Drugs

, Volume 65, Issue 13, pp 1825–1849

Sulfasalazine

A Review of its Use in the Management of Rheumatoid Arthritis

Authors

    • Adis International Limited
  • Katherine F. Croom
    • Adis International Limited
Adis Drug Evaluation

DOI: 10.2165/00003495-200565130-00008

Cite this article as:
Plosker, G.L. & Croom, K.F. Drugs (2005) 65: 1825. doi:10.2165/00003495-200565130-00008

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.

1. Introduction

Rheumatoid arthritis is an autoimmune disease of unknown aetiology that affects about 1% of the adult population, with a female to male ratio of approximately 2.5 to 1.[1,2] It is a chronic, progressive inflammatory disease in which pain, stiffness and swelling of joints are the predominant symptoms. However, the range of presentations of rheumatoid arthritis and the clinical course of the disease are highly variable. Some individuals have mild, self-limiting arthritis, whereas others may develop rapidly progressive multisystem inflammation with a marked effect on morbidity and mortality. In most patients, however, rheumatoid arthritis has an insidious onset followed by a chronic fluctuating course of disease that may lead to progressive joint destruction, deformity, disability and potentially premature death.[1,2]

Sulfasalazine (salazosulfapyridine) [Azulfidine®, Salazopyrin®]1 is a disease-modifying antirheumatic drug (DMARD) that is used in many countries for the treatment of patients with rheumatoid arthritis. Sulfasalazine is also widely used for the treatment of ulcerative colitis; however, the use of sulfasalazine in this or other conditions (e.g. Crohn’s disease) is beyond the scope of the current article. This review focuses on the pharmacology, clinical efficacy and tolerability profile of sulfasalazine in rheumatoid arthritis.

2. Pharmacodynamic Properties

Although sulfasalazine has been used for many years in the management of patients with rheumatoid arthritis, its mechanism of action, and even whether the parent drug and/or its metabolites sulfapyridine and mesalazine (mesalamine; 5-aminosalicylic acid) are responsible for its action, remains unclear.[3] As reviewed by Smedegård and Björk,[3] the action of sulfasalazine in rheumatoid arthritis is most likely mediated by a number of immunomodulatory and anti-inflammatory effects.

2.1 Immunomodulatory Effects

2.1.1 In Vitro

With respect to its potential immunomodulatory effects, several in vitro studies have shown that sulfasalazine and/or its metabolites inhibit the release of cytokines produced by various cell types. Among the cytokines affected by sulfasalazine are T-cell cytokines, such as interleukin (IL)-2,[4] and those produced by monocytes or macrophages, including IL-1,[5] IL-6,[5] IL-12[6] and tumour necrosis factor (TNF)-α.[7] Precisely how sulfasalazine inhibits the release of cytokines has not been fully elucidated. Some studies have shown, for example, that sulfasalazine inhibits TNFα expression in macrophages by inducing apoptosis.[7]

Cytokines mediate and regulate a number of cellular responses, including T-cell proliferation, natural killer cell activity and activation of B cells.[3] Sulfasalazine and, to a lesser extent, its metabolites sulfapyridine and mesalazine have been shown to inhibit these cellular responses in a number of different in vitro systems.[3]

Chronic stimulation of B cells is a characteristic feature of rheumatoid arthritis, and sulfasalazine and its main metabolites have been shown to suppress B cells at clinically relevant concentrations in vitro.[8] At concentrations of 1–10 μg/mL, sulfasalazine, sulfapyridine and mesalazine inhibited the production of IgM and IgG by B cells stimulated with Staphylococcus aureus Cowan I plus IL-2. In contrast, none of these agents suppressed interferon-γ production by immobilised anti-CD3-stimulated CD4+ T cells, thus suggesting preferential suppression of B-cell rather than T-cell function by sulfasalazine and its main metabolites.[8] Other studies have also shown that sulfasalazine inhibits the activation of B cells in vitro, as demonstrated by reductions in immunoglobulin synthesis, rheumatoid factor production or plaque formation.[9,10]

2.1.2 In Vivo

Various lines of evidence from animal models and clinical trials suggest an immunomodulatory action of sulfasalazine.[3] For example, in various studies in mice and rats, sulfasalazine inhibited type II collagen-induced arthritis,[11,12] an effect suggesting immunomodulatory[3] as well as perhaps anti-inflammatory[12] (section 2.2) properties. In addition, sulfasalazine suppressed serum IgG anti-DNA antibody production in autoimmune (NZB/W F1 and MRL/l) mice, an effect apparently mediated by the parent drug on the basis of concurrently conducted in vitro studies using murine spleen cells.[13] Sulfasalazine 20 mg/kg three times weekly was also associated with slightly improved life expectancy (51 vs 42 weeks in the control group; statistical analysis not reported) in NZB/W F1 mice.[13]

In MRL/l mice treated with sulfasalazine 100 or 200 mg/kg three times per week, progression of joint lesions was suppressed compared with control animals.[14] Histopathological analysis showed that sulfasalazine suppressed multiplication of synovial lining cells, subsynovial soft tissue oedema, fibrin exudation, and infiltration by inflammatory cells such as fibroblasts, neutrophils and plasma cells.[14]

Proinflammatory cytokines, such as TNFα and IL-1, were suppressed in patients with rheumatoid arthritis receiving sulfasalazine.[15] Moreover, these effects occurred in tandem with improvements in clinical measures of disease activity.

2.2 Anti-Inflammatory Effects

Sulfasalazine has been shown to inhibit chemotaxis and random migration of inflammatory cells such as neutrophils, and to reduce superoxide and proteolytic enzyme production in various pharmacodynamic studies.[3] Sulfasalazine and sulfapyridine also reduced endothelial cell chemotaxis and proliferation, suggesting a possible role in reducing angiogenesis, a prominent feature associated with rheumatoid arthritis.[16] Other potential anti-inflammatory effects demonstrated in vitro with sulfasalazine include weak inhibition of lysosome release from abdominal macrophages,[12] a slight inhibitory effect on prostaglandin E2 synthetase activity,[12] rapid apoptosis of neutrophils[17] and inhibition of the extracellular release of proinflammatory secretory phospholipase A2.[18]

In addition, a mild inhibitory effect was demonstrated with sulfasalazine in models of chronic inflammation (type II collagen-induced and adjuvant arthritis models),[12] an effect also suggesting immunomodulatory activity of the drug (section 2.1.2).[3] The anti-inflammatory action of sulfasalazine appears to be related to enhanced release of adenosine at sites of inflammation, as demonstrated in in vitro and in vivo models of the inflammatory process.[19] However, unlike NSAIDs, sulfasalazine has shown limited activity in acute models of inflammation, and the difference in pharmacodynamic and clinical profiles between NSAIDs and sulfasalazine suggests that any observed effects of sulfasalazine on the arachidonic cascade (which have generally been weak) are probably not central to its action in rheumatoid arthritis.[3]

2.3 Site of Action

The specific site(s) of action of sulfasalazine in rheumatoid arthritis remain largely unknown, with proposed sites ranging from systemic immune regulatory mechanisms involving gut-associated lymphoid tissues to direct actions on inflammatory processes in the joints.[3] In addition, recent data suggest that dendritic cells, which play a key role in priming and boosting T-cell immunity, may be an important target for sulfasalazine in autoimmune disorders such as rheumatoid arthritis.[20] At a concentration of 1.25 μmol/L in vitro, sulfasalazine prevented the stimulation of T cells and activation of nuclear transcription factor-κB in maturing dendritic cells. Sulfasalazine also inhibited much of the expression of CD83 (a marker of mature dendritic cells), with 50% inhibition occurring at a concentration of 1.5 μmol/L. Maturing human dendritic cells were markedly more sensitive than T cells and natural killer cells to the effects of sulfasalazine.[20] In addition, sulfasalazine inhibited the formation of osteoclasts (which are involved in bone resorption in rheumatoid arthritis) in cocultures of rheumatoid arthritis fibroblast-like synoviocytes and peripheral blood mononuclear cells, an effect that appeared to be primarily mediated by decreasing expression of receptor activator of nuclear factor κB ligand and increasing expression of osteoprotegerin.[21] These results highlight potential underlying mechanisms of an antiresorptive effect of sulfasalazine.

3. Pharmacokinetic Profile

3.1 Absorption and Distribution

The chemical structure of sulfasalazine is made up of two moieties, sulfapyridine and mesalazine, connected by an azo bond.[2224] Following oral administration of sulfasalazine in patients with rheumatoid arthritis, approximately 10–30% of the parent compound is absorbed from the small intestine,[22,23] and extensive enterohepatic recycling occurs.[22] However, in healthy Japanese volunteers the bioavailability of enteric-coated sulfasalazine is <10%.[25] Sulfasalazine that reaches the large intestine is cleaved at the azo bond by bacterial azoreductases, thus releasing sulfapyridine and mesalazine.[22,23] Sulfapyridine is almost completely absorbed (>90%) from the large intestine. In contrast, absorption of mesalazine is only about 20–30%, the remainder being eliminated in the faeces.[22,23]

The bioavailability of enteric-coated sulfasalazine appears to be broadly similar to that of the standard formulation.[23,24] Since most rheumatoid arthritis patients who are treated with sulfasalazine are prescribed enteric-coated tablets, table I summarises pharmacokinetic data primarily from patients with rheumatoid arthritis after multiple-dose administration of enteric-coated sulfasalazine 2 g/day. Pharmacokinetic data from healthy Japanese volunteers who received single or multiple doses of enteric-coated sulfasalazine 1 g/day are presented in table II.[25] Single-dose data from the Japanese study showed that the peak plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC) of sulfasalazine did not increase proportionally with dose (0.5, 1 and 2g), suggesting that oral absorption of sulfasalazine may be saturated at the higher dosage level in this population.[25] Administration of enteric-coated sulfasalazine with food delayed the time to achieve Cmax and reduced AUC and Cmax of both sulfasalazine and sulfapyridine.[25]
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Table I

Pharmacokinetic properties of sulfasalazine and its main metabolites. Unless otherwise stated, data are derived from patients with rheumatoid arthritis who received multiple-dose administration of enteric-coated sulfasalazine 2 g/day orally

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Table II

Pharmacokinetic properties of sulfasalazine and one of its main metabolites, sulfapyridine, in healthy Japanese volunteers. Volunteers received enteric-coated sulfasalazine 1 g/day orally in single-dose and multiple-dose studies[25]

As would be expected on the basis of the main sites of absorption, the Cmax of sulfapyridine (and presumably mesalazine) occurs later than the Cmax of sulfasalazine.[25,26] This was demonstrated in a single-dose study in which patients with rheumatoid arthritis received sulfasalazine 2g (standard formulation).[26] Results showed that sulfasalazine Cmax (12.9 μg/mL) was achieved after 3.5 hours and sulfapyridine Cmax (14.0 μg/mL) was achieved after 14.0 hours. Similar results were observed in Japanese healthy volunteers following a single dose of enteric-coated sulfasalazine 1g (table II).[25]

Following intravenous administration of sulfasalazine to healthy volunteers, the mean volume of distribution of sulfasalazine was 7.5L.[27] Sulfasalazine and sulfapyridine distribute to synovial fluid, with synovial concentrations generally approaching those of plasma concentrations.[23] In plasma, sulfasalazine is extensively (>99%) bound to albumin.[24,27]

3.2 Metabolism and Elimination

Systemically absorbed sulfasalazine is metabolised to some extent in the liver to sulfapyridine and mesalazine;[27] a small proportion of an administered dose of sulfasalazine is eliminated unchanged in the urine.[22,23] The primary route of metabolism of sulfapyridine is by acetylation in the liver to form N-acetyl-sulfapyridine (presumed to be inactive), some of which is eliminated in the urine.[22,23,27] Sulfapyridine and its N-acetyl metabolite also undergo hydroxylation and glucuronidation;[22,27] the glucuronide conjugates are eliminated in the urine[23] and this is also the likely fate of the hydroxylated metabolites (5-hydroxy-sulfapyridine and N-acetyl-5-hydroxy-sulfapyridine[27]). Although 70–80% of mesalazine is eliminated unchanged in the faeces, mesalazine also undergoes both presystemic and systemic acetylation to form acetyl-mesalazine (presumed to be inactive), which is eliminated in the urine.[22,23]

The rate at which sulfapyridine forms its main metabolite (N-acetyl-sulfapyridine) is dependent upon acetylator phenotype.[22,27] In the Caucasian population, there is an approximately equal distribution of fast and slow acetylators.[22,27] The elimination half-life (t1/2) of sulfapyridine is about 50–100% longer in slow acetylators than in fast acetylators, and slow acetylators have higher plasma concentrations of sulfapyridine.[22,29] Although higher plasma sulfapyridine concentrations are thought to be related to the higher prevalence of minor adverse effects observed in slow acetylators,[22,27,29] determination of acetylator status prior to sulfasalazine therapy is not routinely conducted.[22,23] Nevertheless, a recent analysis in 144 Japanese patients with rheumatoid arthritis showed a statistically significant association between adverse effects of sulfasalazine and diplotype configuration at the N-acetyltransferase 2 gene.[30] Among slow acetylators who had no NAT2*4 haplotype, 62.5% experienced adverse events compared with 8% of fast acetylators who had at least one NAT2*4 haplotype (p < 0.001). Other authors have also advocated the use of genotyping prior to starting sulfasalazine therapy in an effort to identify high-risk patients and reduce the frequency of adverse effects.[31]

The t1/2 of sulfasalazine was prolonged in elderly (mean age 74.4 years) versus younger (mean age 40.5 years) patients with rheumatoid arthritis who received multiple-dose administration of enteric-coated sulfasalazine 2 g/day (17.0 vs 6.1 hours; p < 0.01).[28] Although some differences were also observed between elderly and younger patients for the pharmacokinetics of sulfapyridine, the effects of age on the overall pharmacokinetic profile were not considered clinically significant.[28] An overall range of t1/2 values (for older and younger patients and for slow and fast acetylators) following multiple-dose administration of enteric-coated sulfasalazine 2 g/day in patients with rheumatoid arthritis is presented in table I.[28] In addition, table II provides t1/2 values for healthy Japanese volunteers who received enteric-coated sulfasalazine 1 g/day for 8 days.[25]

3.3 Drug Interactions

Since sulfasalazine is sometimes used in combination with other DMARDs (section 4.4), evaluation of sulfasalazine-DMARD pharmacokinetic drug interactions is of interest. Such data appear to be limited to a single evaluation of a potential interaction between sulfasalazine and methotrexate in 15 patients with rheumatoid arthritis.[32] There were no clinically or statistically significant differences in methotrexate pharmacokinetic parameters when methotrexate 7.5mg once weekly was administered with or without concomitant enteric-coated sulfasalazine 1g twice daily. There were also no clinically or statistically significant differences in trough plasma concentrations of sulfasalazine, sulfapyridine and N-acetyl-sulfapyridine when sulfasalazine was administered alone (prior to the main pharmacokinetic analysis) or with methotrexate. In addition, concomitant administration of sulfasalazine reduces the absorption of folic acid and digoxin,[27] although the clinical relevance of these interactions is unclear.

4. Therapeutic Efficacy in Rheumatoid Arthritis

Sulfasalazine has been evaluated in patients with rheumatoid arthritis in several randomised, double-blind, placebo-controlled trials (section 4.1) and in numerous studies comparing sulfasalazine with other DMARDs (section 4.2). In addition, sulfasalazine has been studied for its effects on radiological progression (section 4.3), and a number of trials have evaluated combination therapy using sulfasalazine plus other antirheumatic agents in patients with rheumatoid arthritis (section 4.4).

Several placebo-controlled trials conducted with sulfasalazine have been included in a meta-analysis (Cochrane review), the results of which are presented in section 4.1.[33] These were randomised, double-blind trials in which patients with rheumatoid arthritis received sulfasalazine 2 g/day or placebo for 24–48 weeks.[3437] The studies included 32–120 patients and the most consistently reported measures of disease activity were joint scores. Data from additional trials were excluded from the meta-analysis of clinical efficacy because inadequate measures of disease activity were used.[33] Other data discussed in section 4.1 include a Japanese dose-finding study, which helped to define the optimal dose of sulfasalazine in Japanese patients with rheumatoid arthritis.[38]

Although a number of open-label and/or nonrandomised trials have compared sulfasalazine and other DMARDs, section 4.2 focuses primarily on randomised, double-blind trials. Some of these studies also included a combination treatment arm,[39,40] so there is some overlap with section 4.4. Many of the studies discussed in section 4.2 evaluated <100 patients with rheumatoid arthritis,[4145] although several were larger trials.[37,39,40,46] Some of the studies excluded patients who had previously received DMARDs,[37,39,40,42] while other study protocols permitted previous treatment with these agents but required DMARD therapy to be discontinued prior to study enrolment.[41,43,44,46] Where reported, eligible patients in most double-blind comparative studies had a diagnosis of active rheumatoid arthritis based on the criteria of the American College of Rheumatology (ACR) [section 4.2].[37,3942,44,46] This was also the case for essentially all studies involving combination DMARD therapy (section 4.4).

Studies evaluating the use of sulfasalazine in combination with other antirheumatic agents are reviewed in section 4.4. Trial designs varied and included the following (with some studies falling into more than one category): randomised comparisons, typically in patients with early rheumatoid arthritis (defined as duration <1 year in some trials[39,40] and <2 years in others[4749]); studies involving a ‘step-down’ approach whereby the combination treatment regimen is tapered over the study period;[47] trials that used a ‘step-up’ approach, with treatment intensification mandated at specific intervals;[4951] studies that involved a very flexible treatment protocol to mimic clinical practice;[48] and trials involving the use of additional DMARDs when patients became refractory to DMARD monotherapy.[5257] However, they can be broadly divided into two groups: randomised trials involving combination therapy in patients with early disease (section 4.4.1) and studies using combination therapy in patients with refractory or more long-standing rheumatoid arthritis (duration ≥2 years) [section 4.4.2]. Additional studies evaluated sulfasalazine with corticosteroids,[5860] although most of these trials were designed to evaluate the effect of corticosteroid rather than sulfasalazine therapy and will therefore not be discussed.

For the majority of studies included in section 4, patients were allowed to continue taking NSAIDs (and in some cases low-dose oral corticosteroids and/or a small number of intra-articular corticosteroid injections) during the clinical trial. Many of the placebo-controlled studies did not specify whether sulfasalazine was administered in the standard formulation or as enteric-coated tablets (section 4.1), although essentially all of the randomised, double-blind comparisons with other DMARDs used the enteric-coated formulation of sulfasalazine (section 4.2), as did some of the trials evaluating combination therapy (section 4.4).

4.1 Placebo-Controlled Trials

A meta-analysis of data from four placebo-controlled trials (n = 335)[3437] showed that sulfasalazine 2 g/day had a statistically significant advantage over placebo for several outcome measures of OMERACT (Conference on Outcome Measures in Rheumatoid Arthritis Clinical Trials).[33] These included the weighted mean difference for the tender joint score (−0.49; 95% CI −0.75, −0.36), swollen joint score (−0.49; 95% CI −0.79, −0.12), pain score (−0.42; 95% CI −0.72, −0.12) and ESR (−17.6mm; 95% CI −21.9, −13.2). Both the physician’s (−0.22; 95% CI −0.55, +0.10) and patient’s (−0.32; 95% CI −0.64, 0.00) global assessment of disease status were improved with sulfasalazine versus placebo, although the effect size did not achieve statistical significance, perhaps because fewer patients could be evaluated for these parameters.[33]

One of the larger studies included in the meta-analysis was a 6-month, double-blind trial conducted by the Australian Multicentre Clinical Trial Group.[34] A total of 105 patients with rheumatoid arthritis of <1 year’s duration who had not previously been treated with a DMARD were included in the baseline analysis, and 65 patients (62%) completed the 6-month assessment. Patients randomised to receive enteric-coated sulfasalazine 2 g/day had significantly greater improvements from baseline than placebo recipients for RAI (p = 0.025), the number of swollen and tender joints (p = 0.03) and ESR (p = 0.004) [figure 1]. Although morning stiffness and pain scores also favoured sulfasalazine, differences versus placebo did not achieve statistical significance for these parameters. Compared with baseline values, all measures of disease activity improved significantly after 6 months of sulfasalazine therapy. Improvements from baseline were also noted with placebo, although the magnitude of improvement was more modest than that observed in the sulfasalazine treatment group, and statistical significance versus baseline was not achieved for some parameters.[34]
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Fig. 1

Disease activity measures in a double-blind, placebo-controlled, multicentre trial with sulfasalazine.[34] Patients with rheumatoid arthritis of <12 months’ duration were randomised to receive sulfasalazine 2 g/day (n = 53) or placebo (n = 52) for 6 months. A total of 65 patients completed the 6-month treatment period. ESR = erythrocyte sedimentation rate; RAI = Ritchie articular index; * p < 0.05, ** p < 0.01 vs placebo; statistical comparisons for results at endpoint (6mo) vs baseline are not included.

In an effort to determine the optimal dose of sulfasalazine in Japan, a large, double-blind, dose-finding study was conducted in 299 patients with rheumatoid arthritis.[38] Patients were randomised to receive sulfasalazine 1 g/day (n = 99), 2 g/day (n = 100) or placebo (n = 100) for 16 weeks. Clinical improvement, assessed on the basis of the Japanese Rheumatology Foundation criteria, was achieved in 53%, 50% and 23% of patients in the three respective treatment groups (p < 0.001 for both sulfasalazine regimens vs placebo). Since fewer patients in the sulfasalazine 1 g/day group than in the 2 g/day group experienced adverse events or discontinued therapy during the study period, the optimal dose of sulfasalazine was deemed to be 1 g/day in Japanese patients.[38]

4.2 Comparisons with Other Disease-Modifying Antirheumatic Drugs

A number of studies have compared sulfasalazine with other DMARDs in the treatment of patients with rheumatoid arthritis, including several randomised, double-blind trials summarised in table III. The table includes measures of disease activity that were common to the majority of trials; randomised, double-blind trials were excluded from the table if they did not provide specific results for at least one of these measures, although clinically relevant results from excluded studies are reported in the text of this section. A few of the studies used an intent-to-treat (ITT) analysis,[39,40,46] whereas most studies in table III reported results only for those patients who completed the study.
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Table III

Summary of randomised, double-blind trials comparing the clinical efficacy of sulfasalazine (SSZ) with that of other disease-modifying antirheumatic drugs in patients (pts) with rheumatoid arthritisa

In general, sulfasalazine and the active comparators were associated with statistically significant improvements from baseline to endpoint for most parameters in each of the clinical trials (p-values not shown in table III). However, the only statistically significant difference between monotherapy with sulfasalazine and comparator DMARDs in these head-to-head comparisons was a greater reduction in ESR with sulfasalazine versus leflunomide after 24 weeks of therapy[46] (table III). In general, results suggest that sulfasalazine has broadly similar clinical efficacy to that of leflunomide, hydroxychloroquine, penicillamine, methotrexate and intramuscular gold. However, in many cases the trials included relatively small numbers of patients and may not have been adequately powered to detect differences between active treatment groups.

The clinical efficacy of sulfasalazine was also similar to that of comparator DMARDs when considering parameters assessed in various trials that are not included in table III, such as the proportion of patients achieving a 20% improvement in ACR criteria,[39,46] physician’s and/or patient’s global assessment of disease status,[39,41,46] patient’s assessment of functional status[37,39,40,44,46] and radiological indices (e.g. erosion, damage, total joint and Larsen scores).[39,41,44,46]

In general, results of meta-analyses of comparative clinical trials indicate that sulfasalazine is among the more efficacious traditional DMARDs, with efficacy similar to that of methotrexate, penicillamine and intramuscular gold.[6366] Sulfasalazine also had similar clinical efficacy to that of leflunomide in a 6-month trial (table III),[46] although longer-term results from a double-blind extension period (total treatment duration 2 years) indicate that the beneficial effects (e.g. improvements in ACR 20 response, global assessments and functional ability, and slowing of radiographic disease progression) are sustained to a greater extent with leflunomide than with sulfasalazine.[6769]

In some trials, patients who received sulfasalazine had an earlier response to therapy than patients who were treated with comparator agents.[42,70] This was noted in a double-blind comparison versus hydroxychloroquine (table III)[42] and in a randomised, open-label trial versus auranofin.[70] For example, compared with hydroxychloroquine, sulfasalazine was associated with significantly less pain and greater grip strength as early as week 8.[42]

4.2.1 Adherence to Therapy

Another parameter not included in table III, and which overlaps between clinical efficacy and tolerability, is the proportion of patients who completed the study period. A meta-analysis including more than 6500 patients with rheumatoid arthritis enrolled in clinical trials with DMARDs showed an overall completion rate of just over 75% in 79 clinical trials.[63] In the double-blind trials of up to 12 months’ duration reported in table III, the proportion of patients who completed therapy with sulfasalazine was broadly similar to that with other DMARDs. For example, in the comparison with leflunomide, 83 of 132 patients (63%) in the sulfasalazine group and 96 of 130 patients (74%) in the leflunomide group completed the 24-week trial.[46] About one-half of the patients who withdrew from therapy in both active treatment groups did so because of adverse events. Similar results were noted in other trials comparing sulfasalazine versus hydroxychloroquine (59% vs 74% completed a 6-month study;[41] 70% vs 60% completed a 48-week study[42]), methotrexate (69% vs 78% completed a 52-week trial[39]) or intramuscular gold (68% vs 45% completed a 37-week trial[37]).

Using data from observational and randomised controlled trials in rheumatoid arthritis, along with actuarial survival estimates, a large meta-analysis predicted that 22% of patients who start treatment with sulfasalazine will remain on the drug after 5 years.[71] This result was similar to the predicted value for injectable gold therapy (23%) but lower than that for methotrexate (36%). Comparisons between methotrexate and both sulfasalazine and injectable gold were statistically significant (p < 0.0001), whereas there was no statistical difference between sulfasalazine and injectable gold. After 3 years, the proportion of patients remaining on therapy was approximately 45% for methotrexate, 40% for injectable gold and 35% for sulfasalazine (estimated from survival curves).[71] Broadly similar results were reported after 3 years in a large retrospective practice-based study (methotrexate 50% vs sulfasalazine 25%; p = 0.0001).[72] Five-year follow-up data from an open-label trial comparing sulfasalazine and auranofin in 200 patients with rheumatoid arthritis showed that 31% of patients continued sulfasalazine for at least 5 years compared with only 15% who continued auranofin over this period (p < 0.05).[73]

4.3 Radiological Progression

Evaluation of radiological progression over a 12-month period in a randomised, double-blind trial comparing sulfasalazine 2 g/day and diclofenac 100 mg/day showed that early treatment of rheumatoid arthritis with sulfasalazine was associated with a reduction in joint damage.[74] In the analysis of 111 patients with rheumatoid arthritis of <1 year’s duration, both treatments were associated with improvements from baseline for a number of parameters of disease activity (e.g. RAI, swollen joint counts, pain scores). However, radiographic evaluation of the hands, wrists and feet showed that, at the end of the 12-month study period, the mean number of new erosions was 2.0 (95% CI 0.9, 3.1) with sulfasalazine compared with 7.5 (95% CI 4.1, 10.9) with diclofenac (p = 0.002) in the ITT analysis. Corresponding results for patients who completed 12 months of treatment with sulfasalazine or diclofenac were 2.3 (95% CI 0.6, 4.0) and 10.5 (95% CI 5.0, 15.9) new erosions (p = 0.018).[74]

Not included in table III are results of a randomised, double-blind trial comparing radiological progression of joint damage in 50 patients with rheumatoid arthritis who received either sulfasalazine 2 g/day for 48 weeks or hydroxychloroquine 200mg twice daily for 24 weeks followed by 200mg once daily for a further 24 weeks.[45] Evaluation of x-rays of the hands and feet showed that the median number of erosions was significantly lower in sulfasalazine than hydroxychloroquine recipients at week 48 (5 vs 16 erosions; p < 0.02). Significant advantages favouring sulfasalazine were noted at weeks 24 and 48 for total score of joint damage.[45] Follow-up data showed that the significant difference in joint damage observed in the first year was maintained over a further 2-year period.[75]

Results of a large meta-analysis also support the efficacy of sulfasalazine (and various other DMARDs) in decreasing radiological progression in rheumatoid arthritis.[65] Two outcome measures were used to allow direct comparisons and pooling of data from the 25 longer-term (≥24-week follow-up period) trials included in the analysis — the weighted standardised difference and the odds of progression of x-ray scores (active treatment vs control). For the first parameter (i.e. the effect of treatment on erosion scores), the following drugs were statistically superior to placebo, in rank order: ciclosporin (cyclosporin) [−0.74], infliximab (−0.67), sulfasalazine (−0.50), leflunomide (−0.49), methotrexate (−0.36), parenteral gold (−0.33), corticosteroids (−0.32), auranofin (−0.30) and IL-1 receptor antagonist (−0.27) [table IV]. Nonsignificant and generally smaller effects were noted for other agents including antimalarials and cyclophosphamide. In addition, the weighted standardised differences obtained in the meta-analysis[65] were statistically equivalent to pooled treatment effects (disease-activity scores) from short-term trials for sulfasalazine (−0.50 vs −0.60), methotrexate (−0.36 vs −0.56), parenteral gold (−0.33 vs −0.56) and auranofin (−0.30 vs −0.30), but not for antimalarial drugs (−0.05 vs −0.43; p = 0.006).[64] For the second outcome measure in the meta-analysis (i.e. odds of progression of erosions), the following drugs were statistically superior to placebo, in rank order: infliximab (0.22), leflunomide (0.22), methotrexate (0.32), parenteral gold (0.35), sulfasalazine (0.36) and corticosteroids (0.47).[65]
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Table IV

Efficacy of therapy for preventing radiological progression in rheumatoid arthritis in a large meta-analysis.[65] Summary data are presented as the weighted standard mean difference (SMD) and 95% CI. SMD compares treatment and placebo in terms of a standardised score

Another study which evaluated the Larsen score showed significantly less disease progression with sulfasalazine and leflunomide than with placebo, and changes in eroded joint count were similar between the two active treatment arms.[46]

Also of potential relevance are findings from an in vitro study which showed that sulfasalazine inhibited human osteoclastogenesis (section 2.3). The study highlighted potential underlying mechanisms of an antiresorptive effect of sulfasalazine.

4.4 Trials Involving Combination Therapy

4.4.1 Randomised Comparisons in Early Rheumatoid Arthritis

Two of the studies discussed in section 4.2 and included in table III also evaluated combination therapy with sulfasalazine plus methotrexate in patients with early rheumatoid arthritis (<1 year’s duration).[39,40] In these well conducted double-blind trials, there were almost no statistically significant advantages in patients with rheumatoid arthritis who were randomised to receive combination therapy compared with their counterparts who received monotherapy, and neither trial showed any statistical advantage for combination therapy versus sulfasalazine monotherapy (table III). Moreover, 5-year follow-up data[76] from one of the trials[39] showed that the use of combination therapy with sulfasalazine plus methotrexate during the first year did not affect long-term outcomes such as disability or structural changes.[76]

In an effort to determine the value of short-term intensive combination therapy in patients with early rheumatoid arthritis (duration <2 years) who had very active disease, the randomised, double-blind, multicentre COBRA (Combinatietherapie Bij Reumatoide Artritis) trial compared the combination of sulfasalazine 2 g/day, methotrexate 7.5 mg/week and prednisolone (initially 60 mg/day) with sulfasalazine alone for 56 weeks.[47] Prednisolone and methotrexate doses were gradually tapered in the combination treatment arm and these drugs were discontinued after 28 and 40 weeks, respectively. After week 56, treatment modifications could be made at the discretion of the treating physician. The primary endpoint of the trial was a pooled index summarising the effect of 28 weeks’ treatment on five measures of disease activity, including tender joint count, grip strength, ESR, overall assessment of disease state by an independent investigator (using a 100mm visual analogue scale), and the McMaster Toronto arthritis questionnaire. Higher scores on the pooled index indicated greater benefits; radiographic progression (assessed by the Sharp/Van der Heijde radiographic damage score) and ACR 20 response rates were also evaluated.

The ITT analysis included 76 patients in the combination treatment arm and 79 patients who received sulfasalazine monotherapy; 70 and 56 patients (92% and 71%) in the respective treatment groups completed the 56-week study period.[47] Results of the COBRA trial showed a significantly more favourable mean pooled index at week 28 in the combined treatment group than in the sulfasalazine monotherapy group (1.4 [95% CI 1.2, 1.6] vs 0.8 [95% CI 0.6, 1.0]; p < 0.0001). There was also significantly less radiographic progression in the combined therapy group than in the monotherapy group at week 28 (median increase in radiographic damage score 1 vs 4; p < 0.0001).

At least some of the beneficial effects observed at week 28 may have been a function of the difference in corticosteroid use between treatment groups. However, between-group increases in the mean pooled index at week 56 (2 vs 6 points; p = 0.004) and at week 80 (4 vs 12 points; p = 0.01) were also statistically significant, indicating that beneficial effects were retained for up to 1 year after corticosteroids were discontinued.[47] ACR 20 response at week 28 was achieved in 72% and 49% of recipients of combination therapy or monotherapy, respectively (p = 0.006), and 50% improvement in ACR criteria (ACR 50) was achieved by 49% and 27% of patients (p = 0.007). The clinical difference between groups decreased and was not statistically significant after discontinuation of prednisolone (i.e. beyond week 28).[47]

Long-term follow-up assessments 4–5 years after patients were enrolled in the COBRA trial showed that patients who were randomised to the short-term, intensive combination treatment regimen had sustained suppression of the rate of radiological progression, regardless of subsequent antirheumatic therapy.[77] During the follow-up period, radiographic damage scores increased by 5.6 points per year in the combination therapy group compared with 8.6 points per year in the sulfasalazine monotherapy group, and the difference remained similar (3.7 points per year) after adjustment for differences in disease activity and treatment during follow-up.

Initial aggressive combination therapy in patients with early rheumatoid arthritis (duration <2 years) was also evaluated in the multicentre FIN-RACo (Finnish Rheumatoid Arthritis Combination Therapy) trial.[48] Patients were randomised to receive combination therapy with three DMARDs (initial regimen: sulfasalazine 1 g/day, methotrexate 7.5 mg/week and hydroxychloroquine 300 mg/day) plus prednisolone 5 mg/day or single DMARD treatment (initial regimen: sulfasalazine 2 g/day) with or without prednisolone. Dosage and/or drug adjustments were required and/or permitted at various time points between 3 months and 2 years, generally providing a flexible treatment approach to simulate clinical practice. The primary endpoint was the induction of remission defined according to modified ACR preliminary criteria (see figure 2 for details); ACR 50 response rate and radiographic measurements (Larsen score, number of eroded joints) were important secondary endpoints.
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Fig. 2

Main results of the FIN-RACo (Finnish Rheumatoid Arthritis Combination Therapy) trial.[48] Patients with early rheumatoid arthritis (duration <2 years) were randomised to receive combination therapy with three DMARDs (initial regimen: sulfasalazine 1 g/day, methotrexate 7.5 mg/week and hydroxychloroquine 300 mg/day) plus prednisolone 5 mg/day (combination treatment) or single DMARD treatment (initial regimen: sulfasalazine 2 g/day) with or without prednisolone (single treatment). Dosage and/or drug adjustments were required and/or permitted at various time points between 3 months and 2 years, generally providing a flexible treatment approach to simulate clinical practice. Results are for the intent-to-treat analysis (n = 195); remission (primary endpoint) was defined according to modified American College of Rheumatology (ACR) preliminary criteria (no/minimal morning stiffness, no joint pain, tenderness or swelling, no elevation of erythrocyte sedimentation rate[48,78]) and ACR 50 (secondary endpoint) reflects a 50% improvement in ACR criteria. * p < 0.05, ** p < 0.01 vs single treatment.

A total of 195 patients were included in the ITT analysis; 97 in the combination therapy group and 98 in the single DMARD group.[48] A high proportion of patients in both treatment groups completed the 2-year FIN-RACo study (combination arm: 90%; single DMARD arm: 93%). All patients in the combination treatment arm received prednisolone (median dose 5 mg/day), whereas only 64% of those in the single DMARD group received prednisolone (median dose 5 mg/day), and this may have contributed to some of the findings.

In the ITT analysis, the proportion of patients achieving remission in the combination therapy group was approximately twice that in the single DMARD group at 1 (p = 0.011) and 2 years (p = 0.003) [figure 2].[48] Likewise, the proportion of patients who achieved ACR 50 response criteria at 1 and 2 years was higher in the combination therapy group than in the single DMARD group, although the difference was statistically significant only at the 1-year interval (figure 2). Radiographic progression was also less pronounced in the combination therapy group than in the single DMARD group. After 2 years, Larsen scores had increased from baseline by 2 points (from 2 to 4) in the combination arm and by 10 points (from 2 to 12) in the single DMARD arm (p = 0.002). The increase in the number of eroded joints was also significantly lower in the combination treatment group.

Additional analysis of data from the FIN-RACo trial indicates that, in the single DMARD group, remission was significantly less likely to occur if treatment was started >4 months from the onset of symptoms compared with more rapid initiation of sulfasalazine therapy.[79] Evaluation of cervical spine radiographs after 2 years showed significantly fewer patients in the combination arm than in the single DMARD group with anterior atlantoaxial subluxation (0% vs 6.6%; p = 0.029).[80] In addition, 5-year follow-up data from the trial showed that, compared with single DMARD therapy, early use of aggressive combination DMARD therapy limits peripheral joint damage[81] and is associated with improved outcomes in terms of work productivity (e.g. less sick leave, disability payments)[82] for at least 5 years.

Two-year data from the large (n = 508), randomised BeST trial are also available (reported in an abstract).[49] The study compared four treatment regimens in patients with early rheumatoid arthritis (duration ≤2 years): sequential monotherapy with methotrexate, then sulfasalazine, then leflunomide; step-up combination therapy starting with methotrexate, then adding sulfasalazine, then hydroxychloroquine; initial combination therapy with methotrexate, sulfasalazine plus tapered high-dose prednisone; and initial combination therapy with methotrexate plus infliximab. Although clinical improvements (e.g. mean Health Assessment Questionnaire [HAQ] and disease activity scores) were observed from baseline to 2 years for all four treatment groups, there were no statistically significant differences between sequential monotherapy and step-up combination therapy, and both of these groups were statistically inferior to the initial combination regimens that included tapered high-dose corticosteroids or infliximab.

4.4.2 Studies in Patients with Refractory or Long-Standing Disease

Some studies have evaluated combination therapy in patients with rheumatoid arthritis who had an inadequate response or were refractory to DMARD monotherapy.[5257] One such trial is a 2-year, randomised, double-blind, comparison of methotrexate 7.5–17.5 mg/week as monotherapy (n = 36), the combination of sulfasalazine 1 g/day plus hydroxychloroquine 400 mg/day (n = 35) or the combination of all three drugs (n = 31).[52] Most patients had long-standing rheumatoid arthritis (mean duration 6–10 years across the three treatment groups) and all patients were required to have had a poor response to at least one DMARD (gold, hydroxychloroquine, penicillamine, sulfasalazine or methotrexate). The primary endpoint of the trial was completion of 2 years of treatment with at least 50% improvement in symptoms (modified Paulus criteria: composite of various measures of disease activity including ESR, joint tenderness, joint swelling and morning stiffness) and without evidence of toxicity. The proportion of patients who achieved this endpoint was significantly higher in the group receiving three drugs than among patients treated with sulfasalazine plus hydroxychloroquine (77% vs 40%; p = 0.003) or methotrexate monotherapy (77% vs 33%; p < 0.001).

A larger (n = 171) double-blind trial was conducted by the same group of investigators in which patients were randomised to 2 years of treatment with one of three regimens: methotrexate (7.5–17.5 mg/week) plus hydroxychloroquine (400 mg/day), methotrexate plus sulfasalazine (1–2 g/day) or all three drugs.[56] Patients who had previously received methotrexate and had an inadequate response (≈50% of patients enrolled in the trial) were started on the maximum dosage of methotrexate, whereas the methotrexate dosage was titrated from 7.5 mg/week in other patients. In general, most patients had long-standing disease (mean duration 6.9 years). The primary endpoint of the trial was the proportion of patients who achieved an ACR 20 response. ITT analysis showed that significantly more patients treated with the triple-drug combination than who received methotrexate plus sulfasalazine had an ACR 20 response (78% vs 49%; p = 0.002). The difference between triple-drug therapy and the combination of methotrexate plus hydroxychloroquine approached statistical significance (78% vs 60%; p = 0.05). Among patients with a prior suboptimal response to methotrexate (n = 92), triple-drug therapy produced a significant (p < 0.01) advantage over methotrexate plus sulfasalazine, but not over methotrexate plus hydroxychloroquine, in terms of ACR 20 response (71% vs 36% vs 55%).

Forty patients with rheumatoid arthritis that did not respond adequately to sulfasalazine therapy were randomised to receive sulfasalazine plus methotrexate or methotrexate monotherapy in a 24-week open-label trial.[55] The sulfasalazine dose was not clearly reported; methotrexate 7.5–15 mg/week was used in both treatment groups. The primary endpoint was the mean change in disease activity score (a composite of RAI, ESR, number of swollen joints and general well-being), with greater reductions indicating more marked improvement. Patients receiving sulfasalazine plus methotrexate had a significantly greater change in disease activity score than those who received methotrexate monotherapy (−2.6 vs −1.3; p < 0.001).

A more recent randomised, double-blind trial in 254 patients with rheumatoid arthritis who previously had an inadequate response to sulfasalazine therapy showed that etanercept 25mg twice weekly or the combination of etanercept plus sulfasalazine 2–3 g/day for 24 weeks was significantly more effective than continuing sulfasalazine monotherapy (reported as an abstract/poster).[54] Efficacy was measured using instruments such as the HAQ disability index and the EuroQOL-5D thermometer scale to assess the patient’s functional status and overall health state.

A Japanese open-label trial evaluated the effects of adding sulfasalazine 1 g/day to methotrexate therapy in 62 patients whose rheumatoid arthritis no longer responded adequately to methotrexate monotherapy.[53] After 24 weeks of combined therapy, 57% of patients had a response according to ACR 20 criteria (primary endpoint of the trial) and 36% achieved an ACR 50 response. The combined regimen was deemed to be effective and generally well tolerated in this patient population.[53]

Other studies evaluated combination therapy using a step-up approach.[50,51,57] One such study was a small, noncomparative Japanese trial in 33 patients with rheumatoid arthritis (mean duration 8.6 years and inadequate response to previous DMARD therapy) which demonstrated an 88% response rate with a three-drug regimen of sulfasalazine (0.5–1 g/day), methotrexate (2.5–5 mg/week) and a low-dose sulfhydryl compound such as bucillamine (100–200 mg/day).[50] The study used a step-up approach whereby patients unresponsive to one DMARD were then treated with two DMARDs, then a third DMARD was added if a satisfactory response was still not achieved. Response to the three-drug regimen was assessed according to the physician’s overall assessment of joint symptoms and laboratory data after 6 months of triple DMARD therapy.[50] A similar Japanese trial also showed positive results in patients with refractory rheumatoid arthritis who received a three-drug combination of sulfasalazine, methotrexate and bucillamine.[57]

Another trial evaluated a step-up approach beginning with methotrexate or ciclosporin, followed by the sequential addition of ciclosporin or methotrexate, respectively, and then, if necessary, sulfasalazine.[51] Sulfasalazine was added to the two-drug combination after 12 months in patients without an ACR 50 response. At 18 months, 75 of 84 patients (89%) treated with step-up combination therapy (i.e. methotrexate plus ciclosporin, with or without sulfasalazine) had an ACR 50 response. This compared with an ACR 50 response rate of 24% in another group of 42 patients randomised to receive sulfasalazine monotherapy throughout the 18-month period (statistical analysis not reported).

Another study in patients with long-standing disease (mean duration >2 years) showed that combination DMARD therapy was more effective than DMARD monotherapy.[83] Patients with rheumatoid arthritis (n = 180) were randomised to one of three treatment groups: monotherapy with either sulfasalazine 1–2 g/day, methotrexate 7.5–15 mg/week or hydroxychloroquine 200 mg/day; two DMARDs, either methotrexate plus sulfasalazine or methotrexate plus hydroxychloroquine; or a combination of all three DMARDs. Response, defined as a ≥50% improvement in symptoms according to modified Paulus criteria, was achieved in 49%, 73% and 88% of patients after 2 years in the respective treatment groups. Statistical analysis showed that triple DMARD therapy was significantly better than single or double DMARD therapy (both p < 0.001), and double DMARD therapy was better than DMARD monotherapy (p < 0.001).

5. Tolerability

The most frequently reported adverse events associated with sulfasalazine in patients with rheumatoid arthritis are adverse gastrointestinal effects (e.g. nausea, vomiting, dyspepsia, anorexia), headache, dizziness and rash.[23,27] In general, most adverse events occur during the first few months after starting sulfasalazine treatment and their occurrence decreases with continued use.[84] In clinical practice, most patients with rheumatoid arthritis receive sulfasalazine as enteric-coated tablets.[23] The use of this formulation was shown in a multicentre crossover trial to significantly reduce not only the severity of adverse gastrointestinal effects, but also the incidence of these problems by more than half when compared with the standard formulation of sulfasalazine.[85]

Haematological disturbances (e.g. leukopenia) are reported in ≤3% of sulfasalazine recipients,[27] and less frequently reported adverse events include various blood dyscrasias, hypersensitivity reactions (including systemic lupus erythematosus-like syndrome), dyspnoea and other pulmonary complications, and hepatic dysfunction.[23,27] Oligospermia (or related conditions such as impaired sperm motility) is a relatively common problem associated with sulfasalazine in males and can lead to infertility; however, the condition appears to be reversible upon discontinuation of the drug.[27,86] For a complete list of possible adverse events, local prescribing information should be consulted.

Approximately 20–30% of patients with rheumatoid arthritis who are treated with sulfasalazine experience adverse events leading to discontinuation of therapy.[63,84,87] Adverse gastrointestinal and CNS effects are responsible for approximately two-thirds of these cases.[84,87] For example, in a large, multicentre study evaluating the tolerability of sulfasalazine 2 g/day for 6 months in patients with rheumatoid arthritis, 26.8% of patients discontinued treatment because of adverse events. Of these adverse events, two-thirds involved the gastrointestinal tract or CNS (figure 3).[87]
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Fig. 3

Results of a large, prospective tolerability study of enteric-coated sulfasalazine.[87] A total of 1382 patients with rheumatoid arthritis at 108 centres entered the 6-month open-label trial. Outcomes are available for 1209 patients (87.5%) treated with sulfasalazine. Dosage was gradually titrated to 2 g/day, then the dosage could be adjusted according to clinical response. GI/CNS = gastrointestinal or CNS effects.

Results of a large meta-analysis including data from 79 clinical trials with DMARDs demonstrated that sulfasalazine, like methotrexate, was associated with relatively high potency (section 4.2) and only modest toxicity, although methotrexate was deemed to be slightly better tolerated than sulfasalazine.[63]

Although the use of sulfasalazine in combination with other DMARDs was generally well tolerated in clinical trials (section 4.4), some studies showed an increase in adverse events. Two randomised, double-blind trials compared combination therapy with sulfasalazine plus methotrexate versus monotherapy with either agent for 52 weeks in patients with early rheumatoid arthritis (section 4.4.1).[39,40] The overall incidence of adverse events (91% vs 75% vs 75%; p = 0.025)[39] or the incidence of treatment-related adverse events (64% vs 47% vs 31%; p = 0.023)[40] was significantly higher with combination therapy than with sulfasalazine or methotrexate monotherapy. In both trials, this was primarily due to an increased incidence of nausea in the combination therapy group.

However, in the COBRA[47] and FIN-RACo[48] trials, both of which compared early, aggressive combination therapy including sulfasalazine versus single DMARD therapy with sulfasalazine (section 4.4.1), the frequency and severity of adverse events was similar between treatment groups. For example, in the FIN-RACo trial,[48] adverse events were reported by 70% of those initially treated with the combination of sulfasalazine, methotrexate, hydroxychloroquine and prednisolone compared with 71% of patients who received sulfasalazine with or without prednisolone. Serious adverse events occurred in 3% and 5% of patients, respectively, and the only statistically significant difference between groups in terms of tolerability was with respect to abnormal liver function, which occurred more frequently in the single DMARD group. In two randomised, double-blind, 2-year trials conducted by O’Dell and colleagues[52,56] (section 4.4.2), there were no apparent differences between triple and double DMARD therapy (sulfasalazine, methotrexate plus hydroxychloroquine vs sulfasalazine plus methotrexate vs methotrexate plus hydroxychloroquine),[56] or between triple, double and single DMARD therapy (sulfasalazine, methotrexate plus hydroxychloroquine vs sulfasalazine plus hydroxychloroquine vs methotrexate)[52] in terms of the number of patients who discontinued treatment because of adverse events.

Sulfasalazine appears to be generally safe during pregnancy (US FDA risk category B).[27,88] It should be used cautiously in women who are breast-feeding, as sulfapyridine concentrations in breast-milk are about 30–60% of those in maternal serum,[27,88] and sulfonamides compete with bilirubin for plasma protein binding sites in the newborn and may therefore cause kernicterus.[27] Apparently reversible oligospermia occurs commonly in men taking sulfasalazine. It is important that male patients wishing to become a father should be offered specialist advice.[89]

6. Dosage and Administration

Sulfasalazine is administered orally as enteric-coated tablets, with the dose gradually titrated to minimise adverse gastrointestinal effects. In most countries, the initial recommended dosage is 500 mg/day, increased by 500 mg/day increments at intervals of 1 week to a maximum of 2–3 g/day in two to four divided doses.[23,27,90] In Japan, the upper limit of the approved dosage range is 1 g/day,[91,92] which appears to be based on results of a Japanese dose-finding study (section 4.1).[38]

Local prescribing information should be consulted for a complete list of precautions, contraindications and required dosage adjustments for sulfasalazine in different patient populations.

7. Place of Sulfasalazine in the Management of Rheumatoid Arthritis

The goals of treatment for rheumatoid arthritis are to prevent or control joint damage, prevent loss of function and decrease pain.[2] Ideally, the ultimate goal is to induce a complete remission (absence of inflammatory joint pain, morning stiffness, fatigue, synovitis, radiographic progression and elevated ESR or CRP levels), although this occurs infrequently.

The current treatment paradigm for rheumatoid arthritis involves early intervention with DMARDs, usually within 3 months of diagnosis, to limit joint damage and preserve joint function.[2] In addition, symptomatic relief may be achieved with NSAIDs, analgesics and oral or intra-articular corticosteroids. Changes in the DMARD regimen should be considered for patients who continue to have unacceptable disease activity after a reasonable trial (e.g. 3 months of maximum therapy), experience repetitive disease flares or unacceptable drug toxicity, or have progressive joint damage.[2]

DMARDs comprise a diverse array of drugs, and some of the features of selected agents are presented in table V. Sulfasalazine is a well established DMARD that, along with methotrexate, has a relatively short lag time until its onset of action[2] and is often considered to be one of the more efficacious traditional DMARDs.[63,93] Sulfasalazine also has a similar onset of action to leflunomide and methotrexate, whereas the biological anti-TNFα agents etanercept and infliximab generally have a more rapid onset (table V).[2] Etanercept and infliximab, although effective, particularly in patients not responding to previous DMARD therapy, have the disadvantages of high acquisition costs and requiring parenteral administration.[2]
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Table V

Differential features of selected disease-modifying antirheumatic drugs (DMARDs)[2,90,94,95] a

Although many rheumatologists select methotrexate as the initial choice of DMARD for patients with rheumatoid arthritis,[2,96,97] particularly for those with very active disease or with indicators of a poorer prognosis,[2] sulfasalazine is also favoured by many rheumatologists as initial therapy because of its safety, convenience and cost.[2,97] There also appear to be regional differences for the DMARD of first choice. For example, methotrexate is often selected by rheumatologists in the US,[47] whereas a recent survey of British rheumatologists suggests an approximately equal split between methotrexate (46.5%) and sulfasalazine (43.5%) as the DMARD of first choice.[97] In Japan, sulfasalazine or bucillamine are generally preferred.[50]

In addition, sulfasalazine has advantages over hydroxychloroquine, another DMARD often considered for initial therapy, in that it acts more quickly[2] and has demonstrated efficacy in slowing radiographic progression of rheumatoid arthritis (section 4.3).[45] Sulfasalazine may also have a particular niche in the treatment of women of child-bearing age who are planning a pregnancy or are at risk of becoming pregnant.[23] Sulfasalazine appears to be relatively safe in pregnancy (section 5), whereas effective contraception is required when most DMARDs are prescribed.[2]

Using various measures of disease activity, randomised, double-blind clinical trials have shown that sulfasalazine is superior to placebo (section 4.1) and has broadly similar efficacy to that of other DMARDs, including methotrexate, leflunomide, hydroxychloroquine, penicillamine and intramuscular gold (section 4.2). Many of these head-to-head comparisons with other DMARDs may not have been adequately powered to detect statistically significant differences between groups, and some of the older trials did not use the specific outcome measures currently recommended (e.g. ACR, European League Against Rheumatism, OMERACT). However, data from large meta-analyses showed that sulfasalazine is among the more efficacious traditional DMARDs (section 4.2). Nevertheless, the effectiveness of sulfasalazine (and many other traditional DMARDs) in preventing the progression of joint damage in patients with rheumatoid arthritis who have severe disease activity may be somewhat limited, and more aggressive therapy is generally advocated for these individuals.[2]

Sulfasalazine was generally well tolerated in clinical trials, with the most frequently reported adverse events involving the gastrointestinal tract or CNS (section 5). A large meta-analysis indicated that methotrexate was generally tolerated slightly better than sulfasalazine;[63] however, the tolerability profiles of the various DMARDs vary as does the need for monitoring (table V).

Interest is growing in the use of combination DMARD therapy, not only for patients who do not respond adequately or are refractory to treatment with a single DMARD, but also for patients with early rheumatoid arthritis.[2,96,98100] In general, combination therapy has played an important role in improving control of rheumatoid arthritis in recent years.[2] This area continues to evolve[2] and there is a need for randomised head-to-head comparisons to determine which of the various combinations is optimal in terms of efficacy and tolerability.[96]

Some studies using sulfasalazine in combination with other DMARDs have shown promising results (section 4.4). Triple DMARD therapy with sulfasalazine, methotrexate and hydroxychloroquine (plus low-dose prednisolone) was more effective than single DMARD therapy using sulfasalazine (with or without low-dose prednisolone) in patients with early disease in the FIN-RACo trial (section 4.4.1).[48] Likewise, in a randomised, double-blind trial in which patients had a poor response to at least one DMARD, the triple combination of sulfasalazine, methotrexate and hydroxychloroquine was more effective than methotrexate monotherapy or the double combination of sulfasalazine plus hydroxychloroquine (section 4.4.2).[52] Importantly, combination therapy with sulfasalazine was not associated with an unacceptably high incidence of adverse events in these trials. However, two well conducted randomised, double-blind studies in patients with early disease failed to show superiority of the combination of methotrexate plus sulfasalazine over monotherapy with either drug (section 4.4.1).[39,40] Although this double DMARD regimen was more effective than sulfasalazine monotherapy in patients with early disease in the COBRA trial (section 4.4.1),[47] these results may have been partly due to the mandated use of high-dose tapered corticosteroids in the double DMARD, but not in the sulfasalazine monotherapy, treatment arm.

In conclusion, sulfasalazine is a well established DMARD in terms of its clinical efficacy and tolerability profile. Despite the wide array of agents available for the treatment of rheumatoid arthritis, sulfasalazine remains a viable option for patients starting DMARD therapy. In addition, sulfasalazine has been used successfully in combination with other DMARDs for patients with early and more advanced rheumatoid arthritis.

Footnotes
1

The use of trade names is for product identification purposes only and does not imply endorsement.

 

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