Hepatitis C virus mixed cryoglobulinemia vasculitis: Therapeutic options

With the discovery of hepatitis C virus (HCV) as the etiologic agent for most cases of mixed cryoglobulinemia (Cryovas), new opportunities and problems for crafting therapy of HCV-Cryovas have emerged [1,2]. A new and major concern was the potential adverse effects that immunosuppressive therapy with glucocorticoids and cytotoxic drugs could have on an underlying chronic viral infection. Alternatively, the discovery of HCV provided the opportunity to control HCV-Cryovas with antiviral therapy as the underlying infection drives immune complex formation and resultant vasculitis [3]. The cornerstone of HCV therapy has been and continues to be interferon alpha (IFN) which has the potential to exacerbate autoimmune disease states [4]. Aggressive antiviral therapy with Peg-IFNα and ribavirin should be considered as induction therapy for HCVCryovas with mild to moderate disease severity and activity. Very recent advances using a triple combination with Peg-IFNα, ribavirin and a protease inhibitor, in patients infected by a genotype 1 virus, showed promising results. In patients presenting with severe disease (i.e. worsening of renal function, mononeuritis multiplex, extensive skin disease including ulcers and distal necrosis), an induction phase of immunosuppression is often necessary while awaiting the generally slow response to antiviral treatments. Combination therapy with rituximab and optimal anti-HCV treatment appears logical as it may target both mixed cryoglobulin (MC) producing B-cells and the viral trigger. This review will focus on advances in our understanding of the treatment of HCV-Cryovas. Antiviral agents During the last two decades, the treatment of HCV infection (i.e. in the absence of HCV-Cryovas) has permit to dramatically increase the sustained virological response (SVR) rates, from IFN monotherapy to IFN plus ribavirin [5-9], and more recently pegylated-IFN (Peg-IFNα) plus ribavirin leading to a SVR in nearly 60% of patients. Increasing performances of antiviral treatment have also been shown in Cryovas patients. Mazzaro et al. [10] have first reported on the results of 18 HCVCryovas patients treated with Peg-IFNα2β plus ribavirin for 12 months. At the end of follow-up, only eight (44%) patients were still sustained clinical and virological responders. One major weakness of this study was the lower Peg-IFN dosage used in comparison with that usually recommended in HCV therapeutic guidelines. In a monocentric study [11], 72 consecutive HCV-Cryovas patients received treatment with IFNα-2β (n = 32) (3 millions IU × 3/week) or Peg-IFNα-2β (n = 40) (1.5 μg/kg/week), both combined with oral ribavirin (600 to 1200 mg/d) for at least 6 months. Peg-IFNα plus ribavirin combination achieved a higher rate of complete clinical (67.5% vs 56.2%), virological (62.5% vs 53.1%) and immunological response (57.5% vs 31.2%) as compared with IFNα plus ribavirin, regardless of HCV genotype and viral load. Compared with standard IFN a-2b/ribavirin, there was a shorter duration of HCV therapy (13.2 vs 18.3 months), less frequent use of corticosteroids (35% vs 47%) and a lower rate of death (5 vs 18.7%) with Peg-IFNα2β/ribavirin. An early virologic response (i.e. negativation or > 2 log drop viremia at month +3) (odds ratio [OR], 3.53; 95% CI 1.18 to 10.59) was independently associated with a complete clinical response of Cryovas. A glomerular filtration rate lower than 70 ml/min (OR 0.18; 95% CI 0.05 to 0.67) was negatively associated with a complete clinical response of Cryovas. When compared with IFNα2β/ribavirin, patients who received Peg-IFNα2β/ribavirin had a similar rate of adverse events (53.1% vs 55%, respectively). Recent use of triple therapy with Peg-IFNα, ribavirin, and a specifically targeted antiviral agent (i.e. Boceprevir or Telaprevir) led to improve SVR rates in patients infected with HCV genotype 1. In an open-label prospective single-center cohort study [12], the efficacy of an NS3 protease inhibitor [boceprevir or telaprevir], in combination with Peg-INFa and ribavirin has been evaluated in 13 HCV-Cryovas patients with genotype 1. After 1 month of Peg-IFNα/Ribavirin/protease inhibitor combination, 11 (85%) patients showed an early virological response. Nine patients showed a complete clinical response of Cryovas and four were partial responders. After 3 months of Peg-IFNα/Ribavirin/protease inhibitor combination therapy, MC serum level dropped from 1.3 to 0.3 g/l while C4 serum level increased from 0.09 to 0.13 g/l. All 13 patients experienced at least one treatment side effect including asthenia in 92%, anaemia in 84%, neutropenia and bacterial infection in 53%, nausea and low grade (< 3) skin eruption under Telaprevir in 30%, and thrombocytopenia in 15%. Immunosuppressive agents Immunosuppressive agents have been given for many decades to patients with severe Cryovas disease manifestations such as membranoproliferative glomerulonephritis, severe neuropathy and other life-threatening complication. In a large retrospective study of 105 patients with renal disease associated with Cryovas, 80% were administered corticosteroids and/or cytotoxic agents, while 67% underwent plasmapheresis [13]. Despite this aggressive approach, long lasting remission of the renal disease was achieved in only 14% of cases, and the 10- year survival rate was only 49%. Corticosteroids, used alone or in addition to IFNα, did not favourably affect the response of HCV-Cryovas manifestations in two controlled studies [5,14]. Low dose corticosteroids may help to control minor intermittent inflammatory signs such as arthralgia, but do not succeed in cases of major organ involvement. When used in combination with HCV treatment, plasmapheresis did not modify the virologic response if IFNα was given after each plasma exchange session [15]. Rituximab monotherapy Rituximab is an interesting therapy in Cryovas patients as it targets B-cells which are responsible for the cryoglobulin production, immune complex deposition and finally vasculitis lesions [16-21]. In a literature review [19], 57 patients had a Cryovas secondary to HCV infection (75.4%) or an essential MC (24.6%). Main indication for rituximab therapy was nonresponse to previous other treatments (i.e. mostly IFNα monotherapy and/or steroids). Most patients received four weekly consecutive i.v. infusions of 375 mg/m2 of rituximab. Rituximab infusions proved effective on main vasculitis signs, with a complete clinical response in 24/33 (73%) patients for skin involvement, 16/30 (53%) for arthralgia, 9/25 (36%) for neuropathy, and 9/13 (70%) for glomerulonephritis. Cryovas relapse was noted in 13/36 (36.1%) patients within few days to 19 months (mean 6.7 months) after the last rituximab infusion; 8/13 relapsers showed a complete remission after a second course of rituximab. Recently, De Vita et al. [22] reported the results of a multicenter phase III randomized controlled trial in 57 Cryovas patients (including 53 HCV-positive patients), comparing conventional treatment (i.e. glucocorticoids; azathioprine or cyclophosphamide; or plasmapheresis) and rituximab. None of the HCVpositive patients received concomitant antiviral therapy. Survival of treatment at 12 months (i.e. the proportion of patients who continued taking their initial therapy) was statistically higher in the rituximab group (64.3% vs 3.5%). Sneller et al. [23] reported the results of an open-label, randomized controlled trial of rituximab compared to conventional immunosuppressive therapy (glucocorticoids, cyclophosphamide, plasma exchanges or methotrexate) for HCV-Cryovas patients in whom antiviral therapy had failed to induce remission. Remission at month 6 was statistically higher in the rituximab group (83% vs 8%). The median duration of remission for rituximab-treated patients was 7 months, and the safety profile was good. A phase II single-arm two-stage study to evaluate the efficacy of a lower dosage of rituximab, 250 mg/m2 given twice, for refractory Cryovas is on-going [24]. The overall response rate in the first 24 evaluable patients was 79%, and the mean time to relapse was 6.5 months [similar to the 6.7 months reported in studies with high-dose rituximab]. Side effects were comparable to those seen in patients treated with high-dose. In a prospective study, 19 HCV-Cryovas patients excluded from antiviral therapy, with liver cirrhosis in 15/19 patients, were treated with rituximab [25]. A consistent improvement in Cryovas symptoms was evident at the end of follow-up. Improvement in liver protidosynthetic activity and ascites degree was observed at the end of follow-up, especially in more advanced cases. In most studies, tolerance of rituximab was good. Recent studies in large cohorts of HCV-Cryovas patients did not show significant variation of viremia after rituximab infusions [26]. Some patients may experience systemic drug reactions after rituximab infusion, particularly those with high mixed cryoglobulin levels and low C4 levels and who received 1000 mg highdose rituximab protocol. Therefore, rituximab should be administered with caution in Cryovas patients, with use of the 375 mg/m2 protocol, associated with plasma exchanges prior to rituximab infusion in patients with high baseline MC levels [27]. Rituximab plus Peg-IFNα and ribavirin Based on the limitations of each therapy (i.e. antiviral and rituximab), and the 30% of Cryovas patients that continue to have active disease while receiving rituximab or antiviral therapy, the combination of rituximab with Peg-IFNα-ribavirin appeared logical.