This was the first vasculitis, originally described in 1866. The term polyarteritis nodosa (PAN) was adopted in 1992.¹ In 1994 PAN was separated into two subtypes according to the size of vessel involved in adults: classical PAN - medium-sized vessels. and microscopic polyangiitis (MPA) - small vessels.²

A less severe form called cutaneous polyarteritis nodosa (CPAN) has also been described. Its features include tender subcutaneous nodules, livedo reticularis, cutaneous ulcers and necrosis.³ It is often associated with streptococcal infection. Although progress to classical PAN at a later stage has been reported, generally it is thought to be unlikely.⁴

Epidemiology

• Polyarteritis nodosa (PAN) affects approximately 3.1 and microscopic polyangiitis (MPA) 9.4 per 100,000 people per year.⁵
• 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 with a peak incidence at around 10 years. In adults, the most commonly affected age group is between the ages of 40 and 50.⁶
• In adults, men are more commonly affected than women, but children are equally affected.

Some authors state that the incidence is falling, others that it is rising but this may be due to increased recognition.⁷

Presentation

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

Patients may suffer weakness, weight loss and malaise. Symptoms and signs are attributable to the inflammation and ischaemia of the affected organs. Any organ may be affected, with the exception of the lungs. Peripheral neuropathy, gastrointestinal, osteoarticular and renal artery pathologies are the most common:⁸

• Peripheral neuropathy is usually asymmetric, distal mononeuropathy.⁹
• Gastrointestinal symptoms occur in 14-65% of patients and postprandial abdominal pain from ischaemia is the most common symptom.¹⁰ Bowel necrosis and perforation are associated with a poor prognosis.
• Myalgia is reported in 72% of childhood patients.¹¹
• Renal involvement may be in the glomeruli or renal vasculature and may cause acute kidney injury and hypertension.

The typical presentation in children is one- or two-organ involvement, with constitutional symptoms, and the diagnosis is often based on pathology.⁶

Diagnostic criteria

Adult

Historically these have included the American College of Rheumatology (ACR) and Chapel Hill Consensus criteria.^2,12 The ACR criteria for classifying a patient with vasculitis within a specific disease entity are useful in clinical practice but make no reference to MPA or antineutrophil cytoplasmic antibodies (ANCA). Also in many cases, their application results in overlapping diagnoses, particularly in patients with small vessel vasculitis and classical polyarteritis nodosa (PAN). Therefore, an algorithm based both on the Chapel Hill definitions and the ACR criteria is useful for correctly classifying patients.^13,14

The patient must be at least 16 years old at the time of diagnosis:¹³

• Symptoms/signs must be compatible with (but not necessarily characteristic of) a diagnosis of ANCA-associated vasculitis or PAN.
• There should also be one of the following:
  • Histological proof of vasculitis (including necrotising glomerulonephritis) and/or granuloma formation.
  • Positive serology for ANCA.
  • Specific investigations strongly suggestive of vasculitis and/or granuloma, e.g. angiography or skin biopsy.
  • Eosinophilia (≥10%).
• No other potential diagnosis to produce symptoms or signs particularly:
  • Malignancy.
  • Infection - particularly hepatitis B and hepatitis C, HIV, tuberculosis, subacute bacterial endocarditis.
  • Drugs, e.g. hydralazine, propylthiouracil, cocaine and allopurinol
  • Secondary vasculitis as a result of rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome or connective tissue disease.
  • Behçet's disease, Takayasu's arteritis, giant cell arteritis, Kawasaki's disease, essential mixed cryoglobulinaemia, Henoch Schönlein purpura, anti-GBM disease.
  • Vasculitis mimicking diseases, e.g. cholesterol embolism, calciphylaxis, catastrophic antiphospholipid antibody syndrome, atrial myxoma.
  • Sarcoidosis and other non-vasculitic granulomatous disease.

MPA and classical PAN are distinguished by histology, with MPA having histologically proved small vessel vasculitis or glomerulonephritis. ANCA is considered to be a feature of MPA and not PAN.

Childhood

Classification of childhood PAN requires a systemic inflammatory disease with evidence of necrotising vasculitis or angiographic abnormalities of medium- or small-sized arteries (mandatory criterion) plus one of five criteria:¹¹

• Skin involvement
• Myalgia/muscle tenderness
• Hypertension
• Peripheral neuropathy
• Renal involvement

Differential diagnosis

As polyarteritis nodosa (PAN) presents with nonspecific symptoms, numerous alternative diagnoses must be considered:

• 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 including giant cell arteritis, Henoch-Schönlein purpura, Wegener's granulomatosis, Churg-Strauss syndrome, temporal arteritis and Kawasaki's disease.

Investigations

• Hepatitis B surface antigen is positive in 30%.
• The p-ANCA test is usually positive, but not pathognomonic.
• ESR is raised.
• FBC shows leukocytosis with raised neutrophils.
• Hypergammaglobulinaemia occurs in 30%.
• Arteriography shows microaneurysms in the small-sized and medium-sized arteries of the kidneys and abdominal viscera.¹⁵ Selective renal angiography shows aneurysms in 40% of children.¹⁶
• MRI scans with new techniques, can differentiate haemorrhage from potentially reversible ischaemia.
• Biopsy of small arteries will show evidence of necrotising inflammation.

Associated diseases

Hepatitis B-associated polyarteritis nodosa is a form of classical PAN. The pathogenesis is attributed to immune-complex deposition with antigen excess.¹⁷

Management

• The mainstay of treatment for polyarteritis nodosa (PAN) or microscopic polyangiitis (MPA) is corticosteroid therapy:¹⁸
  • If patients relapse despite steroid therapy, the addition of cyclophosphamide has been shown to reduce relapse rate further.
  • Azathioprine can also be used as maintenance therapy and seems to be effective and well tolerated with fewer long-term side-effects than cyclophosphamide.
  • Immunosuppressants should only be prescribed in the most severe patients with poor prognostic factors.
• In patients with active hepatitis B, antivirals and plasma exchanges prevent the development of long-term hepatic complications of hepatitis B viral infection.¹⁷
• Intravenous immunoglobulin (IV-Ig) and aspirin are effective in childhood PAN but, in resistant cases, either steroid or infliximab have a role.¹⁹
• Cutaneous polyarteritis nodosa (CPAN):³
  • Mild cases may require only non-steroidal anti-inflammatory drugs (NSAIDs) or colchicine.
  • Prednisolone 30 mg daily or less is often effective in more severe cases, but a dosage of 1 mg/kg/day may be required. Unfortunately, exacerbations occur with the tapering of the corticosteroids and adverse effects limit their long-term use.
  • Immunosuppressive agents are frequently effective in CPAN resistant to high-dose corticosteroids, and should be reserved for these severe relentless forms.

Complications

Without treatment, hypertension-induced glomerulonephritis is a cause of great morbidity and mortality. The patient should also be monitored for:

• Headache
• Dementia
• Psychosis
• Encephalopathy
• Cerebrovascular events
• Peripheral neuropathy

Prognosis

Almost half will die within three months of diagnosis if untreated, usually secondary to chronic kidney disease.²⁰ Poor prognostic features include:

• Older age group.
• Renal, CNS or cardiac involvement.

Prevention

Avoidance of hepatitis B (by lifestyle choices and hepatitis B immunisation) may reduce the incidence of hepatitis B-associated polyarteritis nodosa (PAN) but it will not eradicate PAN altogether.

Document references

1. Sunderkotter C, Sindrilaru A; Clinical classification of vasculitis. Eur J Dermatol. 2006 Mar-Apr;16(2):114-24. [abstract]
2. Jennette JC, Falk RJ, Andrassy K, et al; Nomenclature of systemic vasculitides. Proposal of an international consensus Arthritis Rheum. 1994 Feb;37(2):187-92. [abstract]
3. Morgan AJ, Schwartz RA; Cutaneous polyarteritis nodosa: a comprehensive review. Int J Dermatol. 2010 Jul;49(7):750-6. [abstract]
4. Nakamura T, Kanazawa N, Ikeda T, et al; Cutaneous polyarteritis nodosa: revisiting its definition and diagnostic criteria. Arch Dermatol Res. 2008 Sep 19. [abstract]
5. Mohammad AJ, Jacobsson LT, Mahr AD, et al; Prevalence of Wegener's granulomatosis, microscopic polyangiitis, polyarteritis Rheumatology (Oxford). 2007 Aug;46(8):1329-37. Epub 2007 Jun 6. [abstract]
6. Ozen S; Juvenile polyarteritis: is it a different disease? J Rheumatol. 2004 Apr;31(4):831-2.
7. Lane SE, Scott DG, Heaton A, et al; Primary renal vasculitis in Norfolk - increasing incidence or increasing recognition? Nephrol Dial Transplant. 2000 Jan;15(1):23-7. [abstract]
8. Colmegna I, Maldonado-Cocco JA; Polyarteritis nodosa revisited. Curr Rheumatol Rep. 2005 Aug;7(4):288-96. [abstract]
9. Chung S; Neurological Manifestations of Polyarteritis Nodosa, Medscape, Jan 2010
10. Ebert EC, Hagspiel KD, Nagar M, et al; Gastrointestinal involvement in polyarteritis nodosa. Clin Gastroenterol Hepatol. 2008 Sep;6(9):960-6. Epub 2008 Jun 27. [abstract]
11. Ozen S, Pistorio A, Iusan SM, et al; EULAR/PRINTO/PRES criteria for Henoch-Schonlein purpura, childhood polyarteritis Ann Rheum Dis. 2010 May;69(5):798-806. [abstract]
12. Lightfoot RW Jr, Michel BA, Bloch DA, et al; The American College of Rheumatology 1990 criteria for the classification of polyarteritis nodosa. Arthritis Rheum. 1990 Aug;33(8):1088-93. [abstract]
13. Watts R, Lane S, Hanslik T, et al; Development and validation of a consensus methodology for the classification of Ann Rheum Dis. 2007 Feb;66(2):222-7. Epub 2006 Aug 10. [abstract]
14. Kallenberg CG; The last classification of vasculitis. Clin Rev Allergy Immunol. 2008 Oct;35(1-2):5-10. [abstract]
15. Stanson AW, Friese JL, Johnson CM, et al; Polyarteritis nodosa: spectrum of angiographic findings. Radiographics. 2001 Jan-Feb;21(1):151-9. [abstract]
16. Brogan PA, Davies R, Gordon I, et al; Renal angiography in children with polyarteritis nodosa. Pediatr Nephrol. 2002 Apr;17(4):277-83. [abstract]
17. Guillevin L, Mahr A, Callard P, et al; Hepatitis B virus-associated polyarteritis nodosa: clinical characteristics, Medicine (Baltimore). 2005 Sep;84(5):313-22. [abstract]
18. Guillevin L, Pagnoux C; When should immunosuppressants be prescribed to treat systemic vasculitides? Intern Med. 2003 Apr;42(4):313-7. [abstract]
19. Dillon MJ, Eleftheriou D, Brogan PA; Medium-size-vessel vasculitis. Pediatr Nephrol. 2010 Sep;25(9):1641-52. Epub 2009 Nov 28. [abstract]
20. Bourgarit A, Le Toumelin P, Pagnoux C, et al; Deaths occurring during the first year after treatment onset for polyarteritis nodosa, microscopic polyangiitis, and Churg-Strauss syndrome: a retrospective analysis of causes and factors predictive of mortality based on 595 patients. Medicine (Baltimore). 2005 Sep;84(5):323-30. [abstract]

Internet and further reading

• Cutaneous polyarteritis nodosa, Dermnet NZ

Acknowledgements