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

Abstract

The discovery of the strong association between hepatitis C virus (HCV) infection and the development of mixed cryoglobulinemia has motivated active testing of antiviral-directed alternative therapies. Several trials have demonstrated that classic cryoglobulinemia-associated manifestations improve with interferon-alpha (IFNalpha) treatment. Herein we report on 3 HCV-infected patients with severe cryoglobulinemia-related ischemic manifestations who were closely followed up during IFNalpha therapy. Clinical evaluations with special attention to ischemic lesions, liver function tests, and cryocrit determinations were serially performed. In addition to prednisone and immunosuppressive agents, the patients received IFNalpha at 3 x 10(6) units, 3 times per week for 2 months, 3 months, and 4 months, respectively. In all 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 subcondylar amputation, respectively, in 2 of the patients and fingertip necrosis and ulcer enlargement in the third. Skin biopsies performed before IFNalpha therapy and after 2 months of IFNalpha therapy in the third patient showed a significant decrease in subepidermal microvessels. When IFNalpha was discontinued, the lesions finally healed. Cryoglobulinemia-related ischemic lesions may worsen during IFNalpha treatment, presumably through a decrease in inflammation-induced angiogenesis. The anti-angiogenic activity of IFNalpha may delay the appropriate healing of ischemic lesions.

Tissue and Serum Angiogenic Activity Is Associated With Low Prevalence of Ischemic Complications in Patients With Giant-Cell Arteritis

“…According to this hypothesis, we have previously shown that angiogenesis inhibition with interferon ␣ may have devastating effects on ischemic lesions from patients with hepatitis C virus-related cryoglobulinemic vasculitis. 18 Using in vitro and in vivo models, we showed that a strong angiogenic response in temporal artery samples and strong angiogenic activity in serum are associated with a reduced prevalence of ischemic complications in patients with GCA, supporting the concept that the angiogenic response has a significant compensatory role in this disease. The angiogenic response in temporal arteries may not be functionally relevant in compensating for ischemia, but neovascularization may be crucial at distal sites in target organs.…”

“…25 We have proposed that angiogenesis may play a dual role in vasculitis which, in this regard, is unique among chronic inflammatory disorders. [13][14][15][16][17][18] Neovessels are the main site where endothelial cell adhesion molecules for leukocytes are expressed in medium-sized and large vessel vasculitis such as HUVECs differentiate into capillary-like structures on Matrigel. At low (2%) human serum concentration, tubes are incomplete and not well interconnected (A).…”

“…10,12 The role of angiogenesis in vasculitis has begun to be investigated. We have shown that angiogenesis is observed in vascular inflammatory lesions of patients with GCA, [13][14][15] polyarteritis nodosa, 16,17 and cryoglobulinemic vasculitis, 18 and that sera from patients with different types of vasculitis, including Wegener's granulomatosis, Takayasu's disease, and GCA, have angiogenic activity. 19 We have proposed that angiogenesis may have a dual role in vasculitis.…”

Role of IL28B genotyping in patients with hepatitis C virus-associated mixed cryoglobulinemia and response to PEG-IFN and ribavirin treatment

“…Symptoms range from 2 to 50 % of patients with circulating cryoglobulins [40] and the typical presentation is the triad of purpura, arthralgia and weakness in roughly 80 % of symptomatic patients [12]; other manifestation of MC include sicca syndrome (10-25 %), neuropathy (11-30 %) and renal involvement such as membranoproliferative glomerulonephritis (20-25 %) [2,14,29,30]. The main therapeutic approach for MC in HCV patients is to eradicate the infection with standard treatment based on pegylated-interferon (PEG-IFN) and ribavirin (RBV) [32]; vasculitis exacerbation can occur during PEG-IFN administration [5,15], while treatment of symptoms with cytotoxic drugs or steroids should be reserved for limited cases due to difficulty of long-term management [4,19,28,41].…”

Hepatitis-C-Virus-assoziierte Kryoglobulinämie

“…Teilweise ist sogar eine Verschlechterung der vorbestehenden Niereninsuffizienz oder Neuropathie sowie die verzögerte Abheilung offener Hautläsionen während einer IFN-Behandlung beschrieben. Ursächlich hierfür wird eine antiangiogenetische Wirkung des IFN vermutet [9].…”