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

M. Ramos-Casals, O. Trejo, M. García-Carrasco and J. Font


    Introduction
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
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].


    Therapeutic options
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
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.

Antiviral therapy
The drug regimens available for treating chronic HCV infection are monotherapy with interferon {alpha} (IFN-{alpha}) and combined therapy with IFN-{alpha} 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.

Interferon {alpha}
IFN-{alpha} treatment is recommended in patients with autoimmune features and proven evidence of replicative HCV infection. IFN-{alpha} 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 [913] reported the benefits of IFN-{alpha} 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-{alpha} 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-{alpha} 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-{alpha} 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-{alpha} preparation should result in improved tolerability, and recent studies in patients with chronic HCV infection have been completed with good results [1921].

Ribavirin
Ribavirin monotherapy may be effective in IFN-{alpha}-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).

Corticosteroid and immunosuppressive therapies
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-{alpha} 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.


    Management of autoimmune features
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
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, 3739]. However, the potential improvement of symptoms and reduction of viraemia must be balanced against the adverse effects of medication, which include IFN-{alpha}-induced autoimmune phenomena, ribavirin toxicity and possible exacerbation of HCV infection caused by immunosuppressive agents [40].

Articular involvement
Arthralgias
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.

Arthritis
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-{alpha}, 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 [4247]. We suggest step-by-step therapeutic management for HCV-related arthritis according to its severity and response to treatment (Table 1Go). 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.


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TABLE 1. Step-by-step therapeutic management of HCV-related arthritis

 

Muscular involvement
There are various reports of polymyositis (PM) associated with chronic HCV infection [4850] 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-{alpha} monotherapy to treat HCV-related PM with the same controversial outcome: some patients responded well, others presented severe aggravation of PM after IFN-{alpha} discontinuation and several worsened, or IFN-{alpha} precipitated myositis [35, 51]. Alric et al. [35] described the improvement of PM after intravenous gammaglobulin treatment in two patients who relapsed after IFN-{alpha} 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, needing careful individual evaluation when considering the use of corticosteroids and/or IFN-{alpha}. More studies are necessary to define the best treatment for PM associated with HCV.

Cutaneous involvement
Numerous case reports have suggested an association between HCV and vasculitis [2, 52]. Patients with HCV-associated vasculitis may present palpable purpura, urticaria or livedo reticularis, most of which present as leucocytoclastic vasculitis associated with cryoglobulinaemia [52, 53]. The most frequent clinical situation is palpable purpura in the legs, requiring non-aggressive management consisting of changes in posture, rest and, in some cases, low doses of corticosteroids (0.1–0.5 mg/kg/day). Severe cutaneous complications, such as ulcers, necrosis and gangrene (overwhelmingly related to cryoglobulinaemic vasculitis), require intensive immunosuppressive therapy with higher doses of corticosteroids, pulses of cyclophosphamide, intravenous gammaglobulins or prostacyclins, and must be monitored closely. Other cutaneous conditions may be associated with chronic HCV infection. The treatment of HCV patients with porphyria cutanea tarda remains uncertain, although one preliminary report suggests a favourable response after phlebotomy [54]. Lichen planus, psoriasis and vitiligo may be induced or exacerbated by IFN-{alpha} therapy [5562].

Renal involvement
There is epidemiological evidence of an association between chronic HCV infection and renal disease [9, 63]. HCV-associated glomerulonephritis is well documented and includes membranous, membranoproliferative and acute proliferative glomerular disease [9, 12, 64, 65] as well as that associated with cryoglobulinaemia [66, 67]. Approximately 30% of patients with chronic HCV infection and renal involvement have complete or partial remission of their renal disease; 30% suffer from intermittent exacerbations and remissions; 30% have an indolent course and end-stage renal disease may not occur for several years in spite of persistent urinary abnormalities; and 10% may develop chronic renal failure [68, 69]. In HCV-related glomerulonephritis, an important aspect must be considered before the onset of therapy with antiviral and/or immunosuppressive agents: the histological demonstration and classification of inflammatory glomerular damage in the renal biopsy, because other non-inflammatory causes of renal involvement (such as hepatorenal syndrome in cirrhotic patients) may exist in patients with chronic HCV infection.

Membranoproliferative glomerulonephritis
The current understanding of the association between chronic HCV infection, mixed cryoglobulinaemia and glomerular disease has prompted the use of antiviral agents in these patients in monotherapy or combined regimens (Table 2Go). The most frequent treatment used has been IFN-{alpha} monotherapy. In numerous studies of patients with MC and glomerulonephritis, monotherapy with IFN-{alpha} has been proved to decrease proteinuria and stabilize renal function [8, 1113, 65, 70, 71]. Most studies showed a significant decrease in proteinuria in HCV-related membranoproliferative glomerulonephritis (MPGN) after IFN-{alpha} monotherapy [9, 12], while other authors did not obtain a response [11]. The effect of this therapy on renal function is discouraging, because there is no significant change in creatinine level [11, 12]. Case reports of successful treatment with higher doses of IFN-{alpha} [72] have been published, and Yamabe et al. [65] have proposed increasing the dose of IFN-{alpha} to up to 10 million units daily for 2 weeks followed by 10 MIU every other day for 6 weeks.


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TABLE 2. Different therapeutic regimens used for treating HCV-related glomerulonephritis

 
The results of IFN-{alpha} monotherapy for HCV-associated MPGN may support the hypothesis that the therapeutic efficacy of IFN-{alpha} is closely related to its antiviral activity. Unfortunately, when treatment is ceased renal function frequently worsens again, often within 6 months to 1 yr [9, 1113]. Some studies suggest that viral genotype and the disappearance of viraemia appear to predict the therapeutic outcome in patients with hepatitis C-associated renal disease [7375].

Ribavirin monotherapy has also been used successfully to treat MC (with and without MPGN) in isolated cases [76, 77]. More recently, combination therapy has been found to be useful in cases that do not respond to monotherapy with either agent [23]. The treatment of HCV-related glomerulonephritis may include immunosuppressive therapy and corticosteroids [12, 78, 79]. A combination of IFN-{alpha} and steroids was used in one patient with cryoglobulinaemic MPGN, resulting in a marked improvement in the clinical and histological manifestations of the renal disease [78].

It appears that, in mild renal disease, IFN with or without low-dose steroids, is currently the best option. Treatment with IFN-{alpha} reduces proteinuria, suppresses viraemia and stabilizes renal function in chronic HCV infection, although patients often relapse after the cessation of therapy [12]. In patients with more severe disease, such as rapidly progressive glomerulonephritis or nephrotic syndrome with a rising creatinine level, a combination of antiviral agents, steroids, cyclophosphamide and/or plasmapheresis may be needed.

Rapidly progressive glomerulonephritis
In severe cases of MPGN or rapidly progressive glomerulonephritis, initial control of the inflammatory reaction with immunosuppressive drugs may be indicated, and severe cases of cryoglobulinaemic MPGN have been treated with corticosteroids combined with cyclophosphamide and/or plasmapheresis [8083]. However, its effects on the underlying liver disease remains to be determined [82].

Isolated cases of coexisting cryoglobulinaemic and antineutrophil cytoplasmic antibody (ANCA) vasculitis have been reported in patients with chronic HCV infection. Lamprecht et al. [84] described two patients with chronic HCV infection, MC and ANCA, both with renal disease. In one patient, treatment with IFN-{alpha} (10 MIU three times a week) achieve a reduction in proteinuria (from 2.4 to 1.1 g/dl) and negativity for cANCA after 6 months of treatment. The second patient did not respond to prednisolone plus oral cyclophosphamide, and creatinine returned to normal values only after five sessions of plasma exchange.

Membranous glomerulonephritis
There are few studies on the management of patients with HCV-related membranous glomerulonephritis (MGN). Stehman-Breen et al. [70] described three patients with HCV-associated MGN treated with IFN-{alpha}. In two patients there was a striking decrease in proteinuria that coincided with a reduction in the circulating HCV RNA level. The third patient, whose initial underlying renal disease was more severe, suffered deterioration of renal function associated with increased ascites and oedema during IFN-{alpha} therapy, and eventually required haemodialysis.


    Neurological involvement
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
Peripheral neuropathy
In contrast to other HCV-related extrahepatic manifestations, peripheral neuropathy (PN) does not respond as favourably to the different therapeutic regimens. In addition, it has been reported that IFN-{alpha} may cause a worsening of PN in patients with HCV MC, despite the improvement of hepatic function [85, 86]. Five recent studies have described the response of PN to different therapeutic options, including antiviral and immunosuppressive agents [24, 32, 34, 87, 88] (Table 3Go). Of the 30 cases of peripheral neuropathy in patients with chronic HCV infection in which a response to therapy was reported, only half presented a favourable response. IFN-{alpha} monotherapy resulted in improvement or stabilization in three patients, while another seven did not respond. Combination with corticosteroids and/or immunosuppressive agents did not improve PN in three patients. The best result was obtained when plasmapheresis was added to IFN-{alpha} and/or immunosuppressive agents, with improvement/stabilization in eight patients; two did not respond. Spontaneous stabilization without treatment was observed in three patients. Zuckerman et al. [24] used combined antiviral therapy (IFN-{alpha} plus ribavirin) to treat PN resistant to other therapies (IFN-{alpha} monotherapy, corticosteroids, immunosuppressive agents), and obtained stabilization or slight improvement in two of the four patients treated.


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TABLE 3. Treatment of neuropathic involvement associated with chronic HCV infection: published studies

 
We suggest that the management of HCV-related PN should be based on its severity and response to treatment. Treatment with corticosteroids and/or IFN-{alpha} monotherapy should be considered as the best initial option in patients with slight to moderate neuropathy [89, 90]. In patients who do not respond, combined antiviral therapy or intravenous immunoglobulins should be considered. Plasmapheresis seems to be the best option in severe or refractory cases.

CNS involvement
Patients with chronic HCV infection may exceptionally present CNS vasculitis related to cryoglobulinaemia [91]. Dawson and Starkebaum [92] described one HCV patient with isolated cerebral vasculitis associated with cryoglobulinaemia who received an intravenous pulse of methylprednisolone, followed by oral prednisone (60 mg/day) and cyclophosphamide. Warfarin and IFN-{alpha} were added later, with substantial improvement of symptoms, and the patient was able to return to work 18 months after the onset of vasculitis.


    Pulmonary involvement
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
There are few data on the treatment of pulmonary alveolitis in patients with chronic HCV infection [93, 94]. The severity of this situation suggests the need for aggressive treatment combining antiviral and immunosuppressive therapies and plasmapheresis. Our personal experience in one HCV patient with acute alveolitis was that treatment with IFN-{alpha} combined with intravenous pulses of methylprednisolone and cyclophosphamide resulted in improvement of pulmonary infiltrates, although progressive liver disease resulted in death.


    Mucosal involvement
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
Sicca syndrome is a frequent finding in patients with chronic HCV infection. The main studies that include large series of patients [95] show that xerostomia is, on average, observed in 18% of HCV patients and xerophthalmia in 15%. Adequate management of sicca syndrome should include the replacement of oral and ocular fluids, practical advice to the patients about their sicca symptoms and their consequences, and a multidisciplinary approach involving different specialities (odontology, ophthalmology, gynaecology, dermatology).


    Thyroid involvement
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
Although chronic HCV infection is associated with a high prevalence of thyroid autoantibodies [9698], only a few patients develop autoimmune thyroid dysfunction [99], and this association has not been clearly demonstrated in patients with chronic HCV infection not treated with IFN-{alpha} [100, 101]. Most HCV patients with thyroid dysfunction are middle-aged women with asymptomatic hypothyroidism and do not require specific treatment.

However, a more striking association of autoimmune thyroid disease in the setting of chronic HCV infection has emerged during IFN-{alpha} treatment. IFN-{alpha} therapy induces thyroid autoantibodies in patients with chronic HCV infection and may precipitate thyroid dysfunction in patients with pre-existing autoantibodies [102, 103], although biochemical abnormalities usually resolve after therapy ends [104, 105]. The management of IFN-{alpha}-induced thyroid dysfunction in chronic HCV infection remains a matter of debate. Some patients treated with thyroid medication before IFN-{alpha} treatment may require increased doses during therapy and decreased doses after IFN-{alpha} therapy has been completed [106, 107]. However, the presence of low titres of autoantibodies should not be regarded as a contraindication for IFN-{alpha} therapy. Because most patients with increased antibody titres or thyroid dysfunction (especially hypothyroidism) under IFN-{alpha} therapy recover after completing therapy, interruption of IFN-{alpha} therapy may not always be required, although treatment must be interrupted in patients with severe symptoms. Screening for autoantibodies and serum TSH is recommended before, during and after IFN-{alpha} treatment, and patients should be informed of the risk of thyroid dysfunction.


    Systemic vasculitis
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
The most common form of vasculitis in patients with chronic HCV infection is cryoglobulinaemic vasculitis affecting mainly small vessels, although in some patients HCV-related vasculitis may not be due to associated cryoglobulinaemia [5]. Clinical manifestations can vary from mild skin disease (purpura, urticaria) and arthralgias to life-threatening renal, neurological or gastrointestinal involvement. In patients with features of cryoglobulinaemic vasculitis, an assessment of the nature and severity of organ involvement is essential before initiating therapy.

Interferon {alpha} monotherapy
In 1987, Bonomo et al. [108] began treating patients with type II cryoglobulinaemia with daily administration of IFN-{alpha}. After the identification of HCV, various studies analysed the effect of IFN-{alpha} monotherapy in the treatment of HCV-related cryoglobulinaemia. The current data come from prospective trials with relatively large numbers of patients [11, 13, 109113]. These studies display considerable differences in the severity of target organ involvement, the underlying vasculitic process, the number of patients included, the dosage and duration of IFN-{alpha} treatment and the end-of-therapy or sustained response rates (biochemical and/or virological). Despite this heterogeneity, some important results have emerged. Treatment with standard doses of IFN-{alpha} produced a response rate ranging from 53 to 100% [11, 13, 109113], although most patients had mild disease affecting mainly the skin (purpura) and joints (arthralgias). More severe involvement, such as renal and neural manifestations, was the most resistant to therapy. Moreover, when therapy was discontinued, a high relapse rate was observed, and although biochemical and virological responses were often seen at the end of therapy, sustained virological responses were observed in less than 20% of cases [9, 11, 13, 109113]. Higher doses of IFN-{alpha} (3 MU/day for 3 months followed by 3 MU three times a week for 9 months) were associated with long-term clinical and virological response in an uncontrolled study by Casato et al. [111]. This regimen resulted in higher rates of alanine aminotransferase normalization than in previous studies, and disappearance of the clinical manifestations of MC (100 and 62% respectively). These results were accompanied by decreases in viraemia, anti-HCV antibody levels and cryocrit.

The disappearance of cryoglobulinaemic features after successful IFN-{alpha} therapy is closely related to the disappearance of HCV RNA from serum [8, 9, 11, 12]. In a controlled study by Misiani et al. [11] in patients with chronic HCV infection with severe symptomatic cryoglobulinaemia, HCV RNA disappeared in 60% of patients. Clinical and immunological manifestations improved only in these patients. However, after IFN-{alpha} cessation all patients suffered viral relapse, followed by recurrence or exacerbation of symptoms. Certain factors, such as low pretreatment cryocrit, HCV RNA level and genotype 2/3, have been associated with a better response to therapy [109, 114]. The study by Casato et al. [111], in spite of the small number of patients, suggests that HCV genotype 1 responds to IFN-{alpha} in the same way as genotype 2, as does the study by Zuckerman et al. [24]. As mentioned above, a clinical response to therapy is usually observed in patients who clear the circulating virus [11, 109], and the long-term response of the cryoglobulinaemic symptoms is closely associated with a sustained virological response [7, 8, 111]. Recent kinetic studies of patients with chronic HCV infection treated with IFN-{alpha} indicate that eradication of the virus requires both daily and extended (24–36 months) treatment [115, 116]. Patients with type II cryoglobulinaemia may need even longer treatment periods. Although the cryoglobulin level initially falls in tandem with the viraemia, undetectable levels of cryoglobulins (cryocrit <1%) may persist long after the apparent serum clearance of the virus [117]. The study by Casato et al. [111] and these new data on the viral kinetics of HCV suggest that prolonged daily administration of IFN-{alpha} should be considered in future therapeutic protocols.

Combined therapies
The successful use of ribavirin monotherapy has been reported in selected patients with HCV-associated MC [22, 76, 77, 118, 119]. Its use in combination with IFN-{alpha} has been evaluated recently in two studies. Donada et al. [120] studied the efficacy of IFN-{alpha}/ribavirin combination therapy in HCV patients with and without cryoglobulins, and found a reduction in cryocrit levels in patients with cryoglobulinaemia. Zuckerman et al. [24] treated nine patients with HCV-related cryoglobulinaemia (previously refractory to IFN-{alpha} monotherapy) with IFN-{alpha} and ribavirin, and found a substantial improvement in some MC-related symptoms but not in others. Arthralgia and/or arthritis resolved completely after 10 weeks of treatment in seven patients and improved in another, and vasculitic lesions disappeared in seven of eight patients and improved in the remaining patient. In the three patients with renal involvement, a substantial decrease in proteinuria was observed in one, a smaller decrease in another and no effect in the third. However, renal function was not normalized in any of the three patients. Polyneuropathy was resistant to treatment, although some improvement was observed in one patient after 4 months of combination therapy. MC symptoms recurred in four patients 6–9 months after cessation of treatment, but a second course of combination therapy achieved a favourable response similar to the first course. Recently, Cacoub et al. [121] described the response to IFN-{alpha} and ribavirin therapy in 27 patients with chronic HCV infection and systemic vasculitis. This study demonstrated that treatment with combined IFN-{alpha} and ribavirin produced a complete clinical response in most patients, which correlated with the eradication of circulating HCV.

For patients with mild or moderate vasculitic symptoms, such as articular involvement or cutaneous vasculitis, IFN-{alpha} with or without ribavirin may suffice, but for patients with life-threatening organ involvement a combination of antiviral agents and immunosuppressive therapy is suggested, although there are few published data. Lamprecht et al. [32] reported an HCV patient with systemic involvement due to cryoglobulinaemia refractory to intravenous cyclophosphamide and oral corticosteroids that finally responded to plasmapheresis, higher doses of intravenous corticosteroids and oral cyclophosphamide. The age of the patient and reactive depression did not allow the introduction of antiviral therapy. The patient improved rapidly, with regression of her livedo reticularis, polyarthritis, paraesthesia and paresis.

Cacoub et al. [34] have recently analysed the outcome of 10 patients with HCV PAN-type vasculitis, five treated with a combination of prednisone (1 mg/kg/day) and plasma exchanges (12 sessions), and five with IFN-{alpha} (3 MIU three times a week for 18–36 months). All patients showed substantial neurological and physical improvement, with normalized blood pressure and regression of ischaemic abdominal pain, purpuric skin lesions and fever. One patient presented a relapse of PAN after cessation of IFN-{alpha}, which rapidly responded to plasmapheresis, IFN-{alpha}, ribavirin and low-dose steroids, with resolution of viraemia and remission of vasculitis.

In spite of the small number of patients in the studies by Zuckerman et al. [24] and Cacoub et al. [34, 121], it may be concluded that, in selected patients with severe and/or refractory HCV-related cryoglobulinaemia, combined antiviral therapy plus corticosteroids and/or immunosuppressive agents may give symptomatic relief and even long-term remission of the cryoglobulinaemic syndrome. In severe, symptomatic cryoglobulinaemic vasculitis, plasmapheresis should also be considered [122, 123]. The optimum length of treatment remains to be established, and severe cases may need long-term or even lifelong therapy.


    Conclusions
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 
The optimal treatment strategy for HCV-related extrahepatic manifestations remains to be defined. Because few data are available, more information is needed before definitive therapeutic recommendations for these extrahepatic HCV features can be established. The therapeutic guidelines for extrahepatic HCV features should be based on clinical features rather than on the underlying pathogenic mechanisms. However, both antiviral and immunosuppressive therapies, either alone or in combination, seem likely to have an important role, although these treatments should be administered with caution. The exacerbation or precipitation of autoimmune symptoms should be monitored closely. Combined antiviral therapy also appears to be effective in treating symptomatic disease, although the relapse rate after discontinuation is high. Conventional corticosteroid therapy, immunosuppressive agents, intravenous immunoglobulins and/or plasmapheresis should be added in specific severe or refractory cases. When long-term immunosuppressive therapy is anticipated, the addition of combined antiviral treatment is specially indicated: this requires very close monitoring of liver function, HCV RNA levels and cell counts. Treatment should be individualized according to cost, follow-up, relapses, organ involvement, risk of exacerbation of autoimmune disease and the possible consequences of immunosuppression in the setting of chronic HCV infection. Table 4Go lists the most common HCV-associated extrahepatic manifestations and possible treatment options. The search for new antiviral treatments, possibly combined with immunosuppressive agents, is urgently needed because of the significant morbidity and mortality associated with these manifestations. Hopefully, further research will establish a safe and effective regimen for treating HCV-related extrahepatic features.


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TABLE 4. Main therapeutic options for the management of extrahepatic manifestations associated with chronic HCV infection

 


    Acknowledgments
 
The authors wish to thank David Buss for his editorial assistance.


    Notes
 
Correspondence to: M. Ramos-Casals, Department of Autoimmune Diseases, Hospital Clínic, C/Villarroel, 170, 08036 Barcelona, Spain. E-mail: mramos{at}clinic.ub.es Back


    References
 Top
 Introduction
 Therapeutic options
 Management of autoimmune...
 Neurological involvement
 Pulmonary involvement
 Mucosal involvement
 Thyroid involvement
 Systemic vasculitis
 Conclusions
 References
 

  1. Choo QL, Kuo G, Weiner AJ et al. Isolation of cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 1989;244:359–62.[ISI][Medline]
  2. Gumber SC, Chopra S. Hepatitis C: a multifaceted disease. Review of extrahepatic manifestations. Ann Intern Med 1995;123:615–20.[Abstract/Free Full Text]
  3. Trejo O, Ramos-Casals M, García-Carrasco M et al. Cryoglobulinemia: Study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine (Baltimore) 2001;80:252–62.[CrossRef][ISI][Medline]
  4. Agnello V. Therapy for cryoglobulinemia secondary to hepatitis C virus: The need for tailored protocols and multiclinic studies. J Rheumatol 2000;27:9–11.[ISI]
  5. Vassilopoulos D, Calabrese LH. Hepatitis C virus infection and vasculitis. Implications of antiviral and immunosuppressive therapies. Arthritis Rheum 2002;46:585–97.[CrossRef][ISI][Medline]
  6. Hadziyannis SJ, Vassilopoulos D. Complex management issues: management of HCV in the atypical patient. Baillière's Clin Gastroenterol 2000;14:277–91.
  7. Bonomo L, Casato M, Afeltra A. Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med 1987;83:726–30.[ISI][Medline]
  8. Dammacco F, Sansonno D, Han JH et al. Natural interferon alfa versus its combination with 6-methyl-prednisolone in therapy of type II mixed cryoglobulinemia: A long term, randomized, controlled study. Blood 1994;84:3336–43.[Abstract/Free Full Text]
  9. Johnson RJ, Gretch DR, Yamabe H et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993;328:465–70.[Abstract/Free Full Text]
  10. Agnello V, Chung R, Kaplan L. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992;327:1490–5.[Abstract]
  11. Misiani, R Bellavita P, Fenili D. Interferon alpha-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330:751–6.[Abstract/Free Full Text]
  12. Johnson RJ, Gretch DR, Couser WG et al. Hepatitis C virus associated glomerulonephritis. Effect of alpha interferon therapy. Kidney Int 1994;46:1700–4.[ISI][Medline]
  13. Ferri C, Marzo E, Longombardo G. Interferon-alpha in mixed cryoglobulinemia patients: a randomized, crossover-controlled trial. Blood 1993;81:1132–6.[Abstract]
  14. Shindo M, DiBisceglie AM, Hoofnagle JH. Long-term follow-up of patients with chronic hepatitis C treated with alfa interferon. Hepatology 1992;15:1013–6.[ISI][Medline]
  15. Gschwantler M, Schrutka-Kolbl C, Weiss W. Acute exacerbation of anti-liver cytosol antibody-positive autoimmune chronic hepatitis by {alpha}-interferon. Am J Gastroenterol 1995;90:2239–40.[ISI][Medline]
  16. Muratori L, Lenzi M, Cataleta M et al. Interferon therapy in liver/kidney microsomal antibody type 1-positive patients with chronic hepatitis C. J Hepatol 1994;21:199–203.[ISI][Medline]
  17. Davis GL, Balart LA, Schiff ER. Treatment of chronic hepatitis C with recombinant interferon alfa. A multicenter randomized, controlled trial. Hepatitis Interventional Therapy Group. N Engl J Med 1989;321:1501–6.[Abstract]
  18. DiBisceglie AM, Martin P, Kassianides C et al. Recombinant interferon alfa therapy for chronic hepatitis C. N Engl J Med 1989;321:1506–10.[Abstract]
  19. Fried MW, Shiffman ML, Reddy KR et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med 2002;347:975–82.[Abstract/Free Full Text]
  20. Heathcote EJ, Shiffman ML, Cooksley WG et al. Peginterferon alfa-2a in patients with chronic hepatitis C and cirrhosis. N Engl J Med 2000;343:1673–80.[Abstract/Free Full Text]
  21. Zeuzem S, Feinman SV, Rasenack J et al. Peginterferon alfa-2a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666–72.[Abstract/Free Full Text]
  22. Durand JM, Cacoub P, Lunel-Fabiani F. Ribavirin in hepatitis C related cryoglobulinemia. J Rheumatol 1998;25:1115–7.[ISI][Medline]
  23. Misiani R, Bellavita P, Baio P et al. Successful treatment of HCV-associated cryoglobulinaemic glomerulonephritis with a combination of interferon-alpha and ribavirin. Nephrol Dial Transplant 1999;14:1558–60.[Abstract]
  24. Zuckerman E, Keren D, Slobodin G et al. Treatment of refractory, symptomatic, hepatitis C virus related mixed cryoglobulinemia with ribavirin and interferon-{alpha}. J Rheumatol 2000;27:2172–8.[ISI][Medline]
  25. Lam KC, Lai CL, Trepo C, Wu PC. Deleterious effect of prednisolone in HBsAg-positive chronic active hepatitis. N Engl J Med 1981;304:380–6.[Abstract]
  26. Rockstroh JK, Spengler U, Sundho T et al. Immuno-suppression may lead to progression of hepatitis C virus (HCV) associated liver disease in HIV–HCV co-infected hemophiliacs. Am J Gastroenterol 1996;91:2563–8.[ISI][Medline]
  27. Schluger LK, Sheiner PA, Thung SN et al. Severe recurrent cholestasic hepatitis C following orthotopic liver transplantation. Hepatology 1996;23:971–6.[ISI][Medline]
  28. Fong TL, Valinluck B, Govindarajan S, Charboneau F, Adkins RH, Redeker AG. Short-term prednisone therapy affects aminotransferase activity and hepatitis C virus RNA levels in chronic hepatitis C. Gastroenterology 1994;107:196–9.[ISI][Medline]
  29. Margin S, Craxi A, Fabiano C et al. Hepatitis C viremia in chronic liver disease: relationshi to interferon alpha or corticosteroid treatment. Hepatology 1994;19:273–9.[ISI][Medline]
  30. Thiele DL, DuCharme L, Cunningham MR et al. Steroid therapy of chronic hepatitis: characteristics associated with response in anti-hepatitis C virus-positive and -negative patients. Am J Gastroenterol 1996;91:300–8.[ISI][Medline]
  31. Bellary S, Schiano T, Hartman G et al. Chronic hepatitis with combined features of autoimmune chronic hepatitis and chronic hepatitis C: favorable response to prednisone and azathioprine. Ann Intern Med 1995;123:32–4.[Free Full Text]
  32. Lamprecht P, Gause A, Gross WL. Cryoglobulinemic vasculitis resistant to intermittent intravenous pulse cyclophosphamide therapy. Scand J Rheumatol 2000;29:201–2.[CrossRef][ISI][Medline]
  33. Buskila D, Shnaider A, Neumann L. Musculoskeletal manifestations and autoantibody profile in 90 hepatitis C virus infected Israeli patients. Semin Arthritis Rheum 1998;28:107–13.[ISI][Medline]
  34. Cacoub P, Maisonobe T, Gatel A, Servan J, Musset L, Piette JC. Systemic vasculitis in patients with hepatitis C. J Rheumatol 2001;28:109–18.[ISI][Medline]
  35. Alric L, Partensky J, Reynaud D, Rauzy O, Duffaut M. Association between polymyositis and hepatitis C infection. Treatment-related difficulties. Rev Med Intern 2000;21:542–6.[ISI]
  36. Krause I, Wu R, Sherer Y, Patanik M, Peter JB, Shoenfeld Y. In vitro antiviral and antibacterial activity of commercial intravenous immunoglobulin preparations—a potential role for adjuvant intravenous immunoglobulin therapy in infectious diseases. Transfus Med 2002;12:133–9.[CrossRef][ISI][Medline]
  37. Calleja JL, Albillos A, Cacho G, Iborra J, Abreu L, Escartin P. Interferon and prednisone therapy in chronic hepatitis C with non-organ-specific antibodies. J Hepatol 1996;24:308–12.[CrossRef][ISI][Medline]
  38. Tran A, Benzaken S, Yang G et al. Chronic hepatitis C and autoimmunity: good response to immunosuppressive treatment. Dig Dis Sci 1997;42:778–80.[CrossRef][ISI][Medline]
  39. Toda G. Interferon or corticosteroid: treatment of patients with chronic hepatitis C positive for serum markers of autoimmune disease. Intern Med 1997;36:233–5.[ISI][Medline]
  40. Wener MH, Johnson RJ, Sasso EH, Gretch DR. Hepatitis C virus and rheumatic disease. J Rheumatol 1996;23:953–9.[ISI][Medline]
  41. Cacoub P, Renou C, Rosenthal E et al. Extrahepatic manifestations associated with hepatitis C virus infection. A prospective multicenter study of 321 patients. The GERMIVIC. Groupe d'Etude et de Recherche en Medecine Interne et Maladies Infectieuses sur le Virus de l'Hepatite C. Medicine (Baltimore) 2000;79:47–56.[CrossRef][ISI][Medline]
  42. Lovy M, Starkebaum G, Uberoi S. Hepatitis C infection with rheumatic manifestations a mimic of rheumatoid arthritis. J Rheumatol 1996;23:979–83.[ISI][Medline]
  43. Bon E, Cantagrel A, Moulinier L et al. Rheumatic manifestations of chronic hepatitis C and response to treatment with interferon alpha-2b. Rev Rhum Engl Ed 1994;61:435–42.
  44. Siegel LB, Cohn L, Nashel D. Rheumatic manifestations of hepatitis C infection. Semin Arthritis Rheum 1993;23:149–54.[ISI][Medline]
  45. Ueno Y, Kinoshita R, Kishimoto I, Okamoto S. Polyartritis associated with hepatitis C virus infection. Br J Rheumatol 1994;33:289–91.[ISI][Medline]
  46. Ueno Y, Kinoshita R, Tsujinoue H et al. A case of hepatitis C virus (HCV)-associated arteritis: quantitative analisis of HCV RNA of the synovial fluid and the serum. Br J Rheumatol 1995;34:691–2.[ISI][Medline]
  47. Barkhuizen A, Bennett RM. Hepatitis C infection presenting with rheumatic manifestations. J Rheumatol 1997;24:123–9.[ISI][Medline]
  48. Weidensaul D, Imam T, Holyst MM et al. Polymyositis, pulmonary fibrosis and hepatitis C. Arthritis Rheum 1995;38:437–9.[Medline]
  49. Horsmans Y, Geubel AP. Symptomatic myopathy in hepatitis C infection without interferon therapy. Lancet 1995;345:1236.
  50. Harada M, Sata M, Yoshida H et al. Inflammatory myopathy associated with hepatitis C virus infection: a report of four cases. Int Hepatol Commun 1995;4:195–200.[CrossRef][ISI]
  51. Arai H, Tanaka M, Ohta K et al. Symptomatic myopathy associated with interferon therapy for chronic hepatitis C. Lancet 1995;345:582.[CrossRef][Medline]
  52. Manna R, Todaro L, Latteri M et al. Leukocytoclastic vasculitis associated with hepatitis C virus antibodies. Br J Rheumatol 1997;36:124–5.[CrossRef][ISI][Medline]
  53. Karlsberg P, Lee WM, Casey DL. Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia. Arch Dermatol 1995;131:1119–23.[Abstract]
  54. Willson RA, Kirby P, Hart J. Association of chronic hepatitis C and porphyria cutanea tarda [abstract]. Hepatology 1992;16:225A.
  55. Cervoni JP, Serfaty L, Picard O, Imber JC, Poupon R. The treatment of hepatitis B and C with interferon-alpha can induce or aggravate psoriasis. Gastroenterol Clin Biol 1995;19:324–5.
  56. Funk J, Langeland T, Schrumpf E, Hanssen LE. Psoriasis induced by interferon-alpha. Br J Dermatol 1991;125:463–5.[ISI][Medline]
  57. Garcia-Lora E, Tercedor J, Massare E, López-Nebot MA, Skiljo M, García-Mellado V. Interferon-induced psoriasis in a patient with chronic hepatitis C. Dermatology 1993;187:280.[ISI][Medline]
  58. Georgetson MJ, Yarze JC, Lalos AT, Webster GF, Martin P. Exacerbation of psoriasis due to interferon-alpha treatment of chronic active hepatitis. Am J Gastroenterol 1993;88:1756–8.[ISI][Medline]
  59. Areias J, Velho GC, Cerqueira R et al. Lichen planus and chronic hepatitis C: exacerbation of the lichen under interferon-alpha 2a therapy. Eur J Gastroenterol Hepatol 1996;8:825–8.[ISI][Medline]
  60. Protzer U, Ochsendorf FR, Leopolder-Ochsendorf A, Holtermüller KH. Exacerbation of lichen planus during interferon alpha 2a therapy for chronic active hepatitis C. Gastroenterology 1993;104:903–5.[ISI][Medline]
  61. Bernstein D, Reddy KR, Jeffers L, Schiff E. Canities and vitiligo complicating interferon therapy for hepatitis C. Am J Gastroenterol 1995;90:1176–7.[ISI][Medline]
  62. Simsek H, Savas C, Akkiz H, Telatar H. Interferon-induced vitiligo in a patient with chronic hepatitis C infection. Dermatology 1996;193:65–6.[ISI][Medline]
  63. Harle J, Disdier P, Dussol B et al. Membranoproliferative glomerulonephritis and hepatitis C infection. Lancet 1993;341:904.
  64. Davda R, Peterson J, Weiner R, Croker B, Lau J. Membranous glomerulonephritis in association with hepatitis C virus infection. Am J Kidney Dis 1993;22:452–5.[ISI][Medline]
  65. Yamabe H, Johnson R, Gretch D et al. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection responsive to interferon-alpha. Am J Kidney Dis 1995;25:67–9.[ISI][Medline]
  66. Misiani R, Bellavita P, Fenili D et al. Hepatitis virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992;117:573–7.[ISI][Medline]
  67. Cacoub P, Fabiani FL, Nusset L et al. Mixed cryoglobulinemia and hepatitis C virus. Am J Med 1994;96:124–32.[ISI][Medline]
  68. D'Amico G, Fornasieri A. Cryoglobulinemic glomerulonephritis: a membranoproliferative glomerulonephritis induced by hepatitis C virus. Am J Kidney Dis 1995;25:361–9.[ISI][Medline]
  69. Kaupke CJ, Vaziri ND. Renal complications of hepatitis C virus infection. West J Med 1996;164:442–3.[ISI][Medline]
  70. Stehman-Breen C, Alpers CE, Couser WG et al. Hepatitis C virus associated membranous glomerulonephritis. Clin Nephrol 1995;44:141–7.[ISI][Medline]
  71. Gilli P, Stabellini N, Storari A et al. Effect of human leukocyte alpha interferon on cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Nephrol Dial Transplant 1996;11:526–8.[ISI][Medline]
  72. Sarac E, Bastacky S, Johnson J. Response to high-dose interferon-alpha after failure of standard therapy in MPGN associated with hepatitis C virus infection. Am J Kidney Dis 1997;30:113–5.[ISI][Medline]
  73. Kanai K, Kako M, Okamoto H. HCV genotypes in the chronic hepatitis C and response to interferon. Lancet 1992;339:1543.[ISI][Medline]
  74. Karino Y, Toyota J, Sugawara M et al. Early loss of serum hepatitis C virus RNA can predict a sustained response to interferon therapy in patients with chronic hepatitis C. Am J Gastroenterol 1997;92:61–5.[ISI][Medline]
  75. Hino K, Sainokami S, Shimoda K et al. Genotypes and titers of hepatitis C virus for predicting response to interferon in patients with chronic hepatitis C. J Med Virol 1994;42:299–305.[ISI][Medline]
  76. Lopes E, Lopes LV, Silva AE. Mixed cryoglobulinemia and membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Ann Intern Med 1996;125:781–2.[Free Full Text]
  77. Blanche P, Bouscary D. Ribavirin therapy for cryoglobulinemia and thrombocytopenia associated with hepatitis C virus infection. Clin Infect Dis 1997;25:1472–3.[ISI][Medline]
  78. Morosetti M, Sciarra G, Meloni C et al. Membranoproliferative glomerulonephritis and hepatitis C: effects of interferon-alpha therapy on clinical outcome and histological pattern. Nephrol Dial Transplant 1996;11:532–4.[ISI][Medline]
  79. Liaw Y, Sheen I, Lin S et al. Effects of prednisolone pretreatment in interferon alpha therapy for patients with chronic non-A, non-B hepatitis. Liver 1993;13:46–50.[ISI][Medline]
  80. Rollino C, Roccatelli D, Giachino O et al. Hepatitis C virus infection and membranous glomerulonephritis. Nephron 1991;59:319–20.[ISI][Medline]
  81. Treichel U, Wandel E, Gerken G et al. HCV associated cryoglobulinemia presenting with vasculitis, hepatitis, and glomerulonephritis: a therapeutic dilemma. Nephrol Dial Transplant 1996;11:1168–71.[ISI][Medline]
  82. Quigg RJ, Brathwaite M, Gardner DF et al. Successful cyclophosphamide treatment of cryoglobulinemic membranoproliferative glomerulonephritis associated with hepatitis C virus infection. Am J Kidney Dis 1995;25:798–800.[ISI][Medline]
  83. Gournay J, Ferrell LD, Roberts JP, Ascher NL, Wright TL, Lake JR. Cryoglobulinemia presenting after liver transplantation. Gastroenterology 1996;110:265–70.[ISI][Medline]
  84. Lamprecht P, Schmitt WH, Gross WL. Mixed cryoglobulinemia, glomerulonephritis, and ANCA: essential cryoglobulinemic vasculitis or ANCA-associated vasculitis? Nephrol Dial Transplant 1998;13:213–21.[Abstract]
  85. Lidove O, Cacoub P, Hausfater P et al. Cryoglobulinémie et hépatite C: aggravation de la neuropathie périphérique après prise d'interféron alpha. Gastroenterol Clin Biol 1999;23:403–6.[ISI][Medline]
  86. Scelsa SN, Herskowitz S, Reichler B. Treatment of mononeuropathy multiplex in hepatitis C virus and cryoglobulinemia. Muscle Nerve 1998;21:1526–9.[CrossRef][ISI][Medline]
  87. Lidove O, Cacoub P, Maisonobe T et al. Hepatitis C virus infection with peripheral neuropathy is not always associated with cryoglobulinemia. Ann Rheum Dis 2001;60:290–2.[Abstract/Free Full Text]
  88. Heckmann JG, Kayser C, Heuss D, Manger B, Blum HE, Neundörfer B. Neurological manifestations of chronic hepatitis C. J Neurol 1999;246:486–91.[CrossRef][ISI][Medline]
  89. Apartis E, Léger JM, Musset L et al. Peripheral neuropathy associated with essential mixed cryoglobulinemia: a role for hepatitis C virus infection? J Neurol Neurosurg Psychiatry 1996;60:661–6.[Abstract]
  90. Khella SL, Frost SL, Hermann GA et al. Hepatitis C infection, cryoglobulinemia, and vasculitic neuropathy. Treatment with interferon alpha: case report and literature review. Neurology 1995;45:407–11.[Abstract]
  91. Petty GW, Duffy J, Houston D Jr. Cerebral ischemia in patients with hepatitis C virus infection and mixed cryoglobulinemia. Mayo Clin Proc 1996;71:671–8.[ISI][Medline]
  92. Dawson TM, Starkebaum G. Isolated central nervous system vasculitis associated with hepatitis C infection. J Rheumatol 1999;26:2273–6.[ISI][Medline]
  93. Limaye AP, Schmidt RA, Glenny RW, Davis CL, Kowdley KV. Successful treatment of severe hepatitis C-associated pulmonary vasculitis in a liver transplant recipient. Transplantation 1998;65:998–1000.[ISI][Medline]
  94. Gomez-Tello V, Onoro-Canaveral JJ, de la Casa Monje RM et al. Diffuse recidivant alveolar hemorrhage in a patient with hepatitis C virus-related mixed cryoglobulinemia. Intensive Care Med 1999;25:319–22.[CrossRef][ISI][Medline]
  95. Ramos-Casals M, Font J, Ingelmo M. Prevalence and clinical significance of hepatitis C virus infection in systemic autoimmune diseases. Med Clin (Barcelona) 2001;116:701–9.[ISI]
  96. Tran A, Quaranta JF, Beusnel C et al. Hepatitis C virus and Hashimoto's thyroiditis. Eur J Med 1992;1:116–8.[Medline]
  97. Quaranta JF, Tran A, Regnier D et al. High prevalence of antibodies to hepatitis C virus in patients with anti-thyroid autoantibodies. J Hepatol 1993;18:136–8.[ISI][Medline]
  98. Tran A, Quaranta JF, Banzaken S et al. High prevalence of thyroid autoantibodies in a prospective series of patients with chronic hepatitis C before interferon therapy. Hepatology 1993;18:253–7.[ISI][Medline]
  99. Custro N, Montalto G, Scafidi V et al. Prospective study on thyroid autoimmunity and dysfunction related to chronic hepatitis C and interferon therapy. J Endocrinol Invest 1997;20:374–80.[ISI][Medline]
  100. Boadas J, Rodriguez-Espinosa J, Enriquez J et al. Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection. J Hepatol 1995;22:611–5.[CrossRef][ISI][Medline]
  101. Metcalfe RA, Ball G, Kudesia G et al. Failure to find an association between hepatitis C virus and thyroid autoimmunity. Thyroid 1997;7:421–4.[ISI][Medline]
  102. Preziati D, LaRosa L, Covini G et al. Autoimmunity and thyroid function in patients with chronic active hepatitis treated with recombinant interferon-alpha 2a. Eur J Endocrinol 1995;132:587–93.[ISI][Medline]
  103. Watanabe U, Hashimoto E, Hisamitsu T et al. The risk factor for development of thyroid disease during interferon alpha therapy for chronic hepatitis C. Am J Gastroenterol 1994;89:399–403.[ISI][Medline]
  104. Marcellin P, Pouteau U, Benhamou JP. Hepatitis C virus infection, alpha interferon therapy and thyroid dysfunction. J Hepatol 1995;22:364–9.[CrossRef][ISI][Medline]
  105. Baudin E, Marcellin P, Pouteau M et al. Reversibility of thyroid dysfunction induced by recombinant alpha interferon in chronic hepatitis C. Clin Endocrinol 1993;39:657–61.[ISI][Medline]
  106. Willson RA. Extrahepatic manifestations of chronic viral hepatitis. Am J Gastroenterol 1997;92:4–15.[ISI]
  107. Lisker-Melman M, DiBisceglie A, Usala S et al. Development of thyroid disease during therapy of chronic viral hepatitis with interferon alpha. Gastroenterology 1992;102:2155–60.[ISI][Medline]
  108. Bonomo L, Casato M, Afeltra A, Caccavo D. Treatment of idiopathic mixed cryoglobulinemia with alpha interferon. Am J Med 1987;83:726–30.[ISI][Medline]
  109. Adinolfi LE, Utili R, Zampino R, Ragone E, Mormone G, Ruggiero G. Effects of long-term course of alpha-interferon in patients with chronic hepatitis C associated to mixed cryoglobulinaemia. Eur J Gastroenterol Hepatol 1997;9:1067–72.[ISI][Medline]
  110. Polzien F, Schott P, Mihm S, Ramadori G, Hartmann H. Interferon-alpha treatment of hepatitis C virus-associated mixed cryoglobulinemia. J Hepatol 1997;27:63–71.[CrossRef][ISI][Medline]
  111. Casato M, Agnello V, Pucillo LP et al. Predictors of long-term response to high-dose interferon therapy in type II cryoglobulinemia associated with hepatitis C virus infection. Blood 1997;90:3865–73.[Abstract/Free Full Text]
  112. Akriviadis EA, Xanthakis I, Navrozidou C, Papadopoulos A. Prevalence of cryoglobulinemia in chronic hepatitis C virus infection and response to treatment with interferon-alpha. J Clin Gastroenterol 1997;25:612–8.[CrossRef][ISI][Medline]
  113. Mazzaro C, Franzin F, Tulissi P et al. Regression of monoclonal B-cell expansion in patients affected by mixed cryoglobulinemia responsive to alpha-interferon therapy. Cancer 1996;77:2604–13.[CrossRef][ISI][Medline]
  114. Mazzaro C, Carniello GS, Colle R et al. Interferon therapy in HCV-positive mixed cryoglobulinaemia: viral and host factors contributing to efficacy of the therapy. Ital J Gastroenterol Hepatol 1997;29:343–50.[ISI][Medline]
  115. Neumann AU, Lam NP, Dahari H et al. Hepatitis C viral dynamics in vivo and antiviral efficacy of interferon-alpha therapy. Science 1998;282:103–7.[Abstract/Free Full Text]
  116. Bekkering FC, Brouwer JT, Leroux-Roels G, VanVlierberghe H, Elewaut A, Schlam SW. Ultrarapid hepatitis C virus clearance by daily high-dose interferon in non-responders to standard therapy. J Hepatol 1998;28:960–4.[CrossRef][ISI][Medline]
  117. Liu F, Knight GB, Agnello V. Hepatitis C virus but not GB virus C/hepatitis G virus has a role in type II cryoglobulinemia. Arthritis Rheum 1999;42:1898–901.[CrossRef][ISI][Medline]
  118. Safadi R, Shouval D, Kaspa RT, Ashur Y, Llan Y. Beneficial effect of ribavirin on hepatitis C-associated cryoglobulinemia after liver transplantation. Liver Transpl Surg 1996;2:263–8.[Medline]
  119. Pham HP, Feray C, Samuel D et al. Effects of ribavirin on hepatitis C-associated nephritic syndrome in four liver transplant recipients. Kidney Int 1998;54:1311–9.[CrossRef][ISI][Medline]
  120. Donada C, Crucitti A, Donadon V, Chemello L, Alberti A. Interferon and ribavirin combination therapy in patients with chronic hepatitis C and mixed cryoglobulinemia. Blood 1998;92:2983–4.[Free Full Text]
  121. Cacoub P, Lidove O, Maisonobe T et al. Interferon-{alpha} and ribavirin treatment in patients with hepatitis C virus-related systemic vasculitis. Arthritis Rheum 2002;46:3317–26.[CrossRef][ISI][Medline]
  122. Ferri C, Moriconi L, Gremignai G et al. Treatment of the renal involvement in mixed cryoglobulinemia with prolonged plasma exchange. Nephron 1986;43:246–53.[ISI][Medline]
  123. Karmochkine M, Bussel A, Leon A, Jarrousse B, Baudelot J, Guillevin L. Long-term plasma exchange. Analysis of indications, outcome and side effects. Ann Med Intern (Paris) 1994;145:373–5.[ISI]
Submitted 15 October 2002; Accepted 5 February 2003





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