COMPARISON OF SULFASALAZINE AND PLACEBO IN THE TREATMENT OF PSORIATIC ARTHRITIS

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1 ARTHRTS & RHEUMATSM Vol. 39, No. 2. December 996, pp 20> , American College of Rheumatology 203 COMPARSON OF SULFASALAZNE AND PLACEBO N THE TREATMENT OF PSORATC ARTHRTS A Department of Veterans Affairs Cooperative Study DANEL 0. CLEGG, DOMENC J. REDA, EDWN MEJAS, GRANT W. CANNON, MCHAEL H. WESMAN, THOMAS TAYLOR, ELLY BUDMAN-MAK, WARREN D. BLACKBURN, FRANK B. VASEY, MAREN L. MAHOWALD, JOHN J. CUSH, H. RALPH SCHUMACHER, JR., STUART L. SLVERMAN, F. PAUL ALEPA, MCHAEL E. LUGGEN, MRAM R. COHEN, RAMA MAKKENA, CLAR M. HAAKENSON, RCHARD H. WARD, B. J. MANASTER, ROBERT J. ANDERSON, JOHN R. WARD, and WLLAM G. HENDERSON Objective. To determine whether sulfasalazine (SSZ) at a dosage of 2,000 mg/day is effective for the treatment of active psoriatic arthritis (PsA) resistant to nonsteroidal antiinflammatory drug therapy. Methods. Two hundred twenty-one patients with PsA were recruited from 5 clinics, randomized (doubleblind) to SSZ or placebo treatment, and followed up for 36 weeks. Treatment response was based on joint paid Supported by the Cooperative Studies Program (CSP) of the Department of Veterans Affairs (VA) Medical Research Service, and by an unrestricted grant to the Western nstitute for Biomedical Research, nc. (a not for profit foundation) from Kabi Pharrnacia, AB. Daniel 0. Clegg, MD. Grant W. Cannon. MD: VAMC, Salt Lake City, Utah; Domenic J. Reda, MS, William G. Henderson, PhD: Hines CSP Coordinating Center, Hines, llinois; Edwin Mejias. MD: VAMC, San Juan, Puerto Rico; Michael H. Weisman, MD: VAMC, San Diego, California; Thomas Taylor, MD: VAMC, White River Junction, Vermont; Ely Budiman-Mak, MD: VAMC, Hines, llinois; Warren D. Blackburn, MD: VAMC, Birmingham, Alabama; Frank B. Vasey, MD: VAMC, Tampa, Florida: Maren L. Mahowald, MD: VAMC, Minneapolis, Minnesota; John J. Cush, MD: VAMC, Dallas, Texas; H. Ralph Schumacher, Jr., MD: VAMC. Philadelphia. Pennsylvania; Stuart L. Silverman, MD: VAMC, Los Angeles, California; F. Paul Alepa, MD: VAMC, Tucson, Arizona; Michael E. Luggen, MD: VAMC, Cincinnati, Ohio; Miriam R. Cohen, MD: VAMC, Milwaukee, Wisconsin; Rama Makkena, MD: VAMC, New Orleans, Louisiana; Clair M. Haakenson. RPh, MS: Alhuquerque CSP Clinical Research Pharmacy Coordinating Center, Albuquerque, New Mexico; Richard H. Ward, PhD, B. J. Manaster, MD, John R. Ward, MD: University of Utah, Salt Lake City; Robert J. Anderson, PhD: Hines CSP Coordinating Center, Hines, llinois, and University of llinois at Chicago. Address reprint request requests to Daniel 0. Clegg, MD, Division of Rheumatology, 4B200-SOM, 50 North Medical Drive, Salt Lake City, UT Submitted for publication March 9,996; accepted in revised form July 9, 996. tenderness and swelling scores and physician and patient global assessments. Resubs. Longitudinal analysis revealed a trend favoring SSZ treatment (P = 0.3). At the end of treatment, response rates were 57.8% for SSZ compared with 44.6% for placebo (P = 0.05). The Westergren erythrocyte sedimentation rate declined more in the PsA patients taking SSZ than in those taking placebo (P < 0.000). Adverse reactions were fewer than expected and were mainly due to nonspecific gastrointestinal complaints, including dyspepsia, nausea, vomiting, and diarrhea. Conclusion. SSZ at a dosage of 2,000 mg/day is well tolerated and may be more effective than placebo in the treatment of patients with PsA. t is estimated that 6-20% of patients with psoriasis develop an inflammatory arthritis (). Medical therapy of chronically active psoriatic arthritis (PsA) is largely nonspecific and unsatisfactory. Nonsteroidal antiinflammatory drugs (NSADs) are the first-line medications for treating patients with inflammatory arthritis and psoriasis. Second-line, or "disease-modifying," drugs for rheumatoid arthritis, including methotrexate and gold compounds, are used most frequently in PsA patients who continue to have active disease with NSAD therapy. Data from controlled trials of methotrexate and parenteral gold have demonstrated only marginal efficacy (2-4). Several small, short-duration studies have suggested that sulfasalazine (SSZ) may have some benefit in the treatment of both PsA (5-0) and psoriasis (5,9). The purpose of the present study was

2 204 CLEGG ET AL, to evaluate the efficacy and safety of SSZ in the treatment of PsA. PATENTS AND METHODS Study design. The study was a 36-week, multicenter, double-blind, randomized, placebo-controlled parallel trial comparing the efficacy of SSZ (2,000 mg/day) with placebo for the treatment of PsA. The study was conducted under the auspices of the Cooperative Studies Program (CSP) of the Department of Veterans Affairs (VA).* The study was designed by a Planning Committee that consisted of rheumatologists and biostatisticians experienced in the development and execution of clinical trials. Oversight of the study was accomplished by an executive committee, which was composed of the study chairman, the study biostatistician, selected participating investigators, and consultants, as well as an independent Data Safety and Monitoring Board, which consisted of a biostatistician and two experienced rheumatologists who reported directly to the Chiefs of the Coordinating Center and the CSP. Eligibility criteria. Patients were required to have an established diagnosis of psoriasis. f the rash was atypical, the diagnosis was confirmed by dermatology consult or by skin biopsy. Patients must have had one of the following presentations of PsA: distal interphalangeal joint involvement, asymmetric peripheral arthritis, or symmetric polyarthritis. Additionally, at the time of study entry, patients must have had 3 joints with active arthritis, defined as joint tenderness and joint swelling of 22 on a 4-point scale and physiciadpatient global assessments of moderate on a scale of none/mid/moderate/ severe/very severe. Criteria for exclusion included positive rheumatoid factor (RF) or antinuclear antibodies (ANA) >:80, a history of inflammatory bowel disease, or evidence of another systemic rheumatologic disorder. Patients could not have been previously treated with SSZ or have a history of sensitivity to salicylates, sulfa-containing drugs, or tartrazine, which was an excipient in the placebo. Patients with chronic illnesses that, in the opinion of the investigator, would limit successful participation in the trial were excluded. All patients had failed to respond to therapeutic doses of of the NSADs. All patients who took NSADs during the trial were required to be on stable dosages for month prior to entry and throughout the trial. No systemic or intraarticular steroids were allowed. nformed consent. The study protocol was reviewed and approved by nstitutional Review Boards at the VA CSP Coordinating Center in Hines, llinois, and at each of the 5 participating VA Medical Centers and their affiliated university teaching hospitals. Prior to entry into this trial, each potential study participant was informed of the nature, duration, and purpose of the study, the methods and means by which the study drug was to be administered, and all the potential benefits, inconveniences, and hazards that could reasonably be expected. The VA CSP participating centers, investigators, and support staff are listed in full in Comparison of Sulfasalazine and Placebo in the Treatment of Ankylosing Spondylitis: A Department of Veterans Affairs Cooperative Study, which appears elsewhere in this issue of Arthritis and Rheumatism ( ). Study medication. Patients received either 500 mg of enteric-coated SSZ tablets or an identical placebo. Treatment was initiated at study tablet daily for week, and was increased by tablet daily each week until a total of 4 tablets daily (in divided doses) was reached. The medication was to be taken with the morning and evening meals. Clinical assessment. Outcome measures of disease activity and therapeutic efficacy were obtained at the time of screening (not more than 4 weeks before study entry), randomization (week 0), and weeks 2, 4, 2, 20, 28, and 36. Outcome measures included a variety of patient-reported, clinician, laboratory, and radiographic assessments. Patient self-assessment measures included morning stiffness, night pain, patient global assessment, and Spondylitis Functional ndex, as described in the article on SSZ in ankylosing spondylitis, which appears elsewhere in this issue of Arthritis and Rheiirnatisrn ( ). Clinician assessments included joint evaluations for painhenderness and swelling, dactylitis, an Enthesopathy ndex, a Spondylitis Articular ndex, chest expansion, modified Schober s test, fingers-to-floor test, and the physician global assessment as detailed elsewhere ( ). Additionally, the presence of symptomatic iritis was reported on a 5-point qualitative scale (0 = none, = mild, 2 = moderate, 3 = severe, 4 = very severe). Psoriasis assessment. Cutaneous psoriasis was evaluated by the study coordinators at each of the participating centers. The coordinators were instructed by an experienced dermatology metrologist at a training session and were provided with a video tape for future reference. The evaluation was performed as follows: ) patient global assessment of psoriasis activity (4-point scale: none, mild, moderate, severe); 2) estimate of percentage of body surface area affected by psoriasis; 3) estimate of the severity of erythema, induration, and scaling of 2 preselected lesions (4-point scale; for eythenza, 0 = none, = mild [pinwlight red], 2 = moderate [red but still not dark], 3 = severe [very red, possibly dark]; for scaling, 0 = none, = mild [poorly defined scales, possibly dusty appearance], 2 = moderate [defined scales, flat surface edges], 3 = severe [well-defined, raised and lifted scales, possible yellow/brown color]; for elevation, 0 = none [flat], = mild [barely perceptible elevation], 2 = moderate [moderate elevation], 3 = severe [high elevation, firm edge]); and 4) evaluator s global assessment of psoriasis activity (6-point scale, taking into account the percentage of body surface affected and the severity of erythema, scaling, and elevation, as follows: cleared = 00% remission except for residual discoloration, excellent = at least 75% improvement, good = 50-75% improvement, fair = 25-49% improvement, poor = <25% improvement, worse = exacerbation of disease). Laboratory assessment. Laboratory evaluation included a urinalysis and a complete blood cell count, with leukocyte differential and reticulocyte counts. Chemical surveys and a Westergren erythrocyte sedimentation rate (ESR) determination were done at every visit. The C-reactive protein (CRP) level was measured at the first and last visits. At the screening visit, blood was drawn for HLA-B27 typing and RF and ANA determinations. Radiology assessment. At the screening visit, all patients had the following radiographs performed: anteroposte-

3 SSZ VERSUS PLACEBO N PsA 205 Table. Baseline characteristics psoriatic arthritis patients studied Characteristic Demographic Number of patients Age, mean t SD years % male Ethnicity, % White Black Hispanic Other Clinical Duration of disease, mean 2 SD years Weight, mean? SD pounds Sacroiliitis, % positive HLA-B27, % positive Number of involved joints, mean i- SD Joint tenderness, mean 2 SD score Joint swelling, mean? SD score Morning stiffness, mean t SD hours % body surface area, mean i- SD Laboratory Hematocrit, mean f SD % Platelets, mean t SD mm3 (X lo3) Westergren erythrocyte sedimentation rate, mean? SD mm/hour C-reactive protein, mean 2 SD p,g/ml (normal C0.8) Study group Sulfasalazine Placebo Total P f ? ? ? i i i- 4..9? ? ? t ? t.3 96? t t t ? t t ? ? t ? t t f C ? f t i rior views of the pelvis and oblique views of the sacroiliac joints. Adverse drug reactions (ADRs). Patients were screened for ADRs at every visit. Patients were withdrawn from the study medication if any of the following were found: white blood cell count <3,000/mm3, absolute polymorphonuclear cell count <,SOO/mm3, platelet count <OO,OOO/mm', acute or progressive decrease in hemoglobin or hematocrit, proteinuria of >SO0 mg/24 hours, drug fever, or significant rash. Compliance. The patients were queried at each visit regarding the medications they had taken. A tablet count for the trial medication was done at each visit to monitor compliance. Biostatistical considerations. Each patient was classified as a treatment responder or nonresponder based on the following definition. Four assessment measures were selected a priori, and criteria for clinical improvement and worsening criteria were defined for each: patient self-assessment and physician assessment (improvement = decrease by category, worsening = increase by category); joint paidtenderness score and joint swelling score (improvement = decrease by 30%; worsening = increase by 30%). Treatment response was then defined as improvement in at least 2 of these 4 measures, of which must be joint paidtenderness or swelling, and no worsening in any of the 4 measures. The study was designed with a 90% power for detecting a placebo response rate of 30% compared with an SSZ response rate of 5076, assuming a 25% withdrawal rate. This resulted in a target sample size of 240 patients. A detailed description of the analytic methods appears elsewhere in this issue of Arthritis and Rheumatism (). Briefly, the change in primary and secondary outcome measures from baseline to the last available followup were analyzed using t-tests for continuous data and chi-square tests for ordinal and categorical data. Mixed-model analyses (2) were done to characterize the response patterns over time using SAS PROC MXED (3) for continuous data and a freeware program named MXOR (4) for categorical and ordinal data. All other analyses were conducted using SAS version 6.08 (5). All statistical tests were 2-sided and P was the criterion for statistical significance. RESULTS Patient population. Two hundred twenty-one patients entered the study. Of these, 09 were randomized to receive SSZ, and 2 to receive placebo. Table outlines the baseline demographic, clinical, and laboratory variables. As expected in this VA-supported study, most patients were middle-aged, white males. However, recruitment was not limited to veterans. Patient volunteers were selected from participating VA hospitals and affiliated teaching hospitals. One hundred twenty-two patients were veterans; 99 were nonveterans. The duration of disease was -2 years; all patients had psoriasis and peripheral arthritis. The Westergren ESR and CRP levels were mildly elevated. nterestingly, the ESR tended to be higher in the SSZ treatment group and the

4 206 CLEGG ET AL Table 2. Outcome measures in patients with psoriatic arthritis taking sulfasalazine or placebo Study group Sulfasalazine Placebo P Primary, % % responders to treatment Physician global assessment % with improvement % with worsening Patient global assessment % with improvement % with worsening Joint tenderness score % with improvement % with worsening Joint swelling score % with improvement % with worsening Secondary, mean t SD Duration of morning stiffness (hours) Spondylitis Functional ndex (number) Joint tenderness score (number) Joint swelling score (number) Dactylitis score (number) Enthesopathy ndex (number) Spondylitis Articular ndex (number) Chest expansion (cm) Modified Schober s test (cm) Occiput-to-wall (cm) Fingers-to-floor (cm) % body surface area Laboratory, mean t SD Westergren erythrocyte sedimentation rate (mm/hour) C-reactive protein (mglml) t ? t f ? t t t ? t t t C.6 0. t ? t f ? ? C t t t t _f t t t Z f t t t f t f t t t t 9.7. f ? t co.0 0.9

5 SSZ VERSUS PLACEBO N PsA 207 CRP levels tended to be higher in the placebo treatment group. No statistically significant differences in these baseline parameters were noted between the SSZtreated patients and the placebo-treated patients. Compliance. Compliance for both the SSZ and placebo groups was quite high. As assessed by pill count, both groups took -90% of their prescribed medication. Primary outcome measures. The Planning Committee defined response based on a decision rule as outlined in Patients and Methods. Based on that definition of treatment response, using the last-visit analysis, response rates were 57.8% in the SSZ group and 44.6% in the placebo group (P = 0.05). Trends favoring SSZ were noted in components of the response definition; however, the statistical significance of the a priori response definition is much stronger than that of any of the individual components (Table 2). Physician global assessment showed improvement in 4.3% and worsening in 6.4% of the SSZ group compared with improvement in 38.4% and worsening in 0.7% of the placebo group (P = 0.52). Patient global assessment demonstrated 45.9% improved and 7.3% worsened in the SSZ group and 4.% improved and 9.8% worsened in the placebo group (P = 0.69). Joint tenderness demonstrated 58.7% improvement and.9% worsening with SSZ treatment, and 47.3% improvement and 3.4% worsening with placebo (P = 0.22). Joint swelling scores improved in 59.6% and worsened in 9.2% of patients Sulfasalazine -4 - Means with 95% confidence limits (p=0.066) Placebo Figure. Change in the percentage of body surface affected by psoriasis in patients with psoriatic arthritis taking sulfasalazine (SSZ) or placebo. There was a decrease in the total body surface area affected by psoriasis in patients taking SSZ (P = 0.066). Bars show the mean and 95% confidence limits. i Table 3. Longitudinal analysis summary' Outcome measure Primary Treatment response Physician global assessment Patient global assessment Joint paidtenderness score (% improved) Joint swelling score (% improved) Secondary Spondylitis Functional ndex Joint pain/tendemess score Joint swelling score Dactylitis score Enthesopathy ndex Spondylitis Articular ndex Chest expansion Modified Schober's test Occiput-to-wall Fingers-to-floor % body surface area Westergren erythrocyte sedimentation rate P * Model with group, but not with group*time or group*time2. P values represent treatment group differences. taking SSZ compared with 5.8% and 3.4% of patients taking placebo (P = 0.43). Secondary and laboratory outcome measures. Most of the secondary clinical outcome measures did not show a significant difference between SSZ and placebo. Figure shows that there was a trend toward a reduction in the body surface area affected by psoriasis in the SSZ-treated group (P = 0.066). Laboratory outcome measures showed some statistically significant changes. Total neutrophils decreased in the SSZ group, compared with a small increase in the placebo group (P = 0.04). There was a greater decrease in the platelet count in the SSZ group (P < 0.000). The Westergren ESR significantly decreased in the SSZ group compared with the placebo group (P < 0.000). CRP values were not significantly different. Comparison of SSZ responders with nonresponders showed the former to have a greater decrease in the white blood cells (-0.6?.3 versus C.; P = 0.05), platelets ( versus C 37.8; P = O.OOOl), and Westergren ESR ( versus 0.9? 3.6; P = 0.00). There was no difference in the amount of reduction of the CRP level. Longitudinal analysis. The results of this trial using the longitudinal analysis techniques are shown in Table 3. An examination of the response patterns showed the response curves of the two groups to be approximately parallel, indicating that a model which included group, but not group"time or group*time2

6 208 CLEGG ET AL 00% 60% E % 60% c m a v) 5 40% 20% 0% Weeks Since Randomization Figure 2. Time pattern of treatment response in patients with psoriatic arthritis taking sulfasalazine or placebo. would be most appropriate. The treatment response profiles, displayed in Figure 2, show a trend suggesting that SSZ was more effective than placebo (P = 0.3). Only of the 4 components of treatment response showed statistical significance, and that was patient global assessment (P = 0.05) (Figure 3). Physician global assessment (P = 0.2) showed a trend in favor of SSZ. No treatment effect was seen for the joint pain/ tenderness score (P = 0.40) or joint swelling score (P = 0.43). An examination of the response pattern over time showed that treatment differences were small until week 28, and then reached a maximum at week 36. Longitudinal analysis of the secondary and laboratory outcome measures revealed trends toward differences favoring SSZ for the fingers-to-floor test results (P = 0.6) and the percentage of body surface area affected by psoriasis (P = 0.2), and a significantly greater reduction in the ESR (P = 0.0). Restricting the longitudinal analysis to patients who continued to take the study treatment for the 9-month followup period revealed small differences in treatment response in terms of the global assessments and fingers-to-floor test results, but the joint swelling scores (P = 0.3) and chest expansion (P = 0.5) showed 00% Physician Global Assessment Patient Global Assessment 00% +Placebo-lmproved -6ulfasalazine-Worsened - Placebo-Worsened C 60% D a L 40% 5 60% 20% 0% Weeks S i RandameaUon 0% Weeks Since Randomuation 00% Joint Painflenderness 00% Joint Swelling 80% 80% C 60% C 60% 0 5 s 40% a L $ 40% 20% 20% Weeks Since Randomha(lon 0% Weeks Sms Randomization Figure 3. Changes in physician global assessment, patient global assessment, morning stiffness, and back pain among psoriatic arthritis patients treated with sulfasalazine or placebo, by response group.

7 SSZ VERSUS PLACEBO N PsA 209 Table 4. Psoriatic arthritis patient recruitment and exit from study Randomized to treatment Withdrew from study Withdrawal of consent Lost to followup Lack of improvement or worsened hsease ntercurrent illness Adverse drug reaction Gastrointestinal symptoms Dermatologic symptoms Central nervous system symptoms Fever, chills ncreased liver enzyme levels Completed study Sulfasalazine Study group Placebo a stronger trend in favor of SSZ. Other results were consistent with the intention-to-treat analysis. Subset analysis. Subset analyses were performed in an attempt to stratify patients according to disease severity. Analysis of patients with an ESR <5 mmhour showed that 6% responded in the SSZ group and 4% responded in the placebo group (P = 0.3). Among patients with an ESR 25 mm/hour, 5% responded in the SSZ group and 44% responded in the placebo group (P = 0.9). We also found larger treatment differences in patients with lower joint pain/tenderness scores, lower joint swelling scores, and lower CRP at baseline, all of which showed a trend favoring SSZ treatment. These data suggest that the beneficial effects of SSZ are more apparent in patients with less severe articular disease. Withdrawals and adverse drug reactions. Table 4 summarizes the data on patient recruitment and exit from the study. Thirty-five patients withdrew from the SSZ treatment group; 25 withdrew from the placebo group. Thus, the duration of followup tended to be less in those taking SSZ (mean -+ SD 0.58 t 0.26 years) than in those taking placebo ( ) (P = 0.06). ADRs were the most common reasons for withdrawal, accounting for 20 patients (4 taking SSZ; 6 taking placebo). Gastrointestinal complaints occurred most often and included dyspepsia, nausea, vomiting, and diarrhea. Rashes were the next most common complaint. Central nervous system symptoms, including headache, lightheadedness, and confusion, were also seen. Nonspecific constitutional complaints, including lethargy, fatigue, exhaustion, and myalgias, were also noted. None of the ADRs was judged by the investigator to be severe. Ten patients withdrew their consent (5 taking 57 SSZ and 5 taking placebo). Twelve patients withdrew because of no improvement or worsening disease (5 taking SSZ and 7 taking placebo). Three patients developed intercurrent illnesses that required withdrawal from the study ( taking SSZ and 2 taking placebo). These illnesses included proteinuria that was thought to be secondary to hypertension, esophageal stricture, and atrial fibrillation. Fourteen patients were lost to followup and could not be contacted after multiple attempts (0 taking SSZ and 4 taking placebo). DSCUSSON The results of this trial suggest that sulfasalazine may be beneficial in the treatment of psoriatic arthritis. The definition of response was determined a priori and included assessment of joint pain/tenderness and swelling as well as patient and physician global assessments. t seems paradoxical that while the primary outcome measure was statistically significant (P = 0.05), treatment differences favoring SSZ in the 4 components which defined that measure were statistically weaker. SSZ produced a treatment response in 3.2% more patients than did placebo. Looking at the components of response individually, SSZ resulted in 2.9% more patients having improved physician global assessment, 4.4% more having improved patient global assessment,.4% more having improved joint tenderness, and 7.8% more having improved joint swelling. Thus, the magnitude of the treatment response difference appears to be consistent with the treatment effects on joint counts, especially, joint pain/tenderness. ndividually, none of these measures achieved statistical significance because the statistical power was reduced since the components used a 3-point scale (improved, no change, worsened) while treatment response was rated on a 2-point scale (response, no response), i.e., analysis of the components required more statistical degrees of freedom. n addition, none of the treatment differences for the components was as large as for the overall response measure. The longitudinal analysis, which included data over the entire treatment period, demonstrated a statistically weaker treatment effect than did the last-visit analysis. Differences between SSZ and placebo groups were narrow through 28 weeks and reached a maximum at 36 weeks (the last visit). This may indicate that the full effect of SSZ is not seen until 36 weeks or later. The time course of response seen in each of the 4 components was consistent to various degrees with the overall longitudinal response pattern. n subset analyses, the statistical trends suggesting that patients with less severe articular disease activity

8 2020 CLEGG ET AL may experience more clinical benefit from SSZ than other patients were unexpected. We are not aware of other PsA studies that have analyzed data in this manner. There have been 4 placebo-controlled trials evaluating the efficacy of SSZ in PsA (7-0). Three had fewer than 40 patients, was an 8-week followup, and the others were 24 weeks. mprovement favoring the SSZ group was suggested in each of these studies. The largest trial (0) recruited patients with seronegative spondylarthropathies, 36 of whom were thought to have PsA. The PsA subgroup in that trial seemed to have a more positive SSZ response than did the other seronegative spondylarthropathy subgroups. However, the difference appeared to be due to a relatively lower placebo response in the PsA subgroup. SSZ does appear to improve biologic markers of disease activity in PsA. The ESR fell, at least transiently, in each of the trials that reported such results. The fall was sustained and highly statistically significant in the present study. A significant and sustained decrease in platelet count was also seen in SSZ-treated patients in the present study. Newman et a (6) reported a small open study which demonstrated that gm levels also decreased in PsA patients taking SSZ. SSZ was well tolerated in the present trial and in the other large seronegative spondylarthropathy patient trial (0). Two of the smaller controlled trials had withdrawal rates of 240%, but reported no unusual or severe drug reactions (7,8). n summary, SSZ appears to be beneficial in the treatment of persistent, active PsA. The sustained salutary clinical effects are mild when compared with placebo in this study of patients with longstanding, chronically active inflammatory arthritis and psoriasis. The treating physician must weigh the marginal clinical benefit seen with SSZ in this group of patients with chronically active PsA against the risk of adverse effects, which were mainly mild gastrointestinal complaints. REFERENCES. Siniley JD: Psoriatic arthritis. Bull Rheum Dis 44:l-2, Willkens RF, Williams HJ, Ward JR, Egger MJ, Reading JC, Clements PJ, Cathcart ES, Samuelson CO Jr, Solsky MA. Kaplan SB, Guttadauria M, Halla JT, Weinstein A: Randomized, doubleblind, placebo-controlled trial of low-dose pulse methotrexate in psoriatic arthritis. Arthritis Rheum 27: Dorwart BB, Gall EP, Schumacher HR, Krauser R E Chrysotherapy in psoriatic arthritis: efficacy and toxicity compared to rheumatoid arthritis. Arthritis Rheum , Carette S, Calin A, McCafferty JP, Wallin BA, and the Auranofin Cooperating Group: A double-blind placebo-controlled study of auranofin in patients with psoriatic arthritis. Arthritis Rheum 32: Farr M, Kitas GD, Waterhouse L, Jubb R, Felix-Davies D, Bacon PA: Treatment of psoriatic arthritis with sulphasalazine: a one year open study. Clin Rheumatol 7: , Newman ED, Perruquet JL, Harrington TM: Sulfasalazine therapy in psoriatic arthritis: clinical and immunologic response. J Rheumatol 8: , Farr M, Kitas GD, Waterhouse L, Jubb R, Felix-Davies D, Bacon PA: Sulphasalazine in psoriatic arthritis: a double-blind placebocontrolled study. Br J Rheumatol 29: Fraser SM, Hopkins R: Hunter JA, Neuniann V, Capell HA, Bird HA: Sulphasalazine in the management of psoriatic arthritis. Br J Rheumatol 32: , Gupta AK, Grober JS, Hamilton TA, Ellis CN, Siege MT. Voorhees JJ, McCune WJ: Sulfasalazine therapy for psoriatic arthritis: a double blind, placebo controlled trial. J Rheumatol 22: , Dougados M, van der Linden S, Leirisalo-Rep0 M. Huitfeldt B, Juhlin R, Veys E, Zeidler H. Kvien Olivieri, Dijkmans B, Bertouch J, Brooks P. Edmonds J, Major G, Amor B, Calin A: Sulfasalazine in the treatment of spondylarthropathy: a randomized, multicenter, double-blind, placebo-controlled study. Arthritis Rheum 38:68-627, 995. Clegg DO, Reda DJ, Weisman MH, Blackburn WD, Cush JJ, Cannon GW. Mahowald ML, Schumacher HR Jr, Taylor T. Budiman-Mak E, Cohen MR. Vasey FB, Luggen ME, Mejias E, Silverman SL, Makkena R, Alepa FP; Buxbaum J, Haakenson CM, Ward RH. Manaster BJ, Anderson RJ, Ward JR, Henderson WG: Comparison of sulfasalazine and placebo in the treatment of ankylosing spondylitis: a Department of Veterans Affairs cooperative study. Arthritis Rheum 39: , Diggle P,. Liang K, Zeger S: Analysis of Longitudinal Data. Oxford, Clarendon Press, SAS nstitute, nc.: SAS Technical Report P-229, SAWTAT: Changes and Enhancements, Release Cary, NC, SAS nstitute nc., Hedeker D, Gibbons RD: A random-effects ordinal regression model for multilevel analysis. Biornetrics 50: , SAS nstitute, nc.: SAS/STAT User's Guide: Version 6. Fourth edition. Cary, NC. SAS nstitute, 990