Иммунологические эффекты биоаналога ритуксимаба (Ацеллбия, «БИОКАД») у больных ревматоидным артритом

Цель исследования – изучить динамику показателей острой фазы воспаления [СОЭ, С-реактивного белка (СРБ)], аутоантител [IgM/IgA ревматоидных факторов (РФ), антител к цитруллинированным белкам], иммуноглобулинов классов G, M и A, CD19+ В-лимфоцитов у больных ревматоидным артритом (РА) через 12 и 24 нед после начала терапии биоаналогом ритуксимаба (РТМ) в суммарной дозе 1200 мг.
Материал и методы. Обследовано 20 больных с достоверным диагнозом РА (в том числе 18 женщин, медиана возраста – 61,5 [54; 66,5] года, длительности заболевания – 39,5 [20; 84] года, DAS28 – 5,6 [4,9; 6,8]). Всем больным проведено по две инфузии РТМ (Ацеллбия®) в дозе 600 мг внутривенно с интервалом в 2 нед на фоне терапии метотрексатом, нестероидными противовоспалительными препаратами и глюкокортикоидами. Клинические и лабораторные показатели анализировались непосредственно перед началом терапии, а затем через 12 и 24 нед после первой инфузии препарата.
Результаты и обсуждение. У ответивших на терапию индекс DAS28, СОЭ и уровень СРБ достоверно снижались через 12 и 24 нед после применения РТМ. Достоверное снижение концентрации IgM РФ в сыворотках ответчиков выявлено на 12-й и 24-й неделях и составляло 79,7 и 87,1% от исходного уровня. Уровень IgA РФ достоверно снижался на 72 и 85% от исходного уровня на 12-й и 24-й неделях терапии РТМ у больных с хорошим эффектом, а у больных с удовлетворительным ответом – на 59,7% на 12-й неделе и на 67,5% на 24-й неделе. Концентрация антител к циклическому цитруллинированному пептиду в сыворотках ответивших на терапию оставалась высокой на всем протяжении наблюдения. Деплеция CD19+ В-лимфоцитов достигнута к 12-й неделе терапии у всех пациентов (абсолютное содержание – 0), к 24-й неделе отмечено нарастание уровня CD19+ B-лимфоцитов (0,0030 [0,0003; 0,0270] 109/л). Средние уровни иммуноглобулинов как в группе пациентов с хорошим, так и среди больных с удовлетворительным эффектом оставались в пределах нормы.
Заключение. Анализ эффективности двух инфузий биоаналога РТМ в суммарной дозе 1200 мг через 24 нед от начала терапии свидетельствует о его способности вызывать снижение активности заболевания, лабораторных показателей воспалительной активности, концентрации аутоантител, полную деплецию В-лимфоцитов.

1. Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Насонов ЕЛ, Насонова ВА, редакторы. Ревматология. Национальное руководство. Москва: ГЭОТАР-Медиа; 2008. С. 290-331 [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Nasonov EL, Nasonova VA, editors. Revmatologiya. Natsional'noe rukovodstvo [Rheumatology. National guidelance]. Moscow: GEOTARMedia; 2008. P. 290-331 (In Russ.)].

2. Samuels J, Ng YS, Coupillaud C, et al. Impaired early B cell tolerance in patients with rheumatoid arthritis. J Exp Med. 2005;201:1659-67. doi: 10.1084/jem.20042321

3. Насонов ЕЛ. Ритуксимаб. В кн.: Насонов ЕЛ, редактор. Генно-инженерные биологические препараты в лечении ревматоидного артрита. Москва; 2013. С. 200-21 [Nasonov EL. Rituksimab. In: Nasonov EL, editor. Genno-inzhenernye biologicheskie preparaty v lechenii revmatoidnogo artrita [Genetically engineered biological agents in the treatment of rheumatoid arthritis]. Moscow; 2013. P. 200-21 (In Russ.)].

4. Youinou P, Jamin C, Saraux A. B-cell: a logical target for treatment of rheumatoid arthritis. Clin Exp Rheumatol. 2007;25:318-28.

5. Martin F, Chan AC. B cell immunobiology in disease: evolving concepts from the clinics. Ann Rev Immunol. 2006;24:467-96. doi: 10.1146/annurev.immunol.24.021605.090517

6. Reff ME, Carner K, Chambers KS, et al. Depletion of B cells in vivo by a chimeric mouse human antibody to CD20. Blood. 1994;83:435-45.

7. Cornec D, Avouac J, Youinou P, Saraux A. Critical analysis of rituximab-induced serological changes in connective tissue diseases. Autoimmun Rev. 2009;8:515-9. doi: 10.1016/j.autrev.2009.01.007

8. Grosjean C, de Chaisemartin L, Nicaise-Roland P, et al. Prospective cohort study of rituximab effects on rheumatoid factor, anti-cyclic citrullinated peptide antibodies and antinuclear antibodies in patients with long-standing rheumatoid arthritis. Ann Rheum Dis. 2008;67(Suppl II):196.

9. Александрова ЕН, Авдеева АС, Лукина ГВ и др. Клинико-иммунологические эффекты анти-В-клеточной терапии у больных ревматоидным артритом. Научно-практическая ревматология. 2012;50(1):14-21 [Aleksandrova EN, Avdeyeva AS, Lukina GV, et al. The clinical and immunological effects of anti-Bcell therapy in patients with rheumatoid arthritis. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2012;50(1):14-21 (In Russ.)]. doi: 10.14412/1995-4484-2012-498

10. Isaacs JD, Olech E, Tak PP, et al. Autoantibody-positive rheumatoid arthritis patients have enchanced clinical response when compared with seronegative patients. Ann Rheum Dis. 2009;68 Suppl 3:442.

11. Khan A, Mahmud T, Hammond T, et al. Rituximab (RTX) is more effective in active sero-positive RA than sero-negative RA. Arthritis Rheum. 2010;62 Suppl 10:1830.

12. Narvaez J, Torne C, Ruiz J. Predictors of response to rituximab in patients with active rheumatoid arthritis and inadequate response to anti-TNF agents or traditional DMARD. Arthritis Rheum. 2010;62 Suppl. 10:1118.

13. Ferraccioli G, Tolusso B, Pallavicini B, et al. Biomarkers predictors of good EULAR response to B cell depletion therapy (BCDT) in seropositive rheumatoid arthritis patients. Arthritis Rheum. 2010;62 Suppl. 10:1098.

14. Gottenberg J, Ravaud P, Bardin T. Assessment of Real Life efficacy of rituximab in rheumatoid arthritis: predicting factors of the therapeutic maintenance and demonstration of a corticosteroid sparing effect in the autoimmunity and rituximab registry. Arthritis Rheum. 2010;62 Suppl. 10:1790.

15. Quartuccio L, Fabris M, Salvin S, et al. Rheumatoid factor positivity rather then ant-CCP positiviry, a lower disability and a lower number anti-TNF agents failed are associated with response to Rituximab in rheumatoid arthritis. Rheumatology. 2009;48:1557-9. doi: 10.1093/rheumatology/kep314

16. Авдеева АС, Александрова ЕН, Новиков АА и др. Иммунологические предикторы эффекта анти-В-клеточной терапии при ревматоидном артрите. Клиническая лабораторная диагностика. 2014;(3):48-52 [Avdeeva AS, Aleksandrova EN, Novikov AA, et al. Immunological predictors of the effect of anti-B-cell therapy in rheumatoid arthritis. Klinicheskaya Laboratornaya Diagnostika. 2014;(3):48-52 (In Russ.)].

17. Насонов ЕЛ, Зонова ЕВ, Иванова ОН и др. Результаты сравнительного клинического исследования III фазы препаратов ритуксимаба (Ацеллбия® и Мабтера®) при ревматоидном артрите (исследование BIORA). Научно-практическая ревматология. 2016;54(5):510-9 [Nasonov EL, Zonova EV, Ivanova ON, et al. The results of a phase III comparative clinical trial of rituximab (Acellbia® and MabThera®) in rheumatoid arthritis (the BIORA study). Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54:510-9 (In Russ.)]. doi: 10.14412/1995-4484-2016-510-519

18. Bredemeier M, de Oliveira FK, Rocha CM. Low-versus high-dose rituximab for rheumatoid arthritis: a systemic review and metaanalysis. Arthritis Care Res. 2014;66:228-35. doi: 10.1002/acr.22116

19. Buch MH, Smolen JS, Betteridge N, et al. Updated consensus statement on the use of rituximab in patients with rheumatoid arthritis. Ann Rheum Dis. 2011;70:909-20. doi: 10.1136/ard.2010.144998

20. Sacco JJ, Botten J, Macbeth F, et al. The Average Body Surface Area of Adult Cancer Patients in the UK: A Multicentre Retrospective Study. PLoS ONE. 2010;5(1):e8933. doi: 10.1371/journal.pone.0008933

21. Cambridge G, Stohl W, Leandro MJ, et al. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationship with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum. 2006;54:723-32. doi: 10.1002/art.21650

22. Cohen S, Emery P, Greenwald M, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. Results of multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54:2793-806. doi: 10.1002/art.22025 23. Higashida J, Wun T, Schmidt S. Safety and Efficacy of Rituximab in Patients with Rheumatoid Arthritis Refractory to Disease Modifying Antirheumatic Drugs and Anti-Tumor Necrosis Factora Treatment. Rheumatology. 2005;32:2109-15.

23. Tsiakalos A, Avgoustidis N, Moutsopoulos H. Rituximab therapy in Greek patients with rheumatoid arthritis Biologics: Targets Ther. 2008;2:911-6.

24. Bokareva M, Lindholm C, Zendjanchi K, et al. Efficacy of Anti-CD20 treatment in patients with rheumatoid arthritis resistant to a combination of methotrexate/anti-TNF therapy. Scand J Immunol. 2007;66:467-83.

25. Toubi E, Kesser A, Slobodin G, et al. Macrophage function changes following rituximab treatment in patients with rheumatoid arthritis. Ann Rheum Dis. 2007;66:818-20. doi: 10.1136/ard.2006.062505

26. Vizioli C, Viana V, Ribeiro A. Auto-antibody titers for monitoring rituximab therapy in rheumatoid arthritis. Ann Rheum Dis. 2012;71 Suppl 3:667.

27. Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373:659-72. doi: 10.1016/S0140-6736(09)60008-8

28. Ursum J, Bos W, van de Stadt R, et al. Different properties of ACPA and IgM-RF derived from a large dataset: further evidence of two distinct autoantibody systems Arthritis Res Ther.2009;11:R7. doi: 10.1186/ar2704

29. Aletaha D, Blü ml S. Therapeutic implications of autoantibodies in rheumatoid arthritis. RMD Open. 2016;2:e000009. doi: 10.1136/rmdopen-2014-000009

30. Bang H, Lü thke K, Gauliard A, et al. Mutated citrullinated vimentin as a candidate autoantigen for diagnosis and monitoring of disease activity in rheumatoid arthritis. Ann Rheum Dis. 2006;65: Suppl II:144.

31. Roland P, Mignot S, Bruns A. Antibodies to mutated citrullinated vimentin for diagnosing rheumatoid arthritis in anti-CCP-negative patients and for monitoring infliximab therapy. Arthritis Res Ther. 2008;10:R142. doi: 10.1186/ar2570

32. Hassfeld W, Streiner G, Graninger W, et al. Autoantibody to the nuclear antigen RA33: a marker for early rheumatoid arthritis. Br J Rheumatol. 1993;32:199-203. doi: 10.1093/rheumatology/32.3.199

33. Zimmermann C, Hoefler E, Steiner G. Diagnostic value of anti-CCP and anti-mutated citrullinated vimentin (MCV) testing in patients with rheumatoid arthritis. Ann Rheum Dis. 2008;67 Suppl II:149.

34. Aggarwal R, Liao K, Nair R, et al. Anti-citrullinated peptide antibody assays and their role in the diagnosis of rheumatoid arthritis. Arthritis Rheum. 2009;61:1472-83. doi: 10.1002/art.24827

35. Atzeni F, Sarzi-Puttini P, Dell’Acqua D, et al. Adalimumab clinical efficacy is associated with rheumatoid factor and anti-cyclic citrullinated peptide antibody titer reduction: a one-year prospective study. Arthritis Res Ther. 2006;8:R3. doi: 10.1186/ar1851

36. Braun-Moscovici Y, Markovits D, Zinder O, et al. Anti-cyclic citrullinated protein antibodies as a predictor of response to antitumor necrosis factor-alpha therapy in patients with rheumatoid arthritis. J Rheumatol. 2006;33:497-500.

37. Cambridge G, Leandro MJ, Edwards JCW, et al. Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum. 2003;48:2146-54. doi: 10.1002/art.11181

38. Chen H, Lin K, Chen C, et al. The effect of etanercept on anticyclic citrullinated peptide antibodies and rheumatoid factor in patients with rheumatoid arthritis. Ann Rheum Dis. 2006;65:35-9. doi: 10.1136/ard.2005.038851

39. Nydegger UE, Zubler RH, Gabay R, et al. Circulating complement breakdown products in patients with rheumatoid arthritis. J Clin Invest. 1977;59:862. doi: 10.1172/JCI108708

40. Kiener HP, Baghestanian M, Dominkus M, et al. Expression of the C5a receptor (CD88) on synovial mast cells in patients with rheumatoid arthritis. Arthritis Rheum. 1998;41:233-45. doi: 10.1002/1529-0131(199802)41:2<233::AID-ART7>3.0.CO;2-V

41. Nimmerjahn F, Ravetch JV. Fcgamma receptors as regulators of immune responses. Nat Rev Immunol. 2008;8:34-47. doi: 10.1038/nri2206

42. Kerkman PF, Fabre E, van der Voort EI, et al. Identification and characterisation of citrullinated antigen-specific B cells in peripheral blood of patients with rheumatoid arthritis. Ann Rheum Dis. 2016;75(6):1170-6. doi: 10.1136/annrheumdis-2014-207182

43. Griffin DO, Holodick NE, Rothstein TL. Human B1 cells in umbilical cord and adult peripheral blood express the novel phenotype CD20+ CD27+ CD43+ CD70-. J Exp Med. 2011;208:67-80. doi: 10.1084/jem.20101499

44. Wunderlich C, Oliviera I, Figueiredo C, et al. Effects of DMARDs on citrullinated peptide autoantibody levels in RA patients – a longitudinal analysis DMARD effects on anti-CCP2 antibodies levels. Semin Arthritis Rheum. 2017;46(6):709-14. doi: 10.1016/j.semarthrit.2016.09.011

45. Khandpur R, Carmona-Rivera C, Vivekanandan-Giri A, et al. NETs are a source of citrullinated autoantigens and stimulate inflammatory responses in rheumatoid arthritis. Sci Transl Med. 2013;5:178ra40. doi: 10.1126/scitranslmed.3005580

46. Harre U, Georgess D, Bang H, et al. Induction of osteoclastogenesis and bone loss by human autoantibodies against citrullinated vimentin. J Clin Invest. 2012;122:1791-802. doi: 10.1172/JCI60975

47. Harre U, Lang SC, Pfeifle R, et al. Glycosylation of immunoglobulin G determines osteoclast differentiation and bone lose. Nat Communocation. 2015. doi: 10.1038/ncomms7651

48. Насонов ЕЛ. Проблемы иммунопатологии ревматоидного артрита: эволюция болезни. Научно-практическая ревматология. 2017;55(3):277-94 [Nasonov EL. Problems of rheumatoid arthritis immunopathology: Evolution of the disease. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2017;55(3):277-94 (In Russ.)]. doi: 10.14412/1995-4484-2017-277-294

49. Bugatt S, Bogliolo L,Vitolo B, et al. Anti-citrullinated protein antibodies and high levels of rheumatoid factor are associated with systemic bone loss in patients with early untreated rheumatoid arthritis Arthritis Res Ther. 2016;18:226. doi: 10.1186/s13075-016-1116-9

50. Wigerblad G, Bas DB, Fernades-Cerqueira C, et al. Autoantibodies to citrullinated proteins induce joint pain independent of inflammation via a chemokine-dependent mechanism. Ann Rheum Dis. 2016;75:730-8. doi: 10.1136/annrheumdis2015-208094

51. Zhang ZJ, Cao DL, Zhang X, et al. Chemokine contribution to neuropathic pain: respective induction of CXCL1 and CXCR2 in spinal cord astrocytes and neurons. Pain. 2013;154:2185-97. doi: 10.1016/j.pain.2013.07.002

52. Titcombe PJ, Amara K, Barsness LO, et al. Citrullinated self antigen-specific blood B cells carry cross reactive immunoglobulins with effector potential. Ann Rheum Dis. 2016;75 Suppl 1:A28-A29. doi: 10.1136/annrheumdis-2016-209124.68

53. Emery P, Fleishmann R, Filipowicz-Sosnowska A, et al. for the DANCER Study group. The Efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment. Results of a phase IIb randomized, double-blind, placebo-controlled dose-range trial. Arthritis Rheum. 2006;54:1390-400. doi: 10.1002/art.21778

54. Emery P, Deodhar A, Rigby W, et al. Efficacy and Safety of different doses and retreatment of Rituximab: a randomized, placebocontrolled trial in patients who are biologically naive with active rheumatoid arthritis and anadequate response to methotrexate (Study Evaluating Rituximab’s Efficacy in MTX inadequate responders (SERENA)). Ann Rheum Dis. 2010;69:1629-35. doi: 10.1136/ard.2009.119933

55. Rubbert-Roth A, Tak P, Zebrini C, et al. Efficacy and safety of various repeat treatment dosing regimes in Rituximab in patients with active rheumatoid arthritis: results of a phase III randomized study (MIRROR). Rheumatology. 2010;49:1683-93. doi: 10.1093/rheumatology/keq116

56. Roll P, Dorner T, Tony H-P. Anti-CD20 therapy in patients with rheumatoid arthritis: predictors of response and B cell subset regeneration after repeated treatment. Arthritis Rheum. 2008;58:1566-75. doi: 10.1002/art.23473

57. Van Vollenhoven RF, Emery P, Bingham CO, et al. Longterm safety of patients receiving rituximab in rheumatoid arthritis clinical trials. J Rheumatol. 2010;37:558-67. doi: 10.3899/jrheum.090856

58. Mariette X, Kivitz A, Isaacs J, et al. Effectiveness of Rituximab (RTX) + methotrexate (MTX) in patients (pts) with early active rheumatoid arthritis (RA) and disease charaxteristics associated with poor outcomes. Arthritis Rheum. 2009;60 Suppl:631.

59. Tak P, Cohen S, Emery P, et al. Baseline autoantibody status (RF, anti-CCP) and clinical response following the first treatment course with rituximab. Arthritis Rheum. 2006;54 Suppl 9:368.

60. Tak P, Rigby W, Rubbert-Roth A. Inhibition of joint damage and improved clinical outcomes with rituximab plus methotrexate in early active rheumatoid arthritis: the IMAGE trial. Ann Rheum Dis. 2011;70:39-46. doi: 10.1136/ard.2010.137703

61. Silverman G, Schwartzman S, Townsend M, et al. Identification of biomarkers for enhanced benefit to Rituximab in rheumatoid arthritis: role for autoantibodies and inflammatory markers. Arthritis Rheum. 2009;60 Suppl:628.

62. Sellam J, Hendel-Chavez H, Rouanet S, et al. B cell activation biomarkers as predictive factors for the response to rituximab in rheumatoid arthritis: a six-month, national, multicenter, openlabel study. Arthritis Rheum. 2011;63:933-8. doi: 10.1002/art.30233