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Prednisone plus Methotrexate for Polymyalgia Rheumatica: A Randomized, Double-Blind, Placebo-Controlled Trial

Roberto Caporali, MD; Marco A. Cimmino, MD; Gianfranco Ferraccioli, MD; Roberto Gerli, MD; Catherine Klersy, MD; Carlo Salvarani, MD; Carlomaurizio Montecucco, MD, Systemic Vasculitis Study Group of the Italian Society for Rheumatology
[+] Article and Author Information

From the University of Pavia, Pavia, University of Genoa, Genoa, University of Udine, Udine, University of Perugia, Perugia, and Arcispedale Santa Maria Nuova, Reggio Emilia, Italy.


Note: Drs. Caporali and Cimmino contributed equally to the manuscript.

Acknowledgments: The authors thank Franco Barattini, Opera Contract Research Organization, for supporting the trial; Vanni Bascapè, Pharmacology Department at Policlinico San Matteo, for manufacturing the placebos; and Carlo Pesce, MD, PhD, for reviewing the manuscript.

Grant Support: By Società Italiana di Reumatologia and IRCCS Policlinico San Matteo.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Roberto Caporali, MD, Divisione di Reumatologia, Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy; e-mail, caporali@smatteo.pv.it.

Current Author Addresses: Drs. Caporali and Montecucco: IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.

Dr. Cimmino: Department of Internal Medicine, Viale Benedetto XV, 16100 Genova, Italy.

Dr. Ferraccioli: Division of Rheumatology, School of Medicine, Catholic University of the Sacred Heart—CIC, Via Moscati 31, 00168 Rome, Italy.

Dr. Gerli: 1st Medicina Interna e Scienze Oncologiche, Policlinico Monteluce, 06122 Perugia, Italy.

Dr. Klersy: Direzione Scientifica, IRCCS Policlinico San Matteo, Piazzale Golgi 2, 27100 Pavia, Italy.

Dr. Salvarani: Azienda Ospedaliera, Via Umberto I 50, 42100 Reggio Emilia, Italy.

Author Contributions Conception and design: R. Caporali, M.A. Cimmino, G. Ferraccioli, R. Gerli, C. Salvarani, C. Montecucco.

Analysis and interpretation of the data: R. Caporali, M.A. Cimmino, G. Ferraccioli, R. Gerli, C. Klersy, C. Salvarani, C. Montecucco.

Drafting of the article: R. Caporali, M.A. Cimmino, C. Montecucco.

Critical revision of the article for important intellectual content: R. Caporali, M.A. Cimmino, G. Ferraccioli, R. Gerli, C. Salvarani, C. Montecucco.

Final approval of the article: R. Caporali, M.A. Cimmino, G. Ferraccioli, R. Gerli, C. Klersy, C. Salvarani, C. Montecucco.

Provision of study materials or patients: R. Caporali, M.A. Cimmino, G. Ferraccioli, R. Gerli, C. Salvarani, C. Montecucco.

Statistical expertise: C. Klersy.

Obtaining of funding: R. Caporali, C. Montecucco.

Collection and assembly of data: R. Caporali, C. Klersy, C. Montecucco.


Ann Intern Med. 2004;141(7):493-500. doi:10.7326/0003-4819-141-7-200410050-00005
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This randomized, double-blind, placebo-controlled trial shows that the proportion of patients with polymyalgia rheumatica who were free of steroids at 76 weeks was higher in the methotrexate plus prednisone group (28 of 32 patients) than in the placebo plus prednisone group (16 of 30 patients). Results from the sensitivity analysis supported the main analysis, although in the worst-case scenario statistical significance was not reached. The proportion of patients who experienced 1 or more flare-ups was lower in the methotrexate group than in the placebo group (47% vs. 73%), as was the total number of flare-ups (27 episodes vs. 50 episodes).

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Figures

Grahic Jump Location
Figure 1.
Flow of participants through the study.

MI = myocardial infarction; RA = rheumatoid arthritis.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Median cumulative dose of prednisone in the methotrexate group and the placebo group compared with the lowest amount scheduled by treatment protocol.

Vertical bars represent 75th percentiles.

Grahic Jump Location

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Methotrexate in Polymyalgia Rheumatica
Posted on October 13, 2004
Francisco R. Lafita
Gabinet Mèdic. Cambrils 43850 Baix Camp. Spain
Conflict of Interest: None Declared

Caporalli and colleagues (1) have presented a well conducted study on the steroid' sparing effect of methotrexate in polymyalgia rheumatica (PMR). Previous studies (2,3) have failed to show any benefit of methotrexate on PMR but others (4) found some evidence of it. Often PMR requires a course of treatment through 1-2 years and in some cases it can be longer (5). However Caporalli and colleagues study is based in a fast tapering of prednisone (24 weeks) and a short follow up of patients (18 months). Moreover, no data on new flares and the appearing of other related diseases (GCA, R3SPE) after 18 months were found. It should be interesting to know how long the remissions lasted behind that period and if differences in relapses between both groups were found and what treatment was then applied.

1. Caporalli R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, Montecucco C. Prednisone plus methotrexate for polymyalgia rheumatica. A randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2004;141:493-501.

2. Feinberg HL, Sherman JD, Schrepferman CG, Dietzen CJ, Feinberg GD. The use of methotrexate in polymyalgia rheumatica. J Rheumatol. 1996;23(9):1550-2.

3. van der Veen MJ, Dinant HJ, van Booma-Frankfort C, van Albada- Kuipers GA, Bijlsma JW. Can methotrexate be used as a steroid sparing agent in the treatment of polymyalgia rheumatica and giant cell arteritis? Ann Rheum Dis. 1996;55(4):218-23.

4. Ferraccioli G, Salaffi F, De Vita S, Casatta L, Bartoli E. Methotrexate in polymyalgia rheumatica: preliminary results of an open, randomized study. J Rheumatol. 1996;23(4):624-8.

5. Salvarani C, Cantini F, Boiardi L, Hunder GG. Polymyalgia rheumatica. Best Pract Res Clin Rheumatol. 2004;18(5):705-22.

Conflict of Interest:

None declared

The use of methotrexate in the early treatment of polymyalgia rheumatica
Posted on November 11, 2004
Mitsumasa Kishimoto
Department of Rheumatology, New York University/Hospital for Joint Diseases
Conflict of Interest: None Declared

Caporali and colleagues reported that combination therapy with prednisone and methotrexate can be effective in polymyalgia rheumatica and reduce the incidence of flare-ups and the amount of prednisone required to maintain remission (1). This is a well done study, but we have concerns that an unintended consequence of the study will be to promote the use of methotrexate as a first line agent in PMR. The prednisone sparing effect is most (1mg) and since there were no reports of an increased risk of development of Giant Cell Arteritis in the prednisone only group, it is not clear that the use of initial methotrexate provided a meaningful clinical benefit. Moreover, this approach would unnecessarily expose a large number of elderly patients with PMR to treatment with methotrexate. A future study should involve testing the Caporali protocol versus the conventional treatment aproach, namely, the addition of methotrexate to prednisone "failures". Clinically meaningful outcomes would then be the prevention of GCA and serious steroid toxicity (2-5). Therefore, we believe that clinicians should not alter their practice to include the use of methotrexate as an adjunct to prednisone in the early treatment of polymyalgia rheumatica until further studies address these issues.

References 1. Caporali R, Cimmino MA, Ferraccioli G, Gerli R, Klersy C, Salvarani C, Montecucco C. Prednisone plus methotrexate for polymyalgia rheumatica: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2004 Oct 5;141(7):493-500. 2. Salvarani C, Gabriel SE, O'Fallon WM, Hunder GG. The incidence of giant cell arteritis in Olmsted County, Minnesota: apparent fluctuations in a cyclic pattern. Ann Intern Med. 1995 Aug 1;123(3):192-4. 3. Brooks RC; McGee SR. Diagnostic dilemmas in polymyalgia rheumatica. Arch Intern Med. 1997 Jan 27;157(2):162-8. 4. Gonzalez-Gay MA, Hajeer AH, Dababneh A, Makki R, Garcia-Porrua C, et al. Seronegative rheumatoid arthritis in elderly and polymyalgia rheumatica have similar patterns of HLA association. J Rheumatol. 2001 Jan;28(1):122-5. 5. Hoffman GS, Cid MC, Hellmann DB, Guillevin L, Stone JH, et al. A multicenter, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 2002 May;46(5):1309-18.

Conflict of Interest:

None declared

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Summary for Patients

Prednisone plus Methotrexate for Polymyalgia Rheumatica

The summary below is from the full report titled “Prednisone plus Methotrexate for Polymyalgia Rheumatica. A Randomized, Double-Blind, Placebo-Controlled Trial.” It is in the 5 October 2004 issue of Annals of Internal Medicine (volume 141, pages 493-500). The authors are R. Caporali, M.A. Cimmino, G. Ferraccioli, R. Gerli, C. Klersy, C. Salvarani, and C. Montecucco, for the Systemic Vasculitis Study Group of the Italian Society for Rheumatology.

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