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Objectives: To investigate, in anti-CCP antibody-positive individuals with musculoskeletal symptoms but no clinical synovitis (CCP+ at-risk), the additional value of US for the prediction of inflammatory arthritis. Furthermore, to define a concise US protocol for feasible risk prediction., Methods: Demographic and clinical data were collected in 417 CCP+ at-risk (Leeds CCP cohort) with a baseline US scan assessing synovitis and bone erosions in 36 joints, and a follow-up duration ≥24 months. Multivariable binary regression models for inflammatory arthritis development at 24 months evaluated routine clinical variables associated with inflammatory arthritis alone ('clinical' model) and combined with a 36-joint US scanning protocol ('clinical-US extended' model). A 'clinical-US short' model was also developed., Results: At 24 months, 92/417 (22.1%) CCP+ at-risk developed inflammatory arthritis (median time 7 months, interquartile range 3-12). The 'clinical-US extended' model performed better than the 'clinical' model [area under the curve (AUC) 0.788 vs AUC 0.731, respectively, P < 0.001] with an odds ratio for inflammatory arthritis development of 3.18 (95% CI 1.80-5.63) for US synovitis and 2.54 (95% CI 1.21-5.37) for bone erosions. The 'clinical-US short' model, which retained the wrists, knees and MTP5 joints, performed better (AUC 0.782) than the 'clinical' model (P < 0.001) and similarly (difference in Akaike information criteria <2) to the 'clinical-US extended' model., Conclusions: US provides valuable information for predicting progression to inflammatory arthritis in CCP+ individuals both alone and in addition to clinical variables. US synovitis was associated with a 3-fold increase risk of inflammatory arthritis development. A concise US protocol of six joints provides clinically feasible risk prediction in CCP+ at-risk., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Inflammatory arthritis (IA) is considered the last stage of a disease continuum, where features of systemic autoimmunity can appear years before clinical synovitis. Time to progression to IA varies considerably between at-risk individuals, therefore the identification of biomarkers predictive of progression is of major importance. We previously reported on the value of three CD4+T cell subsets as biomarkers of progression. Here, we aim to establish the value of 18 lymphocyte subsets (LS) for predicting progression to IA., Methods: Participants were recruited based on a new musculoskeletal complaint and being positive for anti-citrullinated-peptide antibody. Progression (over 10 years) was defined as the development of clinical synovitis. LS analysis was performed for lymphocyte lineages, naive/memory subsets, inflammation-related cells (IRC) and regulatory cells (Treg/B-reg). Modelling used logistic/Cox regressions., Results: Of 210 patients included, 93 (44%) progressed to IA, 41/93 (44%) within 12 months (rapid progressors). A total of 5/18 LS were associated with progression [Treg/CD4-naïve/IRC (adjusted P < 0.0001), CD8 (P = 0.021), B-reg (P = 0.015)] and three trends (NK-cells/memory-B-cells/plasmablasts). Unsupervised hierarchical clustering using these eight subsets segregated three clusters of patients, one cluster being enriched [63/109(58%)] and one poor [10/45(22%)] in progressors. Combining all clinical and LS variables, forward logistic regression predicted progression with accuracy = 85.7% and AUC = 0.911, selecting smoking/rheumatoid-factor/HLA-shared-epitope/tender-joint-count-78 and Treg/CD4-naive/CD8/NK-cells/B-reg/plasmablasts. To predict rapid progression, a Cox regression was performed resulting in a model combining smoking/rheumatoid factor and IRC/CD4-naive/Treg/NK-cells/CD8+T cells (AUC = 0.794)., Conclusion: Overall, progression was predicted by specific LS, suggesting potential triggers for events leading to the development of IA, while rapid progression was associated with a different set of subsets., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Intervention in the pre-arthritis phase of 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 to identify factors influencing their engagement with prevention. A secondary aim, established during the analytical process, was to understand and compare different approaches to health-related behaviours related to prevention of RA., Methods: Anti-CCP-positive (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 (10 women; age range 35-70 years) participated. Three overarching themes were identified: being CCP + at risk; aiming to prevent RA; and 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, co-morbidities, 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 the attitude towards preventing RA., Conclusion: Findings could inform recruitment and retention in RA prevention research and promote uptake of preventive interventions in clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: The association of periodontal disease in people diagnosed with RA is emerging as an important driver of the RA autoimmune response. Screening for and treating periodontal disease might benefit people with RA. We performed a systematic literature review to investigate the effect of periodontal treatment on RA disease activity., Methods: Medline/PubMed, Embase and Cochrane databases were searched. Studies investigating the effect of periodontal treatment on various RA disease activity measures were included. The quality of included studies was assessed. Data were grouped and analysed according to RA disease outcome measures, and a narrative synthesis was performed., Results: We identified a total of 21 studies, of which 11 were of non-randomized experimental design trials and 10 were randomized controlled trials. The quality of the studies ranged from low to serious/critical levels of bias. RA DAS-28 was the primary outcome for most studies. A total of 9 out of 17 studies reported a significant intra-group change in DAS-28. Three studies demonstrated a significant intra-group improvement in ACPA level after non-surgical periodontal treatment. Other RA biomarkers showed high levels of variability at baseline and after periodontal treatment., Conclusion: There is some evidence to suggest that periodontal treatment improves RA disease activity in the short term, as measured by DAS-28. Further high-quality studies with longer durations of follow-up are needed. The selection of the study population, periodontal interventions, biomarkers and outcome measures should all be considered when designing future studies. There is a need for well-balanced subject groups with prespecified disease characteristics., (© The Author(s) 2022. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: To investigate whether anti-CCP2-positive at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis (CCP2+ at-risk) develop US subclinical synovitis before inflammatory arthritis and if US subclinical synovitis can be predicted., Methods: First, US scans of CCP2+ at-risk individuals who developed inflammatory arthritis ('progressors') were reviewed for subclinical synovitis prior to inflammatory arthritis development. Patients in whom the pre-progression US scan was negative but the scan was conducted >6 months before progression were excluded. Subsequently, regression analyses were performed to identify predictors of US synovitis in CCP2+ at-risk individuals without baseline US abnormalities who had one or more longitudinal US scan and a complete dataset., Results: US subclinical synovitis was detected in one or more scan in 75 of 97 progressors (77.3%) {median time to inflammatory arthritis development from first evidence of US synovitis 26.5 weeks [interquartile range (IQR) 7-60]}, in whom one or more scan was available, excluding those with a negative scan >6 months from inflammatory arthritis development (n = 38). In 220 CCP2+ at-risk individuals with normal baseline US scans, who had one or more longitudinal US scan and a complete dataset, US synovitis was detected in 69/220 (31.4%) [median time to first developing US synovitis 56.4 weeks (IQR 33.0-112.0)]. In the multivariable analysis, only anti-CCP3 antibodies were predictive for the development of US synovitis [odds ratio 4.75 (95% CI 1.97, 11.46); P < 0.01]., Conclusions: In anti-CCP2+ at-risk individuals, a stage of subclinical synovitis usually precedes the development of inflammatory arthritis. Anti-CCP2+/CCP3+ individuals without clinical or US subclinical synovitis may represent the optimal window of opportunity for intervention to prevent joint disease., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective: Individuals with newly diagnosed RA have a distinct microbiome when compared with healthy controls. However, little is known as to when these microbiome perturbations begin. Using a prospective at-risk cohort of individuals positive for anti-citrullinated protein (anti-CCP) antibody with new onset musculoskeletal symptoms, but without clinical arthritis, we investigated for the presence of a gut dysbiosis before the onset of RA., Methods: The gut microbiota of 25 anti-CCP positive individuals without clinical synovitis were sequenced targeting the V4 region of the 16S rRNA gene. Using a publicly available database, a control population of 44 individuals, approximately matched in age, gender, diet and ethnicity was selected for comparison, using the same sequencing methodology. Median interval between sample collection and progression to RA was 188 days. Taxonomic analysis was performed using QIIME and MEGAN, and statistical analysis using R software., Results: There were significant differences (P =0.01) at family level in gut microbiomes of anti-CCP positive individuals vs controls. The anti-CCP positive population had an overabundance of Lachnospiraceae, Helicobacteraceae, Ruminococcaceae, Erysipelotrichaceae and Bifidobacteriaceae, among others. Five individuals progressed to RA between sample collection and analysis. Clustering of the progressor population was observed on a phylogenetic network created using a probabilistic similarity index (Goodall's index)., Conclusions: Anti-CCP positive at-risk individuals without clinical synovitis appear to have a distinct gut microbiome compared with healthy controls. Phylogenetic clustering was observed in individuals who progressed to RA, suggesting that distinct taxa are associated with the development of RA many months before its onset., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objectives: To investigate the prevalence, distribution and predictive value for the development of inflammatory arthritis (IA) of conventional radiography (CR) bone erosions (BE) in anti-CCP positive (CCP+) at-risk individuals with musculoskeletal (MSK) symptoms but without clinical synovitis., Methods: Baseline CR of the hands and feet of 418 CCP+ at-risk individuals were analysed. The presence of US-BE was explored in the anatomical areas in which CR-BE were reported. Hands and feet CR at the time of progression were analysed in a subset of individuals who developed IA (73/123, 59.3%). Logistic regression analyses were performed to calculate the predictive value of baseline CR-BE for the development of IA in 394 CCP+ individuals with ≥1 follow-up visit., Results: BE were detected in 17/418 (4.1%) CCP+ at-risk individuals (median Simple Erosions Narrowing Score-BE = 2.0, IQR: 1.0-2.0; median Sharp van der Heijde score-BE = 4.0, IQR: 3.0-8.5), most frequently in the foot joints (11/17, 64.7% individuals). A total of 123/394 (31.2%) CCP+ at-risk individuals developed IA; 7/17 (41.2%) with, and 116/377 (30.8%) without BE on CR (P = 0.37). US-BE were found in 4/7 (57.1%) individuals with CR-BE who developed IA, but only in 1/10 (10.0%) who did not. At the time of progression, new BE were detected in 4/73 (5.5%) CCP+ individuals on repeated CR. In the regression analyses, baseline CR-BE were not predictive for the development of IA., Conclusions: In CCP+ at-risk individuals with MSK symptoms, CR-detected BE are uncommon and do not predict the development of IA., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)