Pemphigus vulgaris: the autoimmune blistering disease GPs must not miss

A 48-year-old woman with mouth ulcers that have not healed for six weeks. Her GP treats for candidiasis, then aphthous ulcers, then oral lichen planus. Two months later she presents again — now with painful blisters over her trunk and scalp that rupture as soon as they form. A punch biopsy confirms pemphigus vulgaris.

This delay is common. The oral prodrome of pemphigus vulgaris is the critical recognition window for GPs. Identifying it means earlier referral, lower corticosteroid burden, and better outcomes.

A. What pemphigus vulgaris is — and why it matters

Pemphigus vulgaris is an organ-specific autoimmune disease. IgG antibodies target desmoglein-3 (DSG3) and, less commonly, desmoglein-1 (DSG1) — transmembrane glycoproteins that form the desmosomal adhesion complexes holding keratinocytes together. When these bonds are broken by autoantibody, cells separate within the epidermis (acantholysis), producing the characteristic flaccid blisters and erosions.

It is rare — incidence approximately 1–5 per 100,000 — but it is potentially fatal. Before corticosteroid therapy, mortality was up to 75%. Even with treatment, mortality from disease and treatment complications remains 5–10%. Rituximab has substantially improved this picture.

Clinical pattern by antibody:

Antibody	Mucosal involvement	Skin involvement
Anti-DSG3 only	Prominent (mouth, pharynx, genitals)	None or minimal
Anti-DSG3 + Anti-DSG1	Prominent	Widespread blistering
Anti-DSG1 only	Absent	Superficial blistering (pemphigus foliaceus — a distinct condition)

DSG3 predominates in mucosal epithelium; DSG1 in superficial epidermis. This accounts for the oral-first presentation pattern.

B. Recognising the clinical features

Oral cavity: Painful erosions, not intact blisters (blisters rupture immediately on mucosal surfaces). Erosions are ragged, irregular, and slow to heal. Any surface can be affected: buccal mucosa, gingiva, hard and soft palate, tongue, lips. Patients complain of pain on eating and swallowing. Oral erosions often precede cutaneous disease by 4–6 months.

Skin lesions: Flaccid blisters (filled with clear or turbid fluid) on an erythematous or normal-appearing base. They rupture easily, leaving widespread, painful erosions that crust. Unlike bullous pemphigoid, there is no urticarial base and blisters are not tense. Predilection sites include the scalp, face, neck, trunk, axillae, and groin.

Nikolsky sign: Positive — lateral pressure to perilesional skin extends the erosion. The Asboe-Hansen sign (pressure on an intact blister spreads it laterally) is also positive.

Other mucosal sites: Oropharynx (dysphagia), oesophagus (odynophagia), conjunctiva (rare), nasopharynx, vagina, and penis.

Conditions to exclude before or alongside dermatology referral:

• Aphthous ulceration (less painful when non-ulcerated, heals within 2 weeks, no skin lesions)
• Oral candidiasis (white plaques, responds to antifungals)
• Oral lichen planus (white reticular Wickham’s striae, atrophic gingivitis, biopsy different DIF pattern)
• Erythema multiforme and Stevens-Johnson syndrome (acute onset, target lesions, drug trigger)
• Bullous pemphigoid (tense blisters, elderly patients, negative Nikolsky)
• Paraneoplastic pemphigus (underlying lymphoma, anti-envoplakin/periplakin antibodies)

C. Diagnosis — what dermatology will do

The GP’s role is to recognise the pattern and refer. Diagnosis requires:

1. Punch biopsy of perilesional skin: Haematoxylin and eosin staining shows suprabasal acantholysis with intraepidermal clefting (a “tombstone” row of basal cells remaining attached to the basement membrane).

2. Direct immunofluorescence (DIF) of perilesional skin: IgG and/or C3 in a “chicken-wire” intercellular pattern throughout the epidermis. DIF is the diagnostic gold standard and must not be placed in formalin — the sample requires Michel’s transport medium.

3. Indirect immunofluorescence (IIDIF) and ELISA: Anti-DSG3 and anti-DSG1 serum antibody titres. Anti-DSG3 is positive in >90% of pemphigus vulgaris. Titres correlate with disease activity and are used to monitor treatment response and guide dose tapering.

D. Treatment — rituximab as first-line

Treatment initiation is the responsibility of dermatology or immunology. GPs share care for monitoring and complications.

The Ritux 3 trial (Joly, Lancet 2017): Randomised 90 patients with pemphigus vulgaris to rituximab (1000 mg IV ×2, two weeks apart) plus short-course prednisolone versus prednisolone alone. Rituximab arm: 89% complete remission off therapy at 24 months versus 34% for prednisolone alone. Corticosteroid exposure was substantially lower in the rituximab arm.

The PEMPHIX trial (Joly, NEJM 2021): Rituximab plus short-course prednisolone versus mycophenolate mofetil plus prednisolone. Rituximab arm achieved significantly higher complete sustained remission at 52 weeks. Confirmed rituximab as first-line over steroid-sparing alternatives.

Standard rituximab protocol:

• Rituximab 1000 mg IV at week 0 and week 2
• Methylprednisolone pre-medication to reduce infusion reactions
• Repeat dosing at 12 and 18 months (or earlier if anti-DSG3 titres rise or relapse occurs)

PBS listing: Rituximab for pemphigus vulgaris is PBS-listed under Section 100 Highly Specialised Drugs (PBS Item 10801K), authority required. Prescribing is restricted to dermatologists, immunologists, and clinical haematologists with hospital prescribing authority.

Supporting therapies:

• Prednisolone: initial 0.5–1 mg/kg/day; tapered once remission is achieved
• Azathioprine or mycophenolate mofetil: steroid-sparing agents when rituximab is not accessible or as adjuncts
• Dapsone: for mild disease or maintenance in some patients
• Wound care: non-adherent dressings for widespread erosions; emollient mouthwashes; topical anaesthetics (benzocaine gel) for oral lesions
• Antiseptic mouth rinses and attention to oral hygiene

E. GP monitoring and shared care

Once in remission on rituximab-based therapy, shared care includes:

Monitoring parameters:

• Anti-DSG3 ELISA titres (6-monthly or at signs of relapse)
• FBC (rituximab and azathioprine): monitor for lymphopaenia, neutropaenia
• Immunoglobulins: hypogammaglobulinaemia with repeated rituximab cycles — check IgG annually
• Fasting glucose, HbA1c, bone density: corticosteroid effects
• Blood pressure: steroid-related hypertension

Infection risk:

• Rituximab causes prolonged B-cell depletion (typically 6–12 months)
• PJP prophylaxis (trimethoprim-sulfamethoxazole) if sustained lymphopaenia or concurrent high-dose corticosteroids
• No live vaccines while on rituximab or within 6 months of a dose
• Influenza (MBS Item 10655) and pneumococcal vaccines (MBS Item 10659) should ideally be administered before rituximab if treatment timing allows

Wound-related complications:

• Secondary bacterial infection (Staphylococcus aureus, Pseudomonas) of open erosions is a significant cause of morbidity — wound swabs and targeted antibiotics when clinically indicated
• Sepsis is a leading cause of death in active pemphigus — a low threshold for hospital admission in febrile patients with widespread erosions

When to escalate urgently

Arrange same-day hospital assessment if:

• Widespread erosions covering >30% body surface area with fluid/electrolyte loss
• Oropharyngeal or oesophageal involvement preventing adequate oral intake or causing aspiration risk
• Fever or systemic sepsis in the context of open erosions
• Respiratory involvement (laryngeal or bronchial mucosa)
• Ocular involvement (corneal erosions, conjunctival scarring)

For new diagnoses with oral erosions not responding to standard treatments for aphthae, candida, or lichen planus at the 3–4 week mark: urgent dermatology referral (within 1–2 weeks). Do not wait for the skin blisters to appear.

What this article is and is not

This article is an orientation for GPs who may see the oral prodrome of pemphigus vulgaris before dermatology diagnosis, or who are providing shared monitoring care.

It is not a substitute for skin biopsy, DIF interpretation, treatment initiation, or PBS authority applications. All patients with suspected pemphigus require dermatology assessment.

Information is consistent with eTG Dermatology (2024), Australasian College of Dermatologists guidance, PBS listings, and cited trials as at the date of publication. Clinical guidelines evolve; verify current recommendations before applying to individual patients.

Sources cited

1. Therapeutic Guidelines: Dermatology — eTG (2024). Pemphigus. https://tgldcdp.tg.org.au
2. Joly P et al. (2017). First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3). Lancet. https://doi.org/10.1016/S0140-6736(17)31102-5
3. Joly P et al. (2021). Rituximab versus mycophenolate mofetil in patients with pemphigus vulgaris (PEMPHIX). N Engl J Med. https://doi.org/10.1056/NEJMoa2028564
4. Australasian College of Dermatologists. Autoimmune blistering diseases. https://www.dermcoll.edu.au
5. Australian Medicines Handbook. (2024). Rituximab: pemphigus indications. https://amhonline.amh.net.au
6. Hertl M et al. (2015). Pemphigus — European guidelines including diagnostic criteria. J Eur Acad Dermatol Venereol. https://doi.org/10.1111/jdv.12772
7. Royal Australian College of General Practitioners. Dermatology in general practice: blistering disorders. https://www.racgp.org.au/clinical-resources/clinical-guidelines/key-racgp-guidelines/view-all-racgp-guidelines/dermatology-in-general-practice
8. Pharmaceutical Benefits Scheme. Rituximab — pemphigus vulgaris (Item 10801K). https://www.pbs.gov.au/medicine/item/10801K