Poliarteritis Nodosa

01Pathophysiology

Polyarteritis nodosa is a systemic necrotizing vasculitis that selectively targets medium-sized muscular arteries. The disease is driven by the deposition of immune complexes within the arterial wall, which triggers complement activation and recruitment of neutrophils and macrophages. This inflammatory cascade produces transmural inflammation, meaning all three layers of the vessel wall (intima, media, adventitia) are damaged simultaneously. The hallmark histological finding is fibrinoid necrosis, where the vessel wall undergoes coagulative destruction with deposition of fibrin-like material.

The inflammation in PAN is segmental and focal, with a predilection for arterial bifurcation points where turbulent blood flow promotes immune complex deposition. This segmental pattern is why affected arteries show alternating areas of normal and diseased wall. Over time, the necrotized segments weaken, resulting in microaneurysm formation. These aneurysms, when visualized on angiography, produce the classic "string of pearls" or "rosary bead" appearance.

The clinical consequences arise from three mechanisms occurring simultaneously. First, luminal narrowing from inflammation and intimal proliferation produces downstream ischemia. Second, thrombosis at sites of endothelial damage leads to organ infarction. Third, aneurysmal rupture causes hemorrhage. This triad explains why PAN can present with both ischemic and hemorrhagic manifestations in the same patient.

The two features that define PAN and distinguish it from every other vasculitis on the exam are critically important to internalize. PAN does not involve capillaries, venules, or arterioles. Because glomerular capillaries are spared, there is no glomerulonephritis. Because pulmonary capillaries are spared, there is no pulmonary hemorrhage or capillaritis. The kidney is affected through the renal artery and its branches (causing renovascular hypertension and renal infarction), not through the glomerulus. This distinction is the single most tested concept in PAN-related questions.

In approximately 30% of cases, PAN is associated with hepatitis B infection. The mechanism involves HBV antigen-antibody immune complexes that deposit in medium-sized vessel walls, triggering the same cascade of complement-mediated destruction. This subset behaves differently in terms of treatment and must be identified early.

02Classification and Clinical Manifestation

Cutaneous PAN is a limited variant confined to the skin without systemic involvement. It presents with subcutaneous nodules, livedo reticularis, and skin ulcers but carries a benign prognosis. It is important to recognize this variant because it does not require the aggressive immunosuppression used for systemic PAN.

Five-Factor Score (FFS) for Prognosis

The Five-Factor Score guides treatment intensity and predicts mortality:

A score of 0 generally supports corticosteroid monotherapy, while a score of 1 or higher warrants the addition of cyclophosphamide.

03Diagnostic Workup

The workup begins with baseline inflammatory markers and serology. ESR and CRP will be elevated in virtually all patients but are nonspecific. The CBC typically shows leukocytosis with a left shift, anemia of chronic disease, and reactive thrombocytosis. Renal function may be impaired, but the urinalysis is the critical distinguishing test: in PAN, the urine will show no red blood cell casts and no dysmorphic red blood cells. If you see an active urinary sediment with RBC casts, you are dealing with a small-vessel vasculitis (microscopic polyangiitis or granulomatosis with polyangiitis), not PAN.

ANCA testing is essential and must be negative to support a diagnosis of PAN. A positive p-ANCA redirects you toward microscopic polyangiitis. A positive c-ANCA points to granulomatosis with polyangiitis. The ANCA-negative result in PAN is not just a "negative finding" on the exam; it is an active diagnostic criterion you must look for.

Hepatitis B serology must be sent in every patient with suspected PAN. This determines the treatment strategy entirely. If HBsAg is positive, the disease is HBV-associated PAN, and prolonged immunosuppression is contraindicated because it promotes viral replication.

The best initial confirmatory test is mesenteric or renal angiography. This will show the classic findings of multiple microaneurysms (typically 1 to 5 mm) at arterial bifurcation points along with segmental narrowing of affected arteries. The "string of pearls" pattern is considered virtually diagnostic when seen in the appropriate clinical context.

The gold standard is tissue biopsy of a clinically affected organ. The sural nerve is the most commonly biopsied site in patients with neuropathy, and skin biopsy is used when cutaneous lesions are present. The histology shows transmural fibrinoid necrosis with a mixed inflammatory infiltrate (neutrophils in acute phases, lymphocytes and macrophages in chronic phases). Lesions at different stages of evolution within the same vessel are characteristic.

A critical safety note: do not biopsy organs where angiography has demonstrated aneurysms. Biopsy of an aneurysmal vessel carries a high risk of hemorrhage. If angiography is positive and clinically consistent, a tissue biopsy may not be necessary to establish the diagnosis.

04Management and Treatment

For non-HBV PAN with mild disease (FFS of 0, no organ-threatening involvement), corticosteroids alone are the first-line therapy. Prednisone is initiated at 1 mg/kg/day, with a gradual taper beginning after clinical response is achieved (usually within 2 to 4 weeks). The total treatment duration is typically 12 to 18 months. The taper must be slow and monitored, as rapid discontinuation frequently triggers relapse.

For non-HBV PAN with severe disease (FFS of 1 or higher, or any organ-threatening manifestation such as renal failure, mesenteric ischemia, cardiomyopathy, or CNS involvement), the "next best step" is to add cyclophosphamide to corticosteroids. The preferred regimen is IV pulse cyclophosphamide at 15 mg/kg (or approximately 0.6 g/m${}^2^2$) every 2 to 3 weeks for 6 to 12 pulses, as it carries less cumulative toxicity than daily oral dosing. After achieving remission (usually 3 to 6 months), cyclophosphamide is switched to a maintenance agent, either azathioprine (2 mg/kg/day) or methotrexate (15 to 25 mg/week), continued for at least 12 to 18 months.

Cyclophosphamide carries important toxicities that are frequently tested: hemorrhagic cystitis (prevented with adequate hydration and mesna), bladder cancer with prolonged use, bone marrow suppression, and gonadal toxicity (infertility). Monitor CBC regularly during therapy.

HBV-associated PAN requires a fundamentally different approach. Prolonged immunosuppression is dangerous because it suppresses the immune control of hepatitis B, leading to increased viral replication, worsening liver disease, and potential fulminant hepatitis. The correct management is:

1. A short course of corticosteroids (approximately 2 weeks, rapidly tapered) to control the initial inflammatory flare.

2. Antiviral therapy with entecavir or tenofovir to suppress HBV replication and eliminate the source of immune complex formation.

3. Plasmapheresis (plasma exchange) to physically remove circulating immune complexes from the blood.

This combination addresses both the cause (HBV) and the consequence (vasculitis) without the prolonged immunosuppression that would worsen the underlying infection.

Contraindications and cautions:

• Cyclophosphamide is relatively contraindicated in patients with active infection, severe cytopenias, or in those who desire future fertility without prior fertility preservation.

• Methotrexate should be avoided in patients with renal insufficiency () due to impaired clearance and increased toxicity.

• In HBV-associated PAN, do not use prolonged corticosteroids or cyclophosphamide without concurrent antiviral coverage.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The most common way students lose points on PAN questions is by confusing it with microscopic polyangiitis (MPA). Both are systemic necrotizing vasculitides, both can involve the kidneys, and both can present with constitutional symptoms, skin findings, and neuropathy. The exam will present a patient who looks like they could have either one, and the answer hinges on two findings: the ANCA result and the urinalysis. If the ANCA is positive (especially p-ANCA/MPO) and there are RBC casts in the urine, the answer is MPA. If the ANCA is negative and the urine shows no active sediment, the answer is PAN. Students who do not actively look for these two data points in the vignette will select the wrong answer.

The second major trap involves HBV-associated PAN and treatment selection. A vignette will present a classic PAN patient with positive hepatitis B serology, and the question will ask about the best treatment. The wrong answer is long-term cyclophosphamide plus corticosteroids. The correct answer is antiviral therapy with a short corticosteroid course and plasmapheresis. Students who reflexively choose immunosuppression for every vasculitis will miss this. The test is evaluating whether you understand that treating the underlying cause (HBV) is the priority in this subset.

A third trap is the angiography finding. When a vignette describes "string of pearls" or "rosary bead" pattern on renal artery angiography, students may jump to fibromuscular dysplasia (FMD), which also produces a beaded appearance. The discriminator is the clinical context: FMD occurs in young women without systemic inflammation, while PAN occurs in middle-aged men with fever, weight loss, elevated inflammatory markers, and multiorgan involvement.

Finally, remember the two organs PAN never involves: the lungs and the glomeruli. If the vignette includes hemoptysis, pulmonary infiltrates, or RBC casts in the urine, you are not dealing with PAN. This single rule eliminates PAN from the differential instantly and is the most reliable shortcut in vasculitis questions.

The core competency being tested in PAN questions is your ability to classify vasculitis by vessel size, correctly interpret ANCA results, recognize the HBV association and its treatment implications, and avoid the reflexive selection of immunosuppression when an underlying infectious cause is present.