Preview

Научно-практическая ревматология

Расширенный поиск

Метотрексат при ревматоидном артрите – 2015: новые факты и идеи

https://doi.org/10.14412/1995-4484-2015-421-433

Полный текст:

Аннотация

За последнее десятилетие, с широким внедрением новых, эффективных генно-инженерных биологических препаратов (ГИБП), произошли серьезные изменения в стратегии лечения ревматоидного артрита (РА): в ее основу легла концепция «Treat to target» («Лечение до достижения цели»). Подчеркивается, что базовая составляющая стратегии – активная ранняя агрессивная терапия метотрексатом (МТ), а при недостаточной эффективности монотерапии МТ – комбинированная терапия МТ и стандартными базисными противовоспалительными препаратами или МТ и ГИБП. Хотя в рандомизированных плацебоконтролируемых исследованиях (РПКИ) и в клинической практике МТ чаще назначается перорально, в настоящее время наблюдается тенденция к более широкому использованию его подкожной формы. Новые данные, полученные в процессе фундаментальных исследований, касающихся расшифровки механизмов действия МТ, и материалы многочисленных РПКИ, наблюдательных исследований и национальных регистров обосновывают уникальное место МТ в лечении РА, его осложнений и сопутствующих коморбидных заболеваний. Целью обзора является анализ новых данных, касающихся механизмов действия и клинической эффективности и безопасности МТ в ревматологии.

Об авторе

Е. Л. Насонов
ФГБНУ Научно-исследовательский институт ревматологии им. В.А. Насоновой, Москва, Россия 115522 Москва, Каширское шоссе, 34А
Россия

директор ФГБНУ НИИР им. В.А. Насоновой, академик РАН, докт. мед. наук, профессор



Список литературы

1. Siebert S, Tsoukas A, Robertson J, McInnes I. Cytokines as therapeutic targets in rheumatoid arthritis and other inflammatory diseases. Pharmacol Rev. 2015 Apr;67(2):280–309. doi: 10.1124/pr.114.009639

2. Burmester GR, Feist E, Dorner T. Emerging cell and cytokine targets in rheumatoid arthritis. Nar Rev Rheumatol. 2014;10:77–88. doi: 10.1038/nrrheum.2013.168

3. Насонов ЕЛ, редактор. Генно-инженерные биологические препараты в лечении ревматоидного артрита. Москва: ИМА-ПРЕСС; 2013. 549 с. [Nasonov EL, editor. Gennoinzhenernye biologicheskie preparaty v lechenii revmatoidnogo artrita [Genetically engineered biological agents in the treatment of rheumatoid arthritis]. Moscow: IMA-PRESS; 2013. 549 p.].

4. Насонов ЕЛ, Мазуров ВИ, Каратеев ДЕ и др. Проект рекомендаций по лечению ревматоидного артрита Общероссийской общественной организации «Ассоциация ревматологов России» – 2014 (часть 1). Научно-практическая ревматология. 2014;52(5):477–94 [Nasonov EL, Mazurov VI, Karateev DE, et al. Spondyloarthritis: Evolution of a concept. Project: recommendations on treatment of rheumatoid arthritis developed by All-Russian Public organization «Association of Rheumatologists of Russia» – 2014 (part 1). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(5):477–94 (In Russ.)]. doi: 10.14412/1995-4484-2014-477-494

5. Насонов ЕЛ. Лечение ревматоидного артрита 2012: место метотрексата. Научно-практическая ревматология. 2012;51(приложение):1–24 [Nasonov EL. Treatment of rheumatoid arthritis 2012: place of methotrexate. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012;51 Suppl:1–24 (In Russ.)].

6. Насонов ЕЛ, Каратеев ДЕ, Чичасова НВ. Рекомендации EULAR по лечению ревматоидного артрита – 2013: общая характеристика и дискуссионные проблемы. Научно- практическая ревматология. 2013;51(6):609–22 [Nasonov EL, Karateev DE, Chichasova NV. EULAR recommendations for the treatment of rheumatoid arthritis – 2013: general characteristics and disputable problems. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51(6):609–22 (In Russ.)]. doi: 10.14412/1995-4484-2013-609-22

7. Насонов ЕЛ, Каратеев ДЕ, Чичасова НВ. Новые рекомендации по лечению ревматоидного ртрита (EULAR, 2013): место метотрексата. Научно-практическая ревматология. 2014;52(1):8–26 [Nasonov EL, Karateev DE, Chichasova NV. New recommendations for the management of rheumatoid arthritis (EULAR, 2013): the role of methotrexate. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(1):8–26 (In Russ.)]. doi: 10.14412/1995- 4484-2014-8-26

8. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis. 2014;73:492–509. doi: 10.1136/annrheumdis-2013-204573

9. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69:964–75. doi: 10.1136/ard.2009.126532

10. Smolen JS, Breedvald FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2015 May 12. doi: 10.1036/annrheumdis-2015-32075242014 [Epub ahead of print].

11. Smolen JS, Aletaha D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat Rev Rheumatol. 2015 May;11(5):276–89. doi: 10.1038/nrrheum.2015.8

12. Cipriani P, Ruscitti P, Carubbi F, et al. Methotrexate in rheumatoid arthritis: optimizing therapy among different formulations. Current and emerging paradigms. Clin Ther. 2014;36:427–35. doi: 10.1016/j.clinthera.2014.01.014

13. Насонов ЕЛ. Метотрексат: перспективы применения в ревматологии. Москва: Филоматис; 2005. 200 с. [Nasonov EL. Metotreksat: perspektivy primeneniya v revmatologii [Methotrexate: Prospects for use in rheumatology]. Moscow: Filomatis; 2005. 200 p.].

14. Cronstein BN. Low-doses methotrexate: a mainstay in the treatment of rheumatoid arthritis. Pharmacol Rev. 2005;57:163–72. doi: 10.1124/pr.57.2.3

15. Hasko G, Cronstein B. Regulation of inflammation by adenosine. Frontiers Immunol. 2013 ;4:85. doi: 10.33389/fimmunu. 2013.00085

16. Wessels JAM, Huizinga TWJ, Guchelaar H-J. Recent insights in the pharmacological actions of methotrexate in the treatment of rheumatoid arthritis. Rheumatology. 2008;47(3):249–55. doi: 10.1093/rheumatology/kem279

17. Chan ESL, Cronstein BN. Methotrexate-how does it really work. Nat Rev Rheumatol. 2010;6:175–8. doi: 10/1038/nrrheum.2010.5

18. Blits M, Jansen G, Assaraf YG, et al. Methotrexate normalizes up-regulated folate pathway genes in rheumatoid arthritis. Arthritis Rheum. 2013;65:2791–802. doi: 10.1002/art.38094

19. Ducreux J, Durez P, Galant C, et al. Global molecular effects of tocilizumab therapy in rheumatoid arthritis. Arthritis Rheum. 2014;66:15–23. doi: 10.1002/art.38202

20. Насонов ЕЛ, Александрова ЕН, Авдеева АС, Рубцов ЮП. Т-регуляторные клетки при ревматоидном артрите. Научно-практическая ревматология. 2014;52(4):430–7

21. [Nasonov EL, Aleksandrova EN, Avdeeva AS, Rubtsov YuP. T regulatory cells in rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(4):430–7 (In Russ.)]. doi: 10.14412/1995-4484-2014-430-437

22. Lina C, Conghua W, Nan L, Ping Z. Combined treatmebt of etanercept and MTX reserves Th1/Th2, Th17/Treg inbalance in patients with rheumatoid arthritis. J Clin Immunol. 2011;31:596–606. doi: 10.1007/s10875-011-9542-6

23. Ehrenstein MR, Evans JG, Singh A, et al. Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFα therapy. J Exp Med. 2004;200:277–85. doi: 10.1084/jem.20040165

24. Cribbs AP, Kennedy A, Penn H, et al. Treg cell function in rheumatoid arthritis is compromised by CTLA-4 promoter methylation resulting in a failure to activate the indolamine 2,3- deoxygenase pathway. Arthritis Rheum. 2014;66:2344–54. doi: 10.1002/art.38715

25. Cribbs AP, Kennedy A, Penn H, et al. Methotrexate restores regulatory T cell function through demethelation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis Rheum. 2015;67:1182–92. doi: 10.1002/art.39031

26. Cedar H, Bergman Y. Linking DNA methylation and histone modification: patterns and paradigm. Nat Rev Genet. 2009;10:295–304. doi: 10.1038/nrg2540

27. Kennedy A, Schmiudt EM, Cribbs AP, et al. A novel upstream enhancer of FOXP3, sensitive to methylation-induced silencing, exhibit dysregulatrd methylation in rheumatoid arthritis T reg cells. Eur J Immunol. 2014;44:2668–78. doi: 10.1002/eji.201444453

28. Flores-Borja F, Jury EC, Mauru C, et al. Defects in CTLA-4 are associated with abnormal regulatory T cell in rheumatoid arthritis. Proc Natl Acad Sci USA. 2008;105:19396–401. doi: 10.1073/pnas.0806855105

29. Leandro M. B cells and rheumatoid factors in autoimmunity. Int J Rheum Dis. 2015;18:379–81. doi: 10.1111/1756-185X.12690

30. Bohm I. Decrease of B-cells and autoantibodies after low-dose methotrexate. Biomed Pharmacol. 2003;57:278–82. doi: 10.1016/S0753-3322(03)00086-6

31. Anolik JH, Ravikumar R, Barnard J, et al. Anti-tumor necrosis factor therapy in rheumatoid arthritis inhibits memory B lymphocytes via effect on lymphoid germinal centers and follicular dendritis cell network. J Immunol. 2008;180:688–92. doi: 10.4049/jimmunol.180.2.688

32. Glaesener S, Quach TD, Onken N, et al. Distinct effects of methotrexate and etanercept on the B cell compartment in patients with juvenile idiopathic arthritis. Arthritis Rheum. 2014;66:2590–600. doi: 10.1002/art.38736

33. Tussiwand R, Bosco N, Ceredig R, Rolink AG. Tolerance checkpoints in B-cell development: Johny B good. Eur J Immunol. 2009;39:2317–8. doi: 10.1002/eji.200939633

34. Супоницкая ЕВ, Александрова ЕН, Насонов ЕЛ. Клиническое значение BAFF/BLyS и APRIL при системной красной волчанке и ревматоидном артрите. Научно-практическая ревматология. 2014;52(5):545–52

35. [Suponitskya EV, Aleksandrova EN, Nasonov EL. Clinical significance of BAFF/BLyS and APRIL in systemic lupus erythematosus and rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(5):545–52 (In Russ.)]. doi: 10.14412/1995-4484-2014- 545-552

36. Coffey G, Betz A, Graf J, et al. Methotrexate and spleen tyrosine kinase inhibitor cooperate to inhibit responses to peripheral blood B cells in rheumatoid arthritis. Pharm Res Per. 2013;e0006. doi: 10.1002/prp2.16

37. Насонов ЕЛ, Денисов ЛН, Станислав МЛ. Интерлейкин 17 – новая мишень для антицитокиновой терапии иммуновоспалительных ревматических заболеваний. Научно-практическая ревматология. 2013;51(5):545–52 [Nasonov EL, Denisov LN, Stanislav ML. Interleukin-17 is a new target for anti-cytokine therapy of immune inflammatory rheumatic diseases. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51(5):545–52 (In Russ.)]. doi: 10.14412/1995-4484-2013-1547

38. Taylor PC, Genovese MC, Greenwood M, et al. OSKIRA-4: a phase IIb randomised, placebo-controlled study of the efficacy and safety of fostamatinib monotherapy. Ann Rheum Dis. 2014 Jul 29. doi: 10.1136/annrheumdis-2014-205361

39. Nijjar JS, Tindell A, McInnes IB, Siebert S. Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis. Rheumatology. 2013;52:1556–62. doi: 10.1093/rheumatology/ket225

40. Weinblatt ME, Genovese MC, Ho M, et al. Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheum. 2014;66:3255–64. doi: 10.1002/art.38851

41. Genovese MC, van der Heijde DM, Keystone EC, et al. A phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 2 dosing regimens of fostamatinib in patients with rheumatoid arthritis with an inadequate response to a tumor necrosis factor-α antagonist. J Rheumatol. 2014;41:2120–8. doi: 10.3899/jrheum.140238

42. Насонов ЕЛ. Новые подходы к фармакотерапии ревматоидного артрита: тофацитиниб. Научно-практическая ревматология. 2014;52(2):209–21 [Nasonov EL. New approaches to pharmacotherapy of rheumatoid arthritis: tofacitinib. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(2):209–221 (In Russ.)]. doi: 10.14412/1995-4484-2014-209-221

43. O’Shea JJ, Holland SM, Straudt LM. JAKs and STATs in immunity, immunodefficiency and cancer. N Engl J Med. 2013;368:161–70. doi: 10.1056/NEJMra1202117

44. Meyer SC, Levine RL. Molecular pathways: molecular basis for sensitivity and resistence to JAK kinase inhibitors. Clin Cancer Res. 2014;20:2051–9. doi: 10.1158/1078- 0432.CCR-13-0279

45. Thomas S, Fisher KH, Snowden JA, et al. Methotrexate is a JAK/STAT pathway inhibitor. PLoS ONE. 2015; doi: 10.137/journal.pone.0130078

46. Keystone EC, Oaylor PC, Drescher E, et al. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74:333–40. doi: 10.1136/annrheumdis-2014-206478

47. Kuroiwa Y, Takakusagi Y, Kusayanagi T, et al. Identification and characterisation of the direct interaction between metgotrexate (MTX) and high-mobility group box 1 (HMGB1) protein. PLoS One. 2013 May 3;8(5):e63073. doi: 10/1371/jounal.pore.063073

48. Harris HE, Andersson U, Pisetsky DS. HMGB1: a multifunctional alarmin driving autoimmune and inflammatory disease. Nat Rev Rheumatol. 2012;8:195–202. doi: 10.1038/nrrheum.2011.222

49. Spurlock CF III, Tossberg JT, Fucgs HA, et al. Methotrexate increases expression of cell cyclic checkpoint genes via JNK activation. Arthritis Rheum. 2012;64:1780–9. doi:1002/art.34342

50. Hashizume M, Yoshida H, Tanaka K, et al. Interleukin-6 regulates anti-sarthritic effect of methotrexate via reduction of SCL19A1 expression in a mousr model. Arthritis Res Ther. 2012;14:R96. doi: 10.1186/ar3821

51. Авдеева АС, Новиков АА, Александрова ЕН и др. Динамика уровней цитокинов на фоне терапии метотрексатом и адалимумабом у пациентов с ранним ревматоидным артритом (исследование РЕМАРКА). Научно-практическая ревматология. 2014;52(3):254–62 [Avdeeva AS, Novikov AA, Aleksandrova EN, et al. Changes of cytokine levels during therapy with methotrexate and adalimumab in patients with early rheumatoid arthritis (REMARCA study). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2014;52(3):254–62 (In Russ.)]. doi: 10.14412/1995-4484-2014-254-262

52. Yellin M, Paliienko I, Balanescu A, et al. A phase II, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of MDX-1100, a fully human anti-CCXL10 monoclonal antibody, in combination with methotrexate in patients with rheumatoid arthritis. Arthritis Rheum. 2012;64:1730–9. doi: 10.1002/art.34330

53. Boyle DL, Soma K, Hodge J, et al. The JAK inhibitor tofacitinib suppresses synovial JAK1-STAT signaling in rheumatoid arthritis. Ann Rheum Dis. 2015;74:1311–6. doi: 10.1136/annrheumdis- 2014-206028

54. Муравьев ЮВ. Новые возможности контроля эффективности метотрексата при ревматоидном артрите. Научно-практическая ревматология. 2015;53(3):308–11 [Muravyev YuV. New possibilities for monitoring methotrexate efficacy in rheumatoid arthritis. Nauchno- rakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;53(3):308–11 (In Russ.)]. doi: 10.14412/1995-4484-2015-308-311

55. Chabner BA, Allegra CJ, Curt GA, et al. Polyglutamation of methotrexate. Is methotrexate a prodrug? J Clin Invest. 1985;76:907–12. doi: 10.1172/JCI112088

56. Dervieux T, Zablocki R, Kremer J. Red blood cell methotrexate polyglutamates emerge as a function of dosage intensity and route of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology. 2010;49:2337–45. doi: 10.1093/rheumatology/keq216

57. De Rotte MCFJ, den Boer E, Calasan B, et al. Personalized medicine of methotrexate therapy. Ned Tijdschr Klin Chem Labgeneesk. 2012;37:50–3.

58. De Rotte MCFJ, den Boer E, de Jong PHP, et al. Methotrexate polyglutamates in erythrocytes are associated with lower disease activity in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74:408–14. doi: 10.1136/annrheumdis-2013-203725

59. De Rotte MCFJ, de Jong PHP, Pluijm SMF, et al. Association of low baseline levels of erythrocyte folate with treatment nonresponse at three months in rheumatoid arthritis patients receiving methptrexate. Arthritis Rheum. 2013;65:2803–13. doi: 10.1002/art.38113

60. De Rotte MC, de Jong PH, Quax RA, et al. Glucocorticoids and methotrexate have a synergistic working on decrease of rheumatoid arthritis disease activity. Ann Rheum Dis. 2013;72 Suppl:S396. doi: 10.1136/annrheumdis-2013-eular.1207

61. Stamp LK, Barclay ML, O’Donnell JL, et al. Effects of changing from oral to subcutaneous methotrexate on red blood cell methotrexate polyglutamate concentrations and disease activity in patients with rheumatoid arthritis. J Rheumatol. 2011;38:2540–7. doi: 10.3899/jrheum.110481

62. Wolbink GJ, Aarden LA, Dijkmans BA. Dealing with immunogenicity of biologicals: assessment and clinical relevance. Curr Opin Rheumatol. 2009;21:211–5. doi: 10.1097/BOR.0b013e328329ed8b

63. Jani M, Barton A, Warren R, et al. The role of DMARDs in reducing the immunogenicity of TNF inhibitors in chronic inflammatory diseases. Rheumatology. 2014;53:213–22. doi: 10.1093/rheumatology/ket260

64. Александрова ЕН, Насонов ЕЛ. Иммуногенность ингибиторов фактора некроза опухоли α при лечении ревматоидного артрита. Научно-практическая ревматология. 2012;53 (приложение 4):22–7 [Aleksandrova EN, Nasonov EL. Immunogenicity inhibitors of tumor necrosis factor α in the treatment of rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012;53 Suppl 4:22–7 (In Russ.)].

65. Garces S, Demengeot J, Benito-Garcia E. The immunogenicity of anti-TNF therapy in immune-mediated inflammatory diseases: a systematic review of the literature with a meta-analysis. Ann Rheum Dis. 2013;72(12):1947–55. doi: 10.1136/annrheumdis-2012-202220

66. Joseph A, Neff K, Richard J, et al. Transient low-dose methotrexate induces tolerance to murine anti-thymocyte globulin and together they promote long-term allograft survival. J Immunol. 2012;189:732–43. doi: 10.4049/jimmunol.1103601

67. Bendtzen K. Is there a need for immunopharmacologic guidance of anti-tumor necrosis factor therapies? Arthritis Rheum. 2011;63:867–70. doi: 10.1002/art.30207

68. Dervieux T, Weinblatt ME, Kivitz A, et al. Methotrexate polyglutamation in relation to infliximab pharmacokinetics in rheumatoid arthritis. Ann Rheum Dis. 2013;72:908–10. doi: 10.1136/annrheumdis-2012-202591

69. Krieckaert CL, Nurmohamed MT, Wolbink GJ. Methotrexate reduces immunogenicity in adalimumab treated rheumatoid arthritis. Ann Rheum Dis. 2012;71:1914–5. doi: 10.1136/annrheumdis-2012-201544

70. Насонов ЕЛ. Новые рекомендации по лечению ревматоидного артрита (EULAR, 2013): место

71. глюкокортикоидов. Научно-практическая ревматология. 2015;53(3):238–50 [Nasonov EL. New guidelines for the management of rheumatoid arthritis (EULAR, 2013): The place of glucocorticoids. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;53(3):238–50 (In Russ.)]. doi: 10.14412/1995-4484-2015-238-250

72. Verstappen SMM, Owen S-A, Hyrich KL. Prediction of response and adverse events to methotrexate. Int J Clin Rheumatol. 2012;7:559–67. doi: 10.2217/ijr.12.57

73. Romao VC, Cahao H, Fonseca JE. Old drugs, old problems: where do we stand in prediction of rheumatoid arthritis responsiveness to methotrexate and other synthetic DMASRDs? BMC Medicine. 2013;11:17. doi: 10.1186/1741-7015-11-17

74. Favalli EG, Biggioggero M, Meroni PL. Methotrexate for the treatment of rheumatoid arthritis in the biologics era: still an «anchor» DRUG? Autoimmune Rev. 2014;13:1102–8. doi: 10.1016/j.autrev.2014.08.026

75. Lopez-Olivo MA, Siddhanamatha HR, Shea B, et al. Methotrexate for treating rheumatoid arthritis. Cochrane Database Syst Rev. 2014;6:CD000957

76. Agenova S, Steenberg HW, van Nies JAB, et al. Disease-modifying antirheumatic drug-free sustained remission in rheumatoid arthritis: an increasingly achievable outcome with subsidence of disease symptoms. Ann Rheum Dis. 2015. doi: 10.1136/annrheumdis-2014-207080

77. Zhang J, Xie F, Delzell E, et al. Impact of biologic agents with and without concomitant methotrexate and at reduced doses in older rheumatoid arthritis patients. Arthritis Care Res. 2015;67:624–32. doi: 10.1002/acr.22510

78. Curtis JR, Zhang J, Xie F, et al. Use of oral and subcutaneous methоtrexate in rheumatoid arthritis patients in United States. Arthritis Care Res. 2014;11:1604–11. doi: 10.1002/acr.22383

79. Aga A-B, Lie E, Uhling T, et al. Time trends in disease activity, response and remission reates in rheumatoid arthritis during the past decade: results from the NOR-DMARD study 2000-2010. Ann Rheum Dis. 2015;74:381–8. doi: 10.1136/annrheumdis- 1013-204020

80. Asai S, Kojima T, Oguchi T, et al. Effects of concomitant methotrexate on large joint replacement in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: a multicenter retrospective cohort study in Japan. Arthritis Care Res. 2015. doi: 10.1002/acr.22596

81. L’Ami M, Kneepkens E, Krieckaert C, et al. The effect of methotrexate in treatment with adalimumab and etanercept in patients with rheumatoid arthritis. Ann Rheum Dis. 2015;74 Suppl 2:708. doi: 10.1136/annrheumdis-2015-eular.2689

82. Buckley F, Finckh A, Huizinga TWJ, et al. Comparative efficacy of novel DMARDs as monotherapy and in combination with methotrexate in rheumatoid arthritis patients with inadequate response to conventional DMARDs: a network meta-analysis. J Man Care Spec Pharm. 2015;21:409–23.

83. Jorgensen TS, Tarp S, Furst DE, et al. Added-value of combining methotrexate with a biological agent compared to biological monotherapy in patients with rheumatoid arthritis: a systemic review and meta-analysis of randomized traals. Ann Rheum Dis. 2015;74 Suppl 2:239. doi: 10.1136/annrheumdis-2015-eular.3396

84. Burmester GR, Rigby W, van Vollenhoven R, et al. Tocilizumab (TCZ) in combination and monotherapy versus methotrexate (MTX) in MTX-naive patients (pts) with early rheumatoid arthritis (RA): clinical and radiographic outcomes from a randomised, placebo-controlled trial. Ann Rheum Dis. 2013;72(Suppl):OP041. doi: 10.1136/annrheumdis-2013- eular.246

85. Smolen JS, Alethaha D. Interleukin-6 receptor inhibiton with tocilizumab and attaintmant remission: thew role of acute phase reactant. Arthritis Rheum. 2011;63:43–52. doi: 10.1002/art.27740

86. Takeuchi T, Kaneko Y, Atsumi T, et al. Adding tocilizumab or switching to tocilizumab monotherapy in RA patients with inadequate response to methotrexate: 24-week results from a randomized controlled study (SURPRISE study). Ann Rheum Dis. 2013;72 Suppl 3:62. doi: 10.1136/annrheumdis-2013-eular.245

87. Kojima T, Yabe Y, Kaneko A, et al. Importance of methotrexate therapy concomitant with tocilizumab treatment in achieving better clinical outcome for rheumatoid arthritis patients with high disease activity: an observational cohort dtudy. Rheumatiology (Oxford). 2015;54:113–20. doi: 10.1093/rheumatology/keu302

88. Takahashi N, Kojima T, Funashi N, et al. Concomitant methotrexate scarcely augment the clinical efficasy of abatacept in patients with rheumatoid arthritis: a propensity score matching analysis. Ann Rheum Dis. 2015;74 Suppl 2:729. doi: 10.1136/annrheumdis-2015-eular.2121

89. Emery P, Burmester GR, Bykerk V, et al. Evaluating drug-free remission with abatacept in early rheumatoid arthritis: results from the phase 3b multicenter, randomized, active-controlled AVERT study of 24 months, with a 12 months, double-blind treatment period. Ann Rheum Dis. 2015;74:19–26. doi: 10.1136/annrheumdis-2014-206106

90. Graudal N, Hubeck-Graudal T, Faurschou M, et al. Combination thetapy with and without tumor necrosis factor inhibitors in rheumatoid arthritis. A meta-analysis of randomized trials. Arthritis Care Res. 2015 May 18. doi: 10.1002/acr.22618

91. Carson CW, Cannon GW, Egger MJ, et al. Pulmonary disease during the treatment of rheumatoid arthritis with low dose pulse methotrexate. Semin Arthritis Rheum. 1987;16:186–95. doi: 10.1016/0049-0172(87)90021-7

92. McKendry RJ, Dale P. Adverse effects of low dose methotrexate therapy in rheumatoid arthritis. J Rheumatol. 1993;20:1850–6.

93. Sostman HD, Matthay RA, Putman CE, Smith GJ. Methotrexate-induced pneumonitis. Medicine (Baltimore). 1976;55:371–88. doi: 10.1097/00005792-197609000-00002

94. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68:1100–4. doi: 10.1136/ard.2008.093690

95. Sathi N, Chikura B, Kaushik VV, et al. How common is methotrexate pneumonitis? A large prospective study investigates. Clin Rheumatol. 2012;31:79–83. doi: 10.1007/s10067-011- 1758-6

96. Dawson JK, Desmond J, Graham DR. Investigation of the chronic pulmonary effects of low-dose oral methotrexate in patients with rheumatoid arthritis: a prospective study incorporating HRCT scanning and pulmonary function tests. Rheumatology (Oxford). 2002;41:262–7. doi: 10.1093/rheumatology/41.3.262

97. Cottin V, Tebib J, Massonnet B, et al. Pulmonary function in patients receiving long-term low-dose methotrexate. Chest. 1996;109:933–8. doi: 10.1378/chest.109.4.933

98. Saravanan V, Kelly CA. Pulmonary function after methotrexate in rheumatoid arthritis: a one-year follow up study. Rheumatology (Oxford). 2002;41 Suppl 2:S145.

99. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study. Arthritis Rheum. 2010;62:1583–91. doi: 10.1002/art.27405

100. Antin-Ozerkis D, Evans J, Rubinowitz A, et al. Pulmonary manifestations of rheumatoid arthritis. Clin Chest Med. 2010;31:451–78. doi: 10.1016/j.ccm.2010.04.003

101. Cortet B, Perez T, Roux N, et al. Pulmonary function tests and high resolution computed tomography of the lungs in patients with rheumatoid arthritis. Ann Rheum Dis. 1997;56:596–600. doi: 10.1136/ard.56.10.596

102. Бестаев ДВ, Каратеев ДЕ, Насонов ЕЛ. Интерстициальное поражение легких при ревматоидном артрите. Научно-практическая ревматология. 2012;50(6):63–9 [Bestaev DV, Karateev DE, Nasonov EL. Interstitial lung disease in rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012;50(6):63–9 (In Russ.)].

103. Conway R, Low C, Coughlan RJ, et al. Methotrexate and lung disease in rheumatoid arthritis – a meta-analysis of randomized controlled trials. Arthritis Rheum. 2014;66:803–12. doi: 10.1002/art.38322

104. Rojas-Serrano J, Gonzalez-Velasquez E, Mejia M, et al. Interstitial lung disease related to rheumatoid arthritis: evolution after treatment. Reumatol Clin. 2012;8:68–71. doi: 10.1016/j.reuma.2011.12.008

105. Conway R, Low C, Coughlan RJ, et al. Methotrexate use and risk of lung disease in psoriasis, psoriatic arthritis, and inflammatory bowel disease: systemic literature review and mata-analysis of randomized controlled trials. BMJ. 2015;350:h1269. doi: 10.1136/bmj.h1269

106. Conway R, Low C, Coughlan RJ, et al. Risk of liver injury among methotrexate users: a meta-analysis of randomized controlled trials. Semin Arthritis Rheum. 2015 May 19. doi: 10.1016/j.semarthrit.2015.05.003. [Epub ahead of print].

107. Curtis JR, Beukelman T, Onofrei A, et al. Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide. Ann Rheum Dis. 2010;69:43–7. doi: 10.1136/ard.2008.101378

108. Dirven L, Klarenbeek NB, van den Broek M, et al. Risk of alanine transferase (ALT) elevation in patients with rheumatoid arthritis treated with methotrexate in a DAS-steered strategy. Clin Rheumatol. 2013;32:585–90. doi: 10.1007/s10067-012-2136-8

109. Quintin E, Scoazec JY, Marotte H, Miossec P. Rare incidence of methotrexate-specific lesions in liver biopsy of patients with arthritis and elevated liver enzymes. Arthritis Res Ther. 2010;12:R143. doi: 10.1186/ar3085

110. Salliot C, van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systematic literature research. Ann Rheum Dis. 2009;68:1100–4. doi: 10.1136/ard.2008.093690

111. Sokolove J, Strand V, Greenberg JD, et al. Risk of elevated liver enzymes associated with TNF inhibitor utilisation in patients with rheumatoid arthritis. Ann Rheum Dis. 2010;69:1612–7. doi:

112. 1136/ard.2009.112136

113. Rossi RE, Parisi I, Despott EJ, et al. Anti-tumour necrosis factor agent and liver injury: literature review, recommendations for management. World J Gastroenterol. 2014;20:17352–9. doi: 10.3748/wjg.v20.i46.17352

114. Katchamart W, Trudeau J, Phumethum V, Bombardier C. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological diseasemodifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2009;68:1105–12. doi: 10.1136/ard.2008.099861

115. Abasolo L, Leon L, Rodriguez-Rodriguex L, et al. Safety of disease-modiguing antirheumatic drugs and biologic agents for rheumatoid arthritis patients in real-life conditions. Semin Arthr Rheum. 2015;44:506–13. doi: 10.1016/j.semarthrit.2014.11.003

116. Yazici H. Methotrexate and not much harm to the lungs. Clin Exp Rheumatol. 2014;32 Suppl 87:S-10.

117. Rojas-Serrano J, Mateos-Toledo H, Mejia M. Methptrexate and lung disease in rheumatoid arthritis: comment on the article by Conway et al. Arthritis Rheum. 2014;66:2641–2. doi: 10.1002/art.38733

118. Skeoch S, Bruce IN. Atherosclerosis in rheumatoid arthritis: is it all about inflammation? Nat Rev Rheumatol. 2015 Jul;11(7):390–400. doi: 10.1038/nrrheum.2015.40

119. Попкова ТВ, Герасимова ЕВ, Новикова ДС, Насонов ЕЛ. Метотрексат и риск сердечно-сосудистых осложнений при ревматоидном артрите. Научно-практическая ревматология. 2012;50(6);70–9 [Popkova TV, Gerasimova EV, Novikova DS, Nasonov EL. Methotrexate and the risk of ardiovascular events in rheumatoid arthritis. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012;50(6):70–9 (In Russ.)].

120. Popkova TV, Novikova DS, Gasparyan AY, Nasonov EL. Cardiovascular effects of methotrexate in rheumatoid arthritis. Curr Med Chem. 2015;22:1903–10. doi: 10.2174/0929867322666150415122039

121. Micha R, Imamura F, von Ballmoos MV, et al. Systemic review nd meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108:1362–70. doi: 10.1016/j.amjcard. 2011.06.054

122. Westlake SL, Colebatch AN, Baird J, et al. The effect of methotrexate on cardiovascular disease in patients with rheumatoid arthritis: asystemic literature review. Rheumatology. 2010;49:295–307. doi: 10.1093/rheumatology/kep366

123. Roubille C, Richer V, Startino T, et al. The effect of tumor necrosis factor inhibitors, methotrexate, non-steroidal antiinflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systemic review and meta-analysis. Ann Rheunm Dis. 2015;74:480–9. doi: 10.1136/annrheumdis-2014-206624

124. Morrow VA, Foufelle F, Connell JM, et al. Direct activation of AMP-activated protein kinase stimulates nitric-oxide synthesis n human aortic endothelial cells. J Biol Chem. 2003;278:31629–39. doi: 10.1074/jbc.M212831200

125. Kukidome D, Nishikawa T, Sonoda K, et al. Activation of AMPactivated protein kinase reduces hyperglycemia-induced mitochondrial reactive oxygen species production and promotes mitochondrial biogenesis in human umbilical vein endothelial cells. Diabetes. 2006;55:120–7. doi: 10.2337/diabetes.55.01.06.db05-0943

126. Liu C, Liang B, Wang Q, et al. Activation of AMP-activated protein kinase ?1 alleviates endothelial cell apoptosis by increasing the expression of anti-apoptotic proteins Bcl-2 and survivin. J Biol Chem. 2010;285:15346–55. doi: 10.1074/jbc.M110.102491

127. Wang S, Zhang M, Liang B, et al. AMPK ?2 deletion causes aberrant expression and activation of NAD(P)H oxidase and consequent endothelial dysfunction in vivo: role of 26S proteasomes. Circ Res. 2010;106:1117–28. doi: 10.1161/CIRCRESAHA. 109.212530

128. Schulz E, Dopheide J, Schuhmacher S, et al. Suppression of the JNK pathway by induction of a metabolic stress response prevents vascular injury and dysfunction. Circulation. 2008;118:1347–57. doi: 10.1161/CIRCULATIONAHA. 108.784289

129. Thornton CC, Al-Rashed F, Calay D, et al. Methptrexate-mediated activation of an AMPK-CREB-dependent pathway: a novel mechanism for vascular protection in chronic systemic inflammation. Ann Rheum Dis. 2015 Jan 9. doi: 10.1136/annrheumdis-2014-206305

130. Watanabe J, Charles-Schoeman C, Miao Y, et al. Proteomic profiling following immunoaffinity capture of high-density lipoprotein: association of acute-phase proteins and complement factors with proinflammatory high-density lipoprotein in rheumatoid arthritis. Arthritis Rheum. 2012;64:1828–37. doi: 10.1002/art.34363

131. McMahon M, Grossman J, FitzGerald J, et al. Proinflammatory high-density lipoprotein as a biomarker for atherosclerosis in patients with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54:2541–9. doi: 10.1002/art.21976

132. Ronda N, Favari E, Borghi MO, et al. Impaired serum cholesterol efflux capacity in rheumatoid arthritis and systemic lupus erythematosus. Ann Rheum Dis. 2014;73:609–15. doi: 10.1136/annrheumdis-2012-202914

133. Favari E, Calabresi L, Adorni MP, et al. Small discoidal pre-?1 HDL particles are efficient acceptors of cell cholesterol via ABCA1 and ABCG1. Biochemistry. 2009;48:11067–74. doi: 10.1021/bi901564g

134. Rosenson RS, Brewer HB Jr, Davidson WS, et al. Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport. Circulation. 2012;125:1905–19. doi: 10.1161/CIRCULATIONAHA.111.066589

135. Favari E, Ronda N, Adorni MP, et al. ABCA1-dependent serum cholesterol efflux capacity inversely correlates with pulse wave velocity in healthy subjects. J Lipid Res. 2013;54:238–43. doi: 10.1194/jlr.P030452

136. Vigna GB, Satta E, Bernini F, et al. Flow-mediated dilation, carotid wall thickness and HDL function in subjects with hyperalphalipoproteinemia. Nutr Metab Cardiovasc Dis. 2014;24:777–83. doi: 10.1016/j.numecd.2014.02.010

137. Khera AV, Cuchel M, de la Llera-Moya M, et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. 2011;364:127–35. doi: 10.1056/NEJMoa1001689

138. Doonan RJ, Hafiane A, Lai C, et al. Cholesterol efflux capacity, carotid athero-sclerosis, and cerebrovascular symptomatology. Arterioscler Thromb Vasc Biol. 2014;34:921–6. doi: 10.1161/ATVBAHA.113.302590

139. Ronda N, Greco D, Adorni MP, et al. New identified antiatherosclerotic activity of methotrexate and adalimumab. Complementary effects on lipoprotein function and macrophage cholesterol metabolism. Arthritis Rheum. 2015;67:1155–64. doi: 10.1002/art.39039

140. Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:219–38. doi: 10.1016/j.jacc.2009.09.009

141. Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Hemostasis. 2009;7 Suppl 1:332–9. doi: 10.1111/j1538-7836.2009.03404x

142. Everett B, Pradhan AD, Solomon DH, et al. Rationale and design of the cardiovascular inflammation reduction trial: a test of the anflammatory hypothesis of atherothrombosis. Am Heart J. 2013;166;199–207. doi: 10.1016/j.ahj.2013.03.018

143. Erhayiem B, Pavitt S, Baxter P, et al. Coronary artery disease evaluation in rheumatoid arthritis (CADERA): study protocol for a randiomized controlled trial. Trials. 2014;15:436. doi: 10.1186/1745-6215-15-436

144. Wasko MC, Dasgupta A, Hubert H, et al. Propensity-adjustment association of methotrexate with overall survival in rheumatoid arthritis. Arthritis Rheum. 2013;65:334–42. doi: 10.1002/art.37723

145. Landewe RB. Methotrexate saves lives: a pearl of observational research. Arthritis Rheum. 2013;65:307–9. doi: 10.1002/art.37725

146. Hazlewood GS, Thprne JC, Pope JE, et al. The comparative effectiveness of oral versus subcutaneous methotrexate for the treatment of early rheumatoid arthritis. Ann Rheum Dis. 2015. doi: 10.1136/annrheumdis-2014-206504

147. Muller RB, von Kempis J, Haile ER, Schiff MH. Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: a retrospective analysis of real-word data from the St.Gallen cohort. Semin Arthritis Rheum. 2015. doi: 10.1016/j.semarthritis.2015.02.009

148. Yazici Y, Bata Y. Parenteral methotrexate for the treatment of rheumatoid arthritis. Bull Hosp Joint Dis. 2013;71 Suppl 1:S46–8.

149. Schiff MH, Jaffe JS, Freundlich B. Head-to-head, randomized, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at dose ≥15 mg may be overcome with subcutaneous administration. Ann Rheum Dis. 2014;73:1549–51. doi: 10.1136/annrheumdis-2014-205228

150. Burmester G-R, Kivitz AJ, Kupper H, et al. Efficacy and safety of ascending methotrexate dose in combination with adalimumab: a randomised CONCERTO trial. Ann Rheum Dis. 2015;74:1037–44. doi:10.1136/annrheumdis-2013-204769

151. Vogelzang EH, Pouw MF, Nurmohamed M, et al. Adalimumab tough concentrations in patients with rheumatoid arthritis and psoriatic arthritis treated with concomitant disease-modifying antirheumatic drugs. Ann Rherum Dis. 2015;74:474–5. doi: 10.1136/annrheumdis-2014-206588

152. Manders SH, Kievit W, Adang E, et al. Effectiveness of TNF inhibitor treatments with various methotrexate doses in patients with rheumatoid arthritis: results from clinical practice. Ann Rheum Dis. 2015;74:e24. doi: 10.1136/annrheumdis-2014-207005

153. Zeidler H. The issue of bioavailability of oral low dose methotrexate: should we chose only 10 mg of MTX a week in conjuction with anti-TNF therapy? Ann Rheum Dis. 2014;73:e50. doi: 10.1136/annrheumdis-2014-205701

154. Smolen JS, Aletaha D. Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges. Nat Rev Rheumatol. 2015;11(5):276–89. doi: 10.1038/nrrheum.2015.8


Для цитирования:


Насонов Е.Л. Метотрексат при ревматоидном артрите – 2015: новые факты и идеи. Научно-практическая ревматология. 2015;53(4):421-433. https://doi.org/10.14412/1995-4484-2015-421-433

For citation:


Nasonov E.L. METHOTREXATE IN RHEUMATOID ARTHRITIS – 2015: NEW FACTS AND IDEAS. Rheumatology Science and Practice. 2015;53(4):421-433. (In Russ.) https://doi.org/10.14412/1995-4484-2015-421-433

Просмотров: 665


Creative Commons License
Контент доступен под лицензией Creative Commons Attribution 4.0 License.


ISSN 1995-4484 (Print)
ISSN 1995-4492 (Online)