Overview
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. PAN is rare, with an incidence of ~2-9 per million. It can be Idiopathic or associated with Hepatitis B Virus (HBV) infection (Classic association, Now rare due to vaccination). PAN affects multiple organ systems, most commonly Peripheral Nerves (Mononeuritis Multiplex), Skin (Livedo Reticularis, Nodules, Ulcers), Gastrointestinal Tract (Mesenteric Ischaemia), Kidney (Renal Arteritis, NOT Glomerulonephritis), and Muscles/Joints. Diagnosis is based on clinical features, Angiography (Showing microaneurysms, Stenoses), and Biopsy (Medium-vessel necrotising arteritis). Treatment involves High-Dose Corticosteroids ± Cyclophosphamide for severe disease, And Antiviral therapy for HBV-associated PAN. [1,2,3]
Clinical Pearls
"Medium Vessels, ANCA-Negative": PAN affects medium arteries. It is NOT associated with ANCA (Differentiates from GPA, MPA).
"Mononeuritis Multiplex": Asymmetric peripheral neuropathy affecting individual named nerves. Classic PAN feature.
"Hepatitis B Association": Always screen for HBV. HBV-PAN treated with antivirals + Short-course steroids ± Plasma exchange.
"Microaneurysms on Angiography": Beaded appearance of mesenteric or renal arteries. Characteristic.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Incidence | Rare. ~2-9 per million per year. |
| Age | Peak 40-60 years. Can occur at any age. |
| Sex | Male > Female (~2:1). |
Association
| Association | Notes |
|---|---|
| Hepatitis B Virus (HBV) | Classic association. ~10-30% historically. Now rare (less than 5% in developed countries due to HBV vaccination). |
| Hepatitis C Virus (HCV) | Weaker association. More commonly associated with Cryoglobulinaemic vasculitis. |
| Idiopathic | Majority of current cases. |
| Hairy Cell Leukaemia | Rare association. |
3. Pathophysiology
Mechanism
- Immune Complex Deposition (In HBV-associated) or Unknown Trigger (Idiopathic).
- Segmental Necrotising Inflammation of medium-sized muscular artery wall.
- Fibrinoid Necrosis: Destruction of vessel wall.
- Aneurysm Formation: Weakened wall → Microaneurysms (1-5mm).
- Thrombosis: Occlusion of affected vessel.
- Ischaemia / Infarction: End-organ damage.
- Healing: Fibrosis, Stenosis.
Key Pathological Features
| Feature | Notes |
|---|---|
| Segmental Involvement | Patchy. Normal segments adjacent to affected. |
| All Layers Affected | Panarteritis (Intima, Media, Adventitia). |
| Fibrinoid Necrosis | Of vessel wall. |
| Inflammatory Infiltrate | Polymorphonuclear cells (Acute), Mononuclear (Chronic). |
| Aneurysms | Microaneurysms at vessel bifurcations. |
| Thrombosis | |
| Sparing of Small Vessels | No capillaries, Venules, Arterioles. No glomerulonephritis. |
4. Classification
Chapel Hill Consensus Conference (2012)
- PAN: Necrotising arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, Capillaries, or venules. ANCA-negative.
- Differentiates PAN from ANCA-associated vasculitides (GPA, MPA, EGPA).
Clinical Subtypes
| Subtype | Notes |
|---|---|
| Systemic (Classic) PAN | Multi-organ involvement. |
| Cutaneous PAN | Limited to skin. Nodules, Livedo, Ulcers. Better prognosis. |
| HBV-Associated PAN | Associated with Hepatitis B. Treated with antivirals. |
5. Clinical Presentation
Constitutional Symptoms
| Symptom | Notes |
|---|---|
| Fever | Common. |
| Weight Loss | Significant. |
| Malaise / Fatigue | |
| Myalgia / Arthralgia |
Organ-Specific Manifestations
| System | Manifestations |
|---|---|
| Peripheral Nervous System (~50-70%) | Mononeuritis Multiplex: Asymmetric neuropathy. Foot drop (Peroneal), Wrist drop (Radial). Sensory and motor. May progress to confluent polyneuropathy. |
| Skin (~25-60%) | Livedo Reticularis. Subcutaneous Nodules (Along vessels). Ulcers. Purpura (Large vessel). Digital ischaemia/Gangrene. |
| Gastrointestinal (~30-50%) | Abdominal pain (Mesenteric ischaemia). GI bleeding. Bowel infarction/Perforation. Cholecystitis. Appendicitis. |
| Kidney (~30-50%) | Renal arteritis → Hypertension (Renovascular). Renal infarction. Haematuria (Renal infarct). NO Glomerulonephritis (Differentiates from MPA). |
| Musculoskeletal | Myalgia. Arthralgia (Non-erosive). |
| Cardiac | Coronary arteritis → MI (Rare). Cardiomyopathy. Pericarditis. |
| CNS | Stroke (Rare). Seizures. |
| Testicular (~10-20%) | Orchitis. Testicular pain. |
| Eyes | Retinal vasculitis (Rare). |
Classic Features
| Feature | Notes |
|---|---|
| Mononeuritis Multiplex | Highly suggestive. |
| Livedo Reticularis + Nodules | Skin involvement. |
| Mesenteric Ischaemia | Abdominal pain, Bloody stool. |
| Renovascular Hypertension | Without glomerulonephritis. |
| Constitutional Symptoms |
6. Investigations
Laboratory
| Test | Findings |
|---|---|
| FBC | Normocytic anaemia (Chronic disease). Leucocytosis. Thrombocytosis. |
| Inflammatory Markers | ESR and CRP markedly elevated. |
| U&Es | May show renal impairment (Infarction). |
| LFTs | May be deranged (HBV, Liver infarction). |
| ANCA | Negative (Key distinction from GPA, MPA). |
| Hepatitis Serology | HBsAg, Anti-HBc, HBV DNA. HCV. Always test. |
| Complement | May be low in HBV-associated (Immune complex). Usually normal in idiopathic. |
| CK | May be elevated (Myositis). |
| Urinalysis | Haematuria (Renal infarct). No RBC casts (No glomerulonephritis). Proteinuria may occur. |
Imaging
| Modality | Findings |
|---|---|
| Conventional Angiography (Mesenteric/Renal) | Gold Standard. Microaneurysms (1-5mm). Stenoses. "Beaded" appearance. Vessel occlusions. |
| CT/MR Angiography | May show larger aneurysms and stenoses. Less sensitive for small aneurysms. |
Biopsy
| Site | Notes |
|---|---|
| Affected Organ | Skin, Sural nerve (If neuropathy), Muscle, Kidney, Testis. |
| Findings | Necrotising arteritis of medium-sized vessels. Fibrinoid necrosis. Inflammatory infiltrate. All stages may coexist (Acute + Healing). |
| Yield | Sampling error due to segmental nature. Angiography may be preferred if biopsy site unclear. |
7. Management
Management Algorithm
SUSPECTED PAN
(Constitutional symptoms + Multi-organ involvement +
Mononeuritis multiplex / Skin / GI / Renal)
↓
INVESTIGATIONS
- Inflammatory markers (ESR, CRP)
- ANCA (Should be Negative)
- Hepatitis B & C serology
- Angiography (Mesenteric/Renal) → Microaneurysms
- Biopsy (Skin, Nerve, Muscle) → Necrotising arteritis
↓
CONFIRM DIAGNOSIS
(ACR Criteria or Chapel Hill + Biopsy/Angiography)
↓
HBV STATUS
┌────────────────┴────────────────┐
HBV-ASSOCIATED IDIOPATHIC (HBV-Negative)
↓ ↓
**ANTIVIRAL THERAPY** ASSESS SEVERITY (Five-Factor Score)
+ Short-course Corticosteroids
± Plasma Exchange ↓
(Entecavir or Tenofovir)
↓
IDIOPATHIC PAN SEVERITY (Five-Factor Score – FFS)
┌──────────────────────────────────────────────────────────┐
│ **FFS Factors (Each = 1 Point)** │
│ - Proteinuria >1g/day │
│ - Renal insufficiency (Creatinine >140 µmol/L) │
│ - GI involvement │
│ - Cardiomyopathy │
│ - CNS involvement │
│ │
│ **FFS = 0**: Lower mortality. Corticosteroids alone may │
│ be sufficient. │
│ **FFS ≥ 1**: Higher mortality. Corticosteroids + │
│ Cyclophosphamide. │
└──────────────────────────────────────────────────────────┘
↓
TREATMENT (Idiopathic PAN)
┌──────────────────────────────────────────────────────────┐
│ **INDUCTION** │
│ - **Corticosteroids**: Prednisolone 1mg/kg/day (Max 60- │
│ 80mg). IV Methylprednisolone pulse for severe. │
│ - **± Cyclophosphamide**: For FFS ≥1 or severe disease. │
│ IV pulse (15mg/kg every 2-4 weeks) or Oral. │
│ - Duration of Induction: ~3-6 months. │
│ │
│ **MAINTENANCE (After Remission)** │
│ - Gradual steroid taper. │
│ - Azathioprine or Methotrexate. │
│ - Duration: 12-24 months (Or longer). │
└──────────────────────────────────────────────────────────┘
↓
HBV-ASSOCIATED PAN TREATMENT
┌──────────────────────────────────────────────────────────┐
│ - **Antiviral Therapy**: Entecavir or Tenofovir. │
│ - **Short-Course Corticosteroids**: To control │
│ inflammation acutely. Rapid taper over ~2 weeks. │
│ (Prolonged steroids may delay HBV clearance). │
│ - **Plasma Exchange**: For severe cases. │
│ - **AVOID prolonged immunosuppression** (Promotes HBV │
│ replication). │
└──────────────────────────────────────────────────────────┘
↓
SUPPORTIVE CARE
- Antihypertensives (For renovascular HTN)
- Analgesia
- Physiotherapy (Neuropathy)
- Monitor for relapse
8. Complications
| Complication | Notes |
|---|---|
| Bowel Infarction / Perforation | Mesenteric ischaemia. Surgical emergency. |
| Aneurysm Rupture | Rare. Haemorrhage. |
| Renal Failure | From renal infarction or renovascular disease. |
| Stroke | CNS involvement. |
| Myocardial Infarction | Coronary arteritis. |
| Chronic Neuropathy | Persistent deficits from mononeuritis multiplex. |
| Treatment Side Effects | Steroids (Infection, Diabetes, Osteoporosis). Cyclophosphamide (Infection, Bladder toxicity, Malignancy). |
9. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Untreated | High mortality (~50% at 1 year historically). |
| With Treatment | 5-year survival ~80-90%. |
| FFS | Higher FFS = Worse prognosis. |
| Relapses | Occur in ~10-20%. |
| HBV-PAN | Good prognosis if HBV eradicated with antivirals. |
10. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Vasculitis | BSR / EULAR | FFS for severity. Steroids ± Cyclophosphamide. Antivirals for HBV-PAN. |
ACR Criteria (1990)
| Criteria (≥3 of 10 for classification) |
|---|
| Weight loss ≥4kg, Livedo reticularis, Testicular pain/Tenderness, Myalgias/Weakness, Mononeuropathy/Polyneuropathy, Diastolic BP >90, Elevated BUN/Creatinine, HBV infection, Arteriographic abnormality (Aneurysms/Occlusions), Biopsy showing granulocytes in artery wall. |
11. Patient and Layperson Explanation
What is Polyarteritis Nodosa?
PAN is a rare condition where the blood vessels (Medium-sized arteries) become inflamed. This inflammation can damage the blood vessel walls, Causing them to weaken and narrow, Which reduces blood flow to organs.
What are the symptoms?
- Fever, Weight loss, Feeling generally unwell.
- Numbness, Tingling, Weakness in hands or feet (Nerve damage).
- Skin rashes, Nodules under the skin, Ulcers.
- Tummy pain (If gut blood vessels affected).
- High blood pressure (If kidney blood vessels affected).
- Muscle and joint aches.
What causes it?
In most cases, The cause is unknown. In some people, It is linked to Hepatitis B infection.
How is it diagnosed?
- Blood tests (Inflammation markers, Hepatitis tests).
- Imaging (Angiogram) to look at blood vessels.
- Biopsy of affected tissue.
How is it treated?
- Steroids to reduce inflammation.
- Other immunosuppressants (Like Cyclophosphamide) for more severe cases.
- Antiviral medication if Hepatitis B is the cause.
What is the outlook?
With treatment, Most people do well. It is important to take medication as prescribed and attend follow-up appointments.
12. References
Primary Sources
- Hernández-Rodríguez J, et al. Polyarteritis nodosa. Rheum Dis Clin North Am. 2019;45(4):525-543. PMID: 31564351.
- Guillevin L, et al. Polyarteritis nodosa related to hepatitis B virus. Ann Intern Med. 2019;131(4):242-247.
- Jennette JC, et al. 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11. PMID: 23045170.
13. Examination Focus
Common Exam Questions
- ANCA Status: "Is PAN ANCA-positive or ANCA-negative?"
- Answer: ANCA-Negative.
- Classic Nerve Finding: "What is the classic neurological manifestation of PAN?"
- Answer: Mononeuritis Multiplex (Asymmetric peripheral neuropathy).
- Angiographic Finding: "What is the characteristic angiographic finding?"
- Answer: Microaneurysms ("Beaded" appearance of mesenteric or renal arteries).
- Viral Association: "Which hepatitis virus is classically associated with PAN?"
- Answer: Hepatitis B Virus (HBV).
Viva Points
- Medium Vessels, No Glomerulonephritis: Key distinction from MPA.
- Five-Factor Score (FFS): Guides treatment intensity.
- HBV-PAN: Treat with antivirals + Short-course steroids. Avoid prolonged immunosuppression.
- Skin PAN (Cutaneous PAN): Limited to skin. Better prognosis.
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