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Chau KWT, Thet Z, Gardner LS, Khoo TK, Lam AK, Ranganathan D. Therapeutics controversies in antineutrophilic cytoplasmic antibody-associated vasculitis. Clin Exp Nephrol 2025:10.1007/s10157-025-02693-w. [PMID: 40392453 DOI: 10.1007/s10157-025-02693-w] [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: 06/08/2024] [Accepted: 04/26/2025] [Indexed: 05/22/2025]
Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by inflammation of small- to medium-sized blood vessels with ANCAs. Induction therapy has historically involved cyclophosphamide (CYC) and glucocorticoids (GCS), with rituximab (RTX) emerging as a preferred alternative. Studies addressed the efficacy of RTX in severe kidney diseases, showing results comparable to CYC. In severe diseases that are unsuitable for high-dose CYC, combined RTX and low-dose CYC demonstrate promising results. There is a recent trend to administer low-dose GCS to reduce infections and other complications. Recent trials have questioned the broader role of plasma exchange (PLEX), influencing guidelines' updates. Current indications for PLEX include severe kidney dysfunction, positive glomerular basement membrane antibody, and diffuse alveolar hemorrhage that requires oxygen support at presentation. Maintenance therapy options include azathioprine, RTX, and methotrexate. RTX's efficacy as a maintenance agent was demonstrated in trials. However, controversies in dosing frequency persist. The optimal duration of maintenance therapy remains debated, with guidelines suggesting 18-48 months. More recent studies proposed longer durations to reduce the risk of relapse, thus challenging existing guidelines. Complement involvement in AAV has been increasingly recognized. Studies show that complement 3 depositions in the glomeruli correlate with severe disease and complement inhibitors such as avacopan demonstrated efficacy in the management of AAV. Other complement inhibitors, such as eculizumab and vilobelimab, are being explored. In conclusion, AAV management has made significant advances, but controversies persist. Future research should refine therapeutic regimens and explore novel targeted treatments for personalized medicine in AAV.
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Affiliation(s)
- Ken W T Chau
- School of Medicine and Dentistry, Griffith University, G40 8.34, Gold Coast, QLD, 4222, Australia
- Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
| | - Zaw Thet
- School of Medicine and Dentistry, Griffith University, G40 8.34, Gold Coast, QLD, 4222, Australia
- Rockhampton Hospital, Rockhampton, QLD, Australia
| | | | - Tien K Khoo
- School of Medicine and Dentistry, Griffith University, G40 8.34, Gold Coast, QLD, 4222, Australia
- Graduate School of Medicine, University of Wollongong, Wollongong, NSW, Australia
| | - Alfred K Lam
- School of Medicine and Dentistry, Griffith University, G40 8.34, Gold Coast, QLD, 4222, Australia.
- Gold Coast University Hospital, Gold Coast, QLD, Australia.
- Mayne Medical School, University of Queensland, Brisbane, QLD, Australia.
| | - Dwarakanathan Ranganathan
- School of Medicine and Dentistry, Griffith University, G40 8.34, Gold Coast, QLD, 4222, Australia
- Kidney Health Service, Royal Brisbane and Women's Hospital, Brisbane, QLD, Australia
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Ivković V, Windpessl M, Berke I, Geetha D, Callemeyn J, Norouzi S, Bajema IM, Kronbichler A. ANCA-Associated Glomerulonephritis: Diagnosis and Therapy Proceedings of the Henry Shavelle Lectureship. GLOMERULAR DISEASES 2025; 5:26-47. [PMID: 39991195 PMCID: PMC11842095 DOI: 10.1159/000542925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 11/29/2024] [Indexed: 02/25/2025]
Abstract
Background Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) frequently affects the kidney. Glomerulonephritis (GN) in AAV, ANCA-GN, not only dictates therapeutic decisions but is also of relevance for overall survival influencing the risk of cardiovascular disease and serious infections. Summary A diagnosis of ANCA-GN includes laboratory investigations including urinalysis and a thorough assessment of potential organ involvement. A kidney biopsy can be performed to ascertain the diagnosis but has an additional prognostic relevance and tools have been established to predict long-term kidney survival. Experimental biomarkers indicating kidney inflammation include urinary soluble CD163 and the presence of urinary T cells. Therapeutic options are refined and some of these therapies, such as the added value of performing plasma exchange, are the matter of controversial discussions. Safe reduction of cumulative exposure to glucocorticoids and eventually the use of avacopan to substantially reduce glucocorticoid exposure has been implemented in most centers. In the remission of maintenance, the optimal duration of therapy is still unclear, but extended use of rituximab as maintenance agent has shown long-term remission rates, thus limiting the damage accrued by relapsing disease and thus also reducing the risk of end-stage kidney disease (ESKD). Avacopan has been the first agent with a glomerular filtration rate-sparing effect, likely due to more rapid control of kidney inflammation. Those reaching ESKD should be evaluated for kidney transplantation and the risk of remaining on dialysis must be balanced against the risk of recurrence of disease following transplantation. Key Messages The advent of a magnitude of landmark studies in ANCA-GN has refined diagnostic approaches, implemented tools to predict kidney outcome, and eventually led to the approval of newer therapies with avacopan, the latest addition to the armamentarium. Once ESKD is present, patients should be considered for kidney transplantation as remaining on dialysis portends poor overall prognosis.
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Affiliation(s)
- Vanja Ivković
- Department of Internal Medicine, Department of Nephrology, Hypertension, Dialysis and Transplantation, University Hospital Center Zagreb, Zagreb, Croatia
- University of Rijeka Faculty of Health Studies, Rijeka, Croatia
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
| | - Martin Windpessl
- Department of Internal Medicine IV, Nephrology, Klinikum Wels-Grieskirchen, Wels, Austria
| | - Ilay Berke
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
| | - Duvuru Geetha
- Division of Nephrology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Jasper Callemeyn
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
- Nephrology and Renal Transplantation Research Group, Department of Microbiology, Immunology and Transplantation, Leuven, Belgium
- Department of Nephrology and Renal Transplantation, University Hospitals Leuven, Leuven, Belgium
| | - Sayna Norouzi
- Division of Nephrology, Department of Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA
| | - Ingeborg M. Bajema
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center, Groningen, The Netherlands
| | - Andreas Kronbichler
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Internal Medicine IV, Nephrology and Hypertension, Medical University Innsbruck, Innsbruck, Austria
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Casal Moura M, Zubidat D, Liebana MP, Sethi S, Soler MJ, Zand L, dos Santos FG, Nardelli L, Leon-Roman J, Sousa C, Warrington KJ, Specks U, Fervenza FC. Predictive Factors of Renal Recovery and Progression to End-Stage Kidney Disease in Patients With Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis With Severe Kidney Disease. Kidney Int Rep 2024; 9:1284-1297. [PMID: 38707835 PMCID: PMC11068975 DOI: 10.1016/j.ekir.2024.02.1431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2023] [Revised: 02/21/2024] [Accepted: 02/25/2024] [Indexed: 05/07/2024] Open
Abstract
Introduction A significant number of patients with antineutrophil cytoplasmic antibodies (ANCA)- associated vasculitis (AAV) with glomerulonephritis (AAV-GN) still progress to end-stage kidney disease (ESKD, estimated glomerular filtration rate [eGFR] <15 ml/min per 1.73 m2) despite advances in remission-induction treatment. Methods This is a retrospective cohort study on myeloperoxidase (MPO)-ANCA or proteinase 3 (PR3)-ANCA positive patients with AAV (microscopic polyangiitis, MPA; or granulomatosis with polyangiitis, GPA) and eGFR <15 ml/min per 1.73 m2 or ESKD at presentation. Renal recovery, dialysis discontinuation, and persistence of ESKD after standard remission-induction, with or without the use of plasma exchange (PLEX) were analyzed. Results We analyzed 166 patients with biopsy-proven active AAV-GN and eGFR <15 ml/min per 1.73 m2 at the time of diagnosis. Patients received glucocorticoids with cyclophosphamide (CYC) (n = 84) or with rituximab (RTX) (n = 72) for remission-induction, and 49 received PLEX. The predictors of renal recovery were erythrocyte sedimentation rate, serum creatinine (SCr) at diagnosis, and minimal or mild chronicity changes. We further analyzed 71 patients who started dialysis with or without PLEX within 4 weeks of AAV-GN diagnosis. The predictors of dialysis discontinuation were minimal chronicity changes in kidney biopsy at diagnosis (odds ratio = 6.138; 95% confidence interval [CI]: 1.389-27.118; P = 0.017). Predictors of persistence of ESKD within 12 months included higher SCr at diagnosis (incidence rate ratio [IRR] = 1.086; 95% CI: 1.005-1.173; P = 0.037), and moderate (IRR = 3.797; 95% CI: 1.090-13.225; P = 0.036), or severe chronicity changes in kidney biopsy (IRR = 5.883; 95% CI: 1.542-22.439; P =0.009). Conclusion In our cohort, kidney recovery, dialysis discontinuation, and persistence of ESKD in patients with AAV-GN and eGFR <15 ml/min per 1.73 m2 depended on SCr and histologic findings on kidney biopsies at the time of diagnosis and was not affected by the addition of PLEX.
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Affiliation(s)
- Marta Casal Moura
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Dalia Zubidat
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Marc Patricio Liebana
- Servicio de Nefrologia, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Universitari Vall d'Hebron, Barcelona, Catalunya, Spain
| | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Maria Jose Soler
- Servicio de Nefrologia, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Universitari Vall d'Hebron, Barcelona, Catalunya, Spain
| | - Ladan Zand
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Fernanda G. dos Santos
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Luca Nardelli
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Juan Leon-Roman
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
- Servicio de Nefrologia, Centro de Referencia en Enfermedad Glomerular Compleja del Sistema Nacional de Salud (CSUR), Hospital Universitari Vall d'Hebron, Barcelona, Catalunya, Spain
| | - Ciria Sousa
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Kenneth J. Warrington
- Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Ulrich Specks
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, USA
| | - Fernando C. Fervenza
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota, 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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Casal Moura M, Gauckler P, Anders HJ, Bruchfeld A, Fernandez-Juarez GM, Floege J, Frangou E, Goumenos D, Segelmark M, Turkmen K, van Kooten C, Tesar V, Geetha D, Fervenza FC, Jayne DRW, Stevens KI, Kronbichler A. Management of antineutrophil cytoplasmic antibody-associated vasculitis with glomerulonephritis as proposed by the ACR 2021, EULAR 2022 and KDIGO 2021 guidelines/recommendations. Nephrol Dial Transplant 2023; 38:2637-2651. [PMID: 37164940 PMCID: PMC10615627 DOI: 10.1093/ndt/gfad090] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Indexed: 05/12/2023] Open
Abstract
Updated guidelines on the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were released in 2021 by the American College of Rheumatology jointly with the Vasculitis Foundation and, subsequently, in 2022 by the European Alliance of Associations for Rheumatology. In addition, in 2021, the Kidney Disease: Improving Global Outcomes had released updated recommendations on the treatment of AAV with glomerulonephritis (AAV-GN). Kidney involvement is particularly relevant in microscopic polyangiitis and granulomatosis with polyangiitis, but is less frequent in eosinophilic granulomatosis with polyangiitis. The management of AAV-GN has been a focus for drug development and change over the past 10 years. Avoidance of progression to end-stage kidney disease (ESKD) or kidney failure is one of the main unmet needs in the management of AAV, with ESKD having a major impact on morbidity, health costs and mortality risk. Relevant changes in AAV-GN management are related to remission-induction treatment of patients with severe kidney disease, the use of glucocorticoids and avacopan, and remission-maintenance treatment. All the documents provide guidance in accordance with the evidence-based standard of care available at the time of their release. With our work we aim to (i) show the progress made and identify the differences between guidelines and recommendations, (ii) discuss the supporting rationale for those, and (iii) identify gaps in knowledge that could benefit from additional research and should be revised in subsequent updates.
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Affiliation(s)
- Marta Casal Moura
- Division of Pulmonary and Critical Care Medicine, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
- Faculdade de Medicina da Universidade do Porto, Departamento de Biomedicina, Porto, Portugal
| | - Philipp Gauckler
- Department of Internal Medicine IV (Nephrology and Hypertension), Medical University Innsbruck, Innsbruck, Austria
| | - Hans-Joachim Anders
- Department of Internal Medicine IV, Hospital of the Ludwig Maximilians University, Munich, Germany
| | - Annette Bruchfeld
- Department of Health, Medicine and Caring Sciences, Linköping University, Linköping, Sweden
- Department of Renal Medicine, Karolinska University Hospital and CLINTEC Karolinska Institutet, Stockholm, Sweden
| | | | - Jürgen Floege
- Division of Nephrology, RWTH Aachen University Hospital, Aachen, Germany
| | - Eleni Frangou
- Department of Nephrology, Limassol General Hospital, SHSO, Cyprus; Medical School, University of Nicosia, Nicosia, Cyprus
| | - Dimitrios Goumenos
- Department of Nephrology and Renal Transplantation, Patras University Hospital, Patras, Greece
| | - Marten Segelmark
- Division of Nephrology, Department of Clinical Sciences Lund, Lund University and Skane University Hospital, Lund, Sweden
| | - Kultigin Turkmen
- Division of Nephrology, Department of Internal Medicine, Necmettin Erbakan University, Konya, Turkey
| | - Cees van Kooten
- Division of Nephrology and Transplant Medicine, Department of Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Vladimir Tesar
- Department of Nephrology, First Faculty of Medicine and General University Hospital, Charles University, Prague, Czechia
| | - Duvuru Geetha
- Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States of America
| | - Fernando C Fervenza
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - David R W Jayne
- Department of Medicine, University of Cambridge, Cambridge, United Kingdom
| | - Kate I Stevens
- Division of Nephrology and Transplantation, Queen Elizabeth University Hospital, Glasgow, United Kingdom
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Zand L, Fervenza FC. Anti-CD20 should be the first-line treatment in high-risk membranous nephropathy. Clin Kidney J 2023; 16:1420-1425. [PMID: 37669312 PMCID: PMC10468755 DOI: 10.1093/ckj/sfad075] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Indexed: 09/05/2023] Open
Abstract
Membranous nephropathy (MN) is a common cause of nephrotic syndrome (NS) in adults and if untreated can progress to endstage kidney disease. Factors considered to place a patient at high or very high risk for progression include elevated serum creatinine at baseline, declining kidney function, persistent heavy proteinuria (>8 g/24 h), or persistent NS, presence of life-threatening complications related to NS (such as venous thromboembolic events), or very high anti-PLA2R antibody titers (>150 RU/ml). Patients who are at high or very high risk of progression should be treated with immunosuppression therapy to induce remission of proteinuria and to avoid progressive loss of kidney function. Traditional forms of immunosuppression for patients with MN have included the use of cyclic courses of corticosteroids with cyclophosphamide or calcineurin inhibitors. These forms of therapy are associated with significant toxicity, e.g. corticosteroids (infections, diabetes, weight gain), cyclophosphamide (infertility, severe leukopenia, malignancy), and calcineurin inhibitors (hypertension, nephrotoxicity). The introduction of anti-CD20+ B-cell therapies in the late 1990s has changed the landscape. In this article we will argue that anti-CD20+ B therapy should be the treatment of choice for patients at high/very high risk of progression when considering its efficacy and side-effect profile.
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Affiliation(s)
- Ladan Zand
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, USA
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7
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Magri SJ, Ugarte-Gil MF, Brance ML, Flores-Suárez LF, Fernández-Ávila DG, Scolnik M, Sato EI, de Souza AWS, Saldarriaga-Rivera LM, Babini AM, Zamora NV, Felquer MLA, Vergara F, Carlevaris L, Scarafia S, Guppy ERS, Unizony S. Pan American League of Associations for Rheumatology Guidelines for the treatment of ANCA-associated vasculitis. THE LANCET. RHEUMATOLOGY 2023; 5:e483-e494. [PMID: 38251580 DOI: 10.1016/s2665-9913(23)00128-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 01/23/2024]
Abstract
Considerable variability exists in the way health-care providers treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Latin America. The most frequently used treatments for ANCA-associated vasculitis are cyclophosphamide and prolonged glucocorticoid tapers; however, randomised controlled trials conducted over the past 30 years have led to the development of several evidence-based treatment alternatives for these patients. Latin America faces socioeconomic challenges that affect access to care, and the use of certain costly medications with proven efficacy ANCA-associated vasculitis is often restricted. For these reasons, the Pan American League of Associations for Rheumatology developed the first ANCA-associated vasculitis treatment guidelines tailored for Latin America. A panel of local vasculitis experts generated clinically meaningful questions related to the treatment of ANCA-associated vasculitis using the Population, Intervention, Comparator, and Outcome (PICO) format. Following the Grading of Recommendations Assessment, Development, and Evaluation methodology, a team of methodologists conducted a systematic literature review. The panel of vasculitis experts voted on each PICO question and made recommendations, which required at least 70% agreement among the voting members. 21 recommendations and two expert opinion statements for the treatment of ANCA-associated vasculitis were developed, considering the current evidence and the socioeconomic characteristics of the region. These recommendations include guidance for the use of glucocorticoids, non-glucocorticoid immunosuppressants, and plasma exchange.
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Affiliation(s)
- Sebastián Juan Magri
- Rheumatology Unit, Hospital Italiano de La Plata, La Plata, Buenos Aires, Argentina
| | | | | | - Luis Felipe Flores-Suárez
- Primary Systemic Vasculitides Clinic, Instituto Nacional de Enfermedades Respiratorias, Mexico City, Mexico
| | | | - Marina Scolnik
- Rheumatology Unit, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
| | - Emilia Inoue Sato
- Medicine Department, Universidad Federal de São Paulo, São Paulo, Brazil
| | | | | | | | | | | | | | | | - Santiago Scarafia
- Rheumatology Unit, Hospital Municipal San Cayetano, Virreyes, Argentina
| | | | - Sebastian Unizony
- Vasculitis and Glomerulonephritis Center, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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8
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Odler B, Bruchfeld A, Scott J, Geetha D, Little MA, Jayne DRW, Kronbichler A. Challenges of defining renal response in ANCA-associated vasculitis: call to action? Clin Kidney J 2023; 16:965-975. [PMID: 37261001 PMCID: PMC10229283 DOI: 10.1093/ckj/sfad009] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Indexed: 12/06/2023] Open
Abstract
Avoiding end-stage kidney disease in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) has a high therapeutic priority. Although renal response is a crucial measure to capture clinically relevant changes, clinal trials have used various definitions and no well-studied key surrogate markers to predict renal outcome in AAV exist. Differences in clinical features and histopathologic and therapeutic approaches will influence the course of kidney function. Its assessment through traditional surrogates (i.e. serum creatinine, glomerular filtration rate, proteinuria, hematuria and disease activity scores) has limitations. Refinement of these markers and the incorporation of novel approaches such as the assessment of histopathological changes using cutting-edge molecular and machine learning mechanisms or new biomarkers could significantly improve prognostication. The timing is favourable since large datasets of trials conducted in AAV are available and provide a valuable resource to establish renal surrogate markers and, likely, aim to investigate optimized and tailored treatment approaches according to a renal response score. In this review we discuss important points missed in the assessment of kidney function in patients with AAV and point towards the importance of defining renal response and clinically important short- and long-term predictors of renal outcome.
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Affiliation(s)
- Balazs Odler
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Annette Bruchfeld
- Department of Clinical Science, Intervention and Technology, Division of Renal Medicine Karolinska Institutet, Stockholm, Sweden
- Department of Health, Medicine and Caring Sciences, Linköpings Universitet, Linköping, Sweden
| | - Jennifer Scott
- Trinity Health Kidney Center, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Duvuru Geetha
- Division of Nephrology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA
| | - Mark A Little
- Trinity Health Kidney Center, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - David R W Jayne
- Department of Medicine, University of Cambridge, Cambridge, UK
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9
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Morris A, Geetha D. Advances in remission induction therapy for ANCA-associated vasculitis. Best Pract Res Clin Rheumatol 2023; 37:101828. [PMID: 37244804 DOI: 10.1016/j.berh.2023.101828] [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: 03/29/2023] [Revised: 04/09/2023] [Accepted: 04/23/2023] [Indexed: 05/29/2023]
Abstract
Since its first description 40 years ago, huge strides have been made in the management of ANCA-associated vasculitis with improved patient outcomes. The use of cyclophosphamide and/or B-cell depleting therapy alongside glucocorticoids remains the cornerstone of therapy in organ or life-threatening disease, but recent trials have re-evaluated existing treatment strategies, alongside the development of new treatment targets. This has led to refinement of the role of plasma exchange, the use of reduced dosing of oral glucocorticoids with improved patient outcomes, as well as other treatment adjuvants/options of steroid minimization including C5a receptor antagonism and IL-5 inhibition. In this review we examine developments in remission induction therapy for ANCA-associated vasculitis.
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Affiliation(s)
- Adam Morris
- Renal Medicine, Royal Preston Hospital, Preston, UK
| | - Duvuru Geetha
- Division of Nephrology, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
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10
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Habibi MA, Alesaeidi S, Zahedi M, Hakimi Rahmani S, Piri SM, Tavakolpour S. The Efficacy and Safety of Rituximab in ANCA-Associated Vasculitis: A Systematic Review. BIOLOGY 2022; 11:biology11121767. [PMID: 36552276 PMCID: PMC9774915 DOI: 10.3390/biology11121767] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Revised: 11/25/2022] [Accepted: 11/30/2022] [Indexed: 12/12/2022]
Abstract
Background and aim: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a rare multisystem autoimmune disease developed by autoantibody production against human neutrophilic granulocytes, including proteinase-3 (PR3) and myeloperoxidase (MPO). The management of AAV patients is difficult due to the multiorgan involvement, high rate of relapse, and complications of immunosuppressive agents that make it challenging. This study aims to investigate the efficacy and safety of rituximab (RTX) therapy in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) subtypes. Method: The PubMed/Medline database was searched for any studies related to RTX therapy in ANCA-associated vasculitis (GPA and MPA subtypes), from inception to 1 August 2022, and proceeded in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: Our search resulted in 1082 initial records. After the elimination of review papers, irrelevant studies, and non-English records, 223 articles were included, and the data related to the efficacy and safety of RTX therapy were extracted. Several randomized and non-randomized studies showed that RTX is an effective treatment option for patients with AAV. Most of the studies showed the very effective effect of RTX in controlling disease in AAV patients, including pediatrics, adults, and elderlies, although RTX cannot completely prevent relapse. However, maintenance therapy helps delay the disease's relapse and causes sustained remission. Not only the licensed dose (375 mg/m2 intravenous per week for 4 weeks) could induce disease remission, but studies also showed that a single infusion of RTX could be effective. Although RTX could resolve many rare manifestations in AAV patients, there are few reports showing treatment failure. Additionally, few sudies have reported the unexpeted worsening of the disease after RTX administration. Generally, RTX is relatively safe compared to conventional therapies, but some serious adverse effects, mainly infections, cytopenia, hypogammaglobinemia, malignancy, and hypersensitivity have been reported. Conclusions: RTX is an effective and relatively safe therapeutic option for AAV. Studies on the evaluation of the safety profiles of RTX and the prevention of severe RTX-related side effects in AAV patients are required.
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Affiliation(s)
- Mohammad Amin Habibi
- Clinical Research Development Center, Qom University of Medical Sciences, Qom 3719964797, Iran
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran P.O. Box 982166757001, Iran
| | - Samira Alesaeidi
- Rheumatology Research Center, Tehran University of Medical Sciences, Tehran P.O. Box 982188220065, Iran
| | - Mohadeseh Zahedi
- Clinical Research Development Center, Qom University of Medical Sciences, Qom 3719964797, Iran
| | - Samin Hakimi Rahmani
- Clinical Research Development Center, Qom University of Medical Sciences, Qom 3719964797, Iran
| | - Seyed Mohammad Piri
- Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran P.O. Box 982166757001, Iran
| | - Soheil Tavakolpour
- Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA
- Correspondence: ; Tel.: +1-(617)-906-2978
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11
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Casal Moura M, Branco C, Martins-Martinho J, Ferraro JL, Berti A, Nogueira E, Ponte C. A glance into the future of anti-neutrophil cytoplasmic antibody-associated vasculitis. Ther Adv Musculoskelet Dis 2022; 14:1759720X221125979. [PMID: 36353270 PMCID: PMC9638684 DOI: 10.1177/1759720x221125979] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 08/26/2022] [Indexed: 11/06/2022] Open
Abstract
In the past decade, unprecedented progress has been made in understanding the pathogenesis, diagnosis, assessment, and treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). International collaborations and input from several fields (e.g. immunology, rheumatology, and nephrology) have been critical for analyzing demographics, disease manifestations, and outcomes in clinical research studies. Such efforts opened new avenues for generating novel questions and rationale to design better clinical trials. In addition, clinical research has been a source of several biological discoveries and the starting point for knowledge seeking on the pathophysiology of AAV. Interestingly, the blending of clinical and basic research provides a platform for personalized medicine. Despite recent revisions on AAV classification, the incorporation of new findings on disease genetics and immunologic responses may soon result in changes in clinical practice. These advances will enhance the selection of more specific and targeted therapies. However, current unmet needs in the management of AAV are still sizable and heavily impact long-term survival. Especially, frequent relapses, damage accrual, and high morbidity contribute to poor outcomes. Finally, the lack of defined biomarkers for disease activity and the prognosis is a permanent challenge in AAV research. Our work provides an overview of the current state of the art in AAV literature and suggests bridges for the remaining knowledge gaps. It offers potential future directions for the clinical assessment, management, and research in the field toward a more personalized medicine approach.
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Affiliation(s)
- Marta Casal Moura
- Division of Pulmonary and Critical Care
Medicine, Department of Medicine, and Thoracic Research Disease Unit, Mayo
Clinic College of Medicine and Science, 200 First Street, Rochester, MN
55905-0002, USA
- Department of Medicine, Faculty of Medicine,
Porto University, Porto, Portugal
| | - Carolina Branco
- Renal Transplant and Nephrology Department,
Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte,
Centro Académico de Medicina de Lisboa, Lisbon, Portugal
| | - Joana Martins-Martinho
- Rheumatology Department, Hospital de Santa
Maria, Centro Hospitalar Universitário Lisboa Norte, Centro Académico de
Medicina de Lisboa, Lisbon, Portugal
| | - José Luís Ferraro
- Rheumatology Department, Hospital de Santa
Maria, Centro Hospitalar Universitário Lisboa Norte, Centro Académico de
Medicina de Lisboa, Lisbon, Portugal
| | - Alvise Berti
- Division of Pulmonary and Critical Care
Medicine, Department of Medicine, and Thoracic Research Disease Unit, Mayo
Clinic College of Medicine and Science, Rochester, MN, USA
- Rheumatology Department, Santa Chiara Hospital
and Department of Cellular, Computational and Integrative Biology (CIBIO),
University of Trento, Trento, Italy
| | - Estela Nogueira
- Renal Transplant and Nephrology Department,
Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte,
Centro Académico de Medicina de Lisboa, Lisbon, Portugal
| | - Cristina Ponte
- Rheumatology Department, Hospital de Santa
Maria, Centro Hospitalar Universitário Lisboa Norte, Centro Académico de
Medicina de Lisboa, Lisbon, Portugal
- Unidade de Investigação em Reumatologia,
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de
Lisboa, Lisbon, Portugal
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12
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Chevet B, Cornec D, Casal Moura M, Cornec-Le Gall E, Fervenza FC, Warrington KJ, Specks U, Berti A. Diagnosing and treating ANCA-associated vasculitis: an updated review for clinical practice. Rheumatology (Oxford) 2022; 62:1787-1803. [PMID: 36315063 DOI: 10.1093/rheumatology/keac623] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2022] [Revised: 09/14/2022] [Accepted: 10/05/2022] [Indexed: 03/29/2023] Open
Abstract
Abstract
ANCA-associated vasculitides (AAV) are a group of rare, primary, systemic necrotizing small-vessel vasculitides. Granulomatosis with polyangiitis and microscopic polyangiitis account for ∼80–90% of all AAV. Exposure to silica dust, farming and chronic nasal Staphylococcus aureus carriage are associated with increased risk of developing AAV. When a diagnosis of AAV is suspected, as in patients with multisystem organ dysfunction or those with features such as chronic recurrent rhinosinusitis, cavitated lung nodules, palpable purpura or acute kidney injury, then appropriate further investigations are needed, including ANCA testing. In this scenario, a structured clinical assessment should be conducted, evaluating all the organs possibly involved, and tissue biopsy may be necessary for confirmation of the diagnosis. Therapeutic algorithms vary based on the severity of AAV, the clinical diagnosis/ANCA specificity, and the patient’s age, weight, comorbidities and prognosis. Recent data favour rituximab as a preferable option for both induction and maintenance of remission. In addition, regimens with less glucocorticoids are equally effective and safer in inducing remission compared with conventional regimens, and avacopan is an effective glucocorticoid-sparing option. In contrast, there is not compelling evidence to support the routine use of plasma exchange in addition to standard remission-induction therapy in AAV. ANCA and other biomarkers can be helpful in association with clinical assessment to guide diagnosis and treatment decisions. Patients should be frequently evaluated during follow-up for possible disease relapses or treatment-related morbidity, and for monitoring damage accrual, especially metabolic and cardiovascular damage.
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Affiliation(s)
- Baptiste Chevet
- LBAI, UMR1227, Univ Brest, Inserm, Labex IGO, CHU de Brest, Brest, France
| | - Divi Cornec
- LBAI, UMR1227, Univ Brest, Inserm, Labex IGO, CHU de Brest, Brest, France
| | - Marta Casal Moura
- Department Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Thoracic Research Disease Unit, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | | | | | | | - Ulrich Specks
- Department Division of Pulmonary and Critical Care Medicine, Department of Medicine, and Thoracic Research Disease Unit, Mayo Clinic College of Medicine and Science, Rochester, MN, USA
| | - Alvise Berti
- Rheumatology, Santa Chiara Regional Hospital, APSS Trento, and Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Italy
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13
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Sethi S, De Vriese AS, Fervenza FC. Acute glomerulonephritis. Lancet 2022; 399:1646-1663. [PMID: 35461559 DOI: 10.1016/s0140-6736(22)00461-5] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 02/10/2022] [Accepted: 02/28/2022] [Indexed: 12/12/2022]
Abstract
Glomerulonephritis is a heterogeneous group of disorders that present with a combination of haematuria, proteinuria, hypertension, and reduction in kidney function to a variable degree. Acute presentation with full blown nephritic syndrome or rapidly progressive glomerulonephritis is uncommon and is mainly restricted to patients with post-infectious glomerulonephritis, anti-neutrophil cytoplasmic antibodies-associated vasculitis, and anti-glomerular basement membrane disease. Most frequently, patients present with asymptomatic haematuria and proteinuria with or without reduced kidney function. All glomerulonephritis disorders can show periods of exacerbation, but disease flairs characteristically occur in patients with IgA nephropathy or C3 glomerulopathy. The gold standard for the diagnosis of a glomerulonephritis is a kidney biopsy, with a hallmark glomerular inflammation that translates into various histopathological patterns depending on the location and severity of the glomerular injury. Traditionally, glomerulonephritis was classified on the basis of the different histopathological patterns of injury. In the last few years, substantial progress has been made in unravelling the underlying causes and pathogenetic mechanisms of glomerulonephritis and a causal approach to the classification of glomerulonephritis is now favoured over a pattern-based approach. As such, glomerulonephritis can be broadly classified as immune-complex glomerulonephritis (including infection-related glomerulonephritis, IgA nephropathy, lupus nephritis, and cryoglobulinaemic glomerulonephritis), anti-neutrophil cytoplasmic antibodies-associated (pauci-immune) glomerulonephritis, anti-glomerular basement membrane glomerulonephritis, C3 glomerulopathy, and monoclonal immunoglobulin-associated glomerulonephritis. We provide an overview of the clinical presentation, pathology, and the current therapeutic approach of the main representative disorders in the spectrum of glomerulonephritis.
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Affiliation(s)
- Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - An S De Vriese
- Division of Nephrology and Infectious Diseases, AZ Sint-Jan Brugge, Brugge, Belgium; Department of Internal Medicine, Ghent University, Ghent, Belgium
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14
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OUP accepted manuscript. Rheumatology (Oxford) 2022; 61:4056-4064. [DOI: 10.1093/rheumatology/keac046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2021] [Revised: 01/06/2022] [Indexed: 11/12/2022] Open
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15
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Zhang P, Yang X, He X, Hu J, Gao CL, Xia ZK. Relationship between Renal Damage and Serum Complement C3 in Children with Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis. Nephron Clin Pract 2021; 145:633-641. [PMID: 34198299 DOI: 10.1159/000516533] [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: 04/01/2020] [Accepted: 03/21/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND Anti-neutrophil cytoplasmic antibody-associated vasculitis (AAV) disease is a well-known antibody-induced autoimmune disease. The pathogenesis of AAV has not yet been completely clarified, but may be related to heredity, infection, environmental factors, cellular immunity, etc. In recent years, complement in AAV pathogenesis has become the latest research hotspot, and the decrease of serum complement C3 is associated with poor prognosis of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. In the current study, we investigated the associations between serum complement C3 and kidney injury in AAV children. METHODS Twenty-four children with AAV admitted to our hospital from June 2014 to June 2019 were divided into the low C3 group and the normal C3 group. All the children have undergone renal biopsy. The clinical manifestations, laboratory tests, renal pathology, treatment, and prognosis of the 2 groups were observed. The primary end point was end-stage renal disease (ESRD). RESULTS It was shown that kidney injury was more obvious in patients with low C3 than in patients with normal C3 serum. The values of ESR, Scr, and UA before treatment in the low C3 group were higher than those in the normal C3 group (p < 0.01); the values of RBC, Hb, PLT, ALB, LDH, and eGFR in the normal C3 group were higher than those in the low C3 group (p < 0.01). The values of urinary protein and NAG enzyme in the low C3 group were higher than those in the normal C3 group (p < 0.01). The area of glomerular abandonment, sclerosis, segmental sclerosis, crescent, cellular crescent, cellular fibrous crescent, fibrous crescent, segmental loop necrosis, and the number of cases with acute renal tubulointerstitial lesions in the low C3 group were bigger than those in the normal C3 group (p < 0.05 and < 0.01). The number of cases with C3 deposition in the low C3 group was higher than that in the normal C3 group (p < 0.05). The number of patients receiving CRRT and PE in the low C3 group was higher than that in the normal C3 group (p < 0.05 and < 0.01). In this study, 3 children entered the stage of ESRD and 1 died in the low C3 group. CONCLUSION The kidney injury of AAV children with low complement C3 is serious, and the prognosis is poor. We should pay attention to the influence of decreased complement C3 on the condition and prognosis of AAV children.
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Affiliation(s)
- Pei Zhang
- Paediatrics of Jinling Hospital, Nanjing, China,
| | - Xiao Yang
- Paediatrics of Jinling Hospital, Nanjing, China
| | - Xu He
- Paediatrics of Jinling Hospital, Nanjing, China
| | - Jian Hu
- Department of Paediatrics, Jinling Hospital, The First School of Clinical Medicine, Southern Medical University, Guangzhou, China
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16
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Trivioli G, Gopaluni S, Urban ML, Gianfreda D, Cassia MA, Vercelloni PG, Calatroni M, Bettiol A, Esposito P, Murtas C, Alberici F, Maritati F, Manenti L, Palmisano A, Emmi G, Romagnani P, Moroni G, Gregorini G, Sinico RA, Jayne DR, Vaglio A. Slowly progressive anti-neutrophil cytoplasmic antibody-associated renal vasculitis: clinico-pathological characterization and outcome. Clin Kidney J 2021; 14:332-340. [PMID: 33564436 PMCID: PMC7857823 DOI: 10.1093/ckj/sfaa139] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome. METHODS We screened patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction <50% over a 6-month period preceding diagnosis. Data regarding patient features and response to treatment were retrieved. RESULTS Of 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years [interquartile range (IQR) 64-78] and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15-35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670-2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden's classification, 6/28 biopsies (21%) were 'focal', 1/28 (4%) 'crescentic', 9/28 (32%) 'mixed' and 12/28 (43%) 'sclerotic'. At last follow-up (median 32 months, IQR 12-52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT. CONCLUSIONS AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.
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Affiliation(s)
- Giorgio Trivioli
- Department of Biomedical Experimental and Clinical Sciences “Mario Serio”, University of Firenze, and Nephrology Unit, Meyer Children’s Hospital, Firenze, Italy
| | | | - Maria L. Urban
- Department of Experimental and Clinical Sciences, University of Firenze, Firenze, Italy
| | | | | | | | | | - Alessandra Bettiol
- Department of Neurosciences, Psychology, Pharmacology and Child Health, University of Firenze, Firenze, Italy
| | - Pasquale Esposito
- Department of Internal Medicine and Medical Specialties, University of Genova, Genova, Italy
| | - Corrado Murtas
- Nephrology Unit, Nephrology Unit, ASSL Oristano, ATS Sardegna, Oristano, Italy
| | - Federico Alberici
- Nephrology Unit, ASST Spedali Civili, Brescia, Italy
- Department of Medical and Surgical Specialities, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Federica Maritati
- Nephrology, Dialysis and Transplant Unit, Ospedali Riuniti, Ancona, Italy
| | - Lucio Manenti
- Nephrology Unit, Parma University Hospital, Parma, Italy
| | | | - Giacomo Emmi
- Department of Experimental and Clinical Sciences, University of Firenze, Firenze, Italy
| | - Paola Romagnani
- Department of Biomedical Experimental and Clinical Sciences “Mario Serio”, University of Firenze, and Nephrology Unit, Meyer Children’s Hospital, Firenze, Italy
| | | | | | | | | | - Augusto Vaglio
- Department of Biomedical Experimental and Clinical Sciences “Mario Serio”, University of Firenze, and Nephrology Unit, Meyer Children’s Hospital, Firenze, Italy
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17
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Mendel A, Ennis D, Go E, Bakowsky V, Baldwin C, Benseler SM, Cabral DA, Carette S, Clements-Baker M, Clifford AH, Cohen Tervaert JW, Cox G, Dehghan N, Dipchand C, Dhindsa N, Famorca L, Fifi-Mah A, Garner S, Girard LP, Lessard C, Liang P, Noone D, Makhzoum JP, Milman N, Pineau CA, Reich HN, Rhéaume M, Robinson DB, Rumsey DG, Towheed TE, Trudeau J, Twilt M, Yacyshyn E, Yeung RSM, Barra LB, Khalidi N, Pagnoux C. CanVasc Consensus Recommendations for the Management of Antineutrophil Cytoplasm Antibody-associated Vasculitis: 2020 Update. J Rheumatol 2020; 48:555-566. [PMID: 32934123 DOI: 10.3899/jrheum.200721] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/05/2020] [Indexed: 12/14/2022]
Abstract
OBJECTIVE In 2015, the Canadian Vasculitis Research Network (CanVasc) created recommendations for the management of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV) in Canada. The current update aims to revise existing recommendations and create additional recommendations, as needed, based on a review of new available evidence. METHODS A needs assessment survey of CanVasc members informed questions for an updated systematic literature review (publications spanning May 2014 to September 2019) using Medline, Embase, and Cochrane. New and revised recommendations were developed and categorized according to the level of evidence and strength of each recommendation. The CanVasc working group used a 2-step modified Delphi procedure to reach > 80% consensus on the inclusion, wording, and grading of each new and revised recommendation. RESULTS Eleven new and 16 revised recommendations were created and 12 original (2015) recommendations were retained. New and revised recommendations are discussed in detail within this document. Five original recommendations were removed, of which 4 were incorporated into the explanatory text. The supplementary material for practical use was revised to reflect the updated recommendations. CONCLUSION The 2020 updated recommendations provide rheumatologists, nephrologists, and other specialists caring for patients with AAV in Canada with new management guidance, based on current evidence and consensus from Canadian experts.
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Affiliation(s)
- Arielle Mendel
- A. Mendel, MD, MSc, C.A. Pineau, MD, Division of Rheumatology, Lupus and Vasculitis Clinic, McGill University, Montréal, Québec;
| | - Daniel Ennis
- D. Ennis, MD, C. Baldwin, MD, N. Dehghan, MD, N. Dhindsa, MD, Division of Rheumatology, University of British Columbia, Vancouver, British Columbia
| | - Ellen Go
- E. Go, MD, R.S. Yeung, MD, PhD, Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, Ontario
| | - Volodko Bakowsky
- V. Bakowsky, MD, Division of Rheumatology, QEII Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia
| | - Corisande Baldwin
- D. Ennis, MD, C. Baldwin, MD, N. Dehghan, MD, N. Dhindsa, MD, Division of Rheumatology, University of British Columbia, Vancouver, British Columbia
| | - Susanne M Benseler
- S.M. Benseler, MD, PhD, M. Twilt, MD, PhD, Division of Rheumatology, Department of Pediatrics, Alberta Children's Hospital, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta
| | - David A Cabral
- D.A. Cabral, MBBS, Division of Pediatric Rheumatology, BC Children's Hospital, University of British Columbia, Vancouver, British Columbia
| | - Simon Carette
- S. Carette, MD, MPhil, C. Pagnoux, MD, MSc, MPH, Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario
| | - Marie Clements-Baker
- M. Clements-Baker, MD, T.E. Towheed, MD, MS, Division of Rheumatology, Queen's University, Kingston, Ontario
| | - Alison H Clifford
- A.H. Clifford, MD, J.W. Cohen Tervaert, MD, PhD, E. Yacyshyn, MD, Division of Rheumatology, University of Alberta, Edmonton, Alberta
| | - Jan Willem Cohen Tervaert
- A.H. Clifford, MD, J.W. Cohen Tervaert, MD, PhD, E. Yacyshyn, MD, Division of Rheumatology, University of Alberta, Edmonton, Alberta
| | - Gerard Cox
- G. Cox, MB, Firestone Institute for Respiratory Health, McMaster University, Hamilton, Ontario
| | - Natasha Dehghan
- D. Ennis, MD, C. Baldwin, MD, N. Dehghan, MD, N. Dhindsa, MD, Division of Rheumatology, University of British Columbia, Vancouver, British Columbia
| | - Christine Dipchand
- C. Dipchand, MD, MSc, Division of Nephrology, QEII Health Sciences Centre, Dalhousie University, Halifax, Nova Scotia
| | - Navjot Dhindsa
- D. Ennis, MD, C. Baldwin, MD, N. Dehghan, MD, N. Dhindsa, MD, Division of Rheumatology, University of British Columbia, Vancouver, British Columbia
| | - Leilani Famorca
- L. Famorca, MD, S. Garner, MD, MSc, N. Khalidi, MD, Division of Rheumatology, McMaster University, Hamilton, Ontario
| | - Aurore Fifi-Mah
- A. Fifi-Mah, MD, Division of Rheumatology, University of Calgary, Calgary, Alberta
| | - Stephanie Garner
- L. Famorca, MD, S. Garner, MD, MSc, N. Khalidi, MD, Division of Rheumatology, McMaster University, Hamilton, Ontario
| | - Louis-Philippe Girard
- L.P. Girard, MD, MSc, Division of Nephrology, University of Calgary, Calgary, Alberta
| | - Clode Lessard
- C. Lessard, MD, Centre de Recherche Musculo-Squelettique, Trois-Rivières, Québec
| | - Patrick Liang
- P. Liang, MD, Division of Rheumatology, Centre Hospitalier Universitaire de Sherbrooke, Université de Sherbrooke, Sherbrooke, Québec
| | - Damien Noone
- D. Noone, MB, BCh, BAO, MSc, Division of Nephrology, Hospital for Sick Children, University of Toronto, Toronto, Ontario
| | - Jean-Paul Makhzoum
- J.P. Makhzoum, MD, M. Rhéaume, MD, Division of Internal Medicine, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Québec
| | - Nataliya Milman
- N. Milman, MD, MSc, Division of Rheumatology, The Ottawa Hospital, University of Ottawa and Ottawa Hospital Research Institute, Ottawa, Ontario
| | - Christian A Pineau
- A. Mendel, MD, MSc, C.A. Pineau, MD, Division of Rheumatology, Lupus and Vasculitis Clinic, McGill University, Montréal, Québec
| | - Heather N Reich
- H.N. Reich, MD, PhD, Division of Nephrology, University Health Network, University of Toronto, Toronto, Ontario
| | - Maxime Rhéaume
- J.P. Makhzoum, MD, M. Rhéaume, MD, Division of Internal Medicine, Hôpital du Sacré-Coeur de Montréal, Université de Montréal, Montréal, Québec
| | - David B Robinson
- D.B. Robinson, MD, MSc, Section of Rheumatology, University of Manitoba, Winnipeg, Manitoba
| | - Dax G Rumsey
- D.G. Rumsey, MD, MSc, Division of Pediatric Rheumatology, University of Alberta, Edmonton, Alberta
| | - Tanveer E Towheed
- M. Clements-Baker, MD, T.E. Towheed, MD, MS, Division of Rheumatology, Queen's University, Kingston, Ontario
| | - Judith Trudeau
- J. Trudeau, MD, Division of Rheumatology, CISSS Chaudière-Appalaches, Université Laval, Québec City, Québec
| | - Marinka Twilt
- S.M. Benseler, MD, PhD, M. Twilt, MD, PhD, Division of Rheumatology, Department of Pediatrics, Alberta Children's Hospital, Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta
| | - Elaine Yacyshyn
- A.H. Clifford, MD, J.W. Cohen Tervaert, MD, PhD, E. Yacyshyn, MD, Division of Rheumatology, University of Alberta, Edmonton, Alberta
| | - Rae S M Yeung
- E. Go, MD, R.S. Yeung, MD, PhD, Division of Rheumatology, Hospital for Sick Children, University of Toronto, Toronto, Ontario
| | - Lillian B Barra
- L.B. Barra, MD, Division of Rheumatology, Department of Medicine, Western University, London, Ontario, Canada
| | - Nader Khalidi
- L. Famorca, MD, S. Garner, MD, MSc, N. Khalidi, MD, Division of Rheumatology, McMaster University, Hamilton, Ontario
| | - Christian Pagnoux
- S. Carette, MD, MPhil, C. Pagnoux, MD, MSc, MPH, Division of Rheumatology, Mount Sinai Hospital, University of Toronto, Toronto, Ontario
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18
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Casal Moura M, Irazabal MV, Eirin A, Zand L, Sethi S, Borah BJ, Winters JL, Moriarty JP, Cartin-Ceba R, Berti A, Baqir M, Thompson GE, Makol A, Warrington KJ, Thao V, Specks U, Fervenza FC. Efficacy of Rituximab and Plasma Exchange in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis with Severe Kidney Disease. J Am Soc Nephrol 2020; 31:2688-2704. [PMID: 32826324 DOI: 10.1681/asn.2019111197] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 07/19/2020] [Indexed: 01/02/2023] Open
Abstract
BACKGROUND Treatment of patients with ANCA-associated vasculitis (AAV) and severe renal involvement is not established. We describe outcomes in response to rituximab (RTX) versus cyclophosphamide (CYC) and plasma exchange (PLEX). METHODS A retrospective cohort study of MPO- or PR3-ANCA-positive patients with AAV (MPA and GPA) and severe kidney disease (eGFR <30 ml/min per 1.73 m2). Remission, relapse, ESKD and death after remission-induction with CYC or RTX, with or without the use of PLEX, were compared. RESULTS Of 467 patients with active renal involvement, 251 had severe kidney disease. Patients received CYC (n=161) or RTX (n=64) for remission-induction, and 51 were also treated with PLEX. Predictors for ESKD and/or death at 18 months were eGFR <15 ml/min per 1.73 m2 at diagnosis (IRR 3.09 [95% CI 1.49 to 6.40], P=0.002), renal recovery (IRR 0.27 [95% CI 0.12 to 0.64], P=0.003) and renal remission at 6 months (IRR 0.40 [95% CI 0.18 to 0.90], P=0.027). RTX was comparable to CYC in remission-induction (BVAS/WG=0) at 6 months (IRR 1.37 [95% CI 0.91 to 2.08], P=0.132). Addition of PLEX showed no benefit on remission-induction at 6 months (IRR 0.73 [95% CI 0.44 to 1.22], P=0.230), the rate of ESKD and/or death at 18 months (IRR 1.05 [95% CI 0.51 to 2.18], P=0.891), progression to ESKD (IRR 1.06 [95% CI 0.50 to 2.25], P=0.887), and survival at 24 months (IRR 0.54 [95% CI 0.16 to 1.85], P=0.330). CONCLUSIONS The apparent benefits and risks of using CYC or RTX for the treatment of patients with AAV and severe kidney disease are balanced. The addition of PLEX to standard remission-induction therapy showed no benefit in our cohort. A randomized controlled trial is the only satisfactory means to evaluate efficacy of remission-induction treatments in AAV with severe renal involvement.
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Affiliation(s)
- Marta Casal Moura
- Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Maria V Irazabal
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Alfonso Eirin
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Ladan Zand
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Sanjeev Sethi
- Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Bijan J Borah
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota.,Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Jeffrey L Winters
- Division of Transfusion Medicine, Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - James P Moriarty
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota.,Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Rodrigo Cartin-Ceba
- Division of Pulmonary Medicine, Department of Medicine, Mayo Clinic Arizona, Phoenix, Arizona
| | - Alvise Berti
- Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Misbah Baqir
- Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Gwen E Thompson
- Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Ashima Makol
- Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Kenneth J Warrington
- Division of Rheumatology, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Viengneesee Thao
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, Minnesota.,Division of Health Care Policy and Research, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota
| | - Ulrich Specks
- Division of Pulmonary and Critical Care, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
| | - Fernando C Fervenza
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic College of Medicine and Science, Rochester, Minnesota
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19
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Kwon HC, Kim MK, Song JJ, Park YB, Lee SW. Rituximab Biosimilar Prevents Poor Outcomes of Microscopic Polyangiitis and Granulomatosis with Polyangiitis as Effectively as Rituximab Originator. Yonsei Med J 2020; 61:712-719. [PMID: 32734735 PMCID: PMC7393299 DOI: 10.3349/ymj.2020.61.8.712] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 06/06/2020] [Accepted: 06/16/2020] [Indexed: 11/27/2022] Open
Abstract
PURPOSE There has been no extensive study to compare the efficacy between rituximab originator (Mabthera®) and its biosimilar (Truxima®) for microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Here, we investigated the clinical effects of rituximab on poor outcomes of MPA and GPA in Korean patients, and compared those between Mabthera® and Truxima®. MATERIALS AND METHODS We retrospectively reviewed the medical records of a total of 139 patients, including 97 MPA patients and 42 GPA patients. At diagnosis, antineutrophil cytoplasmic antibody positivity and comorbidities were assessed. During follow-up, all-cause mortality, relapse, end-stage renal disease, cerebrovascular accident and acute coronary syndrome were evaluated as poor outcomes. In this study, rituximab was used as either Mabthera® or Truxima®. RESULTS The median age at diagnosis was 60.1 years and 46 patients were men (97 MPA and 42 GPA patients). Among poor outcomes, patients receiving rituximab exhibited a significantly lower cumulative relapse-free survival rate compared to those not receiving rituximab (p=0.002). Nevertheless, rituximab use did not make any difference in other poor outcomes of MPA and GPA except for relapse, which might be a rebuttal to the fact that rituximab use after relapse eventually led to better prognosis. There were no significant differences in variables at diagnosis and during follow-up between patients receiving Mabthera® and those receiving Truxima®. Patients receiving Truxima® exhibited a similar pattern of the cumulative survival rates of each poor outcome to those receiving Mabthera®. CONCLUSION Truxima® prevents poor outcomes of MPA and GPA as effectively as does Mabthera®.
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Affiliation(s)
- Hyeok Chan Kwon
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Minyoung Kevin Kim
- Department of Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Jason Jungsik Song
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Yong Beom Park
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea
| | - Sang Won Lee
- Division of Rheumatology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Institute for Immunology and Immunological Diseases, Yonsei University College of Medicine, Seoul, Korea.
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20
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Abstract
INTRODUCTION Rituximab, an anti-B-cell biological therapy, has been investigated in several clinical trials on antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). AREAS COVERED In this paper, the clinical trials and open-label studies on rituximab efficacy and safety in treating AAVs are reviewed. EXPERT OPINION Rituximab achieved high remission-induction and sustained-maintenance rates for patients with these severe diseases, thereby challenging the cornerstone treatment of corticosteroids and cyclophosphamide followed by azathioprine. Rituximab should be used as first-line therapy with corticosteroids to induce remission of severe AAVs, especially in situations in which cyclophosphamide may be problematic (relapse after cyclophosphamide, women of childbearing age, risk of malignancy). Cyclophosphamide indications are likely to be restricted in the future. Whenever possible, rituximab should be preferred to azathioprine to maintain remission. The current maintenance regimen has been extended to at least 18 months but its optimal duration remains unknown and recent data suggest the possibility to extend treatment to 4 years. Future challenges include defining the best dose regimen: at present, different schedules are used as alternatives to those recognized as standards by health authorities. In addition, it remains to identify which patients will benefit the most from long-term retreatment: potentially those with relapsing disease or anti-proteinase-3 ANCA-positivity.
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Affiliation(s)
- Loïc Raffray
- Department of Internal Medicine, Félix-Guyon University Hospital of La Réunion , Saint-Denis, France
| | - Loïc Guillevin
- Referral Center for Rare Systemic and Autoimmune Diseases, Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes , Paris, France
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21
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Abstract
Rapidly progressive glomerulonephritis (RPGN) is a form of glomerulonephritis characterized by loss of renal function within weeks. Although a variety of underlying causes can trigger RPGN, the ultimate pathologic mechanism is the podocyte and epithelial activation leading to the crescent formation. Rituximab has been increasingly and successfully used for autoimmune conditions in recent years. Treatment of RPGN is based on the underlying condition, but specific clinical guidelines are lacking. In this article, we have tried to establish the role of rituximab in the management of patients with RPGN. All the studies we have used were found in the PubMed database, limited to studies involving adults. Animal studies and studies involving the pediatric population were excluded. The currently available literature does not support switching to rituximab as the first-line agent. It has failed to prove consistently superior to other medications. However, combined with other commonly prescribed treatment regimens, namely corticosteroids, with or without cytotoxic drugs, rituximab has shown efficacy in many studies. Therefore, we have concluded that the most prudent use of rituximab in patients with RPGN would be in those with disease refractory to standard management with corticosteroids and cytotoxic drugs or in those who have intolerable side effects. We believe that clinicians should keep reporting any cases of RPGN treated with rituximab so that a more clear pattern emerges and more exact treatment guidelines can be made.
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Affiliation(s)
- Ivan Cancarevic
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
| | - Bilal Haider Malik
- Internal Medicine, California Institute of Behavioral Neurosciences and Psychology, Fairfield, USA
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22
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McAdoo SP, Medjeral-Thomas N, Gopaluni S, Tanna A, Mansfield N, Galliford J, Griffith M, Levy J, Cairns TD, Jayne D, Salama AD, Pusey CD. Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis. Nephrol Dial Transplant 2019; 34:63-73. [PMID: 29462348 PMCID: PMC6322443 DOI: 10.1093/ndt/gfx378] [Citation(s) in RCA: 96] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 12/18/2017] [Indexed: 01/29/2023] Open
Abstract
Background Current guidelines advise that rituximab or cyclophosphamide should be used for the treatment of organ-threatening disease in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), although few studies have examined the efficacy and safety of these agents in combination. Methods We conducted a single-centre cohort study of 66 patients treated with a combination of oral corticosteroids, rituximab and low-dose pulsed intravenous cyclophosphamide followed by a maintenance regimen of azathioprine and tapered steroid for the treatment of biopsy-proven renal involvement in AAV. Patients were followed for a median of 56 months. Case–control analysis with 198 propensity-matched cases from European Vasculitis Study Group (EUVAS) trials compared long-term differences in relapse-free, renal and patient survival. Results At entry, the median Birmingham Vasculitis Activity Score (BVAS) was 19 and estimated glomerular filtration rate was 25 mL/min. Cumulative doses of rituximab, cyclophosphamide and corticosteroids were 2, 3 and 4.2 g, respectively, at 6 months. A total of 94% of patients achieved disease remission by 6 months (BVAS < 0) and patient and renal survival were 84 and 95%, respectively, at 5 years. A total of 84% achieved ANCA-negative status and 57% remained B cell deplete at 2 years, which was associated with low rates of major relapse (15% at 5 years). The serious infection rate during long-term follow-up was 1.24 per 10 patient-years. Treatment with this regimen was associated with a reduced risk of death {hazard ratio [HR] 0.29 [95% confidence interval (CI) 0.125–0.675], P = 0.004}, progression to end-stage renal disease (ESRD) [HR 0.20 (95% CI 0.06–0.65), P = 0.007] and relapse [HR 0.49 (95% CI 0.25–0.97), P = 0.04] compared with propensity-matched patients enrolled in EUVAS trials. Conclusions This regimen is potentially superior to current standards of care, and controlled studies are warranted to establish the utility of combination drug approaches in the treatment of AAV.
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Affiliation(s)
- Stephen P McAdoo
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.,Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
| | | | | | - Anisha Tanna
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.,Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
| | | | - Jack Galliford
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.,Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
| | - Megan Griffith
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.,Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
| | - Jeremy Levy
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.,Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
| | - Thomas D Cairns
- Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
| | - David Jayne
- Department of Medicine, University of Cambridge, Cambridge, UK
| | - Alan D Salama
- Centre for Nephrology, University College London, London, UK
| | - Charles D Pusey
- Renal and Vascular Inflammation Section, Department of Medicine, Imperial College London, London, UK.,Vasculitis Clinic, Imperial College Healthcare NHS Trust, London, UK
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23
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Tedesco M, Gallieni M, Pellegata F, Cozzolino M, Alberici F. Update on ANCA-associated vasculitis: from biomarkers to therapy. J Nephrol 2019; 32:871-882. [DOI: 10.1007/s40620-019-00628-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Accepted: 07/02/2019] [Indexed: 12/17/2022]
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24
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Rituximab in relapsing and de novo MPO ANCA-associated vasculitis with severe renal involvement: a case series. BMC Nephrol 2019; 20:162. [PMID: 31088509 PMCID: PMC6515642 DOI: 10.1186/s12882-019-1350-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 04/23/2019] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Antineutrophil cytoplasmic antibody associated vasculitis (AAV) is a group of diseases associated in most cases with the presence of anti-neutrophil cytoplasmic antibodies (ANCAs). Rituximab- based remission induction has been proven effective in ANCA associated vasculitis but scarce data exist in forms with severe renal involvement. In this case series, we report the outcomes in patients with de novo or recurrent MPO-AAV and severe renal involvement treated with rituximab without cyclophosphamide (CYC). METHODS In this single centre retrospective study, we analysed patients with a clinical diagnosis of de novo or recurrent AAV who met the following criteria: detection of P-ANCA, creatinine clearance lower than 30 ml/min, induction of remission therapy with rituximab without concomitant CYC and a follow up period of at least 6 months. The primary outcomes were complete remission after induction therapy, renal function recovery and mortality after the induction treatment. RESULTS Eight patients met the inclusion criteria. The M:F ratio was 1:7, the average age was 54 years old and the median follow up was 10 months (7-72); in 2 patients there was a MPA renal limited vasculitis. A renal biopsy was performed in 7 patients. The median BVAS score at rituximab induction was 14(range 6-21). Two patients required haemodialysis before the induction treatment. Four patients developed end stage renal disease (ESRD) that required haemodialysis. These data show a remission of the disease, associated with a stabilization of the kidney function in 50% of patients. In 3 patients who did not show a response, there was also no response to CYC. CONCLUSIONS This study shows a partial efficacy of rituximab in renal function recovery and a low risk of infectious complications in patients with MPO vasculitis with severe renal involvement, in particular in the short term. The optimal treatment in this subgroup of patients still has to be established because data are lacking.
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25
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Hogan JJ. A Case of ANCA-Associated Vasculitis. Clin J Am Soc Nephrol 2019; 14:754-756. [PMID: 30952628 PMCID: PMC6500935 DOI: 10.2215/cjn.14601218] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Affiliation(s)
- Jonathan J Hogan
- Division of Nephrology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
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26
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Salvadori M, Tsalouchos A. Antineutrophil cytoplasmic antibody associated vasculitides with renal involvement: Open challenges in the remission induction therapy. World J Nephrol 2018; 7:71-83. [PMID: 29736379 PMCID: PMC5937030 DOI: 10.5527/wjn.v7.i3.71] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Revised: 03/12/2018] [Accepted: 04/18/2018] [Indexed: 02/06/2023] Open
Abstract
Renal involvement with rapidly progressive glomerulonephritis is a common manifestation of antineutrophil cytoplasmic antibody (ANCA) associated vasculitides, which is characterized by end-stage renal disease and high mortality rates in untreated and/or late referral patients. The long-term renal survival has improved dramatically since the addition of cyclophosphamide (CYC) and recently of rituximab (RTX) in association with corticosteroids in the remission induction therapeutic regimens. However, renal prognosis remains unfavorable for many patients and the mortality rate is still significantly high. In this review, we analyze the open challenges to be addressed to optimize the induction remission therapy, principally in patients with advanced kidney failure. This concern the first-line therapy (CYC or RTX) based on different parameters (estimated glomerular filtration rate at baseline, new or relapsed disease, ANCA specificity, tissue injury, safety), the role of plasma exchange and the role of new therapies. Indeed, we discuss future perspectives in induction remission therapy by reporting recent advances in new targeted therapies with particular reference to avacopan, an orally administered selective C5a receptor inhibitor.
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Affiliation(s)
- Maurizio Salvadori
- Department of Nephrology and Renal Transplantation, Careggi University Hospital, Florence 50139, Italy
| | - Aris Tsalouchos
- Department of Nephrology and Dialysis, Saints Cosmas and Damian Hospital, Pescia 51017, Italy
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27
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Moiseev S, Novikov P, Jayne D, Mukhin N. End-stage renal disease in ANCA-associated vasculitis. Nephrol Dial Transplant 2018; 32:248-253. [PMID: 28186571 DOI: 10.1093/ndt/gfw046] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2015] [Accepted: 02/09/2016] [Indexed: 12/15/2022] Open
Abstract
The outcomes in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis have improved significantly over the past decades, although a significant proportion of them still reach end-stage renal disease (ESRD). Renal replacement therapy (RRT) is associated with a relatively low risk of relapsing vasculitis as a result of anti-rejection treatment after kidney transplantation or quiescence of the autoimmune process in haemodialysis patients, but a flare of vasculitis in the latter setting presents a challenge because the treatment is poorly tolerated. There are benefits of rituximab in haemodialysed patients, as it is more steroid sparing in the treatment of extrarenal disease. More favourable outcomes of kidney transplantation compared with haemodialysis support its use as a preferable method of RRT in patients with vasculitis remission or low disease activity.
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Affiliation(s)
- Sergey Moiseev
- Clinic of Nephrology, Internal and Occupational Diseases, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - Pavel Novikov
- Clinic of Nephrology, Internal and Occupational Diseases, Sechenov First Moscow State Medical University, Moscow, Russian Federation
| | - David Jayne
- Vasculitis and Lupus Clinic, Addenbrooke's Hospital, Cambridge, UK
| | - Nikolay Mukhin
- Clinic of Nephrology, Internal and Occupational Diseases, Sechenov First Moscow State Medical University, Moscow, Russian Federation
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28
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Rituximab for anti-neutrophil cytoplasmic antibodies-associated vasculitis: experience of a single center and systematic review of non-randomized studies. Rheumatol Int 2018; 38:607-622. [PMID: 29322343 DOI: 10.1007/s00296-018-3928-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 01/02/2018] [Indexed: 10/27/2022]
Abstract
Rituximab (RTX) is becoming a standard treatment for patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) but heterogeneity exists regarding its use. We present our uncontrolled experience with RTX in patients with refractory AAV and also the results of a systematic review of non-randomized studies on RTX in AAV patients. We retrospectively reviewed the records of AAV patients treated with RTX following an inadequate response to immunosuppressives between 2011 and 2015. The systematic review covered all English articles listed in PubMed until June 2017. There were 25 AAV patients (21 GPA, four unclassified) treated with RTX (median 2, IQR 1-3 courses; median follow-up 24, IQR 17-50 months). The kidney and the lung were the most commonly affected organs, observed in 14 and 16 patients, respectively. Complete remission rate was 72% at month 6 and 88% at month 12. Two patients had died and three serious adverse events occurred. The systematic review included 56 studies on 1422 patients with the majority being on refractory or relapsing disease. There was wide variability regarding disease characteristics, endpoints, concomitant immunosuppressives and RTX schedule. Most studies reported > 80% complete or partial remission rates with the lowest response (37.5%) for granulomatous lesions. The relapse rate was 30%. Infections and infusion reactions were the main adverse events. Our experience with RTX in refractory AAV is in line with the literature in terms of efficacy and safety. The systematic review underlines many uncertainties on its optimal use.
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29
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McNicholas BA, Griffin TP, Donnellan S, Ryan L, Garrahy A, Coughlan R, Giblin L, Lappin D, Reddan D, Carey JJ, Griffin MD. ANCA-associated vasculitis: a comparison of cases presenting to nephrology and rheumatology services. QJM 2016; 109:803-809. [PMID: 27318367 DOI: 10.1093/qjmed/hcw100] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2015] [Revised: 05/19/2016] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis (AAV) is a disease characterized by inflammation of small vessels and detectable ANCA in the circulation. Patients may develop a broad spectrum of clinical features ranging from indolent sino-nasal disease and rashes to fulminant renal failure or acute life-threatening pulmonary haemorrhage. Consequently, patients with AAV present to a variety of specialties including nephrology and rheumatology, whose training and approaches to management of such patients may differ. There is little literature comparing patients presenting to different specialties and their outcomes. METHODS We compared two cohorts of patients with ANCA-positive AAV presenting to either the rheumatology or nephrology department at Galway University Hospitals from June 2002 to July 2011. A standardized data collection form was used to collect information regarding baseline demographics, manifestations of AAV, initial management, relapses and complications. RESULTS Forty-five patients were included in this study (15 rheumatology/30 nephrology). The nephrology cohort was older, had a higher C-reactive protein, Birmingham Vascular Activity Score and ANCA titer at presentation compared to the rheumatology group. Induction treatment varied between the cohorts with rheumatology patients most commonly receiving a combination of oral corticosteroids (73%) and methotrexate (60%) and nephrology patients receiving a combination of intravenous corticosteroids (93%) and cyclophosphamide (90%). Fifty-three percent of the rheumatology patients who completed induction therapy relapsed compared to 30% of the nephrology patients. CONCLUSION This study presents two different cohorts of patients with the same disease that were managed by two different disciplines. It highlights the heterogeneity of AAV and the importance of interdisciplinary communication and cooperation when managing these patients.
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Affiliation(s)
- B A McNicholas
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - T P Griffin
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Rheumatology Department, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - S Donnellan
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - L Ryan
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - A Garrahy
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - R Coughlan
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Rheumatology Department, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - L Giblin
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - D Lappin
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - D Reddan
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
| | - J J Carey
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
- Rheumatology Department, Galway University Hospitals, Saolta University Health Group, Galway, Ireland
| | - M D Griffin
- From the Nephrology Department , Galway University Hospitals, Saolta University Health Group, Galway, Ireland
- School of Medicine, College of Medicine, Nursing and Health Sciences, National University of Ireland, Galway, Ireland
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Cinetto F, Compagno N, Scarpa R, Malipiero G, Agostini C. Rituximab in refractory sarcoidosis: a single centre experience. Clin Mol Allergy 2015; 13:19. [PMID: 26330764 PMCID: PMC4556310 DOI: 10.1186/s12948-015-0025-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2015] [Accepted: 07/28/2015] [Indexed: 12/27/2022] Open
Abstract
Sarcoidosis is a granulomatous disease whose outcome varies from spontaneous remission to chronic refractory disease. Provided that steroids represent the gold standard as a first line treatment, many immune suppressants drugs are currently used in the disease management. However, refractory disease is still a great challenge. Rituximab is an anti-CD20 chimeric monoclonal antibody, currently used for the treatment of B cell malignancies and systemic autoimmune diseases. There are few case reports describing the successful use of Rituximab in refractory sarcoidosis with lung, eye, lymph nodes and skin involvement. In this paper we described three different case reports in which Rituximab has been used to treat refractory sarcoidosis and we reviewed the existing literature.
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Affiliation(s)
- Francesco Cinetto
- Clinical Immunology, Department of Medicine-DIMED, Padova University Hospital, via Giustiniani 2, 35128 Padua, Italy
| | - Nicolò Compagno
- Clinical Immunology, Department of Medicine-DIMED, Padova University Hospital, via Giustiniani 2, 35128 Padua, Italy
| | - Riccardo Scarpa
- Clinical Immunology, Department of Medicine-DIMED, Padova University Hospital, via Giustiniani 2, 35128 Padua, Italy
| | - Giacomo Malipiero
- Clinical Immunology, Department of Medicine-DIMED, Padova University Hospital, via Giustiniani 2, 35128 Padua, Italy
| | - Carlo Agostini
- Clinical Immunology, Department of Medicine-DIMED, Padova University Hospital, via Giustiniani 2, 35128 Padua, Italy
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