Первое российское стратегическое исследование фармакотерапии ревматоидного артрита (РЕМАРКА)

Международные рекомендации «Treat to target» (T2T) «Лечение до достижения цели» подчеркивают, что важнейшее значение для успеха терапии ревматоидного артрита (РА) имеет стратегия лечения. Очевидно, что для оценки эффективности такого подхода требуются специальные стратегические исследования с «адаптивным» дизайном, которые существенно отличаются от классических рандомизированных клинических исследований и находятся гораздо ближе к клинической практике. До настоящего времени имеются лишь единичные публикации по практическому применению рекомендаций Т2Т, существуют проблема выбора критериев эффективности, а также ряд других важных проблем, связанных с внедрением этих рекомендаций. Российское исследование РЕМАРКА призвано ответить на эти вопросы. Дизайн исследования РЕМАРКА представляет собой практическую адаптацию стратегии Т2Т к лечению больных активным ранним РА и РА в развернутой стадии, имеющих факторы неблагоприятного прогноза, с помощью метотрексата в подкожной форме и генно-инженерных биологических препаратов (ГИБП). Предварительный анализ показывает, что терапия по протоколу РЕМАРКА успешна у большинства пациентов. Достигнута высокая частота низкой активности РА и ремиссии при монотерапии подкожной формой метотрексата. Пациенты, нуждающиеся в подключении ГИБП, возможно, изначально являются более резистентными к терапии. Больные ранним РА имеют более высокие шансы на успешное лечение по принципам Т2Т, чем больные развернутым РА.

ревматоидный артрит, лечение до достижения цели, исследование РЕМАРКА, метотрексат, генно-инженерные биологические препараты

1. <div><p>Насонов Е.Л., Каратеев Д.Е., Балабанова RM. Ревматоидный артрит. В кн.: Ревматология: Национальное руководство. Под ред. Е.Л. Насонова, В.А. Насоновой. M.: ГЭО1АР-Mедиа, 2008; 290-331.</p><p>Klareskog L., Cartina A.I., Paget S. Rheumatoid arthritis. Lancet 2009;373:659-72.</p><p>Scott D.L., Wolfe F., Huizinga T.W.J. Rheumatoid arthritis. Lancet 2010;376;1094—108.</p><p>Ревматология: Клинические рекомендации. Под ред. Е.Л. Насонова. M.: ГЭОTАР-Mедиа, 2010.</p><p>Каратеев Д.Е. Низкая активность и ремиссия при ревматоидном артрите: клинические, иммунологические и морфологические аспекты. Науч-практич ревматол 2009;5:4-12.</p><p>Каратеев Д.Е., Лучихина Е.Л., Тюрина Л.Н. и др. Ранняя диагностика ревматоидного артрита в клинической практике на современном этапе (результаты наблюдений за Mосковской когортой больных ранним артритом в рамках программы РАДИКАЛ). Тер арх 2008;5:8-13.</p><p>Федоренко Е.В., Лукина Г.В., Сигидин Я.А. и др. Сравнительная эффективность современных методов терапии раннего ревматоидного артрита (предварительные результаты). Науч-практич ревматол 2009;5:36-40.</p><p>Pincus T., Cronstein B., Braun J. Methotrexate the anchor drug an introduction. Clin Exp Rheumatol 2010;28:S1-S2.</p><p>Насонов Е.Л. Метотрексат. Перспективы применения в медицине. М.: Филоматис, 2005; 196 с.</p><p>Насонов Е.Л. Лечение ревматоидного артрита 2012: место метотрексата. Науч-практич ревматол 2012;51(Прил.):1-24.</p><p>Visser K., Katchhamart W., Losa E. et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on rheumatoid arthritis: integrating systemic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis 2009;68:1086-93.</p><p>Kuriya B., Arkema E.V., Bykerk V.P., Keystone E.C. Efficacy of initial methotrexate monotherapy versus combination therapy with biological agent in early rheumatoid arthritis: a meta-analysis of clinical and radiographic remission. Ann Rheum Dis 2010;69:1298-304.</p><p>Gaujoux-Viala C., Smolen J.S., Landewe R. et al. Current evidence for management of rheumatoid arthritis with synthetic disease-modifying antirheumatic drugs: a systemic literature review informing EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis 2010;69:1004-9.</p><p>Salliot C., van der Heijde D. Long-term safety of methotrexate monotherapy in patients with rheumatoid arthritis: a systemic literature research. Ann Rheum Dis 2009;68:1100-4.</p><p>KatchamatW., Trudeau J., Phumethum V., Bombardier C.E. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systemic review and meta-analysis. Ann Rheum Dis 2009;68:1105-12.</p><p>Hoekstra M., Haagsma C., Neef C. et al. Bioavailability of high dose methotrexate comparing oral and subcutaneous administration in patients with rheumatoid arthritis. J Rheumatol 2004;31:645-8.</p><p>Dalrymple J.M., Stamp L.K., O'Donnell J.L. et al. Pharmacokinetics of oral methotrexate in patients with rheumatoid arthritis. Arthr Rheum 2008;58:3299-308.</p><p>Dervieux T., Zablocki R., Kremer J. Red blood cell methotrexatee polyglutamates emerge as a function on dosage intensity and rout of administration during pulse methotrexate therapy in rheumatoid arthritis. Rheumatology (Oxford) 2010;49:2337-45.</p><p>Stamp L.K., Barclay M.L., O'Donnell J.L. 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.</p><p>Hamilton R.A., Kremer J.M. Why intramuscular methotrexate may be more efficacious than oral dosing in patients with rheumatoid arthritis. Brit J Rheumatol 1997;36:86-90.</p><p>Rozin A., Scharpira D., Balbir-Gurman A. et al. Relapse of rheumatoid arthritis after substitution of oral for parental administration of methotrexate. Ann Rheum Dis 2002;61:756-7.</p><p>Bingman S.J., Buch M.H., Lindsay S. et al. Parental methotrexate should be given before biological therapy. Rheumatology 2003;42:1009-10.</p><p>Wegrzyn J., Adeleine P., Miossec P. Better efficacy of methotrexate given by intramuscular injection than orally in patients with rheumatoid arthritis. Ann Rheum Dis 2004;63:1232-4.</p><p>Moitra R.K., Ledingham J.M., Hull R.G. et al. Caveats to the use of parental methotrexate in the treatment of rheumatic disease. Rheumatology 2005;44:256-7.</p><p>Osman A., Mulherin D. Is parental methotrexate worth trying. Ann Rheum Dis 2001;60:432.</p><p>Burbage G., Gupta R., Lim K. Intramuscular methotrexate in inflammatory rheumatic disease. Ann Rheum Dis 2001;60:1156.</p><p>Rutkowska-Sak L., Rell-Bakalarska M., Lisowska B. Oral vs. Subcutaneous low-dose methotrexate treatment in reducing gastrointestinal side effects. Rheumatologia 2009;47:207-11.</p><p>Braun J., Kastner P., Flaxenberg P. et al. Comparison of the clinical efficacy and safety of subcutaneous versus oral administration of methotrexate in patients with active rheumatoid arthritis: results of a six-month, multicenter, randomized, double-blind, controlled, phase IV trial. Arthr Rheum 2008;58:73-81.</p><p>Bakker M.F., Jacobs J.W.G., Welsing P.M.J. et al. Are switching from oral to subcutaneous methotrexate or additional of cyclosporine to methotrexate useful steps in tight control treatment strategy for rheumatoid arthritis? A post hoc analysis of the CAMERA study. Ann Rheum Dis 2010;69:1849-52.</p><p>Bykerk V.P., Rowe D.S., Thorne C. et al. Increased remission rates in patients receiving early optimal doses of parental methotrexate vs other therapeutic strategies from a nationwide early rheumatoid cohort. Ann Rheum Dis 2010;69(Suppl 3):65.</p><p>Nixon R.M., Bansback N., Brennan A. Using mixed treatment comparison and meta-regression to perform indirect comparisons to estimate efficacy of biologic treatment in rheumatoid arthritis. Stat Med 2007;26:1237-54.</p><p>Ma M.H.Y. A systematic comparison of combination DMARD therapy and tumour necrosis inhibitor therapy with methotrexate in patients with early rheumatoid arthritis. Rheumatology 2010,49:91-8.</p><p>Gartlehner G., Hansen R.A., Jonas B.L. et al. The comparative efficacy and safety of biologics for the treatment of rheumatoid arthritis: a systemic review and meta-analysis. J Rheumatol 2006;3:2398-407.</p><p>Alonso-Ruiz A., Pijoan J.I., Ansuategui E. et al. Tumor necrosis factor alpha drugs in rheumatoid arthritis: systemic review and meta-analysis of efficacy and safety. BMC Musculoskeletal Disorders 2008;9:52.</p><p>Kristensen L.E., Christensen R., Biddal H. et al. The number needed to treat for adalimumab, etanercept, and infliximab based on ACR50 response in three randomized controlled trials on established rheumatoid arthritis: a systemic literature review. Scand J Rheumatol 2007;36:411-7.</p><p>Wiens A., Venson R., Pharm D. et al. Meta-analysis of the efficacy and safety of adalimumab, etanercept, and infliximab for the treatment of rheumatoid arthritis. Pharmacotherapy 2010;30:339-53.</p><p>Schmitz S., Adams R., Walsh C. et al. A mixed treatment comparison of the efficacy of anti-TNF agents in rheumatoid arthritis for methotrexate non-responders demonstrates differences between treatment: a Bayesian approach. Ann Rheum Dis 2012;71:225-30.</p><p>Aaltonen K.J., Vikki L.M., Malmiaara A. et al. Systemic review and meta-analysis of the efficacy and safety of existing TNF blocking agents in the treatment of rheumatoid arthritis. PLoS ONE 2012;7:e30275.</p><p>Singh J.A., Christensen R., Wells G.A. et al. Biologics for rheumatoid arthritis: an overview of Cochrane reviews. The Cochrane Library. Willey &amp; Sons, Ltd, 2009;4.</p><p>Nam J.L., Wintrop K.L., van Vollenhoven R.F. et al. Current evidence for the management of rheumatoid arthritis with biological disease-modifying antirheumatic drugs: a systemic literature rewires informing the EULAR recommendations for the management of RA. Ann Rheum Dis 2010;69:976-86.</p><p>Salliot C., Finckh A., Katchamart W. et al. Indirect comparisons of the efficacy of biological antirheumatic agents in rheumatoid arthritis in patients with an inadequate response to conventional disease-modifying antirheumatic drugs or to an anti-tumor necrosis factor agents: a meta-analysis. Ann Rheum Dis 2011;70:266-71.</p><p>Bergman G.J., Hochberg M.C., Boers M. et al. Indirect comparison of tocilizumab and other biologic agents in patients with rheumatoid arthritis and inadequate response to disease-modifying antirheumatic drugs. Semin Arthr Rheum 2010;39:425-41.</p><p>Devine E.B., Alfonso-Cristanchp R., Sullivan S.D. Effectiveness of biologic therapies for rheumatoid arthritis: an indirect compari-son approach. Pharmacotherapy 2011;31:39-51.</p><p>Gallego-Galisteo М., Villa-Rubio A., Alergre-del Rau E. et al. Indirect comparison of biological treatments in refractory rheumatoid arthritis. J Clin Pharm Ther 2011 (on line).</p><p>Turksta E., Ng S.-K., Scuffham P.A. A mixed treatment comparison of the short-term efficacy of biologic disease modifying antirheumatic drugs in established rheumatoid arthritis. Curr Med Res Opin 2011;27:1885-97.</p><p>Guyot P., Taylor P., Christensen R. et al. Abatacept with methotrexate versus other biologic agents in treatment of patients with active rheumatoid arthritis despite methotrexate: a network meta-analysis. Arthr Res Ther 2011;13:R204.</p><p>Каратеев Д.Е., Насонов Е.Л., Лучихина Е.Л. и др. Эффективность и безопасность лечения адалимумабом больных активным ревматоидным артритом с резистентностью к стандартной терапии: результаты Российского национального исследования. Тер арх 2012;8:22-8.</p><p>Панасюк Е.Ю., Амирджанова В.Н., Авдеева А.С. и др. Опыт применения тоцилизумаба у больных ревматоидным артритом (по данным многоцентрового исследования ЛОРНЕT). Науч-практич ревматол 2013;52:104-10.</p><p>Goekoop-Ruiterman Y.P.M., de Vries-Bouwstra J.K., Allaart C.F. et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study). Arthr Rheum 2005;52:3381-90.</p><p>Van Vollenhoven R.F., Ernestam S., Geborek P. et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial: 1-year results of a randomized trial). Lancet 2009;374:459-66.</p><p>Nam J.L., Villeneuve E., Hensor E.M.A. et al. Inhibition of structural damage with two intensive treatment strategies using methotrexate or high dose intravenous steroid followed by Treat to Target in DMARD naive rheumatoid arthritis (the IDEA study) -a preliminary report. Ann Rheum Dis 2012;71:(Suppl 3):106.</p><p>Leririsalo-Repo M., Kautiainen H., Laasonen L. et al. A randomized, double-blind, placebo-controlled study on addition of infliximab to the FIN-RACO DMARD combination therapy for initial six month in patients with early active rheumatoid arthritis. The NEO-RACO study. Ann Rheum Dis 2008;67(Suppl II):50.</p><p>Verstappen S.M.M., Jacobs J.W.G., vander Veen M.J. et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for temission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA), open-label strategy trial. Ann Rheum Dis 2007;66:1443-9.</p><p>Baker M., Jacobs J.W.G., Welsing P.M.J. et al. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis. Ann Intern Med 2012;156:329-39.</p><p>Hetland M.L., Stengaard-Pedersen K., Junker P. et al. Combination treatment with methotrexate, cyclosporine, and intraarticular betamethason compared with methotrexate and intramuscular bethamethason in early active rheumatoid arthritis. An investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study. Arthr Rheum 2006;54;1401-9.</p><p>Vermeer M., Kuper H.H., Hoekstra M. et al. Implementation of a Threat-to-Target strategy in very early rheumatoid arthritis. Results of the Dutch Rheumatoid Arthritis Monitoring Remission Induction Cohort Study. Arthr Rheum 2011;63:2865-72.</p><p>Vermeer M., Kuper H.H., Bernelot Moens H.J. et al. Sustained beneficial effects of a protocolized treat-to-target strategy in very early rheumatoid arthritis: three year results of the DREAM remission induction cohort. Arthr Care Res 2013;Feb 12;doi 10.1002/acr.2198.</p><p>Bosello S., Fedele A.L., Peluso G. et al. Very early rheumatoid arthritis is the major predictor of major outcome: clinical ACR remission and radiographic non-progression. Ann Rheum Dis 2011;70:1292-5.</p><p>Wevers-de Boer K., Visser K., Heimans L. et al. Remission induction therapy with methotrexate and prednisolone in patients with early rheumatoid and undifferentiated arthritis (the IMPROVE study). Ann Rheum Dis 2012;71:1472-7.</p><p>Soubrier M., Puechal X., Sibilia J. et al. Evaluation of strategies (initial methotrexate monotherapy vs. its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology 2009;48:1429-34.</p><p>Kavanaugh A., Fleischmann R., Emery P. et al. Clinical, functional and radiographic consequences of achiving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomized, controlled OPTIMA study. Ann Rheum Dis 2013;72:64-71.</p><p>Horslev-Petersen K., Hertland M.L., Junker P. et al. Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA study; an investigator-initiated, randomized, double-blind, parallel-group, placebo-controlled trial. Ann Rheum Dis 2013, March 7;doi:10.1136/annrheumdis-2012-202735.</p><p>Detert J., Bastian H., Listing J. et al. Induction therapy with adalimumab plus methotrexate for 24 weeks followed by methotrexate monotherapy up to week 48 versus methotrexate therapy alone for DMARD-naXve patients with early rheumatoid arthritis: HIT-HARD, an investigator-initiated study. Ann Rheum Dis 2012;June 27; doi:10.1136/annrheumdis-1011-201612.</p><p>Heimans L., Wevers-de Boer K.V.C., Visser K. et al. Remission after one year follow up of the IMPROVED-study, a randomized clinical trial aming at remission in patients with early rheumatoid arthritis. Ann Rheum Dis 2012;71(Suppl 3): 329.</p><p>Emery P., Breedveld F.C., Hall S. et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etaner-cept in active early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial. Lancet 2008;372:375-82.</p><p>Emery P., Breedveld F., van der Heijde D. et al. Two-year clinical and radiological results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis. Arthr Rheum 2010;62:674-82.</p><p>Moreland L.W., O'Dell J.R., Paulus H. et al. TEAR: treatment of early aggressive RA; A randomized, double-blind, 2-year trial comparing immediate triple DMARD versus MTX plus etanercept to step-up from initial MTX monotherapy. Arthr Rheum 2012;64:2824-35.</p><p>De Jong P.H., Hazes J.M., Barendregt PJ. et al. Induction therapy with combination of DMARDs is better than methotrexate monotherapy; first results of the tREACH trial. Ann Rheum Dis 2013;72:72-8.</p><p>Montecucco C., Todoerti M., Sakellariou G. et al. Low-dose oral prednisolon improves clinical and ultrasonographic remission rates in early rheumatoid arthritis: results of a 12-month open-label randomized study. Arthr Res Ther 2012;14:R112.</p><p>Leirisalo-Repo M., Kautianen H., Laasonen L. et al. Infliximab for 6 month added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study). Ann Rheum Dis 2012;June 30; doi:10.1136/annrheumdis-2012-201365.</p><p>Van Vollenhoven R.F., Ernestam S., Geborek P. et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomized trial. Lancet 2009;374:459-66.</p><p>Smolen J.S., Aletaha D., Bijsma J.W.J. et al. For the T2T Expert Committee. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69:631-7.</p><p>Smolen J.S., Landewe R., Breedveld F.C. 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.</p><p>Jurgens M.S., Welsing P.M.J., Jacobs J.W.G. Overview and analysis of treat-to-target trials in rheumatoid arthritis reporting remission Clin Exp Rheumatol 2012;30(Suppl 73):S56-S63.</p><p>Schoels M., Knevel R., Aletaha D. et al. Evidence for treating rheumatoid arthritis to target: results of a systemic literature search. Ann Rheum Dis 2010;69:638-43.</p><p>Schipper L.G., van Hulst L.T., Grop R. et al. Meta-analysis of a tight control strategies in rheumatoid arthritis: protocolized treatment has additional value with respect to the clinical outcome. Rheumatology (Oxford) 2010;49:2154-60.</p><p>Grigor C., Capell H., Stirling A. et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomesed controlled trial. Lancet 2004;364:263-9.</p><p>Verstappen S.M., Jacobs J.W., van der Veen M.J. et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA, an open-label strategy trial). Ann Rheum Dis 2011;63:573-86.</p><p>Goekoop-Ruiterman Y.P., de Vries-Bouwstra J.K., Kerstens P.J. et al. DAS-driven therapy versus routine care in patients with recent-onset active rheumatoid arthritis. Ann Rheum Dis 2010;69:65-9.</p><p>Schipper L.G., Vermeer M., Kuper H.H. et al. A tight control treatment strategy aiming for remission in early rheumatoid arthritis is more effective than usual care treatment in daily clinical practice: a study of two cohorts in the Dutch Rheumatoid Arthritis Monitoring registry. Ann Rheum Dis 2012;71:845-50.</p><p>Schwartz D., Lellouch J. Explanatory and pragmatic attitudes in therapeutical trials. J Chron Dis 1967;20:637-48.</p><p>Buch M.H., Pavitt S., Parmar M., Emery P. Creative trial design in RA: optimizing patient outcomes. Nat Rev Rheumatol 2013;9:183-94.</p><p>Felson D., Smolen J., Wells G. et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis in clinical trials. Arthr Rheum 2011;63:573-86.</p><p>Pincus T. Can RAPID3, an index without formal joint counts and laboratory tests, serve to guide rheumatologists in tight control in tight control of rheumatoid arthritis in usual clinical care? Bull NYU Hosp Jt Dis 2009;67:254-66.</p><p>Pincus T., Castrejon I., Bergman M.J., Yazici Y. Treat-to-target; not as simple as it appears. Clin Exp Rheumatol 2012;30(Suppl 73):S10-S20.</p><p>Szkudlarek M., Wakefield R.J., Backhaus M., Terslev L. The discriminatory capacity of ultrasound in rheumatoid arthritis: active vs inactive, early vs advanced, and more. Rheumatology 2012;51:vii6-vii9.</p><p>Tan T.K., Ostergaard M., Conaghan P.G. Imaging tools in rheumatoid arthritis: ultrasound vs magnetic resonance imaging. Rheumatology 2012;51:vii36-vii42.</p><p>Насонов Е.Л., Александрова Е.Н. Современные технологии и перспективы лабораторной диагностики ревматических заболеваний Тер арх 2010;5:5-9.</p><p>Насонов Е.Л. Ревматоидный артрит: проблемы и значение персонифицированной медицины. Тер арх 2012;5:5-9.</p><p>Насонов Е.Л., Попкова Т.В. Кардиоваскулярные проблемы ревматологии. Науч-практич ревматол 2004;4:4-9.</p><p>Ouellet-Hellstrom R., Herrinton L., Liu L. et al. Changes in cotherapies after initiation of disease-modifying antirheumatic drug therapy in patients with rheumatoid arthritis. Arthr Care Res. (Hoboken) 2011;63:1415-24.</p><p>Tanaka Y. New stage of RA treatment: is TNF inhibitor-free remission a possible treatment goal. Ann Rheum Dis 2012;Dec 19 [Epub. ahead of print].</p><p>Arnrett F.C., Edworth S.M., Bloch D.A. et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthr Rheum 1988;31:315-24.</p><p>Aletaha D., Neogi T., Silman A.J. et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010;69:1580-8.</p></div><br />