الفقاع الشائع والفقاع الورقي

• Pemphigus (Greek "pemphix" = blister) = group of chronic autoimmune blistering diseases; autoantibodies against keratinocyte cell surfaces → loss of cell-cell adhesion (acantholysis).
• Three major forms: pemphigus vulgaris (PV), pemphigus foliaceus (PF), paraneoplastic pemphigus (PNP). PV: mucosal erosions in essentially ALL patients, >50% also have cutaneous blisters (deeper split, just above basal layer). PF: cutaneous only, NO mucosal involvement, superficial split (mostly granular layer). Pemphigus vegetans = PV variant. Pemphigus erythematosus (localized) and fogo selvagem (endemic) = PF variants.
• PNP is distinct: BOTH humoral AND cellular autoimmunity; associated known/occult neoplasm (usually lymphoid); painful severe oral/conjunctival erosions prominent.
• Classification: PV, pemphigus vegetans, PF, pemphigus erythematosus (localized), fogo selvagem (endemic), herpetiform pemphigus, drug-induced pemphigus, PNP, IgA pemphigus.
• Drug-induced pemphigus triggers: ACE inhibitors (captopril), penicillamine > gold, pyritinol, antibiotics (esp. β-lactams), immune checkpoint inhibitors (pembrolizumab), nifedipine, phenobarbital, piroxicam, propranolol, pyrazolone, topical imiquimod.

• Beutner & Jordon 1964: discovered circulating antibodies against keratinocyte cell surface in PV sera; followed by in vivo IgG deposition finding. Late 1970s-early 1980s: pemphigus autoantibodies shown pathogenic (blister induction in organ culture + passive transfer to neonatal mice). Mid-late 1980s: target antigens characterized by immunoprecipitation/immunoblotting. Early 1990s: cDNA cloning showed pemphigus = anti-cadherin autoimmune disease.

• PV and PF roughly equal M:F; mean onset 50-60 years (broad range, elderly/children reported). Worldwide; incidence 0.76-5 new cases/million/year overall, higher in Middle East, Southeast Europe, India. Markedly higher in Jewish ancestry, especially Ashkenazi Jews (16-32/million/year) — including descendants of "conversos" (forced Catholic converts from Iberian peninsula) now in SW USA/Latin America, where ancestry may not be apparent.
• PV > PF in most countries (exceptions: Finland, Tunisia, Brazil). Japan (3.5/million/year): PV:PF = 2:1. France (1.7/million/year): PV ~75% of cases (same in Bulgaria). Finland (0.76/million/year, lowest) and Tunisia (6.7/million/year): PF twice as common as PV. Tunisia also notable for F:M = 4:1 and higher incidence in young women 25-34 (15.5/million/year).
• Fogo Selvagem (endemic PF, Brazil): affects YOUNG adults/children (unlike sporadic PF's middle-aged/elderly pattern), either sex/race, in rural areas near rivers, within 10-15km flying range of black flies (Simulium spp. — suspected vector); also high frequency of hematophagous insects (bedbugs, kissing bugs) in patient homes. Sandfly (Lutzomyia longipalpis) salivary protein shown to induce cross-reactive anti-Dsg1 antibodies. Occurs in genetically related family members (NOT contagious; no blood/body fluid transmission documented). Rural Brazil PF:PV ratio = 17:1; prevalence up to 3.4% in some areas. >50% of NORMAL individuals in endemic areas have anti-Dsg1 IgG; disease onset preceded by sustained non-pathogenic IgG1/IgG4 antibody response; in genetically predisposed individuals, predominant IgG4 against N-terminal EC1/EC2 domains of Dsg1 induces disease.

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• IgG autoantibodies against keratinocyte cell surface = pemphigus hallmark; PRIMARY pathogenic role (not just marker). Neonates of PV mothers can have transient disease from transplacental maternal IgG (resolves as antibody catabolized). IgG fractions induce blisters in skin organ-culture WITHOUT complement/inflammatory cells; passive transfer of patient IgG to neonatal mice reproduces blisters with typical histology. Even monovalent Fab' fragments from PF patients cause blisters — indicates complement activation/cross-linking NOT essential for detachment.

• Immunoelectron microscopy localized PV/PF antigens to DESMOSOMES. PV antigen = 130kDa transmembrane glycoprotein; PF antigen = 160kDa (identical to Dsg1 by comparative immunochemistry). 85kDa plakoglobin co-immunoprecipitates with both antigens. cDNA cloning: both = cadherin supergene family members → pemphigus = anti-cadherin disease. PV antigen named desmoglein 3 (Dsg3).
• Cadherins: calcium-dependent cell-cell adhesion molecules; 2 subgroups — classic cadherins (E-, P-, N-cadherin) and desmosomal cadherins (desmogleins, desmocollins). All have conserved cadherin repeats with calcium-binding motifs in extracellular domain. Cadherin dimers: EC1 domain of one cadherin binds EC1 of opposing cell's cadherin.
• Adherens junction vs Desmosome: Adherens junction — anchors ACTIN microfilaments; transmembrane = classic cadherins; cytoplasmic = α-catenin, β-catenin, plakoglobin. FAST but WEAK adhesion. Desmosome — anchors KERATIN intermediate filaments; transmembrane = desmosomal cadherins (Dsg + Dsc); cytoplasmic = plakoglobin, plakophilin, desmoplakin. SLOW but STRONG adhesion.
• Desmogleins: 4 cadherin repeats (like classic cadherins), 4 isoforms (Dsg1-4). Dsg1/Dsg3 restricted to stratified squamous epithelia (site of pemphigus blistering). Dsg2 expressed in ALL desmosome-containing tissues (simple epithelia, myocardium). Dsg4 = hair follicle adhesion; DSG4 mutations → localized autosomal recessive hypotrichosis.
• Desmocollins: 3 isoforms (Dsc1-3), each with 2 alternatively-spliced products (a/b). Dsg:Dsc heterodimers = fundamental desmosome adhesive unit.
• Plakoglobin, plakophilin, β-catenin = armadillo family (dynamic adhesion/proliferation regulators, not just anchors). Desmoplakin = dumbbell-shaped, central coiled-coil rod + globular termini (intermediate filament + armadillo protein interaction); 2 products (desmoplakin I 250kDa, II 210kDa); plakin family member.
• Essentially ALL pemphigus patients have IgG against Dsg1 and/or Dsg3. Immunoadsorption removal of anti-Dsg IgG from PV/PF/PNP sera → sera no longer pathogenic. Affinity-purified anti-Dsg IgG causes blisters when injected into neonatal mice. Some sera cross-react with Dsg4 (via anti-Dsg1 IgG) but this is NOT pathogenic. Non-desmoglein antibodies (acetylcholine receptors, annexin-like molecules) detected but pathogenic relevance unclear.

• Dsg1 and Dsg3 COMPENSATE for each other when co-expressed in the same cell.
• Skin expression: Dsg1 throughout epidermis (more intense superficially); Dsg3 in lower epidermis (basal/parabasal layers) only.
• Mucosa expression: BOTH Dsg1 and Dsg3 throughout squamous layer, but Dsg1 at MUCH LOWER level than Dsg3.
• Anti-Dsg1 IgG only (PF): superficial epidermal blisters (Dsg3 compensates in deep epidermis) BUT no mucosal blisters (Dsg3 dominant in mucosa, compensates fully). Split occurs between SG2-SG3 layers (IgG doesn't cross SG2 tight junctions).
• Anti-Dsg3 IgG only (mucosal-dominant PV): no/limited skin lesions (Dsg1 compensates in skin) BUT oral erosions (Dsg1 too low in mucosa to compensate).
• Both anti-Dsg1 + anti-Dsg3 IgG (mucocutaneous PV): extensive blisters/erosions of BOTH skin and mucosa.
• Splits occur just ABOVE basal layer (not whole epithelium separating) possibly because: (1) basal/parabasal cell-cell adhesion inherently weaker, (2) autoantibodies penetrating from dermis have better access to lower epithelium.
• Neonatal pemphigus: transplacental antibodies bind fetal epidermis, but neonates develop blisters if mother has PV, RARELY if PF. Explained by compensation theory: neonatal Dsg3 distribution resembles MUCOSA pattern (throughout epidermis, not basal-restricted) — because neonatal skin bathed in amniotic fluid — so anti-Dsg1 IgG (PF) cannot efficiently blister neonatal skin.
• Staphylococcal exfoliative toxins (bullous impetigo, SSSS) specifically CLEAVE Dsg1 → superficial blisters clinically/histologically similar to PF — extending the compensation theory concept.

• Combined direct steric hindrance (antibody binding spatially interferes with Dsg adhesive interaction) PLUS antibody-induced signal transduction.
• Support for steric hindrance: dominant epitopes localize to functionally important N-terminal Dsg regions; pathogenic (not non-pathogenic) anti-Dsg3 monoclonal antibodies recognize the N-terminal adhesive surface; Dsg3 null mouse phenotype resembles human PV.
• Support for signal transduction: PV IgG added to cultured keratinocytes → transient intracellular calcium/IP3 increase, PKC activation, Dsg3 phosphorylation; desmosomal disassembly → Dsg3 internalized/endocytosed with keratin retraction.

• Pemphigus autoantibodies: IgG isotype (isotype-switched), high affinity (affinity-matured), recognize multiple distinct Dsg epitopes.
• HLA associations: DRB10402, DRB11401, DQB10302 (White individuals); DRB114, DQB1*0503 (Japanese) — suggests T cell-dependent autoantibody production.
• Dsg3-reactive T cells found in peripheral blood of BOTH PV patients AND healthy individuals; specific Dsg3 peptides fitting DRB1*0402 pocket stimulate patient T cells.
• Active disease mouse model for PV developed — valuable for mechanism dissection and novel therapy development.

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• Essentially ALL patients: painful oral mucosal erosions. >50%: also flaccid blisters + widespread cutaneous erosions.
• Two subgroups: mucosal-dominant (mucosal erosions, minimal skin) vs mucocutaneous (extensive skin + mucosal involvement).
• Mucosal lesions: painful erosions (intact blisters rare — fragile, break easily); buccal and palatine mucosae most common sites; irregular ill-defined borders; can impair oral intake. Diagnosis often DELAYED when only oral involvement present. Can extend to vermilion lip (fissured hemorrhagic crusts), throat (hoarseness, dysphagia), esophagus (rare cast sloughing), conjunctivae, nasal mucosa, vagina, labia, penis, anus. Vaginal cytology can be misread as malignancy.
• Skin lesions: flaccid, thin-walled, easily ruptured blisters, anywhere on body, normal or erythematous base. Fluid initially clear → hemorrhagic/turbid/seropurulent. Rupture → painful oozing/bleeding erosions, often large/generalized; crusted, poor healing tendency; heal with hyperpigmentation WITHOUT scarring. Pruritus UNCOMMON.
• Unusual presentations: isolated crusted facial/scalp plaque, paronychia/onychomadesis, foot ulcers, dyshidrotic eczema/pompholyx, macroglossia, gingival hyperplasia.
• Nikolsky sign: lateral epidermal movement with slight pressure/rubbing (lack of cohesion). Asboe-Hansen sign ("bulla-spread"/"indirect Nikolsky"/"Nikolsky II"): gentle pressure on intact bulla spreads fluid away from pressure site.
• Untreated: can be FATAL from epidermal barrier loss → fluid loss or secondary infection.

• Rare vegetative PV variant; thought to represent reactive skin pattern to PV autoimmune insult. Flaccid blisters → erosions → fungoid vegetations/papillomatous proliferations, especially intertriginous areas, scalp, face. Early lesions = PUSTULES (not vesicles) → vegetative plaques. Tongue: cerebriform-like changes. Two subtypes: severe Neumann type, mild Hallopeau type. Occasional vegetative response in resistant, long-standing PV lesions.

• Scaly, crusted cutaneous erosions on erythematous base; NO clinically apparent mucosal involvement even with widespread disease.
• Onset subtle: scattered transient crusted lesions, often mistaken for impetigo. Well-demarcated, SEBORRHEIC distribution (face, scalp, upper trunk). Vesicle superficial/fragile — often only crust/scale visible. "Half-half" blisters — seropurulent fluid settles like hypopyon. Can stay localized for years OR progress to generalized/exfoliative erythroderma. Nikolsky sign present. Mucosal involvement EXTREMELY RARE. Patients generally not severely ill but can have burning/pain.

• Localized PF variant; typical scaly/crusted lesions in malar region + other seborrheic areas. Originally described for patients with BOTH LE and pemphigus immunologic features (IgG/C3 on keratinocyte surfaces AND BMZ, plus circulating ANA) — but true concurrent disease is rare.

• Most = PF variant (remainder = PV variant). Features: (1) erythematous urticarial plaques + tense vesicles in herpetiform arrangement, (2) eosinophilic spongiosis + subcorneal pustules with MINIMAL/NO acantholysis, (3) IgG against keratinocyte cell surfaces. Target = Dsg1 (most) or Dsg3 (remainder). Some evolve into classic PF/PV. Pathogenic activity thought WEAKER than classic forms; often clinically less severe but MORE CHRONIC course.

• Penicillamine, captopril most implicated. Penicillamine: PF > PV (~4:1 ratio). Both contain SULFHYDRYL groups speculated to interact with Dsg1/Dsg3 sulfhydryl groups — may modify antigenicity (triggering autoantibody production) or directly interfere with adhesive function. Some cases show acantholysis WITHOUT antibody production. Imiquimod-induced reported; immune checkpoint inhibitors can flare/trigger. Most (not all) remit after drug discontinuation.

• Best biopsy: early lesion, entire small vesicle OR edge of fresh vesicle/bulla + inflammatory rim. DIF: PERILESIONAL (not lesional) skin — avoids false-negative from secondary target antigen degeneration. Mucosal-only disease: biopsy active border of denuded area (intact blisters rare). Tzanck smear: useful bedside screen for acantholytic cells but NOT a substitute for histology (acantholytic cells occur secondarily in other vesiculobullous/pustular diseases too).
• PV: intraepidermal blister from acantholysis WITHOUT keratinocyte necrosis; usually SUPRABASILAR (occasionally higher in stratum spinosum). Basal cells lose lateral desmosomal contact but keep hemidesmosomal basement membrane attachment → "row of tombstones" appearance. Dermal papillae protrude into blister cavity. Blister cavity ± eosinophils; dermal perivascular mononuclear infiltrate with conspicuous eosinophils. Rare early finding: EOSINOPHILIC SPONGIOSIS (long differential list including BP, pemphigoid gestationis, MMP, LABD, arthropod bites, drug eruptions, Wells syndrome, PEP, ETN, incontinentia pigmenti stage 1, AD, contact dermatitis, eosinophilic folliculitis, mycosis fungoides, prurigo pigmentosa, Still disease).
• Pemphigus vegetans: suprabasilar acantholysis + papillomatosis/acanthosis; intense eosinophil-rich infiltrate; intraepidermal eosinophilic microabscesses.
• PF/pemphigus erythematosus/fogo selvagem: identical histology. Acantholysis in UPPER epidermis (within/adjacent to granular layer); acantholytic cells often almond/spindle-shaped (not round). "Missing" horny layer with few acantholytic cells may be only finding. Deeper epidermis usually intact. Histologically INDISTINGUISHABLE from SSSS/bullous impetigo (both target Dsg1). Blister cavity may show neutrophils; eosinophilic spongiosis in very early lesions.
• PNP: variable, reflects clinical polymorphism — unique combination of PV-like, EM-like, AND lichen planus-like features (sometimes same specimen). Suprabasilar acantholysis + individual keratinocyte necrosis + intraepidermal lymphocytes; interface dermatitis features (basal vacuolar change, band-like lymphocytic infiltrate). Eosinophils RARE. Stomatitis biopsies often nonspecific, but perilesional oral epithelium should show suprabasilar acantholysis.
• IgA pemphigus: intraepidermal pustule/vesicle, predominantly NEUTROPHILS; acantholysis usually ABSENT. SPD type: subcorneal pustules. IEN type: suprabasilar pustules involving lower or entire epidermis.

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• Gold standard: demonstration of IgG (or IgA for IgA pemphigus) against keratinocyte cell surface. Methods: DIF, IIF, immunoprecipitation, immunoblotting, ELISA.
• DIF: most reliable/sensitive test for ALL pemphigus forms; perilesional skin/mucosa. IgG deposition up to 100% active PV/PF. NO IgM; occasional IgA. Complement (C3) NOT necessarily seen (dominant IgG4 subclass doesn't fix complement well). PNP: IgG + C3 on cell surfaces AND variably along BMZ. IgA pemphigus: IgA (not IgG) on keratinocyte surfaces. If DIF negative, SERIOUSLY QUESTION pemphigus diagnosis. Caveat: nonspecific cell-surface staining can occur in spongiotic dermatitis, burns, TEN, systemic LE, lichen planus, or ABO blood-group antibody patients.
• IIF: detects circulating IgG; recommended substrates — PV: monkey esophagus; PF: human skin or guinea pig esophagus; PNP: monkey+guinea pig esophagus PLUS rat bladder (anti-plakin); BP/LABD: salt-split human skin; MMP: salt-split human skin + normal oral/genital mucosa/conjunctiva. PV and PF give SIMILAR staining patterns despite different antigens (can't serologically distinguish by IF pattern alone).
• Immunoprecipitation vs immunoblotting: immunoprecipitation detects CONFORMATIONAL epitopes (no denaturation) — superior for 3D-structure-dependent antibodies; immunoblotting detects LINEAR epitopes (requires denaturation) but easier (no radioisotope needed).
• ELISA: recombinant Dsg1/Dsg3-coated plates. Anti-Dsg1+/anti-Dsg3- → PF. Anti-Dsg1-/anti-Dsg3+ → mucosal-dominant PV. Both+ → mucocutaneous PV. ELISA scores parallel disease activity — useful for monitoring, corticosteroid tapering, predicting flares BEFORE clinical evidence. Other ELISA targets: BP180 (NC16A domain), BP230, laminin 332, type VII collagen, envoplakin, periplakin. CLEIA = even more sensitive/rapid.
• PV differential: mucosal — herpetic stomatitis, aphthous stomatitis, EM major/SJS, lichen planus, systemic LE, MMP. Cutaneous — other pemphigus forms, BP, LABD, EM, Hailey-Hailey disease, transient acantholytic dermatosis (Grover disease). BP blisters TENSE (subepidermal). Hailey-Hailey: full-thickness acantholysis ("dilapidated brick wall") + epidermal hyperplasia + impetiginized scale, does NOT extend down follicles. Grover disease: small acantholysis foci PLUS dyskeratosis (absent in pemphigus).
• PF differential: other pemphigus, bullous impetigo, subcorneal pustular dermatosis, subacute cutaneous LE, seborrheic dermatitis. Bacterial superinfection doesn't confirm impetigo diagnosis; superimposed tinea corporis possible especially on systemic corticosteroids.
• Pemphigus vegetans differential: Major — Hailey-Hailey disease, pemphigoid vegetans, blastomycosis-like pyoderma (S. aureus-driven, immunosuppression risk factor), pyodermatitis-pyostomatitis vegetans (PG form). Other — halogenoderma, infections (granuloma inguinale, condylomata lata, dimorphic fungi, chromomycosis, condylomata acuminata, HSV vegetans, chronic verrucous herpes zoster [immunocompromised], amebic granuloma), Buschke-Löwenstein tumors, extramammary Paget disease.
• PNP differential: PV, MMP, EM/SJS, lichen planus, GVHD, persistent HSV/other viral infections; chemotherapy stomatitis limited to 7-14 days (hemorrhagic vermilion lip crust differential: HSV, HSZ, EM major, MIRM/RIME, SJS/TEN, PV, PNP, contact cheilitis). 2/3 of PNP arise with KNOWN neoplasm (may be treated years prior); 1/3 undiagnosed at mucocutaneous onset — needs CT chest/abdomen/pelvis, CBC, flow cytometry, LDH, SPEP/immunofixation. Severe stomatitis extending to vermilion lip = key differentiator from PV/MMP. Gold standard: combination of anti-plakin (immunoprecipitation/immunoblot/ELISA) AND anti-desmoglein (ELISA) antibodies.
• IgA pemphigus differential: subcorneal pustular dermatosis, PF, bullous impetigo, dermatitis herpetiformis, LABD, pustular psoriasis. SPD type clinically/histologically indistinguishable from classic Sneddon-Wilkinson — IgA demonstration essential.

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• Pre-corticosteroid era: usually FATAL (death within 2-5 years) from epidermal barrier loss → fluid loss/infection. PF had better prognosis except acute generalized cases.
• Therapy targets REDUCING AUTOANTIBODY PRODUCTION, not just local inflammation. PDAI and ABSIS = standardized disease severity/response scoring tools.
• Standard treatment: oral prednisone 1mg/kg/day (usually 60mg/day) initial dose; taper based on new blister rate/healing; IIF/ELISA titers guide tapering. IV pulse methylprednisolone 1g/day × 3-5 days (cardiac monitoring) for severe cases.
• Rituximab: 375mg/m² weekly ×4 OR 1g initially + at 2 weeks; may repeat every 3-6 months. FDA-APPROVED for moderate-severe pemphigus; consensus suggests EARLY use, not just for recalcitrant disease. Mechanism: CD20+ B cell depletion (CD20 lost upon plasma cell differentiation) → declining IgG (incl. anti-Dsg) AND decreased Dsg-specific T cells. RCT: greater complete remission off-therapy vs corticosteroids alone. Side effects: infusion reactions, HBV reactivation, PML. Intralesional rituximab reported for refractory disease. Humanized anti-CD20 alternatives: obinutuzumab, ofatumumab.
• Immunosuppressive adjuvants (corticosteroid-sparing): Azathioprine 2-4mg/kg/day (100-300mg/day) — nausea, dose-dependent myelosuppression. Mycophenolate mofetil 2-3g/day — similar to azathioprine, LESS myelosuppression, MORE GI toxicity; RCT showed faster/more durable response vs placebo+corticosteroids. Cyclophosphamide 1-3mg/kg/day oral or 500-1000mg/m² IV q4weeks — hemorrhagic cystitis, sterility, leukopenia, LONG-TERM BLADDER CANCER risk (trend away from daily oral dosing to reduce this). Chlorambucil — myelosuppression, long-term leukemia risk (no bladder toxicity). Cyclosporine 3-5mg/kg/day — RCT showed NO benefit added to corticosteroids. Methotrexate 7.5-20mg/week.
• Combined therapy: once complete remission achieved, maintain immunosuppressive while tapering prednisone; at 5-10mg/day prednisone, attempt immunosuppressive taper/discontinuation. Consider malignancy risk in young patients on long-term immunosuppressives. Elderly with limited disease/steroid contraindication: immunosuppressive MONOTHERAPY option.
• Plasmapheresis: rapid autoantibody titer reduction; for severe disease unresponsive to prednisone+immunosuppressives; MUST combine with corticosteroids+cyclophosphamide to prevent post-plasmapheresis REBOUND antibody production.
• High-dose IVIg 400mg/kg/day ×5 days (may repeat monthly): non-immunosuppressive; RCT-proven effective/safe for steroid-resistant disease. Mechanisms: Fc receptor modulation, anti-idiotypic antibodies, dendritic/T/B cell modulation.
• Emerging: DSG3-CAART (targets Dsg3-specific B cells) — FDA orphan drug designation 2020. Efgartigimod (FcRn inhibitor) — phase II trial showed early disease control in 28/31 PV/PF patients.
• Topical: Class I corticosteroids for localized persistent sites; topical antibiotics; topical immunomodulators (cyclosporine, tacrolimus). Intralesional: corticosteroids, rituximab (5mg/cm²).

• Active/widespread disease: treatment similar to PV. Localized disease (may persist years): superpotent topical corticosteroids alone may suffice — systemic therapy not always necessary. Dapsone useful when neutrophils dominate histologically.

• The immunobullous disorders represent a group of conditions characterised by antibody-mediated autoimmune responses against structural elements of the skin resulting in blistering of the skin and/or mucosae.
• Antibody targets include proteins in the hemidesmosomes basement membrane zone and superficial dermis (pemphigoid group), desmosomes (pemphigus group), and epidermal and tissue-type transglutaminase (dermatitis herpetiformis).
• If left untreated, associated with significant morbidity and mortality — prompt, accurate diagnosis and treatment mandatory. Therapeutic options include corticosteroids, steroid-sparing immunosuppressants (azathioprine, mycophenolate mofetil), and anti-inflammatory agents (dapsone, tetracyclines). In severe/refractory patients, IVIG, immunoadsorption, and anti-B-cell agents such as rituximab may be of benefit.
• Recently, international and European guidelines have recommended rituximab as first-line treatment in moderate and severe pemphigus vulgaris and foliaceus.

• Pemphigus is a group of chronic autoimmune blistering diseases characterised by the presence of antibodies against desmosomal adhesion proteins.
• Classification links: ICD-10: L10.0–L10.5; Snomed CT: 49420001; OMIM: 169610; Orphanet: ORPHA704.

• The term "pemphigus" derives from the Greek pemphix, meaning blister or bubble. Several distinct subgroups have emerged and their relevant autoantigens characterised. Primary pathogenic antibodies directed against desmogleins 1 and/or 3, members of the cadherin family of calcium-dependent cell–cell adhesion molecules contributing to desmosome structure.
• Two main clinical variants: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Characteristic immunopathological features summarised in Table 50.1.

Incidence and prevalence

• Low but variable worldwide, ranging from 0.5 to 16/million/year. PV generally the commoner form, though geographical variation exists — PV more common in Europe, the USA, and India, whereas PF more common in Brazil and Africa. Recent UK data suggests PV incidence may be increasing, reasons uncertain.

• Pemphigus vulgaris and pemphigus vegetans: Direct IMF — intercellular IgG and C3; indirect IMF substrate — mucosa (e.g. primate oesophagus); target antigens — desmoglein 3, desmoglein 1, rarely desmocollins; antigen location — desmosome.
• Pemphigus foliaceus: Direct IMF — intercellular IgG and C3; indirect IMF substrate — normal human skin; target antigens — desmoglein 1; antigen location — desmosome.
• IgA pemphigus: Direct IMF — intercellular IgA and C3; indirect IMF substrate — normal human skin; target antigens — desmoglein 1, desmoglein 3, sometimes desmocollins; antigen location — desmosome.
• Paraneoplastic pemphigus: Direct IMF — intercellular and subepidermal IgG, C3; indirect IMF substrate — mucosa, normal human skin, transitional epithelia (e.g. rat bladder); target antigens — multiple (desmoglein 1, desmoglein 3, envoplakin, desmoplakin I/II, periplakin, epiplakin, α2 macroglobulin-like 1, BP230); antigen location — desmosome, BMZ, stratified/simple/transitional epithelia.
• BMZ, basement membrane zone.

• Can occur at any age but usually seen between the fourth and sixth decades, with variability by country. In Iran, North India, and Pakistan, PV patients have a relatively low age of onset (mean c. 40 years). In endemic PF in Tunisia, young women tend to be affected. Pemphigus rare in childhood but reported as young as 3 years — children usually develop PV rather than PF and disease may be severe.

• Men and women equally affected, although some studies suggest a slight female preponderance.

• PV reported in all ethnic groups, but more common in Ashkenazi Jews, Mediterranean, Iranian, and Indian populations. Genetic variations likely play a major role.

• PV associated with many other autoimmune diseases, particularly thyroid disease and rheumatoid arthritis. A novel disease cluster of PV, thyroid disease, rheumatoid arthritis, and type 1 diabetes recently described, and increasing recognition of a link between pemphigus and neuro-psychiatric disease. Paraneoplastic pemphigus occurs in association with haematological malignancy (described in more detail below).

• Principal target antigens: desmogleins 1 and 3, expressed in skin and mucosal tissue. Distribution varies by epithelium — in skin, high-level expression of desmoglein 1 throughout the epidermis, whereas desmoglein 3 found only in basal and immediate suprabasal layers. In oral epithelium, desmoglein 3 expressed throughout all layers, whereas desmoglein 1 only present at low level.
• The two desmogleins act cooperatively — antibodies against desmoglein 1 unable to destabilise oral mucosa but have marked effect in skin (where little desmoglein 3 compensates). Antibodies against desmoglein 3 lead to severe oral mucosal blistering as there's little desmoglein 1.
• Consequently, PF patients (anti-desmoglein-1 antibodies alone) exhibit skin blistering without mucosal involvement. In PV (anti-desmoglein-3 antibodies predominate), generally marked mucosal blistering.

• While conventionally considered a prototypic antibody-mediated (B-lymphocyte dependent) disorder, increasing evidence that antibody-specific T cells also play a role. Antibody production generally requires T-cell help, and significant MHC class-II associations imply a T-cell role in pathogenic antibody development.
• Antigen-specific Th1 and Th2 cells present in patients and seem to be modulated by therapy. Very recently, genetically modified T cells shown to have utility in highly specific B-cell depletion in pemphigus patients.

• Predominant class of tissue-bound antibody is IgG, demonstrable on direct and indirect immunofluorescence (IF) testing. Less commonly IgM, IgA, and IgE antibodies present.
• Considerable evidence confirms pathogenicity of the IgG fraction. Early observations suggested correlation between intercellular antibody titre and disease severity. Passive transfer experiments with purified IgG autoantibodies from pemphigus sera shown to induce blister development with histological/immunological features typical of pemphigus. In vitro, IgG purified from pemphigus patient sera demonstrates direct effect on dissociation of keratinocyte monolayer cultures.
• Although large body of evidence supports desmoglein 1 and 3 as targets, other antigenic targets implicated. Some patients have active pemphigus with intercellular antibodies detectable on direct/indirect IF but negative desmoglein antibodies on specific ELISA — explained by significant non-desmoglein targets: antibodies against desmocollins, plakoglobin, E-cadherin, collagen XVII/BP180, and acetylcholine receptors reported. Acetylcholine receptor antibodies found in up to 85% of pemphigus patients — may weaken desmosomal junctions by inducing phosphorylation of adhesion molecules and preventing desmosomal reassembly.
• In paraneoplastic pemphigus, particularly good evidence that antibodies develop against multiple epidermal antigens in addition to desmogleins 1 and 3 — not only desmosomal proteins (desmoplakins 1 and 2, envoplakin, periplakin) but also hemidesmosome constituents including the 230-kD bullous pemphigoid antigen-1. Consequently, direct IF of paraneoplastic pemphigus tissue has features of pemphigus as well as basement membrane labelling.

• Key pathological process in PV and PF: separation of keratinocytes from one another (acantholysis). Not pathognomonic of pemphigus, but all subtypes demonstrate this feature to some degree.
• Number of mechanisms suggested: steric hindrance by anti-desmoglein antibodies, protease activation, disruption of intracellular signalling pathways, and redistribution of desmoglein expression. Some features of apoptosis may also play a role, detected in pemphigus skin lesions and induced by PV-IgG in cultured keratinocytes. Pemphigus antibodies can trigger secretion of factors from keratinocytes involved in apoptosis, such as Fas ligand. However, evidence of apoptosis seen late in lesion development, after acantholysis.
• New term "apoptolysis" proposed to explain acantholysis and keratinocyte damage — suggested a series of events follow autoantibody binding to pemphigus antigens, resulting in epidermal growth factor receptor activation with initiation of cell death cascades, basal cell shrinkage, degradation of structural proteins, and apoptosis of acantholytic cells.
• True mechanism most likely a combination of multiple molecular/structural events; further work needed.

• Genetic basis complex. Familial cases reported but few. Presence of low titres of anti-desmoglein antibodies in healthy relatives of PV patients shown as high as 70% in some studies, suggesting genetic control of the relevant immune response.
• Primary genetic association in a number of populations appears to be with class II HLA alleles. Many population studies show strong associations between PV and HLA DRB1\04 and \14 alleles and with DQB1\0503 and \0302. Some class I HLA genes implicated in PV including HLA-A10 and HLA-B38.
• Desmoglein 3 polymorphisms observed in association with HLA class II pemphigus susceptibility alleles, may contribute to PV development. Other non-HLA genes implicated: immunoglobulin heavy chain and pemphigus-relevant cytokine genes such as IL-10.
• Although MHC clearly has a role, this alone cannot explain disease development, as: (a) not all pemphigus patients have the disease-associated alleles; (b) healthy relatives may have the relevant HLA allele(s) but do not develop disease. Supports pemphigus as most likely a multifactorial disease with a polygenic genetic component.

• Role of environmental factors underscored by recognition of an endemic form (fogo selvagem) in several parts of the world, most notably rural Brazil and Tunisia. Clinically and immunologically similar to PF, though tends to affect children and young adults rather than the older population affected by sporadic PF.
• Majority of patients live near rivers; black flies (Simulium spp.) thought to be involved in disease pathogenesis. In endemic areas, as many as 50% of normal individuals have anti-desmoglein-1 antibodies.
• Number of reports suggest smoking may have a protective or beneficial role. Human keratinocytes have both nicotinic and muscarinic receptors for acetylcholine, which may play a role in regulating keratinocyte cell–cell adhesion.
• Pesticides also postulated as possible triggers — increased pemphigus risk shown in exposed individuals. Organophosphate pesticides block the acetylcholine breakdown pathway, potentially leading to acetylcholine accumulation with resulting loss of cell–cell adhesion in the epidermis. Pesticides implicated in contact pemphigus include glyphosate and dihydrodiphenyltrichlorethane.
• A link between diet and disease development suggested but difficult to substantiate. Garlic proposed as a trigger — shown to induce acantholysis in vitro — but this area remains controversial.

• Rare. Most cases associated with drugs containing a thiol group such as penicillamine, although non-thiol drugs including ACE inhibitors and glibenclamide also implicated. Additional group with a phenol group — cephalosporins, rifampicin, pyritinol, phenobarbital, and aspirin — can cause both PV and PF.
• While immune checkpoint inhibitor therapy generally associated with subepidermal immunobullous disease development, pemphigus also reported.
• Historically, penicillamine the most common culprit, occurring in 3–10% of patients on the drug, typically after around 1 year of exposure. Penicillamine-induced pemphigus tends to occur in individuals with other autoimmune disorders such as rheumatoid arthritis, suggesting immune dysregulation may be an underlying factor (though penicillamine tends to be used in patients with underlying immunologically mediated inflammatory disease).
• Genetic factors may also play a role — increase in frequency of HLA-B15 reported in penicillamine-induced pemphigus. In some patients, simple drug withdrawal insufficient to induce remission; others may require corticosteroid and immunosuppressive treatment.

• Nearly all patients have mucosal lesions; PV presents with oral lesions in 50–70% of patients. May precede cutaneous lesions by months or be the only manifestation. Intact bullae rare in the mouth — more commonly patients have ill-defined, irregularly shaped buccal or palatal erosions slow to heal. Erosions extend peripherally with shedding of the epithelium.
• Other mucosal surfaces may be involved: conjunctiva, nasopharynx, larynx, oesophagus, urethra, vulva, and cervix.
• Most patients develop cutaneous lesions. Involvement occasionally remains localised to one site but more commonly becomes widespread. Predilection for the scalp, face, neck, upper chest, and back. Flaccid blisters filled with clear fluid arise on normal skin or a reddish base.
• Contents may become turbid, or blisters rupture, producing painful erosions extending at the edges as more epidermis is lost. At this stage, firm sliding pressure with a finger will separate normal-looking epidermis from dermis, producing an erosion — the Nikolsky sign — although not specific for pemphigus. Healing occurs without scarring, but pigmentary change may occur in resolving lesions.
• Lesions in skin folds may form vegetating granulations, and flexural PV merges with its variant pemphigus vegetans. Nail dystrophies, acute paronychia, and subungual haematomas observed. Occasional patients described with typical PV lesions confined to the skin, sparing mucosae despite presence of anti-desmoglein-3 antibodies. Some patients undergo phenotypic and immunological conversion from PV to PF or vice versa over disease course.
• Pemphigus may deteriorate in pregnancy and the puerperium — close observation required; some patients initially present in pregnancy. Severe pemphigus in pregnancy may be associated with fetal prematurity and death, though difficult to separate effects of treatment from disease. Generally the baby is healthy, although neonatal pemphigus may occur (IgG crosses the placenta) with mucosal or mucocutaneous lesions that are generally short-lived.

• Often regarded as less severe than PV, though can be as challenging to manage. Onset usually insidious with scattered, scaly lesions involving the "seborrhoeic" areas of the scalp, face, chest, and upper back. Individual lesions typically have a fine collarette of scale. Localised disease slowly extends.
• Blistering may not be obvious because cleavage is superficial and small flaccid blisters rupture easily. Scales separate leaving well-demarcated, crusted erosions surrounded by erythema, sometimes with small vesicles along the borders. In severe cases, patient may become erythrodermic with crusted, oozing red skin.
• Although antibodies in PF can cross the placenta, the neonate not usually affected. In two cases where the neonate did develop PF, both mother and neonate had very high antibody titres.

• Rare PV variant characterised by vegetating erosions, primarily in flexures. Two subtypes recognised, representing a clinical spectrum from the severe Neumann type to the milder Hallopeau type.
• Patients have circulating IgG antibodies against desmoglein-3, as in PV. In some cases, antibodies react with desmocollin molecules. Mechanism by which antibody deposition leads to the vegetating change remains unclear.
• Vegetating lesions hyperkeratotic, papillomatous, and acanthotic. Some suprabasal clefts may contain eosinophils but few acantholytic cells present. Intraepidermal eosinophilic abscesses may be present in older lesions. Early lesions in the Neumann type show suprabasal acantholysis and intraepidermal vesicles without eosinophils. Eosinophilic spongiosis or eosinophilic microabscesses common in the early pustular lesions of the Hallopeau type. Dermis contains a heavy infiltrate of lymphocytes and eosinophils with few neutrophils.
• Chiefly affects middle-aged adults. Oral mucosa involvement almost invariable, often with cerebriform changes on the tongue. Elsewhere, lesions primarily flexural, though vegetations may occur at any site.
• In the Neumann type, vesicles and bullae rupture to form hypertrophic granulating erosions that bleed easily, evolving into vegetating masses exuding serum and pus, with edges studded with small pustules. Erosions at lesion edges induce new vegetations, eventually becoming dry, hyperkeratotic, and fissured. In the Hallopeau type, pustules rather than vesicles characterise early lesions, but soon progress to vegetating plaques.

• Rare, atypical pemphigus variant clinically resembling dermatitis herpetiformis. Widespread clusters of pruritic papules and vesicles develop on a reddish background. Biopsies show subcorneal pustules, eosinophilic spongiosis, or features of dermatitis herpetiformis, often without acantholysis, but IF studies reveal intercellular staining.
• Patients possess circulating IgG autoantibodies recognising either desmoglein-1 or desmoglein-3; some patients' sera recognise desmocollins 1 or 3. Condition may evolve into classical PF but has also been described preceding PV. Clinical course generally benign.

• Localised variant of PF, originally described by Senear and Usher. Patients have immunological features of both lupus erythematosus and pemphigus, with granular IgG and C3 at the basement membrane zone, intercellular IgG and C3 in the epidermis, and circulating antinuclear antibodies. Antibodies recognise desmogleins together with Ro, La, and double-stranded DNA antigens. Progression to systemic lupus erythematosus is rare. May be associated with myasthenia gravis or thymoma.
• Reddish, scaly lesions over the nose and cheeks in a butterfly distribution simulate cutaneous lupus erythematosus or seborrhoeic dermatitis. Sunlight may exacerbate the disease. Lesions on the trunk, either localised or generalised, are similar to those in PF.

• PV: Patients with mucosal lesions likely to present to dental surgeons, oral surgeons, or gynaecologists. Erosions may simulate acute herpetic stomatitis, erythema multiforme, aphthous ulcers, lichen planus, or mucous membrane pemphigoid. Bullae transient in the mouth; biopsies of erosions may not be diagnostic. Diagnosis less difficult with cutaneous blisters/erosions, though pemphigoid and its variants, linear IgA disease, and erythema multiforme may need to be ruled out. Blisters in pemphigoid typically more tense than in pemphigus and may be haemorrhagic.
• Vegetating, pustular lesions in flexures must be differentiated from chronic infections or Hailey–Hailey disease (benign familial pemphigus). Vegetating plaques mimicking pemphigus vegetans may occur in IgA pemphigus and paraneoplastic pemphigus; hyperkeratotic lesions of chronic pemphigus vegetans may simulate cutaneous tumours.
• Histological differential diagnosis of PV includes Darier disease, Hailey–Hailey disease, and transient acantholytic dermatosis (Grover disease) — these have distinctive clinical features plus negative IF studies. Eosinophilic spongiosis may be an early histological manifestation of either pemphigus or bullous pemphigoid. Immunofluorescence studies required to confirm diagnosis.
• PF: May resemble seborrhoeic dermatitis or impetigo, but histological/immunopathological features diagnostic. Pemphigus erythematosus needs distinguishing from both seborrhoeic dermatitis and chronic cutaneous lupus erythematosus. PF may occasionally simulate dermatitis herpetiformis both clinically and histologically, but immunopathological studies differentiate the two. Histological features may not be diagnostic in early stages; eosinophilic spongiosis may be an early manifestation. Immunofluorescence studies should always be performed if pemphigus suspected.
• Paraneoplastic pemphigus: in most patients, diagnosis (and treatment) of the underlying malignancy precedes pemphigus development, but not universally. Clinical differential diagnosis includes PV, erythema multiforme, graft versus host disease, lichen planus, and viral infections including herpes simplex.

• Number of severity indices proposed to standardise assessment, including the Pemphigus Disease Area Index (PDAI) and the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) — PDAI most frequently used. At time of writing, an Investigator Global Assessment (IGA) score being developed for PV and PF to fulfil FDA requirements in clinical trials.

• Pemphigus typically has a chronic course, average disease duration 10 years. Great variability in disease length. Various factors suggested to influence this, including site and severity of initial disease, with oral involvement an adverse prognostic factor.
• Immunologically, presence of both anti-desmoglein 1 and 3 antibodies tends to associate with more active disease. Recent data suggest early age of onset and Asian ancestry associate with more prolonged disease activity.
• While pemphigus was associated with high mortality in the era before systemic steroids, this has improved hugely, though there's still excess mortality in treated patients related to effects of immunosuppression and associated disorders.

Histopathology

• Earliest histological changes: intercellular oedema with loss of intercellular attachments in the basal layer. Suprabasal epidermal cells separate from basal cells to form clefts and blisters. Basal cells remain attached to the basement membrane but separate from one another, standing like a "row of tombstones" on the floor of the blister.
• Blister cavities contain rounded-up acantholytic cells, found in smears taken from the base of a blister or oral erosion (Tzanck preparation). Clefting may extend into adnexal walls. Blistering preceded by eosinophilic spongiosis in some cases. Superficial dermis has a mild, superficial, mixed inflammatory infiltrate that may include eosinophils.

Direct immunofluorescence microscopy

• Direct IF the most accurate way to diagnose mucosal pemphigus. Specimens may be transported to a suitable laboratory in Michel's medium if snap-freezing/storage facilities unavailable locally.
• Diagnosis confirmed by direct IF showing IgG and often C3 deposited on the surface of keratinocytes throughout the epidermis in perilesional skin. IgG1 and IgG4 the most common subclasses; IgM and IgA present less frequently than IgG.

Serological assays

• Circulating pemphigus autoantibodies detected by indirect IF in over 80% of patients. Use of more than one substrate improves sensitivity — oesophageal mucosal substrates preferable for detecting antibodies to desmoglein-3, whereas normal human skin shows higher sensitivity for desmoglein-1 antibodies. Rat bladder (transitional epithelium devoid of desmoglein proteins) has proven a useful indirect IF substrate for diagnosing paraneoplastic pemphigus.
• Recombinant desmogleins (Dsg1 and Dsg3) used to develop sensitive/specific ELISA assays. Using ELISA, over 95% of PV patients have detectable desmoglein-3 antibodies and around 50% have desmoglein-1 antibodies. In appropriate dilutions, anti-desmoglein ELISA assays can be used to monitor disease activity.
• Pemphigus-like circulating intercellular antibodies reported in conditions such as thermal burns, toxic epidermal necrolysis, and in first-degree relatives of pemphigus patients.

General principles of management

• Because of pemphigus group rarity, progress with informative RCTs has been slow. Systemic corticosteroid therapy remains the mainstay, generally combined with a steroid-sparing immunosuppressant.

Topical therapy

• Patients presenting with oral disease and mild cutaneous involvement may remain in this localised phase for months. Potent topical or intralesional steroids may reduce the requirement for oral steroids. Good oral hygiene, including periodontal disease treatment, important.
• In patients with widespread blistering, intensive nursing care mandatory. Opportunist infection is the major cause of death in patients with widespread blistering who are also immunosuppressed — potassium permanganate and topical antiseptics may help reduce cutaneous infection risk. Liberal use of emollients will reduce frictional stress on affected skin.

Corticosteroids

• Prednisolone, together with a steroid-sparing adjuvant, is the initial treatment for most PV patients. Prednisolone 0.5–1mg/kg/day in combination with adjuvant immunosuppression and appropriate topical therapy sufficient to initiate disease control in many patients. Little benefit in using higher doses. Once control established, steroid dose should be titrated according to clinical response.
• Patients with generalised disease may require aggressive immunosuppression; major difficulty is balancing risks of high-dose steroid therapy against poorly controlled disease. In this situation, IV pulses of either 1g methylprednisolone or 100mg dexamethasone are safer alternatives, often together with IVIG, immunoadsorption, or plasmapheresis. While steroid pulses shown useful in some studies, others showed no benefit.

Azathioprine

• Widely used at a dose of 2–3mg/kg/day; multiple case series support its use. Combination of prednisolone and azathioprine more effective than prednisolone alone, both in terms of mortality and remission. One RCT found azathioprine the most effective steroid-sparing agent, followed by cyclophosphamide (pulse therapy) and mycophenolate mofetil. Another trial found azathioprine and mycophenolate mofetil equally effective.
• Potential adverse effects: bone marrow suppression, nausea, and liver dysfunction — careful blood monitoring mandatory, particularly in early treatment stages. Azathioprine toxicity more frequent in patients with low thiopurine methyl transferase (TPMT) activity — TPMT activity should be checked prior to treatment wherever possible. In patients with low TPMT levels, azathioprine dose should be adjusted; avoided in patients with absent TPMT.

Mycophenolate mofetil

• 1–3g/day found helpful as a steroid-sparing agent. Pro-drug of mycophenolic acid with relatively selective effect on T and B lymphocytes through inhibition of inosine monophosphate dehydrogenase.
• A double-blind RCT comparing azathioprine and mycophenolate showed no significant efficacy difference, though a trend towards fewer adverse effects and more rapid remission in the mycophenolate group. Adverse effects: bone marrow suppression and GI symptoms — patients require close monitoring in early treatment stages. GI symptoms may respond to enteric-coated delayed release mycophenolic acid in place of mycophenolate mofetil.

Cyclophosphamide

• A potent anti-B-cell agent with significant activity in pemphigus and other antibody-mediated autoimmune diseases. Use limited by significant adverse effects, including gonadal failure, haemorrhagic cystitis, bone marrow suppression, and increased bladder cancer risk.
• Generally reserved for rare patients failing to respond to rituximab and conventional immunosuppression with azathioprine or mycophenolate mofetil. Monthly IV pulses of cyclophosphamide with dexamethasone combined with low-dose oral cyclophosphamide have been used, as has daily oral treatment.

IVIG

• Potentially attractive due to relative lack of immunosuppressive effects compared with most other pemphigus treatments. Generally used at a dose of 2g/kg split over 3–5 days; treatment may need continuation monthly for prolonged periods.
• Mechanisms of action not fully elucidated — one main effect is blockage of the neonatal Fc receptor (FcRn), preventing recycling of IgG from the endothelium to the circulation. May also have anti-idiotypic effects. A multicentre double-blind controlled study in Japan confirmed its effectiveness.
• Generally well tolerated but can cause headaches, "flu-like" symptoms, and hypotension. Anaphylaxis may occur in patients with complete IgA deficiency, which should be excluded prior to treatment.

Rituximab

• Depletion of B lymphocytes using the anti-CD20 monoclonal antibody rituximab shown effective in several case series. Initial regimens used 375mg/m² weekly for 4 weeks, but two infusions of 1g, 2 weeks apart have now become established.
• Mechanism of action likely through B-cell regulatory pathways, as plasma cells (responsible for antibody production) do not express CD20. Interestingly, T-cell responses to desmogleins are suppressed following rituximab therapy, suggesting a broader mechanism than simply the B-cell pathway.
• Onset of action typically 8–16 weeks following first infusion, though may take longer; improvement may persist for 12–18 months. May be combined with conventional steroid therapy and adjuvant immunosuppression, with care to avoid excessive immunosuppression and increased infection risk. In some centres, immunoadsorption combined with rituximab.
• Place of rituximab in the pemphigus treatment hierarchy evolving; first-line use explored. In one recent study, first-line rituximab compared against standard corticosteroid therapy: complete remission off treatment seen in 89% of the rituximab group, compared with 34% in the corticosteroid group. In the rituximab arm, cumulative prednisone dose and number of severe adverse events significantly lower vs prednisone-alone arm.
• In another study comparing rituximab and mycophenolate, sustained complete remission observed in significantly more patients in the rituximab arm. Based on available data, a large international expert panel and the S2 guidelines of the European Academy of Venereology and Dermatology (EADV) have recommended rituximab as first-line treatment in moderate and severe PV and PF.
• Generally well tolerated. Infusion reactions may occur but seem less frequent than when used for B-cell malignancies. Infection has been reported, with particular care needed to avoid viral hepatitis reactivation — patients should be rigorously screened prior to treatment. Late-onset neutropenia recognised but uncommon.

Immunoadsorption and plasmapheresis

• Removal of circulating antibodies by plasmapheresis first used in 1978, theoretically attractive for managing pemphigus in the acute stage, though other studies have not shown benefit. More recently, selective immunoadsorption of IgG using columns containing protein A or other immunoglobulin binders effective at inducing remission, but concomitant immunosuppression with steroids, steroid-sparing adjuvants, or anti-B-cell therapy required to prevent rebound increase in antibody synthesis.

Other therapies

• Although initial case reports suggested ciclosporin benefit, more recent studies cast doubt on this. Topical ciclosporin mouthwash may help in severe oral pemphigus.
• Gold may have a modest effect, though toxic effects limit its utility. Dapsone advocated as an adjunct in mild disease; a recent prospective, placebo-controlled study showed a modest steroid-sparing effect. Dapsone may be of particular utility in pemphigus herpetiformis and IgA pemphigus. Acitretin used in conjunction with prednisolone in pemphigus vegetans.
• Methotrexate now seldom used, though some suggestion it may have a steroid-sparing effect, and moderate doses may permit prednisolone withdrawal in steroid-dependent patients.
• Other therapies used in resistant cases: extracorporeal photopheresis, and TNF inhibitors infliximab and adalimumab reported beneficial, although autoimmune bullous disease has also been reported as a consequence of TNF blockade. Tetracycline antibiotics with or without nicotinamide may help as steroid-sparing agents in some patients.
• Many novel therapies under investigation, including repurposing existing drugs such as veltuzumab and ofatumumab (higher CD20 binding affinities), novel anti-B-cell agents, and cell-based therapies designed to eliminate pathogenic B-cell clones.

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• Two major types: pemphigus vulgaris (PV) and pemphigus foliaceus (PF)
• Pemphigus vulgaris: erosions on mucous membranes and skin; flaccid blisters on skin
• Pemphigus foliaceus: crusted, scaly skin lesions
• Diagnosis depends on:
• Histology showing intraepidermal acantholysis
• Immunofluorescence studies documenting presence of cell surface autoantibodies (bound to patient skin or in serum)
• PV histology: suprabasal acantholysis
• PF histology: subcorneal acantholysis
• Direct immunofluorescence: shows IgG on the keratinocyte cell surface of the patient's skin
• Indirect immunofluorescence: shows IgG in patient serum that binds cell surface of normal keratinocytes
• Autoantigens are desmogleins — transmembrane desmosomal adhesion molecules
• Therapy includes topical and systemic corticosteroids and immunosuppressive agents

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• The term pemphigus refers to a group of autoimmune blistering diseases of skin and mucous membranes
• Characterized histologically by intraepidermal blisters due to acantholysis (separation of epidermal cells from each other)
• Characterized immunopathologically by in vivo bound and circulating immunoglobulin (Ig) directed against the cell surface of keratinocytes
• History covered in Walter Lever's classic monograph Pemphigus and Pemphigoid
• Both PV and PF display a spectrum of disease; various points along the spectra have been given unique names, but presentation is fluid and patients' disease usually crosses these artificial designations over time
• PV may present with localized disease → pemphigus vegetans of Hallopeau → may become more extensive → pemphigus vegetans of Neumann → full-blown PV
• PF may present with localized disease → pemphigus erythematosus → often progresses to more widespread PF
• Discovery by Ernst Beutner and Robert Jordon in 1964 of circulating antibodies against the cell surface of keratinocytes in PV patient sera pioneered understanding of PV as a tissue-specific autoimmune disease of skin and mucosa
• Their work led to discoveries of autoantibodies in other autoimmune bullous diseases of the skin

• Pemphigus can be divided into four major types:

1. Vulgaris
2. Foliaceus
3. Paraneoplastic (see Chapter 55)
4. IgA pemphigus (see Chapter 54)

• In PV: blister in deeper part of epidermis, just above the basal layer
• In PF (also called superficial pemphigus): blister in the granular layer

Pemphigus Subtypes

• Pemphigus vulgaris
• Pemphigus vegetans
• Pemphigus foliaceus
• Pemphigus erythematosus
• Endemic pemphigus foliaceus (e.g., fogo selvagem)
• Immunoglobulin A (IgA) pemphigus
• Subcorneal pustular dermatosis
• Intraepidermal neutrophilic dermatosis
• Paraneoplastic pemphigus

Intraepidermal Blistering Diseases Without Autoantibodies

• Familial benign pemphigus (Hailey–Hailey disease)
• Bullous impetigo, staphylococcal scalded-skin syndrome
• Blisters from herpes simplex and zoster
• Allergic contact dermatitis (e.g., rhus dermatitis)
• Epidermolysis bullosa simplex
• Incontinentia pigmenti

Mouth Ulcers/Erosions Without Autoantibodies

• Aphthous ulcers
• Candidiasis
• Lichen planus
• Behçet disease

Subepidermal Blistering Diseases With Autoantibodies

• Bullous pemphigoid
• Herpes gestationis
• Cicatricial pemphigoid
• Epidermolysis bullosa acquisita
• Linear IgA disease and chronic bullous disease of childhood
• Dermatitis herpetiformis
• Bullous lupus erythematosus

Subepidermal Blistering Diseases Without Autoantibodies

• Erythema multiforme
• Toxic epidermal necrolysis
• Porphyria
• Junctional or dystrophic epidermolysis bullosa

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• Epidemiology is dependent on both area of the world studied and the ethnic population in that area
• PV is more common in:
• Jews
• Probably people of Mediterranean descent
• People from the Middle East
• This ethnic predominance does not exist for PF
• In areas where Jewish/Middle Eastern/Mediterranean populations predominate, the ratio of PV to PF tends to be higher

Regional PV:PF Ratios

Regional PV Incidence

• Prevalence and incidence of PF highly location-dependent
• Endemic foci of PF found in Brazil, Colombia, and Tunisia
• First recognition of endemic PF was in Brazil — called fogo selvagem ("wild fire" in Portuguese)
• Clinically, histologically, and immunopathologically the same as sporadic PF in any individual patient, but epidemiology is unique
• Endemic in rural areas of Brazil, especially along inland riverbeds
• Geographic distribution of disease clustering similar to that of a black fly, Simulium nigrimanum, thought by natives to be a vector
• Study of environmental risk factors implicated the bite of this black fly — significantly more frequent among those with disease compared to age-, sex-, and occupation-matched controls with unrelated dermatoses
• Prevalence on some well-studied Indian reservations in rural Brazil can be as high as 3.4%
• Incidence up to 0.8–4.0 new cases per 1,000 people per year
• On the reservation in Limao Verde, up to 55% of unaffected individuals have a low-level IgG1 antibody response against desmoglein 1 (the PF autoantigen)
• This becomes an IgG4 response of higher titer against a more pathogenic epitope in disease
• Suggests some environmental agent (e.g., insects or other infectious disease agent) may trigger a low-level autoantibody response that becomes pathogenic by intramolecular epitope spreading in genetically susceptible individuals
• 40%–80% of patients from Brazil with insect-borne diseases (onchocerciasis, leishmaniasis, Chagas disease) have low-level anti-desmoglein 1 antibodies
• Patients with other infectious diseases from Brazil rarely have such antibodies
• Fogo selvagem occurs often in children and young adults, unlike sporadic PF (mostly middle-aged and older patients)
• Occurs not infrequently in genetically related family members, although it is not contagious
• Probably implies common exposure as well as genetic susceptibility
• No known racial or ethnic predominance; anyone moving into an endemic area may be susceptible
• Development of rural endemic areas of Brazil decreased the incidence of disease (supporting environmental trigger)

• Sex ratio difficult to estimate accurately due to overall low incidence
• Larger epidemiologic studies (>100 cases) show sex ratio of pemphigus in women vs. men ranges from 1.33 or 2.25 to 1
• Notable exceptions:
• Predominance of women (4:1) in an endemic focus of PF in Tunisia
• Predominance of men (19:1) in an endemic focus of PF in Colombia

• Average age of onset varies by region
• In Turkey, Saudi Arabia, Tunisia, and Iran: mean age of onset ~40 years
• In United States and elsewhere in Europe: average age of onset between 50 and 70 years
• Pemphigus rarely occurs in children, except in regions of endemic disease

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• Pemphigus is an organ-specific, autoantibody-mediated disease of desmosomes
• Development of light microscopy and electron microscopy allowed identification of the morphology and immunopathology
• Patient serum IgG served as a key reagent to help identify both PF and PV antigens
• Cloning and characterization of pemphigus antigens led to development of ELISA tests
• Continued studies on pathophysiology aim to develop safer and effective therapies

• Pemphigus antigens are desmogleins — transmembrane glycoproteins of desmosomes (cell-to-cell adhesion structures)
• Desmogleins are part of the cadherin superfamily of calcium-dependent cell adhesion molecules
• Original family members (e.g., E-cadherin) demonstrate homophilic adhesive interactions (binding between like molecules)
• Desmogleins demonstrate homophilic binding but can also participate in heterophilic adhesion by binding desmocollins (the other major transmembrane glycoprotein of desmosomes)

PF Antigen

• Desmoglein 1 — a 160-kDa protein
• Also the fogo selvagem antigen

PV Antigen

• Desmoglein 3 — a 130-kDa protein
• 64% similar and 46% identical in amino acid sequence to desmoglein 1

Antibody Profiles

• All PV patients have anti-desmoglein 3 antibodies; some also have anti-desmoglein 1 antibodies
• Mucosal-dominant PV → tend to have only anti-desmoglein 3 antibodies
• Mucocutaneous PV → usually have both anti-desmoglein 3 and anti-desmoglein 1 antibodies
• PF patients → typically have antibodies against only desmoglein 1

Evidence That Anti-Desmoglein Antibodies Directly Cause Blisters

• Passive transfer of PV or PF IgG to neonatal mice or human skin causes blisters that clinically and histologically mimic the corresponding type of pemphigus
• Affinity-purified anti-desmoglein 1 and 3 autoantibodies cause PF and PV blisters, respectively
• Adsorption of desmoglein-reactive autoantibodies from PF or PV IgG abrogates disease
• Passive transfer in humans: mothers with even mild PV can pass IgG autoantibodies to fetus → blistering oral and skin disease that resolves by approximately 6 months, concurrent with disappearance of maternal IgG

Desmoglein 4

• Expressed in the developing hair cortex and the superficial epidermis
• Target of some pemphigus antibodies
• Anti-desmoglein 4 antibodies in mucocutaneous PV and PF shown to be a result of cross-reactivity from desmoglein 1 autoantibodies
• Desmoglein 4 reactivity has not been shown to be necessary or sufficient for acantholysis

Other Antigenic Targets

• Acetylcholine receptors and E-cadherin identified as immunologic targets of pemphigus autoantibodies
• Their direct involvement in pathophysiology of pemphigus is unclear

• Unlike many other autoantibody-mediated diseases (e.g., pemphigoid, epidermolysis bullosa acquisita) where the constant region (Fc) of the antibody is required for blister formation (to activate complement or bind antibody receptors on inflammatory cells), in pemphigus the variable region (Fab) of the antibody is sufficient to cause blisters in neonatal mice or human skin
• Significant research has focused on epitopes bound by pathogenic autoantibodies

Epitope Mapping

• Pathogenic PV and PF autoantibodies bind calcium-sensitive, conformational epitopes in the amino-terminal extracellular domains of desmogleins
• Nonpathogenic antibodies tend to bind more membrane-proximal extracellular domains
• Amino-terminal domains bound by pathogenic antibodies = same domains predicted to form key molecular interactions for desmoglein intercellular adhesion (based on cadherin ultrastructure studies)

Steric Hindrance Hypothesis

• Proposes that pathogenic antibodies directly interfere with desmoglein adhesive interactions, causing acantholysis

Desmoglein Internalization

• Loss of intercellular adhesion by pathogenic autoantibodies leads to internalization and degradation of desmogleins
• Other model systems with loss of desmoglein function mimic pemphigus:
• Mice genetically deficient for desmoglein 3 → suprabasal blisters in oral mucosa histologically identical to PV
• Cleavage of desmoglein 1 by staphylococcal exfoliative toxin (in bullous impetigo or staphylococcal scalded skin syndrome) → blisters histologically identical to PF

Desmoglein Compensation

• Explains why blisters in PV and PF have specific tissue localizations that do not necessarily correlate with sites where antibodies bind by immunofluorescence
• In PF: anti-desmoglein 1 antibodies bind throughout the epidermis and mucous membranes, yet blisters occur only in the superficial epidermis
• Concept: autoantibodies against one desmoglein isoform inactivate only that isoform; another isoform coexpressed in the same area can compensate in adhesion

PF (Anti-Dsg1 Antibodies)

• Superficial epidermis of skin: Dsg1 present, Dsg3 absent → acantholysis occurs
• Deep epidermis of skin: Dsg1 + Dsg3 → Dsg3 compensates → no blister
• Mucous membranes: Dsg3 compensates → no blister

PV with Only Anti-Dsg3 Antibodies (Mucosal-Dominant)

• Skin: Dsg1 compensates in both superficial and deep epidermis → no blister
• Mucous membranes (deep): Dsg3 only, no compensatory Dsg1 → blister

PV with Both Anti-Dsg3 and Anti-Dsg1 Antibodies (Mucocutaneous)

• Skin: both Dsg1 and Dsg3 inhibited → blisters in skin (deep, because antibodies diffuse from dermis and interfere first with desmosomes at base of epidermis)
• Mucous membranes: both inhibited → blisters

Neonatal PF

• Explains why neonatal PF is rare: even though maternal anti-desmoglein 1 antibodies cross placenta, in neonatal skin (but not adult skin), desmoglein 3 is coexpressed with desmoglein 1 in the superficial epidermis, providing protection

Cell Signaling Pathways

• Several studies suggest modulation of cell signaling pathways can prevent blister formation after passive transfer of pemphigus IgG in neonatal mouse model:
• p38 MAPK (mitogen-activated protein kinase)
• ρ GTPases
• Others
• Whether signaling is upstream or downstream of loss of intercellular adhesion is controversial
• Current general consensus: desmosomal adhesion is a dynamic process perturbed by pemphigus autoantibodies
• Therapies strengthening keratinocyte adhesion by modulation of signaling pathways may have beneficial effect, regardless of whether cell signaling is a primary pathologic cause

MHC Class II Associations

• PV patients have a markedly increased frequency of certain class II MHC antigens compared to a matched population
• Among Ashkenazi Jews with PV: serologically defined HLA-DR4 haplotype is predominant
• In other ethnic groups with PV: DQ1 allele is more common
• At the genetic level:
• DR4 serotype patients almost all have the unusual allele DRB1*0402
• DQ1 serotype patients almost all have the rare allele DQB1*0503
• Similar, but less restricted, HLA-DR alleles are associated with PF
• Protein chains encoded by PV MHC II alleles vary from controls by only a few amino acids
• MHC class II alleles encode cell surface molecules necessary for antigen presentation to the immune system
• Hypothesis: PV-associated MHC class II molecules allow presentation of desmoglein 3 peptides to T cells
• Certain peptides from desmoglein 3, predicted to fit into the DRB1*0402 peptide-binding pocket, stimulated T cells from patients
• Other studies confirmed immune response in pemphigus is restricted to certain desmoglein peptides and MHC class II alleles

T-Cell Reactivity

• Unexpected observation: T cells of normal people with DRB10402 or DQB10503 respond just as well as those of pemphigus patients to the same desmoglein 3 peptides
• Indicates T-cell reactivity to desmoglein 3 peptides is not sufficient for disease onset
• Factor determining who gets pemphigus proposed to be presence of regulatory T cells that can suppress the autoimmune response in those who do not develop disease

Antibody and T-Cell Receptor Gene Usage

• Cloning of anti-desmoglein antibodies from PV and PF patients shows marked restriction of antibody gene usage, most notably for the heavy chain variable region
• Pathogenic antibodies from different patients bind at or near common epitopes on desmogleins and may share common idiotypes
• More heterogeneity of T-cell receptor variable gene usage in pemphigus patients
• If specific antibody or T-cell receptor gene usage patterns shared among multiple patients → may serve as clinical markers for targeting disease-specific immune cell populations

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Cutaneous Lesions

• Can be pruritic or painful
• Ultraviolet radiation may exacerbate disease activity
• Primary lesion: flaccid blister, may occur anywhere on skin surface, but typically not the palms and soles
• Usually arises on normal-appearing skin, but may develop on erythematous skin
• PV blisters are fragile → most common skin lesions observed are erosions resulting from broken blisters
• Erosions often quite large, with tendency to spread at their periphery

Nikolsky Sign

• Erosions can be extended into visibly normal skin by pulling remnant of blister wall or rubbing at periphery of active lesions
• Erosions can be induced in normal-appearing skin distant from active lesions by pressure or mechanical shear force
• Known as the Nikolsky sign
• Helps differentiate pemphigus from other blistering diseases (e.g., pemphigoid)
• Similar findings can also be elicited in:
• Staphylococcal scalded skin syndrome
• Stevens–Johnson syndrome
• Toxic epidermal necrolysis

Vegetating Lesions

• In certain patients, erosions develop excessive granulation tissue and crusting → vegetating lesions
• Tend to occur more frequently in intertriginous areas, scalp, or face
• Historically split into:
• Pemphigus vegetans of Hallopeau: vegetating and often pustular lesions present from outset, not preceded by bullae, favor flexural regions; prognosis thought to be better with milder disease and higher chance of remission compared to typical PV
• Pemphigus vegetans of Neumann: ordinary PV erosions heal with papillomatous formations; prognosis related to extent of disease activity
• Subsequent analysis by histology and immunofluorescence suggests these are simply clinical variants of PV
• Vegetating type of response may appear in certain lesions resistant to therapy that remain for long periods in one place

Mucous Membrane Lesions

• Most often affected: oropharyngeal cavity
• Intact blisters are rare
• Oropharyngeal erosions can be so painful that patient is unable to eat or drink
• Inability to eat/drink may require inpatient hospitalization for disease control and IV fluid/nutrient repletion
• In the majority of patients, painful mucous membrane erosions are the presenting sign of PV
• May be the only sign for an average of 5 months before skin lesions develop
• In a study from Croatia: painful oral lesions were presenting symptom in 32% of patients
• Most progressed to generalized eruption in 5 months to 1 year
• Some had oral lesions for more than 5 years before generalization
• In Tehran: 62% of patients presented with oral lesions only
• Skin involvement without mucous membrane involvement in PV is less common — accounted for 11% of PV cases in one study

Gastrointestinal Tract Involvement

• Described in esophagus, stomach, duodenum, and anus
• Only biopsies of the esophagus have been proven to be due to suprabasal acantholysis

Other Mucous Membrane Involvement

• Vulvovaginal, nasal, laryngeal, and conjunctival mucosa
• In women, cervicovaginal lesions found in up to 51% of patients with active disease — may be asymptomatic
• Even without obvious lesions, Pap smears may be positive in women with pemphigus
• Acantholytic cells may be misinterpreted as indicative of cervical dysplasia
• Rare case reports of corneal erosions in PV patients — no histologic confirmation of acantholysis

Cutaneous Lesions

• Characteristic lesions: scaly, crusted erosions, often on an erythematous base
• In more localized and early disease: well demarcated, scattered in a seborrheic distribution (face, scalp, upper trunk)
• Primary lesions of small flaccid blisters are typically not found
• Disease may stay localized for years, or rapidly progress to generalized involvement → exfoliative erythroderma
• Like PV, may be exacerbated by ultraviolet radiation
• Patients often complain of pain and burning in skin lesions
• In contrast to PV, PF patients very rarely, if ever, have mucous membrane involvement, even with widespread disease
• Colloquial term for Brazilian endemic pemphigus: fogo selvagem ("wild fire") — reflects:
• Burning feeling of skin
• Exacerbation by sun
• Crusted lesions making patients appear as if burned

Pemphigus Erythematosus (Senear–Usher Syndrome)

• Described in 1926 by Francis Senear and Barney Usher — 11 patients with features of pemphigus–lupus erythematosus overlap
• Also called Senear–Usher syndrome
• Clinical presentation: crusted erosions in a seborrheic distribution, at times concurrent with more lupus-like discoid lesions with "carpet-tack" scale
• Walter Lever noted many patients initially categorized as pemphigus erythematosus went on to develop systemic lupus, or more widespread PF, or even PV (sometimes due to incorrect initial diagnosis)
• Lever proposed pemphigus erythematosus = localized form of PF with better prognosis
• After development of immunofluorescence and ANA testing:
• All demonstrate cell surface staining pattern classic for pemphigus
• ~30% have positive antinuclear antibody titers
• 80% have positive lupus band tests
• Lupus band test positive in only 20%–40% of biopsies on non-sun-exposed skin
• Most patients with pemphigus erythematosus do not develop systemic signs/symptoms of lupus
• Some may progress from localized disease to generalized PF
• Diagnosis is largely one of historic, rather than clinical, significance

• Infants born to mothers with PV may display clinical, histologic, and immunopathologic signs of PV
• Degree of involvement varies from none to severe enough to result in stillbirth
• If infant survives, disease tends to remit as maternal antibody is catabolized
• Mothers with PF may also transmit autoantibodies to the fetus, but neonatal PF occurs only rarely (due to desmoglein compensation — neonatal skin coexpresses Dsg3 with Dsg1 in superficial epidermis)
• Neonatal pemphigus should be distinguished from PV and PF that occur in childhood (similar to autoimmune diseases in adults)

• Sporadic case reports of pemphigus associated with several different drugs
• Most significant association: penicillamine, and perhaps captopril
• Prevalence of pemphigus in penicillamine users: ~7%
• PF (including pemphigus erythematosus) is more common than PV in penicillamine-treated patients (though either may occur)
• Direct and indirect immunofluorescence positive in most of these patients
• Three patients with drug-induced PF and one with drug-induced PV shown to have autoantibodies to same molecules as sporadic pemphigus (desmoglein 1 and desmoglein 3, respectively)
• Both penicillamine and captopril contain sulfhydryl (thiol) groups
• Postulated to interact with sulfhydryl groups in desmoglein 1 and/or 3
• Cause pemphigus either by directly interfering with adhesion molecules or (more likely) by modifying them to become more antigenic
• May also lead to more generalized dysregulation of immune response → production of other autoantibodies (e.g., myasthenia gravis)
• Most, but not all, patients with drug-induced pemphigus go into remission after stopping the offending drug

Dietary Associations

• Rare anecdotal reports of association of dietary intake and pemphigus
• Hypothesis: thiol-containing foods (garlic, leeks, onions) may precipitate disease
• Some patients may note certain foods aggravate oral lesions
• Unlikely that dietary intervention alone will remit disease in most patients

Cholinergic Effects

• Anecdotal case reports of improvement of PV with cigarette smoking
• Improvement with cholinergic agonists: pyridostigmine, carbachol, and pilocarpine
• Activation of cholinergic receptors may regulate signaling pathways modulated by PV IgG, thereby affecting cell adhesion
• Intriguing given clinical benefit of nicotine noted in other inflammatory diseases (e.g., ulcerative colitis)

• Myasthenia gravis, thymoma, or both have been associated with PV and PF
• ~One-half of associated pemphigus cases are vulgaris; one-half are foliaceus or erythematosus
• Most data reported before recognition of paraneoplastic pemphigus as a distinct entity
• Therefore, thymoma may be associated with PV, PF, or paraneoplastic pemphigus (see Chapter 55)
• Myasthenia gravis: tissue-specific autoantibody-mediated disease → skeletal muscle weakness
• Early disease usually affects facial muscles → dysarthria, dysphagia, ptosis, diplopia
• May progress to larger muscles of trunk and extremities
• Potential fatal complications from respiratory muscle involvement
• Thymoma: typically asymptomatic in adults
• In children: more likely to be symptomatic with cough, chest pain, superior vena cava syndrome, dysphagia, and/or hoarseness from localized tumor encroachment
• Myasthenia gravis best evaluated by neurologist → full neurologic examination + test for serum acetylcholine receptor autoantibodies
• Course of myasthenia gravis and pemphigus appear to be independent of each other
• Thymic abnormalities may either precede or follow onset of pemphigus
• Include benign or malignant thymoma and thymic hyperplasia
• PA and lateral chest radiographs ± CT follow-up can detect most thymomas
• Irradiation of thymus or thymectomy: clearly beneficial for myasthenia gravis, may not improve pemphigus disease activity
• Association reported in at least 30 cases; finding of thymoma or myasthenia gravis in PV or PF is still unusual

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• Diagnosis relies on:

1. Skin biopsy of a fresh lesion for histology → determine site of blister formation
2. Confirmatory immunochemical study to document presence of skin autoantibodies:

• Direct immunofluorescence of perilesional skin, OR
• Indirect immunofluorescence or ELISA of patient serum

Pemphigus Vulgaris

• Characteristic finding: suprabasal blister with acantholysis
• Just above the basal cell layer, epidermal cells lose normal cell-to-cell contacts and form a blister
• Often a few rounded-up (acantholytic) keratinocytes in the blister cavity
• Basal cells stay attached to basement membrane but may lose contact with neighbors → appear as a "row of tombstones" — symbolic of the potentially fatal prognosis
• Upper epidermis (from one or two cell layers above basal cells) remains intact — these cells maintain their cell adhesion

Pemphigus Vegetans Histology

• Suprabasilar acantholysis plus:
• Papillomatosis of dermal papillae
• Downward growth of epidermal strands into dermis
• Hyperkeratosis and scale-crust formation
• Intraepidermal abscesses composed of eosinophils and/or neutrophils

Early PV Lesions

• May show eosinophilic spongiosis

Pemphigus Foliaceus

• Early blisters: acantholysis (loss of cell-to-cell contact) just below the stratum corneum and in the granular layer
• Stratum corneum often lost from surface of lesions
• Deeper epidermis below the granular layer remains intact
• Another frequent finding: subcorneal pustules with neutrophils and acantholytic epidermal cells in blister cavity
• Histologic findings often indistinguishable from bullous impetigo/staphylococcal scalded skin syndrome (blisters in those diseases also result from dysfunction of desmoglein 1 due to proteolytic cleavage by staphylococcal exfoliative toxins)
• Therefore, immunochemical studies are essential to confirm diagnosis of PF (would be negative in staphylococcal-mediated blisters)
• Site of blister formation in pemphigus erythematosus is identical to PF

Early PF Lesions

• May also show eosinophilic spongiosis

• Hallmark of pemphigus: finding of IgG autoantibodies against the cell surface of keratinocytes
• First discovered in patients' sera by indirect immunofluorescence; soon thereafter by direct immunofluorescence of patients' skin

Direct Immunofluorescence

• Essentially all patients with active PV or PF have a positive direct immunofluorescence
• Tests for IgG bound to cell surface of keratinocytes in perilesional skin
• Nonquantitative test (either negative or positive)
• Diagnosis of pemphigus should be seriously questioned if direct immunofluorescence is negative
• Important: biopsy must be performed on normal-appearing perilesional skin
• Immune reactants can be difficult to detect in blistered inflamed epidermis → false negative
• In some cases of pemphigus erythematosus: IgG and C3 deposited at the basement membrane zone of erythematous facial skin, in addition to epidermal cell surface IgG → positive lupus band test plus typical pemphigus intercellular pattern

Indirect Immunofluorescence

• Performed by incubating serial dilutions of patients' sera with epithelial substrates
• Reported as a semiquantitative titer (last dilution at which serum demonstrates positive cell surface staining pattern)
• Offered by most major national laboratories
• Can remain positive for weeks to months after healing of skin lesions → good diagnostic test if patient presents with no active lesions (e.g., due to empiric prednisone by referring physician)
• More than 80% of patients with pemphigus have circulating antiepithelial cell surface IgG (depending on substrate)
• Substrate influences sensitivity:
• Monkey esophagus: more sensitive for detecting PV antibodies
• Guinea pig esophagus or normal human skin: superior substrate for detecting PF antibodies
• Patients with early localized disease and those in remission most likely to have negative indirect immunofluorescence → ELISA may help
• PV and PF patients usually display similar direct and indirect immunofluorescence findings (IgG on cell surface throughout epidermis)
• Usually not possible to differentiate the two by immunofluorescence pattern
• Positive but imperfect correlation between titer of circulating anticell surface antibody and disease activity in PV and PF
• Patients in remission often show serologic remission with negative direct and indirect immunofluorescence
• Disease activity in individual patients does not necessarily correlate with indirect immunofluorescence titer
• In day-to-day management: following disease activity is more important than following antibody titer

• For diagnosis: antigen-specific ELISAs have been shown to be more sensitive and specific than immunofluorescence
• Titer correlates better with disease activity than indirect immunofluorescence
• ELISAs are easier to perform and less subjective than immunofluorescence
• May replace immunofluorescence as preferred first diagnostic test, although currently some major national labs do not offer desmoglein ELISA
• Assay method: desmogleins 1 and 3 bound to plates → incubated with patient sera → developed with anti-human IgG reagents (HRP-conjugated)
• Advantage over indirect immunofluorescence: can help differentiate between PV and PF due to different autoantigen profiles

ELISA Results by Disease Type

• PV has rarely evolved into PF, and vice versa (determined by clinical, histologic, and immunochemical criteria)
• A small minority of PF patients may also demonstrate autoantibodies to desmoglein 3 → diagnosis should be based on clinical–serologic correlation
• Some patients (e.g., those with bullous pemphigoid) may demonstrate a low level of anti-desmoglein 3 autoantibodies due to high sensitivity of ELISA
• A result in the indeterminate range should be interpreted carefully — may represent:
• True positive, OR
• False positive (presumably due to formation of nonpathogenic bystander autoantibodies after epidermal damage)
• Correlation of ELISA index value with disease activity is not perfect
• In making treatment decisions: a negative result on desmoglein ELISA is more helpful than a positive result
• Patient with negative ELISA is more likely to achieve remission off immunosuppressives
• Patient with positive ELISA may or may not achieve remission
• Disease activity is the mainstay for determining treatment

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• Before glucocorticoid therapy:
• PV was almost invariably fatal (due to severe blistering → malnutrition, dehydration, sepsis)
• PF was fatal in ~60% of patients
• PF almost always fatal in elderly patients with concurrent medical problems; prognosis without therapy was much better than PV in other patients

• After glucocorticoids and immunosuppressive therapy:
• Prognosis dramatically improved
• Pemphigus is still associated with significant morbidity and mortality
• In the United States: annual mortality rate from pemphigus (age-adjusted) estimated at 0.023 deaths per 100,000
• In the United Kingdom: risk of death in PV patients is 3.3 times greater than for controls
• Infection is often the cause of death; therapy (by causing necessary immunosuppression) is frequently a contributing factor
• With glucocorticoid and immunosuppressive therapy, mortality (from disease or therapy) of PV patients followed from 4 to 10 years is ~10% or less; PF mortality is probably even less

• Study of 40 PV patients:
• 2 patients (5%) died of sepsis
• 17%, after average of 18 months of therapy, went into complete and long-lasting (>4 years, average, thought to be permanent) remission requiring no further therapy
• Another 37% achieved remission but relapsed after therapy stopped; most eventually achieved long-lasting remissions
• Remainder required continual therapy

• Study of 159 PV patients from Croatia:
• Only ~12% went into long-term remission after therapy with glucocorticoids and immunosuppressives
• Most relapsed

• Study from Tehran of 1,206 pemphigus patients seen over 20 years:
• 6.2% of PV and 0.2% of PF patients died, mostly of septicemia
• Only 9.3% were in complete remission without therapy

• In some small studies, higher percentages of patients reported to go into complete remission
• With advent of rituximab therapy, complete remission may become more common

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• Currently no FDA-approved treatments for pemphigus (despite potentially fatal prognosis)
• Approach to therapy varies widely, even among experts
• PV should be treated at onset, even if initially limited in extent:
• Will ultimately generalize
• Prognosis without therapy is very poor
• Easier to control early disease than widespread disease
• Mortality may be higher if therapy is delayed
• PF may be localized for many years with good prognosis without systemic therapy:
• Topical corticosteroids may suffice
• When active and widespread: therapy similar to PV

• Consensus statement on disease definitions and endpoints proposed by international committee of pemphigus experts
• Clinical instruments developed for tracking disease activity
• Standardization will facilitate future clinical trials

Systemic Glucocorticoids

• Prednisone: mainstay of therapy
• Before adjuvant immunosuppressive therapy, very high initial doses of prednisone were used: >2.0 mg/kg/day
• Retrospectively associated with significant morbidity and mortality from therapy
• In many patients, disease can be controlled with 0.5–1.0 mg/kg/day single daily dose
• Especially if used in combination with adjunctive immunosuppressive therapy
• Results in fewer complications and decreased mortality compared to higher dose regimens
• For patients who do not initially respond or worsen: splitting dose (twice or three times daily) may achieve disease control
• Full systemic dose defined in consensus guidelines: 1.5 mg/kg/day of prednisone equivalent for 3 weeks
• Patients whose total daily prednisone exceeds ~100 mg → should be considered for adjunctive treatments
• Some experts still recommend controlling initial refractory disease with escalating doses (increasing by 50% every 1–2 weeks until disease control or prohibitive side effects) with total daily doses as high as 240 mg
• Once disease controlled → taper prednisone to as low a dose as possible
• Minimal therapy defined as 10 mg daily of prednisone equivalent
• If disease fully controlled on minimal dose or lower → glucocorticoid monotherapy may be feasible depending on comorbidities and contraindications
• If continued relapses with daily prednisone ≥10 mg → adjunctive immunosuppressive agents should be considered
• Interesting: prednisone can control blistering within days, at a time when autoantibody titer would be unchanged
• Possible explanation: prednisone may increase synthesis of desmogleins or other cell adhesion molecules, or change posttranscriptional processing to prolong their half-life
• If pemphigus IgG depletes desmosomes of desmogleins, prednisone could counteract this effect

Topical Corticosteroids

• May be used as monotherapy in mild forms of disease, or as adjunctive therapy to help heal new lesions
• Mucosal disease: benefit from glucocorticoid elixirs (swish and spit) or dental trays to apply class I corticosteroid gels or ointments to gingiva
• Class I–IV corticosteroids can be used as topical therapy to help resolve new blisters, even in patients on systemic glucocorticoids

• Used when greater than minimal doses of glucocorticoids required, or contraindications to oral glucocorticoids
• Treatment often begins with immunosuppressive agent and prednisone simultaneously
• Prospective randomized studies: mycophenolate mofetil, azathioprine, and cyclophosphamide have a steroid-sparing effect
• Retrospective studies suggest decreased mortality with adjuvants plus steroids vs. steroids alone
• Important to monitor all patients closely for potential side effects:
• Blood count abnormalities
• Liver and kidney laboratory abnormalities
• Gastrointestinal ulcer disease
• High blood pressure
• Diabetes
• Glaucoma
• Cataracts
• Osteoporosis
• Infection
• Decision to use immunosuppressive agents, particularly in young patients, must account for:
• Potential incidence of malignancies with long-term use
• Risks of infertility (for cyclophosphamide)
• Teratogenicity (mycophenolate mofetil, azathioprine, and cyclophosphamide are all pregnancy category D)

Azathioprine

• Historically considered first-line immunosuppressive agent for pemphigus
• Clinical remission rates of ~50% in retrospective studies
• Prospective randomized trial of high dose methylprednisolone (2.0 mg/kg/day) + azathioprine (2.0 mg/kg/day):
• 72% of patients achieved clinical remission within a mean of 74 days
• 33% experienced significant adverse effects (hyperglycemia, dizziness, abnormal liver enzymes, infection)
• Prodrug → converted to active metabolites: mercaptopurine, thioguanine, and thioinosine, in part by thiopurine methyltransferase (TPMT)
• TPMT levels vary widely in the population:
• 89% of Caucasians → normal to high TPMT levels
• 11% → intermediate
• 0.3% → deficient (do not tolerate azathioprine therapy)
• 1%–2% of Caucasians → "super high" TPMT levels → correlated with both treatment resistance and increased hepatotoxicity from excessive metabolite production
• Estimated 5% of patients will be azathioprine intolerant (genotype–phenotype correlation is imperfect)
• Consensus dosing (that defines treatment failure): 2.5 mg/kg/day for 12 weeks
• Not all laboratories offer TPMT testing
• Since patients with normal TPMT may also experience toxicity: reasonable to start all patients at lower dose (e.g., 50–100 mg daily) and titrate upward until clinical remission, target dose of 2.5 mg/kg/day, or unacceptable side effects
• Frequent blood and liver monitoring should continue, particularly over the first 8–12 weeks when delayed toxicity from metabolite accumulation may emerge

Mycophenolate Mofetil

• Also considered first-line immunosuppressive agent for pemphigus
• In 2006, FDA granted orphan drug status to mycophenolate mofetil for treatment of PV
• Typical doses: 30–40 mg/kg/day dosed twice daily (2.0–3.0 g/day)
• Certain patients (e.g., elderly) may achieve disease control with doses as low as 1.0 g/day
• In case series: shown to have rapid effect in lowering pemphigus antibody titers and decreasing disease activity, even in patients unresponsive to azathioprine

Comparative Trial Data

• Prospective randomized trial comparing methylprednisolone (2.0 mg/kg/day) with azathioprine (2.0 mg/kg/day) or mycophenolate mofetil (2.0 g/day):
• Azathioprine group: 72% clinical remission, mean 74 days
• Mycophenolate group: 95% clinical remission, mean 91 days
• Significant adverse effects: 19% in mycophenolate group vs. 33% in azathioprine group
• None of these differences was statistically significant
• Another prospective randomized study: azathioprine was significantly more effective than mycophenolate mofetil as steroid-sparing agent
• But this study compared full dose azathioprine (2.5 mg/kg/day) to partial dose mycophenolate mofetil (2.0 g/day)

Safety Concerns

• Caution warranted:
• Fatal infection and sepsis in 2%–5% of transplant patients receiving mycophenolate mofetil
• Increased risk of infection with or reactivation of:
• Cytomegalovirus
• Herpes zoster
• Atypical mycobacteria
• Tuberculosis
• JC virus (in progressive multifocal leukoencephalopathy)
• Interestingly: mycophenolate mofetil may offer protection against Pneumocystis carinii infection

Cyclophosphamide

• More toxic than azathioprine or mycophenolate mofetil
• Thought to be very effective in controlling severe disease
• One report: 19 of 23 pemphigus patients achieved complete remission in median time of 8.5 months
• Various regimens evaluated:
• Daily oral therapy: 1.1–2.5 mg/kg/day
• Daily oral therapy (50 mg) with intermittent high-dose IV dexamethasone and cyclophosphamide
• Immunoablative IV cyclophosphamide
• All methods effective in short-term, although none were curative
• Significant side effects with higher-dose regimens:
• Hematuria
• Infection
• Transitional cell carcinoma of the bladder
• One study using lower daily dose (1.1–1.5 mg/kg/day) did not report significantly different safety profile compared with other immunosuppressive agents
• Together with risk of infertility: cyclophosphamide is not generally considered first-line in PV

Dapsone

• Case series and randomized double-blind trial: demonstrated a trend toward efficacy as steroid-sparing drug in maintenance phase PV (results not statistically significant)
• May be used in conjunction with other immunosuppressive agents, particularly rituximab
• Offers additional benefit of Pneumocystis pneumonia prophylaxis

Rituximab

• Very effective therapy for pemphigus refractory to more standard therapy
• Monoclonal anti-CD20 antibody, approved for therapy of B-cell malignancies
• Presumably targets B cells (precursors of antibody-producing plasma cells)
• B cells also act to process autoantigen and present it to T cells that provide "help" in stimulating the autoantibody response
• Dosing regimens:
• 375 mg/m² IV once weekly for 4 weeks
• OR rheumatoid arthritis dosing: 1,000 mg IV on day 1 and day 15
• Course can be repeated in ~6 months for more refractory disease
• A single cycle of rituximab shown to be highly effective:
• 86% of patients experienced complete remission lasting 34 months or greater
• Disease activity usually begins to remit within 1–2 months after course of therapy
• Some experts consider rituximab the therapy of choice for severe pemphigus uncontrolled by corticosteroids and azathioprine or mycophenolate mofetil, or with contraindications to corticosteroids

Rituximab Safety Concerns

• Fatal infections observed:
• Pneumocystis pneumonia
• Reactivation of hepatitis B
• JC virus infection or reactivation causing progressive multifocal leukoencephalopathy
• Complications are rare
• Some experts recommend Pneumocystis prophylaxis for 1 year following rituximab infusion

Intravenous Immunoglobulin (IVIg)

• Another method of decreasing serum autoantibodies
• High-dose IV γ-globulin
• Mechanism: thought to function by saturating circulating neonatal Fc receptor → increasing catabolism of patient's serum antibodies (including pathogenic autoantibodies)
• May be useful as adjuvant therapy in pemphigus patients unresponsive to conventional therapy
• Multicenter, randomized, placebo-controlled, double-blind study confirmed efficacy in pemphigus
• Expensive and probably requires continued infusions for maintenance of remission
• Significant side effects:
• Stroke
• Deep venous thrombosis
• Renal failure with sucrose-containing formulations
• Some centers use IVIg to establish initial control of blistering in severely affected patients (does not increase risk of infection as much as corticosteroids and immunosuppressants)
• IVIg has also been used in combination with rituximab, although unclear whether combination is safer or more effective than either alone

Plasmapheresis

• Sometimes used for severe pemphigus or pemphigus unresponsive to prednisone + immunosuppressive agents
• One controlled study found it ineffective
• Other studies found it both reduces serum levels of pemphigus autoantibodies and controls disease activity
• Plasmapheresis plus IV pulse cyclophosphamide reported to result in PV remissions
• For maximum effectiveness: probably necessary to perform plasmapheresis on patients taking immunosuppressive agents (to prevent antibody-rebound phenomenon after IgG removal)
• Protein A immunoadsorption (selectively removes IgG from plasma) has also been used

Pulsed Intravenous High-Dose Glucocorticoids

• IV pulse methylprednisolone: 250–1,000 mg given over ~3 hours daily for 4–5 consecutive days
• Can result in long-term remissions and decrease total dose of glucocorticoids needed
• Purpose: decrease incidence of complications of long-term steroid use
• Can result in all usual glucocorticoid complications plus cardiac arrhythmias with sudden death → use is controversial
• A controlled trial found adjuvant oral dexamethasone pulse therapy in addition to standard therapy with prednisolone and azathioprine for PV is not beneficial
• Simply giving divided lower doses of prednisone could possibly accomplish the same result with fewer side effects

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• Tremendous advance in therapeutic armamentarium since before glucocorticoids, when PV was a fatal disease
• The "row of tombstones" seen in PV pathology no longer alludes to its prognosis

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• Noninherited chronic blistering (vesicular/bullous) dermatoses: cause usually autoimmune; location of antibody binding at basement membrane zone (BMZ) determines clinical/histologic/immunofluorescent pattern
• Desmoglein compensation hypothesis: differential Dsg1/Dsg3 expression at different epidermal/mucosal levels explains PF vs PV phenotype differences
• Antibodies binding at BMZ → tense bullae; antibodies higher in structure → typically no scarring; antibodies deeper in BMZ → scarring/milia formation
• High-frequency ultrasound anecdotally reported to determine blister location
• Immunofluorescence pattern often critical for diagnosis; antibodies usually found bound in perilesional/nonbullous lesional skin (blistered skin often negative); avoid lower extremity biopsies (prone to false-negatives)
• Salt-split skin: 1M NaCl predictably splits skin at lamina lucida; localization of deposits to roof vs floor is diagnostically useful
• n-serrated pattern = split above basal lamina; u-serrated pattern = sub-lamina densa split — may make salt-split skin unnecessary; best seen where BMZ curves
• C3d immunohistochemical stain may aid diagnosis; immunoprecipitation, ELISA, immunoblotting have revolutionized testing but vary in sensitivity/specificity; BP ELISA can have ≥7% false-positive rate (non-NC16a antibodies or non-pathogenic anti-BP180 NC16a antibodies)
• Transient acantholytic dermatosis (Grover disease): idiopathic nonimmune, may mimic immunobullous histology but negative DIF
• Specific pregnancy dermatoses discussed under herpes gestationis differential
• Treatment landscape improved with rituximab, IVIg, targeted autoantibody-directed therapies (shift from broad immunosuppression); oral/ocular involvement needs early aggressive multidisciplinary therapy

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• Mucosal erosions + thin-walled, flaccid, easily ruptured bullae on normal skin/mucous membranes or erythematous bases; clear fluid → hemorrhagic/seropurulent; ruptures → erosions → crusts with little healing tendency; heals with hyperpigmentation, no scarring
• First appears in mouth in 60% of cases, or at burn/radiation/injury sites; other sites: groin, scalp, face, neck, axillae, genitals
• Nikolsky sign: intact epidermis shears from dermis with pressure/twisting/rubbing
• Asboe-Hansen sign (bulla-spread phenomenon): pressure on intact bulla spreads fluid under adjacent skin
• Scoring tools: ABSIS, PDAI (trial use), PVAS (patient self-assessment)
• Oral erosions painful, mouth odor; lip/vermilion fissured crusts; throat involvement → hoarseness, dysphagia; esophagus — esophagitis dissecans superficialis (cast sloughing) can occur even with controlled cutaneous disease (mucosa lacks Dsg1, depends entirely on Dsg3); conjunctiva, nasal mucosa, vagina, penis, anus may be involved
• Untreated widespread disease may cause death (superinfection, sepsis, fluid/electrolyte imbalance)
• Diagnosis: histology, immunofluorescence of perilesional skin/plucked hairs, IIF of serum, ELISA for anti-Dsg1/Dsg3

• Slight female predominance, 5th–6th decades; rare in young; more common Jewish people, Mediterranean descent; pre-corticosteroid era frequently fatal — now mortality mostly treatment-related

• Antibodies most often anti-Dsg3; both Dsg1+Dsg3 antibodies correlate with mucocutaneous disease; Dsg3-only antibodies → mucosal-predominant (mucosa lacks compensatory Dsg1)
• Both humoral and cellular autoimmunity important; antibody alone insufficient for acantholysis without complement/inflammatory cells
• IgG1 and IgG4 anti-Dsg3 antibodies (targeting EC1/EC2 domains); IgG4 believed pathogenic; nonpathogenic circulating antibodies may coexist
• C3 heavier in acantholytic areas; T-cell role: Th1 suppression, Th2 elevation, increased Th17, decreased Tregs; resident memory cells/γδ-T cells under investigation
• DIF may stay positive years after remission; conversion to negative predicts sustained remission after therapy withdrawal
• Associations: myasthenia gravis, thymoma (classic); emerging: psoriasis, ulcerative colitis, RA, thyroid disease, lupus, Sjögren, hematologic/GI malignancies, neurologic disease; increased cardiovascular risk factors
• PV antigen: 130-kD transmembrane desmosomal glycoprotein, cadherin family homology; IIF positive in 80–90%; circulating intercellular antibodies also seen with burns/drug eruptions (not anti-Dsg3)
• Drug-induced: uncommon; classically penicillamine and ACE inhibitors (thiols with sulfhydryl group, phenols most implicated); penicillamine/captopril can cause acantholysis in organ culture without autoantibody; doses 250–1500 mg/day, average 13 months before onset; also captopril, enalapril, penicillin, thioproline, IL-2, imiquimod, interferon, nifedipine, piroxicam, rifampicin; checkpoint inhibitors (nivolumab), secukinumab reported triggers; DPP-4 inhibitors strongly linked to drug-induced BP (rare PV reports); only 10–15% of drug-induced pemphigus have oral lesions; most resolves on discontinuation; rare vaccine triggers (rabies, tetanus, influenza, hepatitis, COVID) — no consistent epidemiologic signal, likely very low risk
• Genetic: strong association HLA-DRB104:02 and DQB105:03; non-HLA genes: DSG3, TAP2, IL6, ST18; SNPs affecting drug metabolism (personalized medicine potential); Israel has among highest PV incidence worldwide — Ashkenazi Jewish patients 3x risk vs Arab patients, higher in women; HLA-G associated in Jewish patients; relatives may have autoimmune disease predisposition

• Suprabasilar acantholysis, intraepidermal blister; round acantholytic cells, no intercellular bridges; "tombstone row" of basal keratinocytes under bulla; early intact bulla most characteristic; Asboe-Hansen modification of Nikolsky test extends bulla to non-regenerated margin
• IHC for IgG4 may aid diagnosis (PV and PF)
• Early disease: spongiosis with eosinophils without acantholysis (more suggestive of pemphigoid than pemphigus — IF distinguishes)
• DIF: "chicken wire" pattern of intercellular IgG in perilesional skin/plucked hairs; IgA in subset; C3 may be present; uniform not granular staining
• IIF similar pattern; prozone reactions occur — test serial dilutions; ELISA confirms; plucked hairs (anagen pilar sheath) alternative to skin biopsy for IF

• Aggressive immunosuppression warranted (increased mortality); management based on smaller trials/experience/expert opinion; medication continued until antibody disappears; negative DIF predicts sustained remission off therapy
• Remission likelihood correlates with age of onset and initial mucosal involvement; infection risk relates to severity/immunosuppression degree/comorbidities (diabetes); HSV or staph impetiginization can mimic ongoing PV
• Earlier diagnosis/treatment → better prognosis; monitor new lesions/day and healing rate; esophageal substrate titers can track mucosal disease

Topical

• Prolonged daily baths remove crusts/reduce odor; silver sulfadiazine 1% for limited disease; silver nitrate-impregnated cotton batting superior to povidone-iodine (improved healing, shorter stay, lower pain) for extensive disease
• Oral: simethicone+diphenhydramine mixture or viscous lidocaine before meals; antiseptic mouthwashes; potent topical corticosteroids/tacrolimus for limited disease or adjunctive tapering aid; intralesional steroids (rarely rituximab); topical insulin reported

Systemic

• Both corticosteroids and rituximab approved first-line; variability in guidelines
• Prednisone 0.5 mg/kg/day (mild) to 1 mg/kg/day+ (severe), may split to BID if inadequate; begin vitamin D/calcium/weight-bearing exercise/DEXA/bisphosphonate consideration early; Pneumocystis prophylaxis not routine for monotherapy but consider with combination high-dose steroid therapy (dapsone dual benefit)
• If new blisters not suppressed after 4–8 weeks, increase dose or add combination therapy; IV pulse methylprednisolone 1 g/day × 2–3h, daily × 5 days for refractory disease
• Treated-patient deaths mostly from therapy side effects, not disease; taper once ~80% lesions healed and no new lesions × 2 weeks (fast at high doses, slower <20 mg/day)
• Rituximab: increasingly first-line, anti-CD20, reduces CD20+ B cells (possibly Tregs); trend toward earlier use with significant disease; lymphoma dosing slightly better outcomes than RA dosing; relapse associated with CD19+ B cell return, positive Dsg1/Dsg3, low CD4+ count; human anti-chimeric antibody development can limit efficacy; risk of infections including PML
• MMF: usual steroid-sparing choice, 1–1.5 g BID (30–45 mg/kg/day); GI intolerance most common SE (mycophenolic acid may reduce); add plasmapheresis/IVIg if inadequate
• AZA: less expensive alternative; dose by TPMT level (generally 1–3 mg/kg/day; high TPMT 2.5–3 mg/kg/day; midrange 1–2.5 mg/kg/day; TPMT deficient — very low dose or different agent); start 50 mg/day first week to assess SEs; allopurinol interferes with AZA metabolism → toxicity risk
• Other steroid-sparing: IVIg (2 g/kg divided over 2–5 days monthly; IgA-deficient patients need IgA-depleted IVIg), immunoadsorption/plasmapheresis (rapid onset 1–2 weeks, good safety), cyclophosphamide (last resort — daily or pulse dosing with mesna rescue reduces bladder toxicity; early-day dosing + hydration; oral cyclophosphamide successful in 17/20 refractory patients, median remission 8.5 months, treatment duration 17 months; hematuria in 5, infections in 6, one bladder cancer 15 years post-therapy)
• Milder disease: dapsone, nicotinamide, tetracycline; methotrexate, cyclosporine, etanercept, infliximab used successfully in some; chlorambucil (hematologic malignancy risk); gold rarely used now (less effective, but no carcinogenicity/infertility risk, needs 6 months to judge); extracorporeal photochemotherapy in a few patients; platelet-rich plasma beneficial for refractory oral erosions in small study
• Emerging: CAR-T targeting pathogenic antibody-producing cells; ofatumumab, belimumab, veltuzumab (insufficient data); ALXN1830 (humanized IgG4 anti-neonatal Fc receptor) — rapid improvement in pilot study; efgartigimod (FcRn inhibitor) — efficacy in 34 patients with mild-moderate PV/PF; rilzabrutinib (BTK inhibitor) — efficacy/limited SEs in 27-patient trial; JAK inhibitors (tofacitinib) preclinical promise; dupilumab rare case reports; apremilast — keratinocyte stabilization, single case report benefit

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• Localized scalp plaques, or two classic forms: Neumann type (begins/ends as typical PV) and Hallopeau type (usually localized)
• Both show pseudoepitheliomatous hyperplasia; Hallopeau type has eosinophil microabscesses
• Begins as flaccid bullae → erosions → fungating vegetations/papillomatous proliferations, especially body folds/scalp; tongue often cerebriform early
• Verrucous plaques reported on scalp, finger, genitalia, soles, umbilicus, peristomal skin; rare post-surgical reports (C-section, Mohs)
• Same labs/etiology/epidemiology/pathogenesis/treatment as PV; desmocollin-3 antibodies reported in some (hypothesized to explain vegetans vs vulgaris phenotype difference); captopril-induced cases reported
• Differential: halogenoderma, chromoblastomycosis, blastomycosis, granuloma inguinale, blastomycosis-like pyoderma, condyloma lata, amebic granulomas; Hallopeau type distinguished by eosinophils, both types by IF

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• Flaccid bullae + localized/generalized exfoliation; antibodies target Dsg1
• Small flaccid bullae rupture almost immediately → crusting; moist bleeding-tendency surface beneath crust; Nikolsky easily elicited; exfoliative features eventually predominate; cornflake-like adherent scale crusts
• Herpetiform pemphigus: variant with DH-like clinical features but pemphigus immunology; pustular variant mistaken for subcorneal pustular dermatosis/IgA pemphigus/Sneddon-Wilkinson — most represent PF variant (remainder PV); some show desmocollin antibodies
• Oral lesions rare (superficial erosive stomatitis only); some patients shift clinically/serologically between PF and PV, or pemphigus to pemphigoid phenotype; rare single fixed facial/scalp lesion variant
• Most patients not severely ill; burning/pain/pruritus; persists years without health impact; ages 40–50, slight female predominance; much lower Jewish heritage prevalence than PV
• Endemic PF (fogo selvagem): primarily Brazil; HLA DRB1*04 most frequent allele in Brazilian study
• Drugs (more than PV): penicillamine, ACE inhibitors (captopril); rare biologic triggers; topical imiquimod, topical 5-FU, radiation therapy reported to induce; rare post-COVID infection/vaccination reports (believed rare given denominator)
• Histology: acantholysis in upper epidermis (granular layer); stratum corneum missing/separated; elongated acantholytic cells above epidermis or on stratum corneum underside
• DIF: intercellular IgG throughout epidermis, may be more prominent upper epidermis; IIF positive most patients (test wide dilution range for prozone); sensitive/specific ELISA for anti-Dsg1
• Cross-reactivity data: Western blot Dsg1 in ~86% PF, 25% PV; ELISA anti-Dsg1 up to 71% PF, 62% PV; anti-Dsg3 in 19/276 pure-cutaneous PF/fogo selvagem patients (pathogenic in animal models); ELISA must be interpreted with clinical/histologic/IF context; Dsg1 antigen: 260-kD complex of 160-kD (=Dsg1) + 85-kD (placoglobin) polypeptides; N-terminal extracellular domain dominant epitope in both PF/PV; IgG1 and IgG4 subclasses (IgG4 pathogenic in most, IgG1 in subset); E-cadherin autoantibodies often cross-react with Dsg1

• Similar to PV but generally less severe, may not need oral corticosteroids
• Dapsone, tetracycline-class antibiotics, hydroxychloroquine alone (mild) or steroid-sparing; very mild — topical corticosteroids/calcineurin inhibitors; nicotinamide/tetracycline may work better in PF than PV
• Guidelines often align PF management with PV; corticosteroids first-line (lower doses than PV) + AZA/MMF for tapering support
• Rituximab less dramatic data/effect than PV but first-line for severe/recalcitrant; IVIg efficacious; methotrexate, cyclophosphamide for severe cases; immunoadsorption promising adjuvant; efgartigimod helpful in pilot study; tocilizumab (anti-IL6R) and high-dose cyclophosphamide for refractory disease; case reports of IL-17 inhibitor-induced PF AND successful IL-17 inhibitor treatment of coexisting psoriasis+PF; TNF-inhibitor (etanercept) case reports
• HSV superinfection or S. aureus impetigo can mimic PF, consider in recalcitrant/flaring cases

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• Tropical regions: mostly interior Brazil, Colombia, also Peru, Paraguay, Venezuela; also North Africa (Tunisia); northern Spain area with PF > PV rates raises question of other endemic PF areas
• 15% familial; risk alleles: HLA-DRB1 *0404, *1402, *1406, *0102
• Common in children/adolescents/young adults: ~1/3 before age 20, 2/3 by age 40
• Initial flaccid bullae, later eczematoid/psoriasiform/impetiginous/seborrheic appearance; midfacial involvement; melanoderma, verrucous vegetative lesions, exfoliative dermatitis possible; mucous membranes usually spared; Nikolsky present
• Associated with arthropod exposure; possible infectious trigger via mosquitoes/sandflies/black flies/other vectors carrying molecular-mimicry-triggering molecules; 43.2-kD salivary protein of Lutzomyia sandfly cross-reactive with Dsg1 (Brazil); Phlebotomus papatasi salivary proteins implicated in Tunisia; epigenetics may play role
• Histologically/immunohistologically identical to PF; antibodies to desmosomal cadherins and E-cadherin may be present; also linked to kissing bug Triatoma matogrossensis and mercury poisoning; PBMCs produce more IL-1β than controls; strong Th2 bias; IgM anti-Dsg1 antibodies common in fogo selvagem (not other pemphigus forms)
• Distinct Colombian subset: shares immunoreactivity with paraneoplastic pemphigus (not malignancy-associated); resembles Senear-Usher syndrome clinically; systemic form affects internal organs, poorer prognosis; all have anti-Dsg1; many react with desmoplakin I, envoplakin, periplakin; DIF in pilosebaceous unit, neurovascular bundles, meibomian glands; mining region — high environmental mercuric sulfide/selenide exposure found in patient skin; unlike Brazilian form, no Dsg3 reactivity in Colombian sera (vs ~half of Brazilian sera)

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• Rare, overlap between LE and PF; possibly more common in Black patients
• Early lesions: circumscribed erythema/crusting resembling LE; positive lupus band in 80%
• Erythematous, thickly crusted, bullous, or hyperkeratotic lesions on nose/cheeks/ears (typical LE distribution); crusting/impetiginous lesions among bullae on scalp/chest/extremities; indolent course usually
• Drug-induced: penicillamine, captopril, propranolol, heroin, cefuroxime
• Histology as PF; DIF: IgG + complement at BOTH intercellular sites (pemphigus pattern) and BMZ (continuous granular, lupus pattern)
• ANA positive low titer in 30%; anti-Dsg1 (not Dsg3); may target BP230, periplakin
• Responds to low-dose prednisone/topical corticosteroids usually; one report responded to dupilumab; photoprotection essential; immunosuppressants for severe cases; associated with myasthenia/thymoma reports; evaluate all patients for systemic lupus features

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• Pathophysiology: Autoimmune intraepidermal blistering disease caused by IgG autoantibodies targeting Desmoglein 3 (mucosal-dominant) or Desmoglein 1 and 3 (mucocutaneous).
• Histopathology: Suprabasal Acantholysis (loss of keratinocyte cell-to-cell adhesion) leaving a single layer of basal cells attached to basement membrane ("Tombstone Pattern").
• Clinical Presentation:
• Oral Mucosal Erosions: Initial presentation in >80% of cases; painful, slow-healing oral erosions; precedes skin lesions by months.
• Cutaneous Bullae: Flaccid, thin-walled, fragile bullae on normal or erythematous skin → rupture easily leaving painful, bleeding, non-healing erosions.
• Positive Nikolsky Sign: Light lateral digital pressure on normal-appearing skin causes epidermal sloughing.
• Positive Asboe-Hansen Sign: Direct pressure on an intact bulla causes lateral extension of fluid.
• Immunofluorescence:
• Direct Immunofluorescence (DIF): Intraepidermal intercellular IgG and C3 deposition in a net-like or "chicken-wire" pattern.
• Indirect Immunofluorescence (IIF): Circulating anti-Dsg3/anti-Dsg1 IgG antibodies (titer correlates with disease activity).
• Pharmacotherapy:
• Rituximab (Anti-CD20 monoclonal antibody): First-line therapy combined with short-course systemic corticosteroids.
• Systemic Corticosteroids (Prednisone 1.0–1.5 mg/kg/day).
• Steroid-Sparing Immunosuppressants: Mycophenolate mofetil, Azathioprine, Cyclophosphamide, IVIG.

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• Pathophysiology: Autoimmune IgG autoantibodies targeting Desmoglein 1 ONLY.
• Histopathology: Subcorneal Acantholysis (cleavage within stratum granulosum).
• Clinical: ORAL MUCOSA IS CHARACTERISTICALLY SPARED (because Dsg3 compensates in mucosa). Superficial scaly, crusted, erythematous erosions in a seborrheic distribution (scalp, face, upper chest).
• Fogo Selvaggio: Endemic form of Pemphigus Foliaceus in rural Brazil transmitted by Simulium blackfly bites.