o Vasculitis, is a group of diseases, in which the target of inflammation is vessel wall o o The existence of injury in the vessel wall Surrounding tissues have generally normal appearance ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Floresan Mikroskop Sitoplazmik antijenler Sağlıklı insan nötrofili Floresan bağlanmış Anti-human immunoglobulin Hasta serumunda ANCA Cam slide ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Uncontrolled New drugs: corticosteroids in the late 1940s Better outcomes: combination therapy with CYC Due to it s efficacy, no controlled trials needed to be done Optimized and harmonized regimens In WG, studies of MTX as an alternative of CYC also uncontrolled Other CYC-sparing treatments (AZA, MMF, etc.) are not based on controlled trials Remission rates are of 90%; remission is often delayed; Maintenance of remission is < 75% and 50% at 6 months and 5 years respectively; poor quality of life during remissions D. Jayne. Clin and Exp Rheumatol 2007 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Randomized controlled CYCAZAREM: AAV; CYC vs. AZA; maintenance of remission At 18-month, the relapse rate was not different 14% vs.16%, higher in WG patients The number of adverse events was similar NORAM: mild AAV; CYC vs. MTX, induction of remission At 6 month, remission rates were 94% vs. 90%, the time to remission was 2 months longer in the MTX group At 18 months, the relapse rate was higher in the MTX group (70% vs. 47%) ; P = 0.023). Leucopenia is higher in CYC, abnormal LFTs is higher in MTX group Jayne D et al. N. Engl. J. Med. 2003 De Groot Ket al. Arthritis Rheum. 2005 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
q Expression of TNF and TNFR high at vasculitic sites q TNF-activated endothelial cells enhances leukocyte adhesion q Infections may trigger vasculitic attacks q Inhibition of TNF-alpha decreases the formation of granuloma q CD4+ T cells from patients with WG, produce elevated levels of TNF-alpha qtnf-alpha priming enhances degranulation ability of neutrophils upon ANCA stimulation q Blocking with anti-rat TNF-alpha mab, is effective in treating established experimental vasculitis. This, in part, by suppression of the enhanced leukocyte-endothelial interactions Mark A. Little et al. J Am Soc Nephrol 2006 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
A.T. Chan, O. Flosmann, C. Mukhtyar, D.R.W. Jayne, R.A. Luqmani The role of biologic therapies in the management of systemic vasculitis Autoimmunity Reviews (2006) ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Open Label Pilot Study Add-on treatment for active severe patients for remission induction 6 month treatment leads to significant fall in BVAS, efficacious in inducing remissions Stone JH et al. Arthritis Rheum 2001 Randomized Placebo-controlled Trial (WGET) Add-on treatment and etanercept remaining as the sole maintenance therapy 180 pts. etanercept vs. placebo, maintenance of remission New or relapsed WG with severe or non-life threatening disease activity No significant differences to prevent further disease flares and to sustain remission (69.7 percent vs. 75.3 percent, P=0.39) Adverse events were similar, but a number of solid organ cancers were noted in the etanercept arm. N Engl J Med 2005 Stone JH et al. Arthritis Rheum 2006 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Open Studies 54 patients (35 with WG) Remission achieved in more than 43(81%) Sustained remission was observed in 28 out of 33 followed-up patients 10 patients suffered severe infection Infliximab also induce remission in refractory CSS in small case series Infliximab effective in new or relapsed AAV at short-term Bartolucci et al. Rheumatology (Oxford) 2002 Booth et al. J Am Soc Nephrol 2004 Lamprecht P et al. Rheumatology (Oxford) 2002 Mukhtyar C. and Luqmani R Ann. Rheum. Dis. 2005 Gause A. Et al. Z. Rheumatol. 2003 In long-term treatment both the risk of infection and relapse are high ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
The mouse Fab domain of rituximab binds CD20 antigen CD20 presents on the mature B cells, a transmembranous protein RIT does not effect long-lived plasma cells and memory cells RIT leads 98% and 40-70% depletion of B cells in the periphery and lymph nodes. B cells recover in a few months, return to pre-treatment levels within 9-12 months ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Granuloma formation Initiated and maintained by Th1 CD4 T-cells The cells in the structure of granuloma qmonocyte-derived tissue macrophages, qgiant cells, qneutrophils, qcd4+cd28-t-cells, qb cells ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
B cells have been implicated in granuloma formation in WG Activated B cells are present in higher numbers in patients with active vasculitis B cells are effective antigen presenting cells, and can activate T cells B cells also produce TNF-alpha and IL-6 B cell activators (BlyS or BAFF) are increased in AAV Voswinkel J, et al. Ann Rheum Dis 2006 Popa ER, et al. J Allergy Clin Immunol 1999 Mitchison NA. Nat Rev Immunol2004 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Christopher F. Wong. Nephrol Dial Transplant 2007 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Potential targets for biologicals interfering with lymphoid neoformation (PAR)-2: the protease-activated receptor; (TEM): Th1-type effector memory T-cell Lamprechtet al.ann. N.Y. Acad. Sci. 2007 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
KEOGH KA, et al. SPECKS U: Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Rheum. 2005 KEOGH KA, et al. SPECKS U: Rituximab for refractory Wegener s granulomatosis:report of a prospective, open-label pilot trial. Am J Respir Crit Care Med. 2006 ERIKSSON P. J Int Med 2005 OMDAL R, et al. Anti-CD20 therapy of treatment-resistant Wegener s granulomatosis: favourable but temporary response. Scand J Rheumatol. 2005 KOUKOULAKI M, et al, JAYNE DR: Rituximab in Churg-Strauss syndrome. Ann Rheum Dis. 2006 GOTTENBERG JE, et al. Ann Rheum Dis 2005 STASI R, et al. Long-term observation of patients with anti-neutrophil cytoplasmic antibody-associated vasculitis treated with rituximab. Rheumatology (Oxford). 2006 SMITH KG, et al. JAYNE DR: Long-term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re-treatment. Arthritis Rheum. 2006 HENES JC et al. Rituximab for treatment-resistant extensive WG additive effects of a maintenance treatment with leflunomide. Clin Rheumatol 2007 BRIHAYE B et al. Adjunction of rituximab to steroids and immunosuppressants for refractory/relapsing Wegener s granulomatosis: a study on 8 patients. Clin Exp Rheumatol 2007 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
All except one, showed rituximab to be an effective and safe treatment in AAV, with responses in excess of 90% of cases These studies included patients who had active vasculitis and were intolerant of, or refractory to, standard treatment 44/53 (83%) reached complete remission and three achieved partial remission. 14 of these patients subsequently relapsed between 9 and 21 months after treatment Relapses occurred after the reappearance of peripheral B cells and often in association with a rising ANCA titer O Flossmann, R B Jones, D R W Jayne and R A Luqmani Ann Rheum Dis 2006 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Are granulomatous lesions less responsive than other disease manifestations? Omdal et al. 2 retro-orbital granulomatous or sinusoidal mass Aries et al. : granulomatous retro-orbital disease is refractory to monthly RIT (5/8) 1 pulmonary nodule, 2 subglottic stenosis; no decrease in ANCA titer. 2/5 retro orbital disease responded to IV azathioprine By contrast, other granulomatous features such as pulmonary nodules and endobronchial disease responded well to treatment. More work is needed to determine whether or not there is a differential response to rituximab, dependent on the disease manifestation. OMDAL R, WILDHAGEN K, HANSEN T, GUNNARSSON R, KRISTOFFERSEN G: Anti-CD20 therapy of treatment-resistant Wegener s granulomatosis: favourable but temporary response. Scand J Rheumatol. 2005 ARIES PM, HELLMICH B, VOSWINKEL J et al.: Lack of efficacy of rituximab in Wegener s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis.2006 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Is monthly RIT less effective than weekly RIT? No difference in British Registry But, in some series patients who received the regimen as used in the RA trial (2x1 g with an interval of 2 weeks) showed a higher relapse rate than patients treated according to the lymphoma protocol OMDAL R, WILDHAGEN K, HANSEN T, GUNNARSSON R, KRISTOFFERSEN G: Anti-CD20 therapy of treatment-resistant Wegener s granulomatosis: favourable but temporary response. Scand J Rheumatol. 2005 ARIES PM, HELLMICH B, VOSWINKEL J et al.: Lack of efficacy of rituximab in Wegener s granulomatosis with refractory granulomatous manifestations. Ann Rheum Dis.2006 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Stasi et al. 10 pts.; 9 pts. complete 1 patient partial response at 6 months. With 33.5 months median follow-up, 3 pts. had relapse (at 12th,12th,24th months), responded to retreatment with RİT Smith et al. 11 pts.; 9 pts. complete 1 patient partial response; median time 3.5 months 4 pts. had 5 relapses; median time to first 16.5 months; responded to retreatment with RIT J.M. Golbin and U. Specks 28 pts.; 2-5 RIT treatment interval 35 months (7-76) Eriksson et al. 9 pts. ; 6 pts. Complete 1 patient partial response 2 pts. had relapses (at 12th,13th month) ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Infusion reactions: dispne, polyarthritis, fever, hypertension Infections: lower respiratory infections, H. Zoster Hypogammaglobulinemia: corticosteroids and CYC increase the risk; in case of infection, IVIG replacement may needed ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Randomized, multicenter, double-blinded, placebo-controlled trial 200 participants with severe AAV (WG or MPA) randomized 1:1 To determine the efficacy of rituximab (375 mg/m2) and glucocorticoids in the induction of remission Remission induction phase (month 1 through months 3 to 6) The experimental arm, rituximab (375 mg/m2/week times 4) plus oral prednisone The control arm, CYC (2 mg/kg) plus oral prednisone Remission maintenance phase (months 3 to 6 through month 18) The experimental arm, switching placebos The control arm, switch from daily CYC to AZA (2 mg/kg/day) ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Less toxic treatments (CYC and corticosteroids had much) Preventing relapses (maintenance treatments are insufficient) Treatment of chronic mild-moderate patients Treatment of refractory patients or those intolerance to treatments Non-pharmacological modalities (stenosis, corrective surgery, transplantation) P.A. Merkel. The need for novel treatment regimens for ANCA-associated vasculitis. Clin and Exp Rheumatol 2007 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
The response to lymphocyte depletion is delayed, infection risk is high The response to cytokine blockade is rapid but the efficacy may decrease in time, infection risk is high B Cell targeted therapies are promising IVIG does not cause immunosuppresion and also may prevent infections The result of open label studies should be interpreted with caution, some may not be confirmed in RCT D. Jayne Newer therapies for ANCA-associated vasculitis. Clinical and Experimental Rheumatology 2007 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
N Engl J Med 2004;350:2572-81 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
24-week, randomized, double-blind, placebo controlled, dose-ranging phase IIb trial 465 pts., RIT 0.5g (124), RIT 1.0g (192) or placebo (10-25mg MTX) (149) ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
Studies using biologics in patients failing anti-tnf Biological Trial Placebo-C Radiography Adalimumab ReAct no no Abatacept ATTAIN yes no Rituximab REFLEX yes yes Golimumab Tocilizumab ongoing ongoing ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri
ACR responses in patients previously failing anti-tnfs and number of prior biologics 70 60 p<0.001 58 Placebo Rituximab % of patients 50 40 30 20 10 0 p<0.001 42 p<0.001 30 p<0.001 21 22 p<0.001 p<0.0408 14 14 10 7 1 3 3 ACR20 ACR50 ACR70 ACR20 ACR50 ACR70 after 1 anti-tnf* after 2 anti-tnfs** Evaluable patients: *Placebo (n=121), Rituximab (n=179); **Placebo (n=80), Rituximab (n=119) Kremer, et al. Ann Rheum Dis 2006;65(Suppl II):326 ANKARA ROMATOLOJİ SEMPOZYUMU Sağlıkta ve Romatizmal Hastalıklarda B Hücreleri