HCV in relation to cardiovascular conditions - Impact of direct-acting antiviral treatments?

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World J Gastroenterol. Nov 7, 2018; 24(41): 4617-4621

Published online Nov 7, 2018. doi: 10.3748/wjg.v24.i41.4617

Editorial 
Chronic hepatitis C, atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral treatments?

Luigi Elio Adinolfi, Luca Rinaldi, Riccardo Nevola

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Abstract

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro-atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease.

Direct and indirect factors considered responsible for development of atherosclerosis and cardiovascular disease in chronic hepatitis C patients and the possible effect of hepatitis C virus clearance by direct-acting antiviral agents on cardiovascular outcomes. DAAs: Direct-acting antiviral agents; IR: Insulin resistance; OXS: Oxidative stress; LPS: Lipopolysaccharide (endotoxinemia). 

Read the editorial: https://www.wjgnet.com/1007-9327/full/v24/i41/4617.htm

Association of Sjögrens Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis

Research Article
Association of Sjögrens Syndrome in Patients with Chronic Hepatitis Virus Infection: A Population-Based Analysis
Chih-Ching Yeh, Wen-Chang Wang, Chien-Sheng Wu, Fung-Chang Sung, Chien-Tien Su, Ying-Hua Shieh, Shih-Ni Chang, Fu-Hsiung Su PLOS Published: August 25, 2016
http://dx.doi.org/10.1371/journal.pone.0161958

Abstract
Objective
The association between Sjögren’s syndrome (SS) and chronic hepatitis virus infection is inconclusive. Hepatitis B (HBV) and hepatitis C virus (HCV) infections are highly prevalent in Taiwan. We used a population-based case-control study to evaluate the associations between SS and HBV and HCV infections.

Materials and Methods
We identified 9,629 SS patients without other concomitant autoimmune diseases and 38,516 sex- and age-matched controls without SS from the Taiwan National Health Insurance claims data between 2000 and 2011. We utilized multivariate logistic regression to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of the associations between SS and HBV and HCV infections. Sex- and age-specific (<55 and ≥55 years) risks of SS were evaluated.

Results
The risk of SS was higher in patients with HCV than in those without chronic viral hepatitis (OR = 2.49, 95% CI = 2.16–2.86). Conversely, HBV infection was not associated with SS (OR = 1.10, 95% CI = 0.98–1.24). Younger HCV patients were at a higher risk for SS (<55 years: OR = 3.37, 95% CI = 2.62–4.35; ≥55 years: OR = 2.20, 95% CI = 1.84–2.62). Men with HCV were at a greater risk for SS (women: OR = 2.26, 95% CI = 1.94–2.63; men: OR = 4.22, 95% CI = 2.90–6.16). Only men with chronic HBV exhibited a higher risk of SS (OR = 1.61, 95% CI = 1.21–2.14).

Conclusion
HCV infection was associated with SS; however, HBV only associated with SS in men

Discussion Only

Full Text Available @ PLOS ONE

In this large-scale, population-based case-control study in a highly prevalent chronic HBV and HCV infection area, we observed a positive significant association between SS and chronic HCV infection. Sex-stratification analysis also revealed that HBV-infected men had a significantly higher risk of SS.

In 1992, Haddad et al. reported lymphocytic sialadenitis in 57% of HCV-infected patients and 5% of controls [10]; hence, the debate over the association between SS with HCV began two decades ago. Accordingly, numerous HCV-associated SS cases have been reported. SS has been suggested as one of the systematic autoimmune diseases most closely associated with HCV [29]. A higher prevalence of SS was noted in patients with HCV infection (25.9%) than in those with HBV infection (3.4%) in a Japanese study [9]. Ramos-Casals et al. reported that 13% of patients with chronic HCV infection in Spain also had SS [8]. A significant overall association between HCV infection and SS was observed in a recent meta-analysis [11]. There is increasing evidence from experimental [30], virological [31,32], and clinical studies [13,33,34] suggesting that HCV and SS may share some overlapping etiological characteristics. Ramos-Casals and his colleagues proposed the term SS “secondary to HCV” (SS-HCV) to implicate the development of SS in a particular subset of HCV patients [6]. Although there is no significant difference in any histological examination between the groups, SS-HCV tends to present at an older age and at a reduced female to male ratio when compared with primary SS patients without HCV. Ramos-Casals reported a reduced female:male ratio (3:1) and older age (58.3± 1.17 vs 52.7±0.85) of SS-HCV compared with primary SS patients [6]. In the study of Brito-Zeron et al., SS-HCV patients showed a reduced female:male ratio (5:1 vs 14:1) and an older age (mean age of 62.9 years) when compared with primary SS [5]. In our study, the female:male ratio and median age of the SS subjects were 6.7:1 and 55, respectively. Another Taiwanese group reported the female:male ratio of SS to be 7.9 [3]. In Taiwan, in order to be considered for a CIC for SS, patients must fulfill at least four criteria of the 2002 European classification for SS with at least one of the two mandatory criteria (positive salivary gland biopsy or anti-Ro/La antibodies). The application is then reviewed by rheumatologists commissioned by the Bureau of the NHI system for CIC eligibility and coded specifically with ICD-9-CM 710.2 for subsequent services. Although Ramos-Casals et al. proposed the term ‘‘SS secondary to HCV” for patients who fulfill the 2002 classification criteria for SS [6], we still feel confident with our data source. In addition, our data also showed that young HCV carriers carry a higher risk of SS when compared with non-HCV carriers.

SS-HCV patients also demonstrate lower frequencies of autoantibodies against Ro and La human ribonucleoproteins and complementaemia and a higher prevalence of cryoglobulinmic-related immunological markers including rheumatoid factor (RF) than primary SS patients without HCV [7,35]. However, the pathogenesis from autoantibody formation to the full clinical manifestation of HCV-associated SS is not well established. The proposed mechanism involves cross-reactivity between the HCV envelope and host salivary tissue or HCV envelope-mediated immune reaction against salivary glands [36]. Hence, Ramos-Casals et al. suggested that primary SS and SS-HCV are two separate processes [6]. However, whether HCV mimics primary SS or is directly responsible for the development of primary SS in a subset of patients remains controversial [35]. Further studies are needed to clarify this issue.

Some comorbidities have been associated with HCV in the literature including diabetes and CAD [37,38]. Hence, we further analyzed DM and CAD to investigate any possible interaction between HCV and the comorbidities that may have contributed to the association detected in this study between HCV and SS. Our results indicate that CAD and liver cirrhosis are independent risk factors of SS (OR = 1.28, 95% CI = 1.20–1.37 and OR = 2.74, 95% CI = 2.19–3.44, respectively) (Table 5). Interestingly, DM demonstrated an independent protective effect toward SS (OR = 0.78, 95% CI = 0.72–0.84). Further prospective studies are warranted to verify this finding.

In our study, we detected a higher odds ratio among younger patients with SS and HCV. We hypothesize that a gradual change in the HCV genotype and its interaction with environmental factors may underlie this observation. In Taiwan, the 1b HCV genotype has historically been the most prevalent in the general population, dwarfing the prevalence of subtype 2a [39]. The most suspected routes of transmission included illegal medical interventions, such as the use of nondisposable needles, the sharing of syringes and fluid for injection, and blood transfusion-related infections and may have been responsible for the spread of the 1b HCV genotype among older Taiwanese [39]. However, in recent years the 2a genotype has been observed with increasing frequency among younger individuals. These young people are often HIV-positive persons with a history of injection drug use [40]. One study demonstrated a high prevalence of HCV infection among HIV-infected intravenous drug users in Taiwan with a predominance of infection due to genotypes 1a, 6a, and 3a, instead of 1b [41]. 2a was a predominant genotype among acute hepatitis C among HIV-infected individuals in another matched case-control study in Taiwan [42].

HBV-related SS has rarely been investigated and remains controversial. Aprosin et al. suggested the involvement of the virus in the etiology of SS in early 1990 [14,43–46]. Marcos et al. reported that only 5 (0.83%) of 603 patients with SS tested positive for HBsAg, which hints at a null association between chronic HBV infection and SS [15]. In Taiwan, Chen et al. observed that 18 of 175 patients with SS were positive for HBsAg, revealing that SS has a significantly lower prevalence of HBV than the general population (10.3% vs. 17.3%, p < 0.001) [47]. In another Taiwanese study, the prevalence of anti-SSA and anti-SSB autoantibodies was lower in HBV carriers (1.9% and 0%) than in HCV carriers (12.8% and 9.7%). Both anti-SSA and anti-SSB antibodies are critical markers of SS [48]. In a study by Nagao et al., the prevalence of SS in patients with chronic HCV infection was significantly higher than that in patients with chronic HBV infection [9]. Recently, Ram et al. suggested that HBV infection protects against autoimmune disorders, including SS [14].

In our study, we clearly observed that patients with chronic HBV infection are at a lower risk for SS than those with chronic HCV infection. This may be explained through increased an increased risk of extrahepatic manifestations among HCV patients, involving renal, rheumatologic, dermatologic, as well as hematologic abnormalities [49]. Such extrahepatic manifestations are likely to arise from immunologically triggered mechanisms and virus invasion and replication. In HCV, lymphatropic character may explain the cause of HCV-associated extrahepatic manifestations [50] and may also explain why patients with HCV were observed to have a greater risk of SS than those infected with HBV.

A strength of this study is that it is the first to use a nationwide population-based data set to investigate the association between SS and chronic viral hepatitis. The statistical power offered by our large sample size enabled us to stratify our estimates of association by both sex and age, thus allowing us to provide the first sex and age specific estimates to the literature.

Several limitations of this study should be considered. First, it is possible that some patients with hepatitis were misclassified and were included in the control group. This may have occurred if they did not elect to seek medical treatment for their condition and thus did not receive a diagnosis. In any case, assuming that there is a causal association between viral hepatitis infection and SS, this misclassification would bias our estimate toward the null, thus leaving us with a more conservative estimate and greater confidence in the presence of the association.

Second, using ICD-9-CM diagnosis codes to identify patients with SS, HBV, and HCV infections, and comorbidities may not be as accurate as identifying patients in a clinical setting according to more standardized diagnostic criteria. However, the NHI Bureau has several self-policing mechanisms to better ensure for higher coding accuracy and quality of care. These include the scheduled random review of charts and claims along with patient interviews at every hospital with punitive measures being imposed for inconsistencies. The diagnostic accuracy among SS patients can be expected to be particularly high. SS patients are closely vetted prior to their inclusion in the CIC category due to the high economic burden incurred by the state which takes responsibility for the patient’s medical treatment. To minimize the possibility of enrolling patients with secondary SS in our case group, we excluded patients who were diagnosed with other autoimmune diseases before or after SS diagnosis.

Third, while our use of the CIC category enhanced our case validity, our utilization of two data bases may have biased the results of our analysis. By only selecting CIC cases, we may have been able to avoid recruiting patients with sicca syndrome, which is only defined by symptoms, and solely recruit SS cases that require rheumatologists to assess specific diagnostic criteria. However, we used the LHID2000 to select our controls. The stringent diagnostic criteria required for the CIC program produces a difference in the severity of disease found among CIC patients and the general population in the LHID2000. Thus, it is possible that the LHID2000 contained less severe version of SS that were not included in the CIC program. If this were the case, some of our controls may have had mild versions of SS which would have worked to bias our results towards the null and produce a more conservative estimate.

Fourth, some may argue that HBsAg and anti-HCV are not reliable metrics for defining chronic viral hepatitis infections. However, in our previous study, the predictive value of HBsAg testing alone was 97% among 367 adults born prior to the national HBV vaccination [51]. In addition, to further increase the diagnostic accuracy, this study only considered subjects to have HBV and HCV if they received at least three out-patient diagnoses or at least one in-patient diagnosis.

Fifth, nearly all the residents of Taiwan are of Han Chinese ethnicity and our results should be generalized with caution. Due to epidemiological, demographic, and cultural differences, it is likely that the transmission route of viral hepatitis differs between locations and peoples.

Sixth, it is possible that viral hepatitis patients were more likely to be diagnosed with SS purely on account of their increased exposure to the medical community. However, on account of the low out-of-pocket costs, lack of barriers to specialist care, and convenient access across the country provided by the Taiwanese national insurance program, Taiwanese readily seek medical care in the event of any discomfort, thus making this type of bias highly unlikely.

Seventh, laboratory data were unavailable in the claims records; therefore, we could not analyze the risk factors for SS in detail. Finally, according to both prior research and the results of this study presented in Table 5, it is evident that liver cirrhosis is an independent risk factor for SS. While we have statistically adjusted for the effect of liver cirrhosis in each of the analyses performed in this study, it remains possible that our results suffered from residual confounding.

Conclusions
We found evidence indicating that chronic HCV infection associates with SS. However, our results also indicate that patients with chronic HBV infection are at a lower risk for SS when compared with those with chronic HCV infection. Additional studies are warranted to apply our findings to other geographical regions or races, and for clarifying the biological mechanisms underlying the associations detected in this study.

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Dual Antiviral Treatment:Treating HCV-Associated Cryoglobulinemic Vasculitis

Dual Antiviral Treatment May Have Edge in Treating HCV-Associated Cryoglobulinemic Vasculitis

NEW YORK (Reuters Health) - Dual antiviral therapy seems more effective than standard immunosuppression or rituximab only at treating cryoglobulinemic vasculitis associated with hepatitis C virus (HCV) infection, researchers from Russia report.

Cryoglobulinemic vasculitis may affect 5% of patients with HCV infection. Previous research has shown both rituximab and antiviral treatment to be effective in these patients, Dr. Sergey Moiseev and colleagues from First Moscow State Medical University note in Annals of the Rheumatic Diseases, online June 12.

The team looked at outcomes of 65 of their patients with HCV-associated mixed cryoglobulinemic vasculitis who were treated with conventional immunosuppressive drugs (n=30), monotherapy with interferon alpha (n=9), rituximab (n=8), or peginterferon alpha-ribavirin with or without rituximab (n=18).

Relapse-free survival was numerically longer with antiviral treatment than with rituximab or conventional treatment, the researchers found.

More than 70% (5/7) of patients treated with interferon alpha monotherapy experienced deterioration of vasculitis, compared with only one of 18 patients treated with dual antiviral therapy with or without rituximab.

Just over half of patients with genotype 1 (8/15) and all three patients with genotype 2 or 3 infection experienced sustained virological response with combination antiviral treatment. Seven of these 18 patients developed hematological complications.

The researchers acknowledge that lack of randomization and small sample size represent significant limitations of their study.

"Dual antiviral treatment is better tolerated and in our opinion can be offered to patients with higher probability of sustained virological response to peginterferon-alpha/ribavirin, for example, with favorable interleukin-28B polymorphism," the authors conclude.

"Recently, a large scale trial showed high efficacy and excellent safety of the single tablet regimen of ledipasvir-sofosbuvir for primary patients with HCV genotype 1 infection," they add. "The study of these and other interferon-free regimens are also warranted in patients with HCV-associated mixed cryoglobulinemic vasculitis."

Dr. Moiseev did not respond to a request for comments.

SOURCE
Ann Rheum Dis 2014.

The Place of Immunotherapy in the Management of HCV-Induced Vasculitis: An Update

Clin Dev Immunol. 2012; 2012: 315167.

Published online 2012 August 15. doi: 10.1155/2012/315167

PMCID: PMC3426208

 

The Place of Immunotherapy in the Management of HCV-Induced Vasculitis: An Update

 

Laurent Chiche,^{1 ,*} Stanislas Bataille,² Gilles Kaplanski,¹ and Noemie Jourde²

¹Department of Internal Medicine, Centre de Compétence pour les Maladies Autoimmunes Systémiques PACA Ouest, Hôpital de la Conception, Marseille, France

²Department of Nephrology, Hôpital de la Conception, Université Aix-Marseille, Marseille, France

*Laurent Chiche: Email: laurent.chiche@ap-hm.fr

Academic Editor: Domenico Sansonno

Author information ► Article notes ► Copyright and License information ►

Received April 26, 2012; Accepted July 3, 2012.

Copyright© 2012 Laurent Chiche et al.

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

 

.

Abstract

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

 

1. Introduction

Chronic hepatitis C virus (HCV) infection is associated with numerous and mostly autoimmune extrahepatic complications. One of the most serious is cryoglobulinaemic vasculitis (CV), which develops in 5–10% of infected patients. CV is a systemic small-vessel vasculitis that affects mostly skin, joints, nerves, and kidneys and can sometimes have a life-threatening presentation [1]. The identification of HCV as the main causal agent for CV has completely modified the management of this virally induced vasculitis. Indeed, circulating immune complexes responsible for organ damage are the result of B-cell expansion and the production of pathogenic IgMs with rheumatoid-factor activity, which is driven by the underlying chronic viral infection. Thus, obtaining a sustained virological response (SVR) has become the main treatment for HCV-induced CV. Fortunately, the combination of pegylated-interferon α (peg-IFN-α) plus ribavirin has resulted in an SVR in up to two-thirds of patients, depending on the genotype of HCV [2–4].

However, in some situations, immunotherapy alone or in addition to antiviral treatment is necessary to treat HCV-induced CV (Figure 1). For a long time, immunotherapy for CV has been largely empirical, relying on traditional immunosuppressive options. However, recent studies, including some with a prospectively controlled design, have addressed the place of biologics in this setting. Herein, we aim to provide an updated overview of the place of immunotherapy, especially biologics, for the management of HCV-induced cryoglobulinaemic vasculitis.

Figure 1

Immunotherapy to manage HCV-induced vasculitis. (A) Antiviral regimen, ideally a combination of interferon plus ribavirin, is the first-line treatment for HCV-induced cryoglobulinaemic vasculitis (CV) when the severity of its manifestations is mild-to-moderate. (more ...)

 

2. Immunotherapy in HCV-Induced Vasculitis: For Whom and When?

Eradication of HCV with peg-IFN-α plus ribavirin is the first-line treatment for CV (Figure 1(a)). Indeed, when this treatment is not contraindicated and sufficiently well tolerated, it allows an SVR in 50% (genotypes 1, 4, 5, 6) to 80% (genotypes 2 and 3) of patients after 48 and 24 weeks of treatment, respectively [2–4]. In these cases, no immunotherapy is needed. However, immunotherapy needs to be considered, alone or in addition to antiviral treatments, in the following situations.

2.1. Severe or Life-Threatening Manifestations

Because of the delayed and uncertain response to antiviral therapy, severe and rapidly progressive CV manifestations (i.e., acute nephrotic or nephritic syndrome, extensive cutaneous ulcers, central nervous system or gastrointestinal manifestations, and hyperviscosity syndrome) require prompt and aggressive treatment (Figure 1(b)). Indeed, the use of aggressive immunotherapy in these settings is indirectly supported by the results of a recent study that identified a strong association between increased mortality and cutaneous ulcers (hazard ratio (HR) 5.37) or renal insufficiency (HR 3.25) [1]. Concerning peripheral neuropathy, even if not considered a life-threatening manifestation, it is a major cause of morbidity in HCV-associated CV and is often refractory to all treatments. In addition, as any improvement is often delayed, later reevaluation prevents a rapid switch to a different therapeutic option if needed, which increases the risk of definitive sequelae. Thus, in the most severe cases, immunotherapy can be a part of first-line treatments [5].

In patients with severe or rapidly progressive manifestations, antiviral therapy is still an important part of treatment and can be initiated either concomitantly or sequentially. Concomitant administration, ideally, may prevent an increase in HCV viral load and hepatic consequences secondary to an immunosuppressive strategy. However, some data support the short-term safety of a sequential strategy (i.e., starting with an immunosuppressive regimen alone), even in patients with advanced liver disease [6]. Also, sequential administration has some practical advantages. First, it avoids situations where the physician faces the occurrence of a side effect within a combined antiviral and immunosuppressive regimen (e.g., cytopenia), a situation that complicates the imputability of this side effect to a specific drug. Also, when renal function is altered, the use of ribavirin is very limited due to increased toxicity. Finally, some authors have reported a paradoxical exacerbation of CV after the initiation of antiviral regimens [7, 8], which may be prevented when immunotherapy is started first.

2.2. Absence of a Virological Response

The use of peg-IFN-α combined with ribavirin as the standard-of-care for HCV-induced CV is supported by several studies in which this treatment has been found to be safe and well tolerated and has led to an SVR rate similar to that for HCV-infected patients without CV [9, 10]. But, importantly, only patients with complete clearance of HCV achieve a complete and sustained clinical response, and SVR is not always obtained for various reasons. In about one-third of patients, and particularly those with genotype 1 HCV, a well-conducted antiviral regimen fails [2–4]. In addition, peg-IFN-α plus ribavirin is poorly tolerated in 10–20% of patients, leading to early termination of antiviral regimens. Also, some patients have major contraindications to IFN and/or ribavirin, such as advanced age, uncompensated cirrhosis, uncontrolled depressive illness, or untreated thyroid disease. In these patients with CV and no virological response, anti-inflammatory drugs may be warranted to avoid or control severe or debilitating complications (Figure 1(c)). However, a major concern is the potential adverse effects that immunosuppressive therapy could have on the underlying uncontrolled chronic viral infection. Except for severe manifestations (see above), immunotherapy is administered after other therapies have been optimized to obtain an SVR.

A failed standard-of-care, especially in genotype 1 HCV, may benefit from the recent development of two direct-acting antiviral agents, boceprevir and telaprevir [11]. The combination of one of them to the standard-of-care increases SVR rates in genotype 1 HCV infection to >70%. Alternatively, in virological nonresponders, when a clinical and biological improvement has been observed under an antiviral regimen, some physicians may propose longer treatment for up to 48 or 72 weeks, respectively, for genotypes 2 and 3, and for genotypes 1 and 4 [12]. Also, because of its immunomodulatory properties, interferon may precipitate or exacerbate some preexisting and often subclinical disorders, especially those involving the thyroid, but screening before as well as close monitoring during treatment improves detection and early management of these potential complications [13]. Finally, the contraindications listed above may be judged as relative in some patients, when the benefit of treatment may overcome the theoretical risks. This is especially true for advanced age, but also, in some cases, for depressive status, when antidepressant prophylaxis initiated 2 weeks before interferon therapy may be useful for at-risk patients [14].

2.3. “Autonomized” Vasculitis

A few patients may experience biological and/or clinical persistence or relapse of CV despite clearance of their HCV infection. This is probably because B-cell expansion has become, at least in part, independent of HCV stimulation (Figure 1(d)). In this setting, underlying B-cell malignancy must be ruled out first. Indeed, HCV-associated CV has been associated with an increased risk of B-cell lymphoma [15]. Landau et al. reported on eight patients who presented with a relapse in HCV-induced CV, despite having achieved SVRs. In two out of three patients whose symptoms of CV persisted and were associated with elevated cryoglobulin levels, B-cell lymphoma was diagnosed [16].

There is also controversy about the possible role of occult HCV infection, that is, detectable HCV-RNA in the liver or peripheral blood mononuclear cells in the absence of serum HCV-RNA [17, 18]. Indeed, it is conceivable that the virus, or part of it, may still be triggering B-cell proliferation, although it is not detected in the serum. However, a recent exhaustive review on this topic did not reach any firm conclusions [19]. Recently, we reported, for the first time, the presence of HCV-NS3 viral protein in the kidney of a patient with a similar presentation, but we were unable to conclude on the significance of this finding [20]. What is certain for now, is that an ultrasensitive real-time PCR assay should be conducted on the serum and/or cryoprecipitate to rule out low-level infection, which may have been misdiagnosed as occult infection in previous studies [21]. Thus, in patients with an SVR but persistent clinical manifestations of CV, after exclusion of underlying hemopathies and/or low-level HCV-persistent infections, the autoimmune component of the disease may be considered as autonomized and treated similarly to nonvirally related CV [22].

 

3. Immunotherapy in HCV-Induced Vasculitis: Which One?

Various anti-inflammatory drugs that are used successfully to treat other types of vasculitis are also used to treat HCV-induced vasculitis. However, during the last decade, conventional immunosuppressive treatments (i.e., cyclophosphamide and plasmapheresis) have been progressively challenged by biologics. Indeed, the most common cause of death in patients with CV is infection and, in the study of Landau et al. [1], immunosuppressive treatment was associated with an increased risk of death, independently of disease severity (HR 6.51), suggesting that a more targeted immune-based strategy would be beneficial. Apart from the poor effectiveness of TNF-blockade by infliximab or etanercept, reported by us and others [23–25], or the recent anecdotal report of the successful use of an anti-interleukin(IL)-6 strategy [26], rituximab (RTX) is, to date, the only biologic that has sufficient evidence to support its use for this indication. Interestingly, to balance this anti-inflammatory strategy, a recent pilot study reported the success of a proregulatory strategy with low-dose IL-2 [27].

3.1. Anti-Inflammatory Strategy: Rituximab

RTX is a monoclonal antibody against the CD20 antigen, which is selectively expressed on B cells. The rationale underlying RTX treatment is that in CV, CD20-positive cells are expanded, activated, and play a pivotal role in cryoglobulin production [28]. Several studies have demonstrated that RTX is highly effective when CV is refractory to antiviral regimens [5, 6, 29–31], that the association of RTX with an antiviral regimen may induce a better and faster clinical remission [32, 33] and, recently, that RTX is more efficient than traditional immunosuppressive treatments [34, 35].

With some variations according to the different manifestations of CV, the overall response rate to rituximab in patients refractory to antivirals has been reported in recent meta-analyses to be ≥80% [36, 37]. The delay in response is variable, but improvement occurs within 1–6 months. Recent studies that have compared a combined therapy with RTX to antiviral therapy alone show that a combined therapy may be the best choice for patients with severe manifestations of CV. Indeed, in a prospective cohort study of 93 patients, combined therapy reduced the time to clinical remission and improved renal-response rates compared to peg-IFN-α+ ribavirin alone [33]. In another prospective study that included 37 patients, those in the RTX group achieved a complete response more often than patients not receiving RTX (54.5% versus 33.3%) [32].

The rationale for choosing a targeted therapy with RTX instead of conventional immunosuppressive agents has been only poorly supported by evidence, though two recently published studies have filled this gap [34, 35] (Table 1). The first study [34], an open-label randomized controlled trial (RCT) conducted in Italy, compared RTX to conventional therapies (i.e., corticosteroids, plasmapheresis, azathioprine, or cyclophosphamide) in 57 patients with severe manifestations of CV. Of note, patients in the conventional-therapy group, whose treatment failed, had the opportunity to crossover and receive RTX. At 12 months, the proportion of patients who continued their initial therapy was significantly higher in the RTX group, and only 13.8% of patients in the conventional-therapy group continued their initially assigned therapy beyond 3 months. The second study [35], conducted in the US, was also an open-label RCT, which compared RTX and standard therapy in 24 patients with HCV-related CV. Standard therapy was considered to be maintenance or intensification of conventional immunosuppressive therapy, but the patients receiving RTX were allowed to continue their background immunosuppressive therapy. At 6 months, clinical efficacy was clearly greater for RTX compared to conventional immunosuppressive therapy. Thus, even though the design of these studies may have advantaged RTX (Table 1), the data support a preference for targeted B-cell depletion with RTX as the agent of choice for CV. They also provide additional information on the modalities of administration of RTX and its safety.

Table 1

Prospective randomized controlled trials comparing rituximab (R) with a classical immunosuppressive regimen (C).

 

Indeed, as in other autoimmune conditions [38], there is no consensus on the choice of the modality of administration, that is, a “rheumatological” regimen: 4 weekly infusions of 375mg/m² versus a “hematologic” regimen: 2 biweekly infusions of 1000mg, which are equally used in practice as well as in RCT (Table 1). However, Sène et al. have raised the issue of serum sickness following the use of RTX therapy for CV, especially in patients with the highest cryoglobulin levels and the lowest C4 levels [39]. RTX may form a complex with cryoglobulin, which could increase cryoprecipitation and induce severe systemic reactions, including serum sickness. Consequently, these authors propose the use of a lower starting dose of RTX (i.e., rheumatological regimen), possibly preceded by corticosteroids and/or plasmapheresis to avoid side effects. Overall, short-term reactions to RTX infusions do not seem to be more frequent in CV than in other autoimmune conditions that are treated with a classical premedication of 100mg of methylprednisolone, antihistamine drugs, and paracetamol.

The safety of RTX, especially when RTX is used without the cover of antiviral agents, was supported in both RCTs, even though HCV load was not monitored in the Italian study [34]. RTX was not associated with significant liver impairment despite transient increases in HCV viral load, as already reported when RTX was given to patients with liver cirrhosis [6]. Nevertheless, data on HCV load and liver enzymes come from small sample-sized studies [40] with short-term followups, thus, this needs further evidence. RTX is also associated with a significant risk of infection, especially in patients with renal failure and advanced age and in those receiving high doses of corticosteroids [41]. This warrants the same precautions recommended for other autoimmune conditions with regards to vaccination and specific followup [42], including also early identification of rare but potentially severe complications related to RTX (i.e., anti-Pr cold agglutinins syndrome or progressive multifocal leukoencephalopathy).

3.2. Proregulatory Strategy: IL-2

Recently, Saadoun et al. obtained significant expansion of circulating regulatory T lymphocytes (Treg) with concomitant clinical improvement in 8/10 patients with refractory HCV-induced CV using a low dose of subcutaneous IL-2 (Proleukin, 1.5 million IU per day for 5 days, then 3 million IU per day for weeks 3, 6, and 9) [27]. Their patients were refractory to previous antiviral regimens, but only 1/10 patients had previously received rituximab, and only 1/10 had mild renal involvement. Interestingly, these patients did not receive any corticosteroids during the study period. The limitations of this pilot study are the absence of a control group, the short follow-up time (a few months), and some potential confounding factors (i.e., there was also a significant increase of CD56 bright NK cells), which prevent definitively concluding that the clinical benefits were solely due to the observed increase in Treg cells. Indeed, in the study by Koreth et al. (published at the same time), and also using low-dose IL-2 in patients suffering from graft-versus-host-disease, Treg-cell counts increased in all patients but were not statistically different between patients who had and those who did not have a response [43]. Nevertheless, these two studies constitute a proof of principle that low-dose IL-2 can be used safely to promote tolerance, probably through Treg expansion [27, 43].

IL-2 is produced by naive and memory T cells after antigen stimulation and binds to a high-affinity receptor consisting of three subunits: IL-2Rα (CD25), IL-2Rβ (CD122), and γc (CD132). Until recently, almost all clinical trials using IL-2 aimed at boosting effector T lymphocyte (Teff) function and have taken advantage of the immune-stimulating activity of IL-2. Indeed, this approach was successful in a subset of patients suffering from renal cell carcinoma and melanoma [44] and was also tested to boost the immunity of patients with AIDS [45]. The main limitations to the broader use of IL-2 are its very short half-life in the circulation after infusion, which necessitates using IL-2 at levels as high as possible, and its life-threatening nonspecific toxicities, such as vascular-leakage syndrome. Recent studies have shown that the primary function of IL-2 is, actually, the generation and survival of Treg [46], which explains in part why this approach failed in its anticancer indication and supports the possibility that IL-2 may, instead, promote T-cell tolerance in autoimmune conditions, such as CV, where a deficit of Treg has been documented [47].

There are several ways to use IL-2 to boost Treg. IL-2, together with other stimuli, can be used to expand the Treg-cell population ex vivo (Figure 2(a)), in tissue culture, before transferring these expanded cells to patients [48]. But this strategy is probably too complex to broadly translate to the bedside. Conversely, in-vivo expansion using subcutaneous infusion of IL-2 has been already used with variable results in mice and humans. IL-2 can be used at a high dose with coadministration of rapamycin to prevent the activation of Teff cells without affecting the Treg-cell response (Figure 2(b)). This protocol has proved to be beneficial in the treatment of diabetes in NOD mice [49] but, unfortunately, a clinical trial in new-onset type-1 diabetes patients showed that treatment with rapamycin plus a relatively high-dose of IL-2 (4.5 × 106IU/day subcutaneously, three times a week for 4 weeks) resulted in greater loss of insulin secretion at 3 months and, overall, was considered to worsen pancreatic β-cell function [50]. A low dose of IL-2 alone may also be used, which favours the expansion of Treg and has only a minor effect on Teff (Figure 2(c)). This strategy was successful in the two clinical studies already mentioned [27, 43] but warrants confirmation on a larger scale and additional work is needed to fully understand the role of IL-2 on cells other than Treg. Finally, an alternative approach (Figure 2(d)) could be the use of improved IL-2 formulations or IL-2-specific monoclonal antibodies, which allow IL-2 to selectively target Treg cells [51].

Figure 2

Different IL-2 based approaches to promote the expansion of regulatory T cells (Treg). A first approach consists of using IL-2, together with other stimuli, to expand ex vivo the Treg cells collected from a patient's tissue culture before transferring (more ...)

 

4. Biologics in HCV-Induced Vasculitis: Next Steps

In just a few years, biologics have modified the management of HCV-related CV. Their use has also raised many unsolved issues. The first concerns maintenance treatment. In patients refractory to antiviral regimens and who are successfully treated with RTX, more than a third will relapse during B-cell recovery, usually between 6 and 12 months [36, 37]. However, retreatment with RTX after a relapse seems to be effective in most cases [34, 35]. Systematic maintenance of RTX therapy has rarely been reported in CV but may be considered in severe forms [52], though the best modality remains to be determined. Other biologics targeting B cells, such as other anti-CD20 monoclonal (i.e., ocrelizumab and ofatumumab), anti-CD22 (epratuzumab), or anti-BAFF (belimumab) might also prove useful in the management of these conditions.

The second concern is the dosage used in RTX regimens. As already stated, both “haematological” and “rheumatological” regimens are both used in practice. Visentini et al. recently reported preliminary results from 27 patients receiving low-dose rituximab (2 weekly doses of 250mg/m²): they had a response rate similar to that reported for patients treated with standard doses [53]. If confirmed, this regimen could reduce costs, improve safety profiles, and be preferred by patients with nonsevere manifestations. Finally, one additional advantage of using RTX to treat CV may be the reduced exposure to corticosteroids. In the two RCTs [34, 35], responders to RTX therapy received lower total doses of prednisone than those allocated to a conventional immunosuppressive therapy. The possibility to propose a steroid-free regimen in selected patients with CV and to be only treated with RTX warrants additional trials.

In conclusion, patients suffering from HCV-induced vasculitis have and will largely benefit from the progress made in both antiviral and immunologic research. It seems that the place of biologics in the management of this complex condition is likely to increase in a near future.

 

Conflict of Interests

The authors declare that they have no conflict of interests.

 

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