Version May 2024
INTRODUCTION — Salicylazosulfapyridine (sulfasalazine, SSZ) is a nonbiologic (conventional or traditional) disease-modifying antirheumatic drug (DMARD) that was originally proposed as a treatment for rheumatoid arthritis (RA) because of its antiinflammatory and antimicrobial activities [1,2]. It has also been used for other inflammatory joint disorders and for inflammatory bowel disease (IBD).
Initial studies in the 1940s suggested a beneficial effect in patients with RA, but the drug's efficacy was challenged by the findings of a negative, small, open-label 1949 report, which was influential despite a flawed study design [3,4]. Additionally, the introduction of cortisone during this period, an event then hailed as a modern medical miracle, further dampened enthusiasm for the use of SSZ in RA. However, a resurgence of interest in SSZ as a therapeutic agent for rheumatic disorders occurred after beneficial results were reported in a trial performed in the late 1970s and in the first placebo-controlled trial in 1983, and it is widely available [5,6].
The pharmacology, dosing, and adverse effects of SSZ as used in the treatment of RA and other forms of inflammatory arthritis are discussed here. The use and relative efficacy of SSZ in the management of RA and other conditions are presented separately. (See "General principles and overview of management of rheumatoid arthritis in adults" and "Alternatives to methotrexate for the initial treatment of rheumatoid arthritis in adults" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy" and "Treatment of arthritis associated with inflammatory bowel disease", section on 'Management of peripheral arthritis' and "Treatment of peripheral spondyloarthritis", section on 'Resistant to initial therapy' and "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)
PHARMACOLOGY — Sulfasalazine (SSZ) is a prodrug composed of 5-aminosalicylic acid (5-ASA) linked to sulfapyridine through an azo bond (figure 1). Approximately 30 percent of orally administered SSZ, which therapeutically is a relatively inactive chemical, is rapidly absorbed by the small bowel and is then returned, largely unaltered, via the enterohepatic circulation into the bile. Thus, approximately 90 percent of the ingested drug reaches the large intestine as an intact molecule [3,7].
In the colon, SSZ is reduced by the bacterial enzyme azoreductase to its two components, sulfapyridine and 5-ASA. Thus, coliform bacteria are necessary to reduce the relatively inactive parent drug to its active moieties. Nearly all of the sulfapyridine is absorbed, while 5-ASA is largely excreted in the feces, consistent with the utility of 5-ASA in inflammatory bowel disease (IBD).
Sulfapyridine is subsequently metabolized in the liver via hydroxylation and acetylation. The half-life of these components is prolonged in slow acetylators, a property which may affect toxicity but not efficacy [3,7].
No major drug-drug interactions have been reported [3]. However, in vitro studies demonstrated that SSZ can interfere with cellular uptake of methotrexate (MTX), a folate analogue, by the reduced folate carrier (RFC), which transports both folates and MTX across the cell membrane [8]. This does not appear to adversely affect the clinical efficacy of most combination regimens of disease-modifying antirheumatic drugs (DMARDs) that include SSZ [9,10]. The combination of MTX and SSZ was found less effective than MTX combined with hydroxychloroquine (HCQ). This lack of an additive or synergistic effect may be due to inhibition by SSZ of MTX uptake at the RFC.
It has also been shown in in vitro studies that SSZ downregulates multidrug resistance-associated protein (MRP)-1, a protein that exports chloroquine from the cell, resulting in higher intracellular levels of HCQ, which could explain the finding in clinical trials that the same inhibitory effect of SSZ on MTX cellular transport did not detract from the proven overall efficacy of MTX-SSZ-HCQ triple therapy [8].
MECHANISM OF ACTION — Studies directly comparing the efficacy of sulfapyridine with 5-aminosalicylic acid (5-ASA) suggest that sulfapyridine is the active moiety in patients with rheumatoid arthritis (RA), rather than 5-ASA, which is the active metabolite in the treatment of inflammatory bowel disease (IBD) [11-14]. The mechanism of action of sulfapyridine in RA has not been identified, and a positive effect due to the parent molecule alone cannot be entirely excluded [7]. Sulfasalazine (SSZ) and sulfapyridine have antiinflammatory, immunosuppressive, and other effects.
Sulfapyridine, like SSZ [15], may have disease-modifying effects as its administration in patients with RA is associated with decreases in the erythrocyte sedimentation rate (ESR) and serum concentrations of C-reactive protein (CRP) [12,13]. However, there is little interest in further study of sulfapyridine alone because of potential toxicity issues, and the parent molecule remains the well-established agent used therapeutically.
There are several plausible mechanisms of action. One is the inhibition of nuclear factor-kappa B (NFkB). This protein, which is also suppressed by glucocorticoids, induces the transcription of central mediators of the immune response. An in vitro study found that the administration of SSZ strongly inhibited NFkB-dependent transcription in colonic cells [16]. Interestingly, these actions were unique to SSZ and were not observed with sulfapyridine or 5-ASA, thereby suggesting that the parent molecule may have important antiinflammatory properties. SSZ may also inhibit osteoclast formation via modulatory effects on the receptor activator of NFkB (RANK), osteoprotegerin (OPG), and RANK-ligand [17].
In addition, SSZ can inhibit tumor necrosis factor (TNF)-alpha expression via apoptosis of macrophages [18]. Sulfapyridine may reduce secretion of inflammatory cytokines such as interleukin (IL)-8 and monocyte chemoattractant protein (MCP)-1 [14]. Another study has suggested that SSZ and its metabolites preferentially suppress B-cell function but not T-cell function [19], while other data have indicated that SSZ may exert immunoregulatory effects that alter lymphocytes in the mucosa of the small intestine [20].
An additional mechanism that has been proposed is through increased production of adenosine at sites of inflammation, which has been suggested to be an antiinflammatory property of SSZ that it shares with another effective antirheumatic drug, methotrexate (MTX) [21,22].
Since sulfapyridine is a sulfonamide, an antibacterial effect has been entertained; however, the observation that other sulfonamides are ineffective in RA makes this hypothesis unlikely. One 24-week study, for example, directly compared sulfapyridine (1.25 g per day) with cotrimoxazole (trimethoprim-sulfamethoxazole, 480 mg three times daily) in patients with RA [23]. Disease activity either was unchanged or had worsened among patients treated with cotrimoxazole; by comparison, improvement was observed in those administered sulfapyridine.
In another study, SSZ and its metabolites (5-aminosalicylic acid and sulfapyridine) exerted an additive and dose-dependent inhibitory effect on arachidonic acid-induced platelet aggregation in vitro, which was comparable to that of aspirin. This represents a potential mechanism that may contribute to the previously described cardioprotective effect of SSZ in patients with inflammatory arthritis [24].
GENETIC POLYMORPHISMS AFFECTING SSZ EFFICACY — A number of studies have examined the effect of genetic polymorphisms on the efficacy of sulfasalazine (SSZ) in rheumatoid arthritis (RA), although this remains a developing area. There is evidence that some genetic polymorphisms can affect clinical responsiveness, but these variants are not routinely assessed clinically and do not influence clinical practice.
In one study, polymorphic variations in the MTR, SLC19A1, and TYMS genes (all components of the folate pathway) were associated with better clinical response to combination disease-modifying antirheumatic drug (DMARD) regimens containing methotrexate (MTX) and SSZ [25]. Another study noted an association between the MTHFR 677T allele and statistically significant increased frequency of remission [26].
Another study assessed the MDR-1 gene product, P-glycoprotein, one of the most important transporters for drug delivery in humans. The TT-genotype of the 3435C>T MDR-1 gene polymorphism was associated with higher remission rates in rheumatoid patients treated with either MTX and methylprednisolone or SSZ [27].
A meta-analysis of 1077 patients indicates that the N-acetyltransferase 2 slow acetylator genotype is associated with an increased risk of adverse drug reactions, compared with patients who were fast or intermediate acetylators [28].
Studies using human cell cultures have suggested that T cells may develop resistance to SSZ by overexpression of a drug efflux pump, the multidrug resistance transporter BRCP/ABCG2 [29,30]. Though this finding may be clinically relevant, there is no evidence that loss of effectiveness in patients with RA is mediated in this manner.
DOSING AND MONITORING
Pretreatment testing — A complete blood count (CBC), liver transaminases, and creatinine levels should be obtained prior to beginning treatment with sulfasalazine (SSZ) and after significantly increasing the dose. (See 'Dosing, monitoring, and dose adjustment' below.)
We also screen patients at high risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency before initiating therapy, and we avoid this drug in those patients who are deficient because of the increased risk of hemolytic anemia that may be associated with the use of SSZ in patients with this condition.
G6PD deficiency is global in its distribution but varies between different ethnicities. As examples, it is more common in African Americans, groups originating from the Mediterranean region or the Middle East, South African Black populations, and Brazilians of African ancestry, as well as other groups. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency", section on 'Epidemiology'.)
There are conflicting reports regarding the safety of SSZ and the degree of risk associated with its use in deficient patients [31,32]; thus, some experts consider it as "probably safe," and screening is not universally advocated. G6PD deficiency is discussed in detail separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase (G6PD) deficiency".)
Dosing, monitoring, and dose adjustment — After baseline screening, the dose of SSZ should be increased gradually with regular laboratory monitoring to minimize the risk of adverse effects when beginning therapy [33] (see 'Pretreatment testing' above and 'Adverse effects' below). We generally initiate therapy at a dose of 500 mg daily for the first week and subsequently increase the dose by 500 mg daily on a weekly basis until a dose of 2 g daily is achieved.
Several reasonable approaches have been suggested for monitoring [34,35]. We check the CBC one week after each dose increase (before the next dose adjustment). During the first three months of therapy and when the dose is increased, evaluation of CBC, liver transaminases, and creatinine levels should occur every two to four weeks. During the third through sixth months of therapy, levels should be monitored every 8 to 12 weeks, and, after six months, levels should be monitored every 12 weeks [34]. We generally do not adjust the dose, but do monitor regularly as described, in patients with mild renal impairment; in patients with severe chronic kidney disease, we consult with the patient's nephrologist to determine the most appropriate dosing regimen. Observations from one small case series suggest that in patients undergoing hemodialysis, SSZ may be efficacious and tolerated in low doses (500 to 1000 mg daily) with careful monitoring, but additional evidence of the safety of this approach is needed [36].
The dose of SSZ can be lowered to 1500 or 1000 mg per day if the patient develops mild toxicity (see 'Adverse effects' below). The dose can be increased to a maximum of 3 g daily, usually in divided doses, in patients who fail to respond to 2 g daily and who are without significant side effects.
This approach to titration and monitoring is consistent with the 2008 American College of Rheumatology (ACR) guidelines for the use of nonbiologic and biologic disease-modifying antirheumatic drugs (DMARDs) and with the 2012 and 2015 updates of these recommendations [34,37,38].
ADVERSE EFFECTS — Adverse reactions, including idiosyncratic and dose-related effects, are common with sulfasalazine (SSZ); relatively common among these are gastrointestinal, central nervous system, cutaneous, and hematologic adverse effects. These abnormalities sometimes result in drug discontinuation. However, in usual doses, SSZ is generally relatively well tolerated by most patients with rheumatoid arthritis (RA).
Approximately 20 to 25 percent of patients withdraw from clinical trials because of intolerable side effects [3]. Two-thirds of such withdrawals result from symptoms due to gastrointestinal and headaches, and approximately 4 to 5 percent of withdrawals are because of rash [3].
All of the adverse drug reactions described for SSZ are similar in patients with and without RA. The side effects are either idiosyncratic (eg, hypersensitivity-related or immune-related) or dose-related [39]:
●Idiosyncratic effects – Idiosyncratic effects can occur, which require immediate discontinuation of the drug and appropriate therapeutic interventions, depending upon the manifestation; patients with this type of adverse effect should not be rechallenged with the drug. Such reactions include skin reactions, including rare instances of toxic epidermal necrolysis and Stevens-Johnson syndrome (see "Stevens-Johnson syndrome and toxic epidermal necrolysis: Pathogenesis, clinical manifestations, and diagnosis"); hepatitis (see 'Liver function abnormalities' below); pneumonitis; agranulocytosis (see 'Leukopenia and agranulocytosis' below); aplastic anemia; and hemolytic anemia. Hemolytic anemia may be more common in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals but can also occur in patients on SSZ without this genetic variant [32]. (See 'Pretreatment testing' above.)
●Dose-related side effects – Dose-related side effects include gastrointestinal upset, central nervous system symptoms, and some less severe hematologic toxicities. Symptoms and laboratory findings of such involvement include anorexia, headache, nausea, vomiting, diarrhea, gastric distress, leukopenia, hemolytic anemia, macrocytosis, and, rarely, megaloblastic anemia. These problems may resolve with dose reduction.
One study evaluated the side effects and long-term use of SSZ among several hundred patients with RA in whom the drug was administered as a first-line agent for early disease (defined as less than 12 months of disease duration and no prior use of disease-modifying antirheumatic drugs [DMARDs]) [33]. A retention rate of 50 percent at two years was observed among patients administered SSZ, compared with only 20 percent for those given hydroxychloroquine (HCQ). Forty-seven of 186 subjects (25 percent) withdrew because of adverse drug reactions; the majority withdrew within the first three months of the initiation of therapy.
The risk of adverse effects appears to be at least partly genetically determined. As an example, among 144 Japanese patients with RA treated with SSZ, those with N-acetyltransferase genotypes that resulted in slow acetylation of SSZ were more likely to have a side effect than those with fast acetylators of SSZ (63 and 8 percent, respectively) [40].
Liver function abnormalities — SSZ may induce a specific syndrome characterized by fever, rash, and markedly abnormal liver function tests. Among such patients, the drug should be immediately discontinued, and the patient should not be rechallenged [41]. Patients should be warned about the possible induction of this syndrome since it may be mistaken and ignored as an intercurrent viral illness.
In one case series, the frequency of serious hepatotoxicity with SSZ was estimated at 0.4 percent of all treated patients [42]. Increased serum aminotransferase levels with SSZ may be more likely to develop in certain settings, including:
●Serologic evidence of chronic viral hepatitis – When SSZ was given to 9 patients with and 18 patients without serologic evidence of chronic hepatitis B or C virus infection, an increase in serum aminotransferase levels was more common in those chronically infected (56 versus 17 percent) [43].
●Concomitant use of SSZ and isoniazid – An increased risk of transaminase elevation was noted when SSZ and isoniazid were used in the setting of tuberculosis prophylaxis in patients with RA [44].
Leukopenia and agranulocytosis — Adverse effects of SSZ on white blood cells (WBC) may be either idiosyncratic or dose-related. Most episodes of leukopenia, which occur in 1 to 2 percent of patients, are mild and transient, but life-threatening agranulocytosis may also occur [45,46]. Since the number of circulating neutrophils is usually much higher than the number of lymphocytes, most leukopenic patients are neutropenic, although leukopenia may be due to either neutropenia or lymphopenia; as a result, the terms leukopenia, neutropenia, and granulocytopenia are often used interchangeably. (See "Drug-induced neutropenia and agranulocytosis" and "Overview of neutropenia in children and adolescents", section on 'Introduction' and "Approach to the adult with unexplained neutropenia", section on 'Introduction'.)
Patients with leukopenia may require adjustment in drug dosing, although precise levels for such dose adjustment for SSZ have not been established. Our approach in patients with mild leukopenia (total WBC of less than approximately 4000) is to temporarily discontinue SSZ and then to resume treatment when the WBC improves, with a dose reduction and careful weekly monitoring for several weeks with gradually increasing monitoring intervals. SSZ should be discontinued permanently if severe leukopenia develops (total WBC of less than 3000 or absolute neutrophil count of less than 1500), and weekly monitoring of cell counts should be performed until they stabilize in a normal range.
Serious episodes of agranulocytosis, when they do occur, are usually observed within the first three months and often within the first six weeks of therapy [2,46]. Agranulocytosis may be caused by immune-mediated destruction of circulating neutrophils by drug-induced antibodies or by direct toxic effects upon marrow granulocytic precursors. Agranulocytosis caused by a hypersensitivity reaction requires drug discontinuation without rechallenge.
Concurrent use of SSZ and etanercept may result in a greater depression of neutrophil counts than that which occurs with the use of either agent alone. This was noted in a 2005 US Food and Drug Administration (FDA) warning in the prescribing information for etanercept that stated that the combination resulted in a mild decrease in mean neutrophil counts when compared with groups treated with etanercept or SSZ alone. However, the clinical significance of this finding and whether it applies to other TNF inhibitor combinations with SSZ is unknown. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Neutropenia'.)
Pregnancy and reproduction — SSZ may cause reversible oligospermia and reduced male fertility; it is generally considered safe during pregnancy and breastfeeding. These issues are discussed in detail separately. (See "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases", section on 'Sulfasalazine' and "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Sulfasalazine'.)
Other adverse events — Case reports have demonstrated possible relationships between SSZ use and the development of granulomatosis with polyangiitis, reversible encephalopathy, Epstein-Barr virus-associated hypersensitivity syndrome, and hemophagocytic syndrome [47-50].
The rheumatoid nodulosis sometimes observed with methotrexate (MTX) therapy does not appear to occur with SSZ [51], and some reports have suggested that use of SSZ may reduce the size of rheumatoid nodules [51,52].
Desensitization — In patients with sensitivity to SSZ, desensitization can often be accomplished [53,54]. Desensitization is primarily performed in patients with a history of rash to another sulfonamide; it should not be attempted in patients with a history of agranulocytosis. Desensitization should be performed in collaboration with an expert in this technique, typically an allergist. (See "An approach to the patient with drug allergy", section on 'Options for future treatment' and "Rapid drug desensitization for immediate hypersensitivity reactions".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis" and "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Studies directly comparing the efficacy of the two components of sulfasalazine (SSZ), sulfapyridine and 5-aminosalicylic acid (5-ASA), suggest that sulfapyridine is the active moiety in patients with rheumatoid arthritis (RA), unlike in patients with inflammatory bowel disease (IBD), in which 5-ASA is the active metabolite. Benefit in patients with RA is largely attributed to sulfapyridine, although the parent molecule may also have a role. Immunoregulatory effects of SSZ on the mucosa of the small intestine have also been observed. Sulfapyridine is metabolized in the liver via hydroxylation and acetylation, and the half-life of these components is prolonged in slow acetylators, a property which may affect toxicity but not efficacy. No major drug-drug interactions have been reported. (See 'Pharmacology' above and 'Mechanism of action' above.)
●The dose of SSZ should be increased gradually with regular laboratory monitoring to minimize the risk of adverse effects. A complete blood count (CBC), liver transaminases, and creatinine levels should be obtained prior to beginning treatment with SSZ, after significantly increasing the dose, and periodically during therapy, especially during the first three months following initiation of SSZ. The usual starting dose is 500 mg daily, and the usual maximum dose administered is 2 to 3 g daily in divided doses. (See 'Dosing and monitoring' above.)
●Adverse reactions are common with SSZ. Approximately 20 to 25 percent of patients withdrew from clinical trials because of intolerable side effects. Two-thirds of such withdrawals resulted from symptoms due to gastrointestinal and central nervous system toxicity, and approximately 4 to 5 percent of withdrawals were because of rash. However, SSZ is generally relatively well tolerated by most patients with RA. (See 'Adverse effects' above.)
●The side effects of SSZ are either idiosyncratic (eg, hypersensitivity-related or immune-related) or dose-related (see 'Adverse effects' above):
•Idiosyncratic effects include skin reactions, hepatitis, pneumonitis, agranulocytosis, aplastic anemia, and hemolytic anemia. Hemolytic anemia may be more common in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. When such reactions occur, the drug should be immediately stopped, and the patient should not be rechallenged.
•Dose-related side effects include gastrointestinal upset, central nervous system symptoms, and some less severe hematologic toxicities. Symptoms and laboratory findings of such involvement include anorexia, headache, nausea, vomiting, diarrhea, gastric distress, leukopenia, hemolytic anemia, and megaloblastic anemia. These problems may resolve with dose reduction.
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Michael H Weisman, MD, who contributed to an earlier version of this topic review.
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