controlled study to evaluate the addition of methotrexate to etanercept in patients with moderate to severe plaque psoriasis. Br J Dermatol. 2012;167(3):649-57.

21. Zachariae C, Mork NJ, Reunala T, Lorentzen H, Falk E, Karvonen SL, et al. The combination of etanercept and methotrexate increases the effectiveness of treatment in active psoriasis despite inadequate ef fect of methotrexate therapy. Ac ta Derm Venereol. 2008;88(5):495-501.

22. van Bezooijen JS, Prens EP, Pradeepti MS, Atiqi R, Schreurs MW, Koch BC, et al. Combining biologics with methotrexate in psoriasis: a systematic review. Br J Dermatol. 2015;172(6):1676-80.

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23. Mrowietz U, Kragballe K, Reich K, Spuls P, Griffiths CE, Nast A, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. Arch Dermatol Res. 2011;303(1):1-10.

24. Langley RG, Feldman SR, Nyirady J, van de Kerkhof P, Papavassilis C. The 5-point Investigator’s Global Assessment (IGA) Scale: A modified tool for evaluating plaque psoriasis severity in clinical trials. J Dermatolog Treat. 2015;26(1):23-31.

25. Gallo E, Cabaleiro T, Roman M, Solano-Lopez G, Abad-Santos F, Garcia-Diez A, et al. The relationship between tumour necrosis factor (TNF)-alpha promoter and IL12B/IL-23R genes polymorphisms and the efficacy of anti-TNF-alpha therapy in psoriasis: a case-control study. Br J Dermatol. 2013;169(4):819-29.

26. Koder S, Repnik K, Ferkolj I, Pernat C, Skok P, Weersma RK, et al. Genetic polymorphism in ATG16L1 gene influences the response to adalimumab in Crohn’s disease patients. Pharmacogenomics. 2015;16(3):191-204.

27. Davila-Fajardo CL, van der Straaten T, Baak-Pablo R, Medarde Caballero C, Cabeza Barrera J, Huizinga TW, et al. FcGR genetic polymorphisms and the response to adalimumab in patients with rheumatoid arthritis. Pharmacogenomics. 2015;16(4):373-81.

28. Menting SP, van den Reek JM, Baerveldt EM, de Jong EM, Prens EP, Lecluse LL, et al. The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting. Br J Dermatol. 2015;173(3):855-7.

29. Jamnitski A, Krieckaert CL, Nurmohamed MT, Hart MH, Dijkmans BA, Aarden L, et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Annals of the rheumatic diseases. 2012;71(1):88-91.

30. Maini RN, Breedveld FC, Kalden JR, Smolen JS, Davis D, Macfarlane JD, et al. Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis Rheum. 1998;41(9):1552-63.

31. AbbVie Inc. Humira US Prescribing Information 2013 [Available from: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/125057s327lbl.pdf.

32. Nielsen OH, Bjerrum JT, Her far th H, Rogler G. Recent advances using immunomodulators for inflammatory bowel disease. J Clin Pharmacol. 2013;53(6):575-88.

33. Shen DD, Azarnof f DL. Clinical pharmacokinetics of methotrexate. Clin Pharmacokinet. 1978;3(1):1-13.

34. Menting SP, Dekker PM, Limpens J, Hooft L, Spuls PI. Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation. Acta Derm Venereol. 2015.


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3ETHE CORRELATION OF

CLINICAL EFFICACY, SERUM TROUGH LEVELS AND

ANTIDRUG-ANTIBODIES IN USTEKINUMAB TREATED

PSORIASIS PATIENTS IN A CLINICAL PRACTICE SETTING

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abSTRaCT

INTRODUCTION: Ustekinumab is a valuable treatment for plaque type psoriasis and psoriatic arthritis. The purpose of this study is to investigate whether a correlation can be found between clinical efficacy of ustekinumab, ustekinumab trough levels and ADA formation in a clinical practise setting. MATERIALS AND METHOD: Ustekinumab trough levels (by a newly developed ELISA) and antidrug-antibodies (ADA) to ustekinumab (by a newly developed antigen binding test) were measured. The correlation between these factors and the extent of clinical response (measured by Psoriasis Area and Severity Index (PASI)) was investigated in ustekinumab treated psoriasis patients in a daily-practice cohort. RESULTS: At week 16, 27% of 41 patients were good responders. Median ustekinumab trough concentration was 0.41 and 0.42 mg/L at week 16 and 28 and at these time-points, no correlation was found between trough concentration of non- , moderate and good responders (correlation coefficients respectively-0.36/0.022). Amongst patients >100 kg, those treated with 90 mg ustekinumab (n=10) per administration did not attain significantly higher trough levels or greater improvement of median ΔPASI compared to patients receiving 45 mg (n=5). Seven percent (n=3) of patients formed ADA.CONCLUSION: No correlation was found between the extent of clinical response and ustekinumab trough levels. No correlation found, does not mean no such correlation exists; patients might be relatively overexposed to ustekinumab, trough levels may not be an adequate indicator of optimal ustekinumab concentrations or a correlation might be found with a larger sample-size. ADA were found in 7% of patients, due to small numbers, no clinical consequence could be established.

S.P. Menting, J.M.P.A. van den Reek*, E.M. Baerveldt*, E.M.G.J. de Jong, E.P. Prens, L.L.A. Lecluse, G.J. Wolbink, D. van der Kleij, Ph.I. Spuls, T. Rispens

* both authors have contributed equally to this work

Published as letter, Br J Dermatol. 2015 Sep;173(3):855-7.

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InTROduCTIOn

Several therapeutic antibodies are available for the treatment of plaque type psoriasis (further mentioned as psoriasis). Ustekinumab (a monoclonal IL12/23 antagonist) is one of these antibodies. Since 5 years, follow-up data from clinical trials is available and ustekinumab has proven its (long-term) efficacy and safety for the treatment of psoriasis 1,2. The European Medicines Agency (EMA) and the Food and Drug Administration (FDA) have approved ustekinumab for the treatment of psoriasis in 2008 and for the treatment of psoriatic arthritis in 2013. It is currently being investigated for other indications including Crohn’s disease 3.

For adalimumab (a monoclonal tumour necrosis factor α antagonist) a positive correlation is observed between adalimumab trough levels and clinical efficacy 4. In rheumatoid arthritis, a therapeutic range for adalimumab trough level has been established, which can eventually lead to a more personalised way of administering adalimumab 5. The presence of anti-drug antibodies (ADA) negatively impacts trough level 4,6. ADA to adalimumab were reported in 7-49% of cases 4,7 and have been shown to be functionally neutralising 8.

For etanercept (a recombinant tumour necrosis factor α antagonist), it has been shown in rheumatoid arthritis, that patients classified as nonresponders obtain lower trough concentrations 9 and for psoriasis, ADA were reported in 0-18% of cases though they were never shown to be neutralising or of clinical importance 7.

For infliximab (a monoclonal tumour necrosis factor α antagonist) ADA show to negatively impact trough levels. ADA to infliximab were reported in 5-44% of cases 7.

For ustekinumab, the correlation between clinical efficacy, trough level and the presence of ADA is largely unknown.

As illustrated above, for adalimumab, etanercept and infliximab, the frequency of ADA found vary considerably. This might be due to incorrect sampling (sampling should take place at trough level, because presence of the drug interferes with ADA detection) or because of the use of different detection methods 10. For example, one study showed the antigen binding test, which is a radioimmunoassay, to be less susceptible to drug interference compared to the (bridging) enzyme-linked immunosorbent assay (ELISA) 10. For ustekinumab only a bridging ELISA has been used so far 11-13 (in two studies the method used for detecting ADA was not mentioned 1,14) and ADA have been reported in 4-6% 7 of cases and were found to negatively impact efficacy 14. In these studies, populations from randomised controlled trials were used. Due to restricted inclusion criteria, these populations differ from patients in daily practice.

The purpose of this explorative study is to take a first step towards the personalised treatment of psoriasis with ustekinumab by investigating whether a correlation can be found between clinical efficacy of ustekinumab, ustekinumab trough levels (by a newly developed ELISA) and ADA formation (by a newly developed antigen binding test) in a clinical practise setting.

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MaTERIalS & METhOd

CohortMethods and study design are similar to a previously reported prospective cohort of adalimumab patients 4 and are briefly repeated below. All consecutive patients in whom treatment with ustekinumab for psoriasis was started, at the Academic Medical Center (Amsterdam), the Radboud University Nijmegen Medical Centre (Nijmegen) and the Erasmus University Medical Center (Rotterdam) (all in the Netherlands), between May 3, 2010, and January 15, 2014 were approached for this prospective observational cohort study. The study was approved by the ethical committee of the participating hospitals and conducted according to Declaration of Helsinki principles. Patients gave written informed consent. Baseline characteristics (including previous systemic treatments) were collected. Patients were treated with ustekinumab according to the manufacturers’ recommendations and according to daily practice, with an initial dose of 45 mg subcutaneously followed by 45 mg subcutaneously every 12 weeks, starting 4 weeks after the initial dose. The injection was administered in the hospital. According to manufacturers’ recommendations, if a patient weight >100 kg, double dose could be considered. Concomitant antipsoriatic systemic therapy (methotrexate) was allowed. In patients with inadequate response to ustekinumab, concomitant methotrexate could be started.

Treatment could be discontinued in case of nonresponse or adverse events. The reason for termination of treatment was registered. The treating dermatologist was unaware of the trough level and antibody status of the patient. Disease severity was assessed by the treating physician at baseline and at weeks 16, 28, and 52 using the Psoriasis Area and Severity Index (PASI). In some patients an extra visit at week 4 was performed. If baseline PASI was missing, this was replaced by a PASI measured in the 3 months prior to starting ustekinumab treatment. Clinical response was measured as the percentage of change compared to baseline PASI. Nonresponders were defined as patients achieving less than 50% improvement compared to baseline PASI, moderate responders as those achieving 50% to less than 75% improvement, and good responders as those achieving at least 75% improvement 15. Blood samples were obtained before initiation of ustekinumab treatment and at weeks 16, 28, and 52 (just before administration of ustekinumumab, trough levels) and at the early termination visit.

Measurement of ustekinumab trough levels and ADA to ustekinumabTo measure ustekinumab levels an immunoassay was set up analogously to an assay for measuring adalimumab 16, using the target (IL-12) to capture ustekinumab, and rabbit anti-ustekinumab for detection. Maxisorp ELISA plates

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were coated overnight at room temperature with 0.5 μg/ml mouse anti-IL-12 (Diaclone, Besancon Cedex, France) in PBS. Plates were washed five times with PBS/ 0.02% Tween (PT), followed by incubation for 1 h at RT with recombinant human IL-12 (10 ng/ml) (R&D systems, Minneapolis, USA) diluted in high performance ELISA buffer (HPE, Sanquin, Amsterdam, the Netherlands). Next, the plates were washed and incubated for 1 h with patient serum which was serially diluted in HPE. After washing 5 times with PT, plates were incubated for 1 h with biotinylated ustekinumab specific rabbit anti-idiotype (25 ng/ml in HPE). The rabbit anti-ustekinumab antibodies were produced analogously as described for natalizumab 17. After washing, streptavidin-poly-HRP (Sanquin) (1:10,000, in HPE) was added for 1 h at 37 °C. After washing the ELISA was developed with 100 μg/ml tetramethylbenzidine in 0.11 M sodium acetate (pH 5.5) containing 0.003% (v/v) H2O2. The reaction was stopped with 2 M H2SO4. Absorption was measured at 450 nm related to a titration curve of ustekinumab in each plate. The limit of quantitation of this assay was 0.02 mg/L.

Measurement of anti-ustekinumab antibodies was essentially carried out as described before 18,19. One microliter of serum diluted in Freeze buffer (Sanquin) 19 was incubated overnight with 1 mg Protein A Sepharose (GE healthcare, Chalfont St. Giles, UK) and 2.5 ng biotinylated F(ab’)2 ustekinumab in a final volume of 800 μl. Subsequently the samples were washed with PBS 0.005%Tween and ca. 1 ng 125I-labeled streptavidin was added in 800 ul final volume of PBS-AT (PBS / 0.01M EDTA / 0.3% Bovine Serum Albumin / 0.004% Tween-20 / 0.05% NaN3) and incubated overnight. Unbound label was removed by washing, and Sepharose-bound radioactivity was measured. Antibody levels were compared to a standard serum containing ADA and expressed in arbitrary units (AU). The lower limit of detection of 12AU/ml was based on mean + 3 SD measured in a panel of 50 sera from healthy donors and 15 sera containing anti-CCP, ANA, and/or RF. Concentrations between 12 and 100 AU/mL were considered low ADA titers and those above 100AU/mL were considered high ADA titers. If no detectable ADA were present (≤12AU/mL) this result was categorized as “no ADA”.

Statictical analysesThe Mann-Whitney U test and Kruskal Wallis test were used to calculate statistical differences between the groups. The Spearman rank test was used to calculate the correlation coefficients between clinical response and ustekinumab trough level. For missing ustekinumab levels and missing antibody titers, the last observation carried forward method was used. As this is an ongoing cohort, only patients who reached at least week 16 (or patients who were discontinued within 52 weeks of treatment) were included for analyses. SPSS version 20 was used for statistical analysis.

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RESulTS

The analyzed cohort included 41 patients, 27 male and 14 female, with a mean age of 47 years. The mean body mass index was 28.8, and 27% of patients had a diagnosis of psoriatic arthritis. The mean disease duration of psoriasis was 25 years, and the mean PASI at baseline was 14. One patient had a low baseline PASI (1.8) on the maximum dose of fumaric acid esters. The patient wanted to switch back to a biologic due to a previous more optimal experience with biologic treatment. In two patients, baseline PASI was missing. At baseline, 73% of patients had a PASI of at least 8.0 and 78% had used at least 4 previous systemic treatments for psoriasis; the most frequently used previous treatments were methotrexate and UV-B (both in 90% of patients). Ten percent of patients (n=4) had been previously treated with ustekinumab and treatment was terminated because it was received through a randomized clinical trial (RCT). Ten percent of patients (n=4) had not been treated with a biologic previously. See Table 1 for patient characteristics.

Table 1. Patient characteristics

Characteristics Total (n=41)

Mean age y (SD) 47 (11)

Male sex no (%) 27 (66)

Mean disease duration y (SD) 25 (13)

Mean PASI baseline (SD) 14(9)

BMI (SD) 29 (5)

PsA no (%) 11 (27)

Concomitant MTX from week 0 no (%) 1 (2)

Previous systemic therapies no (%)

Methotrexate 37 (90)

Cyclosporine 28 (68)

Fumaric acid 21 (51)

UVB 37 (90)

PUVA 24 (59)

Etanercept 27 (66)

Infliximab 7 (17)

Efalizumab 5 (12)

Adalimumab 23 (56)

Ustekinumab 4 (10)

Mean no of previous treatments (SD) 5 (2)

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Clinical responseFifteen patients were followed until week 52, 2 until week 36, 8 until week 28, 15 until week 16 and one until week 4 (mean follow-up time 32 weeks). At week 16, 31.7% (n=13) of patients were nonresponder (of whom in one patient treatment was early terminated due to nonresponse), 29.3% (n=12) were moderate responders (of whom in one patient treatment was early terminated due to elective surgery) and 26.8% (n=11) were good responders. One patient was early terminated at week 4 due to an adverse event (2.4%). Four patients (9.8%) had a missing visit. At week 28, 26.8 % (n=11) of patients were nonresponders, 12.2% (n=5) were moderate responders and 19.5% (n=8) were good responders. One patient had a missing visit (3.6%) and 3 had been early terminated previously as mentioned before (10.7%). Thirteen of 41 patients had not reached week 28 yet. At week 52, 23.8% (n=5) of patients were nonresponders, 14.3% (n=3) were moderate responders and 33.3% (n=7) were good responders. In total, 6 patients had been early terminated, of whom three are mentioned previously. The other three had been early terminated at week 28 (n=1) and week 36 (n=2), all due to nonresponse. Twenty patients had not reached week 52 yet.

Clinical response and ustekinumab trough levelsAt week 16 (n=36), median ustekinumab trough concentration was 0.41 mg/L (<0.02 to 2.08 mg/L). No significant difference was found between ustekinumab trough levels for nonresponders, moderate responders and good responders (median (range) 0.40 mg/L (<0.02 to 2.00 mg/L), 0.53 mg/L (<0.02 to 1.00 mg/L) and 0.36 mg/L (0.10 to 2.08 mg/L) respectively (Figure 1) (p=0.89). The Spearman rank correlation coefficient was calculated and showed no correlation with a correlation coefficient -0.36.

At week 28 (n=24), median ustekinumab trough concentration was 0.42 mg/L (<0.02 to 3.60 mg/L). No significant difference was found between ustekinumab trough levels for nonresponders, moderate responders and good responders (median (range) 0.44 mg/L (0.06 to 0.68 mg/L), 0.28 mg/L (0.03 to 0.80 mg/L) and 0.41 mg/L (<0.02 to 3.60 mg/L) respectively (p=0.66). The Spearman rank correlation coefficient was calculated and showed no correlation with a correlation coefficient of 0.022.

For week 52 this was not calculated because only few patients had reached week 52.

Ustekinumab dosing and ustekinumab trough levels

45 mg versus 90 mg

No significant difference was observed at week 16 for ustekinumab trough levels between patients receiving 45 mg (n=26) or 90 mg (n=10, all >100kg) (median

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Figure 1 Ustekinumab trough levels at week 16 for the different response levels using PASI. Each figure represents the ustekinumab through concentration for one of the three responder status.

Response is reflected as non-responder (less than PASI50), moderate responder (PASI50-75) and

good responder (at least PASI75). Outliers were included in the analyses. It is shown that no

difference is observed in ustekinumab trough concentration between nonresponders, moderate

responders and good responders.

Nonresponders Moderate Good N=13 Responders Responders N=12 N=11

Ust

ekin

umab

trou

gh le

vel (

mg/

L)

figure 1. ustekinumab trough levels at week 16 for the different response levels using PaSI. Each figure represents the ustekinumab trough concentration for one of the three responder status. Response is reflected as non-responder (less than PASI50), moderate responder (PASI50-75) and good responder (at least PASI75). Outliers were included in the analyses. It is shown that in this cohort no difference is observed in ustekinumab trough concentration between nonreponders, moderate responders and good responders.

(range) respectively 0.40 mg/L (<0.02 to 2.08 mg/L) and 0.58 mg/L (<0.02 to 2.00 mg/L) p=0.179) (figure 2). Also, no significant difference (p=0.138) was observed in median ΔPASI between the groups, 72% (range -92 to 100%)) and 52% (range -172 to 96%) respectively.

No significant difference was observed at week 16 in ustekinumab trough levels between patients >100 kg receiving 45 mg (n=5, median baseline PASI 8.5, median weight 103 kg) or 90 mg (n=10, median baseline PASI 10.1, median weight 113 kg) (median (range) respectively 0.62 mg/L (0.30 to 2.08 mg/l) and 0.58 mg/L (<0.02 to 2.00 mg/L) p=0.138). Also, no significant difference (p=0.391) was observed in median ΔPASI between these groups, 61% (range 37 to 93%) and 52% (range -172 to 96%) respectively.

No patient <100 kg received 90 mg per administration.

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Antibodies to ustekinumabAntibodies to ustekinumab were detected in 3 out of 41 patients (7%). In one patient, ADA were detected at week 4 (ustekinumab trough level <0.02 mg/L, ADA 320 AU/ml, moderate responder). The patient was early terminated at week 16 due to an adverse event (anemia). PASI had declined from 10.5 to 3.7 (moderate responder). Ustekinumab was restarted after 11 months. At the time of reinitiating ustekinumab therapy, no serum was obtained. No improvement of psoriasis was observed. ADA were assessed after 16 weeks of the second treatment episode and were 38.000 AU/ml (ustekinumab trough level <0.02 mg/L).

In the second patient, ADA were detected at week 16 (ustekinumab trough level <0,02 mg/L, ADA 22 AU/ml). PASI had declined from 9.2 at week 0 to 6 at week 16 (nonresponder). At week 28, PASI had declined to 2,7 (moderate responder) and ADA disappeared (ustekinumab trough level 0,03 mg/L). This patient was >100 kg and received 90 mg ustekinumab per administration from initiation of treatment.

In the third patient, first time ADA was detected at week 28 (ustekinumab trough level 0,30 mg/L, ADA 18 AU/ml). PASI had declined from 17.6 at week 0 to 1.7 at week 28. At week 52, ustekinumab trough level was 0.20 mg/L and ADA was 20AU/ml. At week 130 of treatment, PASI increased to 4.6 and for that reason

Figure 2 Ustekinumab trough levels per ustekinumab dosing group at week 16. No significant

difference was observered in ustekinumab trough levels between patients receiving 45 mg (n=26) or

90 mg (n=10, all >100kg) (p=0.179)

45 mg 90 mg

Ust

ekin

umab

trou

gh le

vel (

mg/

L)

figure 2. ustekinumab trough levels per ustekinumab dosing group at week 16. In this cohort, no significant difference was observed in ustekinumab trough levels between patients receiving 45 mg (n=26) or 90 mg (n=10, all >100kg) (p=0.259)

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trough level and ADA were assessed, respectively 0.09 mg/L and <12 AU/ml. At week 182 of treatment, administration frequency of ustekinumab had been intensified from every 12 weeks to every 10 weeks. PASI had increased to 8.7. Ustekinumab trough level was 0.11 mg/L and ADA could not be detected.

dISCuSSIOn

The purpose of this explorative study was to investigate whether a correlation can be found between clinical efficacy of ustekinumab, ustekinumab trough levels (by a newly developed ELISA) and ADA formation (by a newly developed antigen binding test) in a clinical practise setting.

In our cohort, no correlation between the extent of clinical response and ustekinumab trough levels was found. ADA formation was found in only 7% of patients (n=3, mean follow-up time for all patients 32 weeks) and led to a low PASI response in only one patient. Due to the small number of patients forming ADA, no correlation could be calculated between ADA formation and clinical efficacy or ADA formation and ustekinumab trough levels.

With a correlation coefficient of -0.36 at week 16 and 0.022 at week 28, no correlation was found between ustekinumab trough level and the extent of clinical response. Nonresponders, moderate responders and good responders had similar median trough level (respectively 0.40 mg/L, 0.53 mg/L and 0,36 mg/L at week 16 no significant difference). In a previously presented cohort with adalimumab treated patients, a moderately strong correlation coefficient of 0.519 was observed between adalimumab trough levels and clinical response 4. For adalimumab treated rheumatoid arthritis patients, a therapeutic range for adalimumab trough level has even been established 5. No correlation found between ustekinumab trough level and the extent of clinical response does not mean no such correlation exists. In the majority of patients ustekinumab levels might be in the range in which blocking of IL-12/IL-23 is essentially complete during most of the interval between two successive administrations, in other words, many patients might be overexposed to ustekinumab in a way. In a study in which four different dosing schemes of ustekinumab were investigated, no clear correlation between dose and clinical response had been found 20. A second reason might be that trough levels are not the adequate indicator of optimal ustekinumab concentrations, because ustekinumab is infrequently administered as compared to adalimumab (12 vs 2 weeks). A third reason for not finding a correlation might be that the cohort reported here is too small for establishing this.

More research is needed in which frequent sampling provides additional insight in the relationship between ustekinumab concentration and efficacy.

ADA were found in 7% of patients (n=3), which is in accordance with previous studies (4-6%) 7. The patients who formed ADA did so for the first time at week

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4, week 16 and week 28 of treatment. For adalimumab, ADA have been reported in up to 49% of patients and influence trough level and thereby clinical efficacy 4. It is known that adalimumab ADA are neutralising 8. Due to the small number of patients forming antibodies in our cohort, no conclusion could be drawn regarding the influence of ADA on trough level and the effect on efficacy. One patient with ADA (22 AU/ml) had no detectable ustekinumab trough level (<0.02 mg/L), another patient with ADA (22 AU/ml) did have a detectable ustekinumab trough level (18 AU/ml). A trough concentration <0.02 mg/L was also observed in 2 patients without ADA. Others report that patients with ADA to ustekinumab attain a lower trough level and the 64% of ADA are neutralising 1. In two patients, (low) ADA were observed, which had disappeared in a later stadium.

An important question derived from daily practice is whether patients can safely reinitiate biologic therapy after long cessation of therapy. For infliximab it is known that reinitiating therapy after ceasing therapy can cause severe infusion reaction 21. In 4 patients included in this study, ustekinumab had been administered previously. Those four patients did not develop ADA. In four other patients, who were excluded for this cohort because only week 4 serum was available, ustekinumab was also administered previously. No ADA were detected either. In all eight patients, no safety issues occurred. Only one patient used concomitant methotrexate, which is thought to prevent ADA formation with adalimumab4. In the future it would be of great interest to investigate whether methotrexate prevents ADA formation in ustekinumab-treated patients.

This study has some limitations. A relatively small number of patients have experienced ADA formation. Due to this, no conclusion can be drawn regarding the influence of ADA formation on trough level. Mean follow-up time was 32 weeks. It is reported that ADA formation occurs mostly before 78 weeks of treatment 1. A longer observation period might lead to more patients forming ADA. Including patients who have received ustekinumab previously might create a selection bias. For infliximab it is known that retreatment leads to a greater chance of ADA formation. On the other hand, these patients might not be susceptible to ADA formation seen the fact that ustekinumab treatment has been successful in the past, otherwise it would not be restarted.

REfEREnCES

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2. Paul C, Puig L, Kragballe K, et al. Transition to ustekinumab in patients with moderate-to-severe psoriasis and inadequate response to methotrexate: a randomized clinical trial (TRANSIT). Br J Dermatol. 2013.

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3. Sandborn WJ, Gasink C, Gao LL, et al. Ustekinumab induction and maintenance therapy in refractory Crohn’s disease. N Engl J med. 2012;367(16):1519-1528.

4. Menting SP, van Lumig PP, de Vries AC, et al. Extent and Consequences of Antibody Formation Against Adalimumab in Patients With Psoriasis: One-Year Follow-up. Jama Dermatol. 2013.

5. Pouw MF, Krieckaert CL, Nurmohamed MT, et al. Key findings towards optimising adalimumab treatment: the concentration-effect curve. annals of the rheumatic diseases. 2013.

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8. van Schouwenburg PA, van de Stadt LA, de Jong RN, et al. Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation. annals of the rheumatic diseases. 2013;72(1):104-109.

9. Jamnitski A, Krieckaert CL, Nurmohamed MT, et al. Patients non-responding to etanercept obtain lower etanercept concent rat ions compared w i th responding patients. annals of the rheumatic diseases. 2012;71(1):88-91.

10. Hart MH, de VH, Wouters D, et al. Differential effect of drug interference in immunogenicity assays. J.immunol.methods. 2011;372(1-2):196-203.

11. Kauffman CL, Aria N, Toichi E, et al. A phase I study evaluating the safety, pharmacokinetics, and clinical response of a human IL-12 p40 antibody in subjects with plaque psoriasis. J invest Dermatol. 2004;123(6):1037-1044.

12. Krueger GG, Langley RG, Leonardi C, et al. A human interleukin-12/23 monoclonal antibody for the treatment of psoriasis. N Engl J med. 2007;356(6):580-592.

13. Papp KA, Langley RG, Lebwohl M, et al. Ef ficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). lancet. 2008;371(9625):1675-1684.

14. Tsai TF, Ho JC, Song M, et al. Efficacy and safety of ustekinumab for the treatment of moderate-to-severe psoriasis: a phase III, randomized, placebo-controlled trial in Taiwanese and Korean patients (PEARL). J Dermatol sci. 2011;63(3):154-163.

15. Mrowietz U, Kragballe K, Reich K, et al. Definition of treatment goals for moderate to severe psoriasis: a European consensus. arch.Dermatol.res. 2011;303(1):1-10.

16. van Schouwenburg PA, Bartelds GM, Hart MH, Aarden L, Wolbink GJ, Wouters D. A novel method for the detection of antibodies to adalimumab in the presence of drug reveals “hidden” immunogenicity in rheumatoid arthritis patients. Journal of immunological methods. 2010;362(1-2):82-88.

17. Rispens T, Leeuwen A, Vennegoor A, et al. Measurement of serum levels of natalizumab, an immunoglobulin G4 therapeutic monoclonal antibody. analytical biochemistry. 2011;411(2):271-276.

18. Wolbink GJ, Vis M, Lems W, et al. Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis. arthritis and rheumatism. 2006;54(3):711-715.

19. Rispens T, de Vrieze H, de Groot E, et al. Antibodies to constant domains of therapeutic monoclonal antibodies: anti-hinge antibodies in immunogenicity testing. Journal of immunological methods. 2012;375(1-2):93-99.

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20. Gottlieb AB, Cooper KD, McCormick TS, et al. A phase 1, double-blind, placebo-controlled study evaluating single subcutaneous administrations of a human interleukin-12/23 monoclonal antibody in subjects with plaque psoriasis. current medical research and opinion. 2007;23(5):1081-1092.

21. Reich K, Wozel G, Zheng H, van Hoogstraten HJ, Flint L, Barker J. Efficacy and safety of infliximab as continuous or intermittent therapy in patients with moderate-to-severe plaque psoriasis: results of a randomized, long-term extension trial (RESTORE2). Br J Dermatol. 2013;168(6):1325-1334.

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GENERAL DISCUSSION

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dISCuSSIOn

Since the first systemic treatment for psoriasis came available in the ‘50s of the previous century, much has changed in the treatment of psoriasis. Many new drugs came available, attaining complete disease clearance in some patients. In the era of personalized medicine, both new and conventional treatments need further refinement. With this thesis, we have tried to tailor psoriasis therapy, towards a safer and more effective systemic treatment. We tried to contribute to this in two ways. In chapter 2 we focus on the safety and effectiveness of biological and methotrexate treatment by analyzing data from a daily practice setting. In chapter 3 we focus on personalizing the treatment with methotrexate and biologicals for subgroups of patients.

Chapter 2: Safety and effectiveness of biological and methotrexate treatment of psoriasis in a daily practice setting

Registries

As mentioned in the introduction, using registry data could be important for tailoring treatments and can be used as a complement for RCT data (1). In this thesis long-term daily practice data of etanercept, infliximab, adalimumab and ustekinumab treatment of psoriasis is presented (2). All treatments had similar drug survival results. This is in contrast to results from other studies (3-6), which all showed superiority of one of the biologicals. However, which biological had the best drug survival differed across studies. One study showed infliximab to have a better drug survival (3), in two other studies etanercept was more effective (4, 5) (these three studies did not include ustekinumab) and one study showed ustekinumab to have better drug survival (6). This could mean that drug survival of biologicals is not that different. It has to be said though that in our cohort almost all patients treated with etanercept received 2x 50 mg per week for most of the time and that ustekinumab was only administered in biological non-naïve patients. If etanercept would have been administered in the dose of 2x50 mg per week for the first 12 weeks and from then on 1x50 mg per week (as how it is registered) and if ustekinumab would have been administered in biological naïve patients, etanercept might have shown less favorable drug survival and ustekinumab might have shown more favorable drug survival.

When drug survival is used as an outcome, one should be aware of the potential pitfalls of this outcome (7). A general rule of thumb in drug survival analysis is that at least 10-20 events need to be present in each survival curve in order for it to be valid (7). Our drug survival curve on etanercept and adalimumab for naïve patients and our drug survival curve on all biologicals for non-naïve patients contained sufficient events. However, our drug survival curve on infliximab for naïve patients included only 10 events. Not only clinical negative outcomes like loss of effectiveness and

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side effects make a patient and/or treating physician decide to stop treatment. Also clinical positive outcomes, like long lasting complete remission can be a reason for treatment termination, or for example the availability of less costly or safer treatment options. It would be of interest to make separate survival curves for each reason of treatment termination. Also, it would be of interest to analyze other factors influencing drug survival, like co-medication, co-morbidity or age. For making these sub-analyses, we would need more, and more diverse, patients in the registry. Data from different registries could be merged (www.psonet.eu) to attain this. However to be able to do this, or even to be able to compare results between registries, the data collected and outcome measures reported should be standardized. Many different outcome measures are available for defining psoriasis disease activity, as mentioned in the introduction. This heterogeneity in outcome measures hampers comparing and pooling data and as a result evidence based decision-making. Like in rheumatology with OMERACT, in dermatology there is a promising movement toward harmonizing outcome assessments. With the Cochrane Skin Group-Core Outcome Set Initiative (CSG-COUSIN) for dermatology in general, the Harmonizing Outcome Measures for Eczema initiative (HOME) for eczema (8) and the International Dermatology Outcome Measurers (IDEOM) for psoriasis, better analysis of data from studies, clinical practice and registries will be possible, enabling stronger recommendations for clinical practice.

Besides local registries per center, both national (www.badbir.org) and international registries could improve the use of daily practice data. By joining forces, registry datasets will be larger and analyses performed in these datasets will have more power compared to analyses performed in datasets provided by single centers. Also, treatment effects in subgroups of patients can be analyzed and used for tailoring treatment strategies.

Because drug survival is influenced by so many factors, one should not only focus on drug survival when choosing a drug as a preference, but, like mentioned in the introduction also on outcomes like e.g. safety and effectiveness or onset of action, easy for use.

Registries: safety dataBesides drug survival, evaluating long term prospectively collected registry data provides information on safety of biological treatment. This is especially important for treating a chronic disease like psoriasis because patients are often treated for a longer period of time, in which a balance needs to be sought for between effectiveness and side effects.

We specifically focused on the incidence of non-melanoma skin cancer in anti-TNF-α treated psoriasis and rheumatoid arthritis patients as concerns exist about melanoma and non-melanoma skin cancer during anti-TNF-α therapy (9, 10). With PUVA therapy, the incidence of squamous cell carcinoma has shown to be 30 times

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higher compared to the general population in a 30-year cohort study. Malignant melanoma even started to develop as late as 15 years after therapy (11, 12). In the same cohort it was shown that PUVA does not increase the risk of basal cell carcinoma. This illustrates the necessity of long-term follow-up data. As mentioned in the introduction, we were able to collect data of patients treated with anti-TNF-α and to compare a group of psoriasis patients to a group of rheumatoid arthritis patients treated with anti-TNF-α. Our results show that the non-melanoma skin cancer risk was significantly higher in the psoriasis group compared to the rheumatoid arthritis group and the time until occurrence of first non-melanoma skin cancer after the start of anti-TNF-α therapy was significantly shorter in the psoriasis group. The increased risk in psoriasis patients may be related to disease-related factors (like for example previous treatment with UVB therapy). The question remains whether anti-TNF-α causes an increased risk of skin cancer. It would be possible to answer this question if data from a group of psoriasis patients who had received phototherapy and conventional systemic anti-psoriatic therapies, but no anti-TNF-α, was available. In our registry, no such group is available. With expanding data in registries, a group like that might become available and the influence of anti-TNF-α therapy on developing non-melanoma skin cancer can be investigated.

Besides non-melanoma skin-cancer other safety data can be analyzed from registry data as well, leading to better understanding and more awareness of potential side-effects of treatments used for psoriasis in daily practice.

Registries: monitoringLong term data monitoring should be performed with the appropriate tools. An example is liver fibrosis in methotrexate treated patients. Registries can provide insight in the validity of certain tools used for monitoring.

Liver biopsies are still the golden standard for diagnosing liver fibrosis. Years ago, liver biopsies were performed in every patient having used 1500 milligram of methotrexate for the treatment of psoriasis. Now, it is only being performed when there is a suspicion of liver fibrosis. The suspicion is often based on serum markers for liver dysfunction like transaminases. In search for more optimal serum markers for liver fibrosis, PIIINP was discovered.

We evaluated the data of PIIINP from methotrexate treated psoriasis patients in three clinical expertise centers in the Netherlands. All patients who had PIIINP measurements were included. We found that patients with elevated PIIINP series had different characteristics compared to the non-elevated group: a higher BMI, age, disease duration, and more frequently a pre-existent diagnosis with non-alcoholic fatty liver disease (NAFLD). Strikingly, this subgroup used a lower weekly dose of methotrexate and the same cumulative dose as patients without elevated PIIINP. Unfortunately, we could not draw conclusions about the diagnostic

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accuracy of PIIINP from this cohort of patients: only about half of the patients with elevated PIIINP (21/41) had further diagnostics performed for diagnosing liver fibrosis and patients with normal PIIINP hardly ever had further diagnostics. Ideally, all patients in our cohort would have undergone a liver biopsy (the golden standard for diagnosing liver fibrosis). However, this is not feasible due to its invasiveness and possible severe (lethal) complications. Transient elastography (by for example Fibroscan, an ultrasound device) measures liver stiffness showing a pooled sensitivity of 60%, with corresponding specificity of 80% (13). Although it is not yet registered for diagnosing liver fibrosis in methotrexate treated patients, it could help us monitoring psoriasis patients. When it gets registered, it would be possible to screen both patients with and without elevated PIIINP for liver fibrosis so that the validity of PIIINP could be investigated. Though when transient elastography gets registered for diagnosing liver fibrosis, one could question the necessity of using PIIINP. All patients on methotrexate treatment could have transient elastography performed for example every year for screening for liver fibrosis (instead of measuring PIIINP every three months), because it is a non-invasive method.

Chapter 3: Personalizing existing treatments with methotrexate and biologicalsTreatments are applied in a standard manner, though effectiveness differs between patients. For a treatment to be as safe and effective as possible, treatment should be personalized per patient. Prescribers should look at the individual patient and tailor the treatment per patient. Chapter 3 focuses on improving and personalizing existing psoriasis treatments with methotrexate, adalimumab and ustekinumab.

Optimizing methotrexate treatmentWe have tried to optimize methotrexate treatment by means of a systematic review in which we draw conclusions about the use of a test-dose, start dose, dosing scheme, dose adjustments, maximum dose and the use of folic acid (14). Psoriasis patients are often undertreated (15); with the suggestions in this systematic review we try to omit that.

There is no high quality evidence for the use of a start dose. In healthy individuals this only slows down initiation of therapy and we suggest omitting a test dose in these patients. Also methotrexate might be initiated in a higher dose in young healthy adults (for example 15 mg of methotrexate per week) compared to an older adult with co-morbidity (start dose for example 7.5 mg of methotrexate per week). Young healthy patients will hereby reach faster clearance of disease and elder patients with possible co-morbidity will have a safer treatment. A world wide survey showed the majority of dermatologists started with a dose of 10 mg/week (16). We have also made suggestions on the dosing scheme, dose adjustments

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and the maximum dose. The suggestions made are partly evidence based, partly expert opinion. The results of this systematic review are being used for the update of the methotrexate chapter of the Dutch Guideline Psoriasis (expected 2016).

Personalizing biological treatment: the use of serum concentration- and immunogenicity assays for biologicals in daily practice (also published as a chapter in the update of the Dutch Guideline psoriasis (expected 2016)

The arrival of biologicals has changed a lot in the treatment of psoriasis. The cost of a biological is significantly higher than the cost of conventional systemic treatments (17) which makes the rational treatment of psoriasis more relevant. Besides, the care for psoriasis could be further improved by personalizing the biological treatments.

A difference in response is observed between patients who are treated with a biological. Among other factors this might be explained by the large interindividual variation in biological serum concentration levels obtained. The serum concentration is influenced by several factors, for example dosage of the biological and the formation of antibodies against the biological (immunogenicity). For some biologicals, there appears to be a clear relationship between response and serum concentration (18).

Correlation between serum concentration, antibody formation and effectivenessThe extent to which the presence or absence of serum drug concentrations and ADA are correlated to the clinical response appears to depend on the type of biological. As shown in this thesis, there is a clear correlation between clinical effectiveness, adalimumab serum level and the degree of (neutralizing) ADA-formation (19). This relationship has been previously shown for infliximab (18).

For etanercept the association between decreased effectiveness and decreased serum levels has been found in rheumatoid arthritis (20). In psoriasis, this association was not found (21), however, the serum in this small study was not drawn at a standard moment (trough level moment), which is essential (22). The etanercept serum concentration is not influenced by the formation of antibodies because no neutralizing antibodies have been detected. This may be explained by the fact that the sequence of the TNF-α binding part of etanercept is human, which makes the formation of neutralizing antibodies less likely.

For ustekinumab, we have also tried to establish a correlation between clinical effectiveness and ustekinumab trough level. In our cohort, we could not identify this correlation (23). Maybe this is because our cohort was too small (n=41). A second explanation might be that in the majority of patients ustekinumab levels are in the range in which blocking of IL-12/IL-23 is essentially complete during most of the interval between two successive administrations. In other words, many patients might be overexposed to ustekinumab in a way. A third explanation

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might be that IL-12 and IL-23 are regulatory cytokines for keratinocytes instead of effector cytokines (like TNF-α). If this is the case no correlation between serum concentration and effectiveness exists and we should look towards other markers for personalizing ustekinumab treatment. For example a set of serum markers (24) or a certain genotype (HLA-Cw6) (25) predicting treatment success.

For secukinumab only sponsored data is available, in which it is reported that ADA-formation against secukinumab rarely occurs and that it does not affect effectiveness (26). For biosimilars, no data is available yet. To conclude, a correlation between serum concentration and effectiveness only appears to exist for adalimumab and infliximab until this far. The question remains whether it is useful to measure adalimumab and infliximab serum concentration and/or antibody formation in daily practice. Does the result influence clinical decision-making?

Serum concentration- and antibody measurements in daily practiceIn present-day daily practice, antibody measurements are often carried out in case of declining effectiveness; this is in accordance with the Dutch Guideline Psoriasis (2011). Herein it is mentioned that measurement of antibodies can be considered in treatment with adalimumab and infliximab in the case of primary (no effect occurs since start of treatment) or secondary ineffectiveness (previously obtained effectiveness is lost during the treatment) or upon the occurrence of an infusion reaction (only for infliximab). Depending on the presence or absence of antibodies (in high or low concentration), whether or not in combination with serum concentration and whether or not in combination with ineffectiveness, a change in treatment is recommended. For example, in the presence of a low concentration of antibodies (with low serum concentration) and insufficient effectiveness it is advised to intensify the frequency of administration so as to overrule the possible antibody formation.

However, there is still insufficient evidence to base clinical decision making (e.g. intensifying administration frequency, the use of an immunosuppressive agent such as methotrexate as co-medication or switching to a different biological) on antibody and or serum concentrations.

Some clues exist, that measuring serum concentrations can influence clinical decision making. In an observational rheumatoid arthritis cohort (27), some patients who were treated with adalimumab switched to etanercept due to ineffectiveness. In these patients it was observed that those who failed on adalimumab with a low biological serum concentration (often caused by antibody formation) responded better to etanercept than patients who failed adalimumab treatment with a high biological serum concentration. It is assumed that the inflammatory protein TNF-α may play a lesser role in patients in this latter category. In the latter situation, outcome of the serum concentration measurement would affect clinical decision in choosing the sequential biological.

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Future: a therapeutic algorithm?The biological serum concentration is crucial for the effectiveness of the biological. Immunogenicity is a factor which influences the serum concentration. Therefore the primary focus is on the serum concentration and not on immunogenicity. As discussed above, evidence that points toward the usefulness of serum concentration measurements exists.

In this thesis, a clear relationship was found between effectiveness and adalimumab serum concentration in the treatment of psoriasis (19). Also, we determined the optimal serum concentration of adalimumab (therapeutic range) in the treatment of psoriasis in 135 patients. This has been set at 3.51 mg/L up to 7 mg/L (28). For biologicals in which such a therapeutic range can be established (so far this is only the case for adalimumab), a therapeutic algorithm can be designed (see figure). Such a therapeutic algorithm has not been tested prospectively and can therefore not yet be used in daily practice.

Serum levels above the therapeutic range were shown not to improve effectiveness. Therefore, in patients with serum levels above the therapeutic range, dose interval prolongation could lower serum levels to within the therapeutic range. In patients with good effectiveness with suboptimal serum levels (for example, by ADA), it may be considered to stop biological treatment, since no effect is to be expected from the biological and disease activity may be low. In patients with no effectiveness in combination with serum levels within or above the therapeutic range, switching to a biological with a different mechanism of action may be considered. In these patients the disease is likely to be driven by a different target than the target to which this biological intervenes.

In patients with no effectiveness in combination with a suboptimal serum level, one could switch to a biological with the same or different mechanism of action or the dose could be increased.

Adjusting treatment based on biological serum levels (extending the dose interval, continuation of a biological or stopping a biological and start with another biological with a different or similar mechanism of action) has not been prospectively studied for any biological. A treatment algorithm based on serum concentrations is therefore not yet suitable for everyday use and carrying out serum concentration measurements of biologicals is therefore yet to be questioned. Of course, curiosity about reason of loss of effectiveness can be a reason to carry out a serum concentration- and immunogenicity assay. It would be of great interest to prospectively test the therapeutic algorithm described in the near future.

Immunosuppressive co-medication may affect the serum concentration and immunogenicity of a biological. The dose of methotrexate, which is used as co-medication, seems to affect the proportion of patients developing antibodies. The higher the dose of methotrexate, the lower the percentage of patients who tested positive for antibodies (29). Immunosuppressive drugs also suppress inflammation,

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reducing unbound target for the biological and in this way leaving more drug unbound. In comparison with monotherapy, concentrations of TNF-α -blockers are higher when these drugs are combined with methotrexate (30). Whether such synergism may also be achieved within the treatment of psoriasis has not (yet) been investigated. To date, only two RCTs have been published with a biological in combination with methotrexate (both combinations concerned methotrexate + etanercept) (31). In neither of these studies the effect of the addition of methotrexate on the serum concentration or immunogenicity has been reported (the effect on immunogenicity is probably negligible since no neutralizing antibodies have been detected for etanercept). Nevertheless, such combination treatments are more often used in the treatment of moderate to severe psoriasis. In order to investigate the impact on efficacy, safety and pharmacokinetics of the addition of methotrexate to the treatment with adalimumab a multicenter RCT at national level is currently being performed.

Figure Therapeutic algorithm (based on Krieckaert et al (32))

figure. Therapeutic algorithm (based on krieckaert et al (32))

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REfEREnCES

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2. Menting SP, Sitaram AS, Bonnerjee-van der Stok HM, de Rie MA, Hooft L, Spuls PI. Drug survival is not significantly different between biologics in patients with psoriasis vulgaris: a single-centre database analysis. The British journal of dermatology. 2014;171(4):875-83.

3. Gniadecki R, Kragballe K, Dam TN, Skov L. Comparison of drug survival rates for adalimumab, etanercept and infliximab in patients with psoriasis vulgaris. The British journal of dermatology. 2011;164(5):1091-6.

4. Brunasso AM, Puntoni M, Massone C. Drug survival rates of biologic treatments in patients with psoriasis vulgaris. The British journal of dermatology. 2012;166(2):447-9.

5. Esposito M, Gisondi P, Cassano N, Ferrucci G, Del Giglio M, Loconsole F, et al. Survival rate of antitumour necrosis factor-alpha treatments for psoriasis in routine dermatological practice: a multicentre observational study. The British journal of dermatology. 2013;169(3):666-72.

6. Gniadecki R, Bang B, Bryld LE, Iversen L, Lasthein S, Skov L. Comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris. The British journal of dermatology. 2015;172(1):244-52.

7. van den Reek JM, Kievit W, Gniadecki R, Goeman JJ, Zweegers J, van de Kerkhof PC, et al. Drug Survival Studies in Dermatology:Principles, Purposes, and Pitfalls. The Journal of investigative dermatology. 2015;135(7):e34.

8. Schmitt J, Spuls PI, Thomas KS, Simpson E, Furue M, Deckert S, et al. The Harmonising Outcome Measures for Eczema (HOME) statement to assess

clinical signs of atopic eczema in trials. The Journal of allergy and clinical immunology. 2014;134(4):800-7.

9. Pathirana D, Ormerod AD, Saiag P, Smith C, Spuls PI, Nast A, et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. Journal of the European Academy of Dermatology and Venereology : JEADV. 2009;23 Suppl 2:1-70.

10. van Lumig PP, Driessen RJ, Berends MA, Boezeman JB, van de Kerkhof PC, de Jong EM. Safety of treatment with biologics for psoriasis in daily practice: 5-year data. Journal of the European Academy of Dermatology and Venereology : JEADV. 2012;26(3):283-91.

11. Stern RS, Nichols KT, Vakeva LH. Malignant melanoma in patients treated for psoriasis with methoxsalen (psoralen) and ultraviolet A radiation (PUVA). The PUVA Follow-Up Study. The New England journal of medicine. 1997;336(15):1041-5.

12. Stern RS, Study PF-U. The risk of squamous cell and basal cell cancer associated with psoralen and ultraviolet A therapy: a 30-year prospective study. Journal of the American Academy of Dermatology. 2012;66(4):553-62.

13. Maybury CM, Samarasekera E, Douiri A, Barker JN, Smith CH. Diagnostic accuracy of noninvasive markers of liver fibrosis in patients with psoriasis taking methotrexate: a systematic review and meta-analysis. The British journal of dermatology. 2014;170(6):1237-47.

14. Menting SP, Dekker PM, Limpens J, Hooft L, Spuls PI. Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation. Acta Derm Venereol. 2015.

15. Armstrong AW, Robertson AD, Wu J, Schupp C, Lebwohl MG. Undertreatment, treatment trends, and treatment

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dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011. JAMA dermatology. 2013;149(10):1180-5.

16. Gyulai R, Bagot M, Griffiths CE, Luger T, Naldi L, Paul C, et al. Current practice of methotrexate use for psoriasis: results of a worldwide survey among dermatologists. Journal of the European Academy of Dermatology and Venereology : JEADV. 2015;29(2):224-31.

17. D’Souza LS, Payette MJ. Estimated cost efficacy of systemic treatments that are approved by the US Food and Drug Administration for the treatment of moderate to severe psoriasis. Journal of the American Academy of Dermatology. 2015;72(4):589-98.

18. Hsu L, Snodgrass BT, Armstrong AW. Anti-drug Antibodies in Psoriasis: A Systematic Review. The British journal of dermatology. 2013.

19. Menting SP, van Lumig PP, de Vries AC, van den Reek JM, van der Kleij D, de Jong EM, et al. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year fo l low-up. JAMA dermato logy. 2014;150(2):130-6.

20. Jamnitski A, Krieckaert CL, Nurmohamed MT, Hart MH, Dijkmans BA, Aarden L, et al. Patients non-responding to etanercept obtain lower etanercept concentrations compared with responding patients. Annals of the rheumatic diseases. 2012;71(1):88-91.

21. Mahil SK, Arkir Z, Richards G, Lewis CM, Barker JN, Smith CH. Predicting treatment response in psoriasis using serum levels of adalimumab and etanercept: a single-centre, cohort study. The British journal of dermatology. 2013;169(2):306-13.

22. Menting SP, Kleij DV, Rispens T, Spuls PI, Lecluse LL. Comment on ‘Predicting treatment response in psoriasis using serum levels of adalimumab and etanercept: a single-centre, cohort

study’. The British journal of dermatology. 2013;169(5):1170.

23. Menting SP, van den Reek JM, Baerveldt EM, de Jong EM, Prens EP, Lecluse LL, et al. The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting. The British journal of dermatology. 2015.

24. Onderdijk AJ, AS IJ, Menting SP, Baerveldt EM, Prens EP. Potential serum biomarkers of treatment response to ustekinumab in patients with psoriasis: a pilot study. The British journal of dermatology. 2015.

25. Talamonti M, Botti E, Galluzzo M, Teoli M, Spallone G, Bavetta M, et al. Pharmacogenetics of psoriasis: HLA-Cw6 but not LCE3B/3C deletion nor TNFAIP3 polymorphism predisposes to clinical response to interleukin 12/23 blocker ustekinumab. The British journal of dermatology. 2013;169(2):458-63.

26. Klein U. LE, Vogel B., Kolbinger F. , Bruin G., Lloyd P. Immunogenicity of the novel anti-IL-17A antibody, secukinumab, with intravenous and subcutaneous dosing regimens in healthy subjects and patients. Ann Rheum Dis 2013;72(Suppl3):630.

27. Ba r te ld s GM, K r ieckae r t CL , Nurmohamed MT, van Schouwenburg PA, Lems WF, Twisk JW, et al. Development of antidrug antibodies against adalimumab and association with disease activity and treatment failure during long-term follow-up. Jama. 2011;305(14):1460-8.

28. Menting SP, Coussens E, Pouw MF, van den Reek JM, Temmerman L, Boonen H, et al. Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment. JAMA dermatology. 2015;151(6):616-22.


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30. Vogelzang EH, Pouw MF, Nurmohamed M, Kneepkens EL, Rispens T, Wolbink GJ, et al. Adalimumab trough concentrations in patients with rheumatoid arthritis and psoriatic ar thritis treated with concomi tant d i sease -modi f y ing antirheumatic drugs. Annals of the rheumatic diseases. 2015;74(2):474-5.

31. Busard C, Zweegers J, Limpens J, Langendam M, Spuls PI. Combined

use of systemic agents for psoriasis: a systematic review. JAMA dermatology. 2014;150(11):1213-20.

32. Krieckaert CL, Nair SC, Nurmohamed MT, van Dongen CJ, Lems WF, Lafeber FP, et al. Personalised treatment using serum drug levels of adalimumab in patients with rheumatoid arthritis: an evaluation of costs and effects. Annals of the rheumatic diseases. 2015;74(2):361-8.

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CHAPTER 5

SUMMARY AND CONCLUSIONS/ SAMENVATTING VOOR NIET INGEWIJDEN

Summary and concluSionS/ Samenvatting voor niet ingewijden

5

SuMMaRy and COnCluSIOnS: TaIlORInG PSORIaSIS ThERaPy: TOWaRdS a SafER and MORE EffECTIVE SySTEMIC TREaTMEnT.

This thesis focuses on the treatment of plaque type psoriasis with methotrexate and biologicals. The goal is to optimize existing treatments. In the first part we focus on the safety and effectiveness of biological and methotrexate treatment of psoriasis in a daily practice setting. In the second part we focus on personalizing existing treatments with methotrexate and biologicals.

The general introduction in Chapter 1 summarizes the history, epidemiology, comorbidities, clinical features and pathogenesis of psoriasis. It also provides a complete overview of the treatment of psoriasis from a historical perspective.

Because of the difference in patient population and treatment environment between randomized clinical trials and daily practice, there is a difference in drug safety and efficacy between these settings. Therefore, before optimizing existing treatments, we first focus on observing safety and effectiveness of biological and methotrexate treatment in a daily practice setting in Chapter 2.

In Chapter 2a we analyzed the registry of the department of dermatology of the Academic Medical Center in Amsterdam. This registry includes all consecutive patients treated for psoriasis with anti-TNF-α agents (etanercept, adalimumab, infliximab) and ustekinumab since January 2005. Included were baseline characteristics and at every outpatient visit dosing, PASI, Skindex-29 and adverse events were recorded. Patients were divided into those naive or non-naïve for treatment episodes with biologicals. Drug survival did not differ significantly for naive treatment episodes between the biologicals (etanercept 85% to 64%, adalimumab 77% to 77%, infliximab 75% to 75% for year 1– 4), or for non-naïve treatment episodes (etanercept 86% to 42%, adalimumab 84% to 56%, infliximab 68% to 43% for year 1– 4; ustekinumab 84% to 57% for year 1– 3). The naive group showed better drug survival and PASI 75 response at week 12, although the difference was not significant. A similar improvement of mean Δ PASI and mean Δ Skindex-29 was observed at weeks 12 and 52 for all biologics for both groups, although no significant difference was seen between groups. Treatment termination was due mainly to nonresponse for all biologics. We concluded that there was no significant difference in drug survival, mean Δ PASI or Skindex-29 response at weeks 12 or 52 between the biologics or between the naive and non-naive groups. Treatment termination was due mostly to nonresponse. Also we concluded that sequential treatment with the available biologics can be effective.

In daily practice, specific concerns exist about non-melanoma skin cancer (NMSC) being a side effect of anti-TNF- α therapy. In Chapter 2b we analyzed daily practice data from the department of dermatology of the Academic Medical Center in Amsterdam and the departments of dermatology and rheumatology of

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the Radboudumc in Nijmegen. Incidence of non-melanoma skin cancer in patients treated with anti-TNF- α was compared between psoriasis and rheumatoid arthritis patients. The goal was to investigate whether there was a difference in time until first NMSC and the rate of NMSC between psoriasis and rheumatoid arthritis patients on TNF-inhibitors. The NMSC risk was significantly higher in the psoriasis group [fully adjusted hazard ratio 6.0 (1.6–22.4 95%CI)] with a shorter time until first NMSC in psoriasis compared to rheumatoid arthritis. By Poisson regression, psoriasis patients had a 5.5 (2.2–13.4 95%CI) higher rate of NMSC. This indicates that disease-related factors like phototherapy may be important contributing factors to NMSC diagnosed in psoriasis patients treated with TNF-inhibitors.

A concern for patients on long-term methotrexate treatment for psoriasis is the development of liverfibrosis. Liver biopsies are the gold standard for detecting liver fibrosis. Procollageen III aminoterminal peptide (PIIINP) is a non-invasive serum marker used as prescreening for detecting liver fibrosis. It is questioned whether PIIINP is a suitable screening tool. In Chapter 2c we described the results of serial serum PIIINP monitoring in psoriasis patients treated with methotrexate in daily practice. Data on patients with PIIINP concentrations measured between 2006-2012 (including patient- and treatment characteristics, PIIINP concentrations, further diagnostic tests and ALT and γ-GT), using methotrexate for plaque psoriasis were collected from patient files and registries in three hospitals in the Netherlands. Correlations were calculated using Pearson correlation coefficient (PCC). In total, 183 patients with 952 patient years on methotrexate and 546 patient years with PIIINP measurements were available. Normal serial PIIINP concentrations were found in 142 patients (78%) and 41 patients (22%) had elevated PIIINP series. Cumulative methotrexate dose did not differ between these groups. Patients with elevated PIIINP concentrations were significantly older with a longer disease duration and a higher body mass index than patients with normal PIIINP concentrations. Twenty of 41 patients (49%) with elevated PIIINP concentration had further diagnostic tests; one patient had significant fibrosis (Roenigk 3b), 2 patients had possible liver fibrosis on FibroScan (F3) and 14 patients showed signs of hepatic steatosis on ultrasound or on biopsy. PIIINP concentrations showed low correlations with ALT or γ-GT measurements (PCC 0.1 and 0.06 respectively). Major limitation of this study was that only 20 of 41 patients with elevated PIIINP had further diagnostic tests and even fewer had a liver biopsy (the golden standard). More research is needed to draw conclusions regarding the suitability of PIIINP as a screening tool for liver fibrosis.

In Chapter 3 we focus on personalizing existing treatments with methotrexate and biologicals. In daily practice treatment is not personalized per patient. With these set regimens, a wide range of treatment response is observed in patients. This raised the question whether treatments can be tailored: can existing treatments be adjusted per patient?

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First focus is on methotrexate treatment in Chapter 3a. We summarize the evidence for test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and use of folic acid by means of a systematic review. A literature search for randomized controlled trials and guidelines was performed. Twenty-three randomized controlled trials (29 treatment groups) and 10 guidelines were included. Two treatment groups used a test-dose, 5 guidelines recommend it. The methotrexate start-dose in randomized controlled trials varied from 5 to 25 mg/week, most commonly being either 7.5 mg or 15 mg. Guidelines vary from 5 to 15 mg/ week. Methotrexate was administered as a single dose or in a Weinstein schedule in 15 and 11 treatment groups, respectively; both recommended equally in guidelines. A fixed dose (n = 18), predefined dose (n = 3), or dose adjusted on clinical improvement (n = 8) was used, the last also being recommended in guidelines. Ten treatment groups used folic acid; in 2 it was allowed, in 14 not mentioned, and in 3 no folic acid was used. Most guidelines recommend the use of folic acid. Based on these results we made suggestions for methotrexate dosing:• Test-dose: recommended for frail patients (e.g. elderly or patients with impaired

kidney function) • Start dose: 5 to 7.5 mg per week in frail patients and 15 mg per week in healthy

patients with initially frequent monitoring• Administration as single dose. Use of the Weinstein schedule if gastro-intestinal

complaints occur • Dose increase at week 8 to 20 mg per week if an insufficient response is seen.

In good-responders dose reductions should be considered• Maximum dose of 25 mg per week • Folic acid is recommended, in a dosing and frequency of 1-5 mg/day except

on the day of methotrexate administration to 5 mg/week, 24 hours after methotrexate

Next focus is on adalimumab treatment. In Chapter 3b we investigated whether a correlation exists between adalimumab trough level concentration, adalimumab antibody concentration and clinical response. In a previously reported cohort of 29 patients with plaque-type psoriasis followed up for 24 weeks, clinically relevant antidrug antibody (ADA) to adalimumab was frequently found. Long-term data were lacking. We presented the extension of this multicenter cohort study: 80 patients followed up for 1 year. For these patients disease severity was assessed by means of PASI, blood samples were collected, and adalimumab and ADA concentrations was determined at baseline and at weeks 12, 24, and 52. Correlations were calculated by Spearman rank test. ADA were formed in 49% of patients. In 90% of these patients first time ADA formation was found before week 24. Adalimumab and ADA concentrations, clinical response and ADA concentration, and adalimumab concentration and clinical response had correlations of −0.872, −0.606, and 0.519,

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respectively. The adalimumab dose interval was shortened because of lack of efficacy in 15 patients, 7 with and 8 without ADA; improvement in responder status occurred in 1 of 7 and 4 of 8, respectively. We concluded that patients with no ADA formation in the first 24 weeks of treatment have little chance of it in the following 24 weeks. The presence of ADA is strongly correlated with adalimumab concentration and greatly influences clinical response. If ADA are present, dose interval shortening turned out to be less useful in our cohort.

Based on the correlation found between adalimumab serum levels and efficacy found in chapter 3b, we established a therapeutic range for adalimumab trough levels for further refinement of treatment in Chapter 3c. We conducted a multicenter, prospective, observational, daily practice cohort study at an academic hospital with affiliated secondary care hospitals in Belgium (cohort 1) and 2 academic hospitals in the Netherlands (cohort 2). Both cohorts included adult patients treated with adalimumab for plaque-type psoriasis. Cohort 1 comprised 73 patients who were being treated with adalimumab for more than 24 weeks until 401 weeks. In cohort 2 (n = 62), serum samples were obtained between weeks 24 and 52 of treatment. Cohort 2 includes patients presented in the study presented in chapter 3b. Before the start of adalimumab therapy and at time of serum sampling, PASI scores were determined. Adalimumab trough level and PASI score at the time of serum sampling were used to determine the receiver-operator characteristics analyses and to establish the concentration effect curve. By means of receiver-operator characteristics analyses with an area under the curve of 0.756 (SD, 0.046; 95%CI, 0.666-0.847) and a sensitivity of 78% and a specificity of 70%, 3.51mg/L was established as the lower margin for the therapeutic range. By means of a concentration effect curve, 7mg/L was established as the upper margin. One-third of patients had an adalimumab trough concentration exceeding 7mg/L. Based on the established range, a therapeutic algorithm for adalimumab treatment for patients with psoriasis can be developed and validated in a prospective patient cohort. By identifying this range, a step has been taken toward a more rational use of biological therapy in psoriasis. Developing a therapeutic algorithm may lead to less overtreatment of patients and cost savings.

Strategies to optimize treatment outcomes of biological treatment include the use of concomitant methotrexate, which has demonstrated beneficial effects on pharmacokinetics and treatment efficacy in psoriasis and other inflammatory disease such as rheumatoid arthritis. In Chapter 3d the trial protocol of a multicenter RCT is described. It is an investigator initiated study designed to compare combination treatment of adalimumab and methotrexate with adalimumab monotherapy in patients with psoriasis. Primary outcome is adalimumab drug survival at week 49. Other outcomes include improvement in disease severity and quality of life, tolerability and safety. Moreover, anti-adalimumab antibodies and adalimumab serum concentrations will be measured and correlations between genotypes and

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clinical outcomes will be assessed. Patient recruitment started in March 2014. Up to now, 36 patients have been randomized. Many more patients have been (pre)screened.

To investigate whether a therapeutic range could also be developed for ustekinumab treatment, the correlation between ustekinumab trough level, ustekinumab antibody concentration and clinical response was investigated in Chapter 3e. Ustekinumab trough levels (by a newly developed ELISA) and antidrug-antibodies (ADA) to ustekinumab (by a newly developed antigen binding test) were measured. The correlation between these factors and the extent of clinical response (measured by PASI) was investigated in ustekinumab treated psoriasis patients in a multicentre daily-practice cohort. At week 16, 27% of 41 patients were good responders. Median ustekinumab trough concentration was 0.41 and 0.42 mg/L at week 16 and 28 and at these time-points, no correlation was found between trough concentration of non-, moderate and good responders (correlation coefficients respectively-0.36/0.022). Amongst patients >100 kg, those treated with 90 mg ustekinumab (n=10) per administration did not attain significantly higher trough levels or greater improvement of median ΔPASI compared to patients receiving 45 mg (n=5). Seven percent (n=3) of patients formed ADA. No correlation was found between the extent of clinical response and ustekinumab trough levels. No correlation found, does not mean no such correlation exists; patients might be relatively overexposed to ustekinumab, trough levels may not be an adequate indicator of optimal ustekinumab concentrations or a correlation might be found with a larger sample-size. ADA were found in 7% of patients, due to small numbers, no clinical consequence could be established.

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SaMEnVaTTInG VOOR nIET InGEWIjdEn

De behandeling van psoriasis op maat: naar een veiliger en effectievere systemische behandeling.Dit proefschrift richt zich op de behandeling van psoriasis vulgaris met methotrexaat en biologicals. Het doel is om bestaande behandelingen te optimaliseren. In het eerste deel onderzoeken we de veiligheid en effectiviteit van de behandeling met methotrexaat en biologicals van psoriasis in de dagelijkse praktijk. In het tweede deel richten we ons op het optimaliseren van de behandelingen met methotrexaat en biologicals.

De algemene introductie in Hoofdstuk 1 geeft een overzicht van de geschiedenis, epidemiologie, comorbiditeiten, klinische kenmerken en de pathogenese van psoriasis. Het biedt ook een compleet overzicht van de behandeling van psoriasis vanuit een historisch perspectief.

Psoriasis is voornamelijk een huidziekte, die zich kenmerkt door rode, schilferende plekken op de huid. Het kan variëren van enkele plekken maar ook het gehele lichaam kan aangedaan zijn. Ook de nagels en de gewrichten kunnen aangedaan zijn. Behandeling kan bestaan uit zalf, lichttherapie, tabletten, injecties of een infuus. Zoals hierboven genoemd, richt dit proefschrift zich op de behandeling van psoriasis met methotrexaat en biologicals. Deze bestaande behandelingen willen we optimaliseren. Methotrexaat wordt genomen in tabletvorm of als injectie. Het is een behandeling die in de jaren ’50 is ontdekt en sinds de jaren ’70 geregistreerd is voor de behandeling van psoriasis. Biologicals worden toegediend als injectie of infuus. Biologicals bestaan sinds 20 jaar.

Om patiënten te mogen behandelen met een bepaald medicijn, moeten studies gedaan worden die de veiligheid en de effectiviteit van het medicijn aantonen. Dit zijn vaak gerandomiseerde studies, wat wil zeggen dat patiënten met een loting de ene of de andere behandeling krijgen. Die twee behandelingen worden in de studie vergeleken. De patiënten die meedoen aan deze studies zijn vaak gezonder dan patiënten die in de dagelijkse praktijk met het medicijn behandeld zullen worden. Ook worden patiënten in studies beter in de gaten gehouden.

Vanwege het verschil in patiëntenpopulatie en behandelomgeving tussen gerandomiseerd vergelijkend onderzoek en praktijk, is er een verschil in veiligheid en werkzaamheid van medicijnen tussen deze situaties. Voordat we overgaan op het optimaliseren van bestaande behandelingen zullen we ons eerst concentreren op het waarnemen van de veiligheid en effectiviteit van biologicals en methotrexaat in de dagelijkse praktijk in Hoofdstuk 2.

In Hoofdstuk 2a analyseren we het register van de afdeling dermatologie van het Academisch Medisch Centrum in Amsterdam. Dit register bevat alle opeenvolgende patiënten behandeld voor psoriasis met anti-TNF-α (etanercept, adalimumab, infliximab) en ustekinumab (alle vier zijn dit biologicals), sinds januari

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2005. Bij registratie in dit register werden patiënt-karakteristieken geregistreerd. In aanvulling hierop werden op elk polikliek bezoek de dosering, PASI (een maat voor ziekte activiteit), Skindex-29 (een maat om kwaliteit van leven te meten) en de bijwerkingen geregistreerd. De patiënten werden verdeeld in een groep naïef of niet-naïef voor behandeling met biologicals. Drugsurvival (de tijd dat een patiënt met een bepaald medicijn werd behandeld totdat het medicijn werd gestopt) verschilde niet significant voor naïeve behandelepisodes tussen de biologicals (etanercept 85% tot 64%, adalimumab 77% tot 77%, infliximab 75% tot 75% voor jaar 1- 4), of voor niet-naïeve behandel episodes (etanercept 86% tot 42%, adalimumab 84% tot 56%, infliximab 68% tot 43% voor jaar 1- 4; ustekinumab 84% tot 57% voor jaar 1 tot 3). De naïeve groep toonde betere drugsurvival en PASI 75 respons (een 75% verbetering gemeten in PASI vergeleken met de start van het medicijn) op week 12, maar het verschil was niet significant. Een vergelijkbare verbetering van de gemiddelde ΔPASI en ΔSkindex-29 werd waargenomen op week 12 en 52 voor alle biologicals in beide groepen, ook hier werd geen significant verschil waargenomen tussen de groepen. Beëindiging van de behandeling was vooral het gevolg van non-respons. Dit gold voor alle biologicals. We concludeerden dat er geen significant verschil in drugsurvival, gemiddelde ΔPASI of Skindex-29 respons op week 12 of 52 tussen de biologicals of tussen de naïeve en niet-naïeve groepen gevonden werd. Beëindiging van de behandeling was grotendeels te wijten aan non-respons. Ook concludeerden we dat sequentiële behandeling met de beschikbare biologicals effectief kan zijn.

In de dagelijkse praktijk wordt geopperd dat non-melanoom huidkanker (NMSC) een bijwerking is van anti-TNF-α behandeling (anti-TNF-α zijn bepaalde biologicals). NMSC is bijvoorbeeld een basaalcelcarcinoom of een plaveicelcelcarcinoom. In Hoofdstuk 2b analyseren we klinische gegevens van de afdeling dermatologie van het Academisch Medisch Centrum in Amsterdam en de afdelingen dermatologie en reumatologie van het Radboudumc in Nijmegen. De incidentie van non-melanoom huidkanker bij patiënten behandeld met anti-TNF-α werd vergeleken tussen psoriasis en reumatoïde artritis patiënten. Het doel was om te onderzoeken of er een verschil was in de tijd tot de eerste non-melanoom huidkanker en het risico op non-melanoom huidkanker tussen psoriasis en reumatoïde artritis patiënten die anti-TNF-α therapie gebruiken. Het non-melanoom huidkanker risico was significant hoger in de psoriasis groep [adjusted hazard ratio 6,0 (1,6-22,4 95% CI)] met een kortere tijd tot de eerste non-melanoom huidkanker in psoriasis in vergelijking met reumatoïde artritis. Middels Poisson regressie analyse werd berekend dat psoriasis patiënten een 5.5 maal hogere kans hadden op non-melanoom huidkanker (2,2-13,4 95% CI). Dit geeft aan dat ziekte gerelateerde factoren zoals mogelijk bijvoorbeeld fototherapie belangrijke factor zijn die bijdragen aan non-melanoom huidkanker gediagnosticeerd bij psoriasis patiënten die met anti-TNF-α behandeld worden.

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Een zorg voor patiënten die langdurig methotrexaat behandeling voor psoriasis krijgen is de ontwikkeling van leverfibrose (schade aan de lever). Leverbiopten (een hapje uit de lever nemen) zijn de manier voor het aantonen van leverfibrose. Procollageen III aminoterminaal peptide (PIIINP) is een waarde in het bloed welke wordt gebruikt als pre-screening voor het opsporen van leverfibrose.

Het is de vraag of PIIINP een geschikte waarde is. In Hoofdstuk 2c beschreven we de resultaten uit de dagelijkse praktijk van de analyse van PIIINP bepalingen bij psoriasis patiënten behandeld met methotrexaat. Gegevens over patiënten met PIIINP bepalingen gedaan tussen 2006-2012 werden verzameld uit patiënten dossiers en registers in drie ziekenhuizen in de Nederland. Verzameld werden onder andere patiënt- en behandelkenmerken, PIIINP concentraties, verdere diagnostische tests naar leverfibrose en ALT en γ-GT (waarden die het levercelverval aangeven). In totaal waren 183 patiënten met 952 patiëntjaren op methotrexaat en 546 patiëntjaren met PIIINP metingen beschikbaar. Normaal seriële PIIINP-concentraties werden gevonden in 142 patiënten (78%) en 41 patiënten (22%) hadden verhoogde PIIINP series. De cumulatieve dosis methotrexaat (hoeveel methotrexaat iemand in totaal heeft gekregen) verschilde niet tussen de groepen. Patiënten met verhoogde PIIINP concentraties waren beduidend ouder met een langere ziekteduur en een hogere body mass index dan patiënten met normale PIIINP concentraties. Twintig van de 41 patiënten (49%) met verhoogde PIIINP concentraties hadden verdere diagnostische tests; één patiënt had ernstige fibrose (Roenigk 3b) wat bleek uit een biopt, 2 patiënten hadden mogelijk leverfibrose op FibroScan (F3) (Fibroscan is een echo die lever stijfheid meet) en 14 patiënten vertoonden tekenen van leversteatose (vervetting van de lever) op echografie of biopsie. PIIINP concentraties toonde lage correlaties met ALT of γ-GT-metingen (PCC 0,1 en 0,06 respectievelijk). Een belangrijke beperking van deze studie was dat slechts 20 van 41 patiënten met verhoogd PIIINP verdere diagnostische tests (bijvoorbeeld een biopt of FibroScan) naar leverfibrose hebben gehad en nog minder patiënten hebben een leverbiopsie (gouden standaard) gehad. Meer onderzoek is nodig om conclusies te trekken over de geschiktheid van PIIINP als screeningsmethode voor leverfibrose.

In hoofdstuk 3 richten we ons op het optimaliseren van bestaande behandelingen met methotrexaat en biologicals. In de dagelijkse praktijk is de behandeling niet afgestemd per patiënt, er wordt vaak een standaard dosering gehanteerd. Met deze vaste behandelregimes, wordt een breed scala aan respons op de behandeling waargenomen bij patiënten. Dit leidde tot de vraag of de behandeling kan worden geoptimaliseerd: kunnen de bestaande behandelingen worden aangepast per patiënt?

De eerste focus ligt op de behandeling met methotrexaat in Hoofdstuk 3a. Middels een systematic review (het wetenschappelijk samenvatten van alle beschikbare onderzoeken) vatten we het bewijs samen voor een test-dosis, startdosis, dosering frequentie, dosisaanpassing, maximale dosering en het gebruik van foliumzuur.

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We voerden een literatuuronderzoek uit naar gerandomiseerd vergelijkende studies en richtlijnen. Drieëntwintig gerandomiseerd vergelijkende studies (met 29 behandelgroepen) en 10 richtlijnen zijn opgenomen. Twee behandelgroepen gebruikten een test dosis, 5 richtlijnen raden het aan. De methotrexaat startdosis in studies varieerde van 5 tot 25 mg / week, meestal hetzij 7,5 mg of 15 mg. Richtlijnen variëren van 5 tot 15 mg / week. Methotrexaat werd toegediend als een enkele dosis of in Weinstein schema (een dosis verdeeld in drie gelijke porties met twaalf uur tussen iedere portie) in 15 en 11 behandelgroepen respectievelijk; beide werden even vaak aanbevolen in richtlijnen. Een vaste dosis (n = 18), een vooraf gedefinieerde dosis (n = 3) of een dosis aangepast op basis van klinische verbetering (n = 8) werd gebruikt in studies, de laatste wordt aanbevolen richtlijnen. Tien behandelgroepen gebruikten foliumzuur; in 2 mocht men het gebruiken, in 14 werd het niet genoemd, en in 3 werd expliciet vermeld dat het niet gebruikt werd. De meeste richtlijnen raden het gebruik van foliumzuur aan. Op basis van deze resultaten hebben we suggesties voor methotrexaat dosering opgesteld:• Test-dosis: aanbevolen voor kwetsbare patiënten (bijvoorbeeld ouderen of

patiënten met een verminderde nierfunctie)• Start dosering: 5 tot 7,5 mg per week in kwetsbare patiënten en 15 mg per

week bij gezonde patiënten. In beide groepen met aanvankelijk frequente laboratorium controle

• Doseringsfrequentie: enkelvoudige dosis. Gebruik van de Weinstein schema als gastro-intestinale klachten optreden

• Dosisverhoging in week 8 tot 20 mg per week als onvoldoende respons wordt gezien. In goede responders moeten reducties van de dosis worden overwogen

• De maximale dosis is 25 mg per week• Foliumzuur wordt aanbevolen, in een dosering en frequentie variërend

van 1-5 mg / dag behalve op de dag van toediening van methotrexaat tot 5 mg / week, 24 uur na methotrexaat

De volgende focus ligt op adalimumab behandeling. Adalimumab is een biological die TNF-α bindt. In Hoofdstuk 3b hebben we onderzocht of er een correlatie bestaat tussen de adalimumab dalspiegel concentratie (de concentratie adalilmumab gemeten in het bloed vlak voor de volgende injectie), adalimumab anti-medicijn antilichaam concentratie (ADA, antistoffen die het lichaam aanmaakt tegen het medicijn waardoor het niet meer werkt) en klinische respons. In een eerder cohort van 29 patiënten met psoriasis vulgaris gevolgd voor 24 weken werd een relatie geobserveerd tussen ADA vorming en effectiviteit. Lange-termijn gegevens ontbraken. We presenteerden het vervolg van deze multicenter cohort studie: 80 patiënten gevolgd gedurende 1 jaar. Voor deze patiënten werd de ernst van de ziekte vastgesteld door middel van PASI, bloedmonsters werden verzameld en adalimumab en ADA concentraties werden bepaald bij aanvang en in week 12, 24 en 52. Correlaties werden berekend middels

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een Spearman rank test. ADA werd gevormd in 49% van de patiënten. In 90% van deze patiënten werd ADA vorming voor het eerste geconstateerd voor week 24 van behandeling. Adalimumab en ADA concentraties, de klinische respons en ADA concentratie en adalimumab concentratie en klinische respons hadden correlaties van -0,872, -0,606 en 0,519, respectievelijk. Het adalimumab dosis interval werd ingekort wegens gebrek aan effectiviteit bij 15 patiënten, 7 patiënten met en 8 zonder ADA; verbetering van de effectiviteit vond plaats 1 van 7 en 4 van 8 respectievelijk. We concludeerden dat patiënten zonder ADA-vorming in de eerste 24 weken van de behandeling weinig kans hebben op ADA vorming in de volgende 24 weken. De aanwezigheid van ADA is sterk gecorreleerd met afname van de adalimumab concentratie en heeft grote invloed op de effectiviteit. In dit cohort had het verkorten van het dosis interval minder effect bij aanwezigheid van ADA in vergelijking met een situatie waarin geen ADA aanwezig zijn.

Gebaseerd op de correlatie gevonden tussen adalimumab serum concentraties (de hoeveelheid adalimumab in het bloed) en de effectiviteit, beschreven in hoofdstuk 3b, hebben we de optimale concentratie voor adalimumab dal spiegels bepaald in Hoofdstuk 3c welke uiteindelijk gebruikt kan worden voor een meer persoonlijke behandeling. We voerden een multicenter prospectieve observationele cohort studie uit in een academisch ziekenhuis met gelieerde ziekenhuizen in België (cohort 1) en twee academische ziekenhuizen in Nederland (cohort 2). Beide cohorten bestaan uit volwassen patiënten behandeld met adalimumab voor psoriasis vulgaris. Cohort 1 (n = 73) bestaat uit patiënten die langer dan 24 weken tot 401 weken werden behandeld met adalimumab, cohort 2 (n = 62) uit patiënten die tussen de 24 en 52 weken werden behandeld. Vóór aanvang van adalimumab behandeling en op het moment van serum afname (op dal spiegel moment) werd PASI bepaald. Middels een receiver-operator characteristics analyse met een Area Under the Curve van 0,756 (SD = 0,046; 95% CI 0,666-0,847, sensitiviteit: 78%, specificiteit: 70%), werd 3,51 mg / l vastgesteld als minimale waarde voor de optimale concentratie van adalimumab in het bloed. Middels een concentratie-effect curve, werd 7 mg /l vastgesteld als maximale waarde. Een optimale adalimumab concentratie van 3,51 mg / l tot 7,00 mg / l werd vastgesteld, welke correspondeert met het optimale effect. In een derde van de patiënten werd geobserveerd dat de dal spiegel concentratie de optimale concentratie overschreed. Op basis van de vastgestelde optimale concentratie, kan een therapeutisch algoritme voor adalimumab behandeling voor psoriasis patiënten worden ontwikkeld. Deze moet worden gevalideerd in een prospectief cohort. Door het vaststellen van deze optimale concentratie is een stap gezet richting een rationeler gebruik van biologicals bij psoriasis vulgaris. Bij patiënten die een hoeveelheid adalimumab in het bloed hebben die boven de optimale concentratie ligt bijvoorbeeld, kan de dosering misschien wel verlaagd worden. Het ontwikkelen van een therapeutisch algoritme zal leiden tot minder overbehandeling van patiënten en besparing op de zorgkosten.

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Strategieën om behandelresultaten van biologicals te optimaliseren omvatten onder andere gelijktijdig gebruik van methotrexaat. Dit heeft een gunstig effect op de farmacokinetiek en werkzaamheid van enkele biologicals bij psoriasis en andere inflammatoire ziekten zoals reumatoïde artritis. Echter is dit voor methotrexaat bij adalimumab in de behandeling voor psoriasis nog niet in een gerandomiseerde studie onderzocht. In hoofdstuk 3d wordt het onderzoeksprotocol beschreven van een multicenter gerandomiseerde studie. Het is een studie ontworpen om de combinatiebehandeling van adalimumab en methotrexaat te vergelijken met adalimumab monotherapie bij patiënten met psoriasis. De primaire uitkomstmaat is het aantal patiënten wat nog met de initiële therapie behandeld wordt (drug survival) op week 49. Andere uitkomsten zijn onder andere verbetering van de ernst van de ziekte en de kwaliteit van leven, hoe de behandeling verdragen wordt en de veiligheid ervan. Bovendien zullen anti-adalimumab antistoffen en adalimumab serum concentraties worden gemeten en correlaties tussen genotypes (genetisch onderzoek) en klinische resultaten zullen worden bekeken. Patiënten werving is begonnen in maart 2014. Tot nu toe werden 36 patiënten gerandomiseerd.

Om te onderzoeken of een optimale concentratie ook gevonden kon worden voor ustekinumab behandeling (een biologic die ingrijpt op IL12-IL 23), hebben we het verband tussen ustekinumab dalspiegel, ustekinumab antilichaamconcentratie en klinische respons onderzocht in Hoofdstuk 3e. Ustekinumab dalspiegels (bepaald middels een nieuw ontwikkelde ELISA) en anti-medicijn antilichamen (ADA) naar ustekinumab (bepaald middels een nieuw ontwikkelde antigenbindende test) werden gemeten. De correlatie tussen deze factoren en de mate van effectiviteit (gemeten middels PASI) werd onderzocht in een multicenter prospectieve observationele cohort studie. In week 16, werd bij 27% van de 41 patiënten goede effectiviteit geobserveerd. De mediane ustekinumab dalspiegel was 0,41 en 0,42 mg / l in week 16 en 28 en op deze tijdstippen werd geen correlatie gevonden tussen dalspiegel van patiënten met een slechte, matige en goede effectiviteit (correlatiecoëfficiënten respectievelijk-0,36 / 0,022). Bij patiënten> 100 kg, die behandeld werden met 90 mg ustekinumab (n = 10) per toediening werd geen significant hogere dalspiegel of grotere effectiviteit gevonden vergeleken met patiënten die 45 mg per toediening kregen (n = 5). Zeven procent van de patiënten (n = 3) vormde ADA. Geen correlatie werd gevonden tussen de omvang van de effectiviteit en ustekinumab dalspiegels. Dat er geen correlatie gevonden werd, betekent niet dat deze niet bestaat; het kan zijn dat alle patiënten overgedoseerd zijn, ook kan het zijn dat afname op dalspiegel moment geen goed beeld geeft van de optimale ustekinumab concentratie. Het kan ook zijn dat een correlatie pas gevonden wordt bij een grotere groep patiënten dan de door ons gepresenteerde groep. Vanwege het kleine percentage patiënten met ADA (7%) kon geen correlatie met de effectiviteit of serumspiegel worden berekend.

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LIST OF CONTRIBUTING AUTHORSPORTFOLIO

BIBLIOGRAFIECURRICULUM VITAE

DANKWOORD

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lIST Of COnTRIbuTInG auThORS

S.P. Menting, A.S. Sitaram, H.M. Bonnerjee-van der Stok, M.A. de Rie, Ph.I. Spuls, R. Dhaliwal, P.M. Dekker, A.C.Q. de Vries, L.L.A. Lecluse, C.I.M. BusardDepartment of Dermatology, academic medical center, amsterdam, The Netherlands

L. HooftDutch cochrane center, utrecht, the Netherlands

P.P.M. van Lumig, J.M.P.A. van den Reek, P.C.M. van de Kerkhof, E.M.G.J. de Jong, W.W.L. Janssen, ME OteroDepartment of Dermatology, radboud university medical center, Nijmegen, The Netherlands

E. Coussens, J. LambertDepartment of Dermatology, Ghent university Hospital, Gent, Belgium

D. van der Kleij, G.J. Wolbink, T. RispensDepartment of immunopathology, sanquin research, amsterdam

J.S. van Bezooijen, E.P. Prens, M.B. van Doorn, E.M. Baerveldt,Department of Dermatology, Erasmus university medical center rotterdam, rotterdam, The Netherlands

M.F. Pouw Jan van Breemen research institute/reade, amsterdam, the Netherlands and sanquin research and landsteiner laboratory, Department of immunopathology, academic medical centre, university of amsterdam, amsterdam, the Netherlands

J. Limpensmedical library, academic medical center, amsterdam, the Netherlands

P.L.C.M. van Riel, J. Fransen Department of rheumatic Diseases, radboud university medical center, Nijmegen, The Netherlands

W. KievitDepartment for Health Evidence, radboud university medical center, Nijmegen, The Netherlands

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A.C. Heijboer Department of clinical chemistry, Endocrine laboratory, Vu university medical center, amsterdam, the Netherlands

A.E. van Herwaarden, FCGJ Sweep Department of laboratory medicine, radboudumc, Nijmegen, The Netherlands

L.M. de JongDepartment of Dermatology, Ziekenhuis Gelderse Vallei, Ede, The Netherlands

E.T. Tjwa Department of Gastroenterology and Hepatology, radboudumc, Nijmegen, The Netherlands

L. TemmermanDepartment of Dermatology, maria middelares Hospital, Gent, Belgium

H. BoonenDepartment of Dermatology, H Hart Ziekenhuis, mol, Belgium

B.A. Hutten Department of clinical Epidemiology, Biostatistics and Bioinformatics, academic medical center, university of amsterdam

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Phd PORTfOlIO

PhD period: September 2011-November 2016Promotores: Prof. dr. Ph. I. Spuls, Prof. dr. M.A. de RieCo-promotores: Dr. L. HooftInstitution: Department of Dermatology, Academic Medical Center, University of Amsterdam

General courses Year ECTS

AMC world of Science 2011 0.7

Basic course Legislation and Organization for Clinical Researchers (BROK)

2011 1.0

Clinical Data Management 2012 0.3

Practical biostatistics 2012 1.1

Reference manager? Endnote?

Meetings Year ECTS

6th International Congress on Dermato-Epidemiology, IDEA, Malmo, Sweden

2012 0.75

Nederlandse Vereniging voor Experimentele Dermatologie, Lunteren, the Netherlands

2013 0.50

International Investigative Dermatology, Edinburgh, United Kingdom

2013 0.75

Psoriasis International Network Congress, Paris, France 2013 0.75

European Academy of Dermatology and Venereology, Amsterdam, the Netherlands

2014 0.75

From Gene to Clinic, London, United Kindom 2014 0.75

Oral conference presentations Year ECTS

Nederlandse Vereniging voor Experimentele Dermatologie, Lunteren, the Netherlands. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up.

2013 0.5

Psoriasis International Network Congress, Paris, France. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up.

2013 0.25

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Oral conference presentations Year ECTS

European Academy of Dermatology and Venereology, Amsterdam, the Netherlands. Optimizing methotrexate treatment: a systematic review of the use of test-dose, start-dose, dosing scheme, dose adjustments, maximum dose and folic acid supplementation.

2014 0.5

From Gene to Clinic, London, United Kindom, Developing a therapeutic range of adalimumab serum concentrations in management of psoriasis: a step toward personalized treatment.

2014 0.5

Poster presentations Year ECTS

International Investigative Dermatology, Edinburgh, United Kingdom. Extent and consequences of antibody formation against adalimumab in patients with psoriasis: one-year follow-up.

2013 0.5

Coaching student in scientific internships Year ECTS

Reetinder Dhaliwal. Analysis of PIIINP measurements in methotrexate treated psoriasis patients

2012 3

Aashna Sitaram, Drug survival is not significantly different between biologics in patients with psoriasis vulgaris: a single-center database analysis.

2013 3

Seminars, workshops and masterclasses Year ECTS

Stuurgroep Psoriasis, clinical research meeting every two months

2011-2014 1.5

Clinical and Scientific conference, weekly meeting 2011-2014 3.75

PSO-TOP Investigator Meeting, Hamburg, Germany 2011 0.5

DIO dagen, Amersfoort, the Netherlands 2012-2014 0.75

M11-810 Investigator Meeting, Munchen, Germany 2012 0.5

Psoriasis Center of Excellence Meeting, Manchester, United Kingdom

2012 0.5

AIN2312 Investigator Meeting, Barcelona, Spain 2013 0.5

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Awards Year

Breaking News Award Nederlandse Vereniging voor Experimentele Dermatologie: Developing a therapeutic range of adalimumab serum concentrations in management of psoriasis: a step toward personalized treatment.

2015

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bIblIOGRafIE

Towards better triage of infants suspected of cow’s milk allergy: development of a preliminary multivariable diagnostic index. van Thuijl O., Schoemaker A, Menting SP, van Dulmen J, Boeting J, van Aalderen W, ter Riet G, Sprikkelman A. Eur. J. Pediatr, 2013 Mar;172(3):385-91.

Comment on ‘Predicting treatment response in psoriasis using serum levels ofadalimumab and etanercept: a single centre, cohort study’ Menting SP, van der Kleij D, Rispens T, Spuls PhI, Lecluse LLA Br J Dermatol. 2013 Nov;169(5):1170.

Extent and Consequences of Antibody Formation Against Adalimumab in Patients With Psoriasis: One-Year Follow-up.Menting SP, van Lümig PP, de Vries AC, van den Reek JM, van der Kleij D, de Jong EMGJ, Spuls PhI, Lecluse LL.JAMA Dermatol. 2014 Feb 1;150(2):130-6.

Composition of Innate Lymphoid Cell (ILC) Subsets in the Human Skin: Enrichment of NCR+ ILC3 in Lesional Skin and Blood of Psoriasis Patients.Teunissen MB, Munneke JM, Bernink JH, Spuls PhI, Res PC, Te Velde A, Cheuk S, Brouwer MW, Menting SP, Eidsmo L, Spits H, Hazenberg MD, Mjösberg J.J Invest Dermatol. 2014 Sep;134(9):2351-60.

Drug survival not significantly different between biologics in patients with psoriasis vulgaris: a single center database analysis.Menting SP, Sitaram AS, van der Stok HM, de Rie MA, Hooft L, Spuls PI.Br J Dermatol. 2014 Oct;171(4):875-83.

TNF-α-remmers, wees op uw hoede! Menting SP, Engelen JWMNed Tijdschr Derm Ven. 2015 Jan; 25/1: 11-12

An increased risk of non-melanoma skin cancer during TNF-inhibitor treatment in psoriasis patients compared to rheumatoid arthritis patients probably relates to disease-related factors.van Lümig PP, Menting SP, van den Reek JM, Spuls PhI, van Riel PL, van de Kerkhof PC, Fransen J, Kievit W, de Jong EM.J Eur Acad Dermatol Venereol. 2015 Apr;29(4):752-60.

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Developing a Therapeutic Range of Adalimumab Serum Concentrations in Management of Psoriasis: A Step Toward Personalized Treatment.Menting SP, Coussens E, Pouw MF, van den Reek JM, Temmerman L, Boonen H, de Jong EM, Spuls PhI, Lambert J.JAMA Dermatol. 2015 Jun;151(6):616-22.

Nonmelanoma huidkanker tijdens behandeling met TNF-blokkers bij psoriasis en reumatoïde artritis. van Lümig PPM, Menting SP, van den Reek JMPA, Spuls PhI, van Riel PLCM, van de Kerkhof PCM, Fransen J, Kievit W, de Jong EMGJNed Tijdschr Geneeskd. 2015;159:A8865

The correlation of clinical efficacy, serum trough levels and antidrug antibodies in ustekinumab-treated patients with psoriasis in a clinical-practice setting.Menting SP, van den Reek JM, Baerveldt EM, de Jong EM, Prens EP, Lecluse LL, Wolbink GJ, Van der Kleij D, Spuls PhI, Rispens T.Br J Dermatol. 2015 Sep;173(3):855-7.

Potential serum biomarkers of treatment response to ustekinumab in patients with psoriasis: a pilot study.Onderdijk AJ, Ijpma AS, Menting SP, Baerveldt EM, Prens EP.Br J Dermatol. 2015 Dec;173(6):1536-9.

Methotrexate Dosing Regimen for Plaque-type Psoriasis: A Systematic Review of the Use of Test-dose, Start-dose, Dosing Scheme, Dose Adjustments, Maximum Dose and Folic Acid Supplementation.Menting SP, Dekker PM, Limpens J, Hooft L, Spuls PhI.Acta Derm Venereol. 2016 Jan 20;96(1):23-8.

Serumspiegel- en antistofbepaling bij biologicals voor psoriasis in de dermatologische dagelijkse praktijk.Menting SP, Busard CIM, Lecluse LLA, Spuls PhINed Tijdschr Derm Ven. 2016 Mei; 26/5: 238-214

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CuRRICuluM VITaE

Stef Menting werd geboren in Riethoven op 2 juni 1984 als oudste kind van drie. Hij rondde zijn VWO opleiding af aan het Were Di College te Valkenswaard. Na zijn middelbare school is hij in een jaar om de wereld gereisd om vervolgens geneeskunde te studeren aan het Academisch Medisch Centrum in Amsterdam. Tijdens zijn studie geneeskunde heeft hij in zijn tweede jaar een junior coschap chirurgie gevolgd aan het Komfo Anokye Teaching Hospital, Kumasi, Ghana. In zijn vierde jaar heeft hij samen met mede studenten het MPower project opgezet in Mundri, Zuid-Soedan en in zijn zesde jaar heeft hij een keuze coschap dermatologie gevolgd aan de Mount Sinai School of Medicine, New York City, United States. Als wedstrijd roeier was Stef enkele jaren actief bij A.A.S.R. SKØLL. Zijn eerste onderzoeksstage voltooide hij aan de afdeling kinderpulmonologie onder begeleiding van dr. Aline Sprikkelman. Tijdens de coschappen deed hij een extra onderzoeksstage bij prof. dr. Rosalie Luiten op de afdeling experimentele dermatologie. Na zijn oudste coschap dermatologie aan het AMC en het behalen van het artsexamen is hij gestart met zijn promotieonderzoek wat hij combineerde met het uitvoeren van farmaceutische studies. In september 2014 startte hij aan zijn opleiding tot dermatoloog in OLVG Oost onder begeleiding van drs. Jacqueline Engelen.

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dankWOORd

Dit proefschrift had nooit tot stand kunnen komen zonder de belangeloze inzet van vele patiënten. Graag wil ik iedereen bedanken die heeft bijgedragen aan dit proefschrift, op welke manier dan ook. Een aantal personen wil ik in het bijzonder bedanken.

Phyllis, waar te beginnen? Een fijnere promotor kan ik me niet wensen. Altijd kon ik bij je binnen komen stormen en nam je ruim de tijd om mijn stukken kritisch door te nemen. Vervolgens liep ik je kamer uit met meer werk dan waarmee ik binnenkwam, maar altijd met veel nieuwe energie!

Tegenvallers met beurzen, ‘iets’ vergeten (you know what); altijd bleef jij kalm en positief. Binnen de muren van het AMC heb ik ontzettend veel van je geleerd, de vele momenten daarbuiten zijn me zeker net zo dierbaar.

Professor de Rie, hartelijk dank voor uw begeleiding van mijn promotietraject. De grote lijnen hield u altijd op een prettige manier in de gaten en op uw kennis van psoriasis kon ik rekenen.

Lotty. Bij jou kon ik altijd terecht voor methodologische input. Jouw creatieve ideeën hebben mijn promotie verder vorm gegeven en je positieve woorden kwamen op het juiste moment.

Leden van mijn promotiecommissie; professor Lambert, professor van de Kerkhof, dr. Wolbink, professor Bossuyt, professor D’Haens en dr. Mekkes. Ik dank u voor uw deelname aan de commissie en het kritisch beoordelen van het manuscript.

Evelien, toen ik voor de eerste keer de trialkamer binnen kwam en jou achter je bureau zag zitten wist ik dat het een hele mooie tijd zou gaan worden! En nu ben je mijn paranimf! Wat een super mooie tijd, om nooit te vergeten.

Pieter en Vincent, jullie zijn me dierbaar. De talloze etentjes, drankjes, feestjes et cetera blijven hopelijk nog lang voort duren. Piet, jouw voorkant van mijn boekje maakt me iedere keer blij. Vin, naast paranimf ook nog een maand samen door Zuid-Amerika reizen!

Linn, mijn derde paranimf. Met jou kon ik alle promotie perikelen delen. Met een koffietje op het AMC of met onze laptop in een café. Nu promoveren we bijna tegelijk en vieren we samen ons feest. De laptop laten we voortaan thuis!

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Mandy. Tijdens onze “zaaltijd” (jij als zaalarts, ik als oudste co) was onze vriendschap snel beklonken en had je me spoedig bij Phyllis voorgedragen. Ook bij de DIO dagen ben ik in je voetsporen getreden, wie weet wat er nog komen gaat? Een huis in het “groene graf”?

Gabrielle, Marleen, Louise, Celine en Marijke, lieve trialteam collega’s! Samenwerken met jullie was een genot. Zoveel collegialiteit en gezelligheid. Gab, met jou een kamer delen was heel fijn.

Lidian, zonder jouw geleverde werk was mijn promotie in deze vorm niet mogelijk geweest. Jouw antistoffen studie vormt de basis van veel van mijn stukken.

Professor Elke de Jong, Juul en Paula. Er zit wel een heel duidelijk Nijmeegs tintje aan mijn proefschrift! Ontzettend veel dank voor de fijne samenwerking.

Professor Hoekzema. Bij u op de afdeling in het OLVG is mijn dermatologie carrière begonnen. U heeft mijn interesse aangewakkerd. Uw kennis van de dermatologie inspireert mij, gelukkig zullen we nog minstens een aantal jaar samenwerken.

Jacqueline Limpens. Je inzet voor de systematic review heeft me enorm geholpen. Searches die opnieuw gedaan moesten worden, stukken die opnieuw geschreven moesten worden, nooit was dit je teveel.

Professor Jo Lambert en Emma Coussens. Bedankt voor de vlotte samenwerking omtrent de concentratie effect curve studie. Het doet mij goed dat de samenwerking voort blijft duren.

Desiree van der Kleij, Theo Rispens en Gert-Jan Wolbink. Jullie kennis en kunde vormt de basis van een groot aantal studies van mijn proefschrift.

Professor Prens, Sun-Jine van Bezooijen, Martijn van Doorn en Ewout Baerveldt. Dank voor de samenwerking voor de OPTIMAP- en de ustekinumab-studie.

Reetinder en Aashna. Zonder jullie bijdrage in de vorm van een wetenschappelijke stage was het niet gelukt om het PIIINP en drug survival stuk te schrijven.

Collega (oud-) AIOS en staf van de afdeling dermatologie van het AMC en VUMC. Heel veel dank voor de fijne samenwerking en voor jullie interesse in mijn promotie.

Annigje, Ellen, Irina, Jacqueline, Jan-Gert, Leonie en alle andere collega’s van de afdeling dermatologie van het OLVG. Mijn promotie heb ik afgemaakt in mijn OLVG

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tijd. De tweeëneenhalf jaar bij jullie zijn voorbij gevlogen. Een fijner begin van mijn opleiding kon ik niet wensen. Hoop jullie allemaal nog veel te blijven zien.

Dames van het secretariaat van de afdeling dermatologie van het AMC, jullie ondersteuning is goud waard!

Anke, Irma en Yvonne. Dank voor de gezellige avonden en weekenden samen en voor jullie interesse in mijn promotie. Dat we nog veel weekendjes weg mogen hebben! Sophie, Clara en Ro. Vanaf onze Skøll tijd zijn we elkaar nooit uit het oog verloren. Laten we dit zo houden! Wanneer komt er weer een weekend Haag of Scheef? Charlie, vertraagd op een of ander Grieks eiland, Sint en Piet knutselen in de Thalys; mooie momenten. Neeltje, mijn buurmeisje. Door de heg kruipen doen we niet meer vaak, maar gelukkig houden we nog altijd fijn contact. Gonnie, jij reist nog even lekker door, maar onze (wereldreis) basis is sterk!

Gængbångers, wat is het fijn jullie ontmoet te hebben. Rivièra beach voelt als thuis en deze regelmaat van etentjes en feestjes bevalt me uitstekend! Jullie gezelligheid blijft me stimuleren.

Tantes, ooms, nichtjes en neefjes. Dank voor alle betrokkenheid en gezelligheid.

Pa en Ma, jullie onvoorwaardelijke liefde, steun en interesse heeft mij de mogelijkheid gegeven om me te ontwikkelen tot de persoon die ik nu ben. Jullie levenshouding sterkt mij. Ieder weekend bij jullie voelt als een kleine vakantie. Joost en Inge, Bregt en Gijs, (schoon) broer en (schoon) zus, jullie zijn me dierbaar.

Edin. Wat hebben we een fijn leven samen. Met jou kan ik praten, stil zijn, feesten, vakantie vieren, werken, door de stad slenteren, bank hangen en nog 1000 dingen meer. Jouw passie inspireert me en van jouw persoonlijkheid leer ik. Met jou en M op de Lange Leidse kan ik de hele wereld aan.

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uva-dare (digital academic repository) tailoring psoriasis ...plaque type psoriasis, the focus of...

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