Preferences of Patients and At-risk Individuals for Preventive Approaches to Rheumatoid Arthritis

Falahee, Marie; Finckh, Axel; Raza, Karim; Harrison, Mark

doi:10.1016/j.clinthera.2019.04.015

Cited by 30 publications

(22 citation statements)

References 67 publications

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“…Another consideration is that individuals who seek clinical care for joint symptoms and are found to be in a pre-RA state may be more interested in participating in a prevention trial than someone who is at risk but is asymptomatic and/or has little understanding of what RA is-which may be the type of individual identified if broad population-based screening for RA risk was implemented. Informing these issues to some extent, there are studies that have explored "preferences" for prevention in at-risk individuals (64,65). General themes that have emerged include that at-risk individuals would like clarity around what RA is as a disease, their absolute risk of IA/RA, and to know that interventions are highly likely to | 189 be successful as well as well-tolerated and safe.…”

Section: Prevention Trial Design and Duration Of Interventionmentioning

confidence: 99%

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Deane

Holers

2020

Arthritis & Rheumatology

163

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Rheumatoid arthritis (RA) is currently diagnosed and treated when an individual presents with signs and symptoms of inflammatory arthritis (IA) as well as other features, such as autoantibodies and/or imaging findings, that provide sufficient confidence that the individual has RA‐like IA (e.g., meeting established classification criteria) that warrants therapeutic intervention. However, it is now known that there is a stage of seropositive RA during which circulating biomarkers and other factors (e.g., joint symptoms) can be used to predict if and when an individual who does not currently have IA may develop future clinically apparent IA and classifiable RA. Indeed, the discovery of the “pre‐RA” stage of seropositive disease has led to the development of several clinical trials in which individuals are studied to identify ways to delay or prevent the onset of clinically apparent IA/RA. This review focuses on several issues pertinent to understanding the prevention of RA. These include discussion of the pathogenesis of pre‐RA development, prediction of the likelihood and timing of future classifiable RA, and a review of completed and ongoing clinical trials in RA prevention. Furthermore, this review discusses challenges and opportunities to be addressed to effect a paradigm shift in RA, where in the near future, proactive risk assessment focused on prevention of RA will become a public health strategy in much the same manner as cardiovascular disease is managed today.

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Section: Prevention Trial Design and Duration Of Interventionmentioning

confidence: 99%

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Deane

Holers

2020

Arthritis & Rheumatology

163

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“…These individuals present with symptoms of arthralgia and positivity for circulatory autoantibodies (such as anti‐citrullinated protein antibodies [ACPA] or rheumatoid factor [RF]), yet have no clinical signs of inflammation 6 . It is now well established that autoantibodies can precede the onset of clinical symptoms by years in RA patients, 7 thus studying these ‘individuals at risk’ (IAR) may provide important clues in understanding the evolution of RA, and in identifying altered immune responses that may predict disease onset 8 . Although arthralgia along with autoantibody positivity greatly increases the risk of development of RA, reported conversion rates vary between 30 and 70% 9,10 .…”

Section: Introductionmentioning

confidence: 99%

“…6 It is now well established that autoantibodies can precede the onset of clinical symptoms by years in RA patients, 7 thus studying these 'individuals at risk' (IAR) may provide important clues in understanding the evolution of RA, and in identifying altered immune responses that may predict disease onset. 8 Although arthralgia along with autoantibody positivity greatly increases the risk of development of RA, reported conversion rates vary between 30 and 70%. 9,10 Furthermore, blood or tissue biomarkers have not yet been identified in this 'at risk' population.…”

Section: Introductionmentioning

confidence: 99%

Rheumatoid arthritis CD14⁺ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease

et al. 2021

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IntroductionThis study investigates the metabolic activity of circulating monocytes and their impact on pro‐inflammatory responses in RA and explores whether this phenotype is already primed for inflammation before clinical manifestations of disease.MethodsBlood was collected and CD14+ monocytes isolated from healthy control donors (HC), individuals at‐risk (IAR) and RA patients. Monocyte frequency in blood and synovial tissue was assessed by flow cytometry. Inflammatory responses and metabolic analysis ± specific inhibitors were quantified by RT‐PCR, Western blot, migration assays, Seahorse‐XFe‐technology, mitotracker assays and transmission electron microscopy. Transcriptomic analysis was performed on HC, IAR and RA synovial tissue.ResultsCD14+ monocytes from RA patients are hyper‐inflammatory following stimulation, with significantly higher expression of cytokines/chemokines than those from HC. LPS‐induced RA monocyte migratory capacity is consistent with increased monocyte frequency in RA synovial tissue. RA CD14+ monocytes show enhanced mitochondrial respiration, biogenesis and alterations in mitochondrial morphology. Furthermore, RA monocytes display increased levels of key glycolytic enzymes HIF1α, HK2 and PFKFB3 and demonstrate a reliance on glucose consumption, blockade of which abrogates pro‐inflammatory mediator responses. Blockade of STAT3 activation inhibits this forced glycolytic flux resulting in metabolic reprogramming and resolution of inflammation. Interestingly, this highly activated monocytic phenotype is evident in IAR of developing disease, in addition to an enhanced monocyte gene signature observed in synovial tissue from IAR.ConclusionRA CD14+ monocytes are metabolically re‐programmed for sustained induction of pro‐inflammatory responses, with STAT3 identified as a molecular regulator of metabolic dysfunction. This phenotype precedes clinical disease onset and may represent a potential pathway for therapeutic targeting early in disease.

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“…In all cases, understanding the perspectives of patients and caregivers for screening and preventive treatments is important for determining a potential disease management strategy. Studies on preferences for preventive and risk-reducing treatments have been conducted, for example, in individuals at risk of rheumatoid arthritis, 26 , 27 women with the BRCA1/2 gene, 28 and individuals at risk of Alzheimer's disease. 29 …”

Section: Discussionmentioning

confidence: 99%

Parent Preferences for Delaying Insulin Dependence in Children at Risk of Stage III Type 1 Diabetes

DiSantostefano

Sutphin

Hedrick

et al. 2020

Diabetes Technology & Therapeutics

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Background: Autoantibody screening in type 1 diabetes (T1D) may reduce the chances of potentially lifethreatening diabetic ketoacidosis (DKA) at diagnosis by allowing individuals at risk of progression to more actively monitor for and/or manage progression to insulin dependence. We investigated parents' preferences for treatments to delay the onset of insulin dependence in children who are at high risk of developing Stage III T1D. Methods: A web-based survey (n = 1501) was administered to a stratified sample of parents (children <18 years) in the United States from an online panel. Parents were told to hypothetically assume that their youngest child would become insulin dependent within 6 months or 2 years and were offered a series of choices between no treatment and two hypothetical treatments that would delay insulin dependence. Random-parameters logit analysis and maximum acceptable risks were used to evaluate the relative importance of treatment benefits and risks. Results: Most parents chose at least one active treatment (2% always chose monitoring only). For parents of children without T1D (n = 901), delaying insulin dependence and reducing the risk of long-term health complications and serious infection were the most important treatment attributes. In addition, parents of children with T1D (n = 600) also valued reducing the risk of hospitalizations due to DKA. Conclusions: When told to assume their child would develop Stage III T1D, most parents considered active treatments to delay progression. For medicines under development to delay insulin dependence in T1D, the preferences expressed in this survey provide guidance on acceptable benefit-risk trade-offs.

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Preferences of Patients and At-risk Individuals for Preventive Approaches to Rheumatoid Arthritis

Cited by 30 publications

References 67 publications

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Rheumatoid arthritis CD14⁺ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease

Parent Preferences for Delaying Insulin Dependence in Children at Risk of Stage III Type 1 Diabetes

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Preferences of Patients and At-risk Individuals for Preventive Approaches to Rheumatoid Arthritis

Cited by 30 publications

References 67 publications

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Rheumatoid Arthritis Pathogenesis, Prediction, and Prevention: An Emerging Paradigm Shift

Rheumatoid arthritis CD14+ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease

Parent Preferences for Delaying Insulin Dependence in Children at Risk of Stage III Type 1 Diabetes

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Rheumatoid arthritis CD14⁺ monocytes display metabolic and inflammatory dysfunction, a phenotype that precedes clinical manifestation of disease