Marian van Beers-Tas

Background: The aim of this systematic review and meta-analysis was to examine autoantibody positive individuals and define: (a) the relative risk of rheumatoid arthritis (RA) compared with autoantibody negative individuals and (b) the cumulative incidence of RA over time, in different populations. Methods: A systematic literature search was performed in August 2025. Retrospective case control studies of individuals with RA and healthy matched controls were identified and relative risk of RA was calculated. Prospective observational studies or randomised controlled trials of autoantibody positive individuals were identified and pooled survival models were used to estimate cumulative incidence of progression to arthritis. Results: 293 full-text articles fulfilled screening criteria and 26 were eligible for meta-analysis. The presence of serum autoantibodies confers between a 3.1--19.3-fold increase risk of developing RA. Prospective studies of anticyclic citrullinated peptide 2 (CCP2) or CCP3 positive individuals were grouped according to additional criteria; presence of arthralgia, presence/absence of immunoglobulin M rheumatoid factor (IgM-RF) and first-degree or second-degree relatives with RA. The estimated cumulative incidence of RA at 12 months was highest for CCP2 positive individuals with arthralgia and IgM-RF, at 35.2% (95% CI 29.3% to 41.2%). Conclusion: A considerable number of autoantibodies have been examined as predictors for RA; however, the fastest rate of progression to RA in this study occurred in those with CCP2 and IgM-RF in combination with arthralgia. Importantly, the risk of developing RA changes over time for individuals with arthralgia, and they are at the highest risk of progression within the first 24 months of follow-up. PROSPERO registration number: CRD42021231245.

There is a need to better define symptom characteristics associated with arthritis development in individuals at risk of rheumatoid arthritis (RA). We investigated whether reported symptoms in at-r...

Objectives Persons at high risk of rheumatoid arthritis (RA) might benefit from a low-risk pharmacological intervention aimed at primary prevention. Previous studies demonstrated disease-modifying effects of statins in patients with RA as well as an association between statin use and a decreased risk of RA development. A randomised, double-blind, placebo-controlled trial investigated whether atorvastatin could prevent arthritis development in high-risk individuals. Methods Arthralgia patients with anticitrullinated protein antibody (ACPA) >3 xULN or ACPA and rheumatoid factor, without (a history of) arthritis, were randomised to receive atorvastatin 40 mg daily or placebo for 3 years. The calculated sample size was 220 participants. The primary endpoint was clinical arthritis. Cox regression analysis was used to determine the effect of atorvastatin on arthritis development. Results Due to a low inclusion rate, mainly because of an unwillingness to participate, the trial was prematurely stopped. Data of the 62 randomised individuals were analysed. Median follow-up was 14 (inner quartiles 6–35) months. Fifteen individuals (24%) developed arthritis: 9/31 (29%) in the atorvastatin group; 6/31 (19%) in the placebo group: HR 1.40, 95% CI 0.50 to 3.95. Conclusions In this small set of randomised high-risk individuals, we did not demonstrate a protective effect of atorvastatin on arthritis development. The main reason for the low inclusion was unwillingness to participate; this may also impede other RA prevention trials. Further research to investigate and solve barriers for prevention trial participation is needed.

Rheumatoid arthritis (RA) is associated with an increased cardiovascular disease (CVD) risk which may start even before diagnosis. To explore this CVD risk prior to RA, we determined multiple risk factors and two 10-year clinical risk scores in a cohort of individuals at-risk of RA. We also analyzed associations with arthritis development and autoantibody status and compared a subset of at-risk individuals to an age and sex matched seronegative control group. In a cohort of 555 consecutive arthralgia patients positive for rheumatoid factor (RF) and / or anti-citrullinated protein antibody (ACPA) we retrospectively identified patients with preclinical arthritis (i.e. those who developed arthritis), and non-arthritis patients (those without arthritis development during maximum 5 years follow up). Demographics, CVD risk factors and the 10-year cardiovascular risk according to the SCORE and QRISK3 system were determined at baseline. Preclinical arthritis patients (n = 188) had a higher heart rate (68 vs 63 bpm, p = 0.048) and lower cholesterol (5.2 mmol/l vs 5.5, p = 0.006), HDL (1.0 mmol/l vs 1.1, p0.003) and ApoB (0.85 g/l vs 0.91, p = 0.011) compared to non-arthritis patients (n = 367). Lipid levels were associated with ACPA status in both the preclinical arthritis and non-arthritis group. Ten-year CVD risk scores did not differ between preclinical arthritis and non-arthritis patients, in total, 7% (SCORE) and 8% (QRISK3) of seropositive arthralgia patients were classified as high risk. Seropositive at-risk patients (n = 71) had higher total cholesterol (5.4 vs 4.9, p<0.001), TC/HDL ratio (4.0 vs 3.0, p<0.001), triglycerides (1.4 vs 1.0, p = 0.001), ApoB (1.0 vs 0.9, p = 0.019) and 10-year risk scores (median SCORE 1.0 vs 0.0, p = 0.030 and median QRISK3 4.4 vs 3.1, p<0.001) compared to seronegative controls. Our results suggest that lipid changes commence prior to RA diagnosis and that ACPAs might play a role.

Objectives Little is known about relevant events in the at-risk phase of rheumatoid arthritis before the development of clinically apparent inflammatory arthritis (IA). The present study assessed musculoskeletal symptoms, infections and comorbidity in future IA patients. Methods In a nested case–control study using electronic health records of general practitioners, the frequency and timing of 192 symptoms or diseases were evaluated before a diagnosis of IA, using the International Classification of Primary Care coding system. Cases were 2314 adults with a new diagnosis IA between 2012 and 2016; controls were matched 1:2. The frequency of primary care visits was compared using logistic regression. Results The frequency of visits for musculoskeletal symptoms (mostly of shoulders, wrists, fingers and knees) and carpal tunnel syndrome was significantly higher in IA patients vs controls within the final 1.5 years before diagnosis, with ORs of 3.2 (95% CI 2.8 to 3.5), 2.8 (95% CI 2.5 to 3.1) and 2.5 (95% CI 2.2 to 2.8) at 6, 12 and 18 months before diagnosis, respectively. Also, infections (notably of the genital and urinary tracts), IA-comorbidities and chronic diseases were more prevalent in cases than controls, but more evenly spread out over the whole 6-year period before IA. A decision tree was created including all symptoms and diseases. Conclusion There was an increased frequency of primary care visits for musculoskeletal symptoms, infections and comorbidities prior to the diagnosis of IA. This diverging trend is present for 4–6 years, but becomes statistically significant 1.5 years before the diagnosis. Validation of these results is warranted.

Background A phase characterised by the presence of specific autoantibodies and arthralgia’s in the absence of clinically evident synovial inflammation often precedes the onset of rheumatoid arthritis (RA). However, only a subset of these RA-risk individuals will develop active disease in the short term¹. Recent findings show that dominant B-cell receptor (BCR) clones in peripheral blood can accurately predict imminent onset of arthritis in these RA-risk individuals.² Objectives To validate the predictive role of BCR clones in peripheral blood in RA-risk individuals in a larger cohort. Methods The BCR repertoire in peripheral blood was analysed using next-generation BCR sequencing in a prospective cohort study of 129 RA-risk individuals from Reade. Like earlier, BCR clones expanded beyond 0.5% of the total repertoire were labelled highly expanded clones (HECs), shortly referred to as dominant BCR clones, and individuals were labelled BCR-positive if peripheral blood at study baseline showed ≥5 dominant BCR clones. Results We observed that the number of dominant BCR clones was increased in RA-risk individuals who developed arthritis within 3 years, compared to RA-risk individuals who did not 10.6±5.3 vs 2.2±2.8 (mean ±SD; pRA-risk individuals (data not shown). Conclusions In this external validation cohort we could replicate the fact that dominant BCR clones in peripheral blood predict imminent onset of clinical symptoms of RA in seropositive arthralgia patients with high accuracy. Furthermore, a highly significant association correlating a higher number of dominant BCR clones with higher risk was shown. We hope these results will support evaluation of early interventions that prevent onset of arthritis. References [1] Bos WH, et al. Ann. Rheum. Dis2010;69. [2] Tak PP, et al. Ann. Rheum. Dis2017;76. Acknowledgements Intellectual property PCT/EP2017/067047. N de Vries, PP Tak, ME Doorenspleet, PL Klarenbeek. ‘METHOD FOR DETERMINING THE RISK OF DEVELOPING ARTHRITIS’. Disclosure of Interest A. Musters: None declared, M. van Beers-Tas: None declared, M. Doorenspleet: None declared, P. Klarenbeek: None declared, B. van Schaik: None declared, A. van Kampen: None declared, F. Baas: None declared, D. van Schaardenburg: None declared, N. de Vries Grant/research support from: IMI (ABIRISK, BeTheCure), CTMM (TRACER), LSH (MODIRA), Pfizer, Roche, Janssen, GSK, Consultant for: UCB, MSD