What are the symptoms and treatment options for Polyarteritis Nodosa (PAN)?

Polyarteritis Nodosa: Symptoms and Treatment

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis primarily affecting medium-sized vessels, presenting with a constellation of symptoms including fever, weight loss, peripheral neuropathy, cutaneous manifestations, renal involvement, and gastrointestinal symptoms, requiring prompt treatment with immunosuppressive therapy to reduce mortality and morbidity.

Clinical Manifestations

Systemic Symptoms

• Fever and weight loss are common presenting symptoms 1
• Asthenia (profound fatigue) is frequently reported 2

Neurologic Manifestations

• Peripheral neuropathy affects 50-75% of PAN patients and is often one of the earliest symptoms 3
• Mononeuritis multiplex (asymmetric nerve involvement) is a characteristic finding 1
• Central nervous system involvement occurs in only 2-10% of patients, typically later in the disease course 3

Cutaneous Manifestations

• Skin nodules and livedo reticularis (mottled discoloration of the skin) are common 1
• Deep skin biopsy (reaching medium-sized vessels of the dermis) is preferred over superficial punch biopsy for diagnosis 1
• Limb ischemia, though rare, can be a presenting feature 4

Renal Manifestations

• Hypertension is a common finding 1, 2
• Renal insufficiency may occur due to vascular involvement 1
• Unlike microscopic polyangiitis, rapidly progressive glomerulonephritis is not typical in PAN 2

Gastrointestinal Manifestations

• Abdominal pain is frequently reported 1
• Mesenteric ischemia can occur due to involvement of mesenteric vessels 1
• Gastrointestinal hemorrhage may develop in severe cases 5

Other Manifestations

• Musculoskeletal involvement with myalgias and arthritis 2, 4
• Cardiac involvement can lead to heart failure 2, 3
• Pulmonary involvement is typically absent, which helps differentiate PAN from other vasculitides 2

Diagnostic Approach

Imaging Studies

• Abdominal vascular imaging is recommended to aid in establishing diagnosis and determining disease extent 1
• Angiography may reveal saccular or fusiform aneurysms and stenotic lesions in mesenteric, hepatic, and renal arteries 1
• Follow-up abdominal vascular imaging is conditionally recommended for patients with a history of severe PAN with abdominal involvement who become clinically asymptomatic 1

Tissue Biopsy

• Deep skin biopsy is preferred over superficial skin punch biopsy when skin involvement is suspected 1
• Combined nerve and muscle biopsy is recommended over nerve biopsy alone when peripheral neuropathy is present 1
• Typical histologic findings include mixed-cell inflammatory infiltrates in the vessel wall and fibrinoid necrosis, with absence of granulomas and giant cells 1

Laboratory Testing

• ANCA (anti-neutrophil cytoplasmic antibodies) are typically negative in PAN, which helps differentiate it from ANCA-associated vasculitides 4
• Consider testing for deficiency of adenosine deaminase 2 (DADA2) in patients with early-onset PAN-like vasculitis, especially with recurrent strokes 1
• Hepatitis B virus (HBV) testing is important as HBV can be associated with PAN 2, 5

Treatment Recommendations

Initial Treatment Based on Disease Severity

For Severe PAN (life- or organ-threatening manifestations)

• For newly diagnosed active, severe PAN, treatment with cyclophosphamide and high-dose glucocorticoids is recommended over glucocorticoids alone 1, 6
• Intravenous pulse glucocorticoids are preferred over high-dose oral glucocorticoids for initial treatment 1, 6
• Cyclophosphamide therapy should be limited to 3-6 months per course due to toxicity concerns 1, 6

For Non-Severe PAN

• For newly diagnosed active, non-severe PAN, treatment with non-glucocorticoid immunosuppressive agents (typically azathioprine or methotrexate) plus glucocorticoids is recommended over glucocorticoids alone 1, 6

Maintenance Therapy

• After achieving remission with cyclophosphamide, transition to another less toxic immunosuppressive agent such as methotrexate or azathioprine 1, 6
• For patients in remission receiving non-glucocorticoid immunosuppressive therapy, discontinuation after 18 months is recommended rather than continuing indefinitely, provided sustained remission has been achieved 6

Refractory Disease

• For severe PAN refractory to initial treatment with glucocorticoids and non-cyclophosphamide immunosuppressive agents, switching to cyclophosphamide is recommended rather than increasing glucocorticoids alone 1
• Infliximab (TNF inhibitor) has shown efficacy in refractory PAN cases with 89% of patients achieving significant improvement in one study 7

Special Considerations

• For patients with PAN with nerve and/or muscle involvement, physical therapy is recommended 1
• For patients with clinical manifestations of DADA2, tumor necrosis factor inhibitors are strongly recommended over glucocorticoids alone 1
• For HBV-related PAN, treatment differs from idiopathic PAN and may include antiviral drugs and plasma exchanges combined with corticosteroids 2, 3

Prognosis and Monitoring

• Untreated severe PAN has a mortality rate of approximately 40% at 5 years 1
• Serial neurologic examinations are preferred over repeated electromyography/nerve conduction studies for monitoring disease activity in patients with peripheral motor neuropathy 1
• Follow-up abdominal vascular imaging is recommended for patients with a history of severe PAN with abdominal involvement who become clinically asymptomatic 1

Pitfalls and Caveats

• Avoid indefinite routine vascular imaging if abdominal vascular disease is shown to be quiescent 6
• Consider DADA2 in patients with PAN-like syndrome with strokes, as these patients respond better to TNF inhibitors than conventional therapy 1, 6
• Plasmapheresis is not routinely recommended in combination with cyclophosphamide and glucocorticoids for non-HBV-associated PAN 1, 6