Polyarteritis Nodosa

Polyarteritis nodosa (PAN) was the first vasculitis to be described, the earliest report dating to Kussmaul and Maier in 1866. In 1948, the term microscopic polyarteritis was introduced by Davson. The Chapel Hill Consensus Conference on the nomenclature of systemic vasculitis held in 1992 officially adopted the term polyarteritis nodosa. With minor variations, this classification remains.¹

There is a necrotising vasculitis which affects the medium sized arteries in the skin, liver, heart and kidneys. The disease affects multiple systems, including kidneys, musculoskeletal system, nerves, gastrointestinal tract, integumentary, cardiac, and genitourinary systems. The lungs are usually spared. Signs and symptoms of this disease are primarily attributable to diffuse vascular inflammation and ischaemia of affected organs.

• PAN affects between 2 and 6 per 100,000 people per year.
• It is seen in all ethnic groups and appears to be present throughout the world although the incidence is higher in areas where hepatitis B is endemic.
• It can occur from childhood to old age but the most commonly affected age group is between the ages of 40 and 60.
• Men are more commonly affected than women in a ratio of 1.6:1.
• Some authors state that the incidence is falling,² others that it is rising but this may be due to increased recognition.³ A detailed analysis for England is produced by the NHS.⁴

A less severe form called cutaneous polyarteritis nodosa (CPAN) has also been described.⁵ It appears to be limited to the skin, nervous system and musculoskeletal system. Although progress to classical PAN at a later stage has been reported, progression is held by others to be unlikely.⁶

Diagnosis is not easy as it often presents in a vague manner and many different areas can be affected.

Non-specific features

The following are typical of PAN but are entirely non-specific:

• Malaise
• Weakness
• Fever
• Headache
• Arthralgia and arthritis
• Myalgia on activity may occur and is a feature of all patients with CPAN

Genito-urinary system

• About 60% of patients have renal involvement. This can cause chronic renal failure or hypertension.
• Genital involvement may produce testicular or ovarian pain.

Central nervous system

Both central and peripheral nervous systems may be involved. Neurological features are quite a common form of presentation.⁷

• The commonest presenting neurological feature of polyarteritis nodosa is transient ischaemic attacks, typically of monocular blindness.
• Cerebral arteritis is late in the course of the disease, usually in the second to third year of the vasculitis.
• Cerebral arteritis may cause arterial thrombosis with stroke or subarachnoid haemorrhage.
• Global CNS dysfunction can result in encephalopathy and seizures from metabolic derangements of multiple organ failure.
• Acute or subacute myelopathy with paraparesis can occur at any cord level. Myelopathy may result, although rarely, from cord compression by an extramedullary haematoma secondary to a ruptured spinal aneurysm.

Peripheral nervous system

• Peripheral neuropathy affects 60%.
• Vasculitic lesions produce an asymmetrical mononeuritis multiplex, distal polyneuropathy, or cutaneous neuropathy.
• The mononeuritis multiplex may be pure motor, sensory, or mixed sensorimotor polyneuropathy.

Cardiovascular system

• Cardiac disease occurs in 35%. There may be angina pectoris, myocardial infarction, congestive heart failure and pericarditis.
• Small aneurysms, just 1 to 5mm in diameter are present in 90% of patients, in hepatic, renal or mesenteric arteries.
• Gangrene of the extremities may occur, especially in children.

Abdominal problems

The gut can be involved in many ways.

• Abdominal pain
• Nausea and vomiting
• Bleeding
• Bowel infarction and perforation
• Cholecystitis
• Hepatic infarction
• Pancreatic infarction

Dermatological features

Skin lesions occur in 30 to 50% and include :

• Livedo reticularis
• Bullae
• Ulceration
• Cutaneous infarcts
• Purpuric nodules, especially in children
• Raynaud's phenomenon

In 1990 the American College of Rheumatologists produced diagnostic criteria.⁸ Of the 10 features, if 3 or more were present, the diagnosis was positive with a sensitivity of 82.2% and specificity of 86.6%.

• Angiographic abnormality
• Biopsy-proven granulocyte or mixed leukocyte infiltrate in arterial wall
• Neuropathy

The other 3 criteria used in the tree format included:

• Patient's sex
• Weight loss >6.5 kg
• Elevated serum aspartate aminotransferase or alanine aminotransferase levels above the range of normal.

The classification tree yielded a sensitivity of 87.3% and a specificity of 89.3%.⁸
Other criteria for use in epidemiological research have been proposed.⁹

As PAN presents with many non-specific symptoms, numerous alternative diagnoses must be considered, depending on the presenting complaint, these may include:

• Fever caused by viral, bacterial and parasitic infections.
• Ulceration due to pyoderma gangrenosum must be excluded, particularly in children.
• Crohn's disease.
• Connective tissue diseases including systemic lupus erythematosis, rheumatoid arthritis, allergic granulomatosis.
• Vasculitides include giant cell arteritis, Henoch-Schönlein purpura, Wegener's granulomatosis, Churg-Strauss disease, temporal arteritis and Kawasaki disease. Wegener's granulomatosis tends to affect the lungs and kidneys. Lungs are usually spared in PAN.

• Hepatitis B surface antigen is +ve in 30%.
• p-ANCA is usually +ve, but not pathognomic.
• ESR is raised.
• FBC shows leukocytosis with raised neutrophils.
• Hypergammaglobulinaemia occurs in 30%.
• Arteriography shows microaneurysms in the small and medium-sized arteries of the kidneys and abdominal viscera.¹⁰ Selective renal angiography shows aneurysms in 40% of children.¹¹
• MRI scans with new techniques, can differentiate haemorrhage from potentially reversible ischaemia.
• Biopsy of small arteries will show evidence of necrotising inflammation.

As 30% of patients with PAN are hepatitis B surface antigen +ve, this has lent support to the theory that PAN may be caused by circulating complexes of exogenous antigens and antibodies.

Treatment is different for idiopathic PAN than when associated with hepatitis B.¹²

• The mainstay of treatment for PAN and CPAN is corticosteroid therapy.
• If patients relapse despite steroid therapy, the addition of cyclophosphamide has been shown to further reduce relapse rate. Methotrexate has also been used with some success as a second line agent.
• In patients with active hepatitis B, vidarabine and plasma exchange may be used in addition to steroids in order to decrease viral replication and remove immune complexes.²
• Patients with CPAN resistant to steroid therapy have shown some improvement with the addition of colchicines or pentoxifyllin.

Monitoring

The patient should be monitored for:

• Headache
• Uncontrolled hypertension
• Dementia
• Psychosis
• Encephalopathy
• Stroke
• Peripheral neuropathy

Without treatment, hypertension induced glomerulonephritis was the cause of great morbidity and mortality. Other complications include:

• Stroke
• Encephalopathy
• Myelopathy
• Heart failure
• Myocardial infarction
• Pericarditis
• Renal failure
• GI bleeding
• Pancreatitis
• Bowel infarction
• Peripheral neuropathy
• Gangrene of digits

Without treatment, almost half will die within three months of diagnosis, the majority as a result of renal failure and the 5 year survival is in the order of 13%. In a large study of early deaths,¹³ 58% were caused by uncontrolled vasculitis and 26% by infection. Treatment had less effect on early mortality.

Poor prognostic features included, being older, renal involvement, CNS involvement and a trend towards cardiomyopathy.
Corticosteroid treatment improves the 5-year survival rate to 50 to 60%. In combination with other immunosuppressants, the 5-year survival rate is in excess of 80%.

In view of the association with hepatitis B, it may be that avoidance of the infection, by lifestyle and hepatitis B immunisation, will reduce the incidence of PAN but it will not eradicate it.