References

rsp

Научно-практическая ревматология

Rheumatology Science and Practice

1995-44841995-4492

IMA-PRESS, LLC

10.14412/1995-4484-2014-209-221

rsp-1928

Research Article

ПРОГРЕСС В РЕВМАТОЛОГИИ В XXI ВЕКЕ

PROGRESS IN RHEUMATOLOGY IN THE XXI CENTURY

Новые подходы к фармакотерапии ревматоидного артрита: тофацитиниб

NEW APPROACHES TO PHARMACOTHERAPY OF RHEUMATOID ARTHRITIS: TOFACITINIB

Насонов

Е. Л.

Nasonov

E. L.

nasonov@irramn.ru

ФГБУ «Научно- исследовательский институт ревматологии им. В.А. Насоновой РАМН», Москва, РоссияРоссияV.A. Nasonova Research Institute of Rheumatology, Russian Academy of Medical Sciences, Moscow, RussiaRussian Federation

2014

17062014

522

НАУЧНО-ПРАКТИЧЕСКАЯ РЕВМАТОЛОГИЯ 52 No 2-2014

209221

2014

Насонов Е.Л.

Nasonov E.L.

This work is licensed under a Creative Commons Attribution 4.0 License.

https://rsp.mediar-press.net/rsp/article/view/1928

К крупным достижениям фармакологии XXI в. относится разработка нового класса лекарственных средств, представляющих собой низкомолекулярные (<1 кДа) химически синтезированные вещества (small mole- cules), предназначенные для перорального приема. Их точка приложения – тирозинкиназы, ферменты, уча- ствующие в регуляции внутриклеточной сигнализации, определяющей биологическую активность цитоки- нов. Особый интерес представляет тофацитиниб (ТОФА; Tofacitinib, Яквинус; Пфайзер), первый перораль- ный обратимый ингибитор JAK, разрешенный к применению для лечения ревматоидного артрита (РА). Клиническая эффективность и низкая токсичность ТОФА доказаны в серии РПКИ фазы III, объединенных акронимом ORAL, в которые вошли более 5000 пациентов с РА. Необходимы дальнейшие исследования, на- правленные на оценку эффективности и безопасности ТОФА в процессе длительного применения в реаль- ной клинической практике (в том числе в рамках национальных регистров), у пациентов с различными фор- мами РА и коморбидными заболеваниями. Целесообразно проведение «стратегических» исследований ТОФА, спланированных в соответствии с концепцией «Лечение до достижения цели»

One of the breakthroughs in pharmacology of the XXI century is the development of a new class of drugs, which are low molecular weight (<1 kDa), chemically synthesized substances (small molecules) intended for oral administration. Their point of application is tyrosine kinases, the enzymes involved in regulation of intracellular signaling that deter- mines the biological activity of cytokines. Tofacitinib (TOFA, Tofacitinib, Yakvinus; Pfizer), the first oral reversible inhibitor of JAK approved for treatment of rheumatoid arthritis (RA), is of special interest. The clinical efficacy and low toxicity of TOFA have been proved in a series of phase III randomized placebo-controlled studies, combined under the acronym ORAL, which has included more than 5000 patients with RA. Further research is needed, aimed at assessing the efficacy and safety of TOFA during prolonged use in real-life clinical practice (including through national registers) in patients with various forms of RA and comorbid diseases. It is reasonable to conduct «strategic» research of TOFA, designed in accordance with the concept of goal-directed treatment.

ревматоидный артриттофацитинибингибиторы JАK.

rheumatoid arthritistofacitinibJAK inhibitors.

References1

McInnes IB, Schett G. The pathogenesis of rheumatoid arthritis. New Engl J Med. 2012;365(23):2205–19. DOI: 10.1056/NEJMra1004965.

Насонов ЕЛ, Каратеев ДЕ, Балабанова РМ. Ревматоидный артрит. В кн.: Ревматология. Национальное руководство.

Под редакцией Е.Л. Насонова, В.А. Насоновой. Москва: ГЭОТАР-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]

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

Furst DE, Keystone EC, Braun J, et al. Update consensus state- ment on biological agents for the treatment of rheumatic diseases, 2011. Ann Rheum Dis. 2012;71 Suppl 2:i2–45. DOI: 10.1136/annrheumdis-2011-201036.

Smolen JS, Aletaha D, Bijsma JWJ, et al.; for the T2T Expert Committee. Treating rheumatoid arthritis to target: recommenda- tions of an international task force. Ann Rheum Dis. 2010;69(4):631–7. DOI: 10.1136/ard.2009.123919. Epub 2010 Mar 9.

Pincus T, Castrejon I. Evidence that the strategy is more important than the agent to treat rheumatoid arthritis. Data from clinical tri- als of combinations of non-biologic DMARDs, with protocol- driven intensification of therapy of tight control or treat-to-target. Bull Hosp Jt Dis. 2013;71 Suppl 1:S33–40.

Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommen- dations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69(6):964–75. DOI: 10.1136/ard.2009.126532. Epub

May 5.

Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommen-

dations 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:10.1136/annrheumdis-2013-204573.

Насонов ЕЛ, Каратеев ДЕ, Чичасова Н.В. 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: http://dx.doi.org/10.14412/1995-4484-2013-609- 22.

Национальные рекомендации по лечению ревматоидного артрита, 2013 (проект). Доступ по ссылке: www.rheumatolog.ru [Natsional'nye rekomendatsii po lecheniyu revmatoidnogo artrita, 2013 (proekt) [National recommendations about treatment of rheumatoid arthritis, 2013 (project)]. Available from: www.rheumatolog.ru]

Pincus T, Kathryn A, Gibson MD, Castrejon I. Update on methotrexate as the anchor drug for rheumatoid arthritis. Bull Hosp Joint Dis. 2013;71 Suppl 1:S9–19.

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.

Насонов ЕЛ. Ревматоидный артрит: проблемы и значение персонифицированной медицины. Терапевтический архив. 2012;84(5):5–9. [Nasonov EL. Rheumatoid arthritis: problems and significance of personalized medicine. Terapevticheskii arkhiv. 2012;84(5):5–9. (In Russ.)]

Насонов ЕЛ, Денисов ЛН, Станислав МЛ. Интерлейкин 17 – новая мишень для антицитокиновой тепапии 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 rheu- matic diseases. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51(5):545–52. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2013-1547.

Насонов ЕЛ, Денисов ЛН, Станислав МЛ, Ильина АЕ. Перспективы фармакотерапии ревматоидного артрита: моноклональные антитела. Научно-практическая ревматология. 2012;50(3):75–82. [Nasonov EL, Denisov LN, Stanislav ML, Ilyina AE. Prospects of pharmacotherapy for rheumatoid arthritis: Monoclonal antibodies. Nauchno-praktich- eskaya revmatologiya = Rheumatology Science and Practice. 2012;50(3):75–82. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2012-713.

Burmester GR, Feist E, Dorner T. Emerging cell and cytokine tar- gets in rheumatoid arthritis. Nat Rev Rheumatol. 2014;10(2):77–88. DOI: 10.1038/nrrheum.2013.168. Epub 2013 Nov 12.

O’Shea JJ, Holland SM, Straudt LM. JAKs and STATs in immu- nity, immunodefficiency and cancer. N Engl J Med. 2013;368(2):161–70. DOI: 10.1056/NEJMra1202117.

O’Shea JJ, Laurence A, McInnes IB. Back to the future: oral tar- geted therapy for RA and other autoimmune diseases. Nat Rev Rheumatol. 2013; 9(3):173–82. DOI: 10.1038/nrrheum.2013.7. Epub 2013 Feb 19.

Smolen JS, van der Heijde D, Machold KP, et al. Proposal for a new nomenclature of disease-modifying antirheumatic drugs. Ann Rheum Dis. 2014;73(1):3–5. DOI: 10.1136/annrheumdis-2013- 204317. Epub 2013 Sep 26.

Sweeney SE, Firestein GS. Primer: signal transduction in rheu- matic disease–a clinician's guide. Nat Clin Pract Rheumatol. 2007;3(11):651–60. DOI: http://dx.doi.org/10.1038/ncprheum0631.

Ghoreschi K, Laurence A, O’Shea JJ. Janus kinases in immune signaling. Immunol Rev. 2009;228(1):273–87. DOI: 10.1111/j.1600-065X.2008.00754.x.

Alicea-Velazquez NL, Boggon TJ. The use of structural biology in janus kinase targeted drug discovery. Curr Drug Targets. 2011;12(4):546–55. DOI: http://dx.doi.org/10.2174/138945011794751528.

Насонов ЕЛ, Денисов ЛН, Станислав МЛ. Новые аспекты фармакотерапии ревматоидного артрита: ингибиторы малых молекул. Научно-практическая ревматология. 2012;50(2):66–75. [Nasonov EL, Denisov LN, Stanislav MI. New aspects of pharmacotherapy for rheumatoid arthritis: small mole- cule inhibitors. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2012;50(2):66–75. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2012-1276.

Kelly V, Genovese M. Novel small molecule therapeutics in rheumatoid arthritis. Rheumatology (Oxford). 2013 Jul;52(7):1155–62. DOI: 10.1093/rheumatology/kes367. Epub 2013 Jan 7.

Advisory Committee Meeting Tofacitinib for the Treatment of Rheumatoid Arthritis (NDA 203214). Briefing document. May 9, 2012. Available from: http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM3029 60.pdf

Changelian PS, Flanaan ME, Ball DJ, et al. Prevention оf organ allograft rejection by a specific Janus kinase 3 inhibitor. Science. 2003;302(5646):875–8. DOI: http://dx.doi.org/10.1126/scince.1087061.

Flanagan ME, Blumenkopf TA, Brisette WH, et al. Discovery of

CP-690; 550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplantant rejection. J Med Chem. 2010;53(24):8468–84. DOI: 10.1021/jm1004286. Epub 2010 Nov 24.

Karaman MW, Herrgard S, Treiber DK, et al. A quantitative analysis of kinase inhibitor selectivity. Nat Biotechnol. 2008;26(1):127–32. DOI: 10.1038/nbt1358.

Meyer DM, Jesson MI, Li X, et al. Anti-inflammatory activity and neutrophil reductions mediated by the JAK1/JAK3 inhibitor, CP-690,550, in rat adjuvant-induced arthritis. J Inflamm (Lond). 2010;7:41. DOI: 10.1186/1476-9255-7-41.

Cohen S, Zwillich SH, Chow L, et al. Co-administration of JAK inhibitor CP-690,550 and methotrexate is well tolerated in patients with rheumatoid arthritis without need for dose adjustment. Br J Clin Pharmacol. 2010;69(2):143–51. DOI: 10.1111/j.1365- 2125.2009.03570.x.

Ghoreshi K, Jesson M, Li X, et al. Modulation of innate and adaptive immunity responses by tofacitinib. J Immunol. 2011;186(7):4234–43. DOI: 10.4049/jimmunol.1003668. Epub 2011 Mar 7.

Walker JG, Ahern MJ, Coleman M, et al. Expression of Jak3, STAT1, STAT4, and STAT6 in inflammatory arthritis: unique Jak3 and STAT4 expression in dendritic cells in seropositive rheumatoid arthritis. Ann Rheum Dis. 2006;65(2):149–56. DOI: http://dx.doi.org/10.1136/ard.2005.037929. Epub 2005 Aug 11.

Насонов ЕЛ, Александрова ЕН, Авдеева АС, Панасюк ЕЮ. Ингибиция интерлейкина 6 – новые возможности фармакотерапии иммуновоспалительных ревматических заболеваний. Научно-практическая ревматология. 2013;51(4):416–27. [Nasonov EL, Aleksandrova EN, Avdeeva AS, Panasyuk EYu. Interleukin 6 inhibition: new possibilities of phar- macotherapy for immunoinflammatory rheumatic diseases. Nauchno-prakticheskaya revmatologiya = Rheumatology Science and Practice. 2013;51(4):416–27. (In Russ.)]. DOI: http://dx.doi.org/10.14412/1995-4484-2013-1254.

Milici AJ, Kudlacz EM, Audoly L, et al. Cartilage preservation by inhibition of Janus kinase 3 in two rodent models of rheumatoid arthritis. Arthritis Res Ther. 2008;10(1):R14. DOI: 10.1186/ar2365. Epub 2008 Jan 30.

Migita K, Koga T, Komori A, et al. Influence of Janus Kinase inhibition on interleukin 6-mediated induction of acute-phase serum amyloid A in rheumatoid synovium. J Rheumatol. 2011;38(11):2309–17. DOI: 10.3899/jrheum.101362. Epub 2011 Aug 15.

Maeshima K, Yamaoka K, Kubo S, et al. A JAK inhibitor tofaci- tinib regulates synovitis through inhibition of IFN-γ and IL-17 production by human CD4+ T cells. Arthritis Rheum. 2012;64(6):1790–8. DOI: 10.1002/art.34329. Epub 2011 Dec 6.

Migita K, Komori A, Torigoshi T, et al. CP690,550 inhibit onco- statin M-induced JAK/STAT signaling pathway in rheumatoid arthritis. Arthritis Res Ther. 2011;13(3):R72. DOI: 10.1186/ar3333.

Rosengren S, Corr M, Firestein GS, Boyle DL. The JAK inhibitor CP-690, 550 (tofacitinib) inhibits TNF-induced chemokine expression in fibroblast-like synoviocytes: autocrine role of type I interferon. Ann Rheum Dis. 2012;71(3):440–7. DOI: 10.1136/ard2011.150284. Epub 2011 Nov 25.

Yarilina A, Xu K, Chan C, Ivashkiv LB. Regulation of inflamma- tory responses in tumor necrosis factor-activated and rheumatoid arthritis synovial macrophages by JAK inhibitors. Arthritis Rheum. 2012;64(12):3856–66. DOI: 10.1002/art.37691.

Kubo S, Yamaoka K, Kondo M, et al. The JAK inhibitor, tofaci- tinib, reduced the T cell stimulatory capacity of human monocyte- derived dendritic cells. Ann Rheum Dis. 2013 Sep 6. DOI: 10.1136/annrheumdis-2013-203756.

LaBrannche TP, Jesson MI, Radi ZA, et al. JAK inhibition with tofacitinib suppresses arthritic joint structural damage through decreased RANKL production. Arthritis Rheum.

;64(11):3531–42. DOI: 10.1002/art.34649.

Boyle DL, Wei N, Singhal AK, et al. The JAK inhibitor tofacitinib

supresses synovial JAK-STAT1 signalling in rheumatoid arthritris.

Ann Rheum Dis. 2013;72(Suppl3):138.

Lee EY, Lee ZH, Song YW. CXCL10 and autoimmune diseases.

Autoimmun Rev. 2009;8(5):379–83. DOI:

1016/j.autrev.2008.12.002. Epub 2008 Dec 25.

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-CXC10 monoclonal anti- body, in combination with methotrexate in patients with rheuma- toid arthritis. Arthritis Rheum. 2012;64(6):1730–9. DOI: 10.1002/art.34330.

Yamaoka K, Kubo S, Sonomoto K, et al. JAK inhibitor, tafacitinib reduced IL-6 and matrix metalloproteinase-3 production in rheumatoid arthritis with suppressed cartilage destruction. Arthritis Res Ther. 2012;14 (Suppl 1):P77. DOI: http://dx.doi.org/10.1186/ar3678.

Migita K, Izumi Y, Jiuchi Y, et al. Effects of Janus kinase inhibitor tofacitinib on circulating serum amyloid A and interleukin-6 dur- ing treatment for rheumatoid arthritis. Clin Exp Immunol. 2014;175(2):208–14. DOI: 10.111/cei.2014.175.

Genovese MC, Kawabata T, Soma K, et al. Reversibility of phar- macodynamic effects after short- and long-term treatment with tofacitinib in patients with rheumatoid arthritis. Arthritis Rheum. 2013;65 (Suppl):S193.

Kremer JM, Bloom BJ, Breedveld FC, et al. The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis Rheum. 2009;60(7):1895–905. DOI: 10.1002/art.24567.

Coombs JH, Bloom BJ, Breedveld GC, et al. Improved pain, physical function and health status in patients with rheumatoid arthritis treated with CP 690,550, an orally active Janus kinase (Jak) inhibitor: results from a randomized, double-blind, placebo- controlled trial. Ann Rheum Dis. 2010:69(2):413–6. DOI: 10.1136/ard.2009.108159. Epub 2009 Jul 8.

Kremer JM, Cohen S, Wilkinson BE, et al. A phase IIb dose-rang- ing study of the oral JAK inhibitor tofacitinib (CP-690,550) versus placebo in combination with background methotrexate in patients with active rheumatoid arthritis and an inadequate response to methotrexate alone. Arthritis Rheum. 2012;64(4):970–81. DOI: 10.1002/art.33419. Epub 2011 Oct 17.

Fleischman R, Cutolo M, Genovese MC, et al. Phase Ib dose- ranging study of the oral KAK inhibition Tofacitinib (CP-690,550) or adalimumab monotherapy versus placebo in patients with active rheumatoid arthritis with an inadequate response to disease-modi- fying antirheumatic drugs. Arthritis Rheum. 2012;64:617–29. DOI: 10.1002/art.33383.

Tanaka Y, Suzuki M, Nakamura H, et al. Phase II study of tofaci- tinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and an inadequate response to methotrexate. Arthritis Care Res (Hoboken). 2011;63(8):1150–8. DOI: 10.1002/acr.20494.

Tanaka Y, Takeuchi T, Yamanaka H, et al. Tofacitinib (CP-690,550), an oral Janus kinase inhibitor, ad monotherapy in Japanese patients with active rheumatoid arthritis: a 12-week phase 2b study. Arthritis Rheum. 2011;63 Supp 1:2192.

Fleischmann R, Kremer J, Cush J, et al.; ORAL Solo Investigators. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. New Engl J Med. 2012;367(6):495–507. DOI: 10.1056/NEJMoa1109071.

Kremer J, Li Z, Hall S, et al. Tofacitinib in combination with non- biologic disease-modifying antirheumatic drugs in patients with active rheumatoid arthritis. A randomized trial. Ann Intern Med. 2013;159(4):253–61. DOI: 10.7326/0003-4819-159-4-201308200- 00006.

61.

70.

Van der Heijde D, Tanaka Y, Fleischmann R, et al. Tofacitinib (CP-690,550) in patients with rheumatoid arthritis receiving methotrexate: twelve-month data from a twenty-four-month phase III randomized radiographic study. Arthritis Rheum. 2013;65(3):559–70. DOI: 10.1002/art.37816.

Van Vollenhoven RF, Fleischmann R, Cohen S, et al. Tofacitinib or adalimumab versus placebo in rheumatoid arthritis. N Engl J Med. 2012;367(6):508–19. DOI: 10.1136/annrheumdis-2012- 202433. Epub 2013 Jan 11.

Burmester GR, Blanco R, Charles-Schoeman C, et al. Tofacitinib (CP-690,550) in combination with methotrexate in patients with active rheumatoid arthritis with an inadequate response to tumour necrosis factor inhibitors: a randomised phase 3 trial. Lancet. 2013;381(9865):451–60. DOI: 10.1016/S0140-6736(12)61424-X. Epub 2013 Jan 5.

Lee EB, Fleischmann R, Hall S, et al. Radiographic, clinical and functional comparison of tofacitinib monotherapy versus methotrexate in methotrexate-naive patients with rheumatoid arthritis. Arthritis Rheum. 2012;64 Suppl 10:S1049.

Scott LJ. Tofacitinib: a review of its use in adult patients with rheumatoid arthritis. Drugs. 2013;73(8):857–74. DOI: 10.1007/s40265-013-0065-8.

Wollenhaupt J, Silverfield J, Bong E, et al. Tofacitinib, an oral Janus kinase inhibitor, in the treatment of rheumatoid arthritis: an open-label, long term extension safety and efficacy up to 5 years. Arthritis Rheum. 2013;65 (Suppl):S993.

Strand V, Fleischman R, Alten RE, et al. ORAL START: effects of the oral JAK inhibitor tofacitinib monotherapy versus methotrex- ate on patient-reported outcomes in the phase 3 ORAL START trial of active rheumatoid arthritis. Ann Rheum Dis. 2013;2 Suppl 3:252.

Huizinga TM, Fleischman R, van Vollenhoven R, et al. Tofacitinib monotherapy is effective in methotrexate-naive patients with dis- ease duration less than 6 months: a post-hoc analysis or earle rheumatoid arthritis subjects in a phase 3 trial. Ann Rheum Dis. 2013;72 Suppl 3:241.

Winthrop KL, Baddley JW, Chen L, et al. Association between the initiation of anti-tumor necrosis factor therapy and the risk of her- pes zoster. JAMA. 2013;309(9):887–95. DOI: 10.1001/jama.2013.1099.

Van Vollenhoven R, Riese R, Krishnaswami S, et al. Relationship between lymphocyte count and risk of infection in rheumatoid arthritis patients treated with tofacitinib. Ann Rheum Dis. 2013;72 Suppl 3:250.

Sonomoto K, Yamaoka K, Kubo S, et al. Effects of tofacitinib on lymphocytes in rheumatoid arthritis: relation to efficacy and infec- tious adverse events. Rheumatology (Oxford). 2014 Jan 17. DOI: 10.1093/rheumatology/ket466.

Lawendy N, Krishnaswami S, Wang R, et al. Effect of CP-690,550, an oral active Janus kinase inhibitor, on renal func- tion in healthy adult volunteers. J Clin Pharmacol. 2009;49(4):423. DOI: 10.1177/0091270008330982.

McInes IB, Lim H-Y, Lee S-H, et al. Open-label tofacitinib and double-blind atorvastatin in rheumatoid arthritis patients: a ran- domized study. Ann Rheum Dis. 2014 Jan;73(1):124-31. doi: 10.1136/annrheumdis-2012-202442. Epub 2013 Mar 12.

McInes IB, Kaplan I, Boy M, et al. Effects of tofacitinib on lipid biomarkers in patients with active rheumatoid arthritis. Ann Rheum Dis. 2013;72 Suppl 3:416.

Charles-Schoeman C, Wicker P, Gonzalez-Gay MA, et al. Cardiovascular safety findibg in rheumatoid arthritis patients treat- ed with tofacitinib, a novel, oral Janus Kinase inhibitor. Arthritis Rheum. 2013;65 (Suppl):S191.

Lee EB, Curtis JR, Riease R, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of gastrointestinal adverse events across the rheumatoid arthritis clinical program. Arthritis Rheum. 2013;65 (Suppl):S191.

Mariette X, Curtis JR, Lee EB, et al. Tofacitinib, an oral Janus kinase inhibitor: analysis of malignamcy across the rheumatoid arthritis clinical program Arthritis Rheum. 2013;65 (Suppl):S340.

Burmester GR, Charles-Schoeman C, Isaacs JD, et al.

Tofacitinib, an oral kinase inhibitort: safety comparison in patients with rheumatoid arthritis and an inadequate response to nonbio- logic or biologic disease-modifying anti-rheumatic drugs. Arthritis Rheum. 2013;65 (Suppl):S192.

100

Gomez-Reino JJ, Hazra A, Fosser C, et al. Post-hoc analysis of serious infection events and sekected clinical factor in rheumatoid arthritis patients treated with tofacitinib. Arthritis Rheum. 2013;65 (Suppl):S194.

101

Curtis JR, Schulze-Koops H, Takiya L, et al. Efficacy and safety of tofacitinib in older and younger patients with rheumatoid arthritis. Arthritis Rheum. 2013;65 (Suppl):S994.

102

Genovese MC, van Vollenhoven RF, Willinson B, et al. Tofacitinib, an oral Janus kinase inhibitor, in a rheumatoid arthritis open-label extension study following adalimumab therapy in a phase 3 ran- domised clinical trial. Arthritis Rheum. 2013;65 (Suppl):S190.

103

Kremer JM, Greenberg JD, Turesson C, et al. Effects of smoking status on response to treatment with tofacitinib in patients with rheumatoid arthritis. Arthritis Rheum. 2013;65 (Suppl):S599.

104

He Y, Wong AYS, Chan EW, et al. Efficacy and safety of tofacitinib in the treatment of rheumatoid arthritis: a systemic review and meta-analysis. BMC Musculoskeletal Disorders. 2013;14:298. DOI: 10.1186/1471-2474-14-298.

105

Berhan A. Efficacy, safety and tolerability of tofacitinib in patients with an inadequate response to disease modifying anti-rheumatic drugs: a meta-analysis of randomized double-blind controlled studies. BMC Musculoskeletal Disorders. 2013;14:332. DOI: 10.1186/147-2474-14-332.

106

Kawalec P, Mikrut A, Wisniewska N, Pilc A. The effectiveness of tofacitinib, a novel Janus kinase inhibitor. In the treatment of rheumatoid arthritis: a systemic review and metha-analysis. Clin Rheumatol. 2013;32(10):1414–24. DOI: 10.1007/s10067-013- 2329-9. Epub 2013 Jul 23.

107

Keystone E, Fleischman R, van Vollenhoven R, et al. Tofacitinib, an oral janus kinase inhibitor: post-hoc analyses of efficacy and safety of monotherapy versus combination therapy in a phase 3 rheumatoid arthritis population. Ann Rheum Dis. 2013;72 Suppl 3:242.

108

Vieira MC, Wallenstein G, Bradley J, et al. Tofacitinib versus bio- logic treatments in patients with active rheumatoid arthritis who have had an inadequate response to tumor necrosis factor inhibitors – a network meta-analisis. Ann Rheum Dis. 2014;72 Suppl 3:619.

109

Gaujoux-Viala C, Nam JL, Ramiro S, et al. Efficacy of conven- tional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib – a systematic literature review informing the 2013 update of the EULAR recommendations for manage- ment of rheumatoid arthritis. Ann Rheum Dis. 2014;73(3):510–5. DOI: 10.1136/annrheumdis-2013-204588.

110

Genovese MC, Becker JC, Schiff M, et al. Abatacept for rheuma- toid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med. 2005;353(11):1114–23. DOI: http://dx.doi.org/10.1056/NEJMoa050524.

111

Smolen JS, Kay J, Doyle MK, et al. Golimumab in patients with active rheumatoid arthritis after treatment with tumour necrosis factor a inhibitors (GO-AFTER study): A multicentre, ran- domised, double-blind, placebo-controlled, phase III trial. Lancet. 2009;374(9685):210–21. DOI: 10.1016/S0140-6736(09)60506-7. Epub 2009 Jun 26.

112

Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-TNF biologics: results from a 24-week multicenter randomized placebo-controlled trial. Ann Rheum Dis. 2008;67(11):1516–23. DOI: 10.1136/ard.2008.092932. Epub 2008 Jul 14.

113

Cohen SB, Emery P, Greenwald MW, et al. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor thera- py. Results of multicenter, randomized, double-blind, placebo- controlled, phase III trial evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 2006;54(9):2793–806. DOI: http://dx.doi.org/10.1002/art.22025.

114

European Medical Agency. Xeljanz. 2013. Available from: http://www.ema.europa.eu/ema/indexjsp?curl=pages/medicines/h uman/medicines/002542/smops/Negative/human_smop_000501js p&mid=WC0b01ac058001d127 (accessed 25 May, 2014).

115

Committee for Medicinal Products for Human Use (CHMP). Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP). 22–25 July 2013. Available from: http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_ events/news/2013/07/news_detail_001851.jsp&mid=WC0b01ac05 8004d5c1.

116

Pfizer. Pfizer Receives CHMP Negative Opinion Regarding Marketing Authorization In Europe For Rheumatoid Arthritis Treatment XELJANZ (tofacitinib citrate). 2013. Available from: http://press.pfizer.com/press-release/pfizer-receives-chmp-nega- tive-opinion-regarding-marketing-authorization-europe-rheumat (accessed 25 May 2013).

117

Buch MH, Pavitt S, Parmar M, Emery P. Creative trial design in RA: optimizing patient outcomes. Nat Rev Rheumatol. 2013;9(3):183–94. DOI: 10.1038/nrrheum.2013.5. Epub 2013 Feb 5.

The authors declare that there are no conflicts of interest present.