What is the most likely diagnosis and appropriate workup for a woman with a >5‑year history of multiple scattered skin lesions over the entire body that begin as bullae and recur repeatedly?

Bullous Pemphigoid: Most Likely Diagnosis

For a woman with a >5-year history of recurrent skin lesions beginning as bullae scattered over the entire body, bullous pemphigoid (BP) is the most likely diagnosis, particularly given the chronic recurrent nature and widespread distribution. 1

Key Diagnostic Features Supporting Bullous Pemphigoid

Clinical Presentation

• Tense blisters arising on erythematous or normal-appearing skin with widespread distribution over the trunk and extremities are characteristic of BP 1
• The recurrent nature over >5 years is consistent with BP's chronic course, which typically lasts several years without treatment and has a tendency to relapse 1
• BP predominantly affects elderly patients (>70 years), though younger patients can be affected 1
• Intense pruritus often accompanies or precedes blister formation by weeks to months 1

Distinguishing from Other Blistering Diseases

Stevens-Johnson Syndrome/TEN is excluded because these conditions present acutely (reaching maximum severity 5-7 days after onset) rather than chronically over years, and feature purpuric macules with extensive necrolysis rather than recurrent tense bullae 1

Cutaneous mastocytosis is excluded because while it can present with blistering in children (particularly diffuse cutaneous mastocytosis), it typically appears in the first year of life and shows characteristic brown/red macules with positive Darier's sign 1

Essential Diagnostic Workup

First-Line Laboratory Tests

Perilesional skin biopsy for direct immunofluorescence (DIF) is the gold standard diagnostic test 1, 2:

• Obtain biopsy from perilesional skin (not from the blister itself) 2
• Positive finding: Linear deposits of IgG and/or C3 along the dermoepidermal junction 1, 2

Histopathology from early intact bulla placed in formalin 1, 2:

• Shows subepidermal cleft with mixed dermal inflammatory infiltrate containing numerous eosinophils 1

Serological Confirmation

Anti-BP180 IgG ELISA should be performed first, followed by anti-BP230 IgG ELISA if negative 1, 2:

• Anti-BP180 values >27 U/mL indicate increased risk of relapse 2
• These tests are confirmatory only when combined with positive DIF 1

Indirect immunofluorescence using salt-split skin technique demonstrates IgG antibodies binding to the epidermal side of the split 1, 2

Clinical Diagnostic Algorithm

Diagnosis is highly likely when three of four clinical criteria are present with positive DIF 2, 3:

• Age >70 years
• Absence of atrophic scars
• Absence of mucosal involvement
• Absence of predominant bullous lesions on neck and head

This algorithm has 95% specificity 2, 3

Critical Pitfalls to Avoid

Do not biopsy the blister itself for DIF—always use perilesional skin, as this yields the highest diagnostic sensitivity 2

Obtain detailed medication history covering the past 1-6 months before diagnosis, as drug-induced BP can occur with gliptins (DPP-4 inhibitors), furosemide, spironolactone, and neuroleptics 4, 5

Consider dyshidrosiform BP variant if blisters are predominantly on palms/soles, as this rare presentation (occurring in 66% on both palms/soles or 31% on soles alone) can progress to typical BP on other body sites in 77% of cases 6

Pretherapy Screening Required

Before initiating treatment, obtain 1:

• Complete blood count, erythrocyte sedimentation rate, C-reactive protein
• Creatinine, blood electrolytes, fasting glucose
• Liver function tests (transaminases, alkaline phosphatase, bilirubin)
• Serum albumin
• Hepatitis B, C, and HIV serology if immunosuppressive therapy is planned