Pemphigus Vulgaris lect 37 - immune-mediated epithelial diseases-SM-2.pdf

Pemphigus Vulgaris Pemphigus Vulgaris • Pemphigus is general term for a group of rare autoimmune blistering epithelial disorders that results from loss of normal intercellular attachments in epidermis • Two main types: – Pemphigus foliaceus – autoimmune destruction of desmoglein 1 (in epidermis, e...

Pemphigus Vulgaris Pemphigus Vulgaris • Pemphigus is general term for a group of rare autoimmune blistering epithelial disorders that results from loss of normal intercellular attachments in epidermis • Two main types: – Pemphigus foliaceus – autoimmune destruction of desmoglein 1 (in epidermis, esp. scalp). Least severe form of pemphigus. – Pemphigus vulgaris – autoimmune destruction of desmoglein 3 lesions in epidermis and mucous membranes (e.g., in mouth) o 80% of all pemphigus cases worldwide o Affects scalp, face, groin, axillae, flexural surfaces o Can be fatal if untreated Types of Pemphigus Pemphigus vulgaris Pemphigus foliaceus • Deep blistering • Superficial blistering • Immune target = desmoglein 3 • Immune target = desmoglein 1 https://www.merckmanuals.com/professional/dermatologic-disorders/bullous-diseases/pemphigus-vulgaris Predisposition for Pemphigus Vulgaris Epidemiology • Uncommon (0.5-3.2 per 100,000 population) • Most commonly occurs at 40-60 years of age • No gender predisposition https://ucfhealth.com/wpcontent/uploads/2021/03/iStock-477832087.jpg Risk factors • Ashkenazi Jewish or Mediterranean descendants are at increased risk • Genetic factors: MHC class II – DRB*0402, DQB1*0503 • Triggers – not well-understood, but may possibly be induced by drugs (cephalosporin, penicillamine, captopril, NSAIDS, thiol-containing compounds) or chemicals https://minio.scielo.br/documentstore/1806-4841/M6GwT4pRNH7xDySBrKFCPPC/9d7c3536dc62c9ddd67f7cc3cc991e8de5a05f84.jpg https://cdn.lecturio.com/assets/Epidermal-keratinocyte-connections.png Pathophysiology of PV • In genetically susceptible person, trigger causes damage to keratinocytes • Ag processed by resident APCs which activate CD4 Th2 cells • CD4 Th2 cells provide help to autoAg-specific B cells • AutoAbs made to keratinocyte surface Ags, esp. to desmoglein and IgG4 isotype • Ab binding disrupts adhesion between keratinocytes (a response) • Leads to fluid blisters containing free-floating keratinocytes (acanthocytes) • Basal layer of keratinocytes are usually still hanging onto the basement membrane – this is referred to as tombstoning • Positive Nikolsky’s sign = firm sliding pressure with finger separates normal-appearing epidermis, producing an erosion) https://www.mdpi.com/2218-273X/10/10/1432/htm Another Look at the Pathophysiology… Symptoms of Pemphigus Vulgaris • Painful, flaccid, fragile bullae filled with clear fluid and an erythematous base (deep intraepithelial blisters) • Most commonly manifests as erosions/ulcers in the mouth, larynx, and mucous membranes • Other sites of presentation – acute or chronic paronychia (nail infection), subungual hematoma (nails), conjunctiva, nasal mucosa, esophagus, labia/vagina/vulva/cervix, penis/urethra, anus Acanthocyte • Mortality rate – 5-15% with corticosteroid therapy Tombstoning Diagnosis and Treatment of PV Diagnosis • Biopsy ‒ Direct immunofluorescent (IF) staining, showing deposition of anti-desmoglein Ab and C’ byproducts ‒ Presence of acanthocytes (detached keratinocytes in blister fluid) • ELISA of serum for IgG4, IgG1, C’ levels • Tzanck smear (see notes) • Corticosteroids – ↓ mortality but not good long-term IF for anti-desmoglein Treatment • Immunosuppressants – e.g., methotrexate – can reduce need for systemic CCS use • Rituximab – anti-CD20 antibody + IVIG • Anti-TNF drugs – e.g., etanercept THIS IS A DIFFICULT DISEASE TO CONTROL!