Current treatment of hepatitis C-associated rheumatic diseases

Abstract

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.

Figure 1

Strength of association between hepatitis C virus and different diseases in the context of hepatitis C virus syndrome. The spectrum of different hepatitis C virus (HCV)-associated immunological and neoplastic disorders may be classified on the basis of clinico-epidemiological, histopathological, and molecular biology studies in three different 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 significantly 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 specific disease subset. Low: the possible association is suggested by limited clinico-epidemiological observations; a pathogenetic link in at least a specific disease subset from some geographical areas is probable, but needs to be definitely 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.

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 complex-mediated 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 different 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 antigen-content; LDL, low-density lipoprotein; RF, rheumatoid factor.

Figure 3

The therapeutic strategy for mixed cryoglobulinemic syndrome may be modulated according to the clinical status of individual patients. 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 fleeting purpuric lesions on the legs; in these cases monitoring may be sufficient, 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 efficacy and safety. CPX, cyclophosphamide; CS, corticosteroid; LAC, low antigen-content; peg-IFN, peg-interferon; RIBA, ribavirin; RTX, rituximab.

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 insufficiency 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.

Figure 5

Differential diagnosis between some important hepatitis C virus-associated rheumatic manifestations and classical diseases such as primary Sjögren's syndrome and rheumatoid arthritis is possible on the basis of clinico-serological and pathological features. Some important findings may be usefully employed for a correct diagnosis: the histopathological characteristics and severity of salivary gland involvement and specific 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 specific diagnostic findings of classical rheumatoid arthritis, but generally absent in HCV-associated arthritis. However, there is a gray area of clinical overlap between different disorders. RF, rheumatoid factor.

Figure 6

Differential diagnosis among patients with arthritis and concomitant hepatitis C virus infection, and therapeutic strategies. 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 classified 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 leflunomide. On the contrary, biologics (anti-TNFα and anti-CD20 rituximab) have been usefully employed without significant side effects 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 effect 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 first-choice treatment in patients with arthritis in the setting of MCs. Ab, antibody; CCP, cyclic citrullinated peptide; RF, rheumatoid factor.