What is the diagnosis and treatment for an adult patient with a lower extremity (LE) rash and symptoms concerning for vasculitis, possibly with a history of autoimmune disorders?

Polyarteritis Nodosa (PAN) with Lower Extremity Rash and Vasculitis

PAN is a medium-vessel vasculitis that requires aggressive immunosuppression with cyclophosphamide plus glucocorticoids for severe disease (organ-threatening manifestations like renal insufficiency or tissue ischemia), while non-severe disease can be treated with alternative immunosuppressive agents and glucocorticoid-sparing regimens. 1

Diagnosis of PAN

Clinical Presentation

• Lower extremity rash in PAN typically manifests as palpable purpura, livedo reticularis, or cutaneous ulcerations due to medium-vessel inflammation affecting skin blood supply 1, 2
• Constitutional symptoms include fever, fatigue, and weight loss, which are common in medium-vessel vasculitis 3
• Organ involvement may include peripheral neuropathy (mononeuritis multiplex), renal insufficiency, tissue ischemia, and gastrointestinal manifestations 1

Diagnostic Workup

Essential diagnostic procedures for suspected PAN include: 1

• Angiography to identify characteristic microaneurysms and stenoses in medium-sized arteries
• Electromyography/nerve conduction studies if peripheral neuropathy is suspected
• Nerve and muscle biopsy showing necrotizing vasculitis of medium-sized vessels
• Skin biopsy from affected areas, though this may show small-vessel involvement at the dermal level rather than the deeper medium-vessel pathology 4

Laboratory Evaluation

• Complete blood count (often shows neutrophilic leukocytosis) 4
• ESR and CRP (typically elevated) 4
• Screen for hepatitis B virus (HBV), as HBV-associated PAN requires different management 1
• ANCA testing (typically negative in classic PAN, distinguishing it from ANCA-associated vasculitis) 5
• Consider testing for deficiency of adenosine deaminase 2 (DADA2) in patients with early-onset PAN-like syndrome with strokes 1

Treatment Algorithm

Severe Disease (Life- or Organ-Threatening)

For patients with severe manifestations including renal insufficiency, tissue ischemia, or other organ-threatening features: 1

1. Induction therapy:

   • Cyclophosphamide (standard immunosuppressive agent for severe disease)
   • High-dose glucocorticoids (methylprednisolone 1-2 mg/kg/day initially) 5
   • Consider pulse IV methylprednisolone (1,000 mg daily for 1-3 days) for critical presentations 6

2. Maintenance therapy:

   • Transition to alternative immunosuppressive agents after remission induction
   • Gradual glucocorticoid taper

Non-Severe Disease

For patients without life- or organ-threatening manifestations: 1

• Alternative immunosuppressive agents (methotrexate, azathioprine, or mycophenolate mofetil) can be used instead of cyclophosphamide
• Glucocorticoid-sparing regimens are reasonable
• Lower initial glucocorticoid doses with more rapid taper

Special Considerations

DADA2-Associated PAN

If DADA2 is confirmed (particularly in patients with strokes and early-onset disease): 1

• Strongly recommend TNF inhibitors over glucocorticoids alone
• TNF inhibitors prevent strokes more effectively than conventional immunosuppression
• This represents a critical diagnostic distinction requiring genetic testing

HBV-Associated PAN

• Requires antiviral therapy in addition to immunosuppression
• Management differs significantly from idiopathic PAN 1

Common Pitfalls

Diagnostic Challenges

• Do not confuse PAN with small-vessel vasculitis (ANCA-associated vasculitis, leukocytoclastic vasculitis) - vessel size determines treatment approach 3, 5
• Skin biopsy alone may be insufficient as superficial biopsies may miss deeper medium-vessel involvement; angiography or deep tissue biopsy (nerve/muscle) often required 1
• Avoid routinely repeated diagnostic procedures during disease quiescence - not recommended and adds unnecessary burden 1

Treatment Considerations

• PAN remains a disease with high mortality (historically significant), making aggressive treatment of severe disease essential 1
• Adolescents and patients with atypical presentations may be misdiagnosed with other autoimmune conditions like SLE 7
• Drug-induced vasculitis (penicillins, cephalosporins, sulfonamides) should be excluded, as cessation of the offending agent may lead to resolution 4

Monitoring

• Longitudinal vascular imaging may be informative for disease activity assessment, though optimal protocols remain undefined 1
• Biomarkers for disease activity are lacking; clinical assessment remains primary 1

Prognosis

• Classic systemic PAN has high mortality without treatment 1
• Severe disease with renal involvement carries the worst prognosis 5
• Early aggressive treatment improves outcomes and reduces morbidity and mortality 5
• PAN incidence has decreased over recent decades, possibly due to better recognition and treatment of underlying conditions 1