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N Engl J Med. 2014 Jun 19;370(25):2377-86. doi: 10.1056/NEJMoa1310476.

Tofacitinib versus methotrexate in rheumatoid arthritis.

Collaborators (161)

Lue C, Schnitz WM, Baraf HS, Bolster MB, Kivitz AJ, Kimmel SC, Fudman EJ, Quaidoo EA, Churchill MA Jr, Birbara CA, Longley S 3rd, Stohl W, Niemer MW, Payne DD Jr, Kaine JL, Kafka SP, Fleischmann RM, Charles-Schoeman CM, Kavanaugh AF, Kremer JM, Ritter JS, Stack MT, Barron MC, Aelion JA, Griffin RM Jr, Peng SL, Walsh BT, Silverfield JC, Ghirlanda MR, Tate GA, Citera G, Ximenes AC, Radominski SC, Keiserman MW, Zerbini CA, Calabresse RJ, Cabezas PC, Ponce L, Silva MO, Flores AM, Tobias ED, Velez-Sanchez PJ, Raad JJ, Escalante WJ, Alpizar R, Alvarez-Mata R, Diaz-Coto JF, Alvarez-Felix P, Ramos-Remus DC, Esquivel-Valerio JA, Rodriguez-Torres IM, Avila-Armengol HE, Jimenez MO, Romero FJ, Perich R, Salinas AR, Perez RL, Van den Bosch FE, Goranov I, Bichovska D, Stoilov RM, Kopcheva S, Yordanova NG, Oparanov B, Bradna P, Stejfova Z, Mosterova Z, Vencovsky J, Rosypalova M, Fojtik Z, Alten R, Wollenhaupt J, Nuesslein H, Wassenberg S, Rech J, Wagner S, Kurthen R, Schoo U, Szombati I, Kovacs A, Samson L, Nazon S, Peterfai E, Sulyok G, Cseuz R, Rell-Bakalarska M, Dudek A, Grabowicz-Wasko B, Glogowska-Szelag J, Polak P, Belica P, Ujvari I, Szolnokiova A, Lukac J, Meijide JG, Sarabia FN, Nebro AF, Gonzalez-Fernandez CM, Angulo EU, Albizuri JM, Sahlqvist AO, Svensson J, Theander E, Hall S, Nash PT, Rischmueller M, Faraawi R, Rodrigues JF, Cividino AA, McKendry RJ, Jones HN, Jaroszynska AM, Shaikh SR, Bensen WG, Chopra AK, Kadel JK, Veeravalli SC, Sharma R, Venkataiya MK, Pandya S, Wagh S, Lee EB, Yoo B, Park YB, Gun SC, Chow SK, The CL, Gow PJ, Singh GJ, Gilchrist NL, Doube A, Ching DW, Taylor WJ, Ramiterre EB, Tan PP, Eullaran R, Stetsiouk OU, Usova G, Ushakova EN, Esip V, Sarana AM, Maslyanskiy AL, Dorokhov AE, Eliseeva L, Raskina TA, Zonova EV, Izmozherova NV, Lesnyak OM, Tsai WC, Chen DY, Lan JL, Liu MF, Katchamart W, Asavatanabodee P, Kitumnuaypong T, Hrytsenko HM, Petrov AV, Povoroznyuk VV, Stanislavchuk MA, Svintsitskyy AS, Kolomiyets SM.

Author information

1
From Seoul National University College of Medicine, Seoul, South Korea (E.B.L.); Metroplex Clinical Research Center, Dallas (R.F.); Cabrini Health and Monash University, Melbourne, VIC, Australia (S.H.); Pfizer, Groton, CT (B.W., J.D.B., D.G., S.K., G.V.W., C.Z., S.H.Z.); Pfizer, New York (T.K.); and Karolinska Institute, Stockholm (R.F.V.).

Abstract

BACKGROUND:

Methotrexate is the most frequently used first-line antirheumatic drug. We report the findings of a phase 3 study of monotherapy with tofacitinib, an oral Janus kinase inhibitor, as compared with methotrexate monotherapy in patients with rheumatoid arthritis who had not previously received methotrexate or therapeutic doses of methotrexate.

METHODS:

We randomly assigned 958 patients to receive 5 mg or 10 mg of tofacitinib twice daily or methotrexate at a dose that was incrementally increased to 20 mg per week over 8 weeks; 956 patients received a study drug. The coprimary end points at month 6 were the mean change from baseline in the van der Heijde modified total Sharp score (which ranges from 0 to 448, with higher scores indicating greater structural joint damage) and the proportion of patients with an American College of Rheumatology (ACR) 70 response (≥70% reduction in the number of both tender and swollen joints and ≥70% improvement in three of five other criteria: the patient's assessment of pain, level of disability, C-reactive protein level or erythrocyte sedimentation rate, global assessment of disease by the patient, and global assessment of disease by the physician).

RESULTS:

Mean changes in the modified total Sharp score from baseline to month 6 were significantly smaller in the tofacitinib groups than in the methotrexate group, but changes were modest in all three groups (0.2 points in the 5-mg tofacitinib group and <0.1 point in the 10-mg tofacitinib group, as compared with 0.8 points in the methotrexate group [P<0.001 for both comparisons]). Among the patients receiving tofacitinib, 25.5% in the 5-mg group and 37.7% in the 10-mg group had an ACR 70 response at month 6, as compared with 12.0% of patients in the methotrexate group (P<0.001 for both comparisons). Herpes zoster developed in 31 of 770 patients who received tofacitinib (4.0%) and in 2 of 186 patients who received methotrexate (1.1%). Confirmed cases of cancer (including three cases of lymphoma) developed in 5 patients who received tofacitinib and in 1 patient who received methotrexate. Tofacitinib was associated with increases in creatinine levels and in low-density and high-density lipoprotein cholesterol levels.

CONCLUSIONS:

In patients who had not previously received methotrexate or therapeutic doses of methotrexate, tofacitinib monotherapy was superior to methotrexate in reducing signs and symptoms of rheumatoid arthritis and inhibiting the progression of structural joint damage. The benefits of tofacitinib need to be considered in the context of the risks of adverse events. (Funded by Pfizer; ORAL Start ClinicalTrials.gov number, NCT01039688.).

PMID:
24941177
DOI:
10.1056/NEJMoa1310476
[Indexed for MEDLINE]
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