Publications by authors named "Margreet Kloppenburg"

172 Publications

Circulating MicroRNAs Highly Correlate to Expression of Cartilage Genes Potentially Reflecting OA Susceptibility-Towards Identification of Applicable Early OA Biomarkers.

Biomolecules 2021 Sep 13;11(9). Epub 2021 Sep 13.

Department of Biomedical Data Sciences, Section Molecular Epidemiology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.

Objective: To identify and validate circulating micro RNAs (miRNAs) that mark gene expression changes in articular cartilage early in osteoarthritis (OA) pathophysiology process.

Methods: Within the ongoing RAAK study, human preserved OA cartilage and plasma ( = 22 paired samples) was collected for RNA sequencing (respectively mRNA and miRNA). Spearman correlation was determined for 114 cartilage genes consistently and significantly differentially expressed early in osteoarthritis and 384 plasma miRNAs. Subsequently, the minimal number of circulating miRNAs serving to discriminate between progressors and non-progressors was assessed by regression analysis and area under receiver operating curves (AUC) was calculated with progression data and plasma miRNA sequencing from the GARP study ( = 71).

Results: We identified strong correlations (ρ ≥ |0.7|) among expression levels of 34 unique plasma miRNAs and 21 genes, including 4 genes that correlated with multiple miRNAs. The strongest correlation was between let-7d-5p and (ρ = -0.75, = 6.9 × 10). Regression analysis of the 34 miRNAs resulted in a set of 7 miRNAs that, when applied to the GARP study, demonstrated clinically relevant predictive value with AUC > 0.8 for OA progression over 2 years and near-clinical value for progression over 5 years- (AUC = 0.8).

Conclusions: We show that plasma miRNAs levels reflect gene expression levels in cartilage and can be exploited to represent ongoing pathophysiological processes in articular cartilage. We advocate that identified signature of 7 plasma miRNAs can contribute to direct further studies toward early biomarkers predictive for progression of osteoarthritis over 2 and 5 years.
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http://dx.doi.org/10.3390/biom11091356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8468331PMC
September 2021

Improving the measurement of oral health-related quality of life: Rasch model of the oral health impact profile-14.

J Dent 2021 Sep 21;114:103819. Epub 2021 Sep 21.

Section for Outcomes Research, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria; Ludwig Boltzmann Institute for Arthritis and Rehabilitation, 1090, Vienna, Austria. Electronic address:

Objectives: The 14-item Oral Health Impact Profile (OHIP-14) is the most frequently used instrument to measure oral health-related quality-of-life (OHRQoL) in adults. Despite its popularity, its psychometric properties have been predominantly investigated based on the classical test theory while the fundamental principles of measurement have not been fully assessed. Therefore, our aim was to investigate to what extent the OHIP-14 meets the fundamental requirments of measurements.

Methods: We used the Rasch model to explore person-item-targeting, unidimensionality, local independence of items, invariance (differential-item-functioning, DIF), and the order of thresholds between response-options in the German version OHIP-14. We used data from osteoarthritis patients because hand disabilities and joint pain might influence oral hygiene. Furthermore, osteoarthritis in the temporomandibular-joint directly affects oral functioning.

Results: Five-hundred sixteen patients were included (mean age 66.5 years [±10.2; ranging from 34 to 89]; 71.3% [368] females). The OHIP-14 median total score was 0 (interquartile-range from 0 to 4), indicating a right-skewed distribution because many patients reported good OHRQoL. The instrument was found unidimensional. However, there was strong evidence of local dependency, disordered thresholds between response-options, and age-related DIF for item 5. A revised scoring scheme with three instead of five answer-options in all items and eliminating two items resolving local dependency, the newly adapted OHIP-12, showed better reliability and item-fit to the Rasch model than the original OHIP-14.

Conclusions: This study assesses, for the first time, the OHIP-14 in terms of fundamental principles of measurement and proposes an item-reduced OHIP-12 as a psychometrically more accurate version of the instrument.

Clinical Significance: The Rasch model is essential to ensure instruments' precision and clinical meaningfulness when measuring OHRQoL in clinical practice and research. The OHIP-12, derived from the OHIP-14 by deleting two items due to local dependency, with a revised scoring scheme for all items distinguishing three answer-options instead of five, represents a psychometrically improved version of the instrument.
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http://dx.doi.org/10.1016/j.jdent.2021.103819DOI Listing
September 2021

Core outcome measurement instrument selection for physical function in hand osteoarthritis using the OMERACT Filter 2.1 process.

Semin Arthritis Rheum 2021 Sep 15. Epub 2021 Sep 15.

Departments of Rheumatology and Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Objective: Physical function is one of the Outcome Measures in Rheumatology (OMERACT) core outcome domains for hand osteoarthritis studies. Our aim was to select appropriate instrument(s) to measure this domain, as part of the development of a core outcome measurement set.

Methods: Following the OMERACT Filter 2.1 instrument selection process, the (function subscale of) the Australian/Canadian Hand Osteoarthritis Index (AUSCAN), Functional Index for Hand Osteoarthritis (FIHOA) and Michigan Hand Outcomes Questionnaire (MHQ) were assessed for domain match, feasibility, truth and discrimination. Data gathered from available literature, working group and patient surveys, and additional analyses in two hand osteoarthritis cohorts were used to inform a consensus process. Results were summarized in Summary of Measurements Properties tables and reviewed by the OMERACT technical advisory group.

Results: MHQ passed the assessment of domain match and feasibility by the working group and patient research partners. For AUSCAN important limitations in feasibility were noted, but domain match was good. FIHOA did not pass the assessment and was not taken through the follow-up assessment. Based on published literature, reliability and construct/longitudinal validity of both MHQ and AUSCAN fulfilled OMERACT standards. While clinical trial discrimination and thresholds of meaning were good for AUSCAN, results for MHQ were ambiguous.

Conclusion: MHQ was provisionally endorsed as OMERACT core outcome measure for the core domain physical function. While AUSCAN may have better metric properties than MHQ, it received provisional endorsement as a second measure of function due to important feasibility issues. A research agenda to merit full endorsement was set.
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http://dx.doi.org/10.1016/j.semarthrit.2021.08.014DOI Listing
September 2021

Guided internet-based cognitive-behavioral therapy for patients with rheumatic conditions: A systematic review.

Internet Interv 2021 Dec 11;26:100444. Epub 2021 Aug 11.

Institute of Psychology, Health, Medical and Neuropsychology Unit, Leiden University, PO Box 9555, 2300 RB Leiden, the Netherlands.

Context: Rheumatic conditions have a large impact on both patients and society. Many patients experience adjustment problems, such as symptoms of anxiety and depression and sleep problems, contributing to high healthcare costs. Internet-based cognitive-behavioral therapy (iCBT) has shown to support patients with somatic conditions in coping with their disease, with therapist-guided iCBT usually showing larger effects than unguided iCBT. However, the specific relevance of guided iCBT for rheumatic conditions has not been reviewed yet, which could have important implications for implementation.

Objectives: The objective of our review was to give an overview of evaluations of guided iCBT for rheumatic conditions, including physical, psychological, and impact on daily life outcomes.

Methods: This review is registered with PROSPERO with registration number CRD42020154911. The review followed PRISMA guidelines and included an assessment of risk of bias. PubMed, PsycINFO, Embase, Cochrane Library, Web of Science, and Emcare were searched until 5 October 2020. Inclusion criteria were: patients ≥18 years old with a rheumatic condition, randomized controlled trial, accessible full-text English article, original data, inclusion of psychological, and/or physical and/or impact outcomes, and therapist-guided iCBT. Study and sample characteristics, as well as clinical variables were extracted.

Results: A systematic search identified 6089 studies, of which 8 trials were included, comprising of 1707 participants in total. Significant medium to large between-group effects were found for psychological outcomes (depression, anxiety, catastrophizing, self-efficacy) and impact on daily life outcomes (impact on daily life, quality of life), whilst results for physical outcomes (pain intensity, fatigue) were mixed.

Conclusion: Whilst more research is warranted, for instance regarding physical outcomes, cost-effectiveness, safety of the intervention, and moderators of iCBT success, our results show that guided iCBT could be an important addition to medical treatment for rheumatic conditions. Guided iCBT can improve psychological and impact on daily life outcomes in patients with rheumatic conditions, which is promising for iCBT implementation in clinical practice.
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http://dx.doi.org/10.1016/j.invent.2021.100444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8391057PMC
December 2021

Deciphering osteoarthritis genetics across 826,690 individuals from 9 populations.

Cell 2021 Sep 26;184(18):4784-4818.e17. Epub 2021 Aug 26.

Laboratory for Bone and Joint Diseases, RIKEN Center for Integrative Medical Sciences, Tokyo 108-8639, Japan; Department of Orthopedic Surgery, Shimane University, Shimane 693-8501, Japan.

Osteoarthritis affects over 300 million people worldwide. Here, we conduct a genome-wide association study meta-analysis across 826,690 individuals (177,517 with osteoarthritis) and identify 100 independently associated risk variants across 11 osteoarthritis phenotypes, 52 of which have not been associated with the disease before. We report thumb and spine osteoarthritis risk variants and identify differences in genetic effects between weight-bearing and non-weight-bearing joints. We identify sex-specific and early age-at-onset osteoarthritis risk loci. We integrate functional genomics data from primary patient tissues (including articular cartilage, subchondral bone, and osteophytic cartilage) and identify high-confidence effector genes. We provide evidence for genetic correlation with phenotypes related to pain, the main disease symptom, and identify likely causal genes linked to neuronal processes. Our results provide insights into key molecular players in disease processes and highlight attractive drug targets to accelerate translation.
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http://dx.doi.org/10.1016/j.cell.2021.07.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459317PMC
September 2021

Baseline clinical characteristics of predicted structural and pain progressors in the IMI-APPROACH knee OA cohort.

RMD Open 2021 08;7(3)

Rheumatology & Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Objectives: To describe the relations between baseline clinical characteristics of the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) participants and their predicted probabilities for knee osteoarthritis (OA) structural (S) progression and/or pain (P) progression.

Methods: Baseline clinical characteristics of the IMI-APPROACH participants were used for this study. Radiographs were evaluated according to Kellgren and Lawrence (K&L grade) and Knee Image Digital Analysis. Knee Injury and Osteoarthritis Outcome Score (KOOS) and Numeric Rating Scale (NRS) were used to evaluate pain. Predicted progression scores for each individual were determined using machine learning models. Pearson correlation coefficients were used to evaluate correlations between scores for predicted progression and baseline characteristics. T-tests and χ tests were used to evaluate differences between participants with high versus low progression scores.

Results: Participants with high S progressions score were found to have statistically significantly less structural damage compared with participants with low S progression scores (minimum Joint Space Width, minJSW 3.56 mm vs 1.63 mm; p<0.001, K&L grade; p=0.028). Participants with high P progression scores had statistically significantly more pain compared with participants with low P progression scores (KOOS pain 51.71 vs 82.11; p<0.001, NRS pain 6.7 vs 2.4; p<0.001).

Conclusions: The baseline minJSW of the IMI-APPROACH participants contradicts the idea that the (predicted) course of knee OA follows a pattern of inertia, where patients who have progressed previously are more likely to display further progression. In contrast, for pain progressors the pattern of inertia seems valid, since participants with high P score already have more pain at baseline compared with participants with a low P score.
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http://dx.doi.org/10.1136/rmdopen-2021-001759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383877PMC
August 2021

Diagnosis of early stage knee osteoarthritis based on early clinical course: data from the CHECK cohort.

Arthritis Res Ther 2021 08 19;23(1):217. Epub 2021 Aug 19.

Department of General Practice, Erasmus MC University Center Rotterdam, Rotterdam, The Netherlands.

Background: Early diagnosis of knee osteoarthritis (OA) is important in managing this disease, but such an early diagnostic tool is still lacking in clinical practice. The purpose of this study was to develop diagnostic models for early stage knee OA based on the first 2-year clinical course after the patient's initial presentation in primary care and to identify whether these course factors had additive discriminative value over baseline factors.

Methods: We extracted eligible patients' clinical and radiographic data from the CHECK cohort and formed the first 2-year course factors according to the factors' changes over the 2 years. Clinical expert consensus-based diagnosis, which was made via evaluating patients' 5- to 10-year follow-up data, was used as the outcome factor. Four models were developed: model 1, included clinical course factors only; model 2, included clinical and radiographic course factors; model 3, clinical baseline factors + clinical course factors; and model 4, clinical and radiographic baseline factors + clinical and radiographic course factors. All the models were built by a generalized estimating equation with a backward selection method. Area under the receiver operating characteristic curve (AUC) and its 95% confidence interval (CI) were calculated for assessing model discrimination. Delong's method compared AUCs.

Results: Seven hundred sixty-one patients with 1185 symptomatic knees were included in this study. Thirty-seven percent knees were diagnosed as OA at follow-up. Model 1 contained 6 clinical course factors; model 2: 6 clinical and 3 radiographic course factors; model 3: 6 baseline clinical factors combined with 5 clinical course factors; and model 4: 4 clinical and 1 radiographic baseline factors combined with 5 clinical and 3 radiographic course factors. Model discriminations are as follows: model 1, AUC 0.70 (95% CI 0.67-0.74); model 2, 0.74 (95% CI 0.71-0.77); model 3, 0.77 (95% CI 0.74-0.80); and model 4, 0.80 (95% CI 0.77-0.82). AUCs of model 3 and model 4 were slightly but significantly higher than corresponding baseline-factor models (model 3 0.77 vs 0.75, p = 0.031; model 4 0.80 vs 0.76, p = 0.003).

Conclusions: Four diagnostic models were developed with "fair" to "good" discriminations. First 2-year course factors had additive discriminative value over baseline factors.
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http://dx.doi.org/10.1186/s13075-021-02598-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8375192PMC
August 2021

Vitamin K and osteoarthritis: is there a link?

Ann Rheum Dis 2021 05 12;80(5):547-549. Epub 2021 Apr 12.

Department of Rheumatology, LUMC, Leiden, Zuid-Holland, The Netherlands.

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http://dx.doi.org/10.1136/annrheumdis-2020-219765DOI Listing
May 2021

Cripto favors chondrocyte hypertrophy via TGF-β SMAD1/5 signaling during development of osteoarthritis.

J Pathol 2021 Nov 6;255(3):330-342. Epub 2021 Sep 6.

Department of Cell and Chemical Biology, Leiden University Medical Center, Oncode Institute, Leiden, The Netherlands.

Chondrocytes in mice developing osteoarthritis (OA) exhibit an aberrant response to the secreted cytokine transforming growth factor (TGF)-β, consisting in a potentiation of intracellular signaling downstream of the transmembrane type I receptor kinase activin receptor-like kinase (ALK)1 against canonical TGF-β receptor ALK5-mediated signaling. Unfortunately, the underlying mechanisms remain elusive. In order to identify novel druggable targets for OA, we aimed to investigate novel molecules regulating the ALK1/ALK5 balance in OA chondrocytes. We performed gene expression analysis of TGF-β signaling modulators in joints from three different mouse models of OA and found an upregulated expression of the TGF-β co-receptor Cripto (Tdgf1), which was validated in murine and human cartilage OA samples at the protein level. In vitro and ex vivo, elevated expression of Cripto favors the hypertrophic differentiation of chondrocytes, eventually contributing to tissue calcification. Furthermore, we found that Cripto participates in a TGF-β-ALK1-Cripto receptor complex in the plasma membrane, thereby inducing catabolic SMAD1/5 signaling in chondrocytes. In conclusion, we demonstrate that Cripto is expressed in OA and plays a functional role promoting chondrocyte hypertrophy, thereby becoming a novel potential therapeutic target in OA, for which there is no efficient cure or validated biomarker. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
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http://dx.doi.org/10.1002/path.5774DOI Listing
November 2021

[Topical NSAIDs: ineffective or undervalued?]

Ned Tijdschr Geneeskd 2021 05 19;165. Epub 2021 May 19.

Radboudumc, Nijmegen. Afd. Farmacie.

Topical NSAIDs are currently recommended in several national and international guidelines for knee osteoarthritis, hand osteoarthritis and acute musculoskeletal pain. However, there is still widespread skepticism about the effectiveness of this treatment. This article discusses different reasons for this skepticism, a short summary of the pharmacokinetics and pharmacodynamics of topical NSAIDs and an overview of available evidence regarding efficacy and safety. Based on this evidence topical NSAIDs have a clear place in the treatment of knee and hand osteoarthritis and acute musculoskeletal pain. Due to less systemic side effects they should be recommended before an oral NSAID is considered. Topical NSAIDs might even be an option for patients with contra-indications for oral NSAIDs. There is a large variety of available topical NSAIDs. Of the available topical NSAIDs in the Netherlands, diclofenac gel seems the most sensible choice.
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May 2021

White matter hyperintensities associate with cognitive slowing in patients with systemic lupus erythematosus and neuropsychiatric symptoms.

RMD Open 2021 07;7(2)

Department of Radiology, Leiden University Medical Centre, Leiden, the Netherlands.

Objective: To compare cognitive function between patients with different phenotypes of neuropsychiatric systemic lupus erythematosus (NPSLE) and assess its association with brain and white matter hyperintensity (WMH) volumes.

Methods: Patients attending the Leiden University Medical Centre NPSLE clinic between 2007 and 2015 without large brain infarcts were included (n=151; 42±13 years, 91% women). In a multidisciplinary consensus meeting, neuropsychiatric symptoms were attributed to systemic lupus erythematosus (SLE) (NPSLE, inflammatory (n=24) or ischaemic (n=12)) or to minor/non-NPSLE (n=115). Multiple regression analyses were performed to compare cognitive function between NPSLE phenotypes and to assess associations between brain and WMH volumes and cognitive function cross-sectionally.

Results: Global cognitive function was impaired in 5%, learning and memory (LM) in 46%, executive function and complex attention (EFCA) in 39% and psychomotor speed (PS) in 46% of all patients. Patients with inflammatory NPSLE showed the most cognitive impairment in all domains (p≤0.05).Higher WMH volume associated with lower PS in the total group (B: -0.14 (95% CI -0.32 to -0.02)); especially in inflammatory NPSLE (B: -0.36 (95% CI -0.60 to -0.12). In the total group, lower total brain volume and grey matter volume associated with lower cognitive functioning in all domains (all: 0.00/0.01 (0.00;0.01)) and lower white matter volume associated with lower LM, EFCA and PS (all: 0.00/0.01 (0.00;0.01)).

Conclusion: We demonstrated that an association between brain and WMH volumes and cognitive function is present in patients with SLE, but differs between (NP)SLE phenotypes. WMHs associated with PS especially in inflammatory NPSLE, which suggests a different, potentially more severe underlying pathophysiological mechanism of cognitive impairment in this phenotype.
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http://dx.doi.org/10.1136/rmdopen-2021-001650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320250PMC
July 2021

Real-time versus static scoring in musculoskeletal ultrasonography in patients with inflammatory hand osteoarthritis.

Rheumatology (Oxford) 2021 Jul 15. Epub 2021 Jul 15.

Leiden University Medical Center, Leiden, Netherlands.

Objectives: Agreement between real-time and static ultrasonographic has not been studied in musculoskeletal diseases. We studied this agreement in inflammatory hand osteoarthritis.

Methods: Ultrasonography was performed blinded to clinical information of 30 joints of 75 patients with hand osteoarthritis, treated with prednisolone in a randomized placebo-controlled double-blind trial. Images were scored real-time at acquisition and stored images were scored static (paired in known chronological order) for inflammatory features and osteophytes (score 0-3). Agreement between methods was studied at joint level with quadratic weighted kappa. At patient level intra-class correlations (ICC) of sum scores and change in sum-scores (delta baseline-week 6) were calculated. Responsiveness of scoring methods was analyzed with generalized estimating equations (GEE) with treatment as independent and ultrasonography findings as dependent variable.

Results: Agreement at baseline was good to excellent at joint level (kappa 0.72-0.88) and moderate to excellent at patient level (ICC 0.58-0.91). Agreement for change in sum scores was poor to fair for synovial thickening and effusion (ICC 0.18 and 0.34 respectively), while excellent for Doppler signal (ICC 0.80). Real-time ultrasonography discriminated between prednisolone and placebo with a mean between-group difference of synovial thickening of -2.5 (CI:-4.7 to-0.3). Static ultrasonography did not show a decrease in synovial thickening.

Conclusion: While cross-sectional agreement between real-time and static ultrasonography is good, static ultrasonography measurement of synovial thickening did not show responsiveness to prednisone therapy while real-time ultrasonography did. Therefore, when ultrasonography is used in clinical trials, real-time dynamic scoring should remain the standard for now.
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http://dx.doi.org/10.1093/rheumatology/keab556DOI Listing
July 2021

Ultrasonography of Inflammatory and Structural Lesions in Hand Osteoarthritis: An OMERACT Agreement and Reliability Study.

Arthritis Care Res (Hoboken) 2021 Jun 16. Epub 2021 Jun 16.

The Parker Institute, Copenhagen University Hospital Bispebjerg-Frederiksberg, Frederiksberg, Denmark.

Objective: To standardize and assess the reliability of ultrasonographic assessment of inflammatory and structural lesions in patients with hand osteoarthritis (OA).

Methods: The Outcome Measures in Rheumatology (OMERACT) Ultrasound Working Group selected synovial hypertrophy (SH), joint effusion (JE), and power Doppler (PD) signals as the main inflammatory lesions in hand OA, and suggested osteophytes in the scapho-trapezio-trapezoid (STT) and cartilage defects in the proximal interphalangeal (PIP) joints as novel additions to previous structural scoring systems. A complementary imaging atlas provided detailed examples of the scores. A reliability exercise of static images was performed for the inflammatory features, followed by a patient-based exercise with six sonographers testing inflammatory and structural features in twelve hand OA patients. We used Cohen's kappa (κ) for intra-reader and Light's κ for inter-reader reliability for all features except PD, in which Prevalence-Adjusted Bias-Adjusted Kappa (PABAK) was applied. Percentage agreement was also assessed.

Results: The web-based reliability exercise demonstrated substantial intra- and inter-reader reliability for all inflammatory features (κ>0.64). In the patient-based exercise, intra- and inter-reader reliability varied: SH κ=0.73 and 0.45; JE κ=0.70 and 0.55; PD PABAK=0.90 and 0.88; PIP cartilage κ=0.56 and 0.45; STT osteophytes κ=0.62 and 0.36. Percentage close agreement was high for all features (>85%).

Conclusion: With ultrasound, substantial to excellent intra-reader reliability was found for inflammatory features of hand OA. Inter-reader reliability was moderate, but overall high close agreement between readers suggest that better reliability is achievable after further training. Assessment of osteophytes in the STT joint and cartilage in the PIP joints achieved less good reliability and the latter is not endorsed.
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http://dx.doi.org/10.1002/acr.24734DOI Listing
June 2021

Comparison of KOOS Scores of Middle-Aged Patients Undergoing Total Knee Arthroplasty to the General Dutch Population Using KOOS Percentile Curves: The LOAS Study.

J Arthroplasty 2021 08 30;36(8):2779-2787.e4. Epub 2021 Mar 30.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands; Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.

Background: We aimed to investigate the application of the Knee Injury and Osteoarthritis Outcome Score (KOOS) percentile curves, using preoperative and postoperative data of patients with knee osteoarthritis undergoing total knee arthroplasty (TKA).

Methods: We used Longitudinal Leiden Orthopedics Outcomes of Osteo-Arthritis study data of patients between 45 and 65 years and undergoing primary TKA. KOOS scores (0-100) were obtained preoperatively and 6, 12, and 24 months after TKA. Preoperative knee radiographs were assessed according to Kellgren-Lawrence (KL) in a subset (37%) of patients. Comorbidities were self-reported using a standardized questionnaire. The median (interquartile range) population-level KOOS scores were plotted on previously developed population-based KOOS percentile curves. In addition, we assessed the application of the curves on patient level and investigated differences in scores between patients with preoperative KL scores ≤2 and ≥3 and presence (vs absence) of comorbidities.

Results: The study population consisted of 853 patients (62% women, mean age 59 years, body mass index 30 kg/m) with knee osteoarthritis undergoing primary TKA. Preoperatively, median KOOS scores of all subscales were at or below the 2.5 percentile. Scores increased to approximately the 25 percentile 12 months postoperatively. Greater improvements were observed in pain and less improvements in sport and recreational function and quality of life. Patients with higher preoperative KL scores and without comorbidities showed greater improvements.

Conclusion: The KOOS percentile curves provided visual insights in knee complaints of patients relative to the general population. Furthermore, the KOOS percentile curves give insight in how preoperative patient characteristics are correlated with postoperative results.
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http://dx.doi.org/10.1016/j.arth.2021.03.050DOI Listing
August 2021

Fatigue in patients with systemic lupus erythematosus and neuropsychiatric symptoms is associated with anxiety and depression rather than inflammatory disease activity.

Lupus 2021 Jun 28;30(7):1124-1132. Epub 2021 Mar 28.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Introduction: We aimed to investigate risk factors for fatigue in patients with systemic lupus erythematosus (SLE) and neuropsychiatric symptoms in order to identify potential interventional strategies.

Methods: Patients visiting the neuropsychiatric SLE (NPSLE) clinic of the Leiden University Medical Center between 2007-2019 were included. In a multidisciplinary consensus meeting, SLE patients were classified as having neuropsychiatric symptoms of inflammatory origin (inflammatory phenotype) or other origin (non-inflammatory phenotype). Fatigue was assessed with the SF-36 vitality domain (VT) since 2007 and the multidimensional fatigue inventory (MFI) and visual analogue scale (VAS) since 2011. Patients with a score on the SF-36 VT ≥1 standard deviation (SD) away from the mean of age-related controls of the general population were classified as fatigued; patients ≥2 SD away were classified as extremely fatigued. Disease activity was measured using the SLE disease activity index-2000. The influence of the presence of an inflammatory phenotype, disease activity and symptoms of depression and anxiety as measured by the hospital anxiety and depression scale (HADS) was analyzed using multiple regression analyses corrected for age, sex and education.

Results: 348 out of 371 eligible patients filled in questionnaires and were included in this study . The majority was female (87%) and the mean age was 43 ± 14 years. 72 patients (21%) had neuropsychiatric symptoms of an inflammatory origin. Fatigue was present in 78% of all patients and extreme fatigue was present in 50% of patients with an inflammatory phenotype vs 46% in the non-inflammatory phenotype. Fatigue was similar in patients with an inflammatory phenotype compared to patients with a non-inflammatory phenotype on the SF-36 VT (β: 0.8 (95% CI -4.8; 6.1) and there was less fatigue in patients with an inflammatory phenotype on the MFI and VAS (β: -3.7 (95% CI: -6.9; -0.5) and β: -1.0 (95% CI -1.6; -0.3)). There was no association between disease activity and fatigue, but symptoms of anxiety and depression (HADS) associated strongly with all fatigue measurements.

Conclusion: This study suggests that intervention strategies to target fatigue in (NP)SLE patients may need to focus on symptoms of anxiety and depression rather than immunosuppressive treatment.
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http://dx.doi.org/10.1177/09612033211005014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120630PMC
June 2021

The DIGICOD cohort: A hospital-based observational prospective cohort of patients with hand osteoarthritis - methodology and baseline characteristics of the population.

Joint Bone Spine 2021 Jul 6;88(4):105171. Epub 2021 Mar 6.

Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Service de rhumatologie, Hôpital Saint-Antoine, Paris, France; Centre de Recherche Saint-Antoine, Inserm URMS_938, Paris, France. Electronic address:

Objective: Despite its prevalence, there are few worldwide hand osteoarthritis (HOA) cohorts. The main objective of DIGItal COhort Design (DIGICOD) cohort is to investigate prognostic clinical, biological, genetic and imaging factors of clinical worsening after 6years follow-up.

Methods: DIGICOD is a hospital-based prospective cohort including patients>35years-old with symptomatic HOA fulfilling: (i) ACR criteria for HOA with≥2 symptomatic joints among proximal/distal interphalangeal joints or 1st interphalangeal joint with Kellgren-Lawrence (KL)≥2; or (ii) symptomatic thumb base OA with KL≥2. Main exclusion criteria were inflammatory arthritis and crystal arthropathies. Annual clinical evaluations were scheduled with imaging (X-rays of the hands and of other OA symptomatic joints) and biological sampling every 3years. Hand radiographs are scored using KL and anatomical Verbruggen-Veys scores. Follow-up visits are ongoing. Cohort methodology and baseline characteristics are presented.

Results: Between April 2013 and June 2017, from the 436 HOA included patients, 426 have been analysed of whom 357 (84%) are women. Mean age±standard deviation was 66.7±7.3years and mean disease duration was 12.6±9.6years. Metabolic syndrome affected 151 (36.5%) patients. Mean Visual Analog Scale (VAS) hand pain (0-100mm) was 44.4±26.7mm at activity. Mean FIHOA (0-100) was 19.9±18.6. Elevated serum CRP level (≥5mg/L) involved 10% patients. Mean KL score (0-128) was 46.7±18 and the mean number of joint with KL≥2 was 15.1±6.3. Erosive HOA (defined as≥1 Erosive or Remodeling phase joint according to Verbruggen-Veys score) involved 195/426 (45.8%) patients and the median number (interquartile range) of erosive joints in erosive patients was 3.0 (1.0-5.0).

Conclusion: DIGICOD is a unique prospective HOA cohort with a long-term 6years standardized assessment and has included severe radiologically HOA patients with a high prevalence of erosive disease.
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http://dx.doi.org/10.1016/j.jbspin.2021.105171DOI Listing
July 2021

Diagnostic criteria for early hip osteoarthritis; first steps, based on the CHECK study.

Rheumatology (Oxford) 2021 Feb 12. Epub 2021 Feb 12.

Department of General Practice, Erasmus MC University Medical Center Rotterdam, Rotterdam, the Netherlands.

Objectives: Although there is a general focus on early diagnosis and treatment of hip osteoarthritis, there are no validated diagnostic criteria for early-stage hip OA. The current study aimed to take the first steps in developing diagnostic criteria for early-stage hip OA, using factors obtained through history taking, physical examination, radiography and blood testing at the first consultation in individuals presenting with hip pain, suspicious for hip OA, in primary care.

Methods: Data of the 543 individuals with 735 symptomatic hips at baseline who had any follow-up data available from the prospective CHECK cohort study were used. A group of 26 clinical experts (GPs, Rheumatologists and Orthopedic surgeons) evaluated standardized clinical assessment forms of all subjects on the presence of clinically relevant hip OA 5 to 10 years after baseline. Using the expert based diagnoses as reference standard, a backward selection method was used to create predictive models based on pre-defined baseline factors from history taking, physical examination, radiography and blood testing.

Results: Prevalence of clinically relevant hip OA during follow-up was 22%. Created models contained 4 to 8 baseline factors (mainly WOMAC pain items, painful/restricted movements, and radiographic features) and obtained area under the curve between 0.62 ± 0.002 and 0.71 ± 0.002.

Conclusion: Based on clinical and radiographic features of hip OA obtained at first consultation at a GP for pain/stiffness of the hip, the prediction of clinically relevant hip OA within 5 to 10 years was 'poor' to 'fair'.
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http://dx.doi.org/10.1093/rheumatology/keab111DOI Listing
February 2021

Reproducibility of Targeted Lipidome Analyses (Lipidyzer) in Plasma and Erythrocytes over a 6-Week Period.

Metabolites 2020 Dec 31;11(1). Epub 2020 Dec 31.

Department of Rheumatology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands.

It is essential to measure lipid biomarkers with a high reproducibility to prevent biased results. We compared the lipid composition and inter-day reproducibility of lipid measurements in plasma and erythrocytes. Samples from 42 individuals (77% women, mean age 65 years, mean body mass index (BMI) 27 kg/m), obtained non-fasted at baseline and after 6 weeks, were used for quantification of up to 1000 lipid species across 13 lipid classes with the Lipidyzer platform. Intraclass correlation coefficients (ICCs) were calculated to investigate the variability of lipid concentrations between timepoints. The ICC distribution of lipids in plasma and erythrocytes were compared using Wilcoxon tests. After data processing, the analyses included 630 lipids in plasma and 286 in erythrocytes. From these, 230 lipids overlapped between sample types. In plasma, 78% of lipid measurements were reproduced well to excellently, compared to 37% in erythrocytes. The ICC score distribution in plasma (median ICC 0.69) was significantly better than in erythrocytes (median ICC 0.51) (-value < 0.001). At the class level, reproducibility in plasma was superior for triacylglycerols and cholesteryl esters while ceramides, diacylglycerols, (lyso)phosphatidylethanolamines, and sphingomyelins showed better reproducibility in erythrocytes. Although in plasma overall reproducibility was superior, differences at individual and class levels may favor the use of erythrocytes.
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http://dx.doi.org/10.3390/metabo11010026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7823270PMC
December 2020

Suspected Transverse Myelitis with Normal MRI and CSF Findings in a Patient with Lupus: What to Do? A Case Series and Systematic Review.

Neuropsychiatr Dis Treat 2020 22;16:3173-3186. Epub 2020 Dec 22.

Department of Rheumatology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.

Purpose: To evaluate the use of immunosuppressive treatment, clinical outcome and diagnostic strategy in patients with systemic lupus erythematosus (SLE) presenting with clinical features of transverse myelitis (TM), but normal MRI of the spinal cord (sMRI) and normal cerebrospinal fluid (CSF) assessment, and to suggest a clinical guideline.

Patients And Methods: All patients with SLE and clinical features compatible with (sub)acute TM visiting the NPSLE clinic of the LUMC between 2007 and 2020 were included. Information on baseline characteristics, investigations, treatment and outcomes was collected from electronic medical records. In addition, a systematic review of individual participant data was performed up to April 2020 in PubMed, Embase and Web of Science, identifying all patients with TM, SLE and sMRI assessment. Data regarding sMRI, CSF analysis, treatment and outcome were extracted, and outcome was compared between patients with normal sMRI and CSF (sMRI-/CSF-) and patients with abnormalities.

Results: Twelve SLE patients with a clinical diagnosis of TM were identified: four sMRI-/CSF- and one sMRI- with CSF not available. All patients received immunosuppressive treatment, but outcome in sMRI-/CSF- patients was worse: no recovery (n=1) or partial recovery (n=3) compared to partial recovery (n=4) and (nearly) complete recovery (n=3) in MRI+ patients. The systematic literature review yielded 146 articles eligible for inclusion, 90% case reports. A total of 427 SLE patients with TM were identified, of which only four cases were sMRI-/CSF- (1%), showing no improvement (n=1), partial improvement (n=2) and complete recovery (n=1) after immunosuppressive treatment.

Conclusion: Outcome in SLE patients presenting with clinically suspected TM with normal sMRI and CSF is less favorable, despite treatment with immunosuppressive therapy. Taking a functional neurological disorder into consideration may be helpful in order to start other therapeutic strategies. We suggest prescribing immunosuppressive treatment for a restricted period of time to evaluate its effect in cases where a functional disorder initially is considered unlikely.
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http://dx.doi.org/10.2147/NDT.S267000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764958PMC
December 2020

Relationship between motion, using the GaitSmartTM system, and radiographic knee osteoarthritis: an explorative analysis in the IMI-APPROACH cohort.

Rheumatology (Oxford) 2021 08;60(8):3588-3597

Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, The Netherlands.

Objectives: To assess underlying domains measured by GaitSmartTMparameters and whether these are additional to established OA markers including patient reported outcome measures (PROMs) and radiographic parameters, and to evaluate if GaitSmart analysis is related to the presence and severity of radiographic knee OA.

Methods: GaitSmart analysis was performed during baseline visits of participants of the APPROACH cohort (n = 297). Principal component analyses (PCA) were performed to explore structure in relationships between GaitSmart parameters alone and in addition to radiographic parameters and PROMs. Logistic and linear regression analyses were performed to analyse the relationship of GaitSmart with the presence (Kellgren and Lawrence grade ≥2 in at least one knee) and severity of radiographic OA (ROA).

Results: Two hundred and eighty-four successful GaitSmart analyses were performed. The PCA identified five underlying GaitSmart domains. Radiographic parameters and PROMs formed additional domains indicating that GaitSmart largely measures separate concepts. Several GaitSmart domains were related to the presence of ROA as well as the severity of joint damage in addition to demographics and PROMs with an area under the receiver operating characteristic curve of 0.724 and explained variances (adjusted R2) of 0.107, 0.132 and 0.147 for minimum joint space width, osteophyte area and mean subchondral bone density, respectively.

Conclusions: GaitSmart analysis provides additional information over established OA outcomes. GaitSmart parameters are also associated with the presence of ROA and extent of radiographic severity over demographics and PROMS. These results indicate that GaitsmartTM may be an additional outcome measure for the evaluation of OA.
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http://dx.doi.org/10.1093/rheumatology/keaa809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328500PMC
August 2021

Mediation of the association between obesity and osteoarthritis by blood pressure, vessel wall stiffness and subclinical atherosclerosis.

Rheumatology (Oxford) 2021 07;60(7):3268-3277

Department of Rheumatology.

Objective: We investigated the role of blood pressure, vessel wall stiffness [pulse wave velocity (PWV)] and subclinical atherosclerosis markers [carotid intima-media thickness (cIMT), popliteal vessel wall thickness (pVWT)] as mediators of the association of obesity with OA.

Methods: We used cross-sectional data from a subset of the population-based NEO study (n = 6334). We classified clinical hand and knee OA by the ACR criteria, and structural knee OA, effusion and bone marrow lesions on MRI (n = 1285). cIMT was assessed with ultrasonography. pVWT was estimated on knee MRI (n = 1285), and PWV by abdominal velocity-encoded MRIs (n = 2580), in subpopulations. Associations between BMI and OA were assessed with logistic regression analyses, adjusted for age, sex and education. Blood pressure, cIMT, pVWT and PWV were added to the model to estimate mediation.

Results: The population consisted of 55% women, with a mean (s.d.) age of 56(6) years. Clinical hand OA was present in 8%, clinical knee OA in 10%, and structural knee OA in 12% of participants. BMI was positively associated with all OA outcomes. cIMT partially mediated the association of BMI with clinical hand OA [10.6 (6.2; 30.5)%], structural knee OA [3.1 (1.9; 7.3)%] and effusion [10.8 (6.0; 37.6)%]. Diastolic blood pressure [2.1 (1.6; 3.0)%] minimally mediated the association between BMI and clinical knee OA. PWV and pVWT did not mediate the association between BMI and OA.

Conclusions: cIMT and diastolic blood pressure minimally mediated the association of BMI with OA. This suggests that such mediation is trivial in the middle-aged population.
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http://dx.doi.org/10.1093/rheumatology/keaa778DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8516511PMC
July 2021

Emerging pharmaceutical therapies for osteoarthritis.

Nat Rev Rheumatol 2020 12 29;16(12):673-688. Epub 2020 Oct 29.

Rheumatology Department, Lariboisière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.

The prevalence of osteoarthritis (OA) and the burden associated with the disease are steadily increasing worldwide, representing a major public health challenge for the coming decades. The lack of specific treatments for OA has led to it being recognized as a serious disease that has an unmet medical need. Advances in the understanding of OA pathophysiology have enabled the identification of a variety of potential therapeutic targets involved in the structural progression of OA, some of which are promising and under clinical investigation in randomized controlled trials. Emerging therapies include those targeting matrix-degrading proteases or senescent chondrocytes, promoting cartilage repair or limiting bone remodelling, local low-grade inflammation or Wnt signalling. In addition to these potentially disease-modifying OA drugs (DMOADs), several targets are being explored for the treatment of OA-related pain, such as nerve growth factor inhibitors. The results of these studies are expected to considerably reshape the landscape of OA management over the next few years. This Review describes the pathophysiological processes targeted by emerging therapies for OA, along with relevant clinical data and discussion of the main challenges for the further development of these therapies, to provide context for the latest advances in the field of pharmaceutical therapies for OA.
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http://dx.doi.org/10.1038/s41584-020-00518-6DOI Listing
December 2020

Progression of acromegalic arthropathy in long-term controlled acromegaly patients: 9 years of longitudinal follow-up.

J Clin Endocrinol Metab 2021 01;106(1):188-200

Department of Medicine, Division of Endocrinology, and Center for Endocrine Tumors Leiden, Leiden University Medical Center, ZA, Leiden, the Netherlands.

Context: Joint complaints in patients with acromegaly are common, although the long-term disease course is largely unknown.

Objective: This study aims to evaluate the long-term course of acromegalic arthropathy.

Design And Setting: A prospective longitudinal cohort study was conducted in controlled acromegaly patients followed at a tertial referral center, with 3 study visits: at baseline and after a median of 2.6 and 9.1 years.

Patients: We included 31 patients with biochemically controlled acromegaly for 2 or more years (49% female; median age, 60 years) at baseline.

Main Outcome Measures: Radiographic arthropathy of the knee, hip, hand, and cervical and lumbar spine were evaluated using Kellgren and Lawrence (KL) scores, developed for assessment of primary osteoarthritis (OA). Radiographic progression was defined as a KL increase above the smallest detectable change. Joint symptoms were assessed using self-reported questionnaires. Progression was defined using existing clinically important cutoff values. Risk factors for progression were investigated using a multivariable model.

Results: All patients had definite radiographic OA at 1 or more joints at baseline. Radiographic progression was observed in 29%, 48%, 84%, and 94% of patients in the knees, hips, hands, and axial joints, respectively. Deterioration in hand-related pain and function was observed in 10 (32.3%) and 11 patients (35.5%), respectively. Solely baseline KL scores of the hip were associated with hip OA progression (OR 1.88; 95% CI, 1.09-3.16).

Conclusions: Acromegalic arthropathy showed significant radiographic progression over 9.1 years of follow-up in patients in remission, whereas clinical progression was observed less frequently. Future studies should focus on adequate prevention and treatment strategies of acromegalic arthropathy.
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http://dx.doi.org/10.1210/clinem/dgaa747DOI Listing
January 2021

The Added Value of Radiographs in Diagnosing Knee Osteoarthritis Is Similar for General Practitioners and Secondary Care Physicians; Data from the CHECK Early Osteoarthritis Cohort.

J Clin Med 2020 10 21;9(10). Epub 2020 Oct 21.

Department of General Practice, Erasmus MC University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.

Objective: The purpose of this study was to evaluate the added value of radiographs for diagnosing knee osteoarthritis (KOA) by general practitioners (GPs) and secondary care physicians (SPs).

Methods: Seventeen GPs and nineteen SPs were recruited to evaluate 1185 knees from the CHECK cohort (presenters with knee pain in primary care) for the presence of clinically relevant osteoarthritis (OA) during follow-up. Experts were required to make diagnoses independently, first based on clinical data only and then on clinical plus radiographic data, and to provide certainty scores (ranging from 1 to 100, where 1 was "certainly no OA" and 100 was "certainly OA"). Next, experts held consensus meetings to agree on the final diagnosis. With the final diagnosis as gold standard, diagnostic indicators were calculated (sensitivity, specificity, positive/negative predictive value, accuracy and positive/negative likelihood ratio) for all knees, as well as for clinically "certain" and "uncertain" knees, respectively. Student paired -tests compared certainty scores.

Results: Most diagnoses of GPs (86%) and SPs (82%) were "consistent" after assessment of radiographic data. Diagnostic indicators improved similarly for GPs and SPs after evaluating the radiographic data, but only improved relevantly in clinically "uncertain" knees. Radiographs added some certainty to "consistent" OA knees (GP 69 vs. 72, < 0.001; SP 70 vs. 77, < 0.001), but not to the consistent no OA knees (GP 21 vs. 22, = 0.16; SP 20 vs. 21, = 0.04).

Conclusions: The added value of radiographs is similar for GP and SP, in terms of diagnostic accuracy and certainty. Radiographs appear to be redundant when clinicians are certain of their clinical diagnosis.
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http://dx.doi.org/10.3390/jcm9103374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7594082PMC
October 2020

Measures of Hand Function.

Arthritis Care Res (Hoboken) 2020 10;72 Suppl 10:321-341

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http://dx.doi.org/10.1002/acr.24352DOI Listing
October 2020

Mortality in patients with systemic lupus erythematosus and neuropsychiatric involvement: A retrospective analysis from a tertiary referral center in the Netherlands.

Lupus 2020 Dec 20;29(14):1892-1901. Epub 2020 Oct 20.

Department of Rheumatology, Leiden University Medical Center, Leiden, the Netherlands.

Objective: We aimed to evaluate all-cause and cause-specific mortality in patients with systemic lupus erythematosus (SLE) and neuropsychiatric (NP) symptoms in the Netherlands between 2007-2018.

Methods: Patients visiting the tertiary referral NPSLE clinic of the Leiden University Medical Center were included. NP symptoms were attributed to SLE requiring treatment (major NPSLE) or to other and mild causes (minor/non-NPSLE). Municipal registries were checked for current status (alive/deceased). Standardized mortality ratios (SMRs) and 95% confidence intervals (CI) were calculated using data from the Dutch population. Rate ratio (RR) and 95% CI were calculated using direct standardization to compare mortality between major NPSLE and minor/non-NPSLE.

Results: 351 patients were included and 149 patients were classified as major NPSLE (42.5%). Compared with the general population, mortality was increased in major NPSLE (SMR 5.0 (95% CI: 2.6-8.5)) and minor/non-NPSLE patients (SMR 3.7 (95% CI: 2.2-6.0)). Compared with minor/non-NPSLE, mortality was similar in major NPSLE patients (RR: 1.0 (95% CI: 0.5-2.0)). Cause-specific mortality rates demonstrated an increased risk of death due to infections in both groups, whereas death due to cardiovascular disease was only increased in minor/non-NPSLE patients.

Conclusion: Mortality was increased in both major NPSLE and minor/non-NPSLE patients in comparison with the general population. There was no difference in mortality between major NPSLE and minor/non-NPSLE patients.
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http://dx.doi.org/10.1177/0961203320963815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7684795PMC
December 2020

Metabolic Age Based on the BBMRI-NL H-NMR Metabolomics Repository as Biomarker of Age-related Disease.

Circ Genom Precis Med 2020 10 14;13(5):541-547. Epub 2020 Aug 14.

Department of Internal Medicine, Maastricht University Medical Center, the Netherlands (C.D.A.S., C.J.H.v.d.K., M.M.J.v.G.).

Background: The blood metabolome incorporates cues from the environment and the host's genetic background, potentially offering a holistic view of an individual's health status.

Methods: We have compiled a vast resource of proton nuclear magnetic resonance metabolomics and phenotypic data encompassing over 25 000 samples derived from 26 community and hospital-based cohorts.

Results: Using this resource, we constructed a metabolomics-based age predictor (metaboAge) to calculate an individual's biological age. Exploration in independent cohorts demonstrates that being judged older by one's metabolome, as compared with one's chronological age, confers an increased risk on future cardiovascular disease, mortality, and functionality in older individuals. A web-based tool for calculating metaboAge (metaboage.researchlumc.nl) allows easy incorporation in other epidemiological studies. Access to data can be requested at bbmri.nl/samples-images-data.

Conclusions: In summary, we present a vast resource of metabolomics data and illustrate its merit by constructing a metabolomics-based score for biological age that captures aspects of current and future cardiometabolic health.
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http://dx.doi.org/10.1161/CIRCGEN.119.002610DOI Listing
October 2020

Anti-Inflammatory and Proresolving Effects of the Omega-6 Polyunsaturated Fatty Acid Adrenic Acid.

J Immunol 2020 11 2;205(10):2840-2849. Epub 2020 Oct 2.

Department of Rheumatology, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.

Polyunsaturated fatty acids (PUFAs) and their metabolites are potent regulators of inflammation. Generally, omega ()-3 PUFAs are considered proresolving whereas -6 PUFAs are classified as proinflammatory. In this study, we characterized the inflammatory response in murine peritonitis and unexpectedly found the accumulation of adrenic acid (AdA), a poorly studied -6 PUFA. Functional studies revealed that AdA potently inhibited the formation of the chemoattractant leukotriene B (LTB), specifically in human neutrophils, and this correlated with a reduction of its precursor arachidonic acid (AA) in free form. AdA exposure in human monocyte-derived macrophages enhanced efferocytosis of apoptotic human neutrophils. In vivo, AdA treatment significantly alleviated arthritis in an LTB-dependent murine arthritis model. Our findings are, to our knowledge, the first to indicate that the -6 fatty acid AdA effectively blocks production of LTB by neutrophils and could play a role in resolution of inflammation in vivo.
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http://dx.doi.org/10.4049/jimmunol.1801653DOI Listing
November 2020

Cohort profile: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (IMI-APPROACH) study: a 2-year, European, cohort study to describe, validate and predict phenotypes of osteoarthritis using clinical, imaging and biochemical markers.

BMJ Open 2020 07 28;10(7):e035101. Epub 2020 Jul 28.

Rheumatology and Clinical Immunology, UMC Utrecht, Utrecht, The Netherlands.

Purpose: The Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) consortium intends to prospectively describe in detail, preselected patients with knee osteoarthritis (OA), using conventional and novel clinical, imaging, and biochemical markers, to support OA drug development.

Participants: APPROACH is a prospective cohort study including 297 patients with tibiofemoral OA, according to the American College of Rheumatology classification criteria. Patients were (pre)selected from existing cohorts using machine learning models, developed on data from the CHECK cohort, to display a high likelihood of radiographic joint space width (JSW) loss and/or knee pain progression.

Findings To Date: Selection appeared logistically feasible and baseline characteristics of the cohort demonstrated an OA population with more severe disease: age 66.5 (SD 7.1) vs 68.1 (7.7) years, min-JSW 2.5 (1.3) vs 2.1 (1.0) mm and Knee injury and Osteoarthritis Outcome Score pain 31.3 (19.7) vs 17.7 (14.6), except for age, all: p<0.001, for selected versus excluded patients, respectively. Based on the selection model, this cohort has a predicted higher chance of progression.

Future Plans: Patients will visit the hospital again at 6, 12 and 24 months for physical examination, pain and general health questionnaires, collection of blood and urine, MRI scans, radiographs of knees and hands, CT scan of the knee, low radiation whole-body CT, HandScan, motion analysis and performance-based tests.After two years, data will show whether those patients with the highest probabilities for progression experienced disease progression as compared to those wit lower probabilities (model validation) and whether phenotypes/endotypes can be identified and predicted to facilitate targeted drug therapy.

Trial Registration Number: NCT03883568.
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http://dx.doi.org/10.1136/bmjopen-2019-035101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7389775PMC
July 2020

Development of classification criteria for hand osteoarthritis: comparative analyses of persons with and without hand osteoarthritis.

RMD Open 2020 06;6(2)

Rheumatology, Leiden University Medical Center, Leiden, Netherlands.

Objectives: Further knowledge about typical hand osteoarthritis (OA) characteristics is needed for the development of new classification criteria for hand OA.

Methods: In a cross-sectional multi-centre international study, a convenience sample of patients from primary and secondary/tertiary care with a physician-based hand OA diagnosis (n = 128) were compared with controls with hand complaints due to inflammatory or non-inflammatory conditions (n = 70). We examined whether self-reported, clinical, radiographic and laboratory findings were associated with hand OA using logistic regression analyses. Discrimination between groups was assessed by calculating the area under receiver operating curves (AUC).

Results: Strong associations with hand OA were observed for radiographic osteophytes (OR = 1.62, 95% CI 1.40 to 1.88) and joint space narrowing (JSN) (OR = 1.57, 95% CI 1.36 to 1.82) in the distal interphalangeal (DIP) joints with excellent discrimination (AUC = 0.82 for both). For osteophytes and JSN, we found acceptable discrimination between groups in the proximal interphalangeal joints (AUC = 0.77 and 0.78, respectively), but poorer discrimination in the first carpometacarpal joints (AUC = 0.67 and 0.63, respectively). Painful DIP joints were associated with hand OA, but were less able to discriminate between groups (AUC = 0.67). Age and family history of OA were positively associated with hand OA, whereas negative associations were found for pain, stiffness and soft tissue swelling in metacarpophalangeal joints, pain and marginal erosions in wrists, longer morning stiffness, inflammatory biomarkers and autoantibodies.

Conclusions: Differences in symptoms, clinical findings, radiographic changes and laboratory tests were found in patients with hand OA versus controls. Radiographic OA features, especially in DIP joints, were best suited to discriminate between groups.
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http://dx.doi.org/10.1136/rmdopen-2020-001265DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425183PMC
June 2020
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