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Background: Conventional radiographs of hands and feet are used to depict structural damage in rheumatoid arthritis (RA). This is also commonly done in clinical practice in symptomatic patients at risk for RA (clinically suspect arthralgia (CSA)), but its rationale is unclear. We aimed to investigate the prevalence of radiographic erosive disease in patients with CSA and its progression over time., Methods: Patients with symptomatic arthralgia of the Leiden CSA cohort were studied during 2-year follow-up or until development of inflammatory arthritis (IA). Erosive disease was defined according to the radiologist, or according to the RA-specific erosive definition in light of the American College of Rheumatology (ACR)/European Alliance of Associations for Rheumatology (EULAR) 2010 RA criteria. Serial radiographs were evaluated according to the Sharp van der Heijde Scoring method (SHS) and radiographic erosive progression was determined. Additionally, it was evaluated if baseline erosive disease associated with IA development. Analyses were stratified for anticitrullinated protein antibody status., Results: 1497 radiographs of hands and feet of 749 patients with CSA were studied. Median SHS-erosion score at baseline was 0 (IQR 0-1). RA-specific erosive disease was present in 1.7% according to the radiologist, and 2.5% according to the ACR/EULAR criteria. No patients with CSA progressed ≥5 SHS-erosion points during follow-up. Erosive disease at CSA onset was not associated with IA development (HR 0.98 (95% CI 0.40 to 2.44))., Conclusions: At CSA onset, radiographic erosive disease is rare. In addition, it is rarely progressive within the CSA phase and not predictive for IA development. Therefore, for clinical practice, routinely made radiographs of hands and feet (such as regularly done at RA diagnosis) can be omitted in the at-risk stage of arthralgia., Competing Interests: Competing interests: AvdH is an editorial board member for RMD open. Otherwise none., (© 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.)

Objectives: Secondary prevention of rheumatoid arthritis (RA) is generally considered potentially impactful because the entire RA population is believed to experience a symptomatic 'pre-RA' phase. We wondered whether this dogma is correct. Therefore we investigated an inception cohort of patients with newly diagnosed RA and studied among them patients who did and did not present with preceding arthralgia at risk for RA., Methods: Consecutively diagnosed patients with RA between 2012 and 2022 were studied (n=699). These patients had either directly presented with clinically apparent arthritis, or had first presented with clinically suspect arthralgia (CSA). Clinical characteristics at symptom onset and RA diagnosis were compared. Whether certain characteristics frequently occurred together was studied using a K-means algorithm after dimension reduction with partial least squares discriminant analysis. To validate that groups differed in long-term outcomes, sustained disease-modifying anti-rheumatic drug-free remission (SDFR) of the groups was studied during a median follow-up of 5.3 years., Results: Patients with RA who had first presented with CSA were younger, more often had a gradual symptom onset and were more often anti-citrullinated protein antibodies (ACPA)-positive. Studying characteristics at symptom onset and RA diagnosis revealed four patient clusters, of which two clusters included almost all patients with a preceding CSA phase. Patients in these two clusters (55% of RA population) were younger, had a gradual symptom onset, longer symptom duration and were more frequently ACPA-positive. Patients with RA in these clusters achieved SDFR less often (HR 0.51 (95% CI 0.37 to 0.68)) than the patients with RA in the two clusters where preceding CSA was infrequent/absent., Conclusion: These data suggest the notion that the entire RA population has an identifiable symptomatic risk stage should be refuted. This may impact on the scope of preventive interventions targeting the symptomatic risk phase., Competing Interests: Competing interests: None declared., (© 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.)

Objectives: Although joint swelling is traditionally interpreted as synovitis, recent imaging studies showed that there is also inflammation of tenosynovium and intermetatarsal bursae in the forefoot. We aimed to increase our understanding of differences and similarities regarding forefoot involvement between ACPA-positive and ACPA-negative rheumatoid arthritis (RA) at diagnosis. Therefore, we (1) compared metatarsophalangeal (MTP) joint counts, walking disabilities and inflamed tissues between ACPA groups and (2) studied associations of joint swelling/tenderness and walking disabilities with underlying inflamed tissues within ACPA groups., Methods: 171 ACPA-positive and 203 ACPA-negative consecutively diagnosed patients with RA had a physical joint examination (swollen joint count-66/tender joint count-68), filled a Health Assessment Questionnaire including the domain walking and underwent MRI of the MTP joints at diagnosis. Synovitis, tenosynovitis, osteitis and intermetatarsal bursitis (IMB) were assessed. Findings in age-matched healthy controls were applied to define abnormalities on MRI., Results: While ACPA-negative RA patients had more swollen joints (mean SJC 8 vs 6 in ACPA-positives, p=0.003), the number of swollen MTP joints was similar (mean 1 in both groups); walking disabilities were also equally common (49% vs 53%). In contrast, inflamed tissues were all more prevalent in ACPA-positive compared with ACPA-negative RA. Within ACPA-positive RA, IMB was associated independently with MTP-joint swelling (OR 2.6, 95% CI 1.4 to 5.0) and tenderness (OR 3.0, 95% CI 1.8 to 5.0). While in ACPA-negatives, synovitis was associated independently with MTP-joint swelling (OR 2.8, 95% CI 1.4 to 5.8) and tenderness (OR 2.5, 95% CI 1.3 to 4.8). Tenosynovitis contributed most to walking disabilities., Conclusions: Although the forefoot of ACPA-positives and ACPA-negatives share clinical similarities at diagnosis, there are differences in underlying inflamed tissues. This reinforces that ACPA-positive and ACPA-negative RA are different entities., Competing Interests: Competing interests: None declared., (© 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.)

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., Competing Interests: Competing interests: AvdH is an editorial board member for RMDopen. Otherwise none., (© 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.)

Introduction: Subclinical inflammation, detected by MRI, in patients with arthralgia is predictive for development of inflammatory arthritis (IA). However, within patients that develop IA, the course of inflammation at the joint level during this transition is unknown. This longitudinal study assessed progression of inflammation at the joint level., Methods: 350 joints (unilateral metacarpophalangeals (MCPs), wrist, metatarsophalangeal (MTP) joints) of 35 patients presenting with clinically suspect arthralgia (CSA) that progressed to IA were studied at presentation with CSA and subsequently when clinical synovitis was first identified at joint examination (median time interval 17 weeks). At both time points, subclinical inflammation (bone marrow oedema, synovitis, tenosynovitis) was evaluated with MRI and joint examination was performed., Results: At presentation with CSA, 71 joints showed subclinical inflammation. During progression to IA, 20% of these joints had resolution of inflammation, 60% had persistent inflammation and 20% progressed to clinical synovitis. Of all joints that had developed clinical synovitis (n = 45), no prior subclinical inflammation was detected in 69%. Similar results were observed for anticitrullinated protein antibodies (ACPA)-positive and ACPA-negative patients., Conclusions: This longitudinal study demonstrated moderate correlations between joints with subclinical inflammation and joints that developed clinical synovitis. These data imply that IA development is a more systemic rather than a locally outgrowing process., Competing Interests: Competing interests: None declared.

Objectives: Moderate alcohol consumption is protective against rheumatoid arthritis (RA) development and associated with lower levels of systemic inflammation in RA and in the general population. We therefore hypothesised that moderate alcohol consumption is associated with less severe local inflammation in joints in RA, detected by MRI. Since asymptomatic persons can have low-grade MRI-detected inflammation, we also hypothesised that alcohol consumption is associated with the extent of MRI inflammation in asymptomatic volunteers., Methods: 188 newly presenting patients with RA and 192 asymptomatic volunteers underwent a unilateral contrast-enhanced 1.5T MRI of metacarpophalangeal, wrist and metatarsophalangeal joints. The MRIs were scored on synovitis, bone marrow oedema and tenosynovitis; the sum of these yielded the MRI inflammation score. MRI data were evaluated in relation to current alcohol consumption, categorised as non-drinkers, consuming 1-7 drinks/week, 8-14 drinks/week and >14 drinks/week. Association between C reactive protein (CRP) level and alcohol was studied in 1070 newly presenting patients with RA., Results: Alcohol consumption was not associated with the severity of MRI-detected inflammation in hand and foot joints of patients with RA (P=0.55) and asymptomatic volunteers (P=0.33). A J-shaped curve was observed in the association between alcohol consumption and CRP level, with the lowest levels in patients consuming 1-7 drinks/week (P=0.037)., Conclusion: Despite the fact that moderate alcohol consumption has been shown protective against RA, and our data confirm a J-shaped association of alcohol consumption with CRP levels in RA, alcohol was not associated with the severity of joint inflammation. The present data suggest that the pathophysiological mechanism underlying the effect of alcohol consists of a systemic effect that might not involve the joints., Competing Interests: Competing interests: None declared.

Introduction: A phase of arthralgia may precede the emergence of rheumatoid arthritis (RA). Although several studies have focused on biomarkers, the relevance of this phase for patients is less studied. It is unknown if patients already have functional limitations and if this is correlated to the extent of subclinical inflammation. Therefore, we assessed functional disability in patients with clinically suspect arthralgia (CSA), its association with MRI-detected subclinical inflammation and its course during progression to clinical arthritis., Methods: From April 2012 to March 2015, 241 patients had arthralgia for <1 year and were, based on clinical presentation, considered at risk for RA by their rheumatologists. At baseline, Health Assessment Questionnaire (HAQ) scores were determined and unilateral 1.5 T MRI of metacarpophalangeal, wrist and metatarsophalangeal joints were made. Presence of MRI-detected subclinical inflammation was assessed by summing synovitis, tenosynovitis and bone marrow oedema scores (range 0-189). Patients were followed on arthritis development and HAQ scores were repeated when clinical arthritis had developed., Results: The median HAQ score at presentation with CSA was 0.50. Higher MRI-inflammation scores were associated with higher HAQ scores (β=0.017, 95% CI=0.004 to 0.030). During median 103 weeks follow-up, 44 patients progressed to clinical arthritis. HAQ scores ≥1.0 were associated with arthritis development (HR=2.50, 95% CI=1.03 to 6.10). Within converters, median HAQ scores did not increase from presentation with CSA to arthritis development (0.88 and 0.75, p=0.36)., Conclusions: HAQ scores ≥1.0 at presentation were associated with the development of clinical arthritis. Functional limitations in the prearthritis phase of CSA were as serious as in the early clinical phase, demonstrating the relevance of CSA from patients' perspectives., Competing Interests: Competing interests: None declared.

Objective: To group HLA-DRB1 alleles based on acid-base properties of amino acids at positions 13, 70 and 71 and analyse their association with the presence of anticitrullinated peptide antibodies (ACPA) and structural progression in 2 cohorts of early rheumatoid arthritis (RA)., Methods: Patients with RA (N=612) from ESPOIR cohort and from EAC cohort (n=624) were genotyped for HLA-DRB1 alleles. The alleles containing the RAA sequence at positions 72-74 were classified into 3 groups according to the amino acid at positions 13, 70 and 71: BB encoding basic amino acids at positions 13, 70 and 71; A encoding acidic amino acids at positions 70 and 71; and BN encoding either neutral amino acids at position 13 and basic amino acids at positions 70 and 71, or basic amino acid at position 13 and neutral amino acids at positions 70 and 71. The associations between the different alleles and (1) the ACPA presence, and (2) the structural progression were assessed by χ(2) test; a meta-analysis was performed on the 2 cohorts using the Mantel-Haenszel method., Results: After meta-analysis, BB alleles were significantly associated with ACPA presence (OR (95% CI) 4.08 (3.14 to 5.31)) and structural progression (OR (95% CI) 2.33 (1.76 to 3.09)). The alleles protected significantly against ACPA presence (OR (95% CI) 0.37 (0.28 to 0.50)) and structural progression (OR (95% CI) 0.34 (0.23 to 0.50)). This acid-base classification allowed to separate another group BN with an intermediate risk of ACPA production (OR (95% CI) 1.14 (0.91 to 1.44)) and structural progression (OR (95% CI) 1.01 (0.77 to 1.33))., Conclusions: This new classification permitted to make a hierarchy of HLA-DRB1 alleles in terms of association with ACPA presence or structural progression in early RA.

Objective: Fatigue is prevalent and disabling in rheumatoid arthritis (RA). Surprisingly, the long-term course of fatigue is studied seldom and it is unclear to what extent it is influenced by inflammation. This study aimed to determine the course of fatigue during 8 years follow-up, its association with the severity of inflammation and the effect of improved treatment strategies., Methods: 626 patients with RA included in the Leiden Early Arthritis Clinic cohort were studied during 8 years. Fatigue severity, measured on a 0-100 mm scale, and other clinical variables were assessed yearly. Patients included in 1993-1995, 1996-1998 and 1999-2007 were treated with delayed treatment with disease-modifying antirheumatic drugs (DMARDs), early treatment with mild DMARDs and early treatment with methotrexate respectively. After multiple imputation, the serial measurements were analysed using linear quantile mixed models., Results: Median fatigue severity at baseline was 45 mm and remained, despite treatment, rather stable thereafter. Female gender (effect size=4.4 mm), younger age (0.2 mm less fatigue/year), higher swollen and tender joint counts (0.3 mm and 1.0 mm more fatigue/swollen or tender joint) and C reactive protein-levels (0.1 mm more fatigue per mg/L) were independently and significantly (p<0.05) associated with fatigue severity over 8 years. Although improved treatment strategies associated with less severe radiographic progression, there was no effect on fatigue severity (p=0.96)., Conclusions: This largest longitudinal study on fatigue so far demonstrated that the association between inflammation and fatigue is statistically significant but effect sizes are small, suggesting that non-inflammatory pathways mediate fatigue as well. Improved treatment strategies did not result in less severe fatigue. Therefore, fatigue in RA remains an 'unmet need'.