Statistics from Altmetric.com
We read the paper by Gerard et al with interest.1 The authors are to be commended for the modest claims they make about the results of their study. They show that a combination of methotrexate and cyclosporin better retards radiographically visible progression than cyclosporin alone after one year in patients with early rheumatoid arthritis (RA). It raises the question whether cyclosporin A still has a place in the early treatment of this disease. One shortcoming of this study as stated in the paper is the lack of a methotrexate only arm. Furthermore, the study did not use optimal doses of methotrexate in the combined arm. Therefore, the possibility that the additional beneficial effects achieved in the combined arm at least in part might have been seen with methotrexate given in monotherapy cannot be excluded. The authors cite a number of studies supporting a retarding effect of cyclosporin, but fail to cite evidence that cyclosporin is not better than sodium aurothiomalate (Myocrisin) in this respect.2 This study stratified for the use of corticosteroids, in contrast with another often cited paper which claims that cyclosporin is better than a number of comparative disease modifying antirheumatic drugs, including chloroquine.3 The three year follow up of the stratified study still showed no difference in radiographic progression between the arms. Despite strict adherence to safety rules about dosing of cyclosporin, adverse renal effects were seen, which were not completely reversible.4
The safety issue is, however, unsettled, and the main purpose of our comment. Cyclosporin is an indispensable drug in transplantation medicine and of unquestionable value in the treatment of unresponsive patients with conditions such as vasculitis and uveitis. A prospective biopsy study in patients with psoriasis and psoriatic arthritis showed that all of around 30 patients developed interstitial fibrosis and arteriolar wall thickening characteristic of cyclosporin damage.5 A similar study in patients with RA has not been published. A study published in 1996 stated: “Long term continuous treatment of RA with low dose cyclosporin does not result in more structural nephropathy than the disease process itself, in spite of substantial and persistent deterioration of the renal function”.6 This study compared renal biopsy results from 11 patients with RA treated for 24 months with 22 necropsy specimens. Although no morphological differences were apparent, creatinine clearance had diminished by 26% in the patients. The accompanying editorial pointed out the weaknesses of the study, based on small size, lack of pretreatment biopsies, and uncertainty about the control group.7
A registry based study was published in 1996,8 consisting of 60 patients in all. It was not stated how the patients were selected for biopsy. The authors concluded that the low doses that had been given to 22 of the patients had not caused any renal damage. A more recent analysis performed in 1998 of cyclosporin induced nephrotoxicity in autoimmune diseases concluded, however, that the treatment even with doses of 5 mg/kg/day or lower was not without risks, and that renal biopsies should be seriously considered in patients who develop even slight renal function impairment.9 This view is based on the slowly progressive interstitial fibrosis and arterial wall thickening characteristic of cyclosporin toxicity. A review published in 1999 examines the subject of renal toxicity and long term treatment with cyclosporin of autoimmune disease.10 It concludes that even strict adherence to recommended rules carries a substantial risk for irreversible changes after two years’ treatment, and emphasises the need for rigorous risk-benefit analysis in each patient. In view of the lack of long term safety data based inter alia on systematic prospective biopsy results we feel that one should not use cyclosporin in patients with RA until other possible treatments have failed.
After the initial submission of this letter Fox et al published a report showing that cyclosporin A when given to patients with RA also treated with methotrexate, inhibits the oxidation of methotrexate to an inactive metabolite and thereby potentiates the effect of methotrexate. This will thus lead to a potentiation of the methotrexate effect and increased risks of adverse reactions when the drugs are combined.
We thank Saxne and Wollheim for there kind remarks. Indeed, we were interested in whether the beneficial effects in the combination therapy group should be ascribed to the concerted action of the combining drugs rather than to the action of methotrexate alone. To test this hypothesis we selected a sample of 41 patients out of a cohort of 411 patients who all had participated in the methotrexate/folate supplementation study which was published recently.1 These 41 patients were matched with respect to age, sex, disease duration, and clinical disease activity. All 41 patients had early rheumatoid arthritis (RA) and were treated with methotrexate as their first disease modifying antirheumatic drug (DMARD; median dose 15 mg/week). Of these 41 patients, 19 (47%) had an American College of Rheumatology (ACR)20 response after one year of treatment, 9 (22%) had an ACR50 response, and 3 (8%) had an ACR70 response. The proportions of patients who had responded to methotrexate monotherapy were in the same range as the proportions of patients who had responded to cyclosporin monotherapy, and substantially lower than the proportions who responded to cyclosporin plus methotrexate combination therapy in our study.
These results give an indication that the effects seen in the combination therapy arm cannot be ascribed to methotrexate alone. Unfortunately, our study was submitted before the study of Kvien et al2 was published.
The subject of nephrotoxicity of cyclosporin remains highly controversial.
We agree with Saxne and Wollheim that structural damage to the kidney is not clearly demonstrated in patients with RA treated with cyclosporin. Reports in other autoimmune diseases cannot be extrapolated to RA but warrant a careful approach. Most reports on cyclosporin in RA state that impairment of the renal function is reversible if dosage guidelines are strictly followed.2–5 The study of Boers et al showed that nephrotoxicity is reversible.6 The study of Kvien et al7 is an extension of the study of Zeidler et al.8 In the study of Zeidler dose reduction of cyclosporin was required if serum creatinine rose to>50% above the baseline, while guidelines recommend 30%. In the study of Kvien it is clear that it was mainly patients who had a rise in creatinine >50% during cyclosporin treatment who were at risk of creatinine remaining high after discontinuation of cyclosporin. This again underlines the importance of the guidelines. We advocate the use of creatinine clearance measurement or calculation before starting cyclosporin treatment, to select patients at risk.
Data on renal function should be viewed from the point of view that renal function loss is common in patients with RA.9 It is not clear whether the patients in the study of Zeidler and Kvien who were treated on basis of the cyclosporin guidelines (a rise in creatinine no more than 30% is acceptable) were subjected to a greater renal function loss than other patients with RA. Unfortunately, studies from Zachariae (on psoriasis and with higher cyclosporin dosages) and Vercauteren (not concerning patients with RA) do not shed light on this topic. Our conclusion is that on the basis of current knowledge on toxicity there is no reason to withhold cyclosporin from all patients with RA. However, questions about efficacy still have to be answered.
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.