How do drugs trigger bullous pemphigoid?

Drug-Induced Bullous Pemphigoid: Mechanisms and Triggers

Drugs can trigger bullous pemphigoid through autoimmune mechanisms that target components of the basement membrane zone, though the exact pathophysiological process remains incompletely understood. 1, 2

Pathophysiological Mechanisms

• Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease characterized by autoantibodies (primarily IgG) targeting components of the adhesion complex in the basement membrane zone, particularly BP180 (collagen XVII) and BP230 antigens 1
• Drug-induced BP appears immunopathologically similar to idiopathic BP, with autoantibodies directed against the same target antigens in the basement membrane zone 2
• The mechanism likely involves drug-induced alteration of the immune system or modification of basement membrane antigens, leading to loss of self-tolerance and production of autoantibodies 3
• These autoantibodies bind to their target antigens, activate complement, and recruit inflammatory cells, ultimately resulting in subepidermal blister formation 3

Common Drug Triggers

• The strongest evidence for drug-induced bullous pemphigoid exists for the following medications:

  • Gliptins (dipeptidyl peptidase-IV inhibitors) used for diabetes management 1, 2
  • PD-1/PD-L1 inhibitors used in cancer immunotherapy 2
  • Loop diuretics, particularly furosemide 1, 2
  • Penicillin derivatives 2
  • ACE inhibitors, such as captopril, which has been documented in FDA labeling to cause bullous pemphigoid 4

• Other medications with reported associations include:

  • Spironolactone 1
  • Neuroleptics 1
  • Chloroquine 5
  • Ciprofloxacin and other quinolones 6

Clinical Characteristics and Diagnosis

• Drug-induced BP can be challenging to diagnose as it clinically resembles idiopathic BP 2

• The latency between starting the drug and disease onset can range from weeks to several months 1

• Some distinguishing features of drug-induced BP may include:

  • Atypical clinical presentation in some cases, such as acral targetoid lesions 5
  • More frequent pruritus compared to idiopathic pemphigus 1
  • Potential for complete resolution upon drug withdrawal in some cases 1

• Diagnosis requires:

  • Detailed medication history, particularly focusing on recently introduced drugs (within 1-6 months) 1
  • Standard diagnostic criteria for BP including clinical features, histopathology, and direct immunofluorescence showing linear IgG/C3 deposits along the basement membrane zone 1

Management Approach

• The primary management step is identification and discontinuation of the suspected triggering medication 1

• After drug withdrawal, two possible courses may follow:

  • Complete resolution of the disease (drug-triggered pemphigoid) 1
  • Persistence of the disease despite drug withdrawal (drug-induced pemphigoid), which occurs in approximately 50% of cases 1

• For persistent or severe cases, conventional BP treatment is indicated:

  • Superpotent topical corticosteroids (clobetasol propionate) are recommended as first-line therapy 7
  • Systemic corticosteroids may be necessary for widespread disease 7
  • Adjunctive immunosuppressive agents may be required for recalcitrant cases 7

Important Clinical Considerations

• A thorough medication history is essential in all patients presenting with BP, particularly in elderly patients who may be on multiple medications 1
• Poor response to standard treatments should raise suspicion for drug-induced BP 1
• Regular monitoring for disease activity is important, with follow-up visits recommended every 2 weeks for the first 3 months, then monthly for the next 3 months 7
• When managing elderly patients with BP, consider the mortality risk associated with high-dose systemic corticosteroids (prednisolone >40 mg daily) 1
• Drug-induced BP should be distinguished from other drug-induced blistering conditions, including drug-induced pemphigus, which has different target antigens and clinical features 8