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Objectives ACPA-positive and ACPA-negative RA differ in underlying risk factors but have a similar clinical presentation at RA diagnosis. It is unknown what the ACPA-associated differences or similarities are during the symptomatic at-risk stage of RA, i.e. clinically suspect arthralgia (CSA). To deepen insights into these differences/similarities, we compared the course of symptoms/impairments and subclinical joint inflammation in the CSA phase during progression to inflammatory arthritis (IA) or to CSA resolution. Methods A total of 845 CSA patients were followed for a median of 24 months; 136 patients developed IA and an additional 355/505 patients had resolution of CSA according to rheumatologists. Patient burden (pain, morning stiffness, fatigue, functional disabilities, presenteeism) was assessed at baseline and 4, 12 and 24 months and at IA development. Subclinical joint inflammation in the hands and feet was assessed over time with 1.5T MRI. Linear and Poisson mixed models were used. Results In both ACPA-positive and ACPA-negative patients, patient burden increased towards IA development and decreased towards CSA resolution. However, patient burden was lower in ACPA-positive vs ACPA-negative disease at all timepoints. Conversely, subclinical joint inflammation tended to increase more rapidly during development of ACPA-positive IA [incidence rate ratio (IRR) 1.52 (95% CI 0.94, 2.47), P  = 0.089] and remained higher over time in ACPA-positive CSA patients achieving resolution compared with ACPA-negative patients [IRR 1.52 (95% CI 1.07, 2.15), P  = 0.018]. Although correlation coefficients between changes in patient burden and subclinical joint inflammation during progression to IA were weak, they were consistently higher in ACPA-positive than ACPA-negative disease, e.g. ρ = 0.29 vs 0.12 for functional disabilities. Conclusion During RA development and CSA resolution, ACPA-positive CSA patients have lower patient burden but more subclinical joint inflammation than ACPA-negative CSA patients. These data strengthen the notion that the development of ACPA-positive and ACPA-negative RA is pathophysiologically different and encourage further research on these differences. [ABSTRACT FROM AUTHOR]

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Abstract Background Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these “at-risk” stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA. Methods Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables. Results Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, “mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations.” In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P

Background: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA. Methods: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables. Results: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs. Conclusions: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages. Key messages: The development of RA is often preceded by symptomatic phases in which patients do not yet fulfil classification criteria for RA. This study confirms a significant negative impact of symptoms on patient functioning and health-related quality of life in those newly presenting with clinically suspect arthralgia, unclassified arthritis, and RA. Patient burden was associated with measures of disease activity and patient characteristics, and was comparable to serious conditions such as angina, chronic obstructive pulmonary disease and heart failure. Further studies are needed to establish if patients in symptomatic at risk of RA phases may benefit from pharmacological and non-pharmacological interventions to reduce symptom impact and improve quality of life. [ABSTRACT FROM AUTHOR]

Depuis une dizaine d'années, les perspectives des patients atteints de polyarthrite rhumatoïde se sont grandement améliorées, en particulier en cas de positivité des auto-anticorps. Pour optimiser l'évolution de la maladie sur le long terme, la communauté cherche à établir si « le plus tôt est bien le mieux » et s'il serait efficace d'instaurer un traitement dans la phase préarthrite de la polyarthrite rhumatoïde. Cette revue évalue le concept de prévention et examine la probabilité prétest de développer une PR pour différents niveaux de risque. Ces niveaux de risque influencent la probabilité post-test des biomarqueurs utilisés et, par conséquent, la précision avec laquelle le risque de polyarthrite rhumatoïde peut être estimé. En outre, de par leur effet sur la précision de la stratification du risque, ces probabilités prétest sont également associées à la probabilité de résultats faux négatifs (ce que Feinstein a qualifié de « tragédie clinico-statistique »). Les critères employés pour évaluer les effets préventifs sont liés soit à l'apparition effective de la maladie, soit à la sévérité des facteurs de risque de développement d'une polyarthrite rhumatoïde. Les résultats d'études de prévention achevées récemment sont discutés à la lumière de ces considérations théoriques. Ils sont variables et n'ont pas permis de démontrer une prévention claire de la polyarthrite rhumatoïde. Certains traitements (p. ex. méthotrexate) ont systématiquement réduit la sévérité des symptômes, le handicap physique et la sévérité de l'inflammation articulaire visible à l'imagerie, tandis que d'autres (hydroxychloroquine, rituximab, atorvastatine) n'ont pas entraîné d'effets durables. La revue propose en conclusion des perspectives concernant la conception de nouvelles études de prévention, ainsi que des éléments et des impératifs à prendre en considération pour qu'il soit possible d'exploiter les résultats dans la pratique clinique des cabinets de rhumatologie recevant des personnes à risque de polyarthrite rhumatoïde. During the last decade, the outlook for patients with rheumatoid arthritis (RA) has improved greatly, especially for patients with autoantibody-positive RA. To further improve long-term disease outcomes, the field has turned to investigating the efficacy of treatment initiated in the pre-arthritic phase of RA, based on the adage "the sooner the better." In this review, the concept of prevention is evaluated and different risk stages are being examined for their pre-test risks of RA development. These risks affect the post-test risk of biomarkers used at these stages and, consequently, the accuracy with which the risk of RA can be estimated. Furthermore, through their effect on accurate risk stratification, these pre-test risks ultimately also associate with the likelihood of false-negative trial results (the so-called 'clinicostatistical tragedy'). Outcome measures to assess preventive effects are evaluated and relate to either the occurrence of disease itself or to the severity of risk factors for RA development. Results of recently completed prevention studies are discussed in the light of these theoretical considerations. The results vary, but clear prevention of RA has not been demonstrated. While some treatments (e.g. methotrexate) persistently reduced symptom severity, physical disability, and the severity of imaging joint inflammation, other treatments were not reported to produce long-lasting effects (hydroxychloroquine, rituximab, atorvastatin). The review concludes with future perspectives regarding the design of new prevention studies and considerations and requirements before findings can be implemented in daily practice in individuals at risk of RA attending rheumatology practices. [ABSTRACT FROM AUTHOR]

Objectives Autoantibody responses increase years before the onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels also increase years before IA onset. However, the course in the at-risk stage of CSA during progression to disease or non-progression is unknown. To increase the understanding of processes mediating disease development, we studied the course of cytokine, chemokine and related receptors gene expression in CSA patients during progression to IA and in CSA patients who ultimately did not develop IA. Methods Whole-blood RNA expression of 37 inflammatory cytokines, chemokines and related receptors was determined by dual-colour reverse transcription multiplex ligation-dependent probe amplification in paired samples of CSA patients at CSA onset and either at IA development or after 24 months without IA development. ACPA-positive and ACPA-negative CSA patients developing IA were compared at CSA onset and during progression to IA. Generalised estimating equations tested changes over time. A false discovery rate approach was applied. Results None of the cytokine/chemokine genes significantly changed in expression between CSA onset and IA development. In CSA patients without IA development, G-CSF expression decreased (P  = 0.001), whereas CCR6 and TNIP1 expression increased (P  < 0.001 and P  = 0.002, respectively) over a 2 year period. Expression levels in ACPA-positive and ACPA-negative CSA patients who developed IA were similar. Conclusion Whole-blood gene expression of assessed cytokines, chemokines and related receptors did not change significantly from CSA to IA development. This suggests that changes in expression of these molecules may not be related to the final process of developing chronicity and may have occurred preceding CSA onset. Changes in gene expression in CSA patients without IA development may provide clues for processes related to resolution. [ABSTRACT FROM AUTHOR]

Objectives Cross-sectional studies have shown that rheumatoid arthritis is more prevalent among people with a lower educational attainment. No longitudinal data are present on educational attainment in the at-risk phase of clinically suspect arthralgia (CSA). We therefore analysed the association between educational attainment and progression from CSA to inflammatory arthritis (IA), and performed mediation analysis with subclinical joint inflammation to elucidate pathways of this association. Methods A total of 521 consecutive patients presenting with CSA were followed for IA development during median 25 months. Educational attainment was defined as low (lower secondary vocational education), intermediate or high (college/university education). Subclinical inflammation in hand and foot joints was measured at presentation with contrast enhanced 1.5 T-MRI. Cox-regression was used to analyse IA development per educational attainment. A three-step mediation analysis evaluated whether subclinical joint inflammation was intermediary in the path between educational attainment and IA development, before and after age correction. Association between educational attainment and IA development was verified in an independent CSA cohort. Results Low educational attainment was associated with increased IA development (HR = 2.35, 95% CI = 1.27, 4.33, P  = 0.006), independent of BMI and current smoking status (yes/no). Moreover, patients with a low educational attainment had higher levels of subclinical inflammation, which also was associated with IA development. Partial mediation effect of subclinical inflammation was observed in the relationship between education and IA development. Low educational attainment was also associated with increased IA development in the validation cohort (HR = 5.72, 95% CI = 1.36, 24.08, P  = 0.017). Conclusion This is the first study providing evidence that lower educational attainment is associated with a higher risk of progressing from arthralgia to IA. This effect was partially mediated by subclinical joint inflammation. [ABSTRACT FROM AUTHOR]

• Illness perceptions (IP) of patients at risk of RA (i.e. CSA) are largely unknown. • Patients at CSA-presentation and RA-diagnosis have equally severe IP. • IP on physical consequences and treatment-expectations varied between populations. • CSA-patients considered physical workload and genetics important causes of symptoms. • Insight into IP could enhance communication and care in patients at risk of RA. Clinically suspect arthralgia (CSA) is an at-risk stage of rheumatoid arthritis (RA), in which patients experience symptoms and physical limitations. Perceptions of CSA-patients have remained largely unknown. Therefore, we aimed to map perceptions of CSA-patients and compare these to RA-patients. Additionally, we studied changes in perceptions in CSA over time. Three hundred and ninety-nine consecutively included CSA-patients from the Leiden and Rotterdam CSA-cohorts and 100 recently diagnosed RA-patients from the Leiden Early Arthritis Clinic were included. Patients' illness perceptions (IP) were assessed using the Brief Illness Perception Questionnaire (BIPQ), consisting of 8 questions (scale 0–10; higher score indicating more negative IP) covering cognitive, emotional and comprehensibility domains, and one open question about causes of disease. IP were measured at baseline in both populations and during 2 years follow-up in the CSA-cohorts. Total BIPQ-scores were comparable at CSA-presentation and RA-diagnosis (40 ± 11 and 40 ± 10; range 0–80). Comparing dimensions separately revealed that CSA-patients were less worried about physical complaints compared to RA-patients. However, CSA-patients were more negative about expected treatment-effect on symptoms. IP over time in CSA improved in patients without development of clinical arthritis (from 38 ± 11 to 34 ± 14; P = 0.005) but remained similar in CSA-patients who progressed to arthritis/RA (mean 40 at both timepoints). CSA-patients mainly perceived physical strain and heredity as causes of their complaints. Although CSA-patients have not developed clinical arthritis, illness perceptions at CSA-presentation and RA-diagnosis are equally severe. Knowledge on worries and expectations may contribute to improving patient-contact and care in patients at risk of RA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic immuno-inflammatory disease whose outcomes can vary greatly from one patient to another. One of the main prognostic factors is the presence of serum autoantibodies, such as rheumatoid factor (RF) and anti-citrullinated peptide antibodies (ACPA). Indeed, when seropositive, patients with RA are at higher risk of radiographic progression, disability, and increased mortality. Moreover, while the introduction of the 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR) classification criteria has allowed for an earlier diagnosis, studies on large early arthritis cohorts have also shown that these criteria are less capable of identifying seronegative patients, who are therefore at a higher risk of being diagnosed and treated late. In light of these, the major randomized controlled trials have mostly enrolled patients with autoantibody-positive disease. However, in recent years, it became evident that the two serotypes of RA differ significantly from many points of view. Alongside this, a greater understanding of the disease pathogenesis, particularly the presence of antibodies in patients' serum even before the onset of arthritis, has generated significant interest in exploring whether the disease could be prevented by treating patients in the pre-arthritis phases. Once again, emerging trials predominantly enroll subjects positive for RA autoantibodies, potentially overlooking seronegative individuals with arthralgia-at-risk., (© 2024. The Author(s).)

Abstract Objective To determine the usefulness of power Doppler (PD) ultrasound (US) to predict rheumatoid arthritis (RA) development in patients with clinically suspect arthralgia (CSA). Methods Retrospective analysis of a US unit cohort over a 1-year period. Patients with CSA and no previous diagnosis of inflammatory arthritis (IA) were included for analysis. All underwent bilateral US examination of the hands and/or feet according to the EULAR guidelines. Active US inflammation was defined as PD synovitis and/or tenosynovitis ≥1 at any location. RA diagnosis according to clinician criteria 6 months after the US examination was checked. Univariate and multivariate logistic regression models were employed to investigate possible predictive factors of RA development. Results A total of 110 CSA patients (80 females, mean age 53.6 years) were included for analysis. After 6 months of follow-up, 14 (12.7%) developed RA and 34 (30.9%) IA. US active inflammation was present in 38 (34.5%) patients (28.2% showed PD synovitis and 18.2% PD tenosynovitis). Multivariate analysis showed that ACPA (OR 1.0003; 95% CI 1.002–1.006) and ESR (OR 1.054; 95% CI 1.016–1.094) were significantly associated with the detection of US active inflammation at baseline. Only PD tenosynovitis was found to be an independent predictive factor of an evolution towards RA (OR 6.982; 95% CI 1.106–44.057) and IA (OR 5.360; 95% CI 1.012–28.390). Conclusion US is able to detect features of subclinical inflammation in CSA patients, especially in those with higher ESR and ACPA values. Only PD tenosynovitis at baseline US assessment was found to be an independent predictor of RA and IA development in CSA patients.

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.

Background. There is a time sensitive window of opportunity in rheumatoid arthritis (RA) in which therapeutic intervention is more effective, the disease being more susceptible to the immunomodulatory effects of the remissive medication. The goal is to prevent osteo-articular damage, which causes severe functional deficit, and to raise the chance to lead the disease in remission. Evolution towards RA represents a multi-step process. In other medical fields prevention has the same important role as treatment, so could we in the future switch again the therapeutic paradigm in RA, from early treatment to prevention of RA, by treating patients with high risk of developing disease? Initiating treatment in the pre-RA phases could potentially lead to a better immune modulation or even preventing disease development by acting on less mature pathogenic processes. Treating in the initial symptomatic phase of the disease could potentially be more effective in reducing disease persistence and the development of structural lesions. The clinically suspect arthralgia (CSA) definition offers a support of clinical parameters for future longitudinal studies, where together with para clinical parameters, laboratory studies and imagistic studies, could lead to the development of imminent RA classification criteria. Currently there are more ongoing studies that have the primary objective to prove this concept with different subpopulations and treatments, but most of them have inclusion criteria based on the presence of autoantibodies. The publication of this trials results in the next decade will help to better understand the efficacy of therapeutic intervention with the scope of preventing chronic arthritis and what subset of patients at risk to treat. There are no recommendations for management of CSA, but current practice is symptomatic treatment with nonsteroidal anti-inflammatory drugs, pain relievers and of course monitoring.

Abstract Background Established rheumatoid arthritis (RA) patients display differentially expressed genes coding for cytokine/chemokine-mediated immunity compared to healthy controls. It is unclear, however, if in the pre-arthritis phase of clinically suspect arthralgia (CSA) expression of immune genes differ between patients who do or do not develop clinically evident inflammatory arthritis (IA). Methods Two hundred thirty-six consecutive patients presenting with arthralgia clinically suspected for progression to RA were followed until IA development or else for median 24 months (IQR 12–26). Baseline whole blood RNA expression was determined for a previously identified set of 133 genes associated with the innate and adaptive immune system by dual-color reverse-transcription multiplex ligation-dependent probe amplification (dcRT-MLPA) profiling. Cox proportional hazard models were used. Results Twenty percent of CSA patients developed IA. After correction for multiple testing, expression levels of six genes (IFNG, PHEX, IGF-1, IL-7R, CD19, CCR7) at the time of presentation were associated with progression to IA. PHEX and IGF-1 were highly correlated with each other (ρ = 0.97). In multivariable analysis correcting for the different genes, expressions of IL-7R and IGF-1 were independently associated with IA development (p = 0.025, p = 0.046, respectively). Moreover, IL-7R and IGF-1 remained significantly associated even after correction for known predictors (ACPA, CRP, imaging-detected subclinical joint inflammation; p = 0.039, p = 0.005, respectively). These genes are also associated with RA development. Conclusions IL-7R and IGF-1 were differentially expressed between CSA patients who did or did not progress to IA, independent from regularly used predictors. These biomarkers may become helpful in prognostication of CSA patients. Furthermore, because both genes are associated with T cell functioning, T cell dysregulation may mediate progression from arthralgia to arthritis.

Abstract Background We present a study protocol for a randomized, double-blind, placebo-controlled trial that investigates the hypothesis if intervention in the symptomatic phase preceding clinical arthritis (clinically suspect arthralgia (CSA)) is effective in preventing progression from subclinical inflammation to clinically apparent persistent arthritis. Currently, rheumatoid arthritis (RA) can be recognized and diagnosed when arthritis (joint swelling) has become detectable at physical examination. Importantly, at this time, the immune processes have already matured, chronicity is established, and patients require long-standing treatment with disease-modifying anti-rheumatic drugs. The TREAT EARLIER trial studies the hypothesis that intervention in the symptomatic phase preceding clinical arthritis is more often successful in permanent disease modification because of less matured underlying disease processes. Methods A two-level definition to identify patients that are prone to develop RA is used. First, patients should have CSA and recent-onset arthralgia (

Background. There is a time sensitive window of opportunity in rheumatoid arthritis (RA) in which therapeutic intervention is more effective, the disease being more susceptible to the immunomodulatory effects of the remissive medication. The goal is to prevent osteo-articular damage, which causes severe functional deficit, and to raise the chance to lead the disease in remission. Evolution towards RA represents a multi-step process. In other medical fields prevention has the same important role as treatment, so could we in the future switch again the therapeutic paradigm in RA, from early treatment to prevention of RA, by treating patients with high risk of developing disease? Initiating treatment in the pre-RA phases could potentially lead to a better immune modulation or even preventing disease development by acting on less mature pathogenic processes. Treating in the initial symptomatic phase of the disease could potentially be more effective in reducing disease persistence and the development of structural lesions. The clinically suspect arthralgia (CSA) definition offers a support of clinical parameters for future longitudinal studies, where together with para clinical parameters, laboratory studies and imagistic studies, could lead to the development of imminent RA classification criteria. Currently there are more ongoing studies that have the primary objective to prove this concept with different subpopulations and treatments, but most of them have inclusion criteria based on the presence of autoantibodies. The publication of this trials results in the next decade will help to better understand the efficacy of therapeutic intervention with the scope of preventing chronic arthritis and what subset of patients at risk to treat. There are no recommendations for management of CSA, but current practice is symptomatic treatment with nonsteroidal anti-inflammatory drugs, pain relievers and of course monitoring. [ABSTRACT FROM AUTHOR]

Objective: Patients with Clinically Suspect Arthralgia (CSA) are at risk for developing Rheumatoid Arthritis (RA). These patients often report joint swelling while this is not objectified by physical examination. To explore the value of patient-reported swelling in CSA, we aimed to determine its association with subclinical joint-inflammation on imaging and RA-development., Methods: In two independent, similarly designed CSA-cohorts from the Netherlands, symptomatic patients at risk for RA were studied. At baseline, patients indicated whether they had experienced swelling in hand joints. Subclinical joint-inflammation was assessed with MRI or ultrasound (US). Patients were followed for inflammatory arthritis development., Results: In total, 534 CSA-patients from two independent cohorts were studied, patient-reported swelling was present in 57% in cohort 1, and in 43% in cohort 2. In both cohorts patient-reported swelling was associated with subclinical joint-inflammation. Using MRI, it associated specifically with tenosynovitis (OR 3.7 (95%CI 2.0-6.9)) and when using US with synovitis (OR 2.3 (95%CI 1.04-5.3)). CSA-patients with self-reported swelling at baseline developed arthritis more often, with hazard ratios of 3.7 (95%CI 2.0-6.9) and 3.4 (95%CI 1.4-8.4) in cohort 1 and 2, respectively. This was independent of clinical predictors (e.g. morning stiffness), autoantibody-positivity and US-detected subclinical joint-inflammation. However, when corrected for MRI-detected subclinical joint-inflammation, self-reported swelling was no longer an independent predictor., Conclusion: Patient-reported joint swelling in CSA relates to subclinical joint-inflammation and is an independent risk factor for RA-development, but it is less predictive than the presence of MRI-detected subclinical joint-inflammation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objective:Obesity is a moderate low-grade chronic inflammatory condition. The cause of low-grade inflammation in obese patients who have clinically suspect arthralgia (CSA) may be the subject of debate in clinical practice. Our aim is to determine whether inflammation is associated with obesity or rheumatic disease, and the association between leptin, chemerin, visfatin and inflammatory markers in obese patients with/without musculoskeletal symptoms. Methods: Seventy-four obese patients who admitted to our rheumatology clinic with CSA were enrolled. The control group consisted of 40 obese patients who have no rheumatic symptoms. Body mass index (BMI) was calculated in kg/m2 with body weight ratio to height squared, and obesity was defined as BMI 30 or above. Age, gender, BMI, waist and hip circumferences, waist-to-hip ratio (WHR), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), leptin, chemerin, and visfatin were eva - luated. The relationship between all parameters was assessed by Spearman correlation, Wilcoxon Signed- -rank, and paired t-tests. Results: There were no significant differences for age, gender, ESR and CRP between obese patients with CSA and control group. The mean TNF-α, IL-1β, IL-6 concentrations were 60.8 pg/mL, 39.9 pg/ml, and 26.2% in obese patients with CSA, respectively. ESR, CRP, TNF-α, IL-6, and IL-1β concentrations were higher in these patients compared to obese patients without any rheumatic symptoms. The mean WHR and waist circumference were 0.8±0.1 and 107.1±13.4 cm, respectively in patients with CSA. IL-6 correlated with WHR and waist circumference, positively. There were signi - ficant differences for adipokines such as chemerin, visfatin, but not for leptin between both group. Moreover, a significant correlation was found between pro-inflammatory cytokines and visfatin, chemerin. Conclusion: Visfatin and chemerin correlated with inflammation and may be useful indicators of undiffe - rentiated inflammatory arthritis in obese patients with CSA. [ABSTRACT FROM AUTHOR]

• Currently available secondary prevention studies of RA have shown mixed results, but no consistent evidence of prevention. • Accurate stratification of RA-risk at trial inclusion reduces the likelihood of false negative trial results. • Most trials used RA-development as primary endpoint of prevention; reduction of risk factors/risk stages are alternatives. During the last decade, the outlook for patients with rheumatoid arthritis (RA) has improved greatly, especially for patients with autoantibody-positive RA. To further improve long-term disease outcomes, the field has turned to investigating the efficacy of treatment initiated in the pre-arthritic phase of RA, based on the adage "the sooner the better." In this review, the concept of prevention is evaluated and different risk stages are being examined for their pre-test risks of RA development. These risks affect the post-test risk of biomarkers used at these stages and, consequently, the accuracy with which the risk of RA can be estimated. Furthermore, through their effect on accurate risk stratification, these pre-test risks ultimately also associate with the likelihood of false-negative trial results (the so-called "clinicostatistical tragedy"). Outcome measures to assess preventive effects are evaluated and relate to either the occurrence of disease itself or to the severity of risk factors for RA development. Results of recently completed prevention studies are discussed in the light of these theoretical considerations. The results vary, but clear prevention of RA has not been demonstrated. While some treatments (e.g. methotrexate) persistently reduced symptom severity, physical disability, and the severity of imaging joint inflammation, other treatments were not reported to produce long-lasting effects (hydroxychloroquine, rituximab, atorvastatin). The review concludes with future perspectives regarding the design of new prevention studies and considerations and requirements before findings can be implemented in daily practice in individuals at risk of RA attending rheumatology practices. [ABSTRACT FROM AUTHOR]

The rheumatology field is moving towards identifying individuals with an increased risk for rheumatoid arthritis (RA) at a stage when arthritis is still absent but persons having clinically suspect arthralgia (CSA). Incorporating patients' views in rheumatologic care is pivotal; however, the views of persons with CSA on their condition are unknown. We aimed to help fill this gap by exploring illness perceptions of persons with CSA and their views on hypothetical prognoses for developing RA. Persons with CSA were invited to participate in a semi-structured focus group discussion. Illness perceptions according to the Common Sense Model (CSM) and four a priori formulated themes were explored in detail during the group discussion. The discussion was audio-taped and transcribed verbatim. Transcripts were analysed in an interpretative phenomenological approach manner, on the basis of the dimensions of the CSM by three researchers independently. The views of four participants with CSA were explored during one focus group discussion. Four dimensions of the CSM were mainly observed: Identity, Consequences, Personal Control and Concern. None of the patients identified themselves as being a patient. They did experience pain and impairments in daily functioning and were concerned that their symptoms would progress. In the absence of physician-initiated treatment, some patients changed lifestyle in order to reduce pain and to promote health. Patients unanimously said that they could not interpret prognostic information on RA development expressed in hypothetical chances. Persons with CSA do not consider themselves patients. Prognostic information related to the development of RA based on risk percentages was considered as not useful by persons with CSA. Understanding of the illness perceptions of persons with CSA by health care professionals might improve medical management and facilitate shared decision-making. [ABSTRACT FROM AUTHOR]

Objective: Fatigue is a prominent and disabling symptom in patients with rheumatoid arthritis (RA), that is only partially explained by inflammation and responds poorly to DMARD-therapy. We hypothesized that inflammation explains fatigue to a larger extent in the phase of clinically suspect arthralgia (CSA), when persistent clinical arthritis is still absent and fatigue has not yet become chronic. We therefore studied the course of fatigue in CSA during progression to RA and the association with inflammation at CSA-onset and at RA-diagnosis.Methods: 600 consecutive CSA-patients were followed for RA-development. Additionally, 710 early RA-patients were studied at diagnosis. Fatigue was assessed every study visit and expressed on a 0-100 scale. Inflammation was measured with the DAS44-CRP, with and without including subclinical inflammation. The course of fatigue over time was studied with linear mixed models. Associations between fatigue and inflammation were studied with linear regression. Analyses were stratified by ACPA-status.Results: In 88 CSA-patients who developed RA, pre-arthritis fatigue-levels increased gradually with 7 points/year, towards 48 (95%CI=41-55) at RA-development (P=ns). Fatigue decreased in CSA-patients who did not develop RA (4 points/year, P<0.001). At CSA-onset, inflammation was associated with fatigue (β=18, meaning 18 points more fatigue per point increase DAS-score, P<0.01). This association was stronger than at RA-diagnosis (β=5, P<0.001). Fatigue-levels were lower in ACPA-positive pre-RA, but its association with inflammation was stronger compared to ACPA-negative pre-RA.Conclusion: Fatigue increased gradually during progression from arthralgia to clinical arthritis, and fatigue was better explained by inflammation in CSA than in RA. This implies a 'phase-dependent relation' between inflammation and fatigue. [ABSTRACT FROM AUTHOR]

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.)

Rheumatoid arthritis (RA) is a chronic autoimmune disease considered as a multistep process spanning from the interaction of genetic (e.g., shared epitope or non-HLA loci), environmental and behavioral risk factors (e.g., smoking) leading to breaking immune tolerance and autoimmune processes such as the production of autoantibodies (e.g., antibodies against citrullinated proteins ACPA or rheumatoid factors, RF), development of the first symptoms without clinical arthritis, and, finally, the manifestation of arthritis. Despite the typical joint involvement in established RA, the pathogenesis of the disease likely begins far from joint structures: in the lungs or periodontium in association with citrullination, intestinal microbiome, or adipose tissue, which supports normal findings in synovial tissue in ACPA+ patients with arthralgia. The presence of ACPA is detectable even years before the first manifestation of RA. The pre-clinical phase of RA is the period preceding clinically apparent RA with ACPA contributing to the symptoms without subclinical inflammation. While the combination of ACPA and RF increases the risk of progression to RA by up to 10 times, increasing numbers of novel autoantibodies are to be investigated to contribute to the increased risk and pathogenesis of RA. With growing knowledge about the course of RA, new aspiration emerges to cure and even prevent RA, shifting the "window of opportunity" to the pre-clinical phases of RA. The clinical definition of individuals at risk of developing RA (clinically suspect arthralgia, CSA) makes it possible to unify these at-risk individuals' clinical characteristics for "preventive" treatment in ongoing clinical trials using mostly biological or conventional synthetic disease-modifying drugs. However, the combination of symptoms, laboratory, and imaging biomarkers may be the best approach to select the correct target at-risk population. The current review aims to explore different phases of RA and discuss the potential of (non)pharmacological intervention aiming to prevent RA. • Rheumatoid arthritis (RA) is considered a multistep disease. • The interaction of environmental and genetic factors leads to a break of immune tolerance and autoantibodies production. • Anti-citrullinated protein antibodies (ACPA) mediated arthralgia may precede joint inflammation. • The presence of autoantibodies, symptoms, and US/MRI-detected subclinical inflammation may predict RA manifestation. • (Non)pharmacological interventions emerge to cure and even prevent RA, shifting the "window of opportunity" to the pre-RA. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is an autoimmune disease characterized by joint inflammation, which affects approximately 1% of the population. The benefit of early recognition and treatment has led to an increased interest in the early phases of disease. With the aim of classifying patients earlier in their disease course, new RA classification criteria have been developed. Much attention has been devoted to the identification in the prearthritis phase of arthralgia. The discovery of new risk factors and autoantibodies has led to new theories about the putative mechanisms involved in disease development. Finally, the outcome measures have also evolved, with more emphasis on sustained drug-free remission and patient-reported outcomes. This article reviews the new developments in RA research and discusses the latest insights into epidemiology, risk factors, predisease states, and outcomes., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

An increasing interest in treating individuals at risk of rheumatoid arthritis (RA) to prevent the development of this chronic condition has focussed attention on the identification of risk factors of this disease. Most patients who develop RA progress through a preceding symptomatic phase that may take the form of arthralgia, palindromic rheumatism or unclassified arthritis before a disease currently classifiable as RA is established. An understanding of symptoms that identify individuals as being at risk of RA is a critical issue. Constellations of relevant symptoms could (1) form the basis of public health campaigns to encourage rapid consultation, (2) inform primary health care providers regarding which patients to perform additional tests in or whom to refer to a rheumatologist and (3) be included in algorithms to predict RA development. In this review, we present qualitative and quantitative data summarising current understanding of the symptoms experienced by individuals at risk of RA., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)