A CONTROLLED TRIAL COMPARING SULFASALAZINE, GOLD SODIUM THIOMALATE, AND PLACEBO IN RHEUMATOID ARTHRITIS

72 A CONTROLLED TRIAL COMPARING SULFASALAZINE, GOLD SODIUM THIOMALATE, AND PLACEBO IN RHEUMATOID ARTHRITIS H. J. WILLIAMS, J. R. WARD, S. L. DAHL, D.. CLEGG, R. F. WILLKENS, T. OGLESBY. M. H. WEISMAN, S. SCHLEGEL, R. M. MICHAELS, M. E. LUGGEN, R. P. POLISSON, J. Z. SINGER, S. M. KANTOR, J. B. SHIROKY, R. E. SMALL, M. 1. GOMEZ, J. C. READING, and M. J. EGGER One hundred eighty-six patients with active rheumatoid arthritis were evaluated in a double-blind, randomized study that compared treatment with sulfasalazine (SSZ) (2 gm/day), gold sodium thiomalate (GST) (5 mglweek), and placebo (PBO). The 37-week course of therapy was completed by 19 patients. While marked improvement was seen in all 3 treatment groups, the only statistically significant differences between SSZ or GST and PBO were in a decreased erythrocyte sedimentation rate and increased grip strength in the right hand. GST is known to be superior to PBO, and the response of the GST-treated group was similar to that seen in other trials. The response of the PBO group, however, was much greater than in other placebo groups we have studied. SSZ was similar in efficacy to injectable gold, but was better tolerated. Because of adverse drug reactions (most commonly, rash, stomatitis, and proteinuria), 41% of patients were withdrawn from the GST treatment. Untoward drug effects (most frequently, rash and gastrointestinal distress) caused 16% of patients to be withdrawn from SSZ therapy. From the Cooperative Systematic Studies of Rheumatic Diseases Program. Supported by NIADDK contract N1-ARl-224. H. J. Williams, MD; J. R. Ward, MD; S. L. Dahl. PharmD; D.. Clegg, MD; R. F. Willkens, MD; T. Oglesby, MD; M. H. Weisman. MD: S. Schlegel. MD; R. M. Michaels, MD; M. E. Luggen, MD: R. P. Polisson. MD: J. 2. Singer, MD: S. M. Kantor, MD; J. B. Shiroky. MD; R. E. Small, PharmD; M. I. Gomez, MS; J. C. Reading, PhD; M. J. Egger, PhD. Address reprint requests to H. J. Williams, MD, University of Utah Medical Center, 5 North Medical Drive, Salt Lake City, UT 84132. Submitted for publication September 4. 1987; accepted in revised form January 25, 1988. The management of patients with rheumatoid arthritis (RA) is governed by inexact principles, and the most effective treatment varies from patient to patient. Treatment is usually instituted with aspirin or a nonsteroidal antiinflammatory drug (NSAID), rest, and physical therapy. For those patients whose disease is not controlled by this basic program, many second-line agents are available. These second-line agents are sometimes referred to as disease-modifying antirheumatic drugs (DMARDs), although the extent of disease modification is difficult to document, and few remissions are induced by these agents in short-term trials. None of these drugs appears to be curative. Because none of these agents is effective in all patients, and each carries varying risks of toxicity, new agents are constantly sought. The efficacy and relative utility of new compounds are then compared with those of more established DMARDs. Sulfasalazine (SSZ) has been used in the treatment of RA for more than 4 decades, with variable results (1-4). In recent uncontrolled trials, McConkey and coworkers (5,6) noted improvement in RA patients treated with SSZ, including improvement in the patients subjective evaluation and a decrease in both the C-reactive protein (CRP) level and the erythrocyte sedimentation rate (ESR). Other investigators have also suggested that SSZ is an effective and reasonably well-tolerated treatment for RA (7-1 1); however, uncertainties concerning efficacy, tolerability, and safety remain unresolved. This study was designed to compare the relative efficacy, tolerability, and toxicity of SSZ, gold sodium thiomalate (GST), and placebo (PBO) in a prospective controlled, double-blind trial. The efficacy and toxicity of GST have been established (12,13), and GST is Arthritis and Rheumatism, Vol. 31, No. 6 (June 1988)

SSZ, GST, AND PLACEBO IN RA 73 approved for use in RA. It has gained acceptance as a DMARD that can be used early in second-line therapy. PATIENTS AND METHODS Participating clinics. The Cooperative Systematic Studies of Rheumatic Diseases (CSSRD) is funded under a contract with the National Institute of Arthritis, Diabetes, and Digestive and Kidney Diseases (now the National Institute of Arthritis and Musculoskeletal and Skin Diseases). The Coordinating Center (CC) is located at the University of Utah in Salt Lake City. Protocols were developed at the CC with assistance and approval of the member clinics. All protocols were approved by each participating clinic s institutional review board or human rights committee. Data were collected at each clinic and sent to the CC, where they were monitored for completeness and adherence to the protocol, then stored for analysis. The participating clinics and their directors included 1 1 university-based centers, 1 private clinic, and the National Institutes of Health, as follows: University of Alabama at Birmingham, Graciela S. Alarcon, MD; University of California, Los Angeles, Harold E. Paulus, MD; University of California, San Diego, Michael H. Weisman, MD; University of Cincinnati, Michael E. Luggen, MD; Duke University, Durham, NC, Richard P. Polisson, MD; Guthrie Clinic, Sayre, PA, Robert M. Michaels, MD; Johns Hopkins University at Good Samaritan Hospital, Lynn Billingsley, MD; Ohio State University, Seth M. Kantor, MD; NIADDK, Arthritis and Rheumatism Branch, John Klippel, MD; State University of New York Health Sciences Center at Brooklyn, Joyce Z. Singer, MD; University of Utah, Daniel. Clegg, MD; Medical College of VirginiaNirginia Commonwealth University, Ralph E. Small, PharmD; University of Washington, Harborview Medical Center, Robert F. Willkens, MD. Study design. The study was a 37-week, prospective, randomized, double-blind parallel trial that compared PBO, SSZ, and GST therapy in patients with active RA. The randomization for each clinic was performed by the CC. Patients within each participating clinic were randomized in blocks of 8 with proportions of PBO, SSZ, and GST in the ratios of 2:3:3, respectively. Each patient was entered into the study after personnel at the CC had reviewed the entry database to ensure that protocol entry criteria were fulfilled and a signed patient consent form had been received. Entry criteria were revalidated when initial visit forms were received at the CC. Patients ineligible at the initial visit were removed from the study and replaced in the randomization scheme. The excluded patients were not included in any analysis. Patient selection criteria. All patients were 18 years of age or older. Each had definite or classic RA, in accordance with the criteria of the American Rheumatism Association (ARA) (14), of more than 6 months duration, with onset after age 16, and individualized antiinflammatory therapy with salicylates or NSAIDs had failed to completely control their disease. Minimal therapeutic salicylate dosage was defined as 3,6 mg of aspirin per day. Lower dosages were allowed if this dosage produced toxic signs or symptoms or a serum salicylate concentration 2 15 mgdl 4 hours after or immediately preceding a dose. For patients intolerant of or nonresponsive to salicylates, at least one other NSAID was tried. Minimal therapeutic daily dosages of alternative NSAIDs were defined as follows: fenoprofen, 2,4 mg; ibuprofen, 2,4 mg; indomethacin, 75 mg; naproxen, 75 mg; oxyphenbutazone or phenylbutazone, 3 mg; sulindac, 4 mg; tolmetin, 1,2 mg; piroxicam, 2 mg; or meclofenamate, 3 mg. Participating female patients had no childbearing potential or had practiced contraception successfully for at least 3 months before study entry. Each patient had 6 or more swollen joints considered capable of responding to drug therapy, and at least 2 of the following: (a) 9 or more joints that were painful on motion or tender on pressure, (b) morning stiffness 245 minutes, and (c) ESR (Westergren) 228 mndhour. Patients were excluded from the study for any of the following: (a) fulfillment of the ARA exclusion criteria for RA (14); (b) presence of seronegative spondylarthropathy, mixed connective tissue disease (151, or psoriasis; (c) concomitant therapy with another experimental drug; (d) previous treatment with gold, penicillamine, or antimalarial drugs; (e) previous treatment with cytotoxic drugs; (f) chronic dermatitis, except for benign disorders such as acne or limited seborrheic dermatitis; (g) any acute or chronic illness that would jeopardize the patient s ability to participate in the study (such as uncontrolled congestive heart failure, diabetes mellitus, active peptic ulcer disease, or significant hepatic, renal, or hematologic disease); also, patients who manifested proteinuria (>.5 gm/24 hours), thrombocytopenia (platelet count < 15,/mm3)), or leukopenia (total white blood cell count <3,5 cells/mm3 or polymorphonuclear cell count < 1,5 cells/mm3) at visit 1 were excluded; (h) previous therapy with SSZ; or (i) history of sensitivity to salicylates or sulfonamide-containing drugs. Drug administration. All patients received weekly supplies of tablets to be taken orally and were given regular intramuscular injections. Those randomized to the SSZ group received enteric-coated SSZ tablets (5 mg) twice a day for the first week, 3 times daily for the second week, and 4 times daily thereafter. They received PBO injections on the same schedule as patients in the GST group. Those randomized to the GST group received PBO tablets on the same schedule used for the oral medication in the SSZ group, plus GST injections weekly: 1 mg the first week, 25 mg the second week, and 5 mg weekly for 2 injections. The 5-mg GST injections were given every 2 weeks for the final 8 injections. Patients randomized to the PBO group received PBO injections and PBO tablets on the schedules described above. Double-blinding was accomplished by using physically indistinguishable PBO and SSZ tablets and PBO and GST injectable solutions. The patients were examined at the time of each injection, and injections were withheld until the results of a current complete blood count and urinalysis were reviewed. Patients were allowed a stable background medication program of aspirin and/or NSAID, which was kept constant for the duration of the 37-week double-blind study. Phenylbutazone and oxyphenbutazone were not permitted during the trial. A patient could be receiving corticosteroid therapy equivalent to 51 mg of prednisone per day, that had been a stable dosage for I month before study entry and remained constant throughout the trial. The only analgesics allowed

74 WILLIAMS ET AL regularly during the trial were acetaminophen, propoxyphene, or codeine, and a record of their use was maintained. Methods for evaluation. Clinical assessments of disease activity were performed at study entry and every 4 weeks thereafter. The same observer examined each patient throughout the trial. Physicians assessments and patients assessments were accomplished as follows. Physician assessment. The physician s assessment included (a) Joint count for tenderness on pressure and/or pain on motion for 6 diarthrodial joints, graded on a scale of -3, where = none, 1 = positive response on questioning, 2 = spontaneous response elicited, and 3 = withdrawal by patient on examination. (b) Joint swelling for 58 joints, graded on a scale of = none, 1 = detectable synovial thickening without loss of bony contours, 2 = loss of distinctness of bony contours, and 3 = bulging synovial proliferation with cystic characteristics. (c) Joint paidtenderness and joint swelling scores, derived by summing the severity scores for each joint. (d) Grip strength, using a mercury column sphygmomanometer with a standard grip bag (16). (e) Assessment of disease activity on a scale of 1-5, where 1 = asymptomatic, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe. ( Anatomic stage and Steinbrocker functional class (l7), which were assessed at the first and last visit. Patient assessment. The patient s assessment consisted of (a) Duration of morning stiffness on the day before the visit. (b) Overall assessment of disease activity, graded on a scale of 1-5, where 1 = asymptomatic, 2 = mild, 3 = moderate, 4 = severe, and 5 = very severe. Definition of therapeutic benefit. An important question to ask about any therapy is what proportion of the patients who started treatment obtained benefit. A major dilemma in such an analysis is defining benefit. The following definitions were developed for important or significant improvement for several variables, and were used to evaluate the benefit of the treatment for all patients entering the trial, including those who were subsequently withdrawn from the study. Therapeutic remission. Therapeutic remission (ARA criteria) (18) was defined as a minimum of 5 of the following 6 criteria for at least 2 consecutive months: morning stiffness <I5 minutes, no fatigue, no joint pain by history, no joint tenderness, no joint swelling, and ESR (Westergren) <2 mmlhour in men or <3 mmihour in women. Important joint improvement for joint swelling or joint painltenderness. Joint improvement was defined as improvement of 3% in the number of swollen (tender) joints, i.e., the number of joints improved exceeded the number of joints worsened by at least 5% of the joints initially involved and capable of response. Individual joint improvement was defined as change in swelling (tenderness) to none, or improvement from grade 3 to grade 1. Worsening was defined as involvement of a previously uninvolved joint or a change in swelling (tenderness) to grade 3 in a previously involved joint that was grade 2 or lower. For example, a patient who initially had 1 moderately swollen joints, with 8 joints improving but 3 joints worsening or developing swelling during the trial, would have been classified as having significant joint improvement. If 4 joints improved and 2 joints worsened, however, significant joint improve- ment would not have occurred. Sixty joints were evaluated for tenderness and 58 for swelling. Patient assessment. Improvement in patient assessment was defined as positive change by at least 2 grades or to asymptomatic. Physician assessment. Improvement in physician assessment was defined as positive change by at least 2 grades or to asymptomatic. Laboratory studies. A urinalysis and complete blood count that included hematocrit level, red blood cell count, hemoglobin level, white blood cell count, differential cell count, and platelet count were performed weekly. If the white blood cell count decreased to <3,5OO cells/mm3, the absolute polymorphonuclear leukocyte count was < 1,5 cells/mm3, the platelet count was <1,/mm3, or proteinuria was >.5 gm/24 hours, the treatment was discontinued and the results confirmed by a repeat test. If the repeat test results were normal, therapy was reinstituted. Acute or progressive decrease in hemoglobin concentration or hematocrit was also reason for drug withdrawal. A blood chemistries survey, which included serum glutamic oxaloacetic transaminase, serum glutamic pyruvic transaminase, lactate dehydrogenase, alkaline phosphatase, bilirubin, blood urea nitrogen, creatinine, total serum proteins, and albumin, was performed at entry and at 4-week intervals. In addition, the ESR (Westergren) was evaluated every 4 weeks. Roentgenograms of the hands were taken at entry and again on completion of the trial in all patients. Because standard methodology and criteria for evaluating change had not been established, the results of this analysis will be presented in a separate report. Adverse reactions. Patients were interviewed at regular intervals for new symptoms, presence of rash, mouth ulcers, gastrointestinal reactions, or other possible side effects. The physician was asked to express an opinion concerning the relationship of any symptom to the test medications. Only those reactions leading to withdrawal are reported herein. To ascertain the persistence and severity of the untoward effect, all patients who were withdrawn for Table 1. Demographic and clinical Characteristics of 186 patients at study entry, by treatment group* Variable Mean age, years (range) Malelfemale Disease severity Mild Moderate Severe Mean disease duration, months (range) Race, white/black/ other ssz (n = 69) 51 (22-73) 28/41 11 51 7 56 (6-285) 55/1/4 GST (n = 66) 51 ( 18-72) 18/48 5 52 9 85 (6-56) 4811315 PBO (n = 51) P 5.874 (22-73) 16/35.245.196 6 42 1 L 64.346 (6-322) 371618.293 * SSZ = sulfasalazine; GST = gold sodium thiomalate; PBO = placebo.

SSZ, GST, AND PLACEBO IN RA 75 adverse reactions were seen in followup until resolution of the reaction. Compliance. Patients were questioned at each visit to determine adherence to medication dosages for NSAIDs, glucocorticoids, and analgesics. Also, pill counts of the test medication were done. Statistical analysis. The appropriate statistical analysis of any particular variable depends upon the validity of assumptions. If the data did not have a Gaussian distribution, the comparison of the 3 treatment groups was analyzed by the Kruskal-Wallis test, using the difference between the first and last visits. If the assumption of a Gaussian distribution appeared to hold, then the data were analyzed using an analysis of variance on the difference between the first and last visits, or an analysis of covariance on the difference between the first and last visit using the first visit as a covariate. The decision to use analysis of variance or analysis of covariance was made using the criteria of Egger et al (19) and Anderson et a1 (2). To investigate differences between pairs of treatments when there was a statistically significant difference (P <.5) among all 3 treatments, pairwise comparisons of treatments were carried out using either Mann-Whitney rank sum tests or t-tests. Painvise tests were not performed unless there was a significant difference among the 3 groups. Pearson chi-square tests were used to compare the differences in proportions. The initial sample size for each treatment group was calculated based on the assumptions that GST would show a 5% improvement and SSZ would have to produce an 8% improvement to be better than GST. It was also assumed that PBO would show a 15% improvement. To test the null hypothesis of equality of treatments at the a =.5 level with 9% power and assuming a uniform dropout rate of 2%, it was planned that 88 patients would receive SSZ, 88 would receive GST, and 63 would receive PBO, for a total of 239 patients planned for the study. To assess the likelihood of clinically meaningful Type I1 or beta error, detectable differences were calculated. These are the differences between pairs of groups that were detectable with 9% power, at an overall 5% significance level, given the standard deviations that were observed. For continuous variables, these differences were corrected for the relative efficiency of Mann-Whitney rank sum tests versus t-tests. RESULTS Patients studied. One hundred eighty-six patients fulfilled the entry criteria and were admitted to the study. Recruitment to the study was stopped after 186 patients because of lack of patient entry. Sixtynine were assigned to the SSZ group, 66 to the GST group, and 51 to the PBO group. There were no significant differences among the groups at entry (Table 1). Two separate populations of patients were evaluated using 2 different methods of analysis. One analysis determined benefit from each treatment for all 186 patients who were admitted to the study, and therefore included, as treatment failures, all patients who withdrew from the study. The second analysis included only those patients who tolerated the drug therapy and completed the trial. The latter analysis addressed the question of response in patients able to tolerate an adequate period of treatment. One hundred nine patients received 37 weeks of therapy: 47 patients in the SSZ group, 3 in the GST group, and 32 in the PBO group. These groups were also comparable except for an imbalance in the number of men: The SSZ group had 47% men, while the GST group had only 13% and the PBO group had 34%. Compliance and response to treatment of all enrolled patients. Based on pill counts, there were no significant violations of the protocol. For the 186 patients who entered the study, the proportion of the patients who met the definitions for important improvement (see Patients and Methods) were compared among the 3 treatment groups. Therapeutic remissions were seen in 2 patients, 1 from the PBO group and 1 from the SSZ group. Important improvement of at least 5% for the joint paidtenderness count was seen in 57% of the patients who received SSZ, 33% of the GST patients, and 39% of the PBO patients (Figure 1). This was significantly better in the SSZ group than in the GST group (P =.1 1). Important improvement of Tenderness Swel I ing E Physician Assess Patient Assess Figure 1. Percent of patients with important improvement, as defined in Patients and Methods, by treatment group. = sulfasalazine (SSZ); = gold sodium thiomalate (GST); = placebo (PBO). P =.1 I, SSZ versus GST; P =.191, SSZ versus PBO; P =.613, GST versus PBO. * indicates P =.19.

Functional 2 f.6 2 2.6 f.6 2 f.5 2 2.4 f.5 2 f.7 2 f.5 t-.6.5293: class 2 (1-3) 2 (1-3) (- 1-2) 2 (1-3) 2 (1-2) (- 1-1) 2 (1-4) 2 (1-3) (- 1-2) e F: r s c/3 M c3 k r Table 2. Changes in clinical variables between entry and conclusion of the trial for 19 patients completing 37 weeks of therapy* Variable Morning stiffness, minutes Grip strength, mm Hg Right Left SSZ(n = 47) GST (n = 3) PBO (n = 32) ~~ ~~ ~ Entry Week 37 Differencet Entry Week 37 Difference t Entry Week 37 Difference? P 212 2 244.2 23 f 56.9 189 f 237 181 t 263 21 2 32.9 16 f 263.7 268 f 228.1 12 f 117.3 166 f 24.1.513: 12 (-1,229) (-3) 9 (-1,169) 9 (-1,79) 2 (-12) 75 (- 12-1,74) 225 (5-1,139) 6 (-42) 13 (- 12-1,139) 121 2 71.6 162 f 85.5-41 f 43.2 96 t- 61.7 143 f 75.7-46 f 35.8 12 f 81.9 143 t- 82.2-23 f 39.9.19$ 99 (21-3) 147 (36-3) -4 (- 163-23) 76 (23-3) 129 (2-3) -46 (- 111-6) 92 (29-3) 122 (28-3) - 11 (- 167-34) 123 f 69.7 16 t 83.2-37 t- 51.8 1 t 7.1 146 t 84.8-46 f 41.1 122 t 8. 148 t 82.5-26 5 46.8.1313: 99 (35-3) 153 (36-3) - 31 (- 165-82) 76 (2-3) 121 (2-3) - 33 (- 147-3) 93 (24-3) 126 (23-3) - 12 (- 166-53) Anatomic 2 f.8 2 f.7 f.6 2 f.8 2 f.7 f.5 2 f.7 2 f.7 5.5.2357 stage 2 (1-4) 2 (1-4) (- 1-2) 2 (1-3) 2 (1-3) (- 1-1) 2 (1-3) 2 (1-3) (- 1-1) 1 t.8.6623: 1 (-3) 1 f.8.6183: 1 (- 1-2) 15 f 13.8.228$ 16 (- 1-46) 26 t- 2.9.55$ 24 (-9-82).2447 Disease activity assessment Physician 3 f.6 2 f.7 I f.8 3 f.7 2 i.6 1 f.7 3 f.6 2 f.7 3 (2-4) 2 (1-4) 1 (- 1-2) 3 (2-5) 2 (1-3) 1 (-2) 3 (2-5) 2 (1-4) Patient 3 5.7 2 5.7 1 t-.9 3 f.9 2 2.6 1 f 1. 3 f.5 2 f.7 3 (2-4) 2 (1-3) I (- 1-2) 3 (2-5) 2 (1-4) 1 (- 1-3) 3 (2-4) 2 (1-3) Joint pain/ tenderness Count 28 f 12.3 8? 1.7 2 14.2 3 t 12.3 12 f 1.8 18 f 12.1 34 f 13.1 19 f 18.5 25 (7-54) 4 (-54) 2 (- 3-52) 3 (9-56) 9 (-44) 2 (-9-48) 32 (1-6) 12 (-59) Score 41 i 22.3 9 t- 13.2 31 f 23.3 44 i 2.7 14 f 14.5 329 t- (-9-68) 19.2 546 t- (2-16) 2.4 2416 t (-86) 23.3 34 (9-94) 5 (-74) 27 (-44-84) 47 (1-82) 9 (-58) Joint swelling Count 24 f 9. 1 f 8.8 14 f 9.1 26 2 9.9 12 -c 1. 14 f 1.1 26 t 9.5 13 t 8.8 23 (7-46) 7 (-33) 16 (-5-37) 27 (8-45) 11 (-4) 13 (-7-32) 26 (1-49) 13 (-34) 12 f 8.7 12 (-5-34) Score 33 t 16.2 11 t- 1.8 22? 14.1 37 f 18. 14 -+. 12.4 23 15.9 34 f 11.9 16 f 1.8 18 f 12.1.538t 31 (7-73) 7 (-42) 21 (-4-57) 36 (1-92) 12 (-56) 23 (-6-58) 33 (13-58) 14 (-36) 19 (-6-43) * Values are the mean t SD and median (range). Disease activity was graded on a scale of 1-5, where 1 = asymptomatic and 5 = very severe (see Patients and Methods). SSZ = sulfasalazine; GST = gold sodium thiomalate; PBO = placebo. t For all variables except grip strength, a positive value indicates improvement. 3: By Kruskal-Wallis test. P =.474, SSZ versus GST; P =.36, SSZ versus PBO; P =.6, GST versus PBO (by Mann-Whitney ranksum test). ll By analysis of covariance.

SSZ, GST, AND PLACEBO IN RA 77 at least 5% for the joint swelling count was seen in 48% of SSZ patients, 3% of GST patients, and 35% of PBO patients. There were no significant differences among the groups. Important improvement in patient and physician assessment of disease activity was greater in the SSZ group, but there were no statistically significant differences among the groups. Response to treatment in those completing the study. A separate analysis of the 19 patients who completed 37 weeks of therapy (47 SSZ, 3 GST, and 32 PBO) revealed substantial improvement in all 3 groups, but little difference among the groups (Table 2). For example, the median joint padtenderness count decreased by 2 in the SSZ and GST groups and by 16 in the PBO group (P =.228). The only significant difference was in grip strength in the right hand, with a median increase of 4 mm Hg in the SSZ group, 46 mm Hg in the GST group, and 11 mm Hg in the PBO group. Patients taking SSZ and those taking GST were statistically significantly improved over those receiving PBO, but there was no statistical difference between the 2 active drugs. No significant differences among the groups were identified for joint pain/tenderness count or score, joint swelling count or score, morning stiffness, grip strength in the left hand, patient assessment of disease activity, or physician assessment of disease activity. Changes in hemoglobin, platelet count, and ESR were evaluated for all patients who completed the trial. There were no significant differences among the groups for change in hemoglobin concentration or platelet count. The median decrease in ESR was 2 mm/hour for SSZ, 14 mm/hour for GST, and 8 mm/ hour for PBO. Patients who received SSZ or GST were significantly improved over those who took PBO, but were not significantly different from each other. A separate analysis for change in these laboratory variables was used to assess response in patients who had definitively abnormal values at entry. For this analysis, the hemoglobin concentration had to be < 12 gm/dl, the platelet count >45,/mm3 (21), or the ESR >28 mm/hour at study entry. Again, the only statistically significant differences were seen for the change in ESR (Table 3). The median improvement in ESR was 27 mmihour for SSZ, 22 mdhour for GST, and I1 mmlhour for PBO. Improvement in patients taking SST or GST was significantly greater than in those taking PBO, but there was no significant difference between SSZ and GST. Time of response. The change in the median painfulkender joint count over time for all patients who completed the trial is shown in Figure 2. lmprovement was seen in all 3 treatment groups as early as 4 weeks, and continued for all 3 groups after 37 weeks of therapy. Steady improvement was seen in both the SSZ and GST groups, while the PBO group showed more variability. Patient withdrawal. Of the 186 patients entered, 77 were withdrawn during the course of the study (Table 4). Forty-three patients were withdrawn for adverse drug reactions, 19 for lack of response to therapy, and 15 for reasons unrelated to drug treatment, such as moving from clinic area, development of an intercurrent illness, or lack of cooperation. Of the 43 patients withdrawn for adverse drug effects, 27 were in the GST group and represented 41% of the patients in that treatment group. This is significantly greater than either of the other treatment groups (P <.3). In contrast, 11 (16%) of the SSZ patients and 5 (1%) of the PBO patients were withdrawn for untoward effects. Rashes occurred in 16 GST patients, 5 SSZ patients, and 1 PBO patient, and were the major reason for withdrawal. One patient developed severe exfoliative dermatitis in response to GST, which required 2 hospitalizations. Two additional GST patients were withdrawn when they developed pruritus, although no rash was present. Four GST patients, including 3 who also had rash, developed stomatitis. Stomatitis did not lead to withdrawal in either the SSZ or PBO groups. Gastrointestinal complaints were not a reason for withdrawal of GST patients but were reported in 2 SSZ patients and 1 PBO patient. Leukopenia was seen in each treatment group, but thrombocytopenia was seen only in 1 GST patient. A PBO-treated patient was withdrawn when anemia developed. Proteinuria was not seen in SSZ patients but was observed in 3 patients receiving GST and 1 receiving PBO. Elevation of hepatic enzymes resulted in withdrawal of 2 patients, 1 in each group receiving active drug. A pneumonitis developed in 1 SSZ patient, and postinjection flares resulted in withdrawal of 2 patients receiving GST. Lack of efficacy was most frequently seen in the PBO group: 1 patients (2%) from that group were withdrawn for lack of efficacy. However, this differed significantly from the GST group only (P =.23). Six SSZ patients (9%) and 3 GST patients (5%) were withdrawn from the study for lack of response. Withdrawals for reasons unrelated to the trial were similar among the treatment groups: 6 GST patients (9%), 5 SSZ patients (7%), and 4 PBO patients (8%).

78 WILLIAMS ET AL Table 3. Median changes in selected laboratory variables between entry and conclusion of trial, for patients who initially had abnormal values and who completed 37 weeks of therapy* ssz GST PBO Variable n Entry Week 37 Diff.? n Entry Week 37 Diff.t n Entry Week 37 Diff.t PS Hemoelobin. emldl 8 11 13 2.2 9 II 13 1.4 9 11 12.5.83 (<Ifat visit I) Platelets, x I3/mm3 1 52 348 18 6 525 389 151 7 545 473 79.234 (>45 at visit 1) ESR, mmlhour 29 6 23 27 17 57 33 22 2 53 47 11.38 (>28 at visit 1) * ESR = erythrocyte sedimentation rate. See Table 2 for other definitions. t Positive value indicates improvement. $ By Kruskal-Wallis test. I P =.363, SSZ versus GST; P =.1, SSZ versus PBO; P =.3, GST versus PBO (by Mann-Whitney rank sum test). With the exception of 1 GST patient who developed a skin rash that persisted, all adverse reactions resolved after the drug was discontinued. There were no deaths in the trial. Untoward drug effects that did not result in withdrawal from the study were also evaluated. All reactions considered probably or definitely related to the experimental therapy and present on more than 1 visit are listed in Table 5, by treatment group. These effects were not common and were more frequently seen in GST patients. The 2 GST patients with dysgeusia and 2 of the 3 with stomatitis were subsequently withdrawn because of a rash. DISCUSSION The results of this trial, if interpreted without knowledge of other controlled studies, would suggest that there is little difference between SSZ and GST, SSZ and PBO, or GST and PBO; however, previous well-designed, controlled, double-blind trials have confirmed the efficacy of GST as compared with PBO (12,13). The response in patients who tolerated GST for the entire 37-week trial is similar to that seen in other studies. In the present trial, the joint painhenderness count in the GST-treated group decreased by a mean of 15 joints after 21 weeks and 18 joints after 37 weeks. In an earlier CSSRD trial comparing GST with 2 f I I I I I I I 4 8 12 16 2 24 28 32 36 WEEK Figure 2. Median change in joint paidtenderness count over time, by treatment group. = sulfasalazine; W = gold sodium thiomalate; = placebo. Table 4. Reason for withdrawal, by treatment group* Reason Adverse drug reaction Rash Pruritus Stomatitis Gastrointestinal distress Leu kopenia Thromboc ytopenia Anemia Proteinuria Elevated hepatic enzymes Pneumonitis Postinjection flare Lack of response Other Lack of cooperation Intercurrent illness Moved Total patients withdrawn Group (no. at study entry) ssz GST PBO (n = 69) (n = 66) (n = 51) 11 (16) 5 2 2 1 1 6 (9) 5 (7) 3 2 22 (32) * Values are no. (%). See Table 2 for definitions t Three patients with rash also had stomatitis. 27 (41) 5 (1) 16t 1 2 4t 1 I 1 1 I 3 1 1 2 3 (5) 1 (2) 6 (9) 2 4 (8) 3 3 1 1 36 (55) 19 (37)

SSZ, GST, AND PLACEBO IN RA 79 Table 5. Adverse drug effects considered to be drug-related and present on more than one visit but not resulting in drug withdrawal* Reaction ssz GST PBO Gastrointestinal distress 2 1 Rash It Stomatitis 3t Dysgeusia 2 Itching I Leu kopenia 1 * See Table 2 for definitions. I One patient had both rash and stomatitis. auranofin and PBO (13), GST resulted in a mean decrease of 11 painful/tender joints after 21 weeks. The same measures of improvement were used in both trials. A different measurement for joint improvement was used in the Empire Rheumatism Council trial (12), and in that study, ajoint was considered affected if 2 of the 3 features of swelling, tenderness, and limitation of motion were present. Direct comparison between that study and our current study is therefore not possible. However, those researchers observed a mean decrease of 1 in the number of involved joints in GST patients. In both the CSSRD and the Empire Rheumatism Council studies, GST resulted in significantly greater improvement than that found with PBO. In the present study, the mean number of swollen joints in the GST patients completing the trial decreased by 14. This is compared with a mean decrease of 7 in the earlier CSSRD study of GST and auranofin (13). In an ARA Cooperating Clinics trial (22), a mean decrease of 13 joints with active synovitis, which presumably represents swollen joints, was reported in patients treated with GST. The latter result is similar to that seen in the current report but was not statistically significantly different from the decrease in 7 swollen joints seen with PBO in that study. The response to GST, as assessed by important improvement for all patients entering the trial, was similar to that seen in a previous trial, in which the same criteria were used for GST patients (13). In the current trial, important improvement, as defined, occurred in 33% and 3% of GST-treated patients for joint painhenderness and joint swelling, respectively. This is similar to the 35% and 27% of patients with important improvement for joint pain/tenderness and swelling reported earlier. Thus, the efficacy response to GST in this trial, by these criteria, was similar to the response that was anticipated. The response to SSZ was at least equal to, and sometimes exceeded, that seen with GST. SSZ has been tried in the treatment of RA for many years, but the results have been inconclusive (1-4). In 1978, McConkey et al (5) reported the results of an uncontrolled study showing marked improvement in subjective clinical state and significant falls in serum CRP and the ESR 6 weeks after treatment began ; the improvement persisted for the 22 weeks of therapy. Thirty-two patients had entered the study, but 7 discontinued treatment within a month because of side effects. While it cannot be determined what doses the patients received, treatment was initiated with 1.5 gm/day and increased by.5 gm/day at weekly intervals to a total dosage of 3 gmlday unless side effects intervened. In 198, McConkey et a1 reported observations in another uncontrolled study of SSZ treatment in 74 RA patients (6). Enteric-coated SSZ was initiated at.5 gmlday and increased by.5 gm/day at weekly intervals to a maintenance dosage, usually 2 gm/day. Again, patients reported subjective improvement, and there were decreases in the CRP levels and the ESR. Clinical improvement was detected in 4-6 weeks and was progressive to 36 weeks. While not all dropouts were described, 18 patients were withdrawn for failure to respond. Thirty-eight patients continued to take the drug for 1 year. Bird et al (7) undertook an uncontrolled trial in 15 RA patients and observed improvement in both clinical and biochemical measures of disease with SSZ therapy (1.5 gdday for 2 weeks, increased to 2. gdday for the next 2 weeks, and then given in a daily dosage of 3. gm for the next 17 weeks). Improvement in articular measurements was seen at 4 weeks, and morning stiffness and pain improved at 8 weeks. Progressive improvement over 2 weeks was suggested. The authors concluded that SSZ is likely to prove only marginally less effective than d-penicillamine or sodium aurothiomalate on formal clinical testing. This conclusion was consistent with our controlled-study findings, in which SSZ was similar to GST in the treatment of RA. There were no statistically significant differences between the 2 drugs in patients who completed the trial, and there were fewer withdrawals for adverse drug reactions in the SSZtreated group. Our results differ from those reported by Bax and Amos (9) in their uncontrolled comparison of SSZ and GST. They defined success as continued therapy at 2 years, active joint count of or 1 (metacarpophalangeal joints, metatarsophalangeal joints, and proxi-

71 WILLIAMS ET AL ma1 interphalangeal joints considered as single joint groups) and morning stiffness <3 minutes. Thirty-two percent of the SSZ group and 44% of the GST group had a successful response. Fifteen of 59 patients who completed 42 weeks of therapy with SSZ met the ARA criteria for disease remission. Twenty-nine of 84 patients completing 42 weeks of GST also were classified as being in remission. The dosage of SSZ was maintained at 2 gm/day. The authors concluded that the safety profile of SSZ was superior to that of GST, and that SSZ was effective in RA, but less so than GST. A controlled trial of 9 patients, comparing enteric-coated SSZ and GST with PBO (lo), used a maximum dosage of 3 gm/day of SSZ and 5 mg/week of GST. This study compared SSZ with PBO in a double-blind format, but the group receiving GST was not blinded. No significant differences in inflammation variables among any of the 3 treatments were observed at week 24, although SSZ-treated and GSTtreated patients did show significant improvement from the beginning of the trial and PBO-treated patients did not. Variables that improved in the SSZtreated group were ESR, platelet count, articular index, grip strength, and an index of disease activity. GST treatment resulted in improvement in ESR, rheumatoid factor titer, articular index, pain score, and an index of disease activity. However, those investigators also reported a high rate of withdrawal from SSZ for drug toxicity, particularly nausea and vomiting. Nine of the 3 patients receiving SSZ were withdrawn for adverse drug reactions. This is a considerably higher rate of withdrawal than that seen in our SSZ group. In the current study, there were few differences between findings in patients treated with either of the active drugs and those who took PBO; so few differences could even result from the effect of multiple statistical comparisons. Both GST-treated and SSZtreated patients were significantly improved over PBO-treated patients, as measured by ESR and grip strength in the right hand in patients tolerating therapy, but no other differences were seen. No differences were reported between SSZ and PBO in the study comparing SSZ, PBO, and GST (1); however, in a 15-week controlled study that compared SSZ (3 gm/day) with PBO, Pinals et a1 (1 1) reported significant improvement in joint tenderness and swelling, morning stiffness, grip strength, and pain score using enteric-coated SSZ versus PBO. They also reported a 28% withdrawal rate for adverse effects of SSZ, particularly gastrointestinal reactions. The time to response for patients tolerating the treatment in our study was similar for all 3 treatment groups (Figure 2). An earlier study had suggested that GST-treated patients began to show improvement at 8 weeks and continued through 21 weeks (23). Others have suggested that the response to SSZ begins in 4-8 weeks (6,7). This is confirmed in our trial, with response seen by 4 weeks and continuing at the conclusion of the trial. The interpretation of our findings depends on the weight given in the statistical analysis to the relatively large numbers of GST patients withdrawn for adverse drug reactions, as well as the PBO patients who withdrew for lack of efficacy. In the first analysis of all treated patients, the percentages of patients with important improvement in joint paidtenderness were 57%, 33%, and 39% for SSZ, GST, and PBO, respectively (P =.11 for SSZ versus GST). If patients withdrawn for adverse drug reactions and non-drugrelated reasons are not considered in the analysis because efficacy cannot be evaluated, the percentages change to 74%, 67%, and 48% (P =.17 for SSZ versus PBO). If only patients who complete the treatment period are analyzed in this manner, however, the percentages become 83%, 73%, and 63% (P >.5). Thus, SSZ was statistically significantly better than GST when withdrawals for adverse drug reactions were considered treatment failures, but not when such patients were excluded as unevaluable. Although the differences between treatment groups appeared small for many variables in our study, the evidence for or against an occurrence of Type I1 error is conflicting. The effect of the shortfall in patient accrual in the analysis of all 186 patients was counterbalanced by the use of data from withdrawn patients. This increased the effective number of patients by about 3%, more than compensating for the accrual shortfall. The high PBO response observed decreased the power of such analyses, however, so that only pairwise differences of at least 37 percentage points were detectable with 9% power. Thus, Type I1 error was unlikely but possible in these analyses, particularly for nonsignificant comparisons of SSZ versus GST. Power calculations were also performed for continuous efficacy variables, such as joint counts, which were used in the analysis of patients who tolerated 37 weeks of therapy. Such continuous variables often have more precision and, hence, more ability to detect treatment differences than categorical variables. The effects on power of the shortfall in patient accrual were somewhat counterbalanced by

SSZ, GST, AND PLACEBO IN RA 71 1 this increase in precision in the analysis of patients who tolerated 37 weeks of therapy. In the best case, the final sample size in this study provided at least 9% power to detect a difference of 31 percentage points in the percent improvement in CSSRD swelling score between any 2 treatment groups, given the observed standard deviations. Alternatively, to detect a 3-percentage-point difference in swelling score between PBO and GST and 9% power, a minimum of 31 patients tolerating treatment per group would have been required. This is contrasted with the actual minimum sample size of 3 and observed mean percentage changes from baseline of 65 for SSZ, 61 for GST, and 52 for PBO. (These values cannot be obtained from Table 2. The mean percentage change is not equivalent to the percentage differences in mean joint counts.) These calculations assume an overall 5% significance level for all possible pairs of treatment comparisons. For joint variables other than swelling score, lower power was available. Therefore, Type I1 errors were possible, although unlikely for the joint swelling score, in the analysis of patients who tolerated 37 weeks of therapy. The adverse drug reactions seen in GST patients were those anticipated. Rashes accounted for the majority of withdrawals for untoward drug effect, and 3 of the patients with rash also had stomatitis. Severe exfoliative dermatitis occurred in 1 patient. Proteinuria was the next most common adverse reaction to GST, and leukopenia and thrombocytopenia were seen in 1 patient each. Withdrawals for adverse drug effects were much less common in patients receiving SSZ, and occurred in only 16% of those in this treatment group, as compared with the 41% withdrawal for untoward reaction in the GST-treated patients, and was only slightly greater than the 1% withdrawal of patients receiving PBO. The GST withdrawals for adverse effect were higher than anticipated. In our previous study involving GST, 27% withdrew for drug reaction (13). Even the lower rate is considerably higher than that seen for SSZ in the current study. The most common drug reaction leading to withdrawal from SSZ was also rash, but gastrointestinal problems (nausea and vomiting) were seen in 2 patients, and leukopenia also occurred in 2 patients. Neutropenia from SSZ has been reported previously f6,24), and gastrointestinal problems have been the leading cause of withdrawal in other studies, even with enteric-coated SSZ (6,25). One patient receiving SSZ in our study was withdrawn for pneumonitis that was thought to be drug-related (26-28). Withdrawals for reasons unrelated to therapy were similar in all 3 treatment groups; however, PBO patients were more likely to be withdrawn for lack of treatment response than patients receiving either active drug. This suggests that the active medication may have given some improvement not measured by our variables. Since GST has been shown to be superior to PBO, and the response of the GST group was consistent with previous findings, we compared the response of the PBO group with PBO groups in other RA studies done by the CSSRD (23,29,3). The response of the PBO group in the current study was much greater than anticipated and greater than that of any PBO group in our earlier trials. For instance, important improvement in the joint paidtenderness count for all patients entered into the trial was found in 39% of the PBO patients in the current study, whereas the previous highest percentage improvement in this variable while receiving PBO therapy occurred in the comparison of methotrexate and PBO (Table 6) (3). The response to PBO in that study was 11% of PBO patients after 18 weeks of therapy. The reason for the aberrant response to PBO in the current study is not clear. It is not related to severity or duration of RA, clinic variability, early withdrawals in any group, or demographic characteristics of responders or nonresponders. Samples of each treatment agent were analyzed to confirm treatment identity, and no errors were found. This population of patients differed from those in other CSSRD studies only in that patients had not previously received DMARD therapy. When the present study was designed, a 15% positive response to PBO was anticipated in selecting sample sizes. Beecher (31), however, reviewed 15 studies evaluating pain relief, and found that the Table 6. Important improvement in joint paidtenderness in all PBO-treated patients with rheumatoid arthritis in 4 studies by the Cooperative Systematic Studies of Rheumatic Diseases* Duration of % of study patients Study (reference no.) n (weeks) improved SSZ, GST, and PBO (present study) 51 37 39 Methotrexate and PBO (3) 94 18 11 Auranofin, GST, and PBO (23) 5 21 8 D-penicillamine and PBO (29) 54 3 9 * See Table 2 for definitions.

712 WILLIAMS ET AL placebo was beneficial in 35% of patients. Evans (32) also found that placebos gave significant pain relief in 36% of patients in 13 double-blind studies. In a short, 25-day trial in a small number of RA patients, Langley et a1 (33) evaluated the effect of placebos on pain. Nine of 18 patients had a positive response to PBO. These findings are in contrast to those in other CSSRD controlled trials, in which the PBO response, as measured by joint paidtenderness, has been <25%. The current trial had a PBO response, as measured by important improvement in all enrolled patients, of 39% in joint paidtenderness and 35% in joint swelling. These findings are similar to those in the studies cited above. Because of the marked response to PBO, we are unable to report any advantage of GST or SSZ over PBO for joint pain or swelling. GST is known to be superior to PBO. The response of the GST group in this study was similar to that found in other trials. 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