safety of anti-tumor necrosis factor agents in psoriatic arthritis – an update
TRANSCRIPT
1. Introduction
2. Preliminary remarks
3. Data from randomized
controlled trials
4. Data from long-term
open-label studies and
registries
5. Useful additional information
6. Expert opinion
Review
Safety of anti-tumor necrosisfactor agents in psoriaticarthritis -- an updateCarlo Palazzi, Salvatore D’Angelo, Pietro Leccese, Angela Padula &Ignazio Olivieri†
†Rheumatology Department of Lucania - San Carlo Hospital, Contrada Macchia Romana,
Potenza, Italy
Introduction: Tumor necrosis factor (TNF) blockers have represented a real
revolution in the treatment of rheumatoid arthritis and spondyloarthritides
(SpAs). In the case of psoriatic arthritis (PsA), anti-TNF agents are much more
effective than conventional disease modifying antirheumatic drugs on all
manifestations of the disease, that is, axial involvement, peripheral arthritis,
peripheral enthesitis, dactylitis and skin lesions. A complete understanding
of their safety is fundamental in clinical practice.
Areas covered: This article addresses the safety of anti-TNF therapy in PsA.
A systematic literature review was performed using the largest electronic
databases (MEDLINE, EMBASE and COCHRANE). The reported data were
derived from randomized controlled trials, open-observational studies and
meta-analyses. Useful information derived from the experiences in rheuma-
toid arthritis has also been reported.
Expert opinion: Anti-TNF therapies are as safe as conventional disease-
modifying antirheumatic drugs in the management of psoriatic arthritis
when the candidate patients are accurately selected. An adverse event could
still occur when the patient is managed according to current national and/
or international recommendations; therefore, tight controls aimed to detect
adverse events early is mandatory.
Keywords: adalimumab, adverse event, anti-TNF, etanercept, golimumab, infliximab,
psoriatic arthritis, safety
Expert Opin. Drug Saf. [Early Online]
1. Introduction
Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy included in the groupof the spondyloarthritides (SpAs) that affect subjects suffering from cutaneous psori-asis (Ps) or with a family history of Ps [1]. The targets of the disease are peripheral andaxial joints, and other musculoskeletal sites such as tendons, bursae and entheses [1].PsA radiographic features consist of destructive changes (joint erosions, tuft resorp-tion, osteolysis) and new bone formation (periarticular and shaft periostitis, ankylosis,spur formation and nonmarginal syndesmophytes) [2]. These findings can also occurin asymptomatic (occult) manner [3,4].
The administration of conventional disease modifying antirheumatic drugs(DMARDs) is ineffective on axial pain and is often unsatisfactory in controllingsymptoms of the peripheral localizations of PsA. In addition, traditional DMARDsare poorly effective in arresting the progression of the bone damage in the peripheralarthritis and in the axial skeleton [5]. As a consequence, the commercialization ofantitumor necrosis factor (TNF) agents has represented a tangible revolution inthe treatment of PsA. These drugs reduce signs and symptoms of inflammation,improve function and quality of life and hinder the progression of damage in
10.1517/14740338.2014.857655 © 2013 Informa UK, Ltd. ISSN 1474-0338, e-ISSN 1744-764X 1All rights reserved: reproduction in whole or in part not permitted
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peripheral joints [6]. Further, anti-TNF agents are also effec-tive on the skin manifestations of Ps disease [7].This article addresses the safety of anti-TNF therapy in
PsA. A systematic literature review was performed using thelargest electronic databases (MEDLINE, EMBASE andCOCHRANE). The reported data were derived from ran-domized controlled trials, open-observational studies andmeta-analyses.
2. Preliminary remarks
TNFa, a key proinflammatory cytokine, has been identifiedin the Ps skin lesions, the synovial membrane and theinflamed entheses of PsA patients [8-10]. It promotes the pro-duction of several other substances that are also implicatedin inflammatory processes, such as IL-1, IL-6, IL-8,IL-12 and degradative enzymes [8-10]. In addition, TNFaplays an important role in T-cells activation, vascular prolifer-ation (which is a typical feature of the PsA synovial mem-brane) and erosive process at the articular bone surfacesinduced by the activation of osteoclast precursors by theRANK/RANKL system [8-10].At present, four anti-TNF agents are widely used for the
management of PsA: etanercept (ETN), infliximab (IFX),adalimumab (ADA) and golimumab (GOL). The first oneis engineered from the human type II TNF receptor, whereasthe others have been generated as anti-TNF monoclonal anti-bodies. This molecular difference can explain some differencesin the mechanisms of action of these two sub-classes ofanti-TNF agents. When ETN is compared with the otheranti-TNF agents, it does not inhibit interferon-g expression,it scarcely influences the complement-dependent cytotoxicity,and it does not induce apoptosis in some tissues other thansynovium (e.g., the gastrointestinal mucosa) [11-16]. That hasrepercussions on the effectiveness of the two subclasses ofanti-TNFs agents on different disease manifestations: anti-TNF monoclonal antibodies should be preferred in patients
with inflammatory bowel disease and SpA-related anterioruveitis while ETN should be preferred in patients at risk ofdeveloping granulomatous infections [11-16]. In addition, thesmall differences also existing among the three anti-TNFmonoclonal antibodies can have consequences in their clinicaleffectiveness which can vary considerably in the single patient.
IFX is administered by infusional route while ADA, ETNand GOL are given subcutaneously.
The financial burden associated with the cost of anti-TNFagents as well as concerns about their long-term safety sug-gests to reduce the dosage of the drug or to discontinue treat-ment in hopes of a drug-free remission. Unfortunately,discontinuation of therapy in axial SpA (including PsA) andperipheral arthritis is not achievable in the majority of patientswhile the reduction of the dosage is often possible [17]. Only insome patients suffering from peripheral SpA (including PsA),especially in those with isolated enthesitis, it is possible to dis-continue therapy and to achieve a drug-free remission [17].
3. Data from randomized controlled trials
In 2008, a systematic review and meta-analysis was performedby Saad et al. [18]. Six randomized, placebo-controlled trials(RCTs) including 982 patients with PsA were analyzed. Theduration of the examined RCTs lasted from 12 to 24 weeks.ADA was used (40 mg subcutaneous every other week) intwo of these trials [19,20], ETN (25 mg SC twice/week)in other 2 trials [21,22], and IFX (5 mg/kg) in the last two tri-als [23,24]. The authors did not find significant differencesbetween TNF-inhibitors and placebo in withdrawals due toadverse events (AE), in the percentages of patients experienc-ing serious AE (SAE), and in upper respiratory tract infec-tions [18]. By means of indirect analysis, they did not foundsignificant differences among the 3 anti-TNF agents in theproportion of patients experiencing SAE. Four trials, includ-ing 678 patients, reported the proportions of patientsexperiencing injection site reactions [18-22]. ETN showed anincreased rate of this kind of reaction when compared withplacebo (RR 4.27, 95% CI 2.25, 8.13), while ADA did notevidence this. The percentage of subjects experiencing infu-sion reactions was not different between IFX and placebogroups [23,24]. A further analysis [18] concerning the develop-ment of malignancies during anti-TNF therapy was carriedout on 5 of the 6 above-mentioned studies [19,20,22-24]. It didnot show differences between anti-TNF and placebo (onlyone patient of the placebo group developed a skin basal-cellcarcinoma) [18].
Recently, Fenix-Caballero et al. [25] carried out two indirectcomparisons of 4 RCTs [19,22,24,26] on the anti-TNF agentsusually administered for PsA. First, they compared ADA,ETN and GOL versus IFX, and then they compared ADAand GOL versus ETN. The most frequent AE with all thesefour drugs was upper-airway infection, but relevant differencesamong the agents were not found. However, significant differ-ences were found for injection site reactions, with a higher
Article highlights.
. Anti-TNF agents have revolutionized the treatment ofpsoriatic arthritis.
. They reduce signs and symptoms of inflammation,improve function and quality of life and hinder theprogression of damage in peripheral joints.
. Anti-TNF agents are also effective on the skinmanifestations of psoriatic disease.
. Safety of these drugs is similar to that of the lesseffective conventional DMARDs.
. Immunosuppressive effects of anti-TNFs should not bedisregarded and their prescription cannot be trivialized.
. The appearance of serious adverse (especially infections)events cannot be completely abated, also with acareful management.
This box summarizes key points contained in the article.
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reported number in patients treated with ETN compared withADA and GOL [25]. Notwithstanding these data, the Authorsconsider that in PsA patients the four anti-TNF agents offersimilar benefit/risk ratios and that they could be regarded asequivalent alternatives in treating such patients [25].
In 2010, a RCT compared the efficacy over 12 weeks oftwo different ETN regimens (50 mg twice weekly for379 patients or 50 mg once weekly, for 373 patients) givenfor the treatment of skin manifestations of psoriasis, inpatients who also had PsA [27]. In addition, efficacy and safetyover an additional 12-week open-label ETN treatment wasevaluated. ETN was well tolerated in both treatment groupsover 24 weeks; significant differences between the groups inthe incidence of AEs were not found. The most commonlyreported AEs were upper respiratory tract infections, injectionsite reactions, pharyngitis and headache. A total of 26 (3.5%)SAEs were reported, including infections (5 cases). Cases oftuberculosis (TB) or opportunistic infections were notdescribed. Four malignancies were also found: three skin car-cinomas and one breast carcinoma.
4. Data from long-term open-label studiesand registries
The maximum duration of the RCTs cited above is 24 weeks.Are their results concerning the safety reliable also for longertreatments with anti-TNF drugs?
Four out of the six previously cited RCTs (on ADA, ETN,IFX and GOL, respectively [19,22,23,26]), had a 2-year open-label extension. The nature and frequency of AEs duringlong-term treatments were consistent with the safety profileduring short-term treatments [28-31].
A Canadian study enrolling 110 PsA patients from a clinicalsetting (without a control group) analyzed the effects of a 2-yearcourse of ETN therapy (50 mg/week subcutaneously) [32].Nasopharyngitis was the most common AE, occurring in20/110 individuals (18.2%). Twenty SAEs were reportedin 14 subjects. Malignancies and serious infections occurred inthree and six patients, respectively. The most frequentlyreported AE leading to withdrawal from the study was rash,which occurred in two patients. Two deaths were reported inpatients after they had withdrawn the study, but were not con-sidered related to ETN treatment. The absence of a placebogroup makes difficult the interpretation of these data.
In the British Society for Rheumatology Biologics Register,596 PsA patients receiving anti-TNF therapies were comparedwith a control group consisting of 1115 patients with activeRA receiving therapy with standard nonbiologic DMARDs [33].This study was performed using a postal follow-up question-naire sent to rheumatologists. In the anti-TNF cohort(1776 person-years) and in the control group (3410 person-years), 211 and 624 SAEs were reported, respectively. Whenadjusted for age, sex and baseline comorbidity, there were notsignificant differences between the anti-TNF and controlpatients. Infections were the most common SAEs in both
groups, but TB was not reported. Malignancies were observedin 14 anti-TNF patients and 67 DMARD controls. Basal-cellcancer was more frequently seen in the anti-TNF patients(13 in anti-TNF and 4 in controls, respectively) but the overallrisk of cancer was not different between the two cohorts [33].
Data from the South Swedish Arthritis Treatment GroupRegister concerning 261 subjects suffering from active PsAand treated with anti-TNF agents demonstrated that thesedrugs were well tolerated with a rate of SAEs of 5 -- 6% peryear [34]. No unexpected SAEs were reported [34]. A controlgroup was not provided in this study.
The risk of infection in patients treated with anti-TNFagents can vary across therapeutic indications with greatestrisk seen in patients with RA and with inflammatory bowel dis-eases. The lower rates of adverse events found in patients withPs and SpAs could be due to the less frequent use of concomi-tant immunosuppressant drugs, including corticosteroids.
More robust data on long-term safety of TNF blockersderive from clinical registries of patients with RA. Longerfollow-up and a larger number of patients included allowfor capturing rare adverse events more accurately. Evidencefrom such registries suggests that there is no increased riskof solid tumors with TNF inhibitors; however, nonmelanomaskin cancers are more common.
5. Useful additional information
In a recent review, a comprehensive analysis of AEs due to theTNF-blockers used in the treatment of PsA was performed [35].Although this article was also based on several data derived fromstudies concerning other diseases such as RA, it focuses ontopics of particular relevance for PsA treatment withTNF-blockers. The risk of severe TB reactivation (includingextrapulmonary/disseminated forms) has been abated with thedissemination of recommendations for pretreatment screen-ing [36,37]. It requires chest X-rays, tuberculin skin tests (TSTs)and/or interferon gamma release assays (IGRAs) [36,37].Although the accuracy of IGRAs remains to be determined,they are very useful in detecting false positivity of TST testdue to previous vaccination and also false negativity related toimmunosuppressive therapies [36-38]. Isoniazid is usually pro-phylactically administered in cases of suspected latent TB infec-tion (LTBI) [39]. Further, IGRAs can play a role in monitoringLTBI reactivation during anti-TNF administration [38,40].
The pretreatment screening must also evaluate the risk dueto hepatitis B exposure/infection and to other viral infectionssuch as human immunodeficiency virus and varicella zostervirus [39].
Reactivation of hepatitis, in patients with HBV chronicinfection (which is very common in several countries) treatedwith anti-TNF, was reported in 39% of cases [41]. As a conse-quence, antiviral treatment is recommended in HBsAg-positive patients and in HBsAg-negative and HBcAb-positivepatients when the search for HVB-DNA is positive [42]. Con-sidering the long duration of the anti-TNF treatment,
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antiviral drugs showing low resistance rate (tenofovir, entaca-vir) should be preferred [42]. Anti-HBV therapy can bestopped only 6 -- 12 months after the end of the anti-TNFadministration. HBV vaccination may be considered in sero-negative patients [42]. Studies to date suggest that anti-TNFshave not usually negative effects on HCV infection, but theiruse requires, anyway, caution and a close monitoring of serumtransaminases and HCV-RNA [42,43].Vaccination with pneumococcal vaccine is recommended
and annual vaccination against seasonal influenza is recom-mended too [39].Further recommendations concerning PsA patients treated
with anti-TNF to reduce the risks of SAEs such as infections,autoimmune disorders, are well-known because they arewidely applied (as outlined by the manufacturers too) alsoin patient with RA and more recently, in subjects sufferingfrom inflammatory bowel disease [35,39,43]. In particular, acareful clinical follow-up and a periodic search for autoanti-bodies are required to early disclose the development of con-nective tissue disease. All patients, especially those withhigher infection risk (i.e., with diabetes), starting an anti-TNF should be closely monitored for infection.Further, the effect of these drugs in patients with previous
malignancy or that have premalignant conditions is unknown[35,39,43].Anti-TNF should not be initiated in patients with New
York Heart Association (NYHA) Grade 3 or 4 cardiac failureand should be used with caution in the milder grades [35,39,43].Demyelinating disease/multiple sclerosis are contraindica-
tions for starting or continuing anti-TNF therapies [35,39,43].A paradoxical AE of the anti-TNF drugs consists in the
development of Ps form lesions in PsA patients without previ-ous skin involvement and with a family history of Ps [44]. Thecommonest clinical picture is represented by pustular lesionsmainly localized on palms and/or soles [44]. Considering thatin non-anti-TNF patients palmoplantar pustular Ps is rare(< 2% of all cases), the hypothesis that skin lesions occurringduring anti-TNF treatments is a de novo Ps and not an aggra-vation of a preexisting condition has been advanced [44]. Inthese circumstances, we consider the discontinuation of theanti-TNF agents or the association with topical treatmentsor with another systemic drug effective on Ps (e.g., cyclospor-ine). Very recently, the use of ustekinumab has been suggestedin a case report [45]. In the near future, ustekinumab mightoffer an effective therapeutic approach for PsA patients basedon a mechanism of action (IL12 and IL23 blockage), which isalternative to that of the anti-TNF agents [46].A recentmeta-analysis showed that there was a nonsignificant
tendency for an excess of non-melanoma skin cancer risk in RAusing anti-TNF [47]. A very recent nationwide population basedprospective cohort study coming from Sweden reported a 50%increased relative risk of invasive melanoma in RA subjectstreated with anti-TNF drugs [48]. However, the authors con-cluded that the small increase in absolute risk does not signifi-cantly shift the overall risk benefit balance of these drugs.
In 2012, French authors performed a systematic literaturereview focused on the carcinogenic risk of phototherapy forpsoriasis. They reported an increased risk of skin cancerfollowing PUVA treatments, mainly in patients with a historyof high dose exposure. The risk is higher for the developmentof squamous cell carcinomas, while data concerning basal-cellcarcinomas and melanoma are less unequivocal [49]. However,data suggesting an additional carcinogenic risk with the com-bination of PUVA and anti-TNF agents are lacking.
6. Expert opinion
Data concerning the safety of anti-TNF agents administrationin patients suffering from PsA are scarce in comparison withthose available for RA. In any case, they are sufficient to con-firm that safety of these drugs is similar to that of the less-effective conventional DMARDs [50]. Nevertheless, the con-spicuous immunosuppressive effects of anti-TNFs shouldnot be disregarded and their prescription cannot be trivialized.
It should be emphasized that the appearance of SAE cannotbe completely abated, also with a careful management accord-ing to guidelines. Patients must be accurately warned regard-ing the possible risks due to their anti-TNF treatment.Particularly, signs and symptoms of infections must bepromptly reported to the rheumatologist, as well as to thefamily doctor, and the occurrence of uncommon bacterial,fungal or viral infections must be always considered [35].
After the occurrence of a SAE, a retreatment with the sameor another anti-TNF agent must be carefully pondered.Uncertainties persist about the correct administration of thesedrugs in subjects that are more prone to develop infections(e.g., patients with diabetes or with chronic obstructive pul-monary disease) or who have a previous history of cancer. Inthese occasions, anti-TNFs should be prescribed in accor-dance with the other specialists.
When compared with other patients treated with anti-TNFagents, such as RA, ankylosing spondylitis and inflammatorybowel diseases, PsA patients could have an additional risk forskin cancer. Therefore, although studies demonstrating an addi-tional carcinogenic risk with the combination of PUVA andanti-TNF agents are lacking, an increased clinical vigilance forpatients using both these therapies should be recommended.
In several cases of PsA, the dosage of anti-TNFs can bereduced or the interval of their administration can beincreased, during the course of the treatment. Although spe-cific data are still unavailable, we may hypothesize that thesemodifications of the usual therapeutic schedules could play arole in limiting the occurrence of AE.
Declaration of interests
The authors have received honoraria from Abbvie, BMS,MSD, Pfizer, Roche, and UCB to attend scientific meetings.The authors have received no payment in preparation of thismanuscript.
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AffiliationCarlo Palazzi1 MD,
Salvatore D’Angelo2 MD PhD,
Pietro Leccese2 MD, Angela Padula3 MD &
Ignazio Olivieri†4 MD†Author for correspondence1Senior Investigator,
San Carlo Hospital of Potenza and Madonna
delle Grazie Hospital of Matera, Rheumatology
Department of Lucania, Potenza and Matera,
Italy
Tel: +39 0971 613039;
Fax: +39 0971 613036;
E-mail: [email protected],
San Carlo Hospital of Potenza and Madonna
delle Grazie Hospital of Matera, Rheumatology
Department of Lucania, Potenza and Matera,
Italy3Senior Registrar,
San Carlo Hospital of Potenza and Madonna
delle Grazie Hospital of Matera, Rheumatology
Department of Lucania, Potenza and Matera,
Italy4Director,
San Carlo Hospital of Potenza and Madonna
delle Grazie Hospital of Matera, Rheumatology
Department of Lucania, Potenza and Matera,
Italy
C. Palazzi et al.
6 Expert Opin. Drug Saf. (2013) 13(2)
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