Extrahepatic manifestations are frequently observed in patients with chronic HCV infection, with a prevalence of more than 74% . In a prospective study on a large cohort of HCV patients, articular involvement represented the most common extrahepatic manifestation, affecting nearly 20% of patients in a 1-year follow-up .
Although it is not possible to identify a specific pattern of HCV-related arthropathy, two different clinical subsets of arthritis have mainly been described (reviewed in ): a monoarticular–oligoarticular intermittent arthritis affecting large and medium-sized joints and almost invariably associated with the presence of mixed cryoglobulinaemia [3, 15] and a polyarticular symmetrical arthritis closely resembling RA [3, 5, 16]. Differential diagnosis between HCV-related polyarthritis and 'true' RA is often very difficult because most patients with HCV-related polyarthritis fulfil the ACR criteria for RA [4, 5]. Thus, because of the lack of reliable clinical parameters able to differentiate between the two diseases, other markers are needed for the differential diagnosis.
Together with the classical clinical features of the disease, serological abnormalities, such as the presence of RF, are usually useful in the diagnosis of RA, and RF is included in the ACR criteria for RA. However, in cases of HCV-related arthropathy, RF detection is not very useful because it is often observed in sera of patients with HCV. In particular, classic IgM RF can be detected in more than 60% of patients with HCV-related arthropathy . Moreover, even IgA RF, which has been suggested to be useful in distinguishing between RA and HCV-related polyarthritis , failed to demonstrate any specificity for RA compared with HCV-related arthropathy .
Recently, anti-keratin antibodies (AKA) have been shown to be useful in distinguishing between RA and HCV-related arthropathy . However, although characterised by a high specificity, AKA display a rather low sensitivity for RA ; moreover, the detection of AKA is laborious, difficult to standardise and of limited clinical utility. The limits displayed by AKA and later by the tests for detection of anti-filaggrin antibodies  were largely overcome after the discovery of citrulline residues as the main antigenic target of AKA and anti-filaggrin antibodies and the subsequent development of an immunoenzymatic test using cyclic citrullinated peptide to detect anti-CCP antibodies . The currently available so-called second-generation test, anti-CCP2, has been shown to retain a high specificity for RA accompanied by a reasonable (about 80%) sensitivity [7, 9]. In addition, anti-CCP antibodies have been showed to be useful diagnostic tools even in the early stages of the disease and predictive factors both in terms of disease progression and radiological damage [10–13].
In this study we demonstrated that anti-CCP antibodies are able to differentiate patients with HCV-related arthropathy from patients with RA. In our population of consecutive chronic HCV patients we identified eight patients with HCV-related articular involvement. Three patients presented chronic polyarthritis that was clinically indistinguishable from RA. Remarkably, 37.5% (three of eight) of patients with HCV-related articular involvement and 66.7% (two of three) of patients with RA-like polyarthritis were positive for RF, whereas no patients displayed anti-CCP reactivity. In contrast, we confirmed the increased sensitivity of the anti-CCP2 test with a prevalence of 76.6% in our patients with RA, comparable with that obtained in recent studies [7, 8].
In addition, when we retrospectively analysed the prevalence of anti-CCP antibodies in patients presenting with symmetric polyarthritis and HCV infection who subsequently developed a well-established erosive RA, we demonstrated that anti-CCP antibodies were present in 60% of patients at the time of first visit. Although confirmation is needed in a larger cohort of patients with HCV-related RA-like polyarthritis, these results suggest that anti-CCP antibodies can be useful in differential diagnosis with RA.
Differentiating between patients with RA and those with HCV-related arthropathy has great relevance in clinical practice. In fact, in contrast with RA, RA-like HCV-related arthropathy usually shows a relatively benign course that is not associated with bony erosions and joint deformation [4, 5, 16]. Thus, management of HCV-related arthropathy usually does not require the use of heavy immunosuppressive treatment [4, 21], which is associated with potential hepatotoxicity as demonstrated in patients with RA with concomitant chronic HCV infection  or may worsen the evolution of liver damage in HCV-affected patients. Thus, an early differential diagnosis could be of great importance in establishing the correct treatment to prevent joint erosions in patients with 'true' RA as well as chronic HCV infection and reducing the risk of immuno-suppressive therapy in patients with HCV-related arthropathy.