The place of immunotherapy in the management of HCV-induced vasculitis: an update

Abstract

Patients with chronic hepatitis C virus (HCV) can develop systemic cryoglobulinemic vasculitis. Combination of pegylated-interferon α and ribavirin is the first-line treatment of this condition. However, in case of severe or life-threatening manifestations, absence of a virological response, or autonomized vasculitis, immunotherapy (alone or in addition to the antiviral regimen) is necessary. Rituximab is to date the only biologic with a sufficient level of evidence to support its use in this indication. Several studies have demonstrated that rituximab is highly effective when cryoglobulinaemic vasculitis is refractory to antiviral regimen, that association of rituximab with antiviral regimen may induce a better and faster clinical remission, and, recently, that rituximab is more efficient than traditional immunosuppressive treatments. Some issues with regard to the optimal dose of rituximab or its use as maintenance treatment remain unsolved. Interestingly, in balance with this anti-inflammatory strategy, a recent pilot study reported the significant expansion of circulating regulatory T lymphocytes with concomitant clinical improvement in patients with refractory HCV-induced cryoglobulinaemic vasculitis using low dose of subcutaneous interleukin-2. This paper provides an updated overview on the place of immunotherapy, especially biologics, in the management of HCV-induced cryoglobulinaemic vasculitis.

Figure 1

Immunotherapy to manage HCV-induced vasculitis. (A) Antiviral regimen, ideally a combination of interferon plus ribavirin, is the first-line treatment for HCV-induced cryoglobulinaemic vasculitis (CV) when the severity of its manifestations is mild-to-moderate. In addition, short-term low-dose corticotherapy may sometimes be used initially. (B) In cases of severe or life-threatening manifestations (i.e., severe renal involvement), immunotherapy must be initiated immediately. Rituximab has become a preferred choice but, as with other immunosuppressive drugs, careful monitoring of viral load and hepatic functions is necessary. Worsening of vasculitis has been reported in patients just after administration of rituximab, especially in those with serious cryocrit levels, thus, in these patients, corticosteroids and/or plasmapheresis may be initiated before B-cell depletion. An antiviral regimen is initiated either simultaneously or secondarily/sequentially in these patients. (C) When an antiviral regimen is contraindicated, poorly tolerated, or fails to induce a sustained viral remission, immunotherapy is also initiated. Corticosteroids should be avoided when possible. Careful monitoring of viral load/hepatic function is necessary. A prolonged antiviral regimen may be considered when clinical and biological manifestations of MC show an improvement under this regimen in spite of the absence of viral remission. (D) In cases where CV is still active in spite of obtaining a sustained viral response, B-cell malignancy and low-level viremia should be ruled out before considering that the vasculitis is autonomous and before initiating immunotherapy.

Figure 2

Different IL-2 based approaches to promote the expansion of regulatory T cells (Treg). A first approach consists of using IL-2, together with other stimuli, to expand ex vivo the Treg cells collected from a patient's tissue culture before transferring these cells to the patient (A). In vivo, IL-2 can be administered subcutaneously at high doses but can be associated with rapamycin to prevent activation of effector T cells (Teff) (B) or given at a low dose for the same reason (C). IL-2-specific monoclonal antibodies can be used to target IL-2 selectively to Treg cells (D).