THE CLINICAL SPECTRUM OF LYMPHOPROLIFERATIVE DISORDERS IN HCV INFECTION: FROM CRYOGLOBULINEMIA VASCULITIS TO NON HODGKIN LYMPHOMA Patrice Cacoub, MD Department of Internal Medicine and CNRS UMR 7087 Hôpital La Pitié-Salpêtrière Paris France Email: [email protected] Vasculitides can be divided into primary forms, for which the etiology is unknown, and secondary forms that result from an autoimmune condition or known infection. The interest in infection-related vasculitides has been boosted for the last two decades by the development of new molecular techniques and the proof of true associations between viral hepatitis C and systemic vasculitis. A wide variety of extrahepatic manifestations has been reported to be associated with HCV infection, the most frequent being mixed cryoglobulins. Viral factors that avoids immune elimination leads to accumulation of circulating immune complexes, and autoimmune phenomena associated with chronic HCV infection. Extrahepatic manifestations may also be favor by the lymphotropism of HCV which is thought to be involved in the production of autoantibodies and occurence of non-Hodgkin's B-cell lymphoma (B-NHL). More than 40% of HCV-infected patients have circulating immune complexes with cryoprecipitating properties, named mixed cryoglobulins (1,2). Circulating mixed cryoglobulins are frequently detected in HCV infected patients whereas overt cryoglobulinemia vasculitis develops in only 5-10% of cases. Mixed cryoglobulinemia (MC) is a systemic vasculitis, that mainly affects the small and, less frequently, medium size vessels (3,4). MC is characterized by the proliferation of B-cells clones producing pathogenic IgM with rheumatoid factor (RF) activity. MC led to clinical manifestations ranging from the so called MC syndrome (purpura, arthralgia, asthenia) to more serious lesions with neurologic and renal involvement. Shortly after the discovery of HCV in 1989, there has been evidence that more than 80% of cryoglobulinemia vasculitis were associated with HCV infection. The primary role of HCV in the mechanism of cryoprecipitation is mainly suggested by its selective concentration in cryoglobulins (3,4). Molecular evidence of antigen-driven B-cell proliferation is definitively provided in HCV-associated type II MC, and HCV appears as the key trigger. MC not related to HCV infection currently represents less than 10% of mixed cryoglobulinemia. 1) Clinical features of cryoglobulinemia vasculitis The most frequently target organs are skin, joints, nerves and kidney. The disease expression is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threathening complications (glomerulonephritis, widespread vasculitis). Purpura Skin is the most frequently involved target organ and is the direct consequence of the small size vessel vasculitis. The main symptom is palpable purpura which is reported in 70 to 90% of patients (5,6). Readily preceded by sensations of cutaneous burns, it frequently reveals HCV-MC disease, occurs preferentially during winter, is non pruriginous and intermittent. It always begins at the lower limbs and may extend to abdominal area, less frequently to the trunk and upper limbs. It persists 3 to 10 days with a residual brownish pigmentation. Skin