Current treatment of hepatitis C-associated rheumatic diseases

The hepatitis C virus (HCV) is both hepatotropic and lymphotropic, responsible for a great number of hepatic and extrahepatic immune-system disorders that comprise the so-called HCV syndrome. HCV-associated rheumatic diseases are characterized by frequent clinico-serological overlap; therefore, correct classification of individual patients is necessary before therapeutic decisions are made. This is particularly difficult to do, however, because of the coexistence of viral infection and complex autoimmune alterations. In this context, mixed cryoglobulinemia syndrome (MCs) represents the prototype of virus-related autoimmune-lymphoproliferative diseases. MCs can be treated at different levels by means of etiological treatment with antivirals (peg-interferon-alpha plus ribavirin) aimed at HCV eradication and/or pathogenetic/symptomatic treatments directed to both immune-system alterations and the vasculitic process (rituximab, cyclophosphamide, steroids, plasmapheresis, and so on). In clinical practice, the therapeutic strategy should be modulated according to severity/activity of the MCs and possibly tailored to each individual patient's conditions. Cryoglobulinemic skin ulcers may represent a therapeutic challenge, which should be managed by means of both local and systemic treatments. HCV-associated arthritis should be differentiated from the simple comorbidity of HCV infection and classical rheumatoid arthritis. It may be treated with low doses of steroids and/or hydroxychloroquine; the use of biologics (rituximab) may be considered in more severe cases. Primary Sjögren's syndrome is rarely associated with HCV infection, while sicca syndrome and myalgia are frequently detectable in hepatitis C patients, with or without cryoglobulinemic vasculitis. Other autoimmune rheumatic disorders (poly/dermatomyositis, polyarteritis nodosa, osteosclerosis, fibromyalgia, and so on) have been reported as potentially associated with HCV infection in patient populations from different countries, suggesting the role of genetic and/or environmental co-factors. The therapeutic approach to these disorders should be decided according to each individual patient's evaluation, including hepatic, virological, and immunological findings.

organ-and non-organ-specifi c autoantibodies [1]. Interest ingly, the same immunological alterations may also be observed in a signifi cant percentage of individuals with isolated HCV infection [1,6].
HCV is a positive, single-stranded RNA virus without a DNA intermediate in its replicative cycle, so that viral genomic sequences cannot be integrated into the host genome. Much evidence indicates that HCV infection results in chronic stimulation of the immune system, which facilitates the clonal B-lymphocyte expansion [1,2,7]. Figure 2 (left side) summarizes both virus-and host-related co-factors, together with the main biological alterations, of the pathogenetic cascade. Th e result may be classical MCs or other autoimmune disorders, as well as some malignancies, mainly B-cell non-Hodgkin's lymphoma (B-NHL) [1]. Besides MCs, other rheumatic diseases can be related to this virus with variable strength of association [1,3,8,9]. Th e present review focuses on the clinical-serological assessment and therapeutic approach to the main HCV-associated rheumatic disorders.

Mixed cryoglobulinemia (cryoglobulinemic vasculitis)
Th e pathological hallmark of MCs is the leukocytoclastic vasculitis of small arteries, capillaries, and venules; there fore, the disease is currently classifi ed among systemic vasculitides, in the setting of small-vessel vasculitides, and the terms MCs and cryoglobulinemic vasculitis should thus be related to the same clinicopathological condition [1]. MCs represents the crossroad between classical rheumatic diseases, such as rheuma toid arthritis (RA) and primary Sjögren's syndrome (pSS), and other autoimmune lymphoproliferative disorders [1] (Figure 1). It is characterized by the typical clinical triad of purpura, weakness, and arthralgias and by multisystem organ involve ment [1,2]. Th e typical cutaneous and visceral organ involvements, such as purpura, skin ulcers, and glomerulonephritis, are the consequence of the vessel deposition of circulating immune complexes, mainly mixed cryoglobulins and complement [1]. Liver involve ment, generally a mild to moderate chronic hepatitis, may evolve to frank cirrhosis in a minority of patients, and is rarely complicated by hepatocellular carcinoma [4]. Renal involvement is often responsible for membrano proliferative glomerulo nephritis type I; it may severely aff ect the overall prognosis of patients with MCs, often in combination with liver damage [4]. Peripheral neuro pathy and skin ulcers are quite frequent manifes ta tions of MCs; they are barely responsive to treatments and consequently may The spectrum of diff erent hepatitis C virus (HCV)-associated immunological and neoplastic disorders may be classifi ed on the basis of clinicoepidemiological, histopathological, and molecular biology studies in three diff erent levels. High: the association with HCV infection characterizes the large majority of patients; HCV infection is one of the major triggering agents of the disease. Medium: patients with the disease show a signifi cantly higher prevalence of HCV infection compared to controls; the putative pathogenetic role of HCV is also supported by pathogenetic studies and it may identify at least a specifi c disease subset. Low: the possible association is suggested by limited clinico-epidemiological observations; a pathogenetic link in at least a specifi c disease subset from some geographical areas is probable, but needs to be defi nitely demonstrated. Other possible associations have been suggested (see text) on the basis of anecdotal observations. B-cell NHL, B-cell non-Hodgkin's lymphoma; HCC, hepatocellular carcinoma.
compromise the patient's quality of life [4]. Finally, B-NHL and widespread vasculitis may com pli cate a minority of cases; they represent the most harm ful manifestations of the disease [1,2,4]. Besides mixed cryoglobulins in serum, marked reduction of hemolytic comple ment activity, with the typical pattern of low, often undetectable complement C4, is another hallmark of the disease and is particularly useful for disease classifi cation [1,10,11]. However, both complement levels and cryocrit rarely correlate with the activity/severity of MCs; consequently, they are not very useful for clinical monitoring of patients and therapeutic decision-making. In contrast, the correct evaluation of B-cell expansion, which represents the biological substrate of MCs, is mandatory because of the possible complication of overt lymphoma [1,2,7]. Th is latter event should be suspected in the presence of rapid increases of cryocrit and serum levels of monoclonal rheumatoid factor and/or complement C4 [1].
Th e treatment of HCV-associated MCs is particularly challenging due to the complex etiopathogenesis and clinical polymorphism of the disease. In fact, we can treat MCs at three diff erent levels ( Figure 2): the chronic HCV infection; the immune-pathological alterations, mainly Blymphocyte proliferation; and the immune complexmediated cryoglobulinemic vasculitis [1,3]. Moreover, the correct evaluation of diff erent clinical phenotypes, vary ing from mild purpuric lesions, arthralgias, and/or Figure 2. The treatment of mixed cryoglobulinemic syndrome must be decided on the basis of the etiopathogenetic cascade that leads from hepatitis C virus infection to multiple immune-system alterations, mainly B-cell proliferation, and lastly to immune complexmediated small vessel vasculitis. The vasculitic syndrome may be complicated by malignancies, mainly B-cell lymphoma. Accordingly, we can treat mixed cryoglobulinemic syndrome (MCs) at three diff erent levels by means of etiological, pathogenetic, and symptomatic therapies. The use of antivirals, namely peg-interferon-alpha (peg-IFNα) plus ribavirin (RIBA), aims to eradicate the hepatitis C virus (HCV); it represents the etiological treatment of HCV-associated MCs. The anti-CD20 monoclonal antibody rituximab is considered the most useful and safe pathogenetic treatment of MCs. In selected patients with severe, active clinical manifestations, sequential or combined therapy with antivirals and rituximab has been usefully employed (see also Figure 3). CIC, circulating immune complexes; CPX, cyclophosphamide; HLA, human leukocyte antigen; LAC, low antigencontent; LDL, low-density lipoprotein; RF, rheumatoid factor. weakness to severe organ involvement (renal, liver, diff use vasculitis) or malignancies (B-NHL), should direct our therapeutic interventions ( Figure 3).
HCV infection results in chronic stimulation of the immune-system [7], and it may also be responsible for either liver damage or neoplastic complications; in theory, HCV eradication using alpha-interferon and ribavirin should be attempted in all cases [1,3,12,13]. However, a benefi cial eff ect of antivirals may be recorded in less than half of treated patients and they are often associated with important immune-mediated side eff ects, such as peripheral sensory-motor neuropathy, thyroiditis, and rheumatoid-like polyarthritis [1,3,14]. It is plausible that alpha-interferon, which is both an antiviral and immunomodulating agent, can foster or exacerbate these symptoms, possibly in predisposed subjects.
In the near future, a vaccine-based therapy [15] might be able to prevent the progression of HCV infection and possibly to interrupt the self-perpetuating autoimmune mechanism underlying MCs.
Preliminary studies suggested that some immunomodu lat ing therapies in association with antiviral treatment, namely cyclosporine A or TNF inhibitors, have synergistic eff ects in the setting of chronic hepatitis type C [16,17].
Besides etiological treatments, immunomodulating/ immuno suppressive drugs represent the most useful therapies able to aff ect the main pathogenetic mechanisms of MCs, including T-and B-cell proliferation and autoantibody production. Th ese treatments include cyclophosphamide and an anti-CD20 monoclonal antibody (rituximab) [1,3]. During the past decade, rituximab has been increasingly employed for both cutaneous and visceral organ involvement of MCs; it can be regarded as a useful and safe pathogenetic treatment of cryo globulinemic vasculitis [18]. Its safety was also confi rmed in patients with liver damage; interestingly, in patients with HCV-associated MCs and advanced cirrhosis, treatment with rituximab was able to improve both the cryo globulinemic vasculitis and liver function [19]. A compre hensive analysis of the literature regarding the use of rituximab and its role in the therapeutic strategy of MCs patients has been recently published [18]. Very recently, the results of a randomized controlled trial demonstrated that anti-CD20 monotherapy also represents a useful and safe option for patients with severe MCs [20].
Among symptomatic/pathogenetic treatments, a low antigen-content diet can improve the clearance of circulating immune complexes by restoring the activity of the reticulo-endothelial system, which becomes overloaded by large amounts of circulating cryoglobulins [1]. Th is reduction in the alimentary input of macromolecules with potential antigenic activity may improve the function of the mononuclear phagocytic system, which is normally impaired in MCs [21]. A low antigen-content diet can be usefully employed in patients with clinically mild MCs symptoms (arthralgias, weakness, sporadic purpura, and/or mild sensory peripheral neuropathy), often in asso ciation with low doses of steroids (6-methylprednisolone 2 to 4 mg/day) and/or colchicine. Most patients show only mild symptoms for a long time period, and are particu larly sensitive to symptomatic treatments and to small doses of daily steroid (1 to 2 mg). Clinically asymptomatic patients do not usually need any treatment, even in the presence of high levels of cryocrit, but patients with severe vasculitic manifestations must be promptly treated with high doses of steroids and/or plasma exchange and/or immunosuppressors; this combination therapy is often able to improve the most harmful disease complications ( Figure 3) [1,4,22].
Th e treatment of cryoglobulinemic skin ulcers is particularly challenging. Th ese lesions are prevalent in the lower limbs, where other pathogenetic co-factors may be associated -namely, venous insuffi ciency and/or arteriosclerotic alterations, which are not rare in older patients with comorbidities and/or who have received long-term steroid treatment. Th e skin ulcers are painful, non-healing, and often complicated by local infection and they may severely aff ect patients' quality of life [4]. Figure 4 summarizes the therapeutic strategy for treating cryoglobulinemic skin ulcers, including both systemic and local treatments at a wound care clinic [23]. Th e long-term administration of analgesics is often necessary to improve the patient's chronic pain and their com pliance with local wound care. A team of operators with specifi c experience should carry out this integrated therapeutic approach [18,23,24].
More recently, some studies have suggested that sequential or combined antiviral and immunosuppressive therapy could represent a rather useful therapeutic strategy for treating MCs [18,25,26]. Th is more aggressive treatment could be particularly indicated in patients with major clinical manifestations and/or inadequate remission after standard treatments.
On the whole, careful monitoring of a patient's clinical status is mandatory in clinical practice, with particular attention paid to neoplastic complications; in all instances the treatment should be tailored to the individual patient according to the severity of their MCs symptoms ( Figure 3) [1].
Given the rarity of the disease and the diffi culties of recruiting clinically homogeneous series of patients, there are few controlled randomized trials evaluating the usefulness of proposed treatments for MCs. Th e results of a consensus conference based on the available published studies and expert opinions have been summarized in a preliminary core set of therapeutic recommendations [27].

Sicca syndrome/Sjögren's syndrome
A possible pathogenetic role of HCV in pSS has been reported in anecdotal clinical observations [28]. In contrast, the frequent association between sicca syndrome and HCV infection has been demonstrated by both experimental and epidemiological studies focusing on the presence of chronic lymphocytic sialadenitis in patients with HCV infection [29]. HCV can replicate within epithelial cells of the salivary gland of patients with sicca syndrome and HCV infection [30].
In clinical practice, the correct diff erential diagnosis between some HCV-associated rheumatic disorders and classical rheumatic diseases is still under debate, in particular between MCs and pSS; this probably refl ects the lack of standard classifi cation of these diseases in diff erent referral centers. Figure 5 shows the main clinico-pathological and immuno logical diff erences between MCs and other possible HCV-associated diseases. Patients with MCs may develop a mild sicca syndrome in the absence of typical histopathological and/or serological alterations [1]. On the other hand, the detection of mixed cryoglobulins in the serum of a minority of pSS cases seems to identify a particular clinical subset characterized by worse prognosis and frequent evolution to malignant B-NHL [31]. In individual cases the diff erential diagnosis between pSS and MCs may be very diffi cult, mainly in patients with overt sicca syndrome, cryoglobulinemia, and HCV infection [1]. Th erefore, it is correct to classify these patients as overlapping MCs/pSS [1], and the therapeutic approach should consequently be decided after careful evaluation of the main clinical manifes tation(s), including the presence/severity of type C hepatitis.
Antiviral treatment with IFNα and ribavirin seems to improve sicca syndrome in HCV-positive patients, even if serious immune-mediated adverse events have been observed [32]. Besides topical treatments that may We can consider at least four clinical conditions. Mixed cryoglobulinemic syndrome (MCs) may be completely asymptomatic or it may sporadically show very mild manifestations, such as fl eeting purpuric lesions on the legs; in these cases monitoring may be suffi cient, while an attempt at HCV eradication may be considered. On the opposite side are patients with severe, rapidly progressive cryoglobulinemic vasculitis that must be treated with aggressive combined treatment similar to that used for other systemic vasculitides. Sequential or combined treatment with antivirals and rituximab may be usefully employed in selected patients with severe manifestations. The order of sequential treatment may be decided on the basis of prevalent organ manifestation(s), even if the combined therapy seems to be comparable for effi cacy and safety. CPX, cyclophosphamide; CS, corticosteroid; LAC, low antigen-content; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab. partially improve patients' quality of life, there is no specifi c systemic treatment for HCV-associated sicca syndrome. As for classical MCs or pSS, the possible complication with malignant lymphomas must also be taken into account in these patients [28,31].

Arthritis
While arthralgias are one of the most common extrahepatic manifestations of HCV infection, chronic arthritis is signifi cantly less common [4,8,9]. When present, it is often a less aggressive oligo-polyarthritis compared to classical RA. Patients with HCV-associated MCs present with arthralgias, while infl ammatory joint involvement is quite rare and generally characterized by mild oligoarthritis [4]. A symmetrical rheumatoid-like polyarthritis may complicate IFN treatment in HCV-positive patients [9]. Because of the relatively high prevalence of the two diseases, it is not rare to observe a simple association between classical RA and HCV infection. Figure 5 summar izes the main clinico-serological parameters for diff erential diagnosis between classical RA and other HCV-associated disorders [1,3,4,8,28,31,33,34]. In patients presenting with chronic arthritis, the presence of hepatotropic virus infection (that is, HCV and hepatitis B virus) must be ruled out because of the possible severe, often life-threatening side eff ects of disease-modifying antirheumatic drugs (DMARDs) and biologics [35]. Several diff erent viral infections may trigger symmetrical arthritis mimicking classical RA and clinical work-up including virological investigations should therefore be done at the patient's fi rst assessment ( Figure 6).
Patients who present with both HCV infection and arthritis can either have a simple comorbidity of RA and HCV infection or HCV-associated arthritis, with or without MCs. Th e fi rst may be treated with standard strategies used for RA with some precautions in consideration of the concomitant viral infection and possible liver involvement. Some DMARDs, in particular methotrexate and lefl unomide, may be employed after carefully evaluat ing and monitoring liver involvement, while biologics such as anti-TNFα and rituximab have been usefully employed without signifi cant side eff ects in HCV-positive RA patients [36]. Interestingly, these biologic therapies, as well as cyclosporine A, seem to have a potential synergistic eff ect with antiviral treatments for hepatitis C [16,17]. Th erefore, careful hepatologic evaluation of these patients is always mandatory, taking into account the opportunity for antiviral treatment [35].
On the whole, patients with concomitant RA and HCV infection require the same clinical assessment and monitor ing as patients with HCV-associated arthritis with or without MCs; they may have an increased risk to develop some HCV-associated complications, such as B-cell NHL, even as a consequence of immunomodulating therapies.

Figure 4. Therapeutic strategy for treating cryoglobulinemic cutaneous ulcers should be based on both systemic and local treatments.
After clinical work-up considering the entire MCs, including possible comorbidities (venous insuffi ciency and/or arteriosclerotic alterations, diabetes, and so on), and careful examination of the ulcer characteristics, the systemic treatment may be based on etiological, pathogenetic, and/ or symptomatic therapies. More aggressive combined treatments (immunosuppressors, steroids, and plasmapheresis) may be necessary in the presence of very severe, non-healing skin ulcers. Long-term administration of analgesics is often necessary to improve the patient's chronic pain and compliance with local treatment, which should be carried out at a wound care clinic. Wound bed preparation, with particular regard to the prevention and treatment of infections, is crucial for the healing of cryoglobulinemic skin ulcers. CPX, cyclophosphamide; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab. Usually, HCV-associated arthritis is poorly aggressive and the patients may respond to low doses of steroids and hydroxychloroquine. Th e use of other DMARDs presents the above-mentioned limitations. On the contrary, rituximab may be usefully employed, mainly in patients with more aggressive disease, and may represent the fi rst-choice treatment in patients with arthritis in the setting of MCs [18].
Osteosclerosis is a very uncommon condition described in adults infected with HCV and can be defi ned as an acquired, painful skeletal disorder characterized by a marked increase of bone mass [37][38][39][40]. Clinically, osteosclerosis is characterized by nonspecifi c, often diff use bony pain and tenderness over involved bones due to periosteal stretching, in the absence of joint swelling or motion limitation. Radiographic examination shows bony sclerosis and thickening of the long-bone cortices, mainly diaphyseal cortical bone. Laboratory investigations frequently reveal abnormally increased markers of bone formation (alkaline phosphatase, bone-specifi c alkaline Some important fi ndings may be usefully employed for a correct diagnosis: the histopathological characteristics and severity of salivary gland involvement and specifi c autoantibodies (anti-SSA/SSB) are rarely found in hepatitis C virus (HCV)-associated sicca syndrome or mixed cryoglobulinemia syndrome (MCs) patients. Conversely, cutaneous leukocytoclastic vasculitis, visceral organ involvement (hepatitis, membranoproliferative-glomerulonephritis), abnormally low complement C4, and HCV infection, typically found in MCs, are very uncommon in primary Sjögren's syndrome (pSS). Both MCs and pSS may be complicated by B-cell non-Hodgkin's lymphoma (B-cell NHL), and less frequently also rheumatoid arthritis patients. Finally, erosive symmetrical polyarthritis and serum anti-cyclic citrullinated peptide (anti-CCP) antibodies are specifi c diagnostic fi ndings of classical rheumatoid arthritis, but generally absent in HCV-associated arthritis. However, there is a gray area of clinical overlap between diff erent disorders. RF, rheumatoid factor. phosphatase, and osteocalcin); these alterations were mirrored by the marked increase of bone mass (bone mineral density) and enhanced radionuclide uptake at scintigraphy ( 99m Tc-MDP). Bone biopsy shows increased numbers and thick ness of trabeculae with parallel reduction of bone marrow [37][38][39][40]. Th e pathogenesis of this rare syndrome is still unknown. It has been suggested that HCV alone or in combination with other unknown agent(s) may infect and alter bone cells or their precursors in predisposed subjects. Th ese alterations might be mediated by the produc tion of bone growth factors, such as insulin-like growth factors or osteoprotegerin. Th e pathogenetic role of this latter factor seems to be relevant as an imbalance in the osteoprotegerin/RANKL (receptor activator of nuclear factor kappa-B ligand) system leading to a pre dominance of osteoprotegerin has been documented [38]. With regards to therapeutic approaches to osteo sclerosis, attempts to treat with antiresorptive agents in at least seven patients was ineff ective, while symptomatic treatments may provide some benefi t. In some cases a partial or complete spontaneous remission of symptoms and/or bone sclerosis was Clinico-serological and virological work-up is mandatory in patients presenting with chronic arthritis. Patients with polyarthritis and hepatitis C virus (HCV) infection can be classifi ed as either having simple comorbidity, that is, HCV infection and rheumatoid arthritis (RA) or other forms of chronic arthritis, or having HCV-associated arthritis. This latter may represent one extrahepatic manifestation of HCV infection or it can be a symptom of MCs. The comorbidity may be treated with the standard therapeutic strategies for RA, with some precautions because of concomitant viral infection, in particular for methotrexate and lefl unomide. On the contrary, biologics (anti-TNFα and anti-CD20 rituximab) have been usefully employed without signifi cant side eff ects in HCV-positive RA patients. The antiviral therapy of IFNα plus ribavirin (RIBA) can also be employed after careful hepatologic evaluation of patients. Interestingly, anti-TNFα, rituximab, and cyclosporine A seem to have a potential synergistic eff ect if associated with antiviral treatment (IFNα + RIBA). Usually, HCV-associated arthritis is poorly aggressive and may respond to low doses of steroids and hydroxychloroquine (HCQ). The use of other disease-modifying anti-rheumatic drugs (DMARDs) presents the above-mentioned limitations, while rituximab may be usefully employed, especially in patients with more aggressive arthritis. Finally, rituximab may represent the fi rst-choice treatment in patients with arthritis in the setting of MCs. Ab, antibody; CCP, cyclic citrullinated peptide; RF, rheumatoid factor. observed during follow-up [37][38][39][40]. Anecdotally, in a recently published case report the antiviral therapy was followed by a recovery of skeletal sclerosis [40].
Myalgia has been recorded in a signifi cant number (15%) of patients from a large series of HCV-infected individuals [29]. Th e pathogenesis of this symptom remains diffi cult to explain, although the detection of viral genomic sequences within muscle fi bers suggested a direct involvement of HCV in the pathogenesis of diff use muscle pain [41]. Fibromyalgia has also been reported by some studies in a signifi cant percentage of patients with chronic HCV infection [42], but other studies in series of patients with typical fi bromyalgia have not confi rmed this association [9,43]. On the other hand, the diff erential diagnosis between fi bromyalgia and muscle pain, frequently associated with weakness and arthralgias, may be very diffi cult in the setting of HCV-positive patients. With regard to sicca syndrome and pSS, some authors prefer to maintain HCV-associated myalgia and classical fi bromyalgia as distinct entities [9,43].
Several case reports in the literature have documented an association between poly-dermatomyositis and HCV infection [1,8,9,29,44]. Generally, these disorders appear in patients with long-lasting viral infection or may complicate IFNα treatment [45]. Similarly, cases of vasculitis involving medium-sized arteries suggesting the diagnosis of polyarteritis nodosa have been associated with HCV infection [29,46]. In addition, HCV seropositivity has been reported in a signifi cant percentage of patients with polyarteritis nodosa [46]. Th is possible association is not surprising considering the well-known relationship between polyarteritis nodosa and another hepatotropic virus, hepatitis B virus, which is responsible for a signifi cant number of patients with this vasculitis [47]. Poly arteritis nodosa may share numerous clinical symptoms with MCs; thus, patients with suspected HCVassociated polyarteritis nodosa should be correctly classifi ed by means of wide clinico-serological and pathological work-up.
With regard to other possible HCV-associated disorders, namely Beçhet's syndrome, systemic lupus erythema tosus, and antiphospholipid syndrome, data reported in the literature are generally anecdotal [8,9,29,48,49]. Even if a possible causative role of HCV in these autoimmune diseases cannot be totally excluded, these patients might be better classifi ed as having a simple comorbidity. However, they invariably represent a troublesome clinical condition, mainly with regards to therapeutic approach.
As for HCV-associated MCs, patients with concomitant autoimmune systemic disorders, such as poly/ dermatomyositis, polyarteritis nodosa, systemic lupus erythematosus, and HCV infection may be usefully treated with immunesuppressors (for example, cyclo phos phamide and rituximab) with some important pre cautions and limitations due to viral infection. In all instances, a preliminary clinical evaluation of liver condition and viral replication is necessary before any therapeutic decisions are made. Th ese latter may be based on standard immunosuppressive treatments, possibly integrated by sequential/combined antiviral treatment.

Conclusion
HCV-associated disorders include a spectrum of diff erent immunological and neoplastic manifestations, among which are some rheumatic diseases. On the basis of clinico-epidemiological, histopathological, and molecular biology studies, the strength of association between HCV and a given disease varies largely among diff erent diseases and, more interestingly, for each disease among patient series from diff erent countries.
Autoimmune systemic diseases often represent a clinical syndrome, which may include diff erent clinicoserological subsets. Th ese latter are the resulting phenotypes of multiple genetic, environmental, and infectious pathogenetic cofactors. MCs represents an important example of these multifactorial and clinically multifaceted disorders, potentially triggered by HCV infection in a variable percentage of cases. Considering the wide range of clinical phenotypes, some HCV-associated diseases may present important classifi catory/diagnostic diffi culties, and may constitute a real therapeutic dilemma because of the coexistence of autoimmune manifestations and viral infection.