Psychological and biological features influencing the risk for rheumatoid arthritis

The aim of this thesis was to study the at-risk phase of RA development, in a broad spectrum of at-risk populations, with a focus on symptomatology and biomarkers. In Part I, two systematic reviews cover risk factors, screening for and prevention of RA. In Part II, we focused on symptoms and concluded that: 1. Higher scores for depressive mood and lower scores for social support are not directly related with arthritis development, but they increase musculoskeletal symptoms already in the at-risk phase; 2. A newly designed Symptoms in Persons At Risk of Rheumatoid Arthritis (SPARRA) questionnaire can be used to explore symptoms in individuals at-risk for RA; and 3. Patients with inflammatory arthritis (IA), as compared to control patients, had more musculoskeletal symptoms, infections, IA-related diseases and chronic diseases before the IA diagnosis in a large primary care database. In Part III, a wide range of markers was investigated. Serum 14-3-3η (eta) levels and change of rheumatoid factor and anti-citrullinated protein antibodies over time did not predict arthritis development, whereas performing joint ultrasonography and measuring dominant B-cell receptor (BCR) clones in peripheral blood showed potential. Especially the presence of dominant BCR clones is highly predictive of arthritis development within 3 years

How does established rheumatoid arthritis develop, and are there possibilities for prevention?

Established rheumatoid arthritis (RA) is a chronic state with more or less joint damage and inflammation, which persists after a phase of early arthritis. Autoimmunity is the main determinant of persistence. Although the autoimmune response is already fully developed in the phase of early arthritis, targeted treatment within the first months produces better results than delayed treatment. Prevention of established RA currently depends on the success of remission-targeted treatment of early disease. Early recognition is aided by the new criteria for RA. Further improvement may be possible by even earlier recognition and treatment in the at-risk phase. This requires the improvement of prediction models and strategies, and more intervention studies. Such interventions should also be directed at modifiable risk factors such as smoking and obesity. The incidence of RA has declined for decades in parallel with the decrease of smoking rates; however, a recent increase has occurred that is associated with obesit

A prospective cohort study of 14-3-3 eta in ACPA and/or RF-positive patients with arthralgia

14-3-3η (eta) is a novel serum/plasma protein biomarker involved in the upregulation of inflammatory and joint damage factors. We analysed the association of 14-3-3η with the development of clinically apparent arthritis in a cohort of subjects with arthralgia and positivity for at least one serologic marker: rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA). Measurement of 14-3-3η in plasma collected on entry into the cohort. For this study, 144 subjects with a minimum of 2.5 (median and maximum 5) years of follow-up were available. The relationship between presence and levels of 14-3-3η and development of arthritis was investigated. Arthritis occurred in 43 (30 %) of the 144 subjects after a median of 15 months. 14-3-3η was detectable up to 5 years before onset of clinical arthritis and was present significantly more often (36 % versus 14 %; relative risk 2.5, 95 % confidence interval 1.2-5.6; p = 0.02) and at significantly higher levels (median 0.95 versus 0.28 ng/ml; p = 0.02) in subjects developing arthritis compared with those who did not. 14-3-3η levels/positivity and ACPA, but not RF, were univariately associated with the development of arthritis while generalized linear model analysis with RF and ACPA as obligatory factors could not return an incremental benefit with 14-3-3η. 14-3-3η was detectable prior to the onset of arthritis and was associated with arthritis development in arthralgia subjects pre-selected for positivity of RF or ACPA. Its power to predict onset of arthritis independent of ACPA and RF requires a new study in which patients are not pre-selected based on ACPA and/or RF seropositivit

Cardiovascular risk in persons at risk of developing rheumatoid arthritis

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: Our results suggest that lipid changes commence prior to RA diagnosis and that ACPAs might play a role

The value of joint ultrasonography in predicting arthritis in seropositive patients with arthralgia: A prospective cohort study

Background: The value of joint ultrasonography (US) in the prediction of clinical arthritis in individuals at risk of developing rheumatoid arthritis (RA) is still a point of debate, due to varying scanning protocols and different populations. We investigated whether US abnormalities assessed with a standard joint protocol can predict development of arthritis in seropositive patients with arthralgia. Methods: Anti-citrullinated protein antibodies and/or rheumatoid factor positive patients with arthralgia, but without clinical arthritis were included. US was performed at baseline in 16 joints: bilateral metacarpophalangeal 2-3, proximal interphalangeal 2-3, wrist and metatarsophalangeal (MTP) joints 2-3 and 5. Images were scored semi-quantitatively for synovial thickening and for positive signs on power Doppler (PD). Association between US abnormalities and arthritis development at the joint and at the patient level was evaluated. Also, we investigated the added value of US over clinical parameters. Results: Out of 163 patients who underwent US examination, 51 (31%) developed clinical arthritis after a median follow-up time of 12 (interquartile range 5-24) months, of which 44 (86%) satisfied the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria for RA. US revealed synovial thickening and PD in at least one joint in 49 patients (30%) and 7 patients (4%), respectively. Synovial thickening was associated with both development and timing of clinical arthritis in any joint (patient level) when MTP joints were excluded from the US assessment (odds ratio 6.6, confidence interval (CI) 1.9-22), and hazard ratio 3.4, CI 1.6-6.8, respectively, with a mean time to arthritis of 23 versus 45 months when synovial thickening was present versus not present). There was no association between US and arthritis development at the joint level. Predictive capacity was highest in the groups with an intermediate and high risk of developing arthritis based on a prediction rule with clinical parameters. Conclusions: Synovial thickening on US predicted clinical arthritis development at the patient level in seropositive patients with arthralgia when MTPs were excluded from the US assessment. Positive PD signs were infrequently seen in these at-risk individuals and was not predictive. In patients at intermediate risk of RA, US may help to identify those at higher risk of developing arthritis

Depressive mood and low social support are not associated with arthritis development in patients with seropositive arthralgia, although they predict increased musculoskeletal symptoms

Objective Studies on the role of psychosocial vulnerability in the development of arthritis must be performed early in the disease course to exclude the reverse explanation that arthritis leads to psychological symptoms. Therefore, the objective of this study was to investigate the longitudinal (5-year) association between depressive mood, daily stressors, avoidance coping and social support as predictors, and the development of arthritis and other clinical parameters as outcomes, in persons with seropositive arthralgia at risk of developing rheumatoid arthritis. Methods Five-year follow-up data of 231 patients from the Reade seropositive arthralgia cohort were used. Clinical and psychological data were collected using physical examinations and questionnaires. Mixed models and Cox regression analyses were used to assess the 5-year associations between depressive mood, daily stressors, avoidance coping or social support, and the development of arthritis or clinical parameters (tender joint count, Visual Analogue Scale (VAS) pain, VAS morning stiffness and erythrocyte sedimentation rate (ESR)). Results Higher scores for depressive mood and lower scores for social support were not associated with the development of arthritis nor with ESR. However, they were longitudinally associated with an increase in pain (p<0.001), morning stiffness (p<0.01) and tender joint count (p<0.001). No consistent associations were found between daily stressors, avoidance coping and the development of arthritis or other clinical parameters. Conclusion Although an effect on the development of arthritis could not be demonstrated, a strong longitudinal association was found between high depressive mood, low social support and clinical parameters. In persons with seropositive arthralgia, depressive symptoms and low social support may increase musculoskeletal symptoms

Dominant B cell receptor clones in peripheral blood predict onset of arthritis in individuals at risk for rheumatoid arthritis

The onset of seropositive rheumatoid arthritis (RA) is preceded by the presence of specific autoantibodies in the absence of synovial inflammation. Only a subset of these at-risk individuals will develop clinical disease. This impedes efforts to implement early interventions that may prevent onset of clinically manifest disease. Here we analyse whether clonal changes in the B cell receptor (BCR) repertoire can reliably predict onset of signs and symptoms. In a prospective cohort study in 21 individuals at risk for RA based on the presence of autoantibodies, the BCR repertoire of paired peripheral blood and synovial tissue samples was analysed using next-generation BCR sequencing. BCR clones that were expanded beyond 0.5% of the total repertoire were labelled dominant. The relative risk (RR) for onset of arthritis was assessed using the presence of ≥5 dominant BCR clones as cut-off. Findings in peripheral blood were validated in an independent prospective cohort of 50 at-risk individuals. Based on the test cohort, individuals in the validation cohort were considered positive if peripheral blood at study entry showed ≥5 dominant BCR clones. Both in the test and validation cohort, the presence of ≥5 dominant BCR clones in peripheral blood was significantly associated with arthritis development after follow-up (validation cohort RR 6.3, 95% CI 2.7 to 15, p <1×10(-4)). Even when adjusted for a recently described clinical prediction rule the association remained intact (RR 5.0, 95% CI 1.2 to 20, p=0.024). When individuals developed arthritis, dominant BCR clones disappeared from peripheral blood and appeared in synovial tissue, suggesting a direct role of these clones in disease pathogenesis. Dominant BCR clones in peripheral blood predict onset of clinical signs and symptoms of RA in at-risk individuals with high accuracy. Our data suggest that during onset of RA these clones shift from peripheral blood to the target tissu