Polyarteritis Nodosa

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that primarily affects medium-sized muscular arteries, characterized by transmural inflammation leading to segmental arterial damage, aneurysm formation, and ischemic organ injury. It is a rare disease with an estimated incidence of 0.5–9 cases per million people annually and has become increasingly uncommon in developed countries following hepatitis B vaccination; however, it remains clinically significant due to its high morbidity and mortality if untreated (up to 90% five-year mortality without therapy). The disease classically presents in middle-aged adults (peak age 40–60 years) with male predominance (1.5:1), and demonstrates a strong historical association with hepatitis B virus (HBV) infection, though this relationship has declined dramatically in vaccinated populations. PAN is important for board examination preparation because it frequently appears in case scenarios testing knowledge of vasculitis differential diagnosis, and it remains life-threatening requiring rapid recognition and aggressive immunosuppressive therapy.

The pathophysiologic mechanisms of PAN involve complex interplay between immune activation, endothelial injury, and vascular remodeling:

- Immune complex deposition and complement activation: The fundamental mechanism involves circulating immune complex (CIC) deposition within the walls of medium-sized arteries, particularly at branch points where hemodynamic turbulence promotes accumulation. In HBV-associated PAN (historically the most common form), HBV surface antigen (HBsAg), HBV e-antigen (HBeAg), and antibodies form immune complexes that activate the classical complement cascade, generating C3a and C5a anaphylatoxins. These complement components recruit neutrophils and macrophages to the vessel wall, initiating the necrotizing inflammatory cascade. The complement-mediated recruitment explains the transmural inflammation observed on histology and the segmental nature of arterial involvement.

- Endothelial dysfunction and neutrophilic infiltration: Activated endothelial cells upregulate adhesion molecules (ICAM-1, VCAM-1) in response to TNF-α and IL-6 from deposited immune complexes, facilitating neutrophil and monocyte extravasation. Neutrophils undergo degranulation, releasing proteolytic enzymes (elastase, collagenase) and generating reactive oxygen species that directly damage the internal elastic lamina and medial smooth muscle layer. This neutrophilic vasculitis is the histologic hallmark—the inflammatory infiltrate is predominantly neutrophilic in acute lesions, distinguishing PAN from giant cell arteritis (which shows lymphocytic infiltration) and lymphocytic vasculitis. The sequential destruction of all three arterial layers (intima, media, adventitia) leads to loss of vascular structural integrity.

- Arterial wall necrosis and aneurysm formation: The transmural inflammation causes segmental necrosis of the arterial wall, resulting in weakening of the elastic lamina and medial layer. This structural compromise leads to the pathognomonic finding of microaneurysms (50–80% of patients with angiography), which form as the vessel wall loses integrity and bulges outward under systemic pressure. These aneurysms are prone to rupture, causing hemorrhagic complications; additionally, narrowed segments alternate with dilated areas ("beads-on-string" appearance on angiography), producing ischemic injury distal to stenoses. The combination of vascular occlusion from inflammation/thrombosis and rupture from aneurysmal degeneration explains the acute ischemic phenomena (infarction, necrosis) that characterize the clinical presentation.

- Organ-specific ischemic injury: The pathophysiology is organ-specific due to the vascular distribution of medium-sized arteries. In the peripheral nervous system, PAN affects the vasa nervorum of peripheral nerves, causing segmental ischemic nerve infarction manifesting as mononeuritis multiplex (non-contiguous nerve involvement). In the kidneys, PAN affects renal artery branches and mesenteric vessels to the glomeruli, producing renal infarctions and crescentic glomerulonephritis (though less commonly than ANCA-associated vasculitis). In the heart, PAN causes coronary arteritis leading to myocardial infarction and arrhythmias. The GI tract involvement results from mesenteric arteritis with bowel ischemia, infarction, and perforation. Notably, PAN spares the lungs, glomeruli (when involved, minimal immune deposition), and skin superficial vessels—this pattern of organ involvement is critical for differential diagnosis.

- Role of HBV and other triggers: While the classic teaching emphasized HBV-driven immune complex formation, modern understanding recognizes that only 5–10% of current PAN cases are HBV-associated (due to widespread vaccination). The mechanism in HBV-PAN involves persistent viremia allowing continuous antigen generation and immune complex formation. Other infectious triggers (hepatitis C, HIV, streptococcal infection) and genetic predisposition factors remain under investigation. The shift from HBV-associated to predominantly idiopathic PAN in developed countries suggests either environmental cofactors or previously unidentified triggers are important.

- Hepatitis B virus infection: Historically the most important identified cause, accounting for 5–50% of PAN cases depending on geographic region and era of case series. The mechanism involves chronic HBV infection with high viral load and persistent antigenemia, driving continuous CIC formation. The advent of universal HBV vaccination has markedly reduced this association in vaccinated populations. HBsAg-positive patients with PAN remain clinically important and require antiviral therapy (tenofovir or lamivudine) as part of their management. Geographic variation exists, with higher HBV-PAN prevalence in developing nations with lower vaccination coverage.

- Hepatitis C virus infection: While HCV is associated with vasculitis, it typically causes cryoglobulinemic vasculitis (small and medium vessel) rather than classic PAN; however, rare cases of HCV-associated PAN have been documented. The distinction is clinically important because cryoglobulinemic vasculitis is typically ANCA-negative and responds to antiviral therapy.

- Other chronic infections: HIV infection, tuberculosis, syphilis, and atypical mycobacterial infections have been associated with PAN development, though causation is not definitively established. These associations are thought to relate to chronic antigenic stimulation and immune dysregulation rather than direct infection of vessels.

- Idiopathic/primary PAN: Currently the predominant form in developed countries, representing 60–95% of cases depending on series. Idiopathic PAN suggests either unidentified infectious triggers, genetic predisposition, or environmental exposures. No specific genetic polymorphisms have been consistently identified as predisposing factors, though HLA associations have been investigated.

- Drug-induced vasculitis: Medications including amphetamines (particularly methamphetamine with contaminants), antithyroid drugs (propylthiouracil, methimazole), and levamisole-contaminated cocaine have been reported as triggers, though true PAN with aneurysms is rare with these drugs compared to ANCA-associated vasculitis.

- Underlying malignancy: Rarely, PAN has been associated as a paraneoplastic phenomenon with solid tumors and lymphoproliferative disorders, though this association is not well-established.

The clinical presentation of PAN is protean and reflects the multisystem nature of the disease, though certain patterns predominate:

- Constitutional symptoms: Nearly all patients (>90%) present with fever, weight loss, and malaise. These constitutional manifestations often precede organ-specific symptoms by weeks to months, representing the systemic inflammatory state. The fever is typically low-grade and non-specific, without characteristic pattern. Weight loss can be substantial (average 10–15 lbs) and relates to both inflammatory cytokine effects and inadequate oral intake from GI involvement.

- Peripheral nervous system involvement (mononeuritis multiplex): Present in 50–70% of patients at diagnosis and up to 90% over disease course, making it one of the most characteristic findings. Mononeuritis multiplex refers to asynchronous involvement of non-contiguous peripheral nerves—classically presenting as asymmetric foot drop followed by wrist drop, or other combinations of isolated nerve deficits. This pattern distinguishes PAN neuropathy from symmetric distal axonal neuropathy seen in diabetes or toxins. The mechanism is ischemic nerve infarction from vasa nervorum vasculitis. Patients describe sudden onset of weakness in one extremity, followed days to weeks later by weakness in a different limb, creating the characteristic "incomplete and asynchronous" pattern. Sensory symptoms are less prominent than motor deficits. The neuropathy typically requires nerve conduction studies/electromyography (EMG) demonstrating denervation pattern confirming axonal neuropathy.

- Musculoskeletal pain: Present in 50–60% of patients, manifesting as myalgias and arthralgias. Unlike rheumatoid arthritis, joint involvement in PAN is non-erosive and typically non-inflammatory with negative rheumatoid factor; arthritis is uncommon. The myalgias reflect muscle ischemia from vasculitis of muscular arteries. Patients may experience severe diffuse myalgias or focal myositis from segmental muscle infarction.

- Renal involvement: Occurs in 40–60% of patients and is a major cause of morbidity. PAN causes renal artery stenosis (from vasculitis of main renal arteries or segmental branches) leading to renovascular hypertension (secondary hypertension in 30–50% of PAN patients). Acute kidney injury can occur from renal artery thrombosis or infarction. Unlike ANCA-associated vasculitis, PAN rarely causes glomerulonephritis (glomeruli are supplied by small vessels which PAN typically spares); when glomerular involvement occurs, it is usually secondary to renal artery stenosis causing ischemic glomerular changes rather than primary immune complex deposition. Severe hypertension (often >160/100 mmHg) is a clinical hallmark and may be the presenting manifestation in some patients.

- Gastrointestinal involvement: Occurs in 40–60% of patients and represents one of the most serious manifestations. Mesenteric vasculitis causes segmental bowel ischemia manifesting as acute abdominal pain (often postprandial due to increased metabolic demands of ischemic tissue), nausea, vomiting, and diarrhea. Bloody diarrhea indicates mucosal ulceration from ischemia. Severe cases progress to bowel infarction with perforation, peritonitis, and sepsis—this is a medical emergency. Patients may have silent ischemic strictures leading to obstruction. The abdominal pain may be out of proportion to physical exam findings in early mesenteric ischemia, an important clinical clue to vasculitis.

- Cardiac involvement: Present in 10–50% of patients and includes coronary arteritis causing myocardial infarction (can occur in young patients without atherosclerotic risk factors), pericarditis, myocarditis, and congestive heart failure from myocardial necrosis. Coronary vasculitis in a young patient without traditional CAD risk factors should raise suspicion for vasculitis.

- Testicular pain: Present in 5–10% of male patients, from vasculitis of spermatic artery; this finding, though uncommon, is highly specific for PAN when present and can be a presenting symptom.

- Cutaneous involvement: Despite being a systemic vasculitis, cutaneous manifestations are relatively uncommon (10–20% of patients) and when present are typically non-specific. Palpable purpura (when present) usually involves lower extremities and buttocks. Subcutaneous nodules may occur along arteries (reflecting the "nodosa" in the disease name), though this is rare. The absence of prominent skin involvement helps distinguish PAN from other systemic vasculitides.

- Central nervous system involvement: Occurs in 10–15% of patients and includes vasculitic stroke from cerebral arteritis, seizures, encephalopathy, and rarely subarachnoid hemorrhage from aneurysm rupture. These manifestations indicate severe disease and poor prognosis.

The diagnosis of PAN requires integration of clinical presentation, laboratory abnormalities, imaging, and ideally histologic confirmation:

- Clinical diagnostic criteria: The American College of Rheumatology (ACR) 1990 criteria for PAN require the presence of necrotizing vasculitis on biopsy plus ≥3 of the following: weight loss >4 kg, testicular pain/tenderness, myalgias, mononeuritis multiplex/polyneuropathy, diastolic blood pressure >90 mmHg, elevated serum creatinine (>1.5 mg/dL), hepatitis B surface antigen positivity, or abnormalities on arteriography consistent with vasculitis. These criteria have 82% sensitivity and 87% specificity. Notably, the criteria were developed before widespread recognition of HBV vaccination effects and may need updating. More recent classification criteria (EULAR 2009) emphasize medium-sized vasculitis with aneurysm/stenosis on imaging or necrotizing vasculitis with eosinophils on histology.

- Laboratory findings: No single pathognomonic lab test exists for PAN. Elevated inflammatory markers are nearly universal: erythrocyte sedimentation rate (ESR) typically >50 mm/hr (average 60–100), and C-reactive protein (CRP) elevated >3.0 mg/dL. Anemia is present in 60–70% of cases (normocytic, reflecting chronic inflammation). Leukocytosis with left shift is common. Thrombocytosis may occur. ANCA serologies are typically negative in classic PAN—the presence of p-ANCA or c-ANCA should prompt consideration of ANCA-associated vasculitis instead. Complement levels (C3, C4) may be reduced if immune complex disease is active. Rheumatoid factor is typically negative. Cryoglobulins are negative (presence suggests cryoglobulinemic vasculitis instead). HBsAg/anti-HBc testing should be performed in all cases; HBsAg positivity in 5–15% of developed country cases. Transaminases may be mildly elevated. Serum creatinine elevation is present in 40–50% of cases, reflecting renal involvement. Baseline blood cultures are negative. CSF abnormalities (elevated protein, pleocytosis) may occur with CNS involvement.

- Tissue biopsy (gold standard): Histologic confirmation showing necrotizing vasculitis of medium-sized muscular arteries is the diagnostic gold standard. Biopsy sites should target clinically involved organs: peripheral nerve and muscle biopsy (sural nerve or superficial peroneal nerve with adjacent muscle) has highest yield (>60% sensitivity) and is preferred because it is minimally morbid while providing good diagnostic yield. Sural nerve biopsy shows segmental necrotizing vasculitis of the vasa nervorum with neutrophilic infiltration. Muscle biopsy from affected regions shows myonecrosis and arteritis. Renal biopsy shows renal artery or segmental branch vasculitis (less commonly glomerulonephritis). Skin biopsy has low yield (<20%) unless nodules are present. Testicular biopsy is diagnostic when performed but is invasive. The histologic finding of segmental necrotizing vasculitis with fibrinoid necrosis of the arterial wall and absence of glomerulonephritis is characteristic. Important note: the absence of prominent eosinophilic infiltration helps distinguish PAN from granulomatosis with polyangiitis (GPA), which shows granulomas.

- Imaging findings: Angiography (CT or conventional) is highly useful for diagnosis when clinical suspicion is high but tissue biopsy is unavailable or contraindicated. The angiographic hallmark is the "beads-on-string" appearance—alternating segments of arterial stenosis and dilations/microaneurysms in medium-sized vessels (renal, mesenteric, hepatic arteries). This finding is present in 50–80% of patients with active PAN and has 90%+ specificity when present. CT angiography of abdomen/pelvis can identify renal artery stenosis and microaneurysms; MR angiography is useful for vascular imaging without radiation. Renal ultrasound with Doppler may show renal artery stenosis and elevated resistive indices. MRI brain should be obtained if CNS symptoms are present to evaluate for vasculitic infarcts. Cardiac imaging: ECG may show ischemic changes or arrhythmias if coronary involvement; troponin elevation indicates myocardial infarction.

- Electrophysiologic studies: Nerve conduction studies and EMG are essential when mononeuritis multiplex is suspected,