Disclosures: Peter A Merkel, MD, MPH Grant/Research/Clinical Trial Support: Actelion [scleroderma]; Bristol Myers Squibb [vasculitis (abatacept)]; Celgene [vasculitis (apremilast)]; Chemocentryx [vasculitis (experimental agent)]; Genentech/Roche [vasculitis (rituximab)]; GlaxoSmithKline [vasculitis (belimumab)]. Consultant/Advisory Boards: Actelion [scleroderma]; Alexion [vasculitis]; Chemocentryx [vasculitis]; Genzyme/Sanofi [vasculitis, scleroderma]; GlaxoSmithKline [vasculitis (belimumab)]. Gene G Hunder, MD Nothing to disclose. Eric L Matteson, MD, MPH Grant/Research/Clinical Trial Support: Centocor-Janssen [Rheumatoid arthritis]; Celgene [Rheumatoid arthritis (Aprimilast)]; Amgen [Rheumatoid arthritis (Etanercept)]; Genentech [Rheumatoid arthritis (Tocilizumab)]; Mesoblast [Rheumatoid arthritis (Mesoblast)]; Pfizer [Rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica (Tofacitinib, tocilizumab)]; Novartis [Rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica (Certolizumab, secukinumab, canakinumab)]; Regeneron-Sanofi [Rheumatoid arthritis, giant cell arteritis, polymyalgia rheumatica (Sarilumab)]; Roche [Giant cell arteritis, polymyalgia rheumatica (Tocilizumab)]. Monica Ramirez Curtis, MD, MPH Nothing to disclose.
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INTRODUCTION — Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis that predominantly affects medium-sized muscular arteries and often involves small muscular arteries . The approach to treatment of PAN depends upon the following variables, which require assessment before beginning therapy:
●The level of disease severity
●The presence of isolated cutaneous PAN or other isolated/single-organ disease
●The presence or absence of viral hepatitis
The optimal therapy of PAN remains uncertain, and studies of treatment for PAN have been complicated by the admixture of patients with PAN, microscopic polyangiitis (MPA), and sometimes eosinophilic granulomatosis with polyangiitis (Churg-Strauss) within study cohorts [2-4]. The efficacy of glucocorticoids in the majority of patients with mild disease, and of glucocorticoids plus cyclophosphamide in patients with more severe disease, has been well-demonstrated in observational studies in PAN, but there are few randomized trials [2,3,5-9]. The treatment approach in PAN is also derived from indirect evidence of the efficacy of various medications and drug regiments in other forms of necrotizing vasculitis, particularly MPA and granulomatosis with polyangiitis (Wegener’s). (See "Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis" and "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis".)
The prognosis in untreated PAN is relatively poor, with historical one- and five-year survival rates in patients diagnosed between 1948 and 1962 of approximately 50 and 13 percent [5,6]. The outcome has subsequently improved, with approximately 80 percent survival at five years reported in a separate cohort diagnosed between 1963 and 2005 .
The treatment and prognosis of polyarteritis nodosa will be reviewed here. The clinical manifestations, diagnosis, and classification of PAN are presented separately. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)
Baseline evaluation — Prior to treatment for polyarteritis nodosa (PAN), patients should undergo a careful history, physical examination, and laboratory evaluation; this diagnostic evaluation includes determination of the extent and severity of organ system involvement, testing for viral hepatitis (serum hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and hepatitis C antibody), and confirmation of the diagnosis with a tissue biopsy or angiography. Patients in whom the diagnosis was established without a detailed examination and testing still require such testing to obtain the information needed to determine the extent of disease, to evaluate for comorbidities, and to select the most appropriate therapeutic interventions. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)
Severity of disease
Mild versus more severe disease — An important factor in determining which medications will be used and the doses employed is whether the patient has only mild disease or disease that is of greater severity. We use the following definitions, which correspond to distinctions made in clinical trials that have examined the benefits of different agents [3,4,7,10]:
●Mild disease – Patients with mild disease include those with constitutional symptoms, arthritis, anemia, and skin lesions, but with normal renal function and an absence of significant cardiac, neurologic, gastrointestinal, or other organ- or life-threatening manifestations. Patients with mild disease should generally be treated initially with glucocorticoids alone. (See 'Mild PAN' below.)
●Moderate to severe disease – Patients with moderate to severe disease include those who typically exhibit more serious disease manifestations than patients with mild disease, such as any degree of renal insufficiency, new or worsened hypertension considered secondary to the vasculitis, symptomatic arterial stenosis, aneurysms, or any ischemic disease (eg, limb, cardiac, gastrointestinal, and central nervous system ischemia). These patients are generally treated initially with glucocorticoids plus a second immunosuppressive agent, typically cyclophosphamide. Subsequent management for the maintenance of remission usually involves switching from cyclophosphamide to an alternative, less toxic, immunosuppressive agent. (See 'Moderate and severe PAN' below.)
The goals of therapy are the same in both mild and moderate to severe disease. The aim is to achieve remission, defined as the absence of active disease, including the resolution of potentially reversible symptoms and findings and the prevention of further progression of arterial lesions or organ damage.
Isolated versus multi-organ disease — The approach to isolated or single-organ PAN may differ from the approach to multisystem disease, depending upon the affected organ or tissue.
●Cutaneous PAN – PAN confined to the skin is generally treated similarly to mild systemic PAN. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Skin disease' and 'Isolated cutaneous PAN' below.)
●Isolated/single-organ PAN – Patients with isolated or single-organ involvement, sometimes identified at the time of an operative procedure, may not require further therapy, but should be evaluated for evidence of other manifestations and monitored subsequently. (See 'Isolated/single-organ PAN' below.)
ASSOCIATED HEPATITIS B OR C INFECTION — Patients with both vasculitis and hepatitis virus infection also benefit from treatment with antivirals, but the timing of therapy relative to the use of immunosuppressive agents depends upon the severity of the vasculitis. In patients in whom polyarteritis nodosa (PAN) is associated with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, the major focus of therapy is the use of antiviral agents for treatment of the underlying viral disorder. PAN continues to be associated with HBV in a substantial minority of cases, although this rate is decreasing in countries with comprehensive HBV vaccination programs. Many fewer cases of PAN are associated with HCV, which should be differentiated from HCV-associated cryoglobulinemic vasculitis. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Etiology' and "Overview of the management of hepatitis B and case examples", section on 'Who should be treated and how' and "Overview of the management of chronic hepatitis C virus infection" and "Clinical manifestations and diagnosis of the mixed cryoglobulinemia syndrome (essential mixed cryoglobulinemia)".)
In patients with mild PAN and evidence of infection with HBV or HCV, we suggest treating initially with antivirals rather than using immunosuppressive medications. Some patients with severe manifestations of hepatitis virus-associated PAN may benefit from short-term treatment with glucocorticoids and plasma exchange until antiviral therapy becomes effective . There are no randomized trials or large case series to guide decision-making in such patients; we base our approach upon the available trials in viral hepatitis and clinical experience. The treatment of HBV and HCV and the treatment of renal disease due to PAN in patients with one of these infections are discussed in detail separately. (See "Overview of the management of hepatitis B and case examples", section on 'Who should be treated and how' and "Renal disease associated with hepatitis B virus infection", section on 'Polyarteritis nodosa (PAN)' and "Overview of the management of chronic hepatitis C virus infection" and "Overview of renal disease associated with hepatitis C virus infection", section on 'Polyarteritis nodosa'.)
In patients with persistent manifestations of PAN who have an inadequate response of the PAN to treatment for viral hepatitis alone or are intolerant of such treatment, we treat the manifestations of the vasculitis with glucocorticoids and other immunosuppressive medications, depending upon the severity of the vasculitis, using the regimens that would be employed in patients without viral infection (see 'Mild PAN' below and 'Moderate and severe PAN' below). In patients with viral infection who are treated with glucocorticoids and immunosuppressive medications, particular attention should be given to the need for close monitoring of the status of the underlying viral infection and the potential for added toxicity from the immunosuppressive therapies.
MILD PAN — Patients with mild disease or isolated cutaneous disease, and without evidence of hepatitis, can usually be treated initially with glucocorticoids alone, although about half of these patients will require an additional agent at some point during their treatment. The treatment approach in patients with hepatitis B or C infection is discussed separately. (See 'Initial treatment of mild PAN' below and 'Resistant to glucocorticoids alone' below and 'Associated hepatitis B or C infection' above.)
Initial treatment of mild PAN — In patients with relatively mild disease and those with isolated cutaneous disease, we suggest initial monotherapy with oral glucocorticoid (eg, prednisone 1 mg/kg daily, up to a maximum of 60 to 80 mg daily). The initial dose should usually be continued for four weeks, at which time tapering of the glucocorticoids should begin if substantial improvement has occurred. In such patients, substantial improvement would be characterized by findings such as resolution of arthritis/arthralgia, skin lesions, and constitutional symptoms; and by the absence of new disease manifestations and of progression of neuropathy, renal disease, or other arterial lesions. We then taper the dose of prednisone steadily, but fairly slowly as long as the response is maintained, until a dose of 20 mg/day is reached by approximately month three to four. The tapering schedule is then slowed (eg, dose reduction by 2.5 mg daily every 14 days). This results in an overall course of approximately six to eight months until glucocorticoids are discontinued. (See 'Mild versus more severe disease' above and 'Isolated cutaneous PAN' below.)
This approach is based upon the potential benefit of glucocorticoids alone seen in retrospective studies [6-8] and in patients with mild polyarteritis nodosa (PAN) and microscopic polyangiitis in the nonrandomized initial phase of a randomized trial . As examples:
●A retrospective analysis of patients with PAN that was not limited to those with mild disease found that patients treated with glucocorticoids alone, when compared with clinically similar patients who did not received glucocorticoids, experienced substantially longer median survival (63 versus 3 months) and five-year survival (53 versus 12 percent) . Glucocorticoids have not been compared with treatment with placebo alone in a randomized trial.
●In a randomized trial of patients with mild PAN or microscopic polyangiitis designed to compare cyclophosphamide and azathioprine in patients who had sustained disease or relapse despite glucocorticoid therapy, 79 percent of patients achieved remission with initial glucocorticoid therapy prior to the randomized trial period ; half of these patients had a sustained remission without requiring additional immunosuppression.
Alternatively, some experts advocate longer treatment courses with glucocorticoids, especially if no other immunosuppressive agent is prescribed concurrently, but trials have not been performed to prospectively compare the long-term outcomes of different durations of therapy. Some patients may require a slower taper.
Those who respond to glucocorticoids alone are spared the risk of adverse effects associated with the use of cyclophosphamide or other immunosuppressive drugs. However, treatment with glucocorticoids may be associated with multiple adverse effects. The risks of systemic glucocorticoids and prophylaxis for glucocorticoid-induced osteoporosis are discussed in detail separately. (See "Major side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
Resistant to glucocorticoids alone — In patients with mild disease or isolated cutaneous PAN who are resistant to or intolerant of the dose of glucocorticoids required for disease control, we suggest the addition of either azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly) to glucocorticoid therapy to allow use of a lower dose of glucocorticoids while achieving or maintaining disease control. Such patients include those who do not respond to glucocorticoids alone, whose glucocorticoid dose cannot be tapered to an acceptable level (eg, prednisone ≤10 mg/day) without experiencing a relapse of disease, who are at high risk of adverse effects for the expected treatment course with glucocorticoids, or in whom the adverse effects of continued glucocorticoids in the dose being used are unacceptable. The choice between methotrexate and azathioprine depends upon the individual toxicity profiles, and patient and clinician preferences regarding dosing and administration of the drugs. Methotrexate is likely faster-acting, but should be avoided in patients with renal disease or hepatitis. We thus prefer azathioprine in patients with renal disease and in patients with hepatic disease, who should be closely monitored for hepatotoxicity.
In patients with mild disease who require an immunosuppressive agent in addition to glucocorticoids, we suggest treatment with the added immunosuppressive agent for at least one year following attainment of clinical remission, based upon our clinical experience in patients with PAN and other forms of systemic vasculitis. As with other systemic vasculitides, some patients may require an extended course of treatment or resumption of treatment with low-dose glucocorticoids (≤10 mg/day of prednisone) to prevent recurrence of mild symptoms; low-dose glucocorticoids may be required even in patients also receiving another immunosuppressive agent. The approach to tapering of the glucocorticoids is the same as in patients who do not require an additional immunosuppressive agent. (See 'Initial treatment of mild PAN' above.)
There are few randomized trials in patients with PAN that have directly compared the efficacy of azathioprine, methotrexate, cyclophosphamide, and mycophenolate, but we generally avoid the use of cyclophosphamide in patients with mild PAN. One small randomized trial has shown similar benefit but lower toxicity with azathioprine compared with cyclophosphamide in such patients . Additionally, cyclophosphamide has greater toxicity compared with azathioprine or methotrexate in our experience in PAN and in trials in other forms of systemic necrotizing vasculitis, as well as in observational studies [5,8,9]. We prefer to use either methotrexate or azathioprine over mycophenolate (2000 to 3000 mg/day) [12-16]. Mycophenolate has been shown to be less efficacious than azathioprine for maintenance of remission in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis , but there are no trial data in PAN to directly inform practice.
MODERATE AND SEVERE PAN — We generally treat patients with moderate to severe polyarteritis nodosa (PAN) with both high-dose glucocorticoids and a second immunosuppressive drug, such as cyclophosphamide, followed by azathioprine or methotrexate for remission maintenance. (See 'Initial treatment of moderate and severe PAN' below and 'Remission-maintenance immunosuppression' below.)
Patients with concomitant viral hepatitis and moderate to severe PAN may require an initial course of glucocorticoid and immunosuppressive therapy before or concurrently with initiation antiviral medications. The goal of the glucocorticoid and immunosuppressive treatment in this setting is to treat the acute inflammatory process and stabilize the patient until the antiviral therapy becomes effective. The treatment approach in patients with hepatitis B or C infection is discussed separately. (See 'Initial treatment of mild PAN' above and 'Resistant to glucocorticoids alone' above and 'Associated hepatitis B or C infection' above.)
Initial treatment of moderate and severe PAN — In patients with moderate to severe disease (eg, any evidence of renal insufficiency, significant proteinuria, gastrointestinal, cardiac, or neurologic involvement) we recommend treatment with both glucocorticoids and cyclophosphamide. (See 'Glucocorticoid regimen' below and 'Cyclophosphamide regimen' below.)
This approach is supported by observations from long-term follow-up studies in several cohorts of patients with PAN and other vasculitides that patients with more serious disease manifestations (eg, renal insufficiency, cardiac disease, mesenteric artery ischemia) had better outcomes, including rates of survival, when treated with an initial combination of cyclophosphamide and glucocorticoids compared with those who were treated with glucocorticoids alone [3,4,6,8]. In our experience, use of oral and intravenous cyclophosphamide results in a similar degree of benefit. While the comparative efficacy of treatment with oral and intravenous cyclophosphamide has been studied in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis, similar comparisons in patients with PAN have not been performed [17-19].
Additionally, one randomized trial of patients with moderate to severe disease, involving 18 patients with PAN and 47 with microscopic polyangiitis compared treatment with 12 or 6 monthly pulses of cyclophosphamide, in addition to glucocorticoid therapy; the group treated with 12 monthly pulses of cyclophosphamide had a reduced risk of relapse and a higher event free survival rate compared with those receiving only six monthly pulses over a mean follow-up period of 32 months (hazard ratios 0.34 and 0.44, respectively) . Mortality between the groups did not differ. This study did not include a remission-maintenance regimen with an alternative immunosuppressive regimen, and some toxicities of cyclophosphamide only become apparent several years after treatment (eg, premature ovarian failure or bladder cancer).
Further support for the use of cyclophosphamide for remission-induction is more indirect and is based upon randomized trials using these medications in patients with other forms of necrotizing vasculitis. (See "Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis" and "Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)
Glucocorticoid regimen — We use the following glucocorticoid regimens, together with the use of cyclophosphamide, which depend upon the severity of disease:
●In patients with moderate to severe disease, but without organ- or life-threatening involvement or progressive mononeuritis multiplex, we initiate therapy with orally administered glucocorticoids (prednisone 1 mg/kg), using the same treatment regimen as outlined for patients with mild disease, with a gradual taper over six to eight months. (See 'Initial treatment of mild PAN' above.)
●In patients with severe disease, manifested by organ- or life-threatening disease or progressively worsening mononeuritis multiplex, we initiate glucocorticoid therapy with intravenous methylprednisolone (7 to 15 mg/kg to a maximum of 500 to 1000 mg administered intravenously once daily for three days), followed by the oral prednisone regimen. Pulse therapy provides more rapid control of disease, in our experience. This approach is also supported by other experts, but there are no randomized trials comparing pulse with high-dose oral glucocorticoid therapy in patients with PAN .
Cyclophosphamide regimen — We administer intravenous pulse therapy with cyclophosphamide (600 mg/m2) every two weeks for three doses, in addition to the glucocorticoid regimen, then every four weeks for at least four months and until a stable remission has been achieved, but for no greater than 12 months. An alternative regimen favored in patients with severe PAN by some experts, although it has not been formally evaluated in this disorder, is the “CYCLOPS” regimen of intravenous cyclophosphamide (15 mg/kg) administered at weeks zero, two, and four, and then every three weeks . This dosing schedule was comparable to oral cyclophosphamide (2 mg/kg/day) for induction of remission of ANCA-associated vasculitis (granulomatosis with polyangiitis [Wegener’s], which is abbreviated as GPA, and microscopic polyangiitis [MPA]) and has been adopted at some centers for treatment of PAN.
The optimal route, dose, or duration of treatment with cyclophosphamide for PAN is uncertain, and there are no randomized trials comparing intravenous and oral routes of therapy for PAN. However, intravenous cyclophosphamide has been used extensively in this disorder [3,7,10,20,22]. Based upon data in other forms of vasculitis and our experience, we generally avoid courses of cyclophosphamide longer than four months if remission has been achieved by that time.
We prefer intravenous over oral therapy for most patients, based upon its lower cumulative dose and potentially reduced risk of bone marrow, bladder, ovarian, and testicular toxicity. However, oral therapy with cyclophosphamide (2 mg/kg/day) is an alternative preferred by some patients for its convenience and some experts because of the long experience with this approach in ANCA-associated vasculitis, such as GPA and MPA. (See "General principles of the use of cyclophosphamide in rheumatic and renal disease" and "Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis".)
Treatment with cyclophosphamide (oral or intravenous) is associated with a number of potential adverse effects, including cytopenias, gastrointestinal upset, alopecia, amenorrhea, infertility (in men and women) and premature ovarian failure, myelodysplasia, cardiomyopathy, hemorrhagic cystitis, and an increase in the risk of malignancy, especially bladder cancer. For all cyclophosphamide regimens, dose reductions are necessary to adjust for renal insufficiency, advanced age, and evidence of bone marrow suppression and other toxicities. The adverse effects and use of cyclophosphamide, including monitoring and prevention of adverse effects, and strategies for dose adjustment in different clinical settings including renal insufficiency, are discussed in detail separately. (See "General principles of the use of cyclophosphamide in rheumatic and renal disease" and "General toxicity of cyclophosphamide in inflammatory diseases".)
Resistant disease — Infrequently, patients may not respond adequately to glucocorticoids and cyclophosphamide treatment. In patients with moderate to severe PAN who have ongoing severe or worsening disease that is not controlled by treatment with glucocorticoids and cyclophosphamide within two to three months, we treat with pulse glucocorticoids (eg, 1000 mg methylprednisolone administered intravenously daily for three days), followed by prednisone (1 mg/kg daily taken orally), and switch from cyclophosphamide to a different immunosuppressive agent. This approach is based upon the evidence supporting use of this strategy in patients with ANCA-associated vasculitis and our experience in patients with PAN, as there are no direct comparisons of different treatment options in patients with resistant PAN.
We base the choice of alternative immunosuppressive agent on the patient’s history of medication use and comorbidities. We usually prescribe an agent not previously used by the patient from among the following: azathioprine, methotrexate, or mycophenolate (see 'Resistant to glucocorticoids alone' above). Rituximab is an option for the treatment of patients without hepatitis B virus (HBV) infection whose disease is resistant to control with cyclophosphamide and subsequent use for at least three months each of one or two of these alternative immunosuppressive agents. It has not been formally evaluated in this setting, but its use in PAN is supported by the efficacy of this approach in patients with ANCA-associated vasculitis [23,24]. In patients treated with rituximab, we use the same regimen as is utilized in patients with granulomatosis with polyangiitis. (See "Initial immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis".)
Remission-maintenance immunosuppression — In patients who have completed a course of therapy with cyclophosphamide, we switch to another immunosuppressive agent, such as azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly), for a total duration of immunosuppressive therapy (including cyclophosphamide and the subsequent agent) of 18 months. (See 'Cyclophosphamide regimen' above.)
We avoid the continued use of cyclophosphamide for remission maintenance due to its toxicity and prefer to use either azathioprine or methotrexate over mycophenolate for this purpose [12-16]. The choice between methotrexate and azathioprine often depends on the individual toxicity profiles and dosing regimens. Methotrexate is likely faster-acting, but should be avoided in patients with renal disease or hepatitis. In patients with poor tolerance of or contraindications to azathioprine or methotrexate, we use mycophenolate mofetil (2000 to 3000 mg daily). The highest tolerated dose of a given agent, up to the recommended maximum, should be used for several months before presuming it is insufficient, and that another medication is required.
This approach is supported indirectly by randomized trials and experience in patients with ANCA-associated vasculitis, but there are no randomized trials or observational studies that have formally examined this approach or compared azathioprine, cyclophosphamide, methotrexate, and mycophenolate in patients with PAN in this setting . Nonetheless, use of this strategy in patients with PAN has been effective in our experience. The use of this approach in ANCA-associated vasculitis is discussed in detail separately. (See "Treatment and prognosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)" and "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis".)
The monitoring and potential adverse effects of azathioprine, methotrexate, and mycophenolate mofetil are discussed in detail separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Major side effects of low-dose methotrexate" and "Use of methotrexate in the treatment of rheumatoid arthritis" and "Mycophenolate mofetil: Pharmacology and adverse effects when used in the treatment of rheumatic diseases" and "Maintenance immunosuppressive therapy in granulomatosis with polyangiitis and microscopic polyangiitis".)
Hypertension — As with most forms of hypertension, especially in the setting of renal insufficiency, obtaining adequate control of the blood pressure is a key goal of treatment. Hypertension can be a major therapeutic issue in patients with polyarteritis nodosa. The elevation in blood pressure may be severe and is often mediated by ischemia-induced activation of the renin-angiotensin system . The intrarenal large vessel disease in PAN may, therefore, be the functional equivalent of extrarenal vascular disease in bilateral renal artery stenosis. (See "Renal effects of ACE inhibitors in hypertension".)
We suggest the use of angiotensin-converting enzyme (ACE) inhibitors in PAN because they are generally effective in this setting . However, they may worsen renal function due to removal of the effect of angiotensin II on autoregulation and maintenance of the glomerular filtration rate. Switching to other antihypertensive agents (such as calcium channel blockers) may be required if an ACE inhibitor induces a clinically significant elevation (30 percent or greater) in the plasma creatinine concentration. (See "Renal effects of ACE inhibitors in hypertension", section on 'Renovascular hypertension'.)
Limited role of plasma exchange — Plasma exchange has not been shown to be beneficial for the treatment of PAN that is not associated with HBV infection [22,27,28]; however, it may have a role in the acute management of HBV-associated PAN . The treatment of HBV-associated PAN is discussed separately. (See 'Associated hepatitis B or C infection' above and "Renal disease associated with hepatitis B virus infection".)
Pneumocystis jirovecii (PCP) prophylaxis — Prophylaxis for Pneumocystis jirovecii (PCP) infection should be employed in patients being treated for PAN using the regimens associated with such risk in patients with granulomatosis with polyangiitis (Wegener’s), such as a significant dose of glucocorticoids (eg, ≥20 mg of prednisone daily for one month or longer) in combination with a second immunosuppressive drug, particularly a cytotoxic agent (eg, cyclophosphamide). (See "Treatment and prevention of Pneumocystis pneumonia in non-HIV-infected patients", section on 'Indications'.)
ISOLATED AND SINGLE-ORGAN PAN — The approach to isolated or single-organ polyarteritis nodosa (PAN) depends upon the affected organ or tissue. Cutaneous PAN is generally treated similarly to mild systemic PAN (see 'Isolated cutaneous PAN' below), while isolated organ involvement, sometimes identified at the time of an operative procedure, may not require further therapy. (See 'Isolated/single-organ PAN' below.)
Isolated cutaneous PAN — Patients with isolated cutaneous disease are treated similarly to patients with mild PAN, with initial treatment with glucocorticoids alone. A second agent, such as azathioprine, methotrexate, or mycophenolate mofetil, may be added to glucocorticoid therapy for those patients who either do not respond to treatment with glucocorticoids alone or relapse with tapering of glucocorticoids. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Skin disease' and 'Mild PAN' above.)
Patients with isolated cutaneous disease when first seen and initially treated may relapse with disease in other organs, and should be monitored periodically as are other patients with mild disease. (See 'Monitoring of disease' below.)
Isolated/single-organ PAN — Isolated single-organ PAN, other than isolated cutaneous disease, is usually a monocyclic disease, which typically does not relapse, that is diagnosed by histological examination of surgical specimens. Treatment beyond surgical excision (eg, of isolated PAN of the gallbladder) is usually not necessary . However, we fully evaluate such patients initially and provide regular clinical follow-up (every three months in the first year and every 6 to 12 months thereafter) to determine if additional anatomic areas or other clinical features are present or developing. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and 'Monitoring of disease' below.)
MONITORING OF DISEASE — Patients with polyarteritis nodosa (PAN) require regular, long-term follow-up to monitor the disease and drug safety by a clinician familiar with the disease and its treatments. Patients must be monitored for the possibility of disease relapse, particularly in organ systems involved at disease onset. We generally see patients at least monthly during the initial phase of therapy, until clinically stable, then at least every three months during the first two years of treatment.
In patients in remission after two years, we continue to see them every three to six months. In addition to routine physical examinations, including blood pressure testing, a review of systems, and laboratory monitoring for drug toxicities, a serum creatinine and urinalysis should be obtained. New symptoms or findings should be evaluated for their potential to represent recurrent vasculitis, even if such symptoms or findings are different from the original presenting manifestations of disease. Additionally, patients must be followed and treated for the medium- and long-term clinical sequelae of both treatment toxicities and disease-related long-term damage. Relapses may occur years after initial presentation and attainment of remission, which may be defined for patients with PAN as the absence of any evidence of active disease.
Patients with cutaneous-only PAN or other single-organ presentations of PAN must also be followed regularly for the possible development of disease in new organ systems. In addition to clinical examinations and appropriate follow-up of patient-reported symptoms, periodic testing of serum creatinine and a urinalysis can help monitor for asymptomatic renal disease.
Follow-up angiography is not required unless there are signs or symptoms suggestive of new disease, concerns for ischemia that may require intervention, or aneurysms that are at risk for expansion or rupture and may require intervention. Depending on the anatomic location and size of affected arteries, magnetic resonance imaging (MRI) or computed tomographic (CT) angiography may be substituted for catheter-based angiography. The choice of which imaging modality (MR, CT, or catheter-based) to use will depend upon the availability of equipment and expertise at a medical center and may be influenced by an interest in utilizing the same approach used for prior evaluations to allow for direct comparisons.
Some complications of PAN can occur when the disease is clinically inactive, since healing of inflamed vessels can lead to progressive narrowing of the vascular lumina and resultant organ ischemia. Such changes should be distinguished from active disease, as they require appropriate supportive care rather than immunosuppression. As an example, a slowly progressive elevation in the serum creatinine concentration occurs in some patients in whom the signs of active vasculitis (such as systemic symptoms and an active urine sediment) have abated. The primary problem in this situation is diminished glomerular flow, not vascular inflammation. Sometimes serial angiograms or a renal biopsy is required to help differentiate active from inactive disease.
RECURRENT DISEASE — The treatment of recurrent disease depends upon the severity of the flare and whether recurrence occurs on or off immunosuppressive treatment. Mild disease recurrence may be treated by use of glucocorticoids alone, and/or an increase in dose of immunosuppressive drug, depending upon the patient’s treatment at the time of disease exacerbation or recurrence. Moderate to severe relapse requires reinitiation of remission-induction treatment (see 'Initial treatment of moderate and severe PAN' above). If moderate-severe recurrence occurs when the patient is on immunosuppressive treatment, a different immunosuppressive agent should be used. (See 'Resistant disease' above.)
Morbidity and mortality — Untreated polyarteritis nodosa (PAN) is associated with a poor prognosis (13 percent five-year survival) [5,6]. The outcome of PAN has improved in patients receiving treatment; five-year survival is approximately 80 percent . The survival rates for patients with hepatitis B virus (HBV)-associated PAN are lower than for patients with non-HBV-associated disease. In one large cohort, the one- and five-year survival rates were substantially higher among patients diagnosed after 1995 compared with prior to 1995, possibly indicative of more rapid and comprehensive use of cyclophosphamide for more severe disease . Whether prognosis of HBV-associated PAN has improved with the introduction of newer antiviral treatments is not known. Most deaths in patients with PAN due to active disease occur within 18 months of disease onset [4,7]. Survival is better among those with limited organ involvement.
Renal failure and mesenteric, cardiac, or cerebral infarction are the major causes of death. Some of these complications can occur at a time when the disease is clinically inactive, since healing of inflamed vessels can lead to progressive narrowing of the vascular lumina and resultant organ ischemia. Preservation of tissue function is most likely if treatment is instituted early in the course of the disease.
Improvement in renal function may be seen even in patients who initially require dialysis. In this setting, sufficient recovery to allow the patient to be maintained off dialysis for one to two years or more occurs in up to 60 percent of cases  and in approximately 10 percent who undergo dialysis for as long as three to six months .
The French Vasculitis Study Group (FVSG) has established a large, well-characterized longitudinal cohort of patients with PAN and reported a comprehensive series of studies on the natural history and treatment of this disorder . Using regression analytic techniques, this group derived the “Five Factor Score” (FFS) in 1996 as a simple prognostic tool for clinicians to use when evaluating patients with various forms of vasculitis, including PAN [4,10,22]. The FFS was revised in 2011 based upon additional data and for PAN now only includes four factors associated with increased mortality: i) age >65 years, ii) cardiac symptoms, iii) gastrointestinal involvement, and iv) renal insufficiency (plasma creatinine >1.7 mg/dL [150 micromol/L]) . The original FFS had included central nervous system disease (dropped from the score in 2011) but did not include age (included in 2011). The FFS has been used to stratify patients in treatment studies; this tool is helpful in both interpreting the data and formulating an approach to treatment of PAN. However, the FFS is based upon mortality and is not designed to predict either relapse or long-term morbidity, both of which are also important outcomes that influence treatment decisions in PAN.
Relapse rates — Although the proportion of patients with PAN with monocyclic disease courses (ie, a single episode of disease activity without a subsequent relapse) is substantially higher than in many other forms of vasculitis, especially the antineutrophil cytoplasmic antibody (ANCA)-associated diseases (granulomatosis with polyangiitis [Wegener's], microscopic polyangiitis [MPA], and eosinophilic granulomatosis with polyangiitis [Churg-Strauss]), the relapse rate in PAN is still substantial. For example, in a series of 348 patients, the one and five-year relapse rates for patients with non-HBV-associated PAN were at least 9.2 percent and 24 percent, respectively; the relapse rates for HBV-associated PAN were lower .
Renal transplantation — Few data exist concerning the outcome of patients with PAN and end-stage renal disease who undergo renal transplantation. Among 112 patients with PAN reported in the European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) registry, transplantation was associated with significantly lower patient (77 versus 91 percent) and first cadaveric allograft (60 versus 69 percent) survival rates compared with those diagnosed with other renal diseases (eg, glomerulonephritis, interstitial nephritis, toxic nephropathies, and cystic kidney disease) . Thirteen percent of graft failures were reportedly due to recurrent disease.
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 topic (see "Patient information: Polyarteritis nodosa (The Basics)")
SUMMARY AND RECOMMENDATIONS
●For patients with polyarteritis nodosa (PAN) with relatively mild disease (constitutional symptoms, arthritis, anemia, but normal renal function and no gastrointestinal, cardiac, or neurologic manifestations), we suggest initial treatment with oral glucocorticoid monotherapy, rather than combining glucocorticoids and another immunosuppressive medication (Grade 2C). We use an initial dose of prednisone of 1 mg/kg per day (maximum 60 to 80 mg daily), typically for approximately four weeks, at which time slow tapering of the glucocorticoids (over approximately six to eight months) can be started if substantial improvement has occurred. We also employ this approach in patients with isolated cutaneous disease. (See 'Mild PAN' above.)
●In patients with mild disease who are resistant to or intolerant of the dose of glucocorticoids required for disease control, we suggest the addition of azathioprine or methotrexate, rather than adding cyclophosphamide (Grade 2C). Such patients include those who do not respond to glucocorticoids alone, whose glucocorticoid dose cannot be tapered to an acceptable level (eg, prednisone ≤10 mg/day) without experiencing a relapse of disease, who are at high risk of adverse effects for the expected treatment course with glucocorticoids, or in whom the adverse effects of continued glucocorticoids in the dose being used are unacceptable. The usual doses are azathioprine, 2 mg/kg daily; or methotrexate, 20 to 25 mg once weekly. Mycophenolate mofetil (2000 to 3000 mg daily) is an alternative in patients unable to use azathioprine or methotrexate. We also use this approach in patients with isolated cutaneous disease. (See 'Resistant to glucocorticoids alone' above.)
●In patients with moderate to severe disease (eg, any evidence of renal insufficiency, significant proteinuria, gastrointestinal, cardiac, or neurologic involvement), we recommend treatment with both glucocorticoids and cyclophosphamide rather than glucocorticoids alone (Grade 1B). (See 'Initial treatment of moderate and severe PAN' above.)
•In most patients prednisone is administered orally (1 mg/kg daily to a maximum of 60 to 80 mg daily), but in patients with severe, life-threatening manifestations or worsening mononeuritis multiplex we usually administer intravenous methylprednisolone initially (7 to 15 mg/kg to a maximum of 500 to 1000 mg administered intravenously once daily for three days) prior to the oral prednisone regimen. The initial oral prednisone dose is continued for two to four weeks, until significant improvement is observed. The dose should then be tapered slowly, for an overall course of approximately six to eight months. (See 'Glucocorticoid regimen' above.)
•Cyclophosphamide may be administered by either intravenous or oral administration. We prefer the use of intravenous pulse therapy with cyclophosphamide (600 mg/m2) every two weeks for three doses, then every four weeks for at least four months and until a stable remission has been achieved, but for no greater than 12 months. (See 'Moderate and severe PAN' above.)
•In patients treated with cyclophosphamide, we switch for remission maintenance to another immunosuppressive agent, such as azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly), for a total duration of immunosuppressive therapy of 18 months. (See 'Remission-maintenance immunosuppression' above.)
●In the infrequent patient with moderate to severe PAN who has ongoing severe or worsening disease that is not controlled by treatment with glucocorticoids and cyclophosphamide within two to three months, we treat with pulse glucocorticoids (eg, 1000 mg methylprednisolone administered intravenously daily for 3 days), followed by prednisone (1 mg/kg daily taken orally) and switch from cyclophosphamide to a different immunosuppressive agent, azathioprine (2 mg/kg daily) or methotrexate (20 to 25 mg once weekly). Alternatives in patients unresponsive to or intolerant of these agents are mycophenolate mofetil (2000 to 3000 mg daily) or rituximab. (See 'Resistant disease' above.)
●In patients with mild PAN and evidence of infection with hepatitis B virus (HBV) or hepatitis C virus (HCV), we suggest treating most patients initially with antivirals only, rather than also treating initially with immunosuppressive medications (Grade 2C). Some patients with severe manifestations of hepatitis virus-associated PAN may benefit from short-term treatment with glucocorticoids and plasma exchange until antiviral therapy becomes effective. We do not use plasma exchange in patients with idiopathic PAN that is not HBV-related. In patients with persistent manifestations of PAN who are unresponsive to or intolerant of treatment for viral hepatitis alone, we cautiously treat the manifestations of the vasculitis with glucocorticoids and other immunosuppressive medication depending upon the severity of the vasculitis. (See 'Associated hepatitis B or C infection' above.)
●In patients with hypertension, we suggest treatment with an angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor antagonist, rather than using another type of antihypertensive (Grade 2B). Such patients should be monitored closely for worsening of renal function. (See 'Hypertension' above.)
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