Therapies for active rheumatoid arthritis after methotrexate failure.
Author(s): O'Dell JR(1), Mikuls TR, Taylor TH, Ahluwalia V, Brophy M, Warren SR, Lew RA,
Cannella AC, Kunkel G, Phibbs CS, Anis AH, Leatherman S, Keystone E; CSP 551
RACAT Investigators.
Collaborators: 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.
Affiliation(s): Author information:
(1)Veterans Affairs (VA) Nebraska-Western Iowa Health Care System and University of
Nebraska Medical Center, Omaha, NE 68105, USA. james.o'dell@va.gov
Publication date & source: 2013, N Engl J Med. , 369(4):307-18
BACKGROUND: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSIONS: 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
ClinicalTrials.gov number, NCT00405275.)
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