What medications are associated with the development of non-necrotizing granulomas?

Medications Associated with Non-Necrotizing Granulomas

The most common medications associated with non-necrotizing granulomatous inflammation include anti-TNF agents, immune checkpoint inhibitors, phenytoin, allopurinol, sulfasalazine, and mesalamine. 1, 2

Common Medication Causes by Mechanism

Immunomodulatory Drugs

• Anti-TNF agents (infliximab, adalimumab) - can paradoxically cause granulomatous inflammation, particularly in the skin and lungs 3
• Immune checkpoint inhibitors (ICIs) - cause granulomatous reactions in multiple organs:
  • Most commonly affect lymph nodes (52%) and skin (35%)
  • 64% of ICI-induced granulomas are non-necrotizing
  • More severe with combination therapy (anti-CTLA4 + anti-PD1) 2

Anti-Seizure Medications

• Phenytoin - associated with drug hypersensitivity syndrome that can include granulomatous inflammation 4, 5
  • Accounts for 23.1% of DRESS cases in some studies
  • Can present with skin rash, fever, lymphadenopathy, and internal organ involvement 5

Other Common Medications

• Allopurinol - causes granulomatous reactions, particularly with renal involvement 6, 5
  • Associated with longer onset time compared to other drugs (median >16 days)
  • Higher incidence of renal involvement and eosinophilia 5
• Sulfasalazine/Mesalamine - used in inflammatory bowel disease, can cause pulmonary complications including non-necrotizing granulomatous inflammation 3
  • Can present as interstitial lung disease separate from the primary disease

Organ-Specific Patterns

Pulmonary Manifestations

• Medications can cause various patterns of granulomatous lung disease:
  • Non-necrotizing granulomas with interstitial pneumonia
  • Bronchiolitis with granulomatous features
  • Hypersensitivity pneumonitis-like reactions 3

Cutaneous Manifestations

• Skin involvement often presents as:
  • Erythema nodosum (particularly with sulfasalazine/mesalamine) 3
  • Pyoderma gangrenosum (with anti-TNF agents) 3
  • Various granulomatous rashes 2

Renal Manifestations

• Granulomatous interstitial nephritis (GIN) is more frequently due to:
  • Drugs (particularly allopurinol)
  • Less commonly due to infections 1

Diagnostic Considerations

When evaluating non-necrotizing granulomas, consider:

1. Histopathologic features:

   • Well-formed vs. poorly formed granulomas
   • Distribution pattern (airway-centered, random, etc.)
   • Associated features (eosinophilia, fibrosis) 3, 7

2. Differential diagnosis:

   • Sarcoidosis (accounts for 56% of non-necrotizing granulomas)
   • Infections (mycobacteria, fungi)
   • Hypersensitivity pneumonitis
   • Drug-induced granulomatous inflammation 8

3. Clinical correlation:

   • Timing of medication exposure
   • Organ involvement pattern
   • Presence of systemic symptoms 1

Management Approach

1. Identify and discontinue the offending medication
2. Consider systemic corticosteroids for severe reactions
   • 45% of ICI-induced granulomatous reactions require systemic corticosteroids 2
3. Monitor for resolution - most granulomatous reactions resolve with medication discontinuation and appropriate treatment

Important Caveats

• Non-necrotizing granulomas have multiple potential causes - medication etiology is a diagnosis of exclusion
• Always rule out infectious causes before attributing to medication effect
• Some medications (like anti-TNF agents) can both treat and cause granulomatous inflammation
• The diagnosis may change in up to 27% of cases initially attributed to medication effect 8
• Granulomatous reactions can occur weeks to months after medication initiation

Understanding the specific medication patterns can help clinicians recognize and appropriately manage these challenging reactions.