What is bullous pemphigoid caused by?

What Causes Bullous Pemphigoid

Bullous pemphigoid is caused by an autoimmune response in which IgG autoantibodies attack two key hemidesmosomal proteins at the basement membrane zone: BP180 (BPAg2, collagen XVII) and BP230 (BPAg1), resulting in subepidermal blister formation. 1

Primary Autoimmune Mechanism

The fundamental pathophysiology involves:

• Autoantibody production primarily of IgG class (less commonly IgA, IgM, and IgE) that target components of the adhesion complex at the basement membrane zone 1
• BP180 (collagen XVII) is the major pathogenic antigen, with most patients having autoantibodies binding to the NC16A domain, an immunodominant extracellular region 2
• BP230 serves as the second major autoantigen, localizing intracellularly and associating with the hemidesmosomal plaque 2
• The antigen-antibody interaction triggers complement activation, mast cell degranulation, and accumulation of neutrophils and eosinophils, with proteinases released by granulocytes causing loss of cell-matrix adhesion and subepidermal clefting 2

Associated Risk Factors and Triggers

Neurological Disease (Strongest Association)

Bullous pemphigoid is strongly associated with pre-existing neurological conditions including:

• Cerebrovascular disease 1
• Dementia 1
• Parkinson disease 1
• Epilepsy 1
• Multiple sclerosis 1

These conditions pre-date BP onset and are considered risk factors rather than consequences 1

Drug-Induced Bullous Pemphigoid

The strongest evidence for drug triggers exists for:

• Gliptins (dipeptidyl peptidase-IV inhibitors) - particularly in diabetic patients taking these oral hypoglycemic agents with metformin 1, 3
• Furosemide - the only drug showing significant association after adjusting for cardiovascular and neurological disease in a U.K. case-control study 1
• Spironolactone - significant relationship demonstrated in French case-control studies 1
• Neuroleptics - significant association in French case-control studies 1

Key characteristics of drug-induced BP:

• Latency between drug initiation and disease onset ranges from weeks to several months 3
• Approximately 50% of cases persist after drug withdrawal, requiring conventional BP treatment 3
• The mechanism by which drugs induce BP has not been definitively established 1

What Does NOT Cause Bullous Pemphigoid

There is no conclusive evidence for association with:

• Malignancy - large series have concluded no increased incidence compared to age- and sex-matched controls in Western countries 1
• Other autoimmune diseases 1

Clinical Pitfall to Avoid

When evaluating any elderly patient presenting with BP, obtain a thorough medication history focusing on recently introduced drugs, particularly gliptins, loop diuretics, spironolactone, and neuroleptics 3. Poor response to standard treatments should raise suspicion for drug-induced BP, and the suspected medication should be discontinued as the primary management step 3.