Therapeutic management of extrahepatic manifestations in patients with chronic hepatitis C virus infection

The hepatitis C virus (HCV) is a linear, single‐stranded RNA virus of the Flaviviridae family that was identified in 1989 and is recognized as the major causal agent of non‐A, non‐B hepatitis [1]. HCV infection is emerging as an extremely common and insidiously progressive liver disease that is often associated with extrahepatic manifestations, including autoimmune disorders. The clinical relevance of these phenomena is extremely variable, ranging from subclinical features or laboratory abnormalities to overt clinical manifestations that may be severe in some patients. A decade ago, various authors described the association of chronic HCV infection with a heterogeneous group of non‐hepatic conditions, such as pulmonary fibrosis, cutaneous vasculitis, glomerulonephritis, Mooren's ulcer, porphyria cutanea tarda and lichen planus [2], which were regarded as extrahepatic manifestations of chronic HCV infection, though weak association has been found in some of these conditions. More recently, there has been a growing interest in the relationship between chronic HCV infection and systemic autoimmune diseases, mainly Sjögren's syndrome, rheumatoid arthritis (RA), polyarteritis nodosa (PAN), antiphospholipid syndrome and systemic lupus erythematosus, although most of the data are based on small series and case reports. In addition, the predominant role of cryoglobulinaemia in the autoimmune features associated with chronic HCV infection has been increasingly accepted [3]. Diagnosis and treatment of HCV‐related autoimmune features has become a clinical challenge in HCV‐infected patients, in whom chronic liver disease associated with severe autoimmune features may contribute to a very poor prognosis. Although the primary goal in the treatment of patients with chronic HCV infection is the eradication of the virus with combined antiviral therapy, there are few data on the efficiency and safety of this therapy in patients with chronic HCV infection with autoimmune features, as the majority of patients on immunosuppressive regimens or with autoimmune/extrahepatic conditions were excluded from the multicentre trials [4]. The treatment guidelines for HCV‐associated extrahepatic features should be based not only on the pathogenic mechanisms, but also on the accurate, individual assessment of the activity/severity of both extrahepatic clinical features and the underlying liver disease [5]. Adequate management of HCV‐related extrahepatic features should be targeted at two independent (although closely related) goals. The first is the eradication, or at least the reduction, of the circulating viral load with conventional HCV antiviral therapy. The second is the treatment of autoimmune features using corticosteroids, cytotoxic agents and/or plasmapheresis, in order to control the formation, tissue deposition and inflammatory effects of immune complexes. The drug regimens available for treating chronic HCV infection are monotherapy with interferon α (IFN‐α) and combined therapy with IFN‐α and ribavirin [4]. Their use in patients with HCV‐related autoimmune features is controversial due to the lack of available data, as these patients were excluded from multicentre trials due to a potential lack of response to treatment and the appearance of severe side‐effects and/or drug toxicity [6]. However, recent case reports and small series suggest that the use of antiviral therapies in patients with chronic HCV infection and autoimmune manifestations may be efficient and safe. IFN‐α treatment is recommended in patients with autoimmune features and proven evidence of replicative HCV infection. IFN‐α had been proved to be effective in some patients with mixed cryoglobulinaemia (MC) before the identification of HCV and its association with MC [7, 8]. In the 1990s, several groups [9–13] reported the benefits of IFN‐α in HCV‐associated cryoglobulinaemia, although these benefits are limited to patients in whom HCV RNA disappears from serum. This supports other studies in which the clinical and biochemical response to IFN‐α is associated with loss of HCV RNA from serum and long‐term remission of the chronic liver disease is associated with the sustained absence of viraemia [14]. Meticulous monitoring during IFN‐α therapy is needed because, on the one hand, flares of aminotransferases without subsequent HCV RNA clearance have been observed [15, 16] and, on the other hand, IFN‐α therapy is associated with numerous side‐effects, which lead certain patients to discontinue the therapy [17, 18]. Side‐effects occurring during the first 2 weeks of administration include fever, chills, myalgias, anorexia and an influenza‐like syndrome. Long‐term side‐effects include cytopenias, precipitation of autoantibodies, alopecia, lupus‐like autoimmune disease, vasculitis, severe psychological disturbances and increased bacterial infection. The new long‐acting pegylated IFN‐α preparation should result in improved tolerability, and recent studies in patients with chronic HCV infection have been completed with good results [19–21]. Ribavirin monotherapy may be effective in IFN‐α‐intolerant patients with symptomatic HCV cryoglobulinaemia, although its use in patients with renal involvement should be monitored carefully and the effect is not sustained when therapy is discontinued [22]. Misiani et al. [23] found that reduced‐dose ribavirin therapy may produce severe side‐effects in some patients, such as anaemia requiring blood transfusions and erythropoietin therapy, and widespread pruriginous rash resulting in discontinuation of therapy. Zuckerman et al. [24], using an initial dose of 600 mg daily in patients with severe renal failure, described discontinuation of therapy in one patient (due to severe reduction of haemoglobin levels) and a mild reduction in haemoglobin concentration in three others (<2 g/day). Little has been published on the outcome of corticosteroid therapy in patients with chronic HCV infection. The poor disease course of patients with hepatitis B virus treated with corticosteroids [25] led to the suggestion hypothesis that HCV viraemia would be increased in patients treated with these drugs. Some studies have described a rapid progression of liver disease in immunosuppressed patients with chronic HCV infection, i.e. patients coinfected with HIV and HCV and transplanted patients [26, 27]. Other studies found that corticosteroids increased HCV viraemia when given for a short time (1–6 months) and that when corticosteroids were withdrawn the viraemia reverted to previous levels [28, 29]. However, the use of corticosteroids in patients with chronic HCV infection with autoimmune features has been reconsidered recently. Thiele et al. [30] found a favourable response to corticosteroid therapy in patients with chronic HCV infection. Another study showed neither an apparent increase in HCV RNA nor worsened liver function when steroids were combined with IFN‐α to treat HCV‐associated MC [8]. A favourable response of combined autoimmune/HCV hepatitis to prednisone alone or in combination with azathioprine [31] has also been reported. Nevertheless, caution is warranted because the long‐term effects of corticosteroids on the liver function of patients with chronic HCV infection remain unknown [6]. Therapy with immunosuppressive agents in patients with HCV‐related autoimmune features has been little studied. Cyclophosphamide [32], azathioprine [33], plasmapheresis [34] and intravenous immunoglobulins [35] have been used in some patients with chronic HCV infection, although their effects on liver function have not been evaluated and immunoglobulins may also contain anti‐HCV antibodies [36]. We found higher rates of morbidity and mortality in patients with chronic HCV infection receiving immunosuppressive therapies, possibly related to the severity of coexisting hepatic and autoimmune manifestations. Few treatment‐related data are available on the management of the numerous extrahepatic manifestations and autoimmune disorders associated with chronic HCV infection. Recent studies have demonstrated that antiviral therapy, as well as corticosteroids and immunosuppressive therapies, may be effective in managing extrahepatic HCV manifestations, although discontinuation often produces relapses [30, 37–39]. However, the potential improvement of symptoms and reduction of viraemia must be balanced against the adverse effects of medication, which include IFN‐α‐induced autoimmune phenomena, ribavirin toxicity and possible exacerbation of HCV infection caused by immunosuppressive agents [40]. Arthralgias are common in patients with chronic HCV infection: Cacoub et al. [41] reported a prevalence of 19% in a large series of HCV patients. In our opinion, the management of arthralgias in patients with chronic HCV infection should be non‐aggressive, consisting of resting and analgesia with paracetamol 1–4 g/day. The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) requires individual evaluation as they are contraindicated in patients with cirrhosis, although Buskila et al. [33] reported a good response to NSAIDs in eight patients with chronic HCV infection and arthralgias. In selected cases we have used the new anti‐cyclooxygenase 2 (anti‐COX‐2) drugs with a good clinical response and no worsening of liver function. Overt arthritis occurs less frequently than arthralgias, with a prevalence of less than 5% in the main series of patients with chronic HCV infection, and it is usually related to an associated cryoglobulinaemic syndrome. The pattern of arthritis in these patients is intermittent, mono‐ or oligoarticular and non‐erosive, affecting large and medium‐sized joints. Several studies have analysed the therapeutic management of HCV‐related arthritis in small series of patients. Buskila et al. [33] described four patients with arthritis: three responded well to NSAIDs plus low doses of prednisone, whereas the fourth patient showed severe, persistent arthritis refractory to different NSAIDs, oral steroids and intramuscular gold injections; in this patient the addition of azathioprine resulted in a moderate improvement. Lovy et al. [42] reported a good response to hydroxychloroquine and low doses of prednisone (5 mg/day or less) in 19 patients with chronic HCV infection with rheumatic manifestations (15 fulfilling diagnostic criteria for RA), with no evidence of arthritis progression. Bon et al. [43] described four patients with chronic HCV infection with synovitis and/or arthritis who completed a 6‐month course of well‐tolerated IFN‐α, with improvement of articular involvement. Although the optimal treatment for HCV‐related polyarthritis has not yet been determined, it seems that NSAIDs, prednisone and hydroxychloroquine can be used with success and minimal complications [42–47]. We suggest step‐by‐step therapeutic management for HCV‐related arthritis according to its severity and response to treatment (Table 1). The first step should be rest and analgesia, followed by the use of NSAIDs with close monitoring (in non‐cirrhotic patients) or anti‐COX‐2 therapy. The second step should be the use of antimalarial drugs (indicated in patients with a lupus‐like disease) and low doses of corticosteroids (<15 mg/day). The use of immunosuppressive agents, such as methotrexate and azathioprine, should be considered for severe and refractory arthritis in individual cases, with close monitoring of liver function, HCV RNA levels and cell counts. Step‐by‐step therapeutic management of HCV‐related arthritis aRequires close monitoring of liver function, HCV RNA levels and cell counts. Step‐by‐step therapeutic management of HCV‐related arthritis aRequires close monitoring of liver function, HCV RNA levels and cell counts. There are various reports of polymyositis (PM) associated with chronic HCV infection [48–50] and different therapeutic options have been used, with controversial results. On the one hand, corticosteroids have been indicated in some patients. Buskila et al. [33] described in one case a reduction in symptoms and enzyme levels after prednisone therapy, while Alric et al. [35] reported that corticosteroids increased serum alanine aminotransferase in two patients, leading to severe liver damage in one. In some patients, cytotoxic agents were successfully added to prednisone therapy [48]. On the other hand, some authors have used IFN‐α monotherapy to treat HCV‐related PM with the same controversial outcome: some patients responded well, others presented severe aggravation of PM after IFN‐α discontinuation and several worsened, or IFN‐α precipitated myositis [35, 51]. Alric et al. [35] described the improvement of PM after intravenous gammaglobulin treatment in two patients who relapsed after IFN‐α discontinuation. In the light of these results, HCV‐related PM should be considered an extrahepatic condition of chronic HCV infection for which therapeutic management is difficult, individual evaluation when the use of corticosteroids and/or More studies are to the treatment for PM associated with case reports have an association between HCV and with HCV‐associated may or most of which as associated with cryoglobulinaemia The most clinical is in the requiring management consisting of in rest and, in some cases, low doses of corticosteroids cutaneous such as and related to cryoglobulinaemic immunosuppressive therapy with higher doses of corticosteroids, of intravenous or and must be monitored Other cutaneous conditions may be associated with chronic HCV infection. The treatment of HCV patients with porphyria cutanea tarda although one a favourable response after and may be or by IFN‐α therapy There is evidence of an association between chronic HCV infection and renal disease HCV‐associated is well and and disease as well as that associated with cryoglobulinaemia of patients with chronic HCV infection and renal involvement have or remission of their renal from and have an course and renal disease may not for several in of persistent and may chronic renal In HCV‐related glomerulonephritis, an must be considered before the of therapy with antiviral and/or immunosuppressive the and of inflammatory damage in the renal because other of renal involvement as syndrome in patients) may in patients with chronic HCV infection. The of the association between chronic HCV infection, mixed cryoglobulinaemia and disease has the use of antiviral agents in these patients in monotherapy or combined regimens (Table The most treatment used has been IFN‐α In numerous studies of patients with MC and glomerulonephritis, monotherapy with IFN‐α has been proved to and renal function studies showed a in in HCV‐related after IFN‐α monotherapy while other authors not a response The effect of this therapy on renal function is because there is no in reports of treatment with higher doses of IFN‐α have been and et al. have the dose of IFN‐α to to daily for 2 weeks followed by other for The results of IFN‐α monotherapy for HCV‐associated may the hypothesis that the therapeutic of IFN‐α is closely related to its antiviral when treatment is renal function frequently often to Some studies suggest that viral and the of viraemia to the therapeutic outcome in patients with hepatitis renal disease Ribavirin monotherapy has also been used successfully to treat MC and without in cases More recently, combination therapy has been found to be in cases that not to monotherapy with agent The treatment of HCV‐related may include immunosuppressive therapy and corticosteroids A combination of IFN‐α and steroids was used in one patient with cryoglobulinaemic resulting in a improvement in the clinical and manifestations of the renal disease in mild renal disease, with or without is the with IFN‐α viraemia and renal function in chronic HCV infection, although patients often after the of therapy In patients with severe disease, such as progressive or syndrome with a a combination of antiviral agents, and/or plasmapheresis may be therapeutic regimens used for treating HCV‐related therapeutic regimens used for treating HCV‐related In severe cases of or progressive glomerulonephritis, initial control of the inflammatory with immunosuppressive drugs may be and severe cases of cryoglobulinaemic have been treated with corticosteroids combined with and/or plasmapheresis However, its effects on the underlying liver disease to be cases of coexisting cryoglobulinaemic and have been reported in patients with chronic HCV infection. et al. described two patients with chronic HCV infection, MC and both with renal In one treatment with IFN‐α three a a reduction in to and for after of The second patient not to plus oral and to only after of There are few studies on the management of patients with HCV‐related et al. described three patients with HCV‐associated treated with In two patients there was a in that with a reduction in the circulating HCV RNA The initial underlying renal disease was severe, of renal function associated with increased and during IFN‐α therapy, and In to other HCV‐related extrahepatic manifestations, not as to the different therapeutic In addition, it has been reported that IFN‐α may a worsening of in patients with HCV the improvement of hepatic function recent studies have described the response of to different therapeutic including antiviral and immunosuppressive agents (Table the cases of in patients with chronic HCV infection in which a response to therapy was only presented a favourable IFN‐α monotherapy resulted in improvement or in three patients, while not with corticosteroids and/or immunosuppressive agents not in three patients. The result was when plasmapheresis was added to IFN‐α and/or immunosuppressive agents, with in eight two not without treatment was observed in three patients. Zuckerman et al. used combined antiviral therapy plus to treat to other therapies corticosteroids, immunosuppressive and or improvement in two of the four patients We suggest that the management of HCV‐related should be based on its severity and response to with corticosteroids and/or IFN‐α monotherapy should be considered as the initial in patients with to moderate In patients who not combined antiviral therapy or intravenous immunoglobulins should be seems to be the in severe or refractory of involvement associated with chronic HCV infection: published studies of involvement associated with chronic HCV infection: published studies with chronic HCV infection may related to cryoglobulinaemia and described one HCV patient with associated with cryoglobulinaemia who an intravenous of followed by oral prednisone and and IFN‐α were added with improvement of and the patient was to to after the of There are few data on the treatment of pulmonary in patients with chronic HCV infection The severity of this the for treatment antiviral and immunosuppressive therapies and in one HCV patient with was that treatment with IFN‐α combined with intravenous of and resulted in improvement of pulmonary although progressive liver disease resulted in syndrome is a in patients with chronic HCV infection. The main studies that include large series of patients that on observed in of HCV patients and in Adequate management of syndrome should include the of oral and to the patients their symptoms and their and a different Although chronic HCV infection is associated with a prevalence of only a few patients autoimmune and this association has not been demonstrated in patients with chronic HCV infection not treated with IFN‐α HCV patients with are with and not However, a association of autoimmune disease in the of chronic HCV infection has during IFN‐α IFN‐α therapy in patients with chronic HCV infection and may in patients with although biochemical abnormalities usually after therapy The management of IFN‐α‐induced in chronic HCV infection a of Some patients treated with before IFN‐α treatment may increased doses during therapy and doses after IFN‐α therapy has been completed However, the of low of should not be regarded as a for IFN‐α therapy. most patients with increased or IFN‐α therapy after therapy, of IFN‐α therapy may not be although treatment must be in patients with severe for and serum is recommended during and after IFN‐α and patients should be of the of The most common of in patients with chronic HCV infection is cryoglobulinaemic affecting mainly small although in some patients HCV‐related may not be due to associated cryoglobulinaemia [5]. manifestations can from mild disease and arthralgias to or involvement. In patients with features of cryoglobulinaemic vasculitis, an assessment of the and severity of involvement is before therapy. In et al. treating patients with cryoglobulinaemia with daily administration of the identification of various studies analysed the effect of IFN‐α monotherapy in the treatment of HCV‐related The data from trials with large of patients studies in the severity of the underlying the of patients the and of IFN‐α treatment and the or sustained response rates and/or this some results have with doses of IFN‐α a response ranging from to although most patients had mild disease affecting mainly the and More severe such as renal and manifestations, was the most to therapy. when therapy was a was and although biochemical and were often at the of therapy, sustained were observed in less than of cases doses of IFN‐α for followed by three a for months) were associated with long‐term clinical and response in an study by et al. This resulted in higher rates of alanine aminotransferase than in previous and of the clinical manifestations of MC and results were by in anti‐HCV levels and The of cryoglobulinaemic features after IFN‐α therapy is closely related to the of HCV RNA from serum In a study by Misiani et al. in patients with chronic HCV infection with severe symptomatic cryoglobulinaemia, HCV RNA in of patients. and manifestations improved only in these patients. However, after IFN‐α patients viral followed by or exacerbation of such as low HCV RNA and have been associated with a response to therapy The study by et al. in of the small of patients, that HCV to IFN‐α in the same as as the study by Zuckerman et al. a clinical response to therapy is usually observed in patients who the circulating virus and the long‐term response of the cryoglobulinaemic symptoms is closely associated with a sustained response [7, Recent studies of patients with chronic HCV infection treated with IFN‐α that eradication of the virus requires both daily and months) treatment with cryoglobulinaemia may treatment Although the in with the levels of may after the apparent serum clearance of the virus The study by et al. and these new data on the viral of HCV suggest that daily administration of IFN‐α should be considered in therapeutic The use of ribavirin monotherapy has been reported in selected patients with HCV‐associated MC use in combination with IFN‐α has been evaluated in two et al. the of combination therapy in HCV patients with and without and found a reduction in levels in patients with Zuckerman et al. treated patients with HCV‐related cryoglobulinaemia refractory to IFN‐α with IFN‐α and and found a improvement in some symptoms but not in and/or arthritis after weeks of treatment in patients and improved in and in of eight patients and improved in the In the three patients with renal a in was observed in a in and no effect in the However, renal function was not in of the three patients. was to although some improvement was observed in one patient after of combination therapy. MC symptoms in four patients after of but a second course of combination therapy a favourable response to the first Cacoub et al. described the response to IFN‐α and ribavirin therapy in patients with chronic HCV infection and systemic This study demonstrated that treatment with combined IFN‐α and ribavirin a clinical response in most patients, which with the eradication of circulating patients with mild or moderate such as articular involvement or cutaneous vasculitis, IFN‐α with or without ribavirin may but for patients with involvement a combination of antiviral agents and immunosuppressive therapy is although there are few published et al. reported an HCV patient with systemic involvement due to cryoglobulinaemia refractory to intravenous and oral corticosteroids that responded to plasmapheresis, higher doses of intravenous corticosteroids and oral The of the patient and not the of antiviral therapy. The patient improved with of and Cacoub et al. [34] have analysed the outcome of patients with HCV vasculitis, treated with a combination of prednisone and and with IFN‐α three a for patients showed and with blood and of and patient presented a of after of IFN‐α, which responded to plasmapheresis, IFN‐α, ribavirin and with of viraemia and remission of In of the small of patients in the studies by Zuckerman et al. and Cacoub et al. it may be in selected patients with severe and/or refractory HCV‐related cryoglobulinaemia, combined antiviral therapy plus corticosteroids and/or immunosuppressive agents may symptomatic and long‐term remission of the cryoglobulinaemic syndrome. In severe, symptomatic cryoglobulinaemic vasculitis, plasmapheresis should also be considered The of treatment to be and severe cases may long‐term or therapy. The optimal treatment for HCV‐related extrahepatic manifestations to be few data are is needed before therapeutic for these extrahepatic HCV features can be The therapeutic guidelines for extrahepatic HCV features should be based on clinical features than on the underlying pathogenic However, both antiviral and immunosuppressive therapies, alone or in to have an although these should be with The exacerbation or precipitation of autoimmune symptoms should be monitored antiviral therapy also to be effective in treating symptomatic disease, although the after discontinuation is corticosteroid therapy, immunosuppressive agents, intravenous immunoglobulins and/or plasmapheresis should be added in severe or refractory long‐term immunosuppressive therapy is the addition of combined antiviral treatment is this requires very close monitoring of liver function, HCV RNA levels and cell counts. should be according to of exacerbation of autoimmune disease and the possible of in the of chronic HCV infection. the most common HCV‐associated extrahepatic manifestations and possible treatment The for new antiviral possibly combined with immunosuppressive agents, is needed because of the morbidity and mortality associated with these manifestations. a and effective for treating HCV‐related extrahepatic therapeutic options for the management of extrahepatic manifestations associated with chronic HCV infection intravenous aRequires individual therapeutic options for the management of extrahepatic manifestations associated with chronic HCV infection intravenous aRequires individual of The authors to for