Treatment of Intractable Rheumatoid Arthritis With Combined Cyclophosphamide, Azathioprine, and Hydroxychloroquine

Abstract

Cyclophosphamide, azathioprine, and hydroxychloroquine sulfate were prescribed for 31 patients (26 women and five men) with rheumatoid arthritis refractory to conventional therapy. Maintenance drug dosages (mean +/- SD) were as follows: cyclophosphamide, 30 +/- 24 mg/day; azathioprine, 74 +/- 44 mg/day; and hydroxychloroquine sulfate, 210 +/- 92 mg/day. Disease suppression began in 30 patients within three to 24 months (mean, nine months). Results after 43 months (range, 12 to 102 months) were as follows: 16, complete remission; seven, near remission; seven, partial disease suppression; one, no response. None remained in prolonged remission without some form of therapy. Treatment was discontinued in three patients because of pulmonary infection (two) or thrombocytopenia (one). Four patients had five malignant neoplasms (surgical cures) before therapy (two breast, one colon, one melanoma, one endometrial); four patients developed a malignant neoplasm during combined drug therapy (one colon, one endometrial, one lung, one erythroleukemia); and three died. The absolute risk of malignancy from combined drug therapy is still unclear. We concluded that combined use of remittive agents may have promise in treatment of severe rheumatoid arthritis; cyclophosphamide should be replaced with a nonalkylating agent; and the place of combined drug therapy remains uncertain in the absence of controlled trials.

Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease‐modifying antirheumatic drugs: Five‐year experience from the FIN‐RACo study

“…At 2 years, the proportion of patients whose RA was in remission was significantly higher in the combination group than in the single group (40% [95% confidence interval (95% CI) 29-52] versus 18% [95% CI [11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28]; P Ͻ 0.009). After 2 years, the frequency of remissions tended to remain higher in the original combination group than in the single group: at 3 years, 29% (95% CI 19-41) versus 21% (95% CI 13-31); at 4 years, 34% (95% CI 23-45) versus 21% (95% CI 13-32); and at 5 years, 28% (95% CI 18-39) versus 22% (95% CI 14-33).…”

“…There was a trend toward an increase in radiologic progression in both the combination group (median change in the Larsen score 14 [95% CI [11][12][13][14][15][16][17][18][19]) and the single group (median change in the Larsen score 20 [95% CI [17][18][19][20][21][22][23][24]), which was significant in both groups (P Ͻ 0.001 versus baseline). The increase in the Larsen score was statistically significantly lower in the patients included in the combination group compared with those in the single group (P ϭ 0.004).…”

“…In a Finnish study of patients with early RA treated according to the "sawtooth" strategy (8), remission was attained in 27% of patients after 2 years of treatment, and after a followup of 5-6 years, the rate of remissions remained stable at 31% (14). The highest rate of remissions reported thus far was achieved by a combination of cyclophosphamide, azathioprine, and hydroxychloroquine (15). This combi- nation, however, was too toxic for the long-term treatment of RA.…”

Treatment of rheumatoid arthritis

“…There are several other therapies undergoing active investigation in the field; these include sulfasalazine [71], fish oil supplementation [72], cyclosporin A [73], interferon gamma [74], and combination therapy [75]. Sulfasalazine is the only drug currently in our treatment plan that was specifically developed for rheumatoid arthritis.…”

“…Several studies examining the combination of methotrexate plus oral or intramuscular gold, methotrexate plus azathioprine, or hydroxychloroquine plus methotrexate or gold salt therapy are under way. McCarty and colleagues [75,91] performed two pilot studies in which patients received cyclophosphamide 37.5 to 150 mg/day, azathioprine 50 to 150 mg/day, and hydroxychloroquine sulfate 100 to 400 mg/day. There was significant efficacy in these open studies with only 1 of the 31 patients not responding to therapy.…”