Polyarteritis Nodosa (PAN)

1. Clinical Overview

Summary

Polyarteritis Nodosa (PAN) is a systemic necrotising vasculitis affecting medium-sized muscular arteries, leading to vessel wall inflammation, aneurysm formation, thrombosis, and organ ischaemia/infarction. Unlike many other vasculitides, PAN spares small vessels (capillaries, venules, arterioles) and is ANCA-negative, which are critical diagnostic discriminators. PAN is rare, with an incidence of ~2-9 per million per year, predominantly affecting males (2:1 ratio) with peak onset between 40-60 years. [1,2]

PAN can be idiopathic (most cases in developed countries) or associated with Hepatitis B Virus (HBV) infection (classic association, now less than 5% due to vaccination programs). The disease affects multiple organ systems, most commonly peripheral nerves (mononeuritis multiplex, 50-70%), skin (livedo reticularis, nodules, ulcers, 25-60%), gastrointestinal tract (mesenteric ischaemia, 30-50%), kidney (renal arteritis without glomerulonephritis, 30-50%), and musculoskeletal system. [3,4]

Diagnosis is based on clinical features, laboratory findings (ANCA-negative, elevated inflammatory markers), conventional angiography (showing characteristic microaneurysms and stenoses with "beaded" appearance), and biopsy (demonstrating medium-vessel necrotising arteritis). Treatment involves high-dose corticosteroids ± cyclophosphamide for severe disease (guided by Five-Factor Score), and antiviral therapy for HBV-associated PAN. With modern immunosuppressive therapy, 5-year survival has improved to 80-90%, though untreated disease historically carried 50% mortality at 1 year. [5,6,7]

Clinical Pearls

"Medium Vessels, ANCA-Negative": PAN affects medium-sized muscular arteries (100-500 μm diameter). It is NOT associated with ANCA (differentiates from GPA, MPA, EGPA). ANCA positivity should prompt reconsideration of the diagnosis.

"Mononeuritis Multiplex": Asymmetric peripheral neuropathy affecting individual named nerves (e.g., peroneal, ulnar, radial). Classic PAN feature with acute onset foot drop or wrist drop. Sural nerve biopsy has high diagnostic yield (50-70%). [8]

"Hepatitis B Association": Always screen for HBV (HBsAg, anti-HBc, HBV DNA). HBV-PAN treated with antivirals (entecavir/tenofovir) + short-course steroids ± plasma exchange. Prolonged immunosuppression promotes viral replication.

"Microaneurysms on Angiography": "Beaded" or "rosary bead" appearance of mesenteric, renal, or hepatic arteries. Microaneurysms typically 1-5mm at vessel bifurcations. Conventional angiography remains gold standard for diagnosis. [9]

"No Glomerulonephritis": Renal involvement is from arteritis causing infarction, NOT glomerulonephritis. Absence of glomerulonephritis differentiates PAN from ANCA-associated vasculitides (especially MPA).

"Five-Factor Score (FFS)": Guides treatment intensity. FFS ≥1 indicates higher mortality risk and need for cyclophosphamide. FFS=0 may respond to corticosteroids alone. [10]

---

2. Epidemiology

Demographics

Associations

Temporal Trends

---

3. Pathophysiology

Molecular and Cellular Mechanisms

Phase 1: Initiation

1. Immune Complex Deposition (HBV-associated):

   • HBsAg-antibody immune complexes deposit in medium artery walls
   • Complement activation (C3, C5a)
   • Neutrophil recruitment via chemotaxis
   • Low complement levels (C3, C4) characteristic of HBV-PAN [11]

2. Unknown Trigger (Idiopathic):

   • Hypothesised infectious or environmental trigger
   • Possible genetic susceptibility (HLA associations unclear)
   • T-cell and B-cell activation
   • Cytokine dysregulation (TNF-α, IL-1, IL-6, IL-17)

Phase 2: Inflammation and Necrosis

3. Segmental Necrotising Inflammation:

   • Transmural inflammation of medium-sized muscular artery wall
   • Neutrophil infiltration (acute phase)
   • Release of proteolytic enzymes (elastase, myeloperoxidase)
   • Reactive oxygen species generation

4. Fibrinoid Necrosis:

   • Destruction of vessel wall architecture
   • Deposition of fibrin, immunoglobulins, complement
   • Loss of internal elastic lamina
   • Eosinophilic homogeneous appearance on histology (fibrinoid change)

Phase 3: Structural Damage

5. Aneurysm Formation:

   • Weakening of arterial wall (destruction of media layer)
   • Formation of microaneurysms (1-5mm)
   • Predilection for vessel bifurcations (haemodynamic stress points)
   • Risk of rupture (rare but catastrophic)

6. Thrombosis:

   • Endothelial injury exposes prothrombotic surfaces
   • Platelet activation and aggregation
   • Fibrin deposition
   • Vessel occlusion → downstream ischaemia

Phase 4: Healing and Fibrosis

7. Ischaemia / Infarction:

   • End-organ damage from reduced perfusion
   • Tissue necrosis (kidney, bowel, nerve)
   • Release of damage-associated molecular patterns (DAMPs)
   • Further inflammatory amplification

8. Healing Phase:

   • Mononuclear cell infiltration (lymphocytes, macrophages)
   • Granulation tissue formation
   • Fibrosis of vessel wall
   • Luminal stenosis
   • Segmental nature: Different stages coexist in same patient (acute + healing)

Key Pathological Features

Pathophysiological Consequences by Organ System

Why Medium Vessels?

---

4. Classification and Diagnostic Criteria

Chapel Hill Consensus Conference (2012)

PAN Definition: Necrotising arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. Not associated with ANCA. [2]

Key Distinctions:

• Differentiates PAN from ANCA-associated vasculitides (GPA, MPA, EGPA)
• Emphasizes absence of small vessel involvement
• Emphasizes ANCA-negative status

Clinical Subtypes

American College of Rheumatology (ACR) 1990 Criteria

For classification (not diagnosis). ≥3 of 10 criteria = 82% sensitivity, 87% specificity. [12]

Limitations:

• Developed before ANCA testing widespread
• Includes patients now classified as MPA under Chapel Hill
• Better for classification (research) than diagnosis (clinical practice)

Five-Factor Score (FFS) - Prognostic Tool [10]

Original FFS (1996) - Each factor = 1 point:

1. Proteinuria > 1g/day
2. Renal insufficiency (Creatinine > 140 µmol/L or 1.58 mg/dL)
3. GI involvement
4. Cardiomyopathy
5. CNS involvement

Revised FFS (2009) - Removed proteinuria (not independent predictor):

• Same 5 factors, but ENT involvement had protective effect in EGPA (not applicable to PAN)

Interpretation:

Clinical Application:

• Use to guide treatment intensity at diagnosis
• Re-evaluate if relapse occurs
• Not a diagnostic tool (requires confirmed PAN diagnosis first)

---

5. Clinical Presentation

Constitutional Symptoms (> 50% of patients)

Organ-Specific Manifestations

Peripheral Nervous System (50-70%) [8]

Clinical Tip: Mononeuritis multiplex onset is typically acute (patient can recall exact day/time), unlike gradual symmetric polyneuropathies.

Skin (25-60%) [13]

Cutaneous PAN: Isolated skin involvement. No systemic features. Better prognosis. May be associated with streptococcal infection (controversial).

Gastrointestinal Tract (30-50%) [14]

Red Flag: Acute abdominal pain in PAN patient = mesenteric ischaemia until proven otherwise. Requires urgent CT angiography.

Kidney (30-50%) [15]

Critical Distinction: NO glomerulonephritis in PAN. Urinalysis shows haematuria but NOT RBC casts (which indicate glomerular bleeding). Presence of RBC casts/dysmorphic RBCs should prompt consideration of MPA or other ANCA-associated vasculitis.

Musculoskeletal (40-60%)

Biopsy: Muscle biopsy (symptomatic muscle) may show arteritis. Combined muscle + nerve biopsy increases diagnostic yield.

Cardiac (10-20%)

Cardiac involvement is an FFS factor (cardiomyopathy specifically) and indicates poor prognosis.

Central Nervous System (5-10%) [16]

CNS involvement is an FFS factor and indicates poor prognosis and need for aggressive treatment.

Testicular (10-20%)

Clinical Pearl: Testicular pain in a middle-aged man with systemic symptoms → consider PAN.

Eyes (5-10%)

Uveitis is rare (unlike Behçet's disease). If prominent uveitis present, consider alternative diagnosis.

Classic Triad (Historical)

1. Systemic symptoms (fever, weight loss, malaise)
2. Mononeuritis multiplex (peripheral neuropathy)
3. Visceral involvement (kidney, GI, skin)

Atypical Presentations

---

6. Investigations

Laboratory Tests

Haematology

Inflammatory Markers

Biochemistry

Immunology

Virology

ALWAYS screen for HBV in all PAN cases. Treatment paradigm completely different for HBV-PAN vs idiopathic PAN.

Urinalysis

Imaging

Conventional Angiography (Gold Standard for Vascular Imaging) [9]

Advantages:

• High spatial resolution (detects small aneurysms)
• Definitive visualization of characteristic findings
• Allows intervention if needed (rarely)

Disadvantages:

• Invasive
• Contrast-related risks (nephrotoxicity, allergic reactions)
• Radiation exposure
• Requires specialized expertise

Typical Findings:

• Microaneurysms: 1-5mm, saccular or fusiform, at bifurcations
• Stenoses: Focal narrowing, alternating with aneurysms ("beaded" appearance)
• Occlusions: Complete vessel cutoff
• Tortuosity: Irregular vessel course

Sensitivity: 60-90% (depends on extent of disease and vessels imaged)

"Beading" Sign: Alternating areas of stenosis and aneurysmal dilatation → resembles string of beads or rosary.

CT Angiography (CTA)

Typical Findings:

• Larger microaneurysms (> 3mm)
• Vessel stenoses/occlusions
• Bowel wall thickening (ischaemia)
• Renal/splenic infarcts (wedge-shaped, non-enhancing)

MR Angiography (MRA)

Ultrasound

Contrast-Enhanced Ultrasound (CEUS)

Limited availability. Research tool more than routine clinical practice.

Cross-Sectional Imaging (CT/MRI)

Histopathology (Biopsy)

Biopsy Site Selection

Combined Muscle + Nerve Biopsy: Preferred approach if neuropathy present. Single incision (calf). Sural nerve + gastrocnemius muscle. Increases diagnostic yield to 60-80%.

Histopathological Findings

Immunofluorescence: May show IgM, C3 deposition in vessel walls (HBV-PAN). Non-specific. Not routinely required.

Immunohistochemistry: CD68 (macrophages), CD3/CD20 (T/B cells) help characterize infiltrate.

Electron Microscopy: Rarely needed. May show immune complex deposits (HBV-PAN).

Staging of Lesions

Different stages coexist in the same patient (even in adjacent vessels) → characteristic of PAN.

Nerve Conduction Studies (NCS) and Electromyography (EMG)

Utility: Confirms neuropathy pattern. Guides nerve biopsy site (select affected nerve). Monitor response to treatment.

Echocardiography

Electrocardiography (ECG)

Additional Tests

---

7. Differential Diagnosis

Vasculitides

ANCA-Associated Vasculitides (AAV)

Key Discriminator: ANCA status and absence of glomerulonephritis/lung involvement in PAN. [17]

Other Systemic Vasculitides

Infectious Endocarditis

Why Consider: Both have fever, systemic symptoms, elevated inflammatory markers, multiorgan involvement.

Cholesterol Embolism Syndrome (Atheroembolic Disease)

Why Consider: Livedo, renal impairment, multisystem disease in older patient with atherosclerosis.

Connective Tissue Diseases with Vasculitis

Thrombotic Microangiopathies

Malignancy

Infectious Diseases

Drug-Induced Vasculitis

---

8. Management

Diagnostic Confirmation Checklist

Before initiating treatment, confirm diagnosis:

• ✅ Clinical features consistent (constitutional + multisystem)
• ✅ Elevated inflammatory markers (ESR, CRP)
• ✅ ANCA negative
• ✅ HBV status determined (HBsAg, anti-HBc, HBV DNA if positive)
• ✅ Angiography (microaneurysms, stenoses) OR Biopsy (necrotising arteritis)
• ✅ Alternative diagnoses excluded (especially AAV, endocarditis)

Management Algorithm

       SUSPECTED PAN
       (Constitutional symptoms + Multisystem involvement +
        Mononeuritis multiplex / Skin / GI / Renal)
                     ↓
       INVESTIGATIONS
       - Inflammatory markers (ESR, CRP)
       - ANCA (Should be NEGATIVE)
       - Hepatitis B & C serology (HBsAg, anti-HBc, HBV DNA, anti-HCV)
       - Angiography (Mesenteric/Renal) → Microaneurysms, stenoses
       - Biopsy (Skin, Nerve, Muscle) → Necrotising arteritis
       - Exclude differentials (blood cultures, ANA, cryoglobulins)
                     ↓
       CONFIRM DIAGNOSIS
       (Clinical features + ANCA-negative + Angiography/Biopsy)
                     ↓
       DETERMINE HBV STATUS
    ┌────────────────┴────────────────┐
 HBV-ASSOCIATED                   IDIOPATHIC (HBV-Negative)
    ↓                                 ↓
 **ANTIVIRAL THERAPY**             ASSESS SEVERITY (Five-Factor Score)
 + Short-course Corticosteroids    
 ± Plasma Exchange                   ↓
 (Entecavir 0.5-1mg PO daily OR      
  Tenofovir 245mg PO daily)        
                     ↓
       IDIOPATHIC PAN SEVERITY (Five-Factor Score – FFS)
    ┌──────────────────────────────────────────────────────────┐
    │  **FFS Factors (Each = 1 Point)**                        │
    │  1. Proteinuria > 1g/day                                  │
    │  2. Renal insufficiency (Creatinine > 140 µmol/L)         │
    │  3. GI involvement (mesenteric ischaemia)                │
    │  4. Cardiomyopathy (heart failure, reduced LVEF)         │
    │  5. CNS involvement (stroke, seizures)                   │
    │                                                          │
    │  **FFS = 0**: Lower mortality (~12%).                    │
    │    → Corticosteroids alone may be sufficient.            │
    │  **FFS ≥ 1**: Higher mortality (~26-46%).                │
    │    → Corticosteroids + Cyclophosphamide.                 │
    └──────────────────────────────────────────────────────────┘
                     ↓
       TREATMENT (Idiopathic PAN)
    ┌──────────────────────────────────────────────────────────┐
    │  **INDUCTION (3-6 Months)**                              │
    │  ───────────────────────────                             │
    │  **Corticosteroids**:                                    │
    │  - Prednisolone 1mg/kg/day PO (Max 60-80mg daily)        │
    │  - IV Methylprednisolone 500mg-1g daily x 3 days for     │
    │    severe/life-threatening disease                       │
    │  - Continue high-dose for 2-4 weeks, then taper          │
    │                                                          │
    │  **Cyclophosphamide** (if FFS ≥1 or severe disease):     │
    │  - IV Pulse: 15mg/kg (max 1.2g) every 2 weeks x 3, then │
    │    every 3 weeks to 6 months total (6-10 doses)          │
    │  - OR Oral: 2mg/kg/day (adjust for age, renal function) │
    │  - Reduce dose in elderly, renal impairment              │
    │  - Co-prescribe:                                         │
    │    • Mesna (uroprotection if IV route)                   │
    │    • PCP prophylaxis (co-trimoxazole 480mg daily or      │
    │      960mg 3x/week)                                      │
    │    • Antiemetics                                         │
    │    • Fertility counselling (cyclophosphamide is          │
    │      gonadotoxic)                                        │
    │                                                          │
    │  **Alternative to Cyclophosphamide**:                    │
    │  - Rituximab (375mg/m² weekly x 4, or 1g x 2 doses 2     │
    │    weeks apart) - emerging evidence, not yet standard    │
    │                                                          │
    │  **Plasma Exchange** (if severe, refractory):            │
    │  - 7-9 exchanges over 2-3 weeks                          │
    │  - Replace with albumin or FFP                           │
    │                                                          │
    │  **MAINTENANCE (12-24 Months After Remission)**          │
    │  ───────────────────────────────────────────             │
    │  - **Prednisolone**: Taper to 5-10mg daily over 12-18    │
    │    months. Some require low-dose long-term.              │
    │  - **Azathioprine**: 2mg/kg/day (check TPMT first)       │
    │    OR                                                    │
    │  - **Methotrexate**: 15-25mg weekly (if normal renal     │
    │    function) + folic acid 5mg weekly                     │
    │  - **Mycophenolate Mofetil**: 2g daily (alternative)     │
    │                                                          │
    │  **Duration**: 12-24 months minimum. Longer if relapses. │
    └──────────────────────────────────────────────────────────┘
                     ↓
       HBV-ASSOCIATED PAN TREATMENT
    ┌──────────────────────────────────────────────────────────┐
    │  **ANTIVIRAL THERAPY (Cornerstone)**                     │
    │  - **Entecavir**: 0.5-1mg PO daily (preferred)           │
    │    OR                                                    │
    │  - **Tenofovir**: 245mg PO daily                         │
    │  - Duration: Long-term (usually lifelong if HBV not      │
    │    cleared; at least 12 months minimum)                  │
    │  - Monitor HBV DNA (aim for undetectable)                │
    │  - Monitor LFTs                                          │
    │                                                          │
    │  **SHORT-COURSE Corticosteroids**                        │
    │  - Prednisolone 1mg/kg/day for 2 weeks, then rapid taper │
    │    over 2-4 weeks (total ~4-6 weeks)                     │
    │  - Goal: Control acute inflammation while antivirals     │
    │    take effect                                           │
    │  - **AVOID prolonged steroids** (promote HBV             │
    │    replication)                                          │
    │                                                          │
    │  **PLASMA EXCHANGE** (if severe)                         │
    │  - 7-9 sessions over 2-3 weeks                           │
    │  - Removes immune complexes                              │
    │  - Indicated for severe organ involvement (GI, cardiac,  │
    │    CNS)                                                  │
    │                                                          │
    │  **AVOID**:                                              │
    │  - Cyclophosphamide or other long-term immunosuppression │
    │    (promotes viral replication, impairs HBV clearance)   │
    │  - Exception: Life-threatening disease may require brief │
    │    cyclophosphamide + plasma exchange while antivirals   │
    │    initiated                                             │
    └──────────────────────────────────────────────────────────┘
                     ↓
       SUPPORTIVE CARE
       ──────────────
       - **Hypertension Control**:
         • ACEi/ARB (renovascular HTN, proteinuria)
         • Calcium channel blockers
         • Beta-blockers (cardiac involvement)
         • Target BP less than 130/80 mmHg
       
       - **Analgesia**:
         • Paracetamol, opioids for neuropathic pain
         • Neuropathic agents (gabapentin, pregabalin, duloxetine)
       
       - **Physiotherapy**:
         • For mononeuritis multiplex
         • Prevent contractures
         • Gait training (foot drop → AFO)
       
       - **Antiplatelet Therapy** (controversial):
         • Aspirin 75mg (if high thrombotic risk, no bleeding)
         • Balance thrombosis risk vs bleeding risk
       
       - **Gastroprotection**:
         • PPI (omeprazole 20mg daily) while on steroids
       
       - **Bone Protection**:
         • Vitamin D + Calcium supplementation
         • Bisphosphonate (alendronate 70mg weekly) if long-term steroids
         • DEXA scan baseline and monitor
       
       - **PCP Prophylaxis**:
         • Co-trimoxazole 480mg daily or 960mg 3x/week
         • While on cyclophosphamide or prednisolone > 20mg daily x > 1 month
       
       - **Vaccination**:
         • Pneumococcal (before immunosuppression if possible)
         • Annual influenza
         • Avoid live vaccines while immunosuppressed
       
       - **VTE Prophylaxis**:
         • LMWH if hospitalized
       
       - **Fertility Counselling**:
         • Cyclophosphamide is gonadotoxic
         • Discuss sperm banking / oocyte preservation before treatment
       
       - **Psychological Support**:
         • Chronic disease, steroid side effects
                     ↓
       MONITORING DISEASE ACTIVITY
       ──────────────────────────
       **Clinical**:
       - Constitutional symptoms (fever, weight, malaise)
       - Organ-specific symptoms (neuropathy progression, skin lesions, abdominal pain)
       
       **Laboratory**:
       - ESR, CRP (every 4-12 weeks initially, then less frequent)
       - FBC (anaemia, leucocytosis)
       - U&Es, eGFR (renal function)
       - Urinalysis (haematuria, proteinuria)
       - LFTs (if liver involvement or on methotrexate/azathioprine)
       
       **Imaging**:
       - Repeat angiography NOT routinely required
       - CT/MRI if new organ involvement suspected
       
       **Treatment Toxicity Monitoring**:
       - FBC (cyclophosphamide myelosuppression - check every 2 weeks initially)
       - Urinalysis (cyclophosphamide haemorrhagic cystitis)
       - Blood glucose (steroid-induced diabetes)
       - Blood pressure (steroid-induced hypertension)
       - Bone density (DEXA if long-term steroids)
       - Infection surveillance (opportunistic infections)
                     ↓
       REMISSION CRITERIA
       ─────────────────
       - Resolution of constitutional symptoms
       - No new or progressive organ involvement
       - Normalization of inflammatory markers (ESR, CRP)
       - Stable/improved organ function
                     ↓
       RELAPSE RECOGNITION (10-20% of patients)
       ────────────────────────────────────────
       **Signs of Relapse**:
       - Recurrence of constitutional symptoms
       - New organ involvement
       - Rising ESR/CRP
       - Worsening organ function (renal, neurological)
       
       **Action**:
       - Increase corticosteroids (back to induction dose)
       - Consider cyclophosphamide if not previously used or if severe
       - Consider rituximab if cyclophosphamide-refractory
       - Re-evaluate HBV status (if HBV-PAN, check compliance with antivirals, HBV DNA levels)
                     ↓
       REFRACTORY DISEASE
       ─────────────────
       **Definition**: Failure to achieve remission despite:
       - Adequate dose corticosteroids (prednisolone 1mg/kg x 4 weeks)
       - AND cyclophosphamide (at least 3 months)
       
       **Options**:
       - **Rituximab**: 375mg/m² weekly x 4, or 1g x 2 (2 weeks apart)
       - **Plasma Exchange**: If not already tried
       - **IV Immunoglobulin (IVIg)**: 2g/kg over 2-5 days (case reports)
       - **TNF Inhibitors**: Infliximab, etanercept (case reports, limited evidence)
       - **Tocilizumab** (IL-6 inhibitor): Case reports
       - **Clinical Trial**: Novel agents
                     ↓
       SURGICAL MANAGEMENT (Selected Cases)
       ────────────────────────────────────
       **Indications**:
       - **Bowel Perforation**: Emergency laparotomy, resection
       - **Bowel Infarction**: Resection of necrotic bowel
       - **Acute Abdomen**: Diagnostic/therapeutic laparotomy
       - **Aneurysm Rupture**: Rare, emergency surgery/embolization
       - **Cholecystitis**: Cholecystectomy (often acalculous)
       - **Appendicitis**: Appendectomy
       - **Testicular Torsion (Mimic)**: If torsion cannot be excluded
       
       **Peri-operative Considerations**:
       - Continue immunosuppression
       - Stress-dose corticosteroids (if on long-term steroids)
       - VTE prophylaxis
       - Infection risk (immunosuppressed)

Specific Scenarios

Life-Threatening Disease (Mesenteric Ischaemia, Bowel Perforation, Stroke, Cardiac)

1. IV Methylprednisolone Pulse: 500mg-1g daily x 3 days
2. Cyclophosphamide: Start immediately (IV pulse 15mg/kg)
3. Plasma Exchange: Consider 7-9 exchanges
4. Surgical Intervention: If bowel perforation, peritonitis, or infarction
5. Intensive Care: Multi-organ support

Cutaneous PAN (Limited Disease)

1. Mild-Moderate: Prednisolone 0.5-1mg/kg/day, taper over 6-12 months
2. Maintenance: Colchicine (0.5-1mg daily) or hydroxychloroquine (200-400mg daily)
3. Avoid Cyclophosphamide: Not usually needed

Relapse During Steroid Taper

1. Increase Prednisolone: Back to previously effective dose (usually 0.5-1mg/kg)
2. Add/Restart: Steroid-sparing agent (azathioprine, methotrexate)
3. If Severe Relapse: Consider cyclophosphamide or rituximab

Pregnancy and PAN

• Pre-conception Counselling: Ideally achieve remission before pregnancy
• Medication Adjustments:
  • "Continue: Prednisolone (placental metabolism, safe), azathioprine (safe in pregnancy)"
  • "AVOID: Cyclophosphamide (teratogenic), methotrexate (teratogenic), mycophenolate (teratogenic)"
• Monitoring: Close surveillance (relapse risk ~20%)
• Delivery: MDT approach (rheumatology, obstetrics, anaesthetics)

Elderly Patients

• Lower Cyclophosphamide Doses: Reduce by 25-50% (myelosuppression risk)
• Infection Vigilance: Higher risk opportunistic infections
• Bone Protection: Mandatory (osteoporosis risk)
• Renal Dosing: Adjust for age-related GFR decline

---

9. Complications

Acute Complications (During Active Disease)

Chronic Complications (Late, Post-Treatment)

Treatment-Related Complications

Corticosteroids (Prednisolone)

Cyclophosphamide

Azathioprine

Methotrexate

---

10. Prognosis and Outcomes

Historical (Pre-Treatment Era)

Major Causes of Death: Mesenteric ischaemia/perforation, renal failure, stroke, MI.

Modern Era (With Immunosuppression) [18]

Prognostic Factors

Five-Factor Score (FFS) - Most Important [10]

2009 Revised FFS: Excluded proteinuria as not independently predictive.

Other Prognostic Factors

Poor Prognosis:

Good Prognosis:

Long-Term Outcomes

Mortality Causes (Modern Era)

Relapse Pattern

Relapse Triggers: Steroid taper too rapid, infection, unknown triggers.

Comparison: HBV-PAN vs Idiopathic PAN

---

11. Evidence and Guidelines

Key Guidelines

Landmark Studies

Evidence Quality Summary

Gaps in Evidence

• Optimal Maintenance Duration: 12 vs 24 months not rigorously tested
• Rituximab Role: No RCTs in PAN (AAV data suggests efficacy)
• Optimal Cyclophosphamide Regimen: IV pulse vs oral in PAN specifically
• Biomarkers: No disease-specific biomarker (vs ANCA in AAV)

---

12. Patient and Layperson Explanation

What is Polyarteritis Nodosa?

Polyarteritis Nodosa (PAN) is a rare condition where the body's immune system mistakenly attacks medium-sized blood vessels, causing inflammation. This inflammation damages the blood vessel walls, which can weaken them (forming small balloon-like swellings called aneurysms) or narrow them (reducing blood flow).

When blood vessels are damaged, the organs they supply don't get enough blood and oxygen, which causes symptoms.

What causes it?

In most cases, we don't know what triggers PAN (called "idiopathic"). In some people, it is linked to Hepatitis B virus infection (a liver virus), but this is now rare in developed countries due to vaccination.

What are the symptoms?

Symptoms depend on which blood vessels (and therefore which organs) are affected:

• General symptoms: Fever, weight loss, fatigue, muscle aches
• Nerves: Sudden weakness or numbness in hands or feet (e.g., foot drop, difficulty walking)
• Skin: Rash, painful lumps under the skin, ulcers
• Tummy: Severe abdominal pain (especially after eating), blood in stool
• Kidneys: High blood pressure, blood in urine
• Other: Testicular pain (men), chest pain, headaches

How is it diagnosed?

• Blood tests: Look for inflammation and check for viruses like Hepatitis B. An important test called ANCA is negative in PAN (this helps distinguish it from similar conditions).
• Angiogram: A special X-ray of blood vessels that shows characteristic changes (small aneurysms, narrowing)
• Biopsy: Taking a small sample of tissue (e.g., skin, nerve) to look at under a microscope

How is it treated?

The goal is to stop the inflammation and prevent organ damage:

1. Steroids (e.g., prednisolone): Powerful anti-inflammatory medication. Usually started at high dose, then gradually reduced.

2. Immunosuppressants (e.g., cyclophosphamide): If the disease is severe, stronger medications are needed to suppress the immune system.

3. Antivirals (if Hepatitis B is the cause): Medications to treat the virus (e.g., entecavir, tenofovir).

4. Supportive treatments:

   • Blood pressure medications
   • Pain relief
   • Physiotherapy (for nerve problems)

What is the outlook?

• With treatment, most people do well. About 80-90% of patients are alive 5 years after diagnosis.
• Without treatment, PAN was historically very serious (50% mortality at 1 year).
• Some people may have long-term effects (e.g., persistent nerve damage, kidney problems, high blood pressure).
• The disease can sometimes come back (relapse), so regular follow-up is important.

How long is treatment?

• Steroids: Usually 12-24 months, gradually reduced
• Immunosuppressants: 12-24 months (sometimes longer)
• Antivirals (if Hepatitis B): Long-term (often years)

What should I watch out for?

See your doctor urgently if:

• Severe abdominal pain (could indicate bowel problems)
• Sudden weakness or numbness
• Chest pain or difficulty breathing
• Signs of infection (fever, cough) - you are more prone to infections on treatment

Living with PAN

• Take medications as prescribed: Don't stop suddenly (especially steroids)
• Attend all follow-up appointments: Regular blood tests and check-ups are essential
• Report new symptoms early: Early treatment of relapses improves outcomes
• Infection prevention: Vaccinations (flu, pneumonia), good hygiene, avoid sick contacts
• Healthy lifestyle: Balanced diet, exercise (as able), don't smoke
• Bone health: Steroids can weaken bones → ensure adequate calcium/vitamin D

Support and Resources

• Rare disease organizations (e.g., Vasculitis UK, Vasculitis Foundation)
• Patient information leaflets from rheumatology departments
• Genetic counselling (if family planning) - discuss with your doctor

---

13. References

Primary Sources

1. Hernández-Rodríguez J, et al. Polyarteritis nodosa. Rheum Dis Clin North Am. 2019;45(4):525-543. PMID: 31564351. DOI: 10.1016/j.rdc.2019.07.003.

2. Jennette JC, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. PMID: 23045170. DOI: 10.1002/art.37715.

3. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa: a systematic retrospective study of patients diagnosed between 1963 and 2005 and entered into the French Vasculitis Study Group Database. Arthritis Rheum. 2010;62(2):616-626. PMID: 20112390. DOI: 10.1002/art.27240.

4. Guillevin L, et al. Polyarteritis nodosa and microscopic polyangiitis. Clinical aspects and treatment. Autoimmun Rev. 2017;16(9):989-996. PMID: 28572047. DOI: 10.1016/j.autrev.2017.05.021.

5. Ntatsaki E, Watts RA, Scott DG. Epidemiology of ANCA-associated vasculitis. Rheum Dis Clin North Am. 2010;36(3):447-461. PMID: 20688243. DOI: 10.1016/j.rdc.2010.04.002.

6. Guillevin L, Pagnoux C. When should immunosuppressants be prescribed to treat systemic vasculitides? Intern Med. 2003;42(4):313-317. PMID: 12793704. DOI: 10.2169/internalmedicine.42.313.

7. Mukhtyar C, et al. EULAR recommendations for the management of primary small and medium vessel vasculitis. Ann Rheum Dis. 2009;68(3):310-317. PMID: 18413444. DOI: 10.1136/ard.2008.088096.

8. Collins MP, Hadden RD. The nonsystemic vasculitic neuropathies. Nat Rev Neurol. 2017;13(5):302-316. PMID: 28367026. DOI: 10.1038/nrneurol.2017.42.

9. Stanson AW, et al. Polyarteritis nodosa: spectrum of angiographic findings. Radiographics. 2001;21(1):151-159. PMID: 11158651. DOI: 10.1148/radiographics.21.1.g01ja14151.

10. Guillevin L, et al. Prognostic factors in polyarteritis nodosa and Churg-Strauss syndrome. A prospective study in 342 patients. Medicine (Baltimore). 1996;75(1):17-28. PMID: 8569467. DOI: 10.1097/00005792-199601000-00003.

11. Guillevin L, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313-322. PMID: 16148730. DOI: 10.1097/01.md.0000180792.80212.5e.

12. Lightfoot RW Jr, et al. The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990;33(8):1088-1093. PMID: 1975174. DOI: 10.1002/art.1780330805.

13. Khoo BP, Ng SK. Cutaneous polyarteritis nodosa: a case report and literature review. Ann Acad Med Singapore. 1998;27(6):868-872. PMID: 10101566.

14. Ha HK, et al. Radiologic features of vasculitis involving the gastrointestinal tract. Radiographics. 2000;20(3):779-794. PMID: 10835127. DOI: 10.1148/radiographics.20.3.g00ma18779.

15. Jennette JC, Falk RJ. Small-vessel vasculitis. N Engl J Med. 1997;337(21):1512-1523. PMID: 9366584. DOI: 10.1056/NEJM199711203372106.

16. Siva A. Vasculitis of the nervous system. J Neurol. 2001;248(6):451-468. PMID: 11499636. DOI: 10.1007/s004150170123.

17. Kallenberg CG. Key advances in the clinical approach to ANCA-associated vasculitis. Nat Rev Rheumatol. 2014;10(8):484-493. PMID: 24890776. DOI: 10.1038/nrrheum.2014.104.

18. Pagnoux C, Seror R, Henegar C, et al. Clinical features and outcomes in 348 patients with polyarteritis nodosa. Arthritis Rheum. 2010;62(2):616-626. PMID: 20112390. DOI: 10.1002/art.27240.

19. Yates M, et al. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis. 2016;75(9):1583-1594. PMID: 27338776. DOI: 10.1136/annrheumdis-2016-209133.

20. Guillevin L, et al. The Five-Factor Score revisited: assessment of prognoses of systemic necrotizing vasculitides based on the French Vasculitis Study Group (FVSG) cohort. Medicine (Baltimore). 2011;90(1):19-27. PMID: 21200183. DOI: 10.1097/MD.0b013e318205a4c6.

21. Pagnoux C, et al. Azathioprine or methotrexate maintenance for ANCA-associated vasculitis. N Engl J Med. 2008;359(26):2790-2803. PMID: 18625621. DOI: 10.1056/NEJMoa0802311.

22. Watts RA, et al. Epidemiology of systemic vasculitis: changing incidence or definition? Semin Arthritis Rheum. 2011;40(5):389-395. PMID: 20828791. DOI: 10.1016/j.semarthrit.2010.07.002.

---

14. Examination Focus

Common Exam Questions (MCQ/SBA)

1. ANCA Status in PAN

   • Q: "A 50-year-old man presents with fever, weight loss, mononeuritis multiplex, and livedo reticularis. Blood tests show elevated ESR and CRP. Which test result would support a diagnosis of polyarteritis nodosa?"
   • A: ANCA negative. PAN is ANCA-negative by definition. ANCA positivity suggests AAV.

2. Classic Neurological Manifestation

   • Q: "What is the most characteristic neurological finding in polyarteritis nodosa?"
   • A: Mononeuritis multiplex (asymmetric peripheral neuropathy affecting individual named nerves sequentially).

3. Angiographic Finding

   • Q: "What is the characteristic angiographic finding in PAN?"
   • A: Microaneurysms (1-5mm) with stenoses creating a "beaded" or "rosary bead" appearance of mesenteric or renal arteries.

4. Hepatitis Association

   • Q: "Which hepatitis virus is classically associated with polyarteritis nodosa?"
   • A: Hepatitis B Virus (HBV). Now less than 5% of cases in developed countries due to vaccination.

5. Renal Involvement Pattern

   • Q: "Which of the following distinguishes renal involvement in polyarteritis nodosa from microscopic polyangiitis?"
   • A: Absence of glomerulonephritis. PAN causes renal arteritis and infarction, NOT glomerulonephritis. MPA causes pauci-immune glomerulonephritis.

6. Five-Factor Score

   • Q: "Which of the following is NOT a component of the Five-Factor Score in PAN?"
   • A: Options include the 5 FFS factors + decoys. Remember: GI, cardiac, CNS, renal insufficiency, proteinuria (though proteinuria removed in revised FFS).

7. HBV-PAN Treatment

   • Q: "What is the cornerstone of treatment for HBV-associated polyarteritis nodosa?"
   • A: Antiviral therapy (entecavir or tenofovir) + short-course corticosteroids ± plasma exchange. AVOID prolonged immunosuppression.

8. Vessel Size

   • Q: "Which vessel size is primarily affected in polyarteritis nodosa?"
   • A: Medium-sized muscular arteries (100-500 μm diameter).

Viva Voce Points

Opening Statement: "Polyarteritis nodosa is a systemic necrotising vasculitis of medium-sized muscular arteries, characterised by ANCA-negative status, absence of glomerulonephritis, and multisystem involvement including peripheral nerves, skin, GI tract, and kidneys."

Key Differentiators:

• Medium vessels, not small: Distinguishes from ANCA-associated vasculitides
• No glomerulonephritis: Renal involvement is arteritis/infarction, NOT GN (key distinction from MPA)
• ANCA-negative: Essential diagnostic criterion
• Angiography shows microaneurysms: "Beaded" mesenteric/renal arteries

Classic Clinical Scenario: "Middle-aged man with fever, weight loss, livedo reticularis, and acute onset foot drop (peroneal nerve palsy = mononeuritis multiplex). Blood tests show elevated ESR/CRP, ANCA negative, HBsAg positive."

Management Principles:

• Determine HBV status: Fundamentally alters treatment approach
• Five-Factor Score: Guides treatment intensity (FFS ≥1 = corticosteroids + cyclophosphamide)
• HBV-PAN: Antivirals + SHORT steroids (avoid prolonged immunosuppression)
• Idiopathic PAN: Corticosteroids ± cyclophosphamide → maintenance with azathioprine/methotrexate

Prognostic Factors: "Five-Factor Score is the most important prognostic tool. FFS ≥1 indicates higher mortality and need for cyclophosphamide."

Complications: "Most serious acute complications are mesenteric ischaemia with bowel perforation (30-50% mortality if occurs), stroke, and MI. Chronic complications include residual neuropathy, CKD, and renovascular hypertension."

Differential Diagnosis: "Key differentials are ANCA-associated vasculitides (GPA, MPA, EGPA - all ANCA-positive and involve small vessels with GN), infective endocarditis (blood cultures positive), and cholesterol embolism (post-procedure, cholesterol clefts on biopsy)."

OSCE Scenario: History Taking

Scenario: 52-year-old man with 6-week history of weight loss, fever, and recent onset numbness and weakness in right foot.

Key History Points to Elicit:

• Constitutional: Fever pattern, weight loss (quantify), malaise, night sweats
• Neurological: Onset (acute vs gradual), distribution (asymmetric?), previous episodes (other nerves?), functional impact
• Skin: Rashes, nodules, ulcers, mottled discoloration
• GI: Abdominal pain (especially post-prandial), GI bleeding, bowel habit change
• Genitourinary: Haematuria, reduced urine output, testicular pain
• Cardiovascular: Chest pain, palpitations, dyspnoea
• Systemic: Joint pains, muscle pains
• Past Medical History: Hepatitis B (vaccination status, previous infection), other autoimmune diseases
• Drug History: Recent medications, IV drug use
• Family History: Autoimmune diseases, vasculitis

Red Flags to Ask About:

• Severe abdominal pain (mesenteric ischaemia)
• Chest pain (MI)
• Neurological symptoms (stroke)
• Haemoptysis (would suggest alternative diagnosis - NOT PAN)

OSCE Scenario: Examination

Scenario: Examine the peripheral nervous system of this patient with suspected vasculitis.

Findings Consistent with Mononeuritis Multiplex:

• Inspection: Foot drop (peroneal nerve), wrist drop (radial nerve), muscle wasting
• Gait: High-stepping gait (foot drop), difficulty heel walking
• Tone: Normal or reduced (LMN pattern)
• Power: Asymmetric weakness in distribution of specific peripheral nerves
  • "Peroneal: Weak dorsiflexion, eversion"
  • "Ulnar: Weak finger abduction, hypothenar wasting"
  • "Radial: Weak wrist/finger extension"
• Reflexes: Reduced or absent in affected limbs
• Sensation: Asymmetric sensory loss in peripheral nerve distributions
• Coordination: May be impaired by sensory loss

Associated Findings:

• Skin: Livedo reticularis, nodules, ulcers (examine lower limbs, trunk)
• Cardiovascular: BP (hypertension?), peripheral pulses
• General: Cachexia, fever

Presentation: "This patient has an asymmetric lower motor neurone pattern of weakness affecting the right peroneal nerve (foot drop) and left ulnar nerve (hand weakness and sensory loss). The pattern is consistent with mononeuritis multiplex. In combination with [other findings: livedo reticularis, constitutional symptoms], the differential includes systemic vasculitis such as polyarteritis nodosa, diabetes mellitus, sarcoidosis, and leprosy."

Short Answer Question (SAQ)

Q: A 55-year-old man presents with 2-month history of fever, weight loss of 10kg, and painful nodules on his lower legs. He develops sudden onset left foot drop. Investigations show ESR 95 mm/hr, CRP 120 mg/L, ANCA negative, HBsAg positive. Mesenteric angiography shows multiple microaneurysms.

(a) What is the most likely diagnosis? [1 mark]

• A: Hepatitis B virus-associated polyarteritis nodosa (HBV-PAN)

(b) Explain the pathophysiology of this condition. [4 marks]

• A:
  • HBsAg-antibody immune complexes deposit in medium-sized arterial walls [1]
  • Complement activation and neutrophil recruitment cause transmural inflammation [1]
  • Fibrinoid necrosis destroys vessel wall, leading to aneurysm formation and thrombosis [1]
  • Resultant ischaemia/infarction causes end-organ damage (nerve, skin, GI, kidney) [1]

(c) Outline your management plan. [5 marks]

• A:
  • "Antiviral therapy: Entecavir or tenofovir (long-term to suppress HBV) [1]"
  • "Short-course corticosteroids: Prednisolone 1mg/kg/day for 2 weeks, then rapid taper over 2-4 weeks (control acute inflammation while antivirals take effect) [1]"
  • "Plasma exchange: Consider 7-9 sessions (removes immune complexes; indicated for severe disease) [1]"
  • "Supportive care: Antihypertensives, analgesia, physiotherapy for foot drop [1]"
  • "Avoid prolonged immunosuppression (cyclophosphamide): Promotes HBV replication [1]"

---

Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.