Approach Considerations
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.
Idiopathic (Non–HBV-Related) PAN
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.
HBV-Related PAN
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]
HCV-Related PAN
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).
Cutaneous PAN
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.
Consultations
Consultation with a rheumatologist is appropriate. Other consultants should be sought according to organ system involvement and include the following:
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Cardiologist
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Gastroenterologist
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Dermatologist
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Nephrologist
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Neurologist
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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
Long-Term Monitoring
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.
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Nonspecific, firm, tender subcutaneous nodules without livedo reticularis and/or systemic involvement may be the first sign of polyarteritis nodosa (PAN).
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Tender, hyperpigmented, firm subcutaneous nodules with a background of livedo reticularis common in cutaneous polyarteritis nodosa (PAN).
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Tender erythematous nodules with central "punched out" ulcerations common in cutaneous polyarteritis nodosa (PAN).
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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.
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Livedo reticularis in polyarteritis nodosa (PAN).
