Comparison of high and low dose cyclophosphamide therapy in rheumatoid arthritis

Abstract

Eighty-eight patients with active rheumatoid arthritis from 8 Cooperating Clinics were evaluated in a 32-week controlled, double-blind trial comparing 150 mg daily to 75 mg cyclophosphamide daily. Improvement in the arthritis was seen in both groups, and there were no important differences between the two treatment groups in any of the 8 variables used to measure disease activity. Untoward effects were also similar for the two groups. These results differ from preliminary results reported earlier.Cyclophosphamide is an alkylating agent with cytotoxic, immunosuppressive, and antiinflammatory properties (1). It was first used in the treatment of rheumatoid arthritis (RA) by Fosdick et a1 (2) in 1968 who reported improvement in 75% of their patients who had been unresponsive to conventional therapy. In 1970, a controlled 32-week trial of cyclophosphamide therapy in RA was reported by the Cooperating Clinics Committee of the American Rheumatism Association (ARA) (3). Forty-eight patients with severe active RA that failed to improve on conventional therapy were From the Cooperating Clinics for the Study of Rheumatic Diseases, NIAMDD, Coordinating Center, University of Utah, Salt Lake City, Utah 84132.Supported by Grant NOl-AM-6-2218, National Institute of Arthritis, Metabolism and Digestive Diseases, National Institutes of Health.H. James Williams, MD; James C. Reading, PhD; John R. Ward, MD; William M. OBrien, MD.Address reprint requests to H. James Williams, MD, University of Utah Medical Center, 50 North Medical Drive, Salt Lake City, UT 84132.Submitted for publication January 2, 1979; accepted in revised form February I, 1980. randomly assigned to two treatment groups. One group received cyclophosphamide in high dose (up to 150 mg daily) and the other received a negligible dose (up to 15 mg daily). The patients receiving the high dose demonstrated a greater reduction of their arthritis activity in nearly all measurements compared to the group receiving the low dose, but 90% of the patients on the higher dose suffered untoward effects of the medication. These results were confirmed by Townes et a1 in a doubleblind cross-over placebo trial with cyclophosphamide prescribed in a dose of 1.8 mg/kg/day (4).The effective dose for treatment of RA remains controversial. Fosdick used varying doses, with the majority of responders receiving less than 100 mg/day. Smyth et a1 (5) reported improvement in a small group of patients receiving 75 mg daily doses. However, Lidsky et a1 (6) were unable to show benefit from cyclophosphamide administered in a small double-blind trial with doses of 0.87 to 1.0 mg/kg/day. In 1970, the Cooperating Clinics* of the ARA initiated a controlled, double-blind trial to determine if lower doses of cyclophosphamide (575mg/day) had the same therapeutic effects as higher doses (5150 mg/day) with fewer adverse effects. Preliminary results for 54 of 82 patients *The participating clinics and the clinic directors were:

Treatment of refractory rheumatoid arthritis with low-dose cyclophosphamide. Long-term follow-up of 108 patients

“…This is in accordance to recent studies that investigate more agressive DMARD regimen (17,24). In another trial with CYC in RA, however, a 30% reduction in tender and swollen joint count and a reduction of morning stiffness for 30 minutes was considered a marked improvement (27). These less stringent criteria might have contributed to the lower rate of withdrawals (less than 10%) after 32 weeks of treatment with 75 mg per day (27), compared to our data.…”

“…The results of our analysis are difficult to compare to some other studies, where different sets of outcome parameters were applied. These included morning stiffness, walking time, and grip strength, (14,27) as well as ring size and shoe tying time (14). In our cohort, an improvement of swollen joint count of at least 50% was the precondition to continue the treatment, since only a marked improvement was thought to justify the prolonged exposure to CYC.…”

“…The oral application, however, was found to be effective in an uncontrolled study in 1968 (6). Controlled studies confirmed the efficacy of CYC at doses well above 100 mg per day (1,23,27). This was associated, however, with a high incidence of side effects, namely haemorrhagic cystitis and myelosuppression.…”

“…This was, however, a trial with a total of merely 22 patients. A larger study compared the efficacy of 75 mg per day with a daily dose of 150 mg per day in 88 patients (27). Both dosages were found to be equally effective.…”

The Safety of Intravenous Cyclophosphamide in the Treatment of Rheumatic Diseases

“…As described in previous studies, no statistically significant relationships were found between adverse effects and the nominal dose or the duration of the therapy [28,29]. Currently, there are some papers which describe a comparable frequency of adverse effects from the use of CP irrespective of the mode of administration [30], but comparing the use of oral or intravenous cyclophosphamide was not a goal of this paper.…”