Pemphigus vulgaris

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Pemphigus vulgaris is an autoantibody-mediated loss of keratinocyte adhesion. Mucosal desmoglein 3 is often affected first, causing oral erosions that can be mistaken for aphthae, candidiasis, lichen planus or dental trauma for months. Cutaneous involvement adds superficial flaccid bullae and broad erosions because the roof separates within epidermis and breaks easily. In darker skin, active erythema may look violaceous or grey and healed sites may leave prominent post-inflammatory pigment; pain, friability and mucosal distribution remain key.

The diagnosis requires clinicopathological agreement. Histology must include a fresh blister edge rather than an old ulcer, while direct immunofluorescence needs intact perilesional tissue in non-formalin medium. Intercellular epidermal IgG and C3 forms the characteristic chicken-wire or fishnet pattern. Serum desmoglein ELISA supports phenotype and can aid monitoring, but treatment before biopsy, wrong site and technical transport errors can all create false reassurance.

Without immunosuppression, ongoing barrier loss historically carried high mortality. Rituximab is now licensed for moderate-to-severe adult disease and reduces long glucocorticoid exposure when combined with a taper. Treatment itself can cause serious infection, hepatitis B reactivation, hypogammaglobulinaemia, late neutropenia and rare progressive multifocal leukoencephalopathy. Oral pain, dental disease, nutrition and mental health therefore remain core care rather than secondary concerns.

Key points

Pemphigus vulgaris commonly begins with persistent painful oral erosions before skin disease; intact blisters may be rarely seen because the intraepidermal roof is fragile.
Skin lesions are flaccid bullae or irregular raw erosions on normal or erythematous skin, often affecting scalp, face, chest, back and pressure sites.
Gentle lateral pressure may extend an erosion, but Nikolsky sign is neither necessary nor specific and should not be repeatedly elicited on painful skin.
Routine histology from a fresh blister edge shows suprabasal acantholysis; direct immunofluorescence from separate perilesional skin shows intercellular IgG and C3 in a net-like pattern.
Serum desmoglein 3 antibodies align with mucosal disease and desmoglein 1 with skin involvement, but titres are interpreted alongside clinical activity and biopsy.
Moderate-to-severe adult pemphigus vulgaris has a licensed rituximab regimen of 1000 mg intravenously on days 1 and 15 with a tapering glucocorticoid course, followed by defined maintenance when needed.
Before rituximab, screen hepatitis B and other infection risk, update suitable vaccines, check immunoglobulins and blood counts and plan prophylaxis and reproductive safety.
Use non-adherent wound care, bland oral products, potent topical corticosteroid for limited lesions, analgesia and dietetic support; antiseptic or antifungal treatment needs a defined indication.
Disease control is absence of new lesions with healing of established erosions. Relapse and treatment infection can both produce deterioration, so culture and examination precede reflexive immunosuppression escalation.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Desmoglein autoimmunity

Pathogenic IgG develops against desmoglein adhesion proteins, most often desmoglein 3 with additional desmoglein 1 in mucocutaneous disease.

Genetic immune susceptibility

HLA and immune-regulatory factors alter tolerance, while most affected people have no single identifiable environmental precipitant.

Medicine-triggered pemphigus

Thiol and selected other medicines can provoke a pemphigus phenotype, making a precise drug timeline relevant without replacing immunopathological confirmation.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Keratinocyte adhesion fails
Antibody disruption of desmosomes causes acantholysis, so epidermal cells lose cohesion while basal cells remain attached to basement membrane.
2
Mucosa loses protection first
Desmoglein 3 predominance in mucosa explains why oral erosions often appear before skin disease and can persist without obvious bullae.
3
A fragile roof collapses
The split lies within epidermis, leaving only superficial keratinocytes over fluid and producing flaccid blisters that rupture into painful erosions.
4
Barrier failure becomes systemic
Extensive denudation permits fluid loss and microbial invasion, while mucosal pain causes dehydration, malnutrition and impaired medication intake.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Persistent oral erosions

Multiple painful irregular erosions on buccal mucosa, palate, gingiva or lips may precede skin disease and impair eating or tooth care.

Fragile flaccid bullae

Thin-roofed blisters collapse quickly, leaving moist irregular erosions rather than the firm intact bullae typical of pemphigoid.

Scalp and trunk disease

Crusted erosions commonly affect seborrhoeic scalp, face and upper trunk and may be mistaken for infection or eczema.

Multi-mucosal involvement

Pharyngeal, laryngeal, ocular, nasal, genital or anal disease creates site-specific pain and functional threats beyond the mouth.

Infection superimposedRed flag

New purulence, malodour, warmth, fever, hypotension or disproportionate pain suggests bacterial, candidal or herpetic complication rather than immune activity alone.

Treatment-associated warning

New focal neurology, severe infection, jaundice or profound cytopenic symptoms during rituximab or steroid treatment requires urgent medicine-specific assessment.

Red flags requiring action

Dysphagia, hoarseness, dyspnoea, eye pain, photophobia, reduced vision, inability to drink, rapidly increasing erosions, fever, hypotension or disproportionate skin pain requires urgent escalation and reconsideration of SJS/TEN or infection.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Routine histology from a fresh blister edgeFirst step
Why
Show the level of epidermal separation and acantholytic keratinocytes.
Interpretation and limitations
Suprabasal acantholysis leaves basal cells attached in a tombstone-like row, but old erosions lose this architecture and can look nonspecific.
02
Direct immunofluorescence of perilesional skin
Why
Demonstrate tissue-bound pemphigus autoantibodies around keratinocytes.
Interpretation and limitations
Intercellular epidermal IgG with or without C3 in a net-like pattern strongly supports pemphigus; formalin and eroded tissue reduce yield.
03
Desmoglein 1 and 3 antibody ELISA
Why
Support diagnosis, mucosal or cutaneous phenotype and selected activity monitoring.
Interpretation and limitations
Desmoglein 3 predominates in mucosal disease and desmoglein 1 adds skin involvement, but titres can remain positive in remission or miss unusual antigen targets.
04
Erosion cultures and viral testing
Why
Identify bacterial, candidal or herpes infection when morphology or systemic signs change.
Interpretation and limitations
Surface colonisation is expected; sample fresh pus, grouped vesicles or progressive painful edge and integrate with systemic condition before treating.
05
Rituximab pre-treatment screen
Why
Reduce reactivation, infusion and immunodeficiency harm before B-cell depletion.
Interpretation and limitations
Check hepatitis B surface antigen and core antibody, hepatitis C or HIV as indicated, TB risk, FBC, renal and liver tests, immunoglobulins, vaccination status and pregnancy.
06
Nutritional and swallowing assessment
Why
Detect dehydration, weight loss, micronutrient deficiency and unsafe pharyngeal disease.
Interpretation and limitations
Weight trajectory, electrolytes, albumin context and speech-and-language assessment guide diet texture, supplementation and admission; albumin alone is not nutrition diagnosis.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Mucous-membrane pemphigoid

Predominantly mucosal blistering with scarring risk, especially ocular disease, shows linear basement-membrane rather than intercellular immune deposition.

Bullous pemphigoid

Tense itchy bullae on urticarial skin in later life and linear junctional fluorescence favour a deeper subepidermal disorder.

Erosive oral lichen planus

Reticular white change, chronic gingival disease and interface histology distinguish lichenoid mucositis from the suprabasal acantholysis of pemphigus.

Herpes or candidiasis

Vesicular crops, focal recurrence or removable white plaque with supportive microbiology can complicate or mimic immune erosions.

Stevens–Johnson syndrome

Acute skin pain, atypical targets, systemic illness, extensive mucositis and a recent medicine suggest an emergency epidermal-necrosis pathway.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01First diagnostic sequenceConfirm acantholysis before deep immunosuppressionFirst stepPersistent painful mucosal erosions or fragile cutaneous bullae suggest pemphigus vulgaris.

1Map mouth, eyes, nose, pharynx, genital skin and total cutaneous erosions, assess intake and sepsis and photograph fresh lesions with consent.
2Obtain blister-edge tissue for routine histology and a separate intact perilesional sample for direct immunofluorescence before more treatment when clinically safe.
3AlternativeRequest desmoglein 1 and 3 serology and reconcile discordance with biopsy site, lesion age and alternative mucosal disease in a specialist service.

02Acute stabilisationProtect barrier, nutrition and critical mucosaWidespread skin loss, severe oral pain, dysphagia, eye or airway symptoms or infection risk complicates active disease.

1Admit when intake, physiological stability or home wound care is unsafe and involve ophthalmology, ENT, oral medicine or gynaecology according to affected mucosa.
2Use non-adherent dressings, gentle bathing, analgesia, mouth care and dietetic support, culturing and treating defined infection without applying adhesive trauma.
3Begin specialist systemic control promptly after essential samples, while monitoring fluid, glucose, temperature and thrombosis and avoiding treatment delay for every pending antibody result.

03Preferred systemic inductionCombine licensed rituximab with a glucocorticoid taperPreferredAn adult has confirmed moderate-to-severe pemphigus vulgaris and no contraindication to B-cell depletion.

1Complete infection, hepatitis B, immunoglobulin, vaccination, blood, organ and reproductive screening and give required premedication in an infusion-capable setting.
2Administer rituximab 1000 mg intravenously on day 1 and day 15 with a tapering glucocorticoid regimen, plus PJP prophylaxis when indicated by local risk assessment.
3Assess new-lesion cessation, healing and infection; use 500 mg maintenance at months 12 and 18 and later six-monthly only when clinically needed under the product and specialist plan.

04Relapse or non-responseSeparate immune activity from infection and damageNew erosions develop during taper or fail to heal after an adequate induction interval.

1Review adherence, oral trauma, candida, herpes and bacterial infection and confirm that the original immunopathology fits current morphology.
2Use desmoglein trend as supporting information, not the sole reason to redose, and check immunoglobulins, neutrophils and prior cumulative treatment.
3Specialists select relapse rituximab, azathioprine, mycophenolate, intravenous immunoglobulin or another steroid-sparing strategy according to severity, infection and reproductive context.

Key medicines and prescribing safety3 treatments · regimens, roles and cautions

Licensed B-cell depletion for adult moderate-to-severe pemphigus vulgaris that supports remission with lower cumulative corticosteroid exposure.

Rituximab intravenous infusion

Give 1000 mg intravenously on day 1 and day 15 with tapering glucocorticoid; give 500 mg at months 12 and 18 and then every six months only if clinically needed.

Administer with resuscitation facilities and premedication. Screen hepatitis B and infection, update vaccines beforehand, monitor immunoglobulins and late neutropenia, provide the alert card and withhold for serious infection or suspected PML.

Provides immediate suppression while rituximab depletes pathogenic B-cell activity and lesions epithelialise.

Prednisolone with rituximab induction

Use the specialist severity-based oral regimen, commonly about 0.5 mg/kg daily in moderate or 1 mg/kg daily in severe disease, with a planned rapid response-led taper.

Assess infection, diabetes, pressure, mood, bone, eye, gastrointestinal and adrenal risk; use prophylaxis where indicated, avoid abrupt cessation after sustained treatment and do not interpret infection deterioration as automatic flare.

Reduces local inflammation and supports healing when disease area is limited or residual during systemic control.

Potent topical corticosteroid for limited lesions

Apply a thin layer once daily to selected cutaneous lesions for a defined short course, avoiding untreated infection and reviewing before repeat supply.

Match potency to site and avoid prolonged use on face, folds or genital skin; monitor atrophy, candidiasis, herpes, absorption and contact allergy and never apply blindly to the eye.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Fluid and nutritional failure

Painful extensive oral and skin erosions reduce intake and increase losses, causing dehydration, weight loss and electrolyte disturbance.

Bacterial and viral infection

Barrier loss plus corticosteroid and rituximab exposure creates substantial cellulitis, sepsis, candida and disseminated herpes infection risk.

Critical mucosal damage

Ocular, laryngeal or pharyngeal disease can threaten sight, airway and safe swallowing and requires site-specific urgent expertise.

Immunosuppression toxicity

Glucocorticoid metabolic harm and rituximab infusion reactions, hepatitis reactivation, hypogammaglobulinaemia and late neutropenia require coordinated prevention and surveillance.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Record daily or interval new-lesion count, epithelialisation of established erosions, oral pain, dietary intake, weight and functional mucosal symptoms.
Culture or test a changed lesion before escalating immune treatment when new pain, vesicles, crust, purulence or fever suggests infection.
Before and after rituximab monitor immunoglobulins, FBC including late neutropenia, hepatitis B risk, infections and vaccine planning through the specialist schedule.
Track cumulative glucocorticoid dose, glucose, blood pressure, bone protection, eye, muscle, mood and adrenal suppression at every taper decision.
Use desmoglein titres only beside clinical findings; persistent antibodies in healed disease do not mandate infusion by themselves.
Maintain dental, oral medicine, dietetic and psychological support after skin control because mucosal pain and treatment consequences may persist.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

The blister is often missing

Intraepidermal roofs rupture with trivial friction, so painful erosions rather than intact bullae are the usual examination finding.

Mouth can lead by months

Desmoglein distribution allows mucosal disease to precede cutaneous involvement, making persistent non-healing oral erosions an important diagnostic clue.

Histology and fluorescence are partners

Acantholysis establishes the split while intercellular immune deposition establishes mechanism; neither poorly sited sample should be interpreted in isolation.

B-cell depletion outlasts infusion

Infection, vaccine response and late neutropenia risks continue after the infusion visit, requiring longitudinal monitoring and an alert card.

Healing is an activity measure

Complete re-epithelialisation with no new lesions indicates control more directly than a single antibody titre or residual pigment.

11Common pitfallsFrequent interpretation and management errors.

01
Treating months of painful oral pemphigus as recurrent thrush without biopsy.
02
Sampling only an old erosion and missing both suprabasal architecture and intact immune deposits.
03
Starting rituximab without hepatitis B, immunoglobulin, infection and vaccination assessment.
04
Escalating immunosuppression for every new painful erosion without checking herpes, candida or bacteria.
05
Using desmoglein titre alone to define relapse or schedule another infusion.
06
Allowing severe oral disease to cause dehydration and weight loss while concentrating only on skin count.