Cyclosporine plus methotrexate was superior to methotrexate alone for rheumatoid arthritis
ACP J Club. 1996 Jan-Feb;124:4. doi:10.7326/ACPJC-1996-124-1-004
Tugwell P, Pincus T, Yocum D, et al. for the Methotrexate- Cyclosporine Combination Study Group. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. N Engl J Med. 1995 Jul 20;333: 137-41. [PubMed ID: 7791814]
To compare the combination of cyclosporine and methotrexate with methotrexate alone in patients with severe rheumatoid arthritis (RA).
6-month randomized, double-blind, placebo-controlled trial.
2 centers in the United States; 1 center in Canada.
148 patients (mean age 55 y, 72% women, 93% white) who had RA, had partially responded to methotrexate and had improvement in the number of tender joints, had been receiving the maximum tolerable dose of methotrexate for ≥ 3 months, had the same number of tender joints on 2 assessments that were 1 month apart, had active synovitis, and were receiving ≤ 10 mg of prednisone per day or a stable dose of nonsteroidal anti-inflammatory drugs for ≥ 4 weeks, or both. Exclusion criteria were abnormal hepatic or renal function, platelet count < 100 000 cells/mm3, leukocyte count < 3000 cells/mm3, cancer or a history of cancer, or receipt of any experimental drug within 1 month of study entry. 117 patients (79%) completed the treatment regimen.
In addition to their maximum toleratable dose of methotrexate, patients were allocated to cyclosporine, 2.5 mg/kg of body weight per day (n = 75), or placebo (n = 73). The cyclosporine dose was adjusted according to the change from baseline serum creatinine levels and whether actively inflamed joints remained.
Main Outcome Measures
Number of tender joints, number of swollen joints, physician and patient assessment of disease activity, joint pain, degree of disability, and erythrocyte sedimentation rate. Improvement according to American College of Rheumatology criteria was also assessed (20% improvement in number of tender and swollen joints, plus 3 other outcome measures).
Analysis was by intention to treat. At 6 months, patients who received cyclosporine showed a decrease in tender joint count of 7.5 compared with 2.7 in patients receiving placebo (mean improvement, 4.8 joints [25%], 95% CI 0.7 to 8.9, P = 0.02). Patients receiving cyclosporine had improvements in all other outcome measures (P ≤ 0.04). 6 months of methotrexate plus cyclosporine led to more patients meeting the American College of Rheumatology criteria for improvement at 6 months than did methotrexate plus placebo (P < 0.001) (Table).
In patients with severe rheumatoid arthritis who partially responded to methotrexate, combination therapy with cyclosporine and methotrexate resulted in clinically important short-term improvement compared with methotrexate alone.
Sources of funding: Sandoz Canada and Sandoz Pharmaceuticals, USA.
For article reprint: Dr. P. Tugwell, Department of Medicine, University of Ottawa and Ottawa General Hospital, 501 Smyth Road, Ottawa, Ontario K1H 8L6, Canada. FAX 613-737-8141.
Table. Cyclosporine plus methotrexate vs methotrexate alone for rheumatoid arthritis*
|Outcome at 6 mo||Methotrexate plus cyclosporine||Methotrexate||RBI (95% CI)||NNT (CI)|
|Improvement†||48%||16%||192% (69 to 419)||3 (2 to 6)|
*Abbreviations defined in Glossary; RBI, NNT, and CI calculated from data in article.
†Improvement in number of swollen joints plus 3 other outcome measures (American College of Rheumatology criteria).
RA is a common disease that can be crippling to patients and frustrating to physicians, who continue to seek effective treatments to change its course. Toward this end, these 2 important papers by Tugwell and Kirwan and their colleagues address the therapy for this illness.
The study by Tugwell and colleagues shows the efficacy of cyclosporine plus methotrexate (vs methotrexate alone) when used in patients with severe RA who partially responded to only methotrexate. Nonsteroidal anti-inflammatory drugs are the first-choice for early RA. When these agents are insufficient, rheumatologists generally move on to monotherapy with methotrexate, antimalarial agents, gold, penicillamine, sulfasalazine, or more recently, cyclosporine. Using the model of experts in oncology and infectious diseases, this study proposes a combination of therapies and shows that this approach is better than monotherapy with methotrexate alone. Although the study is elegantly designed, it is important to recognize what it does and does not show.
The study by Tugwell and colleagues does not imply that this combination of therapy should be used by primary care physicians to treat patients with uncomplicated RA. First, patients were followed for only 6 months, and the long-term efficacy and toxicity of this combination have yet to be determined. Second, because it is not a benign combination of drugs, the therapy should be used only by physicians who are experienced in its use. Generally, this would mean that it should be administered by rheumatologists only. Third, the patients included in this study had severe RA; therefore, it is unclear whether the results are generalizable to patients with mild disease. Finally, even the study patients who had severe RA should be regarded as a subset because they had already partially responded to methotrexate. This was an appropriate decision given the purpose of the study (i.e., to determine the effectiveness of this combination therapy). It still remains to be determined whether the combined intervention would be effective in patients who have not taken methotrexate or in those whose disease did not respond to methotrexate but who may have less treatable disease. These questions need to be answered before this becomes a standard treatment, even for those with severe RA.
In contrast to the study by Tugwell and colleagues, Kirwan and colleagues studied a milder, more common form of the disease. This study was also well done, although of the 128 patients randomly assigned, 22 to 25 were not available for scheduled radiologic evaluations. Although a clear radiologic response with a slowed progression of RA was observed when prednisolone was given, the clinical importance of this observation is unclear. The authors observed a short-term clinical improvement in their treatment group, but improvement of symptoms did not persist and long-term therapy with corticosteroids cannot be considered totally benign. Thus, although the use of corticosteroids may be physiologically useful, the long-term benefit is not yet established and the true utility of this widely used intervention must still be determined.
Brian L. Strom, MD, MPH
University of Pennsylvania Medical CenterPhiladelphia, Pennsylvania, USA