Classification of Intraepidermal Immunobullous Diseases

A. Pemphigus Group

B. IgA Pemphigus

Management of Pemphigus Vulgaris — 10 Marks

Introduction

Pemphigus vulgaris: (A) Flaccid bullae & erosions on trunk, (B) Oral mucosal erosions, (C) H&E showing suprabasal acantholysis — "tombstone row" of basal keratinocytes

1. Assessment Before Treatment

• Disease severity scoring: Pemphigus Disease Area Index (PDAI) or Autoimmune Bullous Skin disorder Intensity Score (ABSIS)
• Baseline investigations: CBC, LFT, RFT, blood glucose, urine for cyclophosphamide users, hepatitis B/C serology, quantitative anti-Dsg3/Dsg1 ELISA titers, chest X-ray, bone densitometry
• TPMT enzyme assay before azathioprine initiation

2. General/Supportive Measures

• Wound care: non-adherent dressings, topical antiseptics (dilute potassium permanganate soaks), Vaseline gauze to raw areas
• Oral care: antiseptic mouthwashes (chlorhexidine), viscous lignocaine for pain relief
• Nutritional support: high-protein diet; nasogastric feeding if severe oral involvement precludes eating
• Prevention of secondary infection: systemic antibiotics when superinfection occurs
• Avoid triggering drugs (ACE inhibitors, NSAIDs, thiol-containing drugs) and trauma

3. First-Line: Systemic Corticosteroids

• Oral prednisolone: 1 mg/kg/day (usually 60–100 mg/day) as starting dose
• Continue until no new lesions for ≥2 weeks and >80% of existing lesions healed
• Then taper slowly (by 25% every 4–6 weeks) to a maintenance dose (~5–10 mg/day)
• Pulse methylprednisolone (1 g/day IV for 3–5 consecutive days) is reserved for severe, rapidly progressive disease

4. Adjuvant Steroid-Sparing Immunosuppressants

5. Rituximab (B-Cell Depletion Therapy)

• Lymphoma protocol: 375 mg/m² IV once weekly × 4 doses; may repeat every 3–6 months
• Rheumatoid arthritis protocol: 1 g IV initially, then 1 g at 2 weeks (preferred in recent practice)

⚠️ Recent evidence update (2025): A systematic review and meta-analysis (PMID 40787442) confirmed that low-dose rituximab is efficacious and safe in pemphigus, supporting its use in resource-limited settings.

6. Third-Line / Rescue Therapies

High-Dose Intravenous Immunoglobulin (IVIg)

• Dose: 400 mg/kg/day for 5 consecutive days; may be repeated monthly
• Mechanism: Accelerates clearance of pathogenic IgG via Fc receptor saturation; provides anti-idiotypic antibodies; immunomodulatory
• Indication: Steroid-resistant/refractory PV; useful when immunosuppression is contraindicated (pregnancy, active infection)
• Evidence: Multicenter randomized placebo-controlled trial demonstrated safety and efficacy

Plasmapheresis / Immunoadsorption

• Rapidly reduces circulating autoantibody titers
• Useful in severe acute PV with high antibody titers
• Must be combined with immunosuppression (prednisolone + cyclophosphamide) to prevent post-pheresis autoantibody rebound
• 1–2 sessions per week initially

Extracorporeal Photopheresis

• 2 days per month
• Reserved for refractory cases

7. Topical Therapy (Adjunctive)

• Topical Class I corticosteroids (clobetasol propionate): for localized persistent lesions
• Topical antibiotics: prevent secondary infection
• Topical immunomodulators: cyclosporine mouthwash for oral lesions, tacrolimus ointment for localized disease
• Intralesional corticosteroids: for persistent isolated lesions
• Intralesional rituximab (5 mg/cm²): investigational for refractory localized lesions

8. Monitoring and Disease Activity Assessment

• Clinical: number of new blisters/erosions, mucosal activity (PDAI score)
• Serological: quantitative anti-Dsg3 and anti-Dsg1 ELISA — titers correlate with disease activity
• Monitor for side effects: blood glucose, blood pressure, weight, bone density (DEXA scan), ophthalmology review (cataract, glaucoma screening with long-term steroids)
• Prophylaxis during immunosuppression:
  • PCP prophylaxis: co-trimoxazole
  • Pneumococcal, influenza vaccines (before starting immunosuppression)
  • Calcium + Vitamin D + bisphosphonate for corticosteroid-induced osteoporosis prevention
  • PPI for GI protection

9. Defining Remission and Endpoint

• Complete remission on therapy: No new lesions for ≥2 months while on minimal therapy (≤10 mg/day prednisone)
• Complete remission off therapy: No new lesions for ≥2 months after discontinuation of all therapy
• Continue monitoring anti-Dsg titers even after clinical remission — rising titers predict relapse

10. Management Summary (Therapeutic Ladder)

MILD-MODERATE PV
  → Prednisolone 0.5–1 mg/kg/day ± Azathioprine or MMF
  → Topical steroids as adjuvant

MODERATE-SEVERE PV (or rapid progression)
  → Rituximab (1g × 2 doses at 0 and 2 weeks) + short-term prednisolone (0.5 mg/kg/day)
  → OR: Prednisolone 1 mg/kg/day + Azathioprine/MMF/Cyclophosphamide

REFRACTORY PV
  → High-dose IVIg (400 mg/kg/day × 5 days monthly)
  → Plasmapheresis + immunosuppression
  → Extracorporeal photopheresis
  → Clinical trial consideration (e.g., BTK inhibitors, neonatal Fc receptor blockers — efgartigimod)

Prognosis

Short Notes

a) Cutaneous Lymphoid Hyperplasia (CLH)

Definition & Synonyms

• Lymphocytoma cutis
• Lymphadenosis benigna cutis (LABC)
• Spiegler–Fendt sarcoid
• Miliary lymphocytoma

Etiopathogenesis

Clinical Features

• Morphology: Single (occasionally multiple), firm, erythematous to violaceous papule, nodule, or plaque, 1–3 cm in diameter
• Site: Head, neck, face (especially eyelids, cheeks, earlobes), upper extremities
• Surface: Usually smooth, without scale
• Variants: Multiple clustered papules; panniculitis-like deeper nodules
• Borrelia-associated: Often solitary on the ear, breast, or scrotum/nipple (lymphocytoma cutis)
• Drug-induced: May be widespread; may resemble mycosis fungoides

Histopathology

B Cell-Predominant (most common)

• Superficial and deep nodular or diffuse dermal infiltrate of lymphocytes, histiocytes, plasma cells, and eosinophils
• Reactive germinal centers with tangible-body macrophages ("tingible body macrophages" = sign of high turnover — reactive rather than neoplastic)
• Polyclonal B cells (no Ig gene rearrangement)
• IHC: Mixed CD20+ and CD3+ populations; bcl-2 negative in germinal center cells (unlike follicular lymphoma)

T Cell-Predominant (usually drug-induced)

• CD4+ T helper lymphocytes in dermis ± CD8+ cytotoxic T cells
• May show epidermotropism resembling mycosis fungoides
• Usually polyclonal TCR gene rearrangement

Pseudolymphoma: Polymorphous mixed lymphoid infiltrate with germinal center-like aggregates; reactive pattern without clonal atypia — H&E

Differential Diagnosis

Investigations

• Skin biopsy with IHC panel: CD20, CD3, CD4, CD8, CD30, bcl-2, bcl-6, CD10, Ki-67
• Molecular studies: PCR for IgH (B cells) and TCR gene rearrangements — polyclonal = reactive
• Serology: Borrelia antibodies (ELISA/Western blot) in European cases
• PCR for Borrelia DNA from biopsy tissue

Management

1. Remove/eliminate the trigger (withdraw offending drug, treat Borrelia infection with doxycycline, remove tattoo pigment)
2. Borrelia-associated CLH: Doxycycline 100 mg BD × 3–4 weeks
3. Drug-induced: Withdraw causative drug → usually resolves within weeks–months
4. Intralesional corticosteroids: For persistent lesions
5. Topical/intralesional steroids: Useful for localized disease
6. Surgical excision or cryotherapy: For small, persistent lesions
7. Hydroxychloroquine or chloroquine: Used in some persistent cases
8. Low-dose radiotherapy: Rare, refractory cases

Source: Dermatology 2-Volume Set 5e (Bolgnia), Ch. 121; Andrews' Diseases of the Skin, p. 2404

b) Rosacea

Definition

Epidemiology

• Affects ~5–10% of the general population
• More common in women (overall), but severe phymatous forms occur almost exclusively in men
• Celtic/northern European ancestry predisposed; less common in darker skin types
• Age of onset: typically 30–50 years

Etiopathogenesis

1. Vascular dysregulation: Exaggerated neurovascular responses to triggers → flushing → persistent telangiectasia and erythema
2. Innate immune dysregulation: Overexpression of cathelicidin (LL-37) processed by KLK5 (kallikrein) → abnormal antimicrobial peptide signaling → inflammation. TLR2 overexpression is also implicated
3. Demodex folliculorum: Mite density increased in rosacea; releases bacterial products (Bacillus oleronius) → immune activation
4. UV radiation: A major trigger; UV-induced reactive oxygen species → vascular and inflammatory changes
5. Neurogenic inflammation: Transient receptor potential (TRP) channels (TRPV1, TRPA1) involved in heat, spice, and UV-induced flushing
6. Gastrointestinal association: Small intestinal bacterial overgrowth (SIBO) found in a subset; rifaximin treatment improves rosacea in these patients

Classification (ROSCO/NRS Subtypes)

Old NRS subtype classification (still widely used):

Rosacea subtypes: Left — erythematotelangiectatic rosacea with diffuse erythema and telangiectasia; Right — papulopustular rosacea with inflammatory papules and pustules

Clinical Features

• Symmetric central facial erythema — cheeks, nose, chin, central forehead; periocular area spared
• Flushing: Prolonged (>10 min), triggered by heat, stress, alcohol; burning/stinging sensation; no sweating or palpitations
• Telangiectasia: Fine surface vessels on cheeks/nasal alae
• Papules and pustules: No comedones (key distinguishing feature from acne)
• Rhinophyma: Bulbous, lobulated thickening of nose — hypertrophy of sebaceous glands + fibrosis
• Ocular rosacea: Blepharitis, recurrent chalazion, keratitis, abnormal Schirmer test (40% of patients)
• Extrafacial: Flushing of neck, chest, ears

Histopathology

• Perivascular and perifollicular lymphohistiocytic infiltrate
• Telangiectatic vessels with solar elastosis
• In granulomatous rosacea: tuberculoid or sarcoidal granulomas
• Demodex mites may be seen in follicles
• No comedones, unlike acne

Differential Diagnosis

• Acne vulgaris (comedones present; younger age)
• Seborrheic dermatitis (greasy scale in nasolabial folds, eyebrows)
• Systemic lupus erythematosus (photosensitive, butterfly rash; ANA positive)
• Dermatomyositis (heliotrope rash; periorbital; proximal weakness)
• Perioral dermatitis (perioral, not central face)
• Carcinoid syndrome (flushing + diarrhea; ↑5-HIAA)
• Polycythemia vera, mastocytosis (no papules)

Management

1. General Measures

• Identify and avoid trigger factors: sun, heat, spicy food, alcohol, hot beverages
• Sunscreen with broad-spectrum SPF ≥30 (zinc oxide/titanium dioxide preferred for sensitive skin)
• Gentle skin care with non-irritating cleansers

2. Topical Therapy

3. Oral Therapy

4. Surgical & Physical Treatments

5. Management by Subtype

ETR: Trigger avoidance + sunscreen → Brimonidine/Oxymetazoline gel (erythema)
     → IPL/PDL (telangiectasia)

PPR: Topical metronidazole / azelaic acid / ivermectin
     → Add oral doxycycline 40 mg for moderate-severe disease
     → Switch to isotretinoin for refractory cases

Phymatous: Isotretinoin (early) + CO₂ laser / surgery (advanced rhinophyma)

Ocular: Oral doxycycline + warm compresses + cyclosporine eye drops

Prognosis

Sources: Andrews' Diseases of the Skin, p. 4195; Fitzpatrick's Dermatology Vol 1–2, p. 1449; Dermatology 2-Volume Set 5e (Bolgnia)