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Comparison of Treatment Strategies in Early Rheumatoid Arthritis: A Randomized Trial

Yvonne P.M. Goekoop-Ruiterman, MD; Jeska K. de Vries-Bouwstra, MD; Cornelia F. Allaart, MD; Derkjen van Zeben, MD; Pit J.S.M. Kerstens, MD; J. Mieke W. Hazes, MD; Aelko H. Zwinderman, PhD; André J. Peeters, MD; Johanna M. de Jonge-Bok, MD; Constant Mallée, MD; Wim M. de Beus, MD; Peter B.J. de Sonnaville, MD; Jacques A.P.M. Ewals, MD; Ferdinand C. Breedveld, MD; and Ben A.C. Dijkmans, MD
[+] Article and Author 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@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.


Ann Intern Med. 2007;146(6):406-415. doi:10.7326/0003-4819-146-6-200703200-00005
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We randomly assigned a total of 508 patients to receive sequential monotherapy (group 1, n = 126), step-up combination therapy (group 2, n = 121), initial combination therapy with prednisone (group 3, n = 133), or initial combination therapy with infliximab (group 4, n = 128) (Figure 1). At baseline, the groups were balanced with respect to demographic and disease characteristics (Table 1). Enrolled patients had a median disease duration of 23 weeks (interquartile range, 14 to 53 weeks) and had active disease with mean disease activity and HAQ scores of 4.4 (SD, 0.9) and 1.4 (SD, 0.7), respectively. Seventy-two percent of patients had joint erosions at baseline. Over time, 27 patients who were equally distributed across the treatment groups (P = 0.474) were lost to follow-up: 12 withdrew consent (7 declined follow-up, 4 discontinued all medications despite having no adverse events, and 1 moved from the area), 7 had a revised diagnosis, 1 discontinued treatment because of an adverse event, 4 died, and 3 were lost to follow-up for other reasons (2 were admitted to a nursing home and 1 wanted to become pregnant) (Figure 1). Furthermore, 12 (10%), 11 (9%), 14 (11%), and 6 (5%) patients in groups 1, 2, 3, and 4, respectively (P = 0.343), did not adhere to the treatment protocol but were included in the intention-to-treat analysis.

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Figures

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Figure 1.
Study flow diagram.

Revised diagnoses in the first year were paraneoplastic arthritis, gout, systemic lupus erythematosus, mixed connective tissue disease, and Henoch–Schönlein purpura. Revised diagnoses in the second year were gout and scleroderma.

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Figure 2.
Treatment of patients during the second year of follow-up.

*Percentage of patients who did not adhere to the treatment protocol. †Percentage of patients in the initial combination treatment group who discontinued prednisone (pred) because of a sustained disease activity score ≤2.4. ‡Percentage of patients in the initial combination treatment group who discontinued infliximab (IFX) therapy because of a sustained disease activity score ≤2.4. AZA = azathioprine; CSA = cyclosporine; HCQ = hydroxychloroquine; MTX = methotrexate; SSA = sulfasalazine.

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Figure 3.
Clinical and radiographic efficacy outcomes during 2 years of follow-up.

The error bars indicate the 95% CIs. A disease activity score (DAS) <1.6 indicated clinical remission; ACR20 and ACR70 indicated 20% and 70% improvement, respectively, according to the American College of Rheumatology (ACR) criteria. HAQ = Health Assessment Questionnaire; SHS = Sharp–van der Heijde score.

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Grahic Jump Location
Figure 4.
Median change by baseline total Sharp–van der Heijde score (SHS) for the 4 treatment groups.

The solid lines are regression lines.

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Summary for Patients

What Is the Best Treatment Plan for Early Rheumatoid Arthritis?

The summary below is from the full report titled “Comparison of Treatment Strategies in Early Rheumatoid Arthritis. A Randomized Trial.” It is in the 20 March 2007 issue of Annals of Internal Medicine (volume 146, pages 406-415). The authors are 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, and B.A.C. Dijkmans.

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