Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis
- Michael H Weisman, MD
Michael H Weisman, MD
- Director, Division of Rheumatology
- Professor of Medicine
- Cedars-Sinai Medical Center
- Renee Z Rinaldi, MD
Renee Z Rinaldi, MD
- Associate Clinical Professor of Medicine
- The David Geffen School of Medicine, UCLA
- Section Editor
- Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
- Section Editor — Rheumatoid Arthritis
- Emeritus Professor of Rheumatology, Imperial College London
- Visiting Professor, Oxford University
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 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 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".)
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).To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Amos RS. The history of the use of sulphasalazine in rheumatology. Br J Rheumatol 1995; 34 Suppl 2:2.
- SVARTZ N. The treatment of rheumatic polyarthritis with acid azo compounds. Rheumatism 1948; 4:180.
- Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997; 36:382.
- Sinclair RJ, Duthie JJ. Salazopyrin in the Treatment of Rheumatoid Arthritis. Ann Rheum Dis 1949; 8:226.
- McConkey B, Amos RS, Durham S, et al. Sulphasalazine in rheumatoid arthritis. Br Med J 1980; 280:442.
- Pullar T, Hunter JA, Capell HA. Sulphasalazine in rheumatoid arthritis: a double blind comparison of sulphasalazine with placebo and sodium aurothiomalate. Br Med J (Clin Res Ed) 1983; 287:1102.
- Smedegård G, Björk J. Sulphasalazine: mechanism of action in rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl 2:7.
- Jansen G, van der Heijden J, Oerlemans R, et al. Sulfasalazine is a potent inhibitor of the reduced folate carrier: implications for combination therapies with methotrexate in rheumatoid arthritis. Arthritis Rheum 2004; 50:2130.
- O'Dell JR, Haire CE, Erikson N, et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334:1287.
- O'Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46:1164.
- Bird HA. Sulphasalazine, sulphapyridine or 5-aminosalicylic acid--which is the active moiety in rheumatoid arthritis? Br J Rheumatol 1995; 34 Suppl 2:16.
- Pullar T, Hunter JA, Capell HA. Which component of sulphasalazine is active in rheumatoid arthritis? Br Med J (Clin Res Ed) 1985; 290:1535.
- Taggart AJ, Neumann VC, Hill J, et al. 5-Aminosalicylic acid or sulphapyridine. Which is the active moiety of sulphasalazine in rheumatoid arthritis? Drugs 1986; 32 Suppl 1:27.
- Volin MV, Campbell PL, Connors MA, et al. The effect of sulfasalazine on rheumatoid arthritic synovial tissue chemokine production. Exp Mol Pathol 2002; 73:84.
- van der Heijde DM, van Riel PL, Nuver-Zwart IH, et al. Effects of hydroxychloroquine and sulphasalazine on progression of joint damage in rheumatoid arthritis. Lancet 1989; 1:1036.
- Wahl C, Liptay S, Adler G, Schmid RM. Sulfasalazine: a potent and specific inhibitor of nuclear factor kappa B. J Clin Invest 1998; 101:1163.
- Lee CK, Lee EY, Chung SM, et al. Effects of disease-modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor kappaB, osteoprotegerin, and receptor activator of nuclear factor kappaB ligand. Arthritis Rheum 2004; 50:3831.
- Rodenburg RJ, Ganga A, van Lent PL, et al. The antiinflammatory drug sulfasalazine inhibits tumor necrosis factor alpha expression in macrophages by inducing apoptosis. Arthritis Rheum 2000; 43:1941.
- Hirohata S, Ohshima N, Yanagida T, Aramaki K. Regulation of human B cell function by sulfasalazine and its metabolites. Int Immunopharmacol 2002; 2:631.
- Cronstein BN. Therapeutic cocktails for rheumatoid arthritis: the mixmaster's guide. Arthritis Rheum 2004; 50:2041.
- Morabito L, Montesinos MC, Schreibman DM, et al. Methotrexate and sulfasalazine promote adenosine release by a mechanism that requires ecto-5'-nucleotidase-mediated conversion of adenine nucleotides. J Clin Invest 1998; 101:295.
- Astbury C, Hill J, Bird HA. Co-trimoxazole in rheumatoid arthritis: a comparison with sulphapyridine. Ann Rheum Dis 1988; 47:323.
- James HM, Gillis D, Hissaria P, et al. Common polymorphisms in the folate pathway predict efficacy of combination regimens containing methotrexate and sulfasalazine in early rheumatoid arthritis. J Rheumatol 2008; 35:562.
- Pawlik A, Kurzawski M, Gawronska-Szklarz B, et al. The effect of 677C>T and 1298A>C MTHFR polymorphisms on sulfasalazine treatment outcome in rheumatoid arthritis. Braz J Med Biol Res 2009; 42:660.
- Drozdzik M, Rudas T, Pawlik A, et al. The effect of 3435C>T MDR1 gene polymorphism on rheumatoid arthritis treatment with disease-modifying antirheumatic drugs. Eur J Clin Pharmacol 2006; 62:933.
- van der Heijden J, de Jong MC, Dijkmans BA, et al. Development of sulfasalazine resistance in human T cells induces expression of the multidrug resistance transporter ABCG2 (BCRP) and augmented production of TNFalpha. Ann Rheum Dis 2004; 63:138.
- van der Heijden J, de Jong MC, Dijkmans BA, et al. Acquired resistance of human T cells to sulfasalazine: stability of the resistant phenotype and sensitivity to non-related DMARDs. Ann Rheum Dis 2004; 63:131.
- http://www.g6pd.org (Accessed on May 31, 2013).
- Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf 2010; 33:713.
- van Riel PL, van Gestel AM, van de Putte LB. Long-term usage and side-effect profile of sulphasalazine in rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl 2:40.
- Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum 2008; 59:762.
- Chakravarty K, McDonald H, Pullar T, et al. BSR/BHPR guideline for disease-modifying anti-rheumatic drug (DMARD) therapy in consultation with the British Association of Dermatologists. Rheumatology (Oxford) 2008; 47:924.
- Singh JA, Furst DE, Bharat A, et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken) 2012; 64:625.
- Singh JA, Saag KG, Bridges SL Jr, et al. 2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2016; 68:1.
- Dougados M. Sulfasalazine. In: Therapy of Systemic Rheumatic Disorders, van de Putte LBA, Furst DE, Williams HJ, van Riel PLCM (Eds), Marcel Dekker, New York 1998. p.165.
- Tanaka E, Taniguchi A, Urano W, et al. Adverse effects of sulfasalazine in patients with rheumatoid arthritis are associated with diplotype configuration at the N-acetyltransferase 2 gene. J Rheumatol 2002; 29:2492.
- Fuchs HA. Use of sulfasalazine in rheumatic diseases. Bull Rheum Dis 1997; 46:3.
- Jobanputra P, Amarasena R, Maggs F, et al. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008; 9:48.
- Mok MY, Ng WL, Yuen MF, et al. Safety of disease modifying anti-rheumatic agents in rheumatoid arthritis patients with chronic viral hepatitis. Clin Exp Rheumatol 2000; 18:363.
- Vanhoof J, Landewe S, Van Wijngaerden E, Geusens P. High incidence of hepatotoxicity of isoniazid treatment for tuberculosis chemoprophylaxis in patients with rheumatoid arthritis treated with methotrexate or sulfasalazine and anti-tumour necrosis factor inhibitors. Ann Rheum Dis 2003; 62:1241.
- Amos RS, Pullar T, Bax DE, et al. Sulphasalazine for rheumatoid arthritis: toxicity in 774 patients monitored for one to 11 years. Br Med J (Clin Res Ed) 1986; 293:420.
- Farr M, Scott DG, Bacon PA. Side effect profile of 200 patients with inflammatory arthritides treated with sulphasalazine. Drugs 1986; 32 Suppl 1:49.
- Denissen NH, Peters JG, Masereeuw R, Barrera P. Can sulfasalazine therapy induce or exacerbate Wegener's granulomatosis? Scand J Rheumatol 2008; 37:72.
- Mut SE, Kutlu G, Ucler S, et al. Reversible encephalopathy due to sulfasalazine. Clin Neuropharmacol 2008; 31:368.
- Komatsuda A, Okamoto Y, Hatakeyama T, et al. Sulfasalazine-induced hypersensitivity syndrome and hemophagocytic syndrome associated with reactivation of Epstein-Barr virus. Clin Rheumatol 2008; 27:395.
- Capell HA. Clinical efficacy of sulphasalazine--a review. Br J Rheumatol 1995; 34 Suppl 2:35.
- Englert HJ, Hughes GR, Walport MJ. Sulphasalazine and regression of rheumatoid nodules. Ann Rheum Dis 1987; 46:244.
- Bax DE, Amos RS. Sulphasalazine in rheumatoid arthritis: desensitising the patient with a skin rash. Ann Rheum Dis 1986; 45:139.
- MECHANISM OF ACTION
- GENETIC POLYMORPHISMS AFFECTING SSZ EFFICACY
- DOSING AND MONITORING
- Pretreatment testing
- Dosing, monitoring, and dose adjustment
- ADVERSE EFFECTS
- Liver function abnormalities
- Leukopenia and agranulocytosis
- Pregnancy and reproduction
- Other adverse events
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS