Approach

Polyarteritis nodosa (PAN) unrelated to hepatitis B virus (HBV) infection is treated in broadly the same way as other vasculitides, by means of immunosuppression, with an emphasis on early and aggressive therapy, especially in severe disease.

The treatment of HBV-related PAN differs, because although immunosuppression can lead to control of the vasculitis, it is also associated with increased viral replication. A short course of aggressive immunosuppression is followed by plasma exchange and concomitant antiviral therapy.

The 5-factor score

This score can be used to predict survival in PAN.[19] A score of one or more is considered to suggest a poor prognosis and warrants more aggressive therapy.

The five factors, each of which is scored one point if present, are:

  • Proteinuria >1 g/day

  • Creatinine >120.5 mmol/L (>1.58 mg/dL)

  • Cardiomyopathy

  • Gastrointestinal symptoms

  • Central nervous system involvement.

Non-HBV-related PAN

The main goal is to control the activity of the vasculitis and thereby to prevent the progression of organ- and life-threatening disease. Immunosuppression is the mainstay of treatment, so close attention to prevention and detection of complications of therapy is key.

Mortality from PAN has been demonstrated to be high within the first year, with 58% to 73% of early deaths caused by uncontrolled vasculitis.[53][54][55] Therefore, PAN should be treated aggressively and without delay, especially in patients with severe disease (those with a 5-factor score ≥1). Most of the clinical trials published have looked at a combination of patients with different types of primary vasculitis studied together: for example, PAN and Churg-Strauss syndrome. This approach has been adopted because of the relative rarity of these diseases.[55]

Clinical trials in non-HBV-related PAN have demonstrated that the combination of cyclophosphamide and corticosteroids reduces the rate of relapses but does not affect overall 10-year mortality.[56] However, in a retrospective analysis of 278 patients, those with a 5-factor score of ≥2 had a significantly improved survival if they were treated with cyclophosphamide and corticosteroids, compared with corticosteroids alone.[55]

Patients with a 5-factor score of ≥1 are given an oral corticosteroid in a slowly reducing regimen, aiming for withdrawal of corticosteroid by 15 to 18 months. Intravenous pulses of corticosteroid can be given before cyclophosphamide infusions, which may allow for faster tapering of the oral corticosteroid.

Intravenous pulses of cyclophosphamide are preferred because they have been found to be as effective as oral regimens; they also reduce the total amount of exposure to cyclophosphamide and reduce adverse effects.[57][58] Tuberculosis screening should be considered before the use of cyclophosphamide.[59][60] The risk of infertility with cyclophosphamide should be discussed, with options such as oocyte and sperm cryopreservation offered, although in practice this is rarely achieved in severe disease because treatment needs to be started before arrangements can be made for harvesting.[59]

The use of plasma exchange has not been found to reduce relapses or improve mortality compared with corticosteroids alone or compared with corticosteroids plus cyclophosphamide.[61][62] The number of infusions of cyclophosphamide appears to be relevant in patients with poor prognostic scores (i.e., a 5-factor score ≥1). Twelve infusions compared with 6 results in a significantly lower probability of relapse (hazard ratio 0.44, P = 0.02).[63]

After an initial 3- to 6-month course of cyclophosphamide, maintenance of remission with azathioprine, leflunomide, or methotrexate has been shown to be effective in patients with anti-neutrophil associated anticytoplasmic (ANCA)-associated vasculitis.[64][65][66][67] There is no evidence for this approach specifically in PAN, but the findings from one trial in ANCA-associated vasculitides can be extrapolated to PAN, making maintenance with alternatives to cyclophosphamide a potential treatment option.[57][59]

In patients who have a major relapse (defined as being life- or organ-threatening disease), cyclophosphamide should be restarted to try and achieve remission.

The French Vasculitis Group has previously recommended that patients with a 5-factor score of 0 can be treated with corticosteroids alone, adding cyclophosphamide as a second-line agent if there is persistent disease or relapse despite use of corticosteroids. However, this is associated with a 12% mortality.[68] A further study by the same group showed that 80% of patients with a 5-factor score of 0 achieved remission with corticosteroids alone, but remission was only sustained in 40%.[69] In patients who did not achieve remission or relapsed on corticosteroids alone, azathioprine or pulsed intravenous cyclophosphamide was used to induce remission successfully.[69] However, a subsequent study by this group in 2017 showed no additional benefit, in terms of rate of remission or relapse, following the addition of azathioprine to treatment with prednisolone.[70]

In vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA), methotrexate, in place of cyclophosphamide, may be effective in inducing remission in disease without severe features.[71][72][73] However, there have been no such trials in PAN.

HBV-related PAN

Historically, patients were treated with immunosuppression, which could lead to control of the vasculitis but that also promoted ongoing viral replication and, therefore, led to an increase in the chronicity and intensity of HBV infection.[13][74][75][76] Ongoing viral replication has been shown to be a poor prognostic feature in HBV infection, leading to a high risk of cirrhosis and hepatocellular carcinoma.[77][78][79]

Treatment regimens start with aggressive immunosuppression, in the form of high-dose oral corticosteroids for 2 weeks, in order to reduce end-organ damage from uncontrolled vasculitis.

The next stage is to use plasma exchange as a means of physically removing the immune complexes.[80]

Concomitant use of antiviral therapy at this stage reduces viral load, which reduces the drive to produce immune complexes, halts viral replication, and leads to seroconversion.[20][81][82] The antiviral agent of choice is lamivudine, which has been shown to be effective in seroconverting patients with chronic hepatitis B and can be used orally.[83] An observational trial demonstrated clinical remission in 90% of patients by 6 months, and seroconversion from HbeAg positivity to HbeAb in 66.7% of patients within 9 months.[84] It has been reported that a cure can be achieved in those who seroconvert.[81] There have been no randomised controlled trials because of the rarity of the disease.[20]

On relapse of PAN, HBV status should be checked and, if positive, needs to be eradicated before PAN treatment. The treating physician should liaise with his or her local hepatologists for advice about alternative antiviral therapy to treat HBV, rather than simply repeat the course of lamivudine.

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