Skin & Subcutaneous Tissue

Pemphigus vulgaris: diagnosis and management

Clinical Overview and When to Suspect Pemphigus Vulgaris

— Peak onset ages 40–60, both sexes equally affected

— Increased prevalence in Ashkenazi Jewish, Mediterranean, Indian, and Middle Eastern populations

— Strong HLA association: HLA-DRB1\04:02 and HLA-DQB1\05:03

— Middle-aged adult with painful, non-healing oral erosions lasting weeks to months, often mistaken for aphthous ulcers or herpetic stomatitis

— Later development of flaccid cutaneous bullae on scalp, face, axillae, groin, trunk that rupture easily leaving denuded, weeping skin

— Lesions that fail to heal with topical antifungals, antivirals, or steroids prescribed empirically

— Significant pain out of proportion to visible lesions, dysphagia, odynophagia, weight loss

— Mucosal-dominant PV: anti-Dsg3 only → mouth/mucosa

— Mucocutaneous PV: anti-Dsg3 + anti-Dsg1 → mouth plus skin

— Dsg1 is concentrated in superficial epidermis (where pemphigus foliaceus acts); Dsg3 dominates deeper layers and mucosa — the "desmoglein compensation theory" explains why mucosa-only disease lacks anti-Dsg1.

— Thiol-containing drugs: penicillamine, captopril

— Non-thiol: rifampin, NSAIDs, β-blockers

Definition: Pemphigus vulgaris (PV) is an autoimmune intraepidermal blistering disease driven by IgG autoantibodies against desmoglein 3 (Dsg3) ± desmoglein 1 (Dsg1), causing acantholysis (loss of keratinocyte adhesion) and flaccid bullae that rupture into painful erosions.

Epidemiology:

When to suspect on Step 3:

Pathophysiology pearl:

Drug-induced triggers to remember:

Board pearl: In a Step 3 stem, a patient with ≥1 month of oral erosions plus new flaccid skin bullae that easily slough with lateral pressure should prompt biopsy for direct immunofluorescence (DIF) before empiric therapy — delayed diagnosis drives mortality from sepsis and protein-losing erosions.

Presentation Patterns and Key History

— Phase 1 (mucosal prodrome): 60–80% of patients begin with oral lesions preceding skin involvement by weeks to months. Buccal mucosa, palate, gingiva most common.

— Phase 2 (cutaneous spread): flaccid bullae arise on normal-appearing or erythematous skin, rupture within hours, leaving raw erosions with collarettes of epidermis.

— Duration of oral pain, ability to eat/drink, weight loss

— Prior misdiagnoses (recurrent "thrush," "cold sores," "canker sores")

— Drug history: ACE inhibitors, penicillamine, NSAIDs, antibiotics

— Hoarseness, dysphagia, ocular irritation, dysuria, dyspareunia → suggest laryngeal, esophageal, conjunctival, or genital mucosa involvement

— Family history of autoimmune disease; ethnic background

— Vaccination history (rarely a trigger)

— Mucosal-dominant PV: mouth ± pharynx, esophagus, conjunctiva, nasal, anogenital — minimal skin

— Mucocutaneous PV: above plus scalp, face (seborrheic distribution), upper chest, back, intertriginous folds

— Pain dominates over pruritus (contrast with bullous pemphigoid which is itchy)

— Patients often present malnourished, dehydrated, febrile from extensive erosions

— Body surface area (BSA) erosion >10%

— Inability to maintain oral intake

— Signs of secondary infection (cellulitis, sepsis)

Classic temporal pattern:

History questions that score points:

Distribution mapping:

Symptom severity clues:

Red flags requiring urgent workup:

Key distinction: Bullous pemphigoid affects elderly (>60s–70s), presents with tense, pruritic bullae on intact or urticarial skin, and rarely involves mucosa (only ~10–20%). PV is younger, flaccid bullae, mucosa-first, painful, not itchy.

Board pearl: A Step 3 vignette of a 50-year-old with 3 months of refractory oral ulcers misdiagnosed as aphthae, who now develops flaccid blisters on the trunk that wipe away with gentle rubbing, is PV until proven otherwise — order biopsy plus DIF, not empiric acyclovir.

Physical Exam Findings and Severity Assessment

— Flaccid bullae on normal or erythematous skin, thin-roofed, easily ruptured

— Erosions with epidermal collarettes, weeping serous fluid, crusting

— Lesions favor scalp, face, axillae, groin, trunk; palms/soles typically spared

— Healing without scarring but with post-inflammatory hyperpigmentation

— Buccal, palatal, gingival erosions — irregular, painful, slow-healing

— Desquamative gingivitis pattern

— Conjunctival hyperemia, erosions; nasal crusting, epistaxis; laryngeal hoarseness; esophageal odynophagia; vulvovaginal/penile erosions

— Nikolsky sign (positive): lateral pressure on perilesional skin shears the epidermis — reflects acantholysis. Present in PV, SJS/TEN, SSSS.

— Asboe-Hansen sign (bulla spread sign): pressure on an intact bulla extends it laterally into adjacent skin.

— Direct Nikolsky (rubbing normal-appearing skin) suggests active disease.

— PDAI (Pemphigus Disease Area Index) and ABSIS quantify skin, scalp, and mucosal involvement — used to track response.

— Document BSA involved, number of new lesions/day, mucosal sites.

— Vital signs: fever, tachycardia, hypotension → suggest sepsis from breached barrier

— Volume status: extensive erosions cause transepidermal fluid and protein loss mimicking burn physiology

— Weight loss, sarcopenia from poor oral intake

— Examine for secondary infection: purulent crust, surrounding erythema, lymphadenopathy

Skin findings:

Mucosal findings:

Provocative bedside signs:

Severity scoring:

Hemodynamic and systemic assessment:

Key distinction: Positive Nikolsky is not specific — also seen in SJS/TEN and staphylococcal scalded skin syndrome. Combine with mucosal involvement + flaccid bullae on non-erythrodermic skin + subacute timeline to favor PV.

Board pearl: A patient with >10% BSA eroded, fever, tachycardia, and hypoalbuminemia needs admission with burn-unit-style fluid, nutritional, and infection management — not outpatient prednisone alone.

Diagnostic Workup — Initial Labs and Biopsy Logistics

— Lesional biopsy for H&E: take from the edge of a fresh bulla or erosion including a rim of perilesional skin. Histology shows suprabasal acantholysis with intact basal keratinocytes lined up like a "row of tombstones" along the dermal-epidermal junction.

— Perilesional biopsy for direct immunofluorescence (DIF): take from normal-appearing skin within 1 cm of an active lesion, place in Michel's medium or saline (not formalin). DIF shows intercellular IgG and C3 in a "chicken wire" or "fishnet" pattern throughout the epidermis — the gold standard diagnostic finding.

— Indirect immunofluorescence (IIF) on monkey esophagus substrate: circulating IgG anti-intercellular antibodies

— ELISA for anti-Dsg3 and anti-Dsg1: quantitative, correlates with disease activity, useful for monitoring

— Anti-Dsg3 positive in mucosal-dominant PV; both Dsg3 + Dsg1 positive in mucocutaneous PV

— CBC with diff, CMP (glucose, renal, hepatic), albumin (often low)

— Hepatitis B (HBsAg, anti-HBc, anti-HBs), Hepatitis C, HIV — required before rituximab/high-dose steroids

— Quantiferon-TB Gold or PPD

— Lipid panel, fasting glucose/HbA1c, DEXA (baseline before chronic steroids)

— Pregnancy test in women of childbearing age

— TPMT or NUDT15 genotype if planning azathioprine

— G6PD level if considering dapsone

Step 1 — Confirm with skin biopsy (two specimens, two sites):

Step 2 — Serologic confirmation:

Step 3 — Baseline labs before immunosuppression:

CCS pearl: On a CCS case, after exam suggests PV, order: skin biopsy H&E + skin biopsy DIF + anti-Dsg3/Dsg1 ELISA + HBV/HCV/HIV + Quantiferon + CBC + CMP + glucose + DEXA. Do not start high-dose prednisone before drawing infection screen — reactivation of hepatitis B is a tested complication.

Board pearl: DIF of perilesional skin is the single most sensitive and specific test; H&E alone can be mimicked by Hailey-Hailey or Grover disease.

Diagnostic Workup — Advanced and Confirmatory Studies

— Anti-Dsg3 only → mucosal-dominant PV

— Anti-Dsg3 + anti-Dsg1 → mucocutaneous PV

— Anti-Dsg1 only → pemphigus foliaceus (no mucosal disease; superficial subcorneal bullae)

— Titers track disease activity and predict relapse; rising anti-Dsg3 during taper signals imminent flare

— Monkey esophagus — most sensitive for PV

— Normal human skin or salt-split skin — distinguishes pemphigoid (BMZ binding) from pemphigus (intercellular)

— Suprabasal acantholysis ("tombstones") → PV

— Subcorneal/granular layer acantholysis → pemphigus foliaceus or SSSS

— Subepidermal split with eosinophils → bullous pemphigoid

— Full-thickness epidermal necrosis → SJS/TEN

— Severe, refractory stomatitis extending to vermillion border, polymorphous skin lesions (lichenoid, EM-like, target lesions), and palmoplantar involvement

— Often associated with non-Hodgkin lymphoma, CLL, Castleman disease, thymoma

— Anti-plakin antibodies (envoplakin, periplakin, desmoplakins) on immunoblot

— IIF positive on rat bladder epithelium (specific for PNP)

— Order CT chest/abdomen/pelvis, peripheral smear, flow cytometry if PNP suspected

— Indicated for persistent dysphagia, odynophagia, hoarseness, or stridor to map esophageal/laryngeal involvement

— For conjunctival erosions, to prevent symblepharon and visual loss

Anti-desmoglein ELISA interpretation:

Indirect immunofluorescence substrates:

Histologic differential to recognize:

Paraneoplastic pemphigus (PNP) workup — when to suspect:

Endoscopy/laryngoscopy:

Ophthalmology referral:

Key distinction: PV with rat-bladder-positive IIF or anti-envoplakin → paraneoplastic pemphigus, not classic PV. PNP carries high mortality from bronchiolitis obliterans and demands oncologic workup.

Board pearl: Anti-Dsg3/Dsg1 ELISA is the best monitoring test during treatment — order it at baseline, at induction of remission, and during steroid taper to anticipate relapse.

Risk Stratification and First-Line Management Logic

— Limited/mild PV: isolated oral or limited cutaneous involvement, <5% BSA, PDAI low

— Moderate PV: more widespread mucocutaneous involvement, 5–15% BSA

— Severe/extensive PV: >15% BSA, multiple mucosal sites, systemic symptoms, weight loss

— Control phase: stop new lesion formation, existing lesions begin healing (typically 2–4 weeks)

— Consolidation phase: ~80% of lesions healed, no new lesions for ≥2 weeks → begin taper

— Maintenance phase: lowest effective dose to suppress disease

— Complete remission off therapy: no lesions for ≥2 months off all systemic treatment

— Rituximab + tapering prednisone is now first-line for moderate-to-severe PV

— Rituximab achieves higher rates of complete remission off therapy and lower cumulative steroid exposure than steroids + conventional immunosuppressants (Ritux 3 trial)

— Prednisone monotherapy (1 mg/kg/day) remains appropriate for mild disease or when rituximab is contraindicated

— Adjuvant steroid-sparing agents (azathioprine, mycophenolate mofetil) used when rituximab unavailable

— Outpatient management for stable, mild disease with good oral intake and no infection

— Admit for >10% BSA erosion, inability to maintain hydration/nutrition, suspected sepsis, or severe mucosal disease impairing airway/swallowing

Stratification by extent:

Treatment phases (standardized terminology):

First-line regimen — current standard (per 2020 international guidelines and updated AAD guidance):

Disposition logic:

Step 3 management: A 50-year-old with biopsy-confirmed PV, anti-Dsg3 positive, 8% BSA, oral and trunk lesions → start prednisone 1 mg/kg/day PO + schedule rituximab infusion (1 g IV on days 0 and 14) + initiate PJP and osteoporosis prophylaxis + screen HBV/HCV/TB before infusion.

Board pearl: Early rituximab + steroids beats steroid monotherapy for moderate-severe PV — fewer relapses, less cumulative prednisone, and better quality of life.

Pharmacotherapy — First-Line Drug Regimens

— Prednisone 1.0–1.5 mg/kg/day PO until control achieved, then taper

— Methylprednisolone IV pulse (500–1000 mg × 3 days) for severe/refractory disease

— Taper by ~25% every 2 weeks once consolidation reached, slowing below 20 mg/day

— Lymphoma protocol: 375 mg/m² IV weekly × 4 weeks, or

— Rheumatoid arthritis protocol: 1000 mg IV on days 0 and 14 (preferred per Ritux 3 trial)

— Repeat dosing at 6 and 12 months, then as needed based on Dsg3 titers and clinical relapse

— Pre-infusion screening: HBV (HBsAg, anti-HBc), HCV, HIV, TB, CBC, immunoglobulin levels

— Premedicate: acetaminophen, diphenhydramine, IV methylprednisolone

— Azathioprine 1–3 mg/kg/day — check TPMT activity first; risk of myelosuppression, hepatotoxicity, lymphoma

— Mycophenolate mofetil 2–3 g/day — GI side effects, teratogenic, requires REMS counseling

— Cyclophosphamide — reserved for refractory cases due to bladder cancer, infertility risk

— IVIG 2 g/kg/cycle monthly — for refractory, infected, or pregnant patients

— PJP prophylaxis (TMP-SMX) if prednisone ≥20 mg/day for >1 month

— Calcium 1200 mg + vitamin D 800–1000 IU daily

— Bisphosphonate if FRAX risk elevated or prednisone ≥7.5 mg/day for >3 months

— PPI for GI protection if on NSAIDs or high-dose steroids

— Glucose monitoring (steroid-induced diabetes)

— HBV antiviral prophylaxis (entecavir/tenofovir) if anti-HBc positive

— High-potency topical steroids (clobetasol) to localized lesions

— Dexamethasone or clobetasol oral rinses for stomatitis; topical lidocaine for analgesia

Systemic corticosteroids (induction backbone):

Rituximab (anti-CD20 monoclonal):

Steroid-sparing adjuvants (when rituximab unavailable/contraindicated):

Prophylaxis bundle on high-dose steroids/immunosuppression:

Topical adjuncts:

Step 3 management: Always order bone health, infection prophylaxis, and metabolic monitoring the same visit you start systemic steroids — Step 3 rewards bundled preventive care.

Supportive Care, Wound Management, and Refractory Therapy

— Gentle cleansing with saline or dilute chlorhexidine

— Non-adherent dressings (petrolatum gauze, silicone foam) over erosions

— Avoid adhesive tape directly on skin (induces Nikolsky)

— Daily wound assessment for infection; wound cultures if purulent

— Acetaminophen scheduled; opioids for severe mucocutaneous pain

— Magic mouthwash (diphenhydramine + lidocaine + Maalox ± dexamethasone) for oral pain

— Avoid NSAIDs (drug-induced pemphigus risk, GI toxicity with steroids)

— Soft, bland, high-protein, high-calorie diet

— Speech-swallow evaluation for dysphagia; consider NG or PEG if intake inadequate

— Replete albumin, zinc, vitamin D

— Skin and oral erosions colonize with S. aureus, streptococci, Candida, HSV

— Empiric antistaphylococcal coverage (cephalexin, TMP-SMX) for cellulitis; acyclovir if HSV suspected on Tzanck/PCR

— Topical mupirocin to limited areas

— Repeat rituximab cycle

— IVIG 2 g/kg monthly

— Immunoadsorption or plasmapheresis (rapidly lowers Dsg3 antibody load) — typically bridged with rituximab

— Cyclophosphamide pulse in severe/PNP cases

— Emerging: rilzabrutinib (BTK inhibitor), efgartigimod (FcRn antagonist) — investigational

— Administer inactivated vaccines (influenza, pneumococcal PCV20, Tdap, recombinant zoster, COVID-19) before rituximab when possible (B-cell depletion blunts response for 6+ months)

— Avoid live vaccines (MMR, varicella, yellow fever, live zoster) during immunosuppression

Wound and skin care (treat like partial-thickness burns):

Pain control:

Nutrition:

Infection surveillance:

Refractory or relapsing disease — escalation ladder:

Vaccination strategy:

CCS pearl: In severe PV with >20% BSA erosion and sepsis physiology, admit to burn unit or ICU, order blood/wound cultures, broad-spectrum antibiotics, IV fluids, IV methylprednisolone pulse, dermatology consult, and arrange rituximab once infection controlled.

Special Populations — Elderly and Renal/Hepatic Impairment

— Comorbid diabetes, osteoporosis, hypertension, cataracts, glaucoma, infection susceptibility amplify steroid toxicity

— Consider lower starting prednisone (0.5–0.75 mg/kg/day) combined with early rituximab to minimize cumulative steroid exposure

— Higher risk of steroid-induced delirium, psychosis, myopathy, hyperglycemia

— Aggressive fall prevention, bone health (DEXA + bisphosphonate), glucose monitoring

— Screen for latent TB, HBV reactivation, strongyloides (if exposure) before immunosuppression

— Discontinue potential drug-induced pemphigus triggers: penicillamine, captopril, enalapril, rifampin, NSAIDs

— Adjust diabetic, antihypertensive regimens for steroid-induced changes

— Azathioprine: no dose adjustment by GFR, but monitor CBC closely

— Mycophenolate: no renal adjustment but increased GI toxicity in CKD

— Cyclophosphamide: reduce dose if CrCl <50; hemorrhagic cystitis risk — give with mesna and aggressive hydration

— Rituximab: no renal dose adjustment; monitor for infusion reactions

— Steroids worsen fluid retention, hypertension, hyperkalemia indirectly via mineralocorticoid effect — favor prednisone over hydrocortisone

— Azathioprine and methotrexate hepatotoxic — avoid or use cautiously with LFT monitoring

— Mycophenolate generally safer hepatically

— Check HBV serologies and HCV before any immunosuppression; treat chronic HBV with entecavir/tenofovir prophylactically if anti-HBc positive to prevent reactivation

— In very frail elderly, IVIG monotherapy may be preferred (lower infection risk, no marrow toxicity) despite higher cost

Elderly patients (>65):

Polypharmacy review:

Chronic kidney disease:

Hepatic impairment:

Frailty and goals of care:

Step 3 management: A 78-year-old with PV, diabetes, osteoporosis, and CKD stage 3 → prefer rituximab + low-dose prednisone (0.5 mg/kg) rather than high-dose steroid monotherapy, with TB/HBV screen, bisphosphonate, calcium/vitamin D, glucose log, and PJP prophylaxis bundled at the same visit.

Board pearl: In the elderly, cumulative steroid dose is the strongest predictor of mortality in PV — rituximab is steroid-sparing and life-prolonging.

Special Populations — Pregnancy and Pediatric Considerations

— Rare but reported; disease often flares during pregnancy (especially first/second trimester) and postpartum

— Transplacental IgG transfer can cause neonatal pemphigus — transient flaccid bullae in newborn, resolves over weeks as maternal IgG clears

— Maternal complications: preterm birth, low birth weight, intrauterine growth restriction

— Prednisone/prednisolone — first-line; placental 11β-HSD2 inactivates most maternal cortisol; use lowest effective dose; risk of gestational diabetes, hypertension, preterm rupture of membranes

— IVIG — safe and effective adjunct

— Azathioprine — Category D historically but used in pregnancy (transplant data); fetal liver lacks the enzyme to convert it to active 6-MP, providing some protection

— Methotrexate (teratogenic, abortifacient)

— Mycophenolate mofetil (REMS, contraception required, first-trimester loss, congenital malformations — facial clefts, ear anomalies)

— Cyclophosphamide (teratogenic, gonadotoxic)

— Rituximab preferably avoided in 2nd/3rd trimester (fetal B-cell depletion); if used, delay live vaccines in infant for 6 months

— Prednisone <20 mg/day compatible; time feeds 4 hours after dose if higher

— IVIG compatible

— Azathioprine generally considered compatible

— Examine newborn for bullae; supportive care, gentle skin handling, monitor for infection

— Spontaneous resolution within 2–3 weeks

— Similar mucocutaneous presentation; consider PNP if very young child with associated lymphoma

— Same diagnostic workup; rituximab + prednisone effective

— Watch growth velocity, bone age, adrenal axis on chronic steroids

Pemphigus vulgaris in pregnancy:

Safe medications in pregnancy:

Avoid in pregnancy:

Breastfeeding:

Neonatal management:

Pediatric PV (rare):

Key distinction: Pemphigoid gestationis (PG, formerly herpes gestationis) presents in 2nd/3rd trimester with pruritic urticarial plaques and tense bullae starting periumbilically — anti-BP180, subepidermal split. PG ≠ PV.

Board pearl: A pregnant patient with new oral and skin erosions and positive anti-Dsg3 should be co-managed with maternal-fetal medicine and dermatology, treated with prednisone ± IVIG, and the neonate examined at delivery for transient bullae.

Complications and Adverse Outcomes

— Sepsis from breached skin/mucosal barrier — leading cause of PV mortality (5–10% overall)

— Dehydration and electrolyte derangement from transepidermal fluid loss

— Protein-losing dermopathy → hypoalbuminemia, edema

— Malnutrition from oral/esophageal involvement

— Esophageal strictures from chronic mucosal disease

— Laryngeal involvement → airway compromise, stridor

— Ocular scarring (symblepharon) with vision loss

— Genital scarring, dyspareunia, urethral stricture

— Metabolic: hyperglycemia/diabetes, hypertension, weight gain, dyslipidemia

— Bone: osteoporosis, vertebral fractures, avascular necrosis of femoral head

— GI: peptic ulcer disease, pancreatitis

— Ocular: cataracts, glaucoma

— CNS: insomnia, mood swings, steroid psychosis

— Skin: striae, atrophy, purpura, acneiform eruption

— Adrenal: HPA axis suppression → adrenal crisis with abrupt discontinuation

— Infection: opportunistic infections (PJP, candidiasis, reactivation TB/HBV/HSV/VZV)

— Infusion reactions (fever, chills, hypotension) — premedicate

— Hypogammaglobulinemia with repeated cycles → recurrent infections

— Hepatitis B reactivation (boxed warning)

— Progressive multifocal leukoencephalopathy (PML) — rare but devastating; new neurologic symptoms warrant urgent MRI and JC virus PCR

— Late-onset neutropenia

— Cytopenias, hepatotoxicity, increased malignancy risk (lymphoma, NMSC), infertility (cyclophosphamide), hemorrhagic cystitis (cyclophosphamide)

Disease-related complications:

Treatment-related complications — corticosteroids:

Rituximab adverse effects:

Azathioprine/MMF/cyclophosphamide:

Step 3 management: A PV patient on prednisone 60 mg/day for 8 weeks with new fever, dry cough, dyspnea, hypoxemia → suspect Pneumocystis jirovecii pneumonia — order CXR/CT, LDH, induced sputum or BAL for PJP, start TMP-SMX empirically, ensure PJP prophylaxis was prescribed (and chart it for future patients).

Board pearl: New neurologic deficits in a PV patient on rituximab = rule out PML with brain MRI and CSF JC virus PCR.

When to Escalate Care — Admission, Consults, and ICU

— Mild disease (<5% BSA), oral intake intact, no infection, social support adequate

— Patient capable of wound care and follow-up

— BSA erosion >10% or rapidly progressing

— Inability to maintain oral hydration/nutrition (severe stomatitis, esophageal involvement)

— Suspected sepsis (fever, tachycardia, hypotension, leukocytosis)

— Hemodynamic instability or electrolyte abnormalities

— Newly diagnosed severe PV requiring IV methylprednisolone pulse or rituximab initiation

— Refractory disease needing plasmapheresis/immunoadsorption

— Failed outpatient therapy or inadequate adherence

— Septic shock, respiratory failure, airway compromise from laryngeal involvement

— >20% BSA erosion with fluid/electrolyte derangements mirroring burn physiology

— Need for invasive monitoring or vasopressors

— Dermatology — diagnostic confirmation, biopsy, treatment guidance

— Ophthalmology — any ocular symptom or conjunctival lesion to prevent symblepharon

— ENT/laryngoscopy — hoarseness, stridor, odynophagia

— Gastroenterology — persistent dysphagia, suspected esophageal involvement

— Dentistry/oral medicine — gingival hygiene during oral disease (gentle care, no aggressive scaling)

— Nutrition/dietitian — caloric needs, supplementation

— Infectious disease — pre-rituximab screening review, opportunistic infection workup

— Endocrinology — steroid-induced diabetes, adrenal axis

— OB/MFM — pregnant patients

— Hematology/oncology — if paraneoplastic pemphigus suspected

— Stable vitals, controlled pain, oral intake adequate, no new bullae for ≥48 hours, wound care plan in place, follow-up scheduled, prescriptions filled

Outpatient management is appropriate when:

Admit for inpatient management when:

ICU / burn unit transfer triggers:

Consultations to order on a CCS case:

Discharge readiness criteria:

CCS pearl: In a severe PV CCS case, the order set should include: IV access, IVF resuscitation, dermatology + ophthalmology consults, IV methylprednisolone, rituximab planning, wound care, nutrition, PJP prophylaxis, glucose checks, DVT prophylaxis, and HBV screening.

Key Differentials — Same-Category (Autoimmune Blistering)

— Elderly (>60–70), tense, pruritic bullae on urticarial/erythematous base; mucosa usually spared

— Anti-BP180 (BPAG2) and BP230 antibodies; subepidermal split on H&E; linear IgG and C3 at BMZ on DIF; binds roof of salt-split skin

— Superficial scaly erosions on scalp, face, chest (seborrheic distribution); no mucosal involvement

— Anti-Dsg1 only; subcorneal/granular acantholysis; "cornflake" scale

— Fogo selvagem = endemic Brazilian PF

— Severe stomatitis, polymorphous lesions (lichenoid, EM-like, target), palmoplantar involvement

— Anti-plakins, rat bladder IIF positive; associated with NHL, CLL, Castleman disease, thymoma

— High mortality from bronchiolitis obliterans

— Pustular eruption; intercellular IgA on DIF; subcorneal or intraepidermal pustules

— Tense annular bullae in "string of pearls" pattern; linear IgA at BMZ; can be drug-induced (vancomycin classic trigger)

— Pruritic grouped vesicles on extensor surfaces; granular IgA at dermal papillae; gluten-sensitive enteropathy association; treat with dapsone + gluten-free diet

— Tense bullae on trauma-prone sites; anti-type VII collagen; binds floor of salt-split skin

— Predominant mucosal involvement (oral, ocular with symblepharon, genital, esophageal); scarring; multiple BMZ antigens

— Suprabasal split + intercellular IgG ("fishnet") = pemphigus

— Subepidermal split + linear IgG/C3 at BMZ = pemphigoid family

— Mucosa-dominant + flaccid + Dsg3 = PV

— No mucosa + superficial + Dsg1 = PF

Bullous pemphigoid (BP):

Pemphigus foliaceus (PF):

Paraneoplastic pemphigus (PNP):

IgA pemphigus:

Linear IgA bullous dermatosis:

Dermatitis herpetiformis (DH):

Epidermolysis bullosa acquisita (EBA):

Mucous membrane pemphigoid (MMP):

Key distinction summary:

Board pearl: Distinguishing PV from BP on a Step 3 vignette hinges on age (younger vs elderly), bulla type (flaccid vs tense), pruritus (no vs yes), mucosa (yes vs rarely), and DIF pattern (intercellular vs linear BMZ).

Key Differentials — Other-Category Causes

— Drug-triggered (sulfa, anticonvulsants, allopurinol, NSAIDs); abrupt onset within 1–3 weeks of exposure

— Fever, mucositis (oral, ocular, genital), target lesions, dusky erythema, full-thickness epidermal sloughing, positive Nikolsky

— Histology: full-thickness epidermal necrosis (vs PV's suprabasal split)

— Treat with drug withdrawal, supportive burn care; PV-specific therapy not appropriate

— Mostly young children; exfoliative toxin from S. aureus cleaves Dsg1

— Diffuse erythema, superficial peeling, perioral crusting, no mucosal involvement

— Treat with antistaphylococcal antibiotics

— Targetoid lesions on extremities/palms, mucosal erosions; HSV or Mycoplasma trigger

— Less extensive than SJS

— Grouped vesicles on erythematous base; Tzanck smear with multinucleated giant cells; HSV PCR positive; responds to acyclovir

— Small (<1 cm), round, painful ulcers on non-keratinized mucosa; self-limited 7–14 days; no skin lesions, no positive Nikolsky

— Recurrent oral + genital ulcers, uveitis, pathergy; meets International Study Group criteria; HLA-B51

— Wickham striae (reticular white lines), purple pruritic papules on skin; can erode mucosa

— Histology: band-like lymphocytic infiltrate, sawtooth rete ridges

Stevens-Johnson syndrome / Toxic epidermal necrolysis (SJS/TEN):

Staphylococcal scalded skin syndrome (SSSS):

Erythema multiforme major:

Herpetic gingivostomatitis / recurrent HSV:

Aphthous stomatitis (recurrent canker sores):

Behçet disease:

Lichen planus (erosive/mucosal):

Pemphigoid gestationis: as above (pregnancy-specific)

Burns / chemical injury: appropriate history, distribution

Acute graft-versus-host disease: post-transplant timing, GI/hepatic involvement

Drug-induced linear IgA / drug-induced pemphigus: review medications

Key distinction: SJS/TEN onset is acute (days), drug-related, with full-thickness necrosis; PV onset is subacute-chronic (weeks-months), autoimmune, with suprabasal acantholysis — biopsy resolves the question.

Board pearl: Any patient with >30% BSA detachment = TEN, not PV — admit to burn unit, stop offending drug, supportive care; do not give steroids reflexively.

Secondary Prevention, Discharge Medications, and Long-Term Plan

— Prednisone at induction dose with written taper schedule

— Rituximab infusion scheduled (days 0 and 14) if not yet given

— PJP prophylaxis (TMP-SMX SS daily or DS 3×/week) while on prednisone ≥20 mg/day or after rituximab

— Calcium 1200 mg + vitamin D 800–1000 IU daily

— Bisphosphonate (alendronate 70 mg weekly) if elevated fracture risk or steroids ≥7.5 mg/day projected >3 months

— PPI if NSAID co-use or steroid-related GI risk

— Antihypertensive/diabetic regimen adjustment as needed

— HBV antiviral prophylaxis if anti-HBc positive (entecavir or tenofovir)

— Topical clobetasol oral rinse or gel for residual oral lesions

— Magic mouthwash PRN

— Reduce by ~20–25% every 2 weeks once consolidation phase reached

— Slow taper below 20 mg/day (5 mg every 2–4 weeks)

— Below 10 mg/day, taper by 1–2.5 mg every 2–4 weeks

— Avoid abrupt cessation — risk of adrenal insufficiency; consider AM cortisol check before stopping

— Avoid trigger drugs (penicillamine, captopril, rifampin, NSAIDs when possible)

— Sun protection (UV can trigger flares)

— Soft toothbrush, gentle oral hygiene, avoid hard/spicy/acidic foods during active disease

— Smoking cessation, alcohol moderation

— Vaccinations: annual influenza (inactivated), pneumococcal PCV20, Tdap, recombinant zoster (Shingrix), COVID-19, HBV if non-immune — ideally before rituximab

— Avoid live vaccines while immunosuppressed

— Most patients require maintenance therapy for years

— Rituximab redosing at 6 and 12 months, then guided by clinical status and anti-Dsg3 titers

— Discuss realistic expectation of remission (50–75% achieve complete remission off therapy with rituximab-based regimens)

Discharge medication checklist:

Steroid taper principles:

Lifestyle and counseling:

Long-term plan:

Step 3 management: Discharge order set must include taper schedule, PJP/bone/HBV prophylaxis, vaccinations addressed, dermatology follow-up within 2–4 weeks, and patient education on infection precautions.

Follow-Up, Monitoring, and Counseling

— Week 2–4 after discharge: dermatology — assess lesion healing, taper progress, side effects

— Monthly during induction phase until consolidation

— Every 3 months during maintenance, extending to every 6 months in stable remission

— Primary care follow-up between dermatology visits for steroid/immunosuppressant monitoring

— Every 2–4 weeks initially: CBC, CMP (glucose, K, creatinine, LFTs)

— Anti-Dsg3 and anti-Dsg1 titers every 3 months; rising titer predicts relapse

— HbA1c every 3 months while on steroids

— Lipid panel annually

— DEXA baseline and every 1–2 years on chronic steroids

— HBV DNA every 3 months if anti-HBc positive on rituximab

— Immunoglobulin levels before each rituximab cycle (watch for hypogammaglobulinemia)

— Annual TB screening if ongoing immunosuppression

— Age-appropriate screening (mammography, colonoscopy, cervical, lung in eligible)

— Heightened skin cancer surveillance (annual full-skin exam) given immunosuppression

— Lymphoma vigilance with chronic azathioprine

— Annual ophthalmology (cataract, glaucoma screening)

— Dental exam every 6 months with attention to gingival health

— Rehabilitation referrals if deconditioned

— Recognize early signs of flare (new oral lesion, blister) → call promptly

— Recognize infection signs (fever, cough, dysuria, new skin warmth) → seek care

— Never stop steroids abruptly; carry medical alert (adrenal insufficiency risk during stress/illness/surgery)

— Stress-dose steroids for major illness or surgery

— Mental health support — chronic disease and steroid effects raise depression/anxiety risk

— Support groups (International Pemphigus & Pemphigoid Foundation)

Follow-up cadence:

Lab monitoring schedule:

Cancer surveillance:

Eye, dental, and bone follow-up:

Patient counseling pillars:

Step 3 management: Order anti-Dsg3 titer at 3 months as the most efficient single test to anticipate relapse before clinical recurrence — escalate therapy or restart rituximab if titers climb.

Board pearl: Rising anti-Dsg3 with stable clinical exam often precedes relapse by weeks — act early rather than waiting for new bullae.

Ethical, Legal, and Patient Safety Considerations

— Document discussion of infection risk (PJP, sepsis, HBV reactivation), PML, hypogammaglobulinemia, infusion reactions, malignancy risk, off-label use (though now FDA-approved for PV since 2018)

— Ensure patient understands need for lifelong vigilance about infections and vaccinations

— In women of childbearing age on MMF, document REMS counseling, two forms of contraception, and pregnancy testing; contraception continued for 6 weeks after MMF and 12 months after rituximab

— Steroid taper miscommunication between inpatient and outpatient teams is a major source of error — provide a written, dated taper schedule at discharge with explicit instructions and PCP notification

— Medication reconciliation at every transition — patients on prednisone, PJP prophylaxis, bisphosphonate, PPI, antihypertensives, insulin must have each medication addressed

— Adrenal insufficiency risk if steroids stopped abruptly during care transitions — issue medical alert bracelet and stress-dose plan

— Live vaccines contraindicated; document review of vaccine status before starting rituximab to avoid missed opportunity

— If thiol drug (penicillamine, captopril) triggered disease, document discontinuation and adverse drug reaction reporting (FDA MedWatch); update allergy list

— MMF/methotrexate/cyclophosphamide require contraception counseling; ethical duty to disclose teratogenic risk and document refusal/acceptance

— Reactivated TB or new HIV diagnosis on screening → report per state law

— HBV reactivation → no mandatory reporting but engage hepatology

— Frail elderly patient may decline aggressive immunosuppression; respect autonomy after capacity assessment; offer palliative-leaning regimens (lower-dose steroids, IVIG, supportive wound care)

— HBV/HCV/HIV/TB screening, vaccine update, contraception counseling, infection education, written taper, follow-up scheduled — Step 3 expects all six addressed before discharge.

Informed consent for rituximab and immunosuppression:

Transition-of-care safety risks (Step 3 high-yield):

Vaccine timing safety:

Drug-induced pemphigus disclosure:

Pregnancy and teratogenicity:

Mandatory reporting and public health:

Capacity, autonomy, and shared decision-making:

Patient safety bundle when initiating immunosuppression:

Board pearl: A handoff that omits the steroid taper schedule or PJP prophylaxis is a tested patient-safety failure on Step 3 — always document both explicitly.

High-Yield Associations and Rapid-Fire Clinical Facts

Target antigens: Dsg3 (mucosa, deep epidermis) and Dsg1 (superficial epidermis)

HLA associations: HLA-DRB1\04:02, HLA-DQB1\05:03; Ashkenazi Jewish predilection

Histology: Suprabasal acantholysis, "row of tombstones" basal keratinocytes

DIF: Intercellular IgG and C3 — "chicken wire" / "fishnet" pattern

IIF substrate of choice: Monkey esophagus

Best monitoring serology: Anti-Dsg3 ELISA titer

Nikolsky sign: Positive — also positive in SJS/TEN, SSSS; negative in BP

Asboe-Hansen sign: Lateral bulla extension with pressure

First-line therapy (moderate-severe): Rituximab + prednisone (Ritux 3 trial, 2017; AAD/international 2020 guidelines)

Rituximab dosing for PV: 1 g IV × 2 doses 2 weeks apart (RA protocol); FDA-approved for PV in 2018

Pre-rituximab screening: HBV, HCV, HIV, TB, immunoglobulins, vaccinations

PJP prophylaxis threshold: Prednisone ≥20 mg/day for ≥1 month

Bone prophylaxis threshold: Steroids ≥7.5 mg/day projected >3 months

Mortality drivers: Sepsis, complications of immunosuppression, cardiovascular events from chronic steroids

Drug triggers: Penicillamine (highest risk), captopril, enalapril, rifampin, NSAIDs, β-blockers

PNP red flags: Severe stomatitis crossing vermillion, polymorphous lesions, palmoplantar involvement, association with CLL, NHL, Castleman, thymoma, anti-plakin antibodies, rat bladder IIF positive, bronchiolitis obliterans

Pemphigoid contrast: Elderly, tense, pruritic, mucosa-sparing, anti-BP180/230, subepidermal split, linear IgG/C3 at BMZ

Pemphigus foliaceus: Superficial scaly erosions, no mucosa, anti-Dsg1 only

Pregnancy: Prednisone, IVIG, azathioprine relatively safe; avoid MMF, methotrexate, cyclophosphamide

Neonatal pemphigus: Transient, from transplacental IgG, resolves in weeks

Vaccination rule: Inactivated vaccines BEFORE rituximab; no live vaccines during immunosuppression

Key distinction: PV = flaccid, painful, mucosa-first, suprabasal, intercellular IgG, anti-Dsg3. Memorize this six-pack and most PV stems collapse to the diagnosis instantly.

Board pearl: If a stem mentions Ashkenazi heritage + chronic oral erosions + new flaccid blisters, the answer pathway is biopsy + DIF + anti-Dsg3 → prednisone + rituximab + prophylaxis bundle.

Board Question Stem Patterns

Stem 1 — Diagnostic: 48-year-old Ashkenazi Jewish woman with 3 months of painful oral erosions misdiagnosed as aphthae, now with flaccid bullae on trunk that rupture easily. Best next step? → Skin biopsy of perilesional skin for direct immunofluorescence (and lesional for H&E).

Stem 2 — DIF pattern recognition: Biopsy shows intercellular IgG and C3 deposition in a fishnet pattern throughout the epidermis. Most likely diagnosis? → Pemphigus vulgaris.

Stem 3 — Histology recognition: Skin biopsy shows suprabasal cleft with basal keratinocytes adherent to BMZ in a "row of tombstones." → Pemphigus vulgaris.

Stem 4 — Antibody: Patient with mucosal-only PV → anti-Dsg3 antibodies; if skin involvement added → anti-Dsg3 plus anti-Dsg1.

Stem 5 — First-line therapy: Biopsy-confirmed moderate PV in 45-year-old → Prednisone + rituximab is correct over prednisone alone (Ritux 3 data).

Stem 6 — Pre-treatment screening: Before starting rituximab, next step? → Hepatitis B and C, HIV, TB testing, and vaccination update.

Stem 7 — Adverse event: PV patient on prednisone 60 mg/day for 6 weeks presents with fever, dry cough, dyspnea, hypoxia, bilateral interstitial infiltrates → Pneumocystis jirovecii pneumonia → TMP-SMX; ensure PJP prophylaxis on discharge.

Stem 8 — Drug trigger: Patient on penicillamine for Wilson disease develops flaccid bullae and oral erosions → drug-induced pemphigus; stop penicillamine first.

Stem 9 — Differential: Elderly patient with tense, pruritic bullae on erythematous base, no mucosal involvement → bullous pemphigoid, not PV; anti-BP180, subepidermal split, linear IgG/C3 at BMZ.

Stem 10 — Paraneoplastic clue: Patient with severe stomatitis extending to lip vermillion, polymorphous lichenoid skin lesions, palmar lesions, and CLL → paraneoplastic pemphigus; order rat bladder IIF and anti-envoplakin antibodies, CT chest/abdomen/pelvis.

Stem 11 — Monitoring: PV patient in clinical remission on tapering prednisone with rising anti-Dsg3 titer → anticipate relapse; consider repeating rituximab or slowing taper.

Stem 12 — Pregnancy: Pregnant patient with PV → prednisone (low effective dose) ± IVIG; avoid MMF, methotrexate, cyclophosphamide.

Stem 13 — Newborn exam: Newborn of mother with PV with flaccid blisters → transient neonatal pemphigus; supportive care, resolves in weeks.

Board pearl: Step 3 stems often test what to order before starting rituximab (HBV/HCV/HIV/TB + vaccines) and what prophylaxis to bundle with steroids (PJP, bone, glucose, HBV antiviral).

One-Line Recap

Pemphigus vulgaris is an IgG-mediated intraepidermal blistering disease against desmogleins 3 (± 1) that presents with painful mucosal erosions followed by flaccid skin bullae, diagnosed by perilesional-skin DIF showing intercellular "fishnet" IgG/C3 plus anti-Dsg3 ELISA, and treated with rituximab plus tapering prednisone alongside a bundled prophylaxis strategy.

— Clinical: mucosa-first, flaccid bullae, painful, positive Nikolsky, middle-aged adult (often Ashkenazi Jewish)

— Histology: suprabasal acantholysis with "row of tombstones"

— Immunology: DIF intercellular IgG/C3 ("fishnet") + serum anti-Dsg3 (± anti-Dsg1) ELISA

— Induction: prednisone 1 mg/kg/day + rituximab 1 g IV days 0 and 14 (first-line per Ritux 3 / 2020 guidelines / FDA approval 2018)

— Pre-treatment safety screen: HBV, HCV, HIV, TB, immunoglobulins, vaccinations (inactivated, before rituximab; no live vaccines)

— Prophylaxis bundle: PJP (TMP-SMX), calcium/vitamin D + bisphosphonate, PPI if indicated, glucose monitoring, HBV antiviral if anti-HBc positive

— Clinical: PDAI/ABSIS, new lesion count, mucosal mapping

— Serologic: anti-Dsg3 titer every 3 months — rising titer predicts relapse

— Safety: CBC, CMP, HbA1c, DEXA, immunoglobulins, infection vigilance

— PV vs BP: flaccid + mucosal + suprabasal + intercellular IgG vs tense + pruritic + elderly + subepidermal + linear BMZ IgG

— PV vs SJS/TEN: subacute autoimmune vs acute drug-induced full-thickness necrosis

— PV vs PNP: classic vs severe stomatitis + polymorphous lesions + underlying lymphoproliferative malignancy

Diagnostic triad to memorize:

Therapeutic triad to memorize:

Monitoring triad:

Differential anchors:

Board pearl: Master the flaccid + mucosa-first + Dsg3 + fishnet + rituximab + steroid taper + prophylaxis bundle chain, and every Step 3 PV vignette becomes a guided walkthrough rather than a guess.