Rheumatology Case Challenge: A 54-Year-Old Woman With Discolored Toes and Nonhealing Ulcers

Kelsey N. Rigby, DO

Disclosures

April 27, 2023

PAN is a rare form of vasculitis that affects the small and medium arteries, leading to destructive necrotizing inflammation without glomerulonephritis or vasculitis in arterioles, capillaries, or venules. It is not associated with ANCAs.

PAN can affect almost any organ system, which makes diagnosis challenging. The most common clinical features are constitutional symptoms, such as fatigue, fever, and weight loss. Musculoskeletal symptoms include myalgias and/or arthralgias. Neurologic manifestations include peripheral neuropathy or mononeuritis multiplex. Among the gastrointestinal symptoms are abdominal pain, gastrointestinal bleeding, and perforation. Renal manifestations of PAN at presentation include new-onset hypertension, hematuria, and proteinuria. Patients can also have cardiac manifestations of the disease that range from ischemic cardiomyopathy to uncontrolled hypertension and subsequent renal failure. Genitourinary involvement (eg, orchitis) may be present. Of note, PAN spares the lung parenchyma. The presence of lung involvement indicates an alternative diagnosis such as ANCA vasculitis (eg, granulomatosis with polyangiitis or microscopic polyangiitis).[1]

About 4% of patients with PAN have cutaneous manifestations only, as in the patient in this case. The typical presentation of cutaneous PAN involves subcutaneous lesions and tender erythematous nodules. Other skin changes include livedo reticularis or ulcers. Skin manifestations most often affect the lower extremities and can be diffuse or limited. The prevalence of the disease ranges from 2 to 9 per million in Europe and the United States. Cutaneous PAN most commonly occurs in women aged 40-50 years but can affect persons of any age.[1]

PAN can be triggered by infection, malignancy, or medication but is usually idiopathic.[5] PAN is often associated with hepatitis B virus infection, although in areas where hepatitis vaccination and screening of blood products are common, the rate is decreasing. PAN develops in 1%-5% of persons with hepatitis B and typically occurs within the first 6 months of infection. Other secondary causes of PAN include beta-hemolytic streptococcal infection, inflammatory bowel disease, cytomegalovirus infection, parvovirus infection, and tuberculosis. Drugs that have been associated with PAN include minocycline, sulfonamides, and intravenous amphetamines.[1]

The pathogenesis is not fully understood. When PAN is associated with hepatitis B virus infection, it is hypothesized that deposition of immune complexes leads to complement activation, inflammation, and subsequent endothelial injury.[1] In idiopathic PAN, the mechanisms leading to damage are unknown but are thought to be multifactorial (ie, a combination of genetic predisposition and environmental exposures). The response of idiopathic PAN to immunosuppressive therapy suggests an immunologic etiology.

Histopathologic examination reveals localizing necrotizing arteritis with mixed inflammatory infiltrate. Muscle, peripheral nerve, kidney, testes, and rectal tissues provide the best yield.[1]

Imaging can also be helpful in supporting the diagnosis. Magnetic resonance angiography and CT angiography can show multiple small aneurysms, vessel ectasia, and focal occlusive lesions in medium-sized arteries.[1]

The nonspecific features and clinical findings of PAN can make diagnosis difficult; however, the disease should be included in the differential diagnosis for patients with new skin nodules, nonhealing ulcers, or multiorgan involvement. Other types of vasculitis should be ruled out before a diagnosis of PAN is made.[6] Biopsy is confirmatory.

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