Vasculitis: Medium Vessel (PAN)

Does this patient have polyarteritis nodosa (PAN)?

Polyarteritis nodosa (PAN) is a form of necrotizing vasculitis primarily affecting medium-sized arteries with muscular walls, although small arteries can be affected at times. Vascular inflammation is the crucial element defining PAN. PAN has been considered the prototype of vasculitis but is now diagnosed less frequently than in the past.

Inflammation can result in damage to an involved vessel, which may manifest as stenosis or occlusion, aneurysmal dilatation, dissection, or rupture of the involved vessel. Multiple organ systems can be affected, making manifestations protean, with a wide variety of symptoms and physical findings possible. Most manifestations relate to specific organ systems that are involved but constitutional symptoms are common.

Findings overlap with those of other forms of systemic vasculitis. Importantly, anti-neutrophil cytoplasmic antibodies (ANCA) and granulomatous inflammation are not found in patients with PAN and their presence excludes the diagnosis of PAN.

PAN can be seen at any age but has a peak in the sixth decade. There is a slight male predominance in cases. The etiology of PAN is unknown in most cases.

Hepatitis B virus (HBV) infection has been linked to some cases of PAN and HBV infection was included in original classification criteria for PAN. The reduction of HBV infection may partially explain the reduction in PAN diagnosis. Other disorders associated with some cases of PAN are hepatitis C infection and hairy cell leukemia. Minocycline exposure has been linked to some cases of PAN. Loss of function mutations in the gene encoding adenosine deaminase 2 have been found in some children with PAN features.

Diagnosing PAN can be difficult given the wide range of organs that can be affected, and the diverse manifestations. Diagnostic criteria for PAN are not available but classification criteria were promoted by the American College of Rheumatology in 1990. The Chapel Hill Consensus Conference of 2012 published a definition of PAN, defining it mostly as what it is not. PAN was defined as a necrotizing arteritis of medium or small arteries without glomerulonephritis or vasculitis in arterioles, capillaries, or venules, and not associated with ANCA.

Constitutional symptoms can include fever, fatigue, and weight loss. Symptoms and signs related to specific organ involvement are organized by organ systems.

Cutaneous manifestations

Cutaneous manifestations can include livedo reticularis, palpable purpura, tender subcutaneous nodules, and cutaneous ulcers.

Subcutaneous nodules, usually tender to palpation, are a classic feature of PAN, lending to its name. Biopsy can show necrotizing vasculitis affecting the walls of medium-size arteries in the deep dermis or subcutaneous fat.

Palpable purpura may be present, with biopsy showing leukocytoclastic vasculitis involving small vessels, underscoring the fact that PAN can affect small vessels as well as medium-sized arteries. Leukocytoclastic vasculitis is not diagnostic of PAN as it can be seen in a wide variety of other forms of vasculitis, including small vessel vasculitis related to immune-complex deposition, such as connective tissue disease-related vasculitis, Henoch-Schonlein purpura, and cryoglobulinemia, as well as pauci-immune vasculitis such as ANCA-associated vasculitis

Livedo reticularis can be seen in patients with connective tissue disease and antiphospholipid syndrome.

Patients with only skin involvement and no other organ involvement are diagnosed as having cutaneous polyarteritis nodosa.

Gastrointestinal manifestations

Gastrointestinal manifestations are common in PAN, typically presenting as abdominal pain.

Stenosis or occlusion of mesenteric arteries can cause abdominal pain which may be aggravated by eating; so-called intestinal angina. Weight loss is common in such patients and more severe involvement may result in gastrointestinal bleeding or bowel infarction which can present with abdominal pain, melena, or hematochezia.

Rupture of an abdominal artery aneurysm can cause hemoperitoneum or retroperitoneal hemorrhage.

Vascular stenosis or occlusion can cause splenic, hepatic, or renal infarcts, causing abdominal pain.

Isolated vasculitis can affect the gallbladder or appendix and be identified incidentally on pathologic examination following routine surgical procedures.

Renal involvement

Renal involvement results from narrowing of renal arteries or renal artery aneurysms and not from glomerulonephritis.

Most patients with renal involvement are asymptomatic. Hypertension is a common finding with renal involvement and renal insufficiency may occur. The urinary sediment is typically inactive but slight proteinuria or microscopic hematuria without casts may be present. Pain can arise from renal infarction. Rupture of a renal artery aneurysm can result in perinephric hematoma or retroperitoneal bleeding.

Neurologic manifestations

Neurologic manifestations of PAN typically involve the peripheral nervous system, although central nervous system involvement can occur infrequently. Peripheral nerve manifestations can cause sensory and/or motor neuropathies. Mononeuritis multiplex and polyneuropathy are well-recognized findings in patients with PAN.

A wide variety of other vascular beds can be affected in patients with PAN. Muscle involvement can cause myalgia, weakness, and claudication, with elevation of creatine kinase. Coronary artery involvement can lead to angina and ischemic cardiomyopathy. Orchitis with testicular tenderness can occur.

What tests to perform?

Laboratory testing in patients with, or suspected of having, PAN has several purposes:

To establish the diagnosis of PAN and exclude other diagnoses.
To determine the extent of organ system involvement of PAN.
To identify the presence and severity of co-morbidities which might affect treatment decisions and affect prognosis.
To identify adverse effects of therapy.

Biopsy

The most important diagnostic test to establish a diagnosis of PAN is a tissue biopsy which demonstrates vasculitis – inflammation of blood vessel walls. Biopsy should be guided by symptoms, signs, and laboratory features suggesting specific organ involvement. Although vasculitis may be discovered incidentally on biopsy, blind biopsies of muscle, nerve, or other tissues, in the absence of features suggesting involvement of such organs, are usually uninformative.

A punch skin biopsy allows examination of superficial vessels but a deeper biopsy is often needed in patients with subcutaneous nodules. In patients with muscle pain and elevated muscle enzymes, a muscle biopsy can be diagnostic.

Sural nerve biopsy can reveal vasculitis but should only be considered in patients with abnormal electrophysiologic studies given the morbidity of the procedure. Testicular biopsy can be pursued in patients with orchitis. Kidney biopsy can reveal features of PAN, but glomerulonephritis is not a feature, as PAN involves vessels larger than glomerular vessels.

Characteristic biopsy findings in PAN are necrotizing transmural inflammation of muscular arteries, with infiltration of lymphocytes and neutrophils. Karyorrhexis, with abnormalities of neutrophil nuclei, maybe present. Fibrinoid necrosis may be evident. Damage of the blood vessel wall can result in aneurysmal dilatation of the artery, and even dissection or rupture of the vessel. At other times, vessel stenosis or occlusion may occur as a result of vascular inflammation.

Imaging

In cases where it is not possible to obtain an artery for histologic examination, surrogate tests must be considered. Angiography has been utilized as a surrogate test for diagnosis of visceral involvement of PAN. Angiographic findings include arterial stenoses and occlusions, as well as aneurysms.

Magnetic resonance angiography (MRA) and computed tomography angiography (CTA) are performed more often than conventional, catheter-based angiography, but these techniques have poorer spatial resolution than catheter-based angiography, which offers clearer images, especially of smaller parenchymal vessels such as those which can be visualized in the kidneys.

Laboratory

Laboratory tests to exclude other forms of vasculitis are important as the diagnosis of PAN is based on the exclusion of other forms of vasculitis which can have similar manifestations. Although ANCA-associated vasculitides such as granulomatosis with polyangiitis (GPA, Wegener’s) involve small vessels, manifestations can overlap with PAN.

Patients with PAN do not have positive ANCA assays and do not have granulomatous inflammation on biopsy. Laboratory test abnormalities are dependent on specific organ involvement. With GI bleeding or rupture of an arterial aneurysm, microcytic anemia may occur.

Inflammatory markers including erythrocyte sedimentation rate and C-reactive protein are typically elevated and can be followed to help assess disease activity, but do not aid in the differential diagnosis.

As palpable purpura, a sign of small vessel vasculitis, can occur with other forms of vasculitis, screening for rheumatoid factor, CCP antibodies, and antinuclear antibodies can be helpful.

Laboratory tests should include:

CBC with differential.
Chemistry panel, including transaminases and creatinine.
Urinalysis with microscopic examination.
Rheumatoid factor and anti-cyclic citrullinated peptide (CCP) antibody.
Antinuclear antibody.
Myeloperoxidase- and proteinase 3-ANCA assays.
Hepatitis B, hepatitis C, and HIV serologies.
Cryoglobulins.

How should patients with polyarteritis nodosa (PAN) be managed?

General principles

After establishing a diagnosis of PAN, therapy needs to be matched to the severity of the disease. As a general principle, patients with more severe, life-threatening disease require more aggressive interventions than do patients with less severe disease. Patients with isolated vasculitis identified incidentally following cholecystectomy or appendectomy may require no additional therapy.

About half of patients will do well and enter remission with treatment with glucocorticoid (GC) therapy alone. Disease severity, which should suggest early use of immunosuppressive agents, can be assessed by the Five Factor Score (FFS), introduced initially in 1996 and updated in 2011. Patients with increasing numbers of factors in the FFS have increasing mortality from their vasculitis.

Items in the FFS are:

Age > 65 years.
Gastrointestinal involvement with perforation, bleeding, or pancreatitis.
Renal insufficiency, with creatinine > 1.58 mg/dL.
Cardiac insufficiency.
Lack of ENT involvement.

Glucocorticoids

Glucocorticoid (GC) therapy is the mainstay of therapy, and for some patients is the only treatment necessary. GC therapy is generally initiated as prednisone at a dose of approximately 1 mg/kg/day, usually limiting the dose to 60-80 mg daily. With improvement, prednisone can be tapered gradually. Many will continue the initial dose for 2-4 weeks before starting to taper.

Tapering regimens vary. It can be helpful to plan for a specific duration of therapy and plan a tapering schedule based on the response. Tapering plans must be flexible, based on the patient’s response and the development of side effects. A tapering schedule, as follows, allows the dose to be lowered to 10 mg daily within about 4 months:

60 mg daily for 2-4 weeks.
40 mg daily for 2 weeks.
30 mg daily for 2 weeks.
25 mg daily for 2 weeks.
20 mg daily for 2 weeks.
15 mg daily for 2 weeks.
12.5 mg daily for 2 weeks.

After getting to a dose of 10 mg daily, the tapering can be slowed, based on the patient’s response and tolerance of prednisone. After 2-4 weeks at 10 mg daily, prednisone can continue to be tapered by 2.5 mg every 2-4 weeks, or to taper by 1 mg every 1-2 weeks.

Intravenous methylprednisolone, 500-1,000 mg daily for 3 days, can be utilized to begin GC therapy for patients with severe, life-threatening disease.

Immunosuppressive agents

Immunosuppressive agents should be utilized in patients with severe disease, those with persistently active disease despite treatment with GC, or those with side effects from GC which preclude adequate therapy with GC alone. The choice of immunosuppressive agents is largely empiric.

Cyclophosphamide (CYC) has been the standard immunosuppressive agent used. The optimal dosing strategy for CYC has not been determined in controlled studies. For patients with life-threatening disease who require intensive care unit stays, intravenous CYC should be considered.

Typical doses for intravenous CYC are to begin at 750 mg/m2 monthly, adjusting the dose based on the effect on the peripheral blood WBC, aiming to keep the WBC > 4000.

The efficacy of using Mesna to reduce the risk of bladder toxicity is debated. When CYC is used orally, a target dose of 1.5 -2 mg/kg/day is often used. To reduce the risk of bladder toxicity, CYC should be taken as a single daily dose in the morning, with intake of copious amounts of fluid, preferably water, over the course of the day to dilute the urine.

The dose of CYC should be decreased in elderly patients and in those with diminished renal function.

Monitoring for CYC toxicity should include CBC with differential and platelet count weekly for the first month of therapy and after dosage increases, and every 2 weeks thereafter. Urine cytology should be checked because of the risk of bladder toxicity.

Because of concern for long-term toxicity from CYC, patients should be switched to a less risky immunosuppressive agent after remission has been achieved. Many will continue CYC for 1-3 months after remission. The risk of CYC toxicity is related to the cumulative dose of the drug. Immunosuppressive agents to consider for maintenance therapy are methotrexate, azathioprine, and mycophenolate mofetil. No studies have compared the efficacy of these agents for remission maintenance. Duration of therapy has not been studied adequately but using immunosuppressive agents for a total of 12-18 months is typical.

Cutaneous PAN

Treatment of cutaneous PAN represents a unique situation. Inclusion of a dermatologist experienced in the care of vasculitis is often helpful for recommendations about local measures. Cutaneous PAN may respond to nonsteroidal anti-inflammatory drugs, colchicine, hydroxychloroquine, dapsone, or pentoxyphylline, but many patients require immunosuppressive therapy with methotrexate, azathioprine, or mycophenolate mofetil

Side effects of treatment

While on prednisone, attention has to be paid to potential or actual side effects of glucocorticoids. Supplementation with calcium and vitamin D is recommended. For patients with osteoporosis or osteopenia and receiving GC therapy, use of a bisphosphonate should be considered.

Infection with Pneumocystis jirovecii is a concern in patients receiving prednisone greater than or equal to 20 mg daily, and the risk is especially increased in those treated concomitantly with an immunosuppressive agent. Prophylactic treatment with trimethoprim sulfamethoxazole, one single strength tablet daily is strongly recommended. For patients who have a sulfa allergy, alternatives include atovaquone, dapsone, or inhaled pentamidine.

What happens to patients with polyarteritis nodosa (PAN)?

Untreated PAN can have a poor prognosis with hypertension and renal failure being common long term outcomes. Vascular occlusion can cause catastrophic abdominal, cardiac, or central nervous system consequences. First year mortality is usually related to the sequelae of active vasculitis.

Vascular stenosis or occlusion is often an irreversible consequence of active vasculitis and may lead to chronic symptoms which do not represent active vasculitis. Such symptoms should not be treated with GC or immunosuppression. Differentiating symptoms arising from vascular damage from those arising from active vasculitis can be a challenge.

Potential adverse effects of medications are considerable and need to be addressed proactively. Immunization should be updated, including pneumococcal immunization. Patients should receive annual influenza immunization.

Glucocorticoid side effects are frequent. Limiting the dose of GC is encouraged but doing so runs the risk of undertreatment of PAN. Vitamin D level should be checked and vitamin D replacement considered. Routine supplementation with calcium and vitamin D is encouraged. Bisphosphonate treatment should be considered for patients who are anticipated to require GC therapy for 3 months or longer.

Routine monitoring should be in place to identify hematologic and other organ-specific toxicity depending on specific immunosuppressive agents being used. Urine cytology needs to be checked in patients who have received CYC.

Pneumocystis prophylaxis should be given to patients on an immunosuppressive agent and prednisone above 20 mg daily.

How to utilize team care?

Multiple consultants may need to be involved in the care of a patient with PAN. Based on specific manifestations, help from a dermatologist, nephrologist, gastroenterologist, invasive radiologist, neurologist, urologist, and cardiologist, among others, may be needed.

Nursing involvement for patient education and close monitoring of symptoms and medication side effects is needed.

Given the complexity of the medication regimens and potential for toxicity, pharmacist involvement in the care of patients with PAN is important.

Depending on specific organ involvement, physical or occupational therapy may be needed.

Are there clinical practice guidelines to inform decision making?

The European League Against Rheumatism (EULAR) has published evidence-based recommendations regarding care of patients with small and medium vessel vasculitis, including PAN. In regard to PAN, the EULAR recommendations suggest that patients with PAN:

Be managed in collaboration with or at centers of expertise with vasculitis.
Undergo biopsy to assist diagnosis.
Have a structured clinical assessment, including laboratory assessments at each visit.
Be treated with a combination of CYC and GC for remission induction.
Be treated with high dose GC.
Be treated with anti-viral therapy, GC, and plasma exchange if the PAN is associated with HBV.
Undergo workup for unexplained hematuria if they have been treated with CYC.

Other considerations

ICD-9

446.0 Polyarteritis nodosa. ICD-10: M30.0

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Rheumatology