Sulfasalazine Pharmacology

Sulfasalazine is a prodrug of sulfapyridine and 5-aminosalicylic acid used for rheumatoid arthritis, psoriatic and spondyloarthritis (peripheral disease), juvenile arthritis and ulcerative colitis. It is among the safest csDMARDs in pregnancy. Gastrointestinal effects and rare marrow or hypersensitivity reactions limit its use.

Mechanism. Gut bacteria cleave it into sulfapyridine, absorbed and responsible for the antirheumatic and many adverse effects, and 5-aminosalicylic acid, which acts locally in colitis. Anti-inflammatory effects include reduced lymphocyte function and cytokine production.

Pharmacokinetics. About 10 to 30% of the parent drug is absorbed; sulfapyridine is acetylated in the liver, and slow acetylators have higher levels and more toxicity.

Dosing.

• Use enteric-coated tablets for rheumatic disease (better tolerated).
• Start 500 mg daily; increase by 500 mg weekly to 1 g twice daily (maximum 3 g daily; usual 2 to 3 g).
• Children (juvenile arthritis): 30 to 50 mg/kg daily in two divided doses, maximum 2 g.
• Ulcerative colitis: 2 to 4 g daily in divided doses for active disease; 2 g daily for maintenance.
• Onset takes 4 to 12 weeks; stop if no response by 6 months.

Related drugs. Mesalazine and balsalazide deliver the 5-aminosalicylic acid part without sulfapyridine and treat colitis only, not arthritis.

Folate. Sulfasalazine reduces folate absorption, so give folic acid 5 mg daily in pregnancy and with macrocytosis.

• First-line. Triple therapy component for rheumatoid arthritis; peripheral spondyloarthritis and psoriatic arthritis; mild ulcerative colitis.
• Alternative. Methotrexate substitute in women planning pregnancy; juvenile enthesitis-related arthritis.
• Specialist. Combination triple therapy; refractory colitis.
• Emergency. None.

Selection. Choose in patients who cannot take methotrexate or leflunomide, in pregnancy, and in peripheral spondyloarthritis. It does not help axial disease.

Contraindications. Allergy to sulfonamides, salicylates or sulfasalazine; porphyria; severe renal or hepatic impairment; G6PD deficiency (haemolysis risk); age under 2 years (kernicterus risk); intestinal or urinary obstruction.

Serious adverse effects.

• Nausea, headache, loss of appetite, orange discolouration of urine and skin and contact lens staining (harmless).
• Rash, fever, Stevens-Johnson syndrome and DRESS (stop immediately).
• Neutropenia, agranulocytosis, thrombocytopenia, haemolytic anaemia and megaloblastic anaemia.
• Hepatitis, reversible oligospermia, rare lung disease.

Major interactions. Digoxin (lower absorption); ciclosporin; warfarin (raised INR); methotrexate (more marrow toxicity); azathioprine and mercaptopurine (marrow suppression); iron reduces absorption.

Common prescribing errors.

• Starting at full dose.
• No baseline G6PD or blood tests.
• Failing to warn of orange urine.
• Not checking counts in the first 3 months.
• Using plain tablets, causing nausea.

Special groups.

• Pregnancy: compatible; add folic acid 5 mg.
• Breastfeeding: acceptable in healthy term infants; monitor for diarrhoea and jaundice, and avoid with premature or G6PD-deficient infants.
• Children: avoid under 2 years; 30 to 50 mg/kg daily.
• Older adults: lower doses.
• Kidney and liver: reduce or avoid in impairment.
• East Africa: check G6PD where possible; sulfonamide allergy, HIV-associated hypersensitivity (increased rash risk) and malaria co-treatment with sulfadoxine-pyrimethamine need attention; inform patients about orange urine.

Monitoring. Full blood count and liver tests every 2 weeks for 3 months, then monthly for 3 months, then every 3 months; creatinine; urinalysis; rash and mouth ulcers; fever or sore throat.

Referral and escalation. Fever, sore throat or bruising (urgent blood count); severe rash; jaundice; haemolysis; pregnancy planning (folic acid).

Comparison with alternative classes. Sulfasalazine is cheap and safe in pregnancy, but less potent than methotrexate and with more early intolerance. Mesalazine is better tolerated in colitis but does not treat arthritis.