In recent years, the interest in the relationship between HCV infection and autoimmune manifestations, has increased. Indeed, there is ample evidence to attribute a role for HCV-associated autoimmunity for a broad spectrum of autoimmune diseases [12, 13,15-23,52]. These include rheumatic autoimmune diseases, non-rheumatic autoimmune diseases and autoimmune liver disease.
The most firmly established disease associated with HCV infection is mixed cryoglobulinemia syndrome (MCS) [17-19]. HCV is detected in about 80-90% of MCS patients and cryoglobulinemia is found in around 40% of chronic HCV infected subjects. MCS is more frequent in long standing HCV infection, in older patients, in females and in cirrhosis , Among patients with HCV associated MCS, only 10% are also associated with clinical manifestations of vasculitis . The cryoglobulinemic immune response to HCV infection may be manifested by a variety of cutaneous lesions, including urticaria, livedo reticularis, and palpable purpura [54-56], leukocyto-clastic vasculitis, glomerulonephritis, or mononeuritis multiplex [54,57-60]. Recently, Weiner et al. reported a lower prevalence of HCV related cryoglobulinemia in Germany compared with data from Italy and France and suggested a South-North gradient in the prevalence of HCV associated cryoglobulinemia in Europe .
Polyarthralgias and polyarthritis have been associated with HCV infection [22, 62], and HCV RNA has been isolated from synovial fluid [63, 64]. Several patients with rheumatoid arthritis attributed to HCV have been reported as well as others with atypical inflammatory arthritis [22, 23]. In few patients the arthritis was the most prominent manifestation of chronic HCV infection .
Few cases of HCV-associated SLE have been described . Most of them were cases of SLE induced or aggravated by «-interferon treatment. In an uncontrolled investigation of HCV seropositivity in 71 consecutive SLE patients, Marchesoni et al. , reported 4 patients (6% incidence rate) with HCV seropositivity, which was greater than but not significantly different from the expected incidence for the general population in their geographic area. We have assessed recently the prevalence of anti-HCV antibodies in 95 consecutive SLE patients, only one of them had evidence of HCV infection , This is not different from the prevalence of HCV infection in the general Israeli population (0.5%).
Few patients with HCV-associated inflammatory myopathy have been described [63, 64, 69-71]. One HCV patient had anti-Jo-1 positive polymyositis and interstitial lung disease . A preliminary investigation comparing the incidence of HCV in patients with polymyositis/dermatomyositis (PM/DM) versus a control population showed an HCV-seropositive incidence of 10% in PM/DM patients, which was increased but not significantly different from the control group ,
Sicca syndrome also occurs in MCS in about 15% of cases . Salivary gland lesions were found in 49% of HCV infected patients, all had lymphocytic capillaritis, sometimes associated with lymphocytic sialadenitis resembling that of Sjögrens syndrome and Ro/SS-A antibodies . HCV has been reported to occur in Sjogren's syndrome [21, 74], however, others [75, 76] have refuted this finding.
Generalized vasculitis of polyarteritis nodosa (PAN) has been rarely associated with HCV infection [77, 78], The seroprevalence of specific antibodies to HCV in patients with PAN was about 5-8%. Most cases of HCV-associated vasculitis presented as leuko-cytoclastic vasculitis secondary to an HCV-induced cryoglobulinemia [79-81], Unique vasculitis presentations included pulmonary and intestinal vasculitis [81-83],
The frequency and variety of rheumatic manifestations in HCV-infected individuals is not well documented. Few recent studies have attempted to address this issue [84, 85]. Thus, 69% of 42 HCV patients reported musculoskeletal complaints. The majority of these were nonspecific myalgias and arthralgias , In another study , more than 50% of 56 patients with chronic hepatitis expressed rheumatic manifestations including arthralgias, Sicca syndrome and myalgias. We have assessed recently, the fre quency and spectrum of musculoskeletal manifestations in our HCV-infected patients. Rheumatic manifestations were found in 28 subjects (31%), and included arthralgia (9%), arthritis (4%), cryoglobulinemia (11%), sicca symptoms (8%), cutaneous vasculitis (2%), polymyositis (1%), antiphospholipid syndrome (1%). Rheumatic complications were not associated with liver disease severity, or subjects' gender. In addition, 22 patients (24%) reported myalgia, and fibromyalgia was diagnosed in 14 (16%) . The frequency of rheumatic disease was not different among men and women and did not correlate to liver disease severity. Three patients developed autoimmune diseases shortly after diagnosis of HCV infection, namely: myasthenia gravis, polymyositis and antiphospholipid syndrome.
Fibromyalgia syndrome (FS) though not an autoimmune disease, is a common disorder of diffuse pain in the muscles or joints accompanied by tenderness at specific tender points and a constellation of related symptoms. In a recent study, Buskila et al.  found that 15.6% of HCV infected patients were diagnosed to have FS while no subject from healthy control group (with no evidence of HCV infection had FS).
A specific relationship between thyroid dysfunction and chronic HCV infection is currently thought to exist [87, 88]. HCV infection is associated with a higher prevalence of thyroid autoantibodies [50, 89, 90], however, thyroid autoimmune diseases are less frequent . The development of autoimmune thyroiditis has been correlated with HCV antibodies directed against the cDNA clone GOR 47-1 (anti-GOR antibodies) . In general, the association between thyroid dysfunction and chronic hepatitis has been claimed to involve all forms of thyroid disease: hypothyroidism, hyperthyroidism, Hashimoto's disease and isolated increased antithyroid antibodies [80, 92]. I FN-« may induce thyroid autoantibodies in HCV-infected in [89, 93], and precipitate thyroid dysfunction in patients with existing autoantibodies ,
An association between HCV and glomerulonephritis (GMN) has been documented and includes membranous [91,96], membranoproliferative [57,96,97] and acute proliferative glomerular disease  as well as that associated with cryoglobulinemia [57,60], Mild to moderate proteinuria has been detected in 27% of patients with chronic HCV infec tion, whereas microscopic hematuria has been seen in only 9% , Membranoproliferative GMN in HCV infection is seen frequently in the absence of other clinical features of cryoglobulinemia. However, even in such patients, glomerular deposition of IgG, IgM and C3 have been documented. Electron microscopic changes characteristic of cryoglobulin deposition and cryoprecipitates containing HCV RNA and antibodies to HCV nucleocapsid proteins C22-3 have also been demonstrated , Recently, Sansonno et al.  have shown that specific HCV related proteins were detected in glomerular and tubulointerstitial vascular structures in two thirds of HCV positive patients with membranoproliferative glomerulonephritis and in none of HCV negative controls. These authors suggest that kidney deposits consistent of HCV-containing immune complexes, play a direct pathogenic role in the renal support in the use of antiviral agents, such as IFN in its treatment.
Recently two cases of Guillain-Barre syndrome have been reported in patients with chronic HCV infection . The authors speculate that the immunological disorders triggered by HCV infection predisposed the patients to this immune-mediated polyneuropathy.
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