Polyarteritis Nodosa and Extrahepatic Manifestations of HBV Infection: The Case Against Autoimmune Intervention in Pathogenesis

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Numerous extrahepatic manifestations have been reported in patients with both acute and chronic hepatitis B (arthralgias or arthritis, skin rashes, glomerulonephritis and neuritis), all of which are present in polyarteritis nodosa (PAN) which is the most unique and spectacular extrahepatic manifestation. In the 1970s, the frequency of PAN due to the hepatitis B (HBV) reached 30%. Immunization programs explain the decrease and it is now down to 7%. PAN usually occurs within 6 months of infection. Clinical manifestations reflect this most classic form of PAN, Hepatic manifestations including, ALT/AST elevations are mild and usually overlooked. Besides HBV, other viruses may be responsible for cases of vasculitides including PAN, HIV, Parvovirus B19, and EBV. Different pathogenic mechanisms have been identified but immune complexes are mainly thought to be responsible. In glomerulonephritis, detailed immunostaining and ultrastructural findings indicate that HBe antigen (Ag) is more likely to be the responsible antigen. In PAN, fewer reports are available and early studies with poorly defined antibodies need to be revisited. Interestingly almost all cases of HBV/PAN are associated with wild-type HBV infection, characterised by HBe antigenemia and high HBV replication, supporting the concept that lesions could result from the deposit of viral Ag/Ab complexes soluble in Ag excess, possibly involving HBe Ag. The recent observation of PAN cases associated with precore mutation which abrogates the formation of HBe Ag challenges this view. It may suggest that other, still undefined, circulating HBV-related Ag(s) distinct from HBe Ag could be involved. Remarkably, none of the HBV/PAN cases or glomerulonephritis exhibit antineutrophil cycoplasmic antibodies (ANCA) reactivity. Viral PAN can now be completely separated from other form of vasculitis mostly autoimmune in nature. Based on the efficacy of antiviral agents in chronic hepatitis B and of plasma exchanges in PAN we combined both therapies to treat HBV PAN. This was associated with swift recovery, even in the most severe forms. The perfect time correlation between inhibition of virus replication and resolution of all bioclinical signs suggest a direct pathogenic role of the virus possibly via immune complexes. Traditional immunosuppressive and steroid therapy should no longer be used for HBV PAN cases.