Immunologically Mediated Skin Diseases¶
Chapter 62 | Part 2: Cardinal Manifestations and Presentation of Diseases
KEY CLINICAL POINTS¶
- Immunologically mediated skin diseases are autoimmune disorders with cutaneous manifestations, characterized by blistering, erosions, and scarring.
- Key diagnostic tools include direct immunofluorescence microscopy, histopathology, and detection of autoantibodies (e.g., IgG, IgA) against desmosomal proteins (Dsg1, Dsg3, BPAG1, BPAG2).
- Treatment varies by disease: glucocorticoids, immunosuppressants (e.g., rituximab, mycophenolate mofetil), dapsone for dermatitis herpetiformis, and strict gluten-free diets for DH.
- Differential diagnosis includes vasculitis, infections (e.g., Meleney’s ulcer), and drug reactions (e.g., DRESS syndrome).
- Prognosis depends on disease severity, response to treatment, and complications (e.g., ocular involvement in pemphigoid gestationis).
1. DEFINITION & OVERVIEW¶
Immunologically mediated skin diseases are autoimmune disorders characterized by blistering, erosions, and scarring. These conditions involve autoantibodies targeting desmosomal proteins (e.g., Dsg1, Dsg3) or basement membrane antigens (e.g., BPAG1, BPAG2). Clinically, they present with mucocutaneous lesions, pruritus, and disfigurement, with potential complications including secondary infections and systemic involvement.
Table 62-1: Immunologically Mediated Blistering Diseases¶
| DISEASE | CLINICAL MANIFESTATIONS | HISTOLOGY | IMMUNOPATHOLO GY | AUTOANTIGENS |
|---|---|---|---|---|
| Pemphigus vulgaris | Oromucosal lesions, flaccid blisters, denuded skin | Acantholytic blister formed in suprabasal layer of epidermis | Cell surface deposits of IgG on keratinocytes | Dsg3 (plus Dsg1 in patients with skin involvement) |
| Pemphigus foliaceus | Crusts and shallow erosions on scalp, central face, upper chest, and back | Acantholytic blister formed in superficial layer of epidermis | Cell surface deposits of IgG on keratin,ocytes | Dsg1 |
| Paraneoplastic pemphigus | Painful stomatitis with papulosquamous or lichenoid eruptions progressing to blisters | Acantholysis, keratinocyte necrosis, vacuolar interface dermatitis | Cell surface deposits of IgG and C3 on keratinocytes | Plakin protein family members and desmosomal cadherins |
| DISEASE | CLINICAL MANIFESTATIONS | HISTOLOGY | IMMUNOPATHOLO GY | AUTOANTIGENS |
|---|---|---|---|---|
| Bullous pemphigoid | Large tense blisters on flexor surfaces and trunk | Subepidermal blister with eosinophil-rich infiltrate | Linear band of IgG and/or C3 in epidermal BMZ | BPAG1, BPAG2 |
| Pemphigoid gestationis | Pruritic, urticarial plaques rimmed by vesicles and bullae on trunk and extremities | Teardrop-shaped, subepidermal blisters in dermal papillae | Linear band of C3 in epidermal BMZ | BPAG2 (plus BPAG1 in some patients) |
| Dermatitis herpetiformis | Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck | Subepidermal blister with neutrophils in dermal papillae | Granular deposits of IgA in dermal papillae | Epidermal transglutaminase |
| Linear IgA disease | Pruritic papulovesicles on extensor surfaces; occasionally larger, arciform blisters | Subepidermal blister with neutrophil-rich infiltrate | Linear band of IgA in epidermal BMZ | BPAG2 |
| Epidermolysis bullosa acquisita | Blisters, erosions, scars, and milia on trauma-exposed sites | Subepidermal blister with or without leukocytic infiltrate | Linear band of IgG and/or C3 in epidermal BMZ | Type VII collagen |
| Mucous membrane pemphigoid | Erosive and/or blistering lesions of mucous membranes and skin | Subepidermal blister with or without leukocytic infiltrate | Linear band of IgG, IgA, and/or C3 in epidermal BMZ | BPAG2, laminin-332, or others |
1.1 Classification¶
Diseases are categorized into blistering disorders (e.g., pemphigus, bullous pemphigoid), non-blistering (e.g., dermatitis herpetiformis), and those with subepidermal or intraepidermal blistering. Autoantibodies target specific antigens, leading to acantholysis or subepidermal blistering.
1.2 Pathogenesis¶
Autoantibodies (IgG, IgA) bind to desmosomal or basement membrane antigens, triggering complement activation, neutrophil infiltration, and tissue damage. HLA associations (e.g., HLA-DQ β 1*0301, HLA-B8/DRw3) influence disease susceptibility.
2. EPIDEMIOLOGY¶
Pemphigus vulgaris (PV) is most common in adults >40 years, with a prevalence of 1–2/100,000. Bullous pemphigoid (BP) peaks in elderly (60–80 years), with a prevalence of 10–20/100,000. Dermatitis herpetiformis (DH) is more common in adults, with a prevalence of 1–2/100,000. Pemphigoid gestationis (PG) occurs in 1–2/100,000 pregnancies. Risk factors include autoimmune diseases (e.g., inflammatory bowel disease, rheumatoid arthritis), medications (e.g., penicillamine, diuretics), and HLA associations (e.g., HLA-DQ β 1*0301 for BP).
2.1 Demographics¶
PV: >40 years; BP: elderly (60–80 years); DH: adults; PG: women of childbearing age; MMP: rare, no gender predilection.
2.2 Risk Factors¶
Autoimmune diseases (e.g., IBD, RA), medications (e.g., thiol-containing drugs, diuretics), HLA associations (e.g., HLA-B8/DRw3 for DH), and genetic predisposition.
3. ETIOLOGY & PATHOPHYSIOLOGY¶
Autoantibodies target desmosomal proteins (Dsg1, Dsg3) or basement membrane antigens (BPAG1, BPAG2). Complement activation, neutrophil infiltration, and cytokine release mediate tissue damage. HLA associations (e.g., HLA-DQ β 1*0301 for BP, HLA-B8/DRw3 for DH) influence disease susceptibility. Paraneoplastic pemphigus (PNP) is linked to neoplasms (e.g., lymphoma, thymoma).
3.1 Autoimmune Mechanisms¶
IgG autoantibodies bind to desmosomal proteins (Dsg1, Dsg3) or basement membrane antigens (BPAG1, BPAG2), causing acantholysis or subepidermal blistering. Complement activation and neutrophil infiltration exacerbate tissue damage.
3.2 HLA Associations¶
HLA-DQ β 10301 (BP), HLA-B8/DRw3 (DH), HLA-DR2 (EBA), and HLA-DQ β 10301 (PNP) are linked to disease susceptibility.
4. CLINICAL FEATURES¶
PV presents with flaccid blisters, mucosal erosions, and scarring. BP features tense blisters on flexor surfaces. DH has pruritic papules on extensor surfaces. PG causes pruritic plaques on abdomen and extremities. MMP involves mucous membranes (e.g., oral, conjunctival). EBA is a mechanobullous disease with blisters at trauma sites.
4.1 Pemphigus Vulgaris¶
Flaccid blisters, mucosal erosions, scarring. Lesions on oral mucosa are almost invariable. Severe cases may lead to secondary infections and systemic complications.
4.2 Bullous Pemphigoid¶
Tense blisters on flexor surfaces and trunk. Pruritus is prominent. Lesions may rupture to form erosions with crusts. Nontraumatized blisters heal without scarring.
4.3 Dermatitis Herpetiformis¶
Pruritic papules on extensor surfaces (elbows, knees). Associated with gluten-sensitive enteropathy. Lesions may resemble severe seborrheic dermatitis.
5. DIFFERENTIAL DIAGNOSIS¶
Vasculitis, Meleney’s ulcer (infection), cutaneous leishmaniasis, drug reactions (e.g., DRESS syndrome), and fungal infections (e.g., cutaneous candidiasis). Differentiate based on histopathology, immunofluorescence, and clinical context.
5.1 Infections¶
Meleney’s ulcer (synergistic infection), cutaneous leishmaniasis, fungal infections (e.g., dimorphic fungi, amebiasis).
5.2 Drug Reactions¶
DRESS syndrome, drug-induced pemphigus (e.g., penicillamine, captopril).
6. INVESTIGATIONS & DIAGNOSIS¶
Direct immunofluorescence (IgG, IgA, C3 in epidermal basement membrane), histopathology (acantholysis, subepidermal blisters), and autoantibody testing (ELISA, indirect immunofluorescence). Serological markers (e.g., anti-endomysial antibodies for DH) and HLA typing are also critical.
6.1 Diagnostic Tests¶
Direct immunofluorescence: IgG/IgA/C3 in basement membrane. Histopathology: acantholysis (PV), subepidermal blisters (BP). Autoantibody testing: ELISA for Dsg1/Dsg3, IgA for DH.
6.2 Serological Markers¶
Anti-endomysial antibodies (DH), anti-Ro/SSA (SCLE), and HLA typing (e.g., HLA-B8/DRw3 for DH).
7. MANAGEMENT & TREATMENT¶
Systemic glucocorticoids (prednisone), immunosuppressants (rituximab, mycophenolate mofetil), dapsone for DH, and strict gluten-free diets. For severe cases, IVIg or plasmapheresis may be required. Local treatments include topical corticosteroids and photoprotection.
7.1 Pharmacologic Therapy¶
Glucocorticoids (prednisone), rituximab, mycophenolate mofetil, azathioprine, dapsone (DH), and IVIg for refractory cases.
7.2 Non-Pharmacologic¶
Strict gluten-free diet for DH, photoprotection, and wound care for erosions.
8. PROGNOSIS & COMPLICATIONS¶
PV mortality is ~5% with treatment; BP has a better prognosis. Complications include secondary infections, ocular involvement (PG), and systemic complications (e.g., bronchiolitis obliterans in PNP). Long-term management is required for chronic conditions like DH and MMP.
8.1 Mortality¶
PV: ~5% with treatment; PNP: 50% mortality if neoplasm is untreated.
8.2 Complications¶
Secondary infections, scarring, ocular involvement (PG), and systemic complications (e.g., interstitial lung disease in dermatomyositis).
9. SPECIAL CONSIDERATIONS¶
Pregnancy: PG may recur in subsequent pregnancies; DH requires gluten-free diet. Pediatrics: DH in children, EBA in infants. Drug-induced pemphigus (e.g., penicillamine, diuretics).
9.1 Pregnancy¶
PG: recurrence in subsequent pregnancies; DH: gluten-free diet. Avoid corticosteroids in early pregnancy.
9.2 Pediatrics¶
DH in children, EBA in infants, and drug-induced pemphigus (e.g., thiol-containing drugs).
10. KEY POINTS & CLINICAL PEARLS¶
- Use direct immunofluorescence to differentiate blistering diseases. 2. Dapsone is first-line for DH, with strict gluten-free diet. 3. Rituximab is effective for refractory PV. 4. HLA typing aids in diagnosis (e.g., HLA-B8/DRw3 for DH). 5. Monitor for complications (e.g., ocular involvement in PG).