What is the most common cause of skin rash in the quadruple anti-tuberculosis (TB) regimen?

Most Common Cause of Skin Rash in Quadruple Anti-TB Regimen

Pyrazinamide is the most common cause of skin rash among the four first-line anti-tuberculosis drugs (isoniazid, rifampin, pyrazinamide, and ethambutol), with an incidence rate of 2.38%, followed by streptomycin (1.45%), ethambutol (1.44%), rifampin (1.23%), and isoniazid (0.98%). 1

Understanding the Rash Profile

The skin reactions from anti-TB medications typically present as:

• Morbilliform rash (72.3% of cases) - the most common presentation 1
• Urticaria (8.5% of cases) 1
• Erythema multiforme syndrome (8.5% of cases) 1
• Less common presentations include exfoliative dermatitis and lichenoid eruptions 1

Timing and Risk Factors

97% of cutaneous adverse drug reactions occur within two months after initiating anti-TB treatment, with most cases appearing in the first 8 weeks. 1

High-risk populations include:

• HIV-infected patients (27.7% of CADR cases) - the highest risk group 1
• Patients on polypharmacy (21.3% of cases) 1
• Elderly patients (19.1% of cases) 1
• Patients with autoimmune disorders (6.4% of cases) 1
• Pre-existing renal or hepatic impairment (4.3% each) 1

Clinical Characteristics by Drug

Pyrazinamide

• Transient morbilliform rash is usually self-limited and does not require discontinuation 2
• Can cause photosensitive dermatitis 2
• Highest incidence rate among first-line drugs at 2.38% 1

Rifampin

• Pseudojaundice (skin discoloration with normal bilirubin) is usually self-limited and resolves with discontinuation 2
• Orange discoloration of bodily fluids (sputum, urine, sweat, tears) is universal and expected 2
• Can cause leukocytoclastic vasculitis in rare cases 3

Ethambutol

• Lower incidence of rash (1.44%) compared to pyrazinamide 1
• Can cause fever and skin rash as part of hypersensitivity reactions 4

Isoniazid

• Lowest incidence of cutaneous reactions (0.98%) among the four drugs 1

Management Algorithm

When skin rash develops during anti-TB therapy:

1. Assess severity immediately - look for signs of severe cutaneous adverse reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis, DRESS syndrome) 5, 6

2. For mild morbilliform rash (most common):

   • Continue therapy if rash is transient and self-limited, particularly with pyrazinamide 2
   • Monitor closely for progression 1

3. For moderate to severe reactions:

   • Discontinue all anti-TB drugs immediately 5, 4, 6
   • Treat with topical corticosteroids, systemic antihistamines, or short courses of systemic steroids as needed 6

4. Drug rechallenge (staged-fashion exposure test):

   • Reintroduce drugs one at a time with 3-day intervals after resolution of symptoms 1, 4, 3
   • Start with isoniazid (lowest risk), then add rifampin, ethambutol, and finally pyrazinamide 4
   • Monitor for recurrence of rash with each drug addition 4, 3

5. If specific drug identified:

   • Permanently discontinue the offending agent 5, 4
   • Continue treatment with remaining drugs, potentially adding alternative agents 4, 6

Critical Pitfalls to Avoid

• Never ignore bullous or exfoliative skin rash - these require immediate discontinuation of all drugs as they may represent life-threatening reactions like TEN 5
• Do not rechallenge with a drug that caused severe reactions (DRESS syndrome, TEN, leukocytoclastic vasculitis) 5, 6, 3
• Do not overlook HIV status - these patients have significantly higher risk of cutaneous reactions and require closer monitoring 1
• Avoid assuming all rashes require drug discontinuation - transient morbilliform rash from pyrazinamide is typically self-limited and does not necessitate stopping therapy 2