Pemphigus vulgaris
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"pemphigus vulgaris"[MeSH Terms] AND treatment
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Pemphigus Vulgaris
Pemphigus vulgaris (PV) is a severe, potentially fatal autoimmune blistering disease of the skin and mucous membranes, characterized by intraepidermal blister formation due to acantholysis. It is the most common and most serious form within the pemphigus group.
Clinical Presentation
PV is divided into two subgroups:
- Mucosal-dominant type - mucosal erosions with minimal skin involvement
- Mucocutaneous type - extensive skin blisters and erosions in addition to mucosal involvement
Mucosal Lesions
Essentially all patients develop painful erosions of the oral mucosa. In 60% of cases, oral lesions are the first sign. Intact blisters are rarely seen because they are so fragile. Most common sites are the buccal and palatine mucosae. Lesions can extend to:
- Vermilion lip (hemorrhagic crusts)
- Throat (hoarseness, dysphagia)
- Esophagus (sloughing of its entire lining - esophagitis dissecans superficialis)
- Conjunctivae, nasal mucosa, vagina, labia, penis, anus
The mucosa specifically lacks desmoglein 1 expression and depends entirely on desmoglein 3, which is why mucosal disease can remain active even when skin disease appears controlled.
Cutaneous Lesions
The primary skin lesion is a flaccid, thin-walled, easily ruptured blister arising on normal-appearing skin or erythematous bases. Key features:
- Blisters arise anywhere on the body surface
- Fluid is initially clear, may become hemorrhagic, turbid, or seropurulent
- Blisters rupture to form painful erosions that ooze and bleed easily
- Erosions become large and generalized, partially covered with crusts with little tendency to heal
- Healed lesions leave hyperpigmented patches without scarring
- Pruritus is uncommon
Clinical Signs
| Sign | Description |
|---|---|
| Nikolsky sign | Lateral shearing of intact epidermis from dermis with slight tangential pressure |
| Asboe-Hansen sign (Nikolsky II) | Gentle pressure on an intact bulla forces fluid to spread laterally under adjacent skin |
Without treatment, PV can be fatal due to loss of epidermal barrier function, leading to fluid/electrolyte loss and secondary bacterial sepsis.
Epidemiology
- Occurs equally in men and women
- Onset typically in the 5th and 6th decades
- Rare in young persons
- Higher incidence in Jewish (especially Ashkenazi) and Mediterranean populations
- Israel has among the highest incidences worldwide
- Before corticosteroids: frequently fatal; now, morbidity is largely treatment-related
Pathogenesis
The autoantigen is desmoglein (Dsg), a transmembrane desmosomal adhesion molecule (cadherin family). PV antibodies target:
- Anti-Dsg3 alone → mucosal-dominant disease (mucosa lacks Dsg1 to compensate)
- Anti-Dsg1 + Anti-Dsg3 → mucocutaneous disease (correlates with skin involvement)
Pathogenic mechanism:
- Autoantibodies (predominantly IgG4, also IgG1) bind to Dsg3 on the keratinocyte surface
- This disrupts desmosomal adhesion between keratinocytes, causing acantholysis
- Complement, inflammatory cells, and plasminogen activator contribute to blister formation
- T cells (predominantly CD4+, Th2 cytokine profile; also Th1 in chronic disease) drive antibody production
- IgG is found in both involved and clinically normal skin; C3 deposits heavier in acantholytic areas
Genetics: Strong HLA association - HLA-DRB1, HLA-DR4, HLA-DR6, HLA-DQ. Ashkenazi Jews have ~3x elevated risk vs. Arab patients.
Drug-induced PV: Penicillamine, captopril, enalapril, penicillin, nifedipine, piroxicam, rifampicin (drugs containing sulfhydryl or amide groups). Usually resolves on drug withdrawal. Only 10-15% of drug-induced cases have oral lesions.
Associations: Myasthenia gravis, thymoma, ulcerative colitis (elevated rate).
Histopathology
The hallmark is suprabasal acantholysis with intraepidermal blister formation:
- Acantholytic cells are round with no intercellular bridges
- "Tombstone row" appearance - basal keratinocytes remain attached to the basement membrane beneath the blister (the cells appear as tombstones)
- Dermal papillae maintain their outline and often protrude into the blister cavity
- Blister cavity contains few inflammatory cells (eosinophils); moderate perivascular mononuclear infiltrate with eosinophils in dermis
- Early lesions may show eosinophilic spongiosis without visible acantholysis
Note: In oral biopsies, the blister roof is often absent because it ruptures before biopsy. Diagnosis is still made by the location of the split and "tombstone" basal cells.
Immunofluorescence and Diagnosis
| Test | Finding in PV |
|---|---|
| Direct IF (DIF) | IgG (± C3) deposited on the surface of keratinocytes in an intercellular "chicken wire" pattern - perilesional skin or plucked hairs |
| Indirect IF (IIF) | Circulating IgG in intercellular pattern; monkey esophagus is the ideal substrate; positive in 80-90% of patients |
| ELISA | Anti-Dsg3 (mucosal-dominant type); Anti-Dsg1 + Anti-Dsg3 (mucocutaneous type) |
- DIF may remain positive for years after clinical remission
- Conversion of DIF to negative predicts sustained remission after withdrawal of therapy
- Disease activity scoring tools: ABSIS, PVAS, PDAI
Treatment
PV warrants aggressive immunosuppressive treatment. Evidence is largely from open trials and clinical experience.
Topical Treatment
- Prolonged daily baths to remove crusts
- Silver sulfadiazine 1% (Silvadene) for limited disease
- Potent topical corticosteroids or topical tacrolimus for limited disease
- Oral ulcer pain relief: viscous lidocaine, diphenhydramine/simethicone mixture, antiseptic mouthwashes
Systemic Treatment
1. Corticosteroids (first-line)
- Prednisone 1 mg/kg/day as starting dose; if inadequate after 4-8 weeks, increase to 1 mg/kg twice daily or up to 100-150 mg/day
- High doses associated with significant morbidity; adjuvant therapy should be started early
- IV pulse methylprednisolone 1 g/day is used for severe refractory disease
- Start calcium, vitamin D, weight-bearing exercise, and bisphosphonate therapy early
2. Rituximab (anti-CD20 monoclonal antibody)
- Now considered appropriate first-line therapy for patients with severe disease by many experts
- Some combine rituximab with IVIG
3. Adjuvant Steroid-Sparing Agents
- Azathioprine
- Mycophenolate mofetil
- Cyclophosphamide (including imunoablative high-dose regimens)
- Dapsone (also provides some Pneumocystis prophylaxis)
- Methotrexate
- Cyclosporine
4. Other Therapies
- IVIG (intravenous immunoglobulin) - effective, often combined with rituximab
- Plasmapheresis (to reduce circulating antibody titers)
- Tetracycline + niacinamide (mild disease)
Monitoring: Antibody titers fall with effective treatment; DIF conversion to negative is a favorable prognostic indicator.
Prognosis
- Before corticosteroids: mortality ~75%
- Modern era: mortality largely from treatment complications (infection, steroid-induced diabetes, osteoporosis, sepsis)
- Prognosis is more favorable with earlier diagnosis and treatment initiation
- Likelihood of complete remission correlates with younger age of onset and absence of initial mucosal involvement
Differential Diagnosis
| Condition | Key Distinguishing Feature |
|---|---|
| Bullous pemphigoid | Tense (not flaccid) blisters; subepidermal split; anti-BP180/BP230 antibodies; DIF shows linear IgG at BMZ |
| Paraneoplastic pemphigus | Associated malignancy (lymphoma); anti-envoplakin/periplakin/desmoplakin antibodies |
| Mucous membrane pemphigoid | Scarring; subepithelial blisters; linear IgG/IgA at BMZ |
| Erythema multiforme/SJS | Targetoid lesions; epidermal necrosis; not acantholysis |
| Herpetic gingivostomatitis | Viral prodrome; Tzanck smear positive; HSV serology |
Sources: Andrews' Diseases of the Skin, pp. 527-530 | Dermatology 2-Volume Set 5e, pp. 617-618 | Fitzpatrick's Dermatology, p. 939
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Pemphigus Vulgaris
Presentation · PPTX
The deck has 8 slides with a dark navy + crimson medical color scheme:
| Slide | Content |
|---|---|
| 1 | Title slide - dark background with widespread PV clinical image |
| 2 | At a Glance - 8 key fact cards (type, antigen, histology, antibody, blister level, demographics, signs, treatment) |
| 3 | Clinical Features - mucosal vs. skin lesions with embedded clinical photos (skin bulla + oral erosion) |
| 4 | Pathogenesis - Dsg compensation theory, 5-step mechanism flow, T cell involvement |
| 5 | Histopathology & Immunofluorescence - side-by-side detailed tables for DIF / IIF / ELISA |
| 6 | Clinical Signs & DDx - Nikolsky/Asboe-Hansen explained + differential diagnosis table |
| 7 | Treatment - 3-column layout: topical, systemic steroids, adjuvants & biologics (rituximab) |
| 8 | Prognosis & Key Takeaways - mortality stats + 5 numbered clinical pearls |
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