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Colunga-Pedraza PR, Barbosa-Castillo LM, Coronado-Alejandro EU, Vaquera-Alfaro HA, López-Reyna IG, Colunga-Pedraza JE, Gómez-Almaguer D. Low-dose rituximab in steroid-refractory chronic graft-versus-host disease. Transpl Immunol 2023; 81:101959. [PMID: 37972876 DOI: 10.1016/j.trim.2023.101959] [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: 06/19/2023] [Revised: 11/10/2023] [Accepted: 11/12/2023] [Indexed: 11/19/2023]
Abstract
BACKGROUND Chronic graft-versus-host disease (cGvHD) is a major complication that puts patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) at risk of death or infection. Currently, there is no gold standard for the first-line treatment of patients who do not respond to steroids, and there are several therapeutic options being evaluated in clinical trials for this disease to be used even in the first-line treatment for GvHD. There is evidence of the benefit of rituximab, an anti-CD20 antibody, at a standard dose of 375 mg/m2 weekly in the treatment of steroid-refractory chronic graft-versus disease (SR-cGvHD). OBJECTIVE To demonstrate the safety and efficacy of low-dose rituximab in a middle-income center in northeastern Mexico STUDY DESIGN: We report the experience of 26 patients with chronic graft-versus-graft disease who received low-dose rituximab (100 mg weekly for 4 weeks). We utilized the advances in the National Institutes of Health (NIH) criteria for diagnosis, scoring, trial design, and assessment of treatment response. RESULTS We obtained a 5-year overall survival of 23.6%, including four patients with complete response. The 1-year event-free survival was 70% for patients with rituximab. During the treatment, there were 3 hospitalizations, and the causes were: immune thrombocytopenia, a parapneumonic effusion, and a cerebral vascular event. The median length of hospital stay was twelve days. CONCLUSION A low dose of rituximab is an available and cost-effective option for patients with steroid-refractory cGvHD.
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Affiliation(s)
- Perla R Colunga-Pedraza
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico.
| | - Luz María Barbosa-Castillo
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico
| | - Edgar Ulises Coronado-Alejandro
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico
| | - Héctor Alejandro Vaquera-Alfaro
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico
| | - Ingrid Gabriela López-Reyna
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico
| | - Julia E Colunga-Pedraza
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico
| | - David Gómez-Almaguer
- Hematology service, Hospital Universitario "Dr. José Eleuterio González", Universidad Autónoma de Nuevo León, Ave. Francisco I. Madero, Monterrey, Nuevo León 64460, Mexico
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Rajendran N, Rameli PM, Awad H. Risk factors for relapse in non-infectious cryoglobulinemic vasculitis, including type I cryoglobulinemia: a systematic review. Front Immunol 2023; 14:1215345. [PMID: 37483620 PMCID: PMC10361750 DOI: 10.3389/fimmu.2023.1215345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2023] [Accepted: 06/12/2023] [Indexed: 07/25/2023] Open
Abstract
Background Data on non-infectious cryoglobulinemic vasculitis (NICV) is scarce, especially concerning the management of relapses, which are troublesome. We aimed to investigate risk factors for relapse in NICV. Methods A systematic literature search of CINAHL, Embase, MEDLINE, Scopus, and the Web of Science databases was implemented until April 2023. Eligible studies included randomized control trials, observational studies, and case series with ≥4 patients. Two reviewers independently extracted data and assessed the quality of the eligible studies. Results A total of 3,724 articles were retrieved from a database search, with 27 studies meeting the inclusion criteria for review. Most studies (n = 23) detailed relapses, with the time to relapse varying between 1 and 80 months. The relapse rate was reported at 28% in Type I NICV and ranged from 22% to 60% in mixed NICV. Risk factors for relapse in NICV were identified based on the cryoglobulin subtype and correlated with clinical and immunological responses to varying treatment regimens. Type I NICV with an associated lymphoproliferative disorder exhibited a response-relapse pattern. Cutaneous and articular involvement and incomplete clinical and immunological responses to treatment, particularly corticosteroid monotherapy and occasionally rituximab, influence the risk of relapse in Type II and Type III NICV. Conclusion Our findings underscore the significance of attaining both clinical and immunological responses and identifying risk factors for relapse in NICV. Appropriate risk stratification for NICV patients is essential for the successful implementation of effective treatment strategies. Systematic review registration https://www.crd.york.ac.uk/prospero/, identifier CRD42023408140.
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Affiliation(s)
- Nithya Rajendran
- Department of Immunology, Beaumont Hospital, Royal College of Surgeons in Ireland (RCSI) Hospital Group, Dublin, Ireland
| | - Puteri Maisarah Rameli
- Department of Acute Medical Assessment Unit (AMAU)/ General Internal Medicine (GIM), St. James’s Hospital, Trinity College Dublin, Dublin, Ireland
| | - Hanaa Awad
- Department of Immunology, Beaumont Hospital, Royal College of Surgeons in Ireland (RCSI) Hospital Group, Dublin, Ireland
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Sugihara A, Ureshino H, Yamasaki M, Fukuda M, Yoshihara M, Nonaka E, Miyazaki M, Fujita M, Ishii K, Kamachi K, Sano H, Okamoto S, Itamura H, Yoshimura M, Katsuya H, Ando T, Aoki S, Ubara Y, Kimura S. Type II Cryoglobulinemic Membranoproliferative Glomerulonephritis Caused by Mucosa-associated Lymphoid Tissue Lymphoma. Intern Med 2023; 62:1983-1988. [PMID: 37394661 PMCID: PMC10372288 DOI: 10.2169/internalmedicine.0756-22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 07/04/2023] Open
Abstract
A 67-year-old man complained of lower limb edema with a purpuric skin rash. Laboratory tests revealed proteinuria, elevated serum creatinine levels, and low serum albumin levels. The patient was also positive for cryoglobulin in serum, immunoglobulin (Ig) M gammopathy, hypocomplementemia, and rheumatoid factor. He was negative for anti-hepatitis C virus antibodies. A pathological analysis of the renal tissue revealed membranoproliferative glomerulonephritis, common histological features of cryoglobulinemic vasculitis (CV), and mucosa-associated lymphoid tissue lymphoma invasion. Although hematologic malignancy is a rare cause of type II CV, these clinical findings suggest that mucosa-associated lymphoid tissue lymphoma (MALT) lymphoma may have been the cause in the present case.
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Affiliation(s)
- Ayano Sugihara
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Hiroshi Ureshino
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
- Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Japan
| | - Masatora Yamasaki
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Makoto Fukuda
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Maki Yoshihara
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Eriko Nonaka
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Mariko Miyazaki
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Mai Fujita
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Keitaro Ishii
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Kazuharu Kamachi
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Haruhiko Sano
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Sho Okamoto
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Hidekazu Itamura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Mariko Yoshimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Hiroo Katsuya
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Toshihiko Ando
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
| | - Shigehisa Aoki
- Division of Pathology, Department of Pathology and Microbiology, Faculty of Medicine, Saga University, Japan
| | | | - Shinya Kimura
- Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, Faculty of Medicine, Saga University, Japan
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Younger DS. Adult and childhood vasculitis. HANDBOOK OF CLINICAL NEUROLOGY 2023; 195:653-705. [PMID: 37562892 DOI: 10.1016/b978-0-323-98818-6.00008-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/12/2023]
Abstract
Vasculitis refers to heterogeneous clinicopathologic disorders that share the histopathology of inflammation of blood vessels. Unrecognized and therefore untreated, vasculitis of the nervous system leads to pervasive injury and disability, making this a disorder of paramount importance to all clinicians. There has been remarkable progress in the pathogenesis, diagnosis, and treatment of primary CNS and PNS vasculitides, predicated on achievement in primary systemic forms. Primary neurological vasculitides can be diagnosed with assurance after intensive evaluation that incudes tissue confirmation whenever possible. Clinicians must choose from among the available immune modulating, suppressive, and targeted immunotherapies to induce and maintain remission status and prevent relapse, unfortunately without the benefit of RCTs, and tempered by the recognition of anticipated medication side effects. It may be said that efforts to define a disease are attempts to understand the very concept of the disease. This has been especially evident in systemic and neurological disorders associated with vasculitis. For the past 100 years, since the first description of granulomatous angiitis of the brain, the CNS vasculitides have captured the attention of generations of clinical investigators around the globe to reach a better understanding of vasculitides involving the central and peripheral nervous system. Since that time it has become increasingly evident that this will necessitate an international collaborative effort.
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Affiliation(s)
- David S Younger
- Department of Clinical Medicine and Neuroscience, CUNY School of Medicine, New York, NY, United States; Department of Medicine, Section of Internal Medicine and Neurology, White Plains Hospital, White Plains, NY, United States.
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Quartuccio L, Bortoluzzi A, Scirè CA, Marangoni A, Del Frate G, Treppo E, Castelnovo L, Saccardo F, Zani R, Candela M, Fraticelli P, Mazzaro C, Renoldi P, Scaini P, Filippini DA, Visentini M, Scarpato S, Giuggioli D, Mascia MT, Sebastiani M, Zignego AL, Lauletta G, Fiorilli M, Casato M, Ferri C, Pietrogrande M, Pioltelli PE, De Vita S, Monti G, Galli M. Management of mixed cryoglobulinemia with rituximab: evidence and consensus-based recommendations from the Italian Study Group of Cryoglobulinemia (GISC). Clin Rheumatol 2023; 42:359-370. [PMID: 36169798 PMCID: PMC9873783 DOI: 10.1007/s10067-022-06391-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Revised: 09/06/2022] [Accepted: 09/21/2022] [Indexed: 01/28/2023]
Abstract
Cryoglobulinemic vasculitis (CV) or mixed cryoglobulinemic syndrome (MCS) is a systemic small-vessel vasculitis characterized by the proliferation of B-cell clones producing pathogenic immune complexes, called cryoglobulins. It is often secondary to hepatitis C virus (HCV), autoimmune diseases, and hematological malignancies. CV usually has a mild benign clinical course, but severe organ damage and life-threatening manifestations can occur. Recently, evidence in favor of rituximab (RTX), an anti-CD 20 monoclonal antibody, is emerging in CV: nevertheless, questions upon the safety of this therapeutic approach, especially in HCV patients, are still being issued and universally accepted recommendations that can help physicians in MCS treatment are lacking. A Consensus Committee provided a prioritized list of research questions to perform a systematic literature review (SLR). A search was made in Medline, Embase, and Cochrane library, updated to August 2021. Of 1227 article abstracts evaluated, 27 studies were included in the SLR, of which one SLR, 4 RCTs, and 22 observational studies. Seventeen recommendations for the management of mixed cryoglobulinemia with rituximab from the Italian Study Group of Cryoglobulinemia (GISC) were developed to give a valuable tool to the physician approaching RTX treatment in CV.
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Affiliation(s)
- Luca Quartuccio
- Unit of Rheumatology, Department of Medicine (DAME), University of Udine, ASUFC, Udine, Italy.
| | - Alessandra Bortoluzzi
- Section of Rheumatology, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera, Universitaria Di Ferrara, Cona, FE, Italy
| | | | - Antonio Marangoni
- Section of Rheumatology, Department of Medical Sciences, University of Ferrara and Azienda Ospedaliera, Universitaria Di Ferrara, Cona, FE, Italy
| | - Giulia Del Frate
- Unit of Rheumatology, Department of Medicine (DAME), University of Udine, ASUFC, Udine, Italy
| | - Elena Treppo
- Unit of Rheumatology, Department of Medicine (DAME), University of Udine, ASUFC, Udine, Italy
| | - Laura Castelnovo
- Department of Internal Medicine, Hospital of Legnano, Legnano, Italy
| | | | | | | | - Paolo Fraticelli
- Ematologia Ed Immunologia Clinica, Clinica Medica Generale, University of Ancona, Ancona, Italy
| | - Cesare Mazzaro
- Clinical Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081, Aviano, Italy
| | - Piero Renoldi
- UOS Di Immunologia Clinica, Ospedale S. Carlo Borromeo, Milan, Italy
| | | | | | - Marcella Visentini
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Dilia Giuggioli
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Maria Teresa Mascia
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Marco Sebastiani
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | | | | | - Massimo Fiorilli
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Milvia Casato
- Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy
| | - Clodoveo Ferri
- Department of Internal Medicine, Rheumatology Unit, University of Modena and Reggio Emilia, Modena, Italy
| | - Maurizio Pietrogrande
- Department of Medicine, Surgery and Dentistry, Medicina Interna, Policlinico San Marco of Zingonia, University of Milan, Milan, Italy
| | | | - Salvatore De Vita
- Unit of Rheumatology, Department of Medicine (DAME), University of Udine, ASUFC, Udine, Italy
| | - Giuseppe Monti
- Medicina Interna, Ospedale Di Saronno, AO Busto Arsizio, Italy
| | - Massimo Galli
- Infectious Disease Unit, L. Sacco, Department of Clinical Sciences, University of Milan, Milan, Italy
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Mazzaro C, Dal Maso L, Gragnani L, Visentini M, Saccardo F, Filippini D, Andreone P, Zignego AL, Gattei V, Monti G, Galli M, Quartuccio L. Hepatitis B Virus-Related Cryoglobulinemic Vasculitis: Review of the Literature and Long-Term Follow-Up Analysis of 18 Patients Treated with Nucleos(t)ide Analogues from the Italian Study Group of Cryoglobulinemia (GISC). Viruses 2021; 13:1032. [PMID: 34070832 PMCID: PMC8226459 DOI: 10.3390/v13061032] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 05/05/2021] [Accepted: 05/26/2021] [Indexed: 01/05/2023] Open
Abstract
Hepatitis B virus (HBV) chronic infection causes progressive liver damage, although about 20% of patients develop extrahepatic manifestations such as cryoglobulinemic vasculitis (CV). Clinical manifestations range from mild to moderate (purpura, asthenia, arthralgia) to severe (leg ulcers, peripheral neuropathy, glomerulonephritis, non-Hodgkin lymphoma). A comprehensive review of therapeutic options for HBV-related CV is lacking. Nucleos(t)ide analogues (NA) suppress HBV replication in 90-100% of cases and induce clinical response in most patients with mild-to-moderate CV. Plasma exchange can be performed in patients with severe CV and should be considered in severe or life-threatening cases combined with high doses of corticosteroids and antiviral treatment. A cautious use of rituximab can be considered only in association with NA treatment in refractory cases. A review of the literature and an analysis of data collected by six centers of the Italian Group for the Study of Cryoglobulinemia on 18 HBV-CV nucleotide/nucleoside analogues (NAs)-treated patients were carried out.
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Affiliation(s)
- Cesare Mazzaro
- Clinical Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO) IRCCS, 33081 Aviano, Italy;
| | - Luigino Dal Maso
- Cancer Epidemiology Unit, Centro di Riferimento Oncologico (CRO) IRCCS, 33081 Aviano, Italy;
| | - Laura Gragnani
- MASVE Interdepartmental Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, 50121 Firenze, Italy; (L.G.); (A.L.Z.)
| | - Marcella Visentini
- Department of Translational and Precision Medicine, Sapienza University of Rome, 00185 Rome, Italy;
| | - Francesco Saccardo
- Rheumatology Unit, Internal Medicine Unit, Presidio Ospedaliero di Saronno, ASST della Valle Olona, 21047 Saronno, Italy; (F.S.); (G.M.)
| | - Davide Filippini
- Rheumatology Unit, ASST Grande Ospedale Metropolitano Niguarda, 20162 Milan, Italy;
| | - Pietro Andreone
- Division of Internal Medicine, Department of Medical and Surgical Sciences, Maternal-Infantile and Adult, University of Modena and Reggio Emilia, 41124 Modena, Italy;
| | - Anna Linda Zignego
- MASVE Interdepartmental Center, Department of Experimental and Clinical Medicine, University of Florence, Center for Research and Innovation CRIA-MASVE, 50121 Firenze, Italy; (L.G.); (A.L.Z.)
| | - Valter Gattei
- Clinical Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO) IRCCS, 33081 Aviano, Italy;
| | - Giuseppe Monti
- Rheumatology Unit, Internal Medicine Unit, Presidio Ospedaliero di Saronno, ASST della Valle Olona, 21047 Saronno, Italy; (F.S.); (G.M.)
| | - Massimo Galli
- Infectious Diseases, L. Sacco Hospital, Department of Biochemical and Clinical Sciences, University of Milan, 20157 Milan, Italy;
| | - Luca Quartuccio
- Rheumatology Clinic, Department of Medicine (DAME), ASUFC, University of Udine, 33100 Udine, Italy
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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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Muro K, Toda N, Yamamoto S, Yanagita M. The Successful Treatment of a Case of HCV-associated Cryoglobulinemic Glomerulonephritis with Rituximab, Direct-acting Antiviral Agents, Plasmapheresis and Long-term Steroid Despite Serologically Persistent Cryoglobulinemia. Intern Med 2021; 60:583-589. [PMID: 32999232 PMCID: PMC7946495 DOI: 10.2169/internalmedicine.5461-20] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Novel treatments with rituximab or direct-acting antiviral agents (DAAs) were expected to improve the clinical outcomes of hepatitis C virus (HCV)-associated cryoglobulinemia in the last decade. Recently, however, persistent cases of cryoglobulinemia have been reported, and the ideal approach to treating such cases has not been established. We herein report a case of the successful treatment of HCV-associated cryoglobulinemic glomerulonephritis with rituximab, DAAs, occasional plasmapheresis and long-term steroid, with the patient's renal function and proteinuria improving over the long term despite serologically persistent cryoglobulinemia. This case suggests the efficacy of combination treatment with rituximab, DAAs, occasional plasmapheresis and long-term steroid for persistent cryoglobulinemia.
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Affiliation(s)
- Koji Muro
- Department of Nephrology, Kyoto University Graduate School of Medicine, Japan
| | - Naohiro Toda
- Department of Nephrology, Kyoto University Graduate School of Medicine, Japan
| | - Shinya Yamamoto
- Department of Nephrology, Kyoto University Graduate School of Medicine, Japan
| | - Motoko Yanagita
- Department of Nephrology, Kyoto University Graduate School of Medicine, Japan
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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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10
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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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11
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Vacchi C, Manfredi A, Salvarani C, Sebastiani M. Vasculitis in a patient with mixed cryoglobulinemia treated with rituximab biosimilar CT-P10: a case report. Mod Rheumatol Case Rep 2020; 4:102-105. [PMID: 33086972 DOI: 10.1080/24725625.2019.1687804] [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: 10/25/2022]
Abstract
Rituximab represents a milestone in the treatment of mixed cryoglobulinemic vasculitis. Despite usually well-tolerated, rituximab may induce different types of adverse drug reactions, including exacerbation of vasculitis. Rituximab biosimilar have been recently approved in Europe in the treatment of rheumatoid arthritis, but no data are available about effectiveness and safety of rituximab biosimilar in the treatment of mixed cryoglobulinemic vasculitis. We describe a severe skin vasculitis reactivation in a patient affected by rheumatoid arthritis and mixed cryoglobulinemic vasculitis treated with rituximab biosimilar. After 7 days from the first infusion, a severe purpuric rash at lower limbs appeared, that resolved in about 2 weeks with high dose-corticosteroid. Rituximab-induced vasculitis has also been described since 2001, but its pathophysiology is still controversial due to the anecdotical descriptions in literature and the variability of the time between the rituximab infusion and the onset of skin lesions. Up to date, this is the first report describing a vasculitic flare in a patient affected by mixed cryoglobulinemic vasculitis treated with rituximab biosimilar.
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Affiliation(s)
- Caterina Vacchi
- Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Andreina Manfredi
- Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
| | - Carlo Salvarani
- Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy.,S.C. Reumatologia, Azienda USL-IRCCS Reggio Emilia, Reggio Emilia, Italy
| | - Marco Sebastiani
- Rheumatology Unit, Azienda Policlinico di Modena, University of Modena and Reggio Emilia, Modena, Italy
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12
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Mazzaro C, Dal Maso L, Visentini M, Ermacora A, Tonizzo M, Gattei V, Andreone P. Recent news in the treatment of hepatitis B virus-related cryogobulinemic vasculitis. Minerva Med 2020; 111:566-572. [PMID: 32573522 DOI: 10.23736/s0026-4806.20.06771-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
Hepatitis B virus (HBV) is a hepatotropic virus that causes hepatitis, cirrhosis and hepatocellular carcinoma. Twenty percent of HBV patients may develop extra-hepatic manifestations, such as polyarthritis nodosa, glomerulonephritis, dermatitis, poly-arthralgia and arthritis, and aplastic anemia. The association of HBV and cryoglobulinemic vasculitis (CV) has been highlighted by several epidemiological investigations. CV can develop in 0.5-4% of HBV infected patients. It has been demonstrated that suppression of HBV replication by nucleot(s)ide analogues (NAs) effectively induces clinical response in most patients with mild to moderate CV, but low responses are seen in severe CV. Based on this evidence, NAs therapy represents the first line therapeutic option in subjects with mild or moderate HBV related CV. Peg-interferon-Alfa can be an alternative treatment for HBV related CV, but the few studies published so far have shown no encouraging results. In patients with severe vasculitis and/or skin ulcers, peripheral neuropathy and glomerulonephritis treatment with rituximab (RTX) and NAs should be considered as a first line treatment. The long-term administration of low-medium glucocorticoid doses has been widely used in few studies to control clinical symptoms, but it should be used as a second option, when RTX is ineffective or not tolerated and in association with NAs. This review focuses on novel treatments for HBV related CV.
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Affiliation(s)
- Cesare Mazzaro
- Unit of Clinical Experimental Onco-Hematology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy -
| | - Luigino Dal Maso
- Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Marcella Visentini
- Depatment of Clinical Medicine, Laboratory affiliated to Pasteur Italia Institute - Cenci Bolognetti Foundation, Sapienza University, Rome, Italy
| | - Anna Ermacora
- Department of Internal Medicine, Hospital of Pordenone, Pordenone, Italy
| | - Maurizio Tonizzo
- Department of Internal Medicine, Hospital of Pordenone, Pordenone, Italy
| | - Valter Gattei
- Unit of Clinical Experimental Onco-Hematology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Aviano, Pordenone, Italy
| | - Pietro Andreone
- SMECHIMAI Department, University of Modena and Reggio Emilia, Modena, Italy.,Department of Internal and Metabolic Medicine, University Hospital of Modena, Modena, Italy
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13
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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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14
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Bayer G, Agier MS, Lioger B, Lepelley M, Zenut M, Lanoue MC, Maillot F, Jonville-Bera AP. Rituximab-induced serum sickness is more frequent in autoimmune diseases as compared to hematological malignancies: A French nationwide study. Eur J Intern Med 2019; 67:59-64. [PMID: 31279430 DOI: 10.1016/j.ejim.2019.06.009] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2018] [Revised: 05/13/2019] [Accepted: 06/14/2019] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Rituximab induced serum sickness (RISS) is a rare delayed hypersensitivity reaction. The aim of this study was to describe the epidemiological and clinical characteristics of the RISS cases reported in France. METHOD Serum sickness cases involving rituximab were identified from the French PharmacoVigilance Database from 1998 to 2016. RESULTS We analyzed 37 cases of RISS. Rituximab was prescribed for an autoimmune disease in 78% of cases. Serum sickness occurred mainly after the first injection (54%) with a median time to onset of 12 days. The most frequent manifestations were rheumatologic symptoms (92%), fever (87%), and skin lesions (78%). The incidence was significantly higher when rituximab was used for autoimmune diseases than for a hematological malignancies. Taking into account the existence of a Systemic Lupus Erythematosus (SLE) as the indication of rituximab or as a comorbidity, the incidence of RISS in patients with SLE was even higher. DISCUSSION We report on the largest series of RISS studied to date and confirm that this reaction preferentially occurs in patients with autoimmune disease, especially SLE. This may be due to B-cell lysis, leading to the release of intracellular antigens into the serum and subsequent antigen-antibody complex formation, especially in patients with elevated autoantibody production. This could also explain why RISS often occurred after a single injection. CONCLUSION Patients generally recovered from RISS rapidly without obvious benefit from corticosteroid therapy. The risk of recurrence should prompt clinicians to question the use of rituximab after an episode of RISS.
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Affiliation(s)
- Guillaume Bayer
- CHRU de Tours, Service de médecine interne, Tours, France; Université François Rabelais, Tours, France.
| | - Marie-Sara Agier
- CHRU de Tours, Centre Régional de pharmacovigilance Centre Val de Loire, Tours, France
| | | | - Marion Lepelley
- CHRU de Grenoble, Centre Régional de pharmacovigilance, Grenoble, France
| | - Marie Zenut
- CHRU de Clermont-Ferrand, Centre Régional de pharmacovigilance, Clermont-Ferrand, France
| | | | - François Maillot
- CHRU de Tours, Service de médecine interne, Tours, France; Université François Rabelais, Tours, France
| | - Annie-Pierre Jonville-Bera
- CHRU de Tours, Centre Régional de pharmacovigilance Centre Val de Loire, Tours, France; Université de Tours, Université de Nantes, INSERM, SPHERE U1246, Tours, France
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15
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Mazzaro C, Dal Maso L, Visentini M, Gitto S, Andreone P, Toffolutti F, Gattei V. Hepatitis B virus-related cryogobulinemic vasculitis. The role of antiviral nucleot(s)ide analogues: a review. J Intern Med 2019; 286:290-298. [PMID: 31124596 DOI: 10.1111/joim.12913] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Cryoglobulinemic vasculitis (CV) can develop in 1.2-4% of hepatitis B virus (HBV)-infected patients. HBV infection affects about 350 million people worldwide. It can progress from acute or fulminant hepatitis to chronic hepatitis, cirrhosis or hepatocellular carcinoma. Twenty per cent of HBV patients may develop extra-hepatic manifestations, such as polyarteritis nodosa, glomerulonephritis, dermatitis, polyarthralgias and arthritis, lung disease, aplastic anaemia. Our review focuses on the role of antiviral agent nucleot(s)ide analogues (NAs) in treatment of HBV-related CV. The studies in literature have demonstrated that NAs therapy in HBV-related CV yields high virological and satisfying clinical responses in most patients with mild-and-moderate CV, but a low response in severe CV. Overall, NAs represent a promising therapeutic option for HBV-related CV. Obtaining early suppression of HBV viral load should be the main virological and clinical goal in order to prevent organ complications and lymphoproliferative disorders.
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Affiliation(s)
- C Mazzaro
- Clinical Experimental Onco-Haematology Unit, Italy
| | - L Dal Maso
- Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - M Visentini
- Depatment of Clinical Medicine, Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza Unversity of Rome, Rome, Italy
| | - S Gitto
- Department of Medical and Surgical Sciences, Center for the Study and Research of Hepatitis, University of Bologna Policlinico di San Orsola, Bologna, Italy
| | - P Andreone
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - F Toffolutti
- Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Italy
| | - V Gattei
- Clinical Experimental Onco-Haematology Unit, Italy
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16
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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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17
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Lucchini E, Zaja F, Bussel J. Rituximab in the treatment of immune thrombocytopenia: what is the role of this agent in 2019? Haematologica 2019; 104:1124-1135. [PMID: 31126963 PMCID: PMC6545833 DOI: 10.3324/haematol.2019.218883] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 05/09/2019] [Indexed: 01/19/2023] Open
Abstract
The use of rituximab for the treatment of immune thrombocytopenia was greeted enthusiastically: it led to up to 60% response rates, making it, nearly 20 years ago, the main alternative to splenectomy, with far fewer side effects. However, long-term follow-up data showed that only 20-30% of patients maintained the remission. No significant changes have been registered using different dose schedules and timing of administration, while the combination with other drugs seemed promising. Higher response rates have been observed in young women before the chronic phase, but apart from that, other clinical factors or biomarkers predictive of response are still lacking. In this review we examine the historical and current role of rituximab in the management of immune thrombocytopenia, 20 years after its first use for the treatment of autoimmune diseases.
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Affiliation(s)
- Elisa Lucchini
- SC Ematologia, Azienda Sanitaria Universitaria Integrata Trieste, Italy
| | - Francesco Zaja
- SC Ematologia, Azienda Sanitaria Universitaria Integrata Trieste, Italy
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18
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Abstract
The diagnosis of primary central and peripheral nerve vasculitides should be established with certainty if suspected before commencing potent immunosuppressive therapy. The aim of induction therapy is to rapidly control the underlying inflammatory response and stabilize the blood-brain and blood-nerve barriers, followed by maintenance immunosuppression tailored to the likeliest humoral and cell-mediated autoimmune inflammatory vasculitic processes.
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Affiliation(s)
- David S Younger
- Department of Neurology, Division of Neuro-Epidemiology, New York University School of Medicine, New York, NY, USA; School of Public Health, City University of New York, New York, NY, USA.
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19
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Kolkhir P, Grakhova M, Bonnekoh H, Krause K, Maurer M. Treatment of urticarial vasculitis: A systematic review. J Allergy Clin Immunol 2019; 143:458-466. [PMID: 30268388 DOI: 10.1016/j.jaci.2018.09.007] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Revised: 07/03/2018] [Accepted: 09/07/2018] [Indexed: 01/19/2023]
Abstract
Urticarial vasculitis (UV) is a difficult-to-treat condition characterized by long-lasting urticarial rashes and histopathologic findings of leukocytoclastic vasculitis. Treatment is dictated by the severity of skin and systemic involvement and the underlying systemic disease. This is a comprehensive systematic review of the efficacy of current UV treatment options. We searched for relevant studies in 7 databases, including MEDLINE, Scopus, and Web of Science. In total, 261 eligible studies and 789 unique patients with UV were included in the systematic review. Most patients with UV are adult women with chronic (≥6 weeks) and systemic disease. UV is mostly idiopathic but can be associated with drugs, malignancy, autoimmunity, and infections. It usually resolves with their withdrawal or cure. Corticosteroids are effective for the treatment of skin symptoms in more than 80% of patients with UV. However, their long-term administration can lead to potentially serious adverse effects. The addition of immunomodulatory or immunosuppressive agents often allows corticosteroid tapering and improves the efficacy of therapy. Biologicals, including omalizumab, as well as corticosteroids, cyclophosphamide, dapsone, mycophenolate mofetil, plasmapheresis, colchicine, hydroxychloroquine, intravenous immunoglobulin, nonsteroidal anti-inflammatory drugs, and cyclosporine, can be effective for both skin and systemic symptoms in patients with UV. H1-antihistamines, montelukast, danazol, H2-antihistamines, pentoxifylline, doxepin, and tranexamic acid are not effective in most patients with UV. As of yet, no drugs have been approved for UV, and management recommendations are based mostly on case reports and retrospective studies. Prospective studies investigating the effects of treatment on the signs and symptoms of UV are needed.
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Affiliation(s)
- Pavel Kolkhir
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology and Allergy, Allergie-Centrum-Charité, Berlin, Germany; I.M. Sechenov First Moscow State Medical University, Division of Immune-mediated skin diseases, Moscow, Russia
| | | | - Hanna Bonnekoh
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology and Allergy, Allergie-Centrum-Charité, Berlin, Germany
| | - Karoline Krause
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology and Allergy, Allergie-Centrum-Charité, Berlin, Germany
| | - Marcus Maurer
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Dermatology and Allergy, Allergie-Centrum-Charité, Berlin, Germany.
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20
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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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21
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Solomon SR, Sizemore CA, Ridgeway M, Zhang X, Brown S, Holland HK, Morris LE, Solh M, Bashey A. Safety and efficacy of rituximab-based first line treatment of chronic GVHD. Bone Marrow Transplant 2018; 54:1218-1226. [PMID: 30518977 DOI: 10.1038/s41409-018-0399-7] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2018] [Revised: 09/22/2018] [Accepted: 11/08/2018] [Indexed: 11/09/2022]
Abstract
Initial therapy of chronic GVHD (cGvHD) has not changed for over three decades, despite limited efficacy and long-term toxicity. We have previously shown in a small pilot study the feasibility of rituximab-based first-line therapy of cGVHD. To better assess safety and efficacy, we now evaluate 69 patients that received rituximab as part of their initial treatment. Median follow-up for surviving patients was 47 (11-81) months. Resolution of cGVHD occurred in 49 patients with median time to IST discontinuation of 349 (138-920) days. The cumulative incidence (CI) of cGHVD resolution was 41%, 69 and 77% at 1-, 2- and 3-years, respectively. No systemic corticosteroids were used in 27 patients, and 67% received ≤ 10 mg/kg cumulative exposure. Overall survival (OS) at 1-, 2- and 3-years following cGVHD diagnosis was 87, 79 and 77% respectively; corresponding rates of non-relapse mortality (NRM) were 10%, 16 and 19%. The probability of being alive and free of cGVHD at 1-, 2-, and 3-years was 36, 55, and 57% respectively. This study demonstrates the feasibility and efficacy of rituximab-based first-line cGVHD treatment. This approach demonstrates significant activity and avoids long courses of corticosteroids in most patients.
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Affiliation(s)
- Scott R Solomon
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA.
| | - Connie A Sizemore
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - Michelle Ridgeway
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - Xu Zhang
- The University of Texas, Health Science Center at Houston, Houston, TX, USA
| | - Stacey Brown
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - H Kent Holland
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - Lawrence E Morris
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - Melhem Solh
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
| | - Asad Bashey
- The Blood and Marrow Transplant Program at Northside Hospital, Atlanta, GA, USA
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22
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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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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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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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25
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Bunchorntavakul C, Mitrani R, Reddy KR. Advances in HCV and Cryoglobulinemic Vasculitis in the Era of DAAs: Are We at the End of the Road? J Clin Exp Hepatol 2018; 8:81-94. [PMID: 29743799 PMCID: PMC5938331 DOI: 10.1016/j.jceh.2017.11.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2017] [Accepted: 11/30/2017] [Indexed: 12/12/2022] Open
Abstract
Hepatitis C Virus (HCV)-related Mixed Cryoglobulinemia (MC) is a unique condition with complex pathogenesis that involves HCV antigen-driven B-lymphocyte clonal proliferation and mutagenesis. Clinical spectrum of MC ranges from asymptomatic state to clinically-apparent vasculitis involving multiple organs. In the era of Direct-Acting Antiviral (DAA) therapy, patients with HCV-related MC achieve high rates of viral clearance that is commonly accompanied by an improvement in clinical symptoms as well as immunological profiles. Rituximab, either alone or in combination with DAA, has also been shown to be effective. Nevertheless, there have been limited and somewhat conflicting data, particularly over the long-term, regarding the rate and degree of clinical response of MC following DAA therapy. It appears that we have come quite a long way in the last decade with this condition. As with non-MC related HCV, undoubtedly long term outcome data will be forthcoming over the next few years. As we move forward successful therapy of HCV is not likely to be a challenge in contrast to access to therapy.
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Affiliation(s)
- Chalermrat Bunchorntavakul
- Division of Gastroenterology and Hepatology, Department of Medicine, Rajavithi Hospital, College of Medicine, Rangsit University, Rajavithi Road, Ratchathewi, Bangkok 10400, Thailand
| | - Robert Mitrani
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
| | - K. Rajender Reddy
- Division of Gastroenterology and Hepatology, Department of Medicine, University of Pennsylvania, 2 Dulles, 3400 Spruce Street, Philadelphia, PA 19104, USA
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26
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Fabrizi F, Bruchfeld A, Mangano S, Dixit V, Messa P, Martin P. Interferon Therapy for HCV-Associated Glomerulonephritis: Meta-Analysis of Controlled Trials. Int J Artif Organs 2018; 30:212-9. [PMID: 17417760 DOI: 10.1177/039139880703000306] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
Abstract
Background A relationship between hepatitis C virus (HCV) infection and chronic glomerulonephritis (GN) has been asserted on the grounds of epidemiological and experimental data. Although this suggests a role for an antiviral approach to HCV-associated GN instead of the more conventional immunosuppressive (or supportive) therapy, the optimal management of HCV-related glomerulonephritis remains controversial. Objective To compare antiviral with immunosuppressive therapy for HCV-associated GN. Design Meta-analysis of controlled clinical trials (CCTs) of the two treatments (antiviral versus immunosuppressive) of HCV-associated GN. Methods We used the fixed or random effects model of DerSimonian and Laird, with heterogeneity and sensitivity analyses. The rate of proteinuria and serum creatinine decrease after therapy for HCV-associated GN were regarded as the most reliable outcome end-points. Results We identified six studies involving 145 unique patients with HCV-associated GN. Pooling of study results demonstrated that proteinuria decreased more commonly after IFN than corticosteroid therapy (OR 1.92 (95% CI, 0.39; 9.57), NS), P-test for heterogeneity, 0.06 (I2=52.9%). In a sensitivity analysis including only CCTs using standard IFN-doses, OR was 3.86 (95% CI, 1.44; 10.33, (P=0.007)), P-test for heterogeneity, 0.18 (I2=35.9%). No improvement of serum creatinine after IFN compared to immunosuppressive therapy was noted (OR, 0.59 (95% CI, 0.21; 1.65), NS), P-test for heterogeneity, 0.76 (I2=0%). Only three CCTs gave information on the rate of proteinuria decrease over follow-up (OR, 5.08 (95% CI, 0.69; 37.31), NS). A few major side effects were noted after IFN administration. Conclusions Our meta-analysis indicates that standard IFN-doses were more effective than immunosuppressive therapy in lowering proteinuria of patients with HCV-related glomerulonephritis. However, no significant improvement in serum creatinine was seen by IFN or steroid therapy across the studies. Also, information on proteinuria recurrence after the completion of antiviral therapy was not sufficient. Prospective, randomized trials based on combined antiviral therapy (pegylated IFN plus ribavirin) with adequate dose and follow-up are required to assess the efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis.
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Affiliation(s)
- F Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital, IRCCS, Via Commenda 15, 20122 Milan, Italy.
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Mathur P, Emmanuel B, Sneller M, Zhang X, Poonia B, Kottilil S. Recovery of hepatitis C specific T-cell responses after rituximab therapy in hepatitis C mixed cryoglobulinemic vasculitis. J Med Virol 2018; 90:936-941. [PMID: 29236302 DOI: 10.1002/jmv.25002] [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] [Received: 07/23/2017] [Accepted: 12/02/2017] [Indexed: 12/28/2022]
Abstract
Mixed cryoglobulinemic vasculitis is associated with monoclonal B cell expansion in patients with chronic hepatitis C (HCV) infection. B cell depletion therapy using rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from symptomatic disease. This study investigated whether B cell depletion therapy has an impact on activation of HCV-specific T cell phenotype and function. Nineteen patients with Hepatitis C mixed cryoglobulinemic vasculitis were treated with 4 cycles of rituximab (375 mg/m2 ) and variables were measured 6 months after therapy. Using flow cytometry and Enzyme-Linked Immunospot assay, the number of activated and tissue-like B cells and number of T cells expressing Programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and multiple cytokines were measured before and after rituximab therapy. B cell depletion therapy is associated with a significant (P < 0.0001) decline in peripheral T cells with exhaustive phenotype, from pre-therapy to post-therapy-of rituximab (mean ± standard error): CD4+ (16.9 ± 0.9% to 8.9 ± 1.0%) and CD8+ (6.8 ± 0.6% to 3.0 ± 0.5%) T cells expressing PD-1 and CD4+ (11.0 ± 1.0% to 6.1 ± 0.8%) and CD8+ (12.7 ± 0.7% to 6.4 ± 0.4%) T cells expressing TIM-3. In addition, there was a significantly higher percentage of peripheral CD8+ T cells responding to HCV peptide stimulation in vitro secreting IFN-γ (4.55 ± 0.3 to 9.6 ± 1.0 IFN-γ/106 PBMCs, P < 0.0001), and more than one cytokine (1.3 ± 0.1% to 3.8 ± 0.2%, P < 0.0001) after therapy compared to pre-therapy. B cell depletion therapy results in recovery of T cell exhaustion and function in patients with HCV cryoglobulinemic vasculitis.
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Affiliation(s)
- Poonam Mathur
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Benjamin Emmanuel
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Michael Sneller
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Xiaozhen Zhang
- Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
| | - Bhawna Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Shyamasundaran Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, Maryland.,Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland
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28
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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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29
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Ramos-Casals M, Zignego AL, Ferri C, Brito-Zerón P, Retamozo S, Casato M, Lamprecht P, Mangia A, Saadoun D, Tzioufas AG, Younossi ZM, Cacoub P. Evidence-based recommendations on the management of extrahepatic manifestations of chronic hepatitis C virus infection. J Hepatol 2017; 66:1282-1299. [PMID: 28219772 DOI: 10.1016/j.jhep.2017.02.010] [Citation(s) in RCA: 64] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 02/05/2017] [Accepted: 02/06/2017] [Indexed: 12/19/2022]
Affiliation(s)
- Manuel Ramos-Casals
- Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Barcelona, Spain; Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain; Department of Medicine, University of Barcelona, Barcelona, Spain.
| | - Anna Linda Zignego
- Interdepartmental Center MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Clodoveo Ferri
- Chair and Rheumatology Unit, Medical School, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico di Modena, Modena, Italy
| | - Pilar Brito-Zerón
- Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Barcelona, Spain; Department of Autoimmune Diseases, ICMiD, Hospital Clínic, Barcelona, Spain; Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA- Sanitas, Barcelona, Spain
| | - Soledad Retamozo
- Laboratory of Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Barcelona, Spain; Rheumatology Department, Hospital Privado Universitario de Córdoba, INSTITUTO DE INVESTIGACIONES EN CIENCIAS DE LA SALUD (INICSA), National Scientific and Technical Research Council, CONICET - CORDOBA - Argentina
| | - Milvia Casato
- Department of Clinical Immunology, Sapienza University of Rome, Italy
| | - Peter Lamprecht
- Department of Rheumatology & Vasculitis Center, University of Lübeck, Germany
| | - Alessandra Mangia
- Liver Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy
| | - David Saadoun
- Sorbonne Universités, UPMC Université Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 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
| | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, National and Kapodistrian University of Athens, Greece
| | - Zobair M Younossi
- Chairman, Department of Medicine, Inova Fairfax Medical Campus, Vice President for Research, Inova Health System, Professor of Medicine, VCU-Inova Campus, The Claude Moore Health Education and Research Center, Beatty Center for Integrated Research, Falls Church, VA, USA
| | - Patrice Cacoub
- Sorbonne Universités, UPMC Université Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 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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30
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Lauletta G, Russi S, Pavone F, Vacca A, Dammacco F. Direct-acting antiviral agents in the therapy of hepatitis C virus-related mixed cryoglobulinaemia: a single-centre experience. Arthritis Res Ther 2017; 19:74. [PMID: 28388935 PMCID: PMC5385046 DOI: 10.1186/s13075-017-1280-6] [Citation(s) in RCA: 49] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 03/09/2017] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND The efficacy and safety of direct-acting antiviral agents (DAAs) were evaluated in a cohort of prospectively enrolled patients with hepatitis C virus (HCV)-related mixed cryoglobulinaemia (MC), an immune complex-mediated vasculitis of small and medium vessels in which the pathogenetic role of HCV has been clearly established. METHODS Twenty-two patients received DAAs. Clinical and laboratory features were recorded at baseline, every 4 weeks until the end of treatment (EoT), and 12 weeks afterwards. Primary efficacy endpoints were (a) sustained virological response 12 weeks after therapy completion (SVR12), (b) regression of symptomatology (clinical response) and (c) cryoglobulin disappearance or cryocrit reduction ≥50% (immunological response). Complete response (CR) was defined as the occurrence of all three primary endpoints; partial response (PR) was defined as the occurrence of SVR12, with or without either immunological or clinical response; and no response was defined as missing the achievement of all three endpoints. RESULTS All patients reached SVR12. Compared with basal values, mean cryocrit values were significantly decreased at EoT and SVR12. A significant reduction of alanine transaminase and a parallel increase of complement component C4 levels were also detected. Rheumatoid factor activity was significantly reduced at EoT but not at SVR12. At SVR12, a CR was established in 14 patients (63.7%) and a PR in 8 patients (36.3%). In one patient with small lymphocytic lymphoma, the tumour progressed despite viral clearance. Mild adverse events were recorded in nine patients (40.9%). CONCLUSIONS The response rates induced by the use of DAAs in patients with MC were remarkably higher than those previously achieved with pegylated interferon-α/ribavirin, with or without rituximab. A much longer follow-up is desirable to achieve useful information in terms of persistent viral clearance and clinical response.
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Affiliation(s)
- Gianfranco Lauletta
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Piazza G. Cesare, 11-70124, Bari, Italy
| | - Sabino Russi
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Piazza G. Cesare, 11-70124, Bari, Italy
| | - Fabio Pavone
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Piazza G. Cesare, 11-70124, Bari, Italy
| | - Angelo Vacca
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Piazza G. Cesare, 11-70124, Bari, Italy
| | - Franco Dammacco
- Department of Biomedical Sciences and Human Oncology, University of Bari “Aldo Moro”, Piazza G. Cesare, 11-70124, Bari, Italy
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31
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Zignego AL, Ramos-Casals M, Ferri C, Saadoun D, Arcaini L, Roccatello D, Antonelli A, Desbois AC, Comarmond C, Gragnani L, Casato M, Lamprecht P, Mangia A, Tzioufas AG, Younossi ZM, Cacoub P. International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement. Autoimmun Rev 2017; 16:523-541. [PMID: 28286108 DOI: 10.1016/j.autrev.2017.03.004] [Citation(s) in RCA: 73] [Impact Index Per Article: 9.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 02/26/2017] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases. HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths. Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility.
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Affiliation(s)
- Anna Linda Zignego
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.
| | - Manuel Ramos-Casals
- Department of Autoimmune Diseases, ICMiD Josep Font Autoimmune Lab, CELLEX-IDIBAPS, Hospital Clinic, Barcelona, Spain
| | - Clodoveo Ferri
- Chair and Rheumatology Unit, Medical School, University of Modena and Reggio Emilia, Azienda Ospedaliero-Universitaria, Policlinico di Modena, 41124 Modena, Italy
| | - David Saadoun
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 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
| | - Luca Arcaini
- Department of Molecular Medicine, University of Pavia, Pavia, Italy
| | - Dario Roccatello
- Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Center of Research of Immunopathology and Rare Diseases, and Nephrology and Dialysis Unit, San G. Bosco Hospital and University of Turin, Italy
| | - Alessandro Antonelli
- Department of Clinical and Experimental Medicine, University of Pisa, Via Savi 10, Pisa 56126, Italy
| | - Anne Claire Desbois
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 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
| | - Cloe Comarmond
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 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
| | - Laura Gragnani
- Interdepartmental Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Milvia Casato
- Department of Clinical Medicine, Sapienza University of Rome, Viale dell'Università 37, 00185 Rome, Italy.
| | - Peter Lamprecht
- Klinik für Rheumatologie Oberarzt, Ratzeburger Allee 160 (Haus 40), 23538 Lübeck, Germany.
| | - Alessandra Mangia
- Liver Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy.
| | - Athanasios G Tzioufas
- Department of Pathophysiology, School of Medicine, University of Athens, 75 M. Asias st, Building 16, Room, 32 11527 Athens, Greece.
| | - Zobair M Younossi
- Center for Liver Diseases, Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA; Beatty Liver and Obesity Program, Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA
| | - Patrice Cacoub
- Sorbonne University, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 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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Emmanuel B, Sidique N, Zhang X, Poonia B, Sneller MC, Kottilil S. Decline of cellular activation in non-B cells after rituximab treatment in hepatitis C-associated mixed cryoglobulinemia vasculitis. J Viral Hepat 2017; 24:128-131. [PMID: 27666584 PMCID: PMC5733781 DOI: 10.1111/jvh.12618] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2016] [Accepted: 08/19/2016] [Indexed: 12/09/2022]
Abstract
Mixed cryoglobulinemic vasculitis is associated with the monoclonal expansion of pathognomonic B cells in chronic hepatitis C. Recently, treatment with B-cell depletion, including rituximab, a CD20 monoclonal antibody, has been successful in achieving remission from the active disease. We investigated whether B-cell depletion therapy has an impact on activation of non-B cells in the periphery. Results demonstrated that B-cell depletion therapy is associated with a statistically significant decline in activated T cells, from pretherapy to follow-up while on rituximab therapy: CD4+ CD38+ HLA-DR+ (DR+), CD8+ CD38, CD8+ CD38+ DR+, and CD8+ DR+. Birmingham Vasculitis Activity Score and cryoglobulin had a strong correlation coefficient (R) of 0.72 (P=.0005), while cryoglobulin showed moderate correlation with CD8+ DR+ (R=.61), CD3+ CD38+ DR+ (R=.57), CD3+ DR+ (R=.50), CD4+ CD38+ DR+ (R=.53), CD4+ DR+ (R=.52), and CD8+ CD38+ DR+ (R=.67). These results suggest B-cell expansion has a direct and indirect effect on the pathogenesis of Hepatitis C-associated mixed cryoglobulinemic vasculitis.
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Affiliation(s)
- B Emmanuel
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - N Sidique
- Laboratory of Immunoregulation, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - X Zhang
- Laboratory of Immunoregulation, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - B Poonia
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
| | - M C Sneller
- Laboratory of Immunoregulation, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
| | - S Kottilil
- Division of Clinical Care and Research, Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD, USA
- Laboratory of Immunoregulation, Department of Health and Human Services, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Abstract
Cryoglobulinemia is a systemic inflammatory syndrome that generally involves small-to-medium vessel vasculitis due to cryoglobulin-containing immune complexes. The therapeutic management of idiopathic cryoglobulinemic vasculitis has yet to be defined because no study has evaluated the best strategies. However, treatment of severe vasculitis is traditionally based on a combination of corticosteroids and immunosuppressants or plasmapheresis, and more recently rituximab. We report a case of 77-year-old female patient diagnosed with idiopathic cryoglobulinemia, treated successfully with 6 months prednisone tapering and 2 doses of rituximab (1 g each dose). After receiving the above-mentioned treatment, her creatinine went back to normal with resolution of proteinuria and hematuria, normalization of serum complements, and significant improvement in her clinical picture. We conclude that rituximab could be an effective treatment for idiopathic cryoglobulnemia.
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Berera S, Gomez A, Dholaria K, Arosemena LR, Ladino-Avellaneda MA, Barisoni L, Bhamidimarri KR. A Rare Case of Hepatitis C-Associated Cryoglobulinemic Duodenal Vasculitis. ACG Case Rep J 2016; 3:e134. [PMID: 27807586 PMCID: PMC5062685 DOI: 10.14309/crj.2016.107] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Accepted: 02/29/2016] [Indexed: 11/17/2022] Open
Abstract
Intestinal involvement of cryoglobulinemia is an uncommon manifestation and marker of severe vasculitis. We describe the case of a woman admitted to our service for management of acute renal failure and progressive gastrointestinal symptoms after initiating hepatitis C virus treatment with ribavirin and sofosbuvir 4 weeks prior. With an undetectable hepatitis C viral load and persistent symptoms despite hepatitis C virus therapy cessation, an upper endoscopy revealed duodenal sloughing, erythema, and bleeding, sparking suspicion for recurrence of cryoglobulinemic vasculitis.
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Affiliation(s)
- Shivali Berera
- Division of Gastroenterology, Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
| | - Alexandra Gomez
- Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
| | - Kevin Dholaria
- Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
| | - Leopoldo R. Arosemena
- Division of Hepatology, Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
| | - Marco A. Ladino-Avellaneda
- Divison of Nephrology, Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
| | - Laura Barisoni
- Department of Pathology, Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
| | - Kalyan R. Bhamidimarri
- Division of Hepatology, Department of Internal Medicine, University of Miami Miller School of Medicine, Jackson Memorial Hospital, Miami, FL
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Cacoub P, Comarmond C. New insights into HCV-related rheumatologic disorders: A review. J Adv Res 2016; 8:89-97. [PMID: 28149645 PMCID: PMC5272935 DOI: 10.1016/j.jare.2016.07.005] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Revised: 07/17/2016] [Accepted: 07/18/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infected patients are known to be exposed to major liver complications i.e. cirrhosis and hepatocellular carcinoma. In addition, many extrahepatic manifestations including rheumatologic disorders have been reported in up to two-third of HCV infected patients. These manifestations include frank auto-immune and rheumatic diseases (such as arthralgia, myalgia, arthritis, sicca syndrome and vasculitis) which may dominate the course of infection. Until recently, the standard of care of HCV has been the use of interferon-alpha based regimens, which not only had limited effectiveness in HCV cure but were poorly tolerated. In patients with rheumatic diseases interferon-based regimens may be problematic given their association with a wide variety of autoimmune toxicities. Recent therapeutic advances with new direct anti-HCV therapies (interferon-free) which are more effective and better tolerated, make screening for this comorbidity in patients with rheumatic disorders more important than ever. This review aimed to outline main HCV extrahepatic with a special focus on rheumatologic manifestations.
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Affiliation(s)
- Patrice Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 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
| | - Cloé Comarmond
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), F-75005 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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36
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Isnard Bagnis C, Cacoub P. Hepatitis C Therapy in Renal Patients: Who, How, When? Infect Dis Ther 2016; 5:313-27. [PMID: 27388502 PMCID: PMC5019972 DOI: 10.1007/s40121-016-0116-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Indexed: 02/07/2023] Open
Abstract
Renal patients are overexposed to hepatitis C virus (HCV) infection. Hepatitis C virus infection may induce renal disease, i.e., cryoglobulinemic membrano-proliferative glomerulopathy and non-cryoglobulinemic nephropathy. Hepatitis C virus impacts general outcomes in chronic kidney disease, dialysis or transplanted patients. Hepatitis C virus infection is now about to be only part of their medical history thanks to new direct acting antiviral drugs exhibiting as much as over 95% of sustained virological response. All HCV-infected patients potentially can receive the treatment. Control of the virus is associated with better outcomes in all cases, whatever the severity of the hepatic or renal disease. This article focuses on HCV-induced renal diseases, the reciprocal impact of HCV infection on the renal outcome and renal status in liver disease, use of new direct-acting antiviral drugs with dosage adaptations and the most recent safety data.
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Affiliation(s)
- Corinne Isnard Bagnis
- Department of Nephrology AP-HP, Groupe Hospitalier Pitié Salpêtrière, 75013, Paris, France. .,UPMC Univ Paris 06, Paris, France.
| | - Patrice Cacoub
- Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 75005, Paris, France.,INSERM, UMR_S 959, 75013, Paris, France.,Department of Internal Medicine and Clinical Immunology, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, 75013, Paris, France.,Sorbonne University, UPMC Univ Paris 06, UMR 7211, Paris, France
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Abstract
The use of B cell depletion as a mode of treatment for non-Hodgkin’s lymphoma was first utilized in 1997 when Rituximab, a chimeric human-mouse monoclonal antibody which has a high affinity to the CD20 antigen expressed on B cells, became available. Over 500 000 lymphoma patients have been treated worldwide with this drug and it has a good safety record. The notion that B cells might be critical to the development of rheumatoid arthritis led to the extension of the use of B cell depletion to this condition and a recent double blind controlled trial has shown very encouraging results. In addition, B cell depletion either using Rituximab alone, or in combination with cyclophosphamide and corticosteroids has also been reported to have been of great benefit in some patients with severe systemic lupus erythematosus albeit in open label studies. This review considers the mechanism of action of the drug, the clinical trials that have been reported, and tries to place its current use in patients with autoimmune rheumatic disease in context.
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Affiliation(s)
- S A Chambers
- Centre for Rheumatology, The Middlesex Hospital, University College, London, UK
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38
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Retamozo S, Gheitasi H, Quartuccio L, Kostov B, Corazza L, Bové A, Sisó-Almirall A, Gandía M, Ramos-Casals M, De Vita S, Brito-Zerón P. Cryoglobulinaemic vasculitis at diagnosis predicts mortality in primary Sjögren syndrome: analysis of 515 patients. Rheumatology (Oxford) 2016; 55:1443-51. [DOI: 10.1093/rheumatology/kew194] [Citation(s) in RCA: 40] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2015] [Indexed: 11/12/2022] Open
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The expanding spectrum of HCV-related cryoglobulinemic vasculitis: a narrative review. Clin Exp Med 2016; 16:233-42. [PMID: 26935415 DOI: 10.1007/s10238-016-0410-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2016] [Accepted: 02/10/2016] [Indexed: 02/06/2023]
Abstract
Cryoglobulinemic vasculitis (CV) is a small-to-medium-vessel vasculitis that appears in 10-15 % of patients chronically infected with hepatitis C virus (HCV). The classic symptom triad of CV, purpura/asthenia/arthralgia, is accompanied by clinical features that include glomerulonephritis, neuropathy, interstitial pneumonitis, and cardiomyopathy, ranging in their severity from mild to life threatening. The risk of developing non-Hodgkin lymphoma is also higher. The cumulative 10-year survival rate of CV patients is significantly lower than in the age- and sex-matched general population, with death typically caused by nephropathy, malignancies, liver involvement, and severe infections. Unfailing serological stigmata include both a cryoglobulin IgM fraction with rheumatoid factor activity and decreased complement C4 levels. On peripheral B cells, the expression of the CD81 B cell receptor is reduced while that of the CD19 receptor is increased. A monoclonal B cell lymphocytosis develops in almost one-third of patients. HCV-related proteins (but not HCV-RNA genomic sequences) can be detected on biopsy samples by immunofluorescence and immunohistochemistry and involve the vessel lumen, vessel walls, and the perivascular spaces of the skin, kidney, and peripheral nerves, supporting the pathogenetic role of HCV in the onset of a widespread microvasculitis. Based on the demonstration of HCV infection in the large majority of CV patients, a therapeutic regimen consisting of once-weekly pegylated interferon-α and the daily administration of ribavirin results in a sustained virologic response in ~50 % of patients. In those with refractory and relapsing disease, addition of the anti-CD20 monoclonal antibody rituximab has significantly increased the overall response rates. The extension to CV of latest-generation direct-acting antivirals, strikingly successful in non-CV HCV-positive patients, has yielded high complete response rates according to the few studies published thus far.
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Abstract
Patients with chronic hepatitis C virus (HCV) infection frequently present with extrahepatic manifestations covering a large spectrum, involving different organ systems leading to the concept of systemic HCV infection. These manifestations include autoimmune phenomena and frank autoimmune and/or rheumatic diseases and may dominate the course of chronic HCV infection. Chronic HCV infection causes liver inflammation affecting the development of hepatic diseases. HCV is also a lymphotropic virus that triggers B cells and promotes favorable conditions for B lymphocyte proliferation, including mixed cryoglobulinemia (MC) and MC vasculitis, which is the most prominent extrahepatic manifestation of chronic HCV infection. HCV may also promote a low-grade chronic systemic inflammation that may affect the development of some extrahepatic manifestations, particularly cardiovascular and cerebral vascular diseases. Recognition of extrahepatic symptoms of HCV infection could facilitate early diagnosis and treatment. The development of direct-acting antiviral agents (DDAs) has revolutionized HCV treatment. DDAs, as well as new B-cell-depleting or B-cell-modulating monoclonal antibodies, will expand the panorama of treatment options for HCV-related extrahepatic manifestations including cryoglobulinemic vasculitis. In this context, a proactive, integrated approach to HCV therapy should maximize the benefits of HCV therapy, even when liver disease is mild.
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Affiliation(s)
- E Rosenthal
- Service de Médecine Interne, Hôpital de l'Archet, CHU de Nice, Nice; Université de Nice-Sophia Antipolis, Nice, France COREVIH PACA EST, CHU de Nice, France
| | - P Cacoub
- Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), 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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Abstract
Chronic infection with the hepatitis C virus (HCV) is a major cause of liver disease worldwide and is also responsible for extrahepatic manifestations (EHMs) involving the skin, kidneys, salivary glands, eyes, thyroid, and immune system. Mixed cryoglobulinemia is the prototype EHM related to HCV infection. Although these HCV-related EHMs may contribute to significant rates of morbidity affecting patient's quality of life and survival, most of these complications can reverse after HCV eradication by interferon therapy. This notwithstanding, individual patients may have an irreversible injury in various organs that is not reversed by a cure of the HCV infection.
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Affiliation(s)
- Mauro Viganò
- Hepatology Division, Ospedale San Giuseppe, Università degli Studi di Milano, Via San Vittore 12, Milan 20122, Italy
| | - Massimo Colombo
- Division of Gastroenterology and Hepatology, "A. M. and A. Migliavacca" Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Università degli Studi di Milano, Via F. Sforza 35, Milan 20122, Italy.
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42
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Reynaud Q, Killian M, Robles A, Mounsef F, Camdessanché JP, Mariat C, Cathébras P. Le rituximab dans la vraie vie : revue d’utilisation du rituximab de 2010 à 2013 au CHU de Saint-Étienne. Rev Med Interne 2015; 36:800-12. [DOI: 10.1016/j.revmed.2015.06.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Revised: 05/03/2015] [Accepted: 06/05/2015] [Indexed: 12/13/2022]
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Visentini M, Tinelli C, Colantuono S, Monti M, Ludovisi S, Gragnani L, Mitrevski M, Ranieri J, Fognani E, Piluso A, Granata M, De Silvestri A, Scotti V, Mondelli MU, Zignego AL, Fiorilli M, Casato M. Efficacy of low-dose rituximab for the treatment of mixed cryoglobulinemia vasculitis: Phase II clinical trial and systematic review. Autoimmun Rev 2015; 14:889-96. [PMID: 26031898 DOI: 10.1016/j.autrev.2015.05.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 05/24/2015] [Indexed: 01/11/2023]
Abstract
OBJECTIVE To evaluate whether rituximab at a low dose of 250 mg/m(2) × 2 may be as effective as at higher dosages, most commonly 375 mg/m(2)×4, used in previous studies on the treatment of patients with refractory mixed cryoglobulinemia (MC) vasculitis associated with hepatitis C virus (HCV) infection. METHODS We conducted a phase 2, single-arm two-stage trial (EUDRACT n. 2008-000086-38) of low-dose rituximab in 52 patients with HCV-associated MC who were ineligible/intolerant or non-responder to antiviral therapy. The primary outcomes were response of vasculitis evaluated by the Birmingham Vasculitis Activity Score (BVAS) at months 3, 6 and 12, rate of relapses and time to relapse, and rate of adverse events. Our data were compared with those reported in 19 published studies selected among 291 reviewed in a literature search. RESULTS The cumulative response rate (complete and partial) at month 3 was 81% in our patients, and 86% in 208 patients from studies using high-dose rituximab. The relapse rate and median time to relapse were, respectively, 41% and 6 months in our study, and 32% and 7 months in high-dose studies. Treatment-related adverse events were 11.5% in our study and 19.9% in high-dose studies. None of these differences was statistically significant. CONCLUSION Rituximab at a low dosage of 250 mg/m(2) × 2 is as effective as at higher dosages for treating MC vasculitis. This low-dose regimen may improve the cost/benefit profile of rituximab therapy for MC.
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Affiliation(s)
- Marcella Visentini
- Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy.
| | - Carmine Tinelli
- Clinical Epidemiology and Biometric Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
| | | | - Monica Monti
- Research Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Firenze, Firenze, Italy
| | - Serena Ludovisi
- Infectious Diseases Research Laboratories, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
| | - Laura Gragnani
- Research Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Firenze, Firenze, Italy
| | - Milica Mitrevski
- Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
| | - Jessica Ranieri
- Research Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Firenze, Firenze, Italy
| | - Elisa Fognani
- Research Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Firenze, Firenze, Italy
| | - Alessia Piluso
- Research Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Firenze, Firenze, Italy
| | - Massimo Granata
- Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
| | - Annalisa De Silvestri
- Clinical Epidemiology and Biometric Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
| | - Valeria Scotti
- Clinical Epidemiology and Biometric Unit, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
| | - Mario U Mondelli
- Infectious Diseases Research Laboratories, IRCCS Policlinico S. Matteo Foundation, Pavia, Italy
| | - Anna Linda Zignego
- Research Center for Systemic Manifestations of Hepatitis Viruses, Department of Internal Medicine, University of Firenze, Firenze, Italy
| | - Massimo Fiorilli
- Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
| | - Milvia Casato
- Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy
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Basile U, Gragnani L, Piluso A, Gulli F, Urraro T, Dell'Abate MT, Torti E, Stasi C, Monti M, Rapaccini GL, Zignego AL. Assessment of free light chains in HCV-positive patients with mixed cryoglobulinaemia vasculitis undergoing rituximab treatment. Liver Int 2015; 35:2100-2107. [PMID: 25800731 DOI: 10.1111/liv.12829] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2014] [Accepted: 03/08/2015] [Indexed: 12/13/2022]
Abstract
BACKGROUND & AIMS Mixed cryoglobulinaemia (MC) is an HCV-related lymphoproliferative disorder characterized by the presence of circulating immune complexes called cryoglobulins. Treatment with anti-CD20 monoclonal antibody rituximab is proved to be very useful, especially in patients ineligible to interferon-based antiviral therapy. Recently, free light chain (FLC) κ/λ ratio and FLC patterns were associated with MC. The aim of this study was to evaluate changes in FLC-κ, FCL-λ, FLC ratio following rituximab treatment in patients with HCV-related MC and to correlate FLC-κ, FCL-λ and FLC ratio values with therapy response. PATIENTS AND METHODS We retrospectively enrolled 46 patients with HCV infection (26 females, 20 males), including 10 patients without signs/symptoms of MC-related vasculitis, 36 with MC vasculitis. Clinical and biological data were recorded at baseline and 6 months after RTX treatment. Nephelometric measurement of serum FLCs was taken. RESULTS The mean serum FLC-κ level and FLC ratio were significantly higher in patients with MC, compared to HCV patients without MC and to blood donors. An abnormal FLC ratio at baseline correlated with the presence of cryoglobulins, C4 consumption, higher RF level and higher vasculitis rate. To evaluate the predictive value of FLCs, patients with MC were divided into two groups according to RTX therapy outcome (responders and no/partial responders). Abnormal baseline FLC ratio was significantly associated with no/partial response. CONCLUSIONS RTX treatment in HCV-related MC induces a reduction in FLC-κ and RF levels. Moreover, pretreatment FLC ratio, which can be easily assessed by a routine test, may be useful to predict response to this expensive treatment for patients with HCV-related MC ineligible to IFN-based therapy.
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Affiliation(s)
- Umberto Basile
- Department of Laboratory Medicine of the Catholic University of the Sacred Heart, Rome, Italy
| | - Laura Gragnani
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Alessia Piluso
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Francesca Gulli
- Department of Laboratory Medicine of the Catholic University of the Sacred Heart, Rome, Italy
| | - Teresa Urraro
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maria T Dell'Abate
- Department of Laboratory Medicine of the Catholic University of the Sacred Heart, Rome, Italy
| | - Eleonora Torti
- Department of Laboratory Medicine of the Catholic University of the Sacred Heart, Rome, Italy
| | - Cristina Stasi
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Monica Monti
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | - Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MaSVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Quartuccio L, Zuliani F, Corazza L, Scaini P, Zani R, Lenzi M, Tavoni A, Sebastiani M, Baldovino S, Urraro T, Saccardo F, Sbreglia C, Mazzaro C, Pioltelli P, Fraticelli P, Filippini D, Gabrielli A, Perrella O, Scarpato S, Roccatello D, Zignego AL, Ferri C, Bombardieri S, Pietrogrande M, Monti G, Galli M, De Vita S. Retreatment regimen of rituximab monotherapy given at the relapse of severe HCV-related cryoglobulinemic vasculitis: Long-term follow up data of a randomized controlled multicentre study. J Autoimmun 2015; 63:88-93. [DOI: 10.1016/j.jaut.2015.07.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Revised: 07/17/2015] [Accepted: 07/23/2015] [Indexed: 11/25/2022]
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46
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Solomon SR, Sizemore CA, Ridgeway M, Zhang X, Smith J, Brown S, Holland HK, Morris LE, Bashey A. Corticosteroid-Free Primary Treatment of Chronic Extensive Graft-versus-Host Disease Incorporating Rituximab. Biol Blood Marrow Transplant 2015; 21:1576-82. [DOI: 10.1016/j.bbmt.2015.04.023] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2015] [Accepted: 04/27/2015] [Indexed: 11/17/2022]
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47
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Zignego AL, Gragnani L, Piluso A, Sebastiani M, Giuggioli D, Fallahi P, Antonelli A, Ferri C. Virus-driven autoimmunity and lymphoproliferation: the example of HCV infection. Expert Rev Clin Immunol 2015; 11:15-31. [PMID: 25534977 DOI: 10.1586/1744666x.2015.997214] [Citation(s) in RCA: 67] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.
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Affiliation(s)
- Anna Linda Zignego
- Center for Systemic Manifestations of Hepatitis Viruses (MASVE), Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
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Fabrizi F, Cresseri D, Fogazzi GB, Moroni G, Passerini P, Martin P, Messa P. Rituximab therapy for primary glomerulonephritis: Report on two cases. World J Clin Cases 2015; 3:736-742. [PMID: 26301235 PMCID: PMC4539414 DOI: 10.12998/wjcc.v3.i8.736] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/28/2014] [Revised: 12/30/2014] [Accepted: 06/19/2015] [Indexed: 02/05/2023] Open
Abstract
The evidence in the medical literature on the efficacy and safety of rituximab therapy for primary glomerulonephritis is limited and controversial. We describe two male Caucasian patients with rapidly progressive kidney failure due to primary proliferative glomerulonephritis. Both of them received high-dose intravenous corticosteroids and oral cyclophosphamide with limited benefit. The first patient (hepatitis C virus-negative mixed cryoglobulinemia) underwent plasma-exchange with intravenous immunoglobulins; he showed significant benefit on kidney function (he became dialysis independent with serum creatinine going back to 1.6 mg/dL) after one rituximab pulse even if urinary abnormalities were still present. No improvement in renal function or urinary changes occurred in the second patient. Both these individuals developed sepsis over the follow-up, the first patient died two months after rituximab therapy. This report is in keeping with the occurrence of severe infections after rituximab therapy in patients with renal impairment at baseline and concomitant high-dose steroids.
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Cordero-Coma M, Salazar-Méndez R, Yilmaz T. Treatment of severe non-infectious uveitis in high-risk conditions (Part 2): systemic infections; management and safety issues. Expert Opin Drug Saf 2015; 14:1353-71. [PMID: 26118392 DOI: 10.1517/14740338.2015.1061992] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Management of patients with severe immune-mediated uveitis requires the use of immunosuppressive (IS) drugs in selected cases. This may be particularly challenging in certain patients with associated conditions, which may increase the risk of side effects or modify guidelines for the use of such drugs. Chronic viral and mycobacterial infections in the setting of non-infectious uveitis create a number of diagnostic but also therapeutic dilemmas to clinicians because they can be exacerbated by IS therapies with detrimental effects. AREAS COVERED In this review, we will focus on very specific chronic infections that can be affected by IS therapies: human immunodeficiency virus infection, chronic hepatitis virus infection and tuberculosis. The main aim of this review is to provide an updated and comprehensive practical guide for practitioners regarding the therapeutic decision-making and management of patients with non-infectious uveitis affected by the aforementioned infectious conditions. EXPERT OPINION Clinicians should be aware of the risk of viral and mycobacterial reactivation of an underlying infection during IS therapy. However, most of these conditions do not represent an absolute contraindication if one were able to apply an appropriate prior screening and close monitoring of such therapy.
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Affiliation(s)
- Miguel Cordero-Coma
- a 1 University of León, Instituto Biomedicina (IBIOMED), University Hospital of León , León, Spain +34 654403609 ; +34 987 233322 ;
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Retamozo S, Brito-Zerón P, Ramos-Casals M. [Treatment of cryoglobulinemic vasculitis associated with hepatitis C virus infection]. Med Clin (Barc) 2015; 144:410-7. [PMID: 24787686 DOI: 10.1016/j.medcli.2014.02.023] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Revised: 02/13/2014] [Accepted: 02/27/2014] [Indexed: 10/25/2022]
Abstract
Cryoglobulinemia is a heterogeneous systemic autoimmune disease with a wide variety of causes, symptoms and outcomes, and different etiopathogenic pathways involved in the vasculitic organ damage. The discovery of the hepatitis C virus (HCV) in 1989 changed radically the focus of research of the so-called "essential" cryoglobulinemia. Cryoglobulins can be detected in 25-30% of patients with HCV, overwhelmingly representing mixed cryoglobulins. However, only 10-15% of patients present with cryoglobulinemic vasculitis, with a broad spectrum of symptoms including mild or life-threatening manifestations. Consequently, not all patients can be uniformly treated. The key therapeutic points in HCV+ patients with cryoglobulinemic vasculitis cover different aspects. The first is to treat the underlying cause of cryoglobulinemia whenever possible, hence the use of antiviral therapies must always be considered in these patients. An individualized diagnostic approach to assess the number of organs involved and the severity of organ involvement is also essential in the therapeutic planning. This complex clinical scenario leads to an equally complex therapeutic scenario. There are three main treatment strategies for HCV-associated cryoglobulinemic vasculitis: conventional immunosuppression, antiviral treatment and biological therapies. The most recent studies are suggesting a change from the classical therapeutic approach (monotherapeutic regimens) to combination/sequential regimens, including treatments targeting the virus and those directed against the induced autoimmune disease, with the aim of blocking the various etiopathogenic pathways involved.
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Affiliation(s)
- Soledad Retamozo
- Laboratorio de Enfermedades Autoinmunes Josep Font, Centro de Investigación Biomédica CELLEX-Institut d'Investigacions Biomèdiques August Pi i Sunyer (CELLEX-IDIBAPS), Servicio de Enfermedades Autoinmunes, Institut Clínic de Medicina i Dermatologia (ICMiD), Hospital Clínic, Barcelona. España
| | - Pilar Brito-Zerón
- Laboratorio de Enfermedades Autoinmunes Josep Font, Centro de Investigación Biomédica CELLEX-Institut d'Investigacions Biomèdiques August Pi i Sunyer (CELLEX-IDIBAPS), Servicio de Enfermedades Autoinmunes, Institut Clínic de Medicina i Dermatologia (ICMiD), Hospital Clínic, Barcelona. España
| | - Manuel Ramos-Casals
- Laboratorio de Enfermedades Autoinmunes Josep Font, Centro de Investigación Biomédica CELLEX-Institut d'Investigacions Biomèdiques August Pi i Sunyer (CELLEX-IDIBAPS), Servicio de Enfermedades Autoinmunes, Institut Clínic de Medicina i Dermatologia (ICMiD), Hospital Clínic, Barcelona. España.
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