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Article ; Online: Adenosine metabolic signature in circulating CD4+ T cells predicts remission in rheumatoid arthritis.

Brown, Philip M / Anderson, Amy E / Naamane, Najib / Lendrem, Dennis W / Morgan, Ann W / Isaacs, John D / Pratt, Arthur G

RMD open

2024 Volume 10, Issue 1

Abstract: Objectives: Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to ... ...

Abstract	Objectives: Long-term outcomes in rheumatoid arthritis (RA) depend on early and effective disease control. Methotrexate (MTX) remains the first-line disease modifying therapy, however there are no biomarkers with which to identify those most likely to achieve remission. To address this unmet need we explored metabolic pathways involved in MTX mechanism of action within circulating CD4+T cells in a cohort of treatment naive patients with early RA. Methods: Purified CD4+T cells were isolated from peripheral blood of 68 patients with early RA commencing MTX. The expression of a range of putative MTX metabolism and mechanism of action targets were explored by flow-cytometry and transcriptional analysis. From these data significant predictors of Disease Activity Score 28-C reactive protein (DAS28-CRP) remission (<2.4 at 6 months) were determined by logistic regression (clinical; flow-cytometry data) and linear modelling (gene expression data). Results: Low baseline DAS28-CRP was associated with remission at 6 months (p=0.02). Expression of the ectonucleotidase CD39, involved in ATP-ADP conversion during adenosine synthesis, was higher on CD4+CD25 High regulatory T cells at baseline in those achieving remission (molecules of equivalent fluorescence 1264 vs 847; p=0.007). Expression of other adenosine signalling elements in CD4+T cells were also upregulated at baseline in patients achieving remission:
MeSH term(s)	Humans ; Antirheumatic Agents/therapeutic use ; CD4-Positive T-Lymphocytes/metabolism ; Adenosine/therapeutic use ; Treatment Outcome ; Arthritis, Rheumatoid/diagnosis ; Arthritis, Rheumatoid/drug therapy ; Methotrexate/therapeutic use ; Biomarkers ; C-Reactive Protein/metabolism
Chemical Substances	Antirheumatic Agents ; Adenosine (K72T3FS567) ; Methotrexate (YL5FZ2Y5U1) ; Biomarkers ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2024-02-17
Publishing country	England
Document type	Journal Article
ZDB-ID	2812592-7
ISSN	2056-5933 ; 2056-5933
ISSN (online)	2056-5933
ISSN	2056-5933
DOI	10.1136/rmdopen-2023-003858
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Article ; Online: Estimating overdiagnosis in giant cell arteritis diagnostic pathways using genetic data: genetic association study.

Chatzigeorgiou, Charikleia / Barrett, Jennifer H / Martin, Javier / Morgan, Ann W / Mackie, Sarah L

Rheumatology (Oxford, England)

2023

Abstract: Objectives: Giant cell arteritis (GCA) may be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used Human Leucocyte Antigen (HLA) genetic ... ...

Abstract	Objectives: Giant cell arteritis (GCA) may be confirmed by temporal artery biopsy (TAB) but false negatives can occur. GCA may be overdiagnosed in TAB-negative cases, or if neither TAB nor imaging is done. We used Human Leucocyte Antigen (HLA) genetic association of TAB-positive GCA as an "unbiased umpire" test to estimate historic overdiagnosis of GCA. Methods: Patients diagnosed with GCA between 1990-2014 were genotyped. During this era, vascular imaging alone was rarely used to diagnose GCA. HLA region variants were jointly imputed from genome-wide genotypic data of cases and controls. Per-allele frequencies across all HLA variants with p< 1.0x1 0 -5 were compared with population control data to estimate overdiagnosis rates in cases without a positive TAB. Results: Genetic data from 663 GCA patients were compared with data from 2619 population controls. TAB-negative GCA (n = 147) and GCA without TAB result (n = 160) had variant frequencies intermediate between TAB-positive GCA (n = 356) and population controls. For example, the allele frequency of HLA-DRB104 was 32% for TAB-positive GCA, 29% for GCA without TAB result, 27% for TAB-negative GCA and 20% in population controls. Making several strong assumptions, we estimated that around two-thirds of TAB-negative cases and one-third of cases without TAB result may have been overdiagnosed. From these data, TAB sensitivity is estimated as 88%. Conclusions:* Conservatively assuming 95% specificity, TAB has a negative likelihood ratio of around 0.12. Our method for utilising standard genotyping data as an "unbiased umpire" might be used as a way of comparing the accuracy of different diagnostic pathways.
Language	English
Publishing date	2023-12-04
Publishing country	England
Document type	Journal Article
ZDB-ID	1464822-2
ISSN	1462-0332 ; 1462-0324
ISSN (online)	1462-0332
ISSN	1462-0324
DOI	10.1093/rheumatology/kead643
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Article ; Online: Re: Nair et al. Consensus statement on the processing, interpretation and reporting of temporal artery biopsy for arteritis.

Taze, Dilek / Chakrabarty, Aruna / Mackie, Sarah / Luqmani, Raashid / Cid, Maria C / Morgan, Ann W / Griffin, Kathryn

Cardiovascular pathology : the official journal of the Society for Cardiovascular Pathology

2024 Volume 70, Page(s) 107621

Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Letter
ZDB-ID	1134600-0
ISSN	1879-1336 ; 1054-8807
ISSN (online)	1879-1336
ISSN	1054-8807
DOI	10.1016/j.carpath.2024.107621
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Article ; Online: Interplay between demographic, clinical and polygenic risk factors for severe COVID-19.

Crossfield, Samantha S R / Chaddock, Natalie J M / Iles, Mark M / Pujades-Rodriguez, Mar / Morgan, Ann W

International journal of epidemiology

2022 Volume 51, Issue 5, Page(s) 1384–1395

Abstract: Background: We aimed to identify clinical, socio-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) in the general population.: Methods: In this observational study, we identified 9560 UK ... ...

Abstract	Background: We aimed to identify clinical, socio-demographic and genetic risk factors for severe COVID-19 (hospitalization, critical care admission or death) in the general population. Methods: In this observational study, we identified 9560 UK Biobank participants diagnosed with COVID-19 during 2020. A polygenic risk score (PRS) for severe COVID-19 was derived and optimized using publicly available European and trans-ethnic COVID-19 genome-wide summary statistics. We estimated the risk of hospital or critical care admission within 28 days or death within 100 days following COVID-19 diagnosis, and assessed associations with socio-demographic factors, immunosuppressant use and morbidities reported at UK Biobank enrolment (2006-2010) and the PRS. To improve biological understanding, pathway analysis was performed using genetic variants comprising the PRS. Results: We included 9560 patients followed for a median of 61 (interquartile range = 34-88) days since COVID-19 diagnosis. The risk of severe COVID-19 increased with age and obesity, and was higher in men, current smokers, those living in socio-economically deprived areas, those with historic immunosuppressant use and individuals with morbidities and higher co-morbidity count. An optimized PRS, enriched for single-nucleotide polymorphisms in multiple immune-related pathways, including the 'oligoadenylate synthetase antiviral response' and 'interleukin-10 signalling' pathways, was associated with severe COVID-19 (adjusted odds ratio 1.32, 95% CI 1.11-1.58 for the highest compared with the lowest PRS quintile). Conclusion: This study conducted in the pre-SARS-CoV-2-vaccination era, emphasizes the novel insights to be gained from using genetic data alongside commonly considered clinical and socio-demographic factors to develop greater biological understanding of severe COVID-19 outcomes.
MeSH term(s)	Humans ; Male ; Antiviral Agents ; COVID-19/epidemiology ; COVID-19/genetics ; COVID-19 Testing ; Demography ; Immunosuppressive Agents ; Interleukin-10 ; Ligases ; Risk Factors ; SARS-CoV-2
Chemical Substances	Antiviral Agents ; Immunosuppressive Agents ; Interleukin-10 (130068-27-8) ; Ligases (EC 6.-)
Language	English
Publishing date	2022-06-29
Publishing country	England
Document type	Journal Article ; Observational Study ; Research Support, Non-U.S. Gov't
ZDB-ID	187909-1
ISSN	1464-3685 ; 0300-5771
ISSN (online)	1464-3685
ISSN	0300-5771
DOI	10.1093/ije/dyac137
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Article ; Online: Developing consensus in Histopathology: the role of the Delphi method.

Taze, Dilek / Hartley, Collette / Morgan, Ann W / Chakrabarty, Aruna / Mackie, Sarah L / Griffin, Kathryn J

Histopathology

2022 Volume 81, Issue 2, Page(s) 159–167

Abstract: The Delphi method is a well-established research tool, used for consensus building across a number of fields. Despite its widespread use, and popularity in many medical specialities, there is a paucity of literature on the use of the Delphi method in ... ...

Abstract	The Delphi method is a well-established research tool, used for consensus building across a number of fields. Despite its widespread use, and popularity in many medical specialities, there is a paucity of literature on the use of the Delphi method in Histopathology. This literature review seeks to critique the Delphi methodology and explore its potential applications to histopathology-based clinical and research questions. We review those published studies that have utilized the Delphi methodology in Histopathology settings and specifically outline the advantages and limitations of this technique, highlighting situations where its application can be most effective.
MeSH term(s)	Consensus ; Delphi Technique ; Humans ; Surveys and Questionnaires
Language	English
Publishing date	2022-04-24
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	131914-0
ISSN	1365-2559 ; 0309-0167
ISSN (online)	1365-2559
ISSN	0309-0167
DOI	10.1111/his.14650
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Article ; Online: Common co-morbidities in polymyalgia rheumatica and giant cell arteritis: cross-sectional study in UK Biobank.

Chatzigeorgiou, Charikleia / Taylor, John C / Elliott, Faye / O'Sullivan, Eoin P / Morgan, Ann W / Barrett, Jennifer H / Mackie, Sarah L

Rheumatology advances in practice

2023 Volume 7, Issue 3, Page(s) rkad095

Abstract: Objective: The aim was to determine prevalent co-morbidities in cases with PMR or GCA compared with matched controls.: Methods: This was a nested, cross-sectional case-control study within the UK Biobank, which recruited participants aged 40-69 years. ...

Abstract	Objective: The aim was to determine prevalent co-morbidities in cases with PMR or GCA compared with matched controls. Methods: This was a nested, cross-sectional case-control study within the UK Biobank, which recruited participants aged 40-69 years. Case status was defined as self-reported prior diagnosis of PMR or GCA. Ten controls per case were matched for age, sex, ethnicity and assessment centre. Associations with selected self-reported co-morbidities were studied using conditional logistic regression. Results: Of PMR ( Conclusion: Participants with a history of PMR/GCA, including those not currently taking glucocorticoids, rated their health as poorer than matched controls. Some previously described disease associations (hypothyroidism and early menopause) were replicated. Hypertension and cataract, both of which can be exacerbated by long-term glucocorticoid therapy, were over-represented in both diseases, particularly GCA.
Language	English
Publishing date	2023-11-02
Publishing country	England
Document type	Journal Article
ISSN	2514-1775
ISSN (online)	2514-1775
DOI	10.1093/rap/rkad095
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Article ; Online: HLA-DRB1 and HLA-DQA1 associated with immunogenicity to adalimumab therapy in patients with rheumatoid arthritis.

Yap, Chuan Fu / Nair, Nisha / de Vries, Annick / Loeff, Floris C / Morgan, Ann W / Isaacs, John D / Wilson, Anthony G / Hyrich, Kimme L / Barton, Anne / Plant, Darren

Annals of the rheumatic diseases

2024 Volume 83, Issue 2, Page(s) 263–265

MeSH term(s)	Humans ; HLA-DRB1 Chains/genetics ; Adalimumab/therapeutic use ; HLA-DQ alpha-Chains/genetics ; Arthritis, Rheumatoid/drug therapy ; Arthritis, Rheumatoid/genetics ; Alleles ; Genetic Predisposition to Disease ; Autoantibodies
Chemical Substances	HLA-DRB1 Chains ; HLA-DQA1 antigen ; Adalimumab (FYS6T7F842) ; HLA-DQ alpha-Chains ; Autoantibodies
Language	English
Publishing date	2024-01-11
Publishing country	England
Document type	Letter
ZDB-ID	7090-7
ISSN	1468-2060 ; 0003-4967
ISSN (online)	1468-2060
ISSN	0003-4967
DOI	10.1136/ard-2023-223955
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Article ; Online: Dose-dependent oral glucocorticoid cardiovascular risks in people with immune-mediated inflammatory diseases: A population-based cohort study.

Pujades-Rodriguez, Mar / Morgan, Ann W / Cubbon, Richard M / Wu, Jianhua

PLoS medicine

2020 Volume 17, Issue 12, Page(s) e1003432

Abstract: Background: Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. ... ...

Abstract	Background: Glucocorticoids are widely used to reduce disease activity and inflammation in patients with a range of immune-mediated inflammatory diseases. It is uncertain whether or not low to moderate glucocorticoid dose increases cardiovascular risk. We aimed to quantify glucocorticoid dose-dependent cardiovascular risk in people with 6 immune-mediated inflammatory diseases. Methods and findings: We conducted a population-based cohort analysis of medical records from 389 primary care practices contributing data to the United Kingdom Clinical Practice Research Datalink (CPRD), linked to hospital admissions and deaths in 1998-2017. We estimated time-variant daily and cumulative glucocorticoid prednisolone-equivalent dose-related risks and hazard ratios (HRs) of first all-cause and type-specific cardiovascular diseases (CVDs). There were 87,794 patients with giant cell arteritis and/or polymyalgia rheumatica (n = 25,581), inflammatory bowel disease (n = 27,739), rheumatoid arthritis (n = 25,324), systemic lupus erythematosus (n = 3,951), and/or vasculitis (n = 5,199), and no prior CVD. Mean age was 56 years and 34.1% were men. The median follow-up time was 5.0 years, and the proportions of person-years spent at each level of glucocorticoid daily exposure were 80% for non-use, 6.0% for <5 mg, 11.2% for 5.0-14.9 mg, 1.6% for 15.0-24.9 mg, and 1.2% for ≥25.0 mg. Incident CVD occurred in 13,426 (15.3%) people, including 6,013 atrial fibrillation, 7,727 heart failure, and 2,809 acute myocardial infarction events. One-year cumulative risks of all-cause CVD increased from 1.4% in periods of non-use to 8.9% for a daily prednisolone-equivalent dose of ≥25.0 mg. Five-year cumulative risks increased from 7.1% to 28.0%, respectively. Compared to periods of non-glucocorticoid use, those with <5.0 mg daily prednisolone-equivalent dose had increased all-cause CVD risk (HR = 1.74; 95% confidence interval [CI] 1.64-1.84; range 1.52 for polymyalgia rheumatica and/or giant cell arteritis to 2.82 for systemic lupus erythematosus). Increased dose-dependent risk ratios were found regardless of disease activity level and for all type-specific CVDs. HRs for type-specific CVDs and <5.0-mg daily dose use were: 1.69 (95% CI 1.54-1.85) for atrial fibrillation, 1.75 (95% CI 1.56-1.97) for heart failure, 1.76 (95% CI 1.51-2.05) for acute myocardial infarction, 1.78 (95% CI 1.53-2.07) for peripheral arterial disease, 1.32 (95% CI 1.15-1.50) for cerebrovascular disease, and 1.93 (95% CI 1.47-2.53) for abdominal aortic aneurysm. The lack of hospital medication records and drug adherence data might have led to underestimation of the dose prescribed when specialists provided care and overestimation of the dose taken during periods of low disease activity. The resulting dose misclassification in some patients is likely to have reduced the size of dose-response estimates. Conclusions: In this study, we observed an increased risk of CVDs associated with glucocorticoid dose intake even at lower doses (<5 mg) in 6 immune-mediated diseases. These results highlight the importance of prompt and regular monitoring of cardiovascular risk and use of primary prevention treatment at all glucocorticoid doses.
MeSH term(s)	Administration, Oral ; Adult ; Aged ; Cardiovascular Diseases/chemically induced ; Cardiovascular Diseases/epidemiology ; Databases, Factual ; Dose-Response Relationship, Drug ; Female ; Glucocorticoids/administration & dosage ; Glucocorticoids/adverse effects ; Heart Disease Risk Factors ; Humans ; Incidence ; Inflammation/drug therapy ; Inflammation/epidemiology ; Inflammation/immunology ; Inflammatory Bowel Diseases/drug therapy ; Inflammatory Bowel Diseases/epidemiology ; Inflammatory Bowel Diseases/immunology ; Male ; Middle Aged ; Rheumatic Diseases/drug therapy ; Rheumatic Diseases/epidemiology ; Rheumatic Diseases/immunology ; Risk Assessment ; Time Factors ; United Kingdom/epidemiology
Chemical Substances	Glucocorticoids
Language	English
Publishing date	2020-12-03
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2185925-5
ISSN	1549-1676 ; 1549-1277
ISSN (online)	1549-1676
ISSN	1549-1277
DOI	10.1371/journal.pmed.1003432
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Article ; Online: A methodological framework for AI-assisted diagnosis of active aortitis using radiomic analysis of FDG PET-CT images: Initial analysis.

Duff, Lisa / Scarsbrook, Andrew F / Mackie, Sarah L / Frood, Russell / Bailey, Marc / Morgan, Ann W / Tsoumpas, Charalampos

Journal of nuclear cardiology : official publication of the American Society of Nuclear Cardiology

2022 Volume 29, Issue 6, Page(s) 3315–3331

Abstract: Background: The aim of this study was to explore the feasibility of assisted diagnosis of active (peri-)aortitis using radiomic imaging biomarkers derived from [: Methods: The aorta was manually segmented on FDG PET-CT in 50 patients with aortitis ... ...

Abstract	Background: The aim of this study was to explore the feasibility of assisted diagnosis of active (peri-)aortitis using radiomic imaging biomarkers derived from [ Methods: The aorta was manually segmented on FDG PET-CT in 50 patients with aortitis and 25 controls. Radiomic features (RF) (n = 107), including SUV (Standardized Uptake Value) metrics, were extracted from the segmented data and harmonized using the ComBat technique. Individual RFs and groups of RFs (i.e., signatures) were used as input in Machine Learning classifiers. The diagnostic utility of these classifiers was evaluated with area under the receiver operating characteristic curve (AUC) and accuracy using the clinical diagnosis as the ground truth. Results: Several RFs had high accuracy, 84% to 86%, and AUC scores 0.83 to 0.97 when used individually. Radiomic signatures performed similarly, AUC 0.80 to 1.00. Conclusion: A methodological framework for a radiomic-based approach to support diagnosis of aortitis was outlined. Selected RFs, individually or in combination, showed similar performance to the current standard of qualitative assessment in terms of AUC for identifying active aortitis. This framework could support development of a clinical decision-making tool for a more objective and standardized assessment of aortitis.
MeSH term(s)	Humans ; Positron Emission Tomography Computed Tomography/methods ; Fluorodeoxyglucose F18 ; Aortitis/diagnostic imaging ; Radiopharmaceuticals ; Artificial Intelligence ; Retrospective Studies
Chemical Substances	Fluorodeoxyglucose F18 (0Z5B2CJX4D) ; Radiopharmaceuticals
Language	English
Publishing date	2022-03-23
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1212505-2
ISSN	1532-6551 ; 1071-3581
ISSN (online)	1532-6551
ISSN	1071-3581
DOI	10.1007/s12350-022-02927-4
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Article ; Online: Systemic Inflammation Is Associated With Future Risk of Fatal Infection: An Observational Cohort Study.

Drozd, Michael / Pujades-Rodriguez, Mar / Morgan, Ann W / Lillie, Patrick J / Witte, Klaus K / Kearney, Mark T / Cubbon, Richard M

The Journal of infectious diseases

2022 Volume 226, Issue 3, Page(s) 554–562

Abstract: Background: Many diseases are associated with chronic inflammation, resulting in widening application of anti-inflammatory therapies. Although they are effective as disease-modifying agents, these anti-inflammatory therapies increase the risk of serious ...

Abstract	Background: Many diseases are associated with chronic inflammation, resulting in widening application of anti-inflammatory therapies. Although they are effective as disease-modifying agents, these anti-inflammatory therapies increase the risk of serious infection; however, it remains unknown whether chronic systemic inflammation per se is also associated with fatal infection. Methods: Using serum C-reactive protein (CRP) data from 461 052 UK Biobank participants, we defined incidence rate ratios (IRRs) for death from infection, cardiovascular disease, or other causes and adjusted for comorbidities and the use of anti-inflammatory therapies. Results: Systemic inflammation, defined as CRP ≥2 mg/L, was common in all comorbidities considered. After adjusting for confounding factors, systemic inflammation was associated with a higher IRR point estimate for infection death (1.70; 95% confidence interval [CI], 1.51-1.92) than cardiovascular (1.48; CI, 1.40-1.57) or other death (1.41; CI, 1.37-1.45), although CIs overlapped. C-reactive protein thresholds of ≥5 and ≥10 mg/L yielded similar findings, as did analyses in people with ≥2, but not <2, comorbidities. Conclusions: Systemic inflammation per se identifies people at increased risk of infection death, potentially contributing to the observed risks of anti-inflammatory therapies in clinical trials. In future clinical trials of anti-inflammatory therapies, researchers should carefully consider risks and benefits in target populations, guided by research into mechanisms of infection risk.
MeSH term(s)	Anti-Inflammatory Agents ; C-Reactive Protein ; Cardiovascular Diseases ; Cohort Studies ; Humans ; Inflammation
Chemical Substances	Anti-Inflammatory Agents ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2022-06-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiac186
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