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Article ; Online: Modifiable risk factors linked to the development of rheumatoid arthritis: evidence, immunological mechanisms and prevention.

Maisha, Jeba Atkia / El-Gabalawy, Hani S / O'Neil, Liam J

2023 Volume 14, Page(s) 1221125

Abstract: Rheumatoid Arthritis (RA) is a common autoimmune disease that targets the synovial joints leading to arthritis. Although the etiology of RA remains largely unknown, it is clear that numerous modifiable risk factors confer increased risk to developing RA. ...

Abstract	Rheumatoid Arthritis (RA) is a common autoimmune disease that targets the synovial joints leading to arthritis. Although the etiology of RA remains largely unknown, it is clear that numerous modifiable risk factors confer increased risk to developing RA. Of these risk factors, cigarette smoking, nutrition, obesity, occupational exposures and periodontal disease all incrementally increase RA risk. However, the precise immunological mechanisms by which these risk factors lead to RA are not well understood. Basic and translational studies have provided key insights into the relationship between inflammation, antibody production and the influence in other key cellular events such as T cell polarization in RA risk. Improving our general understanding of the mechanisms which lead to RA will help identify targets for prevention trials, which are underway in at-risk populations. Herein, we review the modifiable risk factors that are linked to RA development and describe immune mechanisms that may be involved. We highlight the few studies that have sought to understand if modification of these risk factors reduces RA risk. Finally, we speculate that modification of risk factors may be an appealing avenue for prevention for some at-risk individuals, specifically those who prefer lifestyle interventions due to safety and economic reasons.
MeSH term(s)	Humans ; Arthritis, Rheumatoid/etiology ; Arthritis, Rheumatoid/prevention & control ; Risk Factors ; Autoimmune Diseases ; Inflammation ; Obesity
Language	English
Publishing date	2023-09-12
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1221125
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Article ; Online: Serum proteomic networks associate with pre-clinical rheumatoid arthritis autoantibodies and longitudinal outcomes.

O'Neil, Liam J / Meng, Xiaobo / Mcfadyen, Caitlin / Fritzler, Marvin J / El-Gabalawy, Hani S

Frontiers in immunology

2022 Volume 13, Page(s) 958145

Abstract: Objectives: The development of autoantibody directed towards citrullinated proteins (ACPA) are predictive of RA in at-risk individuals. The biological events that underpin loss of immune tolerance and progression into inflammatory arthritis are not ... ...

Abstract	Objectives: The development of autoantibody directed towards citrullinated proteins (ACPA) are predictive of RA in at-risk individuals. The biological events that underpin loss of immune tolerance and progression into inflammatory arthritis are not known. We sought to identify serum proteomic alterations that drive autoantibody formation, persistence and progression into inflammatory arthritis in a cohort of first-degree relatives (FDR) of RA patients. Methods: We studied baseline serum samples from a cohort of Indigenous FDR (n = 147) and quantified serum proteins using a 48-plex platform. Longitudinal outcomes were defined on the basis of ACPA status and progression into inflammatory arthritis (IA). K-means clustering, differential expression, and principal components analyze group differences. A co-expression module analysis was used to identify enriched networks. Random forest was used to classify ACPA positive samples, while network analysis was used to understand underlying biological processes based on protein expression. Results: We defined 6 proteomic clusters, with enrichment of ACPA positive samples in one of the clusters. 23 of 24 differentially expressed proteins in ACPA positive samples were upregulated. A co-expression network was enriched in ACPA positive sera and individuals who progressed into IA. Random Forest achieved an area under the curve of 0.767 to classify ACPA positive sera in a test dataset. Network analysis revealed upregulation of JAK-STAT signalling as being activated in those at highest risk to develop future IA. Conclusions: The serum proteome provides a rich dataset to understand biological processes in ACPA seropositive individuals. A combination of serum biomarkers, including ACPA, may predict future arthritis onset in at-risk individuals.
MeSH term(s)	Arthritis, Rheumatoid ; Autoantibodies ; Biomarkers ; Humans ; Proteome ; Proteomics
Chemical Substances	Autoantibodies ; Biomarkers ; Proteome
Language	English
Publishing date	2022-09-08
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.958145
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Article ; Online: Disparities in rheumatoid arthritis outcomes for North American Indigenous populations.

Hitchon, Carol A / ONeil, Liam / Peschken, Christine A / Robinson, David B / Fowler-Woods, Amanda / El-Gabalawy, Hani S

International journal of circumpolar health

2023 Volume 82, Issue 1, Page(s) 2166447

Abstract: Advances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA have not achieved the high rates of treatment success observed in other populations. We ...

Abstract	Advances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA have not achieved the high rates of treatment success observed in other populations. We review factors contributing to poor long-term outcomes for INA with RA. We conducted a narrative review of studies evaluating RA in INA supplemented with regional administrative health and clinical cohort data on clinical outcomes and health care utilisation. We discuss factors related to conducting research in INA populations including studies of RA prevention. NA with RA have a high burden of genetic and environmental predisposing risk factors that may impact disease phenotype, delayed or limited access to rheumatology care and advanced therapy. These factors may contribute to the observed increased rates of persistent synovitis, premature end-stage joint damage and mortality. Novel models of care delivery that are culturally sensitive and address challenges associated with providing speciality care to patients residing in remote communities with limited accessibility are needed. Progress in establishing respectful research partnerships with INA communities has created a foundation for ongoing initiatives to address care gaps including those aimed at RA prevention. This review highlights some of the challenges of diagnosing, treating, and ultimately perhaps preventing, RA in INA populations.
MeSH term(s)	Humans ; Arthritis, Rheumatoid/diagnosis ; Arthritis, Rheumatoid/drug therapy ; Longitudinal Studies ; Population Groups ; Indigenous Peoples ; North America
Language	English
Publishing date	2023-01-16
Publishing country	United States
Document type	Review ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1386707-6
ISSN	2242-3982 ; 1239-9736
ISSN (online)	2242-3982
ISSN	1239-9736
DOI	10.1080/22423982.2023.2166447
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Article ; Online: Perceived Access to Health Care of Indigenous Peoples in Canada with Rheumatoid Arthritis and their First-Degree Relatives.

Wiens, Dana / Smolik, Irene A / MacKay, Dylan / Fowler-Woods, Amanda / Robinson, David B / Barnabe, Cheryl / El-Gabalawy, Hani S / O'Neil, Liam J

The Journal of rheumatology

2024

Abstract: Objective: There are complex and interrelated factors that lead to inequitable healthcare delivery in Canada. Many of the factors that underlie these inequities for Canada's geographically dispersed Indigenous Peoples remain underexamined.: Methods: ... ...

Abstract	Objective: There are complex and interrelated factors that lead to inequitable healthcare delivery in Canada. Many of the factors that underlie these inequities for Canada's geographically dispersed Indigenous Peoples remain underexamined. Methods: A cohort of 831 First Nations (FN) individuals from urban and remote communities were recruited into a longitudinal study of rheumatoid arthritis (RA) risk from 2005-2017. Data from each participant's initial enrollment visit was assessed using a survey that captured concerns with health care access. Results: We found that remote participants with RA reported poor access compared to remote First-Degree Relatives (FDR, p<0.001), this difference was not observed for urban RA participants. We observed substantial differences based on sex; Females perceived access to care to be more difficult than males in both urban and remote cohorts (p<0.001). We also observed that male participants with RA reported poor access to care compared to male FDR. Importantly, access to care in remote communities appeared to improve over the duration of the study (p=0.01). In a logistic regression analysis, female sex, remote location, and older age were independent predictors of poor access to care. Predictors of poor access in participants with RA were also female sex, remote location and older age. Conclusion: FN peoples living in remote communities, particularly those with an established RA diagnosis, report more problems accessing healthcare. Sex-based inequities exist, with FN females reporting greater difficulties in accessing appropriate healthcare, irrespective of RA diagnosis. Addressing these sex-based inequities should be a high priority for improving healthcare delivery.
Language	English
Publishing date	2024-03-01
Publishing country	Canada
Document type	Journal Article
ZDB-ID	194928-7
ISSN	1499-2752 ; 0315-162X
ISSN (online)	1499-2752
ISSN	0315-162X
DOI	10.3899/jrheum.2023-1080
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Zs.A 1168: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Beyond the visual analog scale: results from a multimodal pain assessment pilot study in first-degree relatives of patients with rheumatoid arthritis.

McDougall, Cairistin / Wiens, Dana / Smolik, Irene / Lee, Yvonne C / El-Gabalawy, Hani S / O'Neil, Liam J

ACR open rheumatology

2022

Language	English
Publishing date	2022-10-18
Publishing country	United States
Document type	Journal Article
ISSN	2578-5745
ISSN (online)	2578-5745
DOI	10.1002/acr2.11497
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Article ; Online: Disparities in rheumatoid arthritis outcomes for North American Indigenous populations

Carol A Hitchon / Liam ONeil / Christine A Peschken / David B Robinson / Amanda Fowler-Woods / Hani S El-Gabalawy

International Journal of Circumpolar Health, Vol 82, Iss

2023 Volume 1

Abstract: ABSTRACTAdvances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA have not achieved the high rates of treatment success observed in other ... ...

Abstract	ABSTRACTAdvances in rheumatoid arthritis (RA) management have significantly improved clinical outcomes of this disease; however, some Indigenous North Americans (INA) with RA have not achieved the high rates of treatment success observed in other populations. We review factors contributing to poor long-term outcomes for INA with RA. We conducted a narrative review of studies evaluating RA in INA supplemented with regional administrative health and clinical cohort data on clinical outcomes and health care utilisation. We discuss factors related to conducting research in INA populations including studies of RA prevention. NA with RA have a high burden of genetic and environmental predisposing risk factors that may impact disease phenotype, delayed or limited access to rheumatology care and advanced therapy. These factors may contribute to the observed increased rates of persistent synovitis, premature end-stage joint damage and mortality. Novel models of care delivery that are culturally sensitive and address challenges associated with providing speciality care to patients residing in remote communities with limited accessibility are needed. Progress in establishing respectful research partnerships with INA communities has created a foundation for ongoing initiatives to address care gaps including those aimed at RA prevention. This review highlights some of the challenges of diagnosing, treating, and ultimately perhaps preventing, RA in INA populations.
Keywords	Rheumatoid arthritis ; indigenous ; disparities ; phenotype ; outcomes ; prevention ; Arctic medicine. Tropical medicine ; RC955-962
Subject code	610
Language	English
Publishing date	2023-12-01T00:00:00Z
Publisher	Taylor & Francis Group
Document type	Article ; Online
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Article: Functional Disability to Evaluate the Risk of Arthritis in First-degree Relatives of Patients With Rheumatoid Arthritis.

Wiens, Dana / Smolik, Irene / Meng, Xiaobo / Anaparti, Vidyanand / El-Gabalawy, Hani S / O'Neil, Liam J

The Journal of rheumatology

2021 Volume 49, Issue 3, Page(s) 244–250

Abstract: Objective: The events that occur prior to the onset of rheumatoid arthritis (RA) continue to be delineated. We examined the relationship between self-reported joint symptoms, functional disability, and anticitrullinated protein antibody (ACPA) status in ...

Abstract	Objective: The events that occur prior to the onset of rheumatoid arthritis (RA) continue to be delineated. We examined the relationship between self-reported joint symptoms, functional disability, and anticitrullinated protein antibody (ACPA) status in a cohort of first-degree relatives (FDR) of patients with RA who are at risk of future disease development. Methods: We studied a cohort of 279 FDR of First Nations (FN) patients with RA who are at increased risk for future RA development, and analyzed data collected at their enrollment study visit. In parallel, we analyzed data from 279 FN subjects with no family history of RA. A subset of FDR developed inflammatory arthritis and we analyzed longitudinal data in this group. Results: The prevalence of joint symptoms and functional disability was higher in FDR compared to non-FDR (all Conclusion: Compared to population-based controls, FDR have a high burden of joint symptoms and functional disability. Functional disability was most closely associated with ACPA seropositivity in the FDR, suggesting a direct role for ACPA outside of the context of clinically detectable synovitis. HAQ appears to be particularly valuable in the assessment of individuals at risk for future RA development.
MeSH term(s)	Arthritis, Rheumatoid/diagnosis ; Autoantibodies ; Cohort Studies ; Humans ; Peptides, Cyclic ; Synovitis
Chemical Substances	Autoantibodies ; Peptides, Cyclic
Language	English
Publishing date	2021-11-01
Publishing country	Canada
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	194928-7
ISSN	1499-2752 ; 0315-162X
ISSN (online)	1499-2752
ISSN	0315-162X
DOI	10.3899/jrheum.210614
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Zs.A 1168: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Increased frequency of TIGIT+ CD4 T Cell subset in autoantibody-positive first-degree relatives of patients with rheumatoid arthritis.

Anaparti, Vidyanand / Tanner, Stacy / Zhang, Christine / O'Neil, Liam / Smolik, Irene / Meng, Xiaobo / Marshall, Aaron J / El-Gabalawy, Hani

Frontiers in immunology

2022 Volume 13, Page(s) 932627

Abstract: Background: Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell ... ...

Abstract	Background: Despite immune cell dysregulation being an important event preceding the onset of rheumatoid arthritis (RA), the phenotype of T and B cells in preclinical RA is less understood. The aim of this study was to characterize T and B cell populations in RA patients and their autoantibody (aAb) negative and positive first-degree relatives (FDR). Methods: Cryopreserved peripheral blood mononuclear cells (PBMCs) collected at scheduled visits from aAb-(n=25), and aAb+ FDR (n=10) and RA patients (n=13) were thawed and stained using optimized antibody cocktails as per a specific 13-color T or B cell panel. Immunophenotyping was performed using a Cytoflex LX (Beckman-Coulter) flow cytometer and FlowJo software was used for analyzing the frequency of immune cell populations. Results: Multicolor flow cytometry experiments identified an increased TIGIT expression in circulating lymphocytes of aAb+ FDR and RA patients, relative to aAb- FDR (P<0.01). These TIGIT Conclusion: We demonstrate TIGIT as a distinct CD4 T cell marker for differentiating aAb- FDR from aAb+FDR and might play a critical role in regulating T and B cell crosstalk in preclinical RA.
MeSH term(s)	Arthritis, Rheumatoid/genetics ; Arthritis, Rheumatoid/immunology ; Autoantibodies/genetics ; Autoantibodies/immunology ; CD4-Positive T-Lymphocytes/immunology ; Humans ; Leukocytes, Mononuclear/immunology ; Programmed Cell Death 1 Receptor/immunology ; Receptors, Immunologic/genetics ; Receptors, Immunologic/immunology ; T-Lymphocyte Subsets/immunology
Chemical Substances	Autoantibodies ; Programmed Cell Death 1 Receptor ; Receptors, Immunologic ; TIGIT protein, human
Language	English
Publishing date	2022-07-28
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.932627
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Article ; Online: Association of a Serum Protein Signature With Rheumatoid Arthritis Development.

O'Neil, Liam J / Spicer, Victor / Smolik, Irene / Meng, Xiaobo / Goel, Rishi R / Anaparti, Vidyanand / Wilkins, John / El-Gabalawy, Hani S

Arthritis & rheumatology (Hoboken, N.J.)

2020 Volume 73, Issue 1, Page(s) 78–88

Abstract: Objective: The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new ... ...

Abstract	Objective: The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development. Methods: In a cohort of first-degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti-citrullinated protein antibodies (ACPAs) (designated the at-risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development. Results: A preclinical proteomic signature that differentiated RA progressors from at-risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll-like receptor 2 and production of tumor necrosis factor and interleukin-1 as key events that precede RA progression. Conclusion: Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at-risk individuals and to identify molecular pathways involved in the development of clinically detectable RA.
MeSH term(s)	Adolescent ; Adult ; Aged ; Anti-Citrullinated Protein Antibodies/immunology ; Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/immunology ; Asymptomatic Diseases ; Calreticulin/blood ; Disease Progression ; Female ; Humans ; Indians, North American ; Interleukin-1/blood ; Interleukin-1/immunology ; Lectins/blood ; Longitudinal Studies ; Machine Learning ; Male ; Middle Aged ; Proteomics ; Rheumatoid Factor/immunology ; Toll-Like Receptor 2/blood ; Toll-Like Receptor 2/immunology ; Tumor Necrosis Factor-alpha/blood ; Tumor Necrosis Factor-alpha/immunology ; Young Adult ; Ficolins
Chemical Substances	Anti-Citrullinated Protein Antibodies ; Calreticulin ; Interleukin-1 ; Lectins ; TLR2 protein, human ; TNF protein, human ; Toll-Like Receptor 2 ; Tumor Necrosis Factor-alpha ; Rheumatoid Factor (9009-79-4)
Language	English
Publishing date	2020-11-10
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2756371-6
ISSN	2326-5205 ; 2326-5191
ISSN (online)	2326-5205
ISSN	2326-5191
DOI	10.1002/art.41483
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Zs.A 24: Show issues

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Article ; Online: Proteomic Approaches to Defining Remission and the Risk of Relapse in Rheumatoid Arthritis.

O'Neil, Liam J / Hu, Pingzhao / Liu, Qian / Islam, Md Mohaiminul / Spicer, Victor / Rech, Juergen / Hueber, Axel / Anaparti, Vidyanand / Smolik, Irene / El-Gabalawy, Hani S / Schett, Georg / Wilkins, John A

Frontiers in immunology

2021 Volume 12, Page(s) 729681

Abstract: Objectives: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum ... ...

Abstract	Objectives: Patients with Rheumatoid Arthritis (RA) are increasingly achieving stable disease remission, yet the mechanisms that govern ongoing clinical disease and subsequent risk of future flare are not well understood. We sought to identify serum proteomic alterations that dictate clinically important features of stable RA, and couple broad-based proteomics with machine learning to predict future flare. Methods: We studied baseline serum samples from a cohort of stable RA patients (RETRO, n = 130) in clinical remission (DAS28<2.6) and quantified 1307 serum proteins using the SOMAscan platform. Unsupervised hierarchical clustering and supervised classification were applied to identify proteomic-driven clusters and model biomarkers that were associated with future disease flare after 12 months of follow-up and RA medication withdrawal. Network analysis was used to define pathways that were enriched in proteomic datasets. Results: We defined 4 proteomic clusters, with one cluster (Cluster 4) displaying a lower mean DAS28 score (p = 0.03), with DAS28 associating with humoral immune responses and complement activation. Clustering did not clearly predict future risk of flare, however an XGboost machine learning algorithm classified patients who relapsed with an AUC (area under the receiver operating characteristic curve) of 0.80 using only baseline serum proteomics. Conclusions: The serum proteome provides a rich dataset to understand stable RA and its clinical heterogeneity. Combining proteomics and machine learning may enable prediction of future RA disease flare in patients with RA who aim to withdrawal therapy.
MeSH term(s)	Adult ; Aged ; Antirheumatic Agents/therapeutic use ; Arthritis, Rheumatoid/blood ; Arthritis, Rheumatoid/classification ; Arthritis, Rheumatoid/drug therapy ; Biomarkers/blood ; Blood Proteins/analysis ; Female ; Humans ; Male ; Middle Aged ; Proteomics ; Recurrence ; Remission Induction
Chemical Substances	Antirheumatic Agents ; Biomarkers ; Blood Proteins
Language	English
Publishing date	2021-11-18
Publishing country	Switzerland
Document type	Journal Article ; Multicenter Study ; Randomized Controlled Trial ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2021.729681
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