18 results on '"Grayson, Peter C."'
Search Results
2. Neutrophil extracellular trap formation in anti-neutrophil cytoplasmic antibody-associated and large-vessel vasculitis.
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Michailidou D, Kuley R, Wang T, Hermanson P, Grayson PC, Cuthbertson D, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Warrington KJ, Monach PA, Merkel PA, and Lood C
- Subjects
- Humans, Male, Female, Child, Adolescent, Adult, Middle Aged, Aged, Aged, 80 and over, Case-Control Studies, Neutrophils, Extracellular Traps metabolism, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis drug therapy, Granulomatosis with Polyangiitis metabolism, Giant Cell Arteritis metabolism, Microscopic Polyangiitis metabolism, Takayasu Arteritis metabolism, Thrombospondin 1 metabolism
- Abstract
Levels of neutrophil extracellular traps (NETs) were measured in plasma of healthy controls (HC, n = 30) and patients with granulomatosis with polyangiitis (GPA, n = 123), microscopic polyangiitis (MPA, n = 61), Takayasu's arteritis (TAK, n = 58), and giant cell arteritis (GCA, n = 68), at times of remission or activity and correlated with levels of the platelet-derived thrombospondin-1 (TSP-1). Levels of NETs were elevated during active disease in patients with GPA (p < 0.0001), MPA (p = 0.0038), TAK (p < 0.0001), and GCA (p < 0.0001), and in remission for GPA, p < 0.0001, MPA, p = 0.005, TAK, p = 0.03, and GCA, p = 0.0009. All cohorts demonstrated impaired NET degradation. Patients with GPA (p = 0.0045) and MPA (p = 0.005) had anti-NET IgG antibodies. Patients with TAK had anti-histone antibodies (p < 0.01), correlating with presence of NETs. Levels of TSP-1 were increased in all patients with vasculitis, and associated with NET formation. NET formation is a common process in vasculitides. Targeting NET formation or degradation could be potential therapeutic approaches for vasculitides., Competing Interests: Declaration of Competing Interest Dr. Michailidou received Advisory Board fees from ChemoCentryx. Dr. Khalidi received clinical trial support from BMS, Sanofi and Abbvie, travel support from Astra Zeneca, and Advisory Board fee from Roche. Dr. Koening served on the advisory board for Chemocentryx and Genentech. Dr. Specks reports receiving funds for the following activities: Consulting: AstraZeneca, ChemoCentryx. Research Support: AstraZeneca, GlaxoSmithKline, Bristol-Myers Squibb, Genentech/Roche, InflaRx. Dr. Sreih works at Bristol-Myers Squibb and owns Astra Zeneca and Alexion Stocks. Dr. Warrington received clinical trial support from Eli Lilly and Kiniksa. Dr. Monach received consulting fees from Kiniksa, Celgene/BMC, and ChemoCentryx. Dr. Merkel reports receiving funds for the following activities: Consulting and Research Support: AbbVie, AstraZeneca, Boeringher-Ingelheim, Bristol-Myers Squibb, ChemoCentryx, Forbius, Genentech/Roche, Genzyme/Sanofi, GlaxoSmithKline, InflaRx, Takeda. Consulting only: CSL Behring, Dynacure, EMDSerono, Janssen, Kiniksa, Kyverna, Magenta, MiroBio, Neutrolis, Novartis, Pfizer, Sparrow, Talaris. Royalties: UpToDate. Dr. Lood received research funding from Pfizer, Gilead Sciences, Boehringer Ingelheim, Redd Pharma, Amytryx, and Eli Lilly., (Copyright © 2023 Elsevier Inc. All rights reserved.)
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- 2023
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3. Neutrophil activation in patients with anti-neutrophil cytoplasmic autoantibody-associated vasculitis and large-vessel vasculitis.
- Author
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Michailidou D, Duvvuri B, Kuley R, Cuthbertson D, Grayson PC, Khalidi NA, Koening CL, Langford CA, McAlear CA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Warrington KJ, Mustelin T, Monach PA, Merkel PA, and Lood C
- Subjects
- Antibodies, Antineutrophil Cytoplasmic, Autoantibodies, Biomarkers, Humans, Neutrophil Activation, Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis, Giant Cell Arteritis, Granulomatosis with Polyangiitis, Microscopic Polyangiitis, Takayasu Arteritis
- Abstract
Objective: To assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV)., Methods: Levels of fMET, and calprotectin, were measured in the plasma of healthy controls (n=30) and patients with AAV (granulomatosis with polyangiitis (GPA, n=123), microscopic polyangiitis (MPA, n=61)), and LVV (Takayasu's arteritis (TAK, n=58), giant cell arteritis (GCA, n=68)), at times of remission or flare. Disease activity was assessed by physician global assessment. In vitro neutrophil activation assays were performed in the presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H., Results: Levels of calprotectin, and fMET were elevated in patients with vasculitis as compared to healthy individuals. Levels of fMET correlated with markers of systemic inflammation: C-reactive protein (r=0.82, p<0.0001), and erythrocyte sedimentation rate (r=0.235, p<0.0001). The neutrophil activation marker, calprotectin was not associated with disease activity. Circulating levels of fMET were associated with neutrophil activation (p<0.01) and were able to induce de novo neutrophil activation via FPR1-mediated signaling., Conclusion: Circulating fMET appears to propagate neutrophil activation in AAV and LVV. Inhibition of fMET-mediated FPR1 signaling could be a novel therapeutic intervention for systemic vasculitides., (© 2022. The Author(s).)
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- 2022
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4. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Granulomatosis With Polyangiitis.
- Author
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Robson JC, Grayson PC, Ponte C, Suppiah R, Craven A, Judge A, Khalid S, Hutchings A, Watts RA, Merkel PA, and Luqmani RA
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- Adult, Aged, Female, Granulomatosis with Polyangiitis classification, Humans, Male, Middle Aged, Granulomatosis with Polyangiitis diagnosis, Rheumatology
- Abstract
Objective: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in 5 phases: 1) identification of candidate criteria items using consensus methodology, 2) prospective collection of candidate items present at the time of diagnosis, 3) data-driven reduction of the number of candidate items, 4) expert panel review of cases to define the reference diagnosis, and 5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting, or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass, or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1 × 10
9 /liter (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% confidence interval [95% CI] 87-96%) and the specificity was 94% (95% CI 89-97%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research., (© 2022 American College of Rheumatology.)- Published
- 2022
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5. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis.
- Author
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Grayson PC, Ponte C, Suppiah R, Robson JC, Craven A, Judge A, Khalid S, Hutchings A, Luqmani RA, Watts RA, and Merkel PA
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- Adult, Antibodies, Antineutrophil Cytoplasmic blood, Diagnosis, Differential, Europe, Female, Humans, Male, Middle Aged, Myeloblastin immunology, Prospective Studies, Reproducibility of Results, Risk Factors, Sensitivity and Specificity, Societies, United States, Eosinophilic Granuloma classification, Eosinophilic Granuloma diagnosis, Granulomatosis with Polyangiitis classification, Granulomatosis with Polyangiitis diagnosis, Rheumatology standards
- Abstract
Objective: To develop and validate revised classification criteria for eosinophilic granulomatosis with polyangiitis (EGPA)., Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators., Results: The development set for EGPA consisted of 107 cases of EGPA and 450 comparators. The validation set consisted of an additional 119 cases of EGPA and 437 comparators. From 91 candidate items, regression analysis identified 11 items for EPGA, 7 of which were retained. The final criteria and their weights were as follows: maximum eosinophil count ≥1×10
9 /L (+5), obstructive airway disease (+3), nasal polyps (+3), cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3-ANCA positivity (-3), extravascular eosinophilic predominant inflammation (+2), mononeuritis multiplex/motor neuropathy not due to radiculopathy (+1) and haematuria (-1). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having EGPA if the cumulative score was ≥6 points. When these criteria were tested in the validation data set, the sensitivity was 85% (95% CI 77% to 91%) and the specificity was 99% (95% CI 98% to 100%)., Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology Classification Criteria for Eosinophilic Granulomatosis with Polyangiitis demonstrate strong performance characteristics and are validated for use in research., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)- Published
- 2022
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6. Dynamic Changes in the Nasal Microbiome Associated With Disease Activity in Patients With Granulomatosis With Polyangiitis.
- Author
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Rhee RL, Lu J, Bittinger K, Lee JJ, Mattei LM, Sreih AG, Chou S, Miner JJ, Cohen NA, Kelly BJ, Lee H, Grayson PC, Collman RG, and Merkel PA
- Subjects
- Adult, Corynebacterium isolation & purification, Female, Humans, Male, Middle Aged, Staphylococcus isolation & purification, Granulomatosis with Polyangiitis microbiology, Microbiota, Nasal Cavity microbiology
- Abstract
Objective: Little is known about temporal changes in nasal bacteria in granulomatosis with polyangiitis (GPA). This study was undertaken to examine longitudinal changes in the nasal microbiome in association with relapse in GPA patients., Methods: Bacterial 16S ribosomal RNA gene sequencing was performed on nasal swabs from 19 patients with GPA who were followed up longitudinally for a total of 78 visits, including 9 patients who experienced a relapse and 10 patients who remained in remission. Relative abundance of bacteria and ratios between bacteria were examined. Generalized estimating equation models were used to evaluate the association between bacterial composition and 1) disease activity and 2) levels of antineutrophil cytoplasmic antibody (ANCA) with specificity for proteinase 3 (PR3), adjusted for medication., Results: Corynebacterium and Staphylococcus were the most abundant bacterial genera across all nasal samples. Patients with quiescent disease maintained a stable ratio of Corynebacterium to Staphylococcus across visits. In contrast, in patients who experienced a relapse, a significantly lower ratio was observed at the visit prior to relapse, followed by a higher ratio at the time of relapse (adjusted P < 0.01). Species-level analysis identified an association between a higher abundance of nasal Corynebacterium tuberculostearicum and 1) relapse (adjusted P = 0.04) and 2) higher PR3-ANCA levels (adjusted P = 0.02)., Conclusion: In GPA, significant changes occur in the nasal microbiome over time and are associated with disease activity. The occurrence of these changes months prior to the onset of relapse supports a pathogenic role of nasal bacteria in GPA. Our results uphold existing hypotheses implicating Staphylococcus as an instigator of disease and have generated a novel finding involving Corynebacterium as a potential mediator of disease in GPA., (© 2021, American College of Rheumatology.)
- Published
- 2021
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7. Sequence-Based Screening of Patients With Idiopathic Polyarteritis Nodosa, Granulomatosis With Polyangiitis, and Microscopic Polyangiitis for Deleterious Genetic Variants in ADA2.
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Schnappauf O, Sampaio Moura N, Aksentijevich I, Stoffels M, Ombrello AK, Hoffmann P, Barron K, Remmers EF, Hershfield M, Kelly SJ, Cuthbertson D, Carette S, Chung SA, Forbess L, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland L, Pagnoux C, Seo P, Springer JM, Sreih AG, Warrington KJ, Ytterberg SR, Kastner DL, Grayson PC, and Merkel PA
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- Adenosine Deaminase deficiency, Adenosine Deaminase metabolism, Adolescent, Adult, Aged, Cohort Studies, Female, Genetic Testing, High-Throughput Nucleotide Sequencing, Humans, Intercellular Signaling Peptides and Proteins deficiency, Intercellular Signaling Peptides and Proteins metabolism, Male, Middle Aged, Polyarteritis Nodosa metabolism, Sequence Analysis, DNA, Young Adult, Adenosine Deaminase genetics, Granulomatosis with Polyangiitis genetics, Intercellular Signaling Peptides and Proteins genetics, Microscopic Polyangiitis genetics, Polyarteritis Nodosa genetics
- Abstract
Objective: Deficiency of adenosine deaminase 2 (DADA2) is a monogenic form of vasculitis that can resemble polyarteritis nodosa (PAN). This study was undertaken to identify potential disease-causing sequence variants in ADA2 in patients with idiopathic PAN, granulomatosis with polyangiitis (GPA), or microscopic polyangiitis (MPA)., Methods: Patients with idiopathic PAN (n = 118) and patients with GPA or MPA (n = 1,107) were screened for rare nonsynonymous variants in ADA2 using DNA sequencing methods. ADA-2 enzyme activity was assessed in selected serum samples., Results: Nine of 118 patients with PAN (7.6%) were identified as having rare nonsynonymous variants in ADA2. Four patients (3.4%) were biallelic for pathogenic or likely pathogenic variants, and 5 patients (4.2%) were monoallelic carriers for 3 variants of uncertain significance and 2 likely pathogenic variants. Serum samples from 2 patients with PAN with biallelic variants were available and showed markedly reduced ADA-2 enzyme activity. ADA-2 enzyme testing of 86 additional patients revealed 1 individual with strongly reduced ADA-2 activity without detectable pathogenic variants. Patients with PAN and biallelic variants in ADA2 were younger at diagnosis than patients with 1 or no variant in ADA2, with no other clinical differences noted. None of the patients with GPA or MPA carried biallelic variants in ADA2., Conclusion: A subset of patients with idiopathic PAN meet genetic criteria for DADA2. Given that tumor necrosis factor inhibition is efficacious in DADA2 but is not conventional therapy for PAN, these findings suggest that ADA-2 testing should strongly be considered in patients with hepatitis B virus-negative idiopathic PAN., (© 2020 American College of Rheumatology. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)
- Published
- 2021
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8. Subglottic stenosis and endobronchial disease in granulomatosis with polyangiitis.
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Quinn KA, Gelbard A, Sibley C, Sirajuddin A, Ferrada MA, Chen M, Cuthbertson D, Carette S, Khalidi NA, Koening CL, Langford CA, McAlear CA, Monach PA, Moreland LW, Pagnoux C, Seo P, Specks U, Sreih AG, Ytterberg SR, Merkel PA, and Grayson PC
- Subjects
- Adult, Aged, Bronchial Diseases diagnostic imaging, Bronchial Diseases etiology, Female, Granulomatosis with Polyangiitis complications, Granulomatosis with Polyangiitis diagnostic imaging, Granulomatosis with Polyangiitis immunology, Humans, Laryngostenosis etiology, Male, Middle Aged, Myeloblastin immunology, Peroxidase immunology, Tomography, X-Ray Computed, Tracheal Stenosis etiology, Tracheobronchomalacia etiology, Granulomatosis with Polyangiitis physiopathology, Laryngostenosis diagnostic imaging, Tracheal Stenosis diagnostic imaging, Tracheobronchomalacia diagnostic imaging
- Abstract
Objectives: To describe tracheobronchial disease in patients with granulomatosis with polyangiitis (GPA) and evaluate the utility of dynamic expiratory CT to detect large-airway disease., Methods: Demographic and clinical features associated with the presence of subglottic stenosis (SGS) or endobronchial involvement were assessed in a multicentre, observational cohort of patients with GPA. A subset of patients with GPA from a single-centre cohort underwent dynamic chest CT to evaluate the airways., Results: Among 962 patients with GPA, SGS and endobronchial disease were identified in 95 (10%) and 59 (6%) patients, respectively. Patients with SGS were more likely to be female (72% vs 53%, P < 0.01), younger at time of diagnosis (36 vs 49 years, P < 0.01), and have saddle-nose deformities (28% vs 10%, P < 0.01), but were less likely to have renal involvement (39% vs 62%, P < 0.01). Patients with endobronchial disease were more likely to be PR3-ANCA positive (85% vs 66%, P < 0.01), with more ENT involvement (97% vs 77%, P < 0.01) and less renal involvement (42% vs 62%, P < 0.01). Disease activity in patients with large-airway disease was commonly isolated to the subglottis/upper airway (57%) or bronchi (32%). Seven of 23 patients screened by dynamic chest CT had large-airway pathology, including four patients with chronic, unexplained cough, discovered to have tracheobronchomalacia., Conclusion: SGS and endobronchial disease occur in 10% and 6% of patients with GPA, respectively, and may occur without disease activity in other organs. Dynamic expiratory chest CT is a potential non-invasive screening test for large-airway involvement in GPA., (© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2019
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9. Serum cytokine and chemokine levels in patients with eosinophilic granulomatosis with polyangiitis, hypereosinophilic syndrome, or eosinophilic asthma.
- Author
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Pagnoux C, Nair P, Xi Y, Khalidi NA, Carette S, Cuthbertson D, Grayson PC, Koening CL, Langford CA, McAlear CA, Moreland LW, Monach PA, Seo P, Specks U, Sreih AG, Ytterberg SR, Tyrrell PN, and Merkel PA
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- Biomarkers blood, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Asthma blood, Asthma diagnosis, Chemokines blood, Cytokines blood, Granulomatosis with Polyangiitis blood, Granulomatosis with Polyangiitis diagnosis, Hypereosinophilic Syndrome blood, Hypereosinophilic Syndrome diagnosis
- Abstract
Objectives: The pathogenesis of eosinophilic granulomatosis with polyangiitis (EGPA) remains poorly understood, and may overlap with eosinophilic asthma and primary hypereosinophilic syndrome (HES). The aim of this study was to analyse a panel of serum cytokines and chemokines as markers of disease activity in patients with these conditions., Methods: The levels of 54 cytokines and chemokines were measured in the sera of 40 patients with active EGPA, 10 of these patients during inactive disease, 6 patients with HES, 8 with asthma, and 10 healthy controls. Serum cytokine/chemokines measured included interleukin (IL)-1α, 1β, 3, 4, 5, 6, 8, 13, 15, 17A, 17E(25), 18, 23 and 33, soluble IL-2 receptor alpha, eotaxin-1 (CCL11), -2 (CCL24) and -3 (CCL26), macrophage-derived chemokine (MDC/CCL22), macrophage inflammatory protein (MIP)-1a and -1b, and tumour necrosis factor (TNF)-α. Results were compared between disease and control groups using regression analysis, with Bonferroni correction for multiple comparisons (significant p value ≤0.00093)., Results: Significant differences were observed only in serum levels of MDC, IL-8, MIP-1a and -1b, TNF-α, each of which were lower in patients with active EGPA than in healthy controls (p<0.0001). Differences between patients with active disease and other disease groups did not reach significance. Paired comparisons between sera from patients with active or inactive EGPA showed no significant difference for any of the studied cytokines or chemokines., Conclusions: No clear difference in the serum levels of measured cytokines and chemokines helped distinguish between active EGPA or inactive EGPA, or other disease or control groups.
- Published
- 2019
10. Characterisation of the nasal microbiota in granulomatosis with polyangiitis.
- Author
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Rhee RL, Sreih AG, Najem CE, Grayson PC, Zhao C, Bittinger K, Collman RG, and Merkel PA
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- Adult, Aged, Female, Granulomatosis with Polyangiitis drug therapy, Humans, Immunosuppressive Agents therapeutic use, Malassezia isolation & purification, Male, Middle Aged, Propionibacterium isolation & purification, RNA, Ribosomal, 16S, Staphylococcus epidermidis isolation & purification, DNA, Bacterial isolation & purification, DNA, Fungal isolation & purification, Granulomatosis with Polyangiitis microbiology, Microbiota, Nasal Cavity microbiology
- Abstract
Objectives: Prior studies have suggested a potential link between nasal microbes and granulomatosis with polyangiitis (GPA; Wegener's), but these studies relied on culture-dependent methods. This study comprehensively examined the entire community of nasal microbiota (bacteria and fungi) in participants with GPA compared with healthy controls using deep sequencing methods., Methods: 16S rRNA and internal transcribed spacer gene sequencing were performed on nasal microbial DNA isolated from nasal swabs of 60 participants with GPA and 41 healthy controls. Alpha and beta diversity were assessed as well as the relative abundance of the most abundant bacterial and fungal taxa. The effects of covariates including disease activity and immunosuppressive therapies on microbial composition were evaluated., Results: Compared with controls, participants with GPA had a significantly different microbial composition (weighted UniFrac p=0.04) and lower relative abundance of Propionibacterium acnes and Staphylococcus epidermidis (for both, false discovery rate-corrected p=0.02). Disease activity in GPA was associated with a lower abundance of fungal order Malasseziales compared with participants with GPA in remission (p=0.04) and controls (p=0.01). Use of non-glucocorticoid immunosuppressive therapy was associated with 'healthy' nasal microbiota while participants with GPA who were off immunosuppressive therapy had more dysbiosis (weighted UniFrac p=0.01). No difference in the relative abundance of Staphylococcus aureus was observed between GPA and controls., Conclusions: GPA is associated with an altered nasal microbial composition, at both the bacterial and fungal levels. Use of immunosuppressive therapies and disease remission are associated with healthy microbial communities., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2018. No commercial re-use. See rights and permissions. Published by BMJ.)
- Published
- 2018
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11. Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis.
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Grayson PC, Monach PA, Pagnoux C, Cuthbertson D, Carette S, Hoffman GS, Khalidi NA, Koening CL, Langford CA, Maksimowicz-McKinnon K, Seo P, Specks U, Ytterberg SR, and Merkel PA
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers blood, Blood Sedimentation, C-Reactive Protein metabolism, Cell Count, Cohort Studies, Eosinophils pathology, Female, Humans, Immunoglobulin E blood, Longitudinal Studies, Male, Middle Aged, Predictive Value of Tests, Recurrence, Regression Analysis, Diagnostic Tests, Routine methods, Eosinophilia blood, Eosinophilia diagnosis, Granulomatosis with Polyangiitis blood, Granulomatosis with Polyangiitis diagnosis, Severity of Illness Index
- Abstract
Objective: The aim of this study was to assess the clinical value of absolute eosinophil count, serum IgE, ESR and CRP as longitudinal biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA)., Methods: Patients were selected from an observational EGPA cohort. Absolute eosinophil count, IgE, ESR and CRP were measured quarterly. Disease activity was defined by validated assessment tools. The association of tests with disease activity was assessed via regression models, adjusting for repeated measures and treatment status. Survival analysis was used to determine if laboratory tests were predictive of the 3 month future flare risk., Results: Seventy-four per cent of 892 study visits in 141 patients occurred while patients were on treatment, mostly during remission or mild disease activity, defined as a BVAS for Wegener's granulomatosis (BVAS/WG) of 1 or 2. Correlations between absolute eosinophil count, IgE, ESR and CRP were mostly low or non-significant (r = -0.08 to 0.44). There were few weak associations with disease activity [absolute eosinophil count: OR) 1.01/100 U (95% CI 1.01, 1.02); ESR: OR 1.15/10 mg/l increase (95% CI 1.04, 1.27)]. When BVAS/WG ≥1 defined active disease, the absolute eosinophil count [hazard ratio (HR) 1.01/100 U (95% CI 1.01, 1.02)] was weakly predictive of flare. When BVAS/WG ≥3 defined active disease, ESR was weakly predictive of flare [HR 1.52/10 mm/h increase (95% CI 1.17, 1.67)]., Conclusion: The absolute eosinophil count, IgE, ESR and CRP have limitations as longitudinal biomarkers of disease activity or predictors of flare in EGPA. These findings suggest that novel biomarkers of disease activity for EGPA are needed., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- Published
- 2015
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12. Defining the nasal transcriptome in granulomatosis with polyangiitis (Wegener's).
- Author
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Grayson PC, Steiling K, Platt M, Berman JS, Zhang X, Xiao J, Alekseyev YO, Liu G, Monach PA, Kaplan MJ, Spira A, and Merkel PA
- Subjects
- Adult, Aged, Case-Control Studies, Chemotaxis genetics, Desmosomal Cadherins genetics, Extracellular Matrix genetics, Female, Fibronectins genetics, Gene Expression Profiling, Granulomatosis with Polyangiitis metabolism, Humans, Immunity, Innate genetics, Interleukin-10 genetics, Male, Middle Aged, Osteonectin genetics, Osteopontin genetics, Rhinitis, Allergic genetics, Rhinitis, Allergic metabolism, Sarcoidosis genetics, Sarcoidosis metabolism, Granulomatosis with Polyangiitis genetics, Nasal Mucosa metabolism, RNA, Messenger metabolism, Transcriptome
- Abstract
Objective: To determine whether disease processes related to granulomatosis with polyangiitis (Wegener's) (GPA) are reflected in gene expression profiles of the nasal mucosa., Methods: Nasal brushings of the inferior turbinate were obtained from 32 patients with GPA (10 with active nasal disease, 13 with prior nasal disease, and 9 with no history of nasal disease) and a composite comparator group with and without inflammatory nasal disease (12 healthy people, 15 with sarcoidosis, and 8 with allergic rhinitis). Differential gene expression was assessed between subgroups of GPA and comparators., Results: A total of 339 genes were differentially expressed between the GPA and comparator groups (absolute fold change >1.5; false discovery rate <0.05). Top canonical pathways up-regulated in nasal brushings from patients with GPA included granulocyte adhesion and diapedesis (P = 8.6(-22) ), agranulocyte adhesion and diapedesis (P = 1.3(-14) ), IL10 signaling (P = 3.0(-11) ), LXR/RXR activation (P = 4.3(-11) ), and TREM1 signaling (P = 9.0(-11) ). A set of genes differentially expressed in GPA independently of nasal disease activity status included genes related to epithelial barrier integrity (fibronectin 1, desmosomal proteins) and several matricellular proteins (e.g., osteonectin, osteopontin). Significant overlap of differentially expressed genes was observed between active and prior nasal disease GPA subgroups. Peripheral blood neutrophil and mononuclear gene expression levels associated with GPA were similarly altered in the nasal gene expression profiles of patients with active or prior nasal disease., Conclusion: Profiling the nasal transcriptome in GPA reveals gene expression signatures related to innate immunity, inflammatory cell chemotaxis, extracellular matrix composition, and epithelial barrier integrity. Thus, airway-based expression profiling is feasible and informative in GPA., (© 2015, American College of Rheumatology.)
- Published
- 2015
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13. 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for granulomatosis with polyangiitis.
- Author
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Robson, Joanna C., Grayson, Peter C., Ponte, Cristina, Suppiah, Ravi, Craven, Anthea, Judge, Andrew, Khalid, Sara, Hutchings, Andrew, Watts, Richard A., Merkel, Peter A., Luqmani, Raashid A., and DCVAS Investigators
- Abstract
Objective: To develop and validate revised classification criteria for granulomatosis with polyangiitis (GPA).Methods: Patients with vasculitis or comparator diseases were recruited into an international cohort. The study proceeded in five phases: (1) identification of candidate criteria items using consensus methodology, (2) prospective collection of candidate items present at the time of diagnosis, (3) data-driven reduction of the number of candidate items, (4) expert panel review of cases to define the reference diagnosis and (5) derivation of a points-based risk score for disease classification in a development set using least absolute shrinkage and selection operator logistic regression, with subsequent validation of performance characteristics in an independent set of cases and comparators.Results: The development set for GPA consisted of 578 cases of GPA and 652 comparators. The validation set consisted of an additional 146 cases of GPA and 161 comparators. From 91 candidate items, regression analysis identified 26 items for GPA, 10 of which were retained. The final criteria and their weights were as follows: bloody nasal discharge, nasal crusting or sino-nasal congestion (+3); cartilaginous involvement (+2); conductive or sensorineural hearing loss (+1); cytoplasmic antineutrophil cytoplasmic antibody (ANCA) or anti-proteinase 3 ANCA positivity (+5); pulmonary nodules, mass or cavitation on chest imaging (+2); granuloma or giant cells on biopsy (+2); inflammation or consolidation of the nasal/paranasal sinuses on imaging (+1); pauci-immune glomerulonephritis (+1); perinuclear ANCA or antimyeloperoxidase ANCA positivity (-1); and eosinophil count ≥1×109 /L (-4). After excluding mimics of vasculitis, a patient with a diagnosis of small- or medium-vessel vasculitis could be classified as having GPA if the cumulative score was ≥5 points. When these criteria were tested in the validation data set, the sensitivity was 93% (95% CI 87% to 96%) and the specificity was 94% (95% CI 89% to 97%).Conclusion: The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for GPA demonstrate strong performance characteristics and are validated for use in research. [ABSTRACT FROM AUTHOR]- Published
- 2022
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14. Pulmonary involvement in primary systemic vasculitides.
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Makhzoum, Jean-Paul, Grayson, Peter C, Ponte, Cristina, Robson, Joanna, Suppiah, Ravi, Watts, Richard A, Luqmani, Raashid, Merkel, Peter A, Pagnoux, Christian, and Collaborators, for the DCVAS
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HEMOPTYSIS , *LUNG diseases , *FIBROSIS , *DYSPNEA , *TAKAYASU arteritis , *GRANULOMATOSIS with polyangiitis , *POLYARTERITIS nodosa , *VASCULITIS , *MICROSCOPIC polyangiitis , *DISEASE risk factors , *DISEASE complications - Abstract
Objectives This study describes the spectrum and initial impact of pulmonary manifestations in the primary systemic vasculitides. Methods Description and comparison of pulmonary manifestations in adults with Takayasu's arteritis (TAK), GCA, granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic GPA (EGPA), polyarteritis nodosa (PAN) and IgA vasculitis (IgAV), using data collected within the Diagnostic and Classification Criteria in Vasculitis study. Results Data from 1952 patients with primary vasculitides were included: 170 TAK, 657 GCA, 555 GPA, 223 MPA, 146 EGPA, 153 IgAV and 48 PAN. Pulmonary manifestations were observed in patients with TAK (21.8%), GCA (15.8%), GPA (64.5%), MPA (65.9%), EGPA (89.0%), PAN (27.1%) and IgAV (5.9%). Dyspnoea occurred in patients with TAK (14.7%), GCA (7.8%), GPA (41.8%), MPA (43.5%), EGPA (65.8%), PAN (18.8%) and IgAV (2.6%). Cough was reported in TAK (7.6%), GCA (9.3%), GPA (34.8%), MPA (37.7%), EGPA (55.5%), PAN (16.7%) and IgAV (3.3%). Haemoptysis occurred mainly in patients with ANCA-associated vasculitis (AAV). Fibrosis on imaging at diagnosis was documented in GPA (1.9%), MPA (24.9%) and EGPA (6.3%). Only patients with AAV (GPA 2.7%, MPA 2.7% and EGPA 3.4%) required mechanical ventilation. At 6 months, the presence of at least one pulmonary item in the Vasculitis Damage Index was observed in TAK (4.1%), GCA (3.3%), GPA (15.4%), MPA (28.7%), EGPA (52.7%), PAN (6.2%) and IgAV (1.3%). Conclusion Pulmonary manifestations can occur in all primary systemic vasculitides, but are more frequent and more often associated with permanent damage in AAV. [ABSTRACT FROM AUTHOR]
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- 2022
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15. 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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GRANULOMATOSIS with polyangiitis diagnosis ,THERAPEUTIC use of monoclonal antibodies ,RITUXIMAB ,RHEUMATOLOGY ,ANTINEUTROPHIL cytoplasmic antibodies ,EVIDENCE-based medicine ,MEDICAL personnel ,MEDICAL protocols ,GRANULOMATOSIS with polyangiitis ,EXPERTISE ,CHURG-Strauss syndrome ,PROFESSIONAL associations ,IMMUNOSUPPRESSIVE agents ,VASCULITIS ,MICROSCOPIC polyangiitis ,DISEASE remission - 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]
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- 2021
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16. Defining the Nasal Transcriptome in Granulomatosis with Polyangiitis
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Grayson, Peter C., Steiling, Katrina, Platt, Michael, Berman, Jeffrey S., Zhang, Xiaohui, Xiao, Ji, Alekseyev, Yuriy O., Liu, Gang, Monach, Paul A., Kaplan, Mariana J., Spira, Avrum, and Merkel, Peter A.
- Subjects
Adult ,Male ,Desmosomal Cadherins ,Sarcoidosis ,Chemotaxis ,Gene Expression Profiling ,Granulomatosis with Polyangiitis ,Middle Aged ,Rhinitis, Allergic ,Article ,Immunity, Innate ,Extracellular Matrix ,Fibronectins ,Interleukin-10 ,Nasal Mucosa ,Case-Control Studies ,Humans ,Female ,Osteonectin ,Osteopontin ,RNA, Messenger ,Transcriptome ,Aged - Abstract
To determine whether disease processes related to granulomatosis with polyangiitis (Wegener's) (GPA) are reflected in gene expression profiles of the nasal mucosa.Nasal brushings of the inferior turbinate were obtained from 32 patients with GPA (10 with active nasal disease, 13 with prior nasal disease, and 9 with no history of nasal disease) and a composite comparator group with and without inflammatory nasal disease (12 healthy people, 15 with sarcoidosis, and 8 with allergic rhinitis). Differential gene expression was assessed between subgroups of GPA and comparators.A total of 339 genes were differentially expressed between the GPA and comparator groups (absolute fold change1.5; false discovery rate0.05). Top canonical pathways up-regulated in nasal brushings from patients with GPA included granulocyte adhesion and diapedesis (P = 8.6(-22) ), agranulocyte adhesion and diapedesis (P = 1.3(-14) ), IL10 signaling (P = 3.0(-11) ), LXR/RXR activation (P = 4.3(-11) ), and TREM1 signaling (P = 9.0(-11) ). A set of genes differentially expressed in GPA independently of nasal disease activity status included genes related to epithelial barrier integrity (fibronectin 1, desmosomal proteins) and several matricellular proteins (e.g., osteonectin, osteopontin). Significant overlap of differentially expressed genes was observed between active and prior nasal disease GPA subgroups. Peripheral blood neutrophil and mononuclear gene expression levels associated with GPA were similarly altered in the nasal gene expression profiles of patients with active or prior nasal disease.Profiling the nasal transcriptome in GPA reveals gene expression signatures related to innate immunity, inflammatory cell chemotaxis, extracellular matrix composition, and epithelial barrier integrity. Thus, airway-based expression profiling is feasible and informative in GPA.
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- 2015
17. Metabolic pathways and immunometabolism in rare kidney diseases.
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Grayson, Peter C., Eddy, Sean, Taroni, Jaclyn N., Lightfoot, Yaíma L., Mariani, Laura, Parikh, Hemang, Lindenmeyer, Maja T., Wenjun Ju, Greene, Casey S., Godfrey, Brad, Cohen, Clemens D., Krischer, Jeffrey, Kretzler, Matthias, Merkel, Peter A., Ju, Wenjun, and Vasculitis Clinical Research Consortium, the European Renal cDNA Bank cohort, and the Nephrotic Syndrome Study Network
- Abstract
Objectives: To characterise renal tissue metabolic pathway gene expression in different forms of glomerulonephritis.Methods: Patients with nephrotic syndrome (NS), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), systemic lupus erythematosus (SLE) and healthy living donors (LD) were studied. Clinically indicated renal biopsies were obtained at time of diagnosis and microdissected into glomerular and tubulointerstitial compartments. Microarray-derived differential gene expression of 88 genes representing critical enzymes of metabolic pathways and 25 genes related to immune cell markers was compared between disease groups. Correlation analyses measured relationships between metabolic pathways, kidney function and cytokine production.Results: Reduced steady state levels of mRNA species were enriched in pathways of oxidative phosphorylation and increased in the pentose phosphate pathway (PPP) with maximal perturbation in AAV and SLE followed by NS, and least in LD. Transcript regulation was isozymes specific with robust regulation in hexokinases, enolases and glucose transporters. Intercorrelation networks were observed between enzymes of the PPP (eg, transketolase) and macrophage markers (eg, CD68) (r=0.49, p<0.01). Increased PPP transcript levels were associated with reduced glomerular filtration rate in the glomerular (r=-0.49, p<0.01) and tubulointerstitial (r=-0.41, p<0.01) compartments. PPP expression and tumour necrosis factor activation were tightly co-expressed (r=0.70, p<0.01).Conclusion: This study demonstrated concordant alterations of the renal transcriptome consistent with metabolic reprogramming across different forms of glomerulonephritis. Activation of the PPP was tightly linked with intrarenal macrophage marker expression, reduced kidney function and increased production of cytokines. Modulation of glucose metabolism may offer novel immune-modulatory therapeutic approaches in rare kidney diseases. [ABSTRACT FROM AUTHOR]- Published
- 2018
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18. Brief Report: Defining the Nasal Transcriptome in Granulomatosis With Polyangiitis (Wegener's).
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Grayson, Peter C., Steiling, Katrina, Platt, Michael, Berman, Jeffrey S., Zhang, Xiaohui, Xiao, Ji, Alekseyev, Yuriy O., Liu, Gang, Monach, Paul A., Kaplan, Mariana J., Spira, Avrum, and Merkel, Peter A.
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SINUSITIS , *GRANULOMATOSIS with polyangiitis , *NOSE diseases , *ACADEMIC medical centers , *IMMUNITY , *POLYMERASE chain reaction , *REGRESSION analysis , *RESEARCH funding , *REVERSE transcriptase polymerase chain reaction , *MICROARRAY technology , *GENE expression profiling , *PROGNOSIS - Abstract
Objective To determine whether disease processes related to granulomatosis with polyangiitis (Wegener's) (GPA) are reflected in gene expression profiles of the nasal mucosa. Methods Nasal brushings of the inferior turbinate were obtained from 32 patients with GPA (10 with active nasal disease, 13 with prior nasal disease, and 9 with no history of nasal disease) and a composite comparator group with and without inflammatory nasal disease (12 healthy people, 15 with sarcoidosis, and 8 with allergic rhinitis). Differential gene expression was assessed between subgroups of GPA and comparators. Results A total of 339 genes were differentially expressed between the GPA and comparator groups (absolute fold change >1.5; false discovery rate <0.05). Top canonical pathways up-regulated in nasal brushings from patients with GPA included granulocyte adhesion and diapedesis ( P = 8.6−22), agranulocyte adhesion and diapedesis ( P = 1.3−14), IL10 signaling ( P = 3.0−11), LXR/RXR activation ( P = 4.3−11), and TREM1 signaling ( P = 9.0−11). A set of genes differentially expressed in GPA independently of nasal disease activity status included genes related to epithelial barrier integrity (fibronectin 1, desmosomal proteins) and several matricellular proteins (e.g., osteonectin, osteopontin). Significant overlap of differentially expressed genes was observed between active and prior nasal disease GPA subgroups. Peripheral blood neutrophil and mononuclear gene expression levels associated with GPA were similarly altered in the nasal gene expression profiles of patients with active or prior nasal disease. Conclusion Profiling the nasal transcriptome in GPA reveals gene expression signatures related to innate immunity, inflammatory cell chemotaxis, extracellular matrix composition, and epithelial barrier integrity. Thus, airway-based expression profiling is feasible and informative in GPA. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
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