Sulfasalazine vs. Placebo: Two-and-a-Half Cheers

ABSTRACT & COMMENTARY

Synopsis: The results of three multicenter, randomized controlled trials of sulfasalazine support its efficacy in reactive arthritis (Reiter’s syndrome) and in psoriatic arthritis. Post-hoc analysis suggests efficacy in treating non-spinal synovitis in a subgroup of patients with ankylosing spondylitis who have peripheral arthritis.

Source: Clegg DO, et al. Arthritis Rheum 1996;39:2004-2012; 2013-2020; 2021-2017.

Ankylosing spondylitis, psoriatic arthritis, and reactive arthritis are chronic, frequently disabling, disorders. Symptomatic treatment with non-steroidal anti-inflammatory drugs is often unsatisfactory, and active synovitis and enthesitis (inflammation at tendinous and ligamentous attachments to bone) may lead to joint or spinal deformities. Clegg and colleagues conducted three large, cooperative, multicenter trials of sulfasalazine in these disorders.

Ankylosing Spondylitis

Sulfasalazine (SSA) was compared to placebo in 264 patients with ankylosing spondylitis who were followed for 36 weeks. The patients were given a gradually increasing dose of SSA, beginning at 500 mg/d, with weekly increases of 500 mg/d, to a maximum dose of 2000 mg/d, or an equivalent number of placebo tablets. A large number of clinical and laboratory measurements were made at baseline and at intervals during the study. The primary outcome, improvement, was determined before the trial began and was defined as a combination of 30% or greater improvement in back pain or in the duration of morning back stiffness, and improvement by at least one category of either physician global or patient global assessments. If there was no worsening in any other of those four clinical measures, the patient was classified as improved on treatment. The treatment groups were comparable and nearly all male (95%), mostly white (86%), and HLA-B27 positive (81%). Of the 19 variables followed, only the change in erythrocyte sedimentation rate (ESR) was significantly different for the two groups. The SSA- treated group had a decline in ESR of 5.3 mm/hr, while the placebo group’s mean ESR declined 1.7 mm/hr (P = 0.01). The percent "responders" in the two groups were very similar, 38.2% for the SSA group vs. 36.1% for those receiving placebo (P = 0.73). A post-hoc analysis that compared subjects with both peripheral joint involvement and spondylitis, substituted joint pain/tenderness scores, and joint swelling scores was notable for improvement in the peripheral arthritis with SSA (55.9% improved) vs. placebo (30.2% improved; P = 0.023). One patient taking SSA developed a pruritic rash, and one had increased liver enzyme levels; otherwise, adverse drug reactions were mild. Dyspepsia, nausea, vomiting, and diarrhea were the most commonly reported side effects in those receiving SSA.

Psoriatic Arthritis

An accompanying article with a similar study design reports on 221 patients with psoriatic arthritis treated with SSA or placebo for 36 weeks. These patients were also predominantly male (77%), white (81%), but less often HLA-B27 positive (17%). Joint pain/tenderness scores and joint swelling took the place of back pain and morning back stiffness in the composite outcome assessment rule. Of 18 variables followed, the ESR was again the only one that demonstrated a significant change with a mean decline of 6.4 mm/hr for the SSA group vs. an increase of 1.1 mm/hr for the placebo group. Using the definition of improvement, there was a statistically significant difference in treatment response, with 57.8% of those receiving SSA vs. 44.6% of those receiving placebo demonstrating improvement at the end of the 36- week study (P = 0.05). Toxicity in this study was also uncommon, with gastrointestinal complaints and skin rashes being the most frequent reasons for withdrawal from the study.

Reactive Arthritis/Reiter’s Syndrome

The final report in the series concerned a disorder that may occur following gastrointestinal or genito-urinary infections and for which the prototype is Reiter’s syndrome of conjunctivitis, arthritis, and urethritis. Clegg and colleagues refer to these disorders by the term "reactive arthritis." One hundred thirty-four patients with reactive arthritis were recruited and were randomized to receive SSA or placebo. A gradually increasing dose was employed up to 2000 mg/d of SSA and continued up to 36 weeks. The study groups were again comparable and overwhelmingly male (90%), predominantly white (78%), and HLA-B27 positive (71%). The recruitment for the study was slower than hoped for, and it was closed before the target sample of 240 subjects was achieved. As a consequence, and despite favorable trends in physical global assessment, patient global assessment, joint pain/tenderness scores, and joint swelling scores, the 62.3% of subjects on SSA who improved vs. the 47.7% of patients on placebo who improved at the final visit of the study did not achieve a statistically significant difference when the last visit data are compared (P = 0.09). However, a longitudinal analysis of data at six time points yielded a P value of 0.02 for treatment response, a P value less than 0.001 for joint paint/tenderness score, and a P of 0.0001 for joint swelling score. The mean ESR was significantly lower at -12.5 mm/hr for the SSA group vs. -1.6 mm/hr for placebo (P < 0.01). No severe adverse drug reactions were noted.

COMMENT BY JERRY M. GREENE, MD

The message I get from these three studies is that SSA, while not particularly helpful for sacroileitis and spondylitis per se, does have modest efficacy for peripheral joint involvement in the seronegative spondyloarthropathies and in reactive arthritis. Most of those who responded favorably did so by the twelfth week of treatment. The adverse effects were mostly nuisance problems, and it is reassuring that only one adverse drug reaction was judged to be severe in the 309 subjects who received SSA.