Polyarteritis Nodosa

Polyarteritis nodosa (PAN) spares large vessels (the aorta and its major branches), the smallest vessels (capillaries and small arterioles), and the venous system.[7] Vascular lesions affect medium-sized muscular arteries and occur mainly at bifurcations and branch points.

Inflammation may start in the vessel intima and progress to include the entire arterial wall, destroying the internal and external elastic lamina, resulting in fibrinoid necrosis.[7] Aneurysms develop in the weakened vessel, carrying a subsequent risk for rupture and hemorrhage. Thrombi may develop at the site of the lesions. As lesions progress, proliferation of the intima or media may result in obstruction and subsequent tissue ischemia or infarction.[10]

Hepatitis B and PAN

The pathogenesis of polyarteritis nodosa (PAN) is unknown, and no animal model is available for study. Hepatitis B virus (HBV) infection is strongly linked with PAN. Evidence for immune complex–induced disease is confined to HBV-related PAN; the role of immune complexes in non-HBV-related PAN remains unclear.[7]

Impaired function of endothelial cells may be part of idiopathic PAN or a consequence of it; in HBV-PAN, virus replication may directly injure the vessel wall.[11] Endothelial dysfunction can perpetuate the inflammation through cytokine and adhesion molecule production.[10]

HBV-associated vasculitis almost always takes the form of PAN. HBV-PAN may occur at any time during the course of acute or chronic hepatitis B infection, although it typically occurs within 6 months of infection.[11]

The activity of HBV-PAN does not parallel that of the hepatitis, and symptoms are the same as those of idiopathic PAN. Small studies have found that gastrointestinal manifestations, malignant hypertension, renal infarction, and orchiepididymitis were more common in HBV-PAN.[11]

HBV was once the cause of up to 30% of PAN cases.[12] Widespread use of the hepatitis B vaccine has significantly decreased the incidence of HBV-PAN, which is now estimated to account for less than 8% of all PAN cases.[13]

Genetic associations

Loss-of-function mutations in CECR1 (alsoknown as ADA2), the gene that encodes adenosine deaminase 2 (ADA2), have been associated with a spectrum of vascular and inflammatory phenotypes that includes polyarteritis nodosa.[14]  Navon Elkan and colleagues identified six families with multiple cases of systemic and cutaneous polyarteritis nodosa, most of which had onset during childhood. In all the families, disease was traced to recessive mutations in CECR1 that resulted in reduced activity of ADA2.[15]

Possible roles of ADA2 include regulation of the proliferation of activated T cells and macrophages and the differentiation of monocytes to macrophages. Reduction in ADA2 activity  may affect the adenosine inflammatory-response pathway.[15]

Similarly, Gonzalez Santiago et al report two siblings with novel compound heterozygous mutations in CECR1 who were diagnosed with cutaneous PAN in early childhood.[16]

In a study of patients with early-onset livedo reticularis and/or hemorrhagic/ischemic strokes in the context of inflammation or PAN, Caorsi et al detected biallelic homozygous or compound heterozygous CECR1 mutations in 15 of 48 patients from 43 families. In patients with CECR1 mutations, the mean age of onset of disease was 24 months (6 months to 7 years).[17]

Other disease associations

Controversy has surrounded the potential association of hepatitis C virus (HCV) with PAN. HCV may be linked to cutaneous PAN, a benign, limited form of PAN. In a study of 16 patients with cutaneous PAN, 5 tested positive for hepatitis C.[18] HCV-associated PAN has also been described in 31 patients included in a larger 161 patient cohort with HCV-related vasculitis in France.[19] Despite the presence of serum cryoglobulins, these patients were diagnosed with HCV-PAN on the basis of typical histopathologic features of PAN and/or the presence of microaneurysms and/or multiple stenoses on abdominal and/or renal angiography.

A number of other infectious organisms have been reported in association with PAN or PAN-like diseases, but causal evidence is inconsistent. These organisms include varicella-zoster virus, parvovirus B-19, cytomegalovirus, human T-cell leukemia virus, streptococcal species, Klebsiella species, Pseudomonas species, Yersinia species, Toxoplasma gondii, Rickettsiae, trichinosis, and sarcosporidiosis.[20, 21] Recently, reports of associations with PAN and human immunodeficiency virus[22] and cutaneous PAN and tuberculosis[23] have been published as well.

Some syndromes, including rheumatic diseases, malignancies, and infections have been associated with clinical syndromes indistinguishable from idiopathic PAN. Rheumatoid arthritis (RA) and Sjögren syndrome have been associated with PAN. Notably, the incidence of RA-associated vasculitis has decreased greatly since the 1980s, likely attributable to improvements in the management of RA.[24] Cutaneous PAN occurring with HLA-B39 spondyloarthritis,[25] common variable immunodeficiency,[26] and psoriatic arthritis in an 11-year-old boy[27] have also been reported.

Hematologic malignancies, such as hairy cell leukemia and, in one case, angioimmunoblastic T cell lymphoma, have been associated with PAN-like vasculitides.[28, 29]

Occurrence in the United States

Polyarteritis nodosa (PAN) is a rare disease, with an incidence of about 3-4.5 cases per 100,000 population annually. Older estimates placed the prevalence as high as 7.7 cases per 100,000 population, for example, in a population of Alaskan Eskimos hyperendemic for HBV infection.[30]

International occurrence

Depending on the definitions used, the annual estimated incidence of PAN ranges from 1.6 cases per million in south Sweden to 4.6 cases per million in England to 30.7 cases per million adults in Paris, France.[12, 31]

Sex- and age-related demographics

PAN affects men more frequently than women (male-to-female ratio 1.6-2:1). PAN has been diagnosed in persons of every age; however, it is predominantly observed in individuals aged approximately 45-65 years.[10]

Idiopathic (non–HBV-related) PAN

Traditionally, it has been taught that relapses of polyarteritis nodosa (PAN) are rare in individuals who completely recover. However, a study in Sweden described 10 patients with PAN, 57% of whom experienced relapse within 5 years.[31]

Recovery from neurologic deficits due to PAN can take up to 18 months. Central nervous system (CNS) involvement carries a worse prognosis than does peripheral nerve involvement.[20]

The prognosis is markedly worse in patients with acute abdominal syndromes characterized by extensive bowel involvement.[32] Multiple perforations may be found, relapses are common, and the postoperative course is complicated by infections and delayed healing. Surgery performed for cholecystitis or appendicitis does not appear to worsen prognosis in the same way.

The prognosis is better in patients with cutaneous PAN without systemic involvement. This disease is benign but tends to relapse. Kato et al reported higher risk of relapse in patients with cutaneous PAN who had pretreatment cutaneous ulcers, elevated C-reactive protein level, higher absolute neutrophil count (> 4.9 × 103/μL) and neutrophil-to-lymphocyte ratio, and higher systemic immune-inflammation index.[33]

In a retrospective study of 52 patients with childhood-onset PAN who were followed for a mean of 6.2 years, 27 patients (51.9%) were in clinical remission without medication at follow-up, 17 (32.7%) were in clinical remission while on medication, and six patients (11.6%) had a persistent or relapsing disease course. Two patients (3.8%) with severe cerebral involvement died. Cranial nerve palsy occurring during the course of disease was significantly correlated with a worse prognosis. Nephrogenic hypertension at disease onset and seizures during the course of the disease were significantly associated with irreversible organ damage.[34]

Relapses were more frequent among PAN patients with severe gastrointestinal involvement in a retrospective study of 69 pediatric patients, while a higher cumulative dose of cyclophosphamide was associated with a lower relapse risk. During follow-up with a median duration of 6 years, the relapse rate was 35%. The mortality rate was 4%.[35]

HBV-related PAN

Patients who seroconvert usually recover. Once HBV-PAN goes into remission, the risk of recurrence is very low (6% in one series).[13]

HCV-related PAN

One study found that in patients with HCV-related vasculitis, HCV-PAN exhibits a more severe clinical presentation but a higher rate of clinical remission.[19]

Complications

Permanent morbidity due to PAN is relatively rare, although patients may develop peripheral neuropathy, renal insufficiency or renal failure, and/or hypertension. Fever, weight loss, and malaise are present in 50% of patients; renal failure and hypertension, in 60%; arthritis, arthralgia, and myalgia, in 64%; and peripheral neuropathy and mononeuritis multiplex, in 51%.

Complications of PAN include the following:

• Cutaneous ulcerations
• Extremity gangrene ^[36]
• Organ infarction
• Aneurysm rupture (intraorgan bleeding) - Aneurysmal ruptures have been reported to occur in the kidneys, liver, heart, pancreas, and axillary and brachial arteries. ^{[37, 38, 39, 40, 41, 42]}
• Stroke
• Encephalopathy
• Myelopathy
• Heart failure
• Myocardial infarction/li>
• Pericarditis
• Renal failure
• Gastrointestinal (GI) bleeding
• Bowel infarction
• Peripheral neuropathy

Mortality

When left untreated, the 5-year survival rate of PAN is 13%. Nearly half of patients die within the first 3 months of onset. Corticosteroid treatment improves the 5-year survival rate to 50-60%. When the steroid is combined with other immunosuppressants, the 5-year survival rate may increase to greater than 80%.

Death associated with PAN occurs as a result of uncontrolled vasculitis, infectious complications related to treatment-induced immunosuppression, and vascular complications of the disease, such as myocardial infarction and stroke. The mortality rate is higher in patients with acute abdominal syndromes.[32] Intractable hypertension contributes to morbidity and mortality rates.

In a cohort of 161 patients with HCV-related vasculitis, there was no significant difference in mortality between HCV-MC patients and those with HCV-PAN. Overall survival rates at 1, 3, and 5 years in HCV-PAN patients were 95% (95% confidence interval [CI], 0.87-1), 89% (95% CI, 0.75-0.98), and 89% (95% CI, 0.75-1), respectively.[19]

Prognostic score

In a prospective study of 342 patients with PAN, Guillevin et al found 5 factors associated with poor prognosis. They devised a 5-factors score (FFS) to predict survival and help guide treatment decisions.[43] The presence of any of the following 5 factors predicts an increased likelihood of mortality:

• Renal insufficiency (serum creatinine >1.58 mg/dL)>
• Proteinuria (>1 g/d)
• GI involvement (bleeding, perforation, infarction, pancreatitis)
• Cardiomyopathy
• CNS involvement

When the FFS is zero, the predicted mortality rate at 5 years is 11.9%. When the FFS is 1, the mortality rate is 25.9%, and when the FFS is 2 or more, the mortality rate is 45.9%.

Patients should understand that PAN can be a progressive systemic disease, and further complications and the involvement of other organ systems are quite common. Many patients attempt to discontinue their medications after initial symptomatic improvement, owing to the potential for adverse effects. Therefore, the benefits of medical treatments should be discussed clearly with the patient, in addition to the risks associated with the long-term use of immunosuppressants. The use of these medications necessitates close monitoring for many years to come.

For patient education information, see What Is Polyarteritis Nodosa?.

Polyarteritis nodosa (PAN) is an acute multisystem disease with a relatively short prodrome (ie, weeks to months).[7] Delays in diagnosis are not uncommon. The spectrum of disease ranges from single-organ involvement to fulminant polyvisceral failure. Pertinent and common historical features of PAN include the following:

Constitutional and musculoskeletal symptoms

Constitutional and musculoskeletal symptoms of PAN include the following:

• Fever
• Malaise
• Fatigue
• Anorexia and weight loss
• Myalgia
• Arthralgia in large joints or, less commonly, arthritis

Central nervous system symptoms

Transient symptoms of cerebral ischemia, including typical spells of transient monocular blindness, are the most common presenting CNS deficits of PAN. Cerebral arteritis usually presents late in the course of the disease, usually in the second to third year of the vasculitis. Cerebral arteritis may cause arterial thrombosis with cerebral ischemia or intraparenchymal or subarachnoid hemorrhage.

Global CNS dysfunction with encephalopathy and seizures results from metabolic derangements secondary to multiple organ failure. Acute or subacute myelopathy with paraparesis can occur at any cord level. Myelopathy may result, although rarely, from cord compression by an extramedullary hematoma secondary to a ruptured spinal aneurysm. Although CNS lesions usually occur 2-3 years after the onset of PAN, earlier CNS involvement has been reported.

Peripheral nervous system symptoms

Peripheral neuropathy develops in as many as 60% of patients. Vasculitic neuropathy is often asymmetrical and presents as (1) mononeuritis multiplex, (2) distal polyneuropathy, or (3) cutaneous neuropathy. It can take the form of a pure motor, pure sensory, or mixed sensorimotor polyneuropathy.

Cutaneous symptoms

Dermatologic symptoms are very common in PAN, and about 40% of patients manifest with skin lesions including rash, purpura, gangrene, nodules, cutaneous infarcts, livido reticularis, and Raynaud phenomenon. Skin involvement, which can be painful, occurs most frequently on the legs.

Gastrointestinal symptoms

GI involvement usually presents as nonspecific symptoms and signs such as abdominal pain (which may be postprandial) and nausea and vomiting, with or without obvious GI bleeding. Rare and more serious complications of PAN include bowel infarction and perforation, cholecystitis, hepatic infarction, or pancreatic infarction.

Renal symptoms

About 60% of patients with PAN have renal involvement. Flank pain may be present. Ischemic changes in the glomeruli and renal artery vasculitis can cause renal failure, hypertension, or both. A small percentage of patients may require dialysis.

Additional symptoms

Less common symptoms reported in PAN include the following:

• Genitourinary - Patients may develop pain over the testicular or ovarian area. In rare cases, testicular infarction may occur; testicular pain is usually unilateral[44]

• Cardiac - Chest pain, dyspnea, palpitations, pericarditis, myocardial infarction, and congestive heart failure; cardiac disease affects 35% of patients with PAN, but most affected patients are asymptomatic

• Ophthalmologic - Blurred vision

• Neuropsychiatric - Headache, psychosis,[45] and depression

• Muscular - Rarely, PAN may present as only skeletal muscle pain and fever[46]

Because polyarteritis nodosa (PAN) is a systemic disease, a complete examination is essential for diagnosis.

The emergence of multiple mononeuropathies in persons with PAN is an important clue to an underlying arteritis. Evidence of organ or extremity ischemia, including hypertension and renal insufficiency (renovascular disease), are further clues to the diagnosis. Lung involvement is rare and its presence should prompt a search for an alternative to PAN as the diagnosis.

Constitutional and musculoskeletal symptoms

Fever may be observed; Raynaud phenomenon may occur. A nondeforming, asymmetrical arthritis, usually involving the larger joints of the lower extremities, has been reported in PAN.

Neurologic symptoms

Neurologic symptoms in PAN include the following:

• Sensory and/or motor neuropathies - When these occur, they are usually asymmetrical

• Mononeuritis multiplex (multiple mononeuropathy) - This is the successive ischemia or infarction of "named nerves" (eg, ulnar, radial, peroneal, sural). Although nerve involvement is initially asymmetrical, the development of additional nerve lesions can cause the clinical picture to resemble symmetrical polyneuropathy. (A history of asymmetry at the onset and by electrodiagnostic studies can be helpful in this case.)[47]

• CNS involvement - Although rare (≤10% of cases), encephalopathy, focal deficits, strokes, seizures, and, sometimes, brain hemorrhages can occur.[47, 48]

Cutaneous symptoms

Cutaneous symptoms in PAN include the following[7] (see the images below):

• Livedo reticularis that does not blanch with active pressure

• Ulcerations - Especially on the lower extremities, near the malleoli and on the calf

• Digital ischemia - May be accompanied by splinter hemorrhages and, sometimes, gangrene

• Nodules - Usually on the lower extremities (like ulcers); nodules are the least common skin manifestation of PAN

  Tender, hyperpigmented, firm subcutaneous nodules with a background of livedo reticularis common in cutaneous polyarteritis nodosa (PAN).

  Tender erythematous nodules with central "punched out" ulcerations common in cutaneous polyarteritis nodosa (PAN).

  Livedo reticularis in polyarteritis nodosa (PAN).

Gastrointestinal symptoms

Gastrointestinal symptoms include the following[32] :

• Tender abdomen with or without rigidity, guarding, or diminished bowel sounds

• GI bleeding

• Bowel infarction

• Cholecystitis

Renal symptoms

Renal symptoms include the following:

• Hypertension

• Costophrenic tenderness

• Retroperitoneal or intraperitoneal hemorrhage

• Renal failure

Cardiac symptoms

Cardiac symptoms include the following:

• Hypertension

• Tachycardia out of proportion to fever

• Pericardial friction rub

• Arrhythmias

• Congestive heart failure

Ophthalmologic symptoms

Ophthalmologic symptoms of PAN include the following:

• Retinal vasculitis

• Retinal detachment

• Cotton-wool spots

Additional symptoms

The patient may experience testicular tenderness. Psychiatric symptoms, specifically psychosis and depression, may occur.

Unusual presentations

PAN has been reported to present in the muscles alone. One patient had features suggesting polymyositis[49] ; an additional patient had disease limited to the soleus and gastrocnemius muscles of his calf.[50]

Evidence of peripheral neuropathy should be sought carefully with history and electromyography (EMG), since it is a common complication of polyarteritis nodosa (PAN), being found in as many as 60% of patients. Mononeuritis multiplex is the most common form of PAN neuropathy, but other forms can be present.

Many neurologic and systemic disorders can present with headache. Pathologic headaches are often difficult to differentiate from benign headaches solely on clinical grounds. Severe, persistent headaches, with or without neurologic deficit, warrant complete neurologic evaluation, including brain-imaging studies.

Even though stroke is a late complication in many cases of PAN, it certainly can occur early. PAN and other vasculitic diseases should be considered in many patients with stroke with multiple foci or a combination of hemorrhage and infarction.

Electroencephalography (EEG) may show nonspecific findings of generalized slow wave activity during periods of encephalopathy or toxic delirium.

Laboratory studies

Laboratory findings in PAN are nonspecific but can help to establish the systemic nature of the disease. Findings include the following:

• Elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein - These markers may be useful in evaluating some patients for active disease but do not correlate with activity in all patients[7]

• Leukocytosis, normochromic anemia, or thrombocytosis

• Hepatitis B surface antigen and hepatitic C serologies

• Elevated creatinine level

• Mild proteinuria

• Elevated levels of liver enzymes

• Hypergammaglobulinemia - Found in 30% of patients with PAN

Cryoglobulins, circulating immune complexes, and decreased levels of serum complement (ie, C3, C4) may be observed in patients with HBV-related PAN but are otherwise uncharacteristic of idiopathic PAN.

Cerebrospinal fluid findings often are usually normal in PAN, but polymorphonuclear pleocytosis can be seen when meningeal signs are present.

ANCA testing is rarely positive in PAN. If ANCA testing is positive, the tests more commonly show a perinuclear (rather than cytoplasmic) pattern and antibodies to proteinase-3 and myeloperoxidase will be negative.[7] Antinuclear antibodies and rheumatoid factor are generally negative, but low positive titers may be detected.[7]

Angiography

Angiography should be considered if clinically involved tissue is inaccessible. Conventional angiography is preferred. Computed tomography angiography or magnetic resonance angiography are not as sensitive for smaller abnormalities but can reveal larger aneurysms and stenoses.[20, 54]

Positive findings include aneurysms and stenoses of medium-sized vessels. (Note that these findings are not pathognomonic for PAN but rarely occur in MPA).[20]

Aneurysms are most commonly found in the kidney, liver, and mesenteric arteries, and their presence is associated with more severe and extensive disease.

Angiography has a higher yield in cases with evidence of intra-abdominal involvement, including clinical symptoms or signs and laboratory abnormalities of liver or renal function. Arteriograms reveal microaneurysms in the small- and medium-sized arteries of the kidneys and abdominal viscera.

For images and discussion, see Imaging in Polyarteritis Nodosa

Other studies

Turkish investigators report on the use of Doppler ultrasonography in the diagnosis of seven cases of childhood PAN. These authors recommend that Doppler ultrasound be considered in the first-line approach in the diagnosis of PAN, particularly in children.[55]

Computed tomography (CT) scanning and magnetic resonance imaging (MRI) of the GI tract may show nonspecific abnormal findings, including bowel wall thickening, mesenteric vascular engorgement, ascites, bowel obstruction, or diffuse mucosal fold thickening. For PAN with CNS involvement, new techniques, including susceptibility for blood, diffusion, and perfusion-weighted images, make MRI a very powerful modality for differentiating intracranial hemorrhage from potentially reversible ischemia (since PAN lesions are typically irreversible and progressive).

Electromyography (EMG) and nerve conduction studies (NCS) can be useful in revealing axonal nerve involvement and identifying asymmetry in nerve involvement. EMG/NCS can be used to guide a nerve biopsy, if necessary.[20, 47]

When possible, a biopsy sample of involved, accessible tissue should be collected to aid in the diagnosis. The most accessible tissue sites for biopsy include the skin, sural nerve, testes, and skeletal muscle. The results of a retrospective study suggest muscle biopsy may be helpful for the diagnosis of systemic vasculitides, even in the absence of myalgias or creatine kinase level elevation.[56] Kidney biopsy carries a risk of aneurysmal rupture and bleeding.

Biopsies should be performed correctly to allow for adequate sampling of medium-sized arteries. Biopsy samples of skin nodules or ulcers should be collected at the edges and include deep dermis and subcutaneous fat.[7] In addition, nearby central ulcer areas, including subcutaneous tissue, should be included to increase diagnostic yield.[57]

Biopsy of small arteries from the abdominal viscera in conjunction with arteriography facilitates identification of the vasculitis.

Combined nerve and muscle biopsy is preferred. Biopsy of the sural nerve should be full-thickness to include epineural vessels.[47]

Histology reveals a focal necrotizing arteritis of generally mixed cellular infiltrate within the vessel wall. Nerve biopsy characteristically reveals axonal degeneration and fiber loss. Segmental demyelination may also be seen.[47]

When an inflammatory infiltrate is present around a vessel wall without necrotizing changes, features on nerve biopsy that strongly suggest angiopathic nerve injury include Wallerian degeneration and fiber loss in part of a fascicle, perineural necrosis, and neoangiogenesis around the epineurium or perineurium.[47] An occlusion of a muscular artery and leukocytic infiltrate is seen in the slide below.

Polyarteritis nodosa (PAN) is characterized by fibrinoid necrosis of the arterial wall with a leukocytic infiltrate. In this slide, a large, pale occlusion of a muscular artery can be seen. Within this collagenous tissue is a leukocytic infiltrate, which is the hallmark of PAN. Courtesy of Urbana Atlas of Pathology.

Despite a general recommendation to avoid kidney biopsy owing to a risk of aneurysmal rupture and bleeding, renal biopsy abnormalities in PAN patients have been described. Biopsies from 15 patients with PAN with no or mild renal involvement at study entry only showed abnormalities in one patient. This patient, with HBV-related PAN, had renal vasculitis and membranoproliferative glomerulonephritis (MPGN).[58]

The Birmingham Vasculitis Activity Score and disease extent index have been validated to assess the level of disease activity in children with vasculitis, including PAN.[59]

The treatment of polyarteritis nodosa (PAN) has improved dramatically. Previously, untreated PAN was usually fatal within weeks to months, with mortality often associated with kidney failure, cardiac complications, or gastrointestinal (GI) complications. Therefore, early diagnosis and treatment are critical in PAN.

Currently, corticosteroids are the cornerstone of treatment. The addition of cyclophosphamide is the standard of care for patients with idiopathic PAN whose disease is steroid refractory or includes major organ involvement. This combination can provide prolonged survival for these patients.

Cyclophosphamide is not routinely recommended in hepatitis B–related PAN, as the use of steroids with cyclophosphamide in these patients has been demonstrated to enhance viral replication. Instead, treatment for hepatitis B–related PAN consists of schemes that include corticosteroids with antiviral agents and plasmapheresis. Antiviral drugs used include vidarabine or interferon alpha-2b.

Biologic agents have been investigated in patients with steroid-refractory and recurrent PAN. Case reports have described response to treatment with tumor necrosis factor inhibitors,[17] including infliximab[60, 61] and etanercept.[62]  The interleukin-6 antagonist tocilizumab has been used successfully in refractory cases.[63, 64, 65] Single case reports describe successful use of the anti-CD20 agent rituximab[66] and the Janus kinase (JAK) inhibitor tofacitinib in refractory PAN.[66] Plasma exchange has been used in a few patients with severe PAN.[67]

Surgical care

Surgery may be necessary for GI manifestations of PAN, including bowel ischemia, cholecystitis, and appendicitis. Microcoil embolization of cerebral aneurysm may be indicated. Postsurgical care may be needed for patients with PAN who develop bowel infarction.

The optimal management for polyarteritis nodosa (PAN) has not been established. Trial results in PAN are difficult to interpret, as many were conducted prior to the creation of the CHCC definition and included patients with MPA and Churg-Strauss syndrome. Corticosteroids have shown a clear benefit in these vasculitides, resulting in improvement of 5-year survival rates to 50%.[68] Cyclophosphamide may improve the survival rate in patients with severe disease.[69]

Glucocorticoids

No standard regimen for steroid dosing exists in PAN. It is common practice to use high-dose oral prednisone at 1 mg/kg/day.[69] Methylprednisolone could also be given, for example, at a pulse dose of 1,000 mg intravenously daily, repeated over 3 days, prior to initiating oral prednisone.

Tapering of the prednisone can begin as early as 1 month later if the patient's clinical status and ESR normalize. Prednisone taper can continue over the next 12 months until it has been stopped.

When prednisone is combined with cyclophosphamide, the steroid dose is tapered more rapidly, if possible, to reduce the increased risk of infection.

Patients receiving long-term steroid therapy are at risk for glucocorticoid-induced osteoporosis. Calcium and vitamin D supplementation should be given. Bisphosphonates are indicated in patients in whom glucocorticoids are being initiated.

Cyclophosphamide

Cyclophosphamide therapy may be initiated in patients with serious involvement of major organs or steroid-refractory PAN.[7] Cyclophosphamide can be given as a monthly intravenous (IV) pulse or as a daily pill. IV pulse cyclophosphamide has a rapid onset of action, allows a lower cumulative dose to be administered, and exposes the patient to potential toxicity for shorter periods than an oral regimen. In some cases, however, daily oral cyclophosphamide is needed for a satisfactory therapeutic response.

Administration of IV or oral cyclophosphamide requires close monitoring of blood counts and renal function. Dosing should be adjusted accordingly.

Potential toxicities of cyclophosphamide to be discussed with patients include an increased risk of bladder cancer, hematologic malignancies, hemorrhagic cystitis, bladder fibrosis, bone marrow suppression, and gonadal failure.

Guillevin et al suggested that patients with a 5-factors score (FFS) of zero may be treated successfully with corticosteroids alone, with cyclophosphamide administered only as second-line treatment in cases of persistent disease, relapse, or inability to taper steroids. They recommend that, cyclophosphamide should be part of the initial regimen in combination with steroids in patients with an FFS of 1 or more.[43]

Therapy with steroids and cyclophosphamide places patients at high risk for infections. Prophylaxis for Pneumocystis jirovecii pneumonia (PCP) is encouraged in these patients.

PAN in the setting of HBV infection is a special situation. Standard therapies for PAN, including glucocorticoids and cyclophosphamide, enhance prognosis and control of the polyarteritis. However, they are also associated with persistent HBV infection and failure to seroconvert from hepatitis B surface antigen to hepatitis B surface antibody and from hepatitis B e antigen to hepatitis B e antibody. Thus, antiviral medications are essential in the treatment of these patients.

Guillevin and colleagues studied therapeutic strategies, including steroids, antivirals, and plasma exchange (plasmapheresis), and found the regimens below to be successful.[70]

Prednisone (1 mg/kg/d) is administered for the first week. Alternatively, methylprednisolone pulse (15 mg/kg/d for 1-3 d) is used in severely ill patients. Steroids are then tapered rapidly and withdrawn at the end of week two.

Antiviral agents are begun after steroid withdrawal to enhance immunologic clearance of HBV-infected hepatocytes and favor seroconversion. Agents studied included vidarabine,[71] which was replaced by interferon-α2b,[72] and later by lamivudine.[70] It is recommended that lamivudine be continued for 6 months or stopped at the time of seroconversion to hepatitis B surface antibody. (These recommendations may change; combination treatment and prolonged courses of antivirals are currently being investigated in the management of HBV).

Plasma exchanges are used as adjunctive therapy with antivirals. Plasma exchange is performed 3 times per week for 3 weeks, twice weekly for 2 weeks, and then once weekly. Plasma exchanges are stopped once seroconversion from hepatitis B e antigen to hepatitis B e antibody occurs or after clinical recovery is maintained for 2-3 months.

Isolated case reports have demonstrated benefit from the combination of interferon-α2b and lamivudine[73, 74] or the addition of famciclovir and granulocyte-macrophage colony-stimulating factor in patients in whom antiviral therapy alone could not seroconvert and clear their HBV infection.[75]

Critically ill patients who are not responding to treatment may require prolonged steroids and cyclophosphamide in the setting of lamivudine therapy.[70]

Given that the existence of this entity has been controversial, limited data exist to support appropriate treatment. In a French cohort of 161 patients with HCV-associated vasculitis, 31 patients were diagnosed with PAN. Over half the patients were treated with antiviral therapy and nearly half received corticosteroids. Other treatments included rituximab (22.6%), plasmapheresis (35.5%), and immunosuppression with cyclophosphamide or azathioprine (16.1%).[59] More patients with HCV-related PAN achieved clinical remission in this group than those with HCV-associated mixed cryoglobulinemia (79.3% vs 57.5%). Remission was closely correlated with successful HCV clearance. A higher frequency of relapse was seen in the HCV-related PAN patients than in HCV-associated mixed cryoglobulinemia patients (18% at 1 year vs 45% at 1 year).

As with systemic PAN, the optimal management for cutaneous PAN has not been established. Expert recommendations include agents such as NSAIDs, colchicine, and dapsone, if possible.[76] In more severe cases, steroids and stronger immunosuppressive agents such as cyclophosphamide may be used. Success with mycophenolate mofetil in 2 siblings with treatment-refractory, childhood-onset PAN has also been reported.[77] Methotrexate, azathioprine, and mycophenolate mofetil have been reported as effective therapeutic options after remission is achieved.[78]

Reports of success with other agents such as mizoribine,[79] mycophenolate, and pentoxifylline[80] have been published.

Consultation with a rheumatologist is appropriate. Other consultants should be sought according to organ system involvement and include the following:

• Cardiologist
• Gastroenterologist
• Dermatologist
• Nephrologist
• Neurologist
• Physiatrist - Physical and occupational therapies are initiated promptly; once the patient's condition is stable, ambulation and maximization of activities of daily living are the chief goals

   

Patients with polyarteritis nodosa (PAN) should be monitored closely for evidence of relapse or symptoms indicating new organ involvement. Cyclophosphamide dosing should be adjusted according to the level of immunosuppression. The patient’s complete blood count (CBC) should be checked 10-14 days after IV cyclophosphamide is administered and every 2 weeks once oral cyclophosphamide is initiated.

The American College of Rheumatology (ACR) and the Vasculitis Foundation (VF) have released joint guidelines on the management of polyarteritis nodosa (PAN).[81]

Imaging

The guidelines offer the following conditional recommendations[81] :

• Abdominal vascular imaging can aid in establishing a diagnosis and determining the extent of disease
• Follow-up abdominal vascular imaging for patients with a history of severe abdominal PAN who become asymptomatic
• A deep-skin biopsy is preferred over a superficial skin punch biopsy to aid in establishing a diagnosis of PAN involving the skin
• A combined nerve and muscle biopsy is preferred over a nerve biopsy alone to aid in establishing a diagnosis of peripheral neuropathy and suspected PAN
• Serial neurologic examinations instead of repeated electromyography/nerve conduction studies (eg, every 6 months) should be used to monitor disease activity in patients with a history of peripheral motor neuropathy secondary to PAN

Treatment

Conditional recommendations for patients with newly diagnosed severe active disease include[81] :

• Initiating treatment with IV pulse glucocorticoids (GCs) over high-dose oral GCs
• Initiating treatment with cyclophosphamide and high-dose GCs over high-dose GCs alone
• Initiating treatment with cyclophosphamide and GCs over rituximab and GCs
• Treat with other non-GC immunosuppressive agents and GCs over GCs alone for patients unable to tolerate cyclophosphamide
• The use of plasmapheresis combined with cyclophosphamide and GCs is NOT recommended 

For patients with newly diagnosed nonsevere active disease, the guidelines conditionally recommend treatment with non-GC immunosuppressive agents and GCs over GCs alone. For patients with PAN in remission who are receiving non-GC immunosuppressive therapy, discontinuation of non-GC immunosuppressive agents after 18 months over continued (indefinite) treatment is conditionally recommended.[81]

Physical therapy is conditionally recommended for patients with nerve and/or muscle involvement.

The guidelines strongly recommend treatment with tumor necrosis inhibitors over GCs alone for patients with DADA2.

Immunosuppression continues to be the standard therapy for polyarteritis nodosa (PAN). Corticosteroids plus cyclophosphamide (in the case of steroid-refractory disease or major organ involvement) can prolong survival for patients with idiopathic PAN.In contrast, for hepatitis B–related PAN, treatment consists of corticosteroids for early, initial control followed by plasmapheresis and antiviral agents. Stronger immunosuppression using a combinations of steroids and cyclophosphamide is typically avoided in these cases as it can enhance viral replication.

Class Summary

These agents have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Methylprednisolone (Solu-Medrol, Medrol, A-Methapred)

Methylprednisolone is a highly potent synthetic glucocorticoid that causes diverse metabolic effects and modifies the body's immune responses to various stimuli.

Prednisone

Prednisone, a synthetic glucocorticoid analog, acts as a potent immunosuppressant via its effects on multiple cell types and cytokines. It has anti-inflammatory, antipyretic, and, often, analgesic effects in addition to often-adverse metabolic effects.

Class Summary

These agents are chemically related to nitrogen mustards. Because of its immunomodulatory properties, cyclophosphamide is used in conjunction with glucocorticoids, thus reducing the need for higher corticosteroid doses.

Cyclophosphamide

As an alkylating agent, the mechanism of action of the active metabolites of cyclophosphamide may involve cross-linking of deoxyribonucleic acid (DNA), which may interfere with the growth of normal and neoplastic cells.

Methotrexate (Rheumatrex, Trexall)

Methotrexate is a potent anti-inflammatory medication with antiproliferative effects used as a steroid-sparing agent.