Sulfasalazine in the rheumatic disease

Sulfasalazine

in the Rheumatic

Disease

By Robert S. Pinals

M

OST PHYSICIANS are familiar with sulfasalazine (SSZ) as an agent commonly used to treat inflammatory bowel disease for more than 40 years. In 1978, McConkey et al reported preliminary studies suggesting that this sulfonamide might be effective in rheumatoid arthritis (RA).’ The use of SSZ arose from earlier open and controlled trials with a sulfone, dapsone, which had demonstrable efficacy in RA, but the benefits were accompanied by relatively frequent, often unacceptable adverse effects.’ Dapsone was effective in dermatitis herpetiformis, presumably because of immunosuppressive activity. Another therapeutic agent for this skin disorder was sulfapyridine (SP), a drug with a poor record of gastric tolerance. Therefore, McConkey et al elected to try SSZ, a compound that released sulfapyridine in the bowel after passage through the stomach. Ironically, McConkey was initially unaware that SSZ had been synthesized specifically to treat RA in the late 1930s. In 1980, McConkey et al reported their open experience with SSZ in 74 patients treated for up to 1 year.3 The improvement in erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and clinical score (a global evaluation) was similar to that achieved with the disease-modifying antirheumatic drugs (DMARDs), and appeared somewhat sooner, often within 2 months. Moreover, although adverse effects were frequent, they were seldom of sufficient severity to discontinue treatment. This encouraging report led to several controlled trials in the United Kingdom and elsewhere, all confirming the efficacy of this interesting agent. The first study in the United States has been reported4 and, although SSZ has not been

From the Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, New Brunswick, NJ. Robert S. Pinals, MD: Professor of Medicine, Department of Medicine, UMDNJ-Robert Wood Johnson Medical School, and Chairman, Department of Medicine, The Medical Center at Princeton. Address reprint requests to Robert S. Pinals, MD, Department of Medicine, The Medical Center at Princeton Princeton, NJ 08549. 0 1988 by Grune & Stratton, Inc. 0049-0172/88/l 704-0011$5.00/0

246

Seminars

approved by the Food and Drug Administration for use in RA, many rheumatologists have used it as an alternative DMARD because of its availability and long record of safety and efficacy in inflammatory bowel disease. HISTORY

During the 1930s there was a widespread belief that RA might have a bacterial etiology. A careful search for occult infection in the sinuses, teeth, and gastrointestinal (GI) and genitourinary (GU) tracts frequently led to treatment aimed at eradicating these foci of infection by surgical procedures, or other maneuvers such as colonic irrigations, prostatic massage, or autologous vaccines. The development of the sulfonamides, the “wonder drugs” of that era, offered additional therapeutic options. Despite early enthusiasm, the most respected rheumatologists eventually concluded by the mid-1940s that the sulfonamides were probably not effective, based on experience with fairly large numbers of patients in short-term uncontrolled trials. Unfortunately, the dramatic results in treating gonococcal arthritis may have been used as a frame of reference, discouraging longer courses of theraPY. Professor Nanna Svartz, Chief of Rheumatology at the Karolinska Institute in Stockholm, had a particular interest in the sulfonamides and in the possibility of an infectious etiology of RA. Many years later she reported results of her studies on a group B streptococcus often found in milk. Svartz cultured the organism from various sites much more frequently in RA patients than in controls.5 In the late 193Os, sulfonamides were used empirically in virtually all bacterial infections. Since GI intolerance was a major problem with the early sulfonamides and was compounded by concomitant salicylate therapy, Svartz conceived the idea that linking the two drugs by a chemical bond might improve tolerance and allow a dual antiinflammatory and antibacterial attack on the inflammatory process. Chemists from Pharmacia, an Uppsala Sweden pharmaceutical company, were able to accomplish this linkage of SP and salicyclic acid with an azo-bond (Fig 1). This compound, called

in Arthritis

and Rheumatism,

Vol 17. No 4 (May),

1988:

pp 246-259

SULFASALAZINE

IN THE RHEUMATIC

‘N=N’

DISEASE

247

-

Am-reductive cleavage by colonic bacteria

COOH OH

bedrest and physical therapy. Comparisons were made between those treated with SSZ, gold, and salicylates alone, but some patients were not evaluated until weeks after completion of treatment. No significant differences were found between treatment with SSZ and salicylates alone. Cortisone arrived on the therapeutic scene shortly after this report and SSZ was soon discarded as an antirheumatic drug, although it grew in popularity for maintenance therapy of inflammatory bowel disease. During the 30 years before it resurfaced as an antirheumatic drug, SSZ remained on the formularies in several countries in Scandinavia and central Europe and there were a few reports of clinical experience confirming its earlier success.

H, N’ ‘NH, 5-ASA

SP Fig 1.

Structure

of SSZ and its major metabolites.

salazopyrin in most of Europe, sulphasalazine in the United Kingdom, and sulfasalazine in the United States, was administered to over 400 RA patients between 1940 and 1946, with favorable responses in 63%~~ Others also reported good results, including one study from the United States.’ However, a negative report from the influential Edinburgh group dampened interest in SSZ as an antirheumatic agent.* In this study, RA patients were hospitalized and received

Fig 2. Metabolism and pharmacokinetics of SSZ and its major cleavage products, sulfapyridine BP) and 5-aminosalicyiic acid (5-ASA).

PHARMACOLOGY

The pharmacokinetics of SSZ are rather complex’ (Fig 2). After ingestion, SSZ can be detected in the serum within six hours. Daily dosing results in a steady state serum level after four or five days. Approximately 30% is absorbed by the small bowel, most of which returns via the enterohepatic circulation and biliary excretion. Only a small fraction appears in the urine. When SSZ reaches the colon, bacterial enzymes cleave the azo-bond (Fig l), yielding the two major metabolites, 5-aminosalicylic acid (5-ASA) and SP. Most of the 5-ASA is excreted unchanged in

240

ROBERT S. PINALS

the feces. Less than one third is absorbed from the colon, appearing later in the urine as an acetylated metabolite. Serum salicylate levels are inevitably low, even with full therapeutic doses of SSZ, due to poor colonic absorption. Absorption of SP is more efficient, with about two thirds excreted in the urine, particularly as acetylates or glucuronides. The feces contain SP equivalent to only 7% of the ingested dose. As with other drugs, the rate of hepatic acetylation of SP is genetically determined and, in part, determines the serum levels. Thus, slow acetylators will tend to show higher peak levels and a prolonged duration of detection after single doses. Potentially this might have an impact on drug toxicity or efficacy. An additional factor that might determine idiosyncratic toxic reactions to sulfonamides may also be under genetic control. Cytotoxic metabolites are generated by the action of cytochrome P-450 oxidases and are detoxified in part by compounds with free sulfhydry1 groups, such as glutathione.” Since serum sulfhydryl levels are low in RA” in relationship to disease activity, an increase in toxic reactions might be explainable by this mechanism.

CLINICAL TRIALS IN RA

After the resurrection of SSZ by McConkey et al in 1980, a number of controlled investigations were initiated to confirm and extend these findings. Bird et al evaluated SSZ in a test system in which various antirheumatic drugs had been studied previously. A correlation matrix of 26 clinical and biochemical measurements was constructed for RA patients receiving SSZ and the Table 1. Randomized

pattern of improvement resembled that observed with gold and D-penicillamine. Significant reduction of the ESR and CRP occurred after 8 weeks, more rapid than with other DMARDs.‘* The randomized, controlled trials of SSZ in RA are summarized in Table 1. A combined LeedsBirmingham 4-month study compared D-penicillamine and SSZ, using a single clinical examiner who was not informed about the treatment group assignment.r3 Doses of each drug were raised progressively to a maximum for D-penicillamine of 500 mg and for SSZ of 2 g. Significant improvement occurred in both groups from baseline status to completion, with a somewhat more rapid response on SSZ. There were small differences between the two groups favoring SSZ, which produced greater improvement in articular index and grip strength. Another similar study from Australia using identical doses of SSZ and D-penicillamine also reached the conclusion that the two drugs had comparable efficacy.14 Certainly, in view of the small number of patients studied, the possibility of missing a true difference (type II error) cannot be eliminated. In addition, the dose of D-penicillamine and duration of the studies may have been insufficient to demonstrate an optimal effect. Finally, the “blind observer” technique does not eliminate the possibility of bias as well as conventional double-blinding. A 6-month randomized comparison of SSZ with injectable gold and placebo was reported by Pullar et al.” The “blind observer” assessment method was employed, but only patients assigned to the gold group received intramuscular injections. There was a significant improvement from Studies of SSZ in RA

Duration TVpe

b&l

Patients*

Comparison

Groups

Candusians

Blind observer

16

63

SSZ 2 g/d. o-pen 500 mgfd

Equal improvement with both ctuga

Carroll et al”

Single-blind

16

60

SSZ 2 g/d. o-pen 500 mg/d

Equal improvement with both drugs

Pullar et all6

Blind observer

24

so

SSZ 3 g/d, Goldt 50 mg/wk, placebo

Equal improvement with SSZ and

Neumann

et al”

gold; none with placebo, but difference* between soups insignificant Pinals et al’

Double-blind

15

86

Williams”

Double-blind

37

187

SSZ 3 g/d, placebo

SSZ significantly superior to placebo

SSZ 2 g/d, Goldt 60 mg/wk, placebo

Equal improvement with both drugs, but neither superior to placebo due to aberrant response

Abbreviation: D-pen, l

o-penicillamine.

Number in all groups on entry.

TGold sodium thiomalate.

249

baseline in clinical and laboratory indicators of disease activity with both drugs. There was no change in the placebo group, and 16 of the 30 patients on placebo failed to complete the study, mainly for lack of efficacy. In the SSZ and gold groups, 12 of 30 patients dropped out, mainly for adverse reactions. Because the number of patients completing the trial was considerably reduced by dropouts, it was not possible to demonstrate significant differences between the treatment groups. In this study, the benefits of SSZ and gold were indistinguishable, but definite conclusions were limited by the small numbers of patients at completion and the lack of a double-blind design. A 37-week multicenter double-blind study of 187 RA patients was recently reported by the Cooperative Systematic Studies of Rheumatic Diseases Program using the same three treatment groups.16 Placebo injections were given to patients in the groups not receiving gold. The placebo group had an aberrant response and neither active drug could be shown to be superior except for improvement in ESR. Response to gold sodium thiomalate was similar to that found in previous studies by this group. However, SSZ performed as well as gold for all individual variables, and “important improvement” was significantly more frequent with SSZ. There was greater toxicity in the gold group, resulting in withdrawal of 37 of 67 patients. The conclusion was that SSZ had similar efficacy to gold, but less toxicity. This well-designed study with large patient groups was marred only by a surprising and unexplainable placebo response. Superiority of SSZ to placebo was demonstrated in a study in three centers in the United States! The duration was 15 weeks, with a maximum maintenance dose of 3 g daily. Improvement with SSZ was significantly better than with placebo in joint tenderness and swelling, morning stiffness, grip strength, and pain score. This occurred, despite a substantial placebo response, within 2 months after full maintenance doses were reached, confirming previous claims that improvement started earlier with SSZ than with gold and D-penicillamine.‘2~‘5 Long-term open experience with SSZ has shown that the phenomenon of secondary therapeutic failure occurs in a frequency and pattern comparable with other DMARDs. The Birming-

ham group has reported on their attempts to continue treatment indefinitely with either gold, D-penicillamine, dapsone, or SSZ in 240 RA patients.17 Adverse reactions and therapeutic failure, both primary and secondary, resulted in discontinuation in 76% of patients receiving gold and approximately half of patients taking the other drugs after 1 year. Dapsone had the highest withdrawal rate for inefficacy, and gold for adverse reactions. After 2 years, there were few patients remaining in any treatment group, but SSZ and D-pCIIiCibninC had a slight advantage. These investigators updated their experience in a recent report using life-table methods.‘* Risks of treatment termination for all reasons were similar for gold, penicillamine, and SSZ at 5 years. However, gold had some advantage over the other agents in withdrawal for inefficacy. Adverse effects led to withdrawal of gold in 57%, penicillamine in 41%, and SSZ in 37% Serious side effects were less frequent for SSZ compared with the other drugs. Bax and Amos compared RA patients assigned in a nonrandom fashion to receive either gold or SSZ, with follow-up periods up to 42 months.” A “highly satisfactory long-term response” was found in 32% on SSZ and 44% on gold, but adverse reactions were more prominent with the latter. Clinical remission, fulfilling the American Rheumatism Association (ARA) criteria2’ occurred in 25% of patients started on SSZ and 33% of those receiving gold. Little information is available on the influence of SSZ on extra-articular manifestations of RA. In a recent report, regression of rheumatoid nodules was described in four patients after prolonged SSZ treatment.21 A significant decrease in rheumatoid factor titer was found during a 6-month open study of 34 patients from France.22 In another 6-month open trial, RoseWaaler titer improved insignificantly.23 Perhaps the most convincing evidence of disease modifying activity is a reduction in the rate of development of radiographically determined erosions. Generally, a randomized control group must be maintained for a year or more to demonstrate an impact on radiographic change. Such studies have not been performed, but Pullar et al recently reported that SSZ produced a slowing of deterioration in the small joints of the hands

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during the second year of therapy in the minority of patients who continued to take the drug. This effect was independent of improvement in inflammatory indicatorsz4 In his initial open use of SSZ, McConkey tried various doses and schedules. Finding that RA patients had a high frequency of upper GI side effects, he used enteric-coated tablets with a schedule of gradual dose increments up to a final daily maintenance dose of 2 g. Higher doses occasionally seemed to be more effective, but in general had a reduced benefit-morbidity ratio. Controlled comparisons of different doses of SSZ have not yet been reported, and there is only limited information on the dose-response relationship in RA. Some controlled trials have used a 2 g maintenance dose, and others 3 g (Table 1). Comparing groups from separate studies is difficult, but the results with the higher dose do not appear to be superior. Martin et al measured serum concentrations of SSZ in a group of 3 1 RA patients treated openly for 12 weeks with 2 to 3 g daily. ” The serum concentrations did not differ in patients who responded, failed to respond, or were withdrawn for adverse effects of SSZ. Thus, it would appear that in the range of 2 to 3 g daily, efficacy of SSZ is similar. McConkey’s experience would suggest that 1 g daily is ineffective and 1.5 g will only occasionally be sufficient. Since acetylation is an important mechanism in the disposition of both SSZ and its major metabolites, one might expect to find greater efficacy and toxicity in patients who are slow acetylators. Indeed, this was suggested in preliminary work by Pullar et al.” However, further studies by the same investigators on a group of patients treated openly with 3 g/d showed no correlation between acetylator phenotype and therapeutic response, although there was a relationship between slow acetylation and GI side effects.26 More recently, Bax et a123failed to find a significant correlation between efficacy and acetylator phenotype among 79 patients, selected from a larger group because their response status could be clearly categorized. An effort has been made to identify other host prior factors (sex, age, disease duration, DMARD therapy) which might influence clinical response, but none have been clearly demonstrated.27*28Seropositivity does not appear to cor-

ROBERT S. PINALS

relate with response, and relationship to HLA haplotypes has not yet been reported. MECHANISM

OF ACTION

In ulcerative colitis, the active moiety is believed to be the salicylate, 5-ASA, which is cleaved from the parent molecule by colonic bacterial enzymes. Since blood levels are minimal, it probably acts locally in the colon as an inhibitor of inflammatory mediators.29 In addition, the effect of SSZ in ulcerative colitis can be duplicated by both an oral azo-conjugate preparation of 5-ASA and by 5-ASA enemas3’ SP may simply play a passive role as carrier for 5-ASA to its local site of action. The mechanism of action in RA is almost certainly different, but remains unclear at this time. To determine the active moiety of SSZ, Pullar et al studied two groups of RA patients in an open, randomized trial comparing SP and 5-ASA.3’ The sulfonamide gave results comparable to those previously noted with SSZ, while the salicylate was ineffective. Neumann et al came to the same conclusion in a similar study.32 Thus, the “antirheumatic” effect may be due either to SSZ, SP, or both. There are few clues to the actual mechanism of disease suppression. First, there may be true antiinflammatory activity. SSZ has been found to inhibit both the thromboxane synthetase and lipoxygenase pathways in vitro using human platelet and leukocyte systems.33*34Related antiinflammatory effects include inhibition of leukocyte motility35 and proteolytic enzyme activity.36 The inhibition of IgE-mediated mast cell degranulation by SSZ3’ is another potential mechanism, since increased numbers of these cells have been found in rheumatoid synovium. The clinical pattern of response to SSZ suggests that antiinflammatory activity probably plays no more than a supporting role. There is some evidence for immunomodulatory actions but studies of immune function in RA patients treated with SSZ are limited. In a group of 11 RA patients, an initially depressed lymphocyte mitogen response to Con A improved in those patients who improved clinically.38 Abnormal lymphocyte function occurs in ulcerative colitis and may be reversed during SSZ treatment,39 but this does not necessarily indicate a direct effect of the drug. In another study of patients

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IN THE RHEUMATIC DISEASE

with inflammatory bowel disease, SSZ and its metabolites could not be shown to alter lymphocyte subpopulations, antibody-dependent cellular cytotoxicity, and delayed skin test reactiviComer and Jasin4’ reported in ty.40 Recently, vitro studies showing that rheumatoid factor synthesis and mitogen-induced lymphocyte proliferation were inhibited by SSZ, but not by SP or 5-ASA. Symmons et al found an improvement in mitogenesis with SSZ and SP in vitro in concentrations achieved therapeutically in plasma.38 Conversely, both SSZ and SP inhibit NK cell activity in vitro, but at concentrations higher than those achieved in plasma during therapy.42 SSZ produces some alteration of bowel flora, although this is relatively modest in comparison with other antibiotics.43q44 Svartz had originally proposed a bacterial etiology for RA, leading to the development of SSZ. Her successors at the Karolinska Institute pursued studies along a similar line, providing evidence that a bowel flora enriched with Clostridium perfringens might play an etiologic ro1e.45 An interesting animal model was discovered serendipidously in pigs, who developed inflammatory arthritis following a change in their diet. This was also accompanied by an altered intestinal flora rich in clostridia.46 Bowel flora change in relationship to the etiology of RA is a highly speculative area, which has not been pursued by investigators in recent years. However, recent evidence of cross-reactivity between HLA-B27 and enteric bacteria, particularly Klebsiella, in patients with ankylosing spondylitis47 may lead to reconsideration of the possible importance of bowel flora in RA. Finally, the impairment of folate absorption and metabolism produced by SSZ48q49 suggests the possibility that its mode of action might resemble that of methotrexate. SSZ inhibits jejunal hydrolysis of pteroylpolyglutamates and thus the absorption of most dietary folates. In addition, it competitively inhibits three enzymes involved in the metabolism of folic acid. A study of ulcerative colitis patients showed no significant difference in serum folate levels with or without SSZ therapy, but red blood cell (RBC) folate concentration was diminished in patients taking SSZ in doses >2 g daily.” In RA patients, Grindulis and McConkey found modest elevations of RBC mean corpuscular volumes, unrelated to the presence of anemia. However, serum

..-* Table 2. Adverse Resct~onsAttributed to SSZ Gastrointestinal Nausea Vomiting Anorexia Abdominal discomfort Flatulence Heartburn Dysgeusia Diarrhea CNS Irritability Dizziness Headache Depression Insomnia Confusion Hepatotoxic Transient liver function test abnormality Toxic hepatitis Systemic Fever Excessive sweating Malaise Fatigue Palpitations and tachycardia Mucocutaneous Nonspecific drug rash Urticaria Toxic epidermal necrolysis Stevens-Johnson syndrome Exfoliative dermatitis Buccal ulcerations Hair loss Pulmonary Allergic interstitial pneumonitis Fibrosing alveolitis Bronchospasm Hematologic Neutropenia Transient leukopenia Aplastic anemia Thrombocytopenia Megaloblastic anemia Hemolytic anemia Methemoglobinemia Autoimmune “Lupus-like” reactions Hypoglobulinemia Raynaud’s phenomenon Male infertility

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and RBC folate levels did not decrease,5’ suggesting that impairment of folate metabolism is not a significant mode of action of SSZ. This was supported by a recent report in which folate absorption was measured before and after 6 and 12 months of SSZ therapy in RA patients; no change in absorption or in serum or RBC folate levels was noted.52 ADVERSE REACTIONS

Because of its long use in the treatment of inflammatory bowel disease, a great deal of information is available on the toxicity of SSZ (Table 2). Side effects are frequent, but seldom serious or life threatening, generally occurring during the first 2 or 3 months of treatment. In a series of 704 patients with inflammatory bowel disease, most of whom received SSZ 3 g daily, the drug was discontinued in 30% for adverse reactions, mostly G1.53 However, when entericcoated SSZ was substituted for the uncoated tablet, dyspepsia did not recur in more than 80%. Among the 49 patients with extraintestinal reactions, over two thirds had mild rashes, 16 had fever, and two had cytopenias. In short-term RA trials described previously, the withdrawal rate for adverse reactions has been 17% to ~(y&4J3,‘5.16,25 with upper GI symptoms predominating, except in the study of William? in which rash was the most frequent reaction leading to withdrawal. In 774 patients monitored for periods up to 11 years while receiving SSZ for RA in the United Kingdom, treatment was discontinued for toxicity in about a quarter (Table 3).54 About three quarters of these withdrawals occurred within the first 3 months. Most of the Table 3. Adverse Drug Reactions Leading to Withdrawal of SSZ in Patients With Chronic Inflammatory Arthritis % Withdrawn Amos et aIkl = 774) GI/CNSt

19.0

Farr st aI” (n -

200).

12.0

Mucocutaneous

4.6

4.0

Neutropenia

1.0

1.5

Thrombccytopenia

0

1.0

Megaloblastic anemia

0.1

0.5

Hepatotoxicity

0.3

1.5

*Includes 166 RA patients and 34 with other inflammatory arthropathies. tThese categories are combined because patients with CNS aide effects usually have GI symptoms.

adverse events were quickly reversible and there were no deaths or permanent sequelae. In another study of adverse reactions among 200 patients with chronic inflammatory arthritis who had received SSZ for at least 1 year, Farr et al” found that 21.5% required withdrawal from treatment. All reactions resolved after discontinuation of SSZ, but they were judged to be potentially serious in ten patients (5%). The adverse effects can be divided into two major categories. The first is dose-related and may be associated with acetylator phenotype.25v26 This group includes common problems, such as nausea, vomiting, headache, malaise and, perhaps, rare occurrences such as hemolytic anemia and methemoglobinemia. The second group are idiosyncratic or hypersensitivity reactions such as rash, which is fairly common, and rare events including toxic hepatitis, pneumonitis, aplastic anemia, and agranulocytosis. GI and Hepatic Reactions

Nausea, vomiting, anorexia, dyspepsia, and abdominal pain have been the most common complaints, accounting for two thirds of treatment discontinuations. The use of enteric-coated tablets may reduce the frequency considerably,53 suggesting that gastric irritation is an important mechanism for these symptoms. However, despite use of enteric-coated tablets, upper GI symptoms accounted for the majority of patient withdrawals in RA trials. This would suggest a central mechanism for nausea and vomiting, and this is supported by the frequent association with CNS symptoms. Nausea generally disappears within a day or two after discontinuation of SSZ and may also respond to dose reduction and antiemetics. Diarrhea is much less frequent and seldom severe. Transient mild liver enzyme abnormalities are noted occasionally (<5%), without accompanying symptoms. In these cases, treatment may usually be continued. Two RA patients developing markedly raised alkaline phosphatase and aspartate transaminase levels were reported, with resolution after SSZ was discontinued.57 A patient with an RA-polymyositis overlap syndrome had cholestatic jaundice and fatal agranulocytosis.” More examples of serious toxic or allergic hepatitis have been observed in patients receiving SSZ for inflammatory bowel disease.5ga

SULFASALAZINE

IN THE RHEUMATIC

DISEASE

Most patients have fever, rash, lymphadenopathy, hepatomegaly, and marked elevation of hepatic enzymes and hyperbilirubinemia. Eosinophilia has been reported in several cases. Liver biopsy may show hepatocellular necrosis similar to viral hepatitis, cholestasis, or granulomatous hepatitis. These serious hepatotoxic reactions are recognized as rare occurrences with various sulfonamides, generally appearing during the initial weeks of therapy. Undoubtedly, more such cases will be found in the RA population with increasing use of SSZ. It is important to obtain liver function tests promptly on all patients developing rash or fever during SSZ therapy. Mucocutaneous

Reactions

Rash and other cutaneous reactions account for approximately 15% of withdrawals for toxicity during long-term treatment. Most are nonspecific maculopapular rashes that occur soon after onset of treatment and improve quickly following cessation. However, serious reactions may be seen rarely with SSZ and other sulfonamides, including toxic epidermal necrolysis,67 Stevens-Johnson syndrome,68 and exfoliative dermatitis.69 The latter two reactions may be accompanied by hepatic injury. These rare and potentially fatal reactions have apparently not yet been seen in RA patients. Rechallenge should not be attempted in these serious hypersensitivity reactions, but desensitization has been accomplished successfully with nonspecific rashes.59970.7’ Buccal ulceration from SSZ is rare in comparison with gold and D-penicillamine. Hair loss has been noted in three patients treated for inflammatory bowel disease.57 Hematologic Reactions

Blood dyscrasias have been a concern with the sulfonamides ever since their introduction 50 years ago. SSZ has a better safety record than most other sulfonamides in this regard, but over the years it has produced a wide spectrum of adverse effects on the peripheral blood and bone marrow.30V59*72 These include agranulocytosis, leukopenia, aplastic anemia, thrombocytopenia, hemolytic anemia, megaloblastic anemia, methemoglobinemia, and sulfhemoglobinemia. The frequency of these reactions is difficult to ascertain because data on the number of patients treated are generally lacking. In an ongoing

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adverse drug reaction monitoring program using patients in the Group Health Cooperative of Puget Sound, SSZ was prescribed for 875 patients. Four (0.5%) developed granulocytopenia and there were no other major blood dyscrasias.73 All of the patients recovered, and the relationship of the drug to the leukopenia was classified as probable because some of the patients were receiving other medications and there was no attempt to rechallenge with SSZ. In Nielsen’s retrospective survey of 704 patients treated with SSZ for inflammatory bowel disease, two (0.3%) developed blood dyscrasias.53 The mechanism of agranulocytosis is unclear, but bone marrow hypoplasia had been shown in some cases and infiltration of the bone marrow with plasma cells has been reported in two patients with SSZ-induced agranulocytosis.72*74 At least six fatalities due to agranulocytosis have occurred over the many years of its use.58,59Farr et al reported two cases of agranulocytosis requiring discontinuation of SSZ therapy among 180 patients with RA and seronegative spondyloarthropathy.75 Both occurred early during the course of treatment and responded promptly to discontinuation of SSZ. In the long-term toxicity study54 from three centers in the United Kingdom, eight of 774 patients (1%) were withdrawn for leukopenia. A higher incidence was reported in Glasgow,76 where seven of 158 (4%) RA patients were withdrawn for leukopenia. There was no relationship to acetylator phenotype and all patients recovered. Whether SSZ-induced agranulocytosis is more common with RA than with inflammatory bowel disease is uncertain at present. The apparent higher frequency might be due to differences in data collection and patient monitoring. Marked leukopenia developed in three RA patients who had experienced a similar reaction to gold.77 These patients had been treated with SSZ for 1 to 3 weeks and recovered within a similar interval with discontinuation of the drug. A mild to moderate leukopenia without extreme reduction in the absolute granulocyte count may also develop during SSZ therapy, similar to that observed during treatment with gold. Continuation of treatment has been possible in some of these patients after temporary withdrawal and dose reduction.75 Although less common than leukopenia, isolated RBC and platelet aplasia

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have also been reported.78-80 Pancytopenia with megaloblastic changes in the marrow occurred in three patients with inflammatory bowel disease treated with SSZ in doses of 3 to 4 g/d.*’ Acetylator status was determined in two patients and both were found to be slow acetylators. All had a good response to folate therapy. Hemolytic anemia may occur both with and without Heinz bodies. 59There is some evidence that it may be dose related and associated with high serum concentrations of SP. Some patients are genetically predisposed, with underlying problems such as glucose-6-phosphate dehydrogenase deficiency. Methemoglobinemia and sulfhemoglobinemia are rarely recognized even in inflammatory bowel disease patients and have not yet been reported in RA treated with SSZ. Macrocytic anemia has been reported in RA patients, usually after several months of treatment with SSZ.** The highest incidence (14%) was found by Prouse et al**; all of their patients had low serum folate levels and responded to temporary cessation of SSZ and treatment with folic acid. In a long-term toxicity study, only one of 774 patients discontinued SSZ because of megaloblastic anemia, although five others were able to continue therapy with folate supplements.54 Pulmonary Reactions

An allergic interstitial pneumonitis with eosinophilia has been described in five cases.83’84 Patients present with cough, dyspnea, and fever. The prognosis after discontinuation of SSZ has been good, with recovery and radiographic resolution with a few weeks. Other pulmonary reactions include a fatal case of subacute fibrosing alveolitis,85 and tracheolaryngitis with bronchospasm. 86Dyspnea attributed to SSZ occurred in two of 774 patients in the UK long-term toxicity study.54 CNS Reactions Symptoms of CNS dysfunction attributed to SSZ include depression, irritability, headache, and dizziness. The frequency of these complaints is t5%, with occurrence generally early during therapy. Nausea, vomiting, fever, and rash may be present concomitantly. Occasionally, neurologic symptoms are sufficiently severe and persis-

ROBERT S. PINALS

tent to result in withdrawal, but often respond to dose reduction. Autoimmune Reactions

Sulfonamides are usually included in the list of drugs capable of inducing systemic lupus erythematosus (SLE). Several patients with inflammatory bowel disease have developed clinical and serologic evidence of SLE while receiving SSZ.87-89In another patient, Raynaud’s phenomenom was attributed to SSZ.90 The SSZ-induced lupus syndrome is reversible on discontinuation of the drug, but may recur with rechallenge. RA patients with positive antinuclear antibody tests are not more susceptible to adverse reactions from SSZ.55 As with other DMARDs, hypoglobulinemia has rarely been attributed to ssz.55 Male Infertility

An effect on sperm counts, motility and morphology was recognized during the last decade.91-93These abnormalities may develop within 2 months and result in infertility, but are reversible within several weeks after SSZ withdrawal or substitution of 5-ASA. The mechanism is unclear, but antifolate and antiprostaglandin activity have both been suggested. This problem has not yet been studied in RA patients, but must certainly be brought to the attention of male patients before SSZ therapy is initiated. The phenomenon does not appear to be associated with teratogenesis. PRACTICAL POINTS IN TREATMENT OF RA

As with other agents used in the treatment of RA before FDA approval for this indication, SSZ has been given mainly to patients refractory to other DMARDs. However, because of its convenience, relative safety, and fairly rapid onset of action, SSZ may eventually be an appropriate choice for early and mild cases of RA, before the use of gold, D-penicillamine, or methotrexate. Within a few weeks, there is generally some indication of tolerance and efficacy. The antimalarials that have traditionally occupied this position among the DMARDs have not yet been compared directly with SSZ, but probably have a slower onset of response. Antimalarials have often been favored in patients who have

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DISEASE

nondeforming polyarthritis with a positive antinuclear antibody test, since they are appropriate for use in SLE as well as RA. This particular subset has not received sufficient scrutiny to recommend SSZ, and should certainly be approached with caution in view of the rare but recognized potential for SLE induction. A trial period of 4 months is probably sufficient before discarding SSZ as ineffective. To minimize gastrointestinal side effects enteric-coated tablets (500 mg) should be used, starting with one or two tablets for the first week. The dose is raised by 500 mg each week, administered twice daily, up to a maintenance dose of 2 g. The usual NSAIDs may be continued. Upper GI symptoms are managed empirically with dose reduction or temporary discontinuation according to severity. Antiemetics and antacids may be tried, but their benefit is limited. If doses of at least 1.5 g/d cannot be maintained, SSZ is unlikely to be effective. Some patients have suboptimal benefit on 2 g/d and may reasonably be treated with larger doses up to 3 g/d. After a response occurs, the dose can be lowered, but improvement is generally not maintained below 1.5 g/d. When responsive patients are withdrawn abruptly, relapse usually occurs within days or weeks. In general, the exacerbation may be brought under control with resumption of therapy within a shorter period than required for the initial response. Laboratory studies should be performed routinely to monitor for adverse effects, but there is no unanimity about the appropriate intervals. Many gastroenterologists order studies infrequently, or only in response to clinical indications. I obtain a complete blood count (CBC), chemical profile, and urinalysis before treatment, and repeat the CBC every 3 weeks for the first 3 months and every 6 weeks thereafter. The chemical profile may be repeated with half the frequency of CBC, unless there is some clinical indication of an abnormality. A urinalysis every 4 to 6 months is sufficient and may not even be necessary since renal dysfunction has not been attributed to SSZ. However, most patients are receiving other drugs that might affect renal function. More frequent or additional laboratory studies are indicated if adverse reactions occur, particularly fever or rash, which may be asso-

ciated with hepatic dysfunction or blood dyscrasia. Little information is available on therapeutic combinations of SSZ with other DMARDs. In an open trial, Taggart et al treated patients at random with either SSZ alone or in combination with D-penicillamine. Both improvement and toxicity appeared to be greater with the combination.g4 Until appropriate controlled studies are performed, combinations of SSZ and DMARDs or cytotoxic drugs should be avoided. USE IN OTHER RHEUMATIC DISORDERS

Ankylosing Spondylitis Experience with ankylosing spondylitis (AS) has been limited, but two double-blind trials have been performed, both showing clinical improvement and minimal toxicity. Feltelius and Hallgren treated 37 patients at random with SSZ or placebo for 3 months and showed significant improvement in subjective stiffness, determined by a visual analogue scale, and chest Other variables including pain, expansion.g’ Schober index, and ESR showed improvement, but fell short of significance. A controlled trial was also reported from France in which 60 AS patients were randomized to receive either SSZ 2 g daily for 6 months or placebo.g6 Global evaluation and functional index showed significantly greater improvement on SSZ, and NSAID requirement was reduced significantly. Change in the Schober test and chest expansion was similar in both groups. Longer controlled trials will be necessary to study the effect of SSZ on radiographic progression. Seronegative Spondyloarthropathy Belgian investigators have reported uncontrolled studies on HLA-B27 positive patients with peripheral arthritis not responding to standard NSAID therapy.““’ Some of these patients had sacroiliitis and many had clinically apparent or asymptomatic ileocolitis, with histology of a nonspecific nature, not typical of Crohn’s disease or ulcerative colitis. In a recent update,” 48 patients had been treated with SSZ in doses of 2 to 4 g/d, depending on body weight, for periods of 3 to 24 months. Marked improvement occurred in 22 patients and only five had no

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response at all. These findings were confirmed by a recent report from Denver, in which 16 similar patients were found to have occult ileocolitis. In four patients refractory to NSAIDs, both arthritis and enteropathy responded to SSZ.‘@’ Peripheral Arthritis Bowel Disease

of Inflammatory

CONCLUSIONS

In both ulcerative colitis and Crohn’s disease an intermittent, oligoarticular arthritis occurs in 12% to 20% of patients, usually in relationship to the activity of the bowel disorder.“’ SSZ has been used for more than 40 years both for acute episodes and as maintenance therapy; evidence for its efficacy in suppressing bowel inflammation has been reviewed recently.“’ Apparently, no attempt has been made to evaluate the direct effect of SSZ on arthritis. This would be difficult without a controlled trial because (1) the arthritis may improve spontaneously; (2) concomitant treatment with corticosteroids is frequent; and (3) the contribution of suppression of bowel disease by SSZ to the activity of the arthritis cannot be assessed. Juvenile RA

In an open study performed in Turkey,lo3 18 patients with pauciarticular, polyarticular, or systemic juvenile arthritis were treated with SSZ for durations of 4 to 14 months. Significant improvement was observed and only three patients were withdrawn, two for inefficacy and one for mild leukopenia. Additional studies are now in progress in other centers. Generalized

Morphea

unconvincing with the possible exception of a rare scleroderma variant, generalized morphea.104*‘0’ The responses were fairly dramatic in a small number of patients. Certainly a trial of SSZ may be justified in this condition, for which alternative therapy is limited.

and Scleroderma

Several reports have suggested a possible beneficial effect of SSZ on scleroderma, but are

The rediscovery of SSZ as an antirheumatic agent raises many currently unanswerable questions. Its mode of action is obscure, but if it is related to antibacterial activity, important insights into the pathogenesis of RA may be forthcoming. Convincing evidence has been presented documenting its efficacy in suppressing rheumatoid inflammation to a degree comparable with standard DMARDs. However, its impact on the underlying immune process, systemic manifestations, and progressive joint erosion is still uncertain. Adverse reactions are frequent and may result in discontinuation of therapy in about one quarter of patients, but with few exceptions they are readily reversible, not life threatening, and tend to occur largely during the initial 2 or 3 months of treatment. However, serious reactions may occur, including blood dyscrasias and hepatitis. Although its metabolism is related to acetylator status, the evidence from clinical studies does not suggest that slow or rapid acetylators show significant differences in response or toxicity. The active moiety appears to be either SSZ itself or SP. Use of the latter metabolite results in similar clinical effects and toxicity. The spectrum of rheumatic diseases in which SSZ may be a useful therapeutic agent has not yet been defined, but there is evidence for efficacy in AS, reactive arthritis, and possibly juvenile RA.

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IN THE RHEUMATIC

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