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Background Morning stiffness (MS) is characteristic of Rheumatoid Arthritis (RA) that is associated with functional disability. Despite the known parallel in the circadian rhythm of MS and that of several hormones and pro-inflammatory cytokines in the systemic circulation, it is insufficiently known to what extent local inflammatory processes contribute to this symptom. The correlation between MS and the number of swollen joints is relatively weak but may be underestimated by insufficient sensitivity in measuring local inflammation. MRI is more sensitive in detecting local inflammation. Furthermore, MRI-detected tenosynovitis of small joints is increasingly recognized as early feature of RA which is also associated with functional impairments. Recently it was proposed that this may contribute to MS. Objectives We assessed the relationship between MS and MRI-detected inflammation and tenosynovitis in particular. Methods 286 consecutive patients newly presenting with undifferentiated and rheumatoid arthritis underwent contrast-enhanced 1.5T-MRI of (2-5)MCP-, (1-5)MTP-, and wrist-joints. Scans were scored for tenosynovitis according to Haavardsholm and for synovitis, osteitis conform the RAMRIS-method. MS was dichotomized as>60 minutes. Associations between MS and tenosynovitis/synovitis were tested with logistic regression and the presence of a biologic interaction was assessed categorically (solitary or simultaneous presence of synovitis/tenosynovitis). Results MS was present in 40% of patients. Tenosynovitis was more often present in patients with MS than without MS (80% versus 65%), OR 2.11 (95%CI 1.21;3.69). Also synovitis was more often present in patients with MS (58% versus 44%), OR 1.83 (1.12;2.96). In categorized analyses the largest association was found for concurrent synovitis and tenosynovitis OR 2.43 (1.30;4.54); whereas single presence of synovitis was not associated (OR 0.85 (0.21;3.47)). The variance explained in all analyses on morning stiffness was small, ranging 3-6%. Conclusion Tenosynovitis, and simultaneous presence of tenosynovitis and synovitis in particular, was associated with MS. However, effect sizes suggested that the contribution of local inflammation to this symptom is rather limited. Acknowledgement E.C. Newsum and W.P. Nieuwenhuis are acknowledged for scoring MRI-scans. Disclosure of Interests Aleid Boer: None declared, Debbie Boeters: None declared, Ellis Niemantsverdriet: None declared, Annette van der Helm - van Mil Grant/research support from: The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No 714312) and from the Dutch Arthritis Foundation. The funding source had no role in the design and conduct of the study.

Background Presence of MRI-detected subclinical joint inflammation in clinically suspect arthralgia (CSA) is predictive for progression to Rheumatoid Arthritis. Despite high negative predictive values (94%); its positive predictive value (PPV) is moderate (∼31%). Objectives We studied if, in addition to the presence of inflammation, incorporating information on severity, number and combinations of MRI-inflammatory locations improves the predictive accuracy. Methods In the discovery cohort, 225 CSA-patients were followed on clinical arthritis development. Contrast-enhanced 1.5T MRIs were made of unilateral MCP(2-5), wrist and MTP(1-5)-joints at baseline and scored for synovitis, tenosynovitis and bone marrow edema. Severity, number and combination of locations (joint/tendon/bone) with subclinical inflammation were determined, with symptom-free controls of similar age category as reference. Cox regression was used for predictor selection. Predictive values were determined at 1-year follow-up. Results were validated in 266 CSA-patients. Results In both cohorts 15% developed arthritis Conclusion Incorporation of the number of locations with subclinical inflammation and MCP-extensor peritendinitis in MRI-evaluation improved risk stratification, yielding PPVs up to 63-67%. This promotes optimal use of MRI-data in an evidence-based way. Disclosure of Interests Xanthe Matthijssen: None declared, Fenne Wouters: None declared, Debbie Boeters: None declared, Aleid Boer: None declared, Yousra Dakkak: None declared, Ellis Niemantsverdriet: None declared, Saskia Le Cessie: None declared, Annette van der Helm - van Mil Grant/research support from: The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No 714312) and from the Dutch Arthritis Foundation. The funding source had no role in the design and conduct of the study.

Background Over the last 25 years, treatment of rheumatoid arthritis (RA) has changed considerably, and clinically relevant joint damage and deformations have become infrequent. It is unclear to what extent the long-term outcomes mortality, sustained drug-free remission (DFR) and physical functioning have improved, and whether ACPA+ and ACPA- patients have benefited equally from treatment-improvements. Objectives To investigate the influence of treatment strategies that have been improved for 25-years on mortality, DFR and functionality, and whether these effects differed for ACPA+ and ACPA- RA-patients. Methods In the Leiden early arthritis cohort, 1291 patients with RA (1987 criteria) were included between 1993-2016. Patients were treated in routine care; initial and subsequent treatment changed over time; divided in 5 inclusion periods. Patients included between 1993-1996 (n=168) received initial NSAIDs and started DMARDs with delay, patients included 1997-2000 (n=185) were treated early with mild DMARDs (e.g. hydroxychloroquine, penicillamine), in 2001-2005 (n=210) patients started early with methotrexate, in 2006-2010 (n=338) early methotrexate was followed by treat to target treatment adjustments; in 2011-2016 (n=390) this was similar and additional efforts were undertaken for very early referral. Patients were followed yearly including assessments of swollen joints, DAS28-ESR and health assessment questionnaires (HAQ). Mortality data were obtained from the civic registry. DFR was defined as the persistent absence of synovitis after cessation of DMARD-therapy during all available follow-up (≥ 1 year). DAS28-ESR and HAQ data were analysed with linear mixed models; mortality and time to DFR with multivariable and univariable Cox regression. Inclusion period 1993-1996 was used as reference. Analyses were stratified for ACPA-status (anti-CCP2). Results Baseline age, sex and antibody status did not differ between inclusion periods. With 1993-1996 as reference, the DAS28-ESR decreased in the first year and thereafter remained lower in all inclusion periods (all p Compared to 1993-1996, mortality was decreased in all inclusion periods (1997-2000 HR 0.67 (0.46;0.99); 2001-2005 HR 0.66 (0.45;0.97); 2006-2010 HR 0.64 (0.42;0.98); 2011-2016 HR 0.31 (0.14;0.68)). DFR achievement was faster in 2006-2010 (HR 2.68 (1.68;4.29)) and 2011-2016 (3.37 (1.97,5.74)), compared to 1993-1996. Additionally, HAQ over time was lower in 2006-2010 (-0.25 (-0.36;-0.14)) and 2011-2016 (-0.21 (-0.32;-0.10)). Stratification for ACPA revealed that ACPA+ patients in the first two inclusion periods remained to have a higher DAS28-ESR over time (1993-1996 β 0.76 (0.42;1.10); 1997-2000 β 0.40 (0.07;0.74)); thereafter there was no difference in DAS28-ESR between ACPA+ and ACPA- patients. The decrease in mortality was similar for ACPA+ and ACPA- patients. The increased rate of DFR was more prominent in ACPA+ patients than ACPA- patients in the two most recent inclusion periods (2006-2010 HR ACPA+: 3.85 (1.25;11.9); ACPA- 2.27 (1.34;3.83); 2011-2016 HR ACPA+: 6.48 (1.89;22.2); ACPA-: 3.04 (1.66;5.55)). Within ACPA+ RA, the HAQ over time had improved in 2001-2005 (-0.19 (-0.34;-0.04)), 2006-2010 (-0.35 (-0.49;-0.22)) and 2011-2016 (-0.26 (-0.40;-0.13)), compared to 1993-1996. This effect was absent ACPA- RA. Conclusion Improvements in treatment strategies during the last 25 years have resulted in lower disease activity, less mortality, more DFR and better physical functioning of RA-patients. ACPA+ patients, traditionally the most severe subset, benefited most from these improvements and have become more similar to ACPA- patients. Disclosure of Interests Xanthe Matthijssen: None declared, Ellis Niemantsverdriet: None declared, Thomas Huizinga Consultant for: Merck, UCB, Bristol Myers Squibb, Biotest AG, Pfizer, GSK, Novartis, Roche, Sanofi-Aventis, Abbott, Crescendo Bioscience Inc., Nycomed, Boeringher, Takeda, Zydus, Epirus, Eli Lilly, Annette van der Helm - van Mil Grant/research support from: The research leading to these results has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (Starting grant, agreement No 714312) and from the Dutch Arthritis Foundation. The funding source had no role in the design and conduct of the study.

Objective Based on a unique cohort of clinically suspect arthralgia (CSA) patients, we analysed which combinations of MRI features at onset were predictive for rheumatoid arthritis (RA) development. This was done to increase our comprehension of locations of RA onset and improve the predictive accuracy of MRI in CSA. Methods In the discovery cohort, 225 CSA patients were followed on clinical arthritis development. Contrast-enhanced 1.5 T MRIs were made of unilateral metacarpophalangeal (MCP) (2–5), wrist, and metatarsophalangeal (1–5) joints at baseline and scored for synovitis, tenosynovitis, and bone marrow edema. Severity, number, and combinations of locations (joint/tendon/bone) with subclinical inflammation were determined, with symptom-free controls of similar age category as reference. Cox regression was used for predictor selection. Predictive values were determined at 1 year follow-up. Results were validated in 209 CSA patients. Results In both cohorts, 15% developed arthritis Conclusion Tenosynovitis, particularly MCP-extensor peritendinitis, is among the first tissues affected by RA. Incorporating this feature and number of locations with subclinical inflammation improved prediction making with PPVs up to 63–67%.

Background: EULAR-recommendations for management of early arthritis formulated that patients should be referred to, and seen by a rheumatologist, within 6-weeks after symptom onset. Because implementation provides challenges, and evidence supporting that referral ≤6 weeks is better than e.g. 12-weeks. Multivariable Cox regression (SDFR), linear mixed models (radiographic progression), and meta-analyses were used. Findings: Leiden RA-patients encountered the rheumatologist within 6-weeks obtained SDFR more often than patients seen within 7-12-weeks (HR 1·59, 95%CI:1·02-2·49), and >12-weeks (HR 1·54, 95%CI:1·04-2·29). In ESPOIR, similar but non-significant effects were observed; meta-analysis showed that within 6-weeks was better than 7-12-weeks (HR 1·69, 95%CI:1·10-2·57) and >12-weeks (HR 1·67, 95%CI:1·08-2·58). Patients encountered the rheumatologist within 6-weeks had similar radiographic progression than those seen 7-12-weeks, in any cohort, or meta-analysis. Interpretation: Scientific evidence underlying the first EULAR recommendation depends on the outcome of interest; visiting a rheumatologist within 6-weeks of symptom-onset had clear benefits for achieving SDFR, but not for radiographic progression. Funding Statement: EAC was supported by the European Research Council (ERC-Starting grant, No714312) and the Dutch Arthritis Society. ESPOIR was funded by an unrestricted grant from Merck Sharp and Dohme (MSD) for the first 5 years. Additionally, two INSERM grants, The French Society of Rheumatology, Pfizer, Abbvie, Lilly, and Sanofi supported ESPOIR. Declaration of Interests: The authors stated: "None." Ethics Approval Statement: Written informed consent was obtained by all participants and both cohorts received approval by their ethical committees.

Disease-modifying treatment trials are increasingly advanced to the prodromal or preclinical phase of Alzheimer's disease (AD), and inclusion criteria are based on biomarkers rather than clinical symptoms. Therefore, it is of great interest to determine which biomarkers should be combined to accurately predict conversion from mild cognitive impairment (MCI) to AD dementia. However, up to date, only few studies performed a complete A/T/N subject characterization using each of the CSF and imaging markers, or they only investigated long-term (≥ 2 years) prognosis. This study aimed to investigate the association between cerebrospinal fluid (CSF), magnetic resonance imaging (MRI), amyloid- and 18F-FDG positron emission tomography (PET) measures at baseline, in relation to cognitive changes and conversion to AD dementia over a short-term (12-month) period. We included 13 healthy controls, 49 MCI and 16 AD dementia patients with a clinical-based diagnosis and a complete A/T/N characterization at baseline. Global cortical amyloid-β (Aβ) burden was quantified using the 18F-AV45 standardized uptake value ratio (SUVR) with two different reference regions (cerebellar grey and subcortical white matter), whereas metabolism was assessed based on 18F-FDG SUVR. CSF measures included Aβ1–42, Aβ1–40, T-tau, P-tau181, and their ratios, and MRI markers included hippocampal volumes (HV), white matter hyperintensities, and cortical grey matter volumes. Cognitive functioning was measured by MMSE and RBANS index scores. All statistical analyses were corrected for age, sex, education, and APOE ε4 genotype. As a result, faster cognitive decline was most strongly associated with hypometabolism (posterior cingulate) and smaller hippocampal volume (e.g., Δstory recall: β = +0.43 [p, Highlights • FDG-PET and MRI HV are the strongest predictors of cognitive decline and conversion to AD. • Combination of visuospatial construction testing with FDG-PET or MRI HV present high predicting power of conversion. • CSF and amyloid-PET seem less suitable markers of disease progression. • Increased AV45-PET predicts short-term cognitive decline if SUVR is referenced to WM instead of CB.

Introduction Dual-biomarker positron emission tomography (PET), providing complementary information on cerebral blood flow and amyloid-β deposition, is of clinical interest for Alzheimer's disease (AD). The purpose of this study was to validate the perfusion components of early-phase 18F-florbetapir (eAV45), the 18F-AV45 delivery rate (R1), and 18F-FDG against 15O-H2O PET and assess how they change with disease severity. Methods This study included ten controls, 19 amnestic mild cognitive impairment, and 10 AD dementia subjects. Within-subject regional correlations between modalities, between-group regional and voxel-wise analyses of covariance per modality, and receiver operating characteristic analyses for discrimination between groups were performed. Results FDG standardized uptake value ratio, eAV45 (0–2 min) standardized uptake value ratio, and AV45-R1 were significantly associated with H2O PET (regional Pearson r = 0.54–0.82, 0.70–0.94, and 0.65–0.92, respectively; P < .001). All modalities confirmed reduced cerebral blood flow in the posterior cingulate of patients with amnestic mild cognitive impairment and AD dementia, which was associated with lower cognition (r = 0.36–0.65, P < .025) and could discriminate between patient and control groups (area under the curve > 0.80). However, eAV45 was less sensitive to reflect the disease severity than AV45-R1 or FDG. Discussion R1 is preferable over eAV45 for accurate representation of brain perfusion in dual-biomarker PET for AD.

Background:The HLA shared epitope (SE) and smoking are the best known genetic and environmental risk factors for rheumatoid arthritis (RA) development; however, at which pre-RA stage they exert their effect is unknown. The following stages are discerned: an asymptomatic stage in which autoimmune responses can develop, a symptomatic stage (clinically suspect arthralgia (CSA)), and development of clinically apparent inflammatory arthritis (IA). Studies in the general asymptomatic population revealed contrasting results on the associations between SE-alleles and smoking and the presence of anti-citrullinated protein antibodies (ACPA). Furthermore, studies on these risk factors in the symptomatic pre-RA phase are scarce and these data might teach us whether SE-alleles and smoking are involved in symptom development and/or progression to clinical arthritis.Objectives:We aimed to determine at which pre-RA stage SE and smoking exert their effect. In this respect, the analyses were focused on the presence of ACPA, but associations for other anti-modified protein antibodies (anti-carbamylated and anti-acetylated protein antibodies (anti-CarP and AAPA, respectively)) were also studied.Methods:Results from the literature on the association of SE and smoking with ACPA in the asymptomatic population were summarized in inverse-variance weighted meta-analyses. In addition 577 CSA-patients were studied. Associations of SE and smoking with IgG ACPA were studied at baseline (CSA-onset), to assess an effect on symptom development. Additionally, patients were monitored for the development of clinically apparent inflammatory arthritis (IA) for median 2 years and associations of SE, smoking and auto-antibodies with progression to IA were determined. Analyses were stratified for ACPA-status and associations in ACPA-positive patients were validated in meta-analyses with other arthralgia-cohorts. Finally analyses were repeated for anti-CarP and AAPA.Results:Meta-analyses showed that SE is not associated with ACPA-positivity in the asymptomatic population (OR 1.06 (95%CI 0.69-1.64)), whereas smoking was associated (OR 1.37 (1.15-1.63)). At CSA-onset, both SE and smoking associated with ACPA-positivity (OR 2.08 (1.24-3.49) and OR 2.41 (1.31-4.43), respectively). During follow-up of CSA-patients SE associated with IA-development (HR 1.86 (1.23-2.82)), in contrast to smoking. SE conferred risk for IA-development in ACPA-negative CSA-patients (HR 1.71 (0.99-2.96)) and in ACPA-positive patients (CSA-cohort HR 1.29 (0.67-2.47); meta-analysis three arthralgia-cohorts HR 1.52 (1.08-2.15)). Investigating the other autoantibodies revealed that SE and smoking were not associated with anti-CarP or AAPA-positivity at CSA-onset; longitudinally AAPA associated with progression to IA independent from ACPA and RF (HR 1.79 (1.02-3.16)), whilst anti-Carp did not.Conclusion:SE and smoking act in partly different pre-RA stages. Although SE does not associate with ACPA in the general population, it does mediate symptom-development and further progression to clinical arthritis. Smoking confers risk to development of ACPA and/or joint symptoms, but is not further involved in IA-development. The time-specific biologic pathways that are underlying need further exploration. These data enhance the understanding of the timing of key genetic and environmental risk factors in the trajectory of RA development.Disclosure of Interests:None declared

Background:MRI facilitates early recognition of rheumatoid arthritis (RA) by depicting inflammation. Contrast-enhanced T1-weighted and T2-weighted fat-suppressed sequences have been sensitive and thus recommended, but are hampered by invasiveness, costs and long scan time. Therefore we introduced a modified Dixon-sequence (mDixon) which is more patient-friendly, reduces cost, and scan times by 83%. However, it is not known if this mDixon-sequence is reliable in relation to regular MRI-sequences with and without contrast (T1- and T2-weighted, respectively).Objectives:We determined the reliability between regular MRI-sequences with and without contrast (T1- and T2-weighted, respectively) and mDixon-MRI in early arthritis patients.Methods:29 early arthritis patients underwent regular fat-suppressed-MRI (T1- and T2-weighted) and mDixon-sequences, of metacarpophalangeal-2-5 and wrist-joints. Two readers scored erosions, osteitis, synovitis and tenosynovitis. Intraclass correlation coefficients (ICCs) between readers, and comparing the two sequences, were studied. Spearman correlations were determined.Results:Performance between the two readers with the regular-MRI sequences, was good to excellent (ICCs all ≥0.88). The between reader ICC was also good to excellent for the mDixon-MRI (ICCs all ≥0.76). Next, ICCs between the two sequences was investigated to determine the reliability of mDixon. ICCs were good to excellent for total RAMRIS score 0.87 (95%CI 0.74-0.94), for erosions 0.88 (95%CI 0.69-0.95), and total inflammation score 0.84 (95%CI 0.69-0.82). The individual MRI-inflammation scores, had ICCs for osteitis 0.97 (95%CI 0.93-0.98), for tenosynovitis 0.78 (95%CI 0.58-0.89), and for synovitis 0.57 (95%CI 0.26-0.77). In addition, scores were highly correlated for total RAMRIS, erosions, and total MRI-inflammation score (ρ=0.82, ρ=0.81, ρ=0.80, respectively).Conclusion:Regular-MRI sequences and mDixon-MRI perform equally well, this suggests that mDixon-sequence is reliable to detect joint inflammation. Thus, this is the first step towards an simplified and abridged MRI-protocol in small hand-joints in early arthritis patients. The ultimate goal will be implementation of this mDixon-MRI sequence. Validation in larger studies is warranted.Disclosure of Interests:None declared

Background:Pain in metacarpophalangeal (MCP)-joints in patients presenting with clinically suspect arthralgia (CSA) is one of the clinical features by which patients are considered at risk for progression to inflammatory arthritis (IA). As such this symptom is characteristic for CSA and therefore part of a list of clinical parameters determined by an EULAR-taskforce to identify a more homogeneous group of patients within CSA (the EULAR definition of arthralgia suspicious for progression to RA). MRI-detected subclinical inflammation is known to be present in patients with CSA. In general, arthralgia in CSA can be explained by this subclinical inflammation, however to date, the association of subclinical inflammation with pain in MCP-joints specifically is not clear. Subsequently, it is unknown whether this association differs pertinently when investigated with self-reported pain, or with pain in the form of tenderness at physical examination.Objectives:This study will investigate whether MCP-pain and MCP-joint tenderness are associated with MRI-detected subclinical inflammation in patients with CSA, and more specifically those who have progressed to IA.Methods:Between April 2012- February 2019, 602 patients were consecutively included in the Leiden clinically suspect arthralgia (CSA)-cohort. Follow-up ended when patients developed clinically apparent IA (determined at physical examination), or else after 2-years (median follow-up time 25 months). MCP-joints were assessed for self-reported joint pain by the patient using a mannequin and subsequently for joint tenderness by physical examination. Baseline unilateral MRIs of the MCP (2-5)-joints were scored by two readers, blinded for clinical data, on subclinical inflammation (synovitis, tenosynovitis, osteitis). Associations between MCP-pain or MCP-joint tenderness and MRI-detected subclinical inflammation were studied at patient level by logistic regression analyses, entering the mentioned MRI-detected features separately (univariable) and together (multivariable).Results:33% of 227 patients with self-reported MCP-pain had MRI-detected subclinical inflammation and 38% of 226 patients with MCP-joint tenderness had MRI-detected subclinical inflammation. Self-reported MCP-joint pain was univariable associated with subclinical inflammation and synovitis in particular (OR 2.00, 95% CI: 1.21-3.30, OR 2.87, 95% CI: 1.29-6.39). In multivariable analysis this MCP-pain was associated with synovitis (OR 2.54, 95% CI: 1.12-5.77). MCP-joint tenderness was univariable associated with subclinical inflammation, and synovitis and tenosynovitis in particular (OR 1.84, 95% CI: 1.29-2.63, OR 1.76, 95% CI: 1.10-2.81, OR 1.69, 95% CI: 1.12-2.55, respectively). In multivariable analysis, tenosynovitis remained significant (OR 1.54, 95% CI: 1.00-2.36). Of all patients with self-reported MCP-joint pain who developed IA, 50% had MRI-detected subclinical inflammation. For MCP-joint tenderness this was 61%. Patients with MCP-joint tenderness without subclinical inflammation who developed IA, developed clinical arthritis at a joint that was not scanned (85%), hence they may have had subclinical inflammation that was not imaged. The other 15% did develop arthritis in an MCP-joint, suggesting that subclinical inflammation developed after CSA-onset.Conclusion:Arthralgia in the MCP-joints is associated with subclinical inflammation in CSA, in particular with synovitis and tenosynovitis. The prevalence of subclinical inflammation is highest for tender joints at physical examination; this can be acknowledged when applying the EULAR definition of arthralgia suspicious for progression to RA.Disclosure of Interests:None declared

Background:The identification of a pre-RA stage of patients with clinically suspect arthralgia (CSA) has proven to be beneficial in the early detection of Rheumatoid disease. Similarly, genetic susceptibility studies have identified important genetic risk factors for the development of (CCP positive) RA.1 The question that arises is whether these findings represent independent etiological pathways and could therefore be complimentary in the early diagnosis of RA.Objectives:To corroborate the knowledge of genetic differences between HC and RA patients and extend it to include the CSA stage of disease.Methods:We used three datasets sampled from the same region in the Netherlands: 1,085 healthy controls (HC), 530 CSA and 1,277 RA patients. CSA patients were monitored for a median of 2 years for conversion into clinically apparent inflammatory arthritis (CSAc) or not (CSAnc).2 We assessed the association between HLA SE and disease stage using logistic regression. The analysis was repeated in the CCP positive and CCP negative strata of both the CSA and the RA populations.Results:Consistent with previous studies, HLA SE was significantly enriched in RA patients compared to HC (OR 2.28) (Figure 1). HLA SE also differentiated HC vs CSAc (OR 1.69), CSAnc vs CSAc (OR 1.74), and CSAnc vs RA (0R 2.35). No difference was found in HC vs CSAnc and CSAc vs RA.Conclusion:HLA SE is more prevalent in patients who developed (rheumatoid) arthritis than in both healthy controls and CSA patients who do not progress to arthritis. The results presented here seem to indicate a clear distinction between CSA patients who develop arthritis and those who do not. We therefore believe that known RA genetics play a role in the development of arthritis rather than the CSA symptoms. While this relationship varies by CCP status, an independent effect remains. Studies into the broader role of genetics beyond HLA SE are currently underway.Figure 1.Distinguishing ability of HLA SE across HC, CSAc, CSAnc and RA in the full populations as well as in the CCP positive and negative stratifications. The arrowhead indicates the “case” status in each logistic regression. OR’s (95% CI) derived from regression coefficients indicate the change in odds ratio attributable to HLA SE positivity.References:[1]van der Helm-van Mil, A. H., et al. Arthritis and rheumatism, 2006. 54(4): p. 1117–1121.[2]van Steenbergen, H.W., et al. Ann Rheum Dis, 2017. 76(3): p. 491-496.Disclosure of Interests:None declared

Background:The squeeze test (or compression test) is often used to quickly screen for arthritis in metacarpophalangeal (MCP)- and metatarsophalangeal (MTP)-joints. A positive test is traditionally assumed to indicate presence of synovitis. Previous studies in early arthritis indeed showed that a positive squeeze test was associated with presence of swollen MCP- and MTP-joints, as well as with local MRI-detected inflammation. The sensitivity of the test, with MRI-detected synovitis as reference, was 31-33%. The field is moving towards identifying patients at risk for rheumatoid arthritis (RA) in the phase of arthralgia. However, it is unclear if the squeeze test in the phase of clinically suspect arthralgia (CSA) is associated with subclinical inflammation, which can be detected with MRI.Objectives:We aimed to assess if a positive squeeze test in patients with CSA is associated with MRI-detected subclinical inflammation, especially with subclinical synovitis and tenosynovitis (the latter is recently identified as a strong predictor for RA-development).Methods:315 patients with recent-onset (Results:51% of CSA-patients had a positive squeeze test in MCP- or MTP-joints. In univariable analyses a positive test was associated with MRI-detected subclinical synovitis (OR 2.10 (95%CI 1.30-3.40)) and tenosynovitis (OR 1.68 (1.05-2.68)). In multivariable analyses including both inflammatory features only synovitis remained significant (OR 1.90 (1.16-3.13)). Thus, a positive squeeze test is a measure of subclinical synovitis, with a sensitivity of 44% (95%CI 33-55) and specificity of 72% (68-76).A positive squeeze test in CSA was not associated with IA-development in cox regression adjusted for age, gender, CRP and ACPA-status (HR 1.57 (0.77-3.19). This was consistent with the finding that subclinical synovitis was not associated with IA-development in multivariable analysis adjusted for age, gender, CRP, ACPA-status and tenosynovitis (HR 1.40 (0.59-3.31), whilst tenosynovitis was associated (HR 4.94 (2.03-12.06).Conclusion:The squeeze test is a simple test that, when positive in CSA, doubles the probability of presence of subclinical synovitis.Disclosure of Interests:None declared

Background:Electronic Medical Records (EMRs) offer a magnitude of observational data which is currently often manually reviewed to identify patient cases. Machine-Learning (ML) methods are highly efficient tools for data extraction, being able to process the information-rich free-text physician notes from EMRs. [1]We postulate that incorporating this data into an ML pipeline, will enable the high-throughput identification of RA case cohorts qualitatively equal to conventional EULAR/ACR criteria based chart review.Objectives:To investigate the comparability of Rheumatoid arthritis (RA) cases identified through EMR free-text enriched machine-learning algorithms to the field’s gold-standard (GS) of criteria based chart-review.Methods:We developed a classification algorithm using a Support Vector Machine (SVM) trained on 1000 manually reviewed patient EMRs and validated on a separate 1000 records. [2]The SVM assigns a probability of being an RA case to each patient at a speed of >5000 records per second. The probability cutoff for case identification can be tailored to studies’ needs, optimizing on sensitivity, specificity, etc. We optimized on PPV, resulting in a cutoff of 0.48 with a PPV of 0.96.We used the 1987 and 2010 EULAR/ACR criteria based diagnoses of RA at one year after inclusion in a prospective arthritis cohort as GSs and compared the baseline characteristics of ML identified RA cases with both GSs separately and for those fulfilling at least one set of criteria using Pearson chi-squared and Mann-Whitney U tests (α = 0.05).Results:At the 0.48 cutoff the ML model performs very well on the annotated set and when compared to criteria based GSs. (Table 1)Since patients diagnosed with RA do not necessarily meet classification criteria, it is not surprising that the ML cases and GSs do not completely overlap. The ML cases overlap to a larger degree with the 1987 GS than with the 2010 GS. Clinically, the ML identified cases do not differ from the 2010 and 1987 GS cohorts except for a slightly higher CCP2 positivity compared to the 1987 GS (65 vs 51%) and the combined criteria (65 vs 56%). (Table 1 & 2)Table 1.Performance of ML-model in the annotated data†(N = 1000) predicting cases and 1987, 2010 or either criteria based data * (N = 1235, 1218 & 1244 respectively) predicting cases (prob. ≥ 0.48). TP; True Positive, FP; False Positive, TN; True Negative, FN; False Negative, PPV; Positive Predictive Value, NPV; Negative Predictive Value, Spec; Specificity, Sens; SensitivityAccuracyPPVNPVSpecSensAnnotated Cases†0.980.960.981.000.74Criteria Definite Cases 1987*0.820.790.830.920.61Criteria Definite Cases 2010*0.780.810.770.930.55Either Criteria Cases*0.760.900.720.950.51Conclusion:ML algorithms processing clinician notes enable fast and efficient selection of cases that are clinically similar to cases selected by criteria based chart review. This allows a significant reduction of time and effort required to construct high quality research cohorts.Table 2.Comparison of baseline characteristics between 3 ML defined cohorts and a criteria based gold standard.†Not statistically tested; * significantly different to the ML selected cases at α = 0.05, Pearson Chi-Squared for proportions, Mann-Whitney U for mediansPredicted Definite Case1987 Criteria Based Case2010 Criteria Based CaseEither Criteria Based CaseN†335399609666Proportion Women0.670.630.650.65Proportion CCP2 Positive0.650.51*0.610.56*Proportion RF positive0.670.600.690.64Median BMI26.025.525.625.6Median BSE28292626Median CRP9.61199Median Age at Inclusion57.758.757.258.3Median Symptom Duration at Diagnosis (in Days)95.5909189Median Number of Swollen Joints5665References:[1]Maarseveen et al. ARD 2019;78[2]https://github.com/levrex/DiagnosisExtraction_MLAcknowledgments:T. Maarseveen and M. Maurits contributed equally.Disclosure of Interests:Tjardo Maarseveen: None declared, Marc Maurits: None declared, Ellis Niemantsverdriet: None declared, Thomas Huizinga Grant/research support from: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Consultant of: Ablynx, Bristol-Myers Squibb, Roche, Sanofi, Annette van der Helm - van Mil: None declared, Rachel Knevel: None declared

Background:The hypothesis that initiation of DMARD-treatment before arthritis becomes apparent could permanently modulate the disease process, such that persistent RA is prevented, is being studied in several ongoing trials. Essential for such studies is the ability to accurately predict clinically apparent inflammatory arthritis (IA). However there are two hurdles: first, it is insufficiently known whether it is possible to obtain high positive predictive values (PPV) in patients presenting with clinically suspect arthralgia (CSA). Second, none of current predictive models is validated in independent cohorts. We here aimed to evaluate the first question, incorporating improved markers of MRI-detected subclinical inflammation that were recently identified but have not yet been combined with other known predictors.[1]Objectives:To assess the feasibility of achieving high PPVs in prediction of IA-development in patients with CSA by combining clinical, laboratory and imaging parameters.Methods:580 patients with CSA were consecutively included in the Clinically Suspect Arthralgia (CSA)-cohort and followed on the development of IA, determined by physical examination of joints. Unilateral contrast-enhanced 1.5 Tesla MRIs were made of MCP(2-5), wrist and MTP(1-5)-joints at baseline and scored in line with the RAMRIS. The number of locations with subclinical inflammation (0/1-2/≥3) and the presence of MCP peritendinitis were defined as described previously.[1] Other studied clinical and laboratory variables were based on the literature: initial localisation of complaints (small/large joints), functional disability (health assessment questionnaire (HAQ) ≥1), ACPA-positivity (Anti-CCP2), RF-positivity (IgM-RF) and elevated CRP.[2,3] LASSO Cox regression with a 10-fold cross-validated shrinkage parameter was used for predictor selection. Regression coefficients were rounded to the nearest number ending in .5 or .0 and multiplied by two, resulting in a weighted score. Kaplan Meijer curves were used to obtain PPVs of this weighted score and the area under the curve (AUC) was determined at 2-year follow-up.Results:Mean age was 44, 78% was female, and 18% progressed to IA within 2 years. The following parameters were selected with LASSO: RF-positivity, ACPA-positivity, HAQ≥1, >2 locations of subclinical inflammation and presence of MCP-extensor peritendinitis. Based on the beta of LASSO-regression, patients were assigned 2 points for the risk-factors ACPA-positivity and >2 locations of subclinical inflammation, 1 point for RF-positivity and presence of MCP-extensor peritendinitis and 0 points for HAQ≥1. Kaplan Meijer curves show PPVs of 8%, 9%, 30%, 54%, 73%, 79% and 86% at two years (Figure 1). This model yielded an AUC of 0.79.Figure 1.Kaplan Meijer curves on inflammatory arthritis development stratified for number of points based on LASSO regression. Legend: Points were based on the regression coefficients yielded by Cox LASSO-regression. 2 points were assigned for the risk factors ACPA-positivity and >2 locations of subclinical inflammation and 1 point was assigned for RF-positivity and presence of MCP-extensor peritendinitis.Conclusion:High PPVs for IA-development can be achieved in patients with CSA by weighting a combination of known predictors. Although encouraging, these data are based on one observational cohort study and have not been validated in independent cohorts, limiting the relevance. To support future research in the field of arthralgia, it is needed that different research groups work together to come to risk estimations that are validated and accepted.References:[1] Matthijssen XME et al. ART 2019;21(1):249-.[2] van Steenbergen HW et al. ART 2014;16(2):R92.[3] ten Brinck RM et al. RMD Open 2017;3(1):e000419.Disclosure of Interests:None declared

Background:Clinically suspect arthralgia (CSA) can precede development of clinically evident inflammatory arthritis (IA). Autoantibody, C-reactive protein (CRP), and subclinical inflammation are known predictors, but risk estimation remains insufficiently accurate. Especially CRP has a small effect size and is inadequately reflective of inflammation that can be measured systemically. RNA expression in whole blood of patients with rheumatoid arthritis (RA) have shown differences compared to healthy individuals. Therefore, we hypothesized that differences in RNA expression can be found between CSA patients that do and do not progress to IA.Objectives:This study assessed whole blood RNA expression levels of inflammatory and immune genes as potential biomarkers for prediction of IA-development in patients with arthralgia.Methods:Between April 2012-March 2015, 234 patients were consecutively included in the Leiden CSA-cohort. Follow-up ended when patients developed clinically apparent IA (determined at physical examination), or else after 2-years. RNA expression in whole blood, at the moment of inclusion, was determined for 135 genes of the innate and adaptive immune system by dual color Reverse-Transcription Multiplex Ligation-dependent Probe Amplification (dcRT-MLPA) profiling. Cox proportional hazard models were used to associate time-to-event with gene expression level at inclusion, while adjusting for age, gender, and assay plate (model 1). The false discovery rate was used to correct for multiple testing. Genes with significantly different expression were subsequently studied for reproducibility by qPCR, and mutual independence in their association with IA-development. For the latter, we employed a forward selection strategy, starting with the most significantly associated gene and iteratively adding more genes. Resulting mutually independent genes were further investigated for their added predictive value over known risk factors, CRP, ACPA, and subclinical joint inflammation.Results:21% of CSA-patients developed IA after mean 3.6 months (IQR:1.6-10.7) follow-up. After correction for multiple testing, six genes were significantly associated with IA-development (model 1), namely IFN-γ, PHEX, IGF-1, IL7R, CD19, or CCR7 (ordered by significance). For all six genes, a lower expression at inclusion was associated with an increased risk of IA-development. IFN-γ was only weakly expressed in peripheral blood, hampering the technical reproducibility between MLPA and qPCR results, and was excluded for further analyses. PHEX and IGF-1 were highly correlated (R20.97) and only IGF-1, but not PHEX, was included in further analyses. Of the remaining significant genes (IGF-1, IL7R, CD19, CCR7), an independent association with IA-development was observed for IGF-1 and IL7R, but not for CD19 or CCR7. qPCR data of IL7R correlated with MLPA results (pConclusion:Six genes were differentially expressed between CSA-patients that did or did not progress to IA. Expression of IGF-1 and IL7R showed added value to regularly used predictors. Validation is warranted.References:None.Figure 1.Association between RNA expression divided in tertiles of IGF-1 (A) and IL7R (B), and development of inflammatory arthritisDisclosure of Interests:None declared

Background:The forefoot is a preferential location for tendon and joint inflammation in rheumatoid arthritis (RA). Some imaging studies suggested that intermetatarsal and submetatarsal pathology (such as bursitis and Morton’s neuroma) are also involved in RA, but these studies were small and its association was not thoroughly explored.Objectives:To determine whether intermetatarsal bursitis (IMB), Morton’s neuroma (MN) and submetatarsal bursitis (SMB) occur more often in early RA, compared to patients with other early arthritides and healthy controls. Contrast-enhancement in the subcutis that has been described as diffuse submetatarsal alterations (DSMA) were also included.Methods:In this cross-sectional cohort-study, consecutive patients with RA, other arthritides and healthy controls underwent MRI of unilateral forefoot. Two readers, a trained PhD-student an experienced MSK-radiologist, scored IMB, MN, SMB and DSMA in consensus, and measured transverse and dorsoplantar diameters of IMB, MN and SMB. Logistic regression models determined their association with RA, and test characteristics for RA were calculated. Lesion-sizes were plotted.Results:634 participants underwent MRI: 157 consecutive patients with RA (109 women; age 59±11SD), 284 with other early arthritides (158 women; age 56±17SD), and 193 healthy controls (136 women; age 50±16SD). Univariably, IMB, MN and SMB were more prevalent in RA (all PAlthough IMB, MN and SNB were more frequent in RA, the lesion-size was mainly similar in all groups. For MN a dorsoplantar diameter >6mm or transverse diameter >5mm was highly specific (specificity 100% compared to healthy controls), however it was infrequent (sensitivity 12% and 13%, respectively). For IMB and SMB no cut-off size could be distinguished with high specificity.Conclusion:Intermetatarsal bursitis, Morton’s neuroma and submetatarsal bursitis are increased prevalent in early RA and could be considered as disease features.Disclosure of Interests:None declared

Background:EULAR- recommendations for management of early arthritis formulated that patients should be referred to, and seen by a rheumatologist, within 6-weeks after symptom onset. The mentioned period of ≤6-weeks after symptom onset is shorter than ≤12-weeks, the period that is generally considered as the ‘window-of-opportunity’. Because implementation provides challenges, and evidence supporting that referral ≤6-weeks is better than e.g. Objectives:We used an observational study design to investigate in two cohorts if time-to-encounter (TtE) a rheumatologist ≤6-weeks, compared to 7-12-weeks, results in better disease long-term outcomes, measured with sustained DMARD-free remission (SDFR) and radiographic progression.Methods:Consecutive 1987-RA patients of the Leiden EAC (n=1025) and ESPOIR (n=514) were studied during median 7 and 10 years follow-up. Patients were categorized on duration between symptom onset and first encounter with a rheumatologist; ≤6-, 7-12-, and >12-weeks. Multivariable Cox regression (SDFR), linear mixed models (radiographic progression), and meta-analyses were used.Results:Leiden RA-patients encountered the rheumatologist within 6-weeks obtained SDFR more often than patients seen within 7-12-weeks (HR 1·59, 95%CI:1·02-2·49), and >12-weeks (HR 1·54, 95%CI:1·04-2·29). In ESPOIR, similar but non-significant effects were observed; meta-analysis showed that within 6-weeks was better than 7-12-weeks (HR 1·69, 95%CI:1·10-2·57, Figure 1-A) and >12-weeks (HR 1·67, 95%CI:1·08-2·58). Patients encountered the rheumatologist within 6-weeks had similar radiographic progression than those seen 7-12-weeks, in any cohort, or meta-analysis (Figure 1-B).Figure 1Meta-analyses of time-to-encounter the rheumatologist and the chance of achieving sustained DMARD-free remission (A) and radiographic progression (B)Conclusion:Scientific evidence underlying the first EULAR recommendation depends on the outcome of interest; visiting a rheumatologist within 6-weeks of symptom-onset had clear benefits for achieving SDFR, but not for radiographic progression.References:None.Disclosure of Interests:Ellis Niemantsverdriet: None declared, Maxime Dougados Grant/research support from: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Consultant of: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Speakers bureau: AbbVie, Eli Lilly, Merck, Novartis, Pfizer and UCB Pharma, Bernard Combe Grant/research support from: Novartis, Pfizer, Roche-Chugai, Consultant of: AbbVie; Gilead Sciences, Inc.; Janssen; Eli Lilly and Company; Pfizer; Roche-Chugai; Sanofi, Speakers bureau: Bristol-Myers Squibb; Gilead Sciences, Inc.; Eli Lilly and Company; Merck Sharp & Dohme; Pfizer; Roche-Chugai; UCB, Annette van der Helm - van Mil: None declared

Background:Auto-antibodies in rheumatoid arthritis (RA) are often present years before disease onset but their mere presence does not seem enough to induce RA. Because several nested-case control studies have shown that autoantibody-response maturation precedes disease onset, it is suggested that it plays a role in disease triggering. At present, it is undetermined whether autoantibody-response maturation occurs in the symptomatic phase preceding clinical arthritis (i.e. Clinically Suspect Arthralgia, CSA), or whether it occurs even earlier in the asymptomatic phase. Secondly, if autoantibody-response maturation is a final step towards clinical disease development, maturation is expected to be present in the patients that progress from CSA to RA, but not in CSA-patients that do not progress.Objectives:To better understand the timeframe of autoantibody-response maturation and its relation to development of RA, we investigated autoantibody-response maturation in patients with CSA that did and did not progress to clinically apparent inflammatory arthritis (IA).Methods:In serum from 148 CSA-patients, we determined the presence and levels of three autoantibodies (ACPA, anti-CarP and AAPA), with three isotypes each (IgM, IgG, IgA), resulting in 9 autoantibody measurements per patient per time-point. Measurements were performed on sera obtained at first presentation at the outpatient clinic and when patients developed IA or else after two years. In-house ELISA was used for all measurements. Three analyses were performed, in patients that progressed to IA (n=56) and in patients that did not progress (n=92) separately. First, in patients negative for all measurements at baseline, we determined the frequency of conversion to seropositivity. Second, in patients with at least one positive test at baseline, we studied the frequency of autoantibody positivity over time. Finally, we determined the change in autoantibody levels in patients positive for the respective autoantibodies at baseline. Frequencies and medians were reported. Statistical significance was tested with Fisher’s Exact test and GEE, taking into account that measurements within one autoantibody type (ACPA, anti-CarP or AAPA) can be correlated.Results:First we studied patients negative for all antibodies at baseline (54% of patients that progressed to IA and 76% of patients that did not progress). 17% of patients that progressed to IA became positive over time, compared to 6% of the patients that did not develop IA (p=0.12). Then we studied patients in whom at least one autoantibody was present at baseline and evaluated autoantibody-positivity over time. In patients that progressed to IA, the number of autoantibodies detected at baseline did not change significantly during follow-up (median 1.5 (IQR 1-3, max. 6) to 1.0 (IQR 1-4, max. 6) (p=0.18)). In the patients with CSA that did not progress similar findings were made (1.0 (IQR 1-2, max. 4) at baseline and 1.0 (IQR 0-2, max. 5) after 2-years (p=0.07)). Increase in number of positive measurements over time took place in only few patients: in 15% of the patients that progressed to IA and in 18% from those that did not progress (p=1.00). Likewise, autoantibody levels did not significantly change over time, both in patients that progressed and in patients that did not progress.Conclusion:The presence of IgM, IgG and IgA ACPA, anti-CarP and AAPA, as well as autoantibody levels, did not significantly increase over time in patients with CSA; this was similar for patients that did and did not develop clinical arthritis. These findings suggest that antibody-response maturation occurs before presenting with symptoms and also that broadening of the autoantibody response is not specific for progression from arthralgia to RA.Disclosure of Interests:None declared

Background:During the last decennium advanced imaging modalities have refined our understanding of the tissues involved in RA and have shown that not only joints but also bones and tendons can be inflamed at diagnosis. However, the time-order of decrease of these inflammatory features after initiation of DMARDs is unknown. Whether this differs for ACPA-positive and ACPA-negative patients is also unknown.Objectives:To achieve better understanding of the time order in which the different inflamed tissues (joint, tendon, bone) respond to DMARD-treatment and whether this differs between ACPA-subgroups.Methods:216 consecutive patients with early undifferentiated or rheumatoid arthritis, who received DMARD-treatment, were studied. Unilateral 1.5 Tesla contrast-enhanced MRIs of MCPs, wrists and MTPs were performed at baseline (before treatment) and after 4, 12 and 24 months. MRIs were scored for synovitis, osteitis and tenosynovitis in line with the RAMRIS, in known time-order but blinded for clinical data. Data of 4 serial time-points (three time intervals) were studied with autoregressive cross-lagged models. These models evaluated the influence of two time patterns in one model: 1) a simultaneous pattern (“extra change in one inflammatory feature was associated with extra change in another feature”) and 2) a subsequent pattern (“change in one inflammatory feature preceded change in another feature”). All analyses were repeated stratified for ACPA-status (anti-CCP2).Results:In all patients, all combinations of inflammatory features showed significant simultaneous decrease in all time intervals (0 – 4 /4 – 12/12 – 24 months; all pWhen considering ACPA-negative and ACPA-positive patients separately, similar results were obtained. In addition, in ACPA-positive patients, synovitis change between 4 - 12 months preceded osteitis change at 12 – 24 months (p = 0.002); this was significantly different from ACPA-negative patients (pConclusion:This study increased the understanding of the response to treatment on tissue level. In addition to simultaneous decrease of synovitis, osteitis and tenosynovitis, also time orders of inflammation decrease were identified. These differed between ACPA-subgroups, implying a different interaction of synovium and bone in these patients.Disclosure of Interests:None declared

Tenosynovitis is traditionally recognised at physical examination in patients with inflammatory rheumatic diseases, such as, e.g. psoriatic arthritis and (longstanding) rheumatoid arthritis (RA). The increasing use of sensitive imaging techniques (ultrasound, magnetic resonance imaging (MRI)) has recently revealed that subclinical tenosynovitis is prevalent in early RA and in patients in different phases of RA development (asymptomatic state, arthralgia, early arthritis). In this review, the recent findings on MRI-detected tenosynovitis and associations with RA development are highlighted, and an overview of the most reported inflamed tendon locations within the hand and wrist of patients in different disease phases is provided. The data presented show that tenosynovitis is one of the earliest inflammatory features in patients with imminent RA and associated with impairment of activities in daily life. The value of tenosynovitis as an outcome measure in RA is also discussed.

Background: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimers disease (AD). Objective: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. Methods: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. Results: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. Conclusion: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

Increased brain uptake of [18F]-AV45 visualized by PET is a key biomarker for Alzheimers disease (AD). The standardized uptake value ratio (SUVR) is widely used for quantification, but is subject to variability based on choice of reference region and changes in cerebral blood flow. Here we validate the SUVR method against the gold standard volume of distribution (VT) to assess cross-sectional differences in plaque load. Methods: Dynamic 60-min [18F]-AV45 (291 ± 67 MBq) and 1-min [15O]-H2O (370 MBq) scans were obtained in 35 age-matched elderly subjects, including 10 probable AD dementia, 15 amnestic mild cognitive impairment (aMCI) and 10 cognitively healthy controls (HC). [18F]-AV45 VT was determined from two-tissue compartment modeling using a metabolite-corrected plasma input function. Static SUVR was calculated at 50-60 min p.i., using either cerebellar gray matter (SUVRCB) or whole subcortical white matter (SUVRWM) as reference. Additionally, whole cerebellum, pons, centrum semiovale and a composite region were examined as alternative references. Blood flow was quantified by [15O]-H2O SUV. Data are presented as mean ± standard error of the mean (SEM). Results: There was rapid metabolization of [18F]-AV45 with only 35% of unchanged parent remaining at 10 minutes. Compared to VT, differences in cortical Aβ-load between aMCI and AD were overestimated by SUVRWM (+4 ± 2%) and underestimated by SUVRCB (-10 ± 2%). VT correlated better with SUVRWM (Pearsons r: from 0.63 for posterior cingulate to 0.89 for precuneus, p < 0.0001) than with SUVRCB (Pearsons r: from 0.51 for temporal lobe (p = 0.002) to 0.82 for precuneus (p < 0.0001)) in all tested regions. Correlation results for the alternative references were in-between those for CB and WM. [15O]-H2O data showed that blood flow was decreased in AD compared to aMCI in cortical regions (-5 ± 1%) and in the reference regions (CB: -9 ± 8%, WM: -8 ± 8%). Conclusion: Increased brain uptake of [18F]-AV45 assessed by the simplified static SUVR protocol does not truly reflect Aβ load. However, SUVRWM is better correlated with VT and more closely reflects VT differences between aMCI and AD than SUVRCB.

This review focusses on the validation and standardization of Alzheimers disease (AD) cerebrospinal fluid (CSF) biomarkers, as well as on the current clinical indications and rational use of CSF biomarkers in daily clinical practice. The validated AD CSF biomarkers, Aβ1-42, T-tau, and P-tau181, have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnosis. CSF biomarkers should not be routinely used in the diagnostic work-up of dementia and cannot be used to diagnose non-AD dementias. In cognitively healthy subjects, CSF biomarkers can only be applied for research purposes, e.g., to identify pre-clinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.

Altres ajuts: This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND-www.jpnd.eu: Ministry of Health (Italy), Fundaçao para a Ciência e a Tecnologia (Portugal), Instituto de Salud Carlos III (Spain), The Swedish Research Council (Sweden), ZonMw (The Netherlands) Cerebrospinal fluid collection by lumbar puncture (LP) is performed in the diagnostic workup of several neurological brain diseases. Reluctance to perform the procedure is among others due to a lack of standards and guidelines to minimize the risk of complications, such as post-LP headache or back pain. We provide consensus guidelines for the LP procedure to minimize the risk of complications. The recommendations are based on (1) data from a large multicenter LP feasibility study (evidence level II-2), (2) systematic literature review on LP needle characteristics and post-LP complications (evidence level II-2), (3) discussion of best practice within the Joint Programme Neurodegenerative Disease Research Biomarkers for Alzheimer's disease and Parkinson's Disease and Biomarkers for Multiple Sclerosis consortia (evidence level III). Our consensus guidelines address contraindications, as well as patient-related and procedure-related risk factors that can influence the development of post-LP complications. When an LP is performed correctly, the procedure is well tolerated and accepted with a low complication rate.

Background: Evidence suggests that the concordance between amyloid-PET and cerebrospinal fluid (CSF) amyloid-beta (A beta) increases when the CSF A beta(1-42)/A beta(1-40) ratio is used as compared to CSF A beta(1-42) levels alone. Objective: In order to test this hypothesis, we set up a prospective longitudinal study comparing the concordance between different amyloid biomarkers for Alzheimer's disease (AD) in a clinical setting. Methods: Seventy-eight subjects (AD dementia (n = 17), mild cognitive impairment (MCI, n = 48), and cognitively healthy controls (n = 13)) underwent a [F-18] Florbetapir ([F-18]AV45) PET scan, [F-18] FDG PET scan, MRI scan, and an extensive neuropsychological examination. In a large subset (n = 67), a lumbar puncture was performed and AD biomarkers were analyzed (A beta(1-42), A beta(1-40), T-tau, P-tau(181)). Results: We detected an increased concordance in the visual and quantitative (standardized uptake value ratio (SUVR) and total volume of distribution (VT)) [F-18]AV45 PET measures when the CSF A beta(1-42)/A beta(1-40) was applied compared to A beta(1-42) alone. CSF biomarkers were stronger associated to [F-18]AV45 PET for SUVR values when considering the total brain white matter as reference region instead of cerebellar grey matter Conclusion: The concordance between CSF A beta and [F-18]AV45 PET increases when the CSF A beta(1-42)/A beta(1-40) ratio is applied. This finding is of most importance for the biomarker-based diagnosis of AD as well as for selection of subjects for clinical trials with potential disease-modifying therapies for AD.

Background The Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers Aβ1–42, t-tau, and p-tau181 overlap with other diseases. New tau modifications or epitopes, such as the non-phosphorylated tau fraction (p-taurel), may improve differential dementia diagnosis. The goal of this study is to investigate if p-taurel can improve the diagnostic performance of the AD CSF biomarker panel for differential dementia diagnosis. Methods The study population consisted of 45 AD, 45 frontotemporal lobar degeneration (FTLD), 45 dementia with Lewy bodies (DLB), and 21 Creutzfeldt-Jakob disease (CJD) patients, and 20 cognitively healthy controls. A substantial subset of the patients was pathology-confirmed. CSF levels of Aβ1–42, t-tau, p-tau181, and p-taurel were determined with commercially available single-analyte enzyme-linked immunosorbent assay (ELISA) kits. Diagnostic performance was evaluated by receiver operating characteristic (ROC) curve analyses, and area under the curve (AUC) values were compared using DeLong tests. Results The diagnostic performance of single markers as well as biomarker ratios was determined for each pairwise comparison of different dementia groups and controls. The addition of p-taurel to the AD biomarker panel decreased its diagnostic performance when discriminating non-AD, FTLD, and DLB from AD. As a single marker, p-taurel increased the diagnostic performance for CJD. No significant difference was found in AUC values with the addition of p-taurel when differentiating between AD or non-AD dementias and controls. Conclusions The addition of p-taurel to the AD CSF biomarker panel failed to improve differentiation between AD and non-AD dementias. Electronic supplementary material The online version of this article (doi:10.1186/s13195-017-0275-5) contains supplementary material, which is available to authorized users.

With great interest, we read the recently published report by Poppelaars et al in which no excess mortality was observed in 155 patients with rheumatoid arthritis (RA) from the COmbinatie therapie Bij Rheumatoide Artritis (COBRA)-trial, who received early intensive treatment, compared with the general population (Standardised mortality rate (SMR) 0.80 (0.59–1.06)).1 The question whether mortality in RA has normalised is debated, as contradicting results have been published.2–8 In many of the studies on mortality, two important factors are not sufficiently taken into account: follow-up duration and disease subtypes. This might explain the conflicting results. Because thus far none of the reported studies incorporated both factors in the analyses, it is too soon to conclude that mortality is ‘normal’ again, as we will show here. We compliment the authors on emphasising the importance of a long follow-up duration by showing in their meta-analysis that excess mortality in RA becomes fully apparent after >10 years. This implies that previous studies that reported on normalisation of mortality had insufficient follow-up to reach this conclusion.2–5 Some studies with a short follow-up duration even showed a seemingly decreased …

The most common cause of familial frontotemporal lobar degeneration with TAR DNA-binding protein-43 pathology (FTLD-TDP) has been found to be an expansion of a hexanucleotide repeat (GGGGCC) in a noncoding region of the gene C9ORF72. Hippocampal sclerosis (HpScl) is a common finding in FTLD-TDP. Our objective was to screen for the presence of C9ORF72 hexanucleotide repeat expansions in a pathologically confirmed cohort of "pure" hippocampal sclerosis cases (n = 33), outside the setting of FTLD-TDP and Alzheimer's disease (AD). Using a recently described repeat-associated non-ATG (RAN) translation (C9RANT) antibody that was found to be highly specific for c9FTD/ALS, we identified a single "pure" HpScl autopsy case with a repeat expansion in C9ORF72 (c9HpScl). Mutation screening was also performed with repeat-primed polymerase chain reaction and further confirmed with Southern blotting. The c9HpScl patient had a 14-year history of a slowly progressive amnestic syndrome and a clinical diagnosis of probable AD. Neuropsychological testing revealed memory impairment, but no deficits in other cognitive domains. Autopsy showed hippocampal sclerosis with TDP-43 immunoreactive neuronal inclusions relatively limited to limbic lobe structures. Neuritic pathology immunoreactive for p62 was more frequent than TDP-43 in amygdala and hippocampus. Frequent p62-positive neuronal inclusions were present in cerebellar granule neurons as is typical of C9ORF72 mutation carriers. There was no significant FTLD or motor neuron disease. C9RANT was found to be sensitive and specific in this autopsy-confirmed series of HpScl cases. The findings in this patient suggest that the clinical and pathologic spectrum of C9ORF72 repeat expansion is wider than frontotemporal dementia and motor neuron disease, including cases of progressive amnestic dementia with restricted TDP-43 pathology associated with HpScl.

Increased brain uptake of

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

During the past ten years, over 5,000 cerebrospinal fluid (CSF) samples were analyzed at the Reference Center for Biological Markers of Dementia (BIODEM), UAntwerp, for core Alzheimer's disease (AD) CSF biomarkers: amyloid-β peptide of 42 amino acids (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181P). CSF biomarker analyses were performed using single-analyte ELISA kits. In-house validated cutoff values were applied: Aβ1-42 296.5 pg/mL, P-tau181P >56.5 pg/mL. A CSF biomarker profile was considered to be suggestive for AD if the CSF Aβ1-42 concentration was below the cutoff, in combination with T-tau and/or P-tau181P values above the cutoff (IWG2 criteria for AD). Biomarker analyses were requested for following clinical indications: 1) neurochemical confirmation of AD in case of clinical AD, 2) neurochemical confirmation of AD in case of doubt between AD and a non-AD dementia, 3) neurochemical diagnosis of prodromal AD in case of mild cognitive impairment, 4) neurochemical confirmation of AD in case of psychiatric symptoms (like depression, psychosis), or 5) other clinical indications. During these ten years, the number of yearly referred samples increased by 238% and clinical indications for referral showed a shift from neurochemical confirmation of AD in case of clinical AD to differential dementia diagnosis in case of doubt between AD and a non-AD dementia. Four percent of the patients also had a postmortem neuropathological examination. Together, these biomarker data were the basis for several research papers, and significantly contributed to the validation of these biomarkers in autopsy-confirmed subjects.

Intra- and inter-laboratory variability of cerebrospinal fluid (CSF) biomarker analyses remains an important issue. We investigated the clinical-diagnostic impact of CSF biomarker concentration shifts in mild cognitive impairment (MCI) and autopsy-confirmed Alzheimers disease (AD) dementia patients. MCI patients (n = 85), autopsy-confirmed AD dementia patients (n = 72), and cognitively healthy controls (n = 100) were included in this prospective, longitudinal study. AD dementia patients were followed up until death, and controls were included from 1992 until 2003. In-house validated cutoff values of biomarkers were applied: Aβ 1-42 296.5 pg/mL, P-tau181P >56.5 pg/mL. Both increments and decrements (from ± 5% to ± 40% ) were added to the true (=observed) CSF biomarker values, imitating the anticipated differences in biomarker concentrations. Within certain limits, the clinical diagnostic performance of AD CSF biomarkers remains largely unchanged and clinical diagnostic accuracy deviated less than 8.2% from the reference when concentration shifts ranging between 20% and +20% were added to one of the three CSF biomarkers in MCI and autopsy-confirmed AD patients. Notwithstanding the fact that (pre- and post-)analytical parameters can affect the clinical classification, the present exploratory study provides evidence that for a specific context of use, the impact on clinical accuracy of biomarker concentration shifts might be lower than originally expected. In conclusion, induced shifts of ± 20% in only one of the three biomarkers has limited impact on the clinical accuracy of AD CSF biomarkers in MCI and autopsy-confirmed AD patients when using the IWG-2 criteria.

Hypothesizing that non-significant cerebrovascular lesions on structural brain imaging lead to overdiagnosis of a vascular etiology of dementia as compared to autopsy-confirmed diagnosis, we set up at study including 71 patients with autopsy-confirmed diagnoses. Forty-two patients in the population (59%) appeared to have definite Alzheimer's disease (AD), whereas 29 (41%) had a non-AD dementia form. The panel clinically diagnosed possible or probable vascular dementia (VaD) in 27 (38%) patients, whereas only five (19%) patients (p = 0.017) had an autopsy-confirmed diagnosis of VaD. Patients with vascular lesions on structural brain imaging were often misdiagnosed as possible or probable VaD as compared to autopsy-confirmed diagnosis.

Lumbar puncture (LP), also known as spinal tap, is the most frequently used technique through which the restricted compartment of the subarachnoid space is accessed to sample cerebrospinal fluid. An LP can have both diagnostic and therapeutic indications. To perform an LP, the optimal length, size and type of needle should be used, depending on the medical indication. Needles used for LP can differ in length, diameter and design. Head-to-head studies are in favor of atraumatic type and small diameter needles given the lower incidence of post lumbar puncture headache (PLPH) and consensus-based guidelines recommend to use 25G atraumatic needles. The most important contraindication to perform an LP is a posterior fossa mass and intracranial hypertension, given the risk of central nervous system or tonsillar herniation. Other contraindications are local infections at the puncture site, congenital abnormalities and uncorrected bleeding diathesis. The LP procedure is easy to perform by an experienced physician with proper understanding of the anatomical implications, and results in low risks of complications. The most common complaint after an LP is PLPH; other infrequent complications include infections, local hematomas, pain and local discomfort. In conclusion, an LP is a viable therapeutic technique and a common diagnostic procedure, which, if performed correctly, has a low complication rate, a high diagnostic yield, and is usually more tolerable than patients expect.

Hexanucleotide repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) are the most common known genetic cause of frontotemporal dementia (FTD) and motor neuron disease (MND). We assessed whether expansion size is associated with disease severity or phenotype.We did a cross-sectional Southern blot characterisation study (Xpansize-72) in a cohort of individuals with FTD, MND, both these diseases, or no clinical phenotype. All participants had GGGGCC repeat expansions in C9ORF72, and high quality DNA was available from one or more of the frontal cortex, cerebellum, or blood. We used Southern blotting techniques and densitometry to estimate the repeat size of the most abundant expansion species. We compared repeat sizes between different tissues using Wilcoxon rank sum and Wilcoxon signed rank tests, and between disease subgroups using Kruskal-Wallis rank sum tests. We assessed the association of repeat size with age at onset and age at collection using a Spearman's test of correlation, and assessed the association between repeat size and survival after disease onset using Cox proportional hazards regression models.We included 84 individuals with C9ORF72 expansions: 35 had FTD, 16 had FTD and MND, 30 had MND, and three had no clinical phenotype. We focused our analysis on three major tissue subgroups: frontal cortex (available from 41 patients [21 with FTD, 11 with FTD and MND, and nine with MND]), cerebellum (40 patients [20 with FTD, 12 with FTD and MND, and eight with MND]), and blood (47 patients [15 with FTD, nine with FTD and MND, and 23 with MND] and three carriers who had no clinical phenotype). Repeat lengths in the cerebellum were smaller (median 12·3 kb [about 1667 repeat units], IQR 11·1-14·3) than those in the frontal cortex (33·8 kb [about 5250 repeat units], 23·5-44·9; p0·0001) and those in blood (18·6 kb [about 2717 repeat units], 13·9-28·1; p=0·0002). Within these tissues, we detected no difference in repeat length between disease subgroups (cerebellum p=0·96, frontal cortex p=0·27, blood p=0·10). In the frontal cortex of patients with FTD, repeat length correlated with age at onset (r=0·63; p=0·003) and age at sample collection (r=0·58; p=0·006); we did not detect such a correlation in samples from the cerebellum or blood. When assessing cerebellum samples from the overall cohort, survival after disease onset was 4·8 years (IQR 3·0-7·4) in the group with expansions greater than 1467 repeat units (the 25th percentile of repeat lengths) versus 7·4 years (6·3-10·9) in the group with smaller expansions (HR 3·27, 95% CI 1·34-7·95; p=0·009).We detected substantial variation in repeat sizes between samples from the cerebellum, frontal cortex, and blood, and longer repeat sizes in the cerebellum seem to be associated with a survival disadvantage. Our findings indicate that expansion size does affect disease severity, which--if replicated in other cohorts--could be relevant for genetic counselling.The ALS Therapy Alliance, the National Institute of Neurological Disorders and Stroke, the National Institute on Aging, the Arizona Department of Health Services, the Arizona Biomedical Research Commission, and the Michael J Fox Foundation for Parkinson's Research.

Background Based on different genetic and environmental risk factors and histology, it has been proposed that rheumatoid arthritis (RA) consists of 2 types: autoantibody-positive and autoantibody-negative RA. However, until now, this remained hypothetical. To assess this hypothesis, we studied whether the long-term outcomes differed for these 2 groups of RA patients. Methods and findings In the Leiden Early Arthritis Clinic cohort, 1,285 consecutive RA patients were included between 1993 and 2016 and followed yearly. Treatment protocols in routine care improved over time, irrespective of autoantibody status, and 5 inclusion periods were used as instrumental variables: 1993–1996, delayed mild disease-modifying antirheumatic drug (DMARD) initiation (reference period); 1997–2000, early mild DMARDs; 2001–2005, early methotrexate; 2006–2010, early methotrexate followed by treat-to-target adjustments; 2011–2016, similar to 2006–2010 plus additional efforts for very early referral. Three long-term outcomes were studied: sustained DMARD-free remission (SDFR) (persistent absence of clinical synovitis after DMARD cessation), mortality, and functional disability measured by yearly Health Assessment Questionnaire (HAQ). Treatment response in the short term (disease activity) was measured by Disease Activity Score–28 with erythrocyte sedimentation rate (DAS28-ESR). Linear mixed models and Cox regression were used, stratified for autoantibody positivity, defined as IgG anti-CCP2 and/or IgM rheumatoid factor positivity. In total, 823 patients had autoantibody-positive RA (mean age 55 years, 67% female); 462 patients had autoantibody-negative RA (age 60 years, 64% female). Age, gender, and percentage of autoantibody-positive patients were stable throughout the inclusion periods. Disease activity significantly decreased over time within both groups. SDFR rates increased after introduction of treat-to-target (hazard ratio [HR] 2006–2010 relative to 1993–1996: 3.35 [95% CI 1.46 to 7.72; p = 0.004]; HR 2011–2016: 4.57 [95% CI 1.80 to 11.6; p = 0.001]) in autoantibody-positive RA, but not in autoantibody-negative RA. In autoantibody-positive RA, mortality decreased significantly after the introduction of treat-to-target treatment adjustments (HR 2006–2010: 0.56 [95% CI 0.34 to 0.92; p = 0.023]; HR 2011–2016: 0.33 [95% CI 0.14 to 0.77; p = 0.010]), but not in autoantibody-negative RA (HR 2006–2010: 0.79 [95% CI 0.40 to 1.56; p = 0.50]; HR 2011–2016: 0.36 [95% CI 0.10 to 1.34; p = 0.13]). Similarly, functional disability improved in autoantibody-positive RA for the periods after 2000 relative to 1993–1996 (range −0.16 [95% CI −0.29 to −0.03; p = 0.043] to −0.32 [95% CI −0.44 to −0.20; p < 0.001] units of improvement), but not in autoantibody-negative RA (range 0.10 [95% CI −0.12 to 0.31; p = 0.38] to −0.13 [95% CI −0.34 to 0.07; p = 0.20] units of improvement). Limitations to note were that treatment was not randomized—but it was protocolized and instrumental variable analysis was used to obtain comparable groups—and that a limited spread of ethnicities was included. Conclusions Although disease activity has improved in both autoantibody-positive and autoantibody-negative RA in recent decades, the response in long-term outcomes differed. We propose that it is time to subdivide RA into autoantibody-positive RA (type 1) and autoantibody-negative RA (type 2), in the hope that this leads to stratified treatment in RA., In a longitudinal cohort study, Xanthe Matthijssen and colleagues investigate differences between autoantibody-positive and -negative RA., Author summary Why was this study done? Patients with rheumatoid arthritis (RA) have different risk factors and histology (microscopic anatomy) depending on the presence or absence of autoantibodies (anti-citrullinated protein antibodies and rheumatoid factor). Because it is suspected that RA with and without autoantibodies are 2 distinct diseases with different pathophysiology, we hypothesized that these 2 types of RA will have reacted differently to improvements in treatment strategies that have taken place over the last decades. What did the researchers do and find? Since its start in 1993, the inclusion criteria of the Leiden Early Arthritis Clinic cohort have not changed, and included RA patients have remained similar, apart from earlier diagnosis; therefore, RA patients from different years were comparable. Treatment protocols enhanced over time, but were similar for patients with and without autoantibodies. We studied the changes in disease activity and 3 long-term outcomes of RA patients with and without autoantibodies over time (inclusion period was a proxy for treatment strategy). We found that while disease activity improved in both patient groups, the long-term outcomes (the possibility to permanently stop medication, mortality, and functional disability) only improved in RA patients with autoantibodies. What do these findings mean? The disconnection between improvement in disease activity and subsequent improvement in long-term outcomes in RA without autoantibodies suggests that the underlying pathogenesis of RA with and without autoantibodies is different. We propose that it is time to formally subdivide RA into type 1 (with autoantibodies) and type 2 (without autoantibodies).