, Volume 65, Issue 13, pp 1825-1849
Date: 17 Sep 2012

Sulfasalazine

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Summary

Abstract

Sulfasalazine (salazosulfapyridine) [Azulfidine®, Salazopyrin®] is a well established disease-modifying antirheumatic drug (DMARD) used in the treatment of patients with rheumatoid arthritis. Clinical trials with sulfasalazine have used an array of measures of disease activity, such as the number of tender and swollen joints, Ritchie articular index (RAI) and erythrocyte sedimentation rate (ESR). In randomised, double-blind, placebo-controlled trials, sulfasalazine was associated with statistically significant benefits for various measures of disease activity, according to results of individual trials and/or meta-analysis. Sulfasalazine was associated with broadly similar efficacy to that of various other DMARDs in several randomised, double-blind, comparative trials. Promising results have also been demonstrated with sulfasalazine in combination with other DMARDs (e.g. methotrexate and hydroxychloroquine) in patients with early rheumatoid arthritis and in those with more established disease. Sulfasalazine was generally well tolerated in clinical trials, the most frequently reported adverse effects being adverse gastrointestinal effects, headache, dizziness and rash; myelosuppression can also occur. Sulfasalazine has a relatively short lag time until its onset of action and is often considered to be among the more efficacious traditional DMARDs. Based on considerations of safety, convenience and cost, many rheumatologists (particularly outside of the US) select sulfasalazine as initial therapy, although preferred first-line treatment options vary between countries.

Pharmacological Properties

The precise mechanism of action of sulfasalazine has not been fully elucidated, nor is it clear whether the parent drug and/or its main metabolites (sulfapyridine and mesalazine [mesalamine; 5-aminosalicylic acid]) are principally responsible for its beneficial effects in rheumatoid arthritis.

Among the pharmacodynamic effects demonstrated with sulfasalazine, sulfapyridine and/or mesalazine at clinically relevant concentrations in vitro are the inhibition of cytokine release (interleukin [IL]-1, IL-2, IL-6, IL-12 and tumour necrosis factor-α) and IgM and IgG production. Studies in animal models of autoimmune disease also support an immunomodulatory action of sulfasalazine, and proinflammatory cytokines were suppressed at the same time as measures of disease activity improved in patients with rheumatoid arthritis who received sulfasalazine.

Following oral administration of sulfasalazine, approximately 10–30% of the parent drug is absorbed from the small intestine, although systemic absorption in healthy Japanese volunteers is <10%. Sulfasalazine that reaches the large intestine is cleaved by bacterial azoreductases, thus releasing sulfapyridine and mesalazine. Sulfapyridine is almost completely absorbed compared with about 20–30% absorption for mesalazine.

All three moieties — sulfasalazine, sulfapyridine and mesalazine — are extensively metabolised. After multiple-dose administration of enteric-coated sulfasalazine, the mean elimination half-life (t1/2) of sulfasalazine (6.1–17.0 hours) and sulfapyridine (8.0–21.0 hours) in European patients with rheumatoid arthritis ranged widely, depending on patient age and/or acetylator phenotype. In healthy Japanese volunteers, t1/2 of sulfasalazine (3.0 hours) was somewhat shorter.

Therapeutic Efficacy in Rheumatoid Arthritis

Patients with rheumatoid arthritis who were treated for 6 months with entericcoated sulfasalazine 2 g/day had statistically significant improvements in the number of swollen and tender joints, RAI and ESR compared with placebo in a randomised, double-blind trial. The beneficial effects of sulfasalazine were confirmed in a meta-analysis of several placebo-controlled trials. In Japan, a large, double-blind, dose-finding study in patients with rheumatoid arthritis showed that the optimal dose of sulfasalazine is 1 g/day in Japanese patients.

When compared with other DMARDs in head-to-head comparisons of up to 1 year in duration, sulfasalazine (usually 2 g/day) had broadly similar clinical efficacy to that of methotrexate, leflunomide, hydroxychloroquine, penicillamine and intramuscular gold. Measures of disease activity evaluated in these randomised, double-blind trials typically included RAI, grip strength, duration of morning stiffness, ESR, pain, and the number of tender and swollen joints. Importantly, sulfasalazine has also been shown to retard radiographic progression of rheumatoid arthritis.

Two randomised, double-blind trials showed no clear advantage of combination therapy with sulfasalazine plus methotrexate over monotherapy with either agent in patients with early rheumatoid arthritis (duration <2 years). However, in another well conducted trial in this patient population, early aggressive therapy with sulfasalazine, methotrexate and hydroxychloroquine plus low-dose prednisolone was associated with significantly greater remission rates than sulfasalazine with or without prednisolone. Combination regimens, such as sulfasalazine, methotrexate and hydroxychloroquine, have also shown promising results in patients with refractory or long-standing rheumatoid arthritis.

Tolerability

Adverse gastrointestinal effects (e.g. nausea, vomiting, dyspepsia, anorexia), CNS effects (e.g. headache and dizziness) and rash are the most frequently reported adverse events associated with sulfasalazine. The use of enteric-coated sulfasalazine tablets has largely replaced the standard formulation of sulfasalazine in clinical practice, as the enteric-coated formulation markedly reduces the severity and incidence of adverse gastrointestinal effects.

Other adverse events associated with sulfasalazine include haematological disturbances (such as leukopenia) which occur in ≤3% of patients; less frequently reported problems include blood dyscrasias, hypersensitivity reactions, dyspnoea and hepatic dysfunction. In addition, apparently reversible oligospermia (or related conditions) occurs in male patients. Approximately 20–30% of patients with rheumatoid arthritis who are treated with sulfasalazine discontinue therapy because of adverse effects, approximately two-thirds of which involve the gastrointestinal tract or CNS.

Various sections of the manuscript reviewed by: D. Aletaha, Division of Rheumatology, Department of Internal Medicine, University of Vienna, Vienna, Austria; B.A.C. Dijkmans, Department of Rheumatology, VU University Medical Center, Amsterdam, The Netherlands; S. Kawai, Division of Rheumatology, Toho University School of Medicine, Tokyo, Japan; T. Kennedy, Acute Medicine and Rheumatology, Royal Liverpool University Hospital, Liverpool, England; H. Yamanaka, Institute of Rheumatology, Tokyo Women’s Medical University, Tokyo, Japan.

Data Selection

Sources: Medical literature published in any language since 1980 on ‘sulfasalazine’, identified using MEDLINE and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.
Search strategy: MEDLINE search terms were ‘sulfasalazine’ or ‘sulphasalazine’ and ‘rheumatoid arthritis’. EMBASE search terms were ‘sulfasalazine’ or ‘sulphasalazine’ and ‘rheumatoid arthritis’. AdisBase search terms were ‘sulfasalazine’ or ‘sulphasalazine’ and ‘rheumatoid arthritis’. Searches were last updated 8 August 2005.
Selection: Studies in patients with rheumatoid arthritis who received sulfasalazine. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.
Index terms: Sulfasalazine, rheumatoid arthritis, pharmacodynamics, pharmacokinetics, therapeutic use.