Autoimmune Blistering Diseases

Autoimmune blistering diseases are caused by autoantibodies directed against structural proteins of the epidermis or dermo-epidermal junction, producing intraepidermal or subepidermal blisters. They are divided by blister level.

Intraepidermal (pemphigus group)

• Pemphigus vulgaris: IgG autoantibodies to desmoglein 3 (mucosal-dominant) and desmoglein 1 (mucocutaneous), causing acantholysis in the suprabasal layer. Incidence 0.1 to 0.5 per 100,000 per year, onset 40 to 60 years, higher in Ashkenazi Jews and Mediterranean populations (HLA-DRB10402, DQB10503). Mortality was 75% before steroids, now 5 to 10%.
• Pemphigus foliaceus: anti-desmoglein 1, superficial (subcorneal) blisters, no mucosal disease. Endemic form (fogo selvagem) in rural Brazil (sandfly bites).
• Paraneoplastic pemphigus: with lymphoproliferative disease (non-Hodgkin lymphoma, chronic lymphocytic leukaemia, Castleman disease), anti-envoplakin and periplakin, severe stomatitis, and bronchiolitis obliterans.
• IgA pemphigus, drug-induced pemphigus (penicillamine, captopril, thiols).

Subepidermal

• Bullous pemphigoid: the commonest, in the elderly (mean age 75), IgG against BP180 (collagen XVII, NC16A domain) and BP230. Incidence 10 to 40 per million per year, rising. Associated with neurological disease (dementia, Parkinson disease, stroke), drugs (DPP-4 inhibitors (gliptins), loop diuretics, spironolactone, neuroleptics, PD-1/PD-L1 inhibitors, penicillins), and radiotherapy or UV.
• Mucous membrane pemphigoid (cicatricial): BP180, laminin 332 (associated with malignancy), mucosal scarring (eye, mouth, larynx, oesophagus).
• Pemphigoid gestationis: pregnancy, BP180, HLA-DR3/DR4.
• Epidermolysis bullosa acquisita: anti-type VII collagen, mechanobullous or inflammatory, associated with Crohn disease.
• Linear IgA bullous dermatosis: children (chronic bullous disease of childhood) and drug-induced adults (vancomycin).
• Dermatitis herpetiformis: granular IgA in dermal papillae, anti-epidermal transglutaminase, gluten-sensitive enteropathy.
• Anti-p200 pemphigoid, lichen planus pemphigoides.
• Pathogenesis: loss of tolerance with autoreactive B cells and T cells, antibody binding leading to loss of adhesion (direct interference or complement and neutrophil/eosinophil-mediated damage in pemphigoid), blister formation.
• Complications: erosions and infection, sepsis, dehydration and malnutrition (oral disease), ocular scarring and blindness, laryngeal stenosis, venous thromboembolism, steroid and immunosuppressive adverse effects, and mortality (1-year mortality in bullous pemphigoid about 20-30%, related to age and comorbidity).

• Pemphigus vulgaris: flaccid blisters that rupture to painful erosions, mucosal lesions first in 50-70% (oral erosions, painful, persistent), later skin involvement (scalp, face, trunk, flexures), positive Nikolsky sign (pressure on perilesional skin causes separation) and Asboe-Hansen sign (bulla extension). Also pharynx, larynx (hoarseness), oesophagus, genital, nasal and conjunctival mucosa.
• Pemphigus foliaceus: crusted, scaly erosions on seborrhoeic areas (face, scalp, upper trunk) without mucosal involvement, blisters fragile and rarely seen.
• Paraneoplastic pemphigus: severe intractable stomatitis, polymorphous lichenoid and bullous lesions, bronchiolitis obliterans (fatal).
• Bullous pemphigoid: prodromal urticarial or eczematous pruritic phase (weeks to months), then tense bullae on erythematous or normal skin, flexural areas (inner thighs, axillae, flexor forearms, abdomen), Nikolsky sign negative, mucosal involvement in 10-30% (mild). Intense itch. Non-bullous forms (prurigo-like, eczema-like) are frequent.
• Mucous membrane pemphigoid: desquamative gingivitis, erosions, ocular (conjunctivitis, symblepharon, entropion, trichiasis, corneal scarring), nasal, pharyngeal, laryngeal and oesophageal strictures, scarring skin lesions (Brunsting-Perry on head and neck).
• Pemphigoid gestationis: intensely pruritic urticarial plaques around the umbilicus in the 2nd or 3rd trimester, then blisters, risk of prematurity and small for gestational age.
• Epidermolysis bullosa acquisita: skin fragility, blisters and scars on trauma-prone sites, milia, nail dystrophy.
• Linear IgA disease: annular blisters ("string of pearls," "cluster of jewels"), perineum and perioral in children.
• Dermatitis herpetiformis: intensely itchy grouped papulovesicles on extensor surfaces (elbows, knees, buttocks, scalp), excoriations.
• Differential diagnosis: SJS/TEN, erythema multiforme, bullous drug eruption, fixed drug eruption, bullous lupus, porphyria cutanea tarda, bullous impetigo, staphylococcal scalded skin syndrome, herpes simplex or zoster, contact dermatitis, bullous arthropod reactions, scabies (bullous), lichen planus, aphthous stomatitis, and burns.
• Red flags: widespread erosions with infection, mucosal involvement causing weight loss, laryngeal symptoms, ocular scarring, suspected paraneoplastic disease, and Nikolsky-positive lesions with systemic upset.

• Diagnosis requires clinical suspicion, histology, immunofluorescence and serology.
• Skin biopsy for histology: lesional edge or early blister. Pemphigus: suprabasal acantholysis with "tombstone" row of basal cells. Pemphigoid: subepidermal blister with eosinophils (eosinophilic spongiosis in pre-bullous). Dermatitis herpetiformis: papillary microabscesses.
• Direct immunofluorescence (DIF) on perilesional skin or mucosa (not blister) in Michel medium or fresh frozen: pemphigus shows intercellular IgG and C3 ("chicken-wire"), pemphigoid shows linear IgG and C3 along the basement membrane zone, dermatitis herpetiformis shows granular IgA in dermal papillae, linear IgA disease shows linear IgA, EBA shows linear IgG at the dermal side of salt-split skin (u-serrated pattern).
• Indirect immunofluorescence on monkey oesophagus or salt-split skin: circulating autoantibodies (epidermal side = bullous pemphigoid, dermal side = EBA, anti-laminin 332 and anti-p200).
• ELISA: anti-Dsg1 and anti-Dsg3 (pemphigus, titres track disease activity), anti-BP180 NC16A and BP230 (pemphigoid), anti-collagen VII (EBA), anti-tissue transglutaminase and anti-endomysial IgA (dermatitis herpetiformis). Multiplex or BIOCHIP assays.
• Investigations for associated disease and treatment safety: CBC, ESR, liver and renal function, glucose, HbA1c, electrolytes, lipids, chest radiograph, TB screening, hepatitis B and C, HIV, bone density (DEXA), baseline eye examination. Paraneoplastic pemphigus: CT chest/abdomen/pelvis, lymph node biopsy, immunoprecipitation. Mucous membrane pemphigoid: ophthalmology, ENT (laryngoscopy), gastroenterology. Malignancy screening for laminin 332 pemphigoid.
• Thiol-containing and DPP-4 inhibitor drug review.
• Coeliac testing and small bowel biopsy in dermatitis herpetiformis.

Goals: control blisters, prevent relapse with minimal adverse effects, and manage complications. Patients are best managed by a specialist.

General and local care

• Wound care: non-adherent dressings, antiseptic soaks, topical antibiotics for secondary infection, aspiration of tense blisters (leave roof intact), wash with saline. Oral hygiene (chlorhexidine 0.12%, soft toothbrush), topical anaesthetics, nutritional support (soft diet), and DVT prophylaxis in immobile patients.
• Prevent complications: calcium, vitamin D, bone protection (alendronate 70 mg weekly), gastroprotection, glycaemic monitoring, Pneumocystis prophylaxis (co-trimoxazole 960 mg three times weekly) in prolonged immunosuppression, vaccinations (inactivated), and ophthalmology monitoring.

Pemphigus vulgaris and foliaceus

• Rituximab (first line for moderate-severe pemphigus, with or without short prednisolone): 1000 mg IV on days 1 and 15, repeated at 6 months (maintenance 500 mg at months 12 and 18), or 375 mg/m2 weekly for 4 weeks. Complete remission off therapy in about 40-90% at 2 years, higher than prednisolone alone. Monitor for infection (hepatitis B reactivation, progressive multifocal leukoencephalopathy), hypogammaglobulinaemia, and infusion reactions (premedicate with paracetamol, antihistamine, methylprednisolone 100 mg).
• Systemic corticosteroids: prednisolone 0.5 to 1 mg/kg/day (typically 40 to 80 mg), tapered over 6 to 12 months once disease control (no new lesions, healing of lesions) for 2 weeks. Pulse methylprednisolone 500 mg to 1 g IV for 3 days in severe/refractory disease.
• Steroid-sparing agents: azathioprine 1.5 to 2.5 mg/kg/day (TPMT), mycophenolate mofetil 1 to 1.5 g twice daily, methotrexate 10 to 25 mg weekly, cyclophosphamide 50 to 100 mg daily (or pulse), dapsone 50 to 150 mg daily (mild disease).
• Refractory disease: IVIG 2 g/kg/month over 3-5 days, immunoadsorption, plasma exchange, efgartigimod (FcRn antagonist, emerging), and JAK inhibitors.
• Topical: clobetasol 0.05% ointment, intralesional triamcinolone 5-10 mg/mL for persistent erosions, and tacrolimus 0.1% for oral lesions.
• Monitor Dsg antibody titres to guide taper.

Bullous pemphigoid

• Topical corticosteroids (first line, especially in elderly and frail): clobetasol propionate 0.05% cream or ointment 20 to 40 g/day applied to whole body (except face) for 2-4 weeks, tapered over 4-12 months, as effective as oral steroids with lower mortality. For localised disease, apply to affected areas only.
• Oral prednisolone 0.5 mg/kg/day (0.75 mg/kg for extensive disease), tapered after disease control. Avoid high doses in the elderly (mortality).
• Doxycycline 200 mg daily (with or without nicotinamide 1.5 g daily) is an effective steroid-sparing/alternative with lower serious adverse events, in mild-to-moderate disease.
• Steroid-sparing agents: azathioprine, mycophenolate mofetil 1-2 g daily, methotrexate 5-15 mg weekly, dapsone 50-100 mg daily (G6PD).
• Biologics for refractory: rituximab, omalizumab 300 mg SC every 4 weeks (elevated IgE), dupilumab 600 mg then 300 mg every 2 weeks (approved for bullous pemphigoid), IVIG, and eosinophil-targeted agents (benralizumab, mepolizumab).
• Stop triggering drugs (gliptins, diuretics, immune checkpoint inhibitors, if feasible).
• Antihistamines and emollients for itch, gabapentin for neuropathic itch.

Mucous membrane pemphigoid

Mild (oral only): topical high-potency steroids, dapsone 50-150 mg daily, doxycycline. Moderate to severe or ocular/laryngeal: rituximab, mycophenolate, cyclophosphamide 1-2 mg/kg/day with prednisolone for sight-threatening disease, IVIG. Ophthalmic care (lubricants, lid hygiene, topical ciclosporin, surgery for trichiasis, amniotic membrane). ENT/GI dilation for strictures.

Pemphigoid gestationis

• Topical potent steroids, antihistamines, prednisolone 0.5 mg/kg/day if severe, with obstetric monitoring (growth scans, delivery planning). Postpartum flare common, and recurrence in subsequent pregnancies.
• Paraneoplastic pemphigus: treat the underlying neoplasm, with steroids, rituximab, IVIG, ciclosporin, and respiratory support. Prognosis poor.
• Epidermolysis bullosa acquisita: colchicine 1-2 mg daily, dapsone, rituximab, IVIG, ciclosporin.
• Linear IgA disease: dapsone 25-100 mg daily or sulfapyridine, stop the drug in drug-induced forms (vancomycin).
• Dermatitis herpetiformis: strict gluten-free diet (lifelong, controls skin and gut disease over months), dapsone 25-100 mg daily (rapid relief within days, check G6PD, methaemoglobin, monitor haemolysis, neuropathy), and sulfapyridine. Screen for associated autoimmune diseases and lymphoma risk.

Follow-up

Review every 2-4 weeks initially, then every 3 months. Monitor for steroid adverse effects (glucose, blood pressure, bone, infection), cytopenias (azathioprine, mycophenolate), liver function (methotrexate), and relapse on taper (50% in pemphigoid). Duration of treatment is typically 1-2 years for pemphigoid with possible remission, and long term for pemphigus. Educate about skin care and infection signs. Pemphigus patients need ongoing monitoring after rituximab (B-cell recovery 6-12 months, relapse in 30-50% requires re-treatment).