Correspondence

Cyclosporine and Methotrexate for Severe Rheumatoid Arthritis

N Engl J Med 1995; 333:1567-1569December 7, 1995

Article

To the Editor:

Tugwell et al. (July 20 issue)1 found that “patients with severe rheumatoid arthritis and only partial responses to methotrexate had clinically important improvement after combination therapy with cyclosporine and methotrexate.” We are concerned about the manner in which the cyclosporine doses were adjusted. No mention of the patients' serum cyclosporine levels was made. Determination of serum cyclosporine levels might have allowed a better understanding of the results with respect to therapeutic serum ranges of this medication.

The authors state that people with rheumatoid arthritis “have a risk of cancer 20 to 30 times higher than people in general.” Cash and Klippel2 concluded in a 1995 review that patients with rheumatoid arthritis are not at increased risk of cancer overall, although the rates of selected cancers, such as hematologic cancers, especially multiple myeloma and non-Hodgkin's lymphoma, appear to be increased.

Naomi Schlesinger, M.D.
Arthur Huppert, M.D.
Susan Hoch, M.D.
Hahnemann Hospital, Philadelphia, PA 19102

2 References

1. 1

   Tugwell P, Pincus T, Yocum D, et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med 1995;333:137-141
   Full Text | Web of Science | Medline

2. 2

   Cash JM, Klippel JH. Is malignancy a major concern in rheumatoid arthritis patients? J Clin Rheumatol 1995;1:14-22
   CrossRef | Medline

To the Editor:

Tugwell et al. do not define the term “maximal tolerated dose.” They do, however, state that the maximal tolerated dose of methotrexate was 15 mg or less per week. What were the mean and median doses of methotrexate in the two groups? It is not clear whether patients who tolerated larger doses of methotrexate were excluded from the study, whether no patient could tolerate more than 15 mg per week, or whether no patient was offered larger doses of methotrexate. In my experience, as well as that of others,1 it is not uncommon to find children with chronic arthritis who require and tolerate doses of methotrexate that, if considered on the basis of body weight or body-surface area or in terms of the absolute weekly dose, exceed 15 mg per week.

Peter Malleson, M.B., B.S.
University of British Columbia, Vancouver, BC V5Z 4H4, Canada

1 References

1. 1

   Wallace CA, Sherry DD, Mellins ED, Aiken RP. Predicting remission in juvenile rheumatoid arthritis with methotrexate treatment. J Rheumatol 1993;20:118-122
   Web of Science | Medline

To the Editor:

In the study by Tugwell et al., patients with severe rheumatoid arthritis who were receiving methotrexate were randomly assigned to receive either cyclosporine or placebo. Cyclosporine itself is therapeutic in patients with rheumatoid arthritis. What is the justification for continuing methotrexate at the maximal tolerated dose or at any dose? Could the entire benefit of cyclosporine observed in the study have occurred in the absence of methotrexate?

Alfred D. Steinberg, M.D.
Mitre Corporation, McLean, VA 22102

To the Editor:

The reports by Tugwell et al. on rheumatoid arthritis and by Mason et al. (Aug. 3 issue)1 on myocarditis have added to the growing list of potential indications for long-term immunosuppression. The levels of immunosuppression recommended in these studies approach that which has been used in solid-organ transplantation. Although transplant recipients routinely receive prophylactic therapy against fungal infections and Pneumocystis carinii, no such recommendations were included in these latest reports. Regardless of the indication, high-dose combination immunosuppression should be accompanied by prophylaxis against infection.

Joel R. Rosh, M.D.
Morristown Memorial Hospital, Morristown, NJ 07962

Audrey H. Birnbaum, M.D.
Mount Sinai Medical Center, New York, NY 10029

1 References

1. 1

   Mason JW, O'Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333:269-275
   Full Text | Web of Science | Medline

To the Editor:

Tugwell et al. state that “reversible lymphomas have occurred in patients with rheumatoid arthritis who have received either methotrexate or cyclosporine alone.” Although some lymphomas do regress spontaneously on the withdrawal of methotrexate,1,2 not all behave in a benign fashion.

In a series of 18 patients with rheumatoid arthritis or dermatomyositis in whom lymphoma developed between 1987 and 1992, lymphoma associated with Epstein–Barr virus (EBV) developed in 6, suggesting that these tumors were related, at least in part, to a state of immunosuppression.2 In two of these patients the lymphomas regressed spontaneously on the withdrawal of methotrexate, one patient was cured by combination chemotherapy and radiation therapy, and three patients died of disease. Ferraccioli et al.3 describe a patient with rheumatoid arthritis who was treated with a combination of methotrexate and cyclosporine and in whom EBV-associated Hodgkin's disease developed, which only partially regressed on the withdrawal of immunosuppressive therapy. This patient required a combination of chemotherapy and local radiation therapy.

Although a trial in which immunosuppressive therapy is discontinued in patients in whom lymphomas develop appears warranted, physicians caring for such patients should be aware that some EBV-positive lymphoid neoplasms associated with immunosuppressive therapy can cause substantial morbidity and mortality.

Matthijs van de Rijn, M.D., Ph.D.
University of Pennsylvania School of Medicine, Philadelphia, PA 19104-4283

Onsi W. Kamel, M.D.
Stanford University School of Medicine, Stanford, CA 94305-5324

3 References

1. 1

   Kamel OW, van de Rijn M, Weiss LM, et al. Reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 1993;328:1317-1321
   Full Text | Web of Science | Medline

2. 2

   Kamel OW, van de Rijn M, LeBrun DP, Weiss LM, Warnke RA, Dorfman RF. Lymphoid neoplasms in patients with rheumatoid arthritis and dermatomyositis: frequency of Epstein-Barr virus and other features associated with immunosuppression. Hum Pathol 1994;25:638-643
   CrossRef | Web of Science | Medline

3. 3

   Ferraccioli GF, Casatta L, Bartoli E, et al. Epstein-Barr virus-associated Hodgkin's lymphoma in a rheumatoid arthritis patient treated with methotrexate and cyclosporin A. Arthritis Rheum 1995;38:867-868
   CrossRef | Web of Science | Medline

To the Editor:

Tugwell et al. reported that the combination of methotrexate and cyclosporine was more effective in severe rheumatoid arthritis than methotrexate alone. The combination of a short course of methotrexate and a six-month course of cyclosporine was more effective in controlling acute graft-versus-host disease in recipients of HLA-matched marrow than either drug alone, and this regimen is now standard in human marrow grafting.1-3 These observations suggest that a regimen of combined methotrexate and cyclosporine should be explored in other autoimmune diseases and in solid-organ grafting if renal function is normal.

Rainer Storb, M.D.
E. Donnall Thomas, M.D.
Fred Hutchinson Cancer Research Center, Seattle, WA 98104

3 References

1. 1

   Storb R, Deeg HJ, Thomas ED, et al. Preliminary results of prospective randomized trials comparing methotrexate and cyclosporine for prophylaxis of graft-vs.-host-disease after HLA-identical marrow transplantation. Transplant Proc 1983;15:2620-2623
   Web of Science

2. 2

   Storb R, Deeg HJ, Farewell V, et al. Marrow transplantation for severe aplastic anemia: methotrexate alone compared with a combination of methotrexate and cyclosporine for prevention of acute graft-versus-host disease. Blood 1986;68:119-125
   Web of Science | Medline

3. 3

   Storb R, Deeg HJ, Whitehead J, et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft versus host disease after marrow transplantation for leukemia. N Engl J Med 1986;314:729-735
   Full Text | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: Schlesinger et al. ask for details of blood cyclosporine levels and adjustments in the doses. Blood samples were collected, and all were assayed for cyclosporine at the end of this study. The same correlation between blood levels and dose was found as in our previous study of monotherapy with cyclosporine.1 These results confirm our experience in the monotherapy studies, in which no additional benefit was gained by using the serum cyclosporine level in adjusting the dose. The recommended approach is to change the cyclosporine dose on the basis of increases in the serum creatinine concentration. Measurement of cyclosporine may be useful in the occasional patient who insists on taking the medication and who has some impairment of renal function.

Malleson requests details of the “maximal tolerated dose” of methotrexate. In over 75 percent of patients, the dose was maintained at a level of 10 mg per week or more, in 45 percent the dose was more than 12.5 mg per week, and in 26 percent 15 mg per week. At the time of recruitment, it was not usual practice to increase the dose of methotrexate above 15 mg per week, although larger doses are indeed being used now in monotherapy by many rheumatologists.

Steinberg asks why a treatment arm consisting of cyclosporine monotherapy was not included. The inclusion of such a group would not have helped to answer the key research question — namely, whether the stepwise addition of agents in patients with a partial response is efficacious, as is the case in other clinical areas, such as hypertension. We had a responsibility to adapt the traditional study designs to answer the relevant clinical question for rheumatologists.

Rosh and Birnbaum suggest that our patients should have received prophylactic therapy against fungal infections and Pneumocystis carinii. The doses of immunosuppressive agents in our study were much lower than those used in transplantation. We found no evidence of increased infections in our meta-analysis of six randomized clinical trials,2 and another study of our patients found that our regimen had no untoward effects on T-cell subgroups or on the proliferation of mitogens or recall antigens.3 Prophylactic antibiotics are not used with corticosteroid therapy in rheumatoid arthritis, even in cases in which high doses of corticosteroids are used for flares. Thus, we do not recommend prophylactic antibiotic therapy.

Schlesinger et al. and van de Rijn and Kamel comment on the risk of neoplasia. We should have made it clear that we were referring to lymphomas when we stated that the risk of cancer is 20 to 30 times higher for patients with rheumatoid arthritis than for people in general. We acknowledge that EBV has been found to be associated with some, but not all, of these lymphomas. One of us followed titers of EBV during a previous monotherapy trial4 and found no increase in the titers during the course of the study.

We agree with Storb and Thomas that the use of combined therapy should be explored in other autoimmune diseases.

Peter Tugwell, M.D.
University of Ottawa, Ottawa, ON K1H 8L6, Canada

David Yocum, M.D.
University of Arizona Health Sciences Center, Tucson, AZ 85724

Theodore Pincus, M.D.
Vanderbilt University School of Medicine, Nashville, TN 37232

George Wells, Ph.D.
University of Ottawa, Ottawa, ON K1H 8L6, Canada

4 References

1. 1

   Tugwell P, Bombardier C, Gent M, et al. Low-dose cyclosporin versus placebo in patients with rheumatoid arthritis. Lancet 1990;335:1051-1055
   CrossRef | Web of Science | Medline

2. 2

   Wells G, Tugwell P. Cyclosporin A in rheumatoid arthritis: overview and efficacy. Br J Rheumatol 1993;32:Suppl 1:51-56
   CrossRef | Medline

3. 3

   Yocum DE, Cornett M, Olson S, Nordensson K. Effects of methotrexate and methotrexate + cyclosporine on mononuclear cell proliferation and lymphocyte surface markers in rheumatoid arthritis patients: results of a double-blind trial. Arthritis Rheum 1994;37:Suppl:S254-S254 abstract.
   

4. 4

   Yocum DE, Klippel JH, Wilder RL, et al. Cyclosporin A in severe, treatment-refractory rheumatoid arthritis: a randomized study. Ann Intern Med 1988;109:863-869
   Web of Science | Medline