Continuing Education Activity

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis first described in 1866 by Adolph Kussmaul and Rudolph Maier. It typically affects medium-sized arterial vessels but may affect small-sized arterial vessels. Unlike other small-sized arterial vessel vasculitides, polyarteritis nodosa is not typically associated with anti-neutrophil cytoplasmic antibodies (ANCA). It is a systemic disease process though there is a limited form of the disease called cutaneous polyarteritis nodosa (CPAN). This activity reviews the causes, pathophysiology, and presentation of polyarteritis nodosa and highlights the role of the interprofessional team in its management.

Objectives:

• Identify the etiology of polyarteritis nodosa.
• Review the evaluation of a patient with polyarteritis nodosa.
• Outline the treatment and management options available for polyarteritis nodosa.
• Summarize interprofessional team strategies for improving care coordination and outcomes in patients with polyarteritis nodosa.

Introduction

Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis first described in 1866 by Adolph Kussmaul and Rudolph Maier.[1] It typically affects medium-sized arterial vessels but may affect small-sized arterial vessels. Unlike other small-sized arterial vessel vasculitides, polyarteritis nodosa is not typically associated with anti-neutrophil cytoplasmic antibodies (ANCA). It is a systemic disease process; though there is a limited form of the disease called cutaneous polyarteritis nodosa (CPAN). Even with the limited form of the disease, there is significant morbidity secondary to digital ulcerations, ischemia, and painful skin nodules. Though rare, patients with CPAN can progress to systemic polyarteritis nodosa (PAN).

PAN chiefly affects the skin but can also involve other organs. The lungs are usually spared.

Etiology

Primary cases of PAN are idiopathic. Secondary PAN is less frequent and often seen in hepatitis B, hepatitis C, and malignancies such as hairy cell leukemia.[2][3]

Impairment in endothelial function is believed to perpetuate the inflammatory reaction. Patients who develop hepatitis B may develop PAN, usually within the first 6 months of the infection. With the use of the hepatitis B vaccine, the cases of PAN have dropped.

Loss of function mutations in CECR1 has also been linked to PAN. Besides hepatitis B, several other organisms have been linked to PAN including Klebsiella, Toxoplasma, Pseudomonas, trichinosis, parvovirus B-19, and Yersinia species. In addition, PAN has been linked to Sjogren syndrome, rheumatoid arthritis, and hairy cell leukemia.

Epidemiology

PAN is usually diagnosed in middle-aged and older adults. Men tend to be more affected than women. According to a French study, the prevalence of PAN per 1000000 adults was 30.7.[4]

Pathophysiology

Hepatitis B-associated PAN is believed to arise secondary to immune complexes.[5] However, the mechanism in which immune complexes lead to medium vessel inflammation is unknown, and immune complexes play less of a role in other subsets of the disease. Affected vessels become thickened and inflamed through intimal proliferation. This leads to vessel narrowing and decreased blood flow, predisposing affected vessels to thrombosis. Inflammation not only leads to vessel narrowing but the weakening of the vessels which leads to aneurysm development. These changes result in ischemia and infarction, leading to the clinical manifestations seen. PAN affects multiple systems including renal, skin, neurologic, cardiac, gastrointestinal, and muscular. The kidney is the most commonly affected organ. Inflammation of renal arteries can lead to aneurysms and rupture, while intimal proliferation and luminal narrowing can lead to glomerular ischemia.

Histopathology

The histopathology will usually reveal localized necrotizing arteritis and a mixed inflammatory infiltrate. Nerve injury may present as fiber loss and axonal degeneration.

History and Physical

Patients with PAN and renal involvement most often present with hypertension.[6] Long-standing hypertension and vasculitis involving the coronary arteries can lead to heart failure, and patients may report associated symptoms including dyspnea and edema.[7] As in other vasculitides, patients may present with systemic signs. They may report generalized fatigue, weight loss, fevers, arthralgias, and skin lesions. The skin lesions may appear as tender, erythematous nodules similar to erythema nodosum.[8] They also may present with palpable purpura as seen in other forms of vasculitis. Other skin changes include livedo reticularis and ulcerations. The skin manifestations may be limited or diffuse but are often visible in the lower extremities.

A thorough review of symptoms also should include gastrointestinal (GI) and muscular complaints. Patients may report abdominal pain early in the disease process.[9] The pain may be continuous or intermittent but often occurs after meals. This constellation of symptoms has been described as "intestinal angina." Patients also may report nausea, vomiting, melena, or diarrhea. A stool occult blood test should be performed on patients even without an overt history of GI bleeding. GI symptoms are a result of mesenteric arteritis, predominantly affecting the small intestines. Severe disease can lead to ischemia and perforation. If muscle involvement occurs, patients may report myalgias and generalized weakness.

Patients may report symptoms of neurologic disease. The most common neurologic deficit in patients with PAN is mononeuritis multiplex, occurring in nearly 70% of patients with the disease.[10] Radial, ulnar, and peroneal nerves are the most common nerves involved, and patients can experience sensory and motor deficits.

Evaluation

There is no definitive laboratory test for PAN. The diagnosis is mainly clinical. Laboratory studies are most often obtained to assess organ involvement and rule out other disease processes. Laboratory tests should include serum creatinine and urinalysis to assess renal function as well as a liver panel and creatinine kinase. Hepatitis B and hepatitis C serologies are essential to rule out secondary causes of PAN. Erythrocyte sedimentation rate and C-reactive protein may be elevated but are not specific to PAN and often are elevated in other vasculitides. The following lab tests are particularly helpful to assess for other disease processes and vasculitides: antineutrophil cytoplasmic antibodies, antinuclear antibodies, complement levels (C3 and C4), cryoglobulins, serum and urine immunofixation electrophoresis (SPEP and UPEP), rheumatoid factor, and human immunodeficiency virus serology. A biopsy of an affected organ should be performed to confirm the diagnosis.[9] An alternative to biopsy is mesenteric or renal arteriography. These studies will often show aneurysms and constrictions in larger vessels as well as possible occlusion of smaller arteries. Computed tomography (CT) and magnetic resonance imaging (MRI) have been used when a less invasive technique is desired.

Treatment / Management

The treatment for PAN is dependent on the severity of the disease.[11][12] Mild disease is defined as those with constitutional symptoms but with normal renal function and no significant end-organ damage or ischemia. Patients with mild symptoms and those with isolated cutaneous disease may be treated with glucocorticoids. Initial treatment includes prednisone (1 mg/kg per day) with a maximum of 60 to 80 mg per day. This dose of steroids is given over a month and then slowly tapered over six to eight months. Patients with mild disease may be resistant to or intolerant of glucocorticoids. In this population, immune modulators such as azathioprine or methotrexate may be used. In moderate to severe disease, there may be evidence of renal insufficiency, ischemic disease or symptomatic arterial stenosis, or aneurysms. Patients with moderate to severe disease are treated with glucocorticoids and other immunosuppressive agents such as cyclophosphamide.

Over the past few years, the use of biological agents has increased in patients with recalcitrant disease.

Patients with associated hepatitis B or C infection also benefit from treatment with antivirals. For patients with mild PAN, treatment with antivirals should occur before any immunosuppressive medications are added. Patients with severe hepatitis B-associated PAN may benefit from short-term treatment with glucocorticoids and plasma exchange in addition to antiviral therapy.[13]

Hypertension should be treated with an angiotensin-converting enzyme (ACE) inhibitor. The hypertension in PAN is considered to be mediated through the activation of the renin-angiotensin system.[14] However, renal function should be monitored closely, and an alternative agent should be used if the glomerular filtration rate declines by more than 30% upon initiation of therapy. Calcium channel blockers may then be used to control hypertension.

Surgery is often required to manage bowel perforation, cholecystitis, and aneurysms of blood vessels.

Differential Diagnosis

The differential diagnosis of PAN and its manifestations are broad and include infectious processes as well as other vasculitides. Infectious mimics include infective endocarditis, mycotic aneurysm with emboli, and human immunodeficiency virus. Other vasculitides on the differential include granulomatosis with polyangiitis, microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis (Churg-Strauss), immunoglobulin A vasculitis (Henoch-Schönlein purpura), cryoglobulinemic vasculitis, and drug-induced vasculitis.

Prognosis

Though relapse rates for PAN are lower than the ANCA-associated vasculitides, relapse rates remain high.[8] Untreated PAN has a poor prognosis; however, outcomes have significantly improved with treatment. The major causes of death include renal failure and mesenteric, cardiac, or cerebral infarction. Relapses tend to occur with 5 years. More important, recovery is slow and if the CNS is involved, it portends a poor prognosis. Individuals with abdominal involvement also have a poor prognosis because of the risk of perforations.

The prognosis is best for patients who only have skin involvement, but the risk of relapse is still present. Patients with hepatitis B who seroconvert have a low risk of relapse and usually recover.

Without treatment, anywhere from 10%-20% of patients die within 5 years, with 50% dying within the first 3 months. With corticosteroid treatment, the 5-year survival ranges from 50%-60%. Deaths are usually due to complications of immunosuppressive therapy, stroke, bowel perforation, or myocardial infarction. The prognosis worse if patients have the following:

• Proteinuria (more than 1 g/day)
• Renal insufficiency
• Cardiomyopathy
• GI involvement
• CNS involvement

Complications

Complications associated with PAN include the following:

• Gangrene of the extremity
• Skin ulcers
• Infarction
• Aneurysm formation and rupture
• Encephalopathy
• Stroke
• Heart failure
• Renal failure
• Bowel infarction
• GI bleeding
• Peripheral neuropathy

Postoperative and Rehabilitation Care

Long-term monitoring of patients with PAN is necessary as relapse rates are high. In addition, new organs may be involved and the dose of the immunosuppressive drugs needs to be changed. Because of immunosuppression, these patients are susceptible to infections.

Deterrence and Patient Education

Patients with PAN should be educated regarding the disease process and the possibility of progressive disease with complications involving multiple organ systems. Patients should be advised that medication regimen adherence is vital to prevent these complications. Patients should also be thoroughly counseled on the risks associated with long-term use of immunosuppressant medications.

Enhancing Healthcare Team Outcomes

PAN is a multi-system necrotizing vasculitis that has many aspects to its treatment and management which is best accomplished with an interprofessional team approach. Apart from the close involvement of rheumatologists and primary clinicians, consultation with a nephrologist in renal failure and infectious disease clinicians in cases associated with hepatitis B and C is required for many patients. So would be the case involving pharmacists for effective medication management and education. The pharmacist should educate the patient about medication compliance and their adverse effects. Strong communication among the interprofessional team is essential for better outcomes in these patients.