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Selected Publications on Cryoglobulinemia
Cryofiltration apheresis for treatment of
cryoglobulin-induced glomerulonephritis in renal transplant.
Siami, G A, et al. 1995.
TRANSPLANTATION PROCEEDINGS. 27(5):2583-2584.
Cryofiltration apheresis for treatment of cryoglobulinemia associated with
Siami GA; Siami FS; Ferguson P; Stone WJ; Zborowski M. 1995.
Asaio Journal, Jul-Sep, 41(3):M315-8.
Abstract: Cryofiltration apheresis (CA) is a specific therapy for treatment of
patients with cryoglobulinemia. We evaluated the safety and efficacy of CA
in patients with mixed cryoglobulinemia associated with hepatitis C. As
reported previously, the Cryoglobulin Filter comprises a membrane module
inside a refrigeration unit on-line with a Spectra Apheresis System (COBE,
Denver, CO). The efficacy of cryofiltration was measured by comparing the
sieving coefficient of cryoprecipitable proteins (CPP) to that of albumin
and comparing the systemic CPP concentration ratio post to pre treatment.
Five patients were enrolled in this study, and a minimum of 10 procedures
were performed for each patient. The risk for hepatitis C was multiple
blood transfusions, intravenous drug abuse, immunosuppressive therapy, or
renal transplantation. Four patients had Type II mixed cryoglobulinemia,
and one patient had Type III. Four patients had chronic renal failure; one
with liver cirrhosis received alpha interferon along with CA. One patient
had no response to conventional plasma exchange and immunosuppressive
therapy secondary to repeated infections and sepsis; CA was the only viable
therapy for this patient. The maximum CPP concentration before therapy
ranged from 1,440 to 7,440 micrograms/ml. The plasma CPP sieving
coefficient at 1 L filtrate ranged from 0.25 to 0.74 (average +/- SE, 0.51
+/- 0.19; n = 39). The sieving coefficient for albumin was 1 (n = 50). The
systemic CPP ratio post to pre treatment ranged from 0.28 to 0.83 (average
+/- SE, 0.59 +/- 0.20; n = 37). No adverse effects specific to CA were
observed. The CA was safe and effective and possibly the only choice of
therapy in patients with cryoglobulinemic hepatitis C who have no response
to plasma exchange and immunosuppressive therapy.
Clinical trials of a cryoglobulin filter.
Siami GA; Wilkins W; Stone WJ; Koo AP; Zborowski M. 1994.
Asaio Journal 1994 Jul-Sep, 40(3):M658-62.
Abstract: The authors report the results of clinical trials of a high capacity
cryoglobulin filter (Cryofilter) in seven patients with cryoglobulinemia
unresponsive to high doses of prednisone or immunosuppressive drugs who
required plasmapheresis. The objective of this study was to test the safety
and efficacy of the cryofilter in a limited patient population according to
the investigational Device Exemption guidelines of the FDA. The
cryoglobulins were selectively filtered from plasma at 4 degrees C by a
cryofilter characterized by a membrane surface area of 0.135 m2 and an
average pore size of 4.3 microns. Safety was evaluated by patients vital
signs, complement activation, and clinical score of symptoms in the course
of 10 treatments. Efficacy of cryofiltration was evaluated by comparing
sieving of the cryoglobulins to that of albumin; immunoglobulins G, A, and
M; and fibrinogen. All seven patients completed the series of 10 treatments
without notable complement activation or any signs of discomfort. The
cryofilter was particularly selective in patients with high cryoglobulin
concentrations. Improvement in clinical symptoms was observed in all
Hepatitis C Associated Cryoglobulinemia
Haplotype HLA-B8-DR3 confers susceptibility to hepatitis C virus-related mixed cryoglobulinemia.
Blood 1998 Mar 15;91(6):2062-2066
Lenzi M, Frisoni M, Mantovani V, Ricci P, Muratori L, Francesconi R, Cuccia M, Ferri S, Bianchi FB
Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Istituto di Ematologia, Universita di Bologna, Policlinico S. Orsola, Bologna, Italia; Servizio di Reumatologia, Laboratorio Centralizzato, Azienda Policlinico S.Orsola Ma.
Abstract. Our aim was to investigate whether host genetic factors are involved in the onset of hepatitis C virus (HCV)-related mixed cryoglobulinemia (MC). We studied 25 consecutive patients presenting with a full-blown clinical picture of MC by physical examination, blood chemistry, assessment of cryoglobulins and their composition, nonorgan-specific autoantibodies, antibodies to HCV, serum HCV RNA, and HLA polymorphism. Biopsies of liver, bone marrow, and minor salivary glands were also performed in a number of patients. HLA results were compared with those of normal controls and patients with chronic HCV infection without MC and negative for autoimmune phenomena (pathological controls). Type II MC was found in 14 of 25 patients (56%), and type III MC was found in the remaining 11 (44%). All patients were positive for antibodies to HCV and/or serum HCV RNA. HLA-B8 was found in 40% (10 of 25) of patients compared with 10. 1% (38 of 377) of normal controls (P = .00003, Pcorrected = .0005, relative risk [RR] 5.9) and 6.7% (2 of 30) of pathological controls (P = .007, Pcorrected = not significant). As for class II HLA molecules, only DR3 was significantly more frequent in MC patients (40%, 10 of 25) than in normal controls (15.1%, 57 of 377; P = .003, Pcorrected = .03, RR 3.7). Odds ratio (OR) for the risk of developing MC was calculated in patients positive for B8 and/or DR3, and the highest OR (8.2) was observed in individuals possessing both. The results suggest that the development of HCV-related MC is associated with HLA-B8 and DR3 markers.
Interferon therapy in HCV-positive mixed cryoglobulinaemia: viral and host factors contributing to efficacy of the therapy.
Ital J Gastroenterol Hepatol 1997 Aug;29(4):343-350
Mazzaro C, Carniello GS, Colle R, Doretto P, Mazzi G, Crovatto M, Santini GF, Tulissi P, Gregoretti M, Mazzoran L, Russo A, Silvestri F, Pozzato G
First Department of Medicine, Pordenone General Hospital, Italy.
Abstract. BACKGROUND: In a previous paper, we reported on the short-term efficacy of alpha-interferon in the treatment of hepatitis C virus positive mixed cryoglobulinaemia. AIMS: We investigated the long-term effects of therapy in a larger group of patients, and the viral and host factors able to influence the response to treatment. METHODS: In 27 females and 15 males (mean age 54.8 +/- 9.1 years) affected by mixed cryoglobulinaemia, bone marrow biopsy and phenotyping of marrow cells were performed before treatment and at the end of follow-up. A liver biopsy was obtained from patients showing biochemical signs of chronic liver disease. The presence of hepatitis C virus was assessed by detection of serum anti-hepatitis C virus antibodies, and hepatitis C virus-RNA. The treatment schedule was 3 million units of recombinant interferon alpha-2b three times a week for one year. Follow-up lasted for 1 year after the end of treatment. The response was classified as follows: 1) Complete response: Disappearance of the cryocrit (or reduction of more than 50%) and of all clinical manifestations of the disease. 2) Partial response: Disappearance of all clinical signs of the disease, but reduction of cryocrit of less than 50%. 3) Minor response: Reduction of cryocrit of less than 20% associated with the disappearance of one or more (but not all) signs of vasculitis. RESULTS: Anti-hepatitis C virus antibodies were present in 41 (95%) patients, and hepatitis C virus-RNA was detectable in all cases. Before therapy, marrow histology showed a massive monomorphous infiltration by plasmacytoid lymphocytes indicating the presence of low-grade non-Hodgkin lymphoma in 7 cases (16.6%). After therapy, 13 (31%) patients achieved a complete response, 23 patients (55%) a partial response, and 6 patients (14%) a minor response. Seven of the responders and all patients showing partial or minor responses relapsed a few months after withdrawal of therapy. At the end of the follow-up, only 6 patients had obtained complete remission. Bone marrow examination showed that B-lymphocytic monoclonal infiltrate had disappeared in 3 long-term responders. No difference was found between responders and non-responders/relapsers in terms of age, sex, duration of the disease, severity of symptoms, liver function tests, rheumatoid factor or complement levels, while the lack of response was associated with the presence of genotype 1b, liver cirrhosis, and high cryoglobulin level. CONCLUSIONS: Mixed cryoglobulinaemia is associated with a high prevalence of B-cell lymphomas. Alpha-Interferon is an effective agent for the treatment of this disease and seems able to determine regression of the lymphoproliferative disorder. The hepatitis C virus genotype and cryoglobulin level are the most important predictive factors of response to therapy.
Ribavirin therapy for cryoglobulinemia and thrombocytopenia associated with hepatitis C virus infection.
Clin Infect Dis 1997 Dec;25(6):1472-1473
Blanche P, Bouscary D
Service of Internal Medicine, Hopital Saint-Joseph, Paris, France.
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