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Clinical manifestations and diagnosis of polyarteritis nodosa in adults

Clinical manifestations and diagnosis of polyarteritis nodosa in adults
Literature review current through: May 2024.
This topic last updated: Jan 04, 2024.

INTRODUCTION — Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with additional involvement of small arteries [1,2]. Unlike some other vasculitides (eg, microscopic polyarteritis, granulomatosis with polyangiitis), polyarteritis nodosa is not associated with antineutrophil cytoplasmic antibodies (ANCA) [3]. (See "Overview of and approach to the vasculitides in adults".)

Patients typically present with systemic symptoms. The kidneys, skin, joints, muscles, nerves, and gastrointestinal tract are commonly involved, usually in some combination and sometimes all at once by the time of diagnosis. PAN can affect virtually any organ but has a striking tendency to spare the lungs. Clinical variants or subsets of PAN include single-organ disease and cutaneous-only PAN. (See "Cutaneous polyarteritis nodosa".)

The spectrum of disease known as PAN has evolved and narrowed substantially due to the identification and classification of other forms of vasculitis that had previously been considered PAN. Most importantly, the establishment and acceptance of microscopic polyangiitis as a distinct disease, and the routine availability and recognition of ANCA testing as critical to diagnosing vasculitides other than PAN, have led to more patients with vasculitis being classified as not having PAN. Patient cohorts of PAN included in case series and other research studies published prior to the 1990s almost certainly included a mixture of the newer definition of PAN with microscopic polyangiitis and possibly other forms of vasculitis. Thus, case series of PAN published after this time period that specifically exclude patients with MPA provide important updated information about this disease [4]. (See "Overview of and approach to the vasculitides in adults" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

The clinical manifestations and diagnosis of PAN will be reviewed here. Treatment is presented separately. (See "Treatment and prognosis of polyarteritis nodosa".)

Microscopic polyangiitis and other ANCA-associated systemic vasculitides (eg, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis [Churg-Strauss]) that characteristically affect small vessels such as arterioles, capillaries, and venules, as well as muscular arteries, are discussed separately. (See "Overview of and approach to the vasculitides in adults" and "Pathogenesis of antineutrophil cytoplasmic autoantibody-associated vasculitis" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

EPIDEMIOLOGY — Population prevalence estimates for polyarteritis nodosa (PAN) range from 2 to 33 per million [5-7]. The annual incidence in three regions of Europe was estimated to be 4.4 to 9.7 per million [8]. The variation in estimates may be partly explained by differences in diagnostic criteria, but regional variations also appear to exist [8-10]. The marked reduction in hepatitis B virus infection in many parts of the world has been associated with a parallel reduction in prevalence of PAN.

The diagnosis is most commonly made in middle-aged or older adults, and the incidence rises with age, with a peak in the sixth decade of life [5,8,9]. There appears to be a 1.5:1 male predominance. Children can also be affected by PAN. (See "Vasculitis in children: Incidence and classification".)

ETIOLOGY — Most cases of polyarteritis nodosa (PAN) are idiopathic, although drugs (eg, minocycline), hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and hairy cell leukemia are important in the pathogenesis of some cases [11-15]. PAN in these settings is called secondary PAN and is also discussed elsewhere in topics related to the underlying disease. (See "Kidney disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)' and "Overview of kidney disease associated with hepatitis C virus infection", section on 'Polyarteritis nodosa' and "Clinical features and diagnosis of hairy cell leukemia".)

In one report from France, HBV accounted for one-third of the cases of PAN, but even higher prevalence rates are possible in areas with endemic HBV infection [4,11]. HBV-related PAN has the same clinical features as non-HBV-related PAN and typically occurs within four months after the onset of HBV infection.

In some children and young adults with a form of vasculitis that has features similar to PAN, recessive loss of function mutations of the gene encoding adenosine deaminase 2 (ADA2), a growth factor that is the major extracellular adenosine deaminase, have been shown to be associated with the vasculitis [16]. Exome sequencing of genomic deoxyribonucleic acid (DNA) was performed in 24 patients from multiply affected families of Georgian Jewish or German ancestry, or unrelated affected patients of Turkish ancestry, who had been diagnosed clinically with a PAN-like vasculitis. In almost all cases, the onset of disease was during childhood. ADA2 activity was significantly reduced in the serum specimens from the patients when compared with controls. This study, along with a related study also involving ADA2 and vasculopathy, provide data about genetic susceptibility and pathophysiology for at least a subset of patients with PAN-like disease [17]. (See "Ischemic stroke in children and young adults: Epidemiology, etiology, and risk factors", section on 'Metabolic disorders' and "Vasculitis in children: Incidence and classification", section on 'Polyarteritis nodosa' and "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis".)

The understanding of the clinical spectrum of deficiency of ADA2 (DADA2) continues to be described. In a study of 118 patients with PAN, 9 (7.6 percent) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4 percent) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2 percent) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants [18]. Thus, it is important to consider testing for DADA2 in all patients with PAN. (See "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Some patients with PAN have also been diagnosed with the adult-onset inflammatory disorder referred to as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome [19]. Such patients appear to truly have PAN but also have VEXAS, which is currently associated with a quite poor prognosis. VEXAS should be considered in male patients with PAN with unexplained cytopenias and/or highly difficult-to-control symptoms of vasculitis. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome'.)

PATHOGENESIS — The pathogenetic mechanisms in polyarteritis nodosa (PAN) are poorly understood. It seems likely that in terms of pathogenesis and pathophysiology, PAN represents a spectrum of disease rather than a single entity [20]. In some subsets of cases (eg, those associated with hepatitis B), immune complexes are thought to play a role. However, the mechanism(s) through which immune complex-mediated disease leads to medium-sized arterial inflammation and yet mostly spares arterioles, capillaries, and venules in PAN is unknown. In other subsets of this disease, immune complexes may play a less central role.

Thickening of the inflamed vessel wall and intimal proliferation can cause luminal narrowing, reducing blood flow and predisposing to thrombosis of affected vessels. The resulting ischemia or infarction of tissue causes varied clinical manifestations that are discussed in more detail below. As an example, involvement of branches of the renal arteries or intrarenal vessels such as the intralobular or arcuate arteries causes renal ischemia, activation of the renin-angiotensin system, and hypertension [21].

In addition to arterial narrowing and thrombosis, inflammation can cause weakening of the vessel wall that leads to aneurysm formation. Aneurysmal rupture may result in life-threatening bleeding.

PATHOLOGY — Regardless of the initiating event or underlying cause, established polyarteritis nodosa (PAN) is characterized by segmental transmural inflammation of muscular arteries [2]. In contrast to some other forms of systemic vasculitis, PAN does not involve veins. The cellular infiltrate contains polymorphonuclear leukocytes and mononuclear cells. Fragments of white blood cells (leukocytoclasis) may be noted. Necrosis of the arterial wall results in a homogeneous, eosinophilic appearance referred to as fibrinoid necrosis. Disruption of the internal and external elastic lamina is noted and may contribute to the development of aneurysmal dilation [22]. Lesions that appear to be of different ages are typically found within a single sample. Granulomatous inflammation does not occur in PAN, and its presence suggests other diagnoses.

CLINICAL FEATURES — Patients with polyarteritis nodosa (PAN) typically present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain) of multisystem involvement (table 1).

Skin disease — Skin manifestations of PAN may commonly include purpura, livedo reticularis, and ulcers, and less commonly tender erythematous nodules and bullous or vesicular eruption [4,23,24]. The nodules in PAN are reminiscent of erythema nodosum or nodular vasculitis, but adequate biopsy specimens demonstrate necrotizing vasculitis within the walls of medium-sized arteries, usually in the deep dermis or embedded between fat lobules in the subcutaneous fat, as well as small-sized arteries. (See "Panniculitis: Recognition and diagnosis", section on 'Inflammatory disorders'.).

It is important to realize that dermatopathologists view arterial size as relative to those vessels seen in the skin; thus, "medium-sized" arteries in the skin may be smaller than other "medium-sized" arteries elsewhere, such as branches of the celiac axis or coronary arteries. (See "Evaluation of adults with cutaneous lesions of vasculitis".)

The palpable purpuric lesions seen in PAN are identical to those seen in other forms of vasculitis usually associated with small vessel disease (eg, immunoglobulin A vasculitis [Henoch-Schönlein purpura], antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, and mixed cryoglobulinemia). Biopsy of these skin lesions reveals leukocytoclastic vasculitis (picture 1). Such findings illustrate that PAN does not exclusively involve medium-sized, muscular arteries but also includes small arteries [25]. However, presentations consistent with only small-vessel involvement essentially exclude PAN.

Skin lesions may be focal or diffuse and are more frequently and often more marked over the lower extremities. Limb edema is common. Progressive skin involvement may be severe, including infarction and gangrene of the fingers, toes, or other areas and ulceration extending into the subcutaneous tissue. However, digital and limb ischemia often reflects involvement of arteries larger than "medium-sized" skin vessels.

Many of the skin manifestations of PAN result from involvement of vessels within the subcutaneous tissues. For nodules and ulcers, small 2 to 4 mm "punch" biopsies of the skin that sample only the epidermis and superficial dermis are unlikely to include muscular arteries and thus are of limited value. Elliptical surgical skin biopsies that include deeper dermis and subcutaneous fat may be more helpful in diagnosis. As mentioned above, "medium-sized" arteries in the skin may actually be quite small compared with other medium-sized arteries (such as coronary or mesenteric arteries), but they are still muscular and are larger than the small, superficial precapillary arteries associated with purpura.

Kidney disease — In autopsy studies, the kidneys are the most commonly involved organ. Renal involvement frequently leads to variable degrees of renal insufficiency and hypertension. In addition, rupture of renal arterial aneurysms can cause perirenal hematomas. Multiple renal infarctions may also develop in those with severe vasculitis.

Incomplete luminal narrowing of the inflamed arteries leads to glomerular ischemia but not inflammation or necrosis. Thus, the urinalysis, when abnormal, shows only sub-nephrotic and often minimal proteinuria and perhaps modest hematuria, but red blood cell casts (indicative of a glomerular focus of inflammation) are usually absent [1,2]. In patients with red blood cell casts, alternative diagnoses should be considered, including ANCA-associated vasculitis or systemic lupus erythematosus.

Hypertension is a common finding in patients with PAN and renal involvement. As noted above, renal ischemia, leading to activation of the renin-angiotensin system, is thought to be the primary mechanism [21].

Neurologic disease — A mononeuropathy multiplex (or asymmetric polyneuropathy) affecting named nerves (eg, radial, ulnar, peroneal), typically with both motor and sensory deficits, is one of the most common findings in patients with PAN, occurring in up to 70 percent of patients [4,26-28]. The neuropathy is generally asymmetric at onset, but additional nerve branches become affected over time, leading to a more confluent distal symmetric polyneuropathy. Involvement of the central nervous system occurs in 5 to 10 percent of patients with PAN and may include stroke [4,29-31]. Central nervous involvement in PAN should raise concern that deficiency of adenosine deaminase 2 (DADA2) is actually the correct diagnosis. (See 'Etiology' above.)

Gastrointestinal disease — Abdominal pain is an early symptom in patients with mesenteric arteritis [32]. The discomfort may be intermittent or continuous and may be most prominent after meals ("intestinal angina"). Weight loss may ensue due to decreased food intake and/or malabsorption. Progressive disease can result in bowel infarction with perforation [33].

Other gastrointestinal symptoms that may be seen include nausea, vomiting, melena, bloody or nonbloody diarrhea, and life-threatening gastrointestinal bleeding [34]. Perforation during colonoscopy may be more frequent in patients with PAN. If colonoscopy is otherwise indicated in a patient with suspected or known PAN, minimal insufflation during the procedure is recommended; and if ischemic areas of bowel are noted, early termination of the study is recommended [34].

Ischemia due to vasculitis affects the small intestine more commonly than other areas of the gastrointestinal tract. In addition, a subset of patients has predominantly mesenteric arterial involvement with little or no clinical evidence of extraintestinal vasculitis. Rare presentations resembling acute cholecystitis or appendicitis result from acute vasculitis limited to the cystic or appendiceal artery, respectively [32].

Segmental pancreatic infarction and necrotizing pancreatitis, albeit rare, may occur [35].

Coronary artery disease — Although overt myocardial infarction is uncommon, myocardial ischemia may result from narrowing or occlusion of the coronary arteries [36]. Heart failure may result from either vasculitis of the coronary arteries, resulting in ischemic cardiomyopathy, or from uncontrolled hypertension caused by renal disease.

Muscle disease — Muscle involvement is common; symptoms include myalgia and muscle weakness. Serum creatinine kinase levels may be elevated but are seldom high enough to trigger suspicion of an inflammatory myopathy [37]. When muscle pain or claudication are present, muscle biopsy has an approximately 50 percent sensitivity for PAN [38].

Other — Virtually any organ of the body may be affected in patients with PAN:

Orchitis with testicular tenderness and pain occurs in more than 10 percent of patients, and testicular biopsy in patients with these symptoms can often be diagnostic of PAN [39].

Several abnormalities of the eye may occur, including ischemic retinopathy with hemorrhages and retinal detachment, as well as ischemic optic neuropathy [40,41].

Breast and uterine involvement may be seen in selected patients [22]

Involvement of bronchial arteries has been described in PAN [42]. However, the presence of capillaritis or other lung parenchymal involvement by vasculitis strongly suggests another disease process, such as microscopic polyangiitis, granulomatosis with polyangiitis, or eosinophilic granulomatosis with polyangiitis (Churg-Strauss) [42].

Splenic infarction can occur due to arteritis.

DIAGNOSIS — A clinical diagnosis of polyarteritis nodosa (PAN) is suspected based upon the presence of characteristic symptoms, physical findings, and compatible laboratory test results. However, because of the relative rarity of this disease and the potentially severe adverse effects related to treatment, the diagnosis should be confirmed by biopsy whenever possible. In the absence of an obvious site for biopsy, angiography sometimes reveals microaneurysms of blood vessels in the renal, hepatic, or mesenteric circulations.

A general approach to diagnosis in a patient suspected of having vasculitis is discussed in more detail elsewhere (see "Overview of and approach to the vasculitides in adults", section on 'Diagnostic approach'). The following is a brief summary with a focus on those features considered to be of particular importance in PAN.

Arteritis consistent with PAN can occur in individual organs without evident systemic involvement. Such cases may be discovered either through biopsy or angiography during an evaluation for vasculitis or "incidentally" upon pathologic review of a surgical specimen, sometimes obtained for other reasons. Whether to label such cases of medium-vessel vasculitis in a single organ as PAN is controversial. However, in all such cases, a comprehensive evaluation for other manifestations of PAN, as described in this section, is warranted to help establish the diagnosis and determine extent of disease to guide treatment plans.

History — The medical history serves to identify clinical manifestations that might be due to PAN. It may also identify other possible causes of the patient's symptoms (see 'Differential diagnosis' below) such as:

Drug exposure – Including prescription and illicit drugs associated with drug-induced vasculitis (eg, amphetamines, minocycline), or injection drug use and the associated risk of hepatitis B and C virus (HBV and HCV) infection. Almost every class of drugs has been implicated as possibly causal of vasculitis, but not all such drug-induced vasculitides fit the pattern of PAN.

Alternative diagnosis – Other systemic inflammatory diseases (eg, systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis), infectious diseases (eg, chronic viral hepatitis, bacterial endocarditis), embolic disorders (eg, atherosclerosis and recent arterial catheterization), or thrombotic disorders. (See 'Differential diagnosis' below.)

Physical examination — A careful physical examination helps to determine the extent of vascular lesions, the distribution of affected organs, and the presence of additional disease processes. Skin manifestations and the presence of objective evidence of motor weakness (eg, a foot- or wrist-drop) or sensory loss should be sought. A full vascular examination is warranted.

If there is no evidence of overt gastrointestinal bleeding, a positive test for occult blood may be indicative of mesenteric vasculitis.

Laboratory testing — There is no diagnostic laboratory test for PAN. Basic laboratory tests help ascertain the extent of organs affected and their degree of involvement.

Basic laboratory analysis includes complete blood count, serum creatinine, muscle enzyme concentrations, liver function studies, hepatitis (HBV and HCV) serologies, and urinalysis. Acute-phase proteins are typically elevated, as evidenced by increased erythrocyte sedimentation rate and C reactive protein concentrations, but are neither sensitive nor specific enough for the diagnosis of PAN (or most other vasculitides) to substantially impact diagnostic decision making.

Chest radiography is used to exclude diseases, particularly other forms of vasculitis with a greater propensity for involving the lungs.

Blood cultures should be obtained in all patients suspected of having a systemic vasculitis in order to exclude endovascular infection.

Additional laboratory testing is valuable in narrowing the differential diagnosis. This includes the following assays, depending upon the alternative diagnoses being considered based upon the patients signs and symptoms:

Antineutrophil cytoplasmic antibodies (ANCA)

Antinuclear antibodies (ANA)

Complement components (C3 and C4)

Cryoglobulins

Serum and urine immunofixation electrophoresis to test for monoclonal gammopathy

Testing for human immunodeficiency virus

Testing for deficiency of adenosine deaminase 2 (DADA2) (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis')

Testing for VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome')

A positive immunofluorescence test for ANCA, if confirmed by enzyme-linked immunosorbent assay (ELISA) testing to be due to antibodies with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO), strongly argues against PAN and in favor of one of the ANCA-associated vasculitides. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

High titers of ANA suggest an underlying autoimmune disease such as systemic lupus erythematosus (SLE), systemic sclerosis (scleroderma), or an overlap syndrome, all of which may sometimes be associated with vasculitis. In patients with a positive ANA for whom there is clinical suspicion of a systemic rheumatic disease, additional serologic testing is indicated. (See "Clinical manifestations and diagnosis of systemic lupus erythematosus in adults" and "Diagnosis and classification of Sjögren's disease" and "Measurement and clinical significance of antinuclear antibodies".)

In a patient with a history of inflammatory arthritis, testing for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies is helpful when rheumatoid vasculitis is under consideration. RF is also positive in mixed cryoglobulinemia, which is usually associated with HCV. Mixed cryoglobulinemia is suggested by the presence of cryoglobulins and complement consumption. Although cryoglobulinemia is typically associated with small vessel disease (eg, glomerulonephritis, leukocytoclastic vasculitis, capillaritis), it has been linked to some cases of PAN, particularly in the setting of HCV or HBV infection. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis" and "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Lyme disease is a consideration in patients with mononeuropathy multiplex or polyradiculopathy. Serologic testing for Lyme disease is probably unnecessary in the absence of neurologic involvement. (See "Clinical manifestations of Lyme disease in adults" and "Diagnosis of Lyme disease".)

Human immunodeficiency virus (HIV) infection can cause mononeuritis multiplex, and co-infection with HIV is common among patients with HBV or HCV infections. (See "HIV-associated distal symmetric polyneuropathy (HIV-DSPN)".)

Biopsy — The presence of PAN may be suspected from the clinical and radiologic findings, but the diagnosis should ideally be confirmed by biopsy of a clinically affected organ. Biopsy of clinically normal tissue has a much lower yield. This was illustrated in a retrospective study of patients with PAN, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), and other systemic vasculitides with gastrointestinal involvement [32]. Upper and lower gastrointestinal lesions, though frequently apparent at endoscopy, rarely provide histopathologic confirmation of vasculitis; none of the biopsies from the upper gastrointestinal tract obtained in 17 patients showed histologic signs of vasculitis. Colorectal biopsies, performed in six patients, were diagnostic in three (one with PAN and two with granulomatosis with polyangiitis).

Deep or excisional skin biopsies establishing that medium-vessel vasculitis is present are quite helpful diagnostically, even if they are not specific for PAN versus other forms of vasculitis. As is always the case, interpretation of the biopsy results must take into consideration the full clinical situation.

Renal biopsy in classic polyarteritis nodosa may reveal pathognomonic inflammation of the medium-sized arteries (picture 2) [43]. Affected arteries may not be seen due to sampling error. However, the presence of small microaneurysms in the kidneys may increase the risk of bleeding from a renal biopsy; thus, some advocate performing a renal biopsy only in those patients in whom the arteriography is negative.

Biopsies of medium-sized visceral arteries are not safe or practical, and it is not uncommon for PAN to be diagnosed by combining the findings on angiography with other clinical features. This approach should lead clinicians to regularly reassess the patient's case and be open to other diagnoses.

Arteriography and cross-sectional imaging — An alternative to biopsy for diagnosis is conventional mesenteric or renal arteriography [1,2]. These studies will often be diagnostic, demonstrating multiple aneurysms and irregular constrictions in the larger vessels with occlusion of smaller penetrating arteries (image 1 and image 2).

Less invasive angiography techniques (eg, computed tomography [CT] and magnetic resonance imaging [MRI]), can also be used [44,45]. In the proper clinical setting, the finding of wedge-shaped areas of ischemia in the kidney may be of value in demonstrating renal vascular involvement. The demonstration of renal infarctions, however, is less specific for PAN than are the microaneurysms demonstrated most readily by conventional arteriography. CT and MR angiography continue to improve with respect to resolution for vascular disease and utility to both establish the extent of disease in PAN and to allow for serial images to track disease course and treatment response. These techniques have the advantage of helping to avoid repeat catheter-based angiography.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of polyarteritis nodosa (PAN) is broad, including infectious diseases that affect the vasculature or are complicated by systemic vasculitis. Immunosuppressive therapies that might be appropriate for systemic vasculitis may mask the symptoms and delay the diagnosis of an infectious disease. Noninfectious disorders, particularly those that can cause widespread arterial embolism, thrombosis, or vasospasm, must be considered as these diseases are also not appropriately treated with immunosuppression. Other systemic vasculitides, although treated in a similar fashion to PAN, may have distinctive manifestations. The differential diagnosis of vasculitis is discussed in more detail elsewhere. (See "Overview of and approach to the vasculitides in adults", section on 'Differential diagnosis'.)

Among infectious diseases, the following may cause clinical manifestations that either mimic vasculitis or cause vascular inflammation:

Infective endocarditis or other bacteremic disease

Mycotic aneurysm with distal embolization

Hepatitis B or C virus infection

HIV infection

Other disorders that may mimic vasculitis of medium sized arteries include:

Atherosclerosis

Embolic diseases (eg, left atrial myxoma, cholesterol crystals)

Thrombotic disorders (eg, catastrophic antiphospholipid syndrome)

Fibromuscular dysplasia

Ergotism

Radiation fibrosis

Necrotic arachnidism (Loxosceles species spider bites)

Malignant atrophic papulosis (Degos disease or syndrome)

Segmental arterial mediolysis (SAM)

Other causes of malignant hypertension

Other systemic vasculitides to consider are:

Granulomatosis with polyangiitis and microscopic polyangiitis

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Immunoglobulin A vasculitis (Henoch-Schönlein purpura)

Cryoglobulinemic vasculitis

Drug-induced vasculitis

Vasculitis secondary to connective tissue disease (eg, systemic lupus erythematosus, rheumatoid arthritis)

Glomerulonephritis is much more typical of microscopic polyangiitis than PAN. Among patients with glomerulonephritis, the urinalysis typically has mild to moderate proteinuria, with an active sediment containing red cells and cellular and granular casts. (See "Glomerular disease: Evaluation and differential diagnosis in adults".)

A mononeuropathy multiplex (or asymmetric polyneuropathy) with motor and sensory deficits is one of the most common findings in patients with PAN [26-28]. If present, this finding is highly suggestive of vasculitis; diabetic neuropathy is the only other common cause of this problem in developed countries [46]. Other forms of systemic vasculitis commonly associated with mononeuropathy multiplex are the antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides and mixed cryoglobulinemia.

Also consider the presence of genetic disorders that have been associated with PAN:

Adenosine deaminase deficiency (see "Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis", section on 'Diagnosis')

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome (see "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome')

Finally, with the increasing use and availability of cross-sectional abdominal imaging by CT or magnetic resonance (MR), more patients are being identified with incidentally discovered abnormalities of medium-sized arteries. Such patients may be labeled as having PAN, but clinicians need to be careful to avoid misdiagnosis of this rare disease based on radiographic data alone, especially without concomitant and physiologically concordant clinical manifestations of disease and/or evidence of change in arterial disease. Incidentally found medium-vessel disease is a quite difficult clinical scenario for which careful "watchful waiting" without treatment but with repeat imaging in three to six months may be appropriate.

Classification criteria — The American College of Rheumatology (ACR) has established ten criteria for the classification of polyarteritis nodosa in a patient with a vasculitis [47]. A sensitivity and specificity for the diagnosis of polyarteritis of 82 and 87 percent, respectively, has been found in the patient with a documented vasculitis in whom at least three of the following criteria are present:

Otherwise unexplained weight loss greater than 4 kg

Livedo reticularis

Testicular pain or tenderness

Myalgias (excluding that of the shoulder and hip girdle), weakness of muscles, tenderness of leg muscles, or polyneuropathy

Mononeuropathy or polyneuropathy

New-onset diastolic blood pressure greater than 90 mmHg

Elevated levels of serum blood urea nitrogen (>40 mg/dL or 14.3 mmol/L) or creatinine (>1.5 mg/dL or 132 micromol/L)

Evidence of hepatitis B virus infection via serum antibody or antigen serology

Characteristic arteriographic abnormalities not resulting from noninflammatory disease processes (image 1)

A biopsy of small- or medium-sized artery containing polymorphonuclear cells

PAN was defined by the Chapel Hill Consensus Conference (CHCC) as: "Necrotizing inflammation of medium-sized or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules" [48].

It is important to remember that neither the ACR Classification Criteria nor the CHCC nomenclature was meant to be used for the diagnosis of vasculitis [49]. Until validated diagnostic criteria for PAN are established, the diagnosis of PAN is informed by the ACR and CHCC approaches but remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Vasculitis" and "Society guideline links: Polyarteritis nodosa".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Polyarteritis nodosa (The Basics)")

Beyond the Basics topics (see "Patient education: Vasculitis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Definition and epidemiology – Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that typically affects medium-sized muscular arteries, with occasional involvement of small muscular arteries. The spectrum of disease known as PAN has evolved and narrowed substantially due to the identification and classification of other forms of vasculitis that had previously been considered PAN, particularly microscopic polyangiitis (MPA). Unlike MPA, PAN is not associated with the presence of antineutrophil cytoplasmic antibodies (ANCA). The diagnosis is most commonly made in middle-aged or older adults, and the incidence rises with age, with a peak in the sixth decade of life. (See 'Introduction' above and 'Epidemiology' above.)

Etiology, pathogenesis, and pathology – Most cases of PAN are idiopathic, although drugs, hepatitis B virus infection, hepatitis C virus infection, and hairy cell leukemia are important in the pathogenesis of some cases, which are termed secondary PAN. The pathogenetic mechanisms in PAN are poorly understood. It seems likely that, in terms of pathogenesis and pathophysiology, PAN represents a spectrum of disease rather than a single entity. Regardless of the underlying cause, established PAN is characterized by segmental transmural inflammation of muscular arteries; it does not involve veins, unlike other forms of systemic vasculitis. (See 'Etiology' above and 'Pathogenesis' above and 'Pathology' above.)

Clinical features – Patients with PAN typically present with systemic symptoms (fatigue, weight loss, weakness, fever, arthralgias) and signs (skin lesions, hypertension, renal insufficiency, neurologic dysfunction, abdominal pain) of multisystem involvement (table 1). (See 'Clinical features' above.)

Diagnosis – A clinical diagnosis of PAN is suspected based upon the presence of characteristic symptoms, physical findings, and compatible laboratory test results. However, because of the relative rarity of this disease and because of the potentially severe adverse effects related to treatment, the diagnosis should be confirmed by biopsy whenever possible. In the absence of an obvious site for biopsy, angiography sometimes reveals microaneurysms of blood vessels in the renal, hepatic, or mesenteric circulations. (See 'Diagnosis' above.)

Classification criteria – The diagnosis of PAN is informed by the classification criteria developed by the American College of Rheumatology and by the definitions and nomenclature of the Chapel Hill Consensus Conference, but there are no validated diagnostic criteria for PAN. Thus, the diagnosis remains a clinical diagnosis that importantly includes exclusion of entities that mimic this rare disease. (See 'Classification criteria' above.)

Differential diagnosis – The differential diagnosis of PAN is broad, including infectious diseases that affect the vasculature or that are complicated by systemic vasculitis; noninfectious disorders, particularly those that can cause widespread arterial embolism, thrombosis, or vasospasm; and other systemic vasculitides. (See 'Differential diagnosis' above.)

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Topic 8245 Version 35.0

References

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