Sulfasalazine

Sulfasalazine is a compound of 5-aminosalicylic acid and sulphapyridine joined by an azo bond. It is used in rheumatoid arthritis, spondyloarthritis with peripheral disease and ulcerative colitis. It is a safe option in pregnancy and often a component of triple therapy in rheumatoid arthritis.

Class. Aminosalicylate with sulphonamide moiety, conventional synthetic disease-modifying anti-rheumatic drug.

Mechanism. Azo reduction by colonic bacteria releases mesalazine, acting locally in colitis, and sulphapyridine, which is absorbed and thought to account for most of the anti-rheumatic effect through reduced inflammatory cytokine and antigen presentation signalling.

Pharmacokinetics. About 10 to 15 percent of the parent is absorbed in the small bowel; the remainder reaches the colon. Sulphapyridine is acetylated in the liver, so slow acetylators have higher levels and more toxicity. Onset in arthritis takes 8 to 12 weeks.

Rheumatoid arthritis, psoriatic arthritis and peripheral spondyloarthritis (enteric-coated tablets).

• Start 500 mg daily, orally.

• Titrate by 500 mg each week to 1 g twice daily (2 g daily), then to 1.5 g twice daily (3 g daily) if response is inadequate.

• Loading dose: none.

• Maximum dose: 3 g daily in two divided doses.

• Duration: long term; reassess at 3 to 6 months.

Ulcerative colitis, mild to moderate active disease. 2 to 4 g daily in divided doses with a topical rectal therapy as needed; severe attacks up to 6 g daily in specialist hands.

Ulcerative colitis, maintenance. 2 g daily in two divided doses, continued long term; use plain (not enteric-coated) tablets.

Juvenile idiopathic arthritis (6 years and over, specialist). 30 to 50 mg/kg/day in two divided doses, maximum 2 g daily, titrated over 4 weeks.

Folate supplement. Folic acid 5 mg daily is advised in pregnancy and with raised mean cell volume or anaemia because sulfasalazine impairs folate absorption.

Contraindications. Hypersensitivity to sulphonamides or salicylates, porphyria, severe renal or hepatic impairment, intestinal or urinary obstruction, and history of agranulocytosis with the drug. G6PD deficiency is a relative contraindication.

Boxed-warning-level risks. Not a boxed drug in most regions, but agranulocytosis, aplastic anaemia, severe hepatotoxicity, drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome are life-threatening, mostly in the first 3 months.

Adverse effects. Common: nausea, anorexia, headache, rash, orange discolouration of urine and soft contact lenses, reversible oligospermia and male infertility. Serious: leucopenia and agranulocytosis, haemolytic anaemia, hepatitis, pneumonitis, severe cutaneous reaction, interstitial nephritis.

Major interactions. Digoxin (reduced absorption), ciclosporin (reduced level), azathioprine and mercaptopurine (additive myelosuppression), methotrexate (raised toxicity), warfarin (raised INR), folate antagonists and live vaccines.

Common prescribing errors. Starting at full dose; not checking blood counts in the first 3 months; prescribing in sulphonamide allergy.

Special groups.

• Pregnancy: acceptable at usual dose with folic acid 5 mg daily; it is among the preferred disease-modifying drugs.

• Breastfeeding: acceptable in healthy term infants; monitor for diarrhoea and jaundice, and avoid in premature, jaundiced or G6PD-deficient infants.

• Children: weight-based, 30 to 50 mg/kg/day in two divided doses (6 years and over).

• Older adults: start low, monitor blood counts.

• Kidney impairment: eGFR under 30 mL/min, use with caution and good hydration.

• Liver impairment: avoid in severe disease.

• Region: G6PD deficiency occurs in parts of East Africa; test where possible before use.

Formulations. 500 mg enteric-coated tablets (rheumatological use), plain tablets (colitis), and oral suspension. Swallow enteric-coated tablets whole after food.

Baseline. Full blood count with differential, liver enzymes, creatinine, G6PD status where available, and hepatitis serology.

Monitoring. Full blood count and liver enzymes every 2 weeks for the first 3 months, monthly for the next 3 months, then every 3 months. Repeat after dose changes. Counsel the patient to report sore throat, fever, bruising or mouth ulcers immediately.

Stop thresholds. White cell count under 3.5 x 10^9/L, neutrophils under 1.6 x 10^9/L, platelets under 140 x 10^9/L, ALT over twice the upper limit of normal, or any severe rash.

Referral and escalation. Refer to a rheumatologist for non-response at 3 to 6 months, and to a haematologist for unexplained cytopenia.