THE FIRST RUSSIAN STRATEGIC STUDY OF PHARMACOTHERAPY FOR RHEUMATOID ARTHRITIS (REMARCA TRIAL): RESULTS OF 12-MONTH TREATMENT IN 130 PATIENTS

To introduce treat-to-target recommendations is an important task of modern rheumatology; however, there is still a diversity of serious problems relating to a scientific rationale and a clinical one for this strategy and to the possibilities
of its implementation in real clinical practice, in the rheumatology service of the Russian Federation in particular, by taking into account the specific features of funding for high-tech medical care.
Objective: to determine the efficiency and safety of combined therapy with subcutaneous methotrexate (MT) and biological agents (BA) when using the treat-to-target strategy in patients with active early and extended-stage rheumatoid arthritis (RA) who have risk factors for a poor prognosis.
Subjects and methods. The results of the REMARCA (Russian InvEstigation of MethotrexAte and biologicals in eaRly aCtive inflammatory Arthritis) trial of 130 patients followed up for 12 months or more were given. There was a female preponderance; mean age 48.9±13.9 years, rheumatoid factor positivity (86.9%); anti-cyclic citrullinated peptide anti body positivity (89.2%). Seventy patients formed a subgroup of early RA (disease duration ≤6 months (mean 4.17±1.39 months)); 60 patients were a subgroup of advanced-stage RA (disease duration >6 months (mean 30.8±32.7 months)). In all the patients, therapy was initiated by using subcutaneous MT with its rapid dose escalation up to 20–30 mg/week and the achievement of the treatment goal (low disease activity or remission) was checked every 3 months and depending on the result a decision had been taken to add or not to add a biological agent (BA) (a tumor necrosis factor inhibitor or abatacept). If the former was insufficiently
effective, it was substituted for a BA from another class.
Results. Subcutaneous MT monotherapy provided remission or low disease activity in 49 (37.7%) patients; a BA was given to 81 (62.3%) patients. Following 6 and 12 months, low activity or remission according to SDAI was observed significantly more frequently in the patients who continued  ubcutaneous MT monotherapy than in those who received combined therapy with MT and BA. The similar results were obtained by using DAS28 and CDAI to assess a trend in disease activity. After 6- and 12-month follow-up, there was a significantly more marked decline of tender joint count, SDAI and CDAI in early RA than in advanced-stage RA; at 12 months, SDAI remission rate was
45.7% and 28.3%, respectively (p=0.047).
Conclusion. The treat-to-target strategy should be used in real clinical practice
and can yield spectacular results. Active therapy with subcutaneous MT with its rapid dose escalation to the maximally tolerable dose allows identification of a considerable group of patients (38%) with a good response to MT monotherapy.

rheumatoid arthritis, treat-to-target strategy, methotrexate, biologicals

1. Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Ревматология. Национальное руководство. Под. ред. Е.Л. Насонова, В.А. Насоновой. Москва: ГЭО- ТАР-Медиа; 2008. С. 290–331. [Nasonov EL, Karateev DE, Balabanova RM. Rheumatoid arthritis. In: Revmatologiya. Natsional’noe rukovodstvo [Rheumatology. National Guide]. Nasonov EL, Nasonova VA, editors. Moscow: GEOTAR-media; 2008. P. 290–331.]

2. Насонов ЕЛ, редактор. Генно-инженерные биологические препараты в лечении ревматоидного артрита. Москва: ИМА- ПРЕСС; 2013. [Nasonov EL, editor. Genno-inzhenernye biologicheskie preparaty v lechenii revmatoidnogo artrita [Genetically engineered biological preparations in treatment of rheumatoid arthritis]. Moscow: IMA-PRESS; 2013.]

3. Smolen JS, Aletaha D, Bijsma JW, 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. DOI:http://dx.doi.org/10.1136/ard.2009.123919.

4. Jurgens MS, Welsing PM, Jacobs JW. Overview and analysis of treat-to-target trials in rheumatoid arthritis reporting remission. Clin Exp Rheumatol. 2012;30 (Suppl 73):S56–63.

5. Knevel R, Schoels M, Huizinga TWJ, et al. Current evidence for a strategic approach to the management of rheumatoid arthritis with disease-modifying anti-rheumatic drugs: a systematic literature review informing the EULAR recommendations for the management of rheumatoid arthritis. Ann Rheum Dis. 2010;9:987–94. DOI: http://dx.doi.org/10.1136/ard.2009.126748.

6. Schipper LG, van Hulst LTC, Grol R, et al. Meta-analysis of tight control strategies in rheumatoid arthritis: protocolized treatment has additional value with respect to the clinical outcome. Rheumatology (Oxford). 2010;49:2154–64. DOI:http://dx.doi.org/10.1093/rheumatology/keq195.

7. Pincus T, Castrejon I, Bergman MJ, Yazici Y. Treat-to-target: not as simple as it appear. Clin Exp Rheumatol. 2012;30 (Suppl 73): S10–20.

8. Solomon DH, Bitton A, Katz JN, et al. Treat to Target in rheumatoid arthritis: facts, fiction or hypothesis. Arthritis Rheum. 2014. DOI: 10.1002/art.38323. DOI: http://dx.doi.org/10.1002/art.38323.

9. Nasonov EL, Karateev DE. Does Russia need a treat-to-target initiative? Rheumatology (Oxford). 2014. DOI: http://dx.doi.org/10.1093/rheumatology/keu156.

10. Каратеев ДЕ, Лучихина ЕЛ, Муравьев ЮВ и др. Первое российское стратегическое исследование фармакотерапии ревматоидного артрита (РЕМАРКА). Научно-практическая ревматология. 2013;51:117–25. [Karateev DE, Luchikhina EL,Murav'ev YuV, et al. The first Russian strategic study of pharmacotherapy for rheumatoid arthritis (REMARCA). Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51:117–25. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2013-637.

11. 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 randomised controlled trial. Lancet. 2004;364:263–9. DOI: http://dx.doi.org/10.1016/S0140-6736(04)16676-2.

12. Verstappen SM, Jacobs JW, van der Veen MJ, 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. 2007;66:1443–9. DOI: http://dx.doi.org/10.1136/ard.2007.071092.

13. Hetland ML, Horslev-Petersen K. The CIMESTRA study: intraarticular glucocorticosteroids and synthetic DMARDs in a treatto- target strategy in early rheumatoid arhtritis. Clin Exp Rheumatol. 2012; (Suppl 73):S44–9.

14. Vermeer M, Kuper HH, Hoekstra M, et al. Implementation of a treat-to-target strategy in very early rheumatoid arthritis: results of the Dutch Rheumatoid Arthritis Monitoring Remission Induction Cohort Study. Arthritis Rheum. 2011;63:2865–72. DOI: http://dx.doi.org/10.1002/art.30494.

15. Bakker MF, Jacobs JW, Welsing PM, et al. Low-dose prednisone inclusion in a methotrexate-based, tight control strategy for early rheumatoid arthritis: a randomized trial. Ann Intern Med. 2012;156:329–39. DOI: http://dx.doi.org/10.7326/0003-4819- 156-5-201203060-00004.

16. Markusse I, de Vries-Bouwstra J, van der Lubbe P, et al. Feasibility of tailored treatment based on risk stratification in patients with early rheumatoid arthritis. Arthritis Res Ther. 2014; 6:430. DOI: http://dx.doi.org/10.1186/s13075-014-0430-3.

17. 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: http://dx.doi.org/10.1136/ard.2009.126532.

18. 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(3):492–509. DOI: http://dx.doi.org/10.1136/annrheumdis-2013-204573.

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

20. Насонов ЕЛ, Каратеев ДЕ, Чичасова НВ. Новые рекомендации по лечению ревматоидного артрита (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: http://dx.doi.org/10.14412/1995-4484-2014-8-26.

21. 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. 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: http://dx.doi.org/10.14412/1995-4484-2014-477-494.

22. Насонов ЕЛ. Лечение ревматоидного артрита 2012: место метотрексата. Научно-практическая ревматология. 2012;50(приложение):1–24. [Nasonov EL. Treatment of rheumatoid arthritis 2012: methotrexate place. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012;50(Suppl):1–24. (In Russ.)]

23. 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. Arthritis Rheum. 2008;58:73–81. DOI: http://dx.doi.org/10.1002/art.23144.

24. 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: http://dx.doi.org/10.1136/annrheumdis-2014-205228.

25. 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-naive patients with early rheumatoid arthritis: HITHARD, an investigator-initiated study. Ann Rheum Dis. 2013;72:844–50. DOI: http://dx.doi.org/10.1136/annrheumdis-2012-201612.

26. Kavanaugh A, Klareskog L, van der Heijde D, et al. Improvements in clinical response between 12 and 24 weeks in patients with rheumatoid arthritis on etanercept therapy with or without methotexate. Ann Rheum Dis. 2008;67:1444–7. DOI: http://dx.doi.org/10.1136/ard.2008.094524.

27. Kavanaugh A, Keystone E, Feng JY, Hooper M. Is a 12-week trial sufficient to evaluate clinical responses to etanercept of methotrexate in early RA? Rheumatology (Oxford). 2010;49:1201–3. DOI: http://dx.doi.org/10.1093/rheumatology/keq036.

28. Nam JL, Villeneuve E, Hensor EMA, et al. A randomised controlled trial of etanercept and methotrexate to induce remission in early inflammatory arthritis: the EMPIRE trial. Ann Rheum Dis. 2014. DOI: http://dx.doi.org/10.1136/annrheumdis-2013-204882.

29. Stamp LK, Barclay ML, O’Donnel JL, et al. Effect 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(12):2540–7. DOI: http://dx.doi.org/10.3899/jrheum.110481.

30. Soubrier M, Puechal X, Sibilia J, et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology (Oxford). 2009;48:1429–34. DOI: http://dx.doi.org/10.1093/rheumatology/ kep261.

31. Yamanaka H, Ishigurp N, Takeuchi T, et al. Recovery of clinical but not radiographic outcome by the delayed addition of adalimumab to methotrexate-treated Japanese patients with early rheumatoid arthritis: 52-week results of the HOPEFUL-1 trial. Rheumatology (Oxford). 2014;53(5):904–13. DOI: 101093/rheumatology/key465.

32. Moreland LW, O’Dell JR, 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. Arthritis Rheum. 2012;64:2824–35. DOI: http://dx.doi.org/10.1002/art.34498.

33. O’Dell JR, Curtis JR, Mikuls TR, et al. Validation of the methotrexate-first strategy in patients with early, poor-prognosis rheumatoid arthritis. Results from a two-year randomized, doubleblind trial. Arthritis Rheum. 2013;65:1985–94. DOI: http://dx.doi.org/10.1002/art.38012.

34. O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. New Engl J Med. 2013;369(4):307–18. DOI: http://dx.doi.org/10.1056/NEJMoa1303006.

35. Emery P, Breedveld FC, Hall S, et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active early, moderate to severe rheumatoid arthritis (COMET): a randomized, double-blind, parallel treatment trial. Lancet. 2008;372:375–82. DOI: http://dx.doi.org/10.1016/S0140-6736(08)61000-4.

36. Emery P, Breedveld F, van der Heijde D, et al. Two-year clinical and radiographic results with combination etanercept-methotrexate therapy versus monotherapy in early rheumatoid arthritis. A two-year, double-blind, randomized study. Arthritis Rheum. 2010;62:674–82. DOI: 10.1002/art.272668.

37. Gaujoux-Viala C, Mitrovic S, Barnetche T, et al. Efficacy of glucocorticoids for early rheumatoid arthritis: a meta-analysis of randomized controlled trials. Ann Rheum Dis. 2014;73 (Suppl 1). DOI: http://dx.doi.org/10.1136/annrheumdis-2014-eular.5840.

38. Dixon WG, Bansback N. Understanding the side effects of glucocorticoid therapy: shining a light on a drug everyone thinks they know. Ann Rheum Dis. 2012;71:1761–4. DOI: http://dx.doi.org/10.1136/annrheumdis-2012-202021.

39. Volkman ER, Rezai S, Tarp S, et al. We still don't know how to taper glucocorticoids in rheumatoid arthritis, and we can do better. J Rheumatol. 2013;40:10. DOI: http://dx.doi.org/10.3899/jrheum.130019.