Polyarteritis Nodosa: Systemic vs. Cutaneous Vasculitis

Polyarteritis nodosa, commonly abbreviated PAN, is a rare disease in which medium-sized arteries become inflamed and damaged, cutting off blood supply to the organs they feed. It can strike the kidneys, gut, nerves, skin, heart, and other tissues, often in unpredictable combinations that make it one of the more difficult vascular diseases to pin down. PAN was actually the first non-infectious vasculitis ever described in medical literature, and the understanding gained from studying it became the foundation for classifying nearly every other form of vasculitis that followed.¹ Despite that long history, PAN remains tricky to diagnose, sometimes dangerous, and widely misunderstood.

What Happens Inside the Arteries

PAN targets arteries that fall in the “medium” size range, roughly the caliber of the vessels that branch out to supply individual organs. The disease causes patches of intense inflammation in the artery wall, a process called necrotizing vasculitis. In the acute phase, the wall undergoes fibrinoid necrosis, where the normally elastic tissue is replaced by a dense, protein-rich material that weakens the vessel. Over time, the inner lining thickens with scar tissue, which can narrow or block the artery entirely.² Some damaged spots balloon outward into small aneurysms, the “nodosa” part of the name, referring to the bead-like bumps that can be seen on imaging or at surgery.

The result depends on which arteries are hit. A blocked renal artery segment can cause high blood pressure and kidney damage. A weakened mesenteric artery can starve a loop of intestine. A damaged artery feeding a peripheral nerve can cause sudden, painful weakness in a hand or foot. Because the inflammation tends to be patchy rather than continuous, PAN produces a mosaic of problems that varies enormously from one person to the next.

Known Triggers and Causes

For many people with PAN, no specific trigger is ever identified, and the disease is labeled idiopathic. But several well-established causes exist, and identifying them matters because treatment changes depending on the underlying driver.

The best-understood cause is hepatitis B virus infection. In HBV-associated PAN, the immune system forms complexes of viral proteins and antibodies that deposit in artery walls, sparking the destructive inflammation.³ This form of PAN has become much less common in countries with widespread hepatitis B vaccination, but it still occurs in regions where vaccination coverage is lower or in people who were infected before vaccines became routine.

In children, streptococcal infections have been linked to a cutaneous form of PAN. Pediatric cases sometimes show elevated anti-streptolysin O titers, suggesting a recent strep infection triggered the immune response.⁴ One case report described an 8-year-old boy who developed migratory joint pain, skin nodules, and discoloration of his fingers after a streptococcal infection, with elevated strep markers pointing to the connection.⁵ The strep-associated form typically runs a milder course than idiopathic systemic PAN, though it can still require steroids or immunosuppressive therapy to control.

A genetic cause also exists. Deficiency of adenosine deaminase 2, known as DADA2, is an inherited condition caused by mutations in the ADA2 gene. People with DADA2 can develop vasculopathy ranging from a lacy, purplish skin pattern called livedo reticularis all the way to full-blown PAN and life-threatening strokes.⁶ DADA2 is especially important to recognize in children and young adults with PAN-like features, because the treatment approach differs from standard PAN and may include targeted biologic therapies.

How PAN Shows Up

The clinical picture of PAN is notoriously variable. Some people develop full-blown multisystem disease within weeks. Others have smoldering symptoms for months before anyone suspects vasculitis. A case report described a 33-year-old man who experienced four months of recurring inflammatory episodes hitting his abdomen, nervous system, skin, and cardiopulmonary system before the diagnosis was made.⁷ That kind of delay is common, partly because PAN lacks a definitive blood test.

The organs most frequently involved include:

Kidneys: Renal artery inflammation can cause new-onset high blood pressure and declining kidney function. In mild cases, steroid therapy alone may be enough to control it.⁸
Gastrointestinal tract: Gut involvement occurs in roughly 14% to 65% of patients. The most common symptom is abdominal pain after eating, caused by reduced blood flow to the intestines. If the ischemia becomes severe enough to damage the full thickness of the bowel wall, perforation can follow, and the prognosis drops sharply.⁹
Peripheral nerves: Mononeuritis multiplex, where individual nerves are damaged in a scattered pattern, is one of the hallmark features. A person might develop foot drop, wrist weakness, or patchy numbness that does not follow the typical stocking-glove distribution of more common neuropathies.¹⁰
Skin: Tender nodules along arteries, livedo reticularis, and ulcers on the extremities are frequent. Skin findings are sometimes the clue that leads to biopsy and diagnosis.
Heart: Coronary arteries can be involved. In one study of 145 PAN patients, about 13% had coronary artery lesions, often affecting multiple vessels. New-onset hypertension and celiac artery involvement were risk factors for coronary disease in these patients.¹¹

Cutaneous Versus Systemic PAN

Not everyone with PAN has widespread organ involvement. Cutaneous PAN is a milder variant that primarily affects the skin and sometimes the muscles and joints, without causing the kidney, gut, or nerve damage seen in systemic disease. A Korean study of childhood-onset PAN found that one of nine patients had cutaneous PAN while all the rest had the systemic form.¹² That ratio may not hold everywhere, since cutaneous PAN is probably underdiagnosed, but it illustrates that systemic disease dominates the clinical picture in most centers that manage PAN.

Cutaneous PAN can still be uncomfortable and disabling. Patients typically present with painful nodules, livedo reticularis, and sometimes ulcers on the lower legs. The disease can flare and remit over years. When tied to streptococcal infection in children, the course tends to be benign and responsive to anti-inflammatory agents or short courses of steroids.¹³ The key distinction is that cutaneous PAN does not carry the same mortality risk as the systemic form, though clinicians monitor patients to ensure it does not progress.

The Diagnostic Challenge

Diagnosing PAN is genuinely hard. There is no single blood test that confirms it. The disease is typically ANCA-negative, meaning the antibody test used to detect certain other vasculitides usually comes back normal in PAN. Distinguishing PAN from microscopic polyangiitis, a small-vessel vasculitis that can look similar, requires weighing the full clinical picture, including which organs are involved, whether ANCA is positive, and what imaging or biopsy shows.¹⁴ Microscopic polyangiitis tends to hit the lungs and the filtering units of the kidneys (causing a rapidly progressive kidney disease called glomerulonephritis), while PAN spares the lungs and damages the kidneys through artery inflammation rather than glomerular inflammation.

Biopsy of affected tissue can show the characteristic necrotizing inflammation in medium-sized arteries, but superficial biopsies frequently miss the diseased vessels, and the diagnostic yield is low.¹⁵ Angiography, which images the arteries directly, can reveal the tell-tale microaneurysms and irregular narrowing in abdominal or renal vessels, but early in the disease course these findings may not yet be present. A single-organ form, sometimes called isolated necrotizing arteritis, confines the vasculitis to one location and can be confirmed only when a pathologist examines tissue from that organ.¹⁶

How PAN Is Treated

Treatment depends on disease severity and whether an underlying cause like hepatitis B is present. For idiopathic systemic PAN, the backbone of therapy is corticosteroids, often combined with cyclophosphamide for more severe cases. A prospective trial of 62 patients compared corticosteroids plus cyclophosphamide alone against the same regimen with added plasma exchanges. At five years, about 61% of patients were considered cured across both groups. Survival rates were 75% and 88% in the two arms, a difference that was not statistically significant.¹⁷ These numbers show that PAN is treatable but carries real mortality, especially in patients with poor prognostic features.

Hepatitis B-associated PAN is a special case. Long-term immunosuppression can be counterproductive because it suppresses the immune system’s ability to clear the virus. Instead, the preferred approach combines antiviral therapy with plasma exchanges and a short course of corticosteroids. Studies of this strategy have shown good outcomes: one series reported that all treated patients cleared clinical evidence of vasculitis, and viral replication was brought under control.¹⁸ More recent case reports continue to support the combination of antivirals and plasma exchange as effective for HBV-PAN.¹⁹

Biologic Therapies for Refractory Disease

Some patients relapse repeatedly or fail to respond to standard treatment. For them, biologic drugs are an emerging option. A European collaborative study looked at 42 PAN patients who received biologics, including TNF-alpha blockers, rituximab, and tocilizumab. Tocilizumab showed the highest remission rate at 50%, while TNF-alpha blockers achieved remission in 40% and rituximab in about a third. The study suggested tocilizumab may be particularly useful for refractory disease.²⁰ For patients with DADA2, TNF-alpha inhibitors have shown particular promise and are considered by many experts to be the treatment of choice for that genetic subset.²¹

These biologic options are still based on case series and small studies rather than large randomized trials, which is inevitable for a disease this rare. But the evidence is encouraging enough that rheumatologists now consider biologics a reasonable next step when conventional drugs fail.

Predicting Outcomes

Prognosis in PAN varies widely. The tool most commonly used to gauge risk at diagnosis is the Five-Factor Score, originally developed in France and revised in 2009 using data from over 1,100 patients with various forms of necrotizing vasculitis. The factors that predict higher five-year mortality include age over 65, cardiac symptoms, gastrointestinal involvement, and kidney insufficiency above a specific threshold.²² Each factor present at diagnosis adds one point; higher scores correlate with worse survival.

In that large French cohort, overall mortality for PAN was about 25%. A Japanese study confirmed that the Five-Factor Score held up in a different population, with each additional point roughly doubling the hazard of death.²³ People with low scores at diagnosis, meaning no major organ involvement beyond perhaps the skin and peripheral nerves, generally do well with standard treatment. Those with gut perforation or rapidly declining kidney function face a harder road.

Relapse is another concern. The Korean childhood study found that seven of nine patients relapsed over a median follow-up of seven years, and three children with high disease activity scores at diagnosis suffered lasting complications, including brain hemorrhage and finger amputation.²⁴ These are small numbers, but they underscore that childhood PAN, while survivable, can leave permanent damage when disease activity is high.

PAN During Pregnancy

Pregnancy adds layers of complexity to PAN. The disease can flare postpartum, and roughly 40% of PAN cases in pregnancy are associated with hypertensive disorders of pregnancy, which can independently damage blood vessels in the placental bed.²⁵ The overlap between PAN symptoms and conditions like preeclampsia or puerperal infection can delay diagnosis considerably. One case report described a woman whose PAN was initially mistaken for a postpartum infection; it was only when a tender nodule appeared on her forearm and was biopsied that the diagnosis became clear. Treatment with high-dose steroids and cyclophosphamide led to a full recovery, and the baby was healthy.²⁶

The difficulty in distinguishing PAN from pregnancy-related hypertension is not just academic. If PAN is missed and attributed to preeclampsia alone, the underlying vasculitis continues to smolder and can cause acute kidney failure or even heart attack from arterial necrosis. Clinicians caring for pregnant or postpartum patients with unusual combinations of hypertension, skin changes, and multisystem symptoms should keep PAN on the differential.

When the Gut Is the Main Target

Gastrointestinal involvement deserves special attention because it is both common and dangerous. Postprandial abdominal pain, the gut’s equivalent of angina, is the most frequent symptom and reflects reduced blood flow through inflamed mesenteric arteries.²⁷ In mild cases, the pain resolves with immunosuppressive treatment as the arteritis heals. But when ischemia progresses to full-thickness bowel wall necrosis, the consequences can be surgical emergencies: perforation, hemorrhage, or gangrene requiring bowel resection.

A dramatic case illustrated just how severe this can get: a 22-year-old woman required removal of 80% of her small bowel after ischemic necrosis, and imaging revealed that her celiac artery was chronically occluded with small aneurysms scattered through the mesenteric and renal vessels.²⁸ That she survived was considered unusual at the time. Gastrointestinal involvement is one of the prognostic factors in the Five-Factor Score for a reason: it signals aggressive, potentially life-threatening disease.

Heart Involvement and Coronary Risk

PAN can damage the coronary arteries in ways that look nothing like typical atherosclerotic heart disease. In a study of 145 patients, about 13% had coronary lesions attributable to PAN, with the left anterior descending artery most commonly affected and the majority of patients showing disease in multiple vessels. Stent placement was attempted in two patients, but one developed in-stent restenosis within a year, highlighting the challenge of treating inflamed arteries with standard interventional tools.²⁹ The patients who developed coronary disease tended to also have celiac artery involvement and new-onset hypertension, suggesting these findings should raise suspicion for cardiac complications.

This is worth knowing because a young adult showing up with chest pain and multivessel coronary disease on imaging is generally assumed to have premature atherosclerosis or a clotting disorder. PAN-related coronary disease is easy to miss if no one is looking for vasculitis. In patients without the usual risk factors for heart disease, especially those with skin findings, neuropathy, or unexplained kidney problems, PAN should be considered.