Polyarteritis nodosa (PAN)

Polyarteritis nodosa (PAN) is a primary vasculitis of small and medium-sized arteries, characterized by necrosis and the absence of granulomas.

Its lesions are segmental (alternating between healthy and affected areas) and transmural, predominantly affecting arterial bifurcations with possible aneurysmal dilatations or thromboses. The inflammatory infiltrate is mainly composed of neutrophils (PNN). Healing occurs through fibrosis, leading to arterial occlusion. The lesion progression through flare-ups gives a rather characteristic appearance to biopsies: lesions at different stages within the same organ. Any arteries can be affected, except for the pulmonary arteries.

It is a rare disease with a prevalence of 0.2 to 10 per 100,000 inhabitants, depending on the country. It can affect all ages but is more common between the ages of 40 and 60, with a slight male predominance.

Its etiology is unknown, but a viral trigger (more than 10% association with HBV) and a genetic predisposition are suspected.

Clinical Presentation

The clinical presentation is highly variable. The most common symptoms are:

• Fever (35-80%)
• Weight loss (45-70%), fatigue, general malaise
• Multineuropathy (40-70%) distal (++ SPE), with rapid onset
  • Highly suggestive. Multineuritis should always raise suspicion for PAN.
• Myalgias (30-80%) diffuse or localized
• Cutaneous signs (25-60%): vascular purpura, nodules, livedo racemosa/reticularis, ulcerative/necrotic lesions, gangrene.
• Arthralgias (45-60%)
• Renal involvement (15-80%)
  • Severe/malignant hypertension (10-60%)
  • Glomerular involvement: minimal proteinuria, variable hematuria
  • Rapidly progressive renal failure
• Gastrointestinal involvement (15-60%) ++ small intestine: frequent abdominal pain, the occurrence of hemorrhage/perforations is a poor prognostic sign
• Cardiac manifestations (5-20%), ++ myocardial lesions
• Miscellaneous: orchitis (6%), retinal detachment, etc.

In some cases, PAN can appear to be limited to a cutaneous form or involvement of a single organ.

Diagnosis

The diagnosis is challenging, and no validated criteria exist. Histological > angiographic > clinical arguments are used. Laboratory tests are not specific enough.

Clinical Suspicion

PAN should be suspected in patients presenting with fever, weight loss, asthenia, and sweating with multisystemic involvement → look for cutaneous signs (purpura++), renal involvement, and peripheral neuropathy.

Laboratory Tests

Nonspecific abnormalities are observed:

• Inflammatory syndrome: increased ESR, leukocytes, and platelets
• ANCA is rarely present in classic PAN (unlike microscopic polyangiitis where p-ANCA is present in 60% of cases)
• Often altered renal function
• HBsAg in >10%

Angiography (or angio-CT or angio-MRI)

++ celiac/renal/clinically affected organs. It can support the diagnosis in cases of microaneurysms and segmented stenoses of medium-caliber arteries.

Biopsy

Neuromuscular, muscular, or cutaneous biopsies are generally the most useful. Ideally, a clinically affected organ should be biopsied. However, the segmental nature of the lesions can cause a significant number of false negatives.

Therapeutic Management - Treatments

The choice of treatment is based on the overall clinical progression, the revised FFS (Five-Factor Score: age > 65 years, cardiac symptoms, gastrointestinal involvement, creatinine > 150 µM/L), and the response to treatment. The survival rate with proper treatment is 80-90% at 5 years (vs. 10-30% without treatment).

PAN not associated with HBV

• First-line treatment for exclusively cutaneous forms of mild to moderate severity: NSAIDs and rest (alternative: colchicine 0.6 mg 2x/day + dapsone 50-150 mg/day).
• Example of a treatment regimen for other cases:
  • Prednisone: first choice if FFS = 0
    • Initial doses of 1 mg/kg/day for 6 weeks
    • Gradual reduction to 10 mg/day by the 6th month, unless a new flare occurs.
    • Treatment can typically be discontinued at 1 year.
  • Immunosuppressants: to be considered as first-line therapy if FFS > 1, otherwise second-line therapy
    • Cyclophosphamide (Endoxan) orally at 2 mg/kg/day or in monthly IV boluses of 600-750 mg/m² for approximately 1 year
    • Alternative: switch to azathioprine or methotrexate at the 6th month to limit cyclophosphamide toxicity.
    • Third-line therapy (resistant PAN): consider anti-TNF (rituximab).
• Symptomatic treatment: analgesics for multineuritis, high-protein hypercaloric diet for malnourished patients, blood pressure control, etc.
• Prevention of iatrogenic complications:
  • Calcium + vitamin D3 (corticosteroid-induced osteoporosis)
  • Prophylaxis and monitoring (infections due to immunosuppression, side effects of cyclophosphamide: digestive disorders, myelotoxicity, transient alopecia, hemorrhagic cystitis, azoospermia/amenorrhea in the long term, oncogenesis [bladder, myelodysplasia, lymphomas])

PAN associated with HBV

Combination therapy over 6 months of:

• Antiviral treatment with interferon α
• Possible repeat plasma exchanges

Bibliography

EMC, traité de médecine AKOS, Elsevier, 2018

Jameson JL et al., Harrison's Principles of Internal Medicine, 20th edition, McGraw Hill Higher Education, 2018

Merkel PA, Clinical manifestations and diagnosis of polyarteritis nodosa in adults, UpToDate, 2024

Merkel PA, Treatment and prognosis of polyarteritis nodosa, UpToDate, 2024

Micheletti RG, Cutaneous polyarteritis nodosa, UpToDate, 2024