salvarani carlo nuovi farmaci biologici torino gennaio 2011_14° convegno patologia immune e...
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Nuovi Farmaci Biotecnologici nelle Patologie Reumatiche
e AutoimmuniC. Salvarani, N Pipitone,
MG Catanoso, L Magnani, F Muratore,Unità di Reumatologia,
Ospedale di Reggio Emilia
Topics
• TNF-blockers and Tocilizumab in Giant Cell Arteritis and Takayasu Arteritis
• TNF-blockers and Rituximab in ANCA-• TNF-blockers and Rituximab in ANCA-associated Vasculitis
• Rituximab in IgG4-related Systemic Disease
TNF-BLOCKERS AND TOCILIZUMB IN GIANT CELL ARTERITIS AND IN GIANT CELL ARTERITIS AND
TAKAYASU ARTERITIS
B.G., Maschio, 63 aa, iperteso, BMI 35.6
Cefalea di nuova insorgenza in sede fronto-temporale dx
e occipitale
Astenia e febbricola serale (37,5 °C – 38 °C )
Caso Clinico
Astenia e febbricola serale (37,5 °C – 38 °C )
Tosse stizzosa e secca
Incremento indici di flogosi: VES 120 mm/h, PCR 4,25 mg/dl
Caso Clinico: Diagnosi
BIOPSIA A. TEMPORALE DX
DIAGNOSI ISTOLOGICA
Sezioni di vaso arterioso con marcata flogosi linfomonocitaria transparietale con
cellule giganti cellule giganti
Reperto istologico diagnostico di
Arterite a Cellule Giganti
Inizia terapia steroidea con Prednisone 50 mg/die
Caso Clinico: Follow-up Clinico (2007-2010)Inizia terapia con prednisone 50 mg/dì
Recidiva di malattia con prednisone < 15 mg/dì
Comparsa di diabete e frattura vertebrale dorsale
Persistenza elevati indici di flogosi (VES: 80-120 mm/h)
Associazione con MTX 15 mg/sett.
Per inefficacia del MTX come risparmiatore di steroide
dopo 1 anno si associa anti-TNFα (prima Infliximab 5 mg/kg,
quindi dopo 12 mesi per inefficacia passa a Etanercept 50 mg/sett)
Aprile 2010: CT-PET positiva e VES 110 mm/ora
CT-PET Whole Body April 2010
patologico accumulo del FDG a livello delle carotidi interne (prevalente a sx), dell’arco dell’aorta e dell’aorta ascendente espressione
di persistente flogosi vascolare in dette sedi
Caso clinico: inizio Tocilizumab 8 mg/Kg ogni 4 sett .
VESmm/1h 120 25 18 20 8
PCR(mg/dl) 4,70 0,28 0,16 0,36 0,30
Giugno Luglio Agosto Settembre Ottobre
(mg/dl) 4,70 0,28 0,16 0,36 0,30
Prednisone (mg/dì) 12,5 12,5 12,5 10 7,5
Segni/Sintomi Costituzionali SI NO NO NO NO
Glucocorticoids are the treatment of choice for GCA
• Adequate GC doses quickly suppress clinical manifestations of GCA and prevent ischemic complications
• If visual loss has occurred before starting • If visual loss has occurred before starting therapy, it is usually not reversed
• An empiric initial dose of 40-60 mg daily of prednisone (or equivalent) as a single or divided dose is recommended
Salvarani et al, Lancet 2008
Glucocorticoids are the treatment of choice for GCA
• The needed duration of GC therapy is variable, but in most patients it can be discontinued within 1-2 years
• Some patients have a chronic relapsing course and may require low doses of GCs for several years or even indefinitely
Salvarani et al, Lancet 2008
Points to consider in the therapy of GCA
• vision loss or cerebrovascular accidents occur in a minority of patients and are very unusual once GC therapy has been initiated
• The potentially catastrophic thoracic aneurysm and dissection occur only in 7.6% and 1% of patients, years after the onset of the disease
Salvarani et al, Lancet 2008 and Arthritis Rheum 2005
Points to consider in the therapy of GCA
• The morbidity of GCA is related to the impact of long-term therapy with glucocorticoids in elderly patients, who glucocorticoids in elderly patients, who often have many comorbidities
Gucocorticoid-related side-effects in GCA• In a population based study: adverse events
associated with GCs were recorded in 103 (86%) of 120 patients and 2 or more events occurred in 70 patients (58%)
• Age and higher cumulative dose of GCs were associated with the development of adverse GC side effects
Proven et al, Arthritis Rheum 2003
Major adverse events that occurred in 103 of 120 patients with giant cell arteritis
Type of adverse event Patients with the event, numbe r (%)
Diabetes mellitus 11 (9)
Total fractures 46 (38)
Hip fracture 19 (16)
Vertebral fracture 27 (23)Vertebral fracture 27 (23)
Colles' fracture 3 (2.5)
Other fractures 11 (9)
Gastrointestinal bleeding 5 (4)
Hypertension 26 (22)
Infection 37 (31)
Posterior subcapsular cataract
49 (41)
Therapy of GCA
We need effective treatments inGCA to reduce the exposure GCA to reduce the exposure to glucocorticoids
Steroid-sparing agents in GCA: evidence from RCTs
• Methotrexate: 3 RCTs with different results and 1 meta-analysis
• Azathioprine: 1 RCT• Azathioprine: 1 RCT
• Infliximab: 1 RCT
• Etanercept: 1 RCT
• Alternate day GC treatment: 1 RCT
• Pulse GC therapy: 2 RCTs
What is the evidence from randomized controlled trials (RCTs)?
• MTX may have a small steroid-sparing effect• MTX is effective only after a latency period of
24-36 weeks• High MTX dosages (20 -25 mg/week) have not • High MTX dosages (20 -25 mg/week) have not
been adequately studied • MTX does not decrease the incidence of
steroid-related side effects• Azathioprine may have a small steroid-sparing
effect and it may be tried if MTX is contro-indicated or not tolerated
What is the evidence from randomized controlled trials (RCTs)?
• Infliximab does not have a steroid-sparing effect in newly diagnosed patients
• Etanercept could have a steroid-sparing effectin patients with relapsing disease
• Infliximab and etanercept do not reduce the incidence of steroid-related side effects in the short-term
• A GC-sparing effect for infliximab may not be completely excluded: the study was too small to definitively identify small benefits
What is the evidence from randomized controlled trials (RCTs)?
• Before completely excluding a potential therapeutic role for TNF-blockers, a large RCT should be performed enrolling only GCA patients with relapsing diseasepatients with relapsing disease
• Alternate-day GC regimen is not recommended
• Additional investigations are needed on the use of pulse GC at the onset of treatment for GCA to confirm whether this regimen reduces GC toxicity
Future directions in GCA therapy Salvarani et al, Lancet 2008
• RCTs are needed to assess new therapeutic agents
• Strong evidence suggest that IL-6 has a major role in sustaining disease activity in GCA
IL-6 and Disease Activity in GCA• IL-6 concentrations, but not TNF alpha, are
increased in GCA patients• GCs rapidly suppress IL-6 production• There is a close correlation of plasma IL-6
concentrations with clinical symptomsconcentrations with clinical symptoms• Vasculitic lesions in GCA samples are
characterized by in situ production of IL-6, IL-1 beta, and TGF-beta1 mRNA, indicative of macrophage activation
Roche et al, Arthritis Rheum 1993;
Weyand et al, Ann Intern Med 1994
IL-6 and Disease Activity in GCA• Plasma IL-6 is more sensitive than
ESR for indicating disease activity
• Circulating IL-6 may persist • Circulating IL-6 may persist elevated in GCA patients after long-term followup and remain higher in patients with more relapsing disease
Weyand et al, Arthritis Rheum 2000Garcia-Martinez et al, Arthritis Rheum 2010
Points to consider in the therapy of Takayasu Arteritis
• 20% of patients have a self-limited, monophasic inflammatory episode
• 80% have a progressive or relapsing/remitting cours e• Serial angiographic studies show that new lesions c an
be found in 61% of patients, even when the arteriti s is be found in 61% of patients, even when the arteriti s is thought to be in remission
• Fixed vascular lesions are not reversed by drug the rapy • GCs constitute the first line of treatment, with
suggested initial dosages of 0.5 to 1 mg/Kg/dayKerr et al, Ann Intern Med 1994; Liang and Hoffman, Current Opin Rheumatol 2004
Limitations of therapy and a guarded prognosis in an American cohort of TA patients
Maksimowicz-McKinnon et al, Arthritis Rheum 2007
• Results:93% of patients attained disease remission of any duration, but only 28% had sustained remission of at least 6 months' duration after remission of at least 6 months' duration after prednisone was tapered to <10 mg daily
• Conclusion:although improvement of symptoms in TA usually follows GC therapy, relapses and anatomic progression usually occur with dosage reduction
Role of Immunosuppressive Agents in TA
They are addded to GCs:
• Halting disease progression
• Reducing GC-related morbidity
Traditional immunosuppressive agents
• Only open-label pilot studies in GC-resistant cases:- methotrexate- micophenolate mofetil- azathioprine- azathioprine- oral cyclophosphamide
Hoffman et al, Arthritis Rheum 1994; Daina et al, Ann Intern Med 1999;
Shinjo et al, Clin Rheumatol 2007; Valsakumar et al, J Rheumatol 2003;
Shelhamer et al, Ann Intern Med 1985; Hoffman et al, Arthritis Rheum 2004;
Molloy et al, Ann Rheum Dis 2008
Anti- TNF therapy in patients with refractory TA: long-term follow-up
Molloy et al, Ann Rheum Dis 2008
• Methods: Retrospective single-centre study of 25 patients with refractory TA treated with infliximab (21) or etanercept (9) for up to 7 years
• Results: Following anti -TNF therapy remission was • Results: Following anti -TNF therapy remission was achieved and prednisone was discontinued in 15 patients (60%) and successfully tapered below 10 mg/day in an additional 7 patients (28%)
• Conclusions: anti-TNF therapy may lead to durable remission and reduction in glucocorticoid requirements in most patients with refractory TA
IL-6R inhibition in refractory TA
• IL-6R inhibition with tocilizumab improved the clinical manifestations and the abnormal laboratory findings in one patient who needed a daily prednisone dosage of 30 mg/day and was daily prednisone dosage of 30 mg/day and was refractory to several immunosuppressive agents
Nishimoto et al, Arthritis Rheum 2008
IL-6 and Disease Activity in TA
• IL-6 is strongly expressed in aortic tissue of TA patients
• IL-6 is probably locally produced at the site of aortic inflammation
• All patients with active disease have • All patients with active disease have elevated serum IL-6 levels
Seko et al, Circulation 1996Noris et al, Circulation 1999Salvarani et al, Clin Exp Rheumatol 2003Park et al, Rheumatology 2006
IL-6 and Disease Activity in TA
• Clinical improvement was associated with a marked reduction in serum IL-6 levels
• A positive correlation was found between • A positive correlation was found between IL-6 levels and the disease activity score (NIH criteria for disease activity)
Noris et al, Circulation 1999Salvarani et al, Clin Exp Rheumatol 2003Park et al, Rheumatology 2006
Take-Home Messages
•• TNFTNF--blockers as steroidblockers as steroid--sparing agents sparing agents are not effective in GCAare not effective in GCA
•• TNFTNF--blockers are effective in refractory blockers are effective in refractory Takayasu arteritisTakayasu arteritisTakayasu arteritisTakayasu arteritis
•• ILIL--6 inhibition with tocilizumab might be a 6 inhibition with tocilizumab might be a logical target for future RCTs in GCA and logical target for future RCTs in GCA and Takayasu arteritisTakayasu arteritis
Therapy of AAV: RCTs
• Biologic agents- TNF-blockers (etanercept)- TNF-blockers (etanercept)- Rituximab
Wegener’s granulomatosis: Early Outcomes
• Natural History:- Mean survival time: 5 months- Mortality: 82% in 1 year
• Glucocorticoid-treated generalized WG- Mean survival time: 12.5 months
Fauci S and Wolff SM, Medicine 1973
The Fauci-Wolff Protocol: NIH Longitudinal Series (began 1968)
• Cyclophosphamide (CYC) 2 mg/Kg/day• Glucocorticoids:
- Pulse methylprednisolone (1g/day X 3)
- Prednisone 1 mg/Kg/day- Prednisone 1 mg/Kg/day- Tapered to qod after 3 months
• Typical duration of therapy:- Glucocorticoids: 12 months
- CYC: Remission + 12 monthsHoffman GS et al, Ann Intern Med 1992
CYC Therapy for AAV The Good/The Bad
• 91% marked improvement
• 42% permanent morbidity- 46% serious infections- 43% hemorrhagic cystitis- 33-fold risk of bladder CA
• 75% complete remission
- 33-fold risk of bladder CA- 11-fold risk of lymphoma- 57% infertility
Steroid-induced damage:Cushingoid features, weight gain, hypertension, cataracts, fractures
Hoffman et al, Ann Intern Med 1992
Conventional therapy for AAV
• How can we minimize exposure to CYC?
• How can we avoid CYC?
Take-Home Points from RCTs• A short course of CYC for remission induction,
followed by a longer course of methotrexate or azathioprine is an effective treatment strategy for AAV
• The pulse CYC (15 mg/kg pulse q2wkX3, then • The pulse CYC (15 mg/kg pulse q2wkX3, then q3wk) induces remission as well as the daily oral regimen at a reduced cumulative CYC dose and causes fewer cases of leukopenia
Jayne D et al, N Engl J Med 2003 (CYCAZAREM);Pagnoux C et al, N Engl J Med 2008 (WEGENT); de Groot K et al, Ann Intern Med 2009 (CYCLOPS);
Biologic AgentsBiologic Agents
Wegener’s Granulomatosis Etanercept Trial (WGET)
• Etanercept in addition to standard therapy is not effective for the maintenance of remission in pts with WG
- No difference in time to remission- No difference in frequency of remission- No difference in duration of remission- No difference in severity or frequency of flares- Increased risk of cancer in patients treated with
etanercept (6 vs 0, P = 0.01)WGET Research Group, N Engl J Med 2005
Pathogenic immune mechanisms in AAV
Chen M & Kallenberg CGM, Nat Rev Rheumatol 2010
RTX versus CYC in ANCA-Associated Renal Vasculitis (RITUXVAS) Jone RB et al, N Engl J Med 2010
• Randomized (3:1), controlled, open-label• 44 patients• All ANCA-positive, all new diagnosis• All had severe renal disease• Comparing:� RTX plus 2 infusions of CYC (n=33)� Intravenous CYC for 6 months, followed by oral AZA
(n=11)• Everybody remained on ~ 10 mg/day of prednisone• Primary endpoints: sustained remission at 12 months
and severe adverse events
Main RITUXVAS ResultsNo difference between treatment arms of:• Mortality: 18% in each arm• Sustained remission at 12 months:
- RTX 76% vs CYC 82% • Time to remission: RTX 90 days vs CYC 94 days• Relapse rate• Time to relapse• Improvement of renal function• Adverse events rate
Conclusion: over 12 months one course of RTX achieves the same results as 6 months of CYCfollowed by AZAJone RB et al, N Engl J Med 2010
RTX versus CYC for ANCA-Associted Vasculitis (RAVE) Stone JH et al, N Engl J Med 2010
• Randomized (1:1), double blind• 197 patients (newly diagnosed or relapsing disease)• All ANCA-positive• Limited disease (not requiring CYC) and too severe disease
(mechanical ventilation because of alveolar hemorrhage or serum creatinine > 4 mg/dL) were excluded
• Comparing:� RTX plus daily placebo-CYC (n=99), then placebo-AZA for pts in
remission between 3-6 months� Daily CYC (2 mg/Kg) plus placebo-RTX infusions (n= 98), then daily
AZA (2 mg/Kg) for pts in remission between 3-6 months• Primary endpoint: remission without the use of prednisone at 6
month
Main RAVE ResultsNo difference between treatment arms of:• Remission without the use of prednisone at 6 months:
- RTX 64% vs CYC 53%- RTX 67% vs CYC 42% (p=0.01) for relapsing disease
• Improvement of renal function• Adverse events rate• Loss of proteinase 3-ANCA production occurred more frequently
with RTX than with CYC
Conclusion: RTX was not inferior to daily CYC for induction of remission and may be superior inrelapsing disease
Stone JH et al, N Engl J Med 2010
Rituximab Dosage
• RITUXIVAS and RAVE trials used rituximab at a dose of 375 mg per square meter per week for 4 consecutive weeks
• However, in a retrospective evaluation of 65 sequential • However, in a retrospective evaluation of 65 sequential patients receiving RTX for refractory AAV there was no difference in efficacy between 4 infusions of 375 mg/m2 each given 1 week apart or 2 infusions of 1 gm each given 2 weeks apart
Jones RB et al, Arthritis Rheum 2009
Take-Home Messages• Available data do no support the use of anti-TNF therapy
in AVV• Results from 2 RCTs comparing RTX to CYC complement
each other:- RTX is effective as CYC for newly diagnosed pts with
severe AAVsevere AAV- RTX seems to be superior for pts with severe relapses- RTX is preferable for young patients who want to preserve their fertility
• More data on RTX for maintaining remission in AAV are needed
Rituximab in IgG4-related Systemic DiseaseSystemic Disease
IgG4-related systemic disease (IgG4-RSD)
• IgG4-RSD is a recently recognized systemic conditions characterized by unique pathological features:
- extensive lymphoplasmacytic infiltration- abundant IgG4+ plasma cells
- extensive fibrosis
• Increased numbers of IgG4+ plasma cells (more than 10/hpf) strongly support the diagnosis of IgG4-RSD
Smyrk TC et al, Curr Opin Rheumatol 2011
Organ involvement in IgG4-RSDKhosroshahi and Stone, Curr Opin Rheumatol 2011
• Pancreas• Bile duct• Liver• Gastrointestinal tract• Salivary and lacrimal glands
• Mesentery• Aorta• Thyroid• Breast• Lung• Salivary and lacrimal glands
• Orbit• Retroperitoneum• Skin• Lymphonodes
• Lung• Kidney• Pituitary glands• Meninges• Prostate• Pericardium
Conditions recognized to be explained at least part ly by the IgG4-RSD spectrum
Khosroshahi and Stone, Curr Opin Rheumatol 2011Previous name• Mikulicz’s disease• Küttner’s tumor• Riedel’s tyroiditis• Chronic sclerosing aortitis
Target organ(s)• Salivary and lacrimal glands• Submandibular glands• Thyroid• Aorta• Chronic sclerosing aortitis
• Inflammatory abdominal aortitis• Retroperitoneal fibrosis• Autoimmune pancreatitis• Sclerosing cholangitis• Orbital pseudotumor• Eosinophilic angiocentric fibrosis• Multifocal fibrosclerosis
• Aorta• Abdominal aorta• Retroperitoneum• Pancreas• Biliary tree• Orbital adnexa• Sinuses and nasal cavities• Various organs
IgG4-associated sclerosing mesenteritis Salvarani et al, Arthritis Rheum submitted
Rituximab therapy leads to rapid decline of serum I gG4 levels and prompt clinical improvement in IgG4-RSD
Khosroshahi et al, Arthritis Rheum 2010
• Glucocorticoids have become a standard therapy for AIP
• AIP relapses in one third of patients treated with glucocorticoidsglucocorticoids
• Experience with traditional DMARDs as steroid sparing agents is limited
• Treatment with rituximab led to prompt clinical and serological improvement in 4 patients with refractory IgG4-RSD
Take-home message
• Rituximab is a viable treatment option for patients with IgG4-RSD that is refractory to conventional refractory to conventional immunosuppressive therapy
RingraziamentiReumatologiaDr GL Bajocchi, Dr PL Macchioni, Dr N Pipitone,Dr.ssa F Rossi, Dr G Germanò, Dr.ssa L Dardani,Dr.ssa MG Catanoso, Dr A Caruso, Dr.ssa I Chiarolanza, Dr.ssa G Restuccia, Dr.ssa A Ghinoi, Dr L Magnani, Dr F MuratoreAnatomia PatologicaAnatomia PatologicaDr A CavazzaOculisticaDr L CiminoMedicina NucleareDr A VersariRadiologiaDr G Zuccoli, Dr A Levrini
Grazie per l’attenzione