New insights into HCV-related rheumatologic disorders: A review.

Hepatitis C virus (HCV) infected patients are known to be exposed to major liver complications i.e. cirrhosis and hepatocellular carcinoma. In addition, many extrahepatic manifestations including rheumatologic disorders have been reported in up to two-third of HCV infected patients. These manifestations include frank auto-immune and rheumatic diseases (such as arthralgia, myalgia, arthritis, sicca syndrome and vasculitis) which may dominate the course of infection. Until recently, the standard of care of HCV has been the use of interferon-alpha based regimens, which not only had limited effectiveness in HCV cure but were poorly tolerated. In patients with rheumatic diseases interferon-based regimens may be problematic given their association with a wide variety of autoimmune toxicities. Recent therapeutic advances with new direct anti-HCV therapies (interferon-free) which are more effective and better tolerated, make screening for this comorbidity in patients with rheumatic disorders more important than ever. This review aimed to outline main HCV extrahepatic with a special focus on rheumatologic manifestations.

Introduction

Hepatitis C Virus (HCV) infection, a major global health problem leading to heavy costs, is present in 150–170 million people, including 19 million people in Europe [1]. Liver complications, including cirrhosis and liver cancer, are currently reported during chronic HCV infection, with an estimated liver-related mortality of 350,000 people/year. Additionally, extrahepatic manifestations are presented in up to two-third of patients [2]. Several of these manifestations are common and well-described while others are infrequent [3], [4], [5]. In the literature, autoimmune and lymphoproliferative diseases are well-known HCV-related disorders [6]. Other more recently reported HCV-associated disorders include cardio-metabolic, renal, and neurocognitive disorders. With the arrival of direct acting antivirals (DAAs), the perspective of HCV eradication is important in a therapeutic and preventive aspect, for liver and non-liver consequences of the disease. This review aimed to outline most of rheumatologic HCV extrahepatic manifestations that are currently deeper investigated.

Cryoglobulinemia vasculitis

Mixed cryoglobulinemia vasculitis (CryoVas) is a systemic vasculitis which leads to clinical manifestations ranging from purpura, arthralgia and fatigue to more serious lesions with neurologic and renal involvement [7]. Circulating mixed cryoglobulins are detected in 40–60% of patients chronically infected with HCV whereas overt CryoVas is observed in only 5–10% of cases. HCV infection represents the cause of CryoVas in 70–80% of cases [7], [8], [9]. The disease expression may range from mild symptoms to fulminant life-threatening complications. The main skin symptom is a palpable purpura; chronic cutaneous ulcers, Raynaud’s phenomenon, acrocyanosis, and digital ulcerations can also occur [7]. Patients present with arthralgia of large peripheral joints in 70% of cases, rarely with arthritis. The most frequently described neurologic manifestation is a distal sensory or sensory-motor polyneuropathy, with painful, asymmetric paresthesia. Multiple mononeuropathy may occur less frequently. An acute or chronic membranoproliferative glomerulonephritis with sub-endothelial deposits represents the large majority of cryoglobulinemia-renal diseases, strongly linked with the type II IgM kappa mixed cryoglobulinemia (MC). It presents usually with proteinuria, hematuria and a variable intensity of renal insufficiency.

Cryoglobulinemia is defined as the presence protein which precipitates in the serum at 4 °C during 7 days and which dissolved at 37 °C. During chronic HCV infection, mixed cryoglobulinemia are characterized as type II or type III cryoglobulins which consist of polyclonal IgG with monoclonal or polyclonal IgM with rheumatoid factor (RF) activity, respectively [10]. During follow-up, improvement is assessed by the serum level of cryoglobulinemia and surrogate markers (C4, CH50, RF).

Main predictive factors of CryoVas in HCV-infected patients are advanced age, longer duration of infection, type II mixed cryoglobulin, and clonal B-cell expansions in both the blood and liver. The worse pronostic factors are an age older than 60 years and renal manifestations, with a 5 year survival ranging from 90% to 50% in case of kidney involvement. Other causes of mortality include liver disease, cardiovascular disease, infectious disease and lymphoma [11]. Among 231 patients, 79 of 97 deaths were linked to vasculitis (46%), cancer/hemopathy (23%), or liver disease (13%) [12]. HCV-CryoVas may result in progressive (renal involvement) or acute (gut, cardiac, CNS, pulmonary hemorrhage) life-threatening organ damage, with mortality rate ranging from 20% to 80% [13], [14].

Multiple factors predispose patients to develop a CryoVas. HCV-lymphocytes interaction directly modulates B- and T-cell function and results in polyclonal activation and expansion of B-cell producing IgM with RF activity [15]. Regulatory T cell, known to control self-tolerance, is reduced in HCV-CryoVas patients. Regulatory T cell deficiency may contribute to autoreactive B-cell expansion driving autoimmune manifestations in HCV-CryoVas patients [16], [17]. HLA-DR11 increases the risk of CryoVas whereas HLA-DR7 decreases the risk of type II mixed cryoglobulin production [18]. A SNP within an intronic region of NOTCH4 (p = 6.2 ∗ 10–9) and another between HLA-DRB1 and HLA–DQA1 (p = 1.2 ∗ 10–7) on chromosome 6 were associated with HCV-CryoVas [19]. A high prevalence of homozygosity and a great frequency of a particular allele of the BAFF promoter were found in HCV-CryoVas patients compared to HCV patients [20]. Different expression profiles of microRNAs in peripheral blood mononuclear cell associated with lymphoproliferative and autoimmune disorders have been reported [21]. Today, no specific virologic factors have been found.

Most HCV-CryoVas manifestations have been shown to disappear after HCV clearance post antiviral therapy with pegylated interferon (IFN) plus ribavirin [22], [23] whereas virological relapsers usually relapse for the CryoVas [24]. Current treatment of HCV-CryoVas is guided by organ involvement and the severity of the disease (Fig. 1). In case of persistent CryoVas manifestations in patients with a sustained virologic response (SVR), another underlying condition should be considered, especially B-cell lymphoma [25]. Combination therapy with pegylated-IFN/ribavirin plus a NS3/4A protease inhibitor (boceprevir or telaprevir) showed at week 24 post-treatment that 20/30 (67%) patients were complete clinical and SVRs [26], with serious adverse events almost fifty percent. Use of Peg-IFN/ribavirin in combination with boceprevir for 48 weeks in 35 HCV GT1 patients showed a drastic reduction of the cryocrit values, and an improvement of CryoVas symptoms [27]. New interferon-free DAAs are now available which facilitate shortened courses of IFN-free antivirals associated with SVR rates >95% and few side effects. International guidelines (i.e., EASL 2015) [28] state that treatment should be scheduled, not deferred, for patients with clinically significant extra-hepatic manifestations, like CryoVas. In a recent French study, sofosbuvir (400 mg/day) plus ribavirin (200–1400 mg/day) combination for 24 weeks was associated with a high rate of complete clinical response of CryoVas (87.5%) and a low rate of serious adverse events (8.3%) [29]. Other recent studies report both safety and efficacy of IFN-free DAA antivirals including non SOF-based regimens, in difficult-to-treat patients [30], [31]. Sise et al. [32] have reported a retrospective case series of twelve HCV-CryoVas patients treated with SOF-based regimens [median age 61 years, 58% male, 50% cirrhotic]. All patients had undetectable HCV RNA by week 4. A SVR12 was achieved in 10/12 (83%) patients. Individual eGFR changes showed a positive impact in two out of seven patients with active glomerulonephritis; there was a reduction in proteinuria in 3/3 cases. Only two (17%) patients experienced serious adverse events.

Fig. 1

Therapeutic strategies in HCV-CryoVasc.

Rituximab has proved a clear benefit in CryoVas as it targets B-cells which are responsible for cryoglobulin production [33], [34], [35], [36], [37]. In a randomized trial rituximab showed a better efficacy than conventional immunosuppressants [38]. Similar results have been reported in a placebo controlled trial [39]. There was no risk of viral reactivation in HCV patients, contrary to HBV infection [40]. Rituximab plus pegylated-IFN/ribavirin compared to pegylated-IFN/ribavirin led to a shorter time to clinical remission, better renal response rate, and higher rates of cryoglobulin clearance [41], [42].

To summarize, in HCV-CryoVas with mild to moderate disease, an optimal antiviral IFN-free treatment should be given alone. For patients with severe vasculitis (i.e. worsening of renal function, mononeuritis multiplex, extensive skin disease, and intestinal ischemia) control of disease with rituximab, with or without plasmapheresis, is usually required and antiviral IFN-free therapy should be started at the same time [43]. Low-dose corticosteroids may help to control inflammatory signs such arthralgia but do not succeed in case of major organ involvement. Other immunosuppressants should be given only in case of refractory forms of CryoVas, frequently associated with underlying B-cell lymphoma [44].

B-cell lymphoproliferative diseases

Initially, few cohorts reported a high prevalence of HCV infection in patients with B-cell non-Hodgkin’s lymphoma (B-NHL) [45], [46], then this observation was confirmed in meta-analyses [47], [48], [49], [50], [51]. HCV chronic infection was associated with marginal zone B-NHL (OR 2.47) and diffuse large B-NHL (OR 2.24). A serum IgMk gammopathy has been frequently noted in HCV patients [52].

In addition, incidence of B-NHL was lower in patients with SVR [53]. A SVR was associated with NHL regression while a viral relapse was followed by the lymphoma relapse [54], [55]. HCV-positive splenic lymphoma with villous lymphocytes (SLVL) regressed after antiviral therapy [56]. Regression of clonal B-cell expansion following successful antiviral therapy has been described with novel expansion of the same clones in patients who relapsed [57], [58]. This suggests no-return points in the HCV-driven lymphomagenesis, making the pathogenic mechanism progressively less dependent on the viral antigen [59].

HCV-related lymphoproliferative diseases appear to be the result of multiple events such as a sustained B-cells activation, an aberrant B-cell survival, genetic/epigenetic and environmental factors [59], [60]. The role of a prolonged antigenic stimulation has been demonstrated by the lymphotropism of HCV and the presence of HCV antigens in peripheral blood or liver infiltrating lymphocytes and lymph-nodes [61], [62], [63]. The linking of HCV surface E2 protein with the tetraspanin CD81 diminished B-cell activation threshold [64]. BCR sequence analyses and affinity in HCV-related NHL showed conflicting results [65], [66]. Higher prevalence of HCV infection in PBMCs and bone marrow [67], [68] and in vitro studies support the lymphotropism of the virus [69], [70]. The rate of mutations in oncogenes and immunoglobulin genes is increased in HCV-infected cells [71]. The expression of HCV core and lymphoma was correlated in transgenic models [72], [73]. The (14;18) translocation increased Bcl-2 levels and B-cell survival [58], [74], [75] that disappeared after antivirals [57], [76], [77]. The role of cytokines and chemokines [15], [78], [79], [80], [81], including BAFF [20], [60], [82], [83], [84], and the role of microRNAs [21], [85] have been studied extensively in HCV-related lymphoproliferative diseases.

Several studies showed a clinical remission following antivirals in low-grade B-cell NHL, mainly in marginal zone lymphoma [55], [56], [86], [87], [88], [89]. The use of IFN-based therapy in patients with indolent HCV-NHL has been associated with an improved overall survival [89]. IFN-based treatment is difficult because of IFN hematological toxicity. However, antivirals after lymphoma remission showed prolonged disease-free survival [90], [91]. Rituximab alone or with antivirals and/or chemotherapy showed good results in low-grade B-NHL [42], [92]. The recent availability of IFN-free DAAs with a high virological efficacy and no hematological toxicity should easily permit their association with chemotherapy, taking into account possible pharmacological interference.

Arthralgia/myalgia

Arthralgia are found in 30–70% of HCV-infected patients with mixed cryoglobulin [3], [93]. Patients present with bilateral, symmetric, non-deforming joint pains involving mainly knees and hands, more rarely elbows and ankles. HCV arthritis, unlinked to mixed cryoglobulin, is uncommon (<10%). A RF activity is found in 70–80% of CryoVas patients due to the presence of a mixed cryoglobulin; it is not associated with the presence or the activity of joint manifestations. Radiographic joint destruction is not found. Search for antibodies to cyclic citrullinated peptide is negative. IFN-based combinations for HCV may exacerbate arthralgia and myalgia, thus confounding clinical presentation. Clinicians should use main characteristics to differentiate rheumatologic manifestations such as arthralgia, myalgia, and arthritis that may occur in HCV infected patients due to HCV infection itself or to a newly developed rheumatologic disease.

Sicca syndrome

An ocular and/or buccal sicca syndrome is described in 20–30% of HCV infected patients, whereas a definite Sjögren’s syndrome (xerostomia, xerophthalmia, anti-SSA/anti-SSB antibodies and typical salivary gland histology) is reported in less than 5% of HCV-positive patients [3]. The presentation may be confusing between HCV-related sicca syndrome and “true” Sjögren’s syndrome [94]. HCV-positive patients with a Sjögren’s syndrome are older and more likely to have a photosensitivity and a mixed cryoglobulinemia compared to those with a primary Sjögren’s syndrome. Presence of low titers of antinuclear antibodies and a RF are common in HCV patients with sicca syndrome, and the presence of Sjögren’s syndrome autoantibodies (i.e. anti-SSA/SSB antibody) is rare. The sialadenitis found in HCV infected patients may be related to the allotropism of the virus [95]. In transgenic mice, the development of sialadenitis has been associated with the expression of E1- and E2-HCV glycoproteins [96].

Auto-antibodies

HCV infected patients are frequently positive for autoantibodies (up to 53%), i.e. mixed cryoglobulins (60–80%), RF activity (70%), and antinuclear (20–40%), anticardiolipin (aCL) (20–15%), anti-thyroid (12%) and anti-smooth muscle antibodies (7%) [2], [3]. Such autoantibodies have not been associated with connective tissue disease manifestations, except for mixed cryoglobulins and CryoVas. For example, while aCL occurs frequently in viral infections, particularly in HIV (49.75%), HBV (24%) and HCV (20–15%), they are very rarely associated with anti-beta2 glycoprotein I antibodies and are not correlated with a thrombotic risk [97]. In patients with non-autoimmune liver diseases, the production of aCL is a non-specific phenomenon of the liver damage, and it is not associated with thrombotic complications [98]. The HCV-induced activation and proliferation of B cells is the most reported reason for such auto-antibody production, although many other auto-antibodies are not found in HCV infected patients.

Renal insufficiency

The more frequent and severe renal manifestations in HCV infected patients are related to CryoVas (see above). However other mechanisms may be involved leading to renal involvement in such patients. A higher rate of MPGN was found in HCV-positive compared to HCV-negative U.S. hospitalized male veterans (0.36% vs. 0.05%, P < 0.0001), but not membranous glomerulopathy (0.33% vs. 0.19%, P = 0.86) [99]. A higher rate of renal insufficiency has been reported in HCV infected patients compared with subjects without HCV infection, after adjusting for age, gender, race, diabetes, and hypertension [100]. HCV infection may affect renal function in the general population as it has been associated with low GFR, with odds ratio up to 2.80 [101]. In addition, HCV infection appears to increase the risk of proteinuria in healthy individuals, with odds ratio of 1.14–1.99, independently of diabetes mellitus, arterial hypertension, obesity, and dyslipidemia [102], [103], [104], [105], [106].

cardiovascular and glucose metabolism disorders

The main cause of mortality in HCV infected patients is the liver disease [107], [108], [109], [110], [111], [112], [113]. However, HCV infected patients showed increased mortality rates due to extra-hepatic complications (i.e., cardiovascular, renal, tumoral) [111], [112], [114], [115], [116]. Some chronic infections have been suggested as triggers for cardiovascular diseases [117], [118], [119]. Their identification as cardiovascular risk factors may offer new perspectives in cardiovascular disease prevention [120]. HCV seropositivity is associated with high rates of carotid-artery plaques, carotid intima-media thickening, and the risk of stroke independently of other well known atherosclerosis risk factors [117]. The HCV is able to induce the production of pro-atherogenic cytokines [121] that may promote the atherosclerotic plaque instability, supporting a role of the virus in the cerebrovascular diseases risk [122]. In addition, cohort studies suggested a positive impact of antivirals on the incidence of stroke [123].

HCV infection has been shown to increase the risk of coronary artery disease, after adjustment for cardiovascular risk factors [124]. Patients with SVR after antivirals showed an improvement in their myocardial perfusion defect whereas relapsers showed a worsening after a transient improvement [125]. The risk of major cardiovascular events (i.e. cerebrovascular accident and ischemic heart disease) is higher in patients with HCV infection compared to controls, independent of the severity of the liver disease or the common cardiovascular risk factors [126]. The beneficial impact of IFN-based therapy needs to be confirmed with new IFN-free DAAs in prospective studies with extended follow-up.

Insulin-resistance, commonly associated with obesity and metabolic syndrome, can evolve to diabetes mellitus [127]. The presence of insulin-resistance has been analyzed in SVRs after pegylated IFN plus ribavirin. On one hand, the therapeutic response was not altered by insulin-resistance. On the other hand, therapeutic failure and elevated body mass index were independent risk factors for de novo appearance of insulin-resistance after treatment. No new case of insulin-resistance was registered in SVR patients, suggesting a possible prevention of insulin-resistance onset and its evolution to diabetes [128]. Insulin resistance has been found to alter SVR rate to pegIFN plus ribavirin in HIV-HCV coinfected patients [129]. Increased risk of type 2 diabetes in HCV infected patients may arise from interactions between insulin resistance, steatosis and inflammatory mechanisms [130]. Many epidemiologic studies support the link between type 2 diabetes and HCV infection [131], [132], [133]. Type 2 diabetes was more frequent in HCV- than HBV-related cirrhosis (23.6% vs. 9.4%; OR 2.78; 95%CI, 1.6–4.79; P = 0.0002) [134], [135]. In HCV infected patients type 2 diabetes was more frequent in male cirrhotics.

The prevalence and spectrum of rheumatic disorders and autoimmune phenomena in HCV-infected patients have been reported [8], [136]. Many of these extrahepatic manifestations are autoimmune disorders, with added mortality and morbidity due to involvement of multiple organ systems [137]. Until recently, the standard of care of HCV has been the use of interferon-based regimens, which not only have limited effectiveness in curing the underlying viral illness but are poorly tolerated and in patients with rheumatic diseases especially problematic given their association with a wide variety of autoimmune toxicities [138]. CryoVasc can be treated at different levels by means of etiological treatment with antivirals aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis) [133]. In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the CryoVasc and possibly tailored to each individual patient’s conditions. In our review, we investigated clinical and therapeutic facets of HCV-related extrahepatic manifestations.

Conclusions

In summary, beyond the liver manifestations, HCV chronic infection frequently leads to a true systemic disease where many manifestations appear to be in the field of rheumatology. Therefore, rheumatologists should be aware of these numerous manifestations and they should increase the screening of HCV infection in their patients.

Conflict of interest

The authors have declared no conflict of interest.

Compliance with Ethics Requirements

This article does not contain any studies with human or animal subjects.