What is the clinical and investigative approach for an adult patient suspected of having Polyarteritis Nodosa (PAN) with symptoms like fever, weight loss, fatigue, and hypertension?

Clinical and Investigative Approach for Polyarteritis Nodosa (PAN)

Initial Clinical Assessment

For adults with suspected PAN presenting with constitutional symptoms (fever, weight loss, fatigue) and hypertension, immediately assess for organ-threatening manifestations to determine disease severity, as this dictates the diagnostic and therapeutic pathway. 1

Key Clinical Features to Identify

• Peripheral neuropathy (motor and/or sensory) occurs in 50-75% of patients and is often the earliest manifestation 2
• Skin involvement: nodules, livedo reticularis, ulcerations, or rash 3, 4
• Renal manifestations: hypertension, renal insufficiency (but notably PAN does not cause glomerulonephritis) 5
• Gastrointestinal symptoms: abdominal pain suggesting mesenteric ischemia 1
• Musculoskeletal: myalgias, arthralgias 4
• Cardiac: heart failure, coronary arteritis 2
• Testicular pain (uncommon but can be a diagnostic clue in older males) 6
• Notably absent: pulmonary involvement (PAN does not affect the lungs) 5

Severity Classification

Classify as severe PAN if any of the following are present 1, 3:

• Life-threatening or organ-threatening manifestations
• Abdominal involvement with mesenteric ischemia
• Cardiac involvement
• Central nervous system involvement
• Renal insufficiency

Classify as nonsevere PAN if presenting with 3:

• Uncomplicated cutaneous disease only
• Peripheral neuropathy without other organ involvement

Diagnostic Investigations

Laboratory Testing

• Screen for hepatitis B virus (HBV) in all patients, as HBV-associated PAN requires a fundamentally different treatment approach centered on antiviral therapy 5, 2
• Inflammatory markers (ESR, CRP) 4
• Complete blood count, comprehensive metabolic panel 4
• ANCA testing (should be negative; positive ANCA suggests microscopic polyangiitis, not PAN) 4

Imaging Studies

For all patients with suspected PAN, obtain abdominal vascular imaging (CT angiography or MR angiography) to establish diagnosis and determine disease extent. 1 This imaging identifies characteristic findings including:

• Microaneurysms in medium-sized arteries 4
• Arterial stenoses and occlusions 1
• Extent of visceral involvement 1

For patients with severe PAN and abdominal involvement who achieve clinical remission, perform follow-up abdominal vascular imaging to assess disease control and treatment response, particularly when baseline imaging shows aneurysmal disease. 1 However, avoid indefinite routine imaging if vascular disease is quiescent. 1

Tissue Biopsy

The biopsy approach depends on the clinical presentation:

For suspected cutaneous PAN: Obtain a deep-skin biopsy (reaching medium-sized vessels of the dermis) rather than superficial punch biopsy, as deeper tissue sampling is more likely to capture affected medium-sized vessels. 1, 7 A dermatologist can perform this as a deep (or "double") punch biopsy without requiring invasive resection. 1

For suspected PAN with peripheral neuropathy: Obtain a combined nerve and muscle biopsy rather than nerve biopsy alone, as this increases diagnostic yield. 1 Sample involved tissue (not "blind" biopsies), and favor biopsy of a purely sensory nerve (e.g., sural nerve) to avoid motor deficits. 1

Electrophysiologic Studies

• Perform electromyography/nerve conduction studies initially to confirm peripheral neuropathy and characterize the pattern 8, 2
• For monitoring disease activity in patients with established peripheral motor neuropathy, use serial neurologic examinations rather than repeated EMG/NCS (e.g., every 6 months), as repeated EMG is invasive and unnecessary in stable patients 1, 8
• Repeat EMG/NCS only if uncertainty exists about new or worsening neurologic processes 1

Diagnostic Algorithm Summary

1. Assess clinical severity (severe vs. nonsevere based on organ involvement)
2. Test for HBV (determines treatment pathway)
3. Obtain abdominal vascular imaging (all suspected cases)
4. Perform appropriate tissue biopsy:
   • Deep-skin biopsy for cutaneous involvement
   • Combined nerve/muscle biopsy for neuropathy
5. EMG/NCS if peripheral neuropathy suspected
6. Rule out ANCA-associated vasculitis (ANCA should be negative in PAN)

Common Diagnostic Pitfalls

• Superficial skin punch biopsies miss the diagnosis because they fail to reach medium-sized vessels in the deep dermis 7, 3
• Delayed diagnosis occurs when constitutional symptoms are attributed to other causes without considering systemic vasculitis 9
• Confusion with microscopic polyangiitis: Historical studies may have included microscopic polyangiitis patients before this entity was recognized as distinct from PAN 1
• Failure to test for HBV leads to inappropriate treatment, as HBV-associated PAN requires antiviral therapy plus plasma exchange, not standard immunosuppression 5, 2
• Blind biopsies of uninvolved tissue yield false-negative results 1

Treatment Initiation Based on Severity

Severe PAN (Idiopathic, Non-HBV)

Initiate treatment with IV pulse glucocorticoids (methylprednisolone 500-1000 mg/day for 3-5 days) combined with cyclophosphamide, rather than high-dose oral glucocorticoids or glucocorticoids alone. 1 This combination provides rapid suppression of inflammation through both genomic and non-genomic mechanisms. 1

• Cyclophosphamide plus glucocorticoids is preferred over rituximab plus glucocorticoids 1
• Do not use plasmapheresis combined with cyclophosphamide and glucocorticoids, as it provides no additional benefit over cyclophosphamide and glucocorticoids alone 1

Nonsevere PAN (Including Cutaneous PAN)

Treat with non-glucocorticoid immunosuppressive agents (azathioprine or methotrexate) combined with moderate-dose oral glucocorticoids (prednisone 0.25-0.5 mg/kg/day, generally 10-40 mg/day), rather than glucocorticoids alone. 1, 3 This approach provides glucocorticoid-sparing effects and improved disease control. 3

• Azathioprine is the preferred first-line agent; methotrexate is an alternative 3
• Avoid mycophenolate mofetil, as it has not been well studied in PAN 3
• Do not use cyclophosphamide for isolated cutaneous PAN, as this exposes patients to unnecessary toxicity 3

HBV-Associated PAN

Treat with antiviral therapy combined with plasma exchange and short-course corticosteroids, rather than standard immunosuppression 5, 2 This fundamentally different approach targets the underlying viral trigger.

Maintenance and Monitoring

• Discontinue non-glucocorticoid immunosuppressive therapy after 18 months of sustained remission rather than continuing indefinitely 1, 3, 8
• Glucocorticoid taper duration should be guided by clinical condition; optimal duration is not well established 1
• Monitor with serial clinical examinations assessing skin lesions, neurologic function, blood pressure, and systemic symptoms 3, 8
• Assess regularly for glucocorticoid-related adverse effects 3
• Watch for development of systemic manifestations that would reclassify nonsevere disease as severe 3