“What is my risk really?”: A qualitative exploration of preventive interventions among individuals at risk of rheumatoid arthritis

Objectives Intervention in the pre-arthritis phase of rheumatoid arthritis (RA) could prevent or delay the onset of disease. The primary aim of this study was to explore perspectives of being at-risk and potential preventive interventions among individuals at risk of developing RA, and identify factors influencing their engagement with prevention. A secondary aim, established during the analysis process, was to understand and compare different approaches to health-related behaviours related to preventing RA. Methods Anti-cyclic citrullinated peptide positive at-risk (CCP+ at-risk) individuals with musculoskeletal symptoms but no synovitis participated in semi-structured interviews. Data were analysed using reflexive thematic analysis, followed by a secondary ideal-type analysis. Results Nineteen CCP+ at-risk individuals (ten women; age range 35–70) participated. Three overarching themes were identified: i) being CCP+ at risk; ii) aiming to prevent RA; iii) influencers of engagement. Participants described distress related to symptoms and uncertainty about disease progression. Many participants had concerns about medication side effects. In contrast, most participants expressed willingness to make lifestyle changes with the aim of preventing RA. Engagement with preventive measures was influenced by symptom severity, personal risk level, comorbidities, experiences of taking other medications/supplements, knowledge of RA, risk factors and medications, and perceived effort. Three ‘types’ of participants were identified from the data: proactive preventers, change considerers, and fearful avoiders. Overall orientation to health behaviours also impacted on attitude towards preventing RA. Conclusion Findings could inform recruitment and retention in RA prevention research and promote uptake of preventive interventions in clinical practice

Antibodies to leukotoxin A from the periodontal pathogen Aggregatibacter actinomycetemcomitans in patients at an increased risk of rheumatoid arthritis

ObjectivesPeriodontitis and underlying bacteria have been linked to the development of rheumatoid arthritis (RA). One suggested pathogen is Aggregatibacter actinomycetemcomitans (A.a.), which expresses leukotoxin A (LtxA) that can citrullinate human proteins, providing a possible trigger for the production of anti-citrullinated protein antibodies (ACPA). In this study, we seek to determine the presence of antibodies toward LtxA in patients at risk of developing RA.MethodsTwo prospective observational patient cohorts (one Swedish and one British) with symptomatic at-risk patients were studied. Anti-LtxA antibodies were analyzed by a cell-based neutralization assay in baseline serum and compared to 100 Swedish blood donors that served as controls.ResultsSerum anti-LtxA levels or positivity did not differ between patients and blood donors. In the British cohort, anti-LtxA was more prevalent among ACPA-positive arthralgia patients compared with ACPA-negative arthralgia cases (24% vs. 13%, p < 0.0001). In the Swedish at-risk cohort, anti-LtxA positive patients were at increased risk of progression to arthritis (hazard ratio (HR) 2.10, 95% CI 1.04–4.20), but this was not confirmed in the UK at-risk cohort (HR 0.99, CI 0.60–1.65).ConclusionSerum anti-LtxA is not elevated before RA diagnosis, and associations with disease progression and ACPA levels differ between populations. Other features of the oral microbiome should be explored in upcoming periodontitis-related RA research

IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma

What Is the Value of Ultrasound in Individuals ‘At-Risk’ of Rheumatoid Arthritis Who Do Not Have Clinical Synovitis?

The identification of biomarkers that help identify individuals at imminent risk of progression to rheumatoid arthritis (RA) is of crucial importance for disease prevention. In recent years, several studies have highlighted the value of musculoskeletal (MSK) ultrasound (US) in predicting progression to inflammatory arthritis (IA) in individuals ‘at-risk’ of RA. These studies have highlighted the following main aspects: first, in RA-related autoantibody-positive individuals, MSK symptoms seem to develop before ‘sub-clinical’ joint inflammation occurs on US. Second, the detection of ‘sub-clinical’ synovitis (and/or bone erosions) greatly increases the risk of IA development in these ‘at-risk’ individuals. US has a potential key role for better understanding the ‘pre-clinical’ stages in individuals ‘at-risk’ of RA, and for the early identification of those individuals at high risk of developing IA. Further research is needed to address questions on image analysis and standardization. In this review, we provide an overview of the most relevant studies which have investigated the value of US in the prediction of RA development in individuals ‘at-risk’ of RA who have MSK symptoms, but no clinical evidence of IA. We highlight recent insights, limitations, and future perspectives of US use in this important population

MRI inflammation of the hand interosseous tendons occurs in anti-CCP-positive at-risk individuals and may precede the development of clinical synovitis

Interosseous tendon inflammation (ITI) has been described in rheumatoid arthritis (RA). Whether ITI occurs in at-risk individuals before the onset of clinical synovitis is unknown. Objectives To investigate, by MRI, ITI in anti-cyclic citrullinated peptide (CCP)-positive at-risk individuals (CCP +at risk) and to describe the anatomy, prevalence and clinical associations across the RA continuum. Methods Hand MRI was performed in 93 CCP + at risk, 47 early RA (ERA), 28 established ’late’ RA (LRA) and 20 healthy controls (HC) and scored for ITI, flexor tenosynovitis (TSV) and RA MRI scoring at the metacarpophalangeal joints (MCPJs). Cadaveric and histological studies were performed to explore the anatomical basis for MRI ITI. Results The proportion of subjects with ITI and the number of inflamed interosseous tendons (ITs) increased along the disease continuum (p<0.001): 19% of CCP +at risk, 49% of ERA and 57% of LRA had ≥1 IT inflamed . ITI was not found in any HC. ITI was more frequently identified in tender MCPJs compared with nontender MCPJs (28% vs 12%, respectively). No IT tenosynovial sheath was identified in cadavers on dissection or histological studies suggesting MRI findings represent peritendonitis. Dye studies indicated no communication between the IT and the joint. Conclusions I TI occurs in CCP + at-risk individuals and can precede the onset of clinical synovitis. The ITs may be important nonsynovial extracapsular targets in the development and progression of RA.National Institute for Health ResearchDepto. de Anatomía y EmbriologíaFac. de MedicinaTRUEpu

Comorbidities in Anti-Cyclic Citrullinated Peptide Positive At-Risk Individuals Do Not Differ from Those Patients with Early Inflammatory Arthritis

ObjectivesTo compare comorbidities in a cohort of cyclic citrullinated peptide (CCP) antibody positive patients without or prior to onset of inflammatory arthritis (IA) to those in patients with early IA.MethodsBaseline data from two established cohorts were used. The first recruited people at risk of IA: CCP antibody positive cases without IA (CCP Cohort, n = 296). The second cohort [the Inflammatory Arthritis CONtinuum study (IACON)] recruited patients with early IA (n = 725). Proportions of patients with given comorbidities were compared between cohorts and then logistic regression was used to determine odds ratios (OR) for the CCP cohort having specific comorbidities, compared to IACON patients. Analyses adjusted for gender, age, smoking status, and body mass index.ResultsPatients from the CCP cohort were younger (mean age 50, compared to 53 years). The proportion of patients with at least one comorbidity was higher in the IACON than the CCP cohort: (40% compared to 24%, respectively). Results of logistic regression analyses suggested the odds of hypertension, taking a lipid-lowering agent, ischemic heart disease, cerebrovascular disease, lung disease, and diabetes were not increased in either cohort. However, patients in the CCP cohort were more likely to be taking an antidepressant (OR = 1.62, 95% CI 1.03, 2.56, p = 0.037).ConclusionThere was no significant difference in comorbidities among people with CCP antibodies but without IA, compared to those of patients with established IA

Association of gout with brain reserve and vulnerability to neurodegenerative disease.

Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis

Association of gout with brain reserve and vulnerability to neurodegenerative disease.

Studies of neurodegenerative disease risk in gout are contradictory. Relationships with neuroimaging markers of brain structure, which may offer insights, are uncertain. Here we investigated associations between gout, brain structure, and neurodegenerative disease incidence. Gout patients had smaller global and regional brain volumes and markers of higher brain iron, using both observational and genetic approaches. Participants with gout also had higher incidence of all-cause dementia, Parkinson's disease, and probable essential tremor. Risks were strongly time dependent, whereby associations with incident dementia were highest in the first 3 years after gout diagnosis. These findings suggest gout is causally related to several measures of brain structure. Lower brain reserve amongst gout patients may explain their higher vulnerability to multiple neurodegenerative diseases. Motor and cognitive impairments may affect gout patients, particularly in early years after diagnosis