Send to

Choose Destination
N Engl J Med. 2013 Jul 25;369(4):307-18. doi: 10.1056/NEJMoa1303006. Epub 2013 Jun 11.

Therapies for active rheumatoid arthritis after methotrexate failure.

Collaborators (169)

Abrams P, Adamski L, Ageton C, Allen J, Allred D, Ardizzi R, Badua E, Bond C, Boulet C, Brady L, Clairmont J, Clark E, Cxypoliski R, Dailey A, De Guzman E, Detwiler J, Ding G, Dinnella J, Duarte B, Farquharson J, Godina J, Goodfellow E, Guillet C, Hanf H, Huggard A, Jamgotchian N, Khalaghizadeh S, Kittelsrud J, Lea D, Lutz A, Majeski P, Marr C, Martin E, Milton MG, Milton R, Mitchell S, Morean-Wright C, Nelson C, Nelson J, Pattison-Chrisostomo J, Persch J, Petersen V, Rangan B, Richards JS, Rodrigues M, Ruybalid L, Schreiner A, Sharp A, Stanger B, Stocks J, Sutherland S, Warren C, Webb D, West K, Yung N, Ayoub W, Boire G, Bykerk V, Chow A, Colburn K, Daikh D, Davis J 3rd, El-Gabalawy H, Elliott J, Fanciullo J, Gupta S, Hannagan K, Hausch R, Holmberg E, Joseph A, Kazi S, Kolba K, Kent P, Kerr G, Kwoh C, Mahowald M, Martin L, Olenginski T, Peshimam M, Persselin J, Peterson L, Prete P, Pugliese D, Reddy V, Reimold A, Rodrigues J, Schumacher H Jr, Thorne J, Valeriano-Marcet J, Weaver C, Karsh J, Bridges S, Cole B, Overman S, Rosenberger J, Solomon D, Fiore L, Ferguson R, Brophy M, Hannagan K, Costa C, Holmberg E, Lew R, Thwin S, Leatherman S, Zhou C, Kear A, Weil L, Diorio K, Hall R, Best N, Bentzel D, Mo W, Sather M, Warren S, Day J, Fye C, Matzek S, Chambers J, O'Dell J, Keystone E, Hollibaugh M, Weber D, Drupals E, O'Leary T, Huang G, Phibbs C, Chen S, Anis A, Sun H, Bansback N, O'Dell J, Keystone E, Ahluwalia V, Anis A, Brophy M, Lew R, Phibbs C, Taylor T, Warren S, Baker F, Brophy M, Colton T, Clegg D, Daikh D, Deykin D, Fiore L, Haraoui B, Kaufman J, Kazi S, Kerr G, Keystone E, Lavori P, Lew R, Liang M, Li L, Maetzel A, Mikuls T, O'Dell J, Phibbs C, Sharp J, Warren S, Erickson A, Moore T, Sharp J, Bobra S, Cockroft J, Govan D, Humphries D.

Author information

Veterans Affairs (VA) Nebraska-Western Iowa Health Care System and University of Nebraska Medical Center, Omaha, NE 68105, USA. james.o'



Few blinded trials have compared conventional therapy consisting of a combination of disease-modifying antirheumatic drugs with biologic agents in patients with rheumatoid arthritis who have active disease despite treatment with methotrexate--a common scenario in the management of rheumatoid arthritis.


We conducted a 48-week, double-blind, noninferiority trial in which we randomly assigned 353 participants with rheumatoid arthritis who had active disease despite methotrexate therapy to a triple regimen of disease-modifying antirheumatic drugs (methotrexate, sulfasalazine, and hydroxychloroquine) or etanercept plus methotrexate. Patients who did not have an improvement at 24 weeks according to a prespecified threshold were switched in a blinded fashion to the other therapy. The primary outcome was improvement in the Disease Activity Score for 28-joint counts (DAS28, with scores ranging from 2 to 10 and higher scores indicating more disease activity) at week 48.


Both groups had significant improvement over the course of the first 24 weeks (P=0.001 for the comparison with baseline). A total of 27% of participants in each group required a switch in treatment at 24 weeks. Participants in both groups who switched therapies had improvement after switching (P<0.001), and the response after switching did not differ significantly between the two groups (P=0.08). The change between baseline and 48 weeks in the DAS28 was similar in the two groups (-2.1 with triple therapy and -2.3 with etanercept and methotrexate, P=0.26); triple therapy was noninferior to etanercept and methotrexate, since the 95% upper confidence limit of 0.41 for the difference in change in DAS28 was below the margin for noninferiority of 0.6 (P=0.002). There were no significant between-group differences in secondary outcomes, including radiographic progression, pain, and health-related quality of life, or in major adverse events associated with the medications.


With respect to clinical benefit, triple therapy, with sulfasalazine and hydroxychloroquine added to methotrexate, was noninferior to etanercept plus methotrexate in patients with rheumatoid arthritis who had active disease despite methotrexate therapy. (Funded by the Cooperative Studies Program, Department of Veterans Affairs Office of Research and Development, and others; CSP 551 RACAT number, NCT00405275.)

[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Atypon
Loading ...
Support Center