What is the recommended diagnostic workup and treatment strategy for an adult with suspected polyarteritis nodosa, including management of severe organ‑life‑threatening disease, limited disease, and hepatitis B‑associated cases?

Polyarteritis Nodosa: Diagnostic Workup and Treatment Strategy

Diagnostic Workup

For suspected polyarteritis nodosa, obtain tissue biopsy from the most accessible symptomatic site combined with abdominal vascular imaging to confirm diagnosis before initiating treatment. 1

Tissue Biopsy Approach

• Tissue confirmation is preferred over imaging alone for definitive diagnosis 1
• Deep skin biopsy reaching medium-sized vessels is preferred over superficial punch biopsy when cutaneous involvement is present, as superficial biopsies frequently miss the diagnostic vessels 1
• Combined nerve-and-muscle biopsy provides higher diagnostic yield than nerve biopsy alone when evaluating peripheral neuropathy 1
• When performing nerve biopsy, sample a purely sensory nerve (e.g., sural nerve) to avoid iatrogenic motor deficits 1
• Histologic findings should demonstrate mixed-cell inflammatory infiltrates, fibrinoid necrosis, and absence of granulomas 1

Vascular Imaging

• Conventional angiography is the gold-standard for abdominal vascular assessment, offering superior resolution 1
• CT angiography or MR angiography are acceptable non-invasive alternatives when conventional angiography is not feasible 1
• Angiography typically reveals saccular or fusiform aneurysms and stenotic lesions in mesenteric, hepatic, and renal arteries 1

Essential Laboratory Testing

• Screen for hepatitis B virus (HBV) in all patients, as approximately one-third of PAN cases are HBV-associated 2, 3
• Elevated ESR and CRP are common but nonspecific findings 4

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Treatment Strategy for Severe/Life-Threatening Disease

For newly diagnosed severe idiopathic PAN with organ-threatening or life-threatening manifestations (renal insufficiency, tissue ischemia, mesenteric involvement), immediately initiate cyclophosphamide plus high-dose glucocorticoids. 5, 1

Induction Therapy for Severe Disease

• Intravenous pulse glucocorticoids are preferred over high-dose oral glucocorticoids for initial treatment 1
• Cyclophosphamide is strongly preferred over rituximab for newly diagnosed severe PAN 1
• Do not add plasmapheresis to cyclophosphamide and glucocorticoids in idiopathic PAN, as there is no added benefit 1
• Untreated severe PAN carries approximately 40% mortality at 5 years, justifying aggressive initial therapy 1

Maintenance Therapy

• After achieving remission, transition from cyclophosphamide to methotrexate or azathioprine to reduce cumulative toxicity 5, 1
• Continue non-glucocorticoid immunosuppressive therapy for 18 months total 1
• Taper glucocorticoids based on clinical response, with duration guided by disease activity 1
• Discontinue immunosuppression after 18 months if sustained remission is achieved 1

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Treatment Strategy for Limited/Non-Severe Disease

For non-severe PAN without life-threatening or organ-threatening manifestations, treat with non-cyclophosphamide immunosuppressive agents (methotrexate or azathioprine) plus glucocorticoids. 5, 1

• This glucocorticoid-sparing approach is reasonable when patients lack renal insufficiency, tissue ischemia, or mesenteric involvement 5
• The same 18-month maintenance duration applies 1

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Hepatitis B-Associated PAN: Distinct Treatment Paradigm

For HBV-associated PAN, the treatment strategy fundamentally differs from idiopathic PAN and centers on antiviral therapy with plasmapheresis rather than prolonged immunosuppression. 5, 2, 3

HBV-PAN Specific Management

• Initiate antiviral therapy (lamivudine or other nucleos(t)ide analogues) combined with plasmapheresis 2, 3
• Use only short-term corticosteroid therapy rather than prolonged immunosuppression 6
• Avoid prolonged cyclophosphamide in HBV-PAN, as the pathogenesis is viral replication-driven rather than autoimmune 3, 7
• Patients achieving HBV seroconversion obtain complete remission and typically do not relapse, confirming the disease is driven by ongoing viral replication 8
• One case report demonstrated successful treatment with pulse cyclophosphamide, prednisolone, and lamivudine following emergency surgery for fulminant disease, with subsequent HBeAg seroconversion 7

Critical Distinction

• PAN is associated with chronic HBV infection with persistent viremia, not acute infection that resolves spontaneously 8
• Acute HBV infection resolves spontaneously in >95% of immunocompetent adults and does not cause PAN 8

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Special Consideration: DADA2

For patients with clinical manifestations of deficiency of adenosine deaminase 2 (DADA2)—particularly early-onset PAN-like vasculitis with recurrent strokes—strongly recommend treatment with TNF inhibitors over glucocorticoids alone. 5

• DADA2 should be considered in PAN-like syndrome with strokes, especially in childhood-onset cases 5
• TNF inhibitors prevent strokes more effectively than conventional immunosuppressive agents like cyclophosphamide 5
• Diagnosis requires ADA2 sequencing or functional assays 5

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Monitoring and Follow-Up

Vascular Imaging

• Repeat abdominal vascular imaging only if new symptoms suggest relapse, not routinely 1
• In patients with severe PAN and abdominal involvement who achieve remission, conditional follow-up imaging is recommended if initial study showed aneurysmal disease 1
• Indefinite routine imaging is not advised when vascular disease is quiescent 1

Neurologic Monitoring

• Serial neurologic examinations are preferred over routine repeat EMG/nerve conduction studies every six months 1
• Repeat EMG only if new or worsening neurologic symptoms develop, as repeated EMG is invasive and unnecessary in stable patients 1

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Adjunctive Therapy

For patients with nerve and/or muscle involvement, physical therapy is conditionally recommended. 5

• Physical therapy may be particularly beneficial for those with substantial motor involvement 5
• This carries minimal risk with potential benefit 5

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Cardiac Involvement Considerations

In patients with PAN and cardiac manifestations, coronary angiography is useful to exclude atherosclerosis. 5

• Cardiac involvement occurs in an estimated 5-20% of PAN patients, with higher risk in HBV-associated cases 5
• PAN can cause myocardial dysfunction through coronary angiitis, MI, and hypertension 5
• Optimize hypertension control in patients with autoimmune-mediated heart failure 5
• Development of heart failure portends a poor prognosis 5
• Treatment typically involves aggressive immunosuppression with steroids and selective revascularization, with treatment of concomitant active hepatitis B if present 5

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Common Pitfalls to Avoid

• Do not perform superficial skin biopsies, as they frequently miss medium-sized vessels 1
• Avoid blind biopsies of non-symptomatic tissue, as they reduce diagnostic yield 1
• Do not use prolonged immunosuppression for HBV-associated PAN—the treatment paradigm is fundamentally different 3, 6
• Do not add plasmapheresis to idiopathic PAN treatment, as it provides no benefit (reserve for HBV-PAN) 1
• Do not perform routine repeat EMG in stable patients with peripheral neuropathy 1