What are the causes, clinical features, examination, differential diagnoses, investigations, management, and complications of Polyarteritis nodosa (PAN) in adults?

Polyarteritis Nodosa: Comprehensive Clinical Overview

Causes and Etiopathogenesis

Polyarteritis nodosa is primarily idiopathic, but chronic hepatitis B virus infection with persistent viremia is the most important identifiable secondary cause, while acute HBV infection that resolves spontaneously does not cause PAN. 1

• Idiopathic PAN accounts for the majority of cases, with unknown etiology involving necrotizing inflammation of medium-sized arteries 2
• Hepatitis B-associated PAN occurs specifically with chronic HBV infection and active viral replication, not acute infection (which resolves spontaneously in >95% of immunocompetent adults) 1
• Adenosine deaminase 2 deficiency (DADA2) is a critical genetic cause that must be distinguished from primary PAN, as it requires TNF inhibitor therapy rather than standard immunosuppression 3
• The incidence of PAN has declined over time due to better recognition of secondary causes and changing nomenclature 3

Clinical Features (By Prevalence)

The most common manifestations are constitutional symptoms (fever, weight loss), followed by cutaneous involvement, peripheral neuropathy, gastrointestinal disease, and renal involvement. 4, 3

Most Common Presentations:

• Constitutional symptoms: Fever and weight loss are among the most frequent presenting features 4
• Cutaneous manifestations: Skin nodules and livedo reticularis are common 4
• Peripheral neuropathy: Both motor and sensory involvement frequently occurs 5
• Gastrointestinal involvement: Abdominal pain from mesenteric ischemia is frequently reported 4
• Renal disease: Renal insufficiency occurs due to vascular involvement (not glomerulonephritis, which would suggest microscopic polyangiitis) 4

Severe Disease Manifestations:

• Life-threatening features include CNS disease, cardiac involvement, severe renal disease, gastrointestinal perforation, extensive cutaneous/muscle disease, mesenteric ischemia, coronary involvement, and limb/digit ischemia 5

Physical Examination Findings

Focus examination on identifying signs of medium-vessel ischemia and multi-organ involvement:

• Skin: Palpable nodules along arterial pathways, livedo reticularis, ulcerations, digital ischemia 4
• Neurologic: Mononeuritis multiplex (asymmetric peripheral neuropathy), motor weakness, sensory deficits 5
• Cardiovascular: Hypertension (from renal artery involvement), signs of cardiac ischemia 4
• Abdominal: Tenderness suggesting mesenteric ischemia, signs of peritonitis if perforation occurs 4
• Musculoskeletal: Muscle tenderness, inflammatory arthritis 5

Differential Diagnoses and Rule-Outs

The primary differential is microscopic polyangiitis (MPA), which requires ANCA testing and assessment for glomerulonephritis to distinguish from PAN:

Key Differentials:

• Microscopic polyangiitis (MPA): Distinguished by presence of ANCA (typically pANCA/MPO-ANCA), glomerulonephritis, and small vessel involvement 6
• Granulomatosis with polyangiitis: Presence of cANCA/PR3-ANCA, granulomatous inflammation, upper respiratory tract involvement 6
• DADA2: Genetic testing for ADA2 mutations is essential, especially in younger patients or those with early-onset stroke 3
• Other secondary vasculitides: Drug-induced vasculitis, other viral infections, malignancy-associated vasculitis 2

Rule-Out Strategy:

• ANCA testing: Absence of cANCA and pANCA supports PAN over MPA or GPA 6
• Hepatitis B serology: HBsAg, HBeAg, HBV DNA to identify HBV-associated PAN 1
• Complement levels: May show low C3 in active disease 7
• ADA2 genetic testing: Essential in appropriate clinical contexts to identify DADA2 3
• Absence of granulomas on histology: Rules out granulomatosis with polyangiitis 4

Investigations

Obtain tissue biopsy from the most accessible symptomatic site and abdominal vascular imaging before initiating treatment. 4

Diagnostic Imaging:

• Abdominal vascular imaging (CT angiography or MR angiography) is conditionally recommended to establish diagnosis and determine disease extent 5
• Angiography findings: Saccular or fusiform aneurysms and stenotic lesions in mesenteric, hepatic, and renal arteries 4
• Follow-up imaging: For patients with severe PAN and abdominal involvement who become asymptomatic, follow-up abdominal vascular imaging is conditionally recommended 5

Tissue Biopsy:

• Deep skin biopsy (reaching medium-sized vessels of the dermis) is preferred over superficial punch biopsy when skin involvement is suspected 5
• Combined nerve and muscle biopsy is preferred over nerve biopsy alone for patients with peripheral neuropathy 5
• Histologic criteria: Mixed-cell inflammatory infiltrates, fibrinoid necrosis, and absence of granulomas 4

Laboratory Investigations:

• Inflammatory markers: ESR, CRP (typically elevated) 7
• Complete blood count: May show anemia, leukocytosis 7
• Renal function: Creatinine, BUN to assess renal involvement 7
• Hepatitis B serology: HBsAg, anti-HBs, HBeAg, anti-HBe, HBV DNA 1
• ANCA testing: Should be negative (cANCA, pANCA) 7
• Complement levels: C3, C4 7
• ADA2 genetic testing: When DADA2 is suspected 3

Monitoring Disease Activity:

• Serial neurologic examinations are preferred over repeated EMG/nerve conduction studies (e.g., every 6 months) for monitoring peripheral motor neuropathy 5

Detailed Management by Disease Severity

Severe PAN (Life- or Organ-Threatening Disease)

For newly diagnosed active, severe PAN, initiate treatment immediately with cyclophosphamide and high-dose glucocorticoids. 5, 4

Initial Induction Therapy:

• IV pulse glucocorticoids are conditionally recommended over high-dose oral glucocorticoids 5

  • IV methylprednisolone 500-1,000 mg/day for adults (or 30 mg/kg/day for children, maximum 1,000 mg/day) for 3-5 days 5

• Cyclophosphamide plus high-dose glucocorticoids is conditionally recommended over glucocorticoids alone 5

  • Cyclophosphamide is preferred over rituximab for newly diagnosed severe PAN 5, 4

• High-dose oral glucocorticoids following IV pulse: Prednisone 1 mg/kg/day for adults (generally up to 80 mg/day) 5

• Do NOT add plasmapheresis to cyclophosphamide and glucocorticoids in idiopathic PAN, as there is no added benefit 5, 4

Alternative for Cyclophosphamide Intolerance:

• For patients unable to tolerate cyclophosphamide, treat with other non-glucocorticoid immunosuppressive agents (azathioprine, methotrexate, mycophenolate mofetil) plus glucocorticoids over glucocorticoids alone 5

Non-Severe PAN (Without Life- or Organ-Threatening Manifestations)

For newly diagnosed active, non-severe PAN, treat with non-glucocorticoid immunosuppressive agents (methotrexate or azathioprine) plus glucocorticoids. 5, 4

• Non-severe disease includes mild systemic symptoms, uncomplicated cutaneous disease, and mild inflammatory arthritis 5
• Moderate-dose oral glucocorticoids: Prednisone 0.25-0.5 mg/kg/day for adults (generally 10-40 mg/day) 5

Hepatitis B-Associated PAN

HBV-associated PAN requires antiviral therapy combined with plasma exchange, not standard immunosuppression alone. 2

• Antiviral therapy is the primary treatment 2
• Plasma exchange is used in combination with antivirals 2
• Patients who achieve seroconversion obtain complete remission and do not relapse 1

DADA2-Associated Vasculitis

TNF inhibitors are the treatment of choice for DADA2 with vasculitis phenotype, which can prevent morbidity and mortality. 3

• This is a critical distinction from idiopathic PAN, as standard immunosuppression is insufficient 3

Maintenance and Remission Management

After achieving remission with cyclophosphamide, transition to a less toxic immunosuppressive agent (methotrexate or azathioprine). 4

Maintenance Therapy:

• Duration of non-glucocorticoid immunosuppression: Continue for 18 months total, then discontinue if sustained remission is achieved 5, 4
• Glucocorticoid tapering: The optimal duration is not well established and should be guided by clinical condition, values, and preferences (not necessarily tapered off by 6 months) 5
• Low-dose glucocorticoids: Prednisone ≤10 mg/day for adults during maintenance 5

Monitoring for Relapse:

• Repeat vascular imaging if new symptoms suggest relapse 4
• Definition of relapse: Recurrence of active disease following a period of remission 5

Organ-Specific Management

Renal Involvement:

• Treat with cyclophosphamide and high-dose glucocorticoids as part of severe disease protocol 5
• Monitor renal function closely 7
• Hypertension management is essential 4

Gastrointestinal Involvement:

• Mesenteric ischemia requires urgent treatment with cyclophosphamide and glucocorticoids 5
• Surgical consultation for suspected perforation or acute abdomen 4
• Serial abdominal examinations and imaging as needed 4

Neurologic Involvement:

• Combined nerve and muscle biopsy for diagnosis 5
• Serial neurologic examinations for monitoring (not repeated EMG/NCS) 5
• Physical therapy and rehabilitation for motor deficits 8

Cutaneous Involvement:

• Deep skin biopsy for diagnosis 5
• Uncomplicated cutaneous disease can be treated as non-severe PAN 5
• Extensive cutaneous disease with ulceration or necrosis requires severe disease protocol 5

Cardiac Involvement:

• Coronary involvement is considered severe disease requiring cyclophosphamide and high-dose glucocorticoids 5
• Cardiac monitoring and cardiology consultation 4

Complications and Their Management

Disease-Related Complications:

Untreated severe PAN has a mortality rate of approximately 40% at 5 years, but with current treatment regimens, 5-year survival exceeds 80%. 4, 3

Acute Complications:

• Mesenteric ischemia/perforation: Requires emergency surgical evaluation and aggressive immunosuppression 5, 4
• Stroke or CNS involvement: Treat as severe disease with cyclophosphamide and IV pulse glucocorticoids 5
• Myocardial infarction: Cardiac monitoring, standard MI management plus immunosuppression 4
• Renal failure: May require dialysis support while treating underlying vasculitis 4
• Limb/digit ischemia: Vascular surgery consultation, aggressive immunosuppression 5

Chronic Complications:

• Permanent neurologic deficits: Rehabilitation and supportive care 8
• Chronic kidney disease: Long-term nephrology follow-up 4
• Aneurysm rupture: Surgical or interventional radiology management 4

Treatment-Related Complications:

Glucocorticoid Complications:

• Steroid-induced diabetes: Monitor glucose, initiate antihyperglycemic therapy as needed 8
• Osteoporosis: Calcium, vitamin D supplementation, bisphosphonates for prevention 8
• Infections: Prophylaxis for Pneumocystis jirovecii with trimethoprim-sulfamethoxazole 2
• Hypertension: Antihypertensive management 8
• Weight gain and cushingoid features: Dietary counseling, gradual taper 8

Cyclophosphamide Complications:

• Bone marrow suppression: Monitor CBC regularly, dose adjust or hold if severe 2
• Hemorrhagic cystitis: Mesna prophylaxis, adequate hydration 2
• Infertility: Counsel patients of reproductive age, consider fertility preservation 2
• Malignancy risk: Long-term surveillance, limit cumulative dose 2
• Infections: Prophylaxis and prompt treatment of infections 2

Refractory Disease:

For severe PAN refractory to glucocorticoids and non-cyclophosphamide immunosuppressive agents, cyclophosphamide should be considered. 5

• Definition of refractory disease: Persistent active disease despite appropriate immunosuppressive therapy 5
• Consider biologic agents (TNF inhibitors, IL-6 inhibitors) in refractory cases, though evidence is limited 2
• Reassess for secondary causes (especially DADA2 or HBV) if disease is refractory 3

Relapse Management:

Relapse requires reinitiation of induction therapy based on severity of recurrent disease. 5

• Severe relapse: Return to cyclophosphamide and high-dose glucocorticoids 5
• Non-severe relapse: Increase glucocorticoids and optimize non-glucocorticoid immunosuppression 5
• Repeat vascular imaging to assess extent of relapse 4

Common Pitfalls and Caveats

• Do not confuse PAN with microscopic polyangiitis: Check ANCA and assess for glomerulonephritis 6
• Do not miss DADA2: Genetic testing is essential in appropriate contexts, as treatment differs fundamentally 3
• Do not use plasmapheresis in idiopathic PAN: It provides no benefit and adds cost/risk 5, 4
• Do not obtain superficial skin biopsies: Deep biopsies reaching medium-sized vessels are required 5
• Do not treat HBV-associated PAN with immunosuppression alone: Antivirals and plasma exchange are required 2
• Do not continue immunosuppression indefinitely: Discontinue after 18 months if in sustained remission 5, 4
• Do not rely on repeated EMG/NCS for monitoring neuropathy: Serial neurologic examinations are preferred 5
• Ensure patient compliance: Recurrent symptoms often result from poor adherence to therapy 8