Перспективы применения белимумаба при волчаночном нефрите

За последние 50 лет удалось существенно улучшить выживаемость больных системной красной волчанкой (СКВ), однако необходимо создание нового поколения препаратов для терапии волчаночного нефрита (ВН), развитие которого не менее чем у 50% больных СКВ является одним из основных факторов высокого риска летальности. Международное клиническое исследование BLISS-LN продемонстрировало высокую частоту достижения и сохранения почечного ответа (ПО), подтвержденную более высокой частотой достижения ПО первичной эффективности и полного почечного ответа при применении белимумаба (БЛМ) в дополнение к стандартной терапии (СТ) по сравнению с одной СТ у пациентов с волчаночным нефритом (ВН). При применении БЛМ наблюдалось статистически значимое снижение риска развития нежелательных явлений со стороны почек (в частности, ухудшения функции почек) или смертельного исхода в течение 104 нед по сравнению с плацебо. Улучшение исходов ВН было достигнуто в условиях долгосрочного уменьшения применения глюкокортикоидов после индукционной фазы. При терапии БЛМ отмечалось также снижение общей активности СКВ, уменьшение числа тяжелых обострений и улучшение показателей серологических маркеров. Соотношение «польза/риск» при использовании БЛМ в сочетании со СТ для лечения ВН было благоприятным. БЛМ может быть рекомендован для терапии ВН в комбинации со стандартными методами лечения с целью достижения и поддержания ремиссии.

1. Krishnan E, Hubert HB. Ethnicity and mortality from systemic lupus erythematosus in the US. Ann Rheum Dis. 2006 Nov;65(11): 1500-5. doi: 10.1136/ard.2005.040907. Epub 2006 Apr 20.

2. Choi J, Kim S, Craft J. The pathogenesis of systemic lupus erythematosus – an update. Curr Opin Immunol. 2012 Dec;24(6):651-7. doi: 10.1016/j.coi.2012.10.004. Epub 2012 Nov 3.

3. Fava A, Petri M. Systemic Lupus Erythematosus: Diagnosis and Clinical Management. J Autoimmun. 2019 Jan;96: 1-13. doi: 10.1016/j.jaut.2018.11.001. Epub 2018 Nov 16.

4. Lewis MJ, Jawad AS. The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus. Rheumatology (Oxford). 2017 Apr 1;56(suppl_1):i67-i77. doi: 10.1093/rheumatology/kew399.

5. Hanly JG, O'Keeffe AG, Su L, et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford). 2016 Feb;55(2):252-62. doi: 10.1093/rheumatology/kev311. Epub 2015 Sep 5.

6. Basta F, Fasola F, Triantafyllias K, Schwarting A. Systemic Lupus Erythematosus (SLE) Therapy: The Old and the New. Rheumatol Ther. 2020 Sep;7(3):433-46. doi: 10.1007/s40744-020-00212-9.

7. Lipsky PE. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat Immunol. 2001 Sep;2(9):764-6. doi: 10.1038/ni0901-764.

8. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med. 2003 Oct 16;349(16):1526-33. doi: 10.1056/NEJMoa021933.

9. Yurasov S, Wardemann H, Hammersen J, et al. Defective B cell tolerance checkpoints in systemic lupus erythematosus. J Exp Med. 2005 Mar 7;201(5):703-11. doi: 10.1084/jem.20042251. Epub 2005 Feb 28.

10. Cappione A, Anolik JH, Pugh-Bernard A, et al. Germinal center exclusion of autoreactive B cells is defective in human systemic lupus erythematosus. J Clin Invest. 2005 Nov; 115(11):3205-16. doi: 10.1172/JCI24179. Epub 2005 Oct 6.

11. Mamula MJ, Fatenejad S, Craft J. B cells process and present lupus autoantigens that initiate autoimmune T cell responses. J Immunol. 1994 Feb 1;152(3):1453-61.

12. Renaudineau Y, Pers JO, Bendaoud B, et al. Dysfunctional B cells in systemic lupus erythematosus. Autoimmun Rev. 2004 Nov; 3(7-8):516-23. doi: 10.1016/j.autrev.2004.07.035.

13. Horwitz DA, Fahmy TM, Piccirillo CA, La Cava A. Rebalancing immune homeostasis to treat autoimmune diseases. Trends Immunol. 2019 Oct;40(10):888-908. doi: 10.1016/j.it.2019.08.003. Epub 2019 Oct 7.

14. Nardelli B, Belvedere O, Roschke V, et al. Synthesis and release of B-lymphocyte stimulator from myeloid cells. Blood. 2001 Jan 1; 97(1):198-204. doi: 10.1182/blood.v97.1.198.

15. Schneider P, MacKay F, Steiner V, et al. BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med. 1999 Jun 7;189(11):1747-56. doi: 10.1084/jem.189.11.1747.

16. Moore PA, Belvedere O, Orr A, et al. BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science. 1999 Jul 9;285(5425):260-3. doi: 10.1126/science.285.5425.260.

17. Jacob CO, Pricop L, Putterman C, et al. Paucity of clinical disease despite serological autoimmunity and kidney pathology in lupusprone New Zealand mixed 2328 mice deficient in BAFF. J Immunol. 2006 Aug 15; 177(4):2671-80. doi: 10.4049/jimmunol.177.4.2671.

18. Gross JA, Johnston J, Mudri S, et al. TACI and BCMA are receptors for a TNF homologue implicated in B-cell autoimmune disease. Nature. 2000 Apr 27;404(6781): 995-9. doi: 10.1038/35010115.

19. Kayagaki N, Yan M, Seshasayee D, et al. BAFF/BLyS recep-tor 3 binds the B cell survival factor BAFF ligand through a discrete surface loop and promotes processing of NF-κB2. Immunity. 2002 Oct;17(4):515-24. doi: 10.1016/s1074-7613(02)00425-9.

20. Ramanujam M, Wang X, Huang W, et al. Mechanism of action of transmembrane activator and calcium modulator ligand interactor-Ig in murine systemic lupus erythematosus. J Immunol. 2004 Sep 1;173(5):3524-34. doi: 10.4049/jimmunol.173.5.3524.

21. Cheema GS, Roschke V, Hilbert DM, Stohl W. Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases. Arthritis Rheum. 2001 Jun;44(6):1313-9. doi: 10.1002/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S.

22. Stohl W, Metyas S, Tan SM, et al. B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: longitudinal observations. Arthritis Rheum. 2003 Dec;48(12):3475-86. doi: 10.1002/art.11354.

23. Tectonidou MG, Dasgupta A, Ward MM. Risk of end-stage renal disease in patients with lupus nephritis, 1971–2015: a systematic review and Bayesian meta- analysis. Arthritis Rheumatol. 2016 Jun;68(6):1432-41. doi: 10.1002/art.39594.

24. Sprangers B, Monahan M, Appel GB. Diagnosis and treatment of lupus nephritis flares – an update. Nat Rev Nephrol. 2012 Dec;8(12):709-17. doi: 10.1038/nrneph.2012.220. Epub 2012 Nov 13.

25. Furie R, Petri M, Zamani O, et al. A phase III, random-ized, placebo-controlled study of belimumab, a monoclonal antibody that inhibits B lympho-cyte stimulator, in patients with systemic lupus erythematosus. Arthritis Rheum. 2011 Dec;63(12):3918-30. doi: 10.1002/art.30613.

26. Navarra SV, Guzman RM, Gallacher AE, et al. Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, pla-cebo-controlled, phase 3 trial. Lancet. 2011 Feb 26;377(9767): 721-31. doi: 10.1016/S0140-6736(10)61354-2. Epub 2011 Feb 4.

27. Stohl W, Schwarting A, Okada M, et al. Efficacy and safety of subcutaneous belimumab in systemic lupus erythematosus: a fifty-two-week random-ized, double-blind, placebo-controlled study. Arthritis Rheumatol. 2017 May;69(5):1016-27. doi: 10.1002/art.40049. Epub 2017 Apr 7.

28. Collins CE, Dall'Era M, Kan H, et al. Response to belimumab among patients with systemic lupus erythematosus in clinical practice settings: 24-month results from the OBSErve study in the USA. Lupus Sci Med. 2016 Jan 11;3(1):e000118. doi: 10.1136/lupus-2015-000118. eCollection 2016.

29. Cortes J, Andreu JL, Calvo J, et al. Evaluation of use of belimumab in clinical practice settings (observe study) in Spain: health resource utili-zation and labour absenteeism. Value Health. 2014 Nov;17(7):A534. doi: 10.1016/j.jval.2014.08.1703. Epub 2014 Oct 26.

30. Schwarting A, Schroeder JO, Alexander T, et al. First real-world insights into belimumab use and outcomes in routine clinical care of systemic lupus erythematosus in germany: results from the OBSErve Germany study. Rheumatol Ther. 2016 Dec;3(2):271-90. doi: 10.1007/s40744-016-0047-x. Epub 2016 Nov 1.

31. Touma Z, Sayani A, Pineau CA, et al. Belimumab use, clinical outcomes and glucocorticoid reduction in patients with systemic lupus erythematosus receiving belimumab in clinical practice settings: results from the OBSErve Canada Study. Rheumatol Int. 2017 Jun;37(6):865-73. doi: 10.1007/s00296-017-3682-9. Epub 2017 Mar 9.

32. Van Vollenhoven RF, Petri MA, Cervera R, et al. Belimumab in the treatment of systemic lupus erythematosus: high disease activity predictors of response. Ann Rheum Dis. 2012 Aug;71(8):1343-9. doi: 10.1136/annrheumdis2011-200937. Epub 2012 Feb 15.

33. Furie RA, Petri MA, Wallace DJ, Ginzler EM, Merrill JT, Stohl W, et al. Novel evidence-based systemic lupus erythematosus responder index. Arthritis Rheum. 2009 Sep 15; 61(9):1143-51. doi: 10.1002/art.24698.

34. Асеева ЕА, Соловьев СК, Меснянкина АА и др. Результаты наблюдательного проспективного исследования эффективности и безопасности белимумаба (Бенлисты® ) при системной красной волчанке в реальной клинической практике. Научно-практическая ревматология. 2016; 54(1):31-7.

35. Iaccarino L, Andreoli L, Bocci EB, et al. Clinical predictors of response and discontinuation of belimumab in patients with systemic lupus erythematosus in real life setting. Results of a large, multicentric, nationwide study. J Autoimmun. 2018 Jan;86:1-8. doi: 10.1016/j.jaut.2017.09.004. Epub 2017 Sep 19.

36. Atisha-Fregoso Y, Malkiel S, Harris KM, et al. Phase II Randomized Trial of Rituximab Plus Cyclophosphamide Followed by Belimumab for the Treatment of Lupus Nephritis. Arthritis Rheumatol. 2021 Jan; 73(1):121-31. doi: 10.1002/art.41466. Epub 2020 Dec 1.

37. Merrill JT, Ginzler EM, Wallace DJ, et al. Long-term safety profile of belimumab plus standard therapy in patients with systemic lupus erythematosus. Arthritis Rheum. 2012;64(10):3364-73. doi:10.1002/art.34564

38. Doria A, Bass D, Schwarting A, et al. A 6-month open-label extension study of the safety and efficacy of subcutaneous belimumab in patients with systemic lupus erythematosus. Lupus. 2018;27(9):1489-98. doi:10.1177/0961203318777634

39. Andreoli L, Reggia R, Pea L, et al. Belimumab for the treatment of refractory systemic lupus erythematosus: real-life experience in the first year of use in 18 Italian patients. Isr Med Assoc J. 2015;16(10):651-3.

40. Sheikh S, Scheinberg M, ChengChung Wei J, et al. LB0012 Headline results for a phase 4, 52-week, randomised, double-blind, placebo-controlled study to assess adverse events of special interest (AESI) in adults with active, autoantibody-positive systemic lupus erythematosus (SLE) receiving belimumab. Ann Rheum Dis. 2019;78:266.

41. Fredericks CA, Kvam KA, Bear J, et al. A case of progressive multifocal leukoencephalopathy in a lupus patient treated with belimumab. Lupus. 2014;23(7):711-3. doi:10.1177/0961203314524292

42. Leblanc-Trudeau C, Masetto A, Bocti C. Progressive multifocal encephalopathy associated with belimumab in a patient with systemic lupus erythematosus. J Rheumatol. 2015; 42(3):551-2. doi:10.3899/jrheum.140577

43. Raisch DW, Rafi JA, Chen C, Bennett CL. Detection of cases of progressive multifocal leukoencephalopathy associated with new biologicals and targeted cancer therapies from the FDA's adverse event reporting system. Expert Opin Drug Saf. 2016;15(8):1003-11. doi:10.1080/14740338.2016.1198775

44. Guzman M, Hui-Yuen JS. Management of Pediatric Systemic Lupus Erythematosus: Focus on Belimumab. Drug Des Devel Ther. 2020 Jun 25;14:2503-13. doi: 10.2147/DDDT.S216193. eCollection 2020.

45. Dooley MA, Houssiau F, Aranow C, et al. Effect of belimumab treatment on renal outcomes: results from the phase 3 belimumab clinical trials in patients with SLE. Lupus. 2013 Jan;22(1):63-72. doi: 10.1177/0961203312465781.

46. Manzi S, Sanchez-Guerrero J, Merrill JT, et al. Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with Systemic Lupus Erythematosus: combined results from two phase III trials. Ann Rheum Dis. 2012 Nov;71(11):1833-8. doi: 10.1136/annrheumdis-2011-200831. Epub 2012 May 1.

47. Gatto M, Saccon F, Zen M, et al. Early disease and low baseline damage as predictors of response to belimumab in patients with systemic lupus erythematosus in a real-life setting. Arthritis Rheumatol. 2020 Aug;72(8): 1314-24. doi: 10.1002/art.41253. Epub 2020 Jun 12.

48. Collins CE, Cortes-Hernandez J, Garcia MA, et al. Real-word effectiveness of belimumab in the treatment of Systemic Lupus Erythematosus: pooled analysis of multi-country data from the OBSErve studies. Rheumatol Ther. 2020 Dec;7(4):949-65. doi: 10.1007/s40744-020-00243-2. Epub 2020 Nov 18.

49. Hanly JG, O`Keeffe AG, Su, L et al. The frequency and outcome of lupus nephritis: results from an international inception cohort study. Rheumatology (Oxford). 2016 Feb;55(2):252-62. doi: 10.1093/rheumatology/kev311. Epub 2015 Sep 5.

50. Davidson JE, Fu Q, Ji B, et al. Renal remission status and longterm renal survival in patients with lupus nephritis: a retrospective cohort analysis. J Rheumatol. 2018 May; 45(5):671-7. doi: 10.3899/jrheum.161554. Epub 2018 Mar 1.

51. Dall`Era M, Cisternas MG, Smilek DE, et al. Predictors of long-term renal outcome in lupus nephritis trials: lessons learned from the Euro-Lupus Nephritis cohort. Arthritis Rheumatol. 2015 May;67(5):1305-13. doi: 10.1002/art.39026.

52. Yap DY, Tang CS, Ma MK, et al. Survival analysis and causes of mortality in patients with lupus nephritis. Nephrol Dial Transplant. 2012 Aug;27(8):3248-54. doi: 10.1093/ndt/gfs073. Epub 2012 Apr 20.

53. Furie R, Rovin BH, Houssiau F, et al. Two-year, randomized, controlled trial of belimumab in lupus nephritis. N Engl J Med. 2020 Sep 17;383(12):1117-28. doi: 10.1056/NEJMoa2001180.

54. Fanouriakis A, Kostopoulou M, Cheema K, et al. 2019 Update of the Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of lupus nephritis. Ann Rheum Dis. 2020 Jun; 79(6):713-23. doi: 10.1136/annrheumdis2020-216924. Epub 2020 Mar 27.