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Background Predicting progression to clinical arthritis in individuals at-risk of developing rheumatoid arthritis is a prerequisite to developing stratification groups for prevention strategies. Selecting accurate predictive criteria is the critical step to define the population at-risk. While positivity for anti-citrullinated protein antibodies (ACPA) remains the main recruitment biomarker, positivity for other autoantibodies (AutoAbs) identified before the onset of symptoms, may provide additional predictive accuracy for stratification.Objective To perform a multiple AutoAbs analysis for both the prediction and the time of progression to inflammatory arthritis (IA).Methods 392 individuals were recruited based on a new musculoskeletal complaint and positivity for ACPA or rheumatoid factor (RF). ELISAs were performed for ACPA, RF, anti-nuclear Ab, anti-carbamylated protein (anti-CarP) and anti-collagen AutoAbs. Logistic and COX regression were used for analysis.Results Progression to IA was observed in 125/392 (32%) of cases, of which 78 progressed within 12 months. The AutoAbs ACPA, RF, anti-CarP were individually associated with progression (p77%; area under the curve (AUC) >0.789), compared with prediction using only demographic/clinical data (72.9%, AUC=0.760). Multiple AutoAbs testing provided added value, with +6.4% accuracy for number of positive AutoAbs (AUC=0.852); +5.4% accuracy for AutoAbs levels (ACPA/anti-CarP, AUC=0.832); and +6.2% accuracy for risk-groups based on high/low levels (ACPA/RF/anti-CarP, AUC=0.837). Time to imminent progression was best predicted using ACPA/anti-CarP levels (AUC=0.779), while the number of positive AutoAbs was/status/risk were as good (AUC=0.778).Conclusion We confirm added value of multiple AutoAbs testing for identifying progressors to clinical disease, allowing more specific stratification for intervention studies.

Serum anti-citrullinated protein antibodies (ACPAs), present in 70% of people with rheumatoid arthritis (RA), can be detected ≤10years before the onset of clinical disease. RA and periodontitis are epidemiologically associated and we have reported a high incidence of periodontitis in people who are ACPA+ and at risk of RA. Periodontal bacteria may contribute by multiple routes to the generation of RA-autoantibodies. This study aims to characterise the subgingival microbiomes from periodontitis and health in individuals with/without RA and at risk of RA. Forty-five ACPA+ no RA (RA-at-risk; RAR), 31 healthy controls (HC) and 30 ACPA+ RA patients (RA) underwent a periodontal examination. DNA from subgingival plaque from healthy and deep pocket sites were paired-end sequenced using the Illumina HiSeq3000 and data analysed using MG-RAST + DESeq. Metagenomes in RA samples had high proportions of Actinobacteria; RAR microbiomes contained higher proportions of Bacteroidetes than HC. The relative abundance of P. gingivalis was high in periodontitis and RAR; Aggregatibacter actinomycetemcomitans was detected with similar frequency in each group. Other bacteria implicated in periodontitis and/or autoantibody generation (Filifactor alocis, Prevotella spp, Leptotrichia spp.) were detected. Analyses are on-going to elucidate the diversity and functional potential of the subgingival microbiome associated with RA.

Objectives: This work aimed to resolve the conflicting reports on Prevotellaceae abundance in the development of rheumatoid arthritis (RA) and to observe structural, functional and temporal changes in the gut microbiome in RA progressors versus non-progressors., Methods: Individuals at risk of RA were defined by the presence of anticyclic citrullinated protein (anti-CCP) antibodies and new musculoskeletal symptoms without clinical synovitis. Baseline sampling included 124 participants (30 progressed to RA), with longitudinal sampling of 19 participants (5 progressed to RA) over 15 months at five timepoints. Gut microbiome taxonomic alterations were investigated using 16S rRNA amplicon sequencing and confirmed with shotgun metagenomic DNA sequencing on 49 samples., Results: At baseline, CCP+ at risk progressors showed significant differences in Prevotellaceae abundance compared with non-progressors, contingent on intrinsic RA risk factors and time to progression. Longitudinal sampling revealed gut microbiome instability in progressors 10 months before RA onset, a phenomenon absent in non-progressors. This may indicate a late microbial shift before RA onset, with Prevotellaceae contributing but not dominating these changes. Structural changes in the gut microbiome during arthritis development were associated with increased amino acid metabolism., Conclusion: These data suggest conflicting reports on Prevotellaceae overabundance are likely due to sampling within a heterogeneous population along a dynamic disease spectrum, with certain Prevotellaceae strains/clades possibly contributing to the establishment and/or progression of RA. Gut microbiome changes in RA may appear at the transition to clinical arthritis as a late manifestation, and it remains unclear whether they represent a primary or secondary phenomenon., Competing Interests: Competing interests: CMR has received funding from Versus Arthritis and Leeds Cares and in-kind support from 4D Pharma PLC. KM has received grants from Gilead, Lilly, Serac Healthcare, AstraZeneca and DeepCure; consulting fees from AbbVie, UCB, Lilly, Galapagos, Serac Healthcare, Zura Bio and DeepCure; and honoraria from AbbVie, UCB, Lilly, Galapagos, Serac Healthcare, Zura Bio and DeepCure. PE has received grants from AbbVie, BMS, Lilly, Novartis, Pfizer and Samsung; and consulting fees from AbbVie, Activia, AstraZeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Immunovant, Janssen, Lilly and Novartis., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ on behalf of EULAR.)

Multiple clinical trials for rheumatoid arthritis (RA) prevention have been completed. Here, we set out to report on the lessons learnt from these studies. Researchers who conducted RA prevention trials shared the background, rationale, approach and outcomes and evaluated the lessons learnt to inform the next generation of RA prevention trials. Individuals at risk of RA can be identified through population screening, referrals to musculoskeletal programmes and by recognition of arthralgia suspicious for RA. Clinical trials in individuals at risk for future clinical RA have demonstrated that limited courses of corticosteroids, atorvastatin and hydroxychloroquine do not alter incidence rates of clinical RA; however, rituximab delays clinical RA onset, and methotrexate has transient effects in individuals who are anticitrullinated protein antibody-positive with subclinical joint inflammation identified by imaging. Abatacept delays clinical RA onset but does not fully prevent onset of RA after treatment cessation. Additionally, subclinical joint inflammation and symptoms appear responsive to interventions such as methotrexate and abatacept. To advance prevention, next steps include building networks of individuals at risk for RA, to improve risk stratification for future RA and to understand the biological mechanisms of RA development, including potential endotypes of disease, which can be targeted for prevention, thus adopting a more precision-based approach. Future trials should focus on interceptions aimed at preventing clinical RA onset and which treat existing symptoms and imaging-defined subclinical inflammation. These trials may include advanced designs (eg, adaptive) and should be combined with mechanistic studies to further define pathophysiological drivers of disease development., Competing Interests: Competing interests: KDD has received honoraria from BMS, ThermoFisher and Werfen, and in-kind research supplies from Inova Diagnostics; VMH has received equity and funds from Q32 Bio unrelated to this work; PE has received funds for consulting from AnaptysisBio, BMS, Boehringer Ingelheim, Galapagos, Gilead, Janssen, MSD, Lilly, Novartis and support for clinical trials from Abbvie, BMS, Lilly, Novartis and Samsung; KM has received honoraria and/or consulting fees from Abbvie, Lilly, Galapagos, Serac Healthcare, Deepcure, UCB, Zura Bio and research grants from Astra Zeneca, Lilly, Gilead, Serac Healthcare and Deepcure. GS has received funds for consulting from BMS, Janssen and Novartis; JAS has received research support from Boehringer Ingelheim and Bristol Myers Squibb unrelated to this work. He has performed consultancy for AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Gilead, Inova Diagnostics, Janssen, Optum, Pfizer, ReCor, Sobi and UCB unrelated to this work; RT has received funds for consulting from CSL, AbbVie, Nextera, Sandoz, Viela Bio and Janssen-Cilag and received research contracts from CSL and Viela Bio; APC has received consulting and speaker bureau fees from Abbvie, BMS, Galapagos, UCB, Galvani, Janssen, Roche and Arthrogen, and research grant support from BMS, UCB and Janssen, with funds administered by King’s College London., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Early intervention has been the cornerstone of improving outcomes in patients with rheumatoid arthritis. Over the past decade, the boundaries have been pushed in an attempt to achieve effective prevention strategies in those who are at high risk of developing rheumatoid arthritis. Core risk factors including the presence of serum anti-citrullinated protein antibodies, arthralgia and subclinical inflammation on imaging are highly predictive of arthritis development. The influence of air pollution, diet and the role of microbiome on disease progression are less clear. In turn, therapeutic focus has shifted to an earlier pre-arthritis phase of the disease continuum where the clinically apparent arthritis may potentially be intercepted. Seven proof-of-concept interventional trials in at-risk individuals have been conducted so far. Whether true prevention of rheumatoid arthritis is possible remains elusive. Promising signals towards permanent disease modulation and improvement in symptom burden were seen with some immunomodulatory therapies, whilst others were unsuccessful. Long-term follow-up is required to ascertain a true effect. Looking forward, a better understanding of the natural history and underlying biological mechanisms of arthritis development and more accurate, validated risk stratification is needed., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

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.)

Objective: The tapering of biologic disease-modifying antirheumatic drug (b-DMARD) therapy for patients with rheumatoid arthritis (RA) in stable remission is frequently undertaken, but specific guidance on how to successfully taper is lacking. The objective of this study is to identify predictors of flare in patients in stable b-DMARD-induced clinical remission, who did or did not follow structured b-DMARD tapering., Methods: Patients with RA receiving b-DMARD treatment who had achieved sustained remission according to a Disease Activity Score in 28 joints using the C-reactive protein level (DAS28-CRP) <2.6 for ≥6 months were offered tapering. Clinical, ultrasound (US) (total power Doppler [PD]/grayscale abnormalities), CD4 + T cell subsets, and patient-reported outcomes (PROs) were collected at inclusion. The primary endpoint was the occurrence of flare (loss of DAS28-CRP remission) over 12 months. Logistic regression analyses identified predictors of flare. Dichotomization into high/low-risk groups was based on 80% specificity using the area under the receiving operator curve (AUROC)., Results: Of 63 patients choosing tapering, 23 (37%) flared compared with 12 of 60 (20%) on stable treatment (P = 0.043). All patients who flared regained remission upon reinstating treatment. In the tapering group, flare was associated with lower regulatory T cell (Treg) (P < 0.0001) and higher CRP levels (P < 0.0001), erythrocyte sedimentation rate (P < 0.035), and inflammation-related cells (IRCs) (P = 0.054); stepwise modeling selected Tregs (odds ratio [OR] = 0.350, P = 0.004), IRCs (OR = 1.871, P = 0.007), and CRP level (OR = 1.577, P = 0.004) with 81.7% accuracy and AUROC = 0.890. In the continued therapy group, modeling retained the tender joint count, total PD, and visual analog scale pain score, with 82.1% accuracy and AUROC = 0.899. Most patients in the study were considered low risk of flare (80 of 123 patients [65%]). Only 5 of 37 (13.5%) of the low-risk patients who tapered flared, which was notable compared with the continued therapy group (20% flare)., Conclusion: Flare on tapering b-DMARDs was predicted by lower Tregs and elevated inflammation biomarkers (IRCs/CRP level); flare on continued b-DMARDs was associated with raised pain parameters and US inflammation. Knowledge of these biomarkers should improve outcomes by targeted selection for tapering, and by increased monitoring of those on continued therapy predicted to flare., (© 2024 The Authors. ACR Open Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Immune checkpoint inhibitors have revolutionised the treatment of cancer. While very effective, they commonly cause a wide spectrum of immune-related adverse events. These immune-related adverse events can be fatal and often have significant effects on quality of life. They therefore require prompt recognition and management. We report the case of a woman presenting with widespread joint pain and stiffness 6 hours after her first pembrolizumab infusion. She had no joint swelling on physical examination but an ultrasound scan revealed widespread musculoskeletal inflammation, confirming the diagnosis of inflammatory arthritis. To the best of our knowledge, this is the fastest reported inflammatory arthritis onset following immune checkpoint inhibitor treatment. It highlights the importance of timely imaging in patients on immune checkpoint inhibitors who present with new non-specific musculoskeletal pain. Her symptoms improved dramatically with intramuscular triamcinolone injection., Competing Interests: Competing interests: There is no specific grant for this research from any funding agency. KHa, ADM and KHo have no conflicts of interest to declare. KM has grants from Lilly, Gilead and Serac Life Sciences. KM has consulting fees from Serac Life Sciences and Lilly. KM has payment for lectures from AbbVie, Galapagos and UCB. KM has support for attending meetings from AbbVie., (© BMJ Publishing Group Limited 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To investigate the role of third-generation anticyclic citrullinated peptide (anti-CCP3) antibodies in predicting progression to inflammatory arthritis (IA) in individuals with new musculoskeletal (MSK) symptoms and a negative second-generation anti-CCP antibody test (anti-CCP2-)., Methods: 469 anti-CCP2- individuals underwent baseline anti-CCP3 testing (QUANTA Lite CCP3; Inova Diagnostics) and received a post enrolment 12-month questionnaire. A rheumatologist confirmed or excluded diagnosis of IA. Univariable/multivariable analyses were performed to assess the value of anti-CCP3 in predicting IA development in these anti-CCP2- individuals., Results: Only 16/469 (3.4%) anti-CCP2- individuals had a positive anti-CCP3 test. Of these 16 individuals, 4 developed IA. In addition, 61/469 (13.0%) anti-CCP2- individuals self-reported, to have developed, IA. Progression was confirmed in 43/61 of them (70.5%); of whom 30/43 (69.8%) and 13/43 (30.2%) were given a diagnosis of IA and rheumatoid arthritis (RA), respectively. In qualitative univariable analysis, anti-CCP3 positivity was associated with self-reported progression (p<0.01) and IA (p=0.03), but not with RA. Anti-CCP3 levels differed significantly between progressors and non-progressors (p<0.01) for all three categories. At the manufacturer's cut-off, OR for progression ranged from 2.4 (95% CI 0.5 to 18.6; RA) to 7.5 (95% CI 2.3 to 24.0; self-reported progression). Interestingly, when cut-offs for anti-CCP3 were optimised, lower values (≥5 units) significantly increased the OR for progression in all three categories. In multivariable analysis, anti-CCP3 positivity at the manufacturer's cut-off did not remain associated with IA progression, while this lower cut-off value (≥5 units) was associated with diagnosis of RA (p=0.02)., Conclusions: Anti-CCP3 testing could improve the prediction of IA development in anti-CCP2- individuals with new MSK symptoms., Competing Interests: Competing interests: ADM has received speaking fees from Janssen. KM reports personal fees from Abbvie, Lilly, Galapagos, UCB and Serac Healthcare outside the submitted work and research grants from Gilead, Serac Healthcare and Lilly. MM is employed at Werfen, a diagnostic company that commercialises the CCP3 assay. He does not have stocks or shares of the company or other incentives for the product. Testing was done at the University of Leeds and MM was not involved. PE reports providing expert advice to Abbvie, Astra-Zeneca, BMS, Boehringer Ingelheim, Galapagos, Gilead, Lilly, Novartis, Pfizer, Roche, Samsung outside the submitted work. He also reports research grants from AbbVie, BMS, Lilly and Samsung. The remaining authors have declared no conflicts of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the prevalence of poly-refractory rheumatoid arthritis (RA) defined as failure of all biological (b)/targeted synthetic (ts)-disease-modifying drugs (DMARDs). To further investigate whether patients with persistent inflammatory refractory RA (PIRRA) and noninflammatory refractory RA (NIRRA), determined by objective ultrasound (US) synovitis, have distinct clinical phenotypes in both EULAR difficult-to-treat RA (D2T-RA) and poly-refractory RA groups., Methods: A cross-sectional study of 1,591 patients with RA on b/tsDMARDs that evaluated D2T-RA criteria and subclassified as poly-refractory if inefficacy/toxicity to at least one drug of all classes. PIRRA was defined if US synovitis in one or more swollen joint and NIRRA if absent. Univariate tests and multivariate logistic regression were conducted to investigate factors associated with poly-refractory, PIRRA, and NIRRA phenotypes., Results: 122 of 1,591 were excluded due to missing data. 247 of 1,469 (16.8%) had D2T-RA and only 40 of 1,469 (2.7%) poly-refractory RA. This latter group had higher disease activity score 28 C-reactive protein (CRP) (median 5.4 vs 5.02, P < 0.05), CRP levels (median 13 vs 5 mg/l, P < 0.01), and smoking (ever) rates (20% vs 4%, P < 0.01) compared with other D2T patients. Smoking was associated with poly-refractory RA (odds ratio 5.067, 95% CI 1.774-14.472, P = 0.002). Of 107 patients with D2T-RA with recent US, 61 (57%) were PIRRA and 46 (43%), NIRRA. Patients with NIRRA had elevated body mass index (median 30 vs 26, P < 0.001) and higher fibromyalgia prevalence (15% vs 3%, P < 0.05), lower swollen joint count (median: 2 vs 5, P < 0.001), and lower CRP levels (5 vs 10, P < 0.01)., Conclusion: Only 2.7% of D2T-RA failed all classes of b/tsDMARDs. Among D2T-RA, less than 60% had objective signs of inflammation, representing a target for innovative strategies., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of 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.)

Background: Subclinical synovitis occurs in a third of individuals at risk of rheumatoid arthritis. The objective of this study was to assess the reversibility of subclinical synovitis in individuals at risk of rheumatoid arthritis who are positive for anti-cyclic citrullinated peptide (CCP) antibody with musculoskeletal symptoms and investigate factors associated with its resolution within 12 months., Methods: We conducted a single-centre, prospective, cohort study in the UK, recruiting individuals aged 18 years or older who were anti-CCP-positive with a new non-specific musculoskeletal symptom but no clinical synovitis. Referrals were made through primary or secondary care. Participants attended a baseline visit, which included a clinical assessment, blood tests, patient questionnaires, and a musculoskeletal ultrasound scan (ie, of wrists and metacarpophalangeal, proximal interphalangeal, and metatarsophalangeal joints), and then follow-up visits every 3 months for the first year, with a repeat ultrasound scan every 12 months. Participants with subclinical synovitis (ie, grey scale ≥1 and power Doppler ≥1) in at least one joint at baseline were selected for this analysis. Investigation of good prognostic factors by 12 months was done first using univariable analysis to identify significant factors in participants with no missing data. Then receiver operating characteristic (ROC) curves were used to establish the optimal cutoffs for significant continuous variables. Finally, a modified Poisson regression approach was performed to identify the best prediction model and was adjusted for confounders, using data from all participants, with missing values imputed. This study is registered with ClinicalTrials.gov, NCT02012764., Findings: Between June 30, 2008, and Feb 24, 2020, 451 participants consented to participate in the CCP study and 122 (27%) individuals had subclinical synovitis at baseline, of whom 90 (74%) had data available at 12 months. Mean age was 54·1 years (SD 12·5), and 63 (70%) of 90 participants were women and 27 (30%) were men. Subclinical synovitis resolved in 43 (48%) of 90 participants, whereas subclinical synovitis persisted in 47 (52%) participants, 27 (57%) of whom developed clinical synovitis within 12 months. In the multivariable analysis, low anti-CCP titre (relative risk [RR] 1·52, 95% CI 1·04-2·22), negative rheumatoid factor (1·54, 0·92-2·58), subclinical synovitis in only one joint (1·62, 1·04-2·50), and an erythrocyte sedimentation rate of 15 mm/h or lower (1·82, 1·15-2·87) were predictors of subclinical synovitis resolution within 12 months (ie, good prognostic factors). ROC curve showed an area under the curve of 0·84 (95% CI 0·76-0·92; p<0·0001). Resolution occurred in seven (100%) of seven participants with all four factors present, and in only one (7%) of 14 participants with none of the factors present., Interpretation: In individuals who were anti-CCP-positive, subclinical synovitis disappeared in approximately half of the participants by 12 months and was associated with the presence of good prognostic factors. Subclinical synovitis should be interpreted in the context of these additional factors., Funding: National Institute for Health Research Leeds Biomedical Research Centre., Competing Interests: Declaration of interests KM has received grants from Lilly, Gilead, and Serac Life Sciences; consulting fees from Serac Life Sciences; and honoraria from AbbVie, Lilly, and Galapagos. PE has received grants from Lilly and Samsung; received consulting fees from AbbVie, AnaptysBio, BMS, Gilead, Lilly, and Novartis; received honoraria from AbbVie, BMS, Gilead, Lilly, Novartis, and Sandoz; received support for attending meetings from Lilly; and reports participation on data safety monitoring or advisory board by AstraZeneca. LG-M, JK, LD, ADM, JLN, KH, and RC declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Objective: Recent advances imply that early events triggering rheumatoid arthritis (RA) occur at mucosal surfaces. We aimed to evaluate whether intestinal permeability is altered in patients at increased risk of RA, and/or predicts the development of clinical arthritis, by measuring serum zonulin family peptides (ZFP) levels, which are shown to reflect intestinal barrier integrity., Methods: Two independent prospective observational cohorts were studied, including subjects with musculoskeletal symptoms and anticitrullinated protein antibodies (ACPA), but without clinical arthritis at baseline. In Sweden, 82 such at-risk patients were compared to 100 age-matched healthy blood donors. In the UK, 307 at-risk patients were compared to 100 ACPA-negative symptomatic controls. ZFP was measured in baseline sera by enzyme-linked immunoassays., Results: In the Swedish at-risk cohort, ZFP levels were significantly increased in patients compared to controls (mean 41.4 vs 33.6 ng/mL, P < 0.001) and Cox regression analysis showed prognostic value of ZFP for arthritis development (hazard ratio [HZ] 1.04 per ng/mL ZFP increase, 95% CI 1.01-1.07, P = 0.02). Elevated ZFP levels among ACPA-positive at-risk patients compared to symptomatic ACPA-negative controls were confirmed in the UK at-risk cohort (mean 69.7 vs 36.0 ng/mL, P < 0.001), but baseline ZFP were not associated with arthritis development (HR 1.00 per ng/mL ZFP increase, 95% CI 1.00-1.01, P = 0.30)., Conclusion: Serum ZFP levels are elevated in ACPA-positive at-risk patients when compared to both healthy blood donors and symptomatic ACPA-negative controls. Thus, gut barrier function may be of importance in RA-associated autoimmunity. A possible prognostic value of serum ZFP merits further investigation, preferably in larger prospective cohorts., (Copyright © 2024 by the Journal of Rheumatology.)

Objectives: Periodontitis 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., Methods: Two 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., Results: Serum 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)., Conclusion: Serum 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., Competing Interests: KMan reports personal fees from AbbVie, Lilly, and UCB AbbVie, outside the submitted work and research grants from Gilead and Lilly. PE reports consultant fees from BMS, AbbVie, MSD, Pfizer, Novartis, and Roche and personal fees from Abbvie, Gilead, Lilly, and Novartis, outside the submitted work and also reports research grants from AbbVie, BMS, Lilly, and Samsung. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Martinsson, Di Matteo, Öhman, Johansson, Svärd, Mankia, Emery and Kastbom.)

Background: Inflammatory arthritis (IA) is an immune-related condition defined by the presence of clinical synovitis. Its most common form is rheumatoid arthritis., Objective: To develop scores for predicting IA in at-risk persons using multidimensional biomarkers., Design: Prospective observational cohort study., Setting: Single-center, Leeds, United Kingdom., Participants: Persons with new musculoskeletal symptoms, a positive test result for anticitrullinated protein antibodies, and no clinical synovitis and followed for 48 weeks or more or until IA occurred., Measurements: A simple score was developed using logistic regression, and a comprehensive score was developed using the least absolute shrinkage and selection operator Cox proportional hazards regression. Internal validation with bootstrapping was estimated, and a decision curve analysis was done., Results: Of 455 participants, 32.5% (148 of 455) developed IA, and 15.4% (70 of 455) developed it within 1 year. The simple score identified 249 low-risk participants with a false negative rate of 5% (and 206 high-risk participants with a false-positive rate of 72%). The comprehensive score identified 119 high-risk participants with a false-positive rate of 29% (and 336 low-risk participants with a false-negative rate of 19%); 40% of high-risk participants developed IA within 1 year and 71% within 5 years., Limitations: External validation is required. Recruitment occurred over 13 years, with lower rates of IA in later years. There was geographic variation in laboratory testing and recruitment availability., Conclusion: The simple score identified persons at low risk for IA who were less likely to need secondary care. The comprehensive score identified high-risk persons who could benefit from risk stratification and preventive measures. Both scores may be useful in clinical care and should also be useful in clinical trials., Primary Funding Source: National Institute for Health and Care Research Leeds Biomedical Research Centre., Competing Interests: Disclosures: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M23-0272.

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., (© 2023. The Author(s).)

Objectives: Current evidence suggests that periodontal disease could be a causal risk factor for rheumatoid arthritis (RA) onset and progression. Earlier periodontal intervention in individuals at risk of RA could provide a unique opportunity to prevent or delay the onset of RA. This study aimed to explore the acceptability of periodontal treatment as a measure to potentially prevent RA among at-risk individuals and healthcare professionals., Methods: Semistructured interviews were conducted with anti-CCP positive at-risk individuals (CCP+ at risk) and a range of healthcare professionals. At-risk participant data were analysed using reflexive thematic analysis; subsequent coding of healthcare professional data was deductive, based on a preidentified set of constructs., Results: Nineteen CCP+ at-risk and 11 healthcare professionals participated. Three themes (six subthemes) were identified: (1) understanding risk (knowledge of shared at-risk factors; information and communication); (2) oral health perceptions and experiences (personal challenges and opportunities for dental intervention and oral health maintenance; external barriers) and (3) oral health treatment and maintenance (making oral health changes with the aim of preventing RA; acceptability of participation in periodontal research)., Conclusions: Periodontal disease is common in individuals at risk of RA, but the impact of poor oral health may not be well understood. Oral health information should be tailored to the individual. CCP+ at-risk participants and healthcare professionals identified seeking dental treatment can be hindered by dental phobia, treatment costs or inability to access dentists. While CCP+ at-risk individuals may be reluctant to take preventive medications, a clinical trial involving preventive periodontal treatment is potentially acceptable., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: Specific guidelines for managing RA patients in clinical remission for ≥6 months on cs-DMARDs are lacking. Tapering of treatment is encouraged, however, without validated biomarkers for success. We aimed to assess the rate of sustained remission after 12 months in patients who either (i) followed structured cs-DMARD tapering or (ii) continued therapy, focusing on the added value of biomarkers as predictors of outcome., Methods: RA patients fulfilling 3v-DAS28CRP<2.6 for ≥6 months on stable cs-DMARD therapy were included. Patients were offered structured tapering, with 117 accepting tapering and 83 continuing therapy. Clinical, ultrasound, immunological (T-cell subsets) and patient-reported outcome (PRO) data were collected. The primary endpoint was the proportion of patients in sustained remission without relapse after 12 months. Regression analyses were used to identify predictors of sustained remission., Results: Of those who tapered, 64% remained in clinical remission after 12 months compared with 80% (p=0.018) of patients on stable treatment. In the tapering group, higher levels of CRP, TJC, % inflammation-related T-cell (IRC) and PROs were associated with flare (all p<0.05), with a trend for total PD (p=0.066). A model predicting sustained remission retained RAQoL, total PD and IRC (85% accuracy, AUROC=0.893, p<0.0001). In the non-tapering group, higher CRP, ESR, SJC and shorter disease duration (all p<0.05) were associated with flare, with no parameter able to predict sustained remission., Conclusions: In the tapering group, the combination of clinical, PRO, US and T-cell parameters demonstrated added value for predicting sustained remission compared with clinical parameters alone. These data may inform best tapering practice.

Background: Predicting progression to clinical arthritis in individuals at-risk of developing rheumatoid arthritis is a prerequisite to developing stratification groups for prevention strategies. Selecting accurate predictive criteria is the critical step to define the population at-risk. While positivity for anti-citrullinated protein antibodies (ACPA) remains the main recruitment biomarker, positivity for other autoantibodies (AutoAbs) identified before the onset of symptoms, may provide additional predictive accuracy for stratification., Objective: To perform a multiple AutoAbs analysis for both the prediction and the time of progression to inflammatory arthritis (IA)., Methods: 392 individuals were recruited based on a new musculoskeletal complaint and positivity for ACPA or rheumatoid factor (RF). ELISAs were performed for ACPA, RF, anti-nuclear Ab, anti-carbamylated protein (anti-CarP) and anti-collagen AutoAbs. Logistic and COX regression were used for analysis., Results: Progression to IA was observed in 125/392 (32%) of cases, of which 78 progressed within 12 months. The AutoAbs ACPA, RF, anti-CarP were individually associated with progression (p<0.0001) and improved prediction when combined with demographic/clinical data (Accuracy >77%; area under the curve (AUC) >0.789), compared with prediction using only demographic/clinical data (72.9%, AUC=0.760). Multiple AutoAbs testing provided added value, with +6.4% accuracy for number of positive AutoAbs (AUC=0.852); +5.4% accuracy for AutoAbs levels (ACPA/anti-CarP, AUC=0.832); and +6.2% accuracy for risk-groups based on high/low levels (ACPA/RF/anti-CarP, AUC=0.837). Time to imminent progression was best predicted using ACPA/anti-CarP levels (AUC=0.779), while the number of positive AutoAbs was/status/risk were as good (AUC=0.778)., Conclusion: We confirm added value of multiple AutoAbs testing for identifying progressors to clinical disease, allowing more specific stratification for intervention studies., Competing Interests: Competing interests: LAT is mentioned as an inventor on a patent describing a method to detect anti-CarP antibodies., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

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., (© 2022. The Author(s).)

In recent years rheumatologists have begun to shift focus from early rheumatoid arthritis (RA) to studying individuals at risk of developing the disease. It is now possible to use blood, clinical and imaging biomarkers to identify those at risk of progression before the onset of clinical synovitis. The use of imaging, in particular ultrasound (US) and magnetic resonance imaging (MRI), has become much more widespread in individuals at-risk of RA. Numerous studies have demonstrated that imaging can help us understand RA pathogenesis as well as identifying individuals at high risk of progression. In addition, imaging techniques are becoming more sophisticated with newer imaging modalities such as high-resolution peripheral quantitative computed tomography (HR-pQRCT), nuclear imaging and whole body-MRI (WB-MRI) starting to emerge. Imaging studies in at risk individuals are heterogeneous in nature due to the different at-risk populations, imaging modalities and protocols used. This review will explore the available imaging modalities and the rationale for their use in the main populations at risk of RA., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Harnden, Di Matteo and Mankia.)

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.)

Background: Biologic disease-modifying anti-rheumatic drugs (bDMARDs) are effective in treating inflammatory diseases and have been increasingly utilized over the past decade. Patients who receive bDMARDs have been shown to be at an increased risk for surgical site infection following surgical procedures. The severe consequences of infection following orthopaedic surgery have led to the practice of withholding bDMARDs perioperatively; however, there has been no definitive evidence showing a clear benefit of withholding the use of bDMARDs, and in doing so, patients may be at an increased risk for higher disease activity. As such, the purpose of the present study was to compare the risk of infection, delayed wound healing, and disease flares associated with the use of bDMARDs in patients undergoing orthopaedic surgical procedures., Methods: We performed a systematic literature search of MEDLINE, Embase, and PubMed CENTRAL databases for studies comparing continuing and withholding the use of bDMARDs in patients undergoing orthopaedic procedures. Inclusion criteria were established following the PICO (Population, Intervention, Comparison, and Outcomes) approach: Population = patients who underwent orthopaedic surgical procedures and who were taking bDMARDs. Intervention = withholding the use of bDMARDs. Comparator = continuing the use of bDMARDs. Outcomes = surgical site infection, delayed wound healing, and disease flares. Article titles and abstracts were screened prior to review of the full text. Overall odds ratios (ORs) and associated 95% confidence intervals (CIs) for pooled effects were calculated., Results: Eleven studies met the inclusion criteria, providing data for 7,344 patients, including 2,385 patients who continued and 4,959 who withheld their bDMARDs perioperatively. Continuing bDMARDs was associated with a significantly lower risk of disease flares (OR, 0.22; 95% CI, 0.05 to 0.95; p = 0.04) and nonsignificant increases in surgical site infections (OR, 1.11; 95% CI, 0.82 to 1.49; p = 0.49) and wound complications (OR, 2.16; 95% CI, 0.48 to 9.85; p = 0.32)., Conclusions: The present systematic review highlights the limited evidence supporting the current practice of stopping bDMARDs perioperatively. These findings suggest that patients may not be at an increased risk for developing infection or wound complications if bDMARDs are continued but are at an increased risk for disease flare if bDMARDs are withheld. However, our conclusions are limited by the retrospective and heterogenous nature of the data, and possibly by a lack of study power., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G940)., (Copyright © 2022 by The Journal of Bone and Joint Surgery, Incorporated.)

Objectives: To assess antibody and T cell responses to SARS-CoV-2 vaccination in patients with rheumatoid arthritis (RA) on disease-modifying antirheumatic drugs (DMARDs)., Methods: This prospective study recruited 100 patients with RA on a variety of DMARDs for antibody and T cell analysis, pre-vaccination and 4 weeks post-vaccination. Positive antibody response was defined as sera IgG binding to ≥1 antigen. Those that remained seronegative after first vaccination were retested 4 weeks after second vaccination; and if still seronegative after vaccination three. A T cell response was defined an ELISpot count of ≥7 interferon (IFN)γ-positive cells when exposed to spike antigens. Type I IFN activity was determined using the luminex multiplex assay IFN score., Results: After vaccine one, in patients without prior SARS-CoV-2 exposure, 37/83 (45%) developed vaccine-specific antibody responses, 44/83 (53%) vaccine-specific T cell responses and 64/83 (77%) developed either antibody or T cell responses. Reduced seroconversion was seen with abatacept, rituximab (RTX) and those on concomitant methotrexate (MTX) compared to 100% for healthy controls (p<0.001). Better seroconversion occurred with anti-tumour necrosis factor (TNF) versus RTX (p=0.012) and with age ≤50 (p=0.012). Pre-vaccine SARS-CoV-2 exposure was associated with higher quantitative seroconversion (≥3 antibodies) (p<0.001). In the subgroup of non-seroconverters, a second vaccination produced seroconversion in 54% (19/35), and after a third in 20% (2/10). IFN score analysis showed no change post-vaccine., Conclusion: Patients with RA on DMARDs have reduced vaccine responses, particularly on certain DMARDs, with improvement on subsequent vaccinations but with approximately 10% still seronegative after three doses., Competing Interests: Competing interests: BS: Speaker fees for Pfizer and Galapagos, L-AB: Honoraria for UCB, Abbvie and Galapagos, KM: Personal: Abbvie, Lilly, UCB.Grants: Lilly, Gilead, FD: received research support and consultancies, not related to the topic of this manuscript from ABBVIE, AstraZeneca, Boehringer-Ingelheim, Capella, Chemomab, Kymab, Mitsubishi-TanabePaul Emery: Grants : AbbVie, BMS, Lilly, Samsung. Consulting fees: BMS, AbbVie, MSD, Pfizer, Novartis, and Roche. Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events:Abbvie, Gilead, Lilly, Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: There is increasing interest in identifying individuals at-risk of rheumatoid arthritis (RA) and initiating early treatment to prevent or delay the onset of arthritis. We aimed to describe the perceptions and experiences of at-risk individuals and to inform the conduct of clinical trials and studies, and clinical practice., Methods: A systematic review and thematic synthesis of qualitative studies was conducted. Two review authors independently screened studies for inclusion, appraised their methodological quality using the Critical Appraisal Skills Programme checklist and assessed confidence in the findings using the Grading of Recommendations Assessment, Development and Evaluation-Confidence in Evidence from Reviews of Qualitative Research approach., Results: Seven studies involving 115 individuals at-risk of developing RA were included. Three major themes (seven subthemes) were identified: understanding the risk of developing RA (knowledge of RA and identification of potential risk factors); preventive interventions to reduce the risk of developing RA (understanding the value and role of preventive interventions, and engagement with preventive interventions); and perceptions of predictive testing for RA (benefits of predictive testing, decision to undertake predictive testing and concerns about predictive testing). Moderate confidence in most review findings was evident., Conclusion: While there are clear benefits in informing individuals at-risk of RA about their risk following predictive testing and offering preventive treatment, there are potential barriers to engagement, intensified by the burden of uncertainty. Identification of the optimum approaches for presenting risk information, including the risks and benefits of engaging with preventive interventions, is urgently needed to support individuals at-risk of RA in their decision making., Prospero Registration Number: CRD42021236034., Competing Interests: Competing interests: Professor DA is an ARD Board Member., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)

Background: Musculoskeletal (MSK) symptoms are among the commonest reasons for primary care assessments; however, few individuals will be diagnosed with an inflammatory arthritis (IA) within the following year. The purpose of this study was to investigate, in individuals with new MSK symptoms, the association between patient factors and risk of progression to IA, in order to optimise primary care referrals to rheumatology., Methods: Individuals ≥16 years old with new non-specific MSK symptoms and no clinical synovitis were recruited by primary care across the UK from July 2007 until May 2019. Those testing positive for the anti-CCP2 assay (anti-CCP+) were invited to Leeds for follow-up. Subjects with a negative result (anti-CCP-) were sent a 1-year questionnaire, and general practitioners were contacted to confirm whether the individual had been diagnosed with an IA by a rheumatologist. Predictors for progression were assessed using multivariable regression analysis., Results: Six thousand seven hundred eighty individuals were recruited: 3% were anti-CCP+, of whom 45% progressed to IA, predominantly rheumatoid arthritis. Anti-CCP+ participants with high antibody levels had an odds ratio (OR) for progression to IA of 9.42 [P < 0.001, 95% CI (3.13-28.30)], hand pain, OR 2.74 [P = 0.043, 95% CI (1.03-7.27)] and foot pain, OR 4.10 [P = 0.003, 95% CI (1.59-10.54)]. In low-level anti-CCP+ individuals, absence of pain in hands or feet had a negative predictive value of 96% for progression to IA. One-year follow-up data were available for 5640 anti-CCP- individuals, of whom 53 were diagnosed with IA (0.93%). Pain in hands, OR 2.51 [P = 0.018, 95% CI (1.17-5.39)] or knees, OR 3.03 [P = 0.003, 95% CI (1.47-6.25)] were associated with development of IA within 12 months., Conclusions: This is the largest prospective primary care study of individuals at risk of IA, and the first one to prospectively investigate the outcome of MSK symptoms in a large anti-CCP- cohort. High anti-CCP levels and pain in hands/feet indicated an increased likelihood of progression to IA. In patients with low anti-CCP level and no pain in the hands/feet, progression is unlikely. In anti-CCP- patients, those with hand or knee pain were at increased risk of progression. This study demonstrates that routinely available tests and joint symptoms provide useful discrimination that may be used to prioritise referrals to rheumatology and avoid a delayed diagnosis., Trial Registration: NCT, NCT02012764 . Registered 25 January 2007., (© 2022. The Author(s).)

Objectives: The human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis., Methods: We performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA)., Results: Meta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not., Conclusions: HLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

There is increasing evidence supporting an association between periodontal disease (PD) and rheumatoid arthritis (RA), both mechanistically and clinically. Trials have shown that treating PD in people with RA may improve RA disease activity. Patients with musculoskeletal symptoms without arthritis, who test positive for cyclic-citrullinated protein antibodies, are at risk of RA (CCP+ at-risk), with seropositivity preceding arthritis onset by months or years. Importantly, there is evidence to suggest that periodontal inflammation may precede joint inflammation in CCP+ at-risk and, therefore, this could be a trigger for RA. There has been increased research interest in RA prevention and the phenotyping of the pre-RA disease phase. This review will examine the merits of identifying individuals who are CCP+ at-risk and performing screening for PD. In addition, we discuss how PD should be treated once identified. Finally, the review will consider future research needed to advance our understanding of this disease association.

Background: Despite growing interest, there is no guidance or consensus on how to conduct clinical trials and observational studies in populations at risk of rheumatoid arthritis (RA)., Methods: An European League Against Rheumatism (EULAR) task force formulated four research questions to be addressed by systematic literature review (SLR). The SLR results informed consensus statements. One overarching principle, 10 points to consider (PTC) and a research agenda were proposed. Task force members rated their level of agreement (1-10) for each PTC., Results: Epidemiological and demographic characteristics should be measured in all clinical trials and studies in at-risk individuals. Different at-risk populations, identified according to clinical presentation, were defined: asymptomatic, musculoskeletal symptoms without arthritis and early clinical arthritis. Study end-points should include the development of subclinical inflammation on imaging, clinical arthritis, RA and subsequent achievement of arthritis remission. Risk factors should be assessed at baseline and re-evaluated where appropriate; they include genetic markers and autoantibody profiling and additionally clinical symptoms and subclinical inflammation on imaging in those with symptoms and/or clinical arthritis. Trials should address the effect of the intervention on risk factors, as well as progression to clinical arthritis or RA. In patients with early clinical arthritis, pharmacological intervention has the potential to prevent RA development. Participants' knowledge of their RA risk may inform their decision to participate; information should be provided using an individually tailored approach., Conclusion: These consensus statements provide data-driven guidance for rheumatologists, health professionals and investigators conducting clinical trials and observational studies in individuals at risk of RA., Competing Interests: Competing interests: KM: honoraria from Abbvie, Eli Lilly & Co and UCB; grants from Eli Lilly & Co and Gilead. HJS: none declared. AK: speakers bureau, consultancy: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly & Co, Gilead, Merck Sharp and Dohme, Novartis and Pfizer. DAR: scientific advisor for GSK. AIC, JDC and APC: none declared. CID: honoraria from Roche, Chugai, Pfizer, BMS, MSD, Biogen, Abbvie, Sandoz, Janssen, Novartis, Fresenius Kabi and Sanofi; research grants from Pfizer, MSD and Schwa Medico. KR: speaker fees from Abbvie. PE: expert advice to Pfizer, Abbvie, Amgen, MSD, Roche, Sanofi, BMS, Novartis, Eli Lilly & Co, Gilead, Samsung and Celltrion; grants from Abbvie, Eli Lilly & Co, BMS and Samsung., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: There is significant interest in determining risk factors in individuals at risk of rheumatoid arthritis (RA). A core set of risk factors for clinical arthritis development has not been defined., Methods: A literature search and systematic literature review (SLR) was conducted to identify risk factors in individuals at risk of RA using Medline, Embase, PubMed and Central databases., Results: 3854 articles were identified by the literature search. After screening of titles, 138 abstracts were reviewed and 96 articles finally included. Fifty-three articles included data on risk factors including autoantibodies, subclinical inflammation on imaging, clinical features, serum and cellular biomarkers and genetic markers. Risk factors were dependent on the at-risk population. There was good evidence for serum anticitrullinated protein antibodies (ACPA) levels, as risk factors for arthritis in all at-risk populations (n=13 articles). Subclinical inflammation on ultrasound (n=12) and MRI (n=6) was reported as a risk factor in multiple studies in at-risk individuals with musculoskeletal (MSK) symptoms and undifferentiated arthritis (UA). Clinical features were reported as a risk factor in at-risk individuals with MSK symptoms and UA (n=13). Other risk factors, including serum and cellular markers were less frequently reported., Conclusions: Risk factors for arthritis development in RA are specific to the at-risk population. Serum ACPA confers risk in all populations; subclinical inflammation on imaging and clinical features confer risk in at-risk individuals with MSK symptoms. This SLR informed the EULAR taskforce for points to consider on conducting clinical trials and studies in individuals at risk of RA., Competing Interests: Competing interests: KM: honoraria from AbbVie, Lilly, UCB; grants from Lilly, Gilead. HJS: none declared. AK: speakers bureau, consultancy: AbbVie, Bristol-Myers Squibb, Celgene, Eli-Lilly, Gilead, Merck Sharp and Dohme, Novartis and Pfizer. DA-R: scientific advisor for GSK. ADM: none declared. JK: none declared. DA: none declared. PE: expert advice to Pfizer, AbbVie, Amgen, MSD, Roche, Sanofi, BMS, Novartis, Lilly, Gilead, Samsung, Celltrion; grants from AbbVie, Lilly, BMS, Samsung. The review was not registered. Data collection forms and other materials used in the review available from authors on request., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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.)

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.

Objectives: An increased prevalence of periodontitis and perturbation of the oral microbiome has been identified in patients with rheumatoid arthritis (RA). The periodontal pathogen Porphyromonas gingivalis may cause local citrullination of proteins, potentially triggering anti-citrullinated protein antibody production. However, it is not known if oral dysbiosis precedes the onset of clinical arthritis. This study comprehensively characterised the oral microbiome in anti-cyclic citrullinated peptide (anti-CCP) positive at-risk individuals without clinical synovitis (CCP+at risk)., Methods: Subgingival plaque was collected from periodontally healthy and diseased sites in 48 CCP+at risk, 26 early RA and 32 asymptomatic healthy control (HC) individuals. DNA libraries were sequenced on the Illumina HiSeq 3000 platform. Taxonomic profile and functional capability of the subgingival microbiome were compared between groups., Results: At periodontally healthy sites, CCP+at risk individuals had significantly lower microbial richness compared with HC and early RA groups (p=0.004 and 0.021). Microbial community alterations were found at phylum, genus and species levels. A large proportion of the community differed significantly in membership (523 species; 35.6%) and structure (575 species; 39.1%) comparing CCP+at risk and HC groups. Certain core species, including P. gingivalis , had higher relative abundance in the CCP+at risk group. Seventeen clusters of orthologous gene functional units were significantly over-represented in the CCP+at risk group compared with HC (adjusted p value <0.05)., Conclusion: Anti-CCP positive at-risk individuals have dysbiotic subgingival microbiomes and increased abundance of P. gingivalis compared with controls. This supports the hypothesis that the oral microbiome and specifically P. gingivalis are important in RA initiation., Competing Interests: Competing interests: ZC reports scholarship from the China Scholarship Council during the conduct of the study. Dr TD and JM reports grants from Colgate Palmolive, outside the submitted work. KM reports grants from the National Institute for Health Research (NIHR) Leeds Biomedical Research Unit and grants from Leeds Biomedical Research Centre during the conduct of the study. DD reports grants from NIHR, grants from Wellcome Trust, during the conduct of the study; grants from Colgate Palmolive, outside the submitted work. PE reports grants and personal fees from Pfizer, Merck Sharp & Dohme, AbbVie, Bristol-Myers Squibb, Roche, Samsung, Sandoz, and Eli Lilly and Company; and personal fees from Novartis and UCB outside the submitted work., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)