Vesiculobullous Disorders PDF

1/27/25 Vesiculobullous Disorders D A R R E N K E M P T O N , M D , D P T P G Y- 4 D E PA R T M E N T O F D E R M AT O L O G Y 1 2 3 1  1/27/25...

1/27/25 Vesiculobullous Disorders D A R R E N K E M P T O N , M D , D P T P G Y- 4 D E PA R T M E N T O F D E R M AT O L O G Y 1 2 3 1  1/27/25 Classification of Pemphigus Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Fogo selvagem Drug-induced pemphigus Penicillamine – pemphigus foliaceus more common Captopril – pemphigus vulgaris more common Paraneoplastic pemphigus IgA pemphigus 4 5 Pemphigus Vulgaris Autoimmune blistering disease Antibodies to desmoglein 3 ± desmoglein 1 Most common pemphigus variant (~70%) Epidemiology: Older adults (50-60s), M=F 10x risk w Jewish ancestry Associated with HLA-DR4 & DR6 6 2  1/27/25 7 Pemphigus Vulgaris - Clinical Painful erosions of oral and/or other mucosal sites ± cutaneous flaccid bulla with erosions Life threatening!! Mucosal erosions of varying size w irregular borders +++Painful Oral, esophageal, conjunctival, vaginal, penile, anal mucosa can all be involved Skin w flaccid, thin-walled, easily ruptured vesicles/bulla à erosions w crusting, little/no tendency to heal +Nikolsky & Asboe-Hansen signs High-risk for secondary infections (HSV, staph/strep, etc.) Non-scarring 8 9 3  1/27/25 10 11 Pemphigus Vulgaris - Diagnosis Biopsy: hematoxylin & eosin (H&E) AND direct immunofluorescence (DIF) H&E: send in formalin DIF: send in Michel’s medium Blood test: indirect immunofluorescence (IIF) & enzyme-linked immunosorbent assay (ELISA) IIF: substrate = monkey esophagus ELISA: 95% sensitive, 98% specific for circulating desmoglein 3 antibodies C an trend titers to follow disease activity 12 4  1/27/25 13 14 15 5  1/27/25 16 Pemphigus Vulgaris - Treatment Oral steroids (~1 mg/kg/day) Long-time standard of care Oral immunosuppressants Mycophenolate, azathioprine, cyclophosphamide Steroid-sparing long-term therapy, help induce remission Ultra-potent topical steroids Rituximab Moderate/severe, refractory, rapidly progressive, or disease threatening function standard of care initial therapy + oral steroids Prognosis: Rituximab: 70% achieve remission off steroids after 6 months and 90% achieve remission after 2 years Mortality rate: 5-15% B efore prednisone, life expectancy w as ≤ 5 years 17 Schmidt et al, Lancet 2019 18 6  1/27/25 Classification of Pemphigus Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Fogo selvagem Drug-induced pemphigus Paraneoplastic pemphigus IgA pemphigus 19 20 Classification of Pemphigus Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Fogo selvagem Drug-induced pemphigus Paraneoplastic pemphigus IgA pemphigus 21 7  1/27/25 22 Classification of Pemphigus Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Fogo selvagem Drug-induced pemphigus Paraneoplastic pemphigus IgA pemphigus 23 24 8  1/27/25 Classification of Pemphigus Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Fogo selvagem Drug-induced pemphigus Paraneoplastic pemphigus IgA pemphigus 25 26 Classification of Pemphigus Pemphigus vulgaris Pemphigus vegetans Pemphigus foliaceus Pemphigus erythematosus Fogo selvagem Drug-induced pemphigus Paraneoplastic pemphigus IgA pemphigus 27 9  1/27/25 28 Subepidermal Bullous Diseases Bullous pemphigoid Pemphigoid gestationis Cicatricial (mucous membrane) pemphigoid Linear IgA disease Chronic bullous disease of childhood Dermatitis herpetiformis Bullous lupus Epidermolysis bullosa acquisita 29 30 10  1/27/25 31 32 33 11  1/27/25 34 35 Bullous Pemphigoid Most common subepidermal autoimmune blistering disease IgG antibodies to BP180/BPAG2/type XVII collagen and BP230/BPAG1 A ntibodies to B P 180 are pathogenic; antibodies to B P 230 are d/t epitope spreading Epidemiology: Disease of older adults, age > 60 years R R 300-fold higher in 90-year-old com pared w ith 60-year-old Associated with HLA-DQB1*0301 Associated with neurological disorders (multiple sclerosis, Parkinson, dementia, bipolar, stroke) May be medication induced (furosemide, nivolumab) 36 12  1/27/25 Bullous Pemphigoid - Clinical Can be extremely polymorphic Non-bullous Pruritus/excoriations, eczematous, papular and/or urticarial Up to 20% of cases Bullous (classic) Tense vesicles/bullae on normal or erythematous skin w admixed urticarial to infiltrative pink plaques à rupture w eroded and crusted areas, but heal spontaneously M ay predom inant in flexural locations O ral involvem ent in 10-30% +++Pruritus ~50% have peripheral eosinophilia Non-scarring 37 38 39 13  1/27/25 40 41 Pemphigoid Gestationis AKA “Herpes Gestationis” Same mechanism as BP Starts in 2nd trimester Commonly flares at delivery/immediately postpartum Recurs/flares: future pregnancies, menstruation, OCPs Pruritic, urticarial plaques, tense bulla starting near umbilicus and spreading Risk of prematurity and/or small for gestational age in baby Risk correlates w severity of disease, not treatment 10% of infants w skin disease – resolves spontaneously Mother w increased risk for Graves disease 42 14  1/27/25 Bullous Pemphigoid - Diagnosis Review medications Furosemide, captopril, NSAIDs, ACEi, amoxicillin, dipeptidyl peptidase-4 inhibitors (gliptins), checkpoint inhibitors (pembrolizumab) common culprits Biopsy: hematoxylin & eosin (H&E) AND direct immunofluorescence (DIF) H&E: send in formalin DIF: send in Michel’s medium Blood test: indirect immunofluorescence (IIF) & enzyme-linked immunosorbent assay (ELISA) ELISA: ≥ 90% specific ELISA & IIF w comparable sensitivity, ≥ 70-80% 43 44 45 15  1/27/25 46 47 Bullous Pemphigoid - Treatment Mild/localized First-line: super to ultrapotent topical steroids Second-line: doxycycline ± nicotinamide, oral steroids Moderate/severe/refractory First-line: oral steroids + super/ultrapotent topical steroids P O steroids tapered over m onths Second-line: mycophenolate, azathioprine, methotrexate, IVIg, rituximab S tarted w ith oral steroids for steroid-sparing m aintenance therapy Prognosis: Course marked by spontaneous exacerbations 30% w relapse in first year of treatm ent 50% relapse w /in 3 m onths after cessation of treatm ent H igh-titer E LIS A at tim e of therapy cessation is risk factor for relapse Mortality among elderly estimated at 10-40% during first year 48 16  1/27/25 49 50 51 17  1/27/25 52 53 54 18  1/27/25 Dermatitis Herpetiformis Cutaneous manifestation of celiac disease IgA autoantibodies to epidermal transglutaminase (transglutaminase 3) Only 20% have intestinal symptoms at time of diagnosis Epidemiology: Northern Europeans, mean age ~40 years Strong association w HLA-DQ2 (same as celiac disease) S een in 90% Strong association w thyroid disease, particularly Hashimoto thyroiditis 55 Dermatitis Herpetiformis - Clinical Symmetric grouped/herpetiform papulovesicles on an erythematous base w polymorphic urticarial plaques, papules and vesicles Elbows, knees, extensor forearms, back & buttocks favored +++Pruritus C om m only all vesicles are ruptured from scratching and only erosions w crusting present Suspect based on distribution, not presence of vesicles Hemorrhagic acral macules (usually palmoplantar), rare finding 57 58 19  1/27/25 Dermatitis Herpetiformis - Diagnosis Biopsy: hematoxylin & eosin (H&E) AND direct immunofluorescence (DIF) H&E: send in formalin DIF: send in Michel’s medium Blood test: Total serum IgA IgA anti-endomysial antibodies (very specific) Found in 80% of D H & >90% of C D Levels indicate severity of gluten-sensitivity & reflect degree of com pliance to gluten restriction ±IgA anti-tissue transglutaminase 2 antibodies ±IgA anti-tissue transglutaminase 3 antibodies 59 60 61 20  1/27/25 62 Dermatitis Herpetiformis - Treatment Gluten-free diet is most important Curative of both intestinal and skin disease, but slow response (several months) Dapsone for cutaneous disease Rapid relief of pruritus (48-72 hours) Lesions recur in 24-48 hours after stopping dapsone if still eating gluten No effect on intestinal disease Screen for G6PD deficiency before starting 63 64 21  1/27/25 65 22