Hepatitis B virus-related PAN

PAN is the inflammation and subsequent necrosis of medium-sized artery walls that leads to microaneurysm formation and organ infarction.

Epidemiology

PAN is a rare disease that affects all racial groups. Estimates of the annual incidence of PAN-type systemic vasculitides in the general population range from 4.6/1,000,000 in England , and 9.0/1,000,000 in Olmsted County, Minnesota, to 77/1,000,000 in a hepatitis B-hyperendemic Alaskan Eskimo population . In a German study , the PAN incidence was extremely low (0.3–0.4/1,000,000 according to the year and part of the country). In France, PAN prevalence was 34/1,000,000 in Seine-Saint-Denis, a northern suburb of the Paris . Its prevalence was the highest among the vasculitides that were studied (microscopic polyangiitis (MPA), PAN, eosinophilic granulomatosis with polyangiitis (EGPA; Churg–Strauss syndrome) and granulomatosis with polyangiitis (GPA; Wegener)) but its incidence has declined in parallel with that of HBV infection .

In France, HBV infection transmitted by contaminated blood transfusion has now disappeared; the last proven case occurred in 1987 , but intravenous drug abuse has rapidly become a major cause of HBV–PAN , as are cases due to sexual transmission of HBV to individuals at risk who were not vaccinated. The development of vaccines against HBV and their administration to people at risk also explain the dramatically decreased number of new cases observed since 1989. For the last 3 years, HBV–PAN has rarely been observed. Moreover, the frequency of PAN, due to HBV infection or not, has also declined in parallel.

Exposure to HBV before PAN onset is not easy to establish but, for a large series of patients, it was possible to determine the infection route for 43/115 patients . When identified, the mean (±standard deviation (SD)) interval between time of exposure and first manifestation was 596 ± 628 (range, 30–1695) days. The immunological process leading to PAN usually occurs within 12 months of the primary HBV infection. Hepatitis is rarely diagnosed, as it remains mostly silent before PAN becomes clinically patent.

Clinical manifestations

Clinical manifestations are characteristic of those commonly described for historically classical, non-viral PAN, with gastrointestinal involvement (especially perforation and bleeding), malignant hypertension, renal infarction and/or orchiepididymitis. Among patients with HBV–PAN, clinical data were roughly the same as those commonly seen for PAN, but several differences can be noted: HBV–PAN occurs more often in subjects under 40 years of age and is more frequently associated with malignant hypertension, renal infarction and orchiepididymitis (25%) . Concerning other symptoms, we frequently observed abdominal manifestations (53%), especially surgical emergencies. In the study by Sergent et al. , two of the three deaths (among nine patients) were attributed to colon vasculitis. Digestive and renal manifestations resulted from ischaemia and angiography visualised infarctions and microaneurysms . Disappearance of the latter could follow their thrombosis, with evolution to fibrosis. HBV–PAN is acute and initially severe, but its outcome is usually excellent if adequate treatment is prescribed. Antigen (Ag)-to-antibody (Ab) seroconversion usually leads to recovery.

Outcome

In the absence of appropriate antiviral therapy, HBV–PAN outcome is poorer . Sequelae are the consequence of histological damage, including vascular nephropathy, and central and/or peripheral nervous involvements. Hepatic manifestations associated with PAN progression are clinically moderate and transaminase-level rises are usually mild. Whenever performed, liver biopsies showed a chronic hepatitis pattern, in agreement with the overwhelming progression to chronicity . Although most cases of PAN are associated with wild-type HBV strains, thus strengthening the involvement of hepatitis B ‘e’ antigen (HBeAg) in PAN pathogenesis, this aetiology was challenged by the association of some cases with a precore mutation that abrogates HBeAg formation. However, no autoimmune mechanism could be incriminated because antiviral therapy halted virus replication, thereby successfully abrogating the disease . In a large cohort study based on 348 patients with PAN (mean (±SD) follow-up: 68.3 ± 63.5 months), 76 (21.8%) relapsed (63 (28%) non-viral PAN vs. 13 (10.6%) HBV–PAN; P < 0.001) and 86 (24.7%) died (44 (19.6%) non-viral PAN vs. 42 (34.1%) HBV–PAN; P = 0.002) .

Treatment

For many years, HBV–PAN was treated just like non-viral PAN and patients received corticosteroids combined with plasma exchanges. This regimen was often effective in the short term. In a prospective, randomised study enrolling 71 patients , the addition of cyclophosphamide was even shown to be beneficial in preventing relapses and improving the quality of the clinical therapeutic response during long-term follow-up. However, exclusive immunosuppressive therapy (corticosteroids and immunosuppressants) of HBV–PAN allowed relapses and complications associated with virus persistence, such as chronic hepatitis or liver cirrhosis, and resulted in poorer outcomes than for non-viral PAN . The rationale of the therapeutic sequence was: first, rapidly control the most severe life-threatening PAN manifestations with initial corticosteroids; second, control PAN and restore immune reactivity by plasma-exchange removal of immune complexes; third, give vidarabine to inhibit HBV replication; and, lastly, enhance immunological clearance of HBV-infected hepatocytes and favour HBeAg-to-HBeAb seroconversion by abrupt cessation of corticosteroids. Several prospective trials demonstrated the efficacy of that strategy, using different antiviral agents as more potent ones became available during the last few decades. The first study used vidarabine, which induced full clinical recovery in 75% of the patients, and HBeAg-to-HBeAb seroconversion in about 50% of them, while about 20% of the patients obtained hepatitis B surface Ag (HBsAg)-to-HBsAb seroconversion. Later studies enrolling small numbers of patients replaced vidarabine by interferon-alpha (IFNα). The triple-armed regimen, combining plasma exchanges, corticosteroids and IFNα, successfully treats PAN associated with HBV bearing a mutant precore promoter . Other similar antiviral approaches were also effective, including IFNα alone , or combined with famciclovir or lamivudine . Lamivudine was also successful as the first-line antiviral therapy for HBV–PAN .