Polyarteritis nodosa (PAN)

01Definition and overview

Polyarteritis nodosa is, by the 2012 Chapel Hill definition, a necrotising arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries or venules, and not associated with ANCA. It is the classic medium vessel vasculitis of the vasculitis classification. Kussmaul and Maier described it in 1866 as periarteritis nodosa, for the nodules they saw along the arteries; the name means inflammation of many arteries with nodules along them.

Until 1994 the name also covered microscopic polyangiitis, which affects small vessels, inflames the glomeruli and lungs and is associated with ANCA. Older studies of PAN mixed the two. Separated, true PAN has become rare, and rarer still since vaccination against hepatitis B.

Four forms are recognised, and the treatment depends on which:

Rarer settings include hepatitis C and HIV infection, hairy cell leukaemia and myelodysplasia, and familial Mediterranean fever.

02Etiology and pathophysiology

What happens in the artery

PAN attacks the muscular arteries of the viscera and their branches, especially at branch points. Under the microscope the lesions are:

• segmental, affecting part of the circumference and length of an artery, with normal artery between;
• transmural, with fibrinoid necrosis of the wall and a mixed infiltrate of neutrophils, lymphocytes, macrophages and eosinophils;
• of different ages side by side, acute necrosis next to healed, fibrotic scars, a mark of PAN;
• without granulomas, and without involvement of veins, capillaries or glomeruli.

1. 1

   Necrosis

   The inflamed wall loses its internal elastic lamina and muscle, and bulges into small aneurysms, a few millimetres across, which give the nodules felt along superficial arteries.
2. 2

   Thrombosis

   Thrombus forms on the damaged wall and the healing wall scars and narrows, so the artery occludes.
3. 3

   Infarction

   The tissue beyond infarcts: nerves through their vasa nervorum, skin, muscle, kidney, bowel, testis, heart.
4. 4

   Bleeding

   A microaneurysm can rupture, into the kidney's capsule, the abdomen or the liver.

The kidney is injured through its interlobar and arcuate arteries, not its glomeruli: the result is patchy infarcts and ischaemia that drive the renin-angiotensin system, so hypertension is common and can be severe, and the urine shows little blood or protein.

Causes

• Hepatitis B virus: complexes of viral antigen, especially HBsAg and HBeAg, with antibody deposit in artery walls, with antigen in excess. PAN appears within months of infection, during high viral replication, often after infection by drug injection or, in the past, by transfusion. Hepatitis C and HIV are much rarer causes.
• ADA2 deficiency: loss of function of both copies of the ADA2 gene (formerly CECR1). The enzyme, secreted mainly by monocytes and macrophages, seems to steer their development; without it, macrophages are skewed towards a pro-inflammatory type that makes TNF, and the endothelium of small and medium arteries is damaged, in the brain as elsewhere.
• In most systemic PAN the cause is unknown. Cutaneous PAN can follow streptococcal infection, especially in children, and has been linked to minocycline.

03Clinical features

The illness usually builds over weeks to months, with fever, weight loss, fatigue, myalgia and arthralgia, before the infarcts declare it. The figures below are from a French series of 348 patients:

Patients with hepatitis B-associated PAN have neuropathy, abdominal pain, cardiomyopathy, orchitis and hypertension more often than others.

Deficiency of adenosine deaminase 2

The disease usually starts in childhood, sometimes later in adult life, with recurrent fevers, livedo racemosa, a PAN-like vasculitis of the skin, gut and kidneys, and lacunar strokes, often in early childhood, in the deep grey matter and brainstem. Hepatosplenomegaly, low immunoglobulins with infections, and cytopenias, sometimes a pure red cell aplasia, complete the picture. Siblings may be affected.

Cutaneous PAN

Tender nodules, livedo racemosa and ulcers, mostly on the lower legs, come and go over years, sometimes with fever, myalgia, arthralgia and a neuropathy in the same limb. There is no visceral disease, and progression to systemic PAN is rare.

04Diagnosis and management

Tests

Proving the diagnosis

• Biopsy of affected tissue shows necrotising arteritis of a medium-sized artery. American guidance prefers a deep skin biopsy that reaches the subcutaneous fat for skin lesions, since a superficial punch misses the arteries, and a combined nerve and muscle biopsy, rather than nerve alone, for neuropathy. A sural nerve is chosen only if it is affected on nerve conduction testing.
• Angiography of the renal, mesenteric and hepatic arteries shows multiple small aneurysms, irregular narrowing and occlusions, and makes the diagnosis when no tissue can be taken. Catheter angiography finds the smallest aneurysms best; CT angiography is less invasive and often used first. American guidance suggests abdominal vascular imaging in suspected PAN.
• A percutaneous kidney biopsy is avoided in suspected PAN: it can bleed from a microaneurysm, and its small sample often misses the patchy arterial lesions.

Criteria

The 2022 ACR/EULAR criteria did not include PAN, so studies still use the 1990 ACR criteria, which ask for 3 of 10 items: weight loss of 4 kg or more, livedo reticularis, testicular pain or tenderness, myalgia or leg tenderness, mononeuropathy or polyneuropathy, diastolic pressure above 90 mmHg, a raised urea or creatinine, hepatitis B, an abnormal arteriogram, and a biopsy showing granulocytes or mixed leucocytes in the wall of an artery. Three or more classified PAN with a sensitivity of 82 per cent and a specificity of 87 per cent among other vasculitides, but the criteria predate the separation of microscopic polyangiitis and cannot tell the two apart. In children the EULAR/PRINTO/PRES criteria require histology or angiography with one of skin involvement, myalgia, hypertension, neuropathy or kidney involvement.

The differential diagnosis includes microscopic polyangiitis and the other ANCA vasculitides, cryoglobulinaemic vasculitis, lupus, endocarditis, cholesterol emboli, antiphospholipid syndrome, and the non-inflammatory diseases of visceral arteries that also make aneurysms: segmental arterial mediolysis, fibromuscular dysplasia and vascular Ehlers-Danlos syndrome, in which the inflammatory markers are normal.

Judging severity: the Five-Factor Score

The French Vasculitis Study Group's revised Five-Factor Score, from 2009, predicts death in the necrotising vasculitides and guides treatment in PAN. Each factor scores a point:

• age over 65;
• heart involvement (heart failure, infarction, cardiomyopathy);
• gut involvement (bleeding, perforation, infarction, pancreatitis);
• kidney insufficiency, a stable peak creatinine of 150 µmol/L or more;
• the fifth, the absence of ear, nose and throat disease, applies only to granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis.

5-year mortality with a Five-Factor Score of 0

9per cent5-year mortality with a Five-Factor Score of 0

with a score of 1

21per centwith a score of 1

with a score of 2 or more

40per centwith a score of 2 or more

Severe disease, in American guidance, also includes mononeuritis multiplex with motor loss, mesenteric ischaemia, kidney infarcts, coronary or brain involvement, and other organ- or life-threatening disease.

Systemic PAN without hepatitis B

1. 1

   Non-severe disease

   Five-Factor Score 0, without organ-threatening features: prednisolone about 1 mg/kg a day, tapered over months. In a French trial glucocorticoids alone brought remission in most, but 40 per cent needed another drug for failure or relapse, and adding azathioprine from the start did not help in a second trial. American guidance prefers glucocorticoids with methotrexate or azathioprine from the start; French practice adds them for failure, relapse or steroid dependence.
2. 2

   Severe disease

   Intravenous methylprednisolone pulses for three days, then oral prednisolone, with cyclophosphamide, usually as intravenous pulses for 3 to 6 months. American guidance prefers cyclophosphamide to rituximab, for which there is little evidence in PAN, and advises against adding plasma exchange.
3. 3

   Maintenance

   Once in remission, cyclophosphamide is replaced by azathioprine or methotrexate, stopped after about 18 months of remission. Glucocorticoids are tapered as fast as the disease allows; there is no fixed schedule.
4. 4

   Refractory disease

   Disease that resists glucocorticoids and a non-cyclophosphamide drug is switched to cyclophosphamide; TNF inhibitors and tocilizumab have been used in case series.

Alongside: blood pressure control, physiotherapy and splints for foot or wrist drop, co-trimoxazole against Pneumocystis during cyclophosphamide, bone protection, and urgent surgery or embolisation for bowel infarction, perforation or a bleeding aneurysm. Neuropathy is followed by examination, about every 6 months, rather than repeated nerve conduction studies.

Hepatitis B-associated PAN

The aim is to clear the antigen, not to suppress the immune system:

1. glucocorticoids for about two weeks only, to control the life-threatening inflammation;
2. a nucleoside or nucleotide analogue, today entecavir or tenofovir (in the past vidarabine, interferon alfa and lamivudine), to stop viral replication;
3. plasma exchange, several times a week at first, to remove immune complexes until the virus is controlled, ideally with seroconversion from HBeAg to anti-HBe.

Cyclophosphamide and long courses of glucocorticoids increase viral replication and can lead to fulminant hepatitis, so they are avoided. With this strategy, relapse is rare, and it does not happen once the virus is controlled. The rarer PAN with hepatitis C is treated with direct-acting antivirals.

Deficiency of adenosine deaminase 2

TNF inhibitors (etanercept, adalimumab or infliximab) are strongly recommended for the vasculitis and prevent further strokes, which glucocorticoids and conventional immunosuppressants fail to do. Haematopoietic stem cell transplantation is used for marrow failure or severe immunodeficiency. Affected siblings are tested, even without symptoms.

Cutaneous PAN

NSAIDs, colchicine, dapsone or a short course of low-dose glucocorticoids, with methotrexate for frequent relapses; a triggering streptococcal infection is treated, and minocycline stopped.

05Epidemiology

PAN is rare: about 1 to 8 new cases per million people a year in European countries, and about 30 per million adults living with it in a multiethnic district near Paris. It appears mostly between 40 and 60 years, in all ethnic groups, and, unlike most vasculitides, slightly more often in men (about 1.5 to 1). Children have PAN rarely, more often in its cutaneous form.

Hepatitis B once caused more than a third of PAN in adults. With screened blood products and vaccination its share has fallen, in France from almost 40 per cent in the 1970s to about 17 per cent by the turn of the century, and to around 5 per cent of European adults with PAN today; it remains more common where hepatitis B is.

Deficiency of adenosine deaminase 2, described in 2014, is estimated to affect more than 35,000 people worldwide, with founder variants in some populations, such as Georgian Jewish families. Some patients once labelled as childhood PAN or early stroke of unknown cause have turned out to have it.

06Prognosis

Untreated, systemic PAN killed most patients within a few years. With treatment, most patients enter remission, but in the French series of 348 patients, followed for a mean of about 6 years, a fifth relapsed and a quarter died. Relapse was commoner in PAN without hepatitis B (28 against 11 per cent), and especially with skin disease; death was commoner in hepatitis B-associated PAN, most often from gut involvement.

The outlook is worse with:

• age over 65;
• gut involvement, especially when it needs surgery, the main cause of early death;
• heart and kidney involvement and severe hypertension;
• a high Five-Factor Score.

Neuropathy improves slowly, over months to years, and often leaves weakness or pain in the foot or hand. Relapse is less frequent than in ANCA-associated vasculitis, and hepatitis B-associated PAN does not relapse once the virus is controlled. Cutaneous PAN relapses for years but rarely threatens life. Deficiency of adenosine deaminase 2 treated with TNF inhibitors has a much lower risk of stroke, while the marrow and immune defects decide its long-term outcome.

Follow-up watches blood pressure, kidney function and urine, nerves and the harm from treatment, and, after cyclophosphamide, the risks of infection, infertility and bladder cancer.