Lupus (2015) 24, 469–482 http://lup.sagepub.com

SPECIAL ARTICLE

Extrahepatic manifestations in chronic hepatitis C virus carriers E Rosenthal1,2 and P Cacoub3–6 1

Service de Me´decine Interne, Hoˆpital de l’Archet, CHU de Nice, Nice; Universite´ de Nice-Sophia Antipolis, Nice, France; 2COREVIH PACA EST, CHU de Nice, France; 3Sorbonne Universite´s, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France; 4INSERM, UMR_S 959, Paris, France; 5CNRS, FRE3632, Paris, France; and 6AP-HP, Groupe Hospitalier Pitie´-Salpeˆtrie`re, Department of Internal Medicine and Clinical Immunology, Paris, France

Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild. Lupus (2015) 24, 469–482. Key words: Hepatitis C virus; extrahepatic manifestations; cryoglobulinemia; vasculitis

Introduction Hepatitis C virus (HCV) infection is a major public health problem with an estimated 3 million to 4 million people infected each year worldwide; some 130 million to 170 million people or 3% of the world’s population are chronically infected with the HCV. A high proportion of people with chronic HCV infection, ranging from 45% to 85%, are thought to be unaware of their status.1 Each year, more than 350,000 patients die from HCV-related liver diseases, with mortality rates in HCV-infected individuals being up to three times higher than those in the general population.2,3 In the United States (US), chronic hepatitis C is both the most common cause of liver-related death and the main reason for liver transplantation.4 HCV causes chronic systemic infection, which primarily affects Correspondence to: Eric Rosenthal, Service de Me´decine InterneCance´rologie, Hoˆpital Archet 1, 151 route de Saint-Antoine de Ginestie`re, 06202 Nice cedex 3, France. Email: [email protected]

the liver with a risk of developing liver cirrhosis and/or liver cancer. HCV is uniquely associated not only with liver diseases but also with an array of extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection.5,6 These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate its course in almost half of chronic HCV carriers.7 Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases.8,9 HCV is also a lymphotropic virus10 that triggers B cells and promotes favorable conditions for B lymphocyte proliferation. As a consequence, several lymphoproliferative disorders have been associated with the virus, including mixed cryoglobulinemia (MC), B-cell non-Hodgkin’s lymphoma and monoclonal gammopathies.11 HCV may also promote a low-grade chronic systemic inflammation12,13 that may affect the development of some extrahepatic manifestations of HCV, particularly

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cardiovascular and cerebral vascular diseases. Recently, a large community-based cohort study showed that HCV infection was associated not only with death from hepatic, but also from extrahepatic diseases, in particular circulatory diseases.14 In addition, recent findings show that effective clearance of the virus can reduce not only the global mortality as already reported,16–19 but also mortality due to extrahepatic causes.15 The development of direct-acting antiviral agents (DAAs) has revolutionized HCV treatment by resulting in more than 90% of viral eradication and by offering genuine prospects for the first comprehensive cure of a chronic viral infection in humans. Clinicians need to be aware of the burden of the disease, the role of extrahepatic manifestations in mortality, how these might alter patient management,20,21 and how to manage the treatment of these patients. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. This review examines the available data on the extrahepatic manifestations associated with HCV infection, and assesses their clinical implications, focusing on recently described cardiovascular and cerebrovascular features and new therapeutic aspects.

MC vasculitis Pathophysiology and main clinical features Cryoglobulinemia vasculitis is a small-vessel vasculitis involving the skin, the joints, the peripheral nerve system and the kidneys. HCV represents the cause of cryoglobulinemia vasculitis in roughly 80% of cases.5,22,23 Cryoglobulins are readily detectable in 40% to 60% of HCV-infected patients,24 whereas overt cryoglobulinemic vasculitis (or mixed cryoglobulinemia) develops in only 5% to 10% of these cases.24 Although the majority of HCV-infected patients with MC do not have symptomatic extrahepatic disease, they are prone to develop cryoglobulinemia-related symptoms in the future.25 Disease expression is variable, ranging from mild clinical symptoms (i.e. purpura and arthralgia) to fulminant life-threatening complications (i.e. glomerulonephritis and widespread vasculitis). Manifestations of MC associated with HCV infection include systemic vasculitis (prevalence, 4–40%), i.e. palpable purpura (18–33%), fatigue (35–54%), arthralgia-myalgia (35–54%), sicca syndrome (10–25%), neuropathy (11–30%), and renal complications such as membranoproliferative glomerulonephritis (27%).26–31 Careful evaluation

is required to ensure correct diagnosis of MC vasculitis since these symptoms may be observed in other disorders, including rheumatoid arthritis (RA) and primary Sjo¨gren’s syndrome32,33 (Figure 1). The observation of T cells in vascular infiltrates, the presence of autoantibodies (i.e. type II mixed cryoglobulin), and the genetic association between some human leukocyte antigen (HLA) alleles and susceptibility to MC in HCV-infected patients support the suggestion that there is an autoimmune component to this virus-linked condition.34–39 MC appears to result from the interaction between HCV and lymphocytes, which directly modulates the function of B cells and T cells and results in the activation and expansion of B cells that produce immunoglobulin (Ig)M with rheumatoid-factor activity.5,36 In addition, a quantitative defect in regulatory T cells (Tregs) was reported in people with HCV-induced MC.34,24,40 In patients with MC who could be successfully treated for HCV infection, clearance of the virus was associated with the cure of vasculitis and the recovery of Treg levels.41,42 Therefore, Tregs may have beneficial effects for patients with HCV-induced vasculitis. Tregs have a low threshold of response to interleukin-2 receptor signaling, which supports their development and peripheral homeostasis.43 An open-label phase 1–phase 2a trial recently showed that low-dose interleukin-2 led to Tregs recovery and was associated with clinical improvement in eight of 10 patients with HCV-induced vasculitis.44 Treatment HCV-induced MC vasculitis usually responds to clearance of HCV during combination therapy with pegylated-interferon plus ribavirin. In addition, patients experiencing viral suppression on interferon-alpha therapy have a significant improvement in cryoglobulinemia, as demonstrated by two prospective, randomized, controlled trials.45,46 Such patients who relapse to HCV infection after responding to a course of antiviral therapy usually relapse for the vasculitis with the return of viremia.47 In patients with persistent MC, relapse of MC vasculitis might also occur in a few patients despite achieving a sustained virological response (SVR). In patients with persistent MC vasculitis symptoms, a different underlying condition should be considered, especially B-cell lymphoma.40 Rituximab is an interesting therapy in MC, as it targets B cells that are responsible for cryoglobulin production, immune complex deposition and

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Figure 1 Differential diagnosis between mixed cryoglobulinemia and other autoimmune-lymphoproliferative disorders in the context of HCV infection. HCV: hepatitis C virus; MC: mixed cryoglobulinemia; B-NHL: B-cell non-Hodgkin’s lymphoma; RA: rheumatoid arthritis; SS: Sjo¨gren’s syndrome; RF: rheumatoid factor; anti-CCP: anticyclic citrullinated peptide antibodies.

finally vasculitis lesions.48–50 The results of a literature review51 showed that the main indication for rituximab therapy was non-response to other previous treatments (n ¼ 50), intolerance to previous treatments (n ¼ 3), or associated lymphoma (n ¼ 2), or as a first-line therapy for MC (n ¼ 2). Rituximab was reported to reduce signs of vasculitis, with a complete clinical response in 73% of patients for skin involvement, 53% for arthralgia, 36% for neuropathy and 70% for glomerulonephritis. A randomized, controlled trial in 57 patients with cryoglobulinemia vasculitis (including 53 HCV-positive patients) compared conventional treatment (i.e. glucocorticoids, azathioprine or cyclophosphamide, or plasmapheresis) and rituximab.52 No patient received concomitant antiviral therapy, either because it was contraindicated (n ¼ 28) or it had been ineffective or poorly tolerated (n ¼ 25). The proportion of patients who continued their initial therapy 12 months after treatment was statistically higher in the rituximab group (64.3% vs 3.5%). Similar results have been reported in a placebo-controlled trial in the United States (US).53 Based on the limitations of each therapy (antiviral and rituximab), and the fact that at least 30% of MC patients continue to have active disease while receiving rituximab or antiviral

therapy, the combination of rituximab with pegylated-interferon plus ribavirin appeared logical. This approach was initially assessed in a small series of 16 patients with severe refractory HCVrelated vasculitis. Clinical improvement was seen in 15 patients, 10 of whom were complete responders.54 Complete remission of peripheral neuropathy and nephropathy was achieved in 38% and 57% of cases, respectively. Two recent controlled clinical trials confirmed these results. They compared the efficacy and safety profile of pegylated-interferon/ribavirin versus rituximab plus pegylated-interferon/ribavirin in HCV-MC patients. In both studies, patients treated with rituximab plus pegylated-interferon/ribavirin had a shorter time to clinical remission, better renal response rate, and higher rates of cryoglobulin clearance than those who had received pegylatedinterferon plus ribavirin.42,55 Recent use of triple anti-HCV therapy with pegylated-interferon/ribavirin and a specifically targeted antiviral agent led to improved sustained virological response (i.e. viral eradication) rates in patients infected with the HCV genotype 1. In an open-label, prospective, single-center cohort study,56 the safety and efficacy of a combination therapy with pegylated-interferon/ribavirin plus Lupus

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an NS3/4A protease inhibitor (boceprevir or telaprevir) was evaluated in 23 patients with HCV-MC vasculitis. Thirteen patients (56.5%) were complete clinical responders and 10 (43.5%) were partial responders. Grades 3 and 4 adverse events (mainly anemia, neutropenia and thrombocytopenia) were observed in 10 cases (43.5%). This combination seems highly effective in HCV-MC patients; however, such a therapeutic regimen should be administered cautiously considering the high rate of side effects. Other direct-acting antivirals, specifically designed to inhibit three viral proteins (the NS3/4A protease, the NS5A protein, and the NS5B RNA-dependent RNA polymerase) are now becoming available. The NS3/4A inhibitor simeprevir and NS5B inhibitor sofosbuvir have recently been licensed. They are able to reduce the length of antiviral treatment, improve virological response rates, and allow for interferon-free regimens (for some HCV genotypes). These agents seem to facilitate the use of shortened courses of combination interferon-free therapy, which are associated with high (>95%) sustained response rates and relatively few toxicities. International

guidelines57,58 state that treatment should be scheduled, not deferred, for patients with significant liver fibrosis. Recommended treatment options differ according to the exposure to previous HCV therapy, HCV genotype and pretreatment assessment for comorbidities that may influence treatment response. Today no specific treatment recommendation is provided for patients with MC vasculitis. However, insofar as sustained virological clearance has been previously associated with MC vasculitis remission in most patients, no doubt new HCV treatments should show a major benefit in such patients. Therapeutic guidelines Antiviral treatment has been recommended for HCV-related MC vasculitis with mild to moderate disease. For patients with severe vasculitis, including glomerulonephritis with renal insufficiency or intestinal ischemia, control of disease with potent immunosuppressive regimens, with or without plasmapheresis, is usually required before initiation of antiviral therapy59 (Figure 2). In the context of new DDAs that are both highly and rapidly active,

Figure 2 Therapeutic strategies in HCV-related cryoglobulinemic vasculitis. HCV: hepatitis C virus. Lupus Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 27, 2015

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recently published therapeutic guidelines may already look old-fashioned.60 The introduction of new antiviral drugs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related cryoglobulinemic vasculitis, making it possible to individualize the choice of therapeutic combinations according to the patient’s treatment history.

Rheumatologic diseases, sicca syndrome and autoantibody production Rheumatologic manifestations such as polyarthralgia and arthritis are frequently observed in patients with HCV. The relationship between rheumatologic disorders and HCV is difficult to determine. First, symptoms of arthralgia and arthritis are common in adults with other forms of liver disease, and second, some studies suggest that the prevalence of these conditions might be similar in patients with or without HCV.61–63 A causative association has not yet been identified, but several pathogenetic mechanisms might be involved.64 HCV arthritis could be part of the MC syndrome. It might also be linked to a direct invasion of synovial cells by the virus or a cytokine-induced disease.65,66 Polyarthralgia is the most common rheumatologic symptom in HCV-infected patients5 with a prevalence of up to 23%.67 Two subsets of HCV arthritis have been identified, a polyarthritis involving small joints resembling mild RA and an intermittent mono-oligoarthritis associated with the presence of serum cryoglobulins.68 RA-like HCV arthritis is more common, and the presence of rheumatoid factor has been identified in 50–80% of cases.69 However, rheumatoid factor activity is often found in HCV-infected patients because of the presence of type II MC, whether in the presence or absence of joint symptoms, and its occurrence does not necessarily imply a diagnosis of actual RA. Patients with HCV arthritis might present with arthralgia or rarely synovitis. To distinguish between actual RA and HCV arthritis, clinicians should test for anticyclic citrullinated peptide antibodies, which are frequently positive in RA and rarely found in HCVinfected patients with RA-like polyarthritis.70,71 Unlike RA, no erosive joint changes are noted in HCV arthritis, and the condition does not often respond to anti-inflammatory therapy. An association between HCV infection and Gougerot-Sjo¨gren syndrome has been suggested.

The first report of chronic lymphocytic sialadenitis in patients with HCV infection was published in 1992, reporting a prevalence of 57% of HCVinfected patients versus 5% in controls.72 Subsequently, experimental and epidemiological studies showed high rates of salivary gland involvement in patients with HCV infection.73 Analysis of further prospective studies has been made difficult by the different diagnostic scales74,75 used to differentiate Gougerot-Sjo¨gren syndrome from the similar but less severe sicca syndrome.74–76 In cohorts of patients with definite primary Gougerot-Sjo¨gren syndrome, HCV antibodies were found in only 4–11% of patients,77–79 with one study reporting a prevalence of 19%.76 In prospective studies of HCV-infected patients, sicca syndrome is frequently reported at a prevalence ranging from 9% to 67%.5,80–82 The large range might be related to differences between the diagnostic criteria applied.83 Histologic examination of salivary glands in HCV-infected patients usually shows changes different from those found in GougerotSjo¨gren syndrome, including pericapillary and non-pericanalary lymphocytic infiltration, and lack of damage of the glandular canals. Thus, although ocular and/or mouth sicca syndrome is frequently found in HCV-infected patients, definite Gougerot-Sjo¨gren syndrome is rare. There is no frank improvement of such sicca syndrome after HCV treatment, even after SVR is achieved.84 Further research is required to establish whether the observed link between HCV and sicca syndrome has a causal basis.85 Apart from MC production, other immunologic abnormalities are frequently found in HCVinfected patients including antinuclear (17–41%), anti-smooth muscle cell (9–40%), antithyroglobulin (8–13%), and anticardiolipin (20–27%) antibodies.71,81,83,86–88 In general, no clinical correlation has been found between such autoantibodies and hepatic or extrahepatic manifestations. However, a higher prevalence of hypothyroidism in patients receiving interferon alpha has been demonstrated in patients who present with antithyroglobulin antibodies.89 Considering the high prevalence of HCV infection, clinicians should be aware of the high frequency of these autoantibodies, which can lead to misdiagnosis of autoimmune diseases.

Lymphomas Early after its discovery, it was shown that HCV, a hepatotropic virus, is also a lymphotropic virus.10 Lupus

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As a consequence, several lymphoproliferative disorders (LPDs) have been associated with this virus, including MC, B-cell non-Hodgkin’s lymphoma (NHL) and monoclonal gammopathies.11,90 Although clinically benign, MC is a pre-lymphomatous disorder leading to B-NHL in about 5–10% of cases. This makes MC a valuable model for the study of pathogenic mechanisms of HCV-related LPDs. MC was previously interpreted as a lymphoma in situ, being characterized by bone marrow and/or liver infiltrates closely resembling NHL.91,92 Therefore, it was hypothesized that HCV may be involved in the pathogenesis of NHL as well.10,93 An association between lymphomas and HCV has been suggested by the relatively high prevalence of HCV seropositivity (15%) in patients with B-cell LPDs, particularly B-cell NHL.94 Findings from epidemiologic research and meta-analyses indicate that patients positive for anti-HCV had a 2.5-fold increased risk of NHL versus controls.95 After adjusting for sex and age, the overall risk for lymphomas was more than doubled in HCVpositive individuals (relative risk (RR), 2.4) compared with HCV-negative individuals. This positive association with HCV was present regardless of primary site of presentation (nodal NHL (RR, 2.5) and extranodal NHL (RR, 3.7)). The increase in risk was even higher in HCV-infected patients with MC vasculitis (RR, 35).96,97 The association between HCV and cryoglobulinemia, NHL, and even Waldenstrom’s macroglobulinemia was given further strong support in a large analysis of the US Veterans Administration database.98 Some evidence suggests that effective HCV treatment might be beneficial in the management of some subtypes of lymphoma. In a small group of patients with splenic lymphoma featuring villous lymphocytes,97,99 and in some low-grade lymphomas,100 therapy with interferon plus ribavirin achieved lymphoma regression. However, results of sufficiently large, controlled trials on the effect of HCV treatment in a broad spectrum of NHL are not yet available. The biological mechanism linking HCV infection with the development of lymphoma remains under debate.101–104 However, it is likely that the mechanisms involved in MC and NHL pathogenesis share similar features. It is possible that the antigen-driven, benign clonal B-cell lymphoproliferation of HCV-MC might occasionally progress to overt, low-grade NHL on continued antigenic stimulation. Consistent with this, the lymphomas in HCV patients frequently express the same rheumatoid factor-encoding Ig genes as do the cells involved in cryoglobulinemia, strongly suggesting an antigen-dependent component

common to both conditions.105–107 A fundamentally different mechanism probably underlies the development of aggressive, higher-grade HCVrelated NHL in the absence of MC. HCV has been proposed to directly infect B cells, leading to their malignant transformation.108 In a study of 75 patients with chronic HCV infection, a multivariate analysis revealed that the presence of HCV RNA in B cells was an independent risk factor associated with at least one marker of lymphoproliferation.109 HCV has alternatively been postulated to exert its oncogenic potential by an indirect mechanism through HCV antigen stimulation of B cells via an increase in BLyS ligandreceptor activity38,104,110 or directly through growth stimulation of B cells to counter HCVinduced apoptosis.110 Persistent HCV stimulation might initiate growth dysregulation of infected cells as part of a multistep process, eventually giving rise to malignant LPD.36 Worse survival outcomes have been reported for HCV-positive patients with diffuse large B-cell lymphoma compared with non-HCV-infected patients, and this has been attributed to the short-term hepatotoxicity of chemotherapy.111

Renal manifestations Both glomerular and tubulointerstitial diseases associated with HCV have been described.112–117 However, the exact mechanism of these diseases is unclear. An association between HCV infection and albuminuria without overt kidney disease has also been described. Hence, HCV infection may have a greater influence on renal dysfunction than is presently documented.118,119 The most common renal manifestation of HCV infection is MC leading to membranoproliferative glomerulonephritis (MPGN).27,120 Although MPGN is most commonly associated with HCV infection, other glomerulonephritides are also reportedly associated with HCV, including membranous nephropathy, focal segmental glomerulosclerosis, postinfectious glomerulonephritis, thrombotic microangiopathies, IgA nephropathy, and fibrillary or immunotactoid glomerulopathy.121 While the long-term effects of HCV-associated glomerulopathies are unclear, studies have shown that patients with HCV infection, irrespective of etiology, are 40% more likely to develop end-stage renal disease than the general population.122,123 In addition, a large, communitybased cohort study showed that anti-HCV-seropositive patients, particularly anti-HCV-seropositive

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individuals with positive HCV RNA, had an increased risk of dying from renal diseases compared with anti-HCV-seronegative patients.14 As a result of the evidence on this subject, the Kidney Disease Improving Global Outcomes (KDIGO) group has specific guidelines relating to HCV and kidney disease. In these guidelines, KDIGO recommends that all patients with chronic kidney disease should be tested for HCV.124 Despite the lack of well-designed trials, KDIGO also recommends that patients with acute flares of MC and MPGN be treated with interferon-based antiviral therapy. Such recommendations should soon be modified considering new HCV interferon-free regimens.

Glucose disorders The association between type 2 diabetes (T2DM) and chronic hepatitis C was first reported in 1994 by Allison et al., who observed that the prevalence of T2DM was significantly higher in those with HCV-related cirrhosis than those with cirrhosis resulting from other liver diseases.125 The diagnosis of HCV infection and the identification of risk factors for HCV infection preceded the diagnosis and/or onset of T2DM in anti-HCV-positive diabetic patients.126 Generally, the prevalence of anti-HCV seropositivity in the T2DM population ranged from 1.8% to 12.1%, whereas T2DM developed in 14.5–33.0% of patients with chronic hepatitis C.125,127–133 Different background in terms of ethnicity, age, prevalence of T2DM, body mass index (BMI), viral load and genotype may contribute to the divergent results of the epidemiological observations. In contrast, positive HCV infection status was not associated with metabolic syndrome in a multivariate analysis of a National Health and Nutrition Examination Survey database. However, it was associated with high homeostasis model assessment of insulin resistance (HOMA-IR) levels.134 In addition, a large seven-year prospective cohort study of Taiwanese patients found HCV infection to be an independent predictor of diabetes, especially for anti-HCV-positive people who are younger or have a higher BMI.135 Recent meta-analyses based on retrospective studies suggested a significant relationship between HCV and new-onset T2DM after liver and renal transplantation.136,137 Along with these lines of evidence, viral eradication has been shown to effectively ameliorate IR138 and may attenuate the risk of new-onset T2DM.139,140 It remains unknown, however, how treatment of

concomitant HCV infection will influence outcomes in patients with established T2DM. Three processes acting either independently or synergistically to promote IR have been proposed.141 First, IR might result from the fibrosis and possible cirrhosis caused by HCV. Second, HCV has a direct effect on insulin sensitivity. Although the specific mechanisms are not fully elucidated, evidence suggests that alterations in specific proinflammatory cytokines such as tumor necrosis factor-a (TNF-a) might lead to impaired insulin signaling. In addition, TNF-a has been implicated in the development of IR via a downregulation of insulin receptor substrate-1 and a stimulation of lipolysis, leading to increased free fatty acids. Third, obesity in patients with concomitant hepatitis C might play a role in the development of insulin signaling defects, leading to IR and subsequent coexistent steatosis, which might be found in more than 50% of chronically infected patients.142 White adipose tissue from visceral adiposity produces a number of important adipocytokines, including adiponectin, leptin, resistin, visfatin, vaspin, and apelin, as well as TNF-a, interleukin-6, and interleukin-8,65,143 which might contribute to the development or worsening of IR in patients with hepatitis C.66,144,145

Cardiovascular and cerebrovascular diseases Although several reasons such as virus-induced steatosis and/or underlying metabolic abnormalities including IR as well as increased inflammatory process contributing to endothelial dysfunction,146–150 may contribute to cardiovascular diseases in patients infected with HCV (Figure 3), the relationship between HCV infection and circulatory diseases is unclear. Several studies utilizing surrogate markers for coronary artery diseases (CAD) risk suggested that patients with HCV had a 25–185% increased risk of CAD, whereas others failed to show this association.151–155 Some studies have also raised the potential protective role of HCV.156–158 For example, Bilora et al.158 found lower rates of carotid artery atherosclerosis among patients with chronic HCV compared to patients with non-HCV underlying liver disease (27% vs. 56%, p < 0.005). Corey et al.157 found lower levels of low-density lipoprotein (LDL) in HCV-patients compared to uninfected controls (94.3 vs. 120.8 mg/dl, p < 0.0001). Recently, Wong et al. performed a systematic review to further investigate this association.159 The primary Lupus

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Figure 3 Factors associated with hepatitis C virus infection that contribute to the chronic inflammation and its involvement in hepatic and extrahepatic conditions. Adapted from Zampino R, Marrone A, Restive L, et al. Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol 2013; 5: 528–540.161 HCV: hepatitis C virus; HCC: hepatocellular carcinoma.

CAD-related endpoints included myocardial infarction, congestive heart failure, need for coronary artery bypass grafting, or transluminal percutaneous angioplasty. They identified five studies (four cohort studies and one case-control study) that met the defined inclusion criteria. A significant association between HCV and CAD was demonstrated in one cohort study (adjusted hazard ratio (HR) 1.27; 95% confidence interval (CI) 1.22–1.31). One cohort study demonstrated a decreased risk of CAD associated with HCV (adjusted OR 0.74; 95% CI 0.71–0.76). The remaining three studies did not find a significant association between HCV and risk of CAD. An additional study investigated the association between myocardial conditions and HCV in patients with HCV-related chronic hepatitis using thallium-201 myocardial

scintigraphy.160 A myocardial injury was confirmed by severity score, which was calculated as the sum of thallium-201 perfusion defect scores. Severity score was followed prior to and after interferon therapy in 200 patients with chronic hepatitis C. An abnormal electrocardiogram (ECG) was found in 9% of the patients with chronic hepatitis C. Abnormal severity score was found in 87% of the chronic hepatitis C patients. Independent factors related to higher pretreatment severity score were histology activity index score, serum HCV RNA titer, and indocyanine green disappearance rate. After interferon therapy, severity score was improved in patients with sustained virologic response. Among relapsers, severity score improved at the initial disappearance of HCV RNA, but it worsened with the reappearance of HCV RNA.

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Severity score in non-viral responders did not change with interferon therapy. It has been reported that chronic HCV infection is an independent risk factor of cerebrovascular events and deaths.162 Carotid atheromatous plaque destabilization is a critical event that underlies the onset of stroke. Plaque rupture and erosion give rise to thrombus formation and embolization, which leads to brain ischemic injury in 20–30% of all cases of ischemic stroke. Inflammation is the key mediator of plaque rupture and thromboembolism.163 HCV RNA has been isolated and replicates within carotid plaques.164 It has been demonstrated that HCV-infected patients have higher hepatic and systemic markers of inflammation.165,166 A specific association between inflammatory markers and atherosclerosis has been demonstrated in HCVinfected patients.167 Human brain endothelial cells express functional receptors for HCV entry and replication supporting possible direct vascular damage.166 Adinolfi et al. evaluated the prevalence and role of HCV infection in patients who present with a stroke. Overall, 820 consecutive patients were enrolled, 123 with stroke and, as controls, 697 age- and gender-matched (295 with chronic obstructive pulmonary disease; 402 with diseases other than HCV associated).168 Patients were evaluated for HCV and conventional risk factors of stroke. Prevalence of HCV was higher in patients with stroke than that observed in controls (26.8% vs. 6.6%, p ¼ 0.0001). An analysis of stroke patients showed that those HCV positive were younger (p ¼ 0.017), had lower serum levels of cholesterol (p ¼ 0.001) and triglycerides (p ¼ 0.045), and higher serum levels of inflammation markers (erythrocyte sedimentation rate (ESR), p ¼ 0.001; C-reactive protein (CRP), p ¼ 0.0001; fibrinogen, p ¼ 0.012). A multivariate analysis showed that HCV infection was an independent risk factor of stroke (odds ratio (OR) 2.04, 95% CI 1.69–2.46; p ¼ 0.0001). A secondary analysis showed that HCV patients had higher (p ¼ 0.031) prevalence of past ischemic heart disease. This study seems to support a direct HCV role because stroke in HCV population occurs at a younger age, irrespective of sex and in patients with low rates of known risk factors of stroke/atherosclerosis (i.e. cholesterol/triglycerides levels, hypertension). The data also support a pathogenic role of local and/or systemic inflammation induced by HCV infection (Figure 3).161 A contemporaneous published paper evaluating a large population-based cohort showed that HCV infection increased by 23% the risk of ischemic stroke and that interferon-based treatment reduced the risk of ischemic stroke in

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chronic hepatitis C patients. Although future trials are necessary to evaluate the impact of therapeutic HCV clearance on development of atherosclerosis and its cardiac or cerebrovascular complications, these data suggest starting early the treatment of HCV infection, irrespective of liver disease progression.

Cognitive impairment, depression and altered health-related quality of life (HRQOL) Cognitive impairment is well described in chronic HCV infection and is a common symptom in people with end-stage liver disease.170 Whether this impairment is directly attributable to the infection itself or results from one of the several commonly occurring comorbid conditions associated with this population remains contentious. In the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) trial, 33% of 201 HCVinfected patients with advanced liver fibrosis who underwent neuropsychological testing had mild cognitive impairment (i.e. standard score < 40 on at least four of 10 tests) on entering the trial.171 A small pilot study (n ¼ 38) recently suggested that patients with chronic HCV infection who are free from comorbid factors do have higher levels of cognitive impairment than healthy controls.172 A prospective clinical trial (n ¼ 34) has shown that successful eradication of HCV leads to improved cognitive function.173 A frequent and severe cognitive function impairment has also been reported in HCV-MC patients.174 These data suggest a possible impact of HCV on cognitive impairment; however, further investigation is required to draw firm conclusions. Depression has been documented in 28% of chronically HCV-infected patients by using the Structured Clinical Interview for DSM-IV Axis I Disorders: Clinician Version before HCV therapy.175 Fatigue has been reported in more than half of HCV-infected patients before HCV treatment.176 Depression might simply be related to the psychological burden of chronic HCV infection or its treatment, although some studies suggest that HCV might directly affect the CNS through alterations in serotoninergic and dopaminergic neurotransmission, with resultant depressive symptoms.177 This mechanism might explain other CNS symptoms seen in HCV infection, such as fatigue and cognitive impairment, although a causal link remains to be established.174,178 Interestingly, the rate of fatigue has been shown Lupus

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to decrease significantly in patients with SVR, but not in nonresponders or relapsers, suggesting a direct role of the virus.84 HCV infection has been associated with a decreased ability to function both at work and at home, with obvious cost implications. Poor HRQOL can also lead to difficulties with interpersonal relations, decreased feelings of self-value and utility, and depression. On the basis of the Short Form 36 Health Survey questionnaire, patients with chronic HCV infection consistently show deficits in several domains, particularly those involving their physical role, general health, and vitality, versus healthy controls.179–181 Of note, Functional Assessment of Chronic Illness Fatigue scale has been used before and after treatment with a new anti-HCV combination (pegylatedinterferon, ribavirin and sofosbuvir) showing a significant improvement in SVRs.182 Old guidelines recommended, before starting antiviral therapy for HCV, a thorough mental health assessment, because patients with a history of depressive disorder were at greater risk of developing depression during HCV treatment.183,184 In some cases, antidepressant or anxiolytic treatment was considered before initiating HCV therapy.184,185 However, new HCV treatment combinations—interferon free—should now greatly benefit such patients.

Conclusions Deleterious effects of HCV are not confined to the liver alone. Epidemiologic data and to some extent evolution under treatment clearly link HCV infection with MC vasculitis, lymphoproliferative disorders, kidney diseases, IR, T2DM, cerebrovascular and cardiovascular diseases, RA-like polyarthritis, cognitive impairment, depression, altered HRQOL and many other manifestations. The involvement of several body systems other than the liver indicates that chronic HCV infection should be considered as a systemic disease rather than a single liver disease. Physician education programs might help health care providers recognize the less than obvious extrahepatic effects of HCV and specifically motivate them to ask their patients about these effects. The management of diseases previously thought to be unrelated to HCV might need to be modified to allow coordination of care across multiple specialties. In the era of DDAs, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.

Funding This research received no specific grant from any funding agency in the public, commercial, or notfor-profit sectors.

Conflict of interest statement The authors have no conflicts of interest to declare.

References 1 Smith BD, Morgan RL, Beckett GA, et al. Recommendations for the identification of chronic hepatitis C virus infection among persons born during 1945–1965. MMWR Recomm Rep 2012; 61: 1–32. 2 Lavanchy D. The global burden of hepatitis C. Liver Int 2009; 29(Suppl 1): 74–81. 3 Neal KR, Trent Hepatitis C Study Group, Ramsay S, Thomson BJ, Irving WL. Excess mortality rates in a cohort of patients infected with the hepatitis C virus: A prospective study. Gut 2007; 56: 1098–1104. 4 U.S. Department of Health and Human Services. Organ Procurement and Transplantation Network. U.S. liver transplants performed: January 1, 1988–April 30, 2008, http://www.optn.org/ (accessed 30 July 2009). 5 Cacoub P, Poynard T, Ghillani P, et al. Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum 1999; 42: 2204–2212. 6 Misiani R, Bellavita P, Fenili D, et al. Hepatitis C virus infection in patients with essential mixed cryoglobulinemia. Ann Intern Med 1992; 117: 573–577. 7 Sansonno D. Immune-related disorders and extrahepatic diseases in chronic HCV infection. Clin Dev Immunol 2012; 2012: 509309. 8 Matsuki K, Murumata M, Yoshida K, et al. Chronic inflammation associated with hepatitis C virus infection perturbs hepatic transforming growth factor beta signaling, promoting cirrhosis and hepatocellular carcinoma. Hepatology 2007; 46: 48–57. 9 Dalagiorgou G, Vassalaki N, Foka P, et al. High levels of HCV coreþ1 antibodies in HCV patients with hepatocellular carcinoma. J Gen Virol 2011; 92: 1343–1351. 10 Zignego AL, Macchia D, Monti D, et al. Infection of peripheral mononuclear blood cells by hepatitis C virus. J Hepatol 1992; 15: 382–386. 11 Zignego AL, Giannini C, Gragnani L. HCV and lymphoproliferation. Clin Dev Immunol 2012; 2012: 980942. 12 Heydtmann M. Macrophages in hepatitis B and hepatitis C infections. J Virol 2009; 83: 2796–2802. 13 Mencin A, Kluwe J, Schwabe RF. Toll-like receptors as targets in chronic liver diseases. Gut 2009; 58: 704–720. 14 Lee MH, Yang HI, Lu SN, et al. Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: A community-based long-term prospective study. J Infect Dis 2012; 206: 469–477. 15 Berenguer J, Alvarez-Pellicer J, Martı´ n PM, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complications and mortality in patients coinfected with human immunodeficiency virus and hepatitis C virus. Hepatology 2009; 50: 407–413. 16 Deuffic-Burban S, Deltenre P, Louvet A, et al. Impact of viral eradication on mortality related to hepatitis C: A modeling approach in France. J Hepatol 2008; 49: 175–183. 17 Lawson A, Hagan S, Rye K, et al. The natural history of hepatitis C with severe hepatic fibrosis. J Hepatol 2007; 47: 37–45. 18 Picciotto FP, Tritto G, Lanza AG, et al. Sustained virological response to antiviral therapy reduces mortality in HCV reinfection after liver transplantation. J Hepatol 2007; 46: 459–465.

Lupus Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 27, 2015

Extrahepatic manifestations in chronic hepatitis C virus carriers E Rosenthal and P Cacoub

479 19 Iacobellis A, Siciliano M, Perri F, et al. Peginterferon alfa-2b and ribavirin in patients with hepatitis C virus and decompensated cirrhosis: A controlled study. J Hepatol 2007; 46: 206–212. 20 Alberti A. What are the comorbidities influencing the management of patients and the response to therapy in chronic hepatitis C? Liver Int 2009; 29(Suppl 1): 15–18. 21 Zignego AL, Ferri C, Pileri SA, et al. Extrahepatic manifestations of hepatitis C virus infection: A general overview and guidelines for a clinical approach. Dig Liver Dis 2007; 39: 2–17. 22 Saadoun D, Sellam J, Ghillani-Dalbin P, et al. Increased risks of lymphoma and death among patients with nonhepatitis C virusrelated mixed cryoglobulinemia. Arch Intern Med 2006; 166: 2101–2108. 23 Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins: A report of 86 cases. Am J Med 1974; 57: 775–788. 24 Saadoun D, Rosenzwajg M, Landau D, Piette JC, Klatzmann D, Cacoub P. Restoration of peripheral immune homeostasis after rituximab in mixed cryoglobulinemia vasculitis. Blood 2008; 111: 5334–5341. 25 Puchner KP, Berg T. Extrahepatic manifestations of chronic hepatitis C virus infection. Gastroenterol 2009; 47: 446–456. 26 Alpers CE, Smith KD. Cryoglobulinemia and renal disease. Curr Opin Nephrol Hypertens 2008; 17: 243–249. 27 Alric L, Plaisier E, Thebault S, et al. Influence of antiviral therapy in hepatitis C virus-associated cryoglobulinemic MPGN. Am J Kidney Dis 2004; 43: 617–623. 28 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: 3317–3326. 29 Ferri C, Sebastiani M, Giuggioli D, et al. Mixed cryoglobulinemia: Demographic, clinical, and serologic features and survival in 231 patients. Semin Arthritis Rheum 2004; 33: 355–374. 30 Duvoux C, Tran NA, Intrator L, et al. Hepatitis C virus (HCV)related cryoglobulinemia after liver transplantation for HCV cirrhosis. Transpl Int 2002; 15: 3–9. 31 Stefanova-Petrova DV, Tzvetanska AH, Naumova EJ, et al. Chronic hepatitis C virus infection: Prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients. World J Gastroenterol 2007; 13: 6518–6528. 32 Ferri C, Mascia MT. Cryoglobulinemic vasculitis. Curr Opin Rheumatol 2006; 18: 54–63. 33 Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010; 8: 1017–1029. 34 Boyer O, Saadoun D, Abriol J, et al. CD4þCD25þ regulatory T-cell deficiency in patients with hepatitis C-mixed cryoglobulinemia vasculitis. Blood 2004; 103: 3428–3430. 35 Lenzi M, Frisoni M, Mantovani V, et al. Haplotype HLA-B8-DR3 confers susceptibility to hepatitis C virus-related mixed cryoglobulinemia. Blood 1998; 91: 2062–2066. 36 Saadoun D, Landau DA, Calabrese LH, Cacoub P. Hepatitis C-associated mixed cryoglobulinaemia: A crossroad between autoimmunity and lymphoproliferation. Rheumatology (Oxford) 2007; 46: 1234–1242. 37 Cacoub P, Renou C, Kerr G, et al. Influence of HLA-DR phenotype on the risk of hepatitis C virus-associated mixed cryoglobulinemia. Arthritis Rheum 2001; 44: 2118–2124. 38 Se`ne D, Levasseur F, Abel M, et al. Hepatitis C virus (HCV) evades NKG2D-dependent NK cell responses through NS5Amediated imbalance of inflammatory cytokines. PLoS Pathog 2010; 6: e1001184. 39 Landau DA, Saadoun D, Calabrese LH, Cacoub P. The pathophysiology of HCV induced B-cell clonal disorders. Autoimmun Rev 2007; 6: 581–587. 40 Landau DA, Saadoun D, Halfon P, et al. Relapse of hepatitis C virus-associated mixed cryoglobulinemia vasculitis in patients with sustained viral response. Arthritis Rheum 2008; 58: 604–611. 41 Landau DA, Rosenzwajg M, Saadoun D, Tre´beden-Negre H, Klatzmann D, Cacoub P. Correlation of clinical and virologic responses to antiviral treatment and regulatory T cell evolution in patients with hepatitis C virus-induced mixed cryoglobulinemia vasculitis. Arthritis Rheum 2008; 58: 2897–2907.

42 Saadoun D, Resche Rigon M, Sene D, et al. Rituximab plus Peginterferon-alpha/ribavirin compared with Peg-interferonalpha/ ribavirin in hepatitis C-related mixed cryoglobulinemia. Blood 2010; 116: 326–334. 43 Malek TR. The biology of interleukin-2. Annu Rev Immunol 2008; 26: 453–479. 44 Saadoun D, Rosenzwajg M, Joly F, et al. Regulatory T-cell responses to low-dose interleukin-2 in HCV-induced vasculitis. N Engl J Med 2011; 365: 2067–2077. 45 Ferri C, Marzo E, Longombardo G, et al. Interferon-alpha in mixed cryoglobulinemia patients: A randomized, crossover-controlled trial. Blood 1993; 81: 1132–1136. 46 Misiani R, Bellavita P, Fenili D, et al. Interferon alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994; 330: 751–756. 47 Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P. Antiviral therapy for hepatitis C virus-associated mixed cryoglobulinemia vasculitis: A long-term followup study. Arthritis Rheum 2006; 54: 3696–3706. 48 Zaja F, De Vita S, Mazzaro C, et al. Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 2003; 101: 3827–3834. 49 Sansonno D, De Re V, Lauletta G, Tucci FA, Boiocchi M, Dammacco F. Monoclonal antibody treatment of mixed cryoglobulinemia resistant to interferon alpha with an anti-CD20. Blood 2003; 101: 3818–3826. 50 Roccatello D, Baldovino S, Rossi D, et al. Long-term effects of anti-CD20 monoclonal antibody treatment of cryoglobulinaemic glomerulonephritis. Nephrol Dial Transplant 2004; 19: 3054–3061. 51 Cacoub P, Delluc A, Saadoun D, Landau DA, Sene D. Anti-CD20 monoclonal antibody (rituximab) treatment for cryoglobulinemic vasculitis: Where do we stand? Ann Rheum Dis 2008; 67: 283–287. 52 De Vita S, Quartuccio L, Isola M, et al. A randomized controlled trial of rituximab for the treatment of severe cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64: 843–853. 53 Sneller MC, Hu Z, Langford CA. A randomized controlled trial of rituximab following failure of antiviral therapy for hepatitis C virus-associated cryoglobulinemic vasculitis. Arthritis Rheum 2012; 64: 835–842. 54 Saadoun D, Resche-Rigon M, Sene D, Perard L, Karras A, Cacoub P. Rituximab combined with Peg-interferon-ribavirin in refractory HCV-associated cryoglobulinemia vasculitis. Ann Rheum Dis 2008; 67: 1431–1436. 55 Dammacco F, Tucci FA, Lauletta G, et al. Pegylated interferonalpha, ribavirin, and rituximab combined therapy of hepatitis C virus-related mixed cryoglobulinemia: A long-term study. Blood 2010; 116: 343–353. 56 Saadoun D, Resche Rigon M, Thibault V, et al. Peg-IFNa/ ribavirin/protease inhibitor combination in hepatitis C virus associated mixed cryoglobulinemia vasculitis: Results at week 24. Ann Rheum Dis 2014; 73: 831–837. 57 American Association for the Study of Liver Diseases. Infectious Diseases Society of America. Recommendations for testing, managing, and treating hepatitis C, http://www.hcvguidelines.org/sites/ default/files/full_report.pdf (Accessed July 2014) 58 European Association for Study of Liver. EASL Clinical Practice Guidelines: Management of hepatitis C virus infection. J Hepatol 2014; 60: 392–420. 59 Saadoun D, Delluc A, Piette JC, Cacoub P. Treatment of hepatitis C-associated mixed cryoglobulinemia vasculitis. Curr Opin Rheumatol 2008; 20: 23–28. 60 Cacoub P, Terrier B, Saadoun D. Hepatitis C virus-induced vasculitis: Therapeutic options. Ann Rheum Dis 2014; 73: 24–30. 61 Guennoc X, Narbonne V, Jousse-Joulin S, et al. Is screening for hepatitis B and hepatitis C useful in patients with recent-onset polyarthritis? The ESPOIR cohort study. J Rheumatol 2009; 36: 1407–1413. 62 Hsu FC, Starkebaum G, Boyko EJ, Dominitz JA. Prevalence of rheumatoid arthritis and hepatitis C in those age 60 and older in a US population based study. J Rheumatol 2003; 30: 455–458. 63 Maillefert JF, Muller G, Falgarone G, et al. Prevalence of hepatitis C virus infection in patients with rheumatoid arthritis. Ann Rheum Dis 2002; 61: 635–637. Lupus

Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 27, 2015

Extrahepatic manifestations in chronic hepatitis C virus carriers E Rosenthal and P Cacoub

480 64 Zuckerman E, Yeshurun D, Rosner I. Management of hepatitis C virus-related arthritis. BioDrugs 2001; 15: 573–584. 65 Sheikh MY, Choi J, Qadri I, Friedman JE, Sanyal AJ. A case of hepatitis C virus infection: Molecular pathways to metabolic syndrome. Hepatology 2008; 47: 2127–2133. 66 Bajaj M, Suraamornkul S, Hardies LJ, Pratipanawatr T, DeFronzo RA. Plasma resistin concentration, hepatic fat content, and hepatic and peripheral insulin resistance in pioglitazonetreated type II diabetic patients. Int J Obes Relat Metab Disord 2004; 28: 783–789. 67 Rosner I, Rozenbaum M, Toubi E, Kessel A, Naschitz JE, Zuckerman E. The case for hepatitis C arthritis. Semin Arthritis Rheum 2004; 33: 375–387. 68 Palazzi C, Olivieri I, Cacciatore P, Pennese E, D’Amico E. Management of hepatitis C virus-related arthritis. Expert Opin Pharmacother 2005; 6: 27–34. 69 Lormeau C, Falgarone G, Roulot D, Boissier MC. Rheumatologic manifestations of chronic hepatitis C infection. Joint Bone Spine 2006; 73: 633–638. 70 Se`ne D, Ghillani-Dalbin P, Limal N, et al. Anti-cyclic citrullinated peptide antibodies in hepatitis C virus associated rheumatological manifestations and Sjogren’s syndrome. Ann Rheum Dis 2006; 65: 394–397. 71 Cacoub P, Musset L, Amoura Z, et al. Anticardiolipin, anti-beta2glycoprotein I, and antinucleosome antibodies in hepatitis C virus infection and mixed cryoglobulinemia: Multivirc Group. J Rheumatol 1997; 24: 2139–2144. 72 Haddad J, Deny P, Munz-Gotheil C, et al. Lymphocytic sialadenitis of Sjo¨gren’s syndrome associated with chronic hepatitis C virus liver disease. Lancet 1992; 339: 321–323. 73 Ramos-Casals M, Loustaud-Ratti V, De Vita S, et al. SS-HCV Study Group. Sjo¨gren syndrome associated with hepatitis C virus: A multicenter analysis of 137 cases. Medicine 2005; 84: 81–89. 74 Fox RI. Sjo¨gren’s syndrome. Lancet 2005; 366: 321–331. 75 Manthorpe R. Sjo¨gren’s syndrome criteria. Ann Rheum Dis 2002; 61: 482–484. 76 Vitali C, Moutsopoulos HM, Bombardieri S. The European Community Study Group on diagnostic criteria for Sjo¨gren’s syndrome: Sensitivity and specificity of tests for ocular and oral involvement in Sjo¨gren’s syndrome. Ann Rheum Dis 1994; 53: 637–647. 77 Jorgensen C, Legouffe MC, Perney P, et al. Sicca syndrome associated with hepatitis C virus infection. Arthritis Rheum 1996; 39: 1166–1171. 78 Ramos-Casals M, Garcı´ a-Carrasco M, Cervera R, et al. Hepatitis C virus infection mimicking primary Sjo¨gren syndrome. A clinical and immunologic description of 35 cases. Medicine (Baltimore) 2001; 80: 1–8. 79 Verbaan H, Carlson J, Eriksson S, et al. Extrahepatic manifestations of chronic hepatitis C infection and the interrelationship between primary Sjo¨gren’s syndrome and hepatitis C in Swedish patients. J Intern Med 1999; 245: 127–132. 80 Loustaud-Ratti V, Riche A, Liozon E, et al. Prevalence and characteristics of Sjo¨gren’s syndrome or sicca syndrome in chronic hepatitis C virus infection: A prospective study. J Rheumatol 2001; 28: 2245–2251. 81 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. 82 Goh J, Coughlan B, Quinn J, O’Keane JC, Crowe J. Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. Eur J Gastroenterol Hepatol 1999; 11: 833–838. 83 Clifford BD, Donahue D, Smith L, et al. High prevalence of serological markers of autoimmunity in patients with chronic hepatitis C. Hepatology 1995; 21: 613–619. 84 Cacoub P, Ratziu V, Myers RP, et al. Impact of treatment on extra hepatic manifestations in patients with chronic hepatitis C. J Hepatol 2002; 36: 812–818.

85 Carrozzo M. Oral diseases associated with hepatitis C virus infection. Part 1. Sialadenitis and salivary glands lymphoma. Oral Dis 2008; 14: 123–130. 86 De Rosa FG, Pucillo LP, Coviello R, et al. Influence of age and autoimmunity on liver disease in HCV-associated type II mixed cryoglobulinemia. Hum Immunol 2002; 63: 751–757. 87 Zachou K, Liaskos C, Christodoulou DK, et al. Anti-cardiolipin antibodies in patients with chronic viral hepatitis are independent of beta2-glycoprotein I cofactor or features of antiphospholipid syndrome. Eur J Clin Invest 2003; 33: 161–168. 88 Pawlotsky JM, Roudot-Thoraval F, Simmonds P, et al. Extrahepatic immunologic manifestations in chronic hepatitis C and hepatitis C virus serotypes. Ann Intern Med 1995; 122: 169–173. 89 Antonelli A, Ferri C, Pampana A, et al. Thyroid disorders in chronic hepatitis C. Am J Med 2004; 117: 10–13. 90 Hausfater P, Cacoub P, Rosenthal E, et al. Hepatitis C virus infection and lymphoproliferative diseases in France: A national study. The GERMIVIC Group. Am J Hematol 2000; 64: 107–111. 91 Zignego AL, Ferri C, Pileri SA, Caini P, Bianchi FB Italian Association of the Study of Liver Commission on Extrahepatic Manifestations of HCV infection. Extrahepatic manifestations of hepatitis C virus infection: A general overview and guidelines for a clinical approach. Dig Liver Dis 2007; 39: 2–17. 92 Vallat L, Benhamou Y, Gutierrez M, et al. Clonal B cell populations in the blood and liver of patients with chronic hepatitis C virus infection. Arthritis Rheum 2004; 50: 3668–3678. 93 Ferri C, Monti M, La Civita L, et al. Infection of peripheral blood mononuclear cells by hepatitis C virus in mixed cryoglobulinemia. Blood 1993; 82: 3701–3704. 94 Gisbert JP, Garcı´ a-Buey L, Pajares JM, Moreno-Otero R. Prevalence of hepatitis C virus infection in B-cell non-Hodgkin’s Systematic review and meta-analysis. lymphoma: Gastroenterology 2003; 125: 1723–1732. 95 Dal Maso L, Franceschi S. Hepatitis C virus and risk of lymphoma and other lymphoid neoplasms: A meta-analysis of epidemiologic studies. Cancer Epidemiol Biomarkers Prev 2006; 15: 2078–2085. 96 Monti G, Pioltelli P, Saccardo F, et al. Incidence and characteristics of non-Hodgkin lymphomas in a multicenter case file of patients with hepatitis C virus-related symptomatic mixed cryoglobulinemias. Arch Intern Med 2005; 165: 101–105. 97 Saadoun D, Suarez F, Lefrere F, et al. Splenic lymphoma with villous lymphocytes, associated with type II cryoglobulinemia and HCV infection: A new entity? Blood 2005; 105: 74–76. 98 Giordano TP, Henderson L, Landgren O, et al. Risk of nonHodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus. JAMA 2007; 297: 2010–2017. 99 Hermine O, Lefre`re F, Bronowicki JP, et al. Regression of splenic lymphoma with villous lymphocytes after treatment of hepatitis C virus infection. N Engl J Med 2002; 347: 89–94. 100 Gisbert JP, Garcı´ a-Buey L, Pajares JM, Moreno-Otero R. Systematic review: Regression of lymphoproliferative disorders after treatment for hepatitis C infection. Aliment Pharmacol Ther 2005; 21: 653–662. 101 Anderson LA, Engels EA. Hepatitis C virus infection and nonHodgkin lymphoma: Interesting association or causal relationship? Int J Cancer 2008; 122: x–xii. 102 Germanidis G, Haioun C, Pourquier J, et al. Hepatitis C virus infection in patients with overt B-cell non-Hodgkin’s lymphoma in a French center. Blood 1999; 93: 1778–1779. 103 Hausfater P, Cacoub P, Sterkers Y, et al. Hepatitis C virus infection and lymphoproliferative diseases: Prospective study on 1,576 patients in France. Am J Hematol 2001; 67: 168–171. 104 Landau DA, Rosenzwajg M, Saadoun D, Klatzmann D, Cacoub P. The BLyS/BAFF receptor-ligand system in HCV induced B-cell clonal disorders. Ann Rheum Dis 2009; 68: 337–344. 105 Ivanovski M, Silvestri F, Pozzato G, et al. Somatic hypermutation, clonal diversity, and preferential expression of the VH 51p1/VL kv325 immunoglobulin gene combination in hepatitis C virus-associated immunocytomas. Blood 1998; 91: 2433–2442.

Lupus Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 27, 2015

Extrahepatic manifestations in chronic hepatitis C virus carriers E Rosenthal and P Cacoub

481 106 Carbonari M, Caprini E, Tedesco T, et al. Hepatitis C virus drives the unconstrained monoclonal expansion of VH1-69-expressing memory B cells in type II cryoglobulinemia: A model of infection-driven lymphomagenesis. J Immunol 2005; 174: 6532–6539. 107 Franzin F, Efremov DG, Pozzato G, Tulissi P, Batista F, Burrone OR. Clonal B-cell expansions in peripheral blood of HCV-infected patients. Br J Haematol 1995; 90: 548–552. 108 Machida K, Cheng KT, Sung VM, et al. Hepatitis C virus induces a mutator phenotype: Enhanced mutations of immunoglobulin and protooncogenes. Proc Natl Acad Sci USA 2004; 101: 4262–4267. 109 Inokuchi M, Ito T, Uchikoshi M, et al. Infection of B cells with hepatitis C virus for the development of lymphoproliferative disorders in patients with chronic hepatitis C. J Med Virol 2009; 81: 619–627. 110 De Vita S, Quartuccio L, Fabris M. Hepatitis C virus infection, mixed cryoglobulinemia and BLyS upregulation: Targeting the infectious trigger, the autoimmune response, or both? Autoimmun Rev 2008; 8: 95–99. 111 Besson C, Canioni D, Lepage E, et al. Characteristics and outcome of diffuse large B-cell lymphoma in hepatitis C virus-positive patients in LNH 93 and LNH 98 Groupe d’Etude des Lymphomes de l’Adulte programs. J Clin Oncol 2006; 24: 953–960. 112 Johnson RJ, Gretch DR, Yamabe H, Hart J, Bacchi CE. Membranoproliferative glomerulonephritis associated with hepatitis C virus infection. N Engl J Med 1993; 328: 465–470. 113 Altraif IH, Abdulla AS, al Sebayel MI, Said RA, al Suhaibani MO, Jones AA. Hepatitis C associated glomerulonephritis. Am J Nephrol 1995; 5: 407–410. 114 Sabry A, E-Agroudy A, Sheashaa H, et al. HCV associated glomerulopathy in Egyptian patients: Clinicopathological analysis. Virology 2005; 334: 10–16. 115 Kasuno K, Ono T, Matsumori A, Nogaki F, Kusano H. Hepatitis C virus associated tubulointerstitial injury. Am J Kidney Dis 2003; 41: 767–775. 116 Watanabe H, Ono T, Muso E, Matsumori A, Sasayama S. Hepatitis C virus infection manifesting as tubulointerstitial nephritis, cardiomyopathy, and hepatitis. Am J Med 2000; 109: 176–177. 117 Fabrizi F, Plaisier E, Saadoun D, Martin P, Messa P, Cacoub P. Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. Am J Kidney Dis 2013; 61: 623–637. 118 Liangpunsakul S, Chalasani N. Relationship between hepatitis C and microalbuminuria: Results from the NHANES III. Kidney Int 2005; 67: 285–290. 119 Tsui JI, Vittinghoff E, Shlipak MG, O’Hare AM. Relationship between hepatitis C and chronic kidney disease: Results from the Third National Health and Nutrition Examination Survey. J Am Soc Nephrol 2006; 17: 1168–1174. 120 Matignon M, Cacoub P, Colombat M, et al. Clinical and morphologic spectrum of renal involvement in patients with mixed cryoglobulinemia without evidence of hepatitis C virus infection. Medicine (Baltimore) 2009; 88: 341–348. 121 Markowitz GS, Cheng JT, Colvin RB, Trebbin WM, D’Agati VD. Hepatitis C viral infection is associated with fibrillary glomerulonephritis and immunotactoid glomerulopathy. J Am Soc Nephrol 1998; 9: 2244–2252. 122 Tsui JI, Vittinghoff E, Shlipak MG, et al. Association of hepatitis C seropositivity with increased risk for developing end-stage renal disease. Arch Intern Med 2007; 167: 1271–1276. 123 Dalrymple LS, Koepsell T, Sampson J, et al. Hepatitis C virus infection and the prevalence of renal insufficiency. Clin J Am Soc Nephrol 2007; 2: 715–721. 124 Kidney Disease: Improving Global Outcomes (KDIGO). KDIGO clinical practice guidelines for the prevention, diagnosis, evaluation, and treatment of hepatitis C in chronic kidney disease. Kidney Int 2008; 73(Suppl 109): S1–S99. 125 Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for a link between hepatitis C virus infection and diabetes mellitus in a cirrhotic population. J Hepatol 1994; 21: 1135–1139.

126 Knobler H, Schihmanter R, Zifroni A, Fenakel G, Schattner A. Increased risk of type 2 diabetes in noncirrhotic patients with chronic hepatitis C virus infection. Mayo Clin Proc 2000; 75: 355–359. 127 Mason AL, Lau JY, Hoang N, et al. Association of diabetes mellitus and chronic hepatitis C virus infection. Hepatology 1999; 29: 328–333. 128 Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the United States. Ann Intern Med 2000; 133: 592–599. 129 Caronia S, Taylor K, Pagliaro L, et al. Further evidence for an association between non-insulin-dependent diabetes mellitus and chronic hepatitis C virus infection. Hepatol 1999; 30: 1059–1063. 130 Antonelli A, Ferri C, Fallahi P, Pampana A, Ferrari SM, Goglia F, et al. Hepatitis C virus infection: Evidence for an association with type 2 diabetes. Diabetes Care 2005; 28: 2548–2550. 131 Mehta SH, Brancati FL, Strathdee SA, et al. Hepatitis C virus infection and incident type 2 diabetes. Hepatol 2003; 38: 50–56. 132 Lecube A, Herna´ndez C, Genesca` J, Simo´ R. Glucose abnormalities in patients with hepatitis C virus infection: Epidemiology and pathogenesis. Diabetes Care 2006; 29: 1140–1149. 133 Zein CO, Levy C, Basu A, Zein NN. Chronic hepatitis C and type II diabetes mellitus: A prospective cross-sectional study. Am J Gastroenterol 2005; 100: 48–55. 134 Shaheen M, Echeverry D, Oblad MG, Montoya MI, Teklehaimanot S, Akhtar AJ. Hepatitis C, metabolic syndrome, and inflammatory markers: Results from the Third National Health and Nutrition Examination Survey (NHANES III). Diabetes Res Clin Pract 2007; 75: 320–326. 135 Wang CS, Wang ST, Yao WJ, Chang TT, Chou P. Hepatitis C virus infection and the development of type 2 diabetes in a community-based longitudinal study. Am J Epidemiol 2007; 166: 196–203. 136 Chen T, Jia H, Li J, Chen X, Zhou H, Tian H. New onset diabetes mellitus after liver transplantation and hepatitis C virus infection: Meta-analysis of clinical studies. Transpl Int 2009; 22: 408–415. 137 Fabrizi F, Messa P, Martin P, Takkouche B. Hepatitis C virus infection and post-transplant diabetes mellitus among renal transplant patients: A meta-analysis. Int J Artif Organs 2008; 31: 675–682. 138 Conjeevaram HS, Wahed AS, Afdhal N, Howell CD, Everhart JE, Hoofnagle JH. Changes in insulin sensitivity and body weight during and after peginterferon and ribavirin therapy for hepatitis C. Gastroenterology 2011; 140: 469–477. 139 Simo´ R, Lecube A, Genesca` J, Esteban JI, Herna´ndez C. Sustained virological response correlates with reduction in the incidence of glucose abnormalities in patients with chronic hepatitis C virus infection. Diabetes Care 2006; 29: 2462–2466. 140 Arase Y, Suzuki F, Suzuki Y, et al. Sustained virological response reduces incidence of onset of type 2 diabetes in chronic hepatitis C. Hepatology 2009; 49: 739–744. 141 Harrison SA. Liver disease in patients with diabetes mellitus. J Clin Gastroenterol 2006; 40: 68–76. 142 Cacoub P, Carrat F, Be´dossa P, et al. Insulin resistance impairs sustained virological response rate to pegylated interferon plus ribavirin in HIV-hepatitis C virus-coinfected patients: HOMAVIC-ANRS HC02 Study. Antivir Ther 2009; 14: 839–945. 143 Baranova A, Younossi Z. Adipokines in non-alcoholic fatty liver diseases. In: Fantuzzi G, Mazzone T (eds), Nutrition and health. Totowa, NJ: Humana Press Inc, 2006. pp. 291–305. 144 Durante-Mangoni E, Zampino R, Marrone A, et al. Hepatic steatosis and insulin resistance are associated with serum imbalance of adiponectin/tumour necrosis factor-alpha in chronic hepatitis C patients. Aliment Pharmacol Ther 2006; 24: 1349–1357. 145 Tsochatzis E, Papatheodoridis GV, Archimandritis AJ. The evolving role of leptin and adiponectin in chronic liver diseases. Am J Gastroenterol 2006; 101: 2629–2640.

Lupus Downloaded from lup.sagepub.com at GEORGIAN COURT UNIV on March 27, 2015

Extrahepatic manifestations in chronic hepatitis C virus carriers E Rosenthal and P Cacoub

482 146 Volzke H, Robinson DM, Kleine V, et al. Hepatic steatosis is associated with an increased risk of carotid atherosclerosis. World J Gastroenterol 2005; 11: 1848–1853. 147 Gastaldelli A, Kozakova M, Højlund K, et al. Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population. Hepatology 2009; 49: 1537–1544. 148 Sanyal AJ, Contos MJ, Sterling RK, et al. Nonalcoholic fatty liver disease in patients with hepatitis C is associated with features of the metabolic syndrome. Am J Gastroenterol 2003; 98: 2064–2071. 149 Sanyal AJ. Review article: Non-alcoholic fatty liver disease and hepatitis C—risk factors and clinical implications. Aliment Pharmacol Ther 2005; 22: 48–51. 150 Targher G, Bertolini L, Scala L, Zoppini G, Zenari L, Falezza G. Nonalcoholic hepatic steatosis and its relation to increased plasma biomarkers of inflammation and endothelial dysfunction in non-diabetic men: Role of visceral adipose tissue. Diabet Med 2005; 22: 1354–1358. 151 Ishizaka N, Ishizaka Y, Takahashi E, et al. Association between hepatitis C virus seropositivity, carotid-artery plaque, and intimamedia thickening. Lancet 2002; 359: 133–135. 152 Butt AA, Xiaoqiang W, Budoff M, Leaf D, Kuller LH, Justice AC. Hepatitis C virus infection and the risk of coronary disease. Clin Infect Dis 2009; 49: 225–232. 153 Alyan O, Kacmaz F, Ozdemir O, et al. Hepatitis C infection is associated with increased coronary artery atherosclerosis defined by modified Reardon severity score system. Circ J 2008; 72: 1960–1965. 154 Vassalle C, Masini S, Bianchi F, Zucchelli GC. Evidence for association between hepatitis C virus seropositivity and coronary artery disease. Heart 2004; 90: 565–566. 155 Younossi ZM, Stepanova M, Nader F, Younossi Z, Elsheikh E. Associations of chronic hepatitis C with metabolic and cardiac outcomes. Aliment Pharmacol Ther 2013; 37: 647–652. 156 Marzouk D, Sass J, Bakr I, et al. Metabolic and cardiovascular risk profiles and hepatitis C virus infection in rural Egypt. Gut 2007; 56: 1105–1110. 157 Corey KE, Kane E, Munroe C, Barlow LL, Zheng H, Chung RT. Hepatitis C virus infection and its clearance alter circulating lipids: Implications for long-term follow-up. Hepatology 2009; 50: 1030–1037. 158 Bilora F, Rinaldi R, Boccioletti V, Petrobelli F, Girolami A. Chronic viral hepatitis: A prospective factor against atherosclerosis. A study with echo-color Doppler of the carotid and femoral arteries and the abdominal aorta. Gastroenterol Clin Biol 2002; 26: 1001–1004. 159 Wong RJ, Kanwal F, Younossi Z, Ahmed A. Hepatitis C virus infection and coronary artery disease risk: A systematic review of the literature. Dig Dis Sci 2014; 59: 1586–1593. 160 Maruyama S, Koda M, Oyake N, et al. Myocardial injury in patients with chronic hepatitis C infection. J Hepatol 2013; 58: 11–15. 161 Zampino R, Marrone A, Restive L, et al. Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations. World J Hepatol 2013; 5: 528–540. 162 Lee MH, Yang HI, Wang CH, et al. Hepatitis C virus infection and increased risk of cerebrovascular disease. Stroke 2010; 41: 2894–2900. 163 Stoll G, Bendszus M. Inflammation and atherosclerosis: Novel insights into plaque formation and destabilization. Stroke 2006; 37: 1923–1932. 164 Boddi M, Abbate R, Chellini B, et al. Hepatitis C virus RNA localization in human carotid plaques. J Clin Virol 2010; 47: 72–75. 165 Lonardo A, Lombardini S, Scaglioni F, et al. Hepatic steatosis and insulin resistance: Does etiology make a difference? J Hepatol 2006; 44: 190–196.

166 Fletcher NF, Wilson GK, Murray J, et al. Hepatitis C virus infects the endothelial cells of the blood-brain barrier. Gastroenterology 2012; 142: 634–643. 167 Adinolfi LE, Restivo L, Zampino R, et al. Chronic HCV infection is a risk of atherosclerosis. Role of HCV and HCV-related steatosis. Atherosclerosis 2012; 221: 496–502. 168 Adinolfi LE, Restive L, Guerrera B, et al. Chronic HCV infection is a risk factor of ischemic stroke. Atherosclerosis 2013; 231: 22–26. 169 Hsu CS, Kao JH, Chao YC, et al. Interferon-based therapy reduces risk of stroke in chronic hepatitis C patients: A population-based cohort study in Taiwan. Aliment Pharmacol Ther 2013; 38: 415–423. 170 Perry W, Hilsabeck RC, Hassanein TI. Cognitive dysfunction in chronic hepatitis C: A review. Dig Dis Sci 2008; 53: 307–321. 171 Fontana RJ, Bieliauskas LA, Back-Madruga C, et al. Cognitive function in hepatitis C patients with advanced fibrosis enrolled in the HALT-C trial. J Hepatol 2005; 43: 614–622. 172 Lowry D, Coughlan B, McCarthy O, Crowe J. Investigating health-related quality of life, mood and neuropsychological test performance in a homogeneous cohort of Irish female hepatitis C patients. J Viral Hepat 2010; 17: 352–359. 173 Thein HH, Maruff P, Krahn MD, et al. Improved cognitive function as a consequence of hepatitis C virus treatment. HIV Med 2007; 8: 520–528. 174 Casato M, Saadoun D, Marchetti A, et al. Central nervous system involvement in hepatitis C virus cryoglobulinemia vasculitis: A multicenter case-control study using magnetic resonance imaging and neuropsychological tests. J Rheumatol 2005; 32: 484–488. 175 Golden J, O’Dwyer AM, Conroy RM. Depression and anxiety in patients with hepatitis C: Prevalence, detection rates and risk factors. Gen Hosp Psychiatry 2005; 27: 431–438. 176 Poynard T, Cacoub P, Ratziu V, et al. Fatigue in patients with chronic hepatitis C. J Viral Hepat 2002; 9: 295–303. 177 Forton DM. Altered monoaminergic transporter binding in hepatitis C related cerebral dysfunction: A neuroimmunologial condition? Gut 2006; 55: 1535–1537. 178 Weissenborn K, Ennen JC, Bokemeyer M, et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut 2006; 55: 1624–1630. 179 Spiegel BM, Younossi ZM, Hays RD, Revicki D, Robbins S, Kanwal F. Impact of hepatitis C on health related quality of life: A systematic review and quantitative assessment. Hepatology 2005; 41: 790–800. 180 Younossi Z, Kallman J, Kincaid J. The effects of HCV infection and management on health-related quality of life. Hepatology 2007; 45: 806–816. 181 Marcellin P, Chousterman M, Fontanges T, et al. Adherence to treatment and quality of life during hepatitis C therapy: A prospective, real-life, observational study. Liver Int 2011; 31: 516–524. 182 Younossi ZM, Stepanova M, Zeuzem S, et al. Patient-reported outcomes assessment in chronic hepatitis C treated with sofosbuvir and ribavirin: The VALENCE study. J Hepatol 2014; 61: 228–234. 183 Raison CL, Borisov AS, Broadwell SD, et al. Depression during pegylated interferon-alpha plus ribavirin therapy: Prevalence and prediction. J Clin Psychiatry 2005; 66: 41–48. 184 Lang JP, Melin P, Ouzan D, et al. Pegylated interferon-alpha2b plus ribavirin therapy in patients with hepatitis C and psychiatric disorders: Results of a cohort study. Antivir Ther 2010; 15: 599–606. 185 Raison CL, Demetrashvili M, Capuron L, Miller AH. Neuropsychiatric adverse effects of interferon-alpha: Recognition and management. CNS Drugs 2005; 19: 105–123.

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