CONCISE REPORT Sulphasalazine Induced Three-Week Syndrome Resmy Suresh, MRCP,* Sanjay Gupta, MRCP,† and Rosh Sathananthan, FRCP* S ulfasalazine is a second line drug frequently used for treating rheumatoid arthritis (RA) and other seronegative inflammatory arthritis. It is also used for treatment of inflammatory bowel disease. Because of adverse side effects, about 1 in 5 patients have to stop sulfasalazine and it happens usually in the first 3 months of therapy. 1 The majority of the reactions are minor and can be treated with drug withdrawl. Hepatotoxicity is a rare and potentially fatal side effect. We report such a case of sulfasalazine induced hepatotoxicity which was treated with corticosteroids, and N-acetyl cysteine along with drug withdrawl. A 39-year-old African lady was diagnosed with sero-positive RA. Even though she had severe, active, erosive disease at presen- tation, she was started on sulfasalazine as she had not completed her family history. She also required oral prednisolone to achieve symptom control. Three weeks later she developed a generalized itchy rash on her body with facial swelling, vomiting, and reduced appetite. The sulfasalazine was stopped by her general practioner and she con- tacted the rheumatology department for an urgent appointment. She was reviewed 2 days later when she complained of excessive fatigue and shortness of breath. Examination showed facial edema, painful lymphadenopathy, and an itchy erythematous maculopapular rash. She was afebrile and the rest of her examination was unremarkable except for tenderness in the right upper quadrant of her abdomen. On further questioning she denied recent foreign travel, other risk factors for hepatitis, and excessive alcohol intake. She was admitted for further investigations which showed a hemoglobin 10.2 g/dl, white cell count 8.4  10 9 /L, lymphocytes 5  10 9 /L (including atypical lymphocytes), no eosinophils, platelet count 333  10 9 /L (140 – 400) ESR and CRP were raised to 99 mm/first hr (1–12) and 16 mg/L (0 –5) respectively. Urea, electrolytes and serum glucose were normal. Serum alkaline phosphatase was 468 IU/L (42–128), albumin 33 g/L (34 – 48), aminotransferase 1294 U/L (0 –32), bilirubin 30 mol/L (1–20),  glutamyl transferase 658 u/l (6 – 42), prothrombin time (PT) 16 seconds (9.3–11.3), INR 1.56, amylase 114 u/l. Immunoglobulin (Ig) profile showed high levels of IgG, IgA, and IgM in keeping with acute inflammation although IgM was disproportionately raised with a value of -5.7g/l. 2–4 Hepatitis A, B, C serology, cytomegalovirus serology, and HIV 1/2 were negative. Serum ceruloplasmin and -1anti trypsin levels were raised in keeping with the acute phase response and the autoimmune profile was negative. Ultrasound of the abdomen showed appearances consistent with hepa- titis. CT scan chest abdomen and pelvis was normal. Over the next 2 days there was worsening of her liver function tests (Fig. 1) without hepatic encephalopathy or other signs of decompensation. Her aminotransferase rose to above 4000IU/L, PT to 28 seconds and INR to 2.6. A presumptive diagnosis of sulfasalazine induced hepatitis was made and the patient was started on intravenous N-Acetyl cysteine (NAC) for 5 days. The dose of prednisolone was doubled. Vitamin K 10 mg was given for 3 days. Her liver function tests (LFT) subsequently improved and she was discharged home 10 days after admission. A suspected adverse drug reaction form was filled in. On review in Rheumatology clinic 2 weeks later, the lymphadenopathy had resolved. LFT and CRP had normalized and the ESR was 63 mm/first hour. This patient was admitted with probable sulfasalazine in- duced hepatitis 3 weeks after commencing the drug in keeping with the 3-week syndrome. Three week syndrome is clearly rare 1 and in all reported cases it begins between between 2 and 3 weeks after starting the treatment and is characterized with fever, lymphadenop- athy, and wide spread erythematous rash, followed by rising liver enzymes and bilirubin 1 and rarely reported fatal fulminant hepatic failure. 2 Our patient developed lymphadenopathy, rash and progres- sive hepatitis with transient anemia. She had a raised IgM level and large number of activated lymphocytes often noted as “atypical” on the blood film. In a multicenter study of 1382 RA patients treated with sulfasalazine only 1 patient had a similar reaction. 3 Most of the sulfasalazine related adverse effects occur within the first 3 months of therapy. 3 Sulfasalazine is a recognized cause of DRESS syn- drome (Drug reaction with eosinophilia and systemic symptoms) which is a hypersensitivity reaction due to the sulfapyridine moiety and develops within 2– 6 weeks after initiation of the drug. 4 Classic 3-week sulfasalazine syndrome may be a variant of DRESS syn- drome and physicians and rheumatologists should be aware of this condition because it could mimic other systemic disease and could be fatal. NAC is a metabolite of sulfur containing amino acid cysteine. Cysteine acts as a sulfur donor in phase II detoxification and methyl donor in conversion of homocysteine to methionine. NAC is rapidly metabolized to glutathione thus depleting glutathione reserves (de- pleted by toxic drug metabolite). Glutathione is the strongest anti- oxidant in the body. These actions protect hepatocytes from drug induced toxicity. There is anecdotal evidence of role of NAC in From the *Department of Rheumatology, and the †Department of Gastroenterol- ogy, Mayday University Hospital, Croydon, United Kingdom. Correspondence: Dr. Resmy Suresh, Mayday University Hospital, Croydon CR7 7YE, United Kingdom. E-mail: resmy.suresh@mayday.nhs.uk Copyright © 2009 by Lippincott Williams & Wilkins ISSN: 1076-1608/09/1506-0311 DOI: 10.1097/RHU.0b013e3181bbbcea 0 500 1000 1500 2000 2500 3000 3500 4000 4500 0 10 20 30 40 50 60 70 0 100 200 300 400 500 600 A B - - - BIL ….. ALP ( IU / L ) ( IU / L or μmol/L) ── AST FIGURE 1. Trends of alkaline phosphatase, bilirubin, and se- rum alanine transaminase from day 0 (start of sulfasalazine). A) Time N-acetyl cysteine was started and the dose of pred- nisolone was increased. B) Day of cessation of N—acetyl cys- teine therapy. JCR: Journal of Clinical Rheumatology • Volume 15, Number 6, September 2009 311