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LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Sulfasalazine

, MD.

Author Information and Affiliations

Last Update: January 10, 2026.

OVERVIEW

Introduction

Sulfasalazine is an antiinflammatory agent used often in combination with other agents in the chronic, long-term therapy of inflammatory bowel disease. Sulfasalazine is structurally composed of a sulfonamide (sulfapyridine) and 5-aminosalacyclic acid (5-ASA) joined by an azo bond. Sulfasalazine is a rare, but well-known cause of clinically apparent idiosyncratic liver injury.

Background

Sulfasalazine (sul" fa sal’ a zine) is a modified sulfonamide composed of sulfapyridine that is covalently linked to 5-aminosalacyclic acid (5-ASA). Sulfasalazine is poorly absorbed from the upper intestine, but its azo bond is broken by bacteria in the lower intestinal bowel lumen releasing sulfapyridine that is absorbed and 5-ASA, which reaches high levels and acts locally decreasing intestinal inflammation. Sulfasalazine was approved for clinical use in the United States in 1950 and is still used. Current indications are for treatment of active ulcerative colitis and prevention of relapses, both in adults and children. Sulfasalazine is also used for juvenile idiopathic and adult rheumatoid arthritis. Sulfasalazine is available in generic forms in 500 mg tablets and under the commercial name Azulfidine. Both immediate and extended-release forms are available, both of which are used in ulcerative colitis. In contrast, only the extended-release forms are recommended for inflammatory arthritis. The usual dose in adults is 3 to 4 grams daily initially, with maintenance dosage of 2 grams daily (4 divided doses). Common side effects include anorexia, headache, nausea, vomiting, gastrointestinal upset, fever, arthralgias and rash. Serious side effects include low sperm count, hypersensitivity reactions, severe cutaneous adverse reactions [SCAR] such as Stevens Johnson syndrome, toxic epidermal necrosis, and drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), liver and kidney injury and blood dyscrasias.

Hepatotoxicity

Sulfasalazine, like other sulfonamides, can cause a characteristic idiosyncratic liver injury that has features of drug-allergy or hypersensitivity. The presentation, course, and outcome of sulfasalazine associated liver injury varies greatly. The typical onset is sudden development of fever and rash followed by jaundice a few days or weeks later. The latency to onset is usually 2 to 6 weeks and is rarely more than 8 weeks after starting therapy. Shorter latencies can be seen with re-exposures. At least half of cases are accompanied by allergic manifestations such as rash, fever, lymphadenopathy, facial edema, eosinophilia, and atypical lymphocytosis. These features of hypersensitivity may precede the hepatic manifestations but in other cases arise days or weeks after initial presentation with symptoms of liver disease. The pattern of injury is most often mixed, but it can be markedly cholestatic or markedly hepatocellular. For unknown reasons, injury in children and young adults is more often hepatocellular, while cholestatic cases occur more frequently in the elderly. The course of the liver injury may be short-lived with rapid recovery or complicated and prolonged. Cases with cholestatic sulfasalazine related liver injury are often prolonged and some are accompanied by varying degrees of bile duct injury and loss leading to vanishing bile duct syndrome and chronic cholestasis which, if severe, can lead to biliary cirrhosis, chronic liver failure, and death or need for liver transplantation. However, vanishing bile duct syndrome usually improves spontaneously over time, with gradual resolution of jaundice and symptoms, leaving minor alkaline phosphatase and GGT elevations may persist for years.

Sulfasalazine is a well-known cause of drug-reaction with eosinophilia and systemic symptoms (DRESS) syndrome. At least 75% of such cases are associated with some degree of liver injury, usually with only transient and minor elevations of liver related enzymes, but sometimes with moderate or severe liver injury. Finally, rare instances of Stevens Johnson syndrome (SJS) and toxic epidermal necrosis (TEN) have been linked to sulfasalazine therapy. Liver injury is not uncommon with these severe cutaneous reactions, but the liver abnormalities are usually overshadowed by the cutaneous manifestations.

Hepatocellular forms of sulfasalazine vary greatly in severity from asymptomatic aminotransferase elevations to acute hepatitis with jaundice to cases of acute liver failure leading to death or emergency liver transplantation. The fatality rate of sulfasalazine induced acute hepatocellular injury accompanied by jaundice (so called “Hy’s Law cases”) is at least 10%. Nevertheless, most cases of sulfasalazine liver injury resolve rapidly once the medication is withdrawn, usually within 2 to 4 weeks unless cholestasis is severe.

Because sulfasalazine is given chronically, rare instances of late onset of drug induced liver disease have been reported, but the characteristic signature and pattern of injury is different from typical sulfasalazine injury, and the role of other medications or an underlying autoimmune condition in these late onset cases has yet to be resolved. Chronic therapy may also be associated with mild and transient ALT elevations either alone or as a part of a generalized hypersensitivity reaction. Acute hypersensitivity reactions from many medications can be accompanied by granulomas in the liver, but also in the skin, lymph nodes, and other internal organs.

Likelihood score: A (well established cause of clinically apparent acute liver injury)

Mechanism of Injury

The clinical pattern of injury with sulfasalazine suggests a drug-allergy or hypersensitivity mechanism, perhaps through the metabolism of the sulfonamide component to a toxic, reactive or antigenic metabolite. Sulfasalazine associated DRESS syndrome has been linked to HLA-B*13:01 in a large series from China. In large series on DRESS syndrome, sulfasalazine has .

The other component of sulfasalazine is 5-aminosalicyclic acid (5-ASA) with can also cause idiosyncratic liver injury, but far less commonly. 5-ASA is active locally in the large intestine and plasma levels are not very high.

Outcome and Management

Sulfasalazine induced liver injury can result in minor ALT and alkaline phosphatase elevations (sometimes with other signs of hypersensitivity and with hepatic granulomas), acute self-limited hepatitis and even acute liver failure. Most cases resolve rapidly with discontinuation of drug, and full recovery is expected within 2 to 8 weeks. Cases with rash, fever, and other signs of hypersensitivity often treated with a short course of corticosteroids, which appears to shorten the duration of signs and symptoms but has not been shown to change the ultimate outcome of hepatic injury. Corticosteroids do not appear to benefit cholestatic injury without allergic or hypersensitivity manifestations and demonstrate no evidence of benefit for the vanishing bile duct syndrome.

Importantly, rechallenge should not be done, and patients should be told that they are allergic to sulfonamides (“sulfa-drugs”) and should not receive other drugs in this class. The other component of sulfasalazine is 5-aminosalicyclic acid (5-ASA) with can also cause idiosyncratic liver injury. Prednisone has been used with variable success but may be particularly helpful in patients with prominent allergic features with systemic features and fever, severe rash, arthralgias, lymphadenopathy, facial edema, and eosinophilia or atypical lymphocytosis. There are rare reports of recurrence of similar but mild injury after switching from sulfasalazine to products with 5-ASA alone such as mesalamine. But there is no evidence of cross sensitivity to hepatic injury with most other biologic or small molecule drugs used to treat ulcerative colitis or rheumatoid arthritis.

Drug Class: Antiinfective Agents, Sulfonamides

Other agents in this subclass: Dapsone, Sulfadiazine, Sulfadoxine-Pyrimethamine, Sulfamethoxazole-Trimethoprim, Sulfasalazine, Sulfinpyrazone, Sulfisoxazole

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Sulfasalazine – Generic, Azulfidine®

DRUG CLASS

Antiinfective Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Sulfasalazine 599-79-1 C18-H14-N4-O5-S image 134976371 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 10 January 2025

Abbreviations: TMP/SMZ, trimethoprim and sulfamethoxazole

  • Zimmerman HJ. Sulfonamides. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999, pp. 606-9.
    (Expert review of the sulfonamides and sulfones published in 1999; sulfonamides are thought to cause clinically apparent liver injury in 0.5-1.0% of recipients generally with a sudden onset within 14 days of starting, often with immunoallergic features and a hepatocellular or mixed pattern of injury; mortality may be as high as 10%).
  • Moseley RH. Sulfonamides. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 463-82.
    (Review of hepatotoxicity of antibiotics including sulfonamides).
  • MacDougall C. Sulfonamides, trimethoprim-sulfamethoxazole, quinolones, and agents for urinary tract infections. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 1011-1021.
    (Textbook of pharmacology and therapeutics).
  • MacNaughton WK, Sharkey KA. Pharmacotherapy of inflammatory bowel disease. In, Brunton LL, Hilal-Dandan R, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 13th ed. New York: McGraw-Hill, 2018, pp. 945-954.
    (Textbook of pharmacology and therapeutics).
  • Das KM, Eastwood MA, McManus JP, Sircus W. Adverse reactions during salicylazosulfapyridine therapy and the relation with drug metabolism and acetylator phenotype. N Engl J Med 1973; 289: 491-5. [PubMed: 4146729]
    (Slow acetylators of sulfapyridine were more likely to have side effects and high serum levels).
  • Rafoth RJ. Systemic granulomatous reaction to salicylazosulfapyridine (Azulfidine) in a patient with Crohn's disease. Am J Dig Dis 1974; 19: 465-9. [PubMed: 4151115]
    (35 year old woman developed Stevens Johnson syndrome with minimal Alk P elevations, peak bilirubin 1.8 mg/dL, 19 days after starting sulfasalazine [Azulfidine]; liver and lymph node biopsies showed granulomas).
  • Chester AC, Diamond LH, Schreiner GE. Hypersensitivity to salicylazosulfapyridine: renal and hepatic toxic reactions. Arch Intern Med 1978; 138: 1138-9. PMID: 27155 [PubMed: 27155]
    (19 year old woman developed fever, rash, eosinophilia, adenopathy and jaundice arising 3 weeks after starting sulfasalazine [bilirubin 6.5 mg/dL, AST 1060 U/L], with accompanying nephritis, resolving after 2 weeks of prednisone).
  • Callen JP, Soderstrom RM. Granulomatous hepatitis associated with salicylazosulfapyridine therapy. South Med J 1978; 71: 1159-60. PMID: 28568 [PubMed: 28568]
    (36 year old woman developed drug-fever on sulfasalazine with minimal ALT elevations and granulomas on liver biopsy that resolved with discontinuation of drug, follow up biopsy was normal).
  • Sotolongo RP, Neefe LI, Rudzki C, Ishak KG. Hypersensitivity reaction to sulfasalazine with severe hepatotoxicity. Gastroenterology 1978; 75: 95-9. PMID: 45581 [PubMed: 45581]
    (19 year old woman developed nausea 2 weeks after starting sulfasalazine for inflammatory bowel disease followed by fever and rash [bilirubin 0.8 rising to 5.6 mg/dL, AST 109 U/L, Alk P 322 U/L. 10% eosinophils], treated with prednisolone and recovered in 1 month).
  • Jacobs E, Paulet P, Rahier J. Hypersensitivity reaction to sulfasalazine--another case. Gastroenterology 1978; 75: 1193. PMID: 30678 [PubMed: 30678]
    (19 year old female with Crohn disease developed jaundice with high ALT levels, rash, fever, eosinophilia and lymphadenopathy after 8 weeks of sulfasalazine therapy, resolving within 4 weeks).
  • Kanner RS, Tedesco FJ, Kalser MH. Azulfidine- (sulfasalazine-) induced hepatic injury. Am J Dig Dis 1978; 23: 956-8. PMID: 31085 [PubMed: 31085]
    (13 year old girl developed fever, rash, eosinophilia, lymphadenopathy and atypical lymphocytosis 3 weeks after starting sulfasalazine [bilirubin 4.1 mg/dL, AST 228 U/L, Alk P 149 U/L], rechallenge led to severe hepatocellular injury within 1 day).
  • Mihas AA, Goldenberg DJ, Slaughter RL. Sulfasalazine toxic reactions. Hepatitis, fever, and skin rash with hypocomplementemia and immune complexes. JAMA 1978; 239: 2590-1. PMID: PMID: 26816 [PubMed: 26816]
    (26 year old man developed jaundice, fever, rash, adenopathy, atypical lymphocytosis and systemic symptoms 3 weeks after starting sulfasalazine for Crohn disease [bilirubin 1.5 mg/dL, ALT 680 U/L, Alk P 680 U/L, 12% eosinophils], resolving by 12 weeks with prednisone).
  • Gulley RM, Mirza A, Kelly CE. Hepatotoxicity of salicylazosulfapyridine: a case report and review of the literature. Am J Gastroenterol 1979; 72: 561-4. PMID: 43669 [PubMed: 43669]
    (20 year old woman with Crohn disease developed fever 3 weeks after starting sulfasalazine accompanied by a mixed pattern of serum enzyme elevations without jaundice and had recurrence with a similar anicteric pattern 4 days after restarting).
  • Iwarson S, Lundin P. Multiple attacks of jaundice associated with repeated sulfonamide treatment. Acta Med Scand 1979; 206: 219-22. [PubMed: 495230]
    (Four women, ages 20, 30, 35 and 68 years, who had repeated episodes of liver injury after sulfonamides with shortening of latency upon re-exposure, but no worsening of injury [usually hepatocellular] or slowing of resolution, which ranged from 4-12 weeks).
  • Losek JD, Werlin SL. Sulfasalazine hepatotoxicity. Am J Dis Child 1981; 135: 1070-2. [PubMed: 6117199]
    (13 year old boy with Crohn disease developed fever and rash 11 days after starting sulfasalazine with subsequent marked rise in AST [1743 U/L], but normal bilirubin and rapid resolution; positive rechallenge to single dose with rash, fever and minimal ALT elevation within 1 day).
  • Namias A, Bhalotra R, Donowitz M. Reversible sulfasalazine-induced granulomatous hepatitis. J Clin Gastroenterol 1981; 3: 193-8. [PubMed: 6113258]
    (25 year old man developed fever and jaundice [bilirubin rising to 4.0 mg/dL, ALT to ~775 U/L] 19 days after starting sulfasalazine, resolving within 6 weeks of stopping while on prednisone; liver biopsy showed granulomas).
  • Døssing M, Andreasen PB. Drug-induced liver disease in Denmark. An analysis of 572 cases of hepatotoxicity reported to the Danish Board of Adverse Reactions to Drugs. Scand J Gastroenterol 1982; 17: 205-11. [PubMed: 6982502]
    (572 reports of drug induced liver injury from 1968-78 were analyzed, representing 6% of total adverse reaction reports and 12% of those that were fatal; halothane accounted for 25% of cases, chlorpromazine 9%, sulfonamides 9%, antituberculosis agents 7%, oxyphenisatin 4% and methyldopa 2%).
  • Larcan A, Lambert H, Janot C, Perarnaud J, Delorme N, Tonnel F. [Fatal hepatitis during sulfasalazine treatment] Therapie 1982; 37: 315-9. French. PMID: 6127817 [PubMed: 6127817]
    (17 year old with Crohn disease developed rash, eosinophilia, and severe hepatocellular injury with jaundice [bilirubin 3.7 mg/dL, ALT 1050 U/L, Alk P 500 U/L] 3 weeks after starting sulfasalazine, progressing to acute liver failure and death).
  • Smith MD, Gibson GE, Rowland R. Combined hepatotoxicity and neurotoxicity following sulphasalazine administration. Aust N Z J Med 1982; 12: 76-80. [PubMed: 6123306]
    (Two cases of hepatocellular injury arising 3 and 5 weeks after starting sulfasalazine with rash, fever, jaundice, and neurologic signs of confusion, hallucinations, and stiff neck; rapid recovery after stopping and with prednisone therapy).
  • Lennard TW, Farndon JR. Sulphasalazine hepatotoxicity after 15 years’ successful treatment for ulcerative colitis. Br Med J (Clin Res Ed) 1983; 287: 96. [PMC free article: PMC1548387] [PubMed: 6134567]
    (37 year old man with ulcerative colitis developed asymptomatic elevations in Alk P [380 U/L] and AST [49 U/L] after 15 years of sulfasalazine use, with positive rechallenge, prednisone also used and issue of sclerosing cholangitis and autoimmune hepatitis not completely addressed).
  • Holdsworth CD. Sulphasalazine hepatotoxicity after 15 years' treatment. Br Med J (Clin Res Ed) 1983; 287: 759. [PMC free article: PMC1549046] [PubMed: 6137258]
    (Letter in response to Lennard [1983] discussing possibility of sclerosing cholangitis in view of presence of ulcerative colitis).
  • Taffet SL, Das KM. Sulfasalazine. Adverse effects and desensitization. Dig Dis Sci 1983; 28: 833-42. [PubMed: 6136396]
    (Review article on adverse effects of sulfasalazine with mention of 14 case reports of liver injury, 5 with positive rechallenge, some fatal and some with granulomas).
  • Fich A, Schwartz J, Braverman D, Zifroni A, Rachmilewitz D. Sulfasalazine hepatotoxicity. Am J Gastroenterol 1984; 79: 401-2. [PubMed: 6144268]
    (Two cases: 52 year old woman and 32 year old man with inflammatory bowel disease had hypersensitivity reactions to sulfasalazine with ALT and Alk P elevations, but no jaundice, resolving with discontinuation).
  • Farr M, Symmons DP, Bacon PA. Raised serum alkaline phosphatase and aspartate transaminase levels in two rheumatoid patients treated with sulphasalazine. Ann Rheum Dis 1985; 44: 798-800. [PMC free article: PMC1001781] [PubMed: 2865931]
    (Two women, ages 71 and 72 years, had marked Alk P elevations [745 and >2000 U/L] starting within 1 week of starting sulfasalazine for rheumatoid arthritis, without allergic manifestations, resolving slowly after stopping).
  • Haines JD Jr. Hepatotoxicity after treatment with sulfasalazine. Postgrad Med 1986; 79: 193-4, 197-8. [PubMed: 2871549]
    (42 year old man with Crohn disease had onset of rash, fever, and abdominal pain 18 days after starting sulfasalazine followed by jaundice and progressive hepatic failure [ALT 3700 U/L, Alk P 619 U/L, bilirubin 18.4 mg/dL], leading to multiorgan failure and death; autopsy showed massive necrosis).
  • Jennings PE, Blandford RL, Rosenthal FD. Acute sulphasalazine hepatotoxicity. Postgrad Med J 1986; 62: 305-6. [PMC free article: PMC2418655] [PubMed: 2872666]
    (37 year old man with severe hepatocellular injury [bilirubin 6.9 mg/dL, ALT 1994 U/L, Alk P 271 U/L] starting with rash 2 weeks after starting sulfasalazine, slow to resolve).
  • Labadie H, Beaugrand M, Ferrier JP. [Hepatitis and mononucleosis syndrome related to the ingestion of salazosulfapyridine]. Rev Med Interne 1986; 7: 35-40. French. PMID: 2871605 [PubMed: 2871605]
    (25 year old developed fever and rash 7 days after starting sulfasalazine with atypical lymphocytosis, but negative EBV testing [bilirubin 1.5 mg/dL, ALT 1035 U/L, Alk P 250 U/L]).
  • MacGilchrist AJ, Hunter JA. Sulphasalazine hepatotoxicity: lack of a hypersensitivity response. Ann Rheum Dis 1986; 45: 967-8. [PMC free article: PMC1002032] [PubMed: 2878646]
    (50 year old woman with rheumatoid arthritis developed anorexia and abdominal pain 11 weeks after starting sulfasalazine; no features of hypersensitivity [bilirubin normal, ALT 1449 U/L, Alk P 230 U/L], resolving within 17 days of stopping).
  • Poland GA, Love KR. Marked atypical lymphocytosis, hepatitis, and skin rash in sulfasalazine drug allergy. Am J Med 1986; 81: 707-8. [PubMed: 2876632]
    (38 year old man developed rash, fever, myalgias, and facial edema with eosinophilia, atypical lymphocytosis and liver test abnormalities, within 2 weeks of starting sulfasalazine [bilirubin 2.8 mg/dL, ALT 202 U/L, Alk P 465 U/L], resolving rapidly with prednisone).
  • Ribe J, Benkov KJ, Thung SN, Shen SC, LeLeiko NS. Fatal massive hepatic necrosis: a probable hypersensitivity reaction to sulfasalazine. Am J Gastroenterol 1986; 81: 205-8. [PubMed: 2869683]
    (15 year old boy developed severe hepatocellular injury and rash starting within 2 weeks of starting sulfasalazine, treated with prednisone and relapse of jaundice and rash when tapered; patient died of acute hemorrhage, probably from corticosteroids rather than hepatic injury).
  • Coumaros D, Georges C, Zerbe S. Salicylazosulfapyridine (SASP) hepatitis: role of 5-aminosalicylic acid (5-ASA). Scand J Gastroenterol 1989; 24 (suppl 158): 132-3. Not in PubMed
    (26 year old woman found to have elevated ALT [5.5 times ULN] 1 year after starting sulfasalazine, not resolving until both sulfonamide and 5-ASA were stopped).
  • Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ 1989; 298: 82-6. [PMC free article: PMC1835436] [PubMed: 2563951]
    (In a multicenter controlled trial of 5-ASA [mesalazine] vs sulfasalazine in 164 patients, the two agents had similar efficacy, but there were fewer hypersensitivity effects with mesalazine; nevertheless, 3% of 5-ASA treated patients developed raised ALT values and one developed hepatitis with jaundice).
  • Brooks H, Taylor HG, Nichol FE. The three week sulphasalazine syndrome. Clin Rheumatol 1992; 11: 566-8. [PubMed: 1362531]
    (53 year old man with rheumatoid arthritis developed fever, rash, atypical lymphocytes, eosinophilia, and low complement levels, similar to serum sickness 2 weeks after starting sulfasalazine [bilirubin 6.0 rising to 8.9 mg/dL, ALT 231 U/L, Alk P 706 U/L], with slow recovery despite corticosteroids).
  • Hautekeete ML, Bourgeois N, Potvin P, Duville L, Reynaert H, Devis G, Adler M, et al. Hypersensitivity with hepatotoxicity to mesalazine after hypersensitivity to sulfasalazine. Gastroenterology 1992; 103: 1925-7. [PubMed: 1360436]
    (21 year old woman developed rash 3 weeks after starting sulfasalazine, recurring 1 day after starting mesalazine [5-ASA] alone [bilirubin 2.5 mg/dL, ALT 102 U/L, Alk P 560 U/L]; went on to develop liver failure, but ultimately survived).
  • Leroux JL, Ghezail M, Chertok P, Blotman F. Hypersensitivity reaction to sulfasalazine: skin rash, fever, hepatitis and activated lymphocytes. Clin Exp Rheumatol 1992; 10: 427. [PubMed: 1356682]
    (45 year old woman with rheumatoid arthritis developed fever, rash and facial edema 3 weeks after starting sulfasalazine [bilirubin not given, ALT 39 U/L, Alk P 212 U/L, eosinophils 50%], with rapid recovery upon stopping).
  • Cribb AE, Pohl LR, Spielberg SP, Leeder JS. Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins. J Pharmacol Exp Ther 1997; 282: 1064-71. [PubMed: 9262376]
    (Comprehensive review of the major and minor side effects of sulfonamides including discussion of mechanisms).
  • Stoschus B, Meybehm M, Spengler U, Scheurlen C, Sauerbruch T. Cholestasis associated with mesalazine therapy in a patient with Crohn's disease. J Hepatol 1997; 26: 425-8. [PubMed: 9059966]
    (30 year old man developed nausea and jaundice 4 months after starting mesalazine [5-ASA] [bilirubin 6.0 mg/dL, ALT 393 U/L, Alk P 201 U/L]; no hypersensitivity features; resolving within 6 weeks of stopping therapy).
  • Besnard M, Debray D, Durand P, Cézard JP, Navarro J. Sulfasalazine-induced fulminant hepatitis in pediatric Crohn's disease: report of two cases. J Pediatr Gastroenterol Nutr 1998; 26: 119-20. [PubMed: 9443132]
    (2 cases of 10 year olds [1 boy, 1 girl] developing fever, rash, arthralgias, and eosinophilia 2-3 weeks after starting sulfasalazine, both progressing to acute liver failure).
  • Deltenre P, Berson A, Marcellin P, Degott C, Biour M, Pessayre D. Mesalazine (5-aminosalicylic acid) induced chronic hepatitis. Gut 1999; 44: 886-8. [PMC free article: PMC1727547] [PubMed: 10323894]
    (65 year old man developed elevated ALT levels [8-12 times ULN] without jaundice after 6 months of mesalazine therapy that continued for 10 months and was associated with autoantibodies [ANA 1:500, SMA 1:200] and chronic hepatitis on biopsy; resolved rapidly once drug was stopped).
  • Lau G, Kwan C, Chong SM. The 3-week sulphasalazine syndrome strikes again. Forensic Sci Int 2001; 122: 79-84. [PubMed: 11672959]
    (34 year old woman developed fever, rash, and lymphadenopathy 17 days after starting sulfasalazine, with subsequent hepatocellular jaundice [bilirubin 8.9 mg/dL, ALT 10,000 U/L, Alk P 515 U/L], progressing to liver failure and death).
  • Ransford RA, Langman MJ. Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines. Gut 2002; 51: 536-9. [PMC free article: PMC1773410] [PubMed: 12235076]
    (Survey of adverse drug reaction reporting on 5-ASA vs sulfasalazine – UK from 1991-8 – found sulfasalazine more commonly causes liver injury ~0.6 vs 0.32/100,000 exposures).
  • Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, Lenoir C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002; 36: 451-5. [PubMed: 12143055]
    (All adverse drug reactions from French region from 1997-2000 found 34 cases of liver injury, 40 drugs involved, 2 possibly due to sulfasalazine).
  • Halmos B, Anastopoulos HT, Schnipper LE, Ballesteros E. Extreme lymphoplasmacytosis and hepatic failure associated with sulfasalazine hypersensitivity reaction and a concurrent EBV infection--case report and review of the literature. Ann Hematol 2004; 83: 242-6. [PubMed: 13680174]
    (34 year old man with Crohn disease developed fever, rash, atypical lymphocytosis, and hepatic failure after 1 day of restarting sulfasalazine, [bilirubin rising from 4.0 to 10.4 mg/dL, AST 1628 U/L, 10% eosinophilia], with apparent beneficial response to prednisone).
  • Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin North Am 2004; 24: 477-90, vii. PMID: 15242722 [PubMed: 15242722]
    (Review of mechanisms of hypersensitivity to sulfonamides).
  • de Abajo FJ, Montero D, Madurga M, Rodriguez LAG. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Brit J Clin Pharm 2004; 58: 71-80. [PMC free article: PMC1884531] [PubMed: 15206996]
    (Analysis of General Practice Research Database from UK on 1.6 million persons from 1994-2000 found 128 cases of drug induced liver injury [2.4/100,000 person-years]; sulfasalazine was taken by 4 of 128 cases [3%], compared to 5 of 5000 controls [adjusted odds ratio 25.5]).
  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]
    (Among ~50,000 liver transplants done in the US between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, 3 of which were attributed to sulfasalazine and 1 to TMP-SMZ).
  • Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]
    (Among 103 cases of fulminant drug induced liver injury reported to a Swedish registry between 1966 and 2002, 6 cases were attributed to TMP-SMZ, 3 to sulfonamides and 1 to sulfasalazine [~10% overall]).
  • Descloux E, Argaud L, Dumortier J, Scoazec JY, Boillot O, Robert D. Favourable issue of a fulminant hepatitis associated with sulfasalazine DRESS syndrome without liver transplantation. Intensive Care Med 2005; 31: 1727-8. [PubMed: 16283166]
    (45 year old woman developed rash 15 days after starting sulfasalazine and subsequently developed fever, eosinophilia, and progressive liver injury leading to liver failure and death; autopsy showed massive necrosis).
  • Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. [PubMed: 16083708]
    (Reports to a Spanish network between 1994-2004, included 461 cases of drug induced liver disease; sulfonamides were not mentioned in the top 19 causes [drugs with 5 or more cases]).
  • Garcia Rodriguez LA, Ruigomez A, Jick H. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-1101. [PubMed: 16165719]
    (Among 103 cases of fulminant drug induced liver injury reported to a Swedish registry between 1966 and 2002, 6 cases were attributed to TMP-SMZ, 3 to sulfonamides and 1 to sulfasalazine [~10% overall]).
  • Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. [PubMed: 16054882]
    (Survey of drug induced liver fatalities reported to WHO database between 1968-2003 revealed 4690 reports – 89% from the US; 21 drugs were associated with more than 50 cases each, including TMP-SMZ [ranking 10th]).
  • Teo L, Tan E. Sulphasalazine-induced DRESS. Singapore Med J. 2006; 47: 237-9. [PubMed: 16518561]
    (49 year old woman developed purpuric rash and eosinophilia after 4 weeks of sulfasalazine therapy accompanied by serum enzyme elevations [ALT 171 U/L, Alk P 115 U/L] but no jaundice, rapidly resolving after stopping).
  • Jobanputra P, Amarasena R, Maggs F, Homer D, Bowman S, Rankin E, Filer A, Raza K, Jubb R. Hepatotoxicity associated with sulfasalazine in inflammatory arthritis: A case series from a local surveillance of serious adverse events. BMC Musculoskelet Disord 2008; 9: 48. [PMC free article: PMC2329632] [PubMed: 18405372]
    (Ten cases of sulfasalazine hepatotoxicity identified in a UK rheumatology service over 7 year period; usual onset in 2-42 days, 7 with rash, 3 eosinophilia, 5 cases in blacks, two patients required liver transplantation; estimated frequency of 4 per thousand patients exposed).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, et al; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 9 were due to TMP-SMZ, which ranked 4th as a cause).
  • Jobanputra P. BSR DMARD monitoring guidelines: sulfasalazine. Rheumatology (Oxford) 2008; 47:1587-8. [PubMed: 18723518]
    (Letter in response to published guidelines on sulfasalazine stressing the severe, but rare complication of hepatitis [0.4%] which can lead to acute liver failure).
  • Björnsson E, Davidsdottir L. The long-term follow-up after idiosyncratic drug-induced liver injury with jaundice. J Hepatol 2009; 50: 511-7. [PubMed: 19155082]
    (Among 685 patients identified an average of 10 years after an episode of drug induced liver injury, 23 [3.4%] had continuing liver disease, 8 with cirrhosis; none were attributed to a sulfonamide).
  • Gutierrez M, Filippucci E, Bugatti L, Bertolazzi C, Grassi W. [Severe drug hypersensitivity syndrome due to sulphasalazine in patient with rheumatoid arthritis]. Reumatismo 2009; 61: 65-8. Italian. PMID: 19370190 [PubMed: 19370190]
    (60 year old man with rheumatoid arthritis developed rash, facial edema and fever 32 days after starting sulfasalazine [bilirubin normal, ALT 74 U/L, Alk P 142 U/L, 6% eosinophils], resolution with prednisone).
  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: PMID: 2396-404. [PubMed: 20648003]
    (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; dapsone accounted for 17 cases [5.4%] of which 2 were fatal, and TMP-SMZ accounted for 7 cases [2.2%], but none were fatal).
  • Lens S, Crespo G, Carrión JA, Miquel R, Navasa M. Severe acute hepatitis in the DRESS syndrome: Report of two cases. Ann Hepatol 2010; 9 (2): 198-201. [PubMed: 20526017]
    (Two cases of DRESS syndrome; case 1, a 29 year old woman who developed fever, rash, eosinophilia, and jaundice 8 weeks after starting sulfasalazine [bilirubin 13.5 mg/dL, ALT 1117 U/L, Alk P 1171 U/L, INR 3.2] with signs of hepatic failure, but ultimate recovery on corticosteroids within 21 days; case 2 attributed to levetiracetam).
  • Khokhar OS, Lewis JH. Hepatotoxicity of agents used in the management of inflammatory bowel disease. Dig Dis 2010; 28: 508-18. [PubMed: 20926880]
    (Review of liver toxicity of drugs for inflammatory bowel disease; sulfasalazine is cited as causing an acute hypersensitivity like reaction with fever, rash, and liver involvement, and both a granulomatous and a cholestatic form of liver injury and rarely acute liver failure).
  • Rogler G. Gastrointestinal and liver adverse effects of drugs used for treating IBD. Best Pract Res Clin Gastroenterol 2010; 24: 157-65. [PubMed: 20227029]
    (Review of GI and liver side effects of drugs of inflammatory bowel disease; sulfasalazine is listed as causing “abnormal liver function” tests in 4% of patients).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury including 12 due to sulfonamides [9%], 9 due to SMZ/TMP, and 3 due to sulfasalazine).
  • Anelli MG, Scioscia C, Grattagliano I, Lapadula G. Old and new antirheumatic drugs and the risk of hepatotoxicity. Ther Drug Monit 2012; 34: 622-8. [PubMed: 23128910]
    (Review of liver injury caused by antirheumatic agents; sulfasalazine can cause liver injury in 1:1000 recipients, usually arising in the first month of treatment often with immunoallergic features and with typical signs of DRESS syndrome in some patients).
  • Descamps V. [Drug reaction with eosinophilia and systemic symptoms (DRESS)]. Rev Prat 2012; 62: 1347-52. French. PMID: 23424909 [PubMed: 23424909]
    (Review of clinical features of DRESS syndrome in French).
  • Pirklbauer M, Gruber J. [DRESS syndrome following sulfasalazine treatment.]. Z Rheumatol. 2014; 73(2): 180-3. German. PMID: 24337150 [PubMed: 24337150]
    (33 year old woman with juvenile idiopathic arthritis developed fever, rash, and dyspnea with cough 4 weeks after starting sulfasalazine [bilirubin not given, ALT 117 U/L, GGT 422 U/L], with pulmonary manifestations of DRESS syndrome, resolving with prednisone therapy).
  • Girelli F, Bernardi S, Gardelli L, Bassi B, Parente G, Dubini A, Serra L, et al. A new case of DRESS syndrome induced by sulfasalazine and triggered by amoxicillin. Case Rep Rheumatol 2013; 2013: 409152. [PMC free article: PMC3723001] [PubMed: 23936716]
    (53 year old woman developed fever and lymphadenopathy 6 weeks after starting sulfasalazine for spondylitis, with subsequent rash and oral ulcers [bilirubin 2.7 mg/dL, ALT 350 U/L, Alk P 2959 U/L], improving with prednisone therapy).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (In a population-based study of drug induced liver injury from Iceland, 96 cases were identified over a 2-year period, including 2 that were attributed to TMP-SMZ).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, including 39 attributed to antimicrobial agents, but none to dapsone, sulfasalazine, or TMP/SMP).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 31 cases were attributed to TMP/SMZ and only 2 cases to dapsone).
  • Chalasani N, Reddy KRK, Fontana RJ, Barnhart H, Gu J, Hayashi PH, Ahmad J, et al. Idiosyncratic drug induced liver injury in African-Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol 2017; 112: 1382-8. [PMC free article: PMC5667647] [PubMed: 28762375]
    (Among 985 patients enrolled in a US prospective database of drug induced liver injury between 2004 and 2016, SMZ/TMP was the most implicated medication among 144 African Americans [7.6%], but ranked fifth among 841 Caucasians [3.6%] behind amoxicillin-clavulanate, nitrofurantoin, anabolic steroids and isoniazid).
  • Sussman S, Devlin V, Dimitriades VR. A teenager with sulfasalazine-associated dress syndrome after the introduction of amoxicillin. Clin Pediatr (Phila). 2017;56:290-291. [PubMed: 27356629]
    (16 year old male with ulcerative colitis developed fever and abdominal pain 3 weeks after starting sulfasalazine was treated with amoxicillin and presented with rash, lymphadenopathy, and eosinophilia [800 cells/μL] and serum aminotransferase elevations [ALT 255 U/L] without jaundice one week later, symptoms and lab tests resolving with corticosteroids).
  • Liang J, Qu H, Wang X, Wang A, Liu L, Tu P, Li R, Wang M. Drug reaction with eosinophilia and systemic symptoms associated with reactivation of Epstein-Barr virus and/or cytomegalovirus leading to hemophagocytic syndrome in one of two patients. Ann Dermatol. 2018;30:71-74. [PMC free article: PMC5762479] [PubMed: 29386835]
    (Two patients, 38 year old woman and 37 year old man, developed fever followed by pruritus 4 weeks after starting sulfasalazine and 3 weeks after starting a beta lactam antibiotic with ALT 212 and 123 U/L, bilirubin 1.4 mg/dL and normal, both with evidence of Ebstein Barr Virus reactivation).
  • Wu X, Yang F, Chen S, Xiong H, Zhu Q, Gao X, Xing Q, et al. Clinical, viral and genetic characteristics of drug reaction with eosinophilia and systemic symptoms (DRESS) in Shanghai, China. Acta Derm Venereol. 2018;98:401-405. [PubMed: 29242946]
    (Between 2011 and 2016, 52 patients were seen with DRESS syndrome at a single referral center in Shanghai, all had rash and 83% had liver test abnormalities, and 10 with EBV DNA in serum; 18 due to allopurinol, 11 sulfasalazine, and 5 carbamazepine, 3 deaths; HLA-B*13:01 in 7 of 11 sulfasalazine cases [64% vs 15% of controls] and HLA-B*58:01 in all 18 allopurinol cases [100% vs 17% of controls]).
  • Jeimy S, McRae K, Pattani R. A 63-year-old returned traveler with fever, rash, hepatitis and eosinophilia. CMAJ. 2018;190:E831-E835. [PMC free article: PMC6041246] [PubMed: 29986859]
    (63 year old woman with rheumatoid arthritis developed rash and fever 1 month after starting sulfasalazine [bilirubin 0.8 rising to 3.2 mg/dL, ALT 418 U/L, Alk P 402 U/L, eosinophils 1376/μL])
  • Sil A, Bhattacharjee MS, Chandra A, Pramanik JD. Sulfasalazine-induced drug reaction with eosinophilia and systemic symptoms (DRESS) with concomitant acute chikungunya virus infection: possible role of new viral trigger. BMJ Case Rep. 2021;14:e244063. [PMC free article: PMC8513226] [PubMed: 34642219]
    (30 year old Indian man developed fever and rash 2 months after starting sulfasalazine for joint pain was thought to have chikungunya virus infection but developed facial edema and lymphadenopathy with leukocytosis and eosinophilia [21%] and ALT elevation [190 U/L] and was treated with prednisone for suspected DRESS syndrome with gradual response and no relapse when corticosteroids were stopped).
  • Jayachandran M, Koshy V, David R, Santhakumari V, Padmanabhan DS, Surendran S, Tiwari A, et al. Adverse reaction profile of sulfasalazine and its persistence in chronic therapy of rheumatoid arthritis and spondyloarthritis: A multicentric observational study. Int J Clin Pharmacol Ther. 2022;60:327-335.. [PubMed: 35713159]
    (Among 1114 patients with rheumatoid arthritis or spondyloarthritis being treated with sulfasalazine in one of 6 centers across India, 10% discontinued therapy because of adverse events including liver injury, usually during the first year of therapy: Abstract only).
  • Fontana RJ, Kleiner DE, Chalasani N, Bonkovsky H, Gu J, Barnhart H, Li YJ, et al. The impact of patient age and corticosteroids in patients with sulfonamide hepatotoxicity. Am J Gastroenterol. 2023;118:1566-1575.. [PMC free article: PMC10511659] [PubMed: 36848311]
    (Among 105 cases of sulfonamide induced liver injury enrolled in a prospective U.S. database between 2004 and 2020, 93 were attributed to TMP-SMZ, 9 to sulfasalazine, 2 to dapsone, and 1 to sulfadiazine).
  • Kuchinskaya EM, Chikova IA, Kostik MM. Case report: sulfasalazine-induced hypersensitivity. Front Med (Lausanne). 2023;10:1140339. [PMC free article: PMC10244625] [PubMed: 37293296]
    (12 year old girl with juvenile idiopathic arthritis developed fever and rash 17 days after starting sulfasalazine [bilirubin not given, ALT 150 rising to 1436 U/L, Alk P not given, eosinophil count not given] with leukocytosis, atypical lymphocytes, thrombocytopenia and ascites, responding to high dose methylprednisolone and subsequent gradual taper).
  • Chen VL, Rockey DC, Bjornsson ES, Barnhart H, Hoofnagle JH; Drug-Induced Liver Injury Network Investigators. Incidence of idiosyncratic drug-induced liver Injury caused by prescription drugs. Drug Saf. 2025;48:151-160. 39317916. [PMC free article: PMC11785493] [PubMed: 39317916]
    (Analysis of 1284 cases of drug-induced liver injury enrolled in a U.S. prospective study, identified 11 cases [6%] attributed to sulfasalazine placing it in one of the top 25 agents causing liver injury and occurring at an estimated rate of 1 per 820 persons treated [95% CI = 1:370-1:1800]).
  • Bessone F, Hernandez N, Medina-Caliz I, García-Cortés M, Schinoni MI, Mendizabal M, Chiodi D, et al. Drug-induced liver injury in Latin America: 10-year experience of the Latin American DILI (LATINDILI) Network. Clin Gastroenterol Hepatol. 2025;23:89-102.. [PubMed: 38992407]
    (Among 483 cases of drug-induced liver injury enrolled in a prospective Latin American database, only one was attributed to sulfasalazine [0.2%] while 12 cases [0.7%] were reported from a concurrent US database).
  • Karna NK, Osti A, Pokhrel G, Karna N, Thakur RK, Sigdel S. Concurrent acute interstitial nephritis with acute pyelonephritis in DRESS syndrome: a rare case report. Ann Med Surg (Lond). 2025;87:3925-3930. [PMC free article: PMC12140792] [PubMed: 40486566]
    (19 year old Nepalese woman developed fever, rash, and facial edema 2 months after starting sulfasalazine for back pain and TMP/SMZ for urinary tract infections [peak bilirubin 2.3 mg/dL, ALT 1306 U/L, Alk P 196 U/L, eosinophilia 11%, serum albumin 2.0 g/dL, proteinuria 4 g/24 hours] responding to high dose methylprednisolone and tapering doses of corticosteroids with ultimate resolution of both the liver and renal abnormalities).
  • Andrews MB, Patrone MV, Bickston SJ. Drug reaction with eosinophilia and systemic symptoms (dress) syndrome following initiation of sulfasalazine for ulcerative colitis: a yearlong clinical challenge. Case Rep Gastrointest Med. 2025;2025:8870613. [PMC free article: PMC12182433] [PubMed: 40546655]
    (34 year old African American woman with ulcerative colitis developed fever, generalized rash, facial edema, and lymphadenopathy 5 weeks after starting sulfasalazine [bilirubin 2.0 mg/dL, ALT 641 rising to 1847 U/L, Alk P 214 to 265 U/L, INR peak 1.8, peak eosinophils 3000/μL] responding to prednisone and cyclosporin but requiring high doses and relapsing repeatedly when drugs were tapered until 1 year after onset when she finally tolerated withdrawal without relapse).

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