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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. [ABSTRACT FROM AUTHOR]

Objectives Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB. Methods A total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed. Results At presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P  < 0.001). Patients with IMB were more likely to also have subclinical synovitis [OR 3.4 (95% CI 1.8, 6.5)] and tenosynovitis [5.9(2.8, 12.6)]. IMB conferred higher risk of developing arthritis [HR 1.6(1.0–2.7) adjusted for other subclinical inflammation]. IMB-presence predicted arthritis development in ACPA-positive CSA [adjusted HR 2.2(1.0–4.7)], but not in ACPA-negative CSA-patients [0.8(0.4–1.7)]. Conclusion Approximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development. [ABSTRACT FROM AUTHOR]

Objectives: The 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.Methods: We 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).Results: Meta-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.Conclusions: HLA-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. [ABSTRACT FROM AUTHOR]

Objectives: Intermetatarsal bursitis (IMB) represents juxta-articular synovial inflammation of the intermetatarsal bursae. Recent MRI studies identified IMB as feature of early RA, but whether IMB already occurs in the pre-arthritic phase is unknown. We performed a large MRI study in clinically suspect arthralgia (CSA) to assess the occurrence and prognostic value of IMB., Methods: A total of 577 consecutive CSA patients underwent contrast-enhanced MRI of the forefoot, metacarpophalangeal joints and wrist. MRIs were evaluated for subclinical synovitis/tenosynovitis/osteitis in line with the RA MRI scoring system (summed as RAMRIS inflammation) and for IMB. IMB was considered present if uncommon in the general population at the same location (i.e. size scored above the 95th percentile in age-matched symptom-free controls). The relation of IMB with other MRI-detected subclinical inflammation (synovitis/tenosynovitis/osteitis) was studied. Cox-regression assessed the association with clinical arthritis development during median 25 months follow-up. ACPA stratification was performed., Results: At presentation with CSA, 23% had IMB. IMB was more frequent in ACPA-positive than ACPA-negative CSA (47% vs 19%, P < 0.001). Patients with IMB were more likely to also have subclinical synovitis [OR 3.4 (95% CI 1.8, 6.5)] and tenosynovitis [5.9(2.8, 12.6)]. IMB conferred higher risk of developing arthritis [HR 1.6(1.0-2.7) adjusted for other subclinical inflammation]. IMB-presence predicted arthritis development in ACPA-positive CSA [adjusted HR 2.2(1.0-4.7)], but not in ACPA-negative CSA-patients [0.8(0.4-1.7)]., Conclusion: Approximately a quarter of CSA patients have IMB, which is frequently accompanied by subclinical synovitis and tenosynovitis. IMB precedes development of clinical arthritis, particularly in ACPA-positive CSA. These results reinforce the notion that juxta-articular synovial inflammation is involved in the earliest phases of RA development., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

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., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology.)