# Polyarteritis Nodosa and Medium Vessel Vasculitis

## Introduction

Polyarteritis nodosa is a necrotizing vasculitis of medium-sized muscular arteries that is distinguished from the ANCA-associated vasculitides by three critical features: ANCA negativity, exclusive medium artery involvement, and the absence of glomerulonephritis. The incidence of PAN has been declining, largely attributable to the success of hepatitis B vaccination programs, as HBV-associated PAN has decreased markedly over recent decades. Other medium-vessel vasculitides include Kawasaki disease, which predominantly affects children, and primary CNS angiitis, a rare vasculitis confined to the central nervous system.

## Polyarteritis Nodosa

### Epidemiology

The incidence of PAN ranges from 2 to 9 per million per year and continues to decline. There is a mild male predominance with a male-to-female ratio of approximately 1.5 to 1, and peak onset occurs between 40 and 60 years of age. HBV-associated PAN historically accounted for 10 to 30 percent of PAN cases but now comprises fewer than 5 percent due to widespread vaccination programs.

### Pathogenesis

The pathologic hallmark of PAN is necrotizing inflammation of medium-sized muscular arteries. The inflammation is segmental and transmural, progressing through fibrinoid necrosis of the vessel wall to microaneurysm formation, thrombosis, and ultimately organ ischemia and infarction. In HBV-associated PAN, the mechanism is immune complex-mediated, with HBV antigens deposited in vessel walls, often occurring during seroconversion. The pathogenesis of idiopathic PAN remains poorly understood but is presumed to be immune-mediated. A monogenic form of PAN has been identified: deficiency of adenosine deaminase 2, caused by mutations in the CECR1 gene, which presents in childhood with recurrent strokes, livedo reticularis, and fever, and responds dramatically to anti-TNF therapy rather than conventional immunosuppression.

### Clinical Manifestations

#### Constitutional

Constitutional symptoms are prominent in PAN, with fever, malaise, and significant weight loss exceeding 10 percent of body weight occurring in approximately 80 percent of patients. Night sweats and diffuse myalgias are common accompaniments.

#### Skin (40-50%)

Cutaneous manifestations include subcutaneous nodules along the course of arteries, which give the disease its name "nodosa." Livedo reticularis or livedo racemosa produces a branching, violaceous reticular pattern on the skin. Digital ischemia and gangrene reflect end-artery occlusion. Punched-out ulcers predominantly affecting the lower extremities are characteristic. Cutaneous PAN, a variant limited to the skin presenting with nodules and livedo, generally follows a benign course and may not require systemic immunosuppression.

#### Neurologic (50-70%)

Mononeuritis multiplex is the most characteristic neurologic feature of PAN, presenting as an asymmetric motor and sensory neuropathy affecting individual named nerves including the peroneal, tibial, ulnar, and median nerves. Distal symmetric polyneuropathy is less common. Central nervous system involvement is rare and may result from stroke due to mesenteric or cerebral artery involvement.

#### Renal (60-70%)

Renal involvement in PAN manifests as renovascular hypertension resulting from renal artery aneurysms and stenoses, producing renin-mediated hypertension. Renal infarction causes flank pain and hematuria. The absence of glomerulonephritis is a key distinguishing feature that separates PAN from MPA. Perirenal hematoma from ruptured renal aneurysm represents a surgical emergency.

#### Gastrointestinal (30-50%)

Gastrointestinal involvement includes mesenteric ischemia presenting as abdominal pain that is often postprandial, accompanied by nausea and weight loss. Bowel perforation and infarction represent surgical emergencies. Gastrointestinal hemorrhage, acalculous cholecystitis from gallbladder ischemia, and appendicitis from vasculitis of the appendiceal arteries are additional manifestations.

#### Musculoskeletal

Myalgias are common and may be severe. Arthralgias are non-erosive and tend to affect large joints. Muscle infarction, though rare, causes severe focal muscle pain.

#### Cardiac

Cardiac manifestations include coronary arteritis that can produce myocardial infarction, pericarditis, and heart failure, though cardiac involvement is less common than in Kawasaki disease.

#### Genitourinary

Testicular or ovarian pain occurs in approximately 25 percent of patients due to testicular or ovarian artery vasculitis and represents a classic presentation. Testicular biopsy may be diagnostic.

<image>A clinical anatomy diagram of polyarteritis nodosa showing medium-vessel inflammation and its consequences. Show a central cross-section of a medium-sized muscular artery with segmental transmural inflammation: fibrinoid necrosis in the media, inflammatory infiltrate (neutrophils, macrophages), disrupted internal elastic lamina (Verhoeff-van Gieson stain), and resulting microaneurysm formation. Surrounding the artery cross-section, show organ-specific manifestations with arrows: kidneys (renal angiogram showing microaneurysms, "string of beads" appearance, renal infarcts), GI tract (mesenteric ischemia with bowel wall thickening), peripheral nerves (mononeuritis multiplex affecting peroneal nerve), skin (livedo reticularis pattern on lower legs, subcutaneous nodules), and testis (orchitis with arterial inflammation). Label all histologic and clinical findings.</image>

| Feature | PAN | MPA |
|---------|-----|-----|
| Vessel size | **Medium** muscular arteries | **Small** vessels (capillaries, venules, arterioles) |
| ANCA | **Negative** | **MPO-ANCA positive** (60-70%) |
| Glomerulonephritis | **Absent** (no GN) | **Present** (crescentic pauci-immune GN) |
| Renal involvement | Renovascular hypertension, renal infarcts, microaneurysms | RPGN with active sediment |
| Angiography | Microaneurysms, "beading" pattern | Normal or non-specific |
| Biopsy | Medium-artery necrotizing vasculitis; no GN | Pauci-immune crescentic GN; capillaritis |
| Hepatitis B association | **Yes** (historically 10-30%) | No |
| Lung involvement | Rare | DAH, ILD |
| Mononeuritis multiplex | **50-70%** (most characteristic) | ~30% |
| Testicular involvement | **~25%** (classic feature) | Rare |
| Treatment | GC ± CYC (idiopathic); antivirals (HBV) | RTX or CYC + GC; avacopan |

### Diagnosis

#### Laboratory

ESR and CRP are markedly elevated. The complete blood count reveals leukocytosis, anemia, and thrombocytosis. ANCA is negative, and a positive ANCA result should prompt reconsideration of MPA or GPA. Hepatitis B serologies including HBsAg and HBV DNA must be obtained in all PAN patients. Liver function tests may be elevated in HBV-associated PAN. Cryoglobulins should be checked to exclude cryoglobulinemic vasculitis. Complement levels are usually normal but may be low in HBV-associated PAN.

#### Imaging

Conventional angiography remains the gold standard and reveals microaneurysms of 1 to 5 millimeters along with stenoses in the renal, hepatic, and mesenteric arteries, producing the characteristic "beading" or "rosary-bead" pattern. CT angiography and MR angiography are increasingly used and can detect larger aneurysms but may miss small microaneurysms. Aneurysmal vessels should not be biopsied due to the risk of hemorrhage.

#### Biopsy

Sural nerve biopsy, when mononeuritis multiplex is present, demonstrates necrotizing vasculitis of medium-sized epineural arteries with a sensitivity of approximately 50 to 70 percent. Skin biopsy using a deep punch or excisional technique reveals medium-vessel vasculitis in the deep dermis or subcutis. Testicular biopsy is a classic diagnostic site when orchitis is present. Muscle biopsy demonstrates vasculitis of intramuscular arteries when myalgia is prominent. Renal biopsy shows arterial vasculitis without glomerulonephritis, a distinction that separates PAN from AAV.

### Management

#### Five Factor Score (FFS) for PAN - Prognosis and Treatment

The Five Factor Score assigns one point for each of the following: proteinuria exceeding 1 gram per day, serum creatinine above 1.58 milligrams per deciliter, gastrointestinal involvement, cardiomyopathy, and CNS involvement. A score of 0 carries a 5-year mortality of approximately 12 percent, while a score of 1 or greater increases 5-year mortality to approximately 26 to 46 percent.

#### Idiopathic PAN Treatment

For non-severe disease with an FFS of 0, glucocorticoids alone with prednisone at 1 milligram per kilogram per day tapered over 12 to 18 months may suffice. Immunosuppression is added if relapse occurs or glucocorticoids cannot be tapered. For severe disease with an FFS of 1 or greater, glucocorticoids are combined with cyclophosphamide, either as intravenous pulse CYC at 15 milligrams per kilogram every 2 to 4 weeks for 6 to 12 pulses followed by maintenance azathioprine, or as oral CYC for induction followed by azathioprine at 2 milligrams per kilogram per day for maintenance. Rituximab has been reported beneficial in case reports and small series but lacks randomized controlled trial data specific to PAN.

#### HBV-Associated PAN

The management of HBV-associated PAN differs fundamentally from idiopathic PAN because prolonged immunosuppression may worsen HBV viremia. Treatment consists of a short course of glucocorticoids for approximately 2 weeks combined with antiviral therapy using entecavir or tenofovir, with or without plasma exchange. The therapeutic goal is to achieve HBV seroconversion from HBsAg to anti-HBs, at which point disease remission typically follows. Prolonged immunosuppression should be avoided. Lamivudine is no longer recommended due to high resistance rates.

### Prognosis

Five-year survival with treatment is approximately 80 to 90 percent. The relapse rate of 10 to 20 percent is lower than in ANCA-associated vasculitis. HBV-associated PAN carries a good prognosis if seroconversion is achieved. Chronic morbidity includes persistent neuropathy, hypertension, and renal impairment.

## Kawasaki Disease (Brief Overview)

Kawasaki disease is a medium-vessel vasculitis of childhood with peak incidence between 6 months and 5 years of age. Diagnostic criteria require fever of 5 days or longer plus at least 4 of 5 clinical features: bilateral conjunctival injection, oral mucous membrane changes, cervical lymphadenopathy, extremity changes including edema, erythema, and desquamation, and polymorphous rash. Coronary artery aneurysm is the most feared complication, occurring in 15 to 25 percent of untreated children but fewer than 5 percent with appropriate treatment. Treatment consists of intravenous immunoglobulin at 2 grams per kilogram as a single dose plus high-dose aspirin, followed by low-dose aspirin, administered within 10 days of fever onset. Refractory cases may require a second dose of IVIG, infliximab, or methylprednisolone. Long-term coronary artery surveillance is necessary, and adult rheumatologists may encounter adults with prior Kawasaki disease and coronary sequelae.

## Deficiency of ADA2 (DADA2)

Deficiency of adenosine deaminase 2 is a monogenic vasculitis that mimics PAN and follows autosomal recessive inheritance through mutations in the CECR1/ADA2 gene. It presents in childhood with recurrent strokes including lacunar infarcts, livedo reticularis, fever, and hepatosplenomegaly. The vasculopathy involves medium-sized vessels and resembles PAN histologically. Hematologic manifestations include cytopenias, pure red cell aplasia, and lymphoproliferation. Diagnosis is established through demonstration of low serum ADA2 enzyme activity combined with confirmatory genetic testing. Treatment with anti-TNF therapy, either adalimumab or etanercept, dramatically improves the vascular features, representing a fundamentally different approach from conventional immunosuppression with cyclophosphamide, which is ineffective. Bone marrow transplant is considered for severe hematologic manifestations.

<image>A mesenteric angiogram illustration showing the classic findings of polyarteritis nodosa. Show the celiac trunk and superior mesenteric artery branches with multiple microaneurysms (small, round, saccular outpouchings of 1-5 mm) scattered along the hepatic, renal, and mesenteric arterial branches. Demonstrate areas of stenosis (narrowing) between aneurysms creating the "beading" or "string of beads" pattern. Show vascular cutoffs indicating complete occlusion of some branches with resultant organ ischemia (pale kidney infarct). Include labels for: microaneurysms, segmental stenosis, vascular occlusion, and renal infarct. Add a magnified inset of a single microaneurysm showing weakened, inflamed arterial wall with fibrinoid necrosis leading to outpouching.</image>

## Primary CNS Angiitis (PCNSV)

Primary CNS angiitis is a rare medium- and small-vessel vasculitis limited to the brain and spinal cord. The clinical presentation includes headache as the most common symptom, cognitive decline, focal neurologic deficits, seizures, and strokes. MRI demonstrates multifocal white matter lesions, infarcts, and hemorrhage, a pattern that mimics many other conditions. Cerebral angiography reveals alternating stenosis and dilation producing a "beading" pattern, though sensitivity is only approximately 60 percent. Brain biopsy remains the gold standard, demonstrating granulomatous vasculitis with a sensitivity of approximately 75 percent. The differential diagnosis includes reversible cerebral vasoconstriction syndrome, infections, malignancy, and other vasculitides with CNS involvement, all of which must be excluded. Treatment consists of glucocorticoids plus cyclophosphamide for induction, followed by azathioprine for maintenance, though no randomized trials exist to guide therapy.

## Key Clinical Pearls

- PAN is ANCA-negative and does NOT cause glomerulonephritis; if ANCA positive or GN present, reconsider MPA
- Always screen for hepatitis B in PAN; HBV-PAN requires antiviral therapy, NOT prolonged immunosuppression
- Microaneurysms on angiography are characteristic of PAN but not pathognomonic (can occur in SLE, EGPA, mycotic aneurysms, fibromuscular dysplasia)
- DADA2 should be suspected in children or young adults with PAN-like vasculitis and strokes; treatment is anti-TNF, not CYC
- Testicular pain in a young-to-middle-aged man with systemic inflammation should raise suspicion for PAN
- Cutaneous PAN (limited to skin) generally has an excellent prognosis and may not require systemic immunosuppression

## References
1. Hernandez-Rodriguez J, et al. Polyarteritis nodosa. In: Ball GV, Bridges SL, eds. Vasculitis. 3rd ed. Oxford University Press; 2014.
2. Guillevin L, et al. Polyarteritis nodosa: clinical characteristics, outcome, and treatment in 115 patients. Medicine (Baltimore). 2005;84(2):115-128.
3. Navon Elkan P, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370(10):921-931.
4. Guillevin L, et al. Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, outcome, and impact of treatment in 115 patients. Medicine (Baltimore). 2005;84(5):313-322.
5. De Virgilio A, et al. Polyarteritis nodosa: a contemporary overview. Autoimmun Rev. 2016;15(6):564-570.