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Li X, Song D, Hao Y, Ren M, Guo Y, Zhao H, Wang Y, Tang L. Efficacy and safety of rituximab in patients with PLA2R associated membranous nephropathy and resolved HCV infection. Sci Rep 2024; 14:20981. [PMID: 39251782 PMCID: PMC11383943 DOI: 10.1038/s41598-024-72082-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2024] [Accepted: 09/03/2024] [Indexed: 09/11/2024] Open
Abstract
Rituximab occasionally induces reactivation of hepatitis C virus (HCV) in patients with resolved HCV infection, sometimes with fatal consequences. As rituximab has become one of the first-line therapies for the treatment of phospholipase A2 receptor (PLA2R)-associated membranous nephropathy (MN) and is more widely used, there is a lack of studies reporting the effectiveness and safety of rituximab in patients with PLA2R-associated MN and resolved HCV infection. A single-center retrospective study was conducted on PLA2R-associated membranous nephropathy (MN) patients who were HCVAb positive but HCV-RNA negative and treated with rituximab. A total of 598 adult patients with PLA2R-associated MN who underwent rituximab therapy were screened. General clinical information, including gender, age, pathological data, and previous treatment plans, was collected from medical records. Routine blood tests, liver and kidney function assessments, blood lipid profiles, 24-h urine protein levels, anti-PLA2R antibody titers, circulating B-cell counts, and HCV viral loads were measured at the time of rituximab infusion and repeated at intervals of 1-3 months post-rituximab administration. A total of 8 patients were enrolled, with a median follow-up period of 19.00 (range: 16.00-25.25) months. Among the 8 patients, 5 were male, and the mean age was 50.13 ± 4.29 years. Histological findings indicated that tubuloreticular inclusions, mesangial deposits, intramembranous deposits, and subendothelial deposits were not observed in any of the 8 patients. The overall 1-year remission rate for these patients was 75%, accompanied by a significant reduction in proteinuria. Additionally, blood albumin levels increased significantly, and renal function remained stable. No increase in HCV viral load and stable liver function tests were observed throughout the entire follow-up period. This study suggested that on the basis of successful eradication of HCV virus with antiviral drugs, rituximab can effectively induce clinical remission of patients with PLA2R associated MN and resolved HCV infection, and does not lead to a significant increase in HCV virus load. However, this finding is based on a very small sample size and should be confirmed in larger clinical trials.
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Affiliation(s)
- Xiaodan Li
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Dongxu Song
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Yingxuan Hao
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Mingjing Ren
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Yanhong Guo
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Huayan Zhao
- Department of Critical Care Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Yulin Wang
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China
| | - Lin Tang
- Department of Nephropathy, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou, 450052, Henan, China.
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Mokhles MA. Extrahepatic manifestations of HCV where do we stand? Med Clin (Barc) 2024; 162:231-237. [PMID: 37980213 DOI: 10.1016/j.medcli.2023.10.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 10/05/2023] [Accepted: 10/09/2023] [Indexed: 11/20/2023]
Abstract
Hepatitis C virus (HCV) infection has been associated as up 40-70% of patients with extrahepatic manifestations (EHM) and 36 different syndromes. These could be attributed to the fact that HCV is lymphotropic, particularly B lymphotropic, and not merely hepatotropic, and could trigger immunological alterations indirectly by exerting a chronic stimulus on the immune system with production of immunoglobulins having rheumatoid activity forming immune complexes and production of cryoglobulins. Cryoglobulinemoa plays a pivotal role in producing most EHM of HCV such as vasculitis, glomerulonephritis, arthritis and neuropathies. Less frequently; while less frequently, the direct viral cytopathic effect could lead to EHMs independent of cryoglobulinemia. The mainstay of treatment of EMH has been antivirals, since interferon era to direct-acting drugs era, with no differences between the two eras, despite the better virological response. Longer evaluation of virological response and clinical investigation with longer follow-ups are necessary.
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Affiliation(s)
- Mohamed Aly Mokhles
- National Research Center, Internal Medicine Department, Center of Excellence for Medical Research, Egypt.
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Dammacco F, Lauletta G, Vacca A. The wide spectrum of cryoglobulinemic vasculitis and an overview of therapeutic advancements. Clin Exp Med 2023; 23:255-272. [PMID: 35348938 PMCID: PMC8960698 DOI: 10.1007/s10238-022-00808-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/14/2022] [Indexed: 11/11/2022]
Abstract
Immunoglobulins that reversibly precipitate at temperatures below 37 °C are called cryoglobulins (CGs). Cryoglobulinemia often manifests as cryoglobulinemic vasculitis (CV), whose symptoms range in severity from purpuric eruptions to life-threatening features. The majority of CV patients are infected with hepatitis C virus (HCV), whereas lymphoproliferative disorders or connective tissue diseases (CTD) are commonly diagnosed among patients with CV of non-infectious origin. In the absence of detectable associated disease, cryoglobulinemia is classified as "essential" (EMC). All HCV-positive CV patients should be given direct-acting antiviral agents (DAAs) that are consistently able to induce a sustained virologic response (SVR). Glucocorticoids (GCs) can mitigate CV-associated vasculitis, but they have no role as maintenance therapy. Cyclophosphamide restrains the hyperactive phase(s) of the disease and the post-apheresis rebound of newly synthesized CGs. Its use has been largely replaced by rituximab (RTX) in patients unresponsive to DAAs, patients progressing to B-cell non-Hodgkin lymphoma (B-NHL) and patients in whom CV persists or reappears after clearance of HCV. Therapeutic apheresis is an emergency treatment for CV patients with hyperviscosity syndrome. HCV-positive CV patients are at an increased risk of developing NHL, but the achievement of SVR can effectively prevent HCV-related NHL or induce the remission of an already established lymphoma, even without chemotherapy. The treatment of patients with IgM or IgG monoclonal cryoglobulins and an underlying immunoproliferative disorder is based on the regimens adopted for patients with the same B-cell malignancies but without circulating CGs. For patients with CTD, GCs plus alkylating agents or RTX are similarly effective as first-line therapy and in the relapse/refractory setting. In patients with EMC, treatment should consist of GCs plus RTX, with the dose of GCs tapered as soon as possible to reduce the risk of infectious complications.
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Affiliation(s)
- Franco Dammacco
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, Polyclinic, Piazza Giulio Cesare, 11, 70124 Bari, Italy
| | - Gianfranco Lauletta
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, Polyclinic, Piazza Giulio Cesare, 11, 70124 Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro” Medical School, Polyclinic, Piazza Giulio Cesare, 11, 70124 Bari, Italy
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Jadoul M, Awan A, Berenguer M, Bruchfeld A, Fabrizi F, Goldberg D, Jia J, Kamar N, Mohamed R, Pessôa M, Pol S, Sise M, Martin P. KDIGO 2022 Clinical Practice Guideline FOR the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int 2022; 102:S129-S205. [PMID: 36410841 DOI: 10.1016/j.kint.2022.07.013] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 07/27/2022] [Indexed: 11/19/2022]
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Abstract
Purpose of Review Rituximab has transformed the treatment of B-cell malignancies and rheumatoid arthritis in the past 2 decades. More recently, this anti-CD20 monoclonal antibody has seen increasing usage in the field of dermatology. This review highlights the evidence supporting its use in several important dermatologic conditions. Recent Findings Key recent findings include the 2018 FDA approval of rituximab for the treatment of moderate-to-severe pemphigus. Summary Data from randomized controlled trials have demonstrated the efficacy of rituximab in pemphigus, ANCA-associated vasculitis, and cryoglobulinemic vasculitis. More limited data suggests its use in recalcitrant cases of diseases such as pemphigoid, epidermolysis bullosa acquisita, and dermatomyositis. There is scarce evidence and mixed results for rituximab when studied in cutaneous polyarteritis nodosa and cutaneous lupus erythematosus.
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Affiliation(s)
- Connor Cole
- Division of Dermatology, Rush University Medical Center, Chicago, IL USA
| | - Kyle T. Amber
- Division of Dermatology, Rush University Medical Center, Chicago, IL USA
- Department of Internal Medicine, Rush University Medical Center, Chicago, IL USA
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Altomare A, Corrado A, Maruotti N, Cici D, Cantatore FP. Hcv and Autoimmunity in Rheumatic Diseases. Curr Rheumatol Rev 2021; 18:101-107. [PMID: 34387165 DOI: 10.2174/1573397117666210812141524] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 06/04/2021] [Accepted: 06/14/2021] [Indexed: 11/22/2022]
Abstract
HCV is a global health problem affecting mainly the liver and often characterized by extrahepatic manifestions mediated by autoimmune reactions. Among these, arthritis and arthralgia are most frequent, as well as the presence of cryoglobulinemia that may induce vasculitis, and sicca syndrome. Thus, HCV appears to be a trigger for autoimmune response as demonstrated by the finding of autoantibody in a high percentage of serum of these patients. Therefore, it is important that clinicians recognize these autoimmune manifestations as symptoms due to an autoimmune activity triggered by HCV, in order to give the correct diagnosis and start an effective therapy strategy. Therefore, clinical examination, searching of markers of infection as well as autoantibody patterns should be performed to make a correct differential diagnosis. The treatment should be based on antiviral drugs associated to immunosuppressive drugs according to autoimmune manifestations.
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Affiliation(s)
- Alberto Altomare
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Addolorata Corrado
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Nicola Maruotti
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Daniela Cici
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
| | - Francesco Paolo Cantatore
- Rheumatology Clinic "Mario Carrozzo", Department of Medical and Surgical Sciences, University of Foggia, "Policlinico Riuniti" Universitary Hospital, Viale Pinto, 1 - 71121 Foggia. Italy
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Kubodera A, Kume A, Hayashi K, Shimizu R, Miyakawa A, Miyauchi Y, Suzuki Y, Tanaka H. Immune Thrombocytopenic Purpura Complicated by Hepatitis C Virus-related Membranoproliferative Glomerulonephritis after Rituximab Therapy. Intern Med 2021; 60:2469-2473. [PMID: 33583904 PMCID: PMC8381184 DOI: 10.2169/internalmedicine.6758-20] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
We herein report the case of a 54-year-old Japanese man with hepatitis C virus (HCV)-related membranoproliferative glomerulonephritis (MPGN), which developed at the time of relapse of immune thrombocytopenic purpura (ITP) after rituximab therapy. Antiviral therapy for HCV led to the improvement of both MPGN and ITP. Rituximab therapy may have contributed to the exacerbation of HCV infection and induced the development of HCV-related MPGN and the relapse of ITP. Our case suggested that HCV treatment should be prioritized over rituximab therapy for HCV-positive patients with ITP and that antiviral therapy for HCV may be effective for treating ITP itself.
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Affiliation(s)
- Ai Kubodera
- Department of Hematology, Asahi General Hospital, Japan
| | - Ayaka Kume
- Department of Hematology, Asahi General Hospital, Japan
| | | | - Ryo Shimizu
- Department of Hematology, Asahi General Hospital, Japan
| | | | | | - Yoshio Suzuki
- Department of Clinical Pathology, Asahi General Hospital, Japan
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LoRusso S. Infections of the Peripheral Nervous System. Continuum (Minneap Minn) 2021; 27:921-942. [PMID: 34623098 DOI: 10.1212/con.0000000000000981] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE OF REVIEW This article describes infections that affect the peripheral nervous system, including their clinical features, differential diagnoses, and treatments. RECENT FINDINGS Rates of pyomyositis have increased recently in the United States, possibly because of an increase in risk factors such as IV drug use, obesity, and diabetes. Other peripheral nervous system infections, such as diphtheria, have become more common in older patients secondary to a lack of revaccination or waning immunity. Although recommended treatment regimens for most infections remain unchanged over recent years, debate over the ideal dosing and route of administration continues for some infections such as tetanus and leprosy (Hansen disease). SUMMARY Infections of the peripheral nervous system are varied in terms of the type of infection, localization, and potential treatment. Nerve conduction studies and EMG can help determine localization, which is key to determining an initial differential diagnosis. It is important to recognize infections quickly to minimize diagnostic delays that could lead to patient morbidity and mortality.
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Zignego AL, Marri S, Gragnani L. Impact of direct acting antivirals on hepatitis c virus-related cryoglobulinemic syndrome. Minerva Gastroenterol (Torino) 2021; 67:218-226. [PMID: 33793154 DOI: 10.23736/s2724-5985.21.02848-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
INTRODUCTION Mixed cryoglobulinemia (MC) is a B-cell lymphoproliferative disorder largely attributable to HCV infection. MC clinical manifestations are determined by systemic vasculitis of low/medium sized vessels (mixed cryoglobulinemia syndrome or cryoglobulinemic vasculitis and CV) caused by the deposition of cryoglobulins in blood vessels. EVIDENCE ACQUISITION A systematic review was performed via the Medline and Scopus databases to evaluate studies concerning CV treatment with new direct antiviral agents (DAAs) and their effect on the syndrome. EVIDENCE SYNTHESIS The introduction of Interferon-free protocols has led to more evident positive effects than those observed in the treatment of C hepatitis/cirrhosis. In fact, IFN-free, DAA-based therapy minimised side effects permitting the treatment of previously contraindicated patients and led to a particularly high SVR rate and to a clinical/immunological response in the majority of patients, even if at different levels in different patients, from restitutio ad integrum to partial response. In view of the clearly positive evolution in CV management, the persistence of CV manifestations, in partial or non-responders continues to pose problems in the clinical approach to patients who represent a new condition that is still not completely known. CONCLUSIONS Results of DAAs-based therapy strongly confirm the use of anti-HCV therapy as the first-line therapeutic option in CV patients. However, growing evidence of a possible persistence or late relapse of CV suggests the need for longer/more accurate post-DAAs follow-ups as well as biomarkers that are capable of predicting the risk of clinical relapse/persistence to allow for the design of rational post-HCV eradication clinical flow-charts.
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Affiliation(s)
- Anna L Zignego
- MASVE Interdepartmental Hepatology Center, Department of Experimental and clinical Medicine, Center for Research and Innovation CRIAMASVE, University of Florence, Firenze, Italy -
| | - Silvia Marri
- MASVE Interdepartmental Hepatology Center, Department of Experimental and clinical Medicine, Center for Research and Innovation CRIAMASVE, University of Florence, Firenze, Italy
| | - Laura Gragnani
- MASVE Interdepartmental Hepatology Center, Department of Experimental and clinical Medicine, Center for Research and Innovation CRIAMASVE, University of Florence, Firenze, Italy
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Abdelhamid WAR, Shendi A, Zahran M, Elbary EA, Fadda S. Hepatitis C-related membranoproliferative glomerulonephritis in the era of direct antiviral agents. ACTA ACUST UNITED AC 2021; 44:291-295. [PMID: 33605311 PMCID: PMC9269171 DOI: 10.1590/2175-8239-jbn-2020-0148] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 09/18/2020] [Indexed: 12/11/2022]
Abstract
Membranoproliferative glomerulonephritis (MPGN) is the most typical Hepatitis C virus (HCV)-associated glomerulopathy, and the available data about the utilization of direct-acting antivirals (DAA) in HCV-associated glomerulonephritis is inadequate. We evaluated the renal and viral response in two cases of HCV-related MPGN; the first caused by cryoglobulinemia while the second was cryoglobulin-negative. Both patients received immunosuppression besides DAA in different regimens. They achieved partial remission but remained immunosuppression-dependent for more than 6 months after DAA despite sustained virological response, which enabled safer but incomplete immunosuppression withdrawal. Both patients were tested for occult HCV in peripheral blood mononuclear cells and found to be negative. Hence, the treatment of HCV-related MPGN ought to be according to the clinical condition and the effects of drug therapy. It is important to consider that renal response can lag behind the virological response.
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Affiliation(s)
| | - Ali Shendi
- Zagazig University, Faculty of Medicine, Internal Medicine Department, Zagazig, Egypt
| | - Mahmoud Zahran
- Zagazig University, Faculty of Medicine, Internal Medicine Department, Zagazig, Egypt
| | - Eman Abd Elbary
- Zagazig University, Faculty of Medicine, Pathology Department, Zagazig, Egypt
| | - Sawsan Fadda
- Cairo University, Faculty of Medicine, Pathology Department, Cairo, Egypt
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Wang CR, Tsai HW. Human hepatitis viruses-associated cutaneous and systemic vasculitis. World J Gastroenterol 2021; 27:19-36. [PMID: 33505148 PMCID: PMC7789062 DOI: 10.3748/wjg.v27.i1.19] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Revised: 12/19/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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Rossi D, Sciascia S, Fenoglio R, Ferro M, Baldovino S, Kamgaing J, Ventrella F, Kalikatzaros I, Viziello L, Solfietti L, Barreca A, Roccatello D. Cryoglobulinemic glomerulonephritis: clinical presentation and histological features, diagnostic pitfalls and controversies in the management. State of the art and the experience on a large monocentric cohort treated with B cell depletion therapy. Minerva Med 2020; 112:162-174. [PMID: 33198442 DOI: 10.23736/s0026-4806.20.07076-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Cryoglobulinemia is defined by the presence of immunoglobulins having the following characteristics: forming a gel when temperature is <37 °C, precipitate in a reversible manner in the serum, and redissolve after rewarming. The presence of both polyclonal IgG and monoclonal IgM (type II), or of polyclonal IgG and polyclonal IgM (type III) identifies the mixed cryoglobulinemia (MC). The identification of the Hepatitis C virus (HCV) infection in most of the cases previously defined as "essential" represented a cornerstone in the understanding the pathogenesis of this condition. The picture of MC comprehends heterogeneous clinical presentations: from arthralgias, mild palpable purpura, fatigue to severe vasculitis features with skin necrotic pattern, peripheral neuropathy and, less commonly, lungs, central nervous system, gastrointestinal tract, and heart involvement. The kidney represents the most common organ presentation, and the presence of glomerulonephritis is a key element when considering prognosis. We discuss the clinical presentation and histological features, diagnostic pitfalls, and controversies in the management of patients with cryoglobulinemic glomerulonephritis, with a special focus on reporting our experience in treating patients with B cell depletion therapy.
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Affiliation(s)
- Daniela Rossi
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Savino Sciascia
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Roberta Fenoglio
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Michela Ferro
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Simone Baldovino
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Joelle Kamgaing
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Federica Ventrella
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Ileana Kalikatzaros
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Lucia Viziello
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Laura Solfietti
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy
| | - Antonella Barreca
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy.,Patology Division, A.O.U. Città della Salute e della Scienza, Turin, Italy
| | - Dario Roccatello
- Unit of Nephrology and Dialysis (ERKnet Member), Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, San Giovanni Bosco Hospital, University of Turin, Turin, Italy -
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13
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Mazzaro C, Mauro E, Ermacora A, Doretto P, Fumagalli S, Tonizzo M, Toffolutti F, Gattei V. Hepatitis C virus-related cryoglobulinemic vasculitis. Minerva Med 2020; 112:175-187. [PMID: 33198444 DOI: 10.23736/s0026-4806.20.07120-7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
INTRODUCTION Hepatitis C virus (HCV) infection affects about 170 million people worldwide. HCV is responsible for both hepatitis and extra-hepatic manifestations. Chronic infection has been shown to develop in about 70% of cases, and it can progress to cirrhosis or hepatocellular carcinoma. Ten percent of HCV patients may develop extra-hepatic manifestations, including mixed cryoglobulinemia (MC) and non-Hodgkin lymphomas (NHL). Cryoglobulinemic vasculitis (CV) varies, ranging from mild-moderate clinical symptoms (purpura on the legs, asthenia and arthralgias) and chronic hepatitis to severe symptoms (ulcers on the legs, peripheral neuropathy, glomerulonephritis, low-grade NHL to life threatening complications (rapid progressive glomerulonephritis, gastrointestinal vasculitis, acute hyper-viscosity). EVIDENCE ACQUISITION CV is associated with significant morbidity and mortality. Some studies have shown kidney involvement, cirrhosis, central nervous system involvement, and heart involvement as unfavorable prognostic factors. Many studies have demonstrated that, after antiviral therapy, CV can disappear along with HCV. After the introduction of the new direct antiviral agents (DAAs), the combination of pegylated interferon and ribavirin has been abandoned. EVIDENCE SYNTHESIS Several studies on new DAAs have reported remarkable 90% to 100% HCV eradication rates, regardless of genotype. Treatment with DAAs has comparable efficacy on viral eradication in CV patients but definite clinical improvements of vasculitis can be observed only in half the patients. CONCLUSIONS In patients with mild to moderate CV disease, DAAs therapy should be used as first line approach. In patients with severe vasculitis, DAAs therapy and a second-line treatment with RTX with or without aphaeresis are a required.
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Affiliation(s)
- Cesare Mazzaro
- Unit of Clinical of Experimental Onco-Hematology, IRCCS Centro di Riferimento Oncologico (CRO), Aviano, Pordenone, Italy -
| | - Endri Mauro
- Unit of Hematology, Department of Internal Medicine, Cà Foncello Hospital, Treviso, Italy
| | - Anna Ermacora
- Department of Internal Medicine, Pordenone General Hospital, Pordenone, Italy
| | - Paolo Doretto
- Unit of Laboratory, Pordenone General Hospital, Pordenone, Italy
| | - Silvia Fumagalli
- Unit of Hematology, Department of Internal Medicine, Cà Foncello Hospital, Treviso, Italy
| | - Maurizio Tonizzo
- Department of Internal Medicine, Pordenone General Hospital, Pordenone, Italy
| | - Federica Toffolutti
- Unit of Cancer Epidemiology, IRCCS Centro di Riferimento Oncologico (CRO), Aviano, Pordenone, Italy
| | - Valter Gattei
- Unit of Clinical of Experimental Onco-Hematology, IRCCS Centro di Riferimento Oncologico (CRO), Aviano, Pordenone, Italy
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Abstract
INTRODUCTION Hepatitis C virus (HCV) infection is associated with an increased incidence and progression of chronic kidney disease (CKD), as well as higher mortality in CKD and renal transplant patients. Direct acting antiviral agents (DAAs) have revolutionized the treatment of HCV, with viral eradication attained in 90-100% of treated patients. DAAs have an excellent safety and tolerability profile in CKD and renal transplant patients. AREAS COVERED In this review, we discuss the association of HCV with incidence and progression of CKD as well as its effect on outcomes and mortality. We also discuss the available treatment options in patients with CKD and renal transplant and in HCV-associated glomerular disease. EXPERT OPINION The availability of newly available direct acting anti-viral agents has revolutionized the treatment of HCV in persons with advanced CKD and undergoing dialysis. With these regimens, viral eradication can be attained in 90-100% of the treated patients. The safety, tolerability, and efficacy of these drugs in renal transplant patients have also made it possible to use HCV-infected grafts and successful virus eradication at a later stage.
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Affiliation(s)
- Muhammad Umair Khan
- Department of Medicine, Division of Gastroenterology, Hamad Medical Corporation , Doha, Qatar
| | - Mohamed Ibrahim Mahmoud
- Department of Medicine, Division of Gastroenterology, Hamad Medical Corporation , Doha, Qatar
| | - Adeel A Butt
- Weill Cornell Medical College , New York, Qatar.,Department of Medicine, Hamad Medical Corporation , Doha, Qatar
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15
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Kolopp-Sarda MN, Miossec P. Contribution of Hepatitis C Infection to a Large Cohort of Cryoglobulin-Positive Patients: Detection and Characteristics. Front Immunol 2020; 11:1183. [PMID: 32695098 PMCID: PMC7338377 DOI: 10.3389/fimmu.2020.01183] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2020] [Accepted: 05/13/2020] [Indexed: 01/29/2023] Open
Abstract
Cryoglobulins (CGs) are cold precipitating immunoglobulins, and hepatitis C virus (HCV) infection is its most common cause. The purpose of the study was to determine the contribution of HCV in a large cohort of CG. Biological characteristics and specificity of CGs in HCV patients were compared to non-HCV subjects. Cryoglobulin analysis included isotype, clonality, concentration, and rheumatoid factor (RF) in cryoprecipitate and serum complement and RF. This study is an extension of the study carried out on a cohort of 13,439 patients tested for CGs from all medical units, in which 1,675/13,439 (12.5%) patients had a CG, and 680/1,675 (40.6%) had HCV serology or viral load determination (HCV RNA). Among these 680 CG patients tested for HCV, 325 of 680 (47.8%) HCV patients (272 HCV RNA+ and 45 HCV RNA− patients) were compared to 355/680 (52.2%) non-HCV subjects. After a positive detection of CG, HCV status was determined only for 37.7% (256/680) of patients, allowing the diagnosis of a previously unknown HCV infection for 39.8% (102/256). Concentration of HCV RNA+ CGs (median = 80.5 mg/L) was significantly higher than that of HCV RNA− CG (median = 50.5 mg/L, p = 0.001) and HCV− CG (median = 32 mg/L, p < 0.0001). There was no difference of median CG concentration between HCV RNA− patients and non-HCV subjects. Rheumatoid factor titer was significantly higher in type II CG compared to type III CG in HCV RNA+ patients (254 ± 720 vs. 15 ± 21 IU/mL, p < 0.0001) and non-HCV subjects (333 ± 968 vs. 16.8 ± 26 IU/mL, p = 0.0004). Complement functional activity CH50 was lower in HCV RNA+ patients (36 ± 24 U/mL) and in HCV RNA− patients (32 ± 21 U/mL) than in non-HCV subjects (50 ± 25 U/mL, p = 0.001 and p = 0.004). In conclusion, HCV infection and treatment influence CG characteristics. It is essential, and far from always tested, to determine the HCV status of patients with mixed CG, and conversely to search for CG in patients with HCV infection.
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Affiliation(s)
- Marie N Kolopp-Sarda
- Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon, Lyon, France.,Immunology Laboratory, Hospices Civils de Lyon, Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Research Unit EA 4130, University of Lyon, Lyon, France.,Department of Immunology and Rheumatology, Clinical Immunology Unit, Hospices Civils de Lyon, Lyon, France
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16
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Abstract
PURPOSE OF REVIEW The present review focuses on the new therapeutic opportunities offered by the combination of biological drugs, mainly Rituximab, with direct-acting antiviral agents (DAAs). RECENT FINDINGS Hepatitis C virus (HCV) is known to be the etiologic agent in the majority of patients with mixed cryoglobulinemia syndrome. Clinical research has been focused on antiviral drugs and, more recently, on the new, highly potent DAAs. New DAAs assure sustained virologic response (SVR) rates greater than 90% with relief of mild-to-moderate symptoms. SUMMARY Mixed cryoglobulinemia may present with multiorgan vasculitis involving kidneys, joints, skin, and peripheral nerves. Data on DAAs efficacy in HCV-associated cryoglobulinemic vasculitis are disappointing possibly because of the inability of these drugs to suppress the immune-mediated process once it has been triggered. Immunosuppression has often been employed in the past as a first-line therapy in cryoglobulinemic vasculitis despite the potential risk of the infection exacerbation. However, more manageable Rituximab-based therapeutic approaches have been more recently used without increase of viral load. Rituximab substantially changed the outcome of HCV-associated cryoglobulinemic vasculitis by providing long-term remission. A combination schedule of DAAs and Rituximab may result in eradication of both cryoglobulinemic vasculitis and HCV infection.
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17
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Isobe M, Amano K, Arimura Y, Ishizu A, Ito S, Kaname S, Kobayashi S, Komagata Y, Komuro I, Komori K, Takahashi K, Tanemoto K, Hasegawa H, Harigai M, Fujimoto S, Miyazaki T, Miyata T, Yamada H, Yoshida A, Wada T, Inoue Y, Uchida HA, Ota H, Okazaki T, Onimaru M, Kawakami T, Kinouchi R, Kurata A, Kosuge H, Sada KE, Shigematsu K, Suematsu E, Sueyoshi E, Sugihara T, Sugiyama H, Takeno M, Tamura N, Tsutsumino M, Dobashi H, Nakaoka Y, Nagasaka K, Maejima Y, Yoshifuji H, Watanabe Y, Ozaki S, Kimura T, Shigematsu H, Yamauchi-Takihara K, Murohara T, Momomura SI. JCS 2017 Guideline on Management of Vasculitis Syndrome - Digest Version. Circ J 2020; 84:299-359. [PMID: 31956163 DOI: 10.1253/circj.cj-19-0773] [Citation(s) in RCA: 74] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
| | - Koichi Amano
- Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama Medical University
| | - Yoshihiro Arimura
- Department of Rheumatology and Nephrology, Kyorin University School of Medicine.,Internal Medicine, Kichijoji Asahi Hospital
| | - Akihiro Ishizu
- Department of Medical Laboratory Science, Faculty of Health Sciences, Hokkaido University
| | - Shuichi Ito
- Department of Pediatrics, Graduate School of Medicine, Yokohama City University
| | - Shinya Kaname
- Department of Nephrology and Rheumatology, Kyorin University School of Medicine
| | | | - Yoshinori Komagata
- Department of Nephrology and Rheumatology, Kyorin University School of Medicine
| | - Issei Komuro
- Department of Cardiovascular Medicine, The University of Tokyo Graduate School of Medicine
| | - Kimihiro Komori
- Division of Vascular Surgery, Department of Surgery, Nagoya University Graduate School of Medicine
| | - Kei Takahashi
- Department of Pathology, Toho University Ohashi Medical Center
| | - Kazuo Tanemoto
- Department of Cardiovascular Surgery, Kawasaki Medical School
| | - Hitoshi Hasegawa
- Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine
| | - Masayoshi Harigai
- Department of Rheumatology, School of Medicine, Tokyo Women's Medical University
| | - Shouichi Fujimoto
- Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki
| | | | - Tetsuro Miyata
- Vascular Center, Sanno Hospital and Sanno Medical Center
| | - Hidehiro Yamada
- Medical Center for Rheumatic Diseases, Seirei Yokohama Hospital
| | | | - Takashi Wada
- Department of Nephrology and Laboratory Medicine, Graduate School of Medical Sciences, Kanazawa University
| | | | - Haruhito A Uchida
- Department of Chronic Kidney Disease and Cardiovascular Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Hideki Ota
- Department of Advanced MRI Collaboration Research, Tohoku University Graduate School of Medicine
| | - Takahiro Okazaki
- Vice-Director, Shizuoka Medical Center, National Hospital Organization
| | - Mitsuho Onimaru
- Division of Pathophysiological and Experimental Pathology, Department of Pathology, Graduate School of Medical Sciences, Kyushu University
| | - Tamihiro Kawakami
- Division of Dermatology, Tohoku Medical and Pharmaceutical University
| | - Reiko Kinouchi
- Medicine and Engineering Combined Research Institute, Asahikawa Medical University.,Department of Ophthalmology, Asahikawa Medical University
| | - Atsushi Kurata
- Department of Molecular Pathology, Tokyo Medical University
| | | | - Ken-Ei Sada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Kunihiro Shigematsu
- Department of Vascular Surgery, International University of Health and Welfare Mita Hospital
| | - Eiichi Suematsu
- Division of Internal Medicine and Rheumatology, National Hospital Organization, Kyushu Medical Center
| | - Eijun Sueyoshi
- Department of Radiological Science, Nagasaki University Graduate School of Biomedical Sciences
| | - Takahiko Sugihara
- Department of Lifetime Clinical Immunology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University
| | - Hitoshi Sugiyama
- Department of Human Resource Development of Dialysis Therapy for Kidney Disease, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Mitsuhiro Takeno
- Department of Allergy and Rheumatology, Nippon Medical School Graduate School of Medicine
| | - Naoto Tamura
- Department of Internal Medicine and Rheumatology, Juntendo University Faculty of Medicine
| | | | - Hiroaki Dobashi
- Division of Hematology, Rheumatology and Respiratory Medicine Department of Internal Medicine, Faculty of Medicine, Kagawa University
| | - Yoshikazu Nakaoka
- Department of Vascular Physiology, National Cerebral and Cardiovascular Center Research Institute
| | - Kenji Nagasaka
- Department of Rheumatology, Ome Municipal General Hospital
| | - Yasuhiro Maejima
- Department of Cardiovascular Medicine, Tokyo Medical and Dental University
| | - Hajime Yoshifuji
- Department of Rheumatology and Clinical Immunology, Graduate School of Medicine, Kyoto University
| | | | - Shoichi Ozaki
- Division of Rheumatology and Allergology, Department of Internal Medicine, St. Marianna University School of Medicine
| | - Takeshi Kimura
- Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine
| | - Hiroshi Shigematsu
- Clinical Research Center for Medicine, International University of Health and Welfare
| | | | - Toyoaki Murohara
- Department of Cardiology, Nagoya University Graduate School of Medicine
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18
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Lee KC, Cheng YT, Lin CY, Kuo CJ, Chien RN, Yeh CT, Chang ML. Impact of mixed cryoglobulinemia on patients with spontaneous hepatitis C virus clearance: A 13-year prospective cohort study. Eur J Clin Invest 2020; 50:e13189. [PMID: 31782138 DOI: 10.1111/eci.13189] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 10/09/2019] [Accepted: 11/26/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND The prevalence and associations of mixed cryoglobulinemia (MC) in patients with spontaneous clearance of hepatitis C virus (HCV) remain elusive. MATERIALS AND METHODS A 13-year prospective cohort study of patients with spontaneous HCV clearance was conducted in a tertiary care centre. Baseline characteristics, incident cardiovascular and neurologic events and cancers were analysed. RESULTS Of 104 consecutive patients (mean age: 54.08 years old; females: 71 [68%]), 37 (34.6%) had MC and 6 (5.8%) had cirrhosis. MC (+) patients were more female (86% vs 58%, P = .002), had higher rate of cirrhosis (14% vs 1.5%, P = .012), higher levels of Immunoglobulin G (IgG; P = .001), IgM (P = .002) and fibrosis-4 (FIB-4) (P = .004), but lower levels of complement C4 (P = .034) than the MC (-) patients. Female gender (95% confidence interval [CI] of odds ratio: 1.402-26.715), levels of IgG (1.000-1.004), IgM (1.009-1.037) and FIB-4 (1.217-3.966) were independently associated with MC. Baseline rheumatoid factor (RF) levels were independently associated with incident cancer (95% CI hazard ratio [HR]: 1.001-1.030 [HR: 1.015], P = .039). With a cut-off value of 11.3 IU/mL, RF levels significantly predicted incident cancer (area under curve: 0.865, P = .002). No different cumulative incidences of cardiovascular and neurologic events, cancers or mortalities were identified between MC (+) and MC (-) patient. CONCLUSIONS Approximately 1/3 of patients with spontaneous HCV clearance yielded MC, which harboured similar characteristics of MC in patients with chronic hepatitis C. Despite the negligible role of MC in the prognosis of patients with spontaneous HCV clearance, the connection between RF and incident cancer demands further investigation.
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Affiliation(s)
- Kuan-Chieh Lee
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Ya-Ting Cheng
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Cheng-Yu Lin
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chia-Jung Kuo
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Rong-Nan Chien
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Chau-Ting Yeh
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Ling Chang
- Division of Hepatology, Department of Gastroenterology and Hepatology, Liver Research Center, Chang Gung Memorial Hospital, Taoyuan, Taiwan.,Department of Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan
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19
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Nasonov EL, Beketova TV, Ananyeva LP, Vasilyev VI, Solovyev SK, Avdeeva AS. PROSPECTS FOR ANTI-B-CELL THERAPY IN IMMUNO-INFLAMMATORY RHEUMATIC DISEASES. RHEUMATOLOGY SCIENCE AND PRACTICE 2019. [DOI: 10.14412/1995-4484-2019-3-40] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Affiliation(s)
- E L. Nasonov
- V.A. Nasonova Research Institute of Rheumatology; I.M. Sechenov First Moscow State Medical University (Sechenov University), Ministry of Health of Russia
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20
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Efficacy and safety of sofosbuvir-based, interferon-free therapy : The Management of rheumatologic extrahepatic manifestations associated with chronic hepatitis C virus infection. Z Rheumatol 2019; 77:621-628. [PMID: 28795238 DOI: 10.1007/s00393-017-0356-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
BACKGROUND The use of pegylated interferon alpha (IFN) has been of concern in chronic hepatitis C virus (HCV) patients with rheumatologic extrahepatic manifestations (EHM) due to the immunostimulatory effects of IFN. AIM To study the efficacy and safety of sofosbuvir-based, IFN-free antiviral therapy in chronic HCV patients with rheumatologic EHM. MATERIAL AND METHODS Group A included 24 patients with arthropathy (arthralgia or arthritis, n = 15) or vasculitis (n = 9) who received sofosbuvir and ribavirin (n = 17) or sofosbuvir and simeprevir (n = 7). Group B comprised 15 historical controls suffering from arthropathy who had received IFN and ribavirin. All patients were clinically evaluated and by detection of HCV viremia at baseline (V0), at the end of treatment (V1), 12 weeks after end of treatment (V2) and 24 weeks after end of treatment (V3). RESULTS Sustained viral response was obtained in all patients of group A (100%) versus 12 out of 15 of group B (80%). In group A, the tender joint count (TJC) and visual analogue scale for pain (VAS) improved (p = 0.001 for both) while the swollen joint count (SJC) decreased at V1 (p = 0.001) but returned to baseline values at V3. All vasculitis patients improved. Purpura, arthralgia and leg ulcers disappeared, but peripheral neuropathy persisted. In group B, TJC, SJC and VAS increased from baseline values (p = 0.034, 0.03 and 0.001, respectively). Side effects in group A were generally mild, but one patient developed deterioration of arthralgia. CONCLUSION The use of IFN-free regimens is safe and effective in the treatment of most HCV-related rheumatologic EHM.
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21
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Recommendations for managing the manifestations of severe and life-threatening mixed cryoglobulinemia syndrome. Autoimmun Rev 2019; 18:778-785. [PMID: 31181326 DOI: 10.1016/j.autrev.2019.06.008] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2019] [Accepted: 02/22/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVE Some of the manifestations of mixed cryoglobulinemia syndrome (MCS) can be severe or life-threatening, and should be rapidly contained but, as the therapeutic approaches to such conditions are largely based on anecdotal data, a consensus conference was organised by the Italian Group for the Study of Cryoglobulinemia (GISC) with the aim of providing a set of recommendations based on an in-depth survey of the available data and expert opinion. METHODS The consensus panel, which included specialists working in different medical fields involved in the management of MCS patients, was first asked to divide the manifestations of MCS into severe or life-threatening conditions on the basis of their own experience, after which a complete literature review was carried out in accordance with the Cochrane guidelines for systematic reviews. RESULTS Therapeutic plasma exchange (TPE) was considered the elective first-line treatment in the case of life-threatening manifestations of MCS (LT-MCS) and patients with severe clinical symptoms (S-MCS) who fail to respond to (or who are ineligible for) other treatments. The data supporting the combined use of cyclophosphamide and TPE were considered limited and inconclusive. High-dose pulsed glucocorticoid (GCS) therapy can be considered the first-line treatment of severe MCS, generally in association with TPE. Rituximab (RTX)-based treatments should be considered in patients with skin ulcers, peripheral neuropathy or glomerulonephritis, and in patients with persistent LT-MCS after TPE. In patients with hepatitis C virus-related MCS with S-MCS, viral eradication should be attempted as soon as a patient's condition allows the use of direct-acting antivirals.
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22
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Rutledge SM, Chung RT, Sise ME. Treatment of hepatitis C virus infection in patients with mixed cryoglobulinemic syndrome and cryoglobulinemic glomerulonephritis. Hemodial Int 2019; 22 Suppl 1:S81-S96. [PMID: 29694729 DOI: 10.1111/hdi.12649] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cryoglobulinemia is a common extrahepatic manifestation of infection with hepatitis C virus (HCV). When signs and symptoms of systemic vasculitis or glomerulonephritis occur in the presence of circulating cryoglobulins, this syndrome is called "mixed cryoglobulinemia syndrome" (MCS). Historically, interferon-based therapies in HCV have been associated with lower rates of viral cure in patients with MCS than in the general HCV-infected population. The advent of direct-acting antiviral therapies have revolutionized the treatment of HCV, dramatically increasing rates of cure. Early studies of first-generation protease inhibitors (telaprevir and boceprevir) in combination with interferon and ribavirin demonstrated HCV cure rates of 67% and complete clinical response rates of vasculitis symptoms in 60% of patients with MCS; however, regimens were poorly tolerated by patients, 22% discontinued treatment early. More recently, all-oral, interferon-free regimens have become available and combination therapies are now being approved for patients with and without renal impairment. Patients with HCV-MCS achieved sustained virologic response in 297 out of 313 patients (95%) treated with direct-acting antiviral therapy, and 85% had a complete or partial clinical response of MCS symptoms. Current direct-acting antiviral therapies are well tolerated in patients with HCV-MCS and only 1.6% discontinued treatment early. Patients with cryoglobulinemic glomerulonephritis also had an excellent cure rate (94%). The majority improved; 17/52 (33%) experienced full remission and 15/52 (29%) experienced partial remission. There were no reports of worsening kidney function in patients treated with direct-acting antiviral therapies. Less than 5% of patients with HCV-MCS treated with IFN-free direct-acting antiviral therapy required immunosuppression. However, patients with severe vasculitis appear to still require concomitant immunosuppression.
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Affiliation(s)
- Stephanie M Rutledge
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Raymond T Chung
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Meghan E Sise
- Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
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23
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24
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Angeletti A, Cantarelli C, Cravedi P. HCV-Associated Nephropathies in the Era of Direct Acting Antiviral Agents. Front Med (Lausanne) 2019; 6:20. [PMID: 30800660 PMCID: PMC6376251 DOI: 10.3389/fmed.2019.00020] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2018] [Accepted: 01/23/2019] [Indexed: 12/11/2022] Open
Abstract
Hepatitis C virus (HCV) infection is a systemic disorder that frequently associates with extrahepatic manifestations, including nephropathies. Cryoglobulinemia is a typical extrahepatic manifestation of HCV infection that often involves kidneys with a histological pattern of membranoproliferative glomerulonephritis. Other, less common renal diseases related to HCV infection include membranous nephropathy, focal segmental glomerulosclerosis, IgA nephropathy, fibrillary and immunotactoid glomerulopathy. Over the last decades, the advent of direct-acting antiviral therapies has revolutionized treatment of HCV infection, dramatically increasing the rates of viral clearance. In patients where antiviral therapy alone fails to induce renal disease remission add-on B-cell depleting agents represent an alternative to counteract the synthesis of pathogenic antibodies. Immunosuppressive therapies, such as steroids, alkylating agents, and plasma exchanges, may still represent an effective option to inhibit immune-complex driven inflammatory response, but the potentially associated increase of HCV replication and worsening of liver disease represent a serious limitation to their use.
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Affiliation(s)
- Andrea Angeletti
- Nephrology Dialysis and Renal Transplantation Unit, S. Orsola University Hospital, Bologna, Italy
| | - Chiara Cantarelli
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Paolo Cravedi
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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25
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Cacoub P, Si Ahmed SN, Ferfar Y, Pol S, Thabut D, Hezode C, Alric L, Comarmond C, Ragab G, Quartuccio L, Hegazy M, Poynard T, Resche Rigon M, Saadoun D. Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus-Associated Cryoglobulinemia Vasculitis. Clin Gastroenterol Hepatol 2019; 17:518-526. [PMID: 29857143 DOI: 10.1016/j.cgh.2018.05.021] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2018] [Revised: 05/08/2018] [Accepted: 05/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS In small-size and short-term studies of hepatitis C virus-associated cryoglobulinemia vasculitis (HCV-CryoVas), patients had a higher rate of response and tolerance to direct-acting antiviral (DAA) agents than interferon-containing regimens. We collected follow-up data from a clinical trial to determine the long-term effectiveness and tolerance of all-oral, interferon-free DAA regimens in patients with CryoVas. METHODS We collected follow-up data from a prospective international multicenter cohort study of 148 patients with symptomatic HCV-CryoVas (53.7% with cirrhosis and 49.3% naive to treatment with DAAs). All patients received DAA (sofosbuvir plus daclatasvir, n = 53; sofosbuvir plus ribavirin, n = 51; sofosbuvir plus ledipasvir, n = 23; or sofosbuvir plus simeprevir, n = 18), for 12 or 24 weeks, from 2014 through 2017; the median follow-up time was 15.3 months. A complete clinical response was defined as improvement of all organs involved at baseline and the absence of clinical relapse; a partial response was defined as improvement in some but not all organs involved at baseline. The primary end point was clinical response of CryoVas symptoms at week 12 after stopping DAA therapy. RESULTS A complete response was reported for 106 patients (72.6%), a partial response for 33 patients (22.6%), and no response for 7 patients (4.8%). Cryoglobulins were no longer detected in blood samples from 53.1% of patients, and 97.2% of the patients had a sustained virologic response to therapy. Premature DAA withdrawal was reported for 4.1% of patients. Factors associated with no or partial response to therapy included a severe form of CryoVas (odds ratio, 0.33; 95% CI, 0.12-0.91; P = .03) and peripheral neuropathy (odds ratio, 0.31; 95% CI, 0.11-0.84; P = .02). After a median follow-up time of 15.3 months, 4 patients (2.8%) died. The CryoVas manifestation of purpura was cleared from 97.2% of patients, renal involvement from 91.5% of patients, arthralgia from 85.7% of patients, neuropathy from 77.1% of patients, and cryoglobulinemia from 52.2%. CONCLUSIONS In a long-term follow-up analysis of data from a clinical trial, we found that more than 95% of patients with HCV-CryoVas have a full or partial response of symptoms to different DAA treatment regimens. Fewer than 5% of patients stop therapy prematurely and less than 3% die. A severe form of CryoVas and peripheral neuropathy were associated with a lack of response of HCV-CryoVas to DAA therapy.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department, Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France.
| | | | - Yasmina Ferfar
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department, Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Stanislas Pol
- Université Paris Descartes, AP-HP, Unité d'Hépatologie, Hôpital Cochin, Paris, France
| | - Dominique Thabut
- Department of Hepatology, AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, France
| | - Christophe Hezode
- Department of Hepatology, AP-HP, Hôpital Henri Mondor, Créteil, France
| | - Laurent Alric
- Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, Toulouse, France
| | - Cloe Comarmond
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department, Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
| | - Gafaar Ragab
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Luca Quartuccio
- University Hospital "Santa Maria della Misericordia," Udine, Italy
| | - Mohamed Hegazy
- Internal Medicine Department, Rheumatology and Clinical Immunology Unit, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Thierry Poynard
- Department of Hepatology, AP-HP, Groupe Hospitalier Pitié-Salpétrière, Paris, France
| | - Matthieu Resche Rigon
- Department of Biostatistics and Medical Data Processing, INSERM U717, Hôpital Saint-Louis, Paris, France
| | - David Saadoun
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Inflammation-Immunopathology-Biotherapy Department, Paris, France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, Paris, France
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26
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Cacoub P, Comarmond C. Considering hepatitis C virus infection as a systemic disease. Semin Dial 2018; 32:99-107. [PMID: 30549107 DOI: 10.1111/sdi.12758] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis C virus (HCV) infection has been demonstrated to result in several adverse hepatic outcomes and has been associated with a number of important extrahepatic manifestations. The scope of extrahepatic clinical possibilities includes systemic diseases such as vasculitis and lymphoproliferative disorders, cardiovascular disease, myalgia, arthritis, and sicca syndrome. These end-organ effects of HCV may dominate the clinical course beyond the hepatic complications and significantly worsen the long-term prognosis of infected patients. Until several years ago, the standard of care for the treatment of HCV infection had been interferon-alpha-based regimens, which not only had limited effectiveness in achieving a cure but were often poorly tolerated, especially in patients with kidney disease. In those HCV-infected patients with significant systemic manifestations, the interferon-based regimens were problematic given their association with a wide variety of toxicities. The development of highly effective direct-acting antiviral agents to treat HCV infection presented an opportunity to improve the HCV care cascade with the eradication of HCV in most infected patients and by reducing the burden of both hepatic and extrahepatic complications.
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Affiliation(s)
- Patrice Cacoub
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Cloé Comarmond
- UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Sorbonne Universités, UPMC Univ Paris 06, Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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27
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Clinical practice: hepatitis C virus infection, cryoglobulinemia and cryoglobulinemic vasculitis. Clin Exp Med 2018; 19:1-21. [PMID: 30430284 DOI: 10.1007/s10238-018-0536-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Accepted: 10/25/2018] [Indexed: 02/06/2023]
Abstract
Cryoglobulins are circulating immunoglobulins that reversibly precipitate at temperatures below 37 °C. Type-II cryoglobulins consist of monoclonal IgM/polyclonal IgG immune complexes (ICs), whereas in type-III cryoglobulins both IgM and IgG are polyclonal. The clinical condition resulting from the presence of cryoglobulins in the blood is called mixed cryoglobulinemia (MC), which can be asymptomatic or manifest as cryoglobulinemic vasculitis (CV). Type-I cryoglobulins, consisting of a single monoclonal isotype, are detected in patients with lymphoproliferative disorders. It is now established that > 90% of MCs are associated with HCV infection. Clinically, the spectrum of symptoms may range in severity from occasional purpuric eruptions to life-threatening features. In addition to the development of liver cirrhosis and hepatocellular carcinoma, the possible progression of HCV-positive CV patients to B-cell non-Hodgkin lymphoma (B-NHL) has been reported. The pathogenetic role played by HCV infection in the onset of B-NHL is suggested by regression of the latter following the achievement of a sustained virologic response (SVR). For several years, interferon-α alone or combined with ribavirin has been the standard of care. However, the rates of clinical, biochemical, and virologic responses have been low, and the occurrence of relapse frequent. The addition of rituximab has resulted in a higher rate of responses. With the advent of direct-acting antiviral agents, SVR has been achieved in ~ 95% of CV patients. However, in a minority of patients, despite SVR, CV may persist or reappear over variable lengths of time from the completion of therapy. The eventual appearance of B-NHL is also possible.
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28
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Long JD, Rutledge SM, Sise ME. Autoimmune Kidney Diseases Associated with Chronic Viral Infections. Rheum Dis Clin North Am 2018; 44:675-698. [PMID: 30274630 DOI: 10.1016/j.rdc.2018.06.006] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Autoimmune kidney diseases triggered by viruses are an important cause of kidney disease in patients affected by chronic viral infection. Hepatitis B virus (HBV) infection is associated with membranous nephropathy and polyarteritis nodosa. Hepatitis C virus (HCV) infection is a major cause of cryoglobulinemic glomerulonephritis. Patients with human immunodeficiency virus (HIV) may develop HIV-associated nephropathy, a form of collapsing focal segmental glomerulosclerosis, or various forms of immune-complex-mediated kidney diseases. This article summarizes what is known about the pathogenesis, diagnosis, and management of immune-mediated kidney diseases in adults with chronic HBV, HCV, and HIV infections.
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Affiliation(s)
- Joshua D Long
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, 55 Fruit Street, GRB 7, Boston, MA 02114, USA
| | - Stephanie M Rutledge
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, 55 Fruit Street, GRB 7, Boston, MA 02114, USA
| | - Meghan E Sise
- Department of Medicine, Division of Nephrology, Massachusetts General Hospital, 55 Fruit Street, GRB 7, Boston, MA 02114, USA.
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29
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Stubbs A, Kowal C, Askari A, Anthony DD, Mattar M. Achieving Sustained Viral Remission in Patients with Chronic HCV Infection and Cryoglobulinemic Vasculitis Does Not Always Correlate with Normalization of the Serologic Markers. ACTA ACUST UNITED AC 2018; 9:562. [PMID: 30956892 PMCID: PMC6446568 DOI: 10.4172/2155-9899.1000562] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Objective: We aim to describe the persistence of symptoms associated with HCV-associated cryoglobulinemic vasculitis following achievement of (SVR) with IFN- free direct acting antiviral (DAA) therapy. In particular, we describe the persistence of C4 hypocomplementemia and positive Rheumatoid Factor (RF). Methods: We analyzed a case series of four patients enrolled from the Cleveland VA and known to have chronic HCV infection complicated by mixed cryoglobulinemia. The study included patients treated with interferon (IFN) based treatment and IFN free direct acting antiviral (DAA) therapy. Results: Of the four patients, patients 1 and 2 experienced decline of RF without resolution following DAA therapy. Patient 1 continues to have evidence of disease following treatment. Patient 3 did not have resolution of RF during IFN-based treatment and experienced stabilization of kidney function while on treatment. Patient 4, previously a non-responder to IFN based treatment, experienced significant decline in RF titers along with resolution of cryoglobulin-associated rash with DAA therapy. C4 remained low following treatment in patients 1 and 3. Of the four patients, only patient 1 had prolonged persistence of cryoglobulinemia, measured at 3%, 17 months following achievement of SVR. Conclusions: We highlight the complexity of the viral-mediated immunologic mechanism that causes cryoglobulinemic vasculitis. Our cases also emphasize the need to consider cryoglobulinemic vasculitis as part of the differential diagnosis even with treated HCV infection. Recognizing these findings are important in our understanding of the pathophysiology of the disease and management in the era of IFN-free DAA therapy.
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Affiliation(s)
- Aaron Stubbs
- Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, Cleveland, Ohio, USA
| | - Corinne Kowal
- Rheumatology section, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA
| | - Ali Askari
- Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, Cleveland, Ohio, USA.,Division of Rheumatic Diseases, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA
| | - Donald D Anthony
- Rheumatology section, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.,Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, Cleveland, Ohio, USA.,Division of Rheumatic Diseases, University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA.,Cleveland VA Geriatric Research, Education and Clinical Center (GRECC), USA
| | - Maya Mattar
- Rheumatology section, Louis Stokes Cleveland VA Medical Center, Cleveland, Ohio, USA.,Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University, Cleveland, Ohio, USA
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30
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KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl (2011) 2018; 8:91-165. [PMID: 30675443 PMCID: PMC6336217 DOI: 10.1016/j.kisu.2018.06.001] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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31
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Association of Renal Function and Direct-Acting Antiviral Agents for HCV: A Network Meta-Analysis. J Clin Med 2018; 7:jcm7100314. [PMID: 30274298 PMCID: PMC6210726 DOI: 10.3390/jcm7100314] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2018] [Revised: 09/21/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
Abstract
The effectiveness and safety of direct-acting antiviral agents (DAAs) in hepatitis C virus (HCV) patients with renal insufficiency remain controversial. Therefore, this network meta-analysis aims to assess effectiveness and safety of DAAs in populations with different renal function. The pooled data were obtained from Cochrane Library, EMBASE, PubMed, and Web of Science. Thirteen studies recruited 6884 patients with hepatitis C infection and reported their outcomes in relation to different levels of renal function after treatment with DAAs. The results showed no difference in the virologic responses among patients with different renal function. Regarding safety, whereas in patients without chronic kidney disease (CKD) or with early CKD DAAs were associated with a risk ratio (RR) of 0.14 (95% confidence interval (CI), 0.04 to 0.43) for renal disorder, increased risk of renal function deterioration was found in advanced-CKD patients, though this effect may be related to the natural course of advanced CKD. Similarly, patients without CKD or with early CKD showed a lower risk of anemia (RR, 0.34; 95% CI, 0.20 to 0.57) and discontinuation (RR, 0.41; 95% CI, 0.39 to 0.56) than patients with advanced CKD. The efficacy of DAAs for HCV treatment was comparable in patients with advanced CKD and in those with early CKD or without CKD. However, the safety of DAAs should be verified in future studies.
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32
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Zubkin ML, Chervinko VI, Ovchinnikov YV, Kryukov EV, Kotenko ON. [Chronic hepatitis C virus infection: An internist's opinion (Part 1)]. TERAPEVT ARKH 2018. [PMID: 28635859 DOI: 10.17116/terarkh2016886105-113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Hepatitis C virus (HCV) infection results in not only chronic hepatitis and subsequent complications as liver cirrhosis and hepatocellular carcinoma, but also in a significant number of other diseases, the so-called extrahepatic manifestations of chronic HCV infection. This is because of viral hepatotropicity and lymphotropicity. The most striking example of the course of chronic HCV infection, in which the infectious and inflammatory processes are concurrent with autoimmune disorders and carcinogenesis, is mixed cryoglobulinemia and B-cell non-Hodgkin's lymphoma. The pathogenesis of these diseases is based on the clonal expansion of B cells, which occurs under their prolonged stimulation with the virus or viral proteins. Part 1 of this review is devoted to the analysis of a correlation of chronic HCV infection with lymphoproliferative and autoimmune disorders, as well as its association with kidney injury.
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Affiliation(s)
- M L Zubkin
- G.N. Gabrichevsky Moscow Research Institute for Epidemiology and Microbiology, Russian Federal Service for Supervision of Consumer Rights Protection and Human Welfare, Moscow, Russia; Branch, S.M. Kirov Military Medical Academy, Moscow, Russia
| | - V I Chervinko
- Branch, S.M. Kirov Military Medical Academy, Moscow, Russia
| | | | - E V Kryukov
- N.N. Burdenko Main Military Clinical Hospital, Moscow, Russia
| | - O N Kotenko
- City Clinical Hospital Fifty-Two, Moscow Healthcare Department, Moscow, Russia
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33
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Santoriello D, Pullela NK, Uday KA, Dhupar S, Radhakrishnan J, D’Agati VD, Markowitz GS. Persistent Hepatitis C Virus-Associated Cryoglobulinemic Glomerulonephritis in Patients Successfully Treated With Direct-Acting Antiviral Therapy. Kidney Int Rep 2018; 3:985-990. [PMID: 29988995 PMCID: PMC6035133 DOI: 10.1016/j.ekir.2018.03.016] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Affiliation(s)
- Dominick Santoriello
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Nanda K. Pullela
- Department of Medicine, Division of Nephrology, Bronx Lebanon Hospital Center, Bronx, New York, USA
| | - Kalpana A. Uday
- Department of Medicine, Division of Nephrology, Bronx Lebanon Hospital Center, Bronx, New York, USA
| | - Shawn Dhupar
- Department of Medicine, Vassar Brothers Medical Center, Poughkeepsie, New York, USA
| | - Jai Radhakrishnan
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, New York, USA
| | - Vivette D. D’Agati
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
| | - Glen S Markowitz
- Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, USA
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34
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Liao TL, Hsieh SL, Chen YM, Chen HH, Liu HJ, Lee HC, Chen DY. Rituximab May Cause Increased Hepatitis C Virus Viremia in Rheumatoid Arthritis Patients Through Declining Exosomal MicroRNA-155. Arthritis Rheumatol 2018; 70:1209-1219. [PMID: 29575671 DOI: 10.1002/art.40495] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 03/08/2018] [Indexed: 12/18/2022]
Abstract
OBJECTIVE Several studies have shown that rituximab may enhance hepatitis C virus (HCV) activity. MicroRNAs (miRNAs) have been implicated in modulating the host immune response in HCV infection; miRNAs can be packaged into the exosomes and then shuttled by the exosomes to aid biologic functions. However, the role of exosomal miRNAs (exo-miRNAs) in rituximab-related HCV activity enhancement remains unclear. METHODS The association between rituximab and increased HCV activity was examined using an in vitro cell-based assay. Purified exosomes were confirmed using immunoblotting and flow cytometry and quantified using enzyme-linked immunosorbent assay. Exosomal miRNA-155 (exo-miR-155) levels were measured using quantitative reverse transcription-polymerase chain reaction. RESULTS In vitro data showed that B cell-derived miR-155 could inhibit HCV replication in hepatocytes through exosome transmission. Rituximab could both induce B cell depletion and affect intracellular miR-155 production as well as exo-miR-155 transmission and then enhance HCV activity in hepatocytes (P < 0.005). Serum exosome levels were increased in rheumatoid arthritis (RA) patients with HCV infection compared with the levels in RA patients without HCV infection (P < 0.01). The exo-miR-155 levels were significantly increased in RA patients with HCV infection compared with those without infection (P < 0.01). A significantly greater decrement of exo-miR-155 expression was observed after rituximab therapy compared with those observed before therapy (P < 0.01), and hepatitis C viral loads increased simultaneously (P < 0.05). CONCLUSION Circulating exo-miR-155 levels were negatively correlated with hepatitis C viral loads and subsequently associated with rituximab-related HCV activity enhancement in RA patients. Exo-miR-155 may become a potential diagnostic biomarker or therapeutic target.
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Affiliation(s)
- Tsai-Ling Liao
- Taichung Veterans General Hospital and National Chung Hsing University, Taichung, Taiwan
| | - Shie-Liang Hsieh
- Genomics Research Center, Academia Sinica and National Yang Ming University, Taipei, Taiwan
| | - Yi-Ming Chen
- Taichung Veterans General Hospital and National Chung Hsing University, Taichung, Taiwan, and National Yang Ming University, Taipei, Taiwan
| | - Hsin-Hua Chen
- Taichung Veterans General Hospital and National Chung Hsing University, Taichung, Taiwan, and National Yang Ming University, Taipei, Taiwan
| | - Hung-Jen Liu
- National Chung Hsing University, Taichung, Taiwan
| | - Hsiu-Chin Lee
- Taichung Veterans General Hospital, Taichung, Taiwan
| | - Der-Yuan Chen
- Taichung Veterans General Hospital, China Medical University Hospital, and China Medical University, Taichung, Taiwan
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35
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Roccatello D, Sciascia S, Rossi D, Solfietti L, Fenoglio R, Menegatti E, Baldovino S. The challenge of treating hepatitis C virus-associated cryoglobulinemic vasculitis in the era of anti-CD20 monoclonal antibodies and direct antiviral agents. Oncotarget 2018; 8:41764-41777. [PMID: 28454112 PMCID: PMC5522247 DOI: 10.18632/oncotarget.16986] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2016] [Accepted: 03/09/2017] [Indexed: 12/30/2022] Open
Abstract
Mixed cryoglobulinemia syndrome (MC) is a systemic vasculitis involving kidneys, joints, skin, and peripheral nerves. While many autoimmune, lymphoproliferative, and neoplastic disorders have been associated with this disorder, hepatitis C virus (HCV) is known to be the etiologic agent in the majority of patients. Therefore, clinical research has focused on anti-viral drugs and, more recently, on the new, highly potent Direct-acting Antiviral Agents (DAAs). These drugs assure sustained virologic response (SVR) rates >90%. Nevertheless, data on their efficacy in patients with HCV-associated cryoglobulinemic vasculitis are disappointing, possibly due to the inability of the drugs to suppress the immune-mediated process once it has been triggered.Despite the potential risk of exacerbation of the infection, immunosuppression has traditionally been regarded as the first-line intervention in cryoglobulinemic vasculitis, especially if renal involvement is severe. Biologic agents have raised hopes for more manageable therapeutic approaches, and Rituximab (RTX), an anti CD20 monoclonal antibody, is the most widely used biologic drug. It has proved to be safer than conventional immunosuppressants, thus substantially changing the natural history of HCV-associated cryoglobulinemic vasculitis by providing long-term remission, especially with intensive regimens.The present review focuses on the new therapeutic opportunities offered by the combination of biological drugs, mainly Rituximab, with DAAs.
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Affiliation(s)
- Dario Roccatello
- Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy.,Nephrology and Dialysis Unit, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
| | - Savino Sciascia
- Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy.,Nephrology and Dialysis Unit, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
| | - Daniela Rossi
- Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
| | - Laura Solfietti
- Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
| | - Roberta Fenoglio
- Nephrology and Dialysis Unit, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
| | - Elisa Menegatti
- Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
| | - Simone Baldovino
- Department of Clinical and Biological Sciences, Center of Research of Immunopathology and Rare Diseases, Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, S. Giovanni Bosco Hospital and University of Turin, Turin, Italy
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36
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Abstract
Cryoglobulins are immunoglobulins that undergo reversible precipitation at low temperatures. They can induce systemic vasculitis, characterized by purpuric cutaneous lesions, arthritis, peripheral neuropathy, hypocomplementemia and glomerular disease. Renal pathology reveals membranoproliferative glomerulonephritis, with particularly intense mesangial cell proliferation and infiltration by macrophages, associated with intracapillary thrombi. This renal disease presents as a nephritic syndrome, with heavy proteinuria, haematuria severe hypertension and rapidly progressive kidney failure that can lead to end-stage renal disease. Hepatitis C is the main cause of mixed (type 2 or 3) cryoglobulinemia and requires the initiation of a specific antiviral therapy, together with immunosuppressive drugs. Rituximab is now considered as the best immunosuppressive therapy in this situation, inducing B-cell depletion, clearance of circulating cryoglobulin and resolution of renal symptoms. Monoclonal (type 1) cryoglobulinemia, is a rare condition, but it usually reveals an B-cell or a plasma cell proliferation, that require a specific hematological treatment to obtain remission of the renal disease.
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37
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Kolopp-Sarda MN, Miossec P. Cryoglobulins: An update on detection, mechanisms and clinical contribution. Autoimmun Rev 2018. [PMID: 29526627 DOI: 10.1016/j.autrev.2017.11.035] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Cryoglobulins are immunoglobulins precipitating in cold condition. They are classified in 3 types according to the Brouet classification and may lead to vasculitis of small and medium size vessels. Vasculitis is related to vessel obstruction by monoclonal cryoglobulin aggregates in type I cryoglobulins and immune complex deposition in type II and III mixed cryoglobulins. This phenomenon is favored by low temperature, especially in skin, joints, and peripheral nerves, or increased cryoglobulin concentration in kidneys. For their detection, collection and clotting at 37°C are critical pre-analytical conditions. Cryoglobulin characterization and quantification are important to identify the underlying disease. Since detection and identification of cryoglobulins lack standardization, a protocol for such detection, characterization and quantification is proposed.
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Affiliation(s)
- Marie-Nathalie Kolopp-Sarda
- Department of Immunology and Rheumatology, Immunogenomics and inflammation research Unit EA 4130, University of Lyon, Lyon, France; Immunology Laboratory, University Hospital Lyon, France
| | - Pierre Miossec
- Department of Immunology and Rheumatology, Immunogenomics and inflammation research Unit EA 4130, University of Lyon, Lyon, France.
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Abstract
PURPOSE OF REVIEW More than 50% of hepatitis C virus (HCV) infected patients produce a mixed cryoglobulin and two-third of them will develop a symptomatic cryoglobulinemia vasculitis (CryoVas). In the present review, we aim at summarizing the most recent advances in diagnosis and treatment of HCV-CryoVas. RECENT FINDINGS The treatment of HCV-CryoVas has much changed during the last months. The recent emergence of new direct-acting (DAA) interferon (IFN)-free antivirals, enabling high cure rates with a very good safety profile now permit to cure most patients with HCV-CryoVas. Multidisciplinary consensus recommends to consider IFN-free DAAs as first-line treatment for HCV-CryoVas patients. Immunosuppressive treatments (i.e. rituximab, glucocorticosteroids, cyclophosphamide and plasmapheresis) remain an interesting therapeutic approach, in severe form of HCV-CryoVas, failure or contradiction to antiviral treatments. SUMMARY The great efficacy of DAA on HCV-CryoVas represents a major advance in clinical practice, as these new antivirals provide for the first time a well tolerated and definite treatment of such complication for most patients.
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39
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Conventional and biological immunosuppressants in vasculitis. Best Pract Res Clin Rheumatol 2018; 32:94-111. [DOI: 10.1016/j.berh.2018.07.006] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2018] [Revised: 06/18/2018] [Accepted: 07/09/2018] [Indexed: 12/20/2022]
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40
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Jachiet M, Flageul B, Bouaziz JD, Bagot M, Terrier B. Les vascularites urticariennes hypocomplémentémiques. Rev Med Interne 2018; 39:90-98. [DOI: 10.1016/j.revmed.2017.03.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Revised: 01/29/2017] [Accepted: 03/04/2017] [Indexed: 01/21/2023]
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41
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Taha R, El-Haddad H, Almuallim A, Alshaiki F, Obaid E, Almoallim H. Systematic review of the role of rituximab in treatment of antineutrophil cytoplasmic autoantibody-associated vasculitis, hepatitis C virus-related cryoglobulinemic vasculitis, Henoch-Schönlein purpura, ankylosing spondylitis, and Raynaud's phenomenon. Open Access Rheumatol 2018; 9:201-214. [PMID: 29290695 PMCID: PMC5735990 DOI: 10.2147/oarrr.s149373] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Rituximab (RTX) is established for the treatment of rheumatoid arthritis. This systematic review of the literature since 2006 summarizes evidence for the use of RTX in the treatment of additional rheumatological diseases: antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV), hepatitis C virus-related cryoglobulinemic vasculitis, Henoch-Schönlein purpura, ankylosing spondylitis, and Raynaud's phenomenon. Data from randomized controlled trials are available only for AAV, confirming efficacy for remission induction, including in disease resistant to conventional treatment, and maintenance of remission. Further studies are required to confirm optimal maintenance regimens in AAV, important questions needing to be addressed including protocol administration versus treatment in response to clinical relapse and the importance of maintaining B-cell depletion. Sufficient data are available in other diseases to suggest RTX to be useful and that randomized controlled trials should be conducted.
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Affiliation(s)
- Rbab Taha
- Department of Medicine, Dr Soliman Fakeeh Hospital, Jeddah
| | | | | | | | - Elaf Obaid
- Department of Medicine, Faculty of Medicine, Umm Al-Qura University, Mecca
| | - Hani Almoallim
- Department of Medicine, Dr Soliman Fakeeh Hospital, Jeddah.,Department of Medicine, Faculty of Medicine, Umm Al-Qura University, Mecca.,Rheumatic Diseases, Umm Al-Qura University, Mecca, Saudi Arabia
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42
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Zignego AL, Pawlotsky JM, Bondin M, Cacoub P. Expert opinion on managing chronic HCV in patients with mixed cryoglobulinaemia vasculitis. Antivir Ther 2018; 23:1-9. [PMID: 30451151 DOI: 10.3851/imp3246] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/21/2018] [Indexed: 12/11/2022]
Abstract
Mixed cryoglobulinaemia vasculitis (CryoVas) is a small-vessel systemic vasculitis caused by deposition of mixed cryoglobulins and is characterized by a wide range of clinical symptoms. HCV is the primary cause of CryoVas, which is associated with significant morbidity and mortality. The mortality rate among patients with HCV-associated CryoVas is 3× that of the general population, with a 63% 10-year survival rate. First-line treatment for CryoVas is anti-HCV therapy because viral clearance is associated with clinical improvement. The introduction of highly effective, interferon-free, direct-acting antiviral regimens provides additional treatment options for these patients. Here, we review recent studies investigating the effect of antiviral therapy on HCV-associated CryoVas and provide expert opinion for health-care professionals managing these patients.
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Affiliation(s)
- Anna Linda Zignego
- Department of Clinical and Experimental Medicine, Interdepartmental Hepatology Center MASVE, University of Florence, Florence, Italy
| | - Jean-Michel Pawlotsky
- National Reference Center for Viral Hepatitis B, C and D, Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France
- INSERM U955, Créteil, France
| | | | - Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France
- INSERM, UMR_S 959, F-75013, Paris, France
- CNRS, FRE3632, F-75005, Paris, France
- AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Department of Internal Medicine and Clinical Immunology, F-75013, Paris, France
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43
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Comstock E, Kim CW, Murphy A, Emmanuel B, Zhang X, Sneller M, Poonia B, Kottilil S. Transcriptional profiling of PBMCs unravels B cell mediated immunopathogenic imprints of HCV vasculitis. PLoS One 2017; 12:e0188314. [PMID: 29228031 PMCID: PMC5724854 DOI: 10.1371/journal.pone.0188314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2017] [Accepted: 11/03/2017] [Indexed: 01/22/2023] Open
Abstract
B cell depletion therapy using rituximab has been shown to be effective in achieving remission in patients with HCV-mixed cryoglobulinemic (MC) vasculitis. Previously, we have demonstrated abnormalities in peripheral immune cells involving neutrophils, chemotaxis, and innate immune activation among patients with HCV-MC vasculitis when compared to HCV patients without vasculitis. In this study, we evaluated the effect of B cell depletion therapy on transcriptional profiles of peripheral blood mononuclear cells before and after riruximab therapy, in order to unravel the pathogenic mechanism involved in HCV-MC vasculitis induced by abnormal B cell proliferation. DNA microarray analysis was performed using RNA from PBMCs from seven patients with HCV-MC vasculitis and seven normal volunteers. DNA was hybridized to Affymetrix U133A chips. After normalization, differentially expressed gene list with treatment was generated using partitional clustering. RT-PCR, flow cytometry, and enzyme immunoassay (EIA) was used to validate DNA microarray findings. Differentially expressed genes included B cells and non-B cell genes. Validation of genes using purified cell subsets demonstrated distinct effect of B cell depletion therapy on non-B cells, such as monocytes, T cells, and NK cells. Notably, B lymphocyte stimulator (BLyS) levels were persistently elevated in patients who subsequently relapsed. In conclusion, pathogenesis of HCV-MC vasculitis is mediated by abnormal proliferation of B cells, driven by BLyS, leading to significant effects on non-B cells in mediating symptomatology. Future therapeutics using a combination approach of B cell depletion and proliferation may be desired to achieve long-term remission.
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Affiliation(s)
- Emily Comstock
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Cheol-Woo Kim
- Department of Internal Medicine, Inha University, Incheon, South Korea
| | - Alison Murphy
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
| | - Benjamin Emmanuel
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Xi Zhang
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
| | - Michael Sneller
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
| | - Bhawna Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
| | - Shyamasundaran Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, United States of America
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, United States of America
- * E-mail:
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Cacoub P, Vautier M, Desbois AC, Lafuma A, Saadoun D. Effectiveness and cost of hepatitis C virus cryoglobulinaemia vasculitis treatment: From interferon-based to direct-acting antivirals era. Liver Int 2017; 37:1805-1813. [PMID: 28467688 DOI: 10.1111/liv.13465] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 04/21/2017] [Indexed: 12/11/2022]
Abstract
BACKGROUND The net benefits of new hepatitis C virus (HCV) direct-acting antiviral drugs (DAA) in patients with cryoglobulinaemia vasculitis (CryoVas) are unknown. OBJECTIVE To analyse the effectiveness and cost of all treatments used for HCV-CryoVas in the DAA vs pre-DAA era. METHODS A chart review of all HCV-CryoVas patients who received antivirals from 1993 to 2016 in a tertiary centre was performed. Treatment effectiveness was analysed for clinical, immunological and virological responses. Cost analyses included anti-HCV treatments, non-antiviral drugs, plasmapheresis, dialysis and hospitalizations. We compared main data in the pre-DAA vs DAA period. RESULTS About 201 HCV-CryoVas patients were included (women, 53.2%; mean age, 59.2 years; Metavir score F3-F4, 36.7%; genotype 1, 64.2%). Patients in the DAA era (n=27) compared to those in the pre-DAA era (n=174) showed higher rates of clinical (96.3% vs. 78.6%), immunological (89.5% vs. 77.1%), and sustained virological response (75.0% vs. 42.8%). Death rate was 14.8% vs. 24.4% respectively. In the DAA compared to pre-DAA era, mean cost of anti-HCV drugs increased from 11 855 to 57 632 € while mean CryoVas-related cost decreased for both hospitalizations (from 33 510 to 21 347€) and non-antiviral treatments (from 17 347 to 11 397€). CONCLUSION Improved antiviral efficacy of HCV drugs in the DAA era led to increased clinical and immunological efficacy and a lower death rate. Use of DAAs was associated to higher costs for HCV drugs while costs related to both hospitalizations and non-antiviral treatments decreased.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Paris, France.,Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Mathieu Vautier
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Paris, France.,Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.,INSERM, UMR_S 959, Paris, France
| | - Anne Claire Desbois
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Paris, France.,Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
| | - Antoine Lafuma
- CEMKA, Outcomes Research Epidemiology, Bourg la Reine, France
| | - David Saadoun
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, Paris, France.,Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris, France.,INSERM, UMR_S 959, Paris, France.,CNRS, FRE3632, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
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45
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Affiliation(s)
- Richard J. Johnson
- Division of Renal Diseases and Hypertension, University of Colorado, Aurora, Colorado; and
| | - Michiko Shimada
- Division of Cardiology and Nephrology, Hirosaki University Graduate School of Medicine, Hirosaki, Japan
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46
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Ignatova TM, Kozlovskaya LV, Gordovskaya NB, Chernova OA, Milovanova SY, Novikov PI, Nekrasova TP, Beketova TV, Mukhin NA. [Hepatitis C virus-associated cryoglobulinemic vasculitis: A 20-year experience with treatment]. TERAPEVT ARKH 2017. [PMID: 28631698 DOI: 10.17116/terarkh201789546-52] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
AIM To summarize the experience of a multidisciplinary therapy hospital in treating patients with hepatitis C virus (HCV)-associated cryoglobulinemic vasculitis (CV). SUBJECTS AND METHODS Seventy-two patients (mean age, 49.4±10.3 years) with HCV-associated CV were examined and followed up for an average period of 2.8±3.6 years. The efficiency of traditional (corticosteroids ± cyclophosphamide) and selective (rituximab) immunosuppressive therapy (IST) was estimated in 31 and 15 observations, respectively, and that of antiviral therapy (AVT) in 25. Vasculitis activity was assessed using the Birmingham vasculitis activity score (BVAS). The patients' survival was studied; multivariate logistic regression analysis was carried out. RESULTS 24 (33.4%) of the 72 patients had a stage of liver cirrhosis (LC). The pretreatment mean BVAS was 11.9±7.2 (range 2 to 36). Severe CV (BVAS ≥15) was present in 30.6% of the patients. AVT was accompanied by achievement of sustained virologic response in 48% of the patients, clinical remission in 68% and had an advantage over IST in relation to long-term treatment results. Rituximab was significantly more effective than traditional immunosuppressants (remission rates of 73 and 13%, respectively). Combined therapy (rituximab and AVT) was most effective in patients with severe forms of vasculitis. Sixteen patients died from complications of vasculitis (37.5%), infection (37.5%), and LC (25%). The factors adversely affecting prognosis were age >55 years (odds ratio (OR), 4.49), the presence of LC (OR, 3.68), renal failure (OR, 4.66) and the use of glucocorticosteroids (OR, 3.91). CONCLUSION HCV-associated CV can determine the prognosis of chronic HСV infection. AVT is the treatment of choice in all patients with HСV-associated CV. AVT must be combined with rituximab therapy in patients with severe forms of vasculitis.
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Affiliation(s)
- T M Ignatova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia; V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
| | - L V Kozlovskaya
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - N B Gordovskaya
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - O A Chernova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - S Yu Milovanova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia; V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
| | - P I Novikov
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - T P Nekrasova
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
| | - T V Beketova
- V.A. Nasonova Research Institute of Rheumatology, Moscow, Russia
| | - N A Mukhin
- I.M. Sechenov First Moscow State Medical University, Ministry of Health of Russia, Moscow, Russia
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Abstract
Chronic infection with hepatitis C virus (HCV) is a multifaceted disease characterized by many extrahepatic manifestations (EHMs) that affect outcome and quality of life. HCV eradication by antiviral treatment has been proved beneficial in preventing the development of EHMs and is also able to improve many HCV-related severe disorders and neurocognitive outcomes and quality of life. Until recently, antiviral therapy of EHMs was limited to the presence of interferon-based treatment, and was contraindicated in many patients because of hematologic toxicity or risk of exacerbating immune-mediated disorders. The availability of interferon-free regimens solves this issue allowing for enhanced safety and efficacy to provide universal treatment of HCV-related EHMs.
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48
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Cacoub P, Comarmond C, Desbois AC, Saadoun D. Rheumatologic Manifestations of Hepatitis C Virus Infection. Clin Liver Dis 2017; 21:455-464. [PMID: 28689585 DOI: 10.1016/j.cld.2017.03.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
Hepatitis C virus (HCV) infection is associated with a morbidity and mortality due to liver complications. HCV infection is also frequently associated with rheumatic disorders, such as arthralgia, myalgia, cryoglobulinemia vasculitis, and sicca syndrome, as well as the production of autoantibodies. The treatment of HCV infection with interferon alpha (IFN) has been contraindicated for a long time in many rheumatologic autoimmune/inflammatory disorders. New oral IFN-free combinations offer an opportunity for HCV-infected patients with extrahepatic manifestations, including rheumatologic autoimmune/inflammatory disorders, to be cured with a short treatment duration and a low risk of side effects.
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Affiliation(s)
- Patrice Cacoub
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France.
| | - Cloé Comarmond
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France
| | - Anne Claire Desbois
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France
| | - David Saadoun
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), UMR 7211, UPMC Université Paris 06, Sorbonne Universités, Paris F-75005, France; INSERM, UMR_S 959, Paris F-75013, France; CNRS, FRE3632, Paris F-75005, France; Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 83 boulevard de l'hô pital, Paris F-75013, France
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49
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Retamozo S, Brito-Zerón P, Quartuccio L, De Vita S, Ramos-Casals M. Introducing treat-to-target strategies of autoimmune extrahepatic manifestations of chronic hepatitis C virus infection. Expert Rev Clin Pharmacol 2017; 10:1085-1101. [PMID: 28715943 DOI: 10.1080/17512433.2017.1357466] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION The hepatitis C virus (HCV) is recognized as one of the hepatic viruses most often associated with extrahepatic manifestations (EHMs). It is currently accepted that cryoglobulinemic vasculitis (CV) is the key autoimmune extrahepatic disease associated with HCV infection. Therapeutic approaches have mainly been based on the use of old antiviral interferon (IFN)-based regimens and immunosuppressive therapies, often with an inadequate balance between therapeutic benefits and excess side effects. Areas covered: Therapeutic management of HCV patients with EHMs, including both non-autoimmune (cardiovascular, hematological, general features) and autoimmune complications (organ-specific and systemic autoimmune diseases). Therapies included antiviral (IFN, ribavirin, direct-acting antivirals - DAAs-) and non-antiviral (immunosuppressive agents, rituximab, plasma exchanges) options. The review analyses the current evidence for proposing a treat-to-target (T2T) approach for HCV-related autoimmune EHMs based on an organ-by-organ strategy. Expert commentary: Eradication of HCV must be considered the key T2T in the therapeutic approach to HCV-related EHMs, as there has been a disruptive change due to the appearance of direct-acting antivirals (DAAs) as game-changers in HCV therapy, with an efficacy reaching nearly 100%. In this scenario, the central role played until now by IFN and ribavirin is not currently supported and they will not be used in the future.
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Affiliation(s)
- Soledad Retamozo
- a Hospital Privado Universitario de Córdoba , Instituto Universitario para las Ciencias Biomédicas de Córdoba (IUCBC) , Córdoba , Argentina.,b Laboratory of Autoimmune Diseases Josep Font , IDIBAPS-CELLEX , Barcelona , Spain.,g Instituto De Investigaciones En Ciencias De La Salud (INICSA) , Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) , Córdoba , Argentina
| | - Pilar Brito-Zerón
- b Laboratory of Autoimmune Diseases Josep Font , IDIBAPS-CELLEX , Barcelona , Spain.,c Autoimmune Diseases Unit, Department of Medicine , Hospital CIMA- Sanitas , Barcelona , Spain.,d Department of Autoimmune Diseases, ICMiD , Hospital Clínic , Barcelona , Spain
| | - Luca Quartuccio
- e Rheumatology Clinic, Department of Medical and Biological Sciences, Azienda Ospedaliero Universitaria S. Maria della Misericordia , University of Udine , Udine , Italy
| | - Salvatore De Vita
- e Rheumatology Clinic, Department of Medical and Biological Sciences, Azienda Ospedaliero Universitaria S. Maria della Misericordia , University of Udine , Udine , Italy
| | - Manuel Ramos-Casals
- b Laboratory of Autoimmune Diseases Josep Font , IDIBAPS-CELLEX , Barcelona , Spain.,d Department of Autoimmune Diseases, ICMiD , Hospital Clínic , Barcelona , Spain.,f Department of Medicine , University of Barcelona , Barcelona , Spain
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50
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Visentini M, Fiorilli M, Casato M. From the pathogenesis to the cure of indolent B-cell lymphoproliferative disorders associated with hepatitis C virus infection: which role for direct-acting antivirals? Expert Rev Hematol 2017; 10:719-727. [PMID: 28675071 DOI: 10.1080/17474086.2017.1349607] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
INTRODUCTION Hepatitis C virus (HCV) causes monoclonal B cell lymphoproliferative disorders ranging from benign, such as in mixed cryoglobulinemia (MC), to indolent or aggressive lymphomas. MC and indolent lymphomas commonly regress when HCV is eradicated with interferon (IFN) therapy; however, sustained virologic response (SVR) to IFN is achieved only in ~50% of patients. The new all oral direct-acting antivirals (DAA), yielding nearly 100% SVR, promise a breakthrough in the treatment of HCV-associated lymphoproliferative disorders, but experience is still scanty. Areas covered: A literature search was performed to summarize current pathogenetic hypotheses in HCV-associated indolent lymphoproliferative disorders and to identify clinical trials focused on the use of antiviral therapy. Hematological outcomes of IFN-based and IFN-free DAA-based regimens were compared. Expert commentary: While MC appears to regress in most patients after DAA therapy, the still very limited experience with indolent lymphomas suggests that hematologic responses might be less than those observed with IFN. Furthermore, anecdotal observations of early progression to aggressive lymphoma after DAA are disquieting. Large studies are needed to determine the values and limits of DAA for treating HCV-associated indolent lymphomas and to identify subgroups at risk of non-response.
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Affiliation(s)
- Marcella Visentini
- a Department of Clinical Medicine , Sapienza University of Rome , Rome , Italy
| | - Massimo Fiorilli
- a Department of Clinical Medicine , Sapienza University of Rome , Rome , Italy
| | - Milvia Casato
- a Department of Clinical Medicine , Sapienza University of Rome , Rome , Italy
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