Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate®

Sulfasalazine in the treatment of rheumatoid arthritis

Michael H Weisman, MD
Renee Z Rinaldi, MD
Section Editor
Ravinder N Maini, BA, MB BChir, FRCP, FMedSci, FRS
Deputy Editor
Paul L Romain, MD


Salicylazosulfapyridine (sulfasalazine, SSZ) was originally proposed as a treatment for rheumatoid arthritis (RA) because of its antiinflammatory and antimicrobial activities [1,2]. Although early studies suggested a beneficial effect, the drug’s efficacy was challenged by the findings of a negative 1948 report, which was influential despite a severely flawed study design [3,4]. The introduction of cortisone during this period, an event hailed as a modern medical miracle, further dampened enthusiasm for the use of SSZ in RA.

SSZ was resurrected as a therapeutic agent for rheumatic disorders 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 use of SSZ for the treatment of RA is discussed here and in the individual treatment topics on RA. The management of RA and the use of SSZ in inflammatory bowel disease 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 "Sulfasalazine and 5-aminosalicylates in the treatment of inflammatory bowel disease".)


Approximately 30 percent of sulfasalazine (SSZ) 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 sulfapyridine and 5-aminosalicylic acid (5-ASA). Coliform bacteria are, therefore, 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, thereby explaining its utility in inflammatory bowel disease.

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].


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Jul 2017. | This topic last updated: Sep 12, 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Amos RS. The history of the use of sulphasalazine in rheumatology. Br J Rheumatol 1995; 34 Suppl 2:2.
  2. SVARTZ N. The treatment of rheumatic polyarthritis with acid azo compounds. Rheumatism 1948; 4:180.
  3. Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997; 36:382.
  4. Sinclair RJ, Duthie JJ. Salazopyrin in the Treatment of Rheumatoid Arthritis. Ann Rheum Dis 1949; 8:226.
  5. McConkey B, Amos RS, Durham S, et al. Sulphasalazine in rheumatoid arthritis. Br Med J 1980; 280:442.
  6. 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.
  7. Smedegård G, Björk J. Sulphasalazine: mechanism of action in rheumatoid arthritis. Br J Rheumatol 1995; 34 Suppl 2:7.
  8. Bird HA. Sulphasalazine, sulphapyridine or 5-aminosalicylic acid--which is the active moiety in rheumatoid arthritis? Br J Rheumatol 1995; 34 Suppl 2:16.
  9. Pullar T, Hunter JA, Capell HA. Which component of sulphasalazine is active in rheumatoid arthritis? Br Med J (Clin Res Ed) 1985; 290:1535.
  10. 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.
  11. 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.
  12. Astbury C, Hill J, Bird HA. Co-trimoxazole in rheumatoid arthritis: a comparison with sulphapyridine. Ann Rheum Dis 1988; 47:323.
  13. Cronstein BN. Therapeutic cocktails for rheumatoid arthritis: the mixmaster's guide. Arthritis Rheum 2004; 50:2041.
  14. 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.
  15. 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.
  16. 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.
  17. 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.
  18. Hirohata S, Ohshima N, Yanagida T, Aramaki K. Regulation of human B cell function by sulfasalazine and its metabolites. Int Immunopharmacol 2002; 2:631.
  19. 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.
  20. 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.
  21. 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.
  22. http://www.g6pd.org (Accessed on May 31, 2013).
  23. Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Drug Saf 2010; 33:713.
  24. Sulfasalazine in early rheumatoid arthritis. The Australian Multicentre Clinical Trial Group. J Rheumatol 1992; 19:1672.
  25. Hannonen P, Möttönen T, Hakola M, Oka M. Sulfasalazine in early rheumatoid arthritis. A 48-week double-blind, prospective, placebo-controlled study. Arthritis Rheum 1993; 36:1501.
  26. Pinals RS, Kaplan SB, Lawson JG, Hepburn B. Sulfasalazine in rheumatoid arthritis. A double-blind, placebo-controlled trial. Arthritis Rheum 1986; 29:1427.
  27. Weinblatt ME, Reda D, Henderson W, et al. Sulfasalazine treatment for rheumatoid arthritis: a metaanalysis of 15 randomized trials. J Rheumatol 1999; 26:2123.
  28. Williams HJ, Ward JR, Dahl SL, et al. A controlled trial comparing sulfasalazine, gold sodium thiomalate, and placebo in rheumatoid arthritis. Arthritis Rheum 1988; 31:702.
  29. Pullar T, Hunter JA, Capell HA. Effect of sulphasalazine on the radiological progression of rheumatoid arthritis. Ann Rheum Dis 1987; 46:398.
  30. 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.
  31. van der Heijde DM, van Riel PL, Nuver-Zwart IH, van de Putte LB. Sulphasalazine versus hydroxychloroquine in rheumatoid arthritis: 3-year follow-up. Lancet 1990; 335:539.
  32. Smolen JS, Kalden JR, Scott DL, et al. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. European Leflunomide Study Group. Lancet 1999; 353:259.
  33. Strand V, Scott DL, Emery P, et al. Physical function and health related quality of life: analysis of 2-year data from randomized, controlled studies of leflunomide, sulfasalazine, or methotrexate in patients with active rheumatoid arthritis. J Rheumatol 2005; 32:590.
  34. Capell HA. Clinical efficacy of sulphasalazine--a review. Br J Rheumatol 1995; 34 Suppl 2:35.
  35. Azulfidine, EN-Tabs. In: Physicians Desk Reference, 52nd ed, Medical Economics Company, Montvale, NJ 1998. p.2239.
  36. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 1990; 33:1449.
  37. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum 1992; 35:1117.
  38. Goldbach-Mansky R, Wilson M, Fleischmann R, et al. Comparison of Tripterygium wilfordii Hook F versus sulfasalazine in the treatment of rheumatoid arthritis: a randomized trial. Ann Intern Med 2009; 151:229.
  39. Haagsma CJ, van Riel PL, de Jong AJ, van de Putte LB. Combination of sulphasalazine and methotrexate versus the single components in early rheumatoid arthritis: a randomized, controlled, double-blind, 52 week clinical trial. Br J Rheumatol 1997; 36:1082.
  40. Dougados M, Combe B, Cantagrel A, et al. Combination therapy in early rheumatoid arthritis: a randomised, controlled, double blind 52 week clinical trial of sulphasalazine and methotrexate compared with the single components. Ann Rheum Dis 1999; 58:220.
  41. Englert HJ, Hughes GR, Walport MJ. Sulphasalazine and regression of rheumatoid nodules. Ann Rheum Dis 1987; 46:244.
  42. 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.
  43. 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.
  44. 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.
  45. Fleischmann R, Koenig AS, Szumski A, et al. Short-term efficacy of etanercept plus methotrexate vs combinations of disease-modifying anti-rheumatic drugs with methotrexate in established rheumatoid arthritis. Rheumatology (Oxford) 2014; 53:1984.
  46. Moreland LW, O'Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum 2012; 64:2824.
  47. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet 2012; 379:1712.
  48. Boers M, Verhoeven AC, Markusse HM, et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997; 350:309.
  49. Haagsma CJ, van Riel PL, de Rooij DJ, et al. Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open clinical trial in rheumatoid arthritis patients resistant to sulphasalazine therapy. Br J Rheumatol 1994; 33:1049.
  50. Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005; 52:3381.
  51. Grigor C, Capell H, Stirling A, et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004; 364:263.
  52. Möttönen T, Hannonen P, Leirisalo-Repo M, et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999; 353:1568.
  53. Korthals-de Bos I, Van Tulder M, Boers M, et al. Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone. J Rheumatol 2004; 31:1709.
  54. van Tuyl LH, Boers M, Lems WF, et al. Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis. Ann Rheum Dis 2010; 69:807.
  55. Capell HA, Madhok R, Porter DR, et al. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Ann Rheum Dis 2007; 66:235.
  56. Korpela M, Laasonen L, Hannonen P, et al. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum 2004; 50:2072.
  57. Rantalaiho V, Korpela M, Hannonen P, et al. The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish rheumatoid arthritis combination therapy trial. Arthritis Rheum 2009; 60:1222.
  58. Saunders SA, Capell HA, Stirling A, et al. Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies. Arthritis Rheum 2008; 58:1310.
  59. Weisman MH. Progress toward the cure of rheumatoid arthritis? The BeSt study. Arthritis Rheum 2005; 52:3326.
  60. Combe B, Codreanu C, Fiocco U, et al. Etanercept and sulfasalazine, alone and combined, in patients with active rheumatoid arthritis despite receiving sulfasalazine: a double-blind comparison. Ann Rheum Dis 2006; 65:1357.
  61. Combe B, Codreanu C, Fiocco U, et al. Efficacy, safety and patient-reported outcomes of combination etanercept and sulfasalazine versus etanercept alone in patients with rheumatoid arthritis: a double-blind randomised 2-year study. Ann Rheum Dis 2009; 68:1146.
  62. Sparks JA, Krumme AA, Shrank WH, et al. Brief Report: Intensification to Triple Therapy After Treatment With Nonbiologic Disease-Modifying Antirheumatic Drugs for Rheumatoid Arthritis in the United States From 2009 to 2014. Arthritis Rheumatol 2016; 68:1588.
  63. Sauer BC, Teng CC, Tang D, et al. Persistence With Conventional Triple Therapy Versus a Tumor Necrosis Factor Inhibitor and Methotrexate in US Veterans With Rheumatoid Arthritis. Arthritis Care Res (Hoboken) 2017; 69:313.
  64. Klarenbeek NB, Allaart CF, Kerstens PJ, et al. The BeSt story: on strategy trials in rheumatoid arthritis. Curr Opin Rheumatol 2009; 21:291.
  65. 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.
  66. 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.
  67. 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.
  68. 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.
  69. 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.
  70. 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.
  71. Fuchs HA. Use of sulfasalazine in rheumatic diseases. Bull Rheum Dis 1997; 46:3.
  72. 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.
  73. 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.
  74. 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.
  75. 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.
  76. Farr M, Scott DG, Bacon PA. Side effect profile of 200 patients with inflammatory arthritides treated with sulphasalazine. Drugs 1986; 32 Suppl 1:49.
  77. 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.
  78. Denissen NH, Peters JG, Masereeuw R, Barrera P. Can sulfasalazine therapy induce or exacerbate Wegener's granulomatosis? Scand J Rheumatol 2008; 37:72.
  79. Mut SE, Kutlu G, Ucler S, et al. Reversible encephalopathy due to sulfasalazine. Clin Neuropharmacol 2008; 31:368.
  80. 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.
  81. Bax DE, Amos RS. Sulphasalazine in rheumatoid arthritis: desensitising the patient with a skin rash. Ann Rheum Dis 1986; 45:139.