Interferon-alpha may exacerbate cryoglobulinemia-related ischemic manifestations - An adverse effect potentially related to its anti-angiogenic activity

The discovery of the strong association between hepatitis C virus (HCV) inf ection and the development of mixed cryoglobulinemia has motivated active t esting of antiviral-directed alternative therapies. Several trials have dem onstrated that classic cryoglobulinemia-associated manifestations improve w ith interferon-alpha (IFN alpha) treatment. Herein we report on 3 HCV-infec ted patients with severe cryoglobulinemia-related ischemic manifestations w ho were closely followed up during IFN alpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryoc rit determinations were serially performed. In addition to prednisone and i mmunosuppressive agents, the patients received IFN alpha at 3 x 10(6) units , 3 times per week for 2 months, 3 months, and 4 months, respectively. In a ll 3 patients, systemic features improved, liver function results returned to normal, and cryocrit values decreased. However, ischemic lesions became less vascularized and ischemia progressed, leading to transmetatarsal and s ubcondylar amputation, respectively; in 2 of the patients and fingertip nec rosis and ulcer enlargement in the third. Skin biopsies performed before IF N alpha therapy and after 2 months of IFN alpha therapy in the third patien t showed a significant decrease in subepidermal microvessels. When IFNa was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemi c lesions may worsen during IFN alpha treatment, presumably through a decre ase in inflammation-induced angiogenesis, The anti-angiogenic activity of I FN alpha may delay the appropriate healing of ischemic lesions.