Chronic hepatitis C virus (HCV) infection is associated with liver and extrahepatic complications, including B-cell lymphoma, cardiovascular and kidney diseases, glucose metabolism impairment and rheumatic conditions ie, arthralgia, myalgia, cryoglobulinemia vasculitis, sicca syndrome and the production of autoantibodies. The treatment has long been based on interferon alpha (IFN) that was found poorly effective, and contraindicated in many autoimmune/inflammatory disorders because of possible exacerbation of rheumatic disorders. The recent emergence of new oral IFN-free combinations offers an opportunity for HCV infected patients with autoimmune/inflammatory disorders to be cured with a short treatment duration and low risk of side effects.
Key points
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Hepatitis C virus infection is associated with many extrahepatic manifestations, including rheumatic disorders such as arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome.
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The treatment of hepatitis C virus infection has long been based on interferon alfa, which was contraindicated in many autoimmune/inflammatory disorders.
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The emergence of new oral interferon-free combinations now offers an opportunity for patients infected with hepatitis C virus with extrahepatic manifestations, including autoimmune/inflammatory disorders, to be cured with a short treatment duration and a low risk of side effects.
Approximately 130 million to 170 million people are infected with hepatitis C virus (HCV) worldwide. The HCV induces severe morbidity and mortality mainly caused by liver complications (cirrhosis, hepatocellular carcinoma). Shortly after HCV discovery in the early 1990s, this chronic viral infection was recognized to induce many extrahepatic manifestations. Large studies have highlighted increased HCV-related morbidity and mortality caused by cryoglobulinemia vasculitis, B-cell non-Hodgkin lymphoma, arthralgia, myalgia, sicca syndrome, as well as cardiovascular diseases, type 2 diabetes and insulin resistance, and neurocognitive dysfunction. Interferon alfa (IFN) has long been the cornerstone of antiviral combinations in patients infected with HCV with a low rate of efficacy and a poor tolerance. In addition, use of IFN was associated with high rates of severe adverse events. In patients infected by HCV and with autoimmune/inflammatory rheumatic diseases, IFN was either contraindicated or reported to induce a flare of the disease. Recently, new direct-acting antiviral (DAA) IFN-free treatments led to HCV cure in most (>90%) patients with a good safety profile (severe adverse events <5%) and a short duration (12 weeks). This article focuses on the main rheumatologic diseases associated with chronic HCV infection, and the impact of DAAs on such extrahepatic manifestations.
Hepatitis C virus and joint manifestations
Arthralgia/Myalgia
Arthralgia is reported in 6% to 20% of patients infected with HCV. It usually involves large joints, sometimes with effusion, and is bilateral and symmetric. Arthralgia most frequently involve fingers, knees, and back. Arthralgia is significantly more frequent in patients with cryoglobulinemia vasculitis compared with those without vasculitis (28% vs 23% respectively). The presentation may mimic a rheumatoid arthritis. The frequent positivity of a rheumatoid factor activity in patients infected with HCV also leads to misdiagnosis. Smoking and a previous diagnosis of arthritis are independent risk factors for self-reported joint pain (odds ratio [OR], 5 and 4.25, respectively). Myalgia is less common, affecting about 2% to 5% of patients with HCV. Arthritis, unrelated to mixed cryoglobulinemia, is less common (<5% of patient), involving small joints associated with carpal tunnel syndrome and palmar tenosynovitis.
Hepatitis C Virus Mixed Cryoglobulinemia Vasculitis
Mixed cryoglobulinemia vasculitis (CryoVas) is an immune complex small vessel vasculitis involving mainly the skin, the joints, the peripheral nerve system, and the kidneys. Cryoglobulinemia is defined by the presence of circulating immunoglobulins that precipitate at cold temperatures and dissolve with rewarming. CryoVas is related to HCV infection in 70% to 80% of cases, mostly associated with a type II immunoglobulin (Ig) M kappa mixed cryoglobulin. In contrast, 50% to 60% of patients infected with HCV produce a mixed cryoglobulin that leads to CryoVas in 15% of cases. Main symptoms include asthenia, purpura, arthralgia, myalgia, peripheral neuropathy, and glomerulonephritis. In a large cohort of patients with HCV-CryoVas, baseline factors associated with a poor prognosis were the presence of severe liver fibrosis (hazard ratio [HR], 5.31), central nervous system involvement (HR, 2.74), kidney involvement (HR, 1.91), and heart involvement (HR, 4.2). Arthralgia is reported in 40% to 80% of patients infected with HCV and positive for a mixed cryoglobulin. Joint pains are bilateral, symmetric, nondeforming, and involve mainly knees and hands, less commonly elbows and ankles. Rheumatoid factor (RF) activity is found in 70% to 80% of patients with CryoVas, not correlated with the occurrence of joint disease. Anti–cyclic citrullinated peptide (anti-CCP) antibodies are usually absent in patients with HCV. Clinically or on imaging, there is no evidence of joint destruction. Of note, some clinical features might be confusing for clinicians, because IFN treatment used for HCV may lead to exacerbation of arthralgia and myalgia. Sometimes it used to be difficult to distinguish vasculitis flares and side effects of IFN-based treatments.
Sicca Syndrome
Sicca symptoms of either the mouth or eyes have been reported in 10% to 30% of patients infected with HCV. Less than 5% of patients with a defined Sjögren syndrome are HCV positive. In a recent literature review, Younossi and colleagues reported a sicca syndrome prevalence of 11.9% in patients with HCV, with a risk ratio for sicca syndrome of 2.29 in patients infected with HCV compared with uninfected patients. However, the criteria for Sjögren syndrome diagnosis were based on clinical questionnaire in some studies and were not well detailed. Although sicca symptoms are very common in patients infected with HCV, a characterized Sjögren syndrome defined by the presence of anti-SSA or anti-SSB antibodies and a typical salivary gland histology is uncommon. A large cohort study of 137 patients with a definite Sjögren syndrome (1993 international criteria) compared patients with HCV infection with those with a primary form. Patients with HCV-associated Sjögren syndrome were older; more frequently male; and more frequently presented a vasculitis, a peripheral neuropathy, and a neoplasia. They also had a different biological pattern; that is, they more frequently had a positive RF test, a cryoglobulinemia, and less frequently anti-SSA or SSB antibodies. Only 23% of patients with HCV-associated Sjögren syndrome had positive anti-extractable nuclear antigen. The detection of HCV RNA and HCV core antigen in epithelial cells of patients with HCV-associated Sjögren syndrome and the development of Sjögren syndrome–like exocrinopathy in transgenic mice carrying the HCV envelope genes support the possibility of a direct impact of HCV on the development of sialadenitis.
Fibromyalgia and Fatigue
In a large prospective study, 19% of 1614 patients infected with HCV fulfilled the main diagnostic criteria of fibromyalgia (fatigue, arthralgia, and myalgia). Fatigue, with or without a fibromyalgia, was the most frequent extrahepatic manifestation (35%–67%). Many underlying factors were independently associated with fatigue, such as older age, female gender, the presence of arthralgia/myalgia, as well as neuropsychological factors. In contrast, there was no link with alcohol consumption, HCV genotype or viral load, the presence of a cryoglobulin, and thyroid dysfunction. Of note, after IFN-based treatment, only the group of patients with a sustained virologic response showed a beneficial impact on fatigue. A benefit of treatment on arthralgia/myalgia was found in about 50% of patients, independently of the virologic response.
Production of Autoantibodies
The prevalence of circulating autoantibodies is high in patients with chronic HCV infection, which may cause diagnostic difficulties in patients with rheumatic manifestations. The most frequent immunologic abnormalities include mixed cryoglobulins (50%–60%); RF activity (40%); and antinuclear (20%–35%), anticardiolipin (10%–15%), antithyroid (10%), and anti–smooth muscle antibodies (7%). At least 1 immunologic abnormality is present in up to 53% of patients infected with HCV. The presence of such antibodies (ie, RF, antinuclear, or anticardiolipin) is usually not associated with specific clinical symptoms related to autoimmune disease. The most frequent risk factors for the presence of such biological extrahepatic manifestations are the presence of extensive liver fibrosis and older age.
Underlying Mechanisms
There are multiple immunologic factors predisposing patients infected with HCV to develop a CryoVas or other systemic rheumatologic manifestations. Chronic stimulation of B cells by HCV directly modulates B-cell and T-cell function and results in polyclonal activation and expansion of B cell–producing IgM with RF activity. There is an expansion of clonal CD21 -/low IgM + CD27 + marginal zone–like B cells, and a decrease of regulatory T cells. In a genome-wide association study, significant associations were identified on chromosome 6. A higher percentage of a particular allele of the promoter of the B cell–activating factor has been shown. In contrast, specific virologic factors (viral load, genotype) have not been identified. Other factors are related to the infection by HCV of peripheral blood mononuclear cells, including peripheral dendritic cells, monocytes, and macrophages. A persistent viral stimulation enhances expression of lymphomagenesis-related genes, particularly the activation-induced cytidine deaminase, which is critical for somatic hypermutation and could lead to polyclonal and, later, monoclonal expansion of B cells. Under this trigger effect, oligoclonal or monoclonal IgM, which share rheumatoid activity, are produced by a permanent clone of B cells that favors the appearance of immune complexes, formed by circulating HCV, anti-HCV polyclonal IgG, and the monoclonal IgM.
Hepatitis C virus and joint manifestations
Arthralgia/Myalgia
Arthralgia is reported in 6% to 20% of patients infected with HCV. It usually involves large joints, sometimes with effusion, and is bilateral and symmetric. Arthralgia most frequently involve fingers, knees, and back. Arthralgia is significantly more frequent in patients with cryoglobulinemia vasculitis compared with those without vasculitis (28% vs 23% respectively). The presentation may mimic a rheumatoid arthritis. The frequent positivity of a rheumatoid factor activity in patients infected with HCV also leads to misdiagnosis. Smoking and a previous diagnosis of arthritis are independent risk factors for self-reported joint pain (odds ratio [OR], 5 and 4.25, respectively). Myalgia is less common, affecting about 2% to 5% of patients with HCV. Arthritis, unrelated to mixed cryoglobulinemia, is less common (<5% of patient), involving small joints associated with carpal tunnel syndrome and palmar tenosynovitis.
Hepatitis C Virus Mixed Cryoglobulinemia Vasculitis
Mixed cryoglobulinemia vasculitis (CryoVas) is an immune complex small vessel vasculitis involving mainly the skin, the joints, the peripheral nerve system, and the kidneys. Cryoglobulinemia is defined by the presence of circulating immunoglobulins that precipitate at cold temperatures and dissolve with rewarming. CryoVas is related to HCV infection in 70% to 80% of cases, mostly associated with a type II immunoglobulin (Ig) M kappa mixed cryoglobulin. In contrast, 50% to 60% of patients infected with HCV produce a mixed cryoglobulin that leads to CryoVas in 15% of cases. Main symptoms include asthenia, purpura, arthralgia, myalgia, peripheral neuropathy, and glomerulonephritis. In a large cohort of patients with HCV-CryoVas, baseline factors associated with a poor prognosis were the presence of severe liver fibrosis (hazard ratio [HR], 5.31), central nervous system involvement (HR, 2.74), kidney involvement (HR, 1.91), and heart involvement (HR, 4.2). Arthralgia is reported in 40% to 80% of patients infected with HCV and positive for a mixed cryoglobulin. Joint pains are bilateral, symmetric, nondeforming, and involve mainly knees and hands, less commonly elbows and ankles. Rheumatoid factor (RF) activity is found in 70% to 80% of patients with CryoVas, not correlated with the occurrence of joint disease. Anti–cyclic citrullinated peptide (anti-CCP) antibodies are usually absent in patients with HCV. Clinically or on imaging, there is no evidence of joint destruction. Of note, some clinical features might be confusing for clinicians, because IFN treatment used for HCV may lead to exacerbation of arthralgia and myalgia. Sometimes it used to be difficult to distinguish vasculitis flares and side effects of IFN-based treatments.
Sicca Syndrome
Sicca symptoms of either the mouth or eyes have been reported in 10% to 30% of patients infected with HCV. Less than 5% of patients with a defined Sjögren syndrome are HCV positive. In a recent literature review, Younossi and colleagues reported a sicca syndrome prevalence of 11.9% in patients with HCV, with a risk ratio for sicca syndrome of 2.29 in patients infected with HCV compared with uninfected patients. However, the criteria for Sjögren syndrome diagnosis were based on clinical questionnaire in some studies and were not well detailed. Although sicca symptoms are very common in patients infected with HCV, a characterized Sjögren syndrome defined by the presence of anti-SSA or anti-SSB antibodies and a typical salivary gland histology is uncommon. A large cohort study of 137 patients with a definite Sjögren syndrome (1993 international criteria) compared patients with HCV infection with those with a primary form. Patients with HCV-associated Sjögren syndrome were older; more frequently male; and more frequently presented a vasculitis, a peripheral neuropathy, and a neoplasia. They also had a different biological pattern; that is, they more frequently had a positive RF test, a cryoglobulinemia, and less frequently anti-SSA or SSB antibodies. Only 23% of patients with HCV-associated Sjögren syndrome had positive anti-extractable nuclear antigen. The detection of HCV RNA and HCV core antigen in epithelial cells of patients with HCV-associated Sjögren syndrome and the development of Sjögren syndrome–like exocrinopathy in transgenic mice carrying the HCV envelope genes support the possibility of a direct impact of HCV on the development of sialadenitis.
Fibromyalgia and Fatigue
In a large prospective study, 19% of 1614 patients infected with HCV fulfilled the main diagnostic criteria of fibromyalgia (fatigue, arthralgia, and myalgia). Fatigue, with or without a fibromyalgia, was the most frequent extrahepatic manifestation (35%–67%). Many underlying factors were independently associated with fatigue, such as older age, female gender, the presence of arthralgia/myalgia, as well as neuropsychological factors. In contrast, there was no link with alcohol consumption, HCV genotype or viral load, the presence of a cryoglobulin, and thyroid dysfunction. Of note, after IFN-based treatment, only the group of patients with a sustained virologic response showed a beneficial impact on fatigue. A benefit of treatment on arthralgia/myalgia was found in about 50% of patients, independently of the virologic response.
Production of Autoantibodies
The prevalence of circulating autoantibodies is high in patients with chronic HCV infection, which may cause diagnostic difficulties in patients with rheumatic manifestations. The most frequent immunologic abnormalities include mixed cryoglobulins (50%–60%); RF activity (40%); and antinuclear (20%–35%), anticardiolipin (10%–15%), antithyroid (10%), and anti–smooth muscle antibodies (7%). At least 1 immunologic abnormality is present in up to 53% of patients infected with HCV. The presence of such antibodies (ie, RF, antinuclear, or anticardiolipin) is usually not associated with specific clinical symptoms related to autoimmune disease. The most frequent risk factors for the presence of such biological extrahepatic manifestations are the presence of extensive liver fibrosis and older age.
Underlying Mechanisms
There are multiple immunologic factors predisposing patients infected with HCV to develop a CryoVas or other systemic rheumatologic manifestations. Chronic stimulation of B cells by HCV directly modulates B-cell and T-cell function and results in polyclonal activation and expansion of B cell–producing IgM with RF activity. There is an expansion of clonal CD21 -/low IgM + CD27 + marginal zone–like B cells, and a decrease of regulatory T cells. In a genome-wide association study, significant associations were identified on chromosome 6. A higher percentage of a particular allele of the promoter of the B cell–activating factor has been shown. In contrast, specific virologic factors (viral load, genotype) have not been identified. Other factors are related to the infection by HCV of peripheral blood mononuclear cells, including peripheral dendritic cells, monocytes, and macrophages. A persistent viral stimulation enhances expression of lymphomagenesis-related genes, particularly the activation-induced cytidine deaminase, which is critical for somatic hypermutation and could lead to polyclonal and, later, monoclonal expansion of B cells. Under this trigger effect, oligoclonal or monoclonal IgM, which share rheumatoid activity, are produced by a permanent clone of B cells that favors the appearance of immune complexes, formed by circulating HCV, anti-HCV polyclonal IgG, and the monoclonal IgM.
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