Ten-year experience with rituximab for induction and maintenance therapy in patients with ANCA-associated systemic vasculitis

Rituximab (RTM), a monoclonal antibody against CD20+ receptors on the membrane of B-cells, is becoming increasingly important for the induction and maintenance treatment of antineutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis (ANCA-SV). The challenge facing us is to optimize its efficacy, while limiting adverse events (AEs).

Objective: to evaluate the efficacy and safety of RTM used for the induction and maintenance of remission in ANCA-SV on the basis of 10-year single-center experience.

Patients and methods. The paper presents the authors’ own 10-year experience with RTM used for the induction and maintenance of remission in 103 patients with ANCA-SV, including granulomatosis with polyangiitis (GPA) (n=58), microscopic polyangiitis (MPA) (n=35), ANCA-positive eosinophilic granulomatosis with polyangiitis (EGPA) (n=4), and ANCA-negative EGPA (n=6). The duration of a follow-up after initiation of RTM treatment was more than a year (with the exception of death cases) and averaged 25 to 58 months in different ANCA-SV groups. The patients were monitored every 3 months. The intervals between repeated cycles were dependent on the time course of changes in clinical and laboratory parameters. The mean cumulative RTM dose exceeded 3 g; 75% of patients received repeated cycles of RMT usually at a cumulative dose of 0.5–1.0 g at a 4–12-month interval.

Results and discussion. Repeated RTM cycles for ANCA-SV were highly effective; the clinical response rate was 97%, while 90–93% of patients with different types of ANCA-SV achieved complete clinical response. Despite the fact that the examined population included a high proportion of patients with a severe or refractory course of the disease; ANCA-SV patients showed 10% mortality rates during the entire follow-up period. Anti-B-cell therapy with RTM is of great importance in obtaining long-term optimal results, making it possible to improve ANCA-SV control and to minimize the cumulative dose of glucocorticoids. Since in ANCA-SV, the use of repeated cycles of RTM, including that at a reduced dose of 0.5 g, contributes to the higher efficiency of treatment and to the lower risk of relapse, it is advisable to perform long-term (≥2 years) RTM therapy, by controlling the parameters of clinical and immunological activities and the levels of circulating CD20+ B cells and serum immunoglobulins, deficiency of which can potentially increase the risk of infectious AEs. When planning RTM therapy, it is necessary to consider the specific features of the safety profile for individual nosological entities and to make a careful appropriate monitoring of ANCA-SV patients receiving RTM. The risk of late-onset neutropenia was highest in patients with all types of ANCA-SV (3–10%). Infections in patients with GPA and MPA constitute a substantial proportion (10–11%) in serious AEs. Management of EGPA patients requires alertness to the risk of infusion-related reactions, primarily bronchospasm.

Conclusion. There is a need for further investigation of an anti-B-cell therapy strategy, including the efficacy and safety of RTM in ANCA-SV and for clarification of indications and optimal RTM treatment regimens. 

1. Nasonov EL. Prospects for anti-B-cell therapy in rheumatology. NauchnoPrakticheskaya Revmatologiya = Rheumatology Science and Practice. 2018;56(5):539-48. doi: 10.14412/1995-4484-2018-539-548 (In Russ.).

2. Hofmann K, Clauder AK, Manz RA. Targeting B-Cells and Plasma Cells in Autoimmune Diseases. Front Immunol. 2018 Apr 23;9:835. doi: 10.3389/fimmu.2018.00835

3. Nakazawa D, Masuda S, Tomaru U, Ishizu A. Pathogenesis and therapeutic interventions for ANCA-associated vasculitis. Nat Rev Rheumatol. 2019 Feb;15(2):91-101. doi: 10.1038/s41584-018-0145-y

4. Stone JH, Merkel PA, Spiera R, et al; RAVE-ITN Research Group. Rituximab versus cyclophosphamide for ANCA-associated vasculitis. N Engl J Med. 2010;363(3):221-32. doi: 10.1056/NEJMoa0909905

5. Jones RB, Tervaert JW, Hauser T, et al; European Vasculitis Study Group. Rituxima versus cyclophosphamide in ANCA-associated renal vasculitis. N Engl J Med. 2010;363(3): 211-20. doi: 10.1056/NEJMoa0909169

6. Ananieva LP, Soloviyov SK, Beketova TV, et al. Anti-B-cell therapy at immune inflammatory rheumatic diseases: efficacy and tolerability in 229 patients. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2014;52(5):495-506. doi: 10.14412/1995-4484-2014-495-506 (In Russ.).

7. Schioppo T, Ingegnoli F. Current perspective on rituximab in rheumatic diseases. Drug Des Devel Ther. 2017 Oct 3;11:2891-904. doi: 10.2147/DDDT.S139248

8. Yates M, Watts RA, Bajema IM, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75(9):1583-94. doi: 10.1136/annrheumdis-2016-209133

9. Guerry MJ, Brogan P, Bruce IN, et al. Recommendations for the use of rituximab in anti-neutrophil cytoplasm antibody-associated vasculitis. Rheumatology (Oxford). 2012;51(4): 634-43. doi: 10.1093/rheumatology/ker150

10. Silva-Fernandez L, Loza E, MartinezTaboada VM, et al; Systemic Autoimmune Diseases Study Group of the Spanish Society for Rheumatology (EAS-SER). Biological therapy for systemic vasculitis: a systematic review. Semin Arthritis Rheum. 2014;43(4): 542-57. doi: 10.1016/j.semarthrit.2013.07.010

11. Donvik KK, Omdal R. Churg-Strauss syndrome successfully treated with rituximab. Rheumatol Int. 2011;31(1):89-91. doi: 10.1007/s00296-009-1146-6

12. Cartin-Ceba R, Keogh KA, Specks U, et al. Rituximab for the treatment of Churg-Strauss syndrome with renal involvement. Nephrol Dial Transplant. 2011;26(9):2865-71. doi: 10.1093/ndt/gfq852

13. Munoz SA, Gandino IJ, Orden AO, Allievi A. Rituximab in the treatment of eosinophilic granulomatosis with polyangiitis. Reumatol Clin. 2015;11(3):165-9. doi: 10.1016/j.reuma.2014.08.005

14. Mohammad AJ, Hot A, Arndt F, et al. Rituximab for the treatment of eosinophilic granulomatosis with polyangiitis (ChurgStrauss). Ann Rheum Dis. 2016;75(2):396-401. doi: 10.1136/annrheumdis-2014-206095

15. Beketova TV. Diagnostic algorithm for antineutrophil cytoplasmic antibody-associated systemic vasculitis. Terapevticheskiy Arkhiv. 2018;90(5):13-21. doi: 10.17116/terarkh201688586-92 (In Russ.).

16. Masi AT, Hunder GG, Lie JT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum. 1990 Aug;33(8):1094-100. doi: 10.1002/art.1780330806

17. Watts R, Lane S, Hanslik T, et al. Development and validation of a consensus methodology for the classification of the ANCA-associated vasculitides and polyarteritis nodosa for epidemiological studies. Ann Rheum Dis. 2007 Feb;66(2):222-7. doi: 10.1136/ard.2006.054593

18. Mukhtyar C, Lee R, Brown D, et al. Modification and validation of the Birmingham Vasculitis Activity Score (version 3). Ann Rheum Dis. 2009;68(12):1827-32. doi: 10.1136/ard.2008.101279

19. Emmi G, Rossi GM, Urban ML, et al. Scheduled rituximab maintenance reduces relapse rate in eosinophilic granulomatosis with polyangiitis. Ann Rheum Dis. 2018 Jun; 77(6):952-4. doi: 10.1136/annrheumdis2017-211897

20. Thiel J, Troilo A, Salzer U, et al. Rituximab as Induction Therapy in Eosinophilic Granulomatosis with Polyangiitis Refractory to Conventional Immunosuppressive Treatment: A 36-Month Follow-Up Analysis. J Allergy Clin Immunol Pract. 2017;5(6):1556-63. doi: 10.1016/j.jaip.2017.07.027

21. Fanouriakis A, Kougkas N, Vassilopoulos D, et al. Rituximab for eosinophilic granulomatosis with polyangiitis with severe vasculitic neuropathy: Case report and review of current clinical evidence. Semin Arthritis Rheum. 2015;45(1):60-6. doi: 10.1016/j.semarthrit.2015.03.004

22. Pagnoux C, Hogan SL, Chin H, et al. Predictors of treatment resistance and relapse in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis: comparison of two independent cohorts. Arthritis Rheum. 2008;58(9):2908-18. doi: 10.1002/art.23800

23. Rees F, Yazdani R, Lanyon P. Long-term follow-up of different refractory systemic vasculitides treated with rituximab. Clin Rheumatol. 2011;30:1241-5. doi: 10.1007/s10067-011-1756-8

24. Umezawa N, Kohsaka H, Nanki T, et al. Successful treatment eosinophilic granulomatosis with polyangiitis (EGPA; formerly ChurgStrauss syndrome) with rituximab in a case refractory to glucocorticoids, cyclophosphamide, and IVIG. Mod Rheumatol. 2014;24:685-7. doi: 10.3109/14397595.2013.874734

25. Beketova TV. The development of rheumatology at the stage of formation of a new technological paradigm. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2019;57(5):490-5. doi: 10.14412/1995-4484-2019-490-495 (In Russ.).

26. Beketova TV. The value of the Russian National Registry of patients with ANCAassociated systemic vasculitis as an innovative tool of personalized induction and maintenance therapy. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(5):499-507. doi: 10.14412/1995-4484-2016-499-507 (In Russ.).

27. Kronbichler A, Kerschbaum J, Gopaluni S, et al. Trimethoprim-sulfamethoxazole prophylaxis prevents severe/life-threatening infections following rituximab in antineutrophil cytoplasm antibody-associated vasculitis. Ann Rheum Dis. 2018;77(10):1440-7. doi: 10.1136/annrheumdis-2017-212861

28. Niles J, Merkel P, Mertz L, et al. Longterm safety of Rituximab in granulomatosis with polyangiitis or microscopic polyangiitis: Results of the four-year study of Rituximab in ANCA-Associated Vasculitis Registry. Rheumatology. 2019;58(2):327. doi: 10.1093/rheumatology/kez063.051

29. Bouldouyre MA, Cohen P, Guillevin L. Severe bronchospasm associated with rituximab for refractory Churg-Strauss syndrome. Ann Rheum Dis. 2009;68:606. doi: 10.1136/ard.2008.093773

30. Aguirre-Valencia D, Posso-Osorio I, Bravo JC, et al. Sequential rituximab and omalizumab for the treatment of eosinophilic granulomatosis with polyangiitis (ChurgStrauss syndrome). Clin Rheumatol. 2017; 36(9):2159-62. doi: 10.1007/s10067-017- 3780-9

31. Tesfa D, Ajeganova S, H?gglund H, et al. Late-onset neutropenia following rituximab therapy in rheumatic diseases: association with B lymphocyte depletion and infections. Arthritis Rheum. 2011;63(8):2209-14. doi: 10.1002/art.30427