Work-related physical strain and development of joint inflammation in the trajectory of emerging inflammatory and rheumatoid arthritis: a prospective cohort study.

OBJECTIVES: Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently understood. We hypothesised that mechanical stress/physical strain is a risk factor for joint inflammation in RA. Therefore, we studied work-related physical strain in subjects with clinically suspected arthralgia (CSA) as a risk factor for the presence of imaging-detected subclinical joint inflammation and the development of clinical arthritis/RA. METHODS: In 501 CSA patients and 155 symptom-free persons' occupation-related physical strain was quantified using the International Standard Classification of Occupations. Contrast-enhanced hand-MRIs were made and evaluated for joint inflammation (sum of synovitis/tenosynovitis/osteitis). CSA patients were followed on RA development. Age relationship was studied using an interaction term of physical strain with age. RESULTS: The degree of physical strain in CSA is associated with the severity of joint inflammation, independent of educational-level/BMI/smoking (interaction physical strain-age p=0.007; indicating a stronger association with increasing age). Physical strain is associated with higher tenosynovitis scores, in particular. In symptom-free persons, physical strain was not associated with imaging-detected joint inflammation. Higher degrees of physical strain also associated with higher risks for RA development in an age-dependent manner (HR=1.20 (1.06-1.37)/10-year increase in age), independent of educational-level/BMI/smoking. This association was partly mediated by an effect via subclinical joint inflammation. CONCLUSIONS: Work-related physical strain increases the risk of subclinical joint inflammation and of developing RA. The age relationship suggests an effect of long-term stress or that tenosynovium is more sensitive to stress at older age. Together, the data indicate that mechanical stress contributes to the development of arthritis in RA.

When does obesity exert its effect in conferring risk of developing RA: a large study in cohorts of symptomatic persons at risk.

OBJECTIVES: Obesity is a known risk factor for developing rheumatoid arthritis (RA). However, it is unclear whether obesity exerts its risk effect during the asymptomatic or the symptomatic clinically suspect arthralgia (CSA) phase of risk. To improve understanding of the effect of obesity on RA development, we aimed to (1) compare body mass index (BMI) at CSA onset to BMI of the general population and (2) study within CSA patients if obesity increases the risk for progression to RA. METHODS: 1107 symptomatic persons at risk for RA from four cohorts (CSA Leiden, CSA Rotterdam, SONAR and TREAT EARLIER placebo arm) were studied. For the first aim, baseline BMI was compared with age-matched/sex-matched BMI of the general population. Patients were stratified for anticitrullinated protein antibody (ACPA) status. Regarding the second aim, the association between BMI and inflammatory arthritis (IA) development during 2 years was studied with Cox regression analysis within each cohort and via meta-analysis in all cohorts. RESULTS: CSA patients of all cohorts were more often obese than the general population (respectively 21.9% vs 14.0%, 25.7% vs 14.5%, 26.7% vs 14.5% and 33.3% vs 14.9%, in CSA Leiden, CSA Rotterdam, SONAR, TREAT EARLIER placebo arm). Both ACPA-positive and ACPA-negative CSA patients had a higher frequency of obesity. Within CSA, obesity was not associated with IA development compared to normal weight (pooled effect in meta-analysis of four cohorts HR 1.01 (95% CI 0.93 to 1.08)). CONCLUSIONS: Obesity is not associated with RA development within CSA patients but BMI has already increased in CSA compared to the general population. Obesity, therefore, presumably exerts its risk effect at an early asymptomatic phase of RA development, rather than being associated with the disease processes that ultimately result in clinical arthritis.

Patient-reported swelling in arthralgia patients at risk for rheumatoid arthritis: is it of value?

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.

Rheumatoid arthritis presenting with mono- or oligo-arthritis and high VAS remains most fatigued during 5-years follow-up.

OBJECTIVES: The severity of fatigue in rheumatoid arthritis (RA) has hardly improved in recent decades, leaving a large unmet need. Fortunately, not all RA-patients suffer from persistent fatigue, but the subgroup of patients who suffer the most is insufficiently recognizable at diagnosis. As disease activity is partly coupled to fatigue, Disease-Activity-Score (DAS)-components may associate with the course of fatigue. We aimed to identify the RA-patients who remain fatigued by studying DAS-components at diagnosis in relation to the course of fatigue over a 5-year follow-up period in two independent early RA-cohorts. METHODS: 1560 consecutive RA-patients included in the Leiden Early Arthritis Cohort and 415 RA-patients included in the tREACH-Cohort were studied. Swollen joint count, tender joint count, ESR and Patient Global Assessment (Visual Analogue Scale(VAS),0-100 mm) were studied in relation to fatigue(VAS, 0-100mm) during 5-years using linear mixed models. RESULTS: Higher TJC and PGA at diagnosis were associated with a more severe course of fatigue. The SJC, in contrast, showed an inverse association; patients with mono- or oligo-arthritis at diagnosis remained more fatigued. The combination of aforementioned characteristics revealed that patients presenting with a mono- or oligo-arthritis and PGA ≥ 50 remained the most fatigued over time(+20mm vs polyarthritis with PGA < 50), whilst the DAS-course over time was not different. This subgroup comprised 14% of the early RA-population. Data from the tREACH-cohort showed similar findings. CONCLUSION: RA-patients who remain the most fatigued are characterized by mono- or oligo-arthritis and high PGA(VAS ≥ 50) at diagnosis. This understanding may enable early-intervention with non-pharmacological approaches in dedicated patient groups.

Clinically suspect arthralgia patients with a low educational attainment have an increased risk of developing inflammatory arthritis.

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.

Towards a simplified fluid-sensitive MRI protocol in small joints of the hand in early arthritis patients: reliability between modified Dixon and regular Gadolinium enhanced TSE fat saturated MRI-sequences.

OBJECTIVE: MRI of small joints plays an important role in the early detection and early treatment of rheumatoid arthritis. Despite its sensitivity to demonstrate inflammation, clinical use is hampered by accessibility, long scan time, intravenous contrast, and consequent high costs. To improve the feasibility of MRI implementation in clinical practice, we introduce a modified Dixon sequence, which does not require contrast and reduces total acquisition time to 6 min. Because the reliability in relation to conventional MRI sequences is unknown, we determined this. METHODS: In 29 consecutive early arthritis patients, coronal and axial T2-weighted modified Dixon acquisitions on 3.0 T MRI scanner were acquired from metacarpophalangeal 2-5 to the wrist, followed by the standard contrast-enhanced protocol on 1.5 T extremity MRI. Two readers scored osteitis, synovitis and tenosynovitis (summed as total MRI-inflammation), and erosions (all summed as total Rheumatoid Arthritis MRI Score (RAMRIS)). Intraclass correlation coefficients (ICCs) between readers, and comparing the two sequences, were studied. Spearman correlations were determined. RESULTS: Performance between readers was good/excellent. Comparing modified Dixon and conventional sequences revealed good/excellent reliability: ICC for total MRI-inflammation score was 0.84 (95% CI:0.70-0.92), for erosions 0.90 (95% CI:0.79-0.96), and for the total RAMRIS score 0.88 (95% CI:0.77-0.94). The scores of total MRI-inflammation, total erosions, and total RAMRIS were highly correlated (ρ = 0.80, ρ = 0.81, ρ = 0.82, respectively). CONCLUSION: The modified Dixon protocol is reliable compared to the conventional MRI protocol, suggesting it is accurate to detect MRI inflammation. The good correlation may be the first step towards a patient-friendly, short and affordable MRI protocol, which can facilitate the implementation of MRI for early detection of inflammation in rheumatology practice.

The value of MRI for detecting subclinical joint inflammation in clinically suspect arthralgia.

In the last decade, much research has focused on the development of rheumatoid arthritis (RA) and the symptomatic phase preceding the onset of clinical arthritis. Observational studies on imaging have revealed that subclinical joint inflammation in patients with arthralgia at risk for RA precedes and predicts the onset of clinically apparent arthritis. Moreover, the results of two placebo-controlled randomised proof-of-concept trials in patients with arthralgia and MRI-detected subclinical inflammation studies will soon be available. The initial results are encouraging and suggest a beneficial effect of DMARD treatment on subclinical inflammation. Since this may increase the necessity to detect subclinical joint inflammation in persons with arthralgia that are at risk for RA, we will here review what has been learnt about subclinical inflammation in at-risk individuals by means of imaging. We will focus on MRI as this method has the best sensitivity and reproducibility. We evaluate the prognostic value of MRI-detected subclinical inflammation and assess the lessons learnt from MRIs about the tissues that are inflamed early on and are associated with the clinical phenotype in arthralgia at risk for RA, for example, subclinical tenosynovitis underlying pain and impaired hand function. Finally, because long scan times and the need for intravenous-contrast agent contribute to high costs and limited feasibility of current MRI protocols, we discuss progress that is being made in the field of MRI and that can result in a future-proof way of imaging that is useful for assessment of joint inflammation on a large scale, also in a society with social distancing due to COVID-19 restrictions.