103 results on '"Stone, John"'
Search Results
2. Qualitative interviews to support development of a patient-reported companion measure to the Glucocorticoid Toxicity Index.
- Author
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Howell TA, Matza LS, Stone JH, Gelinas D, Stone MN, Rao VTS, and Phillips GA
- Subjects
- Humans, Glucocorticoids therapeutic use, Patient Reported Outcome Measures, Lupus Erythematosus, Systemic, Vasculitis
- Abstract
Introduction: Glucocorticoids (GCs) are associated with multiple toxicities that have substantial impact on patients. We conducted qualitative interviews with patients to identify the toxicities that are most relevant from their perspective, with the goal of creating a patient-reported companion measure to the Glucocorticoid Toxicity Index (GTI), a clinician-facing instrument., Methods: Thirty-one patients with recent or current GC use participated in concept elicitation interviews. Participants received GC treatment for myasthenia gravis, chronic inflammatory demyelinating polyradiculoneuropathy, vasculitis, or systemic lupus erythematosus. Transcripts were coded following a thematic analysis approach., Results: Participants reported more than 100 toxicities they believed to be associated with their GC medications. Common toxicities included weight gain (87%), increased appetite (84%), insomnia/sleep problems (77%), cognitive impairment/brain fog (71%), easy bruising (68%), anxiety (65%), irritability/short temper (65%), and osteoporosis (39%). These toxicities often centered on self-esteem, neuropsychiatric effects, skin toxicities, and musculoskeletal function. They can be categorized into domains such emphasizing neuropsychiatric, metabolic/endocrine, musculoskeletal, and dermatological effects, highlighting aspects of GC toxicity that patients are uniquely positioned to appreciate and report., Conclusion: Our results confirm that the toxicities associated with GCs are pervasive and diverse, with substantial impact on patients' lives. These data will be used to inform the development of a patient-reported outcome measure assessing GC toxicity. This patient-reported instrument will be designed to complement the clinician-reported GTI, facilitating a more detailed understanding of the nuances of change in GC toxicity., Competing Interests: Declaration of competing interest TAH and LSM are employed by Evidera, a company that received funding from argenx for time spent conducting this research. MNS is the CEO of Steritas, LLC, which holds the licensing rights to the Glucocorticoid Toxicity Index, and reports owning stock in Steritas (the intellectual property of the GTI is owned by the Massachusetts General Hospital). MNS is a co-founder of Steritas. JHS reports consulting fees from ChemoCentryx, Amgen, Roche/Genentech, Sanofi, Bristol-Myers Squib, AbbVie, InflaRx, Kyverna, Novartis, Q32Bio, Steritas, Zenas, Horizon, argenx, Spruce, PPD; owning stock in Steritas; commercial research grants from Roche/Genentech, Sanofi, Bristol-Myers Squib; royalties from UpToDate; non-commercial research grants from NIH/NIAID. JHS is a co-founder of Steritas and serves as the unpaid chair of the Scientific Advisory Board. He has no fiduciary responsibility at the company. GAP, VR, and DG are employees of argenx, who sponsored the study., (Copyright © 2024 Elsevier B.V. All rights reserved.)
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- 2024
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3. IgG4-related disease as a variable-vessel vasculitis: A case series of 13 patients with medium-sized coronary artery involvement.
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Katz G, Hedgire SH, Stone JR, Perez-Espina S, Fernandes A, Perugino CA, Wallace ZS, and Stone JH
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- Humans, Male, Female, Coronary Vessels diagnostic imaging, Prospective Studies, Immunoglobulin G, Immunoglobulin G4-Related Disease complications, Vasculitis, Arteritis diagnosis, Arteritis etiology, Cardiomyopathies
- Abstract
Introduction: IgG4-related disease (IgG4-RD) is a systemic autoimmune fibroinflammatory disease that can affect multiple organ systems. Although large-vessel vasculitis is a well-recognized manifestation of IgG4-RD, this condition is generally not regarded as a vasculitis. We aimed to describe coronary artery involvement (CAI), a vascular distribution about which little is known in IgG4-RD., Material and Methods: Patients with IgG4-related CAI were identified from a large, prospective IgG4-RD cohort. CAI was confirmed by imaging evidence of arterial or periarterial inflammation in any coronary artery. We extracted details regarding demographics, features of IgG4-RD, and manifestations of CAI., Results: Of 361 cases in the cohort, 13 (4%) patients had IgG4-related CAI. All were male and all had highly-elevated serum IgG4 concentrations, with a median value of 955 mg/dL (interquartile range [IQR]: 510-1568 mg/dL; reference: 4-86 mg/dL). Median disease duration at the time of CAI diagnosis was 11 years (IQR: 8.23-15.5 years). Extensive disease in the coronary arteries was the rule: all three major coronary arteries were involved in 11 patients (85%). The coronary artery manifestations included wall thickening or periarterial soft tissue encasement (85%), stenosis (69%), calcification (69%), and aneurysms or ectasia (62%). Five patients (38%) had myocardial infarctions, 2 (15%) required coronary artery bypass grafting, and 2 (15%) developed ischemic cardiomyopathy., Discussion: Coronary arteritis and periarteritis are important manifestations of IgG4-RD, which should be regarded as a variable-vessel vasculitis that is among the most diverse forms of vasculitis known. Potential complications of CAI include coronary artery aneurysms, myocardial infarction, and ischemic cardiomyopathy., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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4. Deadly Vasculitides and Reversed Racial/Ethnic Disparity?
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Stone JR
- Subjects
- Humans, Racial Groups, Ethnicity, Vasculitis
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- 2020
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5. Case 14-2017 - A 20-Year-Old Man with Pain and Swelling of the Left Calf and a Purpuric Rash
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Miloslavsky EM, Stone JH, and Moy AP
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- Biopsy, Crohn Disease complications, Diagnosis, Differential, Edema etiology, Exanthema etiology, Humans, IgA Vasculitis complications, IgA Vasculitis pathology, Male, Pain etiology, Purpura etiology, Young Adult, IgA Vasculitis diagnosis, Skin pathology, Vasculitis diagnosis
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- 2017
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6. Case 6-2017. A 57-year-old woman with fatigue, sweats, weight loss, headache, and skin lesions.
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Monach PA, Stone JH, Sharma A, and Nazarian RM
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- Diagnosis, Differential, Fatigue etiology, Female, Headache etiology, Humans, Hypergammaglobulinemia etiology, Middle Aged, Sweating, Vasculitis complications, Vasculitis immunology, Vasculitis pathology, Weight Loss, Immunoglobulin G, Skin Diseases etiology, Temporal Arteries pathology, Vasculitis diagnosis
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- 2017
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7. Challenging mimickers of primary systemic vasculitis.
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Miloslavsky EM, Stone JH, and Unizony SH
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- Autoimmune Diseases diagnosis, Autoimmune Diseases immunology, Diagnosis, Differential, Fibromuscular Dysplasia diagnosis, Humans, Immunoglobulin G immunology, Malignant Atrophic Papulosis diagnosis, Vascular Diseases diagnosis, Antiphospholipid Syndrome diagnosis, Arterial Occlusive Diseases diagnosis, Calciphylaxis diagnosis, Hypereosinophilic Syndrome diagnosis, Lymphomatoid Granulomatosis diagnosis, Vasculitis diagnosis
- Abstract
The need to distinguish true primary systemic vasculitis from its multiple potential mimickers is one of the most challenging diagnostic conundrums in clinical medicine. This article reviews 9 challenging vasculitis mimickers: fibromuscular dysplasia, calciphylaxis, segmental arterial mediolysis, antiphospholipid syndrome, hypereosinophilic syndrome, lymphomatoid granulomatosis, malignant atrophic papulosis, livedoid vasculopathy, and immunoglobulin G4-related disease.
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- 2015
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8. Case records of the Massachusetts General Hospital. Case 22-2011. A 79-year-old man with a rash, arthritis, and ocular erythema.
- Author
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Kroshinsky D, Stone JH, and Nazarian RM
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- Aged, Arthritis etiology, Atrial Fibrillation etiology, Autoimmune Diseases complications, Autoimmune Diseases drug therapy, Diagnosis, Differential, Glucocorticoids therapeutic use, Humans, Male, Prednisone therapeutic use, Purpura etiology, Urticaria etiology, Vasculitis complications, Vasculitis drug therapy, Autoimmune Diseases diagnosis, Complement System Proteins deficiency, Scleritis etiology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Vasculitis diagnosis
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- 2011
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9. A 73-year-old woman with chronic pelvic pain, burning toes, and an eighty-pound weight loss.
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Birnbaum J, Chai TC, Ali TZ, Polydefkis M, and Stone JH
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- Aged, Diagnosis, Differential, Female, Female Urogenital Diseases diagnosis, Gastrointestinal Diseases diagnosis, Humans, Lung Diseases diagnosis, Peripheral Nervous System Diseases diagnosis, Vasculitis pathology
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- 2008
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10. Small-vessel and medium-vessel vasculitis.
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Seo P and Stone JH
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- Antibodies, Antineutrophil Cytoplasmic physiology, Churg-Strauss Syndrome epidemiology, Churg-Strauss Syndrome etiology, Churg-Strauss Syndrome therapy, Humans, Prognosis, Remission Induction, Blood Vessels pathology, Vasculitis epidemiology, Vasculitis etiology, Vasculitis therapy
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- 2007
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11. Vasculitis: a collection of pearls and myths.
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Stone JH
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- Antirheumatic Agents therapeutic use, Behcet Syndrome diagnosis, Churg-Strauss Syndrome diagnosis, Churg-Strauss Syndrome immunology, Cyclophosphamide therapeutic use, Giant Cell Arteritis, Glucocorticoids therapeutic use, Granulomatosis with Polyangiitis complications, Granulomatosis with Polyangiitis drug therapy, Humans, IgA Vasculitis drug therapy, Mythology, Polyarteritis Nodosa drug therapy, Prednisone therapeutic use, Takayasu Arteritis drug therapy, Takayasu Arteritis physiopathology, Thromboangiitis Obliterans diagnosis, Vasculitis diagnosis, Vasculitis drug therapy, Vasculitis physiopathology, Vasculitis therapy
- Abstract
Since Kussmaul and Maier described the index case of vasculitis in 1866, the field has seen many changes. What was considered for decades to be only a single disorder is now known to consist of at least 15 to 20 distinct conditions. Important strides have been made in unraveling the pathophysiology of some individual forms of vasculitis, but many mysteries remain. Over time, numerous myths and occasional pearls have arisen from the care of patients with these disorders. This collection of pearls and myths gathers lessons about the status of clinical care of vasculitis patients in the year 2008.
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- 2007
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12. Microscopic polyangiitis presenting as a "pulmonary-muscle" syndrome: is subclinical alveolar hemorrhage the mechanism of pulmonary fibrosis?
- Author
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Birnbaum J, Danoff S, Askin FB, and Stone JH
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- Aged, Biopsy, Diagnosis, Differential, Female, Hemorrhage physiopathology, Humans, Lung Diseases, Interstitial pathology, Lung Diseases, Interstitial physiopathology, Muscular Diseases pathology, Muscular Diseases physiopathology, Pulmonary Alveoli pathology, Pulmonary Fibrosis diagnosis, Respiratory Muscles blood supply, Respiratory Muscles pathology, Syndrome, Vasculitis diagnosis, Vasculitis pathology, Hemorrhage complications, Pulmonary Alveoli physiopathology, Pulmonary Fibrosis etiology, Pulmonary Fibrosis physiopathology, Vasculitis physiopathology
- Abstract
Microscopic polyangiitis (MPA) may present with a syndrome that resembles idiopathic pulmonary fibrosis (IPF). We describe an MPA patient with the clinical presentation of a "pulmonary-muscle" syndrome in which interstitial lung disease antedated the onset of myopathy. Identification of vasculitis on muscle biopsy was instrumental in recognizing clinical, radiographic, and histopathologic features that were more characteristic of MPA than of IPF. Institution of glucocorticoid and cyclophosphamide therapy led to the induction of a complete remission. The histologic findings in this case implicate subclinical episodes of alveolar hemorrhage as the mechanism of interstitial lung disease in MPA.
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- 2007
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13. The future of damage assessment in vasculitis.
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Seo P, Luqmani RA, Flossmann O, Hellmich B, Herlyn K, Hoffman GS, Jayne D, Kallenberg CG, Langford CA, Mahr A, Matteson EL, Mukhtyar CB, Neogi T, Rutgers A, Specks U, Stone JH, Ytterberg SR, and Merkel PA
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- Disability Evaluation, Europe, Humans, International Cooperation, Outcome Assessment, Health Care, Reproducibility of Results, United States, Vasculitis classification, Severity of Illness Index, Vasculitis pathology, Vasculitis physiopathology
- Abstract
Damage denotes the aspects of chronic disease that do not reverse with therapy. This concept is particularly important for the primary systemic vasculitides, since the careful differentiation between activity and damage may help avoid unnecessary exposure to cytotoxic medications. Damage significantly influences both longterm prognosis and quality of life. Because the primary systemic vasculitides have diverse manifestations, the use of a damage assessment instrument is crucial to ensure reproducibility. The Vasculitis Damage Index (VDI) is the only validated measure for damage assessment in vasculitis. Use of the VDI in recent clinical trials has shown that it may not adequately determine the full spectrum of damage experienced by patients with vasculitis of small- and medium-size vessels. We propose reexamining the way in which damage is assessed, focusing on vasculitides of small- and medium-size vessels, and outline an initiative to create a substantially revised and improved damage assessment instrument using data-driven approaches. This initiative is part of a larger international effort to create a unified approach to disease assessment for the primary systemic vasculitides.
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- 2007
14. Vasculitis and systemic infections.
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Rodríguez-Pla A and Stone JH
- Subjects
- Granulomatosis with Polyangiitis immunology, Humans, Infections complications, Virus Diseases complications, Virus Diseases immunology, Infections immunology, Vasculitis immunology
- Abstract
Purpose of Review: In recent years, many investigators have focused on potential associations between infections and vascular inflammation. We review the principal pathogenic mechanisms that have been implicated for possible roles in the vascular inflammation initiated by infectious agents. We also summarize the most important literature related to this topic., Recent Findings: A novel theory known as autoantigen complementarity suggests that an infectious agent could trigger antineutrophil cytoplasmic antibody-associated vasculitis. Several recent studies investigating the presence of parvovirus B19 and herpesviruses in temporal arteries with giant cell arteritis have yielded contradictory results. A recent study has identified higher frequency of a novel human virus, the 'New Haven coronavirus', in respiratory secretions of children with Kawasaki disease. Many case reports have suggested potential relationships between human pathogens and vasculitis., Summary: There remains considerable interest in the possibilities of primary vasculitic syndromes caused in some fashion by infection. With the exception of a few well sustained associations - for example hepatitis B or C with known vasculitic syndromes - most of the purported links between microbial agents and primary vasculitides remain speculative.
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- 2006
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15. Current status of outcome measures in vasculitis: focus on Wegener's granulomatosis and microscopic polyangiitis. Report from OMERACT 7.
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Merkel PA, Seo P, Aries P, Neogi T, Villa-Forte A, Boers M, Cuthbertson D, Felson DT, Hellmich B, Hoffman GS, Jayne DR, Kallenberg CG, Krischer J, Mahr A, Matteson EL, Specks U, Luqmani R, and Stone J
- Subjects
- Clinical Trials as Topic, Granulomatosis with Polyangiitis diagnosis, Granulomatosis with Polyangiitis physiopathology, Humans, Male, Middle Aged, Peripheral Vascular Diseases diagnosis, Peripheral Vascular Diseases physiopathology, Severity of Illness Index, Vasculitis diagnosis, Vasculitis physiopathology, Granulomatosis with Polyangiitis therapy, Outcome Assessment, Health Care, Peripheral Vascular Diseases therapy, Vasculitis therapy
- Abstract
The complexity of assessing disease activity, disease status, and damage in the vasculitides reflects the multisystemic pathologic manifestations of these often chronic illnesses. Major progress has been made in the past decade in the development of validated and widely accepted outcome measures for use in clinical trials. Over time, these tools have been regularly revised, expanded, and supplemented with new measures of disease prognosis and damage. As a result clinical research in this area has become increasingly complex. This article critically reviews the current status of tools for assessing disease activity and damage in "ANCA-associated" vasculitides (Wegener's granulomatosis and microscopic polyangiitis), summarizes the current level of validation of each measure, addresses central problems and controversies to be considered during development of new vasculitis assessment tools, and proposes a series of research agendas for consideration by the vasculitis research community.
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- 2005
16. Classification and diagnostic criteria in systemic vasculitis.
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Saleh A and Stone JH
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- Guidelines as Topic, Humans, Antibodies, Antineutrophil Cytoplasmic, Vasculitis classification, Vasculitis diagnosis
- Abstract
Approximately 20 different primary forms of vasculitis are recognized, not all of which have been included in classification schemes or consensus statements regarding nomenclature. A variety of classification schemes have been proposed over the past 50 years, many predicated upon the size of the primary type of vessel involved in a given disease, as well as other considerations that include demographic features, organ tropism, the presence or absence of granulomatous inflammation, the role of immune complexes in pathophysiology and the association of autoantibodies with some forms of vasculitis. All classification schemes to date have had shortcomings owing to the substantial gaps in knowledge about vasculitis, but the American College of Rheumatology criteria for the classification of some forms of vasculitis are useful for the purpose of including patients in research studies. The Chapel Hill Consensus Conference has clarified some existing controversies in nomenclature of the systemic vasculitides. Robust diagnostic criteria for the various forms of vasculitis have, however, remained elusive.
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- 2005
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17. Induction of remission by B lymphocyte depletion in eleven patients with refractory antineutrophil cytoplasmic antibody-associated vasculitis.
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Keogh KA, Wylam ME, Stone JH, and Specks U
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- Adolescent, Adult, Aged, Antibodies, Antineutrophil Cytoplasmic blood, Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal, Murine-Derived, Creatinine blood, Drug Therapy, Combination, Female, Glucocorticoids therapeutic use, Humans, Kidney Diseases blood, Kidney Diseases complications, Kidney Diseases therapy, Lymphocyte Count, Male, Middle Aged, Plasma Exchange, Remission Induction, Renal Dialysis, Rituximab, Vasculitis blood, Vasculitis complications, Antibodies, Antineutrophil Cytoplasmic immunology, Antibodies, Monoclonal therapeutic use, B-Lymphocytes drug effects, Vasculitis drug therapy, Vasculitis immunology
- Abstract
Objective: To assess the clinical effects of rituximab therapy in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)., Methods: The study group comprised 11 patients who had active AAV despite receiving maximally tolerated doses of cyclophosphamide or had contraindications for cyclophosphamide use. All patients had ANCA reactive against proteinase 3. The patients received rituximab infusions and glucocorticoids to induce remission. Three patients also received plasma exchange. No other immunosuppressive agents were used. Glucocorticoids were tapered as soon as control of disease activity was achieved. Disease activity was monitored using the Birmingham Vasculitis Activity Score, modified for Wegener's granulomatosis., Results: Rituximab therapy was well tolerated by all patients, and adverse events were rare. Following the rituximab infusions, circulating B lymphocytes became undetectable, and ANCA titers decreased significantly. Remission was achieved in all patients and was maintained while B lymphocytes were absent., Conclusion: The ability to achieve stable remissions with rituximab in patients with AAV refractory to conventional therapy suggests that B lymphocyte depletion may be a safe, effective, mechanism-based treatment modality for treatment of patients with these conditions.
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- 2005
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18. The antineutrophil cytoplasmic antibody-associated vasculitides.
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Seo P and Stone JH
- Subjects
- Cyclophosphamide therapeutic use, Diagnosis, Differential, Ear, Eosinophilia epidemiology, Eye, Heart, Humans, Immunosuppressive Agents therapeutic use, Kidney, Lung, Nose, Peripheral Nerves, Pharynx, Prognosis, Vasculitis drug therapy, Antibodies, Antineutrophil Cytoplasmic immunology, Vasculitis immunology, Vasculitis physiopathology
- Abstract
Wegener's granulomatosis, microscopic polyangiitis, and Churg-Strauss syndrome are small- to medium-vessel vasculitides linked by overlapping pathology and the presence of antineutrophil cytoplasmic antibodies (ANCA). Commonly referred to as the ANCA-associated vasculitides, these diseases are challenging to diagnose and to treat. Distinguishing the ANCA-associated vasculitides from other forms of vasculitis or nonvasculitic processes (such as infection) can be particularly difficult. This review describes the clinical and pathologic hallmarks of the ANCA-associated vasculitides, discusses the role of ANCA assays in diagnosis and treatment, and outlines an approach to the evaluation and management of these diseases.
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- 2004
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19. Current status of tumor necrosis factor inhibition strategies in the treatment of vasculitis.
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Stone JH
- Subjects
- Endothelium, Vascular physiopathology, Humans, Molecular Biology, Tumor Necrosis Factor-alpha chemistry, Tumor Necrosis Factor-alpha metabolism, Vasculitis physiopathology, Tumor Necrosis Factor-alpha antagonists & inhibitors, Vasculitis drug therapy
- Published
- 2003
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20. Targeted therapies in systemic vasculitis.
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Stone JH
- Subjects
- Granulomatosis with Polyangiitis drug therapy, Humans, Interleukins therapeutic use, Tumor Necrosis Factor-alpha antagonists & inhibitors, Biological Factors therapeutic use, Vasculitis therapy
- Published
- 2002
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21. The Effects of Treatment on Body Mass Index in Giant Cell Arteritis: A Post Hoc Analysis of the GiACTA Trial
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Patel, Naomi J., Fu, Xiaoqing, Zhang, Yuqing, Unizony, Sebastian H., Wallace, Zachary S., Choi, Hyon K., and Stone, John H.
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- 2022
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22. Risk factors for serious infections in ANCA-associated vasculitis
- Author
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Odler, Balazs, Riedl, Regina, Gauckler, Philipp, Shin, Jae Il, Leierer, Johannes, Merkel, Peter A, St Clair, William, Fervenza, Fernando, Geetha, Duvuru, Monach, Paul, Jayne, David, Smith, Rona M, Rosenkranz, Alexander, Specks, Ulrich, Stone, John H, Kronbichler, Andreas, RAVE−ITN Research Group, Gauckler, Philipp [0000-0002-5964-0307], Geetha, Duvuru [0000-0001-8353-5542], Jayne, David [0000-0002-1712-0637], Stone, John H [0000-0001-6588-9435], Kronbichler, Andreas [0000-0002-2945-2946], and Apollo - University of Cambridge Repository
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Vasculitis ,Antibodies, Monoclonal, Murine-Derived ,Treatment Outcome ,rituximab ,Risk Factors ,ANCA ,Trimethoprim, Sulfamethoxazole Drug Combination ,Azathioprine ,Remission Induction ,Humans ,Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis ,cyclophosphamide ,Infections - Abstract
Peer reviewed: True, Acknowledgements: We thank all the patients who participated in the RAVE trial. Balazs Odler is a postdoctoral research fellow at the University of Cambridge supported by the Austrian Science Fund (FWF). David Jayne is supported by the NIHR Cambridge Biomedical Research Centre., Funder: NIHR Cambridge Biomedical Research Centre, OBJECTIVES: Severe infections contribute to morbidity and mortality in antineutrophil cytoplasm antibody-associated vasculitis (AAV). This study aimed to identify risk factors associated with severe infections in participants of the Rituximab versus Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial. METHODS: Data on 197 patients recruited into the RAVE trial were analysed. Participants received either rituximab (RTX) or cyclophosphamide (CYC), followed by azathioprine (AZA). Clinical and laboratory data of patients with and without severe infections (≥grade 3, according to the Common Terminology Criteria for Adverse Events version 3.0) were compared. Risk factors for severe infections were investigated using Cox-regression models. RESULTS: Eighteen of 22 (82%) severe infections occurred within 6 months after trial entry, most commonly respiratory tract infections (15/22, 68%). At baseline, lower absolute numbers of CD19+ cells were observed in patients with severe infections either receiving RTX or CYC/AZA at baseline, while CD5+B and CD3+T cells did not differ between groups. In Cox-regression analysis, higher baseline serum immunoglobulin M levels were associated with the risk of severe infections, whereby a higher baseline total CD19+B cell number and prophylaxis against Pneumocystis jirovecii with trimethoprim-sulfamethoxazole (TMP/SMX) with decreased risk of severe infections. Use of TMP/SMX was associated with lower risk of severe infections in both groups, receiving either RTX or CYC/AZA. CONCLUSIONS: The use of low-dose TMP/SMX is associated with reduced risk of severe infections in patients with AAV treated with either RTX or CYC/AZA. Reduced B cell subpopulations at start of treatment might be a useful correlate of reduced immunocompetence.
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- 2023
23. Development and Validation of a Simulation Model for Treatment to Maintain Remission in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis.
- Author
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Wallace, Zachary S., Stone, John H., Fu, Xiaoqing, Merkel, Peter A., Miloslavsky, Eli M., Zhang, Yuqing, Choi, Hyon K., and Hyle, Emily P.
- Subjects
ANTINEUTROPHIL cytoplasmic antibodies ,STANDARD deviations ,VASCULITIS ,CHRONIC kidney failure ,SIMULATION methods & models - Abstract
Objective: Fixed and tailored rituximab retreatment strategies to maintain remission in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) are associated with tradeoffs. The current study was undertaken to develop a simulation model (AAV‐Sim) to project clinical outcomes with these strategies. Methods: We developed the AAV‐Sim, a microsimulation model of clinical events among individuals with AAV initiating treatment to maintain remission. Individuals transition between health states of remission or relapse and are at risk for severe infection, end‐stage renal disease, or death. We estimated transition rates from published literature, stratified by individual‐level characteristics. We performed validation using the mean average percent error (MAPE) and the coefficient of variation of root mean square error (CV‐RMSE). In internal validation, we compared model‐projected outcomes over 28 months with outcomes observed in the Rituximab versus Azathioprine in ANCA‐Associated Vasculitis 2 (MAINRITSAN2) trial, which compared fixed versus tailored retreatment. In external validation, we compared outcomes with fixed rituximab retreatment from the AAV‐Sim to outcomes from the MAINRITSAN1 trial and an observational study. Results: The AAV‐Sim projected outcomes similar to those in the MAINRITSAN2 trial, including minor (AAV‐Sim 6.0% fixed versus 7.3% tailored; MAINRITSAN2 6.2% versus 8.6%; MAPE 3% and 15%) and major relapse (AAV‐Sim 3.5% versus 5.5%; MAINRITSAN2 3.7% versus 7.4%; MAPE 5% and 26%), severe infection (AAV‐Sim 19.4% versus 11.1%; MAINRITSAN2 19.8% versus 10.2%; MAPE 2% and 9%), and relapse‐free survival (AAV‐Sim 84.8% versus 82.3%; MAINRITSAN2 86% versus 84%; CV‐RMSE 2.3% and 2.5%). Similar performance was observed in external validation. Conclusion: The AAV‐Sim projected a range of clinical outcomes for different treatment approaches that were validated against published data. The AAV‐Sim has the potential to inform management guidelines and research priorities. [ABSTRACT FROM AUTHOR]
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- 2023
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24. Comparative Effectiveness of Rituximab‐ Versus Cyclophosphamide‐Based Remission Induction Strategies in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis for the Risk of Kidney Failure and Mortality.
- Author
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Wallace, Zachary S., Fu, Xiaoqing, Cook, Claire, Ahola, Catherine, Williams, Zachary, Doliner, Brett, Hanberg, Jennifer S., Stone, John H., Zhang, Yuqing, and Choi, Hyon K.
- Subjects
MORTALITY risk factors ,RITUXIMAB ,DRUG efficacy ,GLOMERULAR filtration rate ,CONFIDENCE intervals ,KIDNEY failure ,ANTINEUTROPHIL cytoplasmic antibodies ,AUTOIMMUNE diseases ,TREATMENT effectiveness ,CYCLOPHOSPHAMIDE ,DESCRIPTIVE statistics ,ODDS ratio ,VASCULITIS ,DISEASE remission ,LONGITUDINAL method ,DISEASE risk factors ,EVALUATION - Abstract
Objective: To compare rituximab‐ versus cyclophosphamide‐based remission induction strategies for the long‐term risks of kidney failure and death in antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) in a real‐world cohort. Methods: We performed a cohort study using the Mass General Brigham AAV Cohort, which includes proteinase 3–ANCA+ and myeloperoxidase (MPO)‐ANCA+ AAV patients diagnosed from January 1, 2002 to December 31, 2019. We included cases in which the initial remission induction strategy was based either on rituximab or cyclophosphamide. The primary outcome was the composite outcome of kidney failure or death. We used multivariable Cox proportional hazards models and propensity score–matched analyses to assess the association of rituximab‐ versus cyclophosphamide‐based treatment strategies with the composite outcome of kidney failure or death. Results: Of 595 included patients, 352 patients (~60%) received rituximab‐based and 243 patients (~40%) received cyclophosphamide‐based regimens. The mean age was 61 years, 58% of patients were female, 70% of patients were MPO‐ANCA+, and 69% of patients had renal involvement (median estimated glomerular filtration rate 37.3 ml/minute/1.73 m2). There were 133 events at 5 years, and the incidence rates in rituximab‐ and cyclophosphamide‐based regimens were 6.8 and 6.1 per 100 person‐years, respectively. The risk of kidney failure or death was similar in both groups in multivariable‐adjusted analyses (hazard ratio [HR] 1.03 [95% confidence interval (95% CI) 0.55–1.93]) and in propensity score–matched analyses (HR 1.05 [95% CI 0.55–1.99]) at 5 years. Our findings were similar when outcomes were assessed at 1 and 2 years as well as in subgroups stratified according to renal involvement and severity as well as major organ involvement. Conclusion: Rituximab‐ and cyclophosphamide‐based remission induction strategies for AAV are associated with similar risks of kidney failure and death. [ABSTRACT FROM AUTHOR]
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- 2023
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25. Activation of a Latent Epitope Causing Differential Binding of Antineutrophil Cytoplasmic Antibodies to Proteinase 3.
- Author
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Casal Moura, Marta, Thompson, Gwen E., Nelson, Darlene R., Fussner, Lynn A., Hummel, Amber M., Jenne, Dieter E., Emerling, Daniel, Fervenza, Fernando C., Kallenberg, Cees G. M., Langford, Carol A., McCune, W. Joseph, Merkel, Peter A., Monach, Paul A., Seo, Philip, Spiera, Robert F., St. Clair, E. William, Ytterberg, Steven R., Stone, John H., Robinson, William H., and Specks, Ulrich
- Subjects
GENETIC mutation ,ANTINEUTROPHIL cytoplasmic antibodies ,PROTEOLYTIC enzymes ,MONOCLONAL antibodies ,GRANULOMATOSIS with polyangiitis ,IMMUNOASSAY ,COMPARATIVE studies ,ANTIGENS ,VASCULITIS ,LONGITUDINAL method - Abstract
Objective: Proteinase 3 (PR3) is the major antigen for antineutrophil cytoplasmic antibodies (ANCAs) in the systemic autoimmune vasculitis, granulomatosis with polyangiitis (GPA). PR3‐targeting ANCAs (PR3‐ANCAs) recognize different epitopes on PR3. This study was undertaken to study the effect of mutations on PR3 antigenicity. Methods: The recombinant PR3 variants, iPR3 (clinically used to detect PR3‐ANCAs) and iHm5 (containing 3 point mutations in epitopes 1 and 5 generated for epitope mapping studies) immunoassays and serum samples from patients enrolled in ANCA‐associated vasculitis (AAV) trials were used to screen for differential PR3‐ANCA binding. A patient‐derived monoclonal ANCA 518 (moANCA518) that selectively binds to iHm5 within the mutation‐free epitope 3 and is distant from the point mutations of iHm5 was used as a gauge for remote epitope activation. Selective binding was determined using inhibition experiments. Results: Rather than reduced binding of PR3‐ANCAs to iHm5, we found substantially increased binding of the majority of PR3‐ANCAs to iHm5 compared to iPR3. This differential binding of PR3‐ANCA to iHm5 is similar to the selective moANCA518 binding to iHm5. Binding of iPR3 to monoclonal antibody MCPR3‐2 also induced recognition by moANCA518. Conclusion: The preferential binding of PR3‐ANCAs from patients, such as the selective binding of moANCA518 to iHm5, is conferred by increased antigenicity of epitope 3 on iHm5. This can also be induced on iPR3 when captured by monoclonal antibody MCPR2. This previously unrecognized characteristic of PR3‐ANCA interactions with its target antigen has implications for studying antibody‐mediated autoimmune diseases, understanding variable performance characteristics of immunoassays, and design of potential novel treatment approaches. [ABSTRACT FROM AUTHOR]
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- 2023
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26. Autoreactive Plasmablasts After B Cell Depletion With Rituximab and Relapses in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis.
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Berti, Alvise, Hillion, Sophie, Konig, Maximilian F., Moura, Marta Casal, Hummel, Amber M., Carmona, Eva, Peikert, Tobias, Fervenza, Fernando C., Kallenberg, Cees G.M., Langford, Carol A., Merkel, Peter A., Monach, Paul A., Seo, Philip, Spiera, Robert F., Brunetta, Paul, St. Clair, E. William, Harris, Kristina M., Stone, John H., Grandi, Guido, and Pers, Jacques‐Olivier
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RITUXIMAB ,FLOW cytometry ,B cells ,ANTINEUTROPHIL cytoplasmic antibodies ,DISEASE relapse ,RESEARCH funding ,VASCULITIS ,DISEASE remission - Abstract
Objective: Autoreactive B cells are responsible for antineutrophil cytoplasmic antibody (ANCA) production in ANCA‐associated vasculitis (AAV). Rituximab (RTX) depletes circulating B cells, including autoreactive B cells. We aimed to evaluate changes and associations with relapse of the circulating autoreactive B cell pool following therapeutic B cell depletion in AAV. Methods: Sequential flow cytometry was performed on 148 samples of peripheral blood mononuclear cells from 23 patients with proteinase 3 (PR3)–ANCA–positive AAV who were treated with RTX for remission induction and monitored after stopping therapy during long‐term follow‐up in a prospective clinical trial. PR3 was used as a ligand to target autoreactive PR3‐specific (PR3+) B cells. B cell recurrence was considered as the first blood sample with ≥10 B cells/μl after RTX treatment. Results: At B cell recurrence, PR3+ B cell frequency among B cells was higher than baseline (P < 0.01). Within both PR3+ and total B cells, frequencies of transitional and naive subsets were higher at B cell recurrence than at baseline, while memory subsets were lower (P < 0.001 for all comparisons). At B cell recurrence, frequencies of B cells and subsets did not differ between patients who experienced relapse and patients who remained in remission. In contrast, the plasmablast frequency within the PR3+ B cell pool was higher in patients who experienced relapse and associated with a shorter time to relapse. Frequencies of PR3+ plasmablasts higher than baseline were more likely to be found in patients who experienced relapse within the following 12 months compared to those in sustained remission (P < 0.05). Conclusion: The composition of the autoreactive B cell pool varies significantly following RTX treatment in AAV, and early plasmablast enrichment within the autoreactive pool is associated with future relapses. [ABSTRACT FROM AUTHOR]
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- 2023
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27. Current therapy of granulomatosis with polyangiitis and microscopic polyangiitis: the role of rituximab
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Geetha, Duvuru, Kallenberg, Cees, Stone, John H., Salama, Alan D., Appel, Gerald B., Duna, George, Brunetta, Paul, and Jayne, David
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- 2015
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28. IgA and IgG antineutrophil cytoplasmic antibody engagement of Fc receptor genetic variants influences granulomatosis with polyangiitis
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Kelley, James M., Monach, Paul A., Ji, Chuanyi, Zhou, Yebin, Wu, Jianming, Tanaka, Sumiaki, Mahr, Alfred D., Johnson, Sharleen, McAlear, Carol, Cuthbertson, David, Carette, Simon, Davis,, John C., Dellaripa, Paul F., Hoffman, Gary S., Khalidi, Nader, Langford, Carol A., Seo, Phillip, St. Clair, E. William, Specks, Ulrich, Stone, John H., Spiera, Robert F., Ytterberg, Steven R., Merkel, Peter A., Edberg, Jeffrey C., and Kimberly, Robert P.
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- 2011
29. Expert Perspective: Management of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis.
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Patel, Naomi J. and Stone, John H.
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RITUXIMAB , *GLUCOCORTICOIDS , *DRUG tolerance , *IMMUNIZATION , *COVID-19 vaccines , *ANTINEUTROPHIL cytoplasmic antibodies , *CELL receptors , *IMMUNOSUPPRESSION , *GRANULOMATOSIS with polyangiitis , *IMMUNITY , *MICROSCOPIC polyangiitis , *DISEASE management , *VASCULITIS , *DISEASE remission - Abstract
The antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) comprise a major subset of diseases that cause destructive inflammation of small and medium‐sized blood vessels. Although these conditions have a predilection for pulmonary and renal involvement, they are in fact protean diseases that can involve essentially any organ system. AAV is among the most difficult rheumatic diseases to diagnose and treat. Therapy for AAV has evolved over the past two decades. Rituximab, an anti‐CD20 monoclonal antibody, is now the preferred agent for remission induction in conjunction with a reduced‐dose glucocorticoid taper. Rituximab is also often a key therapy for remission maintenance. Glucocorticoid toxicity reduction has become a major priority for treatment regimens. Avacopan, an important new adjunct to remission induction therapy, may reduce glucocorticoid use and its resulting toxicity. The role of avacopan as a remission maintenance agent requires further study. The duration of immunosuppression following remission is guided by a number of factors, including the patient's overall clinical state, the degree of damage from previous disease activity, the tolerability of remission maintenance medications, and SARS–CoV‐2 vaccination and immunity status. Certain features, including history of previous relapse, the presence of ANCA directed against proteinase 3, and a diagnosis of granulomatosis with polyangiitis, favor prolonged remission maintenance therapy. The interval between rituximab doses can usually be lengthened over time during the maintenance phase. [ABSTRACT FROM AUTHOR]
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- 2022
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30. The Clinical and Pathological Features of IgG4-Related Disease
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Khosroshahi, Arezou, Deshpande, Vikram, and Stone, John H.
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- 2011
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31. Serum Biomarkers of Disease Activity in Longitudinal Assessment of Patients with ANCA‐Associated Vasculitis.
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Monach, Paul A., Warner, Roscoe L., Lew, Robert, Tómasson, Gunnar, Specks, Ulrich, Stone, John H., Fervenza, Fernando C., Hoffman, Gary S., Kallenberg, Cees G. M., Langford, Carol A., Seo, Philip, St. Clair, E. William, Spiera, Robert, Johnson, Kent J., and Merkel, Peter A.
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LIPOCALIN-2 ,PROPORTIONAL hazards models ,MATRIX metalloproteinases ,VASCULITIS - Abstract
Objective: Improved biomarkers of current disease activity and prediction of relapse are needed in antineutrophil cytoplasmic antibody–associated vasculitis (AAV). For clinical relevance, biomarkers must perform well longitudinally in patients on treatment and in patients with nonsevere flares. Methods: Twenty‐two proteins were measured in 347 serum samples from 74 patients with AAV enrolled in a clinical trial. Samples were collected at Month 6 after remission induction, then every 3 months until Month 18, or at the time of flare. Associations of protein concentrations with concurrent disease activity and with future flare were analyzed using mixed‐effects models, Cox proportional hazards models, and conditional logistic regression. Results: Forty‐two patients had flares during the 12‐month follow‐up period, and 32 remained in remission. Twenty‐two patients had severe flares. Six experimental markers (CXCL13, IL‐6, IL‐8, IL‐15, IL‐18BP, and matrix metalloproteinase‐3 [MMP‐3]) and ESR were associated with disease activity using all three methods (P < 0.05, with P < 0.01 in at least one method). A rise in IL‐8, IL‐15, or IL‐18BP was associated temporally with flare. Combining C‐reactive protein (CRP), IL‐18BP, neutrophil gelatinase‐associated lipocalin (NGAL), and sIL‐2Rα improved association with active AAV. CXCL13 and MMP‐3 were increased during treatment with prednisone, independent of disease activity. Marker concentrations during remission were not predictive of future flare. Conclusion: Serum biomarkers of inflammation and tissue damage and repair have been previously shown to be strongly associated with severe active AAV were less strongly associated with active AAV in a longitudinal study that included mild flares and varying treatment. Markers rising contemporaneously with flare or with an improved association in combination merit further study. [ABSTRACT FROM AUTHOR]
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- 2022
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32. Validation of Antineutrophil Cytoplasmic Antibody–Associated Vasculitis as the Cause of End‐Stage Renal Disease in the US Renal Data System.
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Cook, Claire E., Fu, Xiaoqing, Zhang, Yuqing, Stone, John H., Choi, Hyon K., and Wallace, Zachary S.
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CHRONIC kidney failure ,KIDNEY diseases ,ANTINEUTROPHIL cytoplasmic antibodies ,LUPUS nephritis ,GRANULOMATOSIS with polyangiitis ,VASCULITIS ,NOSOLOGY - Abstract
Objective: The objective of this study was to validate the diagnosis of antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) as the primary cause of end‐stage renal disease (ESRD) in the US Renal Data System (USRDS). Methods: We identified patients with ESRD in the Mass General Brigham (MGB) health care system who were enrolled in the USRDS. The health records of those with AAV listed as the primary cause of ESRD in the USRDS were reviewed to confirm the diagnosis and estimate positive predictive value (PPV). Sensitivity was estimated by evaluating the primary cause of ESRD listed in the USRDS for patients with ESRD due to AAV in the MGB AAV cohort. Results: We identified 89 MGB patients with ESRD due to AAV in the USRDS. Of these, 85 cases were confirmed to be true cases of AAV (PPV = 94%). Among the patients classified as having AAV, 84 (99%) had an ANCA test, which was predominantly myeloperoxidase/P‐ANCA (47 [55%]); 36 (42%) had a renal biopsy, and all biopsies were supportive of the diagnosis. The majority (81 [90%]) was identified as AAV by International Classification of Diseases Ninth Revision or International Classification of Diseases 10th Revision codes for granulomatosis with polyangiitis (446.4 or M313.1). Of the 77 MGB AAV cohort patients with ESRD who were linked to the USRDS, 41 (53%) had AAV listed as the cause of ESRD; in the remainder, ESRD was attributed to nonspecific nephritis. Conclusion: The diagnosis of AAV as the cause of ESRD in the USRDS has a high PPV; sensitivity was moderate. These findings support the continued use of the USRDS to study ESRD due to AAV. [ABSTRACT FROM AUTHOR]
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- 2022
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33. 2021 American College of Rheumatology/Vasculitis Foundation Guideline for the Management of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Chung, Sharon A., Langford, Carol A., Maz, Mehrdad, Abril, Andy, Gorelik, Mark, Guyatt, Gordon, Archer, Amy M., Conn, Doyt L., Full, Kathy A., Grayson, Peter C., Ibarra, Maria F., Imundo, Lisa F., Kim, Susan, Merkel, Peter A., Rhee, Rennie L., Seo, Philip, Stone, John H., Sule, Sangeeta, Sundel, Robert P., and Vitobaldi, Omar I.
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VASCULITIS ,VASCULAR diseases ,ANTINEUTROPHIL cytoplasmic antibodies ,AUTOANTIBODIES ,CHURG-Strauss syndrome ,AUTOIMMUNE disease diagnosis ,CONSENSUS (Social sciences) ,RHEUMATOLOGY ,AUTOIMMUNE diseases ,EVIDENCE-based medicine ,SEVERITY of illness index ,TREATMENT effectiveness ,DECISION making ,IMMUNOSUPPRESSIVE agents - Abstract
Objective: To provide evidence-based recommendations and expert guidance for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV), including granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA).Methods: Clinical questions regarding the treatment and management of AAV were developed in the population, intervention, comparator, and outcome (PICO) format (47 for GPA/MPA, 34 for EGPA). Systematic literature reviews were conducted for each PICO question. The Grading of Recommendations Assessment, Development and Evaluation methodology was used to assess the quality of evidence and formulate recommendations. Each recommendation required ≥70% consensus among the Voting Panel.Results: We present 26 recommendations and 5 ungraded position statements for GPA/MPA, and 15 recommendations and 5 ungraded position statements for EGPA. This guideline provides recommendations for remission induction and maintenance therapy as well as adjunctive treatment strategies in GPA, MPA, and EGPA. These recommendations include the use of rituximab for remission induction and maintenance in severe GPA and MPA and the use of mepolizumab in nonsevere EGPA. All recommendations are conditional due in part to the lack of multiple randomized controlled trials and/or low-quality evidence supporting the recommendations.Conclusion: This guideline presents the first recommendations endorsed by the American College of Rheumatology and the Vasculitis Foundation for the management of AAV and provides guidance to health care professionals on how to treat these diseases. [ABSTRACT FROM AUTHOR]- Published
- 2021
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34. ANCA-associated Vasculitis Management in the United States: Data From the Rheumatology Informatics System for Effectiveness (RISE) Registry.
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Wallace, Zachary S., Huifeng Yun, Curtis, Jeffrey R., Lang Chen, Stone, John H., Choi, Hyon K., Yun, Huifeng, and Chen, Lang
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VASCULITIS treatment ,ANTINEUTROPHIL cytoplasmic antibodies ,VASCULITIS ,EPIDEMIOLOGY ,PHYSICIAN practice patterns - Abstract
Objective: The management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) has evolved substantially over the last 2 decades. We sought to characterize AAV treatment patterns in the United States.Methods: We identified patients with AAV in the Rheumatology Informatics System for Effectiveness (RISE) registry who had at least 2 rheumatology clinician visits between January 1, 2015, and December 31, 2017. Demographics, medications, laboratory test results, and billing codes were extracted from the medical record. Demographic and prescription trends were assessed overall and across US regions.Results: We identified 1462 patients with AAV, 259 (18%) with new or relapsing AAV. The majority were classified as having granulomatosis with polyangiitis (75%). The mean age was 59.8 years and 59% were female. The majority of patients were in the South (45%) followed by the Mid-West (32%), West (12%), and Northeast (8%). Patients had a median of 3 visits and follow-up of 579 days. The most commonly prescribed medications during the study period were glucocorticoids (86%) followed by rituximab (45%), methotrexate (33%), azathioprine (32%), and mycophenolate mofetil (18%); cyclophosphamide (CYC) was rarely used (7%). At the most recent visits in RISE, 47% of patients were on glucocorticoids. Prescription trends were similar across regions.Conclusion: To our knowledge, this is the first study to evaluate the demographics and management of AAV by rheumatologists outside of major referral centers. Management strategies vary widely, but CYC is rarely used. These observations can be used to inform future research priorities. Additional studies are needed to characterize AAV severity in RISE as well as patient and provider treatment preferences. [ABSTRACT FROM AUTHOR]- Published
- 2021
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35. Tocilizumab vs placebo for the treatment of giant cell arteritis with polymyalgia rheumatica symptoms, cranial symptoms or both in a randomized trial.
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Spiera, Robert, Unizony, Sebastian H., Bao, Min, Luder, Yves, Han, Jian, Pavlov, Andrey, and Stone, John H.
- Abstract
The randomized, placebo (PBO)-controlled GiACTA trial demonstrated the efficacy and safety of tocilizumab (TCZ) in patients with giant cell arteritis (GCA). The present study evaluated the efficacy of TCZ in patients with GCA presenting with polymyalgia rheumatica (PMR) symptoms only, cranial symptoms only or both PMR and cranial symptoms in the GiACTA trial. In GiACTA, 250 patients with GCA received either TCZ weekly or every other week plus a 26-week prednisone taper or PBO plus a 26- or 52-week prednisone taper. This post hoc analysis assessed baseline characteristics, sustained remission rate, number of flares, annualized flare rate, time to flare, cumulative prednisone dose, methotrexate use and safety in patients with PMR symptoms only, cranial symptoms only or both at baseline. Overall, 52 patients had PMR symptoms only, 94 had cranial symptoms only and 104 had both symptoms at baseline. At Week 52, rates of sustained remission were significantly higher with TCZ vs PBO in all 3 groups (PMR only, 45.2% vs 19.0%, P = 0.0446; cranial only, 60.3% vs 19.4%, P = 0.0001; PMR and cranial, 55.0% vs 11.4%, P < 0.0001). Smaller proportions of TCZ-treated patients experienced disease flare than PBO-treated patients across all groups (PMR only, 41.9% vs 57.1%; cranial only, 20.7% vs 47.2%; PMR and cranial, 31.7% vs 81.8%). Annualized flare rate and risk of flare were significantly lower with TCZ vs PBO for patients with cranial symptoms only and both symptoms; they were numerically lower, but did not reach statistical significance, in the smaller group of patients with PMR symptoms only. TCZ improved clinical outcomes in patients who presented with PMR symptoms only, cranial symptoms only or both at baseline, suggesting that TCZ is effective in patients with GCA regardless of the presenting clinical phenotype. [ABSTRACT FROM AUTHOR]
- Published
- 2021
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36. Antineutrophil cytoplasmic antibody positivity in IgG4-related disease: A case report and review of the literature
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Della Torre Emanuel, Lanzillotta Marco, Campochiaro Corrado, Bozzalla Emanuele, Bozzolo Enrica, Bandiera Alessandro, Bazzigaluppi Elena, Canevari Carla, Modorati Giulio, Stone John H, MANFREDI , ANGELO ANDREA M. A., DOGLIONI , CLAUDIO, DELLA TORRE , EMANUEL, Della Torre, Emanuel, Lanzillotta, Marco, Campochiaro, Corrado, Bozzalla, Emanuele, Bozzolo, Enrica, Bandiera, Alessandro, Bazzigaluppi, Elena, Canevari, Carla, Modorati, Giulio, Stone John, H, Manfredi, ANGELO ANDREA M. A., Doglioni, Claudio, and DELLA TORRE, Emanuel
- Subjects
Pathology ,medicine.medical_specialty ,Biopsy ,vasculitis ,Subclass ,Antibodies, Antineutrophil Cytoplasmic ,Diagnosis, Differential ,antineutrophil cytoplasmic antibodies ,03 medical and health sciences ,rituximab ,0302 clinical medicine ,parasitic diseases ,medicine ,Humans ,case report ,Clinical Case Report ,cardiovascular diseases ,030212 general & internal medicine ,IgG4-related disease ,skin and connective tissue diseases ,Anti-neutrophil cytoplasmic antibody ,IgG4 ,030203 arthritis & rheumatology ,granulomatosis with polyangiitis ,integumentary system ,medicine.diagnostic_test ,business.industry ,fungi ,General Medicine ,Middle Aged ,medicine.disease ,Immunoglobulin G ,Female ,Differential diagnosis ,Vasculitis ,business ,Granulomatosis with polyangiitis ,Scleritis ,Research Article - Abstract
BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by serum IgG4 elevation and tissue infiltration of IgG4-positive plasma cells. Substantial overlap between IgG4-RD and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) exists in terms of organ involvement and histopathological features. A positive ANCA assay is regarded as a highly specific finding in favor of an AAV, and generally influences away from a diagnosis of IgG4-RD. Recent reports, however, have raised the possibility that some patients with IgG4-RD are ANCA positive, thus suggesting reconsideration of the role of ANCA in the diagnostic workup. In the present work, we describe the first case of concomitant biopsy-proven IgG4-RD and granulomatosis with polyangiitis (GPA), demonstrating antiproteinase 3 (PR3) ANCA of the IgG4 subclass in the patient's serum. We also review the literature in order to provide clinicians with tools for interpreting ANCA positivity in IgG4-RD patients. CASE SUMMARY: A 51-year-old woman was referred for left exopthalmos due to lacrimal gland enlargement and increased serum IgG4 concentration. IgG4-RD was suspected and further imaging studies disclosed multiple pulmonary masses in the right lung. Histological analysis of the left lacrimal gland was diagnostic for IgG4-RD, but lung biopsy showed typical features of GPA. ANCA assay was positive for anti-PR3 antibodies. Further immunofluorescence studies demonstrated anti-PR3 antibodies of IgG1 and IgG4 subclass. Treatment with rituximab induced swift remission of both IgG4-RD and GPA manifestations. We identified 9 other reports of patients with IgG4-RD and positive ANCA in the English literature, 5 cases with biopsy-proven IgG4-RD and 4 cases in whom IgG4-RD was diagnosed presumptively. Four patients had also histological evidence of concomitant AAV. CONCLUSION: The present work demonstrates that ANCA positivity in patients with biopsy-proven IgG4-RD should prompt the exclusion of a concomitant vasculitic process; a positive ANCA does not exclude the diagnosis of IgG4-RD; confirmation through immunoenzymatic assays of the ANCA specificity, clinical-pathological correlation, and histopathological evaluation remain crucial steps for the differential diagnosis between AAV and IgG4-RD. ZB 0 Z8 0 ZR 0 ZS 0
- Published
- 2016
37. Clinical Utility of Serial Measurements of Antineutrophil Cytoplasmic Antibodies Targeting Proteinase 3 in ANCA-Associated Vasculitis.
- Author
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Thompson, Gwen E., Fussner, Lynn A., Hummel, Amber M., Schroeder, Darrell R., Silva, Francisco, Snyder, Melissa R., Langford, Carol A., Merkel, Peter A., Monach, Paul A., Seo, Philip, Spiera, Robert F., St. Clair, E. William, Stone, John H., and Specks, Ulrich
- Subjects
ANTINEUTROPHIL cytoplasmic antibodies ,VASCULITIS ,PROTEINASES ,PROPORTIONAL hazards models ,DISEASE remission - Abstract
Background: The utility of ANCA testing as an indicator of disease activity in ANCA-associated vasculitis (AAV) remains controversial. This study aimed to determine the association of ANCA testing by various methods and subsequent remission and examine the utility of a widely used automated addressable laser-bead immunoassay (ALBIA) to predict disease relapses. Methods: Data from the Rituximab vs. Cyclophosphamide for ANCA-Associated Vasculitis (RAVE) trial were used. ANCA testing was performed by direct ELISA, capture ELISA, and ALBIA. Cox proportional hazards regression models were used to evaluate the association of PR3-ANCA level and subsequent remission or relapse. The ALBIA results are routinely reported as >8 when the value is high. For this study, samples were further titrated. A decrease and increase in PR3-ANCA were defined as a halving or doubling in value, respectively. Results: A decrease in ANCA by ALBIA at 2 months was associated with shorter time to sustained remission (HR 4.52, p = 0.035). A decrease in ANCA by direct ELISA at 4 months was associated with decreased time to sustained remission (HR 1.77, p = 0.050). There were no other associations between ANCA decreases or negativity and time to remission. An increase in PR3-ANCA by ALBIA was found in 78 of 93 subjects (84%). Eleven (14%) had a PR3-ANCA value which required titration for detection of an increase. An increase of ANCA by ALBIA was associated with severe relapse across various subgroups. Conclusions: A decrease in ANCA by ALBIA at 2 months and by direct ELISA at 4 months may be predictive of subsequent remission. These results should be confirmed in a separate cohort with similarly protocolized sample and clinical data collection. A routinely used automated ALBIA for PR3-ANCA measurement is comparable to direct ELISA in predicting relapse in PR3-AAV. Without titration, 14% of the increases detected by ALBIA would have been missed. Titration is recommended when this assay is used for disease monitoring. The association of an increase in PR3-ANCA with the risk of subsequent relapse remains complex and is affected by disease phenotype and remission induction agent. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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38. All-cause and cause-specific mortality in ANCA-associated vasculitis: overall and according to ANCA type.
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Wallace, Zachary S, Fu, Xiaoqing, Harkness, Tyler, Stone, John H, Zhang, Yuqing, and Choi, Hyon
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CARDIOVASCULAR diseases ,CAUSES of death ,INFECTION ,RESPIRATORY diseases ,TUMORS ,VASCULITIS ,PROPORTIONAL hazards models ,ANTINEUTROPHIL cytoplasmic antibodies - Abstract
Objective The objective of this study was to evaluate causes of death in a contemporary inception cohort of ANCA-associated vasculitis patients, stratifying the analysis according to ANCA type. Methods We identified a consecutive inception cohort of patients newly diagnosed with ANCA-associated vasculitis from 2002 to 2017 in the Partners HealthCare System and determined vital status through the National Death Index. We determined cumulative mortality incidence and standardized mortality ratios (SMRs) compared with the general population. We compared MPO- and PR3-ANCA
+ cases using Cox regression models. Results The cohort included 484 patients with a mean diagnosis age of 58 years; 40% were male, 65% were MPO-ANCA+ , and 65% had renal involvement. During 3385 person-years (PY) of follow-up, 130 patients died, yielding a mortality rate of 38.4/1000 PY and a SMR of 2.3 (95% CI: 1.9, 2.8). The most common causes of death were cardiovascular disease (CVD; cumulative incidence 7.1%), malignancy (5.9%) and infection (4.1%). The SMR for infection was greatest for both MPO- and PR3-ANCA+ patients (16.4 and 6.5). MPO-ANCA+ patients had an elevated SMR for CVD (3.0), respiratory disease (2.4) and renal disease (4.5). PR3- and MPO-ANCA+ patients had an elevated SMR for malignancy (3.7 and 2.7). Compared with PR3-ANCA+ patients, MPO-ANCA+ patients had a higher risk of CVD death [hazard ratio 5.0 (95% CI: 1.2, 21.2]; P = 0.03]. Conclusion Premature ANCA-associated vasculitis mortality is explained by CVD, infection, malignancy, and renal death. CVD is the most common cause of death, but the largest excess mortality risk in PR3- and MPO-ANCA+ patients is associated with infection. MPO-ANCA+ patients are at higher risk of CVD death than PR3-ANCA+ patients. [ABSTRACT FROM AUTHOR]- Published
- 2020
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39. The Pharmacogenomic Association of Fc gamma Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis
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Cartin-Ceba, Rodrigo, Indrakanti, Divya, Specks, Ulrich, Stone, John H., Hoffman, Gary S., Kallenberg, Cees G. M., Langford, Carol A., Merkel, Peter A., Spiera, Robert F., Monach, Paul A., St. Clair, E. William, Seo, Philip, Tchao, Nadia K., Ytterberg, Steven R., Brunetta, Paul G., Song, Huijuan, Birmingham, Dan, Rovin, Brad H., Grp, RAVE-Immune Tolerance Network Res, and Translational Immunology Groningen (TRIGR)
- Subjects
0301 basic medicine ,ANCA-ASSOCIATED VASCULITIS ,Cyclophosphamide ,IMPACT ,Immunology ,Birmingham Vasculitis Activity Score ,GENE POLYMORPHISMS ,THERAPY ,TOXICITY ,03 medical and health sciences ,0302 clinical medicine ,WEGENERS-GRANULOMATOSIS ,Rheumatology ,Prednisone ,medicine ,Immunology and Allergy ,BREAST-CANCER ,AUTOIMMUNE-DISEASE ,Anti-neutrophil cytoplasmic antibody ,Autoimmune disease ,business.industry ,medicine.disease ,LUPUS NEPHRITIS ,RHEUMATOID-ARTHRITIS ,030104 developmental biology ,030220 oncology & carcinogenesis ,Rheumatoid arthritis ,Rituximab ,business ,Vasculitis ,medicine.drug - Abstract
Objective The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fc gamma receptors (Fc gamma R) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively.Methods Functional SNPs for Fc gamma R (Fc gamma RIIa 519G>A, Fc gamma RIIb 695T>C, Fc gamma RIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests.Results No significant associations were identified between complete remission and any Fc gamma R genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of Fc gamma RIIa and complete remission (P=0.01). The 519AA genotype predicted complete remission (P=0.006) and a shorter time to complete remission (PConclusion The finding that the homozygous Fc gamma RIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that Fc gamma RIIa may be broadly involved in disease pathogenesis and response to therapy.
- Published
- 2017
40. Personalized Medicine in ANCA-Associated Vasculitis ANCA Specificity as the Guide?
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Wallace, Zachary S. and Stone, John H.
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INDIVIDUALIZED medicine ,GRANULOMATOSIS with polyangiitis ,VASCULITIS ,PATHOLOGY ,NOSOLOGY ,NECROTIZING pancreatitis ,POLYARTERITIS nodosa - Abstract
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a small- to medium-vessel necrotizing vasculitis responsible for excess morbidity and mortality (1). The AAVs, which include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic granulomatosis with polyangiitis (EGPA), are among the most difficult types of vasculitis to treat. Although clinicopathologic disease definitions have been used traditionally to categorize patients into one of these three diagnoses, more recently ANCA specificity for either proteinase 3 (PR3) or myeloperoxidase (MPO) has been advocated for the purpose of disease classification (2). This is because differences in genetics, pathogenesis, risk factors, treatment responses, and outcomes align more closely with PR3- or MPO-ANCA type than with the clinocopathologic diagnosis. Moreover, classifying patients as GPA or MPA can be challenging because biopsies are not obtained routinely in most cases and existing classification systems can provide discrepant classification for the same patient (3). In this review, we address the recent literature supporting the use of ANCA specificity to study and personalize the care of AAV patients (Table 1). We focus particularly on patients with GPA or MPA. [ABSTRACT FROM AUTHOR]
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- 2019
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41. Association of Pulmonary Hemorrhage, Positive Proteinase 3, and Urinary Red Blood Cell Casts With Venous Thromboembolism in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis.
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Kronbichler, Andreas, Leierer, Johannes, Shin, Jae Il, Merkel, Peter A., Spiera, Robert, Seo, Philip, Langford, Carol A., Hoffman, Gary S., Kallenberg, Cees G. M., St.Clair, E. William, Brunetta, Paul, Fervenza, Fernando C., Geetha, Duvuru, Keogh, Karina A., Monach, Paul A., Ytterberg, Steven R., Mayer, Gert, Specks, Ulrich, and Stone, John H.
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AUTOIMMUNE disease diagnosis ,HEMORRHAGE complications ,THROMBOEMBOLISM risk factors ,RITUXIMAB ,ERYTHROCYTES ,AGE distribution ,AUTOIMMUNE diseases ,CONFIDENCE intervals ,HEART ,HEMATURIA ,LUNG diseases ,MULTIVARIATE analysis ,PROTEOLYTIC enzymes ,RISK assessment ,SEX distribution ,STATISTICS ,URINALYSIS ,VASCULITIS ,VEINS ,TREATMENT effectiveness ,DISEASE duration ,ODDS ratio ,ANTINEUTROPHIL cytoplasmic antibodies ,DISEASE complications - Abstract
Objective: To assess the frequency of venous thromboembolism (VTE) events in the Rituximab in Antineutrophil Cytoplasmic Antibody (ANCA)–Associated Vasculitis (RAVE) trial and identify novel potential risk factors. Methods: VTE events in 197 patients enrolled in the RAVE trial were analyzed. Baseline demographic and clinical characteristics were recorded, and univariate and multivariate analyses were performed to identify factors associated with VTE in ANCA‐associated vasculitis (AAV). Results: VTE occurred in 16 patients (8.1%) with an overall average time to event of 1.5 months (range 1.0–2.75). In univariate analyses with calculation of hazard ratios (HRs) and 95% confidence intervals (95% CIs), heart involvement (HR 17.408 [95% CI 2.247–134.842]; P = 0.006), positive proteinase 3 (PR3)–ANCA (HR 7.731 [95% CI 1.021–58.545]; P = 0.048), pulmonary hemorrhage (HR 3.889 [95% CI 1.448–10.448]; P = 0.008), and the presence of red blood cell casts (HR 15.617 [95% CI 3.491–69.854]; P < 0.001) were associated with the onset of VTE. In multivariate models adjusted for age and sex, the significant associations between VTE events and heart involvement (HR 21.836 [95% CI 2.566–185.805]; P = 0.005), PR3‐ANCA (HR 9.12 [95% CI 1.158–71.839]; P = 0.036), pulmonary hemorrhage (HR 3.91 [95% CI 1.453–10.522]; P = 0.007), and urinary red blood cell casts (HR 16.455 [95% CI 3.607–75.075]; P < 0.001) remained. Conclusion: Patients diagnosed as having AAV with pulmonary hemorrhage, positive PR3‐ANCA, heart involvement, and the presence of red blood cell casts are at an increased risk to develop VTE. Further studies are needed to confirm and expand these findings and to explore the mechanisms of hypercoagulability in these patients with the aim of informing potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]
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- 2019
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42. Disease Activity, Antineutrophil Cytoplasmic Antibody Type, and Lipid Levels in Antineutrophil Cytoplasmic Antibody–Associated Vasculitis.
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Wallace, Zachary S., Fu, Xiaoqing, Liao, Katherine, Kallenberg, Cees G. M., Langford, Carol A., Merkel, Peter A., Monach, Paul, Seo, Philip, Specks, Ulrich, Spiera, Robert, St.Clair, E. William, Zhang, Yuqing, Choi, Hyon, and Stone, John H.
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RITUXIMAB ,CYCLOPHOSPHAMIDE ,AZATHIOPRINE ,APOLIPOPROTEINS ,CARDIOVASCULAR diseases risk factors ,CHOLESTEROL ,CONFIDENCE intervals ,LIPIDS ,LOW density lipoproteins ,OXIDOREDUCTASES ,PROTEOLYTIC enzymes ,T-test (Statistics) ,VASCULITIS ,MULTIPLE regression analysis ,SYMPTOMS ,RANDOMIZED controlled trials ,ANTINEUTROPHIL cytoplasmic antibodies ,DISEASE risk factors ,THERAPEUTICS - Abstract
Objective: Patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) have an elevated risk of cardiovascular disease (CVD). This study was undertaken to develop a clearer understanding of the association between changes in disease activity and lipid levels in AAV, which may inform CVD risk stratification in this population. Methods: Lipid levels were assessed in stored serum samples (obtained at baseline and month 6) from the Rituximab for ANCA‐Associated Vasculitis (RAVE) trial, which randomized patients to receive either rituximab or cyclophosphamide followed by azathioprine. Paired t‐tests and multivariable linear regression were used to assess changes in lipid levels. Results: Of the 142 patients with serum samples available, the mean ± SD age was 52.3 ± 14.7 years, 72 (51%) were male, 95 (67%) were proteinase 3 (PR3)–ANCA positive, 72 (51%) had received a new diagnosis of AAV, and 75 (53%) were treated with rituximab. Several lipid levels increased between baseline and month 6, including total cholesterol (+12.4 mg/dl [95% confidence interval (95% CI) +7.1, +21.0]), low‐density lipoprotein (+10.3 mg/dl [95% CI +6.1, +17.1]), and apolipoprotein B (+3.5 mg/dl [95% CI +1.0, +8.3]). These changes were observed among newly diagnosed and PR3‐ANCA–positive patients but not among those with relapsing disease or myeloperoxidase‐ANCA–positive patients. There was no difference in change in lipid levels between rituximab‐treated patients and cyclophosphamide‐treated patients. Changes in lipid levels correlated with changes in erythrocyte sedimentation rate but not with other inflammatory markers or glucocorticoid exposure. Conclusion: Lipid levels increased during remission induction among patients with newly diagnosed AAV and those who were PR3‐ANCA positive. Disease activity and ANCA type should be considered when assessing lipid profiles to stratify CVD risk in patients with AAV. [ABSTRACT FROM AUTHOR]
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- 2019
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43. Interstitial Immunostaining and Renal Outcomes in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis.
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Geetha, Duvuru, Sethi, Sanjeev, De Vriese, an S., Specks, Ulrich, Kallenberg, Cees G.M., Lim, Noha, Spiera, Robert, St. Clair, E. William, Merkel, Peter a., Seo, Philip, Monach, Paul a., Lepori, Nicola, Fessler, Barri J., Langford, Carol a., Hoffman, Gary S., Sharma, Rishi, Stone, John H., Fervenza, Fernando C., and RAVE-ITN Research Group
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GLOMERULONEPHRITIS ,ANTINEUTROPHIL cytoplasmic antibodies ,IMMUNOSTAINING ,HEALTH outcome assessment ,T cells ,GLOMERULAR filtration rate ,DIAGNOSIS - Abstract
Background: Immunopathologic features predict renal function at baseline and follow-up in antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN). The interstitial infiltrate consists predominantly of T lymphocytes, but their pathophysiologic significance is unclear, especially in light of the success of B-cell-directed therapy.Methods: Renal biopsies from 33 patients treated with cyclophosphamide (CYC; n = 17) or rituximab (RTX; n = 16) in the RTX in ANCA-associated vasculitis (RAVE) trial were classified according to the new ANCA GN classification. T- and B-cell infiltration in the interstitium was assessed by immunostaining for CD3 and CD20. Correlations of clinical and histologic parameters with renal function at set time points were examined.Results: The mean (SD) baseline estimated glomerular filtration rate was 36 (20) mL/min/1.73 m2. ANCA GN class distribution was 46% focal, 33% mixed, 12% sclerotic and 9% crescentic. The interstitial infiltrate consisted of >50% CD3 positive cells in 69% of biopsies, but >50% CD20 positive cells only in 8% of biopsies. In a multiple linear regression model, only baseline glomerular filtration rate (GFR) correlated with GFR at 6, 12, and 18 months. Interstitial B- and T-cell infiltrates had no significant impact on long-term prognosis, independent of the treatment limb. A differential effect was noted only at 6 months, where a dense CD3 positive infiltrate predicted lower GFR in the RTX group and a CD20 positive infiltrate predicted higher GFR in the CYC group.Conclusions: In ANCA-associated GN, the interstitial infiltrate contains mainly T lymphocytes. However, it is neither reflecting baseline renal function nor predictive of response to treatment, regardless of the immunosuppression regimen employed. [ABSTRACT FROM AUTHOR]- Published
- 2017
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44. Association of Serum Calprotectin (S100A8/A9) Level With Disease Relapse in Proteinase 3-Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Pepper, Ruth J., Draibe, Juliana B., Caplin, Ben, Fervenza, Fernando C., Hoffman, Gary S., Kallenberg, Cees G. M., Langford, Carol A., Monach, Paul A., Seo, Philip, Spiera, Robert, William St.Clair, E., Tchao, Nadia K., Stone, John H., Specks, Ulrich, Merkel, Peter A., and Salama, Alan D.
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DISEASE relapse ,ANTIGENS ,BIOMARKERS ,CALCIUM-binding proteins ,CONFIDENCE intervals ,CYTOPLASM ,ENZYME-linked immunosorbent assay ,GLUCOCORTICOIDS ,IMMUNOGLOBULINS ,MEDICAL cooperation ,NEUTROPHILS ,OXIDOREDUCTASES ,PROBABILITY theory ,PROTEOLYTIC enzymes ,RESEARCH ,RESEARCH funding ,STATISTICS ,T-test (Statistics) ,VASCULITIS ,RITUXIMAB ,DATA analysis ,MULTIPLE regression analysis ,RANDOMIZED controlled trials ,PROPORTIONAL hazards models ,BLIND experiment ,RECEIVER operating characteristic curves ,CYCLOPHOSPHAMIDE ,DATA analysis software ,AZATHIOPRINE ,DESCRIPTIVE statistics ,KAPLAN-Meier estimator ,MANN Whitney U Test ,FRIEDMAN test (Statistics) - Abstract
Objective S100A8/A9 (calprotectin) has shown promise as a biomarker for predicting relapse in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). This study was undertaken to investigate serum S100A8/A9 level as a biomarker for predicting future relapse in a large cohort of patients with severe AAV. Methods Serum levels of S100A8/A9 were measured at baseline and months 1, 2, and 6 following treatment initiation in 144 patients in the Rituximab in ANCA-Associated Vasculitis trial (cyclophosphamide/azathioprine versus rituximab [RTX] for induction of remission) in whom complete remission was attained. Results Patients were divided into 4 groups: proteinase 3 (PR3)-ANCA with relapse (n = 37), PR3-ANCA without relapse (n = 56), myeloperoxidase (MPO)-ANCA with relapse (n = 6), and MPO-ANCA without relapse (n = 45). Serum S100A8/A9 level decreased in all groups during the first 6 months of treatment. The percentage reduction from baseline to month 2 was significantly different between patients who experienced a relapse and those who did not in the PR3-ANCA group ( P = 0.046). A significantly higher risk of relapse was associated with an increase in S100A8/A9 level between baseline and month 2 ( P = 0.0043) and baseline and month 6 ( P = 0.0029). Subgroup analysis demonstrated that patients treated with RTX who had increased levels of S100A8/A9 were at greatest risk of future relapse ( P = 0.028). Conclusion An increase in serum S100A8/A9 level by month 2 or 6 compared to baseline identifies a subgroup of PR3-ANCA patients treated with RTX who are at higher risk of relapse by 18 months. Since RTX is increasingly used for remission induction in PR3-ANCA-positive patients experiencing a relapse, S100A8/A9 level may assist in identifying those patients requiring more intensive or prolonged treatment. [ABSTRACT FROM AUTHOR]
- Published
- 2017
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45. The Pharmacogenomic Association of Fcγ Receptors and Cytochrome P450 Enzymes With Response to Rituximab or Cyclophosphamide Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Cartin‐Ceba, Rodrigo, Indrakanti, Divya, Specks, Ulrich, Stone, John H., Hoffman, Gary S., Kallenberg, Cees G. M., Langford, Carol A., Merkel, Peter A., Spiera, Robert F., Monach, Paul A., St.Clair, E. William, Seo, Philip, Tchao, Nadia K., Ytterberg, Steven R., Brunetta, Paul G., Song, Huijuan, Birmingham, Dan, and Rovin, Brad H.
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RITUXIMAB ,CYCLOPHOSPHAMIDE ,DNA analysis ,ACADEMIC medical centers ,COMPARATIVE studies ,CONFIDENCE intervals ,FISHER exact test ,GENETIC polymorphisms ,POLYMERASE chain reaction ,PROBABILITY theory ,RESEARCH funding ,VASCULITIS ,LOGISTIC regression analysis ,GRANULOMATOSIS with polyangiitis ,TREATMENT effectiveness ,DATA analysis software ,DESCRIPTIVE statistics ,SEQUENCE analysis ,ODDS ratio ,GENOTYPES ,ANTINEUTROPHIL cytoplasmic antibodies ,CYTOCHROME P-450 - Abstract
Objective The Rituximab in ANCA-Associated Vasculitis (RAVE) trial compared rituximab to cyclophosphamide as induction therapy for the treatment of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. We undertook the current study to determine whether known single-nucleotide polymorphisms (SNPs) for Fcγ receptors (FcγR) or cytochrome P450 (CYP) enzymes were associated with the response to treatment with rituximab and cyclophosphamide, respectively. Methods Functional SNPs for FcγR (FcγRIIa 519G>A, FcγRIIb 695T>C, FcγRIIIa 559T>G) and CYP enzymes (CYP2B6 1459C>T, CYP2C19 681G>A) were analyzed by direct sequencing of polymerase chain reaction-amplified genomic DNA. Each SNP was tested as a predictor of complete remission at 6 months or remission with continued prednisone administration using logistic regression and including the covariates of baseline Birmingham Vasculitis Activity Score for Wegener's Granulomatosis, ANCA type, and new versus relapsing disease. The associations of these SNPs with the secondary outcomes of time to complete remission, time to relapse, or time to B cell reconstitution were analyzed by Cox proportional hazard tests. Results No significant associations were identified between complete remission and any FcγR genotype in the rituximab group or any CYP genotype in the cyclophosphamide group. However, when the treatment groups were combined, an association was found between the 519AA genotype of FcγRIIa and complete remission ( P = 0.01). The 519AA genotype predicted complete remission ( P = 0.006) and a shorter time to complete remission ( P < 0.001). Conclusion The finding that the homozygous FcγRIIa 519AA variant was associated with complete response and a shorter time to complete response in the RAVE trial, independent of treatment type, implies that FcγRIIa may be broadly involved in disease pathogenesis and response to therapy. [ABSTRACT FROM AUTHOR]
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- 2017
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46. Inpatient complications in patients with giant cell arteritis: decreased mortality and increased risk of thromboembolism, delirium and adrenal insufficiency.
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Unizony, Sebastian, Menendez, Mariano E., Rastalsky, Naina, and Stone, John H.
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THROMBOEMBOLISM risk factors ,RISK of delirium ,ADRENAL insufficiency ,ACADEMIC medical centers ,CONFIDENCE intervals ,STATISTICAL correlation ,DATABASES ,GIANT cell arteritis ,MEDICAL information storage & retrieval systems ,MORTALITY ,MULTIVARIATE analysis ,REGRESSION analysis ,STATISTICS ,T-test (Statistics) ,LOGISTIC regression analysis ,DATA analysis ,RELATIVE medical risk ,CROSS-sectional method ,DATA analysis software ,DESCRIPTIVE statistics ,ODDS ratio ,DISEASE complications ,DISEASE risk factors - Abstract
Objective: The morbidity and mortality of hospitalized GCA patients have been unexplored. The aim of this study was to analyse inpatient complications experienced by patients with GCA. Methods: We used the Nationwide Inpatient Sample database to study a large group of patients admitted for pneumonia, myocardial infarction (MI), ischaemic stroke and femoral neck fracture. Patients were divided into two groups based on whether or not they had a diagnosis of GCA upon admission. Outcomes evaluated included inpatient mortality and the occurrence of adrenal insufficiency, deep vein thrombosis, pulmonary embolism and delirium. Results: From 2008 to 2011, 8203447 patients ≥50 years of age were discharged from US hospitals after admission with pneumonia, MI, stroke and femoral neck fracture. Among these patients, 9311 (0.11%) had GCA. Admissions for pneumonia, stroke and hip fracture were more frequent in GCA patients compared with those without GCA, accounting for 41.5% vs 39.4%, 24.9% vs 19.8% and 15.4% vs 14.2% of hospitalizations, respectively (P ≤ 0.001). Admissions for MI were more common in non-GCA patients (26.6% vs 18.2%, P< 0.001). During hospitalization, 4.1% of the GCA patients died, compared with 4.8% of those without GCA [odds ratio (OR) 0.73, P< 0.001). The GCA population suffered significantly more often from deep vein thrombosis (OR 2.08, P< 0.001), pulmonary embolism (OR 1.58, P< 0.001), delirium (OR 1.60, P< 0.001) and adrenal insufficiency (OR 4.95, P< 0.001). Conclusion: Hospitalized GCA patients have lower mortality compared with the general inpatient population but greater risk of venous thromboembolism, delirium and adrenal insufficiency. [ABSTRACT FROM AUTHOR]
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- 2015
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47. Neutrophil-Related Gene Expression and Low-Density Granulocytes Associated With Disease Activity and Response to Treatment in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Grayson, Peter C., Carmona‐Rivera, Carmelo, Xu, Lijing, Lim, Noha, Gao, Zhong, Asare, Adam L., Specks, Ulrich, Stone, John H., Seo, Philip, Spiera, Robert F., Langford, Carol A., Hoffman, Gary S., Kallenberg, Cees G. M., St.Clair, E. William, Tchao, Nadia K., Ytterberg, Steven R., Phippard, Deborah J., Merkel, Peter A., Kaplan, Mariana J., and Monach, Paul A.
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ACADEMIC medical centers ,ENZYME-linked immunosorbent assay ,FISHER exact test ,GENE expression ,IMMUNOGLOBULINS ,MULTIVARIATE analysis ,NEUTROPHILS ,POLYMERASE chain reaction ,REGRESSION analysis ,RESEARCH funding ,STATISTICS ,VASCULITIS ,LOGISTIC regression analysis ,GENOMICS ,DATA analysis ,SEVERITY of illness index ,REVERSE transcriptase polymerase chain reaction ,DESCRIPTIVE statistics - Abstract
Objective To discover biomarkers involved in the pathophysiology of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) and to determine whether low-density granulocytes (LDGs) contribute to gene expression signatures in AAV. Methods The source of clinical data and linked biologic specimens was a randomized controlled treatment trial in AAV. RNA sequencing of whole blood from patients with AAV was performed during active disease at the baseline visit and during remission 6 months later. Gene expression was compared between patients who met versus those who did not meet the primary trial outcome of clinical remission at 6 months (responders versus nonresponders). Measurement of neutrophil-related gene expression was confirmed in peripheral blood mononuclear cells (PBMCs) to validate the findings in whole blood. A negative-selection strategy isolated LDGs from PBMC fractions. Results Differential expression between responders (n = 77) and nonresponders (n = 35) was detected in 2,346 transcripts at the baseline visit ( P < 0.05). Unsupervised hierarchical clustering demonstrated a cluster of granulocyte-related genes, including myeloperoxidase (MPO) and proteinase 3 (PR3). A granulocyte multigene composite score was significantly higher in nonresponders than in responders ( P < 0.01) and during active disease than during remission ( P < 0.01). This signature strongly overlapped an LDG signature identified previously in lupus (false discovery rate by gene set enrichment analysis <0.01). Transcription of PR3 measured in PBMCs was associated with active disease and treatment response ( P < 0.01). LDGs isolated from patients with AAV spontaneously formed neutrophil extracellular traps containing PR3 and MPO. Conclusion In AAV, increased expression of a granulocyte gene signature is associated with disease activity and decreased response to treatment. The source of this signature is likely LDGs, a potentially pathogenic cell type in AAV. [ABSTRACT FROM AUTHOR]
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- 2015
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48. Peripheral CD5+ B Cells in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
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Unizony, Sebastian, Lim, Noha, Phippard, Deborah J., Carey, Vincent J., Miloslavsky, Eli M., Tchao, Nadia K., Iklé, David, Asare, Adam L., Merkel, Peter A., Monach, Paul A., Seo, Philip, St.Clair, E. William, Langford, Carol A., Spiera, Robert, Hoffman, Gary S., Kallenberg, Cees G. M., Specks, Ulrich, and Stone, John H.
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B cells ,THERAPEUTIC use of biochemical markers ,ACADEMIC medical centers ,AUTOANTIBODIES ,CHI-squared test ,CONFIDENCE intervals ,FISHER exact test ,FLOW cytometry ,MEDICAL cooperation ,PLACEBOS ,RESEARCH ,STATISTICS ,VASCULITIS ,DATA analysis ,RANDOMIZED controlled trials ,PROPORTIONAL hazards models ,BLIND experiment ,SEVERITY of illness index ,DATA analysis software ,MANN Whitney U Test ,PHYSIOLOGY - Abstract
Objective CD5+ B cells have been conceptualized as a possible surrogate for Breg cells. The aim of the present study was to determine the utility of CD5+ B cells as biomarkers in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Methods The absolute and relative numbers (percentages) of CD5+ B cells (explanatory variables) were measured longitudinally during 18 months in 197 patients randomized to receive either rituximab (RTX) or cyclophosphamide (CYC) followed by azathioprine (AZA) for the treatment of AAV (Rituximab in ANCA-Associated Vasculitis [RAVE] trial). Outcome variables included disease activity (status of active disease versus complete remission), responsiveness to induction therapy, disease relapse, disease severity, and, in RTX-treated patients, relapse-free survival according to the percentage of CD5+ B cells detected upon B cell repopulation. Results CD5+ B cell numbers were comparable between the treatment groups at baseline. After an initial decline, absolute CD5+ B cell numbers progressively increased in patients in the RTX treatment arm, but remained low in CYC/AZA-treated patients. In both groups, the percentage of CD5+ B cells increased during remission induction and slowly declined thereafter. During relapse, the percentage of CD5+ B cells correlated inversely with disease activity in RTX-treated patients, but not in patients who received CYC/AZA. No significant association was observed between the numbers of CD5+ B cells and induction treatment failure or disease severity. The dynamics of the CD5+ B cell compartment did not anticipate disease relapse. Following B cell repopulation, the percentage of CD5+ B cells was not predictive of time to flare in RTX-treated patients. Conclusion The percentage of peripheral CD5+ B cells might reflect disease activity in RTX-treated patients. However, sole staining for CD5 as a putative surrogate marker for Breg cells did not identify a subpopulation of B cells with clear potential for meaningful clinical use. Adequate phenotyping of Breg cells is required to further explore the value of these cells as biomarkers in AAV. [ABSTRACT FROM AUTHOR]
- Published
- 2015
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49. Antineutrophil cytoplasmic antibody positivity in IgG4-related disease: A case report and review of the literature
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Della-Torre, Emanuel, Lanzillotta, Marco, Campochiaro, Corrado, Bozzalla, Emanuele, Bozzolo, Enrica, Bandiera, Alessandro, Bazzigaluppi, Elena, Canevari, Carla, Modorati, Giulio, Stone, John H., Manfredi, Angelo, and Doglioni, Claudio
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Clinical Case Report ,antineutrophil cytoplasmic antibodies ,case report ,granulomatosis with polyangiitis ,IgG4 ,IgG4-related disease ,rituximab ,vasculitis - Abstract
Background: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by serum IgG4 elevation and tissue infiltration of IgG4-positive plasma cells. Substantial overlap between IgG4-RD and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) exists in terms of organ involvement and histopathological features. A positive ANCA assay is regarded as a highly specific finding in favor of an AAV, and generally influences away from a diagnosis of IgG4-RD. Recent reports, however, have raised the possibility that some patients with IgG4-RD are ANCA positive, thus suggesting reconsideration of the role of ANCA in the diagnostic workup. In the present work, we describe the first case of concomitant biopsy-proven IgG4-RD and granulomatosis with polyangiitis (GPA), demonstrating antiproteinase 3 (PR3) ANCA of the IgG4 subclass in the patient's serum. We also review the literature in order to provide clinicians with tools for interpreting ANCA positivity in IgG4-RD patients. Case summary: A 51-year-old woman was referred for left exopthalmos due to lacrimal gland enlargement and increased serum IgG4 concentration. IgG4-RD was suspected and further imaging studies disclosed multiple pulmonary masses in the right lung. Histological analysis of the left lacrimal gland was diagnostic for IgG4-RD, but lung biopsy showed typical features of GPA. ANCA assay was positive for anti-PR3 antibodies. Further immunofluorescence studies demonstrated anti-PR3 antibodies of IgG1 and IgG4 subclass. Treatment with rituximab induced swift remission of both IgG4-RD and GPA manifestations. We identified 9 other reports of patients with IgG4-RD and positive ANCA in the English literature, 5 cases with biopsy-proven IgG4-RD and 4 cases in whom IgG4-RD was diagnosed presumptively. Four patients had also histological evidence of concomitant AAV. Conclusion: The present work demonstrates that ANCA positivity in patients with biopsy-proven IgG4-RD should prompt the exclusion of a concomitant vasculitic process; a positive ANCA does not exclude the diagnosis of IgG4-RD; confirmation through immunoenzymatic assays of the ANCA specificity, clinical-pathological correlation, and histopathological evaluation remain crucial steps for the differential diagnosis between AAV and IgG4-RD.
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- 2016
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50. Circulating Angiopoietin-2 as a Biomarker in ANCA-Associated Vasculitis.
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Monach, Paul A., Kümpers, Philipp, Lukasz, Alexander, Tomasson, Gunnar, Specks, Ulrich, Stone, John H., Cuthbertson, David, Krischer, Jeffrey, Carette, Simon, Ding, Linna, Hoffman, Gary S., David Iklé, Kallenberg, Cees G. M., Khalidi, Nader A., Langford, Carol A., Seo, Philip, Clair, E. William St., Spiera, Robert, Tchao, Nadia, and Ytterberg, Steven R.
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ANGIOPOIETIN-2 ,BIOMARKERS ,VASCULITIS ,RECEPTOR-ligand complexes ,INFLAMMATION ,GLOMERULONEPHRITIS - Abstract
The endothelial-specific Angiopoietin-Tie2 ligand-receptor system is an important regulator of endothelial activation. Binding of angiopoietin-2 (Ang-2) to Tie2 receptor renders the endothelial barrier responsive to pro-inflammatory cytokines. We previously showed that circulating Ang-2 correlated with disease severity in a small cohort of critically ill patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis. The current study reassessed Ang-2 as a biomarker of disease activity and relapse in AAV. Circulating Ang-2 was measured in 162 patients with severe AAV (BVAS/ WG≥3, with or without glomerulonephritis) in a clinical trial. Ang-2 levels during active AAV were compared to levels in the same patients during remission (BVAS/WG = 0). Levels in clinical subsets of AAV were compared, and association with future disease course was assessed. Ang-2 levels were elevated in severe disease (median 3.0 ng/ml, interquartile range 1.9-4.4) compared to healthy controls (1.2, 0.9-1.5). However, they did not reliably decline with successful treatment (median 2.6 ng/ml, interquartile range 1.9-3.8, median change 20.1). Ang-2 correlated weakly with BVAS/WG score (r = 0.17), moderately with markers of systemic inflammation (r = 0.25-0.41), and inversely with renal function (r =20.36). Levels were higher in patients with glomerulonephritis, but levels adjusted for renal dysfunction were no different in patients with or without glomerulonephritis. Levels were higher in patients with newly diagnosed AAV and lower in patients in whom treatment had recently been started. Ang-2 levels during active disease did not predict response to treatment, and Ang-2 levels in remission did not predict time to flare. Thus, Ang-2 appears to have limited practical value in AAV as a biomarker of disease activity at time of measurement or for predicting future activity. [ABSTRACT FROM AUTHOR]
- Published
- 2012
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