Polyarteritis nodosa (PAN) is a systemic disease, but variants are cutaneous PAN and single-organ disease. Histologic confirmation of vasculitis in medium-sized arteries is desirable, and biopsies should be obtained from the symptomatic and least invasive sites. Angiography can show multiple microaneurysms in the viscera. Treatment includes high-dose corticosteroids, which are combined with immunosuppressive agents when internal organs are involved and with life-threatening disease. Once remission is achieved, maintenance agents are initiated. PAN is becoming a rare disease. International collaborative efforts are under way to establish better diagnostic and classification for all vasculitides, including PAN.
Key points
- •
Polyarteritis nodosa (PAN) is a necrotizing systemic medium vessel vasculitis, which is typically antineutrophil cytoplasmic antibody (ANCA) negative and rarely affects the lungs.
- •
With the decline of hepatitis B virus (HBV) and the evolving definitions of vasculitis, PAN is becoming a rare disease.
- •
Variants of PAN include single-organ disease and cutaneous PAN. PAN can be idiopathic or secondary to other causes, typically viral infections (HBV, hepatitis C virus, and human immunodeficiency virus).
- •
Treatment is mostly borrowed from literature involving ANCA–associated vasculitides and consists of corticosteroids, with the addition of immunosuppressive agents if corticosteroids are not tolerated, cannot be tapered, or if prognosis is poor.
- •
Treatment of viral-associated PAN is aimed at treating the underlying virus, with escalation of immunosuppression in severe cases.
Introduction
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis, which typically affects medium-sized muscular arteries, particularly affecting the visceral, renal, and soft tissue vasculature. PAN can affect virtually every organ but has a striking tendency to spare the lungs. Small arteries may be involved, but small vessels, including arterioles, capillaries, and venules, are usually spared. Therefore, glomerulonephritis and pulmonary capillaritis are not part of the spectrum of PAN. Antineutrophil cytoplasmic antibodies (ANCAs) are typically negative. These characteristics help differentiate PAN from other systemic necrotizing vasculitides.
PAN may be idiopathic or triggered by specific agents. The most typical is hepatitis B virus (HBV), although other viruses such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) may occasionally be detected. PAN is a systemic disease, but variants are single-organ disease and cutaneous PAN (cPAN).
Introduction
Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis, which typically affects medium-sized muscular arteries, particularly affecting the visceral, renal, and soft tissue vasculature. PAN can affect virtually every organ but has a striking tendency to spare the lungs. Small arteries may be involved, but small vessels, including arterioles, capillaries, and venules, are usually spared. Therefore, glomerulonephritis and pulmonary capillaritis are not part of the spectrum of PAN. Antineutrophil cytoplasmic antibodies (ANCAs) are typically negative. These characteristics help differentiate PAN from other systemic necrotizing vasculitides.
PAN may be idiopathic or triggered by specific agents. The most typical is hepatitis B virus (HBV), although other viruses such as hepatitis C virus (HCV) and human immunodeficiency virus (HIV) may occasionally be detected. PAN is a systemic disease, but variants are single-organ disease and cutaneous PAN (cPAN).
Classification
Since the early description of periarteritis nodosa by Kussmaul and Maier in 1866, investigators have attempted to develop systems for nomenclature and classification of PAN. The American College of Rheumatology (ACR) proposed classification criteria for PAN in 1990, which took into account clinical, laboratory, radiographic, and histologic features of the disease ( Table 1 ). Three of 10 criteria showed a sensitivity of 82.2% and specificity of 86.6% for the classification of PAN. As knowledge has progressed, the ACR criteria seem to have important limitations. They do not recognize microscopic polyangiitis (MPA) as a distinct disease entity from PAN and do not take into account ANCA testing.
| Criterion (≥3 Are Necessary) | Definition |
|---|---|
| Weight loss ≥4 kg | Loss of ≥4 kg of body weight since the illness began, not caused by dieting or other factors |
| Livedo reticularis | Mottled reticular pattern over the skin in portions of the extremities or torso |
| Testicular pain or tenderness | Pain or tenderness of the testicles not caused by infection, trauma, or other causes |
| Myalgias, weakness, or leg tenderness | Diffuse myalgias (excluding shoulder and hip girdle), weakness of muscles, or tenderness of leg muscles |
| Mononeuropathy or polyneuropathy | Development of mononeuropathy, multiple mononeuropathies, or polyneuropathy |
| Diastolic BP >90 mm Hg | Development of hypertension with the diastolic BP >90 mm Hg |
| Increased blood urea nitrogen (BUN) or creatinine level | Increase of BUN >40 mg/dL or creatinine level >1.5 mg/dL, not caused by dehydration or obstruction |
| HBV | Presence of hepatitis B surface antigen or antibody in serum |
| Arteriographic abnormality | Arteriogram showing aneurysms or occlusions of the visceral arteries, not caused by arteriosclerosis, fibromuscular dysplasia, or other noninflammatory causes |
| Biopsy of small or medium-sized artery containing polymorphonuclear neutrophils | Histologic changes showing the presence of granulocytes or granulocytes and mononuclear leukocytes in the artery wall |
The formal distinction between PAN and MPA was made at the Chapel Hill Consensus Conference (CHCC) in 1994. The former was limited to necrotizing inflammation of medium-sized and small arteries without involvement of smaller vessels (ie, arterioles, venules, or capillaries), whereas the latter was described as a pauci-immune (few or no immune deposits) necrotizing vasculitis affecting small vessels, with or without involvement of medium-sized arteries. The CHCC proposed pathologic definitions for vasculitis but recognized that histologic data would not be available for all patients. Surrogate markers of vasculitis and the importance of ANCA were introduced, but neither was included in the definitions of vasculitis. The importance of negativity of ANCA in PAN was subsequently emphasized by the French Vasculitis Study Group (FVSG) and in the updated 2012 Chapel Hill consensus definitions.
Both the ACR criteria (1990) and the CHCC definitions (1994) have been criticized, because there is discordance when they are applied to patient cohorts, with the ACR criteria tending to overdiagnose PAN compared with the CHCC definitions. Although these two criteria have been adopted and used for diagnostic purposes, this was not their intended purpose. The ACR criteria (1990) were designed as classification criteria, to provide a standard method of describing groups of patients for research and to distinguish one type of vasculitis from another, but not to distinguish vasculitis from other diseases. The CHCC criteria aimed to reach a consensus on the names of major vasculitides and provide working definitions of various types of vasculitis but were not intended to be used as diagnostic or classification criteria.
A consensus algorithm was developed by Watts and colleagues by combining ACR and CHCC criteria, ANCA testing, and surrogate markers of vascular inflammation (clinical, laboratory, and imaging tests), for the classification of PAN and ANCA-associated vasculitis (AAV) for use in epidemiologic studies ( Fig. 1 ). To enter this stepwise algorithm, patients must have signs or symptoms compatible with PAN or AAV without other conditions being more likely. This algorithm allows patients to be classified into one category, without many unclassified patients or overlapping diagnoses. Diagnostic criteria have also been attempted and through a survey of 949 patients in the FVSG, HBV positivity, peripheral neuropathy, arteriographic abnormalities, as well as the absence of ANCA, asthma, ear nose and throat signs, glomerulopathy, and cryoglobulinemia were predictive of PAN diagnosis.
Despite these efforts, criteria for systemic vasculitides, particularly for PAN, still remain unsatisfactory, and there is a large international collaborative effort aimed to establish better diagnostic and classification criteria.
Epidemiology/risk factors
PAN is a rare disease that affects all racial groups, affecting men more often than women, and occurring primarily in patients in their 40s to 60s. Children can also be affected by PAN. Most cases of PAN are idiopathic, although HBV, HCV, HIV, parvovirus B19, and hairy cell leukemia have been implicated in the pathogenesis of some cases. In these settings, PAN is termed secondary PAN. HBV-associated and HCV-associated PAN are more prevalent in developed countries, whereas HIV-associated PAN is more prevalent in underdeveloped countries.
PAN is becoming a rare disease. This situation may be caused in part by the decrease in HBV infection as a result of widespread vaccination, as well as other systemic necrotizing vasculitides being increasingly recognized as a result of increased awareness and improved diagnostic techniques. Reports in the 1970s estimated that HBV, the most common and better characterized trigger of PAN, accounted for one-third of the cases of PAN. Since the essential disappearance of contaminated blood transfusions and the large use of vaccinations against people at risk for HBV, the frequency of HBV is less than 5% in developed countries.
Given the confusion of classification and the changing definition of the disease, estimating the true incidence and prevalence of PAN is difficult. Cohorts of patients with PAN before the 1990s almost certainly included patients with a mixture of PAN and MPA, and likely other forms of vasculitis as well. The development of classification criteria and nomenclature for PAN in the 1990s enabled epidemiologic studies to be performed, although with aforementioned limitations.
Prevalence estimates of PAN are about 31 cases/million. The annual incidence ranges from 0 to 8/million in European countries and Australia. Estimates of the annual incidence of PAN range from 4.6/million in England, 9/million in Olmsted County, Minnesota to 77/million in hepatitis B–endemic Alaskan Eskimo populations. In Germany and Spain, the PAN incidence is low (0.3 and 0.9/million, respectively). There are some regional variations in the incidence of PAN even within the same country, but this may be caused in part by differences in case definitions and ascertainment.
A genetic component of PAN was recently recognized. Families with multiple cases of cPAN and systemic PAN consistent with autosomal recessive inheritance were identified, and exome sequencing of genomic DNA was performed. These patients, who were of Georgian Jewish or German ancestry, as well as unrelated affected patients of Turkish ancestry, were found to have a loss of function mutation of the gene encoding adenosine deaminase 2 (ADA2). ADA2 is both the major extracellular adenosine deaminase and an adenosine deaminase–related growth factor. The clinical presentation of PAN in these patients was variable in terms of age of onset, organ involvement, and severity, even among families, although almost all cases showed disease onset in childhood. This study provides important information about the genetic susceptibility and potential pathophysiology for at least a subset of patients with PAN.
Pathogenesis
The pathogenesis of PAN remains poorly understood. In those subsets of cases related to HBV, immune complexes are believed to play a role. However, glomerulonephritis, a characteristic immune complex–mediated lesion, is not associated with PAN. Complement consumption, common in other immune complex–mediated diseases (such as systemic lupus erythematosus), is unusual in PAN. It is postulated that in PAN, viral antigens trigger the complement cascade, resulting in a neutrophil-rich and lymphocyte-rich inflammatory infiltrate within the arterial media, which leads to fibrosis, thrombosis, or aneurysmal degeneration. The mechanism by which immune complexes lead to medium-sized arterial inflammation and yet spare smaller vessels (ie, arterioles, capillaries, and venules) is unknown.
Clinical features
PAN may affect virtually every organ system and has a wide constellation of clinical manifestations ( Table 2 ). Constitutional symptoms, such as fever, myalgias, and weight loss, are found in up to 90% of patients with PAN. The peripheral nervous system and skin are the most frequently involved territories. Mononeuritis multiplex is the most common neurologic manifestation, although symmetric peripheral neuropathy also occurs. Central nervous system involvement is rare. Cutaneous features include purpura, livedoid lesions, subcutaneous nodules, and necrotic ulcers. Limb edema is common.
| Manifestation | Description | Frequency (%) |
|---|---|---|
| General symptoms | Fever, malaise, weight loss, arthralgias, myalgias | 90 |
| Neurologic | Mononeuritis multiplex, peripheral neuropathy | 75 |
| Cutaneous | Nodules, purpura, livedo | 60 |
| Renal | Increased creatinine level, hypertension, hematuria, proteinuria | 50 |
| Gastrointestinal | Abdominal pain, rectal bleeding | 40 |
| Orchitis | Testicular pain, swelling | 20 |
| Other | <10 | |
| Ophthalmologic | Retinal vasculitis/exudates, conjunctivitis, keratitis, uveitis | 8 |
| Vascular manifestations | Claudication, ischemia, necrosis | 6 |
| Cardiac | Cardiomyopathy, pericarditis | 5 |
| Central nervous system | Stroke, confusion | 5 |
| Respiratory | Lung infiltrates, pleural effusions | 3 |
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
