Polyarteritis Nodosa

  1. Overview
  2. Epidemiology
  3. Pathophysiology
  4. Clinical Manifestations
  5. Hepatitis B-Associated PAN
  6. Diagnosis
  7. ACR Classification Criteria
  8. Treatment
  9. Prognosis and Monitoring
  10. References
  11. Connections
  12. Featured Videos

Overview

Polyarteritis nodosa (PAN) is a medium-vessel necrotizing vasculitis affecting medium and small muscular arteries. It is defined by transmural inflammatory destruction of arterial walls — progressing to fibrinoid necrosis, aneurysm formation, thrombosis, and downstream ischemia. The most critical diagnostic distinction from other systemic vasculitides is that PAN is ANCA-negative: antineutrophil cytoplasmic antibodies (p-ANCA and c-ANCA) are absent in true PAN, which separates it entirely from microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). A positive ANCA result effectively rules out PAN and redirects the diagnostic workup toward the ANCA-associated vasculitides (AAV).

PAN spares capillaries, venules, and arterioles — this anatomical restriction has profound clinical consequences. Because the glomerulus is supplied by capillaries, PAN does not cause glomerulonephritis. Renal involvement in PAN is entirely ischemic in mechanism: stenosis or infarction of the renal arteries produces renovascular hypertension and renal cortical infarcts, but there is no proliferative glomerulonephritis, no red cell casts in the urine, and typically no heavy proteinuria — features that would otherwise suggest an ANCA vasculitis. Similarly, PAN spares pulmonary capillaries, so pulmonary capillaritis and diffuse alveolar hemorrhage do not occur. Pulmonary involvement is absent in classic PAN — another key distinguishing feature.

PAN holds the distinction of being the first vasculitis ever described in medicine: Adolf Kussmaul and Rudolf Maier published the seminal case report in 1866, naming the condition "periarteritis nodosa" for the palpable nodules felt along inflamed arteries. Historically, hepatitis B virus (HBV) infection was identified as a causative trigger in 30–50% of PAN cases; widespread hepatitis B vaccination has since reduced HBV-associated PAN to fewer than 10% of cases in developed nations. The ACR/EULAR reclassification frameworks, refined between 2012 and 2022, have substantially narrowed PAN's definition — many cases previously labeled "PAN" have been reclassified as MPA or other ANCA vasculitides as ANCA testing became routine. True idiopathic PAN is now recognized as a comparatively uncommon disease.

Epidemiology

PAN is a rare condition with an estimated annual incidence of 2–9 cases per million population in Western countries. It can occur at any age but peaks between 40 and 60 years. There is a slight male predominance, with a male-to-female ratio of approximately 1.5:1. In regions where hepatitis B vaccination coverage remains incomplete — including parts of sub-Saharan Africa, Southeast Asia, and Eastern Europe — HBV-associated PAN remains proportionally more common and continues to affect younger adults in keeping with the epidemiology of HBV infection in those populations.

Beyond HBV, a small number of well-recognized associations exist. Hairy cell leukemia-associated PAN is a rare but established entity in which the vasculitis may predate or follow the lymphoproliferative diagnosis; clinicians evaluating PAN without a clear infectious trigger should consider hematologic workup. Single-organ or limited forms of PAN — most notably cutaneous PAN (isolated skin involvement with livedo reticularis, subcutaneous nodules, and skin ulcers without systemic features) and appendiceal PAN (an incidental finding at appendectomy) — carry a considerably better prognosis than systemic PAN and rarely require systemic immunosuppression. Isolated cutaneous PAN may follow streptococcal infection in children and adolescents.

Pathophysiology

The core pathologic lesion in PAN is segmental fibrinoid necrosis of medium arterial walls. The inflammatory process begins with transmural neutrophilic infiltration of the vessel wall — neutrophils flood all layers of the artery, releasing proteases and reactive oxygen species that destroy the internal elastic lamina and media. This progresses to coagulative necrosis of the vessel wall (fibrinoid necrosis), structurally weakening the artery at points of maximal hemodynamic stress — particularly at bifurcations and branch points. The weakened wall dilates to form microaneurysms, typically 1–5 mm in diameter; these are the radiographic hallmark of PAN visible on conventional or CT angiography as saccular outpouchings along the mesenteric and renal arterial trees. Superimposed thrombosis at the aneurysm neck or at sites of stenosis produces distal arterial occlusion and end-organ ischemia or infarction. The segmental, skip-lesion distribution — a defining histological feature — means that consecutive segments of the same artery alternate between inflamed/necrotic and normal, explaining why portions of a single organ (e.g., kidney, bowel) can be infarcted while adjacent tissue remains viable.

In HBV-associated PAN, the pathogenic mechanism is immune complex deposition rather than direct viral cytopathic effect. Circulating hepatitis B surface antigen (HBsAg) forms immune complexes with anti-HBs antibodies; these complexes deposit in medium artery walls, activate the complement cascade, and trigger the same transmural necrotizing inflammation seen in idiopathic PAN. The timing is characteristic: vasculitis typically develops within the first year of HBV infection, when circulating HBsAg is abundant and the immune response is generating antibodies against it. This immune complex mechanism also explains why elimination of HBV replication through antiviral therapy — rather than indefinite immunosuppression — can produce sustained vasculitis remission: removing the antigen source eliminates the driver of immune complex formation.

Mononeuritis multiplex, the most clinically distinctive neurological feature of PAN, arises from vasculitis of the epineurial (nutrient) arteries supplying peripheral nerves. The epineurial arteries are medium-sized muscular arteries — squarely within PAN's target range — and their occlusion by necrotizing vasculitis produces focal nerve ischemia. Unlike length-dependent polyneuropathy, where dying-back from the feet occurs symmetrically, mononeuritis multiplex presents as asymmetric deficits that develop in a stepwise fashion: the peroneal nerve is infarcted at one point in time (producing unilateral foot drop), then the ulnar or radial nerve at another, then a different nerve again, each event marking a new arterial occlusion. Over time the cumulative picture may superficially resemble a symmetric polyneuropathy, but careful history reveals the stepwise, non-length-dependent evolution that points to a vasculitic etiology.

Clinical Manifestations

Constitutional symptoms are the most common presenting feature and are present in the majority of patients. Weight loss (present in approximately 70% of cases) is the most frequent constitutional symptom and is often striking — patients commonly lose 5–15 kg over weeks to months before diagnosis. Fever, profound fatigue, myalgia, and diffuse arthralgia accompany weight loss in most cases. These nonspecific symptoms frequently lead to a broad initial differential including malignancy, infection, and inflammatory bowel disease, causing diagnostic delays of months to years. Elevated acute-phase reactants (ESR often 60–120 mm/hr, CRP markedly elevated) are invariably present and may be the laboratory finding that prompts rheumatologic evaluation.

Peripheral neuropathy (mononeuritis multiplex) is the most common specific clinical manifestation, present in 50–75% of patients. Its asymmetric, stepwise character is diagnostically important. Common presentations include unilateral foot drop from peroneal nerve ischemia — the patient reports sudden inability to dorsiflex the foot, with a classic slapping gait — and wrist drop from radial nerve involvement. Sensory symptoms (burning, numbness, or allodynia in the nerve's territory) typically accompany or precede motor deficits. Because axonal injury from ischemia may be permanent, early diagnosis and treatment are essential to limit neurological deficit. Electrodiagnostic studies confirm axonal mononeuritis multiplex and help distinguish PAN neuropathy from demyelinating neuropathies or compression neuropathies. Renal involvement is driven entirely by medium artery ischemia: renovascular hypertension (from renal artery stenosis), renal cortical infarction causing flank pain and hematuria, and ultimately ischemic nephropathy contributing to renal insufficiency. The defining absence is glomerulonephritis — there are no red cell casts on urinalysis, no nephrotic-range proteinuria, and no crescentic changes on biopsy. This profile directly contradicts ANCA vasculitis renal disease and is a critical differentiating point at the bedside.

Gastrointestinal involvement is present in 30–50% of patients and carries the highest mortality risk of any PAN manifestation. Mesenteric artery vasculitis produces postprandial abdominal pain (intestinal angina) as the ischemic bowel fails to hyperemia adequately with meals; patients learn to eat less to avoid pain and lose further weight. More severe ischemia causes GI bleeding, segmental bowel infarction, and perforation — surgical emergencies with high mortality. Hepatic artery involvement can produce liver infarction or rupture of a hepatic artery aneurysm (rare but catastrophic). Appendiceal vasculitis, when present, is usually discovered incidentally at appendectomy performed for presumed appendicitis. Awareness that PAN can cause acute abdominal presentations is essential: an acute abdomen in a patient with unexplained systemic illness and weight loss should prompt consideration of mesenteric vasculitis.

Cutaneous manifestations include livedo reticularis (a lace-like, violaceous mottling of the skin that reflects dermal arteriolar compromise), tender subcutaneous nodules overlying inflamed arteries (most prominent over the lower legs and feet), skin ulcers from cutaneous infarction, and digital gangrene in severe disease. Testicular involvement — orchitis from testicular artery vasculitis producing scrotal pain and swelling — is a pathognomonic association. When a middle-aged man presents with unexplained orchitis refractory to antibiotic therapy, PAN must be considered; testicular biopsy may confirm the vasculitic diagnosis. Hypertension is present in 25–50% of patients, attributable to renovascular disease. Cardiac involvement (coronary arteritis → myocardial infarction, pericarditis) and CNS involvement (cerebral vasculitis → stroke, encephalopathy) occur in a minority of cases but contribute significantly to morbidity and mortality when present.

Hepatitis B-Associated PAN

Hepatitis B-associated PAN is a clinically and mechanistically distinct entity that requires a fundamentally different treatment strategy from idiopathic PAN. HBV-PAN once constituted 30–50% of all PAN diagnoses; universal hepatitis B vaccination programs — which have dramatically reduced new HBV infections in developed nations since the 1990s — have reduced this proportion to fewer than 10% in high-income countries, though it remains more prevalent in regions where vaccination coverage is incomplete. The pathogenic mechanism is immune complex-mediated: circulating HBV surface antigen (HBsAg) combines with anti-HBs antibodies to form immune complexes, which deposit in the walls of medium arteries, activate complement, and trigger the necrotizing vasculitis cascade. Vasculitis typically emerges within the first year of HBV infection, when antigen-antibody dynamics are most active. All patients with newly diagnosed PAN must be tested for HBV (HBsAg, anti-HBc total, HBV DNA) because the diagnosis of HBV-PAN completely changes the treatment algorithm.

Treatment of HBV-PAN prioritizes viral eradication over long-term immunosuppression. Prolonged immunosuppression in HBV infection accelerates viral replication, precipitates hepatitis flares, and risks progression to cirrhosis and hepatocellular carcinoma — making the standard idiopathic PAN regimen of long-term cyclophosphamide and corticosteroids directly harmful if applied to HBV-PAN without modification. The accepted regimen consists of three components: (1) a short initial course of prednisone to suppress the most dangerous organ-threatening inflammation, followed by rapid taper (typically 2–4 weeks); (2) antiviral therapy — tenofovir or entecavir are preferred over the older lamivudine due to superior resistance profiles and potency; and (3) plasma exchange (plasmapheresis) to physically remove circulating immune complexes and HBsAg from the bloodstream, accelerating the immunological clearance process. As antiviral therapy suppresses HBV DNA and drives HBeAg-to-anti-HBe seroconversion (loss of viral replication markers), the immune complex burden falls, complement activation ceases, and the vasculitis enters sustained remission — uniquely achievable without ongoing immunosuppression. Hepatitis B vaccination serves as primary prevention for HBV-PAN and is recommended for all unvaccinated household contacts and sexual partners of HBV-positive individuals.

Diagnosis

The diagnostic workup for PAN begins with establishing the ANCA-negative status and ruling out alternative diagnoses. ANCA testing (both p-ANCA/MPO-ANCA and c-ANCA/PR3-ANCA by ELISA) must be negative — a positive result effectively reassigns the diagnosis to the ANCA-associated vasculitides (MPA for p-ANCA/MPO, GPA for c-ANCA/PR3, or EGPA). HBV serology — HBsAg, total anti-HBc, and HBV DNA quantification — is mandatory in every PAN workup, as the diagnosis of HBV-PAN has direct treatment implications. Hepatitis C serology should be checked because HCV-associated cryoglobulinemic vasculitis can closely mimic PAN clinically, including mononeuritis multiplex and renal involvement, but is a different entity managed with antivirals (and rituximab for severe cases).

Laboratory findings in PAN are nonspecific but characteristically show leukocytosis with neutrophilia, normochromic normocytic anemia of chronic disease, thrombocytosis, markedly elevated ESR and CRP, and elevated acute-phase proteins. Renal function (creatinine, BUN) may be elevated if renovascular disease has compromised renal perfusion. Urinalysis is critically informative: PAN-related renal disease produces hematuria from renal cortical infarction but notably lacks the active urinary sediment of glomerulonephritis — no red cell casts, no white cell casts, and proteinuria below 1 g/day. The presence of red cell casts or >1 g/day proteinuria should redirect the workup toward ANCA-associated GN. Tissue biopsy of a clinically affected organ provides definitive histological diagnosis. Combined sural nerve and muscle biopsy (gastrocnemius) substantially increases diagnostic yield over either alone — the combination approach is standard when mononeuritis multiplex is present. Biopsy shows necrotizing vasculitis of medium and small arteries with transmural neutrophilic infiltration, fibrinoid necrosis, and disruption of the internal elastic lamina; healing lesions may show intimal proliferation and fibrosis.

Angiography (conventional digital subtraction angiography, or CT angiography) of the mesenteric and renal arteries demonstrates the radiographic hallmark of PAN: microaneurysms (typically 1–5 mm) at arterial branch points, accompanied by segmental stenoses and the "beading" appearance of alternating aneurysmal dilatation and stenosis. This angiographic pattern is considered pathognomonic for medium-vessel vasculitis and is reserved for cases where biopsy is not feasible, results are inconclusive, or when visceral involvement is suspected clinically. Critically, renal biopsy should be avoided in PAN because the microaneurysms create a risk of catastrophic hemorrhage; the combination of negative ANCA, absent urinary sediment, and characteristic angiographic findings is typically sufficient for diagnosis without renal tissue sampling. Fibromuscular dysplasia and atherosclerosis must be excluded as alternative explanations for angiographic abnormalities — FMD produces a characteristic "string of beads" in the mid-renal artery without systemic inflammation.

ACR Classification Criteria

The American College of Rheumatology 1990 classification criteria for polyarteritis nodosa were developed to distinguish PAN from other vasculitides in research cohorts. Classification (not diagnosis) requires at least 3 of the following 10 criteria, yielding a sensitivity of 82% and specificity of 87%:

  1. Weight loss of 4 kg or more since illness began, not due to dieting or other factors
  2. Livedo reticularis — mottled reticular pattern over portions of the extremities or torso
  3. Testicular pain or tenderness — not due to infection, trauma, or other cause
  4. Myalgias, weakness, or leg tenderness
  5. Mononeuropathy or polyneuropathy
  6. Diastolic blood pressure greater than 90 mmHg (new hypertension)
  7. Elevated blood urea nitrogen (>40 mg/dL) or creatinine (>1.5 mg/dL), not due to dehydration or obstruction
  8. Presence of hepatitis B surface antigen (HBsAg) or antibody in serum
  9. Arteriographic abnormality — aneurysm or occlusion of visceral arteries not due to arteriosclerosis, fibromuscular dysplasia, or other noninflammatory causes
  10. Biopsy of small or medium artery containing polymorphonuclear cells (PMNs) in the arterial wall

These 1990 criteria predate routine ANCA testing and the 2012 revised Chapel Hill Consensus Conference nomenclature, which formally separated MPA from PAN. The updated 2022 ACR/EULAR classification criteria for PAN incorporate ANCA-negativity and the absence of glomerulonephritis as implicit exclusions, better reflecting current understanding. In clinical practice (as opposed to research classification), a diagnosis of PAN requires excluding ANCA vasculitides, demonstrating pathological or angiographic evidence of medium-vessel vasculitis, and confirming the absence of capillaritis features (no GN, no pulmonary hemorrhage).

Treatment

Treatment of non-HBV (idiopathic) PAN is guided by disease severity, assessed using the Five-Factor Score (FFS). For mild-to-moderate disease (FFS 0), high-dose corticosteroids alone are the initial treatment: prednisone 1 mg/kg/day (typically 60–80 mg/day in adults), tapered gradually over 12–18 months as disease activity is controlled. This regimen achieves remission in the majority of patients with FFS-0 disease, and additional immunosuppression may not be required. The Five-Factor Score assigns one point each for: proteinuria greater than 1 g/day, renal insufficiency (creatinine >1.58 mg/dL), cardiomyopathy, GI involvement, and CNS involvement. Patients with FFS ≥ 1 — particularly those with GI ischemia, renal infarction, mononeuritis multiplex affecting multiple nerve territories, or CNS vasculitis — warrant addition of cyclophosphamide (CYC) to induce remission more rapidly and prevent irreversible organ damage.

When cyclophosphamide is indicated, IV pulse CYC is preferred over daily oral CYC. Evidence from the CYCLOPS trial (conducted in ANCA-associated vasculitis, but the principles apply given the mechanistic overlap of necrotizing vasculitis) demonstrated equivalent remission rates with pulse versus oral CYC at substantially lower cumulative CYC dose — translating to fewer infections, lower rates of bladder toxicity (hemorrhagic cystitis, bladder cancer), and reduced gonadotoxicity. The standard pulse regimen is 15 mg/kg IV every 2–3 weeks for 6–9 pulses. After remission induction with cyclophosphamide, transition to a maintenance agent — azathioprine (2 mg/kg/day) or methotrexate (20–25 mg/week) — is standard to prevent relapse while minimizing CYC cumulative toxicity. Maintenance is typically continued for 18–24 months after achieving remission. Biologic agents — including rituximab and TNF inhibitors — are not currently standard of care for PAN (in contrast to their established role in GPA and MPA); evidence for their use in PAN is limited to small case series and expert opinion. HBV-associated PAN requires the distinct antiviral-centered regimen described in the dedicated section above; long-term cyclophosphamide is contraindicated without concomitant antiviral therapy.

Adjunctive management is essential. Renovascular hypertension requires aggressive blood pressure control — ACE inhibitors or ARBs are preferred (though care is needed in severe bilateral renal artery stenosis). Anticoagulation may be considered for thrombotic complications at aneurysm sites, balancing thrombotic risk against hemorrhage risk at aneurysm walls. Prophylaxis against opportunistic infections (Pneumocystis jirovecii pneumonia with trimethoprim-sulfamethoxazole; gastric protection with proton pump inhibitors; calcium and vitamin D supplementation for steroid osteoporosis) should accompany all immunosuppressive regimens. Physical and occupational therapy are important for rehabilitation of mononeuritis multiplex deficits, given that axonal regeneration and functional recovery occur over months to years following successful vasculitis treatment.

Prognosis and Monitoring

The natural history of untreated PAN is severe: historical series from the pre-treatment era reported 5-year survival rates as low as 13%. Modern immunosuppressive treatment has transformed outcomes, with 5-year survival now exceeding 80% in most contemporary cohorts. The Five-Factor Score remains the most validated prognostic tool: patients with FFS 0 achieve approximately 93% 5-year survival; FFS 1 approximately 82%; FFS ≥ 2 approximately 74%. The leading causes of death in PAN are: uncontrolled vasculitis with visceral ischemia (GI perforation, renal failure, cardiac ischemia); treatment-related complications (serious infections from immunosuppression, bladder toxicity from cyclophosphamide); and cardiovascular events from chronic hypertension and accelerated atherosclerosis driven by years of systemic inflammation. Relapse is less common in PAN than in ANCA-associated vasculitides — a single course of treatment achieves long-term remission in many patients, particularly in HBV-PAN where viral clearance removes the antigenic stimulus entirely. Mononeuritis multiplex deficits may recover partially or completely over 1–3 years following successful treatment, reflecting slow axonal regeneration; patients should be counseled about the extended timeline for neurological recovery and the importance of physical therapy.

Disease monitoring should be systematic and lifelong given the risk of relapse and treatment complications. At each follow-up visit: ESR and CRP (sensitive markers of active vasculitis); renal function (BUN, creatinine) and urinalysis (to detect emerging GN if the diagnosis were to shift or a superimposed process develop); blood pressure measurement (target below 130/80 mmHg); assessment for new neurological deficits (new foot drop, wrist drop, or sensory changes suggesting new nerve ischemia); and symptom review for GI or testicular involvement. Angiographic follow-up (repeat CT or MR angiography) is indicated at 12–18 months to document resolution or stabilization of microaneurysms; persistent or enlarging aneurysms suggest ongoing active disease and prompt treatment reassessment. In HBV-PAN, serial HBV DNA quantification and liver function tests guide antiviral therapy duration and confirm viral suppression. Cardiovascular risk factor management — lipid control, blood pressure, smoking cessation, exercise — is integral to long-term follow-up given the additive cardiovascular burden of chronic vasculitis and steroid-related metabolic effects.

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References

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Connections

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