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Holle JU, Kubacki T, Aries P, Hellmich B, Kernder A, Kneitz C, Lamprecht P, Schirmer JH, Schreiber A, Berlit P, Bley TA, Blödt S, Decker L, de Groot K, Engel S, Jordans I, Frye B, Haubitz M, Holl-Ulrich K, Kötter I, Laudien M, Milger-Kneidinger K, Muche-Borowski C, Müller-Ladner U, Neß T, Nölle B, Reinhold-Keller E, Ruffer N, Scheuermann K, Venhoff N, von Vietinghoff S, Wiech T, Zänker M, Moosig F. [Diagnosis and treatment of ANCA-associated vasculitis : S3 guideline of the German Society for Rheumatology and Clinical Immunology e. V. (DGRh) and German Society for Internal Medicine e. V. (DGIM), German Society for Nephrology e. V. (DGfN), German Society for ENT Medicine and Head and Neck Surgery e. V. (DGHNO-KHC), German Ophthalmological Society e. V. (DOG), German Society for Neurology e. V. (DGN), German Society for Pneumology and Respiratory Medicine e. V. (DGP), German Society for Pathology e. V. (DGP), German Radiological Society, Society for Medical Radiology e. V. (DRG), Federal Association of German Pathologists, Federal Kidney Association e. V., German Rheumatism League Federal Association e. V.]. Z Rheumatol 2025; 84:1-49. [PMID: 40178542 DOI: 10.1007/s00393-024-01597-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/25/2024] [Indexed: 04/05/2025]
Affiliation(s)
- J U Holle
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster/Kiel, Deutschland.
| | - T Kubacki
- Klinik für Innere Medizin II-Nephrologie, Rheumatologie, Diabetologie u. Allg. Innere Medizin, Universitätsklinikum Köln, Köln, Deutschland
| | - P Aries
- Immunologikum Hamburg, Hamburg, Deutschland
| | - B Hellmich
- Klinik für Innere Medizin, Rheumatologie, Pneumologie, Nephrologie, Medius Kliniken Nürtingen/Esslingen, Deutschland
| | - A Kernder
- Rheumazentrum Ruhrgebiet Herne, Ruhr-Universität Bochum, Bochum, Deutschland
| | - C Kneitz
- Rheumatologische Praxisgemeinschaft, Schwerin, Deutschland
| | - P Lamprecht
- Klinik für Rheumatologie und Klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Deutschland
| | - J H Schirmer
- Klinik für Innere Medizin I, Sektion Rheumatologie und klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - A Schreiber
- Medizinische Klinik, Schwerpunkt Nephrologie, Charité Universitätsmedizin, Berlin, Deutschland
| | - P Berlit
- Deutsche Gesellschaft für Neurologie
| | - T A Bley
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | | | - L Decker
- Medizinisches Versorgungszentrum HNO Dormagen, Rheinland Klinikum, Dormagen, Deutschland
| | - K de Groot
- Klinik für Nephrologie und Rheumatologie, Sana Kliniken Offenbach, Offenbach, Deutschland
| | - S Engel
- Deutsche Rheuma-Liga Bundesverband e. V
| | | | - B Frye
- Department Innere Medizin, Klinik für Pneumologie, Universitätsklinikum Freiburg, Freiburg, Deutschland
| | - M Haubitz
- Medizinische Klinik III (Nephrologie), Klinikum Fulda, Fulda, Deutschland
| | - K Holl-Ulrich
- Konsultations- und Referenzzentrum für Vaskulitisdiagnostik, Labor Lademannbogen, Hamburg, Deutschland
| | - I Kötter
- III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
- Klinik für Rheumatologie und Immunologie, Klinikum Bad Bramstedt, Bad Bramstedt, Deutschland
| | - M Laudien
- Klinik für HNO-Heilkunde, Kopf- und Halschirurgie, Christian-Albrechts-Universität zu Kiel, Kiel, Deutschland
- Deutsche Gesellschaft für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie e. V., Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - K Milger-Kneidinger
- Medizinische Klinik und Poliklinik V, Ludwig-Maximilians-Universität München, München, Deutschland
| | | | - U Müller-Ladner
- Abteilung für Rheumatologie und Klinische Immunologie, Justus-Liebig-Universität, Gießen, Campus Kerckhoff, Bad Nauheim, Deutschland
| | - T Neß
- Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Freiburg, Deutschland
| | - B Nölle
- Klinik für Ophthalmologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | | | - N Ruffer
- III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
- Arbeitsgemeinschaft Junge Rheumatologie, Deutsche Gesellschaft für Rheumatologie e. V., Berlin, Deutschland
| | | | - N Venhoff
- Klinik für Rheumatologie und Klinische Immunologie, Vaskulitis-Zentrum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Deutschland
| | - S von Vietinghoff
- Medizinische Klinik und Poliklinik I, Sektion für Nephrologie, Universitätsklinikum Bonn und Universität Bonn, Bonn, Deutschland
| | - T Wiech
- Institut für Pathologie, Sektion Nephropathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - M Zänker
- Klinik für Innere Medizin, Rheumatologie, Nephrologie, Immanuel Klinikum Bernau, Medizinische Hochschule Brandenburg, Deutschland
| | - F Moosig
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster/Kiel, Deutschland
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Holle JU, Kubacki T, Aries P, Hellmich B, Kernder A, Kneitz C, Lamprecht P, Schirmer JH, Schreiber A, Berlit P, Bley TA, Blödt S, Decker L, de Groot K, Engel S, Jordans I, Frye B, Haubitz M, Holl-Ulrich K, Kötter I, Laudien M, Milger-Kneidinger K, Muche-Borowski C, Müller-Ladner U, Neß T, Nölle B, Reinhold-Keller E, Ruffer N, Scheuermann K, Venhoff N, von Vietinghoff S, Wiech T, Zänker M, Moosig F. [Diagnosis and treatment of ANCA-associated vasculitis : SHORT VERSION of the S3 guideline of the German Society for Rheumatology and Clinical Immunology e. V. (DGRh) and German Society for Internal Medicine e. V. (DGIM), German Society for Nephrology e. V. (DGfN), German Society for Otorhinolaryngology and Head and Neck Surgery e. V. (DGHNO-KHC), German Ophthalmological Society e. V. (DOG), German Society for Neurology e. V. (DGN), German Society for Pneumology and Respiratory Medicine e. V. (DGP), German Society for Pathology e. V. (DGP), German Radiological Society, Society for Medical Radiology e. V. (DRG), Federal Association of German Pathologists, Federal Kidney Association e. V., German Rheumatism League Federal Association e. V.]. Z Rheumatol 2025; 84:225-251. [PMID: 40172651 DOI: 10.1007/s00393-024-01596-7] [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] [Accepted: 10/21/2024] [Indexed: 04/04/2025]
Abstract
Vasculitis associated with anti-neutrophil cytoplasmic antibodies (ANCA) is a rare disease with a potentially severe course. Affected patients should be diagnosed as quickly as possible and given suitable treatment according to the current study situation. Considerable progress has been made in the treatment of this disease in recent years, so that a largely evidence-based therapy with immunosuppressants and biologics is now possible. The guideline on the diagnosis and treatment of ANCA-associated vasculitis was raised from S1 level (2017) to S3 level. This guideline is the first German guideline on the diagnosis and treatment of ANCA-associated vasculitis at S3 level.
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Affiliation(s)
- J U Holle
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster/Kiel, Deutschland.
| | - T Kubacki
- Klinik für Innere Medizin II-Nephrologie, Rheumatologie, Diabetologie u. Allg. Innere Medizin, Universitätsklinikum Köln, Köln, Deutschland
| | - P Aries
- Immunologikum Hamburg, Hamburg, Deutschland
| | - B Hellmich
- Klinik für Innere Medizin, Rheumatologie, Pneumologie, Nephrologie, Medius Kliniken Nürtingen/Esslingen, Deutschland
| | - A Kernder
- Rheumazentrum Ruhrgebiet Herne, Ruhr-Universität Bochum, Bochum, Deutschland
| | - C Kneitz
- Rheumatologische Praxisgemeinschaft, Schwerin, Deutschland
| | - P Lamprecht
- Klinik für Rheumatologie und Klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Deutschland
| | - J H Schirmer
- Klinik für Innere Medizin I, Sektion Rheumatologie und klinische Immunologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - A Schreiber
- Medizinische Klinik, Schwerpunkt Nephrologie, Charité Universitätsmedizin, Berlin, Deutschland
| | - P Berlit
- Deutsche Gesellschaft für Neurologie
| | - T A Bley
- Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Würzburg, Würzburg, Deutschland
| | | | - L Decker
- Medizinisches Versorgungszentrum HNO Dormagen, Rheinland Klinikum, Dormagen, Deutschland
| | - K de Groot
- Klinik für Nephrologie und Rheumatologie, Sana Kliniken Offenbach, Offenbach, Deutschland
| | - S Engel
- Deutsche Rheuma-Liga Bundesverband e. V
| | | | - B Frye
- Department Innere Medizin, Klinik für Pneumologie, Universitätsklinikum Freiburg, Freiburg, Deutschland
| | - M Haubitz
- Medizinische Klinik III (Nephrologie), Klinikum Fulda, Fulda, Deutschland
| | - K Holl-Ulrich
- Konsultations- und Referenzzentrum für Vaskulitisdiagnostik, Labor Lademannbogen, Hamburg, Deutschland
| | - I Kötter
- III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
- Klinik für Rheumatologie und Immunologie, Klinikum Bad Bramstedt, Bad Bramstedt, Deutschland
| | - M Laudien
- Klinik für HNO-Heilkunde, Kopf- und Halschirurgie, Christian-Albrechts-Universität zu Kiel, Kiel, Deutschland
- Deutsche Gesellschaft für Hals-Nasen-Ohrenheilkunde, Kopf- und Halschirurgie e. V., Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | - K Milger-Kneidinger
- Medizinische Klinik und Poliklinik V, Ludwig-Maximilians-Universität München, München, Deutschland
| | | | - U Müller-Ladner
- Abteilung für Rheumatologie und Klinische Immunologie, Justus-Liebig-Universität, Gießen, Campus Kerckhoff, Bad Nauheim, Deutschland
| | - T Neß
- Klinik für Augenheilkunde, Universitätsklinikum Freiburg, Freiburg, Deutschland
| | - B Nölle
- Klinik für Ophthalmologie, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Kiel, Deutschland
| | | | - N Ruffer
- III. Medizinische Klinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
- Arbeitsgemeinschaft Junge Rheumatologie, Deutsche Gesellschaft für Rheumatologie e. V., Berlin, Deutschland
| | | | - N Venhoff
- Klinik für Rheumatologie und Klinische Immunologie, Vaskulitis-Zentrum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Deutschland
| | - S von Vietinghoff
- Medizinische Klinik und Poliklinik I, Sektion für Nephrologie, Universitätsklinikum Bonn und Universität Bonn, Bonn, Deutschland
| | - T Wiech
- Institut für Pathologie, Sektion Nephropathologie, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Deutschland
| | - M Zänker
- Klinik für Innere Medizin, Rheumatologie, Nephrologie, Immanuel Klinikum Bernau, Medizinische Hochschule Brandenburg, Deutschland
| | - F Moosig
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster/Kiel, Deutschland
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Morales E, Rúa-Figueroa I, Callejas Rubio JL, Ávila Bernabéu A, Blanco Alonso R, Cid Xutgla MC, Fernández Juárez G, Mena-Vázquez N, Ríos Blanco JJ, Manrique Escola J, Narváez García FJ, Sopeña B, Quintana Porras LF, Romero-Yuste S, Solans Laqué R. Recommendations for the diagnosis and treatment of anti-neutrophil cytoplasmic autoantibody associated vasculitis. Nefrologia 2025; 45:15-58. [PMID: 39855968 DOI: 10.1016/j.nefroe.2025.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Accepted: 07/30/2024] [Indexed: 01/27/2025] Open
Abstract
Anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis is characterised by small vessel necrotising inflammatory vasculitis. Prior to immunosupressant therapy availability it usually led to a fatal outcome. Current treatment has changed ANCA-associated vasculitis into a condition with a significant response rate, although with a not negligible relapse occurrence and cumulative organ lesions, mostly due to drug-related toxicities. The use of glucocorticoids, cyclophosphamide and other immunosupressants (such as azathioprine, mychophenolate and methotrexate) was optimised in a series of clinical trials that established the treatment of reference. In recent years, a better knowledge of B lymphocyte function and the role of complement inhibition has transformed the course of this disease while minimising treatment-related adverse effects. This multidisciplinary document of recommendations is based on the consensus of three scientific societies (Internal Medicine, Nephrology and Rheumatology) and on the best available evidence on diagnosis, treatment and follow-up of patients with ANCA-associated vasculitis, including some special situations. The aim of this document is to provide updated information and well-grounded clinical recommendations to practising physicians as to how to improve the diagnosis and treatment outcome of our patients.
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Affiliation(s)
- Enrique Morales
- Servicio de Nefrología, Hospital Universitario 12 de Octubre, Instituto de investigación i + 12 de Hospital 12 de Octubre, Departamento de Medicina de la Universidad Complutense de Madrid, Madrid, Spain.
| | - Iñigo Rúa-Figueroa
- Servicio de Reumatología, Hospital de Gran Canaria Doctor Negrín, Las Palmas, Spain
| | - José Luis Callejas Rubio
- Unidad de Enfermedades Sistémicas, Servicio de Medicina Interna, Hospital Universitario Clínico San Cecilio, Granada, Spain
| | - Ana Ávila Bernabéu
- Servicio de Nefrología, Hospital Universitario Doctor Peset, Valencia, Spain
| | - Ricardo Blanco Alonso
- Servicio de Reumatología, Hospital Universitario Marqués de Valdecilla, IDIVAL, Santander, Spain
| | - María C Cid Xutgla
- Servicio de Enfermedades Autoinmunes, Hospital Clínic, Universidad de Barcelona, IDIBAPS, Barcelona, Spain
| | | | - Natalia Mena-Vázquez
- UGC de Reumatología, Instituto de Investigación Biomédica de Málaga (IBIMA)-Plataforma Bionand, Hospital Regional Universitario de Málaga, Málaga, Spain
| | - Juan José Ríos Blanco
- Unidad de Enfermedades Autoinmunes, Servicio de Medicina Interna, Hospital Universitario La Paz, Instituto de Investigación Sanitaria del Hospital Universitario La Paz (IdiPAZ), Madrid, Spain
| | | | | | - Bernardo Sopeña
- Unidad de Enfermedades Autoinmunes Sistémicas, Servicio de Medicina Interna, Hospital Clínico Universitario de Santiago, Facultad de Medicina, Santiago de Compostela, Spain
| | - Luis F Quintana Porras
- CSUR Enfermedad Glomerular Compleja, Servicio de Nefrología y Trasplante Renal, Hospital Clinic, Universidad de Barcelona, Barcelona, Spain
| | - Susana Romero-Yuste
- Servicio de Reumatología, Complexo Hospitalario Universitario de Pontevedra, Pontevedra, Spain
| | - Roser Solans Laqué
- Unidad de Enfermedades Sistémicas Autoinmunes, Departamento de Medicina Interna, Hospital Universitario Vall d'Hebron, Barcelona, Spain
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Madan U, Goel V, Shah J, Ahmad H, Cassol C, Edrees A. Granulomatosis with polyangiitis with rapidly progressive glomerulonephritis treated with a multipronged approach-a case based review. CEN Case Rep 2024:10.1007/s13730-024-00959-y. [PMID: 39704740 DOI: 10.1007/s13730-024-00959-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Accepted: 11/23/2024] [Indexed: 12/21/2024] Open
Abstract
Granulomatosis with polyangiitis is an ANCA-associated vasculitis that involves small to medium-sized vessels. The extent of renal involvement varies, which is also associated with disease prognosis, with aggressive renal involvement having worse outcomes. Rapidly progressive glomerulonephritis with severe inflammatory features and extensive crescent formation can be challenging to treat. Usually, induction regimes utilize a combination of pulse dose methylprednisolone followed by rituximab or cyclophosphamide. Resistant diseases pose additional treatment challenges, and individualized treatment regimens have been described without accumulated outcome data. Cyclophosphamide, rituximab, azathioprine, methotrexate, and mycophenolate with or without plasmapheresis have been variably used, but there is a lack of consensus on a standardized regime in literature. Our case adds to the existing literature on the treatment-refractory granulomatosis with polyangiitis, which was treated with high-dose corticosteroid in combination with rituximab, low-dose cyclophosphamide, plasmapheresis, and brief use of hemodialysis. It also reiterates that the use of a variety of low-dose cyclophosphamide with rituximab could be beneficial for treatment-refractory cases or patients with severe renal involvement, in addition to better tolerance with low dose cyclophosphamide in comparison with full-dose cyclophosphamide.
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Affiliation(s)
- Ujjwal Madan
- Division of Internal Medicine, University of Missouri, Kansas City, MO, 64108, USA.
| | - Vishesh Goel
- Division of Internal Medicine, Lady Hardinge Medical College, New Delhi, 110001, India
| | - Jignesh Shah
- Division of Nephrology, University of Missouri, Kansas City, MO, 64108, USA
| | - Hameed Ahmad
- Division of Nephrology, University of Missouri, Kansas City, MO, 64108, USA
| | - Clarissa Cassol
- Nephropathologist, Arkana Laboratories, Little Rock, AR, 72211, USA
| | - Amr Edrees
- Division of Rheumatology, University of Missouri, Kansas City, MO, 64108, USA
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Hellmich B, Sanchez-Alamo B, Schirmer JH, Berti A, Blockmans D, Cid MC, Holle JU, Hollinger N, Karadag O, Kronbichler A, Little MA, Luqmani RA, Mahr A, Merkel PA, Mohammad AJ, Monti S, Mukhtyar CB, Musial J, Price-Kuehne F, Segelmark M, Teng YKO, Terrier B, Tomasson G, Vaglio A, Vassilopoulos D, Verhoeven P, Jayne D. EULAR recommendations for the management of ANCA-associated vasculitis: 2022 update. Ann Rheum Dis 2024; 83:30-47. [PMID: 36927642 DOI: 10.1136/ard-2022-223764] [Citation(s) in RCA: 227] [Impact Index Per Article: 227.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Accepted: 02/21/2023] [Indexed: 03/18/2023]
Abstract
BACKGROUND Since the publication of the EULAR recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in 2016, several randomised clinical trials have been published that have the potential to change clinical care and support the need for an update. METHODS Using EULAR standardised operating procedures, the EULAR task force undertook a systematic literature review and sought opinion from 20 experts from 16 countries. We modified existing recommendations and created new recommendations. RESULTS Four overarching principles and 17 recommendations were formulated. We recommend biopsies and ANCA testing to assist in establishing a diagnosis of AAV. For remission induction in life-threatening or organ-threatening AAV, we recommend a combination of high-dose glucocorticoids (GCs) in combination with either rituximab or cyclophosphamide. We recommend tapering of the GC dose to a target of 5 mg prednisolone equivalent/day within 4-5 months. Avacopan may be considered as part of a strategy to reduce exposure to GC in granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Plasma exchange may be considered in patients with rapidly progressive glomerulonephritis. For remission maintenance of GPA/MPA, we recommend rituximab. In patients with relapsing or refractory eosinophilic GPA, we recommend the use of mepolizumab. Azathioprine and methotrexate are alternatives to biologics for remission maintenance in AAV. CONCLUSIONS In the light of recent advancements, these recommendations provide updated guidance on AAV management. As substantial data gaps still exist, informed decision-making between physicians and patients remains of key relevance.
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Affiliation(s)
- Bernhard Hellmich
- Klinik für Innere Medizin, Rheumatologie und Immunologie, Medius Kliniken, Akademisches Lehrkrankenhaus der Universität Tübingen, Kirchheim unter Teck, Germany
| | | | - Jan H Schirmer
- Rheumatology & Clinical Immunology and Cluster of Excellence Precision Medicine in Chronic Inflammation, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Alvise Berti
- CIBIO, Universita degli Studi di Trento, Trento, Italy
- Rheumatology, Santa Chiara Hospital, Trento, Italy
| | - Daniel Blockmans
- Department of Internal Medicine, University Hospital of Leuven, Leuven, Belgium
| | - Maria C Cid
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Julia U Holle
- Rheumazentrum Schleswig-Holstein Mitte, Neumuenster, Germany
| | - Nicole Hollinger
- Klinik für Innere Medizin, Rheumatologie und Immunologie, Medius Kliniken, Akademisches Lehrkrankenhaus der Universität Tübingen, Kirchheim unter Teck, Germany
| | - Omer Karadag
- Division of Rheumatology, Department of Internal Medicine, Vasculitis Research Center, Hacettepe University School of Medicine, Anakra, Turkey
| | - Andreas Kronbichler
- Department of Internal Medicine IV, Medical University, Innsbruck, Austria
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Mark A Little
- Trinity Health Kidney Centre, Trinity College Dublin, Dublin, Ireland
| | - Raashid A Luqmani
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Science (NDORMs), University of Oxford, Oxford, UK
| | - Alfred Mahr
- Klinik für Rheumatologie, Kantonspital St Gallen, St Gallen, Switzerland
| | - Peter A Merkel
- Division of Rheumatology, Department of Medicine, Division of Epidemiology, Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Aladdin J Mohammad
- Department of Medicine, University of Cambridge, Cambridge, UK
- Department of Clinical Sciences, Lund University & Department of Rheumatology, Skåne Hospital, Lund, Sweden
| | - Sara Monti
- Department of Internal Medicine and Therapeutics, Università di Pavia, Pavia, Italy
- Division of Rheumatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
| | - Chetan B Mukhtyar
- Vasculitis Service, Rheumatology Department, Norfolk and Norwich University Hospital NHS Trust, Norwich, UK
| | - Jacek Musial
- 2nd Department of Internal Medicine, Jagiellonian University Medical College, Kraków, Poland
| | | | - Mårten Segelmark
- Division of Nephrology, Department of Clinical Sciences, Lund University, Skane University Hospital, Lund, Sweden
| | - Y K Onno Teng
- Centre of Expertise for Lupus-, Vasculitis-, and Complement-Mediated Systemic Autoimmune Diseases (LuVaCs), Department of Internal Medicine, Section Nephrology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Benjamin Terrier
- National Referral Center for Rare Systemic Autoimmune Diseases, Université Paris Descartes, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France
| | - Gunnar Tomasson
- Department of Epidemiology and Biostatistics, Faculty of Medicine, University of Iceland, Reykjavik, Iceland
- Department of Rheumatology and Centre for Rheumatology Research, University Hospital Reykjavik, Reykjavik, Iceland
| | - Augusto Vaglio
- Nephrology Unit, Meyer Children's Hospital, and Department of Biomedical, Experimental and Clinical Science, University of Florence, Florence, Italy
| | - Dimitrios Vassilopoulos
- 2nd Department of Medicine and Laboratory, Clinical Immunology-Rheumatology Unit, National and Kapodistrian University of Athens, School of Medicine, Hippokration General Hospital, Athens, Greece
| | - Peter Verhoeven
- Dutch Patient Vasculitis Organization, Haarlem, The Netherlands
| | - David Jayne
- Department of Medicine, University of Cambridge, Cambridge, UK
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Berti A, Alsawas M, Jawaid T, Prokop LJ, Lee JM, Jeong GH, Quintana LF, Moiseev S, Vaglio A, Tesar V, Geetha D, Shin JI, Kronbichler A. Induction and maintenance of remission with mycophenolate mofetil in ANCA-associated vasculitis: A systematic review and meta-analysis. Nephrol Dial Transplant 2021; 37:2190-2200. [PMID: 34910216 DOI: 10.1093/ndt/gfab357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2021] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Uncertainties exist about the use of mycophenolate mofetil (MMF) in anti-neutrophil cytoplasmatic antibody (ANCA)-associated vasculitis (AAV), particularly for remission maintenance. METHODS Systematic review and meta-analysis of phase II and III trials assessing the use of MMF in AAV (granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA)). A comprehensive search of several databases (Medline, EMBASE, Cochrane, Web of Science, Scopus) from inception to May 5th, 2020 has been conducted. Trial data were extracted to estimate odds ratios (ORs) and estimates (ES) for MMF efficacy (remission-induction and maintenance). Severe adverse effects (SAEs) were collected. RESULTS From 565 articles captured, 10 met the predefined criteria, five phase II and five III trials, 4 assessed remission-induction, 3 remission-maintenance, 3 both. The pooled OR for remission-induction at 6 months was 1.06 (95% CI: [0.74, 1.52]), with no significant difference by subgroup meta-analysis of trials stratified by different study-level features (i.e. kidney disease, MPA, myeloperoxidase-ANCA-positivity, newly diagnosed disease) (p > 0.05).The overall ES for remission-maintenance at the end of follow-up ranged between 51%-91% (I2 = 74.8%). Subgroup meta-analysis identified kidney involvement as a possible source of heterogeneity, yielding a significantly higher rate of sustained remission in trials enrolling only patients with kidney involvement (92% [76%-100%]) versus those enrolling patients with and without kidney involvement (56% [45%-66%]). Results were similar in multiple sensitivity analyses.During follow-up, the frequency of SAEs in MMF-based treatment arms was 31.8%. CONCLUSIONS In AAV, MMF use significantly associated with higher sustained remission rates in trials enrolling only patients with kidney involvement. These findings might influence clinical practice.
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Affiliation(s)
- Alvise Berti
- Santa Chiara Regional Hospital and Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Rheumatology, Trento, Italy
| | - Mouaz Alsawas
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA.,Department of Pathology, University of Iowa, IA City, IA, USA
| | - Tabinda Jawaid
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
| | | | - Jiwon M Lee
- Korea Disease Control and Prevention Agency, Division of Rare Disease Management, Republic of Korea
| | - Gwang Hun Jeong
- College of Medicine, Gyeongsang National University, Jinju, Republic of Korea
| | - Luis F Quintana
- Reference Center in Complex Glomerular Disease of the National Health System (CSUR), Nephrology and Renal Transplantation Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, Spain. Institut d'Investigacions Biomediques August Pi I Sunyer (IDIBAPS), Barcelona, Spain
| | - Sergey Moiseev
- Tareev Clinic of Internal Diseases, Sechenov First Moscow State Medical University, Moscow, Russia
| | - August Vaglio
- Department of Biomedical Experimental and Clinical Sciences 'Mario Serio', University of Firenze, and Nephrology Unit, Meyer Children's Hospital, Firenze, Italy
| | - Vladimir Tesar
- Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czechia
| | - Duvuru Geetha
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jae Il Shin
- Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Andreas Kronbichler
- Department of Medicine, University of Cambridge, Cambridge, UK.,Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Cambridge University Hospitals, Cambridge, UK
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7
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Kuzuya K, Morita T, Kumanogoh A. Efficacy of mycophenolate mofetil as a remission induction therapy in antineutrophil cytoplasmic antibody: associated vasculitis-a meta-analysis. RMD Open 2021; 6:rmdopen-2020-001195. [PMID: 32371435 PMCID: PMC7299518 DOI: 10.1136/rmdopen-2020-001195] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Revised: 03/25/2020] [Accepted: 03/29/2020] [Indexed: 01/01/2023] Open
Abstract
Objectives A few studies on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treatments have shown the therapeutic efficacy of mycophenolate mofetil (MMF). However, the therapeutic efficacy of MMF compared with that of cyclophosphamide (CYC) in patients with AAV has not been established. We conducted a systematic review and meta-analysis to assess the efficacy of MMF as a remission induction therapy in patients with AAV comparing it with the efficacy of CYC. Methods We searched randomised controlled trials (RCTs) comparing the efficacy of MMF with that of CYC in patients with AAV on three different websites: PubMed, Cochrane Library and Google Scholar. We compared the difference in the relative risk (RR) of each outcome based on a Mantel-Haenszel random-effects model. Results We analysed data from four RCTs with 300 patients for the study. The 6-month remission rate (RR 1.09, 95% CI 0.86 to 1.38, p=0.48), the 6-month ANCA negativity (RR 1.31, 95% CI 0.91 to 1.90, p=0.15) and the long-term relapse rate (RR 1.36, 95% CI 0.80 to 2.31, p=0.26) were all similar between the two treatments. The rates of death, infection and leucopenia were also similar between the two groups (RR 1.05, 95% CI 0.40 to 2.74, p=0.93; RR 1.26, 95% CI 0.79 to 2.01, p=0.33; RR 0.45, 95% CI 0.16 to 1.32, p=0.15, respectively). Conclusions We found no difference between the therapeutic efficacy of MMF and that of CYC in patients with AAV. MMF may be an alternative remission induction therapy in patients with non-life-threatening AAV.
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Affiliation(s)
- Kentaro Kuzuya
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Takayoshi Morita
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan .,Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita, Japan
| | - Atsushi Kumanogoh
- Department of Respiratory Medicine and Clinical Immunology, Osaka University Graduate School of Medicine, Suita, Japan.,Laboratory of Immunopathology, World Premier International Immunology Frontier Research Center, Suita, Japan.,Integrated Frontier Research for Medical Science Division, Institute for Open and Transdisciplinary Research Initiatives, Osaka University, Suita, Japan
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8
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Nozaki Y. New Insights Into Novel Therapeutic Targets in ANCA-Associated Vasculitis. Front Immunol 2021; 12:631055. [PMID: 33868250 PMCID: PMC8047311 DOI: 10.3389/fimmu.2021.631055] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Accepted: 03/18/2021] [Indexed: 11/13/2022] Open
Abstract
Biologics targeting inflammation-related molecules in the immune system have been developed to treat rheumatoid arthritis (RA), and these RA treatments have provided revolutionary advances. Biologics may also be an effective treatment for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, particularly in patients with resistance to standard treatments. Despite the accumulation of clinical experience and the increasing understanding of the pathogenesis of vasculitis, it is becoming more difficult to cure vasculitis. The treatment of vasculitis with biologics has been examined in clinical trials, and this has also enhanced our understanding of the pathogenesis of vasculitis. A humanized anti-interleukin-5 monoclonal antibody known as mepolizumab was recently demonstrated to provide clinical benefit in the management of eosinophilic granulomatosis with polyangiitis in refractory and relapsing disease, and additional new drugs for vasculitis are being tested in clinical trials, while others are in abeyance. This review presents the new findings regarding biologics in addition to the conventional immunosuppressive therapy for ANCA-associated vasculitis.
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Affiliation(s)
- Yuji Nozaki
- Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Japan
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9
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Xiong A, Xiong C, Yang G, Shuai Y, Liu D, He L, Guo Z, Zhang L, Liu Y, Yang Y, Cui B, Shuai S. The Role of Mycophenolate Mofetil for the Induction of Remission in ANCA-Associated Vasculitis: A Meta-Analysis. Front Med (Lausanne) 2021; 8:609924. [PMID: 33732714 PMCID: PMC7956966 DOI: 10.3389/fmed.2021.609924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 02/10/2021] [Indexed: 02/05/2023] Open
Abstract
Objectives: The successful introduction of mycophenolate mofetil (MMF) as a treatment for renal allograft reduced the incidence of acute rejection. The inspiring effects obtained by the MMF have led to an evaluation of its therapeutic potency on ANCA-associated vasculitis (AAV). However, there is little evidence of the MMF's efficacy on the AAV. The meta-analysis is carried out to evaluate the efficacy of MMF as a remission induction therapy in AAV. Methods: Up to June 30th, 2020, PubMed, Cochrane Library, and Embase have been searched comprehensively. According to heterogeneity, the pooled remission rates are synthesized by either fixed-effect or random-effect models. Results: The eight included studies comprising 230 patients who were treated with MMF as induction therapy are included in our analysis. The pooled overall remission rate is 74% (95% CI: 0.68–0.80). The remission rate, the infection rate and the rate of leukopenia of four randomized controlled trials aimed at comparing the effects of MMF with cyclophosphamide (CYC) during induction therapy for AAV have no statistical significance (P > 0.05). Conclusion: MMF may be an alternative to CYC for remission induction therapy in AAV with MPO-ANCA, mild to moderate renal involvement and non-life-threatening state. Whether to observe the effect of MMF in AAV or to compare the difference between MMF and CYC in the future studies, risk stratification and subgrouping of AAV patients should be first carried out to correctly identify the AAV subgroup suitable for MMF.
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Affiliation(s)
- Anji Xiong
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Chen Xiong
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Guancui Yang
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Yu Shuai
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Deng Liu
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Linqian He
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Zepeng Guo
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Liangwen Zhang
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
| | - Yi Liu
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Yuan Yang
- Department of Rheumatology and Immunology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Beibei Cui
- Department of Rheumatology and Immunology, West China Hospital, Sichuan University, Chengdu, China
| | - Shiquan Shuai
- Department of Rheumatology and Immunology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, China
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10
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Garner S, Khalidi N. Updates in the treatment of granulomatosis with polyangiitis and microscopic polyangiitis: At a crossroad. Presse Med 2020; 49:104038. [PMID: 32634467 DOI: 10.1016/j.lpm.2020.104038] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
There have been great advances in the management of ANCA associated vasculitis over the past decades. We have gone from an era where the disease was almost universally fatal to trying to prevent long-term side effects of treatment regimens. With the ability to use pulse cyclophosphamide or rituximab as alternates to oral cyclophosphamide for induction of remission, side effects of therapy have been greatly reduced. New approaches have drastically changed our approach to maintenance and we now favor much longer durations of maintenance therapy, as they are more successful in preventing relapse. Steroids have long been the bane of treatment as they are associated with a significant risk of infection and metabolic consequences. We are now in a steroid-sparing and looking ahead to a steroid-free era with new data being published showing lower doses of steroids being equally effective and several ongoing seminal trials looking at agents that could completely replace steroids very early on.
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11
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Carpenter S, Cohen Tervaert JW, Yacyshyn E. Advances in therapeutic treatment options for ANCA-associated vasculitis. Expert Opin Orphan Drugs 2020. [DOI: 10.1080/21678707.2020.1760837] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Affiliation(s)
- Shealynn Carpenter
- University of Alberta, Department of Medicine, Division of Rheumatology, Edmonton, Alberta, Canada
| | - Jan Willem Cohen Tervaert
- University of Alberta, Department of Medicine, Division of Rheumatology, Edmonton, Alberta, Canada
- Maastricht University, School for Mental Health and Neuroscience, Maastricht, The Netherlands
| | - Elaine Yacyshyn
- University of Alberta, Department of Medicine, Division of Rheumatology, Edmonton, Alberta, Canada
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12
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Abstract
Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a small to medium vessel vasculitis associated with excess morbidity and mortality. This review explores how management of AAV has evolved over the past two decades with pivotal randomized controlled trials shaping the management of induction and maintenance of remission. Contemporary AAV care is characterized by approaches that minimize the cumulative exposure to cyclophosphamide and glucocorticoids, increasingly use rituximab for remission induction and maintenance, and consider therapies with less toxicity (for example, methotrexate, mycophenolate mofetil) for manifestations of AAV that do not threaten organ function or survival. Simultaneously, improvements in outcomes, such as renal and overall survival, have been observed. Additional trials and observational studies evaluating the comparative effectiveness of agents for AAV in various patient subgroups are needed. Prospective studies are necessary to assess the effect of psychosocial interventions on patient reported outcomes in AAV. Despite the expanding array of treatments for AAV, little guidance on how to personalize AAV care is available to physicians.
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Affiliation(s)
- Zachary S Wallace
- Clinical Epidemiology Program, Division of Rheumatology, Allergy, and Immunology, Mongan Institute, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Eli M Miloslavsky
- Rheumatology Unit, Division of Rheumatology, Allergy, and Immunology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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13
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Schirmer JH, Aries PM, de Groot K, Hellmich B, Holle JU, Kneitz C, Kötter I, Lamprecht P, Müller-Ladner U, Reinhold-Keller E, Specker C, Zänker M, Moosig F. [S1 guidelines Diagnostics and treatment of ANCA-associated vasculitis]. Z Rheumatol 2019; 76:77-104. [PMID: 29204681 DOI: 10.1007/s00393-017-0394-1] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Jan Henrik Schirmer
- Klinik für Innere Medizin I, Universitätsklinikum Schleswig-Holstein, Campus Kiel, Arnold-Heller-Str. 3, 24105, Kiel, Deutschland.
| | - Peer M Aries
- Rheumatologie im Struenseehaus, Hamburg, Deutschland
| | - Kirsten de Groot
- Medizinische Klinik III, Sana Klinikum Offenbach, Offenbach, Deutschland
- KfH Nierenzentrum Offenbach, Offenbach, Deutschland
| | - Bernhard Hellmich
- Klinik für Innere Medizin, Rheumatologie und Immunologie, Vaskulitiszentrum Süd, Medius Klinik Kirchheim, Kirchheim, Deutschland
| | - Julia U Holle
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster, Deutschland
| | - Christian Kneitz
- Klinik für Innere Medizin II, Rheumatologie, klinische Immunologie und Geriatrie, Klinikum Südstadt, Rostock, Deutschland
| | - Ina Kötter
- Abteilung für Rheumatologie, klinische Immunologie und Nephrologie, Asklepios Klinikum Altona, Hamburg, Deutschland
| | - Peter Lamprecht
- Klinik für Rheumatologie und klinische Immunologie, Universität zu Lübeck, Lübeck, Deutschland
| | - Ulf Müller-Ladner
- Abteilung für Rheumatologie und Klinische Immunologie, Campus Kerckhoff, Justus-Liebig Universität Giessen, Bad Nauheim, Deutschland
| | - Eva Reinhold-Keller
- Klinik für Rheumatologie und klinische Immunologie, Klinikum Bad Bramstedt, Bad Bramstedt, Deutschland
| | - Christof Specker
- Klinik für Rheumatologie und klinische Immunologie, Universitätsmedizin Essen, St. Josef Krankenhaus Werden, Essen, Deutschland
| | - Michael Zänker
- Abteilung für Innere Medizin, Immanuel Klinikum Bernau Herzzentrum Brandenburg, Bernau, Deutschland
- Medizinische Hochschule Brandenburg, Neuruppin, Deutschland
| | - Frank Moosig
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster, Deutschland
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14
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Koukoulaki M, Iatrou C. The role of mycophenolate in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis. World J Nephrol 2019; 8:75-82. [PMID: 31523631 PMCID: PMC6715575 DOI: 10.5527/wjn.v8.i4.75] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 07/09/2019] [Accepted: 07/16/2019] [Indexed: 02/06/2023] Open
Abstract
Mycophenolic acid, the active metabolite for mycophenolate mofetil and mycophenolic sodium, is a strong, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase, the key enzyme in de novo synthesis of guanosine nucleotides leading to selective inhibition of lymphocyte proliferation. Mycophenolic acid has been evaluated as induction and remission maintenance agent in the treatment of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Since the course of disease of AAV usually requires long term immunosuppression, mycophenolate has been explored as a less toxic agent compared to cyclophosphamide and azathioprine. Mycophenolate is a potent immunosuppressive agent in the therapy of AAV, non-inferior to other available drugs with comparable side effect profile. Therefore, it could be a valuable alternative in cases of toxicity with life threatening side effects or intolerance to cyclophosphamide or azathioprine, in cases with high cumulative dose of cyclophosphamide, but also in cases with insufficient response. Several studies have shown a higher relapse rate following discontinuation of mycophenolate or in mycophenolate treated subjects that raises concerns about its usefulness in the treatment of AAV. This review describes the efficacy of mycophenolate in AAV as remission induction agent, as remission maintenance agent, and as therapeutic option in relapsing AAV disease, the relapse rate following discontinuation of mycophenolate, and the adverse events related to mycophenolate treatment.
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Affiliation(s)
- Maria Koukoulaki
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia – Piraeus “Agios Panteleimon”, Piraeus, Nikaia 18454, Greece
| | - Christos Iatrou
- Center for Nephrology “G. Papadakis”, General Hospital of Nikaia – Piraeus “Agios Panteleimon”, Piraeus, Nikaia 18454, Greece
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15
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Tuin J, Stassen PM, Bogdan DI, Broekroelofs J, van Paassen P, Cohen Tervaert JW, Sanders JS, Stegeman CA. Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Randomized, Controlled Trial. Clin J Am Soc Nephrol 2019. [PMID: 31253599 DOI: 10.2215/cjn.11801018/-/dcsupplemental] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/04/2023]
Abstract
BACKGROUND AND OBJECTIVES Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA- and myeloperoxidase-ANCA-associated vasculitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years. RESULTS Eighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil-treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17). CONCLUSIONS We did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.
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Affiliation(s)
- Janneke Tuin
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
| | | | - Daria I Bogdan
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan Broekroelofs
- Division of Nephrology, Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands; and
| | - Pieter van Paassen
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jan Willem Cohen Tervaert
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
- Department of Medicine, University of Alberta, Edmonton, Canada
| | - Jan-Stephan Sanders
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Coen A Stegeman
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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16
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Tuin J, Stassen PM, Bogdan DI, Broekroelofs J, van Paassen P, Cohen Tervaert JW, Sanders JS, Stegeman CA. Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission in Nonlife-Threatening Relapses of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Randomized, Controlled Trial. Clin J Am Soc Nephrol 2019; 14:1021-1028. [PMID: 31253599 PMCID: PMC6625631 DOI: 10.2215/cjn.11801018] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2018] [Accepted: 05/17/2019] [Indexed: 11/23/2022]
Abstract
BACKGROUND AND OBJECTIVES Cyclophosphamide has been the mainstay of treatment of ANCA-associated vasculitis. However, cyclophosphamide has unfavorable side effects and alternatives are needed. Evidence suggests that mycophenolate mofetil can induce sustained remission in nonlife-threatening disease. The purpose of this study was to compare the efficacy and safety of mycophenolate mofetil versus cyclophosphamide for the induction treatment of nonlife-threatening relapses of proteinase 3-ANCA- and myeloperoxidase-ANCA-associated vasculitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a multicenter randomized, controlled trial. Participants with a first or second relapse of ANCA-associated vasculitis were randomized to induction treatment with cyclophosphamide or mycophenolate mofetil both in combination with glucocorticoids. Maintenance therapy consisted of azathioprine in both arms. Primary outcome was remission at 6 months, and secondary outcomes included disease-free survival at 2 and 4 years. RESULTS Eighty-four participants were enrolled, of whom 41 received mycophenolate mofetil and 43 received cyclophosphamide. Eighty-nine percent of participants were proteinase 3-ANCA positive. At 6 months, 27 (66%) mycophenolate mofetil-treated participants versus 35 (81%) cyclophosphamide-treated participants were in remission (P=0.11). Disease-free survival rates at 2 and 4 years were 61% and 39% for cyclophosphamide, respectively, and 43% and 32% for mycophenolate mofetil, respectively (at 4 years, log rank test, P=0.17). CONCLUSIONS We did not demonstrate mycophenolate mofetil to be similarly effective as cyclophosphamide in inducing remission of relapsed ANCA-associated vasculitis. However, mycophenolate mofetil might be an alternative to cyclophosphamide for the treatment of selected patients with nonlife-threatening relapses.
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Affiliation(s)
- Janneke Tuin
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
| | | | - Daria I Bogdan
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Jan Broekroelofs
- Division of Nephrology, Department of Internal Medicine, Medisch Centrum Leeuwarden, Leeuwarden, The Netherlands; and
| | - Pieter van Paassen
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands
| | - Jan Willem Cohen Tervaert
- Department of Internal Medicine, Maastricht University Medical Center, Maastricht, The Netherlands.,Department of Medicine, University of Alberta, Edmonton, Canada
| | - Jan-Stephan Sanders
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
| | - Coen A Stegeman
- Division of Nephrology, Department of Internal Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands
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Jones RB, Hiemstra TF, Ballarin J, Blockmans DE, Brogan P, Bruchfeld A, Cid MC, Dahlsveen K, de Zoysa J, Espigol-Frigolé G, Lanyon P, Peh CA, Tesar V, Vaglio A, Walsh M, Walsh D, Walters G, Harper L, Jayne D. Mycophenolate mofetil versus cyclophosphamide for remission induction in ANCA-associated vasculitis: a randomised, non-inferiority trial. Ann Rheum Dis 2019; 78:399-405. [PMID: 30612116 DOI: 10.1136/annrheumdis-2018-214245] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 11/30/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023]
Abstract
OBJECTIVES Cyclophosphamide induction regimens are effective for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but are associated with infections, malignancies and infertility. Mycophenolate mofetil (MMF) has shown high remission rates in small studies of AAV. METHODS We conducted a randomised controlled trial to investigate whether MMF was non-inferior to cyclophosphamide for remission induction in AAV. 140 newly diagnosed patients were randomly assigned to MMF or pulsed cyclophosphamide. All patients received the same oral glucocorticoid regimen and were switched to azathioprine following remission. The primary endpoint was remission by 6 months requiring compliance with the tapering glucocorticoid regimen. Patients with an eGFR <15 mL/min were excluded from the study. RESULTS At baseline, ANCA subtype, disease activity and organ involvement were similar between groups. Non-inferiority was demonstrated for the primary remission endpoint, which occurred in 47 patients (67%) in the MMF group and 43 patients (61%) in the cyclophosphamide group (risk difference 5.7%, 90% CI -7.5% to 19%). Following remission, more relapses occurred in the MMF group (23 patients, 33%) compared with the cyclophosphamide group (13 patients, 19%) (incidence rate ratio 1.97, 95% CI 0.96 to 4.23, p=0.049). In MPO-ANCA patients, relapses occurred in 12% of the cyclophosphamide group and 15% of the MMF group. In PR3-ANCA patients, relapses occurred in 24% of the cyclophosphamide group and 48% of the MMF group. Serious infections were similar between groups (26% MMF group, 17% cyclophosphamide group) (OR 1.67, 95% CI 0.68 to 4.19, p=0.3). CONCLUSION MMF was non-inferior to cyclophosphamide for remission induction in AAV, but resulted in higher relapse rate. TRIAL REGISTRATION NUMBER NCT00414128.
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Affiliation(s)
- Rachel B Jones
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Thomas F Hiemstra
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
- Cambridge Clinical Trials Unit, Addenbrooke's Hospital, Cambridge, UK
| | - Jose Ballarin
- Department of Nephrology, Fundació Puigvert, Barcelona, Spain
| | | | - Paul Brogan
- Department of Paediatric Rheumatology, University College London Great Ormond Street Institute of Child Health, London, UK
- Department of Paediatric Rheumatology, Great Ormond Street Hospital NHS Foundation Trust, London, UK
| | - Annette Bruchfeld
- Department of Renal Medicine, Karolinska University Hospital, Stockholm, Sweden
| | - Maria C Cid
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Karen Dahlsveen
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Janak de Zoysa
- Renal Service, Waitemata District Health Board, Auckland, New Zealand
- Department of Medicine, University of Auckland, Auckland, New Zealand
| | - Georgína Espigol-Frigolé
- Department of Autoimmune Diseases, Hospital Clinic, University of Barcelona, Institut d'investigacions Biomediques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - Peter Lanyon
- Department of Rheumatology, Nottingham University Hospitals NHS Trust, Nottingham, UK
| | - Chen Au Peh
- Department of Renal Medicine, Royal Adelaide Hospital, Adelaide, South Australia, Australia
| | - Vladimir Tesar
- Department of Nephrology, Charles University and General University Hospital, Prague, Czech Republic
| | - Augusto Vaglio
- Department of Biomedical, Experimental and Clinical Sciences 'Mario Serio', University of Firenze, Firenze, Italy
- Nephrology and Dialysis Unit, Meyer Children's University Hospital, Firenze, Italy
| | - Michael Walsh
- Departments of Medicine and Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Dorothy Walsh
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK
| | - Giles Walters
- Department of Renal Medicine, Canberra Hospital, Canberra, Australian Capital Territory, Australia
| | - Lorraine Harper
- Institute of Clinical Sciences, University of Birmingham, Birmingham, UK
| | - David Jayne
- Department of Renal Medicine, Addenbrooke's Hospital, Cambridge, UK
- School of Clinical Medicine, University of Cambridge, Cambridge, UK
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18
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van der Geest KSM, Brouwer E, Sanders JS, Sandovici M, Bos NA, Boots AMH, Abdulahad WH, Stegeman CA, Kallenberg CGM, Heeringa P, Rutgers A. Towards precision medicine in ANCA-associated vasculitis. Rheumatology (Oxford) 2018; 57:1332-1339. [PMID: 29045715 DOI: 10.1093/rheumatology/kex367] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Indexed: 12/18/2022] Open
Abstract
ANCA-associated vasculitis (AAV) is characterized by inflammation and destruction of small and medium-sized vessels. Current management strategies for AAV have been validated in large groups of patients. However, recent insights indicate that distinct patient subsets may actually exist within AAV, thereby justifying the development of more personalized treatment strategies. In this review, we discuss current evidence for a better classification of AAV based on ANCA type. We describe how thus defined categories of AAV patients may differ in genetic background, clinical presentation, immune pathology, response to treatment and disease outcome. We also explore how these insights may provide a rationale for targeted treatments in different categories of AAV patients. Finally, we provide recommendations on how to further establish precision medicine in AAV.
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Affiliation(s)
- Kornelis S M van der Geest
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Elisabeth Brouwer
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Jan-Stephan Sanders
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Maria Sandovici
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Nicolaas A Bos
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Annemieke M H Boots
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Wayel H Abdulahad
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Coen A Stegeman
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Nephrology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Cees G M Kallenberg
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Peter Heeringa
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Abraham Rutgers
- Vasculitis Expertise Center Groningen, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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19
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Cornec D, Cornec-Le Gall E, Specks U. Clinical trials in antineutrophil cytoplasmic antibody-associated vasculitis: what we have learnt so far, and what we still have to learn. Nephrol Dial Transplant 2017; 32:i37-i47. [PMID: 28087591 DOI: 10.1093/ndt/gfw384] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 09/28/2016] [Indexed: 02/06/2023] Open
Abstract
The prognosis of the antineutrophil cytoplasmic antibody associated vasculitides (AAV), microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic GPA (EGPA), has been fundamentally improved over the last five decades by the use of glucocorticoids and immunosuppressants, turning them from consistently fatal diseases into chronic conditions. The long-term course is now largely determined by the frequency of disease flares and by accruing damage caused by disease activity and treatment-related comorbidities. This review summarizes the evidence derived from clinical trials performed during the last 30 years and the remaining clinical unmet needs that new studies aim to address. In MPA and GPA, ongoing studies assess (i) different strategies to reduce cumulative glucocorticoid doses currently used for induction and maintenance of remission, (ii) the efficacy of new drugs and (iii) the optimal duration of immunosuppression and the use of biomarkers to individualize therapy. Prospective randomized trials also target disease-associated cardiovascular risk and infections. The first prospective controlled trials specifically designed for EGPA have recently been launched and could lead to new therapeutic options for patients diagnosed with this rare disease. This is an exciting time for researchers in the field of AAV, and for patients as collaborative efforts raise the hope of developing new therapies and more individualized approaches to the management of the diseases, maximizing efficacy while minimizing treatment toxicities.
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Affiliation(s)
- Divi Cornec
- Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, MN, USA.,European University of Brittany and Brest University Hospital, Brest, France
| | - Emilie Cornec-Le Gall
- European University of Brittany and Brest University Hospital, Brest, France.,Division of Nephrology, Mayo Clinic Rochester, MN, USA
| | - Ulrich Specks
- Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic Rochester, MN, USA
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20
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Yates M, Watts RA, Bajema IM, Cid MC, Crestani B, Hauser T, Hellmich B, Holle JU, Laudien M, Little MA, Luqmani RA, Mahr A, Merkel PA, Mills J, Mooney J, Segelmark M, Tesar V, Westman K, Vaglio A, Yalçındağ N, Jayne DR, Mukhtyar C. EULAR/ERA-EDTA recommendations for the management of ANCA-associated vasculitis. Ann Rheum Dis 2016; 75:1583-94. [PMID: 27338776 DOI: 10.1136/annrheumdis-2016-209133] [Citation(s) in RCA: 785] [Impact Index Per Article: 87.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 05/27/2016] [Indexed: 12/13/2022]
Abstract
In this article, the 2009 European League Against Rheumatism (EULAR) recommendations for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) have been updated. The 2009 recommendations were on the management of primary small and medium vessel vasculitis. The 2015 update has been developed by an international task force representing EULAR, the European Renal Association and the European Vasculitis Society (EUVAS). The recommendations are based upon evidence from systematic literature reviews, as well as expert opinion where appropriate. The evidence presented was discussed and summarised by the experts in the course of a consensus-finding and voting process. Levels of evidence and grades of recommendations were derived and levels of agreement (strengths of recommendations) determined. In addition to the voting by the task force members, the relevance of the recommendations was assessed by an online voting survey among members of EUVAS. Fifteen recommendations were developed, covering general aspects, such as attaining remission and the need for shared decision making between clinicians and patients. More specific items relate to starting immunosuppressive therapy in combination with glucocorticoids to induce remission, followed by a period of remission maintenance; for remission induction in life-threatening or organ-threatening AAV, cyclophosphamide and rituximab are considered to have similar efficacy; plasma exchange which is recommended, where licensed, in the setting of rapidly progressive renal failure or severe diffuse pulmonary haemorrhage. These recommendations are intended for use by healthcare professionals, doctors in specialist training, medical students, pharmaceutical industries and drug regulatory organisations.
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Affiliation(s)
- M Yates
- Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK Norwich Medical School, University of East Anglia, Norwich, UK
| | - R A Watts
- Norwich Medical School, University of East Anglia, Norwich, UK Department of Rheumatology, Ipswich Hospital NHS Trust, Ipswich, Suffolk, UK
| | - I M Bajema
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - M C Cid
- Vasculitis Research Unit, Department of Autoimmune Diseases, Hospital Clínic, University of Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
| | - B Crestani
- Assistance Publique-Hôpitaux de Paris, Department of Pulmonology, Bichat-Claude Bernard University Hospital, Paris, France
| | - T Hauser
- Immunologie-Zentrum Zürich, Zürich, Switzerland
| | - B Hellmich
- Vaskulits-Zentrum Süd, Klinik für Innere Medizin, Rheumatologie und Immunologie, Kreiskliniken Esslingen, Kirchheim-Teck, Germany
| | - J U Holle
- Rheumazentrum Schleswig-Holstein Mitte, Neumünster, Germany
| | - M Laudien
- Department of Otorhinolaryngology, Head and Neck Surgery, University of Kiel, Kiel, Germany
| | - M A Little
- Trinity Health Kidney Centre, Tallaght Hospital, Dublin, Ireland
| | - R A Luqmani
- Nuffield Department of Orthopaedics Rheumatology and Musculoskeletal Sciences, Botnar Research Centre, University of Oxford, Oxford, United Kingdom
| | - A Mahr
- Department of Internal Medicine, Hôpital Saint-Louis, Université Paris 7 René Diderot, Paris, France
| | - P A Merkel
- Division of Rheumatology and the Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - J Mills
- Vasculitis UK, West Bank House, Winster, Matlock, UK
| | - J Mooney
- Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK
| | - M Segelmark
- Department of Medical and Health Sciences, Linköping University, Linköping, Sweden Department of Nephrology, Linköping University, Linköping, Sweden
| | - V Tesar
- Department of Nephrology, 1st School of Medicine, Charles University, Prague, Czech Republic
| | - K Westman
- Department of Nephrology, Lund University, Skåne University Hospital, Lund and Malmö, Sweden
| | - A Vaglio
- Nephrology Unit, University Hospital of Parma, Parma, Italy
| | - N Yalçındağ
- Department of Ophthalmology, School of Medicine, Ankara University, Ankara, Turkey
| | - D R Jayne
- Lupus and Vasculitis Unit, Addenbrooke's Hospital, Cambridge, UK
| | - C Mukhtyar
- Department of Rheumatology, Norfolk and Norwich University Hospital, Norwich, UK
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21
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Chen Y, Ding Y, Liu Z, Zhang H, Liu Z, Hu W. Long-term outcomes in antineutrophil cytoplasmic autoantibody-positive eosinophilic granulomatosis with polyangiitis patients with renal involvement: a retrospective study of 14 Chinese patients. BMC Nephrol 2016; 17:101. [PMID: 27461086 PMCID: PMC4962371 DOI: 10.1186/s12882-016-0319-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2015] [Accepted: 07/20/2016] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The clinic-pathological features and outcomes of Chinese patients with antineutrophil cytoplasmic autoantibody (ANCA)-positive eosinophilic granulomatosis with polyangiitis (EGPA) and renal involvement have not been studied. METHODS Fourteen EGPA patients with renal involvement were included. All patients underwent renal biopsy. Clinic-pathological features and outcomes were retrospectively analyzed. RESULTS The most common initial symptom of EGPA was asthma (57.1 %), followed by hemoptysis (21.4 %), gross hematuria (14.3 %), and arthritis (7.1 %). All patients had positive serum ANCA (anti-MPO in 12, anti-PR3 in 2). Elevated eosinophils (median 15 %, range 10-45 %) were found in all patients. The median serum IgE level was 463 g/L (range 200-1000 g/L). All patients presented with renal dysfunction, with a median SCr of 5.4 mg/dL (range 1.47-11 mg/dL), seven patients (50 %) required initial renal replacement therapy. Thirteen patients showed hematuria and proteinuria (median 1.1 g/24 h, range 0.5-7.8 g/24 h). Renal biopsy showed pauci-immune segmental necrotizing glomerulonephritis with crescents in 13 patients and acute interstitial nephritis in one patient. Twelve patients (85.7 %) showed renal interstitial eosinophil infiltration, among whom three had eosinophilic granuloma. Among seven patients (71.4 %) who required initial dialysis, 5 discontinued dialysis, one died, one received maintenance dialysis after glucocorticoids plus immunosuppressive for induction treatment. Twelve patients were followed up for a median of 43.5 months (range 6-83 months), during follow-up, two patients progressed to end-stage renal disease, nine had chronic kidney disease with eGFR < 60 mL/min, and two patients had normal eGFR. CONCLUSIONS Renal involvement in ANCA-positive EGPA could be severe and showed varied renal histology. Although intensive immunosuppressive therapy effectively improved the renal function, the long-term renal survival was poor. Early diagnosis and treatment are essential to improve long-term renal survival.
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Affiliation(s)
- Yinghua Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China
| | - Yuemei Ding
- Jiangsu Jiangyin People's Hospital, Jiangyin, China
| | - Zhengzhao Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China
| | - Haitao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China
| | - Weixin Hu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210002, Jiangsu, China.
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22
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Chen Y, Gao E, Yang L, Liu X, Li K, Liu Z, Zeng C, Zhang H, Liu Z, Hu W. Long-term outcome of mycophenolate mofetil treatment for patients with microscopic polyangiitis: an observational study in Chinese patients. Rheumatol Int 2016; 36:967-74. [PMID: 27169414 DOI: 10.1007/s00296-016-3492-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 05/04/2016] [Indexed: 12/14/2022]
Abstract
This study aimed to retrospectively analyze the long-term outcome of mycophenolate mofetil (MMF) therapy for microscopic polyangiitis (MPA) with mild to moderate renal involvement in Chinese patients. Thirty-four MPA patients (24 females, 10 males, aged 44.7 ± 17 years, BVAS score 13.8 ± 3.2, SCr 2.2 ± 1.1 mg/dl) with SCr < 5 mg/dl and who received glucocorticoids plus MMF therapy for inducing and maintaining remission were included in this study. The remission and relapse rates, patient and renal survival rates and adverse events were retrospectively analyzed. We found that 31 (91.2 %) of 34 patients achieved remission and were continuously treated with glucocorticoids plus MMF for maintaining remission. The median duration of MMF treatment was 24 months (IQR 15-53 months) and follow-up time was 86 months (IQR 29-124 months). During the follow-up, 7 (22.6 %) patients relapsed, one patient died, and one patient progressed into end-stage renal disease. The 5-year patient and renal survival rates were 92.8 and 95.2 %, respectively. 11 (32.4 %) patients suffered 16 adverse events, 13 of which were pulmonary infection. In conclusion, glucocorticoids plus MMF regimen as induction and maintenance therapy could achieve high remission rate and good long-term renal survival in MPA patients with mild to moderate renal involvement. Prospective controlled trials with a large sample size are needed to confirm the efficacy of MMF in this population.
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Affiliation(s)
- Yinghua Chen
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Erzhi Gao
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Liu Yang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Xia Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Kang Li
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Zhengzhao Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Caihong Zeng
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Haitao Zhang
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Zhihong Liu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China
| | - Weixin Hu
- National Clinical Research Center of Kidney Diseases, Jinling Hospital, Nanjing University School of Medicine, 305 East Zhongshan Road, Nanjing, 210016, Jiangsu, China.
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23
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Draibe J, Poveda R, Fulladosa X, Vidaller A, Zulberti C, Gomà M, Pujol R, Ripoll È, Torras J, Grinyó JM. Use of mycophenolate in ANCA-associated renal vasculitis: 13 years of experience at a university hospital. Nephrol Dial Transplant 2015; 30 Suppl 1:i132-7. [PMID: 25805744 DOI: 10.1093/ndt/gfv061] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
INTRODUCTION Standard therapy with corticosteroids (CS) and cyclophosphamide (CYC) followed by azathioprine has been shown to improve renal and patient survival in ANCA-associated renal vasculitis (rAAV). Mycophenolate mofetil (MF) has been progressively introduced for the treatment of rAAV in the last years because of its immunosuppressive efficacy combined with a lower toxicity profile. In this study, we retrospectively analyse the results of the introduction of MF for maintenance and induction therapy in rAAV in our institution from 2001 to 2013. RESULTS We reported 67 patients treated with MF as a maintenance treatment, divided by baseline serum creatinine (>500 µmol/L: Group 1 and <500 µmol/L: Group 2) and treatment schedule. Twenty-nine of the 67 patients were also treated with MF as induction treatment, mostly in Group 2. During the follow-up (2 years after the diagnosis) creatinine levels for serum glomerular filtration rate, ANCA titres, C-reactive protein and percentage of haematuria decreased in all groups. In Group 2, parameters and also relapse rates were similar at 24 months in patients treated with CYC or MF as an induction treatment (Subgroups 2a and 2b, respectively). Median dose of MF in maintenance treatment was 1000 mg daily and prednisone dose was tapered to 10 mg daily from Month 3. After 24 months, 82% of patients remained on MF therapy, 18% had discontinued the treatment, seven of them due to medical indication and two because of gastrointestinal intolerance. The percentage of patients that started renal replacement therapy was irregular in Group 1 depending on the subgroup (25-100%), and 10% in Group 2. Adverse effects, such as neutropenia, infections and neoplasia, were more prevalent in groups treated with CYC. CONCLUSION In conclusion, in our patients with rAAV, MF demonstrated to be an effective and well-tolerated option for maintenance treatment. As an induction treatment, MF seems to be similar to CYC for patients with moderate renal failure in the diagnosis.
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Affiliation(s)
- J Draibe
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - R Poveda
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - X Fulladosa
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - A Vidaller
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - C Zulberti
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - M Gomà
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - R Pujol
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - È Ripoll
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - J Torras
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
| | - J M Grinyó
- Nephrology Department, Internal Medicine Department, Pathology Department, Hospital Universitari de Bellvitge, IDIBELL, Barcelona, Spain
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24
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Tseng ST, Tseng MH, Huang JL. Concurrent pulmonary hemorrhage and deep vein thrombosis in a child with ANCA-associated vasculitis: case report and review of literature. Pediatr Rheumatol Online J 2015; 13:20. [PMID: 26058459 PMCID: PMC4461945 DOI: 10.1186/s12969-015-0015-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 05/15/2015] [Indexed: 11/10/2022] Open
Abstract
Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is an uncommon but potentially life threatening disease in children. Pulmonary hemorrhage (PH) is a well recognized but lethal complication. The incidence of venous thromboembolism (VTE) is higher in patients with AAV, especially in those with active disease. However, the simultaneous occurrence of both PH and VTE has rarely been reported. Herein, we describe a 14-year-old female with AAV who developed concomitant deep vein thrombosis (DVT) and PH within 3 days after hospitalization. She was successfully treated with timely plasmapheresis and methylprednisolone pulse therapy. VTE did not occur during discontinuation of anticoagulant. On reviewing the English literature, 5 AAV patients with coexisting VTE and PH have been reported. When faced with PH, whether or not to keep anti-coagulation treatment is a dilemma. Some of the patients kept receiving anti-coagulation treatment, whereas others undergoing inferior vena cava filter implantation. Glucocorticoids and cyclophosphamide or other immunosuppressant agents were prescribed in all patients. All of the cases survived after treatment for concurrent VTE and PH, and received short- or long-term anticoagulation treatment after discharge. To the best of our knowledge, this is the first report of a pediatric patient with AAV presenting with coexistent VTE and PH. VTE should be considered to be a sign of disease flare-up, and early plasmapheresis with immunosuppressant therapy can rescue this fatal complication.
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Affiliation(s)
- Shi-Ting Tseng
- Division of Pediatric Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Linkou 5, Fu-Hsin Street, Taoyuan, Taiwan.
| | - Min-Hua Tseng
- Division of Pediatric Nephrology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Linkou 5, Fu-Hsin Street, Taoyuan, Taiwan.
| | - Jing-Long Huang
- Division of Pediatric Allergy, Asthma and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital and Chang Gung University, Linkou 5, Fu-Hsin Street, Taoyuan, Taiwan.
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Hilhorst M, van Paassen P, Tervaert JWC. Proteinase 3-ANCA Vasculitis versus Myeloperoxidase-ANCA Vasculitis. J Am Soc Nephrol 2015; 26:2314-27. [PMID: 25956510 DOI: 10.1681/asn.2014090903] [Citation(s) in RCA: 158] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In patients with GN or vasculitis, ANCAs are directed against proteinase 3 (PR3) or myeloperoxidase (MPO). The differences between PR3-ANCA-associated vasculitis (AAV) and MPO-AAV described in the past have been supplemented during the last decade. In this review, we discuss the differences between these two small-vessel vasculitides, focusing especially on possible etiologic and pathophysiologic differences. PR3-AAV is more common in northern parts of the world, whereas MPO-AAV is more common in southern regions of Europe, Asia, and the Pacific, with the exception of New Zealand and Australia. A genetic contribution has been extensively studied, and there is a high prevalence of the HLA-DPB1*04:01 allele in patients with PR3-AAV as opposed to patients with MPO-AAV and/or healthy controls. Histologically, MPO-AAV and PR3-AAV are similar but show qualitative differences when analyzed carefully. Clinically, both serotypes are difficult to distinguish, but quantitative differences are present. More organs are affected in PR3-AAV, whereas renal limited vasculitis occurs more often in patients with MPO-AAV. For future clinical trials, we advocate classifying patients by ANCA serotype as opposed to the traditional disease type classification.
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Affiliation(s)
- Marc Hilhorst
- Clinical and Experimental Immunology, Maastricht University, Maastricht, The Netherlands
| | - Pieter van Paassen
- Clinical and Experimental Immunology, Maastricht University, Maastricht, The Netherlands
| | - Jan Willem Cohen Tervaert
- Clinical and Experimental Immunology, Maastricht University, Maastricht, The Netherlands jw.cohentervaert@maastrichtuniversity
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Jones RB, Walsh M, Chaudhry AN, Smith KGC, Jayne DRW. Randomized trial of enteric-coated mycophenolate sodium versus mycophenolate mofetil in multi-system autoimmune disease. Clin Kidney J 2014; 7:562-8. [PMID: 25859373 PMCID: PMC4389135 DOI: 10.1093/ckj/sfu096] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2014] [Accepted: 08/19/2014] [Indexed: 12/13/2022] Open
Abstract
Background The use of mycophenolate mofetil (MMF) in autoimmune disease is often limited by adverse effects. In this single-centre, open label, parallel design study, we investigated whether enteric-coated mycophenolate sodium (MS) is better tolerated and therefore more efficacious than MMF in primary systemic vasculitis (PSV) and systemic lupus erythematosus (SLE). Methods Forty patients with vasculitis or systemic lupus erythematosus (SLE) due to commence MMF for active disease or remission maintenance were randomized to receive either 1440 mg/day MS or 2000 mg/day MMF (18 PSV, 2 SLE per group) in addition to corticosteroids. Random allocation was performed by minimization for age, diagnosis and renal function using a computer algorithm. Twenty-five were treated for active disease (5 first-line therapy, 20 salvage therapy) and 15 for remission maintenance. The composite primary end point was treatment failure and/or drug intolerance over 12 months. Treatment failure was defined as failure to achieve remission by 6 months or disease relapse and treatment intolerance was defined as inability to tolerate and maintain the target dose of MS or MMF within 12 months. Results Forty patients were included in the analyses. MS was associated with a lower primary end point rate [hazard ratio (HR) 0.37; 95% CI 0.17–0.80; P = 0.012] (11/20, 55% patients) compared with MMF (17/20, 85% patients). Treatment failure alone was less common in the MS group (HR 0.28; 95% CI 0.095–0.82; P = 0.020), although drug intolerance did not differ between groups (HR 0.53; 95% CI 0.20–1.42; P = 0.21). Despite randomization, patients in the MMF group may have had a higher baseline risk for treatment failure; more MMF patients had refractory disease and granulomatosis with polyangiitis (Wegener's). A glomerular filtration rate (GFR) ≤40 mL/min was associated with intolerance. Serious adverse events were common (55% MMF and 45% MS patients). Conclusions No differences in treatment tolerance were observed between the MS and MMF groups. Despite similar treatment intolerance, MS was associated with improved efficacy in PSV and SLE compared with MMF. However, baseline group imbalances in factors potentially affecting remission and relapse may have influenced the results. Treatment intolerance was common and strongly associated with low GFR. Further treatment trials are warranted to investigate the effect of GFR on mycophenolic acid pharmacokinetics and clinical outcomes (ISRCTN83027184; EUDRACT 2005-002207-16; Funding Novartis UK).
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Affiliation(s)
- Rachel B Jones
- Vasculitis and Lupus Clinic , Addenbrooke's Hospital , Cambridge , UK
| | - Michael Walsh
- Departments of Medicine and Clinical Epidemiology & Biostatistics , McMaster University , Hamilton, Canada
| | - Afzal N Chaudhry
- Vasculitis and Lupus Clinic , Addenbrooke's Hospital , Cambridge , UK
| | - Kenneth G C Smith
- Vasculitis and Lupus Clinic , Addenbrooke's Hospital , Cambridge , UK ; Cambridge Institute of Medical Research , University of Cambridge School of Clinical Medicine , Cambridge , UK ; Department of Medicine , University of Cambridge School of Clinical Medicine , Cambridge , UK
| | - David R W Jayne
- Vasculitis and Lupus Clinic , Addenbrooke's Hospital , Cambridge , UK ; Department of Medicine , University of Cambridge School of Clinical Medicine , Cambridge , UK
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Zand L, Specks U, Sethi S, Fervenza FC. Treatment of ANCA-associated vasculitis: new therapies and a look at old entities. Adv Chronic Kidney Dis 2014; 21:182-93. [PMID: 24602467 DOI: 10.1053/j.ackd.2014.01.009] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2013] [Revised: 01/14/2014] [Accepted: 01/15/2014] [Indexed: 01/30/2023]
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small-vessel vasculitis that primarily comprises 2 clinical syndromes: granulomatosis with polyangiitis and microscopic polyangiitis. Cyclophosphamide and glucocorticoids have traditionally been used for induction of remission. However, more recent studies have shown that rituximab is as effective as cyclophosphamide for induction therapy in patients with newly diagnosed severe AAV and superior for patients with relapsing AAV. There is also accumulating evidence indicating a potential role of rituximab for maintenance therapy in AAV. In this article, we will review the evidence supporting the various treatment choices for patients with AAV.
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Abstract
The introduction of (oral) cyclophosphamide (CYC) in the treatment of ANCA-associated vasculitides (AAV) has strongly improved prognosis but the side effects of long-term CYC treatment are serious. A number of recent randomized controlled studies have shown that the cumulative dose of CYC can be strongly reduced in the treatment of AAV or even reduced to zero. Maintenance treatment can be performed with azathioprine (AZA), or methotrexate (MTX) in case of intolerance, although the intensity and duration of maintenance treatment is still under discussion. More insight into the mechanisms involved in relapsing disease might allow individualized treatment. Induction of remission can be achieved in cases of mild disease expression with MTX but requires maintenance treatment to prevent relapses. Generalized disease can be treated with pulses of i.v. CYC or, possibly, with MMF. However, recent studies demonstrate the efficacy of RTX in inducing remission without the concomitant use of immunosuppressives. Corticosteroids are part of treatment in all regimens but the intensity and duration of steroid treatment is still being discussed. In life-threatening disease, the adjunctive efficacy of plasma exchange has been demonstrated and its usefulness in less severe disease is under investigation. Taken together, there are, indeed, alternatives for CYC in AAV.
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Affiliation(s)
- Cees G M Kallenberg
- Department of Rheumatology & Clinical Immunology, AA21, University of Groningen, University Medical Center Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.
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Wilfong EM, Seo P. Vasculitis in the intensive care unit. Best Pract Res Clin Rheumatol 2013; 27:95-106. [PMID: 23507060 DOI: 10.1016/j.berh.2013.01.002] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2013] [Accepted: 01/02/2013] [Indexed: 10/27/2022]
Abstract
The systemic vasculitides are a diverse set of diseases linked by the presence of blood-vessel inflammation and are often associated with life-threatening or critical complications, including glomerulonephritis, diffuse alveolar haemorrhage, pulmonary arterial hypertension and airway compromise. The protean manifestations of the systemic vasculitides make them challenging to diagnose. Early recognition, however, is crucial to improving outcomes. This article serves as an introduction to these complex diseases, reviewing the manifestations of systemic vasculitis that may be encountered in an intensive care setting, and outlines an overall approach to their treatment.
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Affiliation(s)
- Erin M Wilfong
- Johns Hopkins University School of Medicine, 1830 E. Monument St., Baltimore, MD 21205, USA.
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Abstract
Cyclophosphamide has greatly improved prognosis in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and proliferative lupus nephritis (LN). However, the side effects of long-term cyclophosphamide treatment are considerable prompting a search for alternatives to cyclophosphamide. For maintenance treatment in AAV, azathioprine is the preferred drug with methotrexate as an alternative in the case of intolerance to azathioprine. Data on mycophenolate mofetil (MMF) for the induction of remission in AAV are being awaited, but rituximab appears as effective as cyclophosphamide in newly diagnosed patients with AAV, and is probably even better for relapsing patients, while the possibility of maintenance treatment with intermittent low-dose infusions of rituximab is being explored. In LN, low-dose intravenous cyclophosphamide is as effective as high-dose cyclophosphamide for the induction of remission, with azathioprine being used for maintenance treatment. MMF can be used in the case of intolerance to cyclophosphamide and might be the first choice in black and Hispanic patients. In the case of intolerance to both cyclophosphamide and MMF, azathioprine with pulses of methylprednisolone can be used. Here, the role of rituximab has not been established. In conclusion, alternatives are available for cyclophosphamide both in AAV and proliferative LN.
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Affiliation(s)
- Cees G M Kallenberg
- Department of Rheumatology & Clinical Immunology, AA21 PO Box 30.001, Groningen 9700 RB, The Netherlands.
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31
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Iglesias-Gamarra A, Peñaranda-Parada E, Cajas-Santana LJ, Quintana-López G, Restrepo-Suárez JF, Arbeláez-Cortés Á, Rondón-Herrera F. Historia del tratamiento de las vasculitis primarias. REVISTA COLOMBIANA DE REUMATOLOGÍA 2012; 19:131-157. [DOI: 10.1016/s0121-8123(12)70022-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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32
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Yunt ZX, Frankel SK, Brown KK. Diagnosis and management of pulmonary vasculitis. Ther Adv Respir Dis 2012; 6:375-90. [DOI: 10.1177/1753465812454693] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023] Open
Abstract
The pulmonary vasculitides are a heterogeneous group of disorders characterized pathologically by vascular destruction with cellular inflammation and necrosis. These disorders can affect small, medium, and large vessels and may be primary or occur secondary to a variety of conditions. Vasculitis involving the lungs is most commonly due to primary, idiopathic, small-vessel antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, which includes granulomatosis with polyangiitis (formerly Wegener’s granulomatosis), Churg–Strauss syndrome, and microscopic polyangiitis. From a clinical perspective these remain among the most challenging of diseases both in terms of diagnosis and treatment. This review will focus on diagnosis and management of ANCA-associated vasculitides.
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Affiliation(s)
- Zulma X. Yunt
- National Jewish Health, A542, 1400 Jackson Street, Denver, CO 80206, USA
| | - Stephen K. Frankel
- Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, and Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, CO, USA
| | - Kevin K. Brown
- Division of Pulmonary Medicine, Department of Medicine, National Jewish Health, and Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado Denver, CO, USA
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Abstract
PURPOSE OF REVIEW Induction treatment of antineutrophil cytoplasmic antibodies (ANCA) associated vasculitis (AAV) is not always successful and nonresponding patients are considered refractory. RECENT FINDINGS Refractory disease should be subdefined to the treatment that was received. Cyclophosphamide refractory AAV occurs in up to 5% of patients. Many more patients develop contraindications to cyclophosphamide or relapse frequently. The latter two patient groups might also benefit from treatment used for cyclophosphamide refractory AAV. SUMMARY The most promising drug for treating refractory AAV is rituximab.
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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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Chapter 13: Pauci-immune focal and segmental necrotizing glomerulonephritis. Kidney Int Suppl (2011) 2012; 2:233-239. [PMID: 25018938 PMCID: PMC4089768 DOI: 10.1038/kisup.2012.26] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
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Abstract
Numerous physiologic variations, including urinary protein excretion, low serum albumin concentrations, and reductions in kidney function (clearance), exist in patients with glomerulonephritis. These factors could alter the disposition of numerous drugs. The purpose of the current article was to review the influence of glomerulonephritis on the pharmacokinetics of drugs used clinically or experimentally in the treatment of these conditions. Several articles or presentations were located that reported on the pharmacokinetics of immunosuppressant, cytotoxic, and therapeutic antibody drugs in populations with glomerulonephritis. Most publications reported an increase in systemic clearance in glomerulonephritis as compared with populations in whom the drugs were typically used and in patients with nonglomerular forms of chronic kidney disease. It appears that the increase in systemic clearance is predominantly through nonrenal clearance pathways, although enhancement of renal clearance has also been appreciated for some drugs. Available preliminary data suggest specific alterations in the activity of individual pathways of drug metabolism and transport. Recommendations are provided for the design of future studies of drugs in the glomerulonephritis population and for inclusion of patients with urinary protein excretion in studies that assess drug pharmacokinetics.
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Affiliation(s)
- Melanie S Joy
- Division of Nephrology and Hypertension, Department of Pharmacotherapy and Experimental Therapeutics, University of North Carolina, CB 7155, 7005 Burnett Womack Building, Chapel Hill, NC 27599-7155, USA.
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Smith RM, Jones RB, Jayne DRW. Progress in treatment of ANCA-associated vasculitis. Arthritis Res Ther 2012; 14:210. [PMID: 22569190 PMCID: PMC3446448 DOI: 10.1186/ar3797] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Autoantibodies to neutrophil cytoplasmic antigen-associated vasculitis (AAV) is characterised by inflammation of blood vessels. The introduction of immunosuppressive therapy with glucocorticoids and cyclophosphamide transformed AAV from a fatal condition to a largely treatable condition. Over the past 30 years, considerable progress has been made refining immunosuppressive regimens with a focus on minimising toxicity. There is, however, a high unmet need in the treatment of AAV. A proportion of patients are refractory to current therapies; 50% experience a relapse within 5 years and treatment toxicity contributes to mortality and chronic disability. As knowledge of the pathogenesis of vasculitis grows, it is mirrored by the availability of biological agents, which herald a revolution in the treatment of vasculitis. Lymphocyte-targeted and cytokine-targeted agents have been evaluated for the treatment of AAV and are entering the routine therapeutic arena with the potential to improve patient outcomes. As rare diseases, treatment advances in vasculitis depend on international collaborative research networks both to establish an evidence base for newer agents and to develop recommendations for patient management.
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Affiliation(s)
- Rona M Smith
- Department of Renal Medicine, Addenbrooke's Hospital, Hills Road, Cambridge CB20QQ, UK.
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Homeister JW, Willis MS. The Molecular Biology and Treatment of Systemic Vasculitis in Children. MOLECULAR AND TRANSLATIONAL VASCULAR MEDICINE 2012. [PMCID: PMC7121654 DOI: 10.1007/978-1-61779-906-8_2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Primary systemic vasculitides are rare in childhood but are associated with significant morbidity and mortality. The cause of the majority of vasculitides is unknown, although it is likely that a complex interaction between environmental factors, such as infections and inherited host responses, triggers the disease and determines the vasculitis phenotype. Several genetic polymorphisms in vasculitides have now been described, which may be relevant in terms of disease predisposition or development of disease complications. Treatment regimens continue to improve with the use of different immunosuppressive medications and newer therapeutic approaches such as biologic agents. This chapter reviews recent studies shedding light on the pathogenesis of vasculitis with emphasis on molecular biology where known, and summarizes current treatment strategies. We discuss new emerging challenges particularly with respect to the long-term cardiovascular morbidity for children with systemic vasculitis and emphasize the importance of future international multicenter collaborative studies to further increase and standardize the scientific base investigating and treating childhood vasculitis.
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Affiliation(s)
- Jonathon W. Homeister
- grid.410711.20000 0001 1034 1720, The University of North Carolina, McAllister Heart Institute, 101 Manning Drive, Chapel Hill, 27599-7525 USA
| | - Monte S. Willis
- grid.410711.20000 0001 1034 1720, The University of North Carolina, McAllister Heart Institute, 103 Mason Farm Road, Chapel Hill, 27599-7525 USA
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Rashidi AA, Alajmi M, Hegazi MO. Mycophenolate mofetil as a maintenance therapy for lupus-related diffuse alveolar hemorrhage: a case report. Lupus 2011; 20:1551-1553. [DOI: 10.1177/0961203311411353] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Diffuse alveolar hemorrhage (DAH) is a life-threatening complication of systemic lupus erythematosus (SLE). Cases complicated with DAH often have active SLE with multi-organ involvement, especially lupus nephritis. We describe a rare case of DAH as the first presenting manifestation of SLE in the absence of lupus nephritis. Remission was induced by IV methylprednisolone, IV cyclophosphamide, and plasmapheresis. Further cycles of cyclophosphamide were prevented by recurrent infections. Maintenance of remission was successfully achieved with oral mycophenolate mofetil 1 g twice daily, with a good control of SLE and without further DAH episodes.
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Affiliation(s)
| | - M Alajmi
- Medical Department, Al Adan Hospital, Kuwait
| | - MO Hegazi
- Medical Department, Al Adan Hospital, Kuwait
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The 2010 Nephrology Quiz and Questionnaire. Clin J Am Soc Nephrol 2011. [DOI: 10.2215/01.cjn.0000927140.19894.ba] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/03/2023]
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Glassock RJ, Bleyer AJ, Bargman JM, Fervenza FC. The 2010 nephrology quiz and questionnaire: part 2. Clin J Am Soc Nephrol 2011; 6:2534-47. [PMID: 21903985 DOI: 10.2215/cjn.06500711] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Presentation of the Nephrology Quiz and Questionnaire (NQQ) has become an annual "tradition" at the meetings of the American Society of Nephrology. It is a very popular session judged by consistently large attendance. Members of the audience test their knowledge and judgment on a series of case-oriented questions prepared and discussed by experts. They can also compare their answers in real time, using audience response devices, to those of program directors of nephrology training programs in the United States, acquired through an Internet-based questionnaire. As in the past, the topics covered were transplantation, fluid and electrolyte disorders, end-stage renal disease and dialysis, and glomerular disorders. Two challenging cases representing each of these categories along with single best answer questions were prepared by a panel of experts (Drs. Hricik, Palmer, Bargman, and Fervenza, respectively). The "correct" and "incorrect" answers then were briefly discussed, after the audience responses and the results of the questionnaire were displayed. The 2010 version of the NQQ was exceptionally challenging, and the audience, for the first time, gained a better overall correct answer score than the program directors, but the margin was small. Last month we presented the transplantation and fluid and the electrolyte cases; in this issue we present the remaining end-stage renal disease and dialysis and the glomerular disorder cases. These articles try to recapitulate the session and reproduce its educational value for a larger audience--that of the readers of the Clinical Journal of the American Society of Nephrology. Have fun.
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Han F, Liu G, Zhang X, Li X, He Q, He X, Li Q, Wang S, Wang H, Chen J. Effects of mycophenolate mofetil combined with corticosteroids for induction therapy of microscopic polyangiitis. Am J Nephrol 2011; 33:185-92. [PMID: 21311184 DOI: 10.1159/000324364] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2010] [Accepted: 01/12/2011] [Indexed: 11/19/2022]
Abstract
AIMS We prospectively compared the effects of oral mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) combined with corticosteroids for induction therapy of microscopic polyangiitis (MPA) with renal involvement over a follow-up period of 6 months. METHODS 41 MPA patients were randomly assigned to either the open-label MMF group or the IVC group. Patients in the MMF group (n = 19) received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) and patients in the IVC group (n = 22) received IVC in monthly pulses of 1.0 g per pulse (0.8 g per pulse for patients with a body weight <50 kg). Both groups received intravenous methylprednisolone 360-500 mg/day for 3 days, followed by oral prednisone 0.6-0.8 mg/kg/day and gradual tapering. RESULTS There was no significant difference of estimated glomerular filtration rate (eGFR) level between the IVC and MMF groups at baseline. At 6 months, the eGFR level increased significantly in both groups, but there was no significant difference between the two. Three patients in the IVC group and 1 in the MMF group received maintenance dialysis within 6 months (p = 0.36). The remission rate was 63.6% in the IVC group and 78.9% in the MMF group (p = 0.23). CONCLUSION MMF is effective for inducing remission in Chinese MPA patients and may represent an alternative therapy to monthly impulses of IVC.
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Affiliation(s)
- Fei Han
- Kidney Disease Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, PR China
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Seror R, Pagnoux C, Ruivard M, Landru I, Wahl D, Rivière S, Aussant S, Mahr A, Cohen P, Mouthon L, Guillevin L. Treatment strategies and outcome of induction-refractory Wegener's granulomatosis or microscopic polyangiitis: analysis of 32 patients with first-line induction-refractory disease in the WEGENT trial. Ann Rheum Dis 2010; 69:2125-30. [PMID: 20643762 DOI: 10.1136/ard.2010.131953] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVES To study the efficacy of rescue treatment strategies and outcomes in patients with Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) not achieving remission with first-line induction with corticosteroids (CS) and intravenous cyclophosphamide (CYC). METHODS 159 eligible patients in the Wegener's Granulomatosis-Entretien (WEGENT) trial newly diagnosed with systemic or renal WG or MPA with ≥ 1 poor prognosis factors were included in this prospective study. Rescue treatment strategies and outcomes in patients with induction-refractory disease were analysed and patient characteristics at diagnosis were compared with those of induction-responders. RESULTS Most patients (n=126, 79.2%) achieved remission; 1 stopped induction because of allergy and 32 were induction-refractory (24 WG and 8 MPA); 11 died rapidly within a median of 2.5 months, 6 of uncontrolled disease, 1 of an infectious complication and 4 of both. Treatment was discontinued in 1 patient with MPA with end-stage renal disease. Induction was switched to oral CYC in 20 patients, combined with infliximab in 1; 15 (75%) achieved remission or low disease activity state, 3 subsequently died of uncontrolled disease and 2 entered remission using several other agents including biological agents. Alveolar haemorrhage and a creatinine level >200 μmol/l were independently associated with induction-refractory disease. Among patients with induction-refractory disease, massive alveolar haemorrhage was associated with higher mortality. CONCLUSION Switching to oral CYC can be an effective rescue treatment for patients with systemic forms of WG or MPA who fail to achieve remission with first-line CS and intravenous CYC. However, a more rapidly effective regimen remains to be identified for most severely affected patients whose outcomes can be rapidly fatal.
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Affiliation(s)
- Raphaèle Seror
- Department of Internal Medicine, National Referral Center for Necrotizing Vasculitides and Systemic Sclerosis, Hôpital Cochin, Assistance Publique-Hôpitaux de Paris, Université Paris-Descartes, Paris, France.
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Differences in Clearance of Mycophenolic Acid Among Renal Transplant Recipients, Hematopoietic Stem Cell Transplant Recipients, and Patients With Autoimmune Disease. Ther Drug Monit 2010; 32:606-14. [DOI: 10.1097/ftd.0b013e3181efd715] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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ANCA-Associated Small Vessel Vasculitis: Clinical and Therapeutic Advances. Curr Rheumatol Rep 2010; 12:406-13. [DOI: 10.1007/s11926-010-0137-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
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Walsh M, Merkel PA, Mahr A, Jayne D. Effects of duration of glucocorticoid therapy on relapse rate in antineutrophil cytoplasmic antibody-associated vasculitis: A meta-analysis. Arthritis Care Res (Hoboken) 2010; 62:1166-73. [PMID: 20235186 DOI: 10.1002/acr.20176] [Citation(s) in RCA: 158] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVE Disease relapses are common for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The role of low-dose glucocorticoids (GC) in relapse prevention is controversial. We undertook a systematic review and meta-analysis to determine if GC target doses influence relapses of AAV. METHODS Medline, EMBase, and Cochrane databases were searched for observational studies and randomized controlled trials of treatment of AAV that included a predefined GC treatment plan. The association of GC target dose with the proportion of relapses in studies was assessed using meta-regression and multilevel generalized linear modeling. RESULTS Thirteen studies (983 patients) were identified for inclusion. There were no studies directly comparing GC regimens. We classified 288 patients as having a nonzero GC target dose by study end and 695 patients as having a zero GC target dose by study end. The pooled proportion of patients with a relapse was 36% (95% confidence interval [95% CI] 25-47%). GC regimen was the most significant variable explaining the variability between the proportions of patients with relapses. The proportion of patients with a relapse was 14% (95% CI 10-19%) in nonzero GC target dose studies and 43% (95% CI 33-52%) in zero GC target dose studies. Differences other than GC regimens exist between studies that complicate the comparability of trials and isolation of the variability in relapses due to GC target alone. CONCLUSION Studies with longer courses of GC in AAV are associated with fewer relapses. These results have implications for study design and outcome assessment in clinical trials of AAV.
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Holle JU, Laudien M, Gross WL. Clinical Manifestations and Treatment of Wegener's Granulomatosis. Rheum Dis Clin North Am 2010; 36:507-26. [DOI: 10.1016/j.rdc.2010.05.008] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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