---

Bullous (Blistering) Disorders

---

Level of Blister Formation

---

1. Pemphigus Vulgaris

---

2. Pemphigus Foliaceus

---

3. Paraneoplastic Pemphigus

---

4. Bullous Pemphigoid (BP)

---

5. Dermatitis Herpetiformis (DH)

---

Comparison Table

---

Key Concepts to Remember

1. Acantholysis (loss of intercellular adhesion) = hallmark of pemphigus group; absent in bullous pemphigoid and dermatitis herpetiformis.
2. Blister level predicts pathomechanism: desmosomes (upper epidermis) → pemphigus; hemidesmosomes/BMZ → pemphigoid and DH.
3. IgA + granular papillary tips on DIF = pathognomonic of dermatitis herpetiformis.
4. Linear IgG at BMZ on DIF = bullous pemphigoid.
5. Gluten-free diet helps both celiac disease and dermatitis herpetiformis, and may reduce lymphoma risk in DH.

---

Systemic Lupus Erythematosus (SLE)

---

Epidemiology

• Prevalence: up to 1 in 2500 in certain populations
• Female predominance: 9:1 (F:M) in the reproductive age group (17-55 years); ratio drops to 2:1 in childhood-onset or >65 years
• Peak onset: 20s and 30s
• More prevalent and severe in individuals of African, Hispanic, and Asian descent in the United States

---

Pathogenesis

Genetic Factors

• HLA associations (HLA-DR2, HLA-DR3)
• Deficiency of complement components (C1q, C2, C4) - impairs clearance of immune complexes and apoptotic debris
• Variants in TLR signaling and IFN-regulatory genes
• X-chromosome gene effects (partly explain female predominance, independent of hormones)

Immunologic Abnormalities

• Failure of apoptotic clearance: UV irradiation and other insults cause cell apoptosis; nuclear antigens (DNA, histones, Ro, La) are not cleared and accumulate
• TLR activation: Self nucleic acids mimic microbial patterns and activate TLRs on B cells and dendritic cells, driving production of type I interferons (IFN-α)
• Defective B- and T-cell tolerance: Self-reactive lymphocytes survive and are stimulated by nuclear antigens
• Positive feedback cycle: Autoantibodies form immune complexes → Fc receptor binding on B cells and DCs → internalization of nucleic acids → more TLR engagement → more autoantibodies and interferons

Environmental Factors

• UV light: Induces apoptosis, enhances TLR recognition of altered DNA, stimulates keratinocyte IL-1
• Sex hormones: Estrogen promotes immune activation
• Drugs: Hydralazine, procainamide, D-penicillamine can induce a drug-induced lupus-like syndrome

---

Autoantibodies in SLE

Anti-dsDNA and Anti-Sm are the most specific antibodies for SLE.

---

Mechanisms of Tissue Injury

1. Type III hypersensitivity (immune complex deposition) - responsible for most systemic lesions (nephritis, vasculitis, skin, serositis)
2. Type II hypersensitivity (direct antibody binding) - hemolytic anemia, thrombocytopenia
3. Antiphospholipid antibodies - thrombosis, miscarriages (secondary antiphospholipid syndrome)
4. Neuropsychiatric - antibodies crossing blood-brain barrier binding neurons/neurotransmitter receptors; cytokine effects

---

1997 ACR Diagnostic Criteria (≥4 of 11 for diagnosis)

1. Acute cutaneous lupus - malar (butterfly) rash; photosensitivity
2. Chronic cutaneous lupus - discoid rash (erythematous raised patches with keratotic scaling + follicular plugging)
3. Nonscarring alopecia
4. Oral/nasal ulcers (usually painless)
5. Nonerosive arthritis (≥2 peripheral joints)
6. Serositis - pleuritis or pericarditis
7. Renal disorder - proteinuria >0.5 g/24h or red cell casts
8. Neurologic disorder - seizures, psychosis, myelitis, neuropathy

---

Organ Involvement and Morphology

Prevalence of Manifestations

Skin

• Butterfly (malar) rash: Fixed erythema over nose and cheeks (~50% of patients); photosensitive
• Histology: vacuolar degeneration of basal layer, dermal edema, perivascular inflammation, fibrinoid necrotizing vasculitis
• Immunofluorescence: IgG + complement deposits along the dermoepidermal junction ("lupus band test")

Kidney - Lupus Nephritis (ISN/RPS Classification)

• Class I & II: Mild; excellent prognosis; minimal or no therapy needed
• Class III & IV: Active proliferative; treat with high-dose steroids + cyclophosphamide or mycophenolate mofetil
• Class IV most severe - high anti-dsDNA, low complement, hematuria, RBC casts, proteinuria, hypertension

Cardiovascular

• Libman-Sacks endocarditis: Non-bacterial vegetations on both surfaces of mitral/aortic valves (pathognomonic); caused by immune complex deposition
• Pericarditis: up to 50% of patients
• Myocarditis: less common; causes tachycardia + ECG changes
• Accelerated coronary atherosclerosis: young patients with long-standing disease (multifactorial - immune complex + antiphospholipid antibody-mediated endothelial damage + corticosteroid effects)

Joints

• Nonerosive synovitis - contrasts with rheumatoid arthritis (which is erosive)
• No joint deformity despite significant pain

Blood Vessels

• Acute necrotizing vasculitis (fibrinoid necrosis) of capillaries, arterioles, small arteries in any tissue
• Chronic: fibrotic thickening with luminal narrowing

Spleen

• Splenomegaly, follicular hyperplasia
• "Onion-skin" lesions: concentric intimal smooth muscle hyperplasia of penicillary arteries (characteristic but not pathognomonic)

Serosal Cavities

• Pleuritis, pleural/pericardial effusions (up to 50%)
• Fibrinous exudate in acute phase → fibrous thickening and obliteration in chronic phase

Lungs

• Pleuritis, pleural effusions
• Chronic interstitial fibrosis, secondary pulmonary hypertension

CNS

• Neuropsychiatric lupus: psychosis, seizures, cognitive dysfunction
• Non-inflammatory occlusion of small vessels (intimal proliferation)
• No clear histologic abnormality in most cases

Hematologic

• Hemolytic anemia (Coombs positive)
• Leukopenia/lymphopenia
• Thrombocytopenia
• LE bodies (hematoxylin bodies) in bone marrow - strongly indicative of SLE

---

LE Cell (Historical)

• A phagocytic leukocyte (neutrophil/monocyte) that has engulfed the denatured nucleus of an injured cell (coated with ANAs)
• LE cell test: now largely of historical interest, replaced by ANA immunofluorescence assay

---

Variants of Lupus

---

Clinical Course and Prognosis

• Highly variable - from indolent (mild skin and urinary changes for years) to rapidly fatal
• ~90% 5-year survival, ~80% 10-year survival with treatment
• Disease flares correlate with rising anti-dsDNA titers and falling complement (hypocomplementemia)
• Main causes of death: renal failure, intercurrent infections, cardiovascular disease

---

Treatment Overview

• Hydroxychloroquine (antimalarial): cornerstone for mild-moderate disease; reduces flares and mortality
• NSAIDs: for arthritis and serositis
• Corticosteroids: for moderate-severe flares
• Immunosuppressives: cyclophosphamide or mycophenolate mofetil for severe nephritis/CNS disease
• Belimumab (anti-BLyS/BAFF): approved biologic for active SLE
• Sun protection (UV avoidance)

---

SLE - Dermatological Manifestations

---

Classification of Lupus-Specific Skin Lesions

---

1. Acute Cutaneous Lupus Erythematosus (ACLE)

Malar (Butterfly) Rash - Classic ACLE

• Appearance: Fixed erythematous rash over the malar eminences and nasal bridge, characteristically sparing the nasolabial folds
• Seen in 30-60% of SLE patients
• Often triggered by UV/sun exposure (photosensitive)
• Distribution: sun-exposed face, neck, extensor arms, dorsal hands; skin over knuckles relatively spared
• Lesions may be transient (hours to days) or persistent
• When severe: facial edema may be prominent; oral lesions often concurrent
• Superficial inflammation - little propensity to scar

Key characteristics of ACLE:

• Strong association with systemic disease activity - the appearance/worsening of ACLE often heralds a flare
• Skin biopsy usually NOT performed on malar rash (transient, biopsy scar, other diagnostic means available)

Differential diagnosis of Malar Rash:

---

2. Subacute Cutaneous Lupus Erythematosus (SCLE)

• Morphology: Two main types:
  • Annular-polycyclic: Ring-shaped erythematous plaques with central clearing and scaly edge
  • Papulosquamous/psoriasiform: Scaly erythematous plaques resembling psoriasis
• Distribution: Sun-exposed areas - arms, upper trunk, neck, sides of face; midfacial area usually spared (unlike ACLE)
• Predominantly affects fair-skinned individuals
• Strongly associated with anti-Ro/SSA antibodies
• Lesions resolve with hypopigmentation or depigmentation - rarely scar (intermediate between ACLE and DLE)
• ~15% of patients with SCLE have or will develop significant systemic disease (SLE, Sjogren's, or overlap)

Drug-induced SCLE:

• Causes: hydrochlorothiazide, proton pump inhibitors, terbinafine (seen in ~1/3 of SCLE cases)
• Resolves after stopping the offending drug

Differential: Psoriasis, tinea corporis, polymorphous light eruption, erythema multiforme

---

3. Chronic Cutaneous LE (CCLE)

A. Discoid Lupus Erythematosus (DLE)

• Most common of the persistent lupus-specific skin lesions
• Active lesions: Erythematous indurated papules/plaques; palpably firm due to dense dermal lymphocytic infiltrate
• Established lesions: Dyspigmentation (central hypopigmentation/depigmentation + peripheral hyperpigmentation); follicular plugging; scarring
• Sites: Scalp, ears, face - usually above the neck; mucosal surfaces occasionally involved
• Scarring alopecia when scalp involved (permanent hair loss)
• Hypertrophic DLE: variant with thickened epidermis
• Sun exposure may exacerbate (but lesions also occur in sun-protected areas of scalp/ears)
• Risk of SLE: ~5-10% progress to systemic SLE; up to 15-20% may meet ACR criteria (often based on mucocutaneous findings)
• ~35% have positive generic ANA; anti-dsDNA rarely present
• Complications: Squamous cell carcinoma can develop in long-standing DLE lesions
• Blacks have 3-5x higher incidence than whites

• Interface (vacuolar/lichenoid) dermatitis: vacuolar degeneration of basal keratinocytes
• Dense perivascular and periappendageal lymphocytic infiltrate (deep, involving follicles)
• Follicular plugging, epidermal atrophy
• Dermal mucin deposition
• Scarring in chronic lesions

• Lupus Band Test: Granular IgG deposits at the dermal-epidermal junction of lesional skin only (unlike SLE where non-lesional skin also positive)

B. Tumid Lupus Erythematosus (TLE)

• Erythematous, indurated, boggy papules/plaques with substantial lymphocytic infiltrate and abundant dermal mucin
• No epidermal abnormalities, follicular involvement, or scarring (key distinction from DLE)
• Most common on the face; may be reproduced by phototesting
• Low risk for SLE
• DIF: Ig deposits NOT generally present
• Controversial - some argue TLE is the same as Jessner lymphocytic infiltrate

C. Lupus Panniculitis (LEP) / Lupus Profundus

• Inflammation in subcutaneous fat → deep, firm, indurated plaques → disfiguring depressed atrophic areas after resolution
• Sites: face, scalp, upper trunk, breasts, upper arms, buttocks, thighs
• Some patients with LEP have or will develop SLE
• Must be differentiated from panniculitic lymphoma (clinical mimicker)

---

4. Lupus-Nonspecific Skin Lesions

---

Histology of SLE Skin Lesions

1. Vacuolar/interface dermatitis: vacuolar degeneration of basal layer keratinocytes
2. Perivascular lymphocytic infiltrate (superficial in ACLE; deep/periappendageal in DLE)
3. Dermal edema and mucin deposition
4. Epidermal atrophy (in chronic lesions)
5. Follicular plugging (in DLE)

---

Lupus Band Test (Direct Immunofluorescence)

• Granular IgG (± C3, IgM, IgA) deposits at the dermal-epidermal junction
• Lesional skin: Positive in DLE, SCLE, SLE - diagnostically useful
• Non-lesional (normal) skin:
  • Positive → strongly indicative of SLE (indicates systemic immune complex deposition)
  • Negative → suggests localized/cutaneous-only disease

---

Comparison of Major Cutaneous Subtypes

---

Treatment of Cutaneous Lupus

1. Sun protection: Broad-spectrum SPF, protective clothing - critical for all photosensitive subtypes; tobacco cessation (exacerbates disease, reduces drug response)
2. Topical therapy (first-line for localized disease):
   • Topical corticosteroids (most commonly used)
   • Intralesional corticosteroids (for DLE)
   • Topical calcineurin inhibitors (tacrolimus, pimecrolimus)
   • Topical retinoids
3. Systemic - first line: Hydroxychloroquine (antimalarial) - backbone of cutaneous lupus treatment
4. Antimalarial-resistant: Chloroquine, add quinacrine; baricitinib (JAK inhibitor) for familial chilblain lupus
5. Refractory disease: Methotrexate, mycophenolate mofetil, dapsone (especially for bullous LE), thalidomide/lenalidomide
6. Systemic corticosteroids: for severe/widespread acute flares

---

Leprosy (Hansen Disease)

---

The Pathogen

---

The Spectrum of Disease - Ridley-Jopling Classification

Immunologic Poles

---

WHO Classification (Practical/Treatment-Based)

---

Clinical Presentations by Type

1. Tuberculoid Leprosy (TT) - Paucibacillary

• Few (1-3) well-defined lesions with sharply demarcated, raised, hyperpigmented borders and central hypopigmentation/atrophy
• Anesthesia/hypoesthesia within lesions (loss of pain, temperature, touch) - hallmark
• Alopecia within plaques (loss of hair follicles)
• Anhidrosis within lesions
• Asymmetric distribution - face and extremities common
• Peripheral nerve involvement: asymmetric, single or few nerves enlarged, painful
  • Nerve damage causes skin anesthesia, muscle atrophy, contractures, paralysis
  • Facial nerve involvement → lagophthalmos → corneal ulceration
• Palpably enlarged nerves: most commonly affected - ulnar (claw hand), common peroneal (foot drop), great auricular, radial cutaneous, posterior tibial
• Bacilli almost never found on smear or biopsy

2. Lepromatous Leprosy (LL) - Multibacillary

• Multiple, widespread, symmetric lesions
• Initially poorly defined erythematous macules, papules, nodules, plaques
• Progression to massive skin infiltration:
  • Leonine facies: thickened, nodular facial skin (lion-face)
  • Madarosis: loss of eyebrows and eyelashes
  • Saddle nose deformity: destruction of nasal septum cartilage
  • Infiltration of earlobes (thickened, nodular)
  • Acquired ichthyosis on lower extremities
• Anesthesia: glove-and-stocking distribution (symmetric)
• Peripheral nerves: symmetrically invaded with bacteria but minimal inflammation; loss of sensation and trophic changes
• Nasal involvement: persistent inflammation, bacilli-laden discharge
• Ocular: lagophthalmos (facial/trigeminal nerve involvement), corneal anesthesia
• Testes: extensive destruction → sterility
• Systemic: lymph nodes (foamy macrophage aggregates), liver, spleen in advanced disease
• CNS and vital organs: NOT affected (too warm for M. leprae replication)

3. Borderline Leprosy (BT / BB / BL)

• Intermediate features between tuberculoid and lepromatous poles
• Clinically and immunologically unstable - can shift toward either pole
• BT (Borderline Tuberculoid): asymmetric; larger plaques with less defined borders than TT; hypoesthetic; 1-5 lesions
• BB (Mid-borderline): symmetric; annular plaques with "Swiss cheese" appearance (central clearing); ill-defined outer borders; 5-20 lesions
• BL (Borderline Lepromatous): symmetric; macules, papules, annular plaques; multiple widespread lesions; may have normal sensation

4. Indeterminate Leprosy

• Earliest form - not yet classified into a pole
• 1-3 hypopigmented or erythematous macules, asymmetric
• Face, lateral upper arms, lateral thighs, trunk
• Mild hypoesthesia
• May resolve spontaneously OR progress to any type on the spectrum

---

Histopathology

Tuberculoid Pattern

• Epithelioid granulomas closely resembling tuberculosis (non-caseating)
• Granulomas surround and invade dermal nerves, adnexa, and vessels
• Dense lymphocytic infiltrate (CD4+ Th1)
• Bacilli absent (or extremely rare)
• Strong T-cell immunity = paucibacillary

Lepromatous Pattern

• Virchow cells (lepra cells): foamy, lipid-laden macrophages packed with masses of bacilli ("globi")
• Grenz zone (Unna band): band of normal-appearing dermis separating epidermis from the infiltrate - characteristic
• Plasma cells, few lymphocytes
• Minimal inflammation around nerves despite heavy bacillary load
• Staining: Fite-Faraco stain (preferred, more sensitive) or Ziehl-Neelsen stain → bacilli stain bright red
• Multibacillary - readily visualized in tissue

Borderline Pattern

• Intermediate between the two; number of granulomas and bacilli inversely proportional to immunity

---

Leprosy Reactions (Complications)

Type 1 - Reversal Reaction

Type 2 - Erythema Nodosum Leprosum (ENL)

Lucio Phenomenon

• Seen in diffuse lepromatous leprosy (Mexico/Central America; M. lepromatosis)
• Necrotic ulcers, retiform purpura → necrotizing vasculitis
• Associated with antiphospholipid antibodies + thrombosis
• Severe, potentially fatal
• On a worldwide basis, leprosy is a common cause of cutaneous vasculitis in low-income countries

---

Disabilities and Deformities

---

Diagnosis

---

Treatment: WHO Multidrug Therapy (MDT)

After the first dose, the patient is no longer infectious to others.

Key Drug Side Effects

Treating Reactions

• Type 1 (Reversal): Oral prednisone
• Type 2 (ENL): Thalidomide (drug of choice) + prednisolone; clofazimine can reduce frequency

Alternative Drugs (resistance/intolerance)

• Minocycline, clarithromycin, ofloxacin/moxifloxacin/levofloxacin
• ROM scheme (Rifampicin + Ofloxacin + Minocycline): for PB disease, even single-dose for single-lesion

---

Key Comparisons Summary