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Objectives Around 30% of patients with RA have an inadequate response to MTX. We aimed to use routine clinical and biological data to build machine learning models predicting EULAR inadequate response to MTX and to identify simple predictive biomarkers. Methods Models were trained on RA patients fulfilling the 2010 ACR/EULAR criteria from the ESPOIR and Leiden EAC cohorts to predict the EULAR response at 9 months (± 6 months). Several models were compared on the training set using the AUROC. The best model was evaluated on an external validation cohort (tREACH). The model's predictions were explained using Shapley values to extract a biomarker of inadequate response. Results We included 493 therapeutic sequences from ESPOIR, 239 from EAC and 138 from tREACH. The model selected DAS28, Lymphocytes, Creatininemia, Leucocytes, AST, ALT, swollen joint count and corticosteroid co-treatment as predictors. The model reached an AUROC of 0.72 [95% CI (0.63, 0.80)] on the external validation set, where 70% of patients were responders to MTX. Patients predicted as inadequate responders had only 38% [95% CI (20%, 58%)] chance to respond and using the algorithm to decide to initiate MTX would decrease inadequate-response rate from 30% to 23% [95% CI: (17%, 29%)]. A biomarker was identified in patients with moderate or high activity (DAS28 > 3.2): patients with a lymphocyte count superior to 2000 cells/mm3 are significantly less likely to respond. Conclusion Our study highlights the usefulness of machine learning in unveiling subgroups of inadequate responders to MTX to guide new therapeutic strategies. Further work is needed to validate this approach.

Objective: Intermetatarsal bursae in the forefeet possess a synovial lining similar to joints and tendon sheaths. Inflammation of these bursae (intermetatarsal bursitis [IMB]) was recently identified as specific for early rheumatoid arthritis (RA). The present study was undertaken to determine if IMB is indeed an RA feature by assessing the following: 1) the association with other local inflammatory measures (synovitis, tenosynovitis, and osteitis), 2) the association with clinical signs, and 3) whether it responds to disease-modifying antirheumatic drug (DMARD) therapy similarly to other local inflammatory measures. Methods: One hundred fifty-seven consecutive early RA patients underwent unilateral contrast-enhanced 1.5T forefoot magnetic resonance imaging (MRI) at diagnosis. MRIs were evaluated for IMB presence and for synovitis, tenosynovitis, and osteitis in line with the RA MRI Scoring (RAMRIS) system (summed as RAMRIS inflammation). MRIs at 4, 12, and 24 months were evaluated for IMB presence and size in patients who had IMB at baseline and received early DMARD therapy. Logistic regression and generalized estimating equations were used. Anti-citrullinated protein antibody (ACPA) stratification was performed. Results: Sixty-nine percent of RA patients had >= 1 IMB. In multivariable analysis on bursa level, presence of IMB was independently associated with local presence of synovitis and tenosynovitis, with odds ratios (OR) of 1.69 (95% confidence interval [95% CI] 1.12, 2.57) and 2.83 (95% CI 1.80, 4.44), respectively, but not osteitis. On the patient level, IMB presence was most strongly associated with tenosynovitis (OR 2.92 [95% CI 1.62, 5.24]). IMB presence was associated with local joint swelling (OR 2.7 [95% CI 1.3, 5.3]) and tenderness (OR 1.7 [95% CI 1.04, 2.9]) independent of RAMRIS inflammation. During treatment, IMB size decreased between 0 and 12 months. This decrease associated with decrease in RAMRIS inflammation, which was driven by synovitis decrease. Within ACPA-positive and ACPA-negative RA, similar results were obtained. Conclusion: IMB particularly accompanies inflammation of the synovial lining of joints and tendon sheaths, showed a similar treatment response after DMARD initiation, and associates with typical clinical signs. These findings suggest that IMB represents a frequently present novel RA feature of juxtaarticular synovial inflammation.

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.

Objectives We investigated whether work participation is affected in patients with arthralgia during transition to RA. Arthralgia patients with symptom resolution and early RA patients at diagnosis were used as a reference. Methods Three groups of patients were studied: arthralgia patients converting to RA (n = 114), arthralgia patients with spontaneous symptom resolution (n = 57), and early RA patients (n = 617). Both presenteeism (i.e. working while sick, scale 0–10) and absenteeism (i.e. sick leave) were taken into account. Work ability 1 year prior to clinical arthritis was estimated (in absolute numbers). The course of work restriction over time was studied using linear mixed models (β coefficient; delta per month) within each patient group. Results One-year prior to the development of clinical arthritis, mean presenteeism was 7.0 (95% CI 5.8, 8.1) in patients with arthralgia, indicating 30% loss, and further worsened to 6.1 (95% CI 5.3, 6.6) at RA diagnosis, thus indicating 39% loss. In early RA patients, presenteeism improved over time after DMARD initiation (β 0.052 per month 95% CI 0.042, 0.061, P Conclusion In the months preceding RA, presenteeism was already apparent, and it worsened further during progression to clinical arthritis and diagnosis. This underlines the relevance of the symptomatic pre-RA phase for patients. The observed reversibility in arthralgia patients with symptom resolution may suggest that intervention in pre-RA could improve work participation.

Objectives Morning stiffness (MS) is characteristic of RA and associates with markers of systemic and local inflammation in RA patients. In patients with arthralgia, MS is a cardinal symptom to recognize arthralgia at-risk for RA development [i.e. clinically suspect arthralgia (CSA)]. In CSA, MS is also assumed to reflect inflammation, but this has never been studied. Therefore we aimed to study whether MS in CSA patients is associated with systemic and subclinical joint inflammation. Methods A total of 575 patients presenting with CSA underwent laboratory investigations and contrast-enhanced 1.5 T MRI of the hand and forefoot (scored according to the Rheumatoid Arthritis MRI Score method). Associations of MS (duration ≥60 min) with the presence of subclinical joint inflammation (synovitis, tenosynovitis and osteitis) and increased CRP (≥5 mg/l) were determined with logistic regression. Additionally, the effect of MS duration (≥30, ≥60 and ≥120 min) was studied. Results A total of 195 (34%) CSA patients experienced MS. These patients more often had subclinical synovitis [34% vs 21%; odds ratio (OR) 1.95 (95% CI 1.32, 2.87)], subclinical tenosynovitis [36% vs 26%; OR 1.59 (95% CI 1.10, 2.31)] and increased CRP [31% vs 19%; OR 1.93 (95% CI 1.30, 2.88)] than patients without MS. In multivariable analyses, subclinical synovitis [OR 1.77 (95% CI 1.16, 2.69)] and CRP [OR 1.78 (95% CI 1.17–2.69)] remained independently associated with MS. In CSA patients who later developed RA, and thus in retrospect were ‘pre-RA’ at the time of CSA, MS was more strongly associated with subclinical synovitis [OR 2.56 (95% CI 1.04, 6.52)] and CRP [OR 3.86 (95% CI 1.45, 10.24)]. Furthermore, associations increased with longer MS durations. Conclusion Inflammation associates with MS in the CSA phase that preceded clinical arthritis. These results increase our understanding of MS when assessing arthralgia in clinical practice.

Objectives New onset undifferentiated large joint inflammatory arthritis can be diagnostically challenging. It is unknown how often these patients progress to RA, and how they can be identified at first presentation. We assessed clinical and serological features associated with RA development in patients with an undifferentiated mono- or oligo-articular large joint arthritis, and with keen interest in whether an MRI of the small joints of the hand and foot would aid diagnosis. Methods Leiden Early Arthritis Clinic includes 4018 patients; this prospective study follows 221 consecutively included patients with new onset undifferentiated large joint arthritis. Baseline clinical data and serology were obtained. Forty-five patients had MRIs (hand and foot). MRIs were scored according to the OMERACT RAMRIS. Univariable and multivariable logistic regression were assessed. Test characteristics, predictive values and net reclassification index (NRI) for RA were determined. Results Patients mostly presented with knee or ankle mono-arthritis. During the 12 months’ follow-up 17% developed RA. Autoantibody positivity (ACPA and/or RF) and MRI-detected synovitis in hands and feet were independently associated with RA development in multivariable analyses [odds ratio 10.29 (P = 0.014) and 7.88 (P = 0.017), respectively]. Positive predictive value of autoantibodies, MRI-detected synovitis and combination of both features was 63%, 55% and 100%, respectively. The addition of MRI-detected synovitis to autoantibody status improved diagnostic accuracy (NRI 18.1%). Conclusion In patients presenting with undifferentiated large joint arthritis, 17% will develop RA. Autoantibody positivity and subclinical synovitis are independent predictors. The data suggest MRI of small joints is beneficial for early identification of RA in large joint arthritis.

ObjectivesThe human leukocyte antigen-shared epitope (HLA-SE) alleles and smoking are the most prominent genetic and environmental risk factors for rheumatoid arthritis (RA). However, at which pre-arthritis stage (asymptomatic/symptomatic) they exert their effect is unknown. We aimed to determine whether HLA-SE and smoking are involved in the onset of autoantibody positivity, symptoms (clinically suspect arthralgia (CSA)) and/or progression to clinical arthritis.MethodsWe performed meta-analyses on results from the literature on associations of HLA-SE and smoking with anti-citrullinated protein antibodies (ACPAs) in the asymptomatic population. Next, we studied associations of HLA-SE and smoking with autoantibody positivity at CSA onset and with progression to clinical inflammatory arthritis (IA) during follow-up. Associations in ACPA-positive patients with CSA were validated in meta-analyses with other arthralgia cohorts. Analyses were repeated for rheumatoid factor (RF), anti-carbamylated protein antibodies (anti-CarP) and anti-acetylated protein antibodies (AAPA).ResultsMeta-analyses showed that HLA-SE is not associated with ACPA positivity in the asymptomatic population (OR 1.06 (95% CI:0.69 to 1.64)), whereas smoking was associated (OR 1.37 (95% CI: 1.15 to 1.63)). At CSA onset, both HLA-SE and smoking associated with ACPA positivity (OR 2.08 (95% CI: 1.24 to 3.49), OR 2.41 (95% CI: 1.31 to 4.43)). During follow-up, HLA-SE associated with IA development (HR 1.86 (95% CI: 1.23 to 2.82)), in contrast to smoking. This was confirmed in meta-analyses in ACPA-positive arthralgia (HR 1.52 (95% CI: 1.08 to 2.15)). HLA-SE and smoking were not associated with RF, anti-CarP or AAPA-positivity at CSA onset. Longitudinally, AAPA associated with IA development independent from ACPA and RF (HR 1.79 (95% CI: 1.02 to 3.16)), anti-CarP did not.ConclusionsHLA-SE and smoking act at different stages: smoking confers risk for ACPA and symptom development, whereas HLA-SE mediates symptom and IA development. These data enhance the understanding of the timing of the key risk factors in the development of RA.

BackgroundClinically suspect arthralgia (CSA) is characterised by arthralgia of small joints and considered a risk stage for development of rheumatoid arthritis (RA). However, it remains unknown if the function of the hands is already affected and what mechanisms underlie impaired hand-function in CSA.MethodsWe studied various measures of hand function in two CSA populations. CSA patients in the TREAT EARLIER-trial (n=236) were evaluated at baseline for: grip strength on a dynamometer (GS), patient-reported difficulties in the grip domain of the Health Assessment Questionnaire (HAQ) questionnaire and incomplete fist closure at physical examination. Findings were validated in an independent CSA cohort (n=600) where hand function was measured as: GS evaluated by squeezing the examiner’s fingers, grip domain of the HAQ questionnaire and fist closure. Contrast-enhanced MRI of the hands measured synovitis, tenosynovitis and bone marrow oedema (summed as subclinical inflammation) in both cohorts.ResultsGS (on a dynamometer) was reduced in 75% compared with reference values in healthy controls, 60% reported grip difficulties and 13% had incomplete fist closure. Reduced GS was associated with subclinical inflammation (−0.38 kg/point inflammation, 95% CI −0.68 to −0.08). Studying separate MRI features, GS reduction was independently associated with tenosynovitis, decreasing with −2.63 kg (95% CI −2.26 to −0.33)/point tenosynovitis (range observed tenosynovitis scores: 0–20). Similar relations with tenosynovitis were seen for patient-reported grip difficulties (OR 1.12/point, 95% CI 1.07 to 1.42) and incomplete fist closure (OR 1.36/point, 95% CI 1.03 to 1.79). In the validation cohort, 36% had decreased examiner-assessed GS, 51% reported grip difficulties and 14% incomplete fist closure: all were associated with tenosynovitis. Decreased dynamometer-measured GS was most sensitive for detecting tenosynovitis (75%), while incomplete fist closure was most specific (88%–90%).ConclusionHand function is already often affected before RA development. These limitations are related to subclinical inflammation and tenosynovitis in particular.

Objective. To investigate whether established genetic predictors for rheumatoid arthritis (RA) differentiate healthy controls, patients with clinically suspect arthralgia (CSA), and RA patients.Methods. Using analyses of variance, chi-square tests, and mean risk difference analyses, we investigated the association of an RA polygenic risk score (PRS) and HLA shared epitope (HLA-SE) with all participant groups, both unstratified and stratified for anti-citrullinated protein antibody (ACPA) status. We used 3 separate data sets sampled from the same Dutch population (1,015 healthy controls, 479 CSA patients, and 1,146 early classified RA patients). CSA patients were assessed for conversion to inflammatory arthritis over a period of 2 years, after which they were classified as either CSA converters (n = 84) or CSA nonconverters (n = 395).Results. The PRS was increased in RA patients (mean +/- SD PRS 1.31 +/- 0.96) compared to the complete CSA group (1.07 +/- 0.94) and compared to CSA converters (1.12 +/- 0.94). In ACPA- strata, PRS distributions differed strongly when comparing the complete CSA group (mean +/- SD PRS 1.05 +/- 0.94) and CSA converters (0.97 +/- 0.87) to RA patients (1.20 +/- 0.94), while in the ACPA+ strata, the complete CSA group (1.25 +/- 0.99) differed clearly from healthy controls (1.05 +/- 0.94) and RA patients (1.41 +/- 0.96). HLA-SE was more prevalent in the RA group (prevalence 0.64) than the complete CSA group (0.45), with small differences between RA patients and CSA converters (0.64 versus 0.60) and larger differences between CSA converters and CSA nonconverters (0.60 versus 0.42). HLA-SE prevalence differed more strongly within the ACPA+ strata as follows: healthy controls (prevalence 0.43), CSA nonconverters (0.48), complete CSA group (0.59), CSA converters (0.66), and RA patients (0.79).Conclusion. We observed that genetic predisposition increased across pre-RA participant groups. The RA PRS differed in early classified RA and inflammatory pre-disease stages, regardless of ACPA stratification. HLA-SE prevalence differed between arthritis patients, particularly ACPA+ patients, and healthy controls. Genetics seem to fulfill different etiologic roles.

Objective To investigate the negative predictive value (NPV) of musculoskeletal US (MSUS) in arthralgia patients at risk for developing inflammatory arthritis. Methods An MSUS examination of hands and feet was performed in arthralgia patients at risk for inflammatory arthritis in four independent cohorts. Patients were followed for one-year on the development of inflammatory arthritis. Subclinical synovitis was defined as greyscale ≥2 and/or power Doppler ≥1. NPVs were determined and compared with the prior risks of not developing inflammatory arthritis. Outcomes were pooled using meta-analyses and meta-regression analyses. In sensitivity analyses, MSUS imaging of tender joints only (rather than the full US protocol) was analysed and ACPA stratification applied. Results After 1 year 78, 82, 77 and 72% of patients in the four cohorts did not develop inflammatory arthritis. The NPV of a negative US was 86, 85, 82 and 90%, respectively. The meta-analysis showed a pooled non-inflammatory arthritis prevalence of 79% (95% CI 75%, 83%) and a pooled NPV of 86% (95% CI 81, 89%). Imaging tender joints only (as generally done in clinical practice) and ACPA stratification showed similar results. Conclusion A negative US result in arthralgia has a high NPV for not developing inflammatory arthritis, which is mainly due to the high a priori risk of not developing inflammatory arthritis. The added value of a negative US (

Objectives Although sustained DMARD-free remission (SDFR; sustained absence of clinical-synovitis after DMARD-discontinuation) is increasingly achievable in RA, prevalence differs between ACPA-negative (40%) and ACPA-positive RA (5–10%). Additionally, early DAS remission (DAS4months Methods A total of 198 RA patients (94 ACPA-negative, 104 ACPA-positive) underwent repeated MRIs (0/4/12/24 months) and were followed on SDFR development. The course of MRI-detected total inflammation, and synovitis/tenosynovitis/osteitis individually were compared between RA patients who did and did not achieve SDFR, using Poisson mixed models. In total, 174 ACPA-positive RA patients from the AVERT-1 were studied as ACPA-positive validation population. Results In ACPA-negative RA, baseline MRI-detected inflammation levels of patients achieving SDFR were similar to patients without SDFR but declined 2.0 times stronger in the first year of DMARD treatment [IRR 0.50 (95% CI; 0.32, 0.77); P Conclusion Compared with RA patients without disease resolution, ACPA-positive RA patients achieving SDFR have less severe joint inflammation from diagnosis onwards, while ACPA-negative RA patients present with similar inflammation levels but demonstrate a stronger decline in the first year of DMARD therapy. These different trajectories suggest different mechanisms underlying resolution of RA chronicity in both RA subsets.

With great interest, we read the recently published report by Myasoedova et al in which a significant increase in incidence of rheumatoid factor (RF)-negative rheumatoid arthritis (RA) was found, in contrast to RF-positive RA.1 Studies on trends of RA-incidence stratified for autoantibodies are scarce. Moreover, both an increase and decrease in incidence of RF-negative RA has been reported.2 3 Because validation is important, we determined trends in incidence of RA over two decades in our region. We defined autoantibody-positivity as autocitrullinated protein antibodies (ACPA)-positivity, since RF is less specific for RA and more often present in healthy controls, especially at older age.4 Second, because autoantibody-negative RA has an higher age-of-onset than autoantibody positive RA,5 we hypothesised that part of the incidence increase is explained by ageing of the population. Therefore, we also assessed the influence of the population age-distribution on the trends of incidence of RA. Incidence rates were calculated based on the inclusion rate of patients with RA in the Leiden Early Arthritis Cohort (EAC). The Leiden University Medical Center (LUMC) is the only rheumatology referral centre within the Leiden area and inclusion in the EAC of newly presenting patients with early arthritis has been part of regular care since 1993.6 All consecutively included patients with RA (defined as clinical diagnosis plus fulfilling the 1987 …

Objective Mucosal initiated immune responses may be involved in the pathophysiology of RA. The most abundant immunoglobulin at mucosal surfaces is IgA, of which two subclasses exist: IgA1 and IgA2. IgA2 is mainly present at mucosal sites and has been ascribed pro-inflammatory properties. As IgA subclasses might provide insights into mucosal involvement and pro-inflammatory mechanisms, we investigated IgA responses in sera of RA patients. Methods In two cohorts of RA patients, the EAC and IMPROVED, total IgA1 and IgA2 were measured by ELISA. Furthermore, IgA subclass levels of RF and anti-citrullinated protein antibodies (anti-CCP2) were determined. The association of these IgA subclass levels with CRP and smoking was investigated. Results Total IgA1 and IgA2 were increased in RA patients compared with healthy donors in both cohorts. This increase was more pronounced in seropositive RA vs seronegative RA. For RF and anti-CCP2, both IgA1 and IgA2 could be detected. No strong associations were found between IgA subclasses (total, RF and anti-CCP2) and CRP. In smoking RA patients, a trend towards a selective increase in total IgA2 and RF IgA1 and IgA2 was observed. Conclusion RA patients have raised IgA1 and IgA2 levels. No shift towards IgA2 was observed, indicating that the increase in total IgA is not due to translocation of mucosal IgA into the bloodstream. However, mucosal inflammation might play a role, given the association between smoking and total IgA2 levels. Despite its pro-inflammatory properties, IgA2 does not associate strongly with pro-inflammatory markers in RA patients.

ObjectiveThe aim of the current study was to evaluate the 2-year cost-utility ratio between tapering conventional synthetic disease-modifying antirheumatic drugs (csDMARD) first followed by the tumour necrosis factor (TNF)-inhibitor, or vice versa, in patients with rheumatoid arthritis (RA).MethodsTwo-year data of the Tapering strategies in Rheumatoid Arthritis trial were used. Patients with RA, who used both a csDMARD and a TNF-inhibitor and had a well-controlled disease (disease activity score ≤2.4 and swollen joint count≤1) for at least 3 months, were randomised into gradual tapering the csDMARD first followed by the TNF-inhibitor, or vice versa. Quality-adjusted life years (QALYs) were derived from the European Quality of life questionnaire with 5 dimensions. Healthcare and productivity costs were calculated with data from patient records and questionnaires. The incremental cost-effectiveness ratio and the incremental net monetary benefit were used to assess cost effectiveness between both tapering strategies.Results94 patients started tapering their TNF-inhibitor first, while the other 95 tapered their csDMARD first. QALYs (SD) were, respectively, 1.64 (0.22) and 1.65 (0.22). Medication costs were significantly lower in the patients who tapered the TNF-inhibitor first, while indirect cost were higher due to more productivity loss (p=0.10). Therefore, total costs (SD) were €38 833 (€39 616) for tapering csDMARDs first, and €39 442 (€47 271) for tapering the TNF-inhibitor (p=0.88). For willingness-to-pay (WTP) levels €83 800 tapering the TNF-inhibitor first has the highest probability.ConclusionOur economic evaluation shows that costs are similar for both tapering strategies. Regardless of the WTP, tapering either the TNF-inhibitor or the csDMARD first is equally cost effective.Trial registration numberNTR2754.

Summary Background The first recommendation of the European League Against Rheumatism for the management of early arthritis states that patients should be referred to, and seen by, a rheumatologist within 6 weeks after symptom onset. However, implementation of this recommendation is a challenge, and evidence supporting this timeframe compared with longer timeframes is absent. Therefore, we aimed to investigate whether visiting a rheumatologist within 6 weeks of symptom onset relates to improved long-term outcomes compared with visiting a rheumatologist between 7 and 12 weeks after symptom onset. Methods In this observation cohort study, consecutive patients with rheumatoid arthritis from the Leiden Early Arthritis Clinic (EAC) and the French Etude et Suivi des Polyarthrites Indifferenciees Recentes (ESPOIR) were included. In this analysis, we included patients who were diagnosed with rheumatoid arthritis and classified according to 1987 American College of Rheumatology criteria, and with symptom onset and remission data available. Patients were categorised into groups based on time between symptom onset and first encounter with a rheumatologist: within 6 weeks, between 7 weeks and 12 weeks, and after 12 weeks. The main outcomes were sustained disease-modifying antirheumatic drug (DMARD)-free remission and radiographic progression. Multivariable Cox regression, linear mixed models, and meta-analyses were used. Findings 1025 patients with rheumatoid arthritis included in the EAC between Jan 1, 1996, and Dec 31, 2017, and 514 patients with rheumatoid arthritis included in ESPOIR between Nov 1, 2002, and April 30, 2005, were included in this analysis. Median follow-up was 7·1 years (IQR 3·9–12·2) in the EAC and 10·0 years (9·0–10·0) in ESPOIR. After 7 years of follow-up in the EAC, 30 (24%) of 127 patients with a time to encounter of 6 weeks or less, 45 (20%) of 223 patients with a time of 7–12 weeks, and 100 (15%) of 675 patients with a time of more than 12 weeks achieved sustained DMARD-free remission. After 10 years of follow-up in ESPOIR, three (27%) of 11 patients with a time to encounter of 6 weeks or less, 11 (11%) of 100 patients with a time of 7–12 weeks, and 41 (10%) of 403 patients with a time of more than 12 weeks had sustained DMARD-free remission. In the EAC multivariable analysis, patients who encountered a rheumatologist within 6 weeks obtained sustained DMARD-free remission more often than those seen between 7 and 12 weeks (hazard ratio [HR] 1·59 [95% CI 1·02–2·49], p=0·042), and after 12 weeks (1·54 [1·04–2·29], p=0·032). In the ESPOIR multivariable analysis, similar but non-significant effects were observed (HR 2·81 [95% CI 0·75–10·53], p=0·12, for within 6 weeks vs 7–12 weeks and 3·05 [0·89–10·49], p=0·077, for within 6 weeks vs more than 12 weeks). The meta-analysis of both cohorts showed that the time to encounter of 6 weeks or less was associated with a higher chance of achieving sustained DMARD-free remission than a time of 7–12 weeks (HR 1·69 [95% CI 1·10–2·57], p=0·016) and a time of more than 12 weeks (1·67 [1·08–2·58], p=0·020). The multivariable analysis showed that patients who encountered a rheumatologist within 6 weeks had similar radiographic progression to those seen between 7 and 12 weeks in both cohorts (β=1·00 [95% CI 0·95–1·05], p=0·96, in the EAC and 0·93 [0·80–1·07], p=0·30, in ESPOIR) and to those seen after 12 weeks (β=0·96 [95% CI 0·92–1·00], p=0·064, in the EAC and 0·89 [0·77–1·02], p=0·10, in ESPOIR). In the meta-analysis, a time to encounter of 6 weeks or less was not associated with less radiographic progression than a time of 7–12 weeks (β=0·99 [95% CI 0·95–1·04], p=0·75) but was associated with less radiographic progression than a time of more than 12 weeks (0·95 [0·91–0·99], p=0·028). Interpretation Visiting a rheumatologist within 6 weeks of symptom onset had benefits for achieving sustained DMARD-free remission, but not for radiographic progression. Funding European Research Council, Dutch Arthritis Society, Merck Sharp & Dohme, INSERM, The French Society of Rheumatology, Pfizer, AbbVie, Lilly, and Sanofi.

Objective: Radiographic joint erosions are a hallmark of rheumatoid arthritis (RA). Magnetic resonance imaging (MRI) is more sensitive than radiographs in detecting erosions. It is unknown whether MRI-detected erosions are predictive for RA development in patients with clinically suspect arthralgia (CSA). Therefore, we investigated the prognostic value of MRI-detected erosions, defined as any MRI erosion, or MRI erosion characteristics that were recently identified as specific for RA in patients with evident arthritis. Method: Patients presenting with CSA (n = 490) underwent contrast-enhanced 1.5 T MRI of the wrist, metacarpophalangeal (MCP) and metatarsophalangeal (MTP) joints. MRIs were scored according to the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system (RAMRIS). Presence of any MRI erosion (present in

Objectives International guidelines stress timely DMARD initiation in early arthritis as well as when classification criteria are not yet fulfilled. Consequently, undifferentiated arthritis (UA) patients may be increasingly treated with DMARDs. Since UA is a diagnosis of exclusion, the introduction of the 2010 classification criteria presumably decreased the UA population, as former UA patients became regarded as RA. Consequently, the contemporary definition of UA has changed into: no clinical diagnosis and not fulfilling the 1987 nor 2010 RA-criteria. Importantly, placebo-controlled trials on DMARD efficacy in contemporary UA are absent. We aimed to study whether enhanced treatment strategies across the last 25 years improved outcomes in contemporary UA, whereby inclusion period was used as instrumental variable for DMARD treatment. Methods UA was defined, retrospectively, as clinical arthritis (joint swelling at physical examination) neither fulfilling the 1987 nor 2010 RA-criteria or any other clinical diagnosis. In total, 1132 UA patients consecutively included in the Leiden Early Arthritis Clinic between 1993 and 2019 were divided into five inclusion periods: 1993–1997, 1998–2005, 2006–2010, 2011–2014 and 2015–2019. The frequency of DMARD initiation was compared across the inclusion periods, as were the following outcomes: 28-joint DAS with CRP (DAS28-CRP) and the HAQ Disability Index (HAQ-DI) during follow-up, prevalence of DMARD-free-status within 10 years (DFS; spontaneous remission or sustained remission after DMARD stop) and progression to RA (according 1987/2010 criteria). Results The contemporary UA population is mainly autoantibody negative, with a median swollen joint count of 2, tender joint count of 3 and HAQ score of 0.6. These characteristics were similar across the inclusion periods. DMARD treatment increased from 17% (1993–1997) to 52% (2015–2019) and methotrexate became more common. The DAS28-CRP during follow-up improved from 2011 onwards (−0.18 to −0.25 DAS units; P Conclusion Although intensified DMARD treatment slightly improved disease activity scores, physical functioning and long-term outcomes did not improve. This suggests overtreatment in the contemporary UA population and underlines the importance of developing stratification methods suitable for this patient-population.

Objectives The squeeze test of MTP joints is frequently used because it is easy and cheap. It is traditionally perceived as a test for synovitis. Besides classic intra-articular synovitis, also tenosynovitis and intermetatarsal bursitis (IMB) represent synovial inflammation, albeit juxta-articularly located. Both are frequently present in RA and occasionally in other arthritides. Therefore we hypothesized that tenosynovitis and IMB contribute to a positive MTP squeeze test. Methods A cross-sectional study design was used. A total of 192 early arthritis patients and 693 clinically suspect arthralgia patients underwent the MTP squeeze test and forefoot MRI at first presentation. MRI measurements in age-matched healthy controls were used to define positivity for synovitis, tenosynovitis and IMB. Logistic regression was used. Results In early arthritis patients, synovitis [odds ratio (OR) 4.8 (95% CI 2.5, 9.5)], tenosynovitis [2.4 (1.2, 4.7)] and IMB [1.7 (1.2, 2.6)] associated with MTP squeeze test positivity. Synovitis [OR 3.2 (95% CI 1.4, 7.2)] and IMB [3.9 (1.7, 8.8)] remained associated in multivariable analyses. Of patients with a positive MTP squeeze test, 79% had synovitis or IMB: 12% synovitis, 15% IMB and 52% both synovitis and IMB. In clinically suspect arthralgia patients, subclinical synovitis [OR 3.0 (95% CI 2.0, 4.7)], tenosynovitis [2.7 (1.6, 4.6)] and IMB [1.7 (1.2, 2.6)] associated with MTP squeeze test positivity, with the strongest association for synovitis in multivariable analysis. Of positive MTP squeeze tests, 39% had synovitis or IMB (10% synovitis, 15% IMB and 13% both synovitis and IMB). Conclusion Besides synovitis, IMB contributes to pain upon compression in early arthritis, presumably due to its location between MTP joints. This is the first evidence showing that MTP squeeze test positivity is not only explained by intra- but also juxta-articular inflammation.

Objective: The autoimmune response in rheumatoid arthritis (RA) is marked by the presence of anti–citrullinated protein antibodies (ACPAs). A notable feature of IgG ACPA is the abundant expression of N-linked glycans in the variable domain. However, the presence of ACPA variable domain glycosylation (VDG) across disease stages, and its response to therapy, are poorly described. To understand its dynamics, we investigated the abundance of IgG ACPA VDG in 1,498 samples from individuals in different clinical stages. Methods: Using liquid chromatography, we analyzed IgG ACPA VDG profiles in 7 different cohorts from Japan, Canada, The Netherlands, and Sweden. We assessed 106 healthy individuals, 228 individuals with presymptomatic RA, 277 individuals with arthralgia, 307 patients with new-onset/early RA, and 117 RA patients after prespecified treatment regimens. Additionally, we measured VDG in 234 samples from patients with RA who did or did not achieve long-term drug-free remission (DFR) during up to 16 years follow-up. Results: IgG ACPA VDG significantly increased (P < 0.0001) toward disease onset and was associated with ACPA levels and epitope spreading prior to diagnosis. A slight increase in VDG was observed in patients with established RA, with a moderate influence of treatment (P = 0.007). In patients in whom DFR was later achieved, IgG ACPA VDG was already reduced at the time of RA onset. Conclusion: The abundance of IgG ACPA VDG increases toward RA onset and correlates with maturation of the ACPA response. While IgG ACPA VDG levels are fairly stable in established disease, a lower degree of VDG at RA onset correlates with DFR. Although the underlying biologic mechanisms remain elusive, our data support the concept that VDG relates to an expansion of the ACPA response in the pre-disease phase and contributes to disease development.

Objective The relationship between functional disability and magnetic resonance imaging (MRI) inflammation has been studied for the hands, but has not been well established for the feet, even though walking difficulties are common. Therefore, our objective was to study whether walking difficulties were associated with MRI inflammation at metatarsophalangeal (MTP) joints in early arthritis patients, at diagnosis and during 24 months of follow-up. Methods A total of 532 consecutive patients presenting with early arthritis reported on the presence and severity of walking difficulties (Health Assessment Questionnaire question 4a, scale 0-3), and underwent unilateral contrast-enhanced MRI of MTP joints 1-5 at baseline. In total, 107 patients had clinical and MRI data at follow-up (4, 12, and 24 months). MRI inflammation (synovitis, tenosynovitis, and osteitis) was scored in line with the Rheumatoid Arthritis Magnetic Resonance Imaging Scoring system. At baseline, the association of walking disability with MRI inflammation was assessed using regression. Longitudinally, the association between a change in walking disability with a change in MRI inflammation was studied with linear mixed models. Results At baseline, 81% of patients with walking disabilities had MRI inflammation at MTP joints, versus 68% without walking disabilities (P < 0.001). Total MRI inflammation (i.e., the sum of tenosynovitis, synovitis, and osteitis) was associated with severity of walking disability (beta = 0.023, P < 0.001). Studying the MRI features separately, tenosynovitis, synovitis, and osteitis were all univariably associated with severity of walking disability (P < 0.001, P < 0.001, and P = 0.014, respectively). In multivariable analysis, the association was strongest for tenosynovitis. During follow-up, a decrease in MTP inflammation was associated with a decrease in walking disability (beta = 0.029, P = 0.001); in multivariable analyses only, tenosynovitis was independently associated (beta = 0.073, P = 0.049). Conclusion Of the different inflamed tissues in MTP joints, predominantly MRI-detected tenosynovitis was associated with walking disabilities. Likewise a reduction in tenosynovitis related to a decrease in walking disabilities. These results increase our understanding of the involvement of tenosynovitis in walking disabilities in early arthritis.

Objectives Identifying patients that will develop RA among those presenting with undifferentiated arthritis (UA) remains a clinical dilemma. Although MRI is helpful according to EULAR recommendations, this has only been determined in UA patients not fulfilling 1987 RA criteria, while some of these patients are currently considered as RA because they fulfil the 2010 criteria. Therefore, we studied the predictive value of MRI for progression to RA in the current UA population, i.e. not fulfilling RA classification criteria (either 1987 or 2010 criteria) and not having an alternate diagnosis. Additionally, the value of MRI was studied in patients with a clinical diagnosis of UA, regardless of the classification criteria. Methods Two UA populations were studied: criteria-based UA as described above (n = 405) and expert-opinion-based UA (n = 564), i.e. UA indicated by treating rheumatologists. These patients were retrieved from a large cohort of consecutively included early arthritis patients that underwent contrast-enhanced MRI scans of hand and foot at baseline. MRIs were scored for osteitis, synovitis and tenosynovitis. Patients were followed for RA development during the course of 1 year. Test characteristics of MRI were determined separately for subgroups based on joint involvement and autoantibody status. Results Among criteria-based UA patients (n = 405), 21% developed RA. MRI-detected synovitis and MRI-detected tenosynovitis were predictive for progression to RA. MRI-detected tenosynovitis was independently associated with RA progression (odds ratio (OR) 2.79; 95% CI 1.40, 5.58), especially within ACPA-negative UA patients (OR 2.91; 95% CI 1.42, 5.96). Prior risks of RA development for UA patients with mono-, oligo- and polyarthritis were 3%, 19% and 46%, respectively. MRI results changed this risk most within the oligoarthritis subgroup: positive predictive value was 27% and negative predictive value 93%. Similar results were found in expert-opinion-based UA (n = 564). Conclusion This large cohort study showed that MRI is most valuable in ACPA-negative UA patients with oligoarthritis; a negative MRI could aid in preventing overtreatment.

ObjectivesThe impact of inflammatory arthritis (IA) on male fertility remains unexplored. Our objective was to evaluate the impact of IA on several male fertility outcomes; fertility rate (number of biological children per man), family planning, childlessness and fertility problems.MethodsWe performed a multicentre cross-sectional study (iFAME-Fertility). Men with IA 40 years or older who indicated that their family size was complete were invited to participate. Participants completed a questionnaire that included demographic, medical and fertility-related questions. To analyse the impact of IA on fertility rate, patients were divided into groups according to the age at the time of their diagnosis: ≤30 years (before the peak of reproductive age), between 31 and 40 years (during the peak) and ≥41 years (after the peak).ResultsIn total 628 participants diagnosed with IA were included. Men diagnosed ≤30 years had a lower mean number of children (1.32 (SD 1.14)) than men diagnosed between 31 and 40 years (1.60 (SD 1.35)) and men diagnosed ≥41 years (1.88 (SD 1.14)).This was statistically significant (p=0.0004).The percentages of men diagnosed ≤30 and 31–40 years who were involuntary childless (12.03% vs 10.34% vs 3.98%, p=0.001) and who reported having received medical evaluations for fertility problems (20.61%, 20.69% and 11.36%, p=0.027) were statistically significant higher than men diagnosed ≥41 years.ConclusionsThis is the first study that shows that IA can impair male fertility. Men diagnosed with IA before and during the peak of reproductive age had a lower fertility rate, higher childlessness rate and more fertility problems. Increased awareness and more research into the causes behind this association are urgently needed.

Objectives According to guidelines, clinical arthritis is mandatory for diagnosing RA. However, in the absence of clinical synovitis, imaging-detected subclinical synovitis is increasingly used instead and is considered as a starting point for DMARD therapy. To search for evidence we studied the natural course of arthralgia patients with subclinical synovitis from three longitudinal cohorts and determined the frequencies of non-progression to clinically apparent inflammatory arthritis (IA) (i.e. ‘false positives’). Methods Subclinical synovitis in the hands or feet of arthralgia patients was visualized with US (two cohorts; definition: greyscale ≥2 and/or power Doppler ≥1) or MRI (one cohort; definition: synovitis score ≥1 by two readers). Patients were followed for 1 year on for IA development; two cohorts also had 3 year data. Analyses were stratified for ACPA. Results Subclinical synovitis at presentation was present in 36%, 41% and 31% in the three cohorts. Of the ACPA-positive arthralgia patients with subclinical synovitis, 54%, 44% and 68%, respectively, did not develop IA. These percentages were even higher in the ACPA-negative arthralgia patients: 66%, 85% and 89%, respectively. Similar results were seen after 3 years of follow-up. Conclusion Replacing clinical arthritis with subclinical synovitis to identify RA introduces a high false-positive rate (44–89%). These data suggest an overestimation regarding the value of ACPA positivity in combination with the presence of subclinical synovitis in patients with arthralgia, which harbours the risk of overtreatment if DMARDs are initiated in the absence of clinical arthritis.

C-C chemokine receptor 5 (CCR5) and polymorphisms in CCR5 gene are associated with sarcoidosis and Löfgren’s syndrome. Löfgren’s syndrome is an acute and usually self-remitting phenotype of sarcoidosis. We investigated whether the single nucleotide polymorphism (SNP) rs1799987 is associated with susceptibility for Löfgren’s syndrome and has an effect on CCR5 expression on monocytes and function of CCR5. A total of 106 patients with Löfgren’s syndrome and 257 controls were genotyped for rs1799987. Expression of CCR5 on monocytes was measured by flowcytometry. We evaluated calcium influx kinetics following stimulation upon N-formylmethionyl-leucyl-phenylalanine (fMLP) and macrophage inflammatory protein-1α (MIP-1α) on monocytes by measuring the median fluorescence intensity (MFI). The frequency of the G allele of rs1799987 was significantly higher in Löfgren’s syndrome than in healthy controls (p = 0.0015, confidence interval (CI) 1.22–2.32, odds ratio (OR) 1.680). Patients with a GG genotype showed higher CCR5 expression on monocytes than patients with the AA genotype (p = 0.026). A significantly (p = 0.027) lower count of patients with the GG genotype showed a calcium influx reaction to simulation upon MIP-1 α, compared with patients with the AA genotype. The rs1799987 G allele in CCR5 gene is associated with susceptibility to Löfgren’s syndrome and with quantitative and qualitative changes in CCR5, potentially effecting the inflammatory response.

With great interest we read the article of Gessl et al that studied whether tenderness of non-swollen small hand joints was explained by subclinical inflammation as detected by ultrasound (US). Interestingly, the findings in rheumatoid arthritis (RA) were dependent on the disease stage: tenderness in longstanding RA (mean disease duration 7.2 years) was not associated with subclinical inflammation, while in early RA (disease duration

Inleiding Om de vroege herkenning van artritis te bevorderen kunnen huisartsen in Leiden en omstreken bij twijfel over de aanwezigheid van artritis verwijzen naar een anderhalvelijnsinlooppoli voor gewrichts-onderzoek door een reumatoloog. In andere regio’s is deze laagdrempelige service niet beschikbaar. Om deze regio’s een handvat te bieden onderzochten we op basis van gegevens van de inlooppoli of een eenvoudige scorelijst behulpzaam kan zijn bij het herkennen van artritis. Methode Patienten die van september 2010 tot en met september 2015 werden verwezen vanwege twijfel over de aanwezigheid van artritis (n = 1288) vulden een vragenlijst in over hun symptomen. Voor het ontwikkelen en valideren van de scorelijst verdeelden we ze in twee groepen. Vragenlijstonderdelen die samenhingen met de aanwezigheid van artritis bij het gewrichtsonderzoek door de reumatoloog namen we op in een gewogen scorelijst. Deze geeft de kans op artritis weer. Resultaten We stelden artritis vast bij 41% van de patienten. De scorelijst bevat slechts zeven factoren: mannelijk geslacht, leeftijd ≥ 60, symptoomduur 60 minuten, 1-3 pijnlijke gewrichten, door de patient gerapporteerde gewrichtszwelling en moeite met het maken van een vuist. Het gebied onder de ROC-curve was in het ontwikkelingscohort en validatiecohort respectievelijk 0,74 (95%-BI 0,70 tot 0,78) en 0,71 (95%-BI 0,67 tot 0,75). Conclusie Bij twijfel over de aanwezigheid van artritis kan een eenvoudige scorelijst huisartsen helpen bepalen of zij de patient moeten verwijzen. Validatie van de lijst in de eerste lijn is echter nodig.

Summary There is a current imperative to unravel the hierarchy of molecular pathways that drive the transition of early to established disease in rheumatoid arthritis (RA). Herein, we report a comprehensive RNA sequencing analysis of the molecular pathways that drive early RA progression in the disease tissue (synovium), comparing matched peripheral blood RNA-seq in a large cohort of early treatment-naive patients, namely, the Pathobiology of Early Arthritis Cohort (PEAC). We developed a data exploration website (https://peac.hpc.qmul.ac.uk/) to dissect gene signatures across synovial and blood compartments, integrated with deep phenotypic profiling. We identified transcriptional subgroups in synovium linked to three distinct pathotypes: fibroblastic pauci-immune pathotype, macrophage-rich diffuse-myeloid pathotype, and a lympho-myeloid pathotype characterized by infiltration of lymphocytes and myeloid cells. This is suggestive of divergent pathogenic pathways or activation disease states. Pro-myeloid inflammatory synovial gene signatures correlated with clinical response to initial drug therapy, whereas plasma cell genes identified a poor prognosis subgroup with progressive structural damage., Graphical Abstract, Highlights • Deep phenotyping and RNA-seq of early rheumatoid arthritis individuals pre-treatment • Synovial plasma cell gene expression predicts future progressive joint damage on X-ray • Blood interferon gene signature associates with synovial B and plasma cell infiltration • Interactive website enables RNA-seq and clinical data to be fully explored, Lewis et al. use histology and RNA-seq of synovial biopsies from a cohort of early rheumatoid arthritis individuals to identify three histological pathotypes and reveal gene modules associated with disease severity and clinical response.

The favourable long-term results of early treatment in patients with classified rheumatoid arthritis have resulted in an increasing interest in the diseases phases preceding clinical arthritis. The hypothesis to test is that an intervention in these early phases may better prevent or reduce disease persistence than an intervention when arthritis has become clinically manifest. While several placebo-controlled trials are still ongoing, to date there is no firm evidence that this hypothesis truly holds. Therefore, it is important to reflect on the current status of arthralgia preceding clinical arthritis. Inherent to every new field of research, attitudes are conflicting, with opinions propagating innovation (based on the fear of undertreatment) on the one hand, and critical sounds pleading for more restraint (fear of overtreatment) on the other hand. In this Viewpoint, we will examine these divergent opinions, relate them to a preferred ultimate scenario and provide considerations for future studies and daily practice.

Objectives Tenosynovitis (inflammation of the synovial lining of the sheath surrounding tendons) is frequently observed on MRI of early arthritis patients. Since visual assessment of tenosynovitis is a laborious task, we investigated the feasibility of automatic quantification of tenosynovitis on MRI of the wrist in a large cohort of early arthritis patients. Methods For 563 consecutive early arthritis patients (clinically confirmed arthritis ≥ 1 joint, symptoms

Objectives Advanced imaging modalities have shown that not only joints but also bones and tendon sheaths can be inflamed at diagnosis of RA. We aimed to better understand the time-order in which the inflamed tissues respond to DMARD treatment. Also, because ACPA status may reflect a different pathophysiology, differences in time-order of inflammation decrease were hypothesized between these disease types. Methods A total of 216 consecutive patients presenting with RA (n = 176) or undifferentiated arthritis (n = 40), who all started with conventional synthetic DMARD treatment, were studied. 1.5T contrast-enhanced hand and foot MRIs were performed before treatment and after 4, 12 and 24 months. Cross-lagged models evaluated the influence of two time patterns: a simultaneous pattern (‘change in one inflammatory feature associated with change in another feature’) and a subsequent pattern (‘change in one inflammatory feature preceded change in another feature’). ACPA stratification was performed. Results The median symptom duration at presentation was 13 weeks. Forty-four percent of patients was ACPA-positive. All pairs of inflammatory features decreased simultaneously in all time intervals (0–4/4–12/12–24 months; P 4–12 months; P = 0.02 and 4–12 to >12–24 months; P = 0.03). Largely similar results were obtained in both ACPA subgroups. Additionally, in ACPA-positive but not ACPA-negative patients, synovitis decrease preceded osteitis decrease (4–12 to >12–24 moths; P = 0.002). Conclusion This study increased the understanding of the response to treatment on the tissue level. In addition to simultaneous decrease of inflammation, synovitis decrease preceded tenosynovitis decrease. Differences in time-order of inflammation decrease between ACPA subgroups suggest differences in underlying inflammatory pathways.

Background/Aims Early diagnosis and intervention improves outcomes of immune mediated rheumatic and musculoskeletal diseases (RMDs) but may be hampered by diagnostic uncertainty. The extent to which rationally selected molecular parameters add value to clinical characteristics for diagnostic prediction in undifferentiated disease states warrants investigation. B lymphocytes play an increasingly recognised role in rheumatoid arthritis (RA) pathogenesis, and cell-specific methylation patterns link environmental exposures to genetic risk. We derived and tested the practical utility of a B lymphocyte-derived DNA methylation signature for predicting RA in an early arthritis clinic cohort. Methods CD19+ B cell and peripheral blood mononuclear cell (PBMC) whole genome DNA methylation array data were available, respectively, from 109 inflammatory arthritis patients naïve to immunomodulatory drugs (Newcastle, UK; 38% confirmed to have a diagnosis of RA within 1 year) and 50 untreated undifferentiated arthritis (UA) patients (Leiden, The Netherlands; 68% classifiable RA within 1 year by 1987 ACR criteria versus alternate diagnoses). A bespoke machine learning pipeline employed a sequential model-based optimisation (SMBO) procedure for selecting, tuning and applying methods amongst ten feature-selection, six data-sampling and two classification algorithms in the Newcastle “training cohort.” The predictive performance of the resultant optimised molecular classifier was assessed in the independent Leiden “test cohort” alongside a previously described clinical prediction rule, using comparative area under receiver operating characteristic (AUROC) curves. A modification to the clinical prediction rule that incorporated a single parameter to reflect molecular classification was also assessed. The pipeline was implemented using the R machine learning package mlr. Results Using the SMBO approach, 27 CpGs maximally discriminatory for RA were selected from B lymphocyte DNA methylome training data, and a molecular classifier was derived using the random forest algorithm. Applied to the independent PBMC methylome in UA patients, the classifier and the validated Leiden prediction rule performed similarly in predicting RA (AUROC [95% CI] = 0.8 [0.66-0.94] versus 0.78 [0.64-0.92]). Interestingly, incorporating a molecular risk score based on the 27-CpG signature into the validated Leiden clinical prediction rule significantly improved its performance (AUROC [95% CI] = 0.89 [0.79-0.98] versus 0.78 [0.64-0.92]; p = 0.048). When applied to the sub-cohort of 25 patients in the Leiden cohort who were negative for anti-citrullinated peptide autoantibodies (ACPA), enhanced performance of the modified over the un-modified clinical prediction rule was maintained (AUROC [95% CI] = 0.82 [0.65-1] versus 0.70 [0.45-0.95], respectively), although the difference did not reach statistical significance in this smaller cohort. Conclusion We provide a proof of principle for the application of a B lymphocyte-derived epigenetic signature to enhance prediction of RA in UA patients using stored PBMCs. Further refinement of our pipeline represents a plausible means to expedite the diagnosis in undifferentiated RMDs and could offer pathophysiological insight. Disclosure N. Naamane: None. E. Niemantsverdriet: None. N. Thalayasingam: None. N. Nair: None. A.D. Clark: None. K. Murray: None. B. Hargreaves: None. L.N. Reynard: None. S. Eyre: None. A. Barton: None. A.H.M. van der Helm-van Mil: None. A.G. Pratt: None.

Several nested case-control studies have shown that autoantibody-response maturation in rheumatoid arthritis (RA) precedes clinical arthritis development.1–3 This suggests a role in disease triggering. However, nested case-control studies have, similar to case-control studies, the disadvantage that controls are selected and that prospective data from non-progressing patients in a similar predisease stage are absent. The phase preceding clinically apparent inflammatory arthritis (IA) can be distinguished into an asymptomatic and symptomatic (ie, clinically suspect arthralgia, CSA) subphase. It is unknown whether autoantibody-response maturation occurs in the symptomatic phase. Likewise, its role in progression to clinical arthritis is undetermined; if autoantibody-response maturation relates to disease development, maturation is expected to be more pronounced in patients with CSA that progress compared with patients with CSA that do not. To better understand the relation between autoantibody-response maturation in time and development of clinical arthritis (RA/IA), we performed a longitudinal study on autoantibody-response maturation in patients with CSA that did and did not progress. In serum from 147 patients with CSA, we determined with in-house ELISAs the presence and levels of IgM, IgG, IgA anti-citrullinated, anti-carbamylated and anti-acetylated protein antibodies (ACPA, anti-CarP, AAPA), resulting in nine autoantibody measurements per patient per timepoint. Autoantibody-response maturation was defined as increase in number of autoantibody reactivities or isotypes, and/or increase in autoantibody levels. Patients with CSA with paired samples at first presentation at the outpatient clinic and at IA development (n=55) or else after 2 years (n=92) were selected. Analyses were repeated with the outcome RA (the subgroup of patients with IA that fulfilled …

Rheumatoid arthritis (RA) patients show an earlier circadian rhythm (i.e. serum melatonin peaks earlier during the night, indicating an earlier timing of the internal circadian pacemaker). In the current study, we examined whether the chronotype, which is influenced by the circadian rhythm, is also earlier. In addition, we explored whether chronotype is related to disease activity and patient-reported outcomes.The chronotype (Munich Chronotype Questionnaire) of patients with RA (n = 121; mean age 60 years, 73% female) was compared with that of subjects from the general population (norm group; n = 1695) with a one-sample t test. In addition, we investigated chronotype in relation to disease activity (Disease Activity Score; DAS), reported morning stiffness, fatigue (Checklist Individual Strength), and health-related quality of life (RAND-36).The chronotype of patients with RA was, on average, 23 min (95% CI, 15 to 31 min) earlier than that of the norm group (t(115) = - 5.901, p 0.001, d = 0.55). Chronotype was not related to disease activity or patient-reported outcomes (p 0.05).As expected, chronotype was earlier in RA patients. However, in this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm has a positive influence on these outcomes. This insight could improve our understanding of the pathophysiology of RA and contribute to exploring new treatment possibilities. Key Points • This is the first study examining chronotype in patients with rheumatoid arthritis, and how chronotype relates to disease activity and patient-reported outcomes. • We found an earlier chronotype in patients with rheumatoid arthritis than in subjects from the general population. • In this correlational study, chronotype was not related to disease activity or patient-reported outcomes. An experimental study is needed to examine whether delaying the circadian rhythm positively influences these outcomes.

Early diagnosis and management of patients with inflammatory arthritis (IA) are critical to improve long-term patient outcomes. Assessment of joint swelling at joint examination is the reference of IA identification; early access clinics are constructed to promote this early recognition. Due to the COVID-19 pandemic, the face-to-face capacity of such services is severely reduced.1 This raises the concern of a major step backward after the important progress that has been made in the past 15 years.1 Telemedicine has recently become rapidly implemented. Although probably a valuable alternative in the management of established rheumatoid arthritis (RA), there is also the fear that this might cause delay in the speed of diagnosis.2 A symptom that evidently raises suspicion for IA during remote evaluation is the presence of patient-reported swelling. This symptom is also included in triage tools.3 4 The accuracy of patient-reported swelling in comparison with joint examination has been extensively evaluated in established RA. Heterogeneous results are reported; correlation coefficients were higher when patient scored their swelling on mannequins (ρ: 0.31–0.67) than when determined with questions.5 Hypothetically, the accuracy of patient-reported joint swelling for first recognition of IA is different than for flare detection in patients with established RA. To promote evidence-based care in the era of telemedicine, we determined the accuracy of patient-reported joint swelling for actual presence of IA in persons suspected of …