Comparison of Treatment Strategies in Early Rheumatoid Arthritis

A Randomized Trial

20 March 2007 | Volume 146 Issue 6 | Pages 406-415

Background: In patients with early rheumatoid arthritis, initial combination therapies provide earlier clinical improvement and less progression of joint damage after 1 year compared with initial monotherapies (as demonstrated in the BeSt study).

Objective: To evaluate whether the initial clinical and radiographic efficacy of combination therapies could be maintained during the second year of follow-up in patients with early rheumatoid arthritis.

Design: Randomized, controlled clinical trial with blinded assessors.

Setting: 18 peripheral and 2 university medical centers in the Netherlands.

Patients: 508 patients with early active rheumatoid arthritis.

Intervention: Sequential monotherapy (group 1), step-up combination therapy (group 2), initial combination therapy with tapered high-dose prednisone (group 3), or initial combination therapy with infliximab (group 4). Trimonthly treatment adjustments were made to achieve low disease activity.

Measurements: Primary end points were functional ability (Health Assessment Questionnaire) and Sharp–van der Heijde score for radiographic joint damage.

Results: Groups 3 and 4 had more rapid clinical improvement during the first year; all groups improved further to a mean functional ability score of 0.6 (overall, P = 0.257) and 42% were in remission (overall, P = 0.690) during the second year. Progression of joint damage remained better suppressed in groups 3 and 4 (median scores of 2.0, 2.0, 1.0, and 1.0 in groups 1, 2, 3, and 4, respectively [P = 0.004]). After 2 years, 33%, 31%, 36%, and 53% of patients in groups 1 through 4, respectively, were receiving single-drug therapy for initial treatment. There were no significant differences in toxicity.

Limitations: Patients and physicians were aware of the allocated group, and the assessors were blinded.

Conclusions: Currently available antirheumatic drugs can be highly effective in patients with early rheumatoid arthritis in a setting of tight disease control. Initial combination therapies seem to provide earlier clinical improvement and less progression of joint damage, but all treatment strategies eventually showed similar clinical improvements. In addition, combination therapy can be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies.

Editors' Notes Context First-year results of the BeSt study showed that initial combination therapy for rheumatoid arthritis produced more rapid clinical improvement and less radiologic evidence of progression of joint damage than did initial monotherapy. Contribution The investigators assessed clinical and radiologic outcomes during year 2 while following a scheduled program of step-up and step-down medication adjustment based on disease activity score. All treatment groups achieved similar disease activity after 2 years, although initial monotherapy was often converted to combination therapy during follow-up. Implications Although all regimens were equally effective in eventually controlling disease activity, the rapid control produced by initial combination therapy may translate into decreased joint damage. —The Editors

 

Author and Article Information

From Leiden University Medical Center, Leiden, the Netherlands; VU Medical Center, Jan van Breemen Institute, Slotervaart Hospital, and Amsterdam Medical Center, Amsterdam, the Netherlands; Sint Franciscus Hospital and Erasmus Medical Center, Rotterdam, the Netherlands; Reinier de Graaf Gasthuis, Delft, the Netherlands; Groene Hart Hospital, Gouda, the Netherlands; Kennemer Gasthuis, Haarlem, the Netherlands; Medical Center Haaglanden, Leidschendam, the Netherlands; Oosterschelde Hospital, Goes, the Netherlands; and Haga Hospital, The Hague, the Netherlands.

Acknowledgments: The authors thank the following participants of the Foundation for Applied Rheumatology Research for their contributions to the design and the conduct of the study: M.H.W. de Bois, MD, Medical Center Haaglanden, The Hague, the Netherlands; G. Collée, MD, Medical Center Haaglanden; A.H. Gerards, MD, Vlietland Hospital, Schiedam, the Netherlands; B.A.M. Grillet, MD, De Honte Hospital, Terneuzen, the Netherlands; J.H.L.M. van Groenendael, MD, Franciscus Hospital, Roosendaal, the Netherlands; K.H. Han, MD, S int Medical Center Rijnmond Zuid, Rotterdam, the Netherlands; H.M.J. Hulsmans, MD, Haga Hospital, The Hague, the Netherlands; M.H. de Jager, MD, Albert Schweitzer Hospital, Dordrecht, the Netherlands; M.V. van Krugten, MD, Walcheren Hospital, Vlissingen, the Netherlands; H. van der Leeden (retired); W.F. Lems, MD, Slotervaart Hospital, Amsterdam, the Netherlands; M.F. van Lieshout-Zuidema, MD, Spaarne Hospital, Hoofddorp, the Netherlands; A. Linssen, MD, Kennemer Gasthuis, Haarlem, the Netherlands; P.A.H.M. van der Lubbe, MD, Vlietland Hospital; H.K. Markusse (deceased); H.K. Ronday, MD, Haga Hospital; D. van Schaardenburg, MD, VU Medical Center and Jan van Breemen Institute, Amsterdam, the Netherlands; P.E.H. Seys, MD, Lievensberg Hospital, Bergen op Zoom, the Netherlands; R.M. van Soesbergen (retired); I. Speyer, MD, Bronovo Hospital, The Hague, the Netherlands; J.P. Terwiel MD, Spaarne Hospital, Hoofddorp, the Netherlands; A.E. Voskuyl, MD, VU Medical Center; M.L. Westedt, MD, Bronovo Hospital; and S. ten Wolde, MD, Kennemer Gasthuis.

Grant Support: This study was supported by a government grant from the Dutch College of Health Insurances (College Voor Zorgverzekeringen). Schering-Plough BV and Centocor Inc. provided additional grants and supplied the study medication for patients in group 4.

Potential Financial Conflicts of Interest: Consultancies: F.C. Breedveld (Schering-Plough Centocor, Merck & Co. Inc., Pfizer Inc., Wyeth, Abbott, Amgen); Honoraria: C.F. Allaart (Schering-Plough); Grants received: C.F. Allaart (BeSt study).

Requests for Single Reprints: Yvonne P.M. Goekoop-Ruiterman, MD, Department of Rheumatology, Leiden University Medical Center, C1-R, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail, y.p.m.goekoop{at}lumc.nl.

Current Author Addresses: Drs. Goekoop-Ruiterman, Allaart, and Breedveld: Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands.

Drs. de Vries-Bouwstra and Dijkmans: VU Medical Center, PO Box 7057, 1007 MB Amsterdam, the Netherlands.

Dr. van Zeben: Sint Franciscus Hospital, Kleiweg 500, 3045 PM Rotterdam, the Netherlands.

Dr. Kerstens: Jan van Breemen Institute, Dr. Jan van Breemenstraat 2, 1056 AB Amsterdam, the Netherlands.

Dr. Hazes: Erasmus Medical Center, PO Box 2040, 3000 CA GD Rotterdam, the Netherlands.

Dr. Zwinderman: Amsterdam Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.

Dr. Peeters: Reinier de Graaf Gasthuis, Reinier de Graafweg 3-11, 2625 AD Delft, the Netherlands.

Dr. de Jonge-Bok: Groene Hart Hospital, Bleulandweg 10, 2803 HH Gouda, the Netherlands.

Dr. Mallée: Kennemer Gasthuis, PO Box 417, 2000 AK Haarlem, the Netherlands.

Dr. de Beus: Medical Center Haaglanden, Burg. Banninglaan 1, 2262 BA Leidschendam, the Netherlands.

Dr. de Sonnaville: Oosterschelde Hospital, Postbus 106, 4460 BB Goes, the Netherlands.

Dr. Ewals: Haga Hospital, Sportlaan 600, 2566 MJ The Hague, the Netherlands.

Author Contributions: Conception and design: Y.P.M. Goekoop-Ruiterman, C.F. Allaart, D. van Zeben, P.J.S.M. Kerstens, J.M.W. Hazes, A.H. Zwinderman, A.J. Peeters, J.M. de Jonge-Bok, C. Mallée, W.M. de Beus, P.B.J. de Sonnaville, J.A.P.M. Ewals, F.C. Breedveld, B.A.C. Dijkmans.

Analysis and interpretation of the data: Y.P.M. Goekoop-Ruiterman, J.K. de Vries-Bouwstra, C.F. Allaart, P.J.S.M. Kerstens, J.M.W. Hazes, A.H. Zwinderman, F.C. Breedveld, B.A.C. Dijkmans.

Drafting of the article: Y.P.M. Goekoop-Ruiterman, J.K. de Vries-Bouwstra, C.F. Allaart, P.J.S.M. Kerstens, J.M.W. Hazes, B.A.C. Dijkmans.

Critical revision of the article for important intellectual content: J.K. de Vries-Bouwstra, C.F. Allaart, D. van Zeben, P.J.S.M. Kerstens, J.M.W. Hazes, A.H. Zwinderman, A.J. Peeters, J.M. de Jonge-Bok, C. Mallée, W.M. de Beus, P.B.J. de Sonnaville, J.A.P.M. Ewals, F.C. Breedveld, B.A.C. Dijkmans.

Final approval of the article: Y.P.M. Goekoop-Ruiterman, J.K. de Vries-Bouwstra, C.F. Allaart, D. van Zeben, P.J.S.M. Kerstens, J.M.W. Hazes, A.H. Zwinderman, A.J. Peeters, J.M. de Jonge-Bok, C. Mallée, W.M. de Beus, P.B.J. de Sonnaville, J.A.P.M. Ewals, F.C. Breedveld, B.A.C. Dijkmans.

Provision of study materials or patients: C.F. Allaart, D. van Zeben, P.J.S.M. Kerstens, A.J. Peeters, J.M. de Jonge-Bok, C. Mallée, W.M. de Beus, P.B.J. de Sonnaville, J.A.P.M. Ewals, F.C. Breedveld.

Statistical expertise: A.H. Zwinderman.

Obtaining of funding: C.F. Allaart, D. van Zeben, F.C. Breedveld.

Administrative, technical, or logistic support: Y.P.M. Goekoop-Ruiterman, J.K. de Vries-Bouwstra, P.J.S.M. Kerstens, F.C. Breedveld.

Collection and assembly of data: Y.P.M. Goekoop-Ruiterman, J.K. de Vries-Bouwstra, P.J.S.M. Kerstens.