Pemphigus vulgaris

Meet the patient

A 52-year-old woman has had painful mouth ulcers for three months that her dentist treated as aphthae. Now flaccid, fluid-filled blisters are appearing on her chest and scalp, bursting within a day to leave raw, weeping erosions ringed by a ragged collar of skin. She is losing weight because eating hurts, and lateral pressure on apparently normal skin peels the epidermis away — Nikolsky positive.^[1][9]

Two questions frame every pemphigus case and everything below: where in the epidermis is the split? — suprabasal, and that single fact drives the histology, the immunofluorescence and the whole differential — and which desmoglein is the antibody blocking? Hold those two and the disease falls into place.^[1][2]

One antibody, one split, two faces — the desmoglein compensation theory

The whole clinical puzzle of pemphigus collapses onto a single mechanism: which desmoglein the antibody blocks. Desmoglein 3 sits in the deep epidermis and the mucosa; desmoglein 1 sits in the upper epidermis and the skin surface.^[1][2]

Block Dsg3 alone and the upper-skin Dsg1 compensates, so the skin holds — you get mucosal-dominant disease, the patient whose mouth is destroyed but whose skin looks near-normal. Block both Dsg3 and Dsg1 and there is no compensation left: the skin gives way too, and you get mucocutaneous pemphigus. That is the entire theory, and examiners love it.^[2]

The antibody is almost always IgG4 (pathogenic) with some IgG1, binding the cadherin extracellular domain of the desmoglein and pulling desmosomes apart so keratinocytes round up and detach — acantholysis. The split sits just above the basal layer, leaving basal cells anchored to the basement membrane like a row of tombstones: the histology signature that earns marks.^[1][2]

Etymology for viva gold: pemphigus comes from the Greek pemphix, a blister; acantholysis from akantha, the prickle-cell layer, plus lysis, a loosening — the prickle cells let go of each other. Every word in the diagnosis is a description of the pathology.^[2]

Meet the family — pemphigus is not one disease

The pemphigus family shares IgG- or IgA-driven acantholysis but splits on antigen, phenotype and prognosis, and recognising the variant changes the plan. The classic teaching line: an isolated oral eruption in an older patient with lymphadenopathy is paraneoplastic until proven otherwise, and a verrucous flexural plaque is vegetans, not Hailey-Hailey.^[2][10]

^{[1] [3] [4] [11]}

The discriminator line: PV splits suprabasally and stains chicken-wire intercellular IgG; foliaceus splits in the uppermost granular layer and spares mucosa; paraneoplastic pemphigus adds plakin antibodies and a dual DIF pattern; IgA pemphigus is pustular with intercellular IgA.^[1][13]

Drug triggers worth a named mention: thiol-containing drugs (D-penicillamine, captopril, tiopronin) and checkpoint inhibitors (pembrolizumab, nivolumab) — the latter increasingly examined. Drug-induced pemphigus often resembles foliaceus and may remit on withdrawal, though antibodies can linger for months.^[2][8]

Why it happens — the immune circuit and the rituximab rationale

Pathogenic IgG4 binds Dsg3 (and often Dsg1), disrupts the desmosome, and rounds up the keratinocytes — acantholysis. The blister is therefore intraepidermal and suprabasal, fragile by design: there is no intact roof to keep it intact, so it ruptures within a day. This is why the clinical sign is a flaccid blister and an erosion, never a tense bulla.^[1][2]

The same circuit is the reason rituximab works: deplete the CD20-positive B cells that produce the autoantibody and you switch off the disease at its source. That mechanistic logic, not empirical luck, is why rituximab moved from salvage to first-line.^[5][6]

How common, who, and what killed them before rituximab

^{[5] [14]}

PV is rare but it clusters fiercely in Ashkenazi Jewish, Mediterranean, Middle Eastern and Indian or South Asian populations, driven by HLA class II alleles — HLA-DRB104:02 and DQB105:03 — that present Dsg3 peptides to autoreactive T cells.^[2][3][8]

The mortality story is the viva gift. Before corticosteroids, around three-quarters died within a year — dehydration, sepsis, a lost skin barrier. Corticosteroids cut that to roughly a quarter; steroid-sparing immunosuppression to under a third; and the rituximab era has driven disease-specific mortality under 5 percent at five years. Infection has now replaced disease activity as the leading cause of death — pneumonia, bacterial sepsis, PJP under combination immunosuppression. That single pivot is why monitoring matters as much as the induction drug.^[5][7][8]

Read the blister like the microscopist does

A flaccid blister that ruptures within a day, leaving a painful erosion with a collarette of detached epidermis, plus a positive Nikolsky sign, is pemphigus until disproven. The tense, robust bulla of pemphigoid it is not.^[1][12]

• Skin: flaccid blisters on normal or erythematous skin across trunk, scalp, face and proximal limbs, rupturing into erosions with a peripheral collarette of detached epidermis. Nikolsky sign positive (lateral pressure shears the epidermis); Asboe-Hansen sign positive (pressure extends the blister).^[1]
• Mucosa: involved in 50-70 percent, often the presenting feature and preceding skin by months — oral erosions (buccal, palate, gingival, tongue), then pharyngeal, oesophageal (dysphagia, odynophagia), conjunctival, genital, nasal. Examine every mucosal surface.^[9]
• Severity: score with the Pemphigus Disease Area Index (PDAI) — 12 body areas and three activity types, total 0-250; active disease over 15, complete remission off therapy is 0 for two months.^[1]

The classic trap: tense bullae on an urticarial base in an 80-year-old is bullous pemphigoid, not pemphigus — the split is subepidermal, Nikolsky is negative, and DIF is linear at the basement membrane. Confusing the two sends you down the wrong biopsy and the wrong first drug.^[1][13]

Face-off — pemphigus vulgaris versus its closest mimics

^{[1] [13]}

The diagnostic triad — three tests, one disease

Diagnosis needs three investigations together; no single test is enough. Take the histology biopsy from a lesion and the DIF biopsy from perilesional skin — two separate sites, a recurring trainee error.^[2][4]

1. Histology of a lesional biopsy — a blister cavity just above the basal layer (suprabasal acantholysis), basal cells still anchored to the basement membrane like tombstones, and rounded acantholytic keratinocytes floating free.^[1][2]
2. Direct immunofluorescence of perilesional skin — the pathognomonic finding: intercellular IgG4 (and C3) deposition throughout the epidermis in a chicken-wire (fishnet) pattern. The single most specific test.^[1]
3. Serology — indirect immunofluorescence on monkey oesophagus, plus anti-Dsg3 and anti-Dsg1 ELISA; titres track disease activity and guide retreatment, so they are a monitoring tool as well as a diagnostic one.^[3]

A practical biomarker rule: serial ELISA values are a monitoring tool, not only a diagnostic one. Anti-Dsg1 values track the skin course closely, and a value over 20 U/mL predicted cutaneous relapse in follow-up (79% positive and 84% negative predictive value). Anti-Dsg3 values over 14 U/mL appeared in every patient who relapsed but also in many in mucosal remission, so a rising Dsg3 titre flags risk without confirming relapse.^[15]

Management — steroids plus rituximab, and screen hepatitis B first

First-line is now systemic corticosteroids plus rituximab together. RITUX 3 showed first-line rituximab plus short-course prednisone outperformed prednisone alone, PEMPHIX showed rituximab outperformed mycophenolate, and the EADV 2020 S2K guideline made rituximab first-line for moderate-to-severe disease.^[4][5][14]

• Oral prednisolone 0.5-1.5 mg/kg/day induces remission, then tapers over months; RITUX 3 tapered prednisone alone from 1-1.5 mg/kg/day over 12-18 months, and used a shorter 0.5-1 mg/kg/day course over 3-6 months alongside rituximab.^[14]
• Rituximab depletes CD20-positive B cells and cuts autoantibody production with it. First-line dosing: 1000 mg IV on days 1 and 15, repeated as 500 mg at months 12 and 18 (RITUX 3); PEMPHIX gave 1000 mg on days 168 and 182.^[5][6][14]
• Mycophenolate mofetil 2 g/day reduces steroid exposure but is inferior to rituximab for sustained remission off therapy (40% vs 10% at week 52 in PEMPHIX).^[5]

Refractory disease: beyond the first-line trials, evidence thins out. High-dose IVIG (400 mg/kg/day for five days, single cycle) beat placebo in a double-blind randomised trial of patients relatively resistant to systemic steroids.^[16] For paraneoplastic pemphigus, diagnosis follows formal criteria and treatment rests on case reports and expert opinion rather than controlled trials.^[11]

Supportive care is not optional: topical steroids for residual erosions, pain control, a soft or liquid diet (nasogastric if oesophageal), and a true multidisciplinary team — dermatology, oral medicine, ophthalmology, gynaecology or urology, gastroenterology and ENT.^[1]

The dosing reference — doses, routes, monitoring

^{[5] [14] [16]}

How patients with pemphigus come to harm (the preventable list)

• Fatal hepatitis B reactivation after rituximab given without a screen — the textbook preventable death^[4]
• Overwhelming infection under high-dose steroid plus rituximab with no PJP prophylaxis or vaccination^[7]
• Malnutrition and dehydration from untreated oral and oesophageal erosions — feed early, nasogastric if needed^[9]
• Missed paraneoplastic pemphigus labelled severe aphthous stomatitis while a lymphoma or thymoma goes untreated^[10]
• Steroid monotherapy pushed ever higher when rituximab was the guideline first-line all along^[5]
• Pregnancy on rituximab — B-cell depletion in the neonate; plan and switch^[1]

Special populations

Pregnancy: pemphigus can flare; corticosteroids and azathioprine are relatively safe, but rituximab is avoided because it depletes neonatal B cells. Track anti-Dsg titres through pregnancy.^[1]

Elderly and frail: prefer rituximab over escalating steroids to spare bone, glucose and infection risk, with vigilant infection surveillance — the group most likely to die of treatment, not disease.^[7][8]

Paraneoplastic pemphigus: investigate and treat the underlying malignancy first; the skin disease often follows the tumour.^[10][11]

Prognosis, surveillance and prevention

With rituximab, complete remission off therapy is now achievable in the majority, and anti-Dsg3 titres track activity and predict relapse — monitor every 3-6 months in active disease and 6-12 months in remission, and check immunoglobulins if rituximab is repeated.^[5]

There is no primary prevention — it is autoimmune. Secondary prevention means early diagnosis, treatment to remission, infection prevention (vaccination, PJP prophylaxis) and sun protection, since UV can trigger flares. Family screening is not routine; penetrance is low.^[1]

The mantra, and the memory device

^[1]

The mantra: suprabasal split, chicken-wire IgG, steroids plus rituximab, screen hepatitis B, and watch for infection.^[1][5]

Ward-round test — three stems, thirty seconds each

Stem 1 — three months of mouth ulcers, now blistering skin (answer)ShowHide

A 52-year-old with a three-month history of painful oral erosions now has flaccid blisters on her trunk that rupture into erosions with a skin collarette; Nikolsky is positive. Name the first tests and the first drug. Model: Biopsy lesional skin for histology AND perilesional skin for direct immunofluorescence — two separate biopsies — plus anti-Dsg3 and anti-Dsg1 ELISA. Expect intraepidermal acantholysis and IgG at keratinocyte cell surfaces on DIF. Start oral prednisolone 0.5-1 mg/kg/day and plan first-line rituximab on the RITUX 3 schedule once the hepatitis B screen is back. Examine all mucosal surfaces and protect nutrition given the oral involvement.^{[1][3][9][14][17]}

Stem 2 — tense blisters on an urticarial base in an 80-year-old (answer)ShowHide

An 80-year-old man has tense, robust bullae on red urticarial plaques across his thighs and flexures; his mouth is spared; Nikolsky is negative. Is this pemphigus? Model: No — this is bullous pemphigoid, and the distinction is mechanistic and histological. BP splits subepidermally (not suprabasally), shows linear IgG/C3 at the basement membrane (not intercellular chicken-wire), targets BP180 and BP230 (not desmogleins), and classically spares mucosa in an older patient. Treat with topical or systemic steroids, doxycycline or dupilumab — rituximab is not first-line here. Mixing up the two wastes the biopsy and misdirects therapy.^[1][13]

Stem 3 — pemphigus refractory to high-dose steroids, now febrile (answer)ShowHide

A patient with known PV on prednisolone 1 mg/kg/day for six weeks has worsening erosions and now fever and hypoxia. Next steps? Model: Two simultaneous problems. First, treat presumed infection — send cultures and start antibiotics while holding further immunosuppression; rituximab-treated patients had more serious adverse events than mycophenolate controls in PEMPHIX. Second, escalate the pemphigus rather than pushing steroids higher: rituximab if not yet given, or high-dose IVIG (400 mg/kg/day for five days) if the disease has resisted steroids. Re-check anti-Dsg titres to gauge activity, since anti-Dsg1 values over 20 U/mL predict cutaneous relapse.^{[5][7][15][16]}

References17ShowHide

1. [1]Schmidt E, Kasperkiewicz M, Joly P. Pemphigus Lancet, 2019.PMID 31498102
2. [2]Kasperkiewicz M, Ellebrecht CT, Takahashi H, et al. Pemphigus Nat Rev Dis Primers, 2017.PMID 28492232
3. [3]Malik AM, Tupchong S, Huang S, et al. An Updated Review of Pemphigus Diseases Medicina (Kaunas), 2021.PMID 34684117
4. [4]Joly P, Horvath B, Patsatsi A, et al. Updated S2K guidelines on the management of pemphigus vulgaris and foliaceus initiated by the european academy of dermatology and venereology (EADV) J Eur Acad Dermatol Venereol, 2020.PMID 32830877
5. [5]Werth VP, Joly P, Mimouni D, et al. Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris N Engl J Med, 2021.PMID 34097368
6. [6]Hebert V, Joly P. Rituximab in pemphigus Immunotherapy, 2018.PMID 29064314
7. [7]Kaegi C, Wuest B, Schreiner J, et al. Systematic Review of Safety and Efficacy of Rituximab in Treating Immune-Mediated Disorders Front Immunol, 2019.PMID 31555262
8. [8]Kridin K. Pemphigus group: overview, epidemiology, mortality, and comorbidities Immunol Res, 2018.PMID 29479654
9. [9]Alramadhan SA, Islam MN. Vesiculobullous Lesions of the Oral Cavity Oral Maxillofac Surg Clin North Am, 2023.PMID 37019505
10. [10]Anderson HJ, Huang S, Lee JB. Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome: Part I. Clinical overview and pathophysiology J Am Acad Dermatol, 2024.PMID 37597771
11. [11]Huang S, Anderson HJ, Lee JB. Paraneoplastic pemphigus/paraneoplastic autoimmune multiorgan syndrome: Part II. Diagnosis and management J Am Acad Dermatol, 2024.PMID 37714216
12. [12]Ingold CJ, Sathe NC, Khan MAB. Pemphigus Vulgaris 2026.PMID 32809695
13. [13]Holtsche MM, Boch K, Schmidt E. Autoimmune bullous dermatoses J Dtsch Dermatol Ges, 2023.PMID 37070500
14. [14]Joly P, Maho-Vaillant M, Prost-Squarcioni C, et al. First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3) Lancet, 2017.PMID 28342637
15. [15]Abasq C, Mouquet H, Gilbert D, et al. ELISA testing of anti-desmoglein 1 and 3 antibodies in the management of pemphigus Arch Dermatol, 2009.PMID 19451496
16. [16]Amagai M, Ikeda S, Shimizu H, et al. A randomized double-blind trial of intravenous immunoglobulin for pemphigus J Am Acad Dermatol, 2009.PMID 19293008
17. [17]Baker FA, Tatour M, Yehya A, et al. Hepatitis B screening, antiviral prophylaxis, and reactivation risk in rituximab-treated patients Dig Dis Sci, 2026.PMID 42240959