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PITYRIASIS RUBRA PILARIS (PRP)

3rd Year Dermatology PG Theory Examination — 5 Marks

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DEFINITION

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AETIOLOGY & PATHOGENESIS

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CLASSIFICATION — GRIFFITHS (1980), Modified

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CLINICAL FEATURES

1. Scaliness and erythema of scalp → spreads to face, neck
2. Predilection for sides of neck, extensor surfaces (especially dorsum of proximal phalanges — "knuckle pads")
3. Papules coalesce into red-orange scaling plaques
4. Progresses to erythroderma over 2–3 months

• Islands of sparing (nappes claires) — sharply demarcated areas of normal skin within erythroderma (hallmark sign)
• Waxy, diffuse, yellowish palmoplantar keratoderma — extends up the sides of the soles ("sandal distribution")

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HISTOPATHOLOGY

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DIAGNOSIS

• Psoriasis (most important) — PRP has no nail pitting, no Auspitz sign; islands of sparing; checkerboard parakeratosis on histology
• Ichthyosis, seborrhoeic dermatitis, erythroderma of other causes

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TREATMENT

Topical

• Emollients (mainstay of symptomatic relief)
• Keratolytics: salicylic acid, urea
• Topical corticosteroids, calcineurin inhibitors, vitamin D analogues

Systemic (first-line)

Second-line / Refractory

• Biologics: TNF-α inhibitors (infliximab, etanercept, adalimumab); ustekinumab (anti-IL-12/23); anti-IL-17 agents
• Cyclosporine (5 mg/kg/day)
• Azathioprine (100–150 mg/day)
• Apremilast (PDE4 inhibitor)
• Fumaric acid esters

Phototherapy

• PUVA (psoralen + UVA) / Narrowband UVB — adjunctive role; used with caution as some PRP can worsen with UVB

HIV-associated (Type VI)

• Antiretroviral therapy (ART) — may lead to clearance

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PROGNOSIS

• Type I (classic adult): spontaneous remission in ~80% within 3 years
• Type III (classic juvenile): remission within 1–2 years
• Type II and V: chronic, lasting >20 years; may require long-term retinoids
• Type IV: unpredictable; may resolve in late teens

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Key exam points to remember:

1. Follicular papules + islands of sparing + waxy PPK = classic triad
2. Checkerboard pattern of parakeratosis on histology is pathognomonic
3. Nails never pitted → key distinction from psoriasis
4. CARD14 mutations → familial/Type V PRP
5. Acitretin is first-line systemic treatment

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SCLERODERMA (SYSTEMIC SCLEROSIS)

3rd Year Dermatology PG Theory Examination — 10 Marks

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DEFINITION

1. Vasculopathy (obliterative microangiopathy)
2. Immune dysregulation (autoimmunity, inflammation)
3. Progressive fibrosis of the skin and internal organs

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EPIDEMIOLOGY

• Female : Male ratio = 3:1 to 14:1
• Age of onset: 30–50 years
• SSc has the highest case-specific mortality of any autoimmune rheumatic disease
• Incidence: 0.6–16 per million; Prevalence: 2–233 per million
• Blacks develop disease younger and with greater severity than whites

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CLASSIFICATION

A. Based on Extent of Skin Involvement (LeRoy, 1988)

B. Other Subsets

• SSc sine scleroderma — vascular + immunologic features without skin sclerosis (1.5%)
• Early/undifferentiated SSc — Raynaud's + autoantibodies, not yet fulfilling ACR criteria
• Overlap syndromes — mixed connective tissue disease (MCTD), SSc–myositis, SSc–lupus

C. Localised Scleroderma (Morphoea) — skin only, no systemic involvement

• Plaque, linear, generalised, pansclerotic subtypes

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PATHOGENESIS

GENETIC PREDISPOSITION + ENVIRONMENTAL TRIGGERS
               ↓
        VASCULAR INJURY
               ↓
     IMMUNE DYSREGULATION
               ↓
     FIBROBLAST ACTIVATION
               ↓
     PROGRESSIVE FIBROSIS

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1. GENETIC SUSCEPTIBILITY

• HLA associations: HLA-DRB1, DQB1, DPB1 alleles linked to SSc and specific autoantibody profiles
• Non-HLA genes: STAT4, IRF5, CD247 (T cell signalling), BANK1, BLK (B cell activation)
• CARD14 mutations in familial cases (also seen in PRP)
• ~6.5% of cases are familial
• Concordance in identical twins is only ~5%, emphasising the role of environmental triggers

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2. VASCULOPATHY — The Initiating Event

Mechanism:

• Endothelial cell (EC) injury → triggered by auto-antibodies, reactive oxygen species (ROS), granzyme B from cytotoxic T cells, and viral antigens (CMV molecular mimicry)
• Injured EC → loss of normal vasoregulatory function → imbalance between:
  • Vasoconstrictors (↑ endothelin-1, ↑ thromboxane A₂)
  • Vasodilators (↓ nitric oxide, ↓ prostacyclin)
• Platelet activation → release of TGF-β, PDGF, serotonin → smooth muscle proliferation
• Intimal proliferation and adventitial fibrosis → luminal narrowing → ischaemia

Vascular consequences:

Impaired angiogenesis:

• Despite ischaemia, paradoxically defective neovascularisation occurs — VEGF is elevated but its receptor (VEGFR-2) is dysfunctional
• Circulating endothelial progenitor cells (EPCs) are reduced and dysfunctional

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3. IMMUNE DYSREGULATION — The Amplifying Event

Innate Immunity:

• Type I interferons (IFN-α, IFN-β) are elevated — "interferon signature" seen in SSc
• Toll-like receptors (TLR3, TLR7, TLR8, TLR9) activated by endogenous nucleic acids released from damaged cells → NF-κB activation → pro-inflammatory cytokines (IL-1, IL-6, TNF-α)
• Mast cells — increased in SSc skin; release histamine, TGF-β, chymase → fibroblast activation
• Macrophages — M2 polarisation (alternatively activated) → IL-4, IL-13, TGF-β → pro-fibrotic

Adaptive Immunity:

• CD4⁺ T helper cells (Th2 skewing) predominate in lesional skin
• Th2 cytokines (IL-4, IL-13) → directly stimulate fibroblast collagen synthesis
• Th17 cells → IL-17 → synergises with TGF-β in fibrosis
• Regulatory T cells (Tregs) → reduced/dysfunctional → loss of immune tolerance
• CD8⁺ T cells (cytotoxic) → injure endothelial cells via perforin/granzyme B

• Autoantibodies — hallmark of SSc (almost mutually exclusive):

• Autoantibodies against PDGFR (platelet-derived growth factor receptor) → directly stimulate fibroblast ROS production and collagen synthesis
• B cells also act as antigen-presenting cells perpetuating T cell activation

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4. FIBROBLAST ACTIVATION AND FIBROSIS — The End-Effector

Key pro-fibrotic mediators:

TGF-β Signalling (Central Pathway):

TGF-β binds TGF-βRI/II receptors
        ↓
SMAD2/3 phosphorylation → SMAD4 complex
        ↓
Nuclear translocation → Transcription of COL1A1, COL3A1, ACTA2, CTGF
        ↓
↑ Collagen I & III, fibronectin, TIMP-1
        ↓
↓ Matrix metalloproteinases (MMP-1, MMP-3)
        ↓
NET FIBROSIS (dermis, lungs, kidneys, GI, heart)

Myofibroblast transformation:

• Normal fibroblasts → activated myofibroblasts (α-smooth muscle actin positive, α-SMA⁺)
• Myofibroblasts are autonomous — continue producing ECM even without external TGF-β stimulation
• Epigenetic modifications (DNA methylation, histone modification) lock fibroblasts in a pro-fibrotic state

Epithelial-Mesenchymal Transition (EMT):

• Epithelial cells (e.g., alveolar epithelium) transition to mesenchymal/myofibroblast phenotype under TGF-β → contributes to lung fibrosis

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INTEGRATED PATHOGENESIS — SUMMARY DIAGRAM

GENETIC SUSCEPTIBILITY (HLA, STAT4, IRF5)
            +
ENVIRONMENTAL TRIGGER (silica, virus, oxidants)
            ↓
    ┌───────────────────┐
    │  VASCULAR INJURY  │ ← EC apoptosis, ROS, anti-EC antibodies
    │  (earliest event) │
    └────────┬──────────┘
             ↓
    Platelet activation → TGF-β, PDGF release
    Raynaud's, digital ulcers, PAH, renal crisis
             ↓
    ┌──────────────────────┐
    │  IMMUNE ACTIVATION   │ ← T cells (Th2/Th17), B cells, macrophages (M2)
    │  Autoantibodies       │   IFN signature, IL-4, IL-13, IL-17
    │  (ACA, anti-Scl-70)  │
    └──────────┬───────────┘
               ↓
    ┌──────────────────────────┐
    │  FIBROBLAST ACTIVATION   │ ← TGF-β (SMAD pathway), PDGF, CTGF, ET-1
    │  Myofibroblast           │
    │  transformation (α-SMA⁺) │
    └──────────┬───────────────┘
               ↓
    ┌──────────────────────────┐
    │  PROGRESSIVE FIBROSIS    │
    │  Skin, lungs, GI,        │
    │  kidneys, heart          │
    └──────────────────────────┘

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HISTOPATHOLOGY

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CLINICAL FEATURES (Brief Overview)

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DIAGNOSIS

• Skin thickening of fingers extending proximal to MCP joints (score 9 — sufficient alone)
• Sclerodactyly, fingertip pitting scars/digital ulcers
• Abnormal nailfold capillaroscopy
• PAH and/or ILD
• Raynaud's phenomenon
• SSc-specific autoantibodies (ACA, anti-Scl-70, anti-RNA Pol III)
• Total score ≥9 = definite SSc

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TREATMENT PRINCIPLES

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PROGNOSIS

• dcSSc: 10-year survival ~60–70%; main causes of death = PAH, lung fibrosis, renal crisis
• lcSSc: better prognosis; main late complication = isolated PAH
• Scleroderma renal crisis: >90% mortality before ACE inhibitors; now manageable if treated early

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Key exam points to remember:

1. SSc pathogenesis = Vasculopathy → Immune dysregulation → Fibrosis (in sequence)
2. TGF-β / SMAD pathway is the central driver of fibrosis
3. Earliest event = endothelial injury → Raynaud's
4. Anti-Scl-70 → dcSSc + ILD; Anticentromere → lcSSc/CREST + PAH; Anti-RNA Pol III → renal crisis
5. ACE inhibitors are life-saving in scleroderma renal crisis
6. SSc has highest mortality of all autoimmune rheumatic diseases

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SCLERODERMA (SYSTEMIC SCLEROSIS)

3rd Year Dermatology PG Theory Examination — 10 Marks

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DEFINITION

1. Vasculopathy (obliterative microangiopathy)
2. Immune dysregulation (autoimmunity + inflammation)
3. Progressive fibrosis of the skin and internal organs

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EPIDEMIOLOGY

• F : M ratio = 3:1 to 14:1
• Age of onset: 30–50 years
• Blacks develop disease younger and with greater severity
• SSc carries the highest case-specific mortality of any autoimmune rheumatic disease

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CLASSIFICATION

A. Based on Extent of Skin Involvement (LeRoy, 1988)

B. Other Subsets

• SSc sine scleroderma — vascular + immunological features, no skin sclerosis (~1.5%)
• Early/undifferentiated SSc — Raynaud's + autoantibodies, not yet fulfilling ACR criteria
• Overlap syndromes — SSc + myositis, SSc + SLE, MCTD

C. Localised Scleroderma (Morphoea)

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PATHOGENESIS

GENETIC PREDISPOSITION + ENVIRONMENTAL TRIGGERS
                 ↓
         VASCULAR INJURY  (initiating event)
                 ↓
      IMMUNE DYSREGULATION  (amplifying event)
                 ↓
      FIBROBLAST ACTIVATION  (end-effector)
                 ↓
       PROGRESSIVE FIBROSIS (skin, lungs, GI, kidneys, heart)

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1. GENETIC SUSCEPTIBILITY

• HLA associations: HLA-DRB1, DQB1, DPB1 alleles — linked to specific autoantibody profiles
• Non-HLA genes: STAT4, IRF5 (interferon pathway), CD247 (T cell signalling), BANK1, BLK (B cell activation)
• ~6.5% of cases are familial
• Twin concordance is only ~5% → environmental triggers are essential

• Silica dust — underground coal/gold miners have 190× increased risk of SSc
• Polyvinyl chloride, organic solvents, bleomycin (dose-dependent, reversible)
• Viral triggers — CMV molecular mimicry (anti-UL83 antibodies cross-react with anti-topoisomerase I)

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2. VASCULOPATHY — The Initiating Event

Mechanism of endothelial injury:

• Anti-endothelial cell antibodies (AECA) → complement activation → EC apoptosis
• Reactive oxygen species (ROS) from activated neutrophils and ischaemia-reperfusion
• CD8⁺ cytotoxic T cells → perforin/granzyme B → EC lysis
• CMV-derived antigens → molecular mimicry → autoimmune EC attack

Consequences of EC injury:

Clinical vascular manifestations:

• Raynaud's phenomenon — episodic vasospasm of digital arteries (earliest sign)
• Digital ulcers / gangrene — obliterative endarteritis
• PAH — intimal hyperplasia + medial hypertrophy of pulmonary arterioles
• Scleroderma renal crisis (SRC) — hyperplastic arteriolosclerosis → RAAS activation → malignant hypertension
• Nailfold capillaroscopy — giant loops, avascular areas, haemorrhages (diagnostic tool)

Impaired angiogenesis (paradox):

• Despite ischaemia, VEGF is elevated but its receptor VEGFR-2 is dysfunctional
• Circulating endothelial progenitor cells (EPCs) are reduced and functionally impaired
• → Net result: inadequate vessel repair → progressive vascular obliteration

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3. IMMUNE DYSREGULATION — The Amplifying Event

Innate Immunity:

• Type I interferons (IFN-α, IFN-β) — elevated; "interferon signature" present in SSc blood
• TLR3, TLR7, TLR8, TLR9 activated by endogenous nucleic acids from damaged cells → NF-κB → IL-1, IL-6, TNF-α
• Mast cells — increased in SSc lesional skin; release TGF-β, chymase, histamine → fibroblast activation
• Macrophages — M2 (alternatively activated) polarisation → IL-4, IL-13, TGF-β → pro-fibrotic milieu

Adaptive Immunity — T cells:

• Th2 skewing in lesional skin — IL-4, IL-13 → directly stimulate collagen synthesis by fibroblasts
• Th17 cells — IL-17 → synergises with TGF-β to drive fibrosis
• Tregs (regulatory T cells) — reduced and dysfunctional → loss of peripheral tolerance
• CD8⁺ cytotoxic T cells — injure endothelium via perforin/granzyme B

Adaptive Immunity — B cells and Autoantibodies:

These autoantibodies are almost mutually exclusive in any one patient and serve as prognostic markers.

• Anti-PDGFR antibodies → directly stimulate fibroblast ROS production and collagen synthesis
• B cells also function as antigen-presenting cells → perpetuate T cell autoimmunity

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4. FIBROBLAST ACTIVATION AND FIBROSIS — The End-Effector

Key pro-fibrotic mediators:

TGF-β / SMAD Signalling Pathway (Central):

TGF-β  →  TGF-βR I/II (serine-threonine kinase)
                    ↓
          SMAD2/3 phosphorylation
                    ↓
          SMAD2/3 + SMAD4 complex (nuclear translocation)
                    ↓
     Transcription of:
     • COL1A1, COL3A1 (Collagen I & III)
     • ACTA2 (α-smooth muscle actin)
     • CTGF, fibronectin, TIMP-1
                    ↓
     ↓ MMP-1, MMP-3 (collagen-degrading enzymes)
                    ↓
         NET DERMAL AND VISCERAL FIBROSIS

Myofibroblast Transformation:

• Normal dermal fibroblasts → activated myofibroblasts (α-SMA⁺, contractile)
• Myofibroblasts produce vast amounts of collagen, fibronectin, and CTGF
• They become autonomous — continue ECM synthesis even without external TGF-β (due to autocrine loops)
• Epigenetic locking: DNA methylation of anti-fibrotic genes (FLI1, PPAR-γ); histone modifications → constitutive pro-fibrotic gene expression

Epithelial-Mesenchymal Transition (EMT):

• Under TGF-β, alveolar/tubular epithelial cells transition to myofibroblast phenotype
• Contributes to pulmonary fibrosis and renal interstitial fibrosis

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INTEGRATED PATHOGENESIS SUMMARY

GENETIC SUSCEPTIBILITY (HLA, STAT4, IRF5)
             +
ENVIRONMENTAL TRIGGER (silica, CMV, oxidants)
             ↓
  ┌─────────────────────────┐
  │    VASCULAR INJURY      │ ← AECA, ROS, CD8⁺ T cells
  │  (EC apoptosis/damage)  │
  └──────────┬──────────────┘
             │
   Platelet activation: TGF-β, PDGF, serotonin
   Imbalance: ↑ET-1, ↑TXA₂ vs ↓NO, ↓Prostacyclin
   → Raynaud's, digital ulcers, PAH, SRC
             ↓
  ┌─────────────────────────────────┐
  │     IMMUNE DYSREGULATION        │
  │  Th2/Th17, M2 macrophages,      │
  │  Mast cells, Type I IFN         │
  │  Autoantibodies (ACA, Scl-70,   │
  │  RNA Pol III)                   │
  └──────────────┬──────────────────┘
                 │ TGF-β, IL-4, IL-13, PDGF, CTGF, ET-1
                 ↓
  ┌─────────────────────────────────┐
  │    FIBROBLAST ACTIVATION        │
  │  TGF-β/SMAD pathway             │
  │  Myofibroblast transformation   │
  │  Epigenetic locking             │
  └──────────────┬──────────────────┘
                 ↓
  ┌─────────────────────────────────┐
  │     PROGRESSIVE FIBROSIS        │
  │  Skin → Lungs → GI → Kidney     │
  │  → Heart                        │
  └─────────────────────────────────┘

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HISTOPATHOLOGY

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CLINICAL FEATURES — OVERVIEW

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DIAGNOSIS

• Skin thickening proximal to MCPJs — score 9 (sufficient alone)
• Sclerodactyly, fingertip pitting scars/digital ulcers
• Abnormal nailfold capillaroscopy
• PAH / ILD
• Raynaud's phenomenon
• SSc-specific autoantibodies (ACA, anti-Scl-70, anti-RNA Pol III)

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TREATMENT PRINCIPLES

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Key exam points — must-know:

1. Pathogenesis triad: Vasculopathy → Immune dysregulation → Fibrosis (sequential and interdependent)
2. TGF-β / SMAD pathway is the central driver of fibrosis — know it step-by-step
3. Earliest clinical event = Raynaud's phenomenon (endothelial injury)
4. Anti-Scl-70 → dcSSc + ILD | Anticentromere → lcSSc/CREST + PAH | Anti-RNA Pol III → Renal crisis
5. ACE inhibitors in renal crisis reduced mortality from >90% to manageable levels
6. SSc has highest mortality of all autoimmune rheumatic diseases
7. Myofibroblast transformation + epigenetic locking = why fibrosis is irreversible once established