Brain age as a biomarker for pathological versus healthy ageing - a REMEMBER study.

OBJECTIVES: This study aimed to evaluate the potential clinical value of a new brain age prediction model as a single interpretable variable representing the condition of our brain. Among many clinical use cases, brain age could be a novel outcome measure to assess the preventive effect of life-style interventions. METHODS: The REMEMBER study population (N = 742) consisted of cognitively healthy (HC,N = 91), subjective cognitive decline (SCD,N = 65), mild cognitive impairment (MCI,N = 319) and AD dementia (ADD,N = 267) subjects. Automated brain volumetry of global, cortical, and subcortical brain structures computed by the CE-labeled and FDA-cleared software icobrain dm (dementia) was retrospectively extracted from T1-weighted MRI sequences that were acquired during clinical routine at participating memory clinics from the Belgian Dementia Council. The volumetric features, along with sex, were combined into a weighted sum using a linear model, and were used to predict 'brain age' and 'brain predicted age difference' (BPAD = brain age-chronological age) for every subject. RESULTS: MCI and ADD patients showed an increased brain age compared to their chronological age. Overall, brain age outperformed BPAD and chronological age in terms of classification accuracy across the AD spectrum. There was a weak-to-moderate correlation between total MMSE score and both brain age (r = -0.38,p < .001) and BPAD (r = -0.26,p < .001). Noticeable trends, but no significant correlations, were found between BPAD and incidence of conversion from MCI to ADD, nor between BPAD and conversion time from MCI to ADD. BPAD was increased in heavy alcohol drinkers compared to non-/sporadic (p = .014) and moderate (p = .040) drinkers. CONCLUSIONS: Brain age and associated BPAD have the potential to serve as indicators for, and to evaluate the impact of lifestyle modifications or interventions on, brain health.

The course of cytokine and chemokine gene expression in clinically suspect arthralgia patients during progression to inflammatory arthritis.

OBJECTIVES: Autoantibody responses increase years before the onset of inflammatory arthritis (IA) and are stable during transitioning from clinically suspect arthralgia (CSA) to IA. Cytokine and chemokine levels also increase years before IA onset. However, the course in the at-risk stage of CSA during progression to disease or non-progression is unknown. To increase the understanding of processes mediating disease development, we studied the course of cytokine, chemokine and related receptors gene expression in CSA patients during progression to IA and in CSA patients who ultimately did not develop IA. METHODS: Whole-blood RNA expression of 37 inflammatory cytokines, chemokines and related receptors was determined by dual-colour reverse transcription multiplex ligation-dependent probe amplification in paired samples of CSA patients at CSA onset and either at IA development or after 24 months without IA development. ACPA-positive and ACPA-negative CSA patients developing IA were compared at CSA onset and during progression to IA. Generalised estimating equations tested changes over time. A false discovery rate approach was applied. RESULTS: None of the cytokine/chemokine genes significantly changed in expression between CSA onset and IA development. In CSA patients without IA development, G-CSF expression decreased (P = 0.001), whereas CCR6 and TNIP1 expression increased (P < 0.001 and P = 0.002, respectively) over a 2 year period. Expression levels in ACPA-positive and ACPA-negative CSA patients who developed IA were similar. CONCLUSION: Whole-blood gene expression of assessed cytokines, chemokines and related receptors did not change significantly from CSA to IA development. This suggests that changes in expression of these molecules may not be related to the final process of developing chronicity and may have occurred preceding CSA onset. Changes in gene expression in CSA patients without IA development may provide clues for processes related to resolution.

The Role of Genetics in Clinically Suspect Arthralgia and Rheumatoid Arthritis Development: A Large Cross-Sectional Study.

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.

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

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

Investigating Tissue-Specific Abnormalities in Alzheimer's Disease with Multi-Shell Diffusion MRI.

BACKGROUND: Most studies using diffusion-weighted MRI (DW-MRI) in Alzheimer's disease (AD) have focused their analyses on white matter (WM) microstructural changes using the diffusion (kurtosis) tensor model. Although recent works have addressed some limitations of the tensor model, such as the representation of crossing fibers and partial volume effects with cerebrospinal fluid (CSF), the focus remains in modeling and analyzing the WM. OBJECTIVE: In this work, we present a brain analysis approach for DW-MRI that disentangles multiple tissue compartments as well as micro- and macroscopic effects to investigate differences between groups of subjects in the AD continuum and controls. METHODS: By means of the multi-tissue constrained spherical deconvolution of multi-shell DW-MRI, underlying brain tissue is modeled with a WM fiber orientation distribution function along with the contributions of gray matter (GM) and CSF to the diffusion signal. From this multi-tissue model, a set of measures capturing tissue diffusivity properties and morphology are extracted. Group differences were interrogated following fixel-, voxel-, and tensor-based morphometry approaches while including strong FWE control across multiple comparisons. RESULTS: Abnormalities related to AD stages were detected in WM tracts including the splenium, cingulum, longitudinal fasciculi, and corticospinal tract. Changes in tissue composition were identified, particularly in the medial temporal lobe and superior longitudinal fasciculus. CONCLUSION: This analysis framework constitutes a comprehensive approach allowing simultaneous macro and microscopic assessment of WM, GM, and CSF, from a single DW-MRI dataset.

Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial.

BACKGROUND: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. METHODS: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. FINDINGS: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0·81, 95% CI 0·45 to 1·48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0·09, 95% CI -0·16 to -0·03; p=0·0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p<0·0001), morning stiffness of joints (-12, -16 to -8; p<0·0001), presenteeism (-8%, -13 to -3; p=0·0007), and MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. INTERPRETATION: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo. FUNDING: Dutch Research Council (NWO; Dutch Arthritis Society).

Central Role of Semaphorin 3B in a Serum-Induced Arthritis Model and Reduced Levels in Patients With Rheumatoid Arthritis.

OBJECTIVE: Semaphorin 3B (Sema3B) decreases the migratory and invasive capacities of fibroblast-like synoviocytes (FLS) in rheumatoid arthritis (RA) and suppresses expression of matrix metalloproteinases. We undertook this study to examine the role of Sema3B in a mouse model of arthritis and its expression in RA patients. METHODS: Clinical responses, histologic features, and FLS function were examined in wild-type (WT) and Sema3B-/- mice in a K/BxN serum transfer model of arthritis. Protein and messenger RNA expression of Sema3B in mouse joints and murine FLS, as well as in serum and synovial tissue from patients with arthralgia and patients with RA, was determined using enzyme-linked immunosorbent assay, immunoblotting, quantitative polymerase chain reaction, and RNA sequencing. FLS migration was determined using a wound closure assay. RESULTS: The clinical severity of serum-induced arthritis was significantly higher in Sema3B-/- mice compared to WT mice. This was associated with increased expression of inflammatory mediators and increased migratory capacity of murine FLS. Administration of recombinant mouse Sema3B reduced the clinical severity of serum-induced arthritis and the expression of inflammatory mediators. Sema3B expression was significantly lower in the synovial tissue and serum of patients with established RA compared to patients with arthralgia. Serum Sema3B levels were elevated in patients with arthralgia that later progressed to RA, but not in those who did not develop RA; however, these levels drastically decreased 1 and 2 years after RA development. CONCLUSION: Sema3B expression plays a protective role in a mouse model of arthritis. In RA patients, expression levels of Sema3B in the serum depend on the disease stage, suggesting different regulatory roles in disease onset and progression.

Associating Alzheimer's disease pathology with its cerebrospinal fluid biomarkers.

Alzheimer's disease CSF biomarkers 42 amino acid long amyloid-ß peptide (Aß1-42), total tau protein (T-tau), and tau protein phosphorylated at threonine 181 (P-tau181) are considered surrogate biomarkers of Alzheimer's disease pathology, and significantly improve diagnostic accuracy. Their ability to reflect neuropathological changes later in the disease course is not well characterized. This study aimed to assess the potential of CSF biomarkers measured in mid to late stage Alzheimer's disease to reflect post-mortem neuropathological changes. Individuals were selected from two autopsy cohorts of Alzheimer's disease patients in Antwerp and Amsterdam. Neuropathological diagnosis was performed according to the updated consensus National Institute on Aging-Alzheimer's Association guidelines, which includes quantification of amyloid-ß plaque, neurofibrillary tangle, and neuritic plaque load. CSF samples were analysed for Aß1-42, T-tau, and P-tau181 by ELISA. One hundred and fourteen cases of pure definite Alzheimer's disease were included in the study (mean age 74 years, disease duration 6 years at CSF sampling, 50% females). Median interval between CSF sampling and death was 1 year. We found no association between Aß1-42 and Alzheimer's disease neuropathological change profile. In contrast, an association of P-tau181 and T-tau with Alzheimer's disease neuropathological change profile was observed. P-tau181 was associated with all three individual Montine scores, and the associations became stronger and more significant as the interval between lumbar puncture and death increased. T-tau was also associated with all three Montine scores, but in individuals with longer intervals from lumbar puncture to death only. Stratification of the cohort according to APOE ε4 carrier status revealed that the associations applied mostly to APOE ε4 non-carriers. Our data suggest that similar to what has been reported for Aß1-42, plateau levels of P-tau181 and T-tau are reached during the disease course, albeit at later disease stages, reducing the potential of tau biomarkers to monitor Alzheimer's disease pathology as the disease progresses. As a consequence, CSF biomarkers, which are performant for clinical diagnosis of early Alzheimer's disease, may not be well suited for staging or monitoring Alzheimer's disease pathology as it progresses through later stages.

Intermetatarsal Bursitis, a Novel Feature of Juxtaarticular Inflammation in Early Rheumatoid Arthritis Related to Clinical Signs: Results of a Longitudinal Magnetic Resonance Imaging Study.

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.

MRI-detected synovitis of the small joints predicts rheumatoid arthritis development in large joint undifferentiated inflammatory arthritis.

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.

Diagnostic Performance of Automated MRI Volumetry by icobrain dm for Alzheimer's Disease in a Clinical Setting: A REMEMBER Study.

BACKGROUND: Magnetic resonance imaging (MRI) has become important in the diagnostic work-up of neurodegenerative diseases. icobrain dm, a CE-labeled and FDA-cleared automated brain volumetry software, has shown potential in differentiating cognitively healthy controls (HC) from Alzheimer's disease (AD) dementia (ADD) patients in selected research cohorts. OBJECTIVE: This study examines the diagnostic value of icobrain dm for AD in routine clinical practice, including a comparison to the widely used FreeSurfer software, and investigates if combined brain volumes contribute to establish an AD diagnosis. METHODS: The study population included HC (n = 90), subjective cognitive decline (SCD, n = 93), mild cognitive impairment (MCI, n = 357), and ADD (n = 280) patients. Through automated volumetric analyses of global, cortical, and subcortical brain structures on clinical brain MRI T1w (n = 820) images from a retrospective, multi-center study (REMEMBER), icobrain dm's (v.4.4.0) ability to differentiate disease stages via ROC analysis was compared to FreeSurfer (v.6.0). Stepwise backward regression models were constructed to investigate if combined brain volumes can differentiate between AD stages. RESULTS: icobrain dm outperformed FreeSurfer in processing time (15-30 min versus 9-32 h), robustness (0 versus 67 failures), and diagnostic performance for whole brain, hippocampal volumes, and lateral ventricles between HC and ADD patients. Stepwise backward regression showed improved diagnostic accuracy for pairwise group differentiations, with highest performance obtained for distinguishing HC from ADD (AUC = 0.914; Specificity 83.0%; Sensitivity 86.3%). CONCLUSION: Automated volumetry has a diagnostic value for ADD diagnosis in routine clinical practice. Our findings indicate that combined brain volumes improve diagnostic accuracy, using real-world imaging data from a clinical setting.

Prediction of the Progression of Undifferentiated Arthritis to Rheumatoid Arthritis Using DNA Methylation Profiling.

OBJECTIVE: The term "undifferentiated arthritis (UA)" is used to refer to all cases of arthritis that do not fit a specific diagnosis. A significant percentage of UA patients progress to rheumatoid arthritis (RA), others to a different definite rheumatic disease, and the rest undergo spontaneous remission. Therapeutic intervention in patients with UA can delay or halt disease progression and its long-term consequences. It is therefore of inherent interest to identify those UA patients with a high probability of progressing to RA who would benefit from early appropriate therapy. This study was undertaken to investigate whether alterations in the DNA methylation profiles of immune cells may provide information on the genetically or environmentally determined status of patients and potentially discriminate between disease subtypes. METHODS: We performed DNA methylation profiling of a UA patient cohort, in which progression to RA occurred for a significant proportion of the patients. RESULTS: We found differential DNA methylation in UA patients compared to healthy controls. Most importantly, our analysis identified a DNA methylation signature characteristic of those UA cases that differentiated to RA. We demonstrated that the methylome of peripheral mononuclear cells can be used to anticipate the evolution of UA to RA, and that this methylome is associated with a number of inflammatory pathways and transcription factors. Finally, we designed a machine learning strategy for DNA methylation-based classification that predicts the differentiation of UA toward RA. CONCLUSION: Our findings indicate that DNA methylation profiling provides a good predictor of UA-to-RA progression to anticipate targeted treatments and improve clinical management.

Tenosynovitis has a high sensitivity for early ACPA-positive and ACPA-negative RA: a large cross-sectional MRI study.

OBJECTIVES: Clinically evident tenosynovitis can be seen in established rheumatoid arthritis (RA). Imaging research has recently shown that tenosynovitis at small joints occurs in early RA, contributes to typical RA symptoms (including joint swelling) and is infrequent in healthy controls. Imaging-detectable tenosynovitis is often not recognisable at joint examination, hence its prevalence can therefore be underestimated. We hypothesised that if MRI-detectable tenosynovitis is a true RA feature, the sensitivity for RA is high, in both anti-citrullinated protein antibodies (ACPA)-positive and ACPA-negative RA, and lower in other diseases that are associated with enthesitis (such as spondyloarthritis (SpA) and psoriatic arthritis (PsA)). So far, no large MRI study addressed these questions. METHODS: Consecutive patients with early arthritis (n=1211) from one healthcare region underwent contrast-enhanced 1.5T MRI of hand and foot at diagnosis. MRIs were scored for synovitis and tenosynovitis by two readers blinded for clinical data. All included patients with ACPA-positive RA (n=250), ACPA-negative RA (n=282), PsA (n=88), peripheral SpA (n=24), reactive arthritis (n=30) and self-limiting undifferentiated arthritis (UA; n=76) were studied. Sensitivity was calculated. RESULTS: The sensitivity of tenosynovitis in RA was 85%; 88% for ACPA-positive RA and 82% for and ACPA-negative RA (p=0.19). The sensitivity for RA was significantly higher than for PsA (65%; p=0.001), SpA (53%; p<0.001), reactive arthritis (36%; p<0.001) and self-limiting UA (42%; p<0.001). The observed sensitivity of MRI synovitis was 91% in RA and ranged from 83% to 54% in other groups. CONCLUSIONS: MRI-detected tenosynovitis has a high sensitivity for early ACPA-positive and ACPA-negative RA. This supports that both juxta-articular (tenosynovitis) and intra-articular synovial involvement is characteristic of RA.

Differing time-orders of inflammation decrease between ACPA subsets in RA patients suggest differences in underlying inflammatory pathways.

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 < 0.05). Moreover, time-orders were identified: synovitis decrease preceded tenosynovitis decrease (0-4 to >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.

The value of inquiring about functional impairments for early identification of inflammatory arthritis: a large cross-sectional derivation and validation study from the Netherlands.

OBJECTIVES: Healthcare professionals other than rheumatologists experience difficulties in detecting early inflammatory arthritis (IA) by joint examination. Self-reported symptoms are increasingly considered as helpful and could be incorporated in online tools to assist healthcare professionals, but first their discriminative ability must be assessed. As part of this effort, we evaluated whether inquiring about functional impairments could aid early IA identification. DESIGN: Cross-sectional derivation and validation study. SETTING: Data from two Early Arthritis Recognition Clinics (EARC) in the Netherlands were studied, which are easy access outpatient rheumatology clinics intermediary between primary and secondary care for patients in whom general practitioners suspect but are unsure about IA presence. PARTICIPANTS: Between 2010 and 2014, 997 patients consecutively visited the Leiden-EARC (derivation cohort). Patients consecutively visiting the Groningen EARC (2010-2014, n=506) and Leiden-EARC (2015-2018, n=557) served as validation cohorts. PRIMARY AND SECONDARY OUTCOME MEASURES: Physical functioning was assessed with the Health Assessment Questionnaire Disability-Index (HAQ); IA presence by physical joint examination by rheumatologists. HAQ questions were studied individually regarding discriminative ability for IA presence. For the best discriminating question, ORs and positive predictive values (PPVs) for IA presence were determined. RESULTS: IA was ascertained in 43% (derivation cohort), 53% and 35% (validation cohorts). In the derivation cohort, IA presence associated with higher mean HAQ scores (0.84 vs 0.73, p=0.003). One question on difficulties with dressing equalled discriminative ability of the total HAQ score. 'Difficulties with dressing' yielded ORs for IA presence of 1.8 (95% CI 1.4 to 2.4) in the derivation cohort; 2.0 (1.4 to 2.9) and 2.1 (1.5 to 3.1) in the validation cohorts. After adjustments for clinical characteristics these were 1.7 (1.3 to 2.3), 1.6 (1.1 to 2.5) and 1.9 (1.2 to 2.9). PPVs (probabilities of IA for positive answers) ranged 42%-60% and negative predictive values (probabilities of no IA for negative answers) ranged 57%-74%. CONCLUSIONS: Patient-reported difficulties with dressing in patients with suspected IA associated with actual IA presence. Although further validation is required, for example, in primary care, this simple question could be of help in future early IA detection tools for healthcare professionals with limited experience in joint examination.

Genome-wide association study of Alzheimer's disease CSF biomarkers in the EMIF-AD Multimodal Biomarker Discovery dataset.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and the most common form of dementia in the elderly. Susceptibility to AD is considerably determined by genetic factors which hitherto were primarily identified using case-control designs. Elucidating the genetic architecture of additional AD-related phenotypic traits, ideally those linked to the underlying disease process, holds great promise in gaining deeper insights into the genetic basis of AD and in developing better clinical prediction models. To this end, we generated genome-wide single-nucleotide polymorphism (SNP) genotyping data in 931 participants of the European Medical Information Framework Alzheimer's Disease Multimodal Biomarker Discovery (EMIF-AD MBD) sample to search for novel genetic determinants of AD biomarker variability. Specifically, we performed genome-wide association study (GWAS) analyses on 16 traits, including 14 measures derived from quantifications of five separate amyloid-beta (Aß) and tau-protein species in the cerebrospinal fluid (CSF). In addition to confirming the well-established effects of apolipoprotein E (APOE) on diagnostic outcome and phenotypes related to Aß42, we detected novel potential signals in the zinc finger homeobox 3 (ZFHX3) for CSF-Aß38 and CSF-Aß40 levels, and confirmed the previously described sex-specific association between SNPs in geminin coiled-coil domain containing (GMNC) and CSF-tau. Utilizing the results from independent case-control AD GWAS to construct polygenic risk scores (PRS) revealed that AD risk variants only explain a small fraction of CSF biomarker variability. In conclusion, our study represents a detailed first account of GWAS analyses on CSF-Aß and -tau-related traits in the EMIF-AD MBD dataset. In subsequent work, we will utilize the genomics data generated here in GWAS of other AD-relevant clinical outcomes ascertained in this unique dataset.