Diagnosis of Bullous Pemphigoid
Bullous pemphigoid diagnosis requires positive direct immunofluorescence (DIF) showing linear IgG and/or C3 deposits along the dermoepidermal junction from perilesional skin—this is the single most essential test and cannot be omitted. 1
Clinical Recognition
Suspect bullous pemphigoid when you encounter:
- Age >70 years with tense bullae on erythematous or normal skin 1
- Pruritus preceding blisters by weeks to months—this prodromal phase is highly characteristic 2
- Distribution pattern: symmetric bullae on flexural surfaces of limbs, inner thighs, and abdomen 2
- Absence of atrophic scars, minimal mucosal involvement, and absence of predominant bullous lesions on neck/head 1
- Recent drug intake within 1-6 months, particularly diuretics, psycholeptic drugs, or checkpoint inhibitors 3
- Refractory itch of unknown cause in elderly patients, even without bullae present 1, 3
Diagnostic Algorithm
Step 1: Obtain Tissue Biopsies
For DIF (the most critical test):
- Biopsy perilesional skin (not from the blister itself) 4
- Transport specimen in cryotube with liquid nitrogen, Michel's fixative, or 0.9% NaCl solution 1
- Positive finding: Linear (n-serrated) deposits of IgG and/or C3 along the dermoepidermal junction 1, 4
- Sometimes IgA and IgE show similar pattern 1, 4
For histopathology:
- Biopsy an early intact bulla arising on erythematous skin and place in formalin 4
- Expected findings: Subepidermal bullae containing eosinophils and/or neutrophils, dermal infiltrate of eosinophils/neutrophils, marginalization of eosinophils along the dermoepidermal junction 1
Critical pitfall: A small percentage (1.73%) of patients initially have negative DIF results 5. If clinical suspicion remains high despite negative DIF, repeat the biopsy from different perilesional skin 2, 5. False-negative results occur from sampling lesional skin or subthreshold immune complex quantities 5.
Step 2: Serological Testing
First-line serological test:
- ELISA for anti-BP180 IgG antibodies (most sensitive) 1, 4
- If negative, perform ELISA for anti-BP230 IgG antibodies 1, 4
- Anti-BP180 ELISA >27 U/mL indicates increased relapse risk 2, 4
Alternative if ELISA unavailable:
- Indirect immunofluorescence (IIF) on 1 mol L⁻¹ NaCl-separated normal human skin (salt-split skin) 1, 3, 4
- Positive finding: IgG antibodies binding to the epidermal side (sometimes both epidermal and dermal) of the split 1, 4
- Sensitivity: detects autoantibodies in up to 80% of cases 1
Important caveat: IIF and ELISA may be positive in other pruritic skin diseases and healthy subjects—they are confirmatory only when combined with positive DIF 1.
Step 3: Apply Clinical Criteria
Diagnosis is highly likely when positive DIF is present plus three of four clinical characteristics: 3, 4
- Age >70 years
- Absence of atrophic scars
- Absence of mucosal involvement
- Absence of predominant bullous lesions on neck and head
Treatment of Bullous Pemphigoid
For extensive or generalized bullous pemphigoid, use clobetasol propionate cream 40 g/day applied over the whole body rather than oral prednisone, as it achieves similar disease control with lower mortality. 6
Treatment Algorithm by Disease Severity
Localized or Mild Disease
Superpotent topical corticosteroids (clobetasol propionate cream) 7, 6
- Apply to affected areas
- Effective for limited disease without need for systemic therapy 7
Extensive or Generalized Disease
First-line: Clobetasol propionate cream 40 g/day applied over the whole body 6
- Achieves complete skin healing at day 21 in 99.8% of patients (vs. 92.4% with oral prednisone) 6
- Reduces mortality at one year (26.5% vs. 36.3% with oral prednisone, RR 0.73) 6
- Reduces severe complications compared to oral prednisone (RR 0.65) 6
Alternative regimen: Mild clobetasol propionate cream regimen (10-30 g/day) 6
- Achieves similar disease control as standard 40 g/day regimen (98% complete healing at day 21 in both groups) 6
- Similar mortality rates at one year 6
- Consider for patients who cannot tolerate or apply higher doses 6
When Topical Therapy Fails or Is Impractical
Oral prednisone (dose not specified in guidelines, but avoid >0.75 mg/kg/day in elderly) 2
- Standard treatment when topical therapy insufficient 7
- Critical warning: Oral prednisone >0.75 mg/kg/day leads to significant mortality in elderly patients 2
Adjuvant immunosuppressants for steroid-sparing effect: 7
- Azathioprine
- Mycophenolate mofetil
- Often combined with systemic corticosteroids 7
Alternative for Patients Who Cannot Tolerate Steroids
Doxycycline 200 mg/day 6
- Less effective for disease control than prednisolone (73.8% vs. 91.1% complete healing at 6 weeks) 6
- However, significantly reduces mortality at one year (2.4% vs. 9.7% with prednisolone, RR 0.25, NNTB=14) 6
- Improves quality of life compared to prednisolone (1.8 points lower on DLQI) 6
- Reduces severe or life-threatening treatment-related adverse events (RR 0.59) 6
- Consider as first-line in frail elderly patients where mortality risk outweighs need for rapid disease control 6
Nicotinamide plus tetracycline: Evidence too limited to recommend 6
Monitoring During Treatment
Regular laboratory monitoring should include: 4
- Complete blood count
- Erythrocyte sedimentation rate
- C-reactive protein
- Creatinine and blood electrolytes
- Fasting glucose
- Liver function tests
- Serum albumin
Disease activity monitoring: 4
- Anti-BP180 IgG by ELISA can assess disease activity and predict relapse 4
Critical Treatment Pitfalls
- Never delay hospitalization if necrotizing fasciitis is suspected—pain disproportionate to physical findings, systemic toxicity (fever, tachycardia, hypotension) requires immediate hospitalization and surgical consultation 2
- Avoid oral prednisone >0.75 mg/kg/day in elderly patients due to significant mortality risk 2
- Do not assume infection based on culture alone—bullous pemphigoid lesions are frequently colonized with bacteria (Staphylococcus aureus, Pseudomonas aeruginosa); obtain fungal stain to distinguish true infection from colonization 2, 8