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Cyclosporin and methotrexate therapy
  1. P G Conaghan1,
  2. P Emery1
  1. 1Academic Unit of Musculoskeletal Disease, University of Leeds, UK
  1. Correspondence to:
    Professor Paul Emery, Department of Rheumatology Old Nurses Home, Great George Street, Leeds LS1 3EX, UK;
  1. A H Gerards2,
  2. B A C Dijkmans2,
  3. R B M Landewé3
  1. 2VU Medical Centre and Jan van Breemen Instituut, Amsterdam, The Netherlands
  2. 3University Hospital Maastricht, The Netherlands

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    We read with interest the report by Gerard et al on the efficacy of cyclosporin monotherapy compared with methotrexate and cyclosporin combination therapy in patients with early rheumatoid arthritis.1 It is pleasing to see the increasing trend of publications looking at appropriate management strategies in early disease. We have previously reported a study comparing combination methotrexate, cyclosporin A, and intra-articular corticosteroids with sulfasalazine in a similar patient group.2

    In our 48 week study there was no difference in American College of Rheumatology response, remission rates, or radiographic progression between the two groups at 48 weeks. The current cohort is similar in age though with shorter disease duration and a higher proportion of rheumatoid factor positive patients. Our study did show significantly fewer withdrawals due to lack of efficacy in the combination group than in the sulfasalazine monotherapy group (1/40 v 10/42), adding weight to the suggestion of the current study which demonstrated more effective retardation of radiographic progression in the combination treated group. These data suggest that the combination may be more effective in a larger study group.

    However, combinations involving cyclosporin must be considered in the light of its significant toxicity. Both the current study and our own had significant periods of modestly raised serum creatinine and episodes of hypertension.

    The difference in radiographic progression in the Gerards’ study compared with our own is interesting. The mean doses of cyclosporin and methotrexate in the combination therapy group at 48 weeks were similar in both studies, and it tempting to speculate that the difference in outcomes between the two studies reflects the difference in the comparator treatment—namely, sulfasalazine versus cyclosporin monotherapy. It appears that monotherapy with sulfasalazine is more effective than cyclosporin at retarding disease progression measured by radiographic erosion progression rate. We note that the corticosteroid dose in the Gerards’ trial is not reported, although it was presumably low judged by the number of injections given. Thus it would appear reasonable to conclude that although cyclosporin (as suggested by its mode of action) is effective in early disease, the benefits are insufficient compared with its toxicity to warrant routine use as first line treatment, either as monotherapy or in combination.


    Authors’ reply

    With interest we read the remarks of Conaghan and Emery concerning the differences between our report and the study of Proudman et al.1

    The Proudman study compared the combination of methotrexate, cyclosporin, and intra-articular injections with sulfasalazine monotherapy in rheumatoid arthritis (RA). Like in our study, Proudman et al noticed fewer withdrawals due to inefficacy in the combination therapy group, which underlines the importance of testing combination therapy in early disease.

    Although tempting, it is difficult to compare outcome measures in Proudman’s study and our study because of the differences in the study group and the lack of randomisation. We think that erosion scores in the two studies should not be compared when the interobserver differences are not known. We do not know if sulfasalazine or cyclosporin is better in retarding radiological progression, on the basis of the information from these two studies.

    Conaghan and Emery conclude that cyclosporin cannot be used as a first line treatment in early RA, either as monotherapy or in combination therapy. We do not share that view. Cyclosporin toxicity was well controlled in a earlier study in early RA.2 The issue of nephrotoxicity with any treatment including cyclosporin is not resolved, although the guidelines state that toxicity is acceptable when dosage rules are closely guarded.3–6 We did not advocate the combination of methotrexate and cyclosporin as first line treatment in early RA because the data on efficacy were not sufficient. On the other hand, there is no evidence that the combination cannot be used because of toxicity.


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