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Kojima M, Shibata M, Tomita S, Ueda R, Kasai R, Yamamoto E, Ban A, Suzuki S, Maruyama S. Recurrent localized fever caused by cryoglobulinemic vasculitis following hemodialysis: A case report. CEN Case Rep 2025; 14:151-156. [PMID: 39102128 PMCID: PMC11958887 DOI: 10.1007/s13730-024-00923-w] [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: 05/20/2024] [Accepted: 07/29/2024] [Indexed: 08/06/2024] Open
Abstract
Post-dialysis fever is commonly reported in patients undergoing hemodialysis (HD). However, it is often challenging to identify the underlying cause owing to the wide variety of potential factors that can lead to fever. In this case, a 66-year-old Japanese man experienced recurrent fever after HD treatment. Initially, antibiotics were prescribed to treat pneumonia, but it was later discovered that the pneumonia was an alveolar hemorrhage caused by cryoglobulinemic vasculitis. It is believed that cryoglobulin was sensitized by cold exposure owing to the dialysate temperature, which resulted in fever being experienced only after HD. Although treatment for vasculitis required prednisolone and rituximab, simple plasma exchange and a dialysate temperature of 37.5 °C dramatically suppressed the occurrence of post-dialysis fever. Cryoglobulinemia should be considered as a potential cause of fever, as it may be a common occurrence in patients undergoing HD and could be overlooked as a possible cause of localized fever following HD treatment.
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Affiliation(s)
- Mitsuharu Kojima
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan.
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan.
| | - Maki Shibata
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Saori Tomita
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Reina Ueda
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Rina Kasai
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Eriko Yamamoto
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Ayako Ban
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Satoshi Suzuki
- Department of Nephrology, Kainan Hospital, Kainan Hospital Aichi Prefectural Welfare Federation of Agricultural Cooperatives, Yatomi, Aichi, 498-8502, Japan
| | - Shoichi Maruyama
- Department of Nephrology, Nagoya University Graduate School of Medicine, 65 Tsurumai-Cho, Showa-Ku, Nagoya, 466-8550, Japan
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Perricone C, Castellucci A, Cafaro G, Calvacchi S, Bruno L, Dal Pozzolo R, Tromby F, Colangelo A, Gerli R, Bartoloni E. Rational approach to the prescription of anti-rheumatic drugs in rheumatoid arthritis: a product leaflet-based strategy in Italy. Front Immunol 2024; 15:1398314. [PMID: 38979406 PMCID: PMC11228816 DOI: 10.3389/fimmu.2024.1398314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2024] [Accepted: 05/06/2024] [Indexed: 07/10/2024] Open
Abstract
The treatment of patients with rheumatoid arthritis (RA) has dramatically changed in the past 30 years. Currently, numerous conventional, biologic, and targeted synthetic DMARDs have been licensed and used following recommendations provided by international and national scientific societies. However, the availability of biosimilars and the increasing necessity of savings impacted on the local/national prescription of these drugs. The information provided by data sheet of every single drug is a decisive factor on the choice of a certain treatment merged with the patient's profile. Thus, our purpose was to construct a rational algorithm for the treatment strategy in RA according to costs and the product leaflet of the biologic and targeted-synthetic DMARDs currently licensed in Italy. We used the most recent available recommendations and then we performed a review of the literature considering all the factors that are known to influence drug safety/effectiveness. All these factors were considered in the context of the data sheets of currently available originators and biosimilars.
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Affiliation(s)
- Carlo Perricone
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Andrea Castellucci
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giacomo Cafaro
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Santina Calvacchi
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Lorenza Bruno
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Roberto Dal Pozzolo
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Francesco Tromby
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Anna Colangelo
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Roberto Gerli
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Elena Bartoloni
- Rheumatology, Department of Medicine and Surgery, University of Perugia, Perugia, Italy
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Mazzaro C, Adinolfi LE, Pozzato G, Nevola R, Zanier A, Serraino D, Andreone P, Fenoglio R, Sciascia S, Gattei V, Roccatello D. Extrahepatic Manifestations of Chronic HBV Infection and the Role of Antiviral Therapy. J Clin Med 2022; 11:6247. [PMID: 36362478 PMCID: PMC9657147 DOI: 10.3390/jcm11216247] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 09/27/2022] [Accepted: 10/12/2022] [Indexed: 08/30/2023] Open
Abstract
The hepatitis B virus (HBV) infection leads to chronic hepatitis, cirrhosis, and hepatocarcinoma. However, about 20% of patients experience extrahepatic manifestations such as polyarteritis nodosa, non-rheumatoid arthritis, non-Hodgkin lymphoma, cryoglobulinemic vasculitis, and glomerulonephritis. These influence the patient's morbidity, quality of life and mortality. The treatment of an HBV infection is based on nucleotide analogues (NAs) which are safe and effective for the suppression of HBV-DNA in almost 100% of cases. A few studies have shown that NAs induce a viral response and an improvement of extrahepatic diseases. There is a lack of a thorough analysis of the available treatments for extrahepatic HBV manifestations. In 90% to 100% of cases, the NAs stop the HBV replication, and they produce a clinical response in the majority of patients with mild to moderate extrahepatic signs/symptoms. Arthritis can definitely disappear after the HBV elimination and, in some cases, the HBV eradication following NAs therapy appears to improve the renal function in HBV-related nephropathies. Plasma exchange can be used in subjects who are suffering from the most aggressive forms of cryoglobulinemic vasculitis and glomerulonephritis, progressive peripheral neuropathy, and life-threatening cases, and this can be combined with glucocorticosteroids and antiviral agents. In selected refractory patients, the use of rituximab in conjunction with NAs therapy can be considered. The review provides an update on extrahepatic conditions that are linked to HBV and the impact of treating HBV with NAs.
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Affiliation(s)
- Cesare Mazzaro
- Clinical of Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Luigi Elio Adinolfi
- Unit Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, 80138 Naples, Italy
| | - Gabriele Pozzato
- Department of Clinical and Surgical Sciences, Maggiore Hospital University of Trieste, 34149 Trieste, Italy
| | - Riccardo Nevola
- Unit Internal Medicine, Department of Advanced Medical and Surgery Sciences, Luigi Vanvitelli University of Campania, 80138 Naples, Italy
| | - Ada Zanier
- Department of Internal Medicine, Pordenone General Hospital, 33170 Pordenone, Italy
| | - Diego Serraino
- Cancer Epidemiology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, 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
| | - Roberta Fenoglio
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) CMID-Nephrology and Dialysis Unit, San Giovanni Bosco Hub Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy
| | - Savino Sciascia
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) CMID-Nephrology and Dialysis Unit, San Giovanni Bosco Hub Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy
| | - Valter Gattei
- Clinical of Experimental Onco-Haematology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, 33081 Aviano, Italy
| | - Dario Roccatello
- University Center of Excellence on Nephrologic, Rheumatologic and Rare Diseases (ERK-Net, ERN-Reconnect and RITA-ERN Member) CMID-Nephrology and Dialysis Unit, San Giovanni Bosco Hub Hospital, Department of Clinical and Biological Sciences, University of Turin, 10154 Turin, Italy
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4
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Fenoglio R, Sciascia S, Rossi D, Naretto C, Alpa M, Roccatello D. Non HCV-Related Mixed Cryoglobulinemic Vasculitis With Biopsy-Proven Renal Involvement: The Effects of Rituximab. Front Med (Lausanne) 2022; 9:819320. [PMID: 35419372 PMCID: PMC8995745 DOI: 10.3389/fmed.2022.819320] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2021] [Accepted: 03/03/2022] [Indexed: 11/17/2022] Open
Abstract
In the countries where HCV infection is still endemic, about 90% of subjects with mixed cryoglobulinemia had previously been infected with HCV and about 80% are RNA positive. Remarkable results in severe HCV-related cryoglobulinemic vasculitis have been obtained with Rituximab. Details of the clinical characteristics and effective treatment of non HCV-related cryogloulinemic syndromes are presently lacking. This paper reports on a prospective single-Center open study aimed at evaluating the clinical presentation and effects of Rituximab administered alone in patients with severe non HCV-related cryoglobulinemic syndrome. The study group included 11 patients followed for at least 6 months. Three patients had type I cryoglobulinemia, 6 had type II and the remaining 2 patients had type III. Mean cryocrit was 2.5%. Four out of 11 patients had symptomatic sicca complex with anti-SSA (Ro)/anti SSB (La) antibodies. All 11 patients presented with biopsy-proven renal involvement, 4 out of 11 with leukocytoclastic vasculitis, and 8 with involvement of the peripheral nervous system. Renal biopsy revealed diffuse membranoproliferative glomerulonephritis (MPGN) in 9 out of 11 patients. Extracapillary proliferation and necrosis of the glomerular tuft was observed in 1 of these 9 cases. Interstitial nephritis together with mesangial expansion and capillary immune deposits were observed in 1 patient. Prevalent interstitial fibrosis and glomerular sclerosis were detected in the remaining case. Patients underwent treatment with rituximab alone. After 6 months we observed a remarkable improvement in the necrotizing skin ulcers and a substantial amelioration of the electrophysiological parameters of motor and sensory peripheral neuropathy. Improvement in both renal function (from 2.8 to 1.4 mg/dl, p < 0.001) and proteinuria (from 4.2 g/24 to 0.4 g/24 h, p < 0.001) was found in 10 out of 11 patients, while 1 could not be fully treated because of a severe infusion reaction and sudden development of anti-Rituximab antibodies. Good renal response was confirmed at the end of follow-up (38.4 months). Three patients had a relapse at 6, 12, and 48 months, respectively. In our cohort the administration of 4 once-weekly infusions of Rituximab followed by 2 more infusions after 1 and 2 months proved to be effective in the management of these rare patients.
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Affiliation(s)
- Roberta Fenoglio
- Nephrology and Dialysis Unit (The European Rare Kidney Disease Reference Network, The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, and the European Reference Network That Aims at Improving the Care of Patients With Rare Immunological Disorders), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
| | - Savino Sciascia
- Nephrology and Dialysis Unit (The European Rare Kidney Disease Reference Network, The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, and the European Reference Network That Aims at Improving the Care of Patients With Rare Immunological Disorders), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
| | - Daniela Rossi
- Nephrology and Dialysis Unit (The European Rare Kidney Disease Reference Network, The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, and the European Reference Network That Aims at Improving the Care of Patients With Rare Immunological Disorders), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
| | - Carla Naretto
- Nephrology and Dialysis Unit (The European Rare Kidney Disease Reference Network, The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, and the European Reference Network That Aims at Improving the Care of Patients With Rare Immunological Disorders), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
| | - Mirella Alpa
- Nephrology and Dialysis Unit (The European Rare Kidney Disease Reference Network, The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, and the European Reference Network That Aims at Improving the Care of Patients With Rare Immunological Disorders), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
| | - Dario Roccatello
- Nephrology and Dialysis Unit (The European Rare Kidney Disease Reference Network, The European Reference Network on Rare and Complex Connective Tissue and Musculoskeletal Diseases, and the European Reference Network That Aims at Improving the Care of Patients With Rare Immunological Disorders), Center of Research of Immunopathology and Rare Diseases- Coordinating Center of the Network for Rare Diseases of Piedmont and Aosta Valley, Department of Clinical and Biological Sciences, University of Turin and S. Giovanni Bosco Hub Hospital, Turin, Italy
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5
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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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Comarmond C, Cacoub P, Saadoun D. Treatment of chronic hepatitis C-associated cryoglobulinemia vasculitis at the era of direct-acting antivirals. Therap Adv Gastroenterol 2020; 13:1756284820942617. [PMID: 32782479 PMCID: PMC7383649 DOI: 10.1177/1756284820942617] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 06/12/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatitis C virus (HCV) infection is responsible for both hepatic and extrahepatic manifestations. Before the era of direct-acting antivirals (DAA), cryoglobulinemia was related to HCV infection in 70-90% of cases. Observed in 30% to 40% of patients with hepatitis C, mixed cryoglobulinemia is mainly asymptomatic. Conversely, symptomatic cryoglobulinemia vasculitis (CV) can occur in 5-10% of patients with HCV-associated cryoglobulinemia. CV is a small-vessel systemic vasculitis, and organ damage results from circulation and precipitation of cryoglobulins and complement activation. A wide range of clinical symptoms can be observed during CV, and manifestations are potentially life-threatening. The most frequent manifestations occurring in CV are cutaneous, with recurrent purpura, articular with joint pains, neurologic with peripheric neuropathy, and renal with membranoproliferative glomerulonephritis. DAA have drastically changed chronic HCV therapy. DAA induce sustained virological response (SVR) rates greater than 95%, and also improve extrahepatic manifestations such as CV. We review recent studies investigating the clinical and immune effects of DAA therapy on HCV-CV.
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Affiliation(s)
- Cloé Comarmond
- Sorbonne Université, Département de Médecine Interne et Immunologie Clinique, Paris, France, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence Maladies Auto-Immunes Systémiques Rares, Centre National de Référence Maladies Auto-Inflammatoires et Amylose Inflammatoire INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière
| | - Patrice Cacoub
- Sorbonne Université, Département de Médecine Interne et Immunologie Clinique, Paris, France, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Centre National de Référence Maladies Auto-Immunes Systémiques Rares, Centre National de Référence Maladies Auto-Inflammatoires et Amylose Inflammatoire INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hospitalier Pitié-Salpêtrière
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7
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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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8
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Sebastiani M, Milazzo L, Atzeni F, Vacchi C, Manfredi A, Quartuccio L, Scirè C, Gaeta GB, Lapadula G, Armignacco O, Tavio M, D'Angelo S, Meroni P, Bazzichi L, Grassi W, Mathieu A, Mastroianni C, Sagnelli E, Santantonio T, Foppa CU, Puoti M, Sarmati L, Airò P, Epis OM, Scrivo R, Gargiulo M, Riva A, Ciancio G, Zehender G, Taliani G, Meroni L, Sollima S, Sarzi-Puttini P, Galli M. Italian consensus recommendations for the management of hepatitis C infection in patients with rheumatoid arthritis. Mod Rheumatol 2019; 29:895-902. [PMID: 30582388 DOI: 10.1080/14397595.2018.1558918] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Objectives: The recent introduction of direct-acting antiviral agents (DAAs) which can eliminate Hepatitis C virus (HCV) had revolutionized the treatment of HCV infections also in a complex clinical setting such as the patients with rheumatoid arthritis (RA). HCV elimination is also opportune due to the availability of more efficient immunosuppressive drugs, whose effect on the course of HCV infection is largely unknown.Methods: Consensus process was endorsed by the Italian Society of Rheumatology (SIR) and the Italian Society of Infectious and Tropical Diseases (SIMIT) to review the available evidence and produce practical, hospital-wide recommendations. The consensus panel consisted of 18 infectious diseases consultants, 20 rheumatologists and one clinical epidemiologist, who used the criteria of the Oxford Centre for Evidence-based Medicine to assess the quality of the evidence and the strength of their recommendations.Results: A core-set of statements about management of patients with RA and infection by HCV have been developed to help clinicians in their clinical practice.Conclusions: A screening for HCV should be performed in all RA patients and it is mandatory before starting an immunosuppressive therapy. Finally, a DAA treatment should be considered in all HCV-infected patients.Significance and InnovationsHCV antibodies should be investigated at the time of diagnosis of RA and, in any case, before starting immunosuppressive therapy with disease-modifying antirheumatic drugs (DMARDs).HCV eradication with DAA should be attempted as soon as possible, depending on patient conditions allowing a continuous oral treatment lasting 8-12 weeksConventional and biological DMARDs are allowed in patients with HCV infection, but they should be used cautiously in presence of advanced liver disease.
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Affiliation(s)
- Marco Sebastiani
- Rheumatology Unit, Department of Medical and Surgical Science, University of Modena, Azienda Policlinico of Modena, Modena, Italy
| | - Laura Milazzo
- Infectious Diseases Unit, University of Milano, Luigi Sacco Hospital, Milan, Italy
| | - Fabiola Atzeni
- Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
| | - Caterina Vacchi
- Rheumatology Unit, Department of Medical and Surgical Science, University of Modena, Azienda Policlinico of Modena, Modena, Italy
| | - Andreina Manfredi
- Rheumatology Unit, Department of Medical and Surgical Science, University of Modena, Azienda Policlinico of Modena, Modena, Italy
| | - Luca Quartuccio
- Department of Medical and Biological Sciences, Rheumatology Clinic, University of Udine, Udine, Italy
| | - Carlo Scirè
- Epidemiology Unit, Italian Society for Rheumatology (SIR), Milan, Italy
| | - Giovanni Battista Gaeta
- Infectious Diseases and Viral Hepatitis Unit, Department of Internal and Specialistic Medicine, Second University of Naples, Naples, Italy
| | - Giovanni Lapadula
- Department of Medicine - Rheumatology Unit, Medical School, University of Bari, Bari, Italy
| | | | - Marcello Tavio
- Unit of Emerging and Immunosuppressed Infectious Diseases, Department of Gastroenterology and Transplantation, Azienda Ospedaliero-Universitaria "Ospedali Riuniti", Torrette Ancona, Italy
| | - Salvatore D'Angelo
- Rheumatology Department of Lucania, San Carlo Hospital of Potenza and Madonna delle Grazie Hospital of Matera, Potenza, Italy
| | - Pierluigi Meroni
- Division of Rheumatology, Department of Clinical Sciences and Community Health, Gaetano Pini Orthopedic Institute, University of Milan, Milan, Italy
| | - Laura Bazzichi
- Rheumatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Walter Grassi
- Department of Rheumatology, Università Politecnica delle Marche, Ospedale "C. Urbani", Jesi Ancona, Italy
| | - Alessandro Mathieu
- Rheumatology Unit, University Clinic and AOU of Cagliari, Cagliari, Italy
| | - Claudio Mastroianni
- Infectious Diseases Unit, Department Public Health and Infectious Disease, "Sapienza" University of Rome, Rome, Italy
| | - Evangelista Sagnelli
- Department of Mental Health and Public Medicine, Second University of Naples, Naples, Italy
| | | | - Caterina Uberti Foppa
- Department of Infectious Diseases, San Raffaele Scientific Institute, Università Vita-Salute, Milan, Italy
| | - Massimo Puoti
- Department of Infectious Diseases, AO Niguarda Ca' Granda, Milano, Italy
| | - Loredana Sarmati
- Clinical Infectious Diseases, Tor Vergata University, Rome, Italy
| | - Paolo Airò
- Rheumatology and Clinical Immunology Unit, Spedali Civili of Brescia, Brescia, Italy
| | | | - Rossana Scrivo
- Department of Internal Medicine and Medical Specialties-Rheumatology Unit, Sapienza University of Rome, Rome, Italy
| | - Miriam Gargiulo
- Third Department of Infectious Diseases- D. Cotugno Hospital- AORN dei Colli, Naple, Italy
| | - Agostino Riva
- Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
| | - Giovanni Ciancio
- Rheumatology Unit, Department of Medical Sciences, University of Ferrara and Sant'Anna University Hospital, Ferrara, Italy
| | | | - Gloria Taliani
- Infectious Diseases Unit, Department Public Health and Infectious Disease, "Sapienza" University of Rome, Rome, Italy
| | - Luca Meroni
- Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
| | | | | | - Massimo Galli
- Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
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KDIGO 2018 Clinical Practice Guideline for the Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C in Chronic Kidney Disease. Kidney Int Suppl (2011) 2018; 8:91-165. [PMID: 30675443 PMCID: PMC6336217 DOI: 10.1016/j.kisu.2018.06.001] [Citation(s) in RCA: 116] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
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Abstract
Cryoglobulinaemia refers to the serum presence of cryoglobulins, which are defined as immunoglobulins that precipitate at temperatures <37 °C. Type I cryoglobulinaemia consists of only one isotype or subclass of monoclonal immunoglobulin, whereas type II and type III are classified as mixed cryoglobulinaemia because they include immunoglobulin G (IgG) and IgM. Many lymphoproliferative, infectious and autoimmune disorders have been associated with mixed cryoglobulinaemia; however, hepatitis C virus (HCV) is the aetiologic agent in most patients. The underlying mechanism of the disorder is B cell lymphoproliferation and autoantibody production. Mixed cryoglobulinaemia can cause systemic vasculitis, with manifestations ranging from purpura, arthralgia and weakness to more serious lesions with skin ulcers, neurological and renal involvement. This Primer focuses on mixed cryoglobulinaemia, which has a variable course and a prognosis that is primarily influenced by vasculitis-associated multiorgan damage. In addition, the underlying associated disease in itself may cause considerable mortality and morbidity. Treatment of cryoglobulinaemic vasculitis should be modulated according to the underlying associated disease and the severity of organ involvement and relies on antiviral treatment (for HCV infection), immunosuppression and immunotherapy, particularly anti-CD20 B cell depletion therapies.
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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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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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13
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Abstract
Cryoglobulinemia is a distinct entity characterized by the presence of cryoglobulins in the serum. Cryoglobulins differ in their composition, which has an impact on the clinical presentation and the underlying disease that triggers cryoglobulin formation. Cryoglobulinemia is categorized into two main subgroups: type I, which is seen exclusively in clonal hematologic diseases, and type II/III, which is called mixed cryoglobulinemia and is seen in hepatitis C virus infection and systemic diseases such as B-cell lineage hematologic malignancies and connective tissue disorders. Clinical presentation is broad and varies between types but includes arthralgia, purpura, skin ulcers, glomerulonephritis, and peripheral neuropathy. Life-threatening manifestations can develop in a small proportion of patients. A full evaluation for the underlying cause is required, because each type requires a different kind of treatment, which should be tailored on the basis of disease severity, underlying disease, and prior therapies. Relapses can be frequent and can result in significant morbidity and cumulative organ impairment. We explore the spectrum of this heterogeneous disease by discussing the disease characteristics of 5 different patients.
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Sise ME, Bloom AK, Wisocky J, Lin MV, Gustafson JL, Lundquist AL, Steele D, Thiim M, Williams WW, Hashemi N, Kim AY, Thadhani R, Chung RT. Treatment of hepatitis C virus-associated mixed cryoglobulinemia with direct-acting antiviral agents. Hepatology 2016; 63:408-417. [PMID: 26474537 PMCID: PMC4718772 DOI: 10.1002/hep.28297] [Citation(s) in RCA: 190] [Impact Index Per Article: 21.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2015] [Accepted: 10/12/2015] [Indexed: 12/11/2022]
Abstract
UNLABELLED Hepatitis C virus (HCV) is the most common cause of mixed cryoglobulinemia syndrome (MCS). The efficacy and safety of all-oral direct-acting antiviral (DAA) therapy in HCV-associated MCS (HCV-MCS) is largely unknown. The authors studied case series of patients with HCV-MCS who were treated with sofosbuvir-based regimens and historical controls treated with pegylated interferon and ribavirin in a single health care network. HCV-MCS was defined by circulating cryoglobulin associated with systemic vasculitis symptoms. Renal involvement (n = 7) was established by kidney biopsy (n = 5) or by two or more of the following clinical findings: reduced kidney function, proteinuria, or hematuria with other causes excluded (n = 2). Twelve patients received DAA therapy between December 2013 and September 2014. Median age was 61 years, 58% were male, and 50% had cirrhosis. Median baseline serum creatinine was 0.97 mg/dL (range 0.7-2.47). Four patients received rituximab concurrent with DAA therapy. Sustained virological response rate at 12 weeks (SVR12) was 83% overall. Patients with glomerulonephritis who achieved SVR12 experienced an improvement in serum creatinine and a reduction in proteinuria. Cryoglobulin levels decreased in 89% of patients, with median percent decreasing from 1.5% to 0.5% and completely disappearing in four of nine cases who had cryoglobulins measured after treatment. Serious adverse events were infrequent (17%). In contrast, the historical cohort treated with pegylated interferon and ribavirin experienced only 10% SVR12, with 100% experiencing at least one adverse event and 50% experiencing premature discontinuation due to adverse events. CONCLUSION SVR12 rates for sofosbuvir-based DAA regimens in HCV-MCS were 83%, significantly higher than historical controls treated with pegylated interferon and ribavirin; patients with glomerulonephritis experienced improvement in renal function, including those not concomitantly treated with immunosuppression.
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Affiliation(s)
- Meghan E. Sise
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Allyson K. Bloom
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital
| | - Jessica Wisocky
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
| | - Ming V. Lin
- Division of Gastroenterology and Hepatology, Department of Medicine, Brigham and Women’s Hospital
| | - Jenna L. Gustafson
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
| | - Andrew L. Lundquist
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - David Steele
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Michael Thiim
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
| | - Winfred W. Williams
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Nikroo Hashemi
- Division of Gastroenterology and Hepatology, Department of Medicine, Brigham and Women’s Hospital
| | - Arthur Y. Kim
- Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital
| | - Ravi Thadhani
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital
| | - Raymond T. Chung
- Liver Center, Gastrointestinal Division, Department of Medicine, Massachusetts General Hospital
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15
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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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16
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Fabrizi F, Martin P, Cacoub P, Messa P, Donato FM. Treatment of hepatitis C-related kidney disease. Expert Opin Pharmacother 2015; 16:1815-27. [DOI: 10.1517/14656566.2015.1066333] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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17
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Lutalo PMK, D'Cruz DP. Biological drugs in ANCA-associated vasculitis. Int Immunopharmacol 2015; 27:209-12. [PMID: 25907243 DOI: 10.1016/j.intimp.2015.04.023] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2015] [Revised: 04/13/2015] [Accepted: 04/13/2015] [Indexed: 12/20/2022]
Abstract
The anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides granulomatosis with polyangiitis (GPA), eosinophilic granulomatosis with polyangiitis (EGPA) and microscopic polyangiitis (MPA) constitute a wide spectrum of clinical manifestations of systemic vasculitis which may range from limited disease to organ or life-threatening disease. The introduction of biologics for the management of severe ANCA-associated vasculitis and severe, relapsing disease refractory to conventional immunosuppressants, has significantly improved the clinical prognosis of these autoimmune disorders. Rituximab, an anti-CD20 monoclonal antibody is licenced for remission induction in severe GPA and MPA and the management of severe relapsing, refractory GPA and MPA. Belimumab, an anti-B lymphocyte stimulatory monoclonal antibody is in clinical trials for the management of the ANCA-associated vasculitis GPA. Mepolizumab and Omalizumab are biologics which have been reported to be efficacious in refractory asthma associated with EGPA. The role of anti-TNF therapy and T cell targeting drugs in ANCA-associated vasculitis is less clear due to limited study data. This review will summarise the clinical trials and clinical practice use of biologic treatment strategies for the management of ANCA-associated vasculitis.
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Affiliation(s)
- Pamela M K Lutalo
- Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
| | - David P D'Cruz
- Louise Coote Lupus Unit, Guy's and St Thomas' NHS Foundation Trust, Guy's Hospital, Great Maze Pond, London SE1 9RT, United Kingdom.
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18
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Cryoglobulinemic vasculitis and skin ulcers. Our therapeutic strategy and review of the literature. Semin Arthritis Rheum 2015; 44:518-526. [DOI: 10.1016/j.semarthrit.2014.10.004] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Revised: 10/07/2014] [Accepted: 10/10/2014] [Indexed: 02/06/2023]
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Fabrizi F, Dixit V, Messa P. Antiviral therapy of symptomatic HCV-associated mixed cryoglobulinemia: meta-analysis of clinical studies. J Med Virol 2013; 85:1019-27. [PMID: 23588727 DOI: 10.1002/jmv.23562] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/28/2013] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection may be associated with extra-hepatic illness including mixed cryoglobulinemia. Evidence on HCV-related mixed cryoglobulinemia in the non-transplantation setting exists even if its appropriate management remains unclear. The cornerstone of treatment for symptomatic HCV-associated mixed cryoglobulinemia is antiviral therapy but little is known about its activity. A systematic review of the literature with a meta-analysis of clinical studies was performed in order to assess efficacy and safety of combination antiviral therapy for symptomatic HCV-associated mixed cryoglobulinemia in non-immunosuppressed individuals. The random effects model of DerSimonian and Laird was used, with heterogeneity and sensitivity analyses. The primary outcome was sustained virological response (as a measure of efficacy), and the secondary outcome was the rate of patients stopping (or dose reducing) antiviral agents (as a measure of tolerability). Ten clinical studies (300 unique patients) were identified; the rate of baseline kidney involvement ranged between 4% and 39%. The summary estimate of frequency of sustained viral response was 0.42 with a 95% confidence interval (CI) of 0.31; 0.54 (random effects model). Significant heterogeneity occurred (P = 0.00001; I(2) = 77.6%). Stratified analysis showed higher efficacy in those studies using combination therapy with pegylated-than conventional IFN; the summary estimate of sustained viral response being 0.52 (95% CI, 0.40; 0.63) and 0.32 (95% CI, 0.15; 0.49), respectively. There was good association between viral and clinical response, weighted K 0.634 (95% CI, 0.455; 0.814), by a meta-analysis at individual level on a subset of reports (n = 3; 74 unique patients). The summary estimate of frequency of patients stopping (or dose reducing) antiviral agents was 0.15 (95% CI, 0.08; 0.21); no heterogeneity occurred (P = 0.05; I(2) = 51%). In summary, combination antiviral therapy (pegylated IFN plus ribavirin) gives satisfactory response in more than the half of patients with symptomatic mixed cryoglobulinemia associated with HCV. HCV-related mixed cryoglobulinemia is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed to evaluate efficacy and safety of antiviral therapy in non-immunosuppressed individuals.
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Affiliation(s)
- Fabrizio Fabrizi
- Division of Nephrology, Maggiore Hospital, IRCCS Foundation, Milan, Italy.
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20
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Affiliation(s)
- Franco Dammacco
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy.
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21
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Rituximab-based novel strategies for the treatment of immune-mediated glomerular diseases. Autoimmun Rev 2013; 12:854-9. [DOI: 10.1016/j.autrev.2012.09.002] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2012] [Indexed: 11/23/2022]
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Furst DE, Fleischman R, Kalden J, Kavanaugh A, Sieper J, Mease P, Smolen J, Breedveld F. Documentation of off-label use of biologics in Rheumatoid Arthritis. Ann Rheum Dis 2013; 72 Suppl 2:ii35-51. [PMID: 23532442 DOI: 10.1136/annrheumdis-2013-consensusapp] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
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23
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Antiviral therapy of symptomatic HCV-mixed cryoglobulinemia after liver transplant: case report and literature review. Int J Artif Organs 2013; 36:367-72. [PMID: 23446762 DOI: 10.5301/ijao.5000199] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/17/2012] [Indexed: 01/25/2023]
Abstract
Hepatitis C virus (HCV) infection may be associated with extra-hepatic illness including mixed cryoglobulinemia (MC). Consistent evidence exists on HCV-MC in the non-transplantation setting but information on HCV-related cryoglobulinemia after solid organ transplantation is limited, particularly after liver transplantation (LT). We report on a 48-year-old man who developed HCV-associated cryoglobulinemic vasculitis with recurrent hepatitis after liver transplant. One year after transplant for HCV-positive
cirrhosis, he presented severe cutaneous manifestations, and biopsy-proven cryoglobulinemic membrano-proliferative glomerulonephritis (MPGN). HCV RNA clearance occurred within a few weeks of antiviral therapy; sustained viral response (SVR) was obtained by one year of anti-HCV combination therapy (eight months of pegylated IFN/ribavirin and four months of standard IFN/ribavirin). SVR was linked to complete remission of skin, liver, and kidney abnormalities. Tolerance to the pegylated IFN/ribavirin regimen was not excellent due to the occurrence of lobar pneumonia with anemia; thus, peg-IFN was replaced by recombinant IFN, with a favorable outcome. Clinical and viral remission persisted over a 48-month follow-up. HCV-associated mixed cryoglobulinemia flareups following LT were successfully managed with combined antiviral therapy. HCV-related MC is uncommon in developed countries and this clearly hampers randomized controlled clinical trials aimed at evaluating the efficacy and safety of anti-HCV therapy after solid organ transplantation or in the non-transplantation setting.
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Fabrizi F, Fogazzi GB, Cresseri D, Passerini P, Martin P, Donato MF, Rumi MG, Messa P. Antiviral therapy for HCV-associated cryoglobulinemic glomerulonephritis: case report and review of the literature. Kidney Blood Press Res 2013; 35:687-93. [PMID: 23307115 DOI: 10.1159/000345515] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2012] [Accepted: 10/25/2012] [Indexed: 12/28/2022] Open
Abstract
We describe the case of a 51-year-old woman with HCV-associated cryoglobulinemic glomerulonephritis (GN). She presented mild deterioration of kidney function, non-nephrotic proteinuria, and active urinary sediment. Kidney biopsy showed features of membranoproliferative changes with some sclerosis. Sustained viral response (SVR) was obtained by 6 months of antiviral therapy (peg-IFN-α2a plus ribavirin). SVR was linked with improvement of kidney function and remission of proteinuria. Clinical and virological remission persists over a 25-month follow-up. This case report emphasizes efficacy and safety of antiviral treatment of HCV-associated glomerulonephritis--preliminary but encouraging results exist. We identified by systematic review of the literature 9 studies (156 unique patients); the pooled estimate of frequency of sustained virological response after IFN-based therapy was 0.49 (95% confidence interval, CI: 0.21, 0.77; p < 0.0005; random effects model). Heterogeneity was found (I(2) = 98.9%, p < 0.0001). Two possible regimens should be considered for the treatment of HCV-associated cryoglobulinemic GN according to the clinical presentation. Immunosuppressive therapy is recommended for HCV-related kidney disease having aggressive course, and recent evidence supports rituximab (RTX) use with a reduced exposure to corticosteroids. We identified six studies (66 unique patients) on RTX therapy for HCV-associated kidney disease; at the end of RTX therapy, the pooled estimate of the mean decrease in proteinuria was 1.4 g/24 h (95% CI: 0.75, 2.05, p < 0.001); The p test for heterogeneity gave a value of 0.94 (I(2) = 0). Several questions related to RTX use remain. HCV-induced GN is uncommon among CKD patients of developed countries, and this clearly hampers prospective controlled clinical trials aimed to evaluate efficacy and safety of antiviral or immunosuppressive therapy in this population.
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Affiliation(s)
- Fabrizio Fabrizi
- Division of Nephrology, Maggiore Hospital, IRCCS Foundation, Milan, Italy. fabrizi @ policlinico.mi.it
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Roccatello D. Novel diagnostic approaches and cost-benefit balance of treatment of immune-mediated and rare disease in the era of biologic drugs: lessons from the 15th Turin Congress on Immune Pathology and Orphan Disease. Autoimmun Rev 2012; 12:793-5. [PMID: 23219772 DOI: 10.1016/j.autrev.2012.11.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Fabrizi F, Plaisier E, Saadoun D, Martin P, Messa P, Cacoub P. Hepatitis C virus infection, mixed cryoglobulinemia, and kidney disease. Am J Kidney Dis 2012; 61:623-37. [PMID: 23102733 DOI: 10.1053/j.ajkd.2012.08.040] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2012] [Accepted: 08/28/2012] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) may instigate mixed cryoglobulinemia; the most significant accompanying kidney lesion is type I membranoproliferative glomerulonephritis, usually occurring in the context of type II mixed cryoglobulinemia. Additionally, recent data support a link between HCV infection and proteinuria in population-based studies, raising the possibility that kidney diseases associated with HCV may be more common than previously thought. A number of strategies have been used to treat HCV-related glomerulonephritis, including antiviral agents, immunosuppressive therapies such as corticosteroids and cytotoxic agents, and plasma exchange. Limited but encouraging data about the utility of antiviral treatment in the setting of HCV-associated glomerulonephritis exist, with one pooled analysis noting a sustained viral response of 42%, albeit with significant heterogeneity. Immunosuppressive therapy may be most useful for cryoglobulinemic kidney disease, with individualized approaches considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis based on the level of proteinuria and kidney failure. Of note, rituximab, a chimeric monoclonal antibody that blocks CD20 receptors on B cells, has been reported to be effective for the treatment of mixed cryoglobulinemia symptoms, including glomerulonephritis.
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Affiliation(s)
- Fabrizio Fabrizi
- Division of Nephrology, Maggiore Policlinico Hospital, IRCCS Foundation, Milano, Italy.
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27
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Fabrizi F. Hepatitis C virus, cryoglobulinemia, and kidney: novel evidence. SCIENTIFICA 2012; 2012:128382. [PMID: 24278667 PMCID: PMC3820459 DOI: 10.6064/2012/128382] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Accepted: 06/26/2012] [Indexed: 05/10/2023]
Abstract
Hepatitis C virus infection can lead to chronic active hepatitis, cirrhosis, and liver failure; however, it is also associated with a wide range of extra-hepatic complications. HCV is associated with a large spectrum of histopathological lesions in both native and transplanted kidneys, and it is increasingly recognized as an instigator of B cell lympho-proliferative disorders including mixed cryoglobulinemia. Mixed cyoglobulinemia is a systemic vasculitis primarily mediated by immune complexes; it is characterized by variable organ involvement including skin lesions, chronic hepatitis, glomerulonephritis, peripheral neuropathy, and arthralgias. The most frequent HCV-associated nephropathy is type I membranoproliferative glomerulonephritis, usually in the context of type II mixed cryoglobulinemia. Various approaches have been tried for the treatment of HCV-related glomerulonephritis, including immunosuppressive therapy (corticosteroids and cytotoxic agents), plasma exchange and antiviral agents. Data on the antiviral treatment of HCV-associated glomerulonephritis are not abundant but encouraging results have been provided. Immunosuppressive therapy is particularly recommended for cryoglobulinemic kidney disease. Recent evidence has been accumulated on rituximab therapy for HCV-related cryoglobulinemic glomerulonephritis exists but several questions related to its use remain unclear. Distinct approaches should be considered for the treatment of HCV-associated cryoglobulinemic glomerulonephritis according to the level of proteinuria and kidney failure.
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Affiliation(s)
- Fabrizio Fabrizi
- Division of Nephrology and Dialysis, Maggiore Hospital and IRCCS Foundation, Pad. Croff, Via Commenda 15, 20122 Milano, Italy
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Choudhry M, Rao N, Juneja R. Successful treatment of cryoglobulinaemia with rituximab. CASE REPORTS IN NEPHROLOGY AND UROLOGY 2012. [PMID: 23197959 PMCID: PMC3482085 DOI: 10.1159/000339400] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Cryoglobulinaemia is a systemic inflammatory condition characterised by immune complex-mediated small-to-medium-sized vasculitis. It has a wide variety of presentations ranging from bruising, neuropathy, and hepatosplenomegaly to acute renal failure. Mixed cryoglobulinaemia is the most common type and is strongly associated with hepatitis C. Management approaches include use of cyclophosphamide, prednisolone, and plasmapheresis, with differing views on alternative treatments in resistant cases. Rituximab has emerged as an attractive option in resistant cases on account of its potent immunosuppressive effects on B cells. We describe a case of type 2 mixed cryoglobulinaemia in association with non-Hodgkin's lymphoma resistant to standard treatments which responded well to rituximab. This case is remarkable as mixed cryoglobulinaemia associated with non-Hodgkin's lymphoma presenting with nephritis is unusual, and, contrary to the high rate of recurrence in lymphoma-related cryoglobulinaemia, our patient has not shown any recurrence over 24 months. This highlights an alternative treatment modality which can be used in patients not responsive to existing managements for this condition with benefits of minimal side effects and no oncogenetic potential.
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Affiliation(s)
- M Choudhry
- Department of Renal Medicine, Flinders Medical Centre, Bedford Park, S.A., Australia
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Affiliation(s)
- Megan A. Kinney
- Department of Dermatology; Wake Forest University School of Medicine; Winston-Salem; North Carolina; USA
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Lin KM, Lin JC, Tseng WY, Cheng TT. Rituximab-induced hepatitis C virus reactivation in rheumatoid arthritis. JOURNAL OF MICROBIOLOGY, IMMUNOLOGY, AND INFECTION = WEI MIAN YU GAN RAN ZA ZHI 2012; 46:65-7. [PMID: 22627098 DOI: 10.1016/j.jmii.2011.12.020] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2011] [Revised: 10/20/2011] [Accepted: 11/03/2011] [Indexed: 11/25/2022]
Abstract
The B-cell depletion agent rituximab (RTX) is used in lymphoma and rheumatoid arthritis (RA), and there have been several case reports of an RTX-induced reactivation of hepatitis C virus in patients with lymphoma. However, there have been no papers detailing hepatitis C virus reactivation after RTX therapy in a patient with RA. Here we report a case of RTX-induced hepatitis C virus reactivation in a patient with RA. Physicians should be aware that a close follow-up of liver function and viral load is mandatory after RTX therapy in patients with RA and concomitant hepatitis C.
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Affiliation(s)
- Ko-Ming Lin
- Division of Allergy and Immunology and Rheumatology, Chang Gung Memorial Hospital, Chia-yi, Taiwan
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31
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Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, Dörner T, Emery P, Fleischmann R, Gibofsky A, Kalden JR, Kavanaugh A, Kirkham B, Mease P, Sieper J, Singer NG, Smolen JS, Van Riel PLCM, Weisman MH, Winthrop K. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2011. Ann Rheum Dis 2012; 71 Suppl 2:i2-45. [PMID: 22460137 DOI: 10.1136/annrheumdis-2011-201036] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Affiliation(s)
- D E Furst
- Rheumatology Department, David Geffen School of Medicine, UCLA - RM 32-59, 1000 Veteran Avenue, Los Angeles, California 90025, USA.
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Ramanath V, Nistala R, Chaudhary K. Update on the role of rituximab in kidney diseases and transplant. Expert Opin Biol Ther 2011; 12:223-33. [DOI: 10.1517/14712598.2012.646984] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
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Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Baldovino S, Menegatti E, La Grotta R, Modena V. Intensive short-term treatment with rituximab, cyclophosphamide and methylprednisolone pulses induces remission in severe cases of SLE with nephritis and avoids further immunosuppressive maintenance therapy. Nephrol Dial Transplant 2011; 26:3987-3992. [DOI: 10.1093/ndt/gfr109] [Citation(s) in RCA: 49] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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Sciascia S, Naretto C, Rossi D, Bazzan M, Roccatello D. Treatment-induced downregulation of antiphospholipid antibodies: effect of rituximab alone on clinical and laboratory features of antiphospholipid syndrome. Lupus 2011; 20:1106-1108. [DOI: 10.1177/0961203311400115] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Affiliation(s)
- S Sciascia
- Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID), SC a Direzione Universitaria di Immunologia Clinica, Università di Torino, Turin, Italy
| | - C Naretto
- Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID), SC a Direzione Universitaria di Immunologia Clinica, Università di Torino, Turin, Italy
| | - D Rossi
- Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID), SC a Direzione Universitaria di Immunologia Clinica, Università di Torino, Turin, Italy
| | - M Bazzan
- SSD Ematologia, Dipartimento di Malattie Rare, Immunologiche, Ematologiche ed Immunoematologiche, Università di Torino, Turin, Italy
| | - D Roccatello
- Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID), SC a Direzione Universitaria di Immunologia Clinica, Università di Torino, Turin, Italy
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Visentini M, Ludovisi S, Petrarca A, Pulvirenti F, Zaramella M, Monti M, Conti V, Ranieri J, Colantuono S, Fognani E, Piluso A, Tinelli C, Zignego AL, Mondelli MU, Fiorilli M, Casato M. A phase II, single-arm multicenter study of low-dose rituximab for refractory mixed cryoglobulinemia secondary to hepatitis C virus infection. Autoimmun Rev 2011; 10:714-9. [DOI: 10.1016/j.autrev.2011.04.033] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Ferri C, Cacoub P, Mazzaro C, Roccatello D, Scaini P, Sebastiani M, Tavoni A, Zignego AL, De Vita S. Treatment with rituximab in patients with mixed cryoglobulinemia syndrome: results of multicenter cohort study and review of the literature. Autoimmun Rev 2011; 11:48-55. [PMID: 21821153 DOI: 10.1016/j.autrev.2011.07.005] [Citation(s) in RCA: 122] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2011] [Accepted: 07/19/2011] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Mixed cryoglobulinemia syndrome (MCs) is a systemic vasculitis characterized by multiple organ involvement due to the vascular deposition of immune-complexes, mainly the cryoglobulins. B-lymphocyte expansion represents the underlying pathological alteration frequently triggered by hepatitis C virus (HCV) infection. The treatment of MCs syndrome is generally based on antiviral drugs and/or immunosuppressors, among which rituximab, an anti-CD20 monoclonal antibody, has been usefully employed for both cutaneous and visceral MCs organ involvement. This multicenter study retrospectively evaluated the effects of rituximab in a large series of patients with active MCs. The observed results were compared to those emerging from the updated review of the literature on this topic. METHODS The study included 87 patients (male/female 19/68, mean age 62.3±11.4SD years, mean disease duration 9±6.2SD years, HCV infection in 92% of cases) with active cryoglobulinemic vasculitis evaluated before rituximab monotherapy and after 6-month follow-up by means of main clinico-serological parameters. A PubMed search up to May 31, 2011, was done to find published clinical studies, including case reports of MCs treated with rituximab. RESULTS A significant clinical improvement was observed in a relevant percentage of cases, regardless the presence/absence of associated HCV infection; namely, complete/partial remission of pre-treatment active manifestations was observed in 74% of skin purpuric lesions, up to 87% of non-healing vasculitic leg ulcers, and 44% of the peripheral neuropathy, mainly paresthesias (patient's visual analogical scale from 62±25 to 37±27; p≤.0001). Moreover, cryoglobulinemic nephropathy, observed in 38 patients, significantly improved in 95% of cases (serum creatinine from 1.8±1.1SD to 1.4±0.8SD mg/dl, p≤.0001; 24-hour proteinuria from 2.2±2.1SD to 0.9±1.7SD g/24h, p≤.0001), with complete remission in the 50%. Among 6 patients with complicating non-Hodgkin's B-cell lymphoma a complete or partial remission was observed in 5/6. A complete remission of abdominal vasculitis was also observed in one patient. These beneficial effects were mirrored by the improvement of cryoglobulinemic serological hallmarks, namely cryocrit and low complement C4, in half cases. The safety of rituximab was confirmed by the small number of side effects recorded during the 6-month follow-up. On the whole, the results of the present study are in keeping with those reported in 39 papers present in world literature, including a total of 279 MCs patients. CONCLUSIONS Rituximab may be regarded as useful and safe pathogenetic treatment of cryoglobulinemic vasculitis. The actual role of this drug should be definitely confirmed by randomized controlled trials, as well as its position in the therapeutical strategy, mainly with respect to antiviral treatment in HCV-associated MCs.
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Affiliation(s)
- C Ferri
- Rheumatology Unit, Department of Internal Medicine, University of Modena e Reggio Emilia, Medical School, Via del Pozzo 71, Modena, Italy.
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Roccatello D, Sciascia S, Rossi D, Alpa M, Naretto C, Russo A, Menegatti E, Baldovino S. Long-term effects of rituximab added to cyclophosphamide in refractory patients with vasculitis. Am J Nephrol 2011; 34:175-80. [PMID: 21757891 DOI: 10.1159/000329535] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2011] [Accepted: 05/19/2011] [Indexed: 11/19/2022]
Abstract
BACKGROUND Current therapies have changed systemic vasculitis from a disease with a high rate of mortality to a chronic curable condition. A limited percentage of patients either remains refractory to conventional treatment or experiences dose-limiting side effects. METHODS 11 patients (4 affected by idiopathic systemic microscopic polyangiitis, 5 by Wegener's granulomatosis, and 2 by Churg-Strauss syndrome) intolerant or refractory to conventional therapies including cyclophosphamide were enrolled. All patients received rituximab as a rescue therapy and were followed for 30-54 months. Following rituximab administration, immunosuppressive drugs were rapidly tapered and no immunosuppressive maintenance therapy was given. RESULTS Significant decreases in levels of serum creatinine, proteinuria, erythrocyte sedimentation rate, C-reactive protein, and ANCA titers were observed during the follow-up (at least 30 months after rituximab administration). Arthralgia and weakness rapidly disappeared in all patients. Out of 7 patients, 5 reported a decrease in the degree of paresthesia and in the electrophysiologic parameters. Six months after rituximab administration the mean dose of prednisone was 5.5 mg/day. CONCLUSION In this sample of patients with systemic vasculitis who were refractory or intolerant to more conventional treatment, rituximab proved to be safe and effective in a long-term follow-up, and showed steroid- and immunosuppressive-sparing effects allowing the persistence of long-lasting remissions without maintenance therapy.
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Affiliation(s)
- Dario Roccatello
- Dipartimento di Malattie Rare, Immunologiche, Ematologiche ed Immunoematologiche, Centro di Ricerche di Immunopatologia e Documentazione su Malattie Rare (CMID), Struttura Complessa a Direzione Universitaria di Immunologia Clinica, Ospedale Torino Nord Emergenza San G. Bosco ed Università di Torino, Italia. dario.roccatello @ unito.it
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Sandri AM, Elewa U, Poterucha JJ, Fervenza FC. Treatment of hepatitis C-mediated glomerular disease. Nephron Clin Pract 2011; 119:c121-9; discussion c129-30. [PMID: 21757949 DOI: 10.1159/000325220] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Chronic kidney disease (CKD) is becoming a major public health issue worldwide, mainly due to the increasing prevalence of hypertension, diabetes and aging population. Chronic hepatitis C virus (HCV) infection commonly involves the kidneys, can be a cause of CKD, and significantly impacts morbidity and mortality in these patients. Prompt recognition and knowledge of how to best manage these patients are essential in order to have a successful renal outcome. Patients with HCV and kidney involvement can often be managed with a specific combination of antiviral drugs, immunosuppressants, plasmapheresis, and newer monoclonal antibodies. However, no large randomized controlled trials have been conducted in this patient population, optimal management of HCV-mediated kidney diseases is not well defined, and treatment itself can be associated with significant toxicity in patients with CKD. This article reviews the recent literature, discusses the limitations of current therapies, as well as toxicity associated with treatment, and suggests future areas for research.
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Affiliation(s)
- Ana Maria Sandri
- Division of Infectious Diseases, Hospital São Lucas da PUCRS, Porto Alegre, Brazil
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Abstract
Retiform purpura consists of branching purpuric lesions caused by a complete blockage of blood flow in the dermal and subcutaneous vasculature. The differential diagnosis for retiform purpura is broad, including vasculitides of the small and medium vessels as well as microvascular occlusion due to thrombotic, infectious, and embolic phenomena. Determining the etiology of this important dermatologic sign can be a diagnostic challenge; however, an organized approach can improve the speed and accuracy of diagnosis and identify an effective treatment. This review focuses on early recognition, evaluation, and treatment of hospitalized patients with retiform purpura. Specifically, vasculitis, protein C and S deficiencies, heparin necrosis, warfarin necrosis, antiphospholipid antibody syndrome, disseminated intravascular coagulation, cryoglobulinemia, calciphylaxis, and cholesterol embolization syndrome will be discussed in detail. These conditions are commonly seen in consultative dermatology and can have multiorgan involvement, complicated laboratory evaluation, and long-term therapeutic implications.
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Affiliation(s)
- Ashley Wysong
- Department of Dermatology, Stanford University, Stanford, CA, USA
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Engel P, Gómez-Puerta JA, Ramos-Casals M, Lozano F, Bosch X. Therapeutic targeting of B cells for rheumatic autoimmune diseases. Pharmacol Rev 2011; 63:127-56. [PMID: 21245206 DOI: 10.1124/pr.109.002006] [Citation(s) in RCA: 77] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Autoreactive B cells are characterized by their ability to secrete autoantibodies directed against self-peptides. During the last decade, it has become increasingly apparent that B lymphocytes not only produce autoantibodies but also exert important regulatory roles independent of their function as antibody-producing cells. This is especially relevant in the context of autoimmunity, because autoreactive B cells have been shown to possess the ability to activate pathogenic T cells, to produce pro-inflammatory cytokines, and to promote the formation of tertiary lymphoid tissue in target organs. The production of monoclonal antibodies against B-cell-surface molecules has facilitated the characterization of several distinct B lymphocyte subsets. These cell-surface molecules have not only served as useful cell differentiation markers but have also helped to unravel the important biological functions of these cells. Some of these molecules, all of which are expressed on the cell surface, have proven to be effective therapeutic targets. In both animal models and in clinical assays, the efficient elimination of B lymphocytes has been shown to be useful in the treatment of rheumatoid arthritis and other autoimmune diseases. The treatment of most rheumatic autoimmune diseases relies mainly on the use of cytotoxic immunosuppressants and corticosteroids. Although this has resulted in improved disease survival, patients may nonetheless suffer severe adverse events and, in some cases, their relapse rate remains high. The increasing need for safer and more effective drugs along with burgeoning new insights into the pathogenesis of these disorders has fueled interest in biological agents; clinical trials involving the B-cell depletion agent rituximab have been especially promising. This article reviews the current knowledge of B-cell biology and pathogenesis as well as the modern therapeutic approaches for rheumatic autoimmune diseases focusing in particular on the targeting of B-cell-specific surface molecules and on the blocking of B-cell activation and survival.
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Affiliation(s)
- Pablo Engel
- Immunology Unit, Department of Cell Biology, Immunology and Neuroscience, Faculty of Medicine, University of Barcelona, Barcelona, Spain
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41
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Furst DE, Keystone EC, Braun J, Breedveld FC, Burmester GR, De Benedetti F, Dörner T, Emery P, Fleischmann R, Gibofsky A, Kalden JR, Kavanaugh A, Kirkham B, Mease P, Sieper J, Singer NG, Smolen JS, Van Riel PLCM, Weisman MH, Winthrop K. Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010. Ann Rheum Dis 2011; 70 Suppl 1:i2-36. [PMID: 21339216 DOI: 10.1136/ard.2010.146852] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- D E Furst
- David Geffen School of Medicine, UCLA-RM 32-59, 1000 Veteran Avenue, Los Angeles, CA 90025, USA.
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Abstract
The treatment of systemic necrotizing vasculitis has made great strides in both efficacy and outcomes. Standard therapies, however, are associated with numerous side effects, and not all patients will respond to conventional immunosuppression. These realities have prompted the search for safer and more efficacious treatments, most notably among biologic agents. For example, the role of TNF-α in the pathophysiology of several vasculitides has led to the investigation of targeted inhibitors of this cytokine, albeit with mixed results. There have been some disappointing results in the area of giant cell arteritis and Wegener's granulomatosis (granulomatosis with polygiitis), but anti-TNF therapy has shown promise in the treatment of Takayasu's arteritis, although additional trials to demonstrate its efficacy are required. Anti-B-cell therapy seems to be the most promising advance in the management of these diseases. Complete and partial responses have been seen in both primary and secondary mixed cryoglobulinemic vasculitis. Recent trials have demonstrated that rituximab is effective for the treatment of Wegener's granulomatosis and microscopic polyangiitis. These trials have, however, raised concerns regarding the long-term safety of these agents. The future holds promise for additional targeted therapies with improved patient response and fewer side effects.
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Affiliation(s)
- Charles F Henderson
- 5501 Hopkins Bayview Circle, JHAAC, Room 1B.1A, Johns Hopkins University Division of Rheumatology, MD 21224, USA
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Jacobson IM, Cacoub P, Dal Maso L, Harrison SA, Younossi ZM. Manifestations of chronic hepatitis C virus infection beyond the liver. Clin Gastroenterol Hepatol 2010; 8:1017-29. [PMID: 20870037 DOI: 10.1016/j.cgh.2010.08.026] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/07/2010] [Revised: 08/20/2010] [Accepted: 08/24/2010] [Indexed: 02/06/2023]
Abstract
In addition to its effects in the liver, chronic hepatitis C virus (HCV) infection can have serious consequences for other organ systems. Extrahepatic manifestations include mixed cryoglobulinemia (MC) vasculitis, lymphoproliferative disorders, renal disease, insulin resistance, type 2 diabetes, sicca syndrome, rheumatoid arthritis-like polyarthritis, and autoantibody production; reductions in quality of life involve fatigue, depression, and cognitive impairment. MC vasculitis, certain types of lymphoma, insulin resistance, and cognitive function appear to respond to anti-HCV therapy. However, treatments for HCV and other biopsychosocial factors can reduce quality of life and complicate management. HCV treatment has a high overall cost that increases when extrahepatic manifestations are considered. HCV appears to have a role in the pathogenesis of MC vasculitis, certain types of lymphoma, and insulin resistance. Clinicians who treat patients with HCV infections should be aware of potential extrahepatic manifestations and how these can impact and alter management of their patients.
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Affiliation(s)
- Ira M Jacobson
- Center for the Study of Hepatitis C, Joan and Sanford I. Weill Medical College of Cornell University, New York, New York 10021, USA.
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Mannu GS. An interesting rash: leucocytoclastic vasculitis with type 2 cryoglobulinaemia. JRSM SHORT REPORTS 2010; 1:54. [PMID: 21234117 PMCID: PMC2994356 DOI: 10.1258/shorts.2010.010070] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Wink F, Houtman PM, Jansen TLTA. Rituximab in cryoglobulinaemic vasculitis, evidence for its effectivity: a case report and review of literature. Clin Rheumatol 2010; 30:293-300. [PMID: 21053035 DOI: 10.1007/s10067-010-1612-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Revised: 10/12/2010] [Accepted: 10/20/2010] [Indexed: 01/13/2023]
Abstract
Cryoglobulinaemia associated with systemic vasculitis mediated by immune complexes is a rare combination. These immune complexes are composed of immunoglobulins and precipitate when exposed to cold temperature. Cryoglobulinaemic vasculitis, treated or untreated, may lead to substantial morbidity and even mortality. Novel targeted therapies may well provide new therapeutic options following or perhaps even prior to the classical cytotoxic therapies. Systemic B cell depletion with rituximab, a chimeric monoclonal antibody against CD20 antigen, is commonly applied in patients with non-Hodgkin's lymphoma or in refractory rheumatoid factor-positive rheumatoid arthritis. Since B cell clones are the source of cryoglobulins, therapeutic effectiveness of rituximab in cryoglobulinaemic vasculitis may be expected. We describe a 72-year-old woman with mixed cryoglobulinaemia type 2, who has successfully been treated with rituximab infusions after failing on prednisone and azathioprine. We reviewed the literature and found 142 cases of cryoglobulinaemic vasculitis, 138 mixed (type 2 or 3) and four, type 1. Rituximab was applied mostly after failure on other treatments. Significant reduction in levels of rheumatoid factor, cryoglobulins and IgM were reported after rituximab therapy. Of the total 142, cases 119 could be evaluated for the response on rituximab therapy, the other 23 cases only regarding side effects. Of the 119 evaluated patients, 71 (60%) had complete response; 28 (23%), partial response and 20 patients (17%), no response. Data were not blinded or placebo-controlled. Side effects were seen in 27 of the 142 patients. Occurrence of the side effects was associated with high baseline levels of cryoglobulins, with a high dose of rituximab infusion of 1,000 mg and with a high level of complement activation. Death was reported four times and was related with the disease.
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Affiliation(s)
- Freke Wink
- Department of Rheumatology, Medical Centre Leeuwarden, Leeuwarden, The Netherlands
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Hiura M, Onizuka R, Narita R, Abe S, Tabaru A, Harada M. A case of severe acute hepatitis C and delayed antibody production due to rituximab therapy. Clin J Gastroenterol 2010; 3:254-8. [PMID: 26190331 DOI: 10.1007/s12328-010-0171-z] [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] [Received: 12/25/2009] [Accepted: 08/06/2010] [Indexed: 11/29/2022]
Abstract
A 59-year-old male patient underwent surgical treatment for non-Hodgkin's lymphoma of the right scrotum in October 2007. He received a total of 4 courses of two different adjuvant chemotherapy regimens including rituximab from January to April 2008. In June 2008 he was hospitalized due to severe liver dysfunction with an alanine aminotransferase of 2039 IU/l and a prothrombin time of 23.3%. He was diagnosed with acute hepatitis C by the detection of hepatitis C virus (HCV) RNA and negative anti-HCV antibody, and his hepatic function improved with bed rest during hospitalization; however, the production of anti-HCV antibodies was not detected until January 2009. Severe liver dysfunction is uncommon among patients with acute hepatitis C, and the long window (8 months) between HCV infection and the development of anti-HCV antibodies observed in the present case may have been due, at least in part, to a B cell disorder caused by rituximab therapy. In addition to the well-known risk of reactivation of hepatitis B virus infection in patients undergoing chemotherapy, physicians should be aware of the potential effects of chemotherapy on the clinical course of HCV infection.
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Affiliation(s)
- Masaaki Hiura
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan.
| | - Ryo Onizuka
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Ryoichi Narita
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Shintaro Abe
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Akinari Tabaru
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
| | - Masaru Harada
- Third Department of Internal Medicine, University of Occupational and Environmental Health, Japan School of Medicine, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu, 807-8555, Japan
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Amador-Cañizares Y, Dueñas-Carrera S. Early interferon-based treatment after detection of persistent hepatitis C virus infection: a critical decision. J Interferon Cytokine Res 2010; 30:817-24. [PMID: 20836713 DOI: 10.1089/jir.2010.0013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Approximately 170 million people are infected with the hepatitis C virus (HCV) worldwide. Infection with this pathogen is persistent in more than 80% of cases, frequently developing severe forms of liver damage such as cirrhosis and hepatocellular carcinoma. No preventive vaccine is available against HCV, and current treatment based on the combination of pegylated interferon and ribavirin is effective in ∼55% of patients infected with genotype 1, the most prevalent genotype. This review analyzes several factors influencing the achievement of a sustained virological response, namely undetectable HCV RNA at 6 months after conclusion of therapy. Particularly, the relevant issue of age and duration of infection is discussed in detail. Indeed, the final decision for starting treatment should be a case-by-case point. However, the cost-benefit analysis seems to indicate that in patients who are motivated and without contraindications, starting the treatment as early as possible is probably the best choice for success.
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Affiliation(s)
- Yalena Amador-Cañizares
- Center for Genetic Engineering and Biotechnology , Hepatitis C Department, Vaccines Division, Havana, Cuba
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Essential mixed cryoglobulinemia type III with leukocytoclastic vasculitis: remission by rituximab. Clin Rheumatol 2010; 32 Suppl 1:S19-20. [DOI: 10.1007/s10067-010-1412-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2010] [Revised: 02/03/2010] [Accepted: 02/17/2010] [Indexed: 01/06/2023]
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49
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Abstract
Cryoglobulins are serum immunoglobulins that precipitate at temperatures below 37 degrees C and re-dissolve on warming. Cryoglobulinaemia leads to variable symptoms including characteristic purpura, ischaemia of extremities, renal failure, peripheral neuropathy, abdominal pain secondary to intestinal ischaemia and arthralgias. Cryoglobulin testing is underutilized in clinical practice. It has been neglected in clinical laboratories and by clinicians due to several factors, such as the length of time it takes for serum cryoglobulin analysis to be performed in the laboratory, the perceived difficulty in getting optimal sampling conditions and a failure to appreciate that even apparently low levels of cryoglobulin can be associated with severe symptoms in some patients. The most important variable confounding standardization of cryoglobulin testing is improper sample handling. A recent report critically appraising the current practice of cryoglobulin evaluation in 137 laboratories in Europe by United Kingdom National External Quality Assurance Scheme (UKNEQAS) illustrated the wide variability in practice. Although many clinical laboratories perform cryoglobulin evaluation, there are widespread differences in the methodology used and the care with which this is carried out and this leads to considerable intralaboratory and interlaboratory variability. The most common sources of error are false-negative results due to loss of cryoprecipitate during transport and storage. Better standardization is needed to avoid missed diagnoses and improve the comparability of results. Laboratories should ensure that sample temperature is maintained at 37 degrees C until the serum is separated. In this article, we briefly review the classification and clinical features of cryoglobulins and suggest best practice guidelines for laboratory detection and identification of cryoglobulins.
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Affiliation(s)
- Ravishankar Sargur
- Clinical Immunology Unit, Department of Immunology, Northern General Hospital, Herries Road, Sheffield S5 8YD, UK.
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Perosa F, Prete M, Racanelli V, Dammacco F. CD20-depleting therapy in autoimmune diseases: from basic research to the clinic. J Intern Med 2010; 267:260-77. [PMID: 20201920 DOI: 10.1111/j.1365-2796.2009.02207.x] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The B lymphocyte-associated antigen CD20 is becoming an important immunotherapy target for autoimmune diseases, although its biological function has not been defined. Besides rheumatoid arthritis, growing experience with B cell-depleting therapy indicates that it may be effective in Sjögren's syndrome, dermatomyositis-polymyositis, systemic lupus erythematosus and some types of vasculitides. However, controlled clinical trials are still lacking for some of these indications. Infection has not been seen as a major limitation to this therapy, but reports of progressive multifocal leukoencephalopathy in an extremely small number of patients are of concern. Here, we review the therapeutic actions of anti-CD20 antibodies, and the recent and ongoing clinical trials with CD20-depleting therapy in autoimmune diseases.
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Affiliation(s)
- F Perosa
- Department of Internal Medicine and Clinical Oncology (DIMO), University of Bari Medical School, I-70124Bari, Italy.
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