6 Biologicals in rheumatoid arthritis TNF-α inhibitorsAdalimumab: humanised monoclonal antibody against TNF-αCertolizumab: Fab fragment of a humanised TNF-α inhibitor monoclonal antibodyEtanercept: humanised soluble recombinant TNF-α type II receptor-IgG1 fusion proteinGolimumab: human monoclonal antibody against TNF-α (awaiting NICE appraisal for use in rheumatoid arthritis)Infliximab: a chimeric mouse-human monoclonal antibody against TNF-αOthersAnakinra: human recombinant interleukin 1 receptor antagonistAbatacept: an immunoglobulin and extracellular CTLA4 domain fusion protein that selectively inhibits T cell co-stimulationRituximab: chimeric monoclonal anti-CD20 antibody that depletes B cellsTocilizumab: humanised monoclonal anti-interleukin 6 receptor antibody*currently licensed for the treatment of RAKlarenbeek NB et al. BMJ 2010
8 Overall results of biologics versus control Singh JA The Cochrane Library 2011, Issue 2
9 Adverse effects of biologics in rheumatoid arthritis: a network meta-analysis and Cochrane overview …………..There is an urgent need for more research regarding the long-term safety of biologics and the comparative safety of different biologics.Singh JA The Cochrane Library 2011, Issue 2
11 ANCA-associated vasculitis Vascular necrosis and perivascular inflammation in small vesselsSystemic disease because of renal and lung involvementsOur common interest is the study of the pathogenesis of AAV which are characterized by vascular necrosis and perivascular inflammation in small vessels. They are sytemic disease because of renal, lung and upper airway involvements. Here you can see the presence of a lung granuloma in a patient with Wegener’s granulomatosis. These diseases are characterized by the presence of ANCA directed either against proteinase 3 in Wg and which give a cytoplasmic pattern of fluorescence or against MPO in other types of vasculitis then giving a perinuclear fluorescence pattern.Diagnostic value of ANCAanti-MPOanti-PR3anti-PR3Wegener’s granulomatosis % %Microscopic polyangiitis 70 % %Crescentic necrotizing GN % %Churg-Strauss 38 % %anti-MPO
12 Treatment of ANCA-associated vasculitis InductionCorticosteroidsCyclophosphamide (IV, oral)Plasma exchangesRituximab ?MaintenanceAzathioprineMethotrexatePagnoux C et al, N Engl J Med 2008
14 RAVE RITUXVAS Prednisone + CYC IV, 3 à 6 months Azathioprine Nothing 197 patients44 patients1 à 3 pulse methylprednisolone11 patients33 patientsPrednisone +CYC IV, 3 à 6 monthsRituximab 375 x 4prednisone2 bolus CYCPrednisone +CYC oral, 3 à 6 months+ placebo RituximabRituximab375 X 4+ prednisone+ placebo CYCAzathioprine12-15 moisPlaceboAzathioprineNothingJones RB et al. N Engl J Med 2010; 363:Stone JH et al. N Engl J Med 2010; 363:
15 ConclusionsRituximab was as efficient as IV CYC (RITUXVAS) or oral CYC (RAVE) in the induction of remission in ANCA-associated vasculitis.In RITUXVAS, patients in the rituximab arm received two pulses of CYC, not in RAVEAdverse events were more frequent than expected under rituximab (as frequent as observed in patients reveiving oral CYC in RAVE).In RITUXVAS 6/33 patients died in the rituximab arm vs 2/11 in the control groupThe results of long term follow up in RAVE should inform us on the duration of remission in patients who received rituximab as an induction treatment and no maintenance therapy.
16 MAINRITSANMAINtenance of remission using RITuximab in Systemic ANCA associated vasculitidesInductionMaintenanceMP pulses D1 - 3CS10 mg/d5 mo+/- PlasmapheresisRITUXIMAB 500 mg D1,14, 6, 12, 18 mo6-10using IV CYC pulses until remission then they will be randomized for maintenance to compare azathioprine and rituximab. the latter would be given as a single dose of 1 g/m2, possibly reinjected at 6-month intervals according to the persistence or reappearance of ANCA or CD20 B lymphocytes.The initial statistical hypothesis would be at least a 50% reduction of the relapse rate with rituximab at the end of the 18 months of maintenance.Funding for this study might be obtained from the Paris Hospital and Research Program provided that industry wants to participate and will supply free of charge rituximab, which seems to be real possibility based on the latest information we have received.IV CYC D then /3 wkAzathioprine 2 mg/kg/j18 mo112 patients3-6 mo21-24 mo
17 MAINRITSAN: event free survival Event-free supprimer le e dans la caseGuillevin L et al. ACR 2012 Washington
18 B lymphocyte maturation in Wegener’s granulomatosis CD20 expression in an endonasal lesion from a case of Wegener’s granulomatosisPR3 expression in a WG endonasal lesionCD38 expression in a WG endonasal lesionVoswinkel J et al. Ann Rheum Dis 2006;65:859–864
20 Classification criteria for SLE (ARA 1982)* Malar rashDiscoid lupusPhotosensitivityOral or nasal ulcersNon erosive arthritis ≥ 2 peripheral jointsPericarditis, pleuresisProtéinuria ≥ 0,5 g/dSeizure or psychosisHemolytic anemia orLeucopenia < 4000/µl on two occasions orLymphopenia < 1500/µl on two occasions orThrombocytopenia < /µlLE cells oranti-native, double strand DNA orAnti-Sm orPositive VDRL (negative TPHA) on two occasions at six months intervalsAbnormal ANA titer in the absence of drug*4 criteria simultaneous/successive to assess the diagnosis of SLE(sensitivity and specificity of 96%).
21 Adapt treatment to disease severity Skin and joint involvementhydroxychloroquineNSAIDtopical corticosteroidslow dose oral CSNever use immunosuppressantsVisceral involvementhydroxychloroquine (prevention of relapses)High dose CS (1 mg/kg)Eventually pulse MPImmunosuppressantsanti-CD20, plasma exchanges…Pleuritis, pericarditishydroxychloroquine (Plaquénil)NSAIDCS 0,5 mg/kgNo immunosuppressants
22 EXPLORER (I) Efficacy of rituximab in moderately to severely active SLE 169 patients257 patients88 patientsMerrill JT Arthritis Rheum 2010
23 Proportion of patients experiencing a major clinical response (MCR), a partial clinical response (PCR), and no clinical response (NCR) at 52 weeksMerrill JT Arthritis Rheum 2010
24 A Study to Evaluate the Efficacy and Safety of Rituximab in Subjects With ISN/RPS Class III or IV Lupus Nephritis (LUNAR)Phase III, randomized, double-blind, placebo-controlled, multicenter study to evaluate the efficacy and safety of rituximab in combination with MMF compared with placebo in combination with mycophenolate mofetil (MMF) in subjects diagnosed with ISN/RPS 2003 Class III or IV Lupus Nephritis.
25 B-cell-depletion therapy in SLE--what are the current prospects for its acceptance? Favas C, Isenberg DA. Nat Rev Rheumatol Dec;5(12):711-6.The failure of rituximab, a monoclonal antibody that induces B-cell depletion, to meet its primary and secondary end points in trials of nonrenal SLE (EXPLORER) and renal (LUNAR) lupus nephritis has been disappointing given the success reported in many open-label studies. Concluding that B-cell-depletion therapy is not effective in SLE seems rather extreme.Further analysis of the as-yet unpublished results and their comparison with data from published studies might provide insight into whether B-cell depletion will eventually be accepted as a useful approach for the treatment of SLE.
26 B lymphocyte stimulator (BLyS) Litinskiy et al. Nat Immunol. 2002; 3:822-9
27 Benlysta (belimumab): anti-BAFF in SLE Seropositive SLE patients (ie, antinuclear antibody positive and/or anti-DNA positive) without active nephritis or active central nervous system disease were enrolled in two phase II/III studies (BLISS-52 and BLISS-76) and treated with placebo, 1 mg/kg of anti-BAFF, or 10 mg/kg of anti-BAFF.Primary endpoint: SRI (SLE Responder Index),Both studies showed superiority of the 10 mg/kg dose to placebo at 12 months (56.7% of patients have shown improvement when treated with a 10 mg/kg dose of belimumab in addition to standard treatment as opposed to 43.6% improvement under standard treatment and placebo).Benlysta (belimumab): agreement US FDA (july 2011).Wallace DJ et al. Arthritis Care Res (Hoboken) 2009 ; 62 : 580 – 1 .Petri M et al. Arthritis Rheum 2010;62:S190 (abstract).
28 Only three drugs were FDA-approved for the treatment of SLE: PrednisoneAspirinHydroxychloroquineBelimumab efficacy is 'mild' but market potential still great: anticipating us approval of the first lupus drug since Weintraub B. BioDrugs Jun 1;25(3):203-5.
29 EMBLEM: epratuzumab (anti-CD22) in SLE Wallace DJ et al EMBLEM: epratuzumab (anti-CD22) in SLE Wallace DJ et al (abstract) EULAR
30 EMBLEM: epratuzumab (anti-CD22) in SLE Wallace DJ et al EMBLEM: epratuzumab (anti-CD22) in SLE Wallace DJ et al (abstract) EULAR
31 There is a need for cost-benefit studies « Biologics »« Old drugs »The exemple for systemic lupus erythematosus…….
32 Potential future targets and relevant drugs in connection with B-cells and T-cells in the management of SLEHaubitz M. Biologics: Target & therapy 2010
34 Progressive Multifocal Leukoencephalopathy Complicating Treatment with Natalizumab and Interferon Beta-1a for Multiple Sclerosis Kleinschmidt-DeMasters BK & Tyler KL. N Engl J Med 2005;353:A 46-year-old woman with relapsing–remitting multiple sclerosis died from progressive multifocal leukoencephalopathy (PML) after having received 37 doses of natalizumab (300 mg every four weeks) as part of a clinical trial of natalizumab and interferon beta-1a.
35 Discovery and development of natalizumab 3 cases of progressive leukoencephalopathy withdrawn by its manufacturer(in combination with INF-b).a4-b1 integrin key molecule homing human brainPhase II: decreased relapses in MSReturned to the US market under a special program.Phase IstudY19921995199719992002200420052006201031 cases of PML attributed to natalizumab. FDA re-approved natalizumab for patients with all relapsing forms of MS as a first-line or second-line therapyReversal of relapsing paralysis demonstrated with a4-b1 integrin blockadePhase IstudyFDA approval relapsing remitting MS
36 Ocrelizumab (anti-CD20) Ocrelizumab had reached Phase III clinical trials for rheumatoid arthritis and systemic lupus erythematosus, and Phase II for multiple sclerosis and hematological cancer.In March 2010, Roche announced the suspension of clinical trials in rheumatoid arthritis and lupus erythematosus. This step followed excess deaths due to opportunistic infections.Development for multiple sclerosis continues
37 ConclusionsLarge number of biologics available, new generations coming upBiologics: revolution in the treatment of rheumatoid arthritisCost-benefit studies are necessaryImprove efficacy: increase immunosuppressionFrom the use of biologics we learn from the pathophysiology of autoimmune diseasesNew treatments: new risks