ARTHRITIS RHEUMATISM

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1 ARTHRITIS & RHEUMATISM OFFICIAL JOURNAL OF THE AMERICAN RHEUMATISM ASSOCIATION SECTION OF THE ARTHRITIS FOUNDATION 52 1 COMPARISON OF HIGH AND LOW DOSE CYCLOPHOSPHAMIDE THERAPY IN RHEUMATOID ARTHRITIS H. JAMES WILLIAMS, JAMES C. READING, JOHN R. WARD, and WILLIAM M. OBRIEN 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 Supported by Grant NOl-AM , 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 Submitted for publication January 2, 1979; accepted in revised form February I, 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: Georgetown University, Georgetown Hospital, A. Sliwinski; University of Illinois, St. Joseph Hospital, I. Steck and J. Holloman; University of Michigan, University Hospital, I. Duff and W. Mikkelsen; State University of New York, Downstate Hospital, S. Wallace and D. Kaplan; University of Rochester, University Hospital, R. Jacox; University of Tennessee, City of Memphis Hospital, S. Kaplan; University of Washington, Harbor View Hospital, R. Willkens, and Mason Clinic, L. Healey; Yale University, Yale Hospital, G. DeForest and J. Kenney. Arthritis and Rheumatism, Vol. 23, No. 5 (May 1980)

2 522 WILLIAMS ET AL who had completed the trial were reported in 1972 (7). No benefits were claimed for the low dose group. The present report analyzes all patients who entered the trial. PATIENTS AND METHODS Patient selection. Eighty-eight patients from 8 Cooperating Clinics who had definite or classic RA by the ARA Criteria (8) were randomly assigned to high dose or low dose cyclophosphamide treatment groups. The disease had to be present for at least 2 years with onset after the age of 16 years. The patient must have failed to improve during the 6 months prior to entry into the study on conventional therapy with salicylates and at least one other drug (corticosteroids, gold, antimalarials, indomethacin, or phenylbutazone). During the study and for 4 weeks preceding the initial evaluation, patients could not receive gold or phenylbutazone, and no nontrial immunosuppressive drugs were allowed. There were no other medication restrictions. Previous therapy with immunosuppressive drugs excluded patients from the trial, as did presence or history of psoriasis, cystitis, ankylosing spondylitis, recent major surgery, concurrent serious illness, lack of reliability, and leukopenia (defined as a white blood cell count of less than 5,000/mm3). Clinical assessment. Patients were seen at the beginning of the study and at 8-week intervals, and assessment of rheumatoid disease activity was performed by methods previously described (9). At each visit they were evaluated by the same rheumatologist. The clinical evaluation included an estimation of the duration of morning stiffness, measurement of grip strength for both hands, time required to walk 50 feet, enumeration of tender and swollen joints, and determination of the erythrocyte sedimentation rate (ESR) by the Westergren method. The physician and the patient each reported an overall assessment of status ranging from very good to very bad, as well as a comparison to the status at a clinic visit for monitoring adverse reactions 2 weeks earlier with gradations from much better to much worse. These gradations were scored with 1 representing the most favorable and 5 representing the least favorable rating. Monitoring for side effects and toxicity was performed weekly for the first 4 weeks of the study and at least every 2 weeks thereafter. This assessment included inquiry about adverse reactions and medication history, and evaluation of urinalysis, white blood cell count, and hemoglobin concentration. Drug treatment. Cyclophosphamide was supplied in 25 mg and 50 mg tablets that were identical in appearance. Patients assigned to the low dose (LD) treatment group received 25 mg tablets while those in the high dose (HD) treatment group received 50 mg tablets. Both the patient and the physician did not know the assigned dose. Each patient received one tablet of trial medication by mouth daily for 4 weeks. Dosage was increased to 2 tablets daily for the next 4 weeks, and then to 3 tablets daily for the final 24 weeks. Maximum dose in the LD group was 75 mg cyclophosphamide per day while the HD group received a maximum of 150 mg per day. Reduction in dosage of the study drug was at the dis- cretion of the attending physician and was based on the white blood cell count, urinalysis, and undesirable side effects. Trial medication was discontinued if the white blood cell count fell to 2,500 cells/mm3 or less or if hemorrhagic cystitis occurred. Statistical methods. Each efficacy variable was analyzed as the difference between the baseline value and the value at 32 weeks, and the median differences between the HD and the LD groups were compared. Since some efficacy variables to be analyzed were not normally distributed, the rank-sum test (10) was used to compare the changes. The t- test, which is slightly more powerful than the rank-sum test for Gaussian data, was also calculated for the appropriate variables but showed trivial differences in results, so only the rank-sum results for efficacy variables are presented below. Additional analysis was performed to determine if patients who had meaningful response differed in the times of response in weeks between LD and HD groups. Meaningful response was defined as 30% reduction in swollen joints for those with at least four initially swollen joints; 30% reduction in tender joints for those with at least four initially tender joints; and /z hour reduction in time of morning stiffness for those with at least /z hour initial morning stiffness. The Mantel-Haenszel2 test was used for testing statistical significance. Pearson s x2 test for 2 X 2 tables, with Yates correction for continuity, was used to test for differences in the two treatment groups in the number of patients exhibiting the following adverse reactions: nausea, vomiting, upper respiratory infection, micturition pain, diarrhea, stomatitis, alopecia, hematuria, proteinuria, and white blood cell counts. The rank-sum test was used to compare changes in hemoglobin concentration. RESULTS Patients entered. Of the 88 patients initially considered for the study, 44 were randomly assigned to high dose cyclophosphamide therapy and an equal number were placed on low dose cyclophosphamide. Thirteen patients were subsequently disqualified from analysis (6 HD and 7 LD); of these patients, 2 were removed because of unrelated surgery, 1 developed severe unrelated intercurrent illness, 6 were unwilling to cooperate, 2 died of traumatic causes, 1 was unable to reach the maximum dose of trial medication, and 1 was removed for unknown reasons. Of the 38 patients remaining in the HD group, 12 were men and 26 were women with a mean age of 49.9 years (range 21-70). The 37 patients in the LD group, which consisted of six men and Table 1. disease Mean values and ranges for duration and severity of Low dose, High dose, Variable mean (range) mean (range) Duration of RA (years) 9.0 (0-45) 10.5 (0-43) ARA stage 2.5 (-4) 2.5 (0-4) Functional class 2.4 (1-4) 2.4 (2-3)

3 3 CYCLOPHOSPHAMIDE THERAPY IN RA 523 Table 2. Median and median change and ranges in variables from baseline by treatment Low dose High dose Variable n* Oweeks 32weeks Changet n* Oweeks 32weeks Change? Morning stiffness (day before), minutes (30-420) (15-600) ( ) (15-660) (0-360) (-42&+240) Grip strength both hands, mm Hg (27-197) (18-250) ( ) (20-265) (40-290) ( ) 50-foot walking time, seconds (5-5 1) (8-53) ( ) (6-60) (942) ( ) Number of swollen joints (1-41) (0-36) ( ) (243) (0-33) (-32-+lo) Number of tender joints I1 (4-53) (0-51) ( ) (7-57) (1-65) ( ) Patient assessment score (2-5) ( 1-41 (-3-+2) (2-5) (1-4) (-3-+2) Physician assessment score (2-5) (1-4) (-3-+2) (2-4) (1-4) (-2-+I) Erythrocyte sedimentation rate mm/hr (10-105) (8-110) ( ) (16-106) (9-119) ( ) ~ ~~ * n varies because of missing data on some patients. t Median change is the median for the differences between week 0 and week 32 for the individual patients. + Westergren method. P = women, were older with a mean age of 55.5 (32-74). The two groups were comparable in duration and severity of disease (Table 1). Response to therapy. There were no important differences between the two treatment groups for any of the eight variables used to measure disease activity (Table 2), though there was a tendency for HD patients to have greater improvement. The only variable that showed statistically significant difference at the 5% level was the ESR. The median change in ESR was a drop of 2 mm for the LD group and an increase of 9 mm for the HD group. These same variables were examined for those patients who were able to maintain the maximum dose of the trial drug and did not require lowering of the dose for adverse effects of the medication. Twenty-four patients in the LD group and 15 patients in the HD group qualified for this analysis. The results were similar, although there was a significant difference in physician assessment with the physicians indicating more improvement in the LD group. The trial drug was given in a fixed dose and the patients varied in size and weight. Thus, it was considered that the dose per unit weight might influence the results. Consequently, the dose of cyclophosphamide was calculated for each patient on a mg/kg/day basis. For patients who had been unable to maintain the maximum dose of cyclophosphamide, the average or usual " ' a 0. o 0. tenderness 0 swelling '- I I 1 J 1 I Average Dose rng/kg/day Figure 1. A comparison of the difference in the number of joints involved with tenderness (0) and swelling (0) between week 0 and week 32 to the average dose of cyclophosphamide in mg of drug per kilogram of body weight per day.

4 524 WILLIAMS ET AL Table 3. Time of first noticed meaningful response by variable and treatment for those responding* Week of response Treat- Variable ment* Totalst Tenderness LD HD Swelling LD HD Morning stiffness LD HD LD = low dose; HD = high dose. * P values were all greater than j Totals differ since patients were required to meet initial criteria for meaningful response (see Patients and Methods section). dose of cyclophosphamide was estimated. If the medication dosage varied considerably and demonstrated no pattern, the patient was excluded from this portion of the analysis. A scattergram was constructed that compared drug dose in mg/kg/day to improvement in joint swelling or tenderness, but no relationship was found (Figure 1). Since there were no significant differences between the response to cyclophosphamide in high or low dose, the time of onset of meaningful response following initiation of therapy was evaluated for responders. Only trivial differences were found between the two groups (Table 3). It is interesting to note that almost half of all patients who achieved a meaningful response obtained that response by the eighth week of the study when the daily dose of cyclophosphamide was only 50 mg and 100 mg for the LD and HD groups, respectively. Withdrawals. Six patients withdrew from the study before completion because of inadequate response to therapy or adverse reactions (Table 4). There was one withdrawal for treatment failure in both the LD and HD groups. An equal number of withdrawals for adverse reactions was found in both.groups, although both withdrawals in the HD group were for leu- Table 4. Withdrawals Treatment Week withdrawn Reason LD (N = 37) 1 Nausea LD 22 Inadequate response LD 24 Leukopenia-died HD (N = 38) 20 Leukopenia HD 20 Inadequate response HD 12 Leukopenia kopenia, whereas one patient in the LD group was withdrawn for leukopenia and one was withdrawn after 1 week in the trial because of severe nausea. The adverse reactions in withdrawn patients were minor, except for one death that occurred in the LD group because of intraabdominal infection following rupture of a diverticulum. Untoward effects. The variables that were compared in the two groups to assess differences in untoward reactions are listed in Table 5. Significant difference was found only for leukopenia, defined as fewer than 3,500 cells/mm3. Similar significance was found for patients with white blood cell counts below 2,500 cells/mm3. With the exception of proteinuria, hematuria, and leukopenia, all the data in Table 5 were obtained from subjective responses of the patient to questioning. Severity was assessed as mild, moderate, or severe. Any episode of stomatitis or upper respiratory infection of any severity was included in the tabulation. The presence of nausea or diarrhea of moderate severity or vomiting or micturition pain of any severity for two consecutive visits or for 25% of the total visits was also included. Alopecia of any severity for three consecutive visits or for the final two visits was tabulated. Proteinuria was defined as the presence of 1+ or more protein on dipstick examination, and hematuria consisted of five or more red blood cells per high power field on microscopic examination of the urinary sediment. Alopecia was common in both treatment groups but was more frequent and severe with the higher doses of medication. Statistical significance was borderline (P = 0.06). In addition to the hematologic variables listed in Table 5, the hemoglobin concentrations for each group Table 5. Percent of patients showing adverse reactions by treatment Treatment Low High dose dose P Adverse reaction (N = 36); (N = 38) value Alopecia Nausea Vomiting Upper respiratory infection Micturition pain Diarrhea Stomatitis Hematuria Proteinuria Leukopenia * N = 37 for nausea. Patient withdrawn after 1 week of therapy and not included in other adverse reactions.

5 CYCLOPHOSPHAMIDE THERAPY IN RA 525 were compared. The difference between the mean values at 0 and 32 weeks was gm/100 ml for the LD group and gm/100 ml for the HD group which is statistically significant (P = 0.04). DISCUSSION Final analysis of the results of this study differs from the preliminary report (7). It was initially indicated that high doses of cyclophosphamide (average 1.78 mg/kg/day) were effective in the treatment of severe aggressive RA, but lower doses (average 0.74 mg/ kg/day) had no more effect than negligible doses (15 mg/day) given to a control group in another trial (3). Our analysis revealed no significant differences in efficacy between high and low doses, and both groups were improved on the medication. Of the eight variables evaluated, only one variable (change in ESR) indicated a statistically significant difference between the two groups and that was in the direction of deterioration for the HD group. While high dose cyclophosphamide has been reported to suppress rheumatoid arthritis, the present study demonstrates no important difference in efficacy between the two doses. In fact, many of the observed meaningful responses occurred before the patients received the maximum doses of cyclophosphamide allowable in the trial. There are several possible explanations for the differing results between this analysis and the original report (7). The early report analyzed the data on 54 patients who had completed the trial. As any drug trial progresses, recruitment of patients becomes more difficult, and subtle changes in patient population may occur. Using less than the total sample size also increases the risk that random variation inordinately influences the data. Disclosing information before completion of a study can influence or bias subsequent observations (1 1). Furthermore, in the present analysis, eight variables for efficacy were employed, whereas in the previous report only five variables were examined, and no formal analysis was described. The method of comparing the high dose group to a high dose group in a prior and remote trial and the low dose to the placebo group of that trial is a questionable practice. The only valid comparison is between the two treatment groups in the same trial, although investigators may discuss their results in the context of previous related studies. We recognize that inability to show a difference between two treatments does not prove that the treatments are equally effective. The null hypothesis states that HD is equal to LD, and failure to reject this hy- pothesis when a real difference exists is termed a type I1 error. An important difference might, in fact, be present, and there is a risk that the conclusion of equal efficacy is erroneous. There was a trend for greater improvement in the HD group for most variables, but the differences were small. However, if the two treatment groups had included sufficiently large numbers of patients, statistical significance might have been obtained for the variables used to measure efficacy. To investigate the possibility of a type I1 error in this trial, sample sizes for each variable were determined that would give statistical significance (a = 0.05) and sufficient power (0.90) to detect a clinically meaningful difference assuming the variability we actually encountered. For the calculations, a clinically meaningful difference between the two groups was defined as a difference in percentage improvement of 40%. In addition, geometric means were used to measure the average percentage change in each group. In order to calculate a sample size which will detect the above difference, raw mean changes must be estimated corresponding to the desired 40% difference between high and low dose groups. To obtain these values, we arbitrarily chose to assume a uniform change over all patients in the direction which would increase the distance between drug group means. The resulting differences in raw means were used in the traditional manner to calculate sample sizes. It should be noted that sample size calculations are easily performed for differences in the actual values of the variables; however, with variables such as joint counts, a percentage change was considered more meaningful. Thus for variables other than ESR, sample sizes in excess of 200 in each group would be needed to detect a 40% difference between groups. For ESR, a sample size of 66 in each group would be necessary to detect the above expressed difference. If smaller changes between the two groups were expected, much larger numbers would be required to detect the differences. Consequently it is possible that a type I1 error has been committed and that a difference of clinical importance has not obtained statistical significance because of inadequate sample size. While the study of Fosdick et a1 (2) was not designed to compare high and low doses of cyclophosphamide, 10 of 54 patients with classic or definite rheumatoid arthritis had a complete remission, and half of these patients received maximum doses of 75 mg/day. Complete remission was defined as a generalized feeling of well being with no fatigue, subjective and objective absence of pain and swelling beyond that of poor mechanical function, and a normal ESR. Less im-

6 526 WILLIAMS ET AL pressive results for low dosage cyclophosphamide were seen in 19 patients who had partial remissions with marked improvement in energy level and general feeling of well being, marked subjective and objective decrease in joint tenderness and swelling, and a decrease in ESR to % of the baseline value. Four (21%) of these patients received a maximum dose of 50 mg daily. Smyth et a1 (5) demonstrated that patients on 75 mg cyclophosphamide and low doses of prednisone (3-15 mg/ day) had significant improvement in their arthritis compared to patients on similar doses of prednisone and placebo. These results are in contrast to the double-blind study of Lidsky et a1 (6) who reported that patients with rheumatoid arthritis treated with mg of cyclophosphamide a day were not significantly different from patients who received placebo. Possible explanations for this difference are lack of control for concomitant treatment and the small sample size in the Lidsky series. The significant difference in ESR in the present study is not consistent with other reports. Considering the number of variables for which comparisons were made in our patients, this one borderline statistical difference may be attributed to random variation. Townes et a1 (4) in a double-blind comparison of high dose cyclophosphamide and placebo in 24 patients noted no significant reduction in ESR between the two patient groups, although cyclophosphamide did significantly af fect other measures of disease activity including number of painful joints, swollen joints, morning stiffness, and grip strength. Lidsky et a1 (6) and Smyth et a1 (5) reported no significant change in sedimentation rate, and in the initial study by the Cooperating Clinics (3) the ESR was similar in both groups while the other five measures of disease activity showed improvement in patients receiving high doses of cyclophosphamide. Smyth et a1 (5) reported a remarkable reduction of toxic reactions in patients on 75 mg cyclophosphamide daily compared with patients on a higher dose (average 105 mg). Others have had similar results (6). Low dose cyclophosphamide would be a very useful treatment modality if equal results were obtained with less toxicity. In the present study, leukopenia and a decrease in hemoglobin concentration were more common in patients on high dose medication, but there was no other advantage in adverse reactions for the LD group. There was no significant difference in the numbers of patients withdrawn from the study for adverse reactions, and the only death as a result of therapy occurred in the LD group. Hemorrhagic cystitis, bladder fibrosis and telangiectasia, and cancer of the bladder are serious adverse effects of cyclophosphamide. The latter two are long term effects, but hematuria was uncommon and mild in this trial. Sterility as a result of cyclophosphamide therapy is well documented (12,13) but was not evaluated in this study. Delayed toxicity such as mutogenesis (14) and oncogenesis (15,16) cannot be effectively evaluated in a short term project, but there exists a potential advantage for lower dose medication in this important area. While patients in the HD group had more leukopenia, response to therapy was not necessarily related to the degree of white blood cell depression. This finding is in agreement with others (2,3). Our data indicate that there is no apparent important dose dependence in the range of mg/day, and it can be suggested that the antiinflammatory effect of cyclophosphamide (1) is of primary importance and that this effect is achievable with lower doses than those currently recommended. The minimal effective dose has not yet been determined. Fifteen milligrams per day have not been effective (3), and the minimal effective dose presumably lies between 15 mg/day and 75 mg/day. While it is a reasonable hypothesis that the lower the dose the lower the frequency of adverse reactions, we did not find confirmation of that hypothesis for the dosages used in this study. Cyclophosphamide appears to be effective in the treatment of RA in a dose of 75 mg/day but is accompanied by serious toxic effects that can be life threatening. The potential for neoplastic induction is still not well defined. This drug should be reserved for patients with severe, active, progressive disease that is unresponsive to conventional therapy, and treatment with this agent should be instituted only when both the patient and the physician understand the potential benefit and the attendant risk. REFERENCES 1. Hurd ER: Immunosuppressive and antiinflammatory properties of cyclophosphamide, azathioprine and methotrexate. Arthritis Rheum 16:84-88, Fosdick WM, Parsons JL, Hill DF: Long-term cyclophosphamide therapy in rheumatoid arthritis. Arthritis Rheum 11: , Cooperating Clinics Committee of the American Rheumatism Association: A controlled trial of cyclophosphamide in rheumatoid arthritis. N Engl J Med 283: , Townes AS, Sowa JM, Shulman LE: Controlled trial of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum , Smyth CJ, Bartholomew BA, Mills DM, et al: Cyclophos-

7 CYCLOPHOSPHAMIDE THERAPY IN RA phamide therapy for rheumatoid arthritis. Arch Intern Med 135: , 1975 Lidsky MD, Sharp JT, Billings S: Double-blind study of cyclophosphamide in rheumatoid arthritis. Arthritis Rheum 16: , 1973 Cooperative Clinics Committee of the American Rheumatism Association: A controlled trial of high and low doses of cyclophosphamide in 82 patients with rheumatoid arthritis. Arthritis Rheum 15:434, 1972 Ropes MW, Bennett GA, Cobb S, et a revision of diagnostic criteria for rheumatoid arthritis. Bull Rheum Dis 9: , 1958 Cooperating Clinics Committee of the American Rheumatism Association: A seven-day variability study of 499 patients with peripheral rheumatoid arthritis. Arthritis Rheum 8: , 1965 Siege1 S: Nonparametric Statistics. New York, McGraw- Hill Book Company, 1956, pp Armitage P, McPherson CK, Rowe BC: Repeated significance tests on accumulating data. J. R. Statistical SOC., Series A 132: , Fairley KR, Barrie JU, Johnson W: Sterility and testicular atrophy related to cyclophosphamide therapy. Lancet 1~ , Uldall PR, Kern DNS, Tacchi D: Sterility and cyclophosphamide. Lancet 1: , McCann J, Simmon V. Streitwieser D, et a1 Mutogenicity of chloroacetaldehyde, a possible metabolic product of 1, 2-dichlorethane (ethylene chloride), chloroethanol (ethylene chlorohydrin), vinyl chloride, and cyclophosphamide. Proc Nat Acad Sci USA 72: , Fahey JL: Cancer in the immunosuppressed patient. Ann Intern Med 75: , Pollock BH, Barr JH, Stoker BL, et al: Neoplasm and cyclophosphamide. Arthritis Rheum 16:524525, 1973