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Key points
- Pemphigus vulgaris (PV): rare autoimmune intraepidermal blistering disease affecting skin/mucous membranes, with incidence of 0.7/100,000 person-years; common in Ashkenazi Jewish, Iranian, Indian, and Mediterranean populations.
- Aetiology: caused by IgG autoantibodies targeting desmoglein 3 (and sometimes desmoglein 1), disrupting keratinocyte adhesion and leading to acantholysis (intraepidermal blister formation).
- Risk factors: age (40–60 years), genetic predisposition (HLA types), medications (e.g. ACEi, ARBs, penicillamine), and paraneoplastic syndrome (e.g. lymphoma, Castleman disease).
- Clinical features: painful oral erosions (common initial sign), flaccid skin blisters, mucous membrane involvement (conjunctiva, pharynx, anogenital areas), and positive Nikolsky sign (epidermal shearing).
- Investigations: skin biopsy with histology (intraepidermal acantholysis, ‘tombstoning’) and direct immunofluorescence (net-like IgG deposition); ELISA detects anti-desmoglein 1/3 antibodies.
- Differential diagnoses: bullous pemphigoid (tense bullae, negative Nikolsky sign), pemphigus foliaceus (no mucosal involvement), IgA pemphigus (IgA antibodies on immunofluorescence).
- Management: systemic steroids (e.g. prednisolone), immunosuppressants (azathioprine, rituximab), IVIG for refractory cases; supportive care includes fluid correction, nutritional support, wound care.
- Complications: secondary infections, treatment side effects (e.g. steroid-induced), malnutrition (due to oral lesions), and psychological distress.
Introduction
Pemphigus vulgaris (PV) is a rare autoimmune intraepidermal blistering disease primarily affecting the skin and mucous membranes. It typically manifests in individuals between 40 and 60 years of age, affecting males and females equally.1
In the United Kingdom, the incidence is reported as 0.7 cases per 100,000 person-years.2 It is more common in Ashkenazi Jewish, Iranian, Indian and Mediterranean populations.3
Aetiology
The exact aetiology of PV remains unclear, but it is primarily considered an autoimmune disease. The condition arises when the immune system mistakenly produces autoantibodies, predominantly IgG, that target desmosomal proteins, particularly desmoglein 3 and sometimes desmoglein 1.1
While the exact trigger for this autoimmune response remains unclear, several factors have been implicated. These include genetic predisposition, with certain HLA genotypes associated with increased risk. Environmental factors may also contribute to disease onset, including medications, viral infections and stress.1
Pathophysiology
The pathophysiology of PV involves the production of autoantibodies targeting desmoglein 3, a crucial component of desmosomes responsible for keratinocyte cohesion. In some cases, autoantibodies may also target desmoglein 1.
This autoimmune attack disrupts desmosome function, leading to acantholysis (the loss of adhesion between keratinocytes in the epidermis). This breakdown in cellular cohesion results in the formation of intraepidermal blisters, which are characteristic of PV.1, 4
Risk factors
Risk factors for PV include:1, 4
- Age: typically affects individuals between 40 and 60 years of age
- Medications: drugs such as angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), cephalosporins and penicillamine have been associated with drug-induced pemphigus vulgaris
- Genetic predisposition: certain HLA genotypes are associated with increased risk
- Paraneoplastic syndrome: pemphigus can be triggered by cancers, especially lymphoma and Castleman disease
Clinical features
History
When taking a history for suspected PV, important features include:1
- Painful oral cavity erosions: often the initial presentation
- Skin blisters: rupture easily, leaving painful erosions
- Mucous membrane involvement (e.g. conjunctiva, nasal mucosa, larynx, pharynx and anogenital area)
- Constitutional symptoms: generally not present, except in severe widespread disease
Important areas of the history
Other important areas of the history to cover include:
- Medication history: recent changes, especially new medications including ACEi, ARBs and cephalosporins
- Family history: given the potential genetic predisposition, other family members may have been affected
Clinical examination
A thorough dermatological examination of the lesions should be performed.
Typical examination findings of PV include:
- Flaccid blisters: these rupture easily, forming painful erosions that may coalesce to form large, denuded areas
- Oral lesions: erosions and ulcerations are often the initial presentation
- Other mucosal lesions: involvement of the conjunctiva, nasal mucosa, pharynx, larynx and anogenital region may be seen
- Secondary infection: can occur within the lesions, particularly in extensive disease
Nikolsky sign
This is where slight friction on the skin results in the shearing of the epidermis.
Nikolsky sign is pathognomonic of PV and is also seen in Steven-Johnson Syndrome/toxic epidermal necrolysis and staphylococcal scalded syndrome.
Differential diagnoses
Other blistering diseases present similarly to PV. Differential diagnoses include:
- Bullous pemphigoid: usually presents in older adults with tense bullae, unlike the flaccid blisters in PV. Nikolsky sign is negative
- Pemphigus foliaceus: autoimmune blistering disease similar to PV but does not affect the oral mucosa. Primarily due to anti-Dsg1 antibodies
- IgA pemphigus: presents with painful blisters like PV but does not typically affect oral mucosa. Direct immunofluorescence shows IgA deposits instead of IgG
Table 1. Comparison of bullous pemphigoid and pemphigus vulgaris 1, 4-6
| Bullous pemphigoid | Pemphigus vulgaris | |
| Age group | Elderly | Middle-aged |
| Blister location | Sub-epidermal | Intraepidermal |
| Blister characteristics | Tense, firm | Rupture easily, flaccid |
| Mucosal involvement | Less common | Very common |
| Nikolsky sign | Negative | Positive |
| Autoantigens | BP 180, BP 230 | Desmoglein 1, Desmoglein 3 |
| Histology | Subepidermal blisters with eosinophils | Intraepidermal acantholysis |
| Prognosis | Better | More chronic course, with higher morbidity and mortality |
Pemphigoid and pemphigus
PemphigoiD = Deep and pemphiguS = Superficial
This shows the fundamental difference between the two conditions, their level of involvement and, therefore, their pathophysiology.
Investigations
The diagnosis of PV typically involves a combination of skin biopsy and blood tests.
Laboratory investigations
Blood tests are crucial in the diagnostic process. These include:
- Indirect immunofluorescence: to detect circulating autoantibodies
- Enzyme-linked immunosorbent assay (ELISA): identifies anti-desmoglein 1 (anti-Dsg1) and anti-desmoglein 3 (anti-Dsg3) antibodies
Skin biopsy
Two skin biopsy samples are usually required. The first sample is taken from the edge of a blister (lesional) for histological examination. This typically reveals intraepidermal acantholysis, supra-basal cleft formation and ‘tombstoning’ of the keratinocytes at the cleft site.
The second sample is obtained from the skin within 2 cm of the blister (perilesional) for direct immunofluorescence (DIF) testing, which typically shows a net-like pattern of IgG in the epidermis, often with C3 deposition.
Management
The management of PV requires a comprehensive approach encompassing both systemic treatments and supportive care. The introduction of steroid treatment, and now rituximab, has reduced the mortality rate from over 90% within 1 year to 15-30%.
Supportive management
Supportive care is crucial in PV and includes:
- Correction of fluid and electrolyte imbalances
- Nutritional support
- Pain management
- Wound care
Medical management
Medical management of PV includes:
- Systemic steroids: first-line to induce remission (e.g. prednisolone)
- Topical therapy: including topical steroids and emollients to manage localised lesions and promote healing
- Immunosuppressive agents: used concomitantly and may include azathioprine, mycophenolate mofetil, rituximab and dapsone, with rituximab having strong evidence for inducing remission4
- Intravenous immunoglobulin (IVIG): considered if refractory to standard treatment1
Regular follow-up is essential to monitor disease activity, adjust treatment as needed, and manage any potential complications or treatment side effects.
Complications
Complications of PV include:
- Secondary infections: bacterial or viral
- Adverse effects from treatment: particularly associated with steroids or immunosuppressive medications
- Impacts on food intake and nutrition, particularly with oral involvement
- Psychological distress
Reviewer
Dr Matt Alexander
Consultant Dermatologist
Editor
Dr Jess Speller
References
- Ingold CJ, Sathe NC, Khan MAB. Pemphigus Vulgaris. StatPearls. Treasure Island (FL). 2024. Available from: [LINK].
- Langan SM, Smeeth L, Hubbard R, et al. Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study. BMJ. 2008. Available from: [LINK].
- Griffiths C, Barker J, Bleiker T, et al. Rook’s Textbook of Dermatology. 9th edition. Wiley-Blackwell. 2016.
- Ngan V, Oakley A, Shakel M. DermNet. Pemphigus vulgaris. 2022. Available from: [LINK]
- Baigrie D, Nookala V. Bullous Pemphigoid. StatPearls. Treasure Island (FL). 2023. Available from: [LINK].
- Oakley A, Coulson I. DermNet. Bullous pemphigoid. 2024. Available from: [LINK].
Image references
- Figure 1. DermNet. Pemphigus vulgaris. License: [CC BY-NC-ND 3.0 NZ]
- Figure 2. DermNet. Pemphigus vulgaris. License: [CC BY-NC-ND 3.0 NZ]
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