What are the potential adverse effects of sulphasalazine (disease-modifying antirheumatic drug) in patients, particularly those with a history of sulfa allergy?

Adverse Effects of Sulphasalazine

Sulphasalazine carries a significant risk of adverse effects occurring in up to 58% of patients, with 20-30% requiring drug discontinuation, most commonly due to gastrointestinal symptoms, hematologic toxicity, and hypersensitivity reactions that can be life-threatening. 1, 2

Life-Threatening and Serious Adverse Effects

Hematologic Toxicity

• Agranulocytosis, aplastic anemia, and other blood dyscrasias have resulted in deaths and require immediate discontinuation of sulphasalazine 1
• Neutropenia occurs in approximately 2% of patients, thrombocytopenia in 1%, and pan-hypogammaglobulinemia in 1% 2
• Thrombocytopenia can occur in up to 15% of patients taking 5-ASA compounds including sulphasalazine 3
• Monitor complete blood counts every 2 weeks for the first 3 months, monthly for the second 3 months, and every 3 months thereafter 3
• Clinical warning signs include sore throat, fever, pallor, and purpura—discontinue treatment immediately while awaiting blood test results 1

Severe Hypersensitivity Reactions

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is a severe, life-threatening systemic hypersensitivity reaction that can occur even without rash 1
• Early manifestations include fever and lymphadenopathy; evaluate immediately and discontinue if no alternative etiology exists 1
• Internal organ involvement may include hepatitis, nephritis, myocarditis, mononucleosis-like syndrome, hematological abnormalities (including hematophagic histiocytosis), and pneumonitis with eosinophilic infiltration 1
• Rechallenge after hypersensitivity reaction can lead to serious and possibly fatal reactions, particularly if the initial reaction was severe 4

Severe Cutaneous Adverse Reactions

• Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), exfoliative dermatitis, and acute generalized exanthematous pustulosis (AGEP) have been reported 1
• These reactions can be fatal and occur most commonly within the first month of treatment 1
• Discontinue immediately at the first appearance of signs or symptoms 1

Hepatic and Renal Toxicity

• Deaths have been reported from liver and renal damage 1
• Jaundice may indicate serious hepatotoxicity 1
• Discontinue sulphasalazine if renal function deteriorates during therapy 1
• Monitor urinalysis with careful microscopic examination frequently 1

Serious Infections

• Fatal sepsis and pneumonia have been reported, some associated with agranulocytosis, neutropenia, or myelosuppression 1
• Discontinue sulphasalazine if a patient develops a serious infection 1
• Exercise caution in patients with history of recurring or chronic infections or conditions predisposing to infections 1

Irreversible Neurologic Damage

• Deaths have been reported from irreversible neuromuscular and central nervous system changes 1

Fibrosing Alveolitis

• Fatal fibrosing alveolitis has been reported 1

Common and Dose-Dependent Adverse Effects

Gastrointestinal Effects (Most Common)

• Gastrointestinal side effects occur in up to 35% of patients, including nausea, vomiting, diarrhea, abdominal pain, and dyspepsia 5, 2
• Upper gastrointestinal problems and nausea are especially common in initial weeks of treatment 6
• The sulfapyridine moiety (not the 5-ASA component) is responsible for most adverse effects 5
• Switch to mesalamine (2-3g/day) or balsalazide if gastritis develops, as these provide similar efficacy with fewer gastrointestinal side effects 5

Central Nervous System Effects

• Headache and dizziness occur in 19% of patients 2
• These are relatively minor but common 2

Dermatologic Reactions

• Rash is a frequently reported adverse effect 7, 2
• Allergic reactions including rash, fever, and arthralgia may respond to desensitization programs 8

Reproductive Effects

• Oligospermia and infertility have been observed in men treated with sulphasalazine 1
• These effects appear to reverse upon withdrawal of the drug 1
• Sulphasalazine is safe for use during pregnancy and lactation 8

Metabolic Effects

• Sulphasalazine interferes with folate metabolism; ensure folate supplementation 5
• Chronic low-grade hemolysis can occur and requires monitoring and folic acid supplementation when necessary 8

Timing and Monitoring Strategy

Critical Monitoring Period

• 76% of adverse events requiring permanent discontinuation occur within 3 months of starting therapy 9
• 66% of potentially serious adverse effects occur within 3 months 9
• Few worrying problems occur after the first year of therapy 9
• Most reactions are self-limiting after drug withdrawal 9

Laboratory Monitoring Protocol

• Complete blood counts every 2 weeks for first 3 months, monthly for second 3 months, then every 3 months 3
• Urinalysis with careful microscopic examination frequently 1
• Liver function tests periodically 3
• Recheck CBC within 1-2 weeks after discontinuation due to thrombocytopenia to confirm improvement 3

Overall Toxicity Profile

• Toxicity is common with a relative risk of 2.37 (95% CI 1.58-3.55) for any adverse event compared to placebo 10
• 20-30% of patients discontinue treatment due to adverse reactions 6, 9
• Most common reasons for discontinuation: gastrointestinal symptoms, mucocutaneous manifestations, hepatic enzyme abnormalities, and hematological abnormalities 10
• In inflammatory joint disease, 58% of patients develop one or more adverse reactions, with 21.5% requiring drug withdrawal 2
• An additional 28% continue at reduced doses due to adverse effects 2
• Side effects are more frequent in inflammatory joint disease compared to inflammatory bowel disease 2

Special Considerations for Sulfa Allergy

• Most patients intolerant or hypersensitive to sulphasalazine can safely take 5-ASA preparations (mesalamine, balsalazide) without similar reactions 4
• There is no evidence that patients with aspirin allergy cannot safely take 5-ASA preparations 4
• Sulphasalazine is NOT contraindicated based on NSAID allergy alone 4
• Desensitization is contraindicated when there was internal organ involvement 4