Objective: To examine the pain relief effects of comparators (placebos and untreated control groups) in hand osteoarthritis trials and the impact of contextual factors. Methods: We systematically... Show moreObjective: To examine the pain relief effects of comparators (placebos and untreated control groups) in hand osteoarthritis trials and the impact of contextual factors. Methods: We systematically searched PubMed, EMBASE and CENTRAL from inception to December 26, 2021. We included randomised controlled trials of people with hand osteoarthritis with a placebo or an untreated control group. We assessed the Risk of Bias with Cochrane Risk-of-Bias tool version 2. Each comparator was contrasted with a null-arm, imputed as having a zero change from baseline with the same standard deviation as the comparator. We combined the standardised mean differences with a random effects meta-analysis. The contextual factors’ effect was explored in meta-regression and stratified models with pain as the dependent variable. Results: 84 trials (7262 participants) were eligible for quantitative synthesis, of which 76 (6462 participants) were eligible for the stratified analyses. Placebos were superior to their matched null-arms in relieving pain with an effect size of −0.51 (95% confidence interval −0.61 to −0.42), while untreated control groups were not. When analysing all comparators, blinded trial designs and low risk of bias were associated with higher pain relief compared to an open-label trial design and some concern or high risk of bias. Conclusion: The placebo response on pain for people with hand osteoarthritis was increased by appropriate blinding and a lower risk of bias assessment. Placebos were superior to a null-arm, while untreated control groups were not. Results emphasise the importance of using appropriate comparators in clinical trials. PROSPERO registration ID: CRD42022298984 Show less
Binvignat, M.; Emond, P.; Mifsud, F.; Miao, B.; Courties, A.; Lefèvre, A.; ... ; Sellam, J. 2023
ObjectiveTo investigate host and gut-microbiota related Tryptophan metabolism in hand osteoarthritis (HOA).MethodsThe baseline serum concentration of 20 Tryptophan metabolites was measured in 416... Show moreObjectiveTo investigate host and gut-microbiota related Tryptophan metabolism in hand osteoarthritis (HOA).MethodsThe baseline serum concentration of 20 Tryptophan metabolites was measured in 416 HOA patients in a cross-sectional analysis of the DIGICOD cohort. Tryptophan metabolites levels, metabolite-ratios and metabolism pathway activation were compared between erosive (N = 141) and non-erosive HOA (N = 275) by multiple logistic regressions adjusted on age, BMI and sex. The association between Tryptophan metabolite levels and HOA symptoms was investigated by a Spearman's rank correlation analysis.ResultsFour serum Tryptophan metabolites, eight metabolite ratios and one metabolism pathway were associated with erosive HOA. Erosive HOA was negatively associated with Tryptophan (odds ratio (OR) = 0.41, 95% confidence interval [0.24–0.70]), indole-3-aldehyde (OR = 0.67 [0.51–0.90]) and 3-OH-anthranilic acid (OR = 1.32 [1.13–1.54]) and positively with 5-OH-Tryptophan levels (OR = 1.41 [1.13–1.77]). The pro-inflammatory kynurenine–indoleamine 2,3-dioxygenase pathway was upregulated in erosive HOA (OR = 1.60 [1.11–2.29]). Eleven metabolites were correlated with HOA symptoms and were mostly pain-related. Serotonin and N-acetyl serotonin levels were negatively correlated with number of tender joints. Indole-3-aldehyde level was negatively correlated and 3-OH-anthranilic acid, 3-OH-kynurenine and 5-OH-Tryptophan levels were positively correlated with number of patients-reported painful joints. Quinolinic acid and 3-OH-kynurenine levels correlated positively with AUSCAN pain.ConclusionsTryptophan metabolites disturbance is associated with erosive HOA and pain and emphasize the role of low-grade inflammation and gut dysbiosis in HOA. Show less
Stadt, L.A. van de; Haugen, I.K.; Felson, D.; Kloppenburg, M. 2023
Objective: Prolonged morning stiffness (>60 min) is considered a symptom of inflammatory arthritis, but has a poor discriminative ability. Knowledge about morning stiffness in patients with hand... Show moreObjective: Prolonged morning stiffness (>60 min) is considered a symptom of inflammatory arthritis, but has a poor discriminative ability. Knowledge about morning stiffness in patients with hand osteoarthritis (OA) is lacking. We therefore studied morning stiffness in patients with hand OA. Design: Patients with primary hand OA according to their treating rheumatologist in the Hand OSTeo-Arthritis in Secondary care (HOSTAS) cohort were studied. Severity of morning stiffness was examined with Australian/Canadian hand OA index (AUSCAN) and presence and duration of morning stiffness were examined with a standardized questionnaire. Association of patient and disease characteristics with prolonged morning stiffness (>60 min) were analyzed with logistic regression. Results: In total 519 of 538 patients had available data about duration of morning stiffness, of whom 89 (17%) had prolonged morning stiffness. Severity of stiffness was mild in 158 of 525 (30%), intermediate in 194 (37%), severe in 97 (18%) and extreme in 19 (4%) patients. Patients with prolonged morning stiffness reported more pain, worse physical function and had a reduced mental and physical quality of life. Patients with prolonged morning stiffness also had more severe radiographic disease, although the association did not reach statistical significance. Conclusions: Prolonged and severe morning stiffness are frequently present in patients with hand OA. Patients with these symptoms report more pain in general and have a lower quality of life than patients that do not report these symptoms. Prolonged morning stiffness does not preclude a diagnosis of hand OA. (c) 2022 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Objective: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine... Show moreObjective: To investigate the test-retest precision and to report the longitudinal change in cartilage thickness, the percentage of knees with progression and the predictive value of the machine-learning-estimated structural progression score (s-score) for cartilage thickness loss in the IMI-APPROACH cohort - an exploratory, 5-center, 2-year prospective follow-up cohort. Design: Quantitative cartilage morphology at baseline and at least one follow-up visit was available for 270 of the 297 IMI-APPROACH participants (78% females, age: 66.4 +/- 7.1 years, body mass index (BMI): 28.1 +/- 5.3 kg/m(2), 55% with radiographic knee osteoarthritis (OA)) from 1.5T or 3T MRI. Test-retest precision (root mean square coefficient of variation) was assessed from 34 participants. To define progressor knees, smallest detectable change (SDC) thresholds were computed from 11 participants with longitudinal test-retest scans. Binary logistic regression was used to evaluate the odds of progression in femorotibial cartilage thickness (threshold: similar to 211 mu m) for the quartile with the highest vs the quartile with the lowest s-scores. Results: The test-retest precision was 69 mu m for the entire femorotibial joint. Over 24 months, mean cartilage thickness loss in the entire femorotibial joint reached -174 mu m (95% CI: [-207, -141] mu m, 32.7% with progression). The s-score was not associated with 24-month progression rates by MRI (OR: 1.30, 95% CI: [0.52, 3.28]). Conclusion: IMI-APPROACH successfully enrolled participants with substantial cartilage thickness loss, although the machine-learning-estimated s-score was not observed to be predictive of cartilage thickness loss. IMI-APPROACH data will be used in subsequent analyses to evaluate the impact of clinical, imaging, biomechanical and biochemical biomarkers on cartilage thickness loss and to refine the machine-learning-based s-score. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Tuerlings, M.; Janssen, G.M.C.; Boone, I.; Hoolwerff, M. van; Ruiz, A.R.; Houtman, E.; ... ; Meulenbelt, I. 2023
Objective: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele... Show moreObjective: To explore the co-expression network of the osteoarthritis (OA) risk gene WWP2 in articular cartilage and study cartilage characteristics when mimicking the effect of OA risk allele rs1052429-A on WWP2 expression in a human 3D in vitro model of cartilage. Method: Co-expression behavior of WWP2 with genes expressed in lesioned OA articular cartilage (N = 35 samples) was explored. By applying lentiviral particle mediated WWP2 upregulation in 3D in vitro pellet cultures of human primary chondrocytes (N = 8 donors) the effects of upregulation on cartilage matrix deposition was evaluated. Finally, we transfected primary chondrocytes with miR-140 mimics to evaluate whether miR-140 and WWP2 are involved in similar pathways. Results: Upon performing Spearman correlations in lesioned OA cartilage, 98 highly correlating genes (| r| > 0.7) were identified. Among these genes, we identified GJA1, GDF10, STC2, WDR1, and WNK4. Sub-sequent upregulation of WWP2 on 3D chondrocyte pellet cultures resulted in a decreased expression of COL2A1 and ACAN and an increase in EPAS1 expression. Additionally, we observed a decreased expression of GDF10, STC2, and GJA1. Proteomics analysis identified 42 proteins being differentially expressed with WWP2 upregulation, which were enriched for ubiquitin conjugating enzyme activity. Finally, upregu-lation of miR-140 in 2D chondrocytes resulted in significant upregulation of WWP2 and WDR1. Conclusions: Mimicking the effect of OA risk allele rs1052429-A on WWP2 expression initiates detri-mental processes in the cartilage shown by a response in hypoxia associated genes EPAS1, GDF10, and GJA1 and a decrease in anabolic markers, COL2A1 and ACAN.(c) 2022 The Author(s). Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/). Show less
Loef, M.; Stadt, L. van de; Bohringer, S.; Bay-Jensen, A.C.; Mobasheri, A.; Larkin, J.; ... ; Kloppenburg, M. 2022
Objective: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. Design: We used... Show moreObjective: To investigate the association of the lipidomic profile with osteoarthritis (OA) severity, considering the outcomes radiographic knee and hand OA, pain and function. Design: We used baseline data from the Applied Public-Private Research enabling OsteoArthritis Clinical Headway (APPROACH) cohort, comprising persons with knee OA fulfilling the clinical American College of Rheumatology classification criteria. Radiographic knee and hand OA severity was quantified with Kellgren-Lawrence sum scores. Knee and hand pain and function were assessed with validated questionnaires. We quantified fasted plasma higher order lipids and oxylipins with liquid chromatography with tandem mass spectrometry (LC-MS/MS)-based platforms. Using penalised linear regression, we assessed the variance in OA severity explained by lipidomics, with adjustment for clinical covariates (age, sex, body mass index (BMI) and lipid lowering medication), measurement batch and clinical centre. Results: In 216 participants (mean age 66 years, mean BMI 27.3 kg/m2, 75% women) we quantified 603 higher order lipids (triacylglycerols, diacylglycerols, cholesteryl esters, ceramides, free fatty acids, sphingomyelins, phospholipids) and 28 oxylipins. Lipidomics explained 3% and 2% of the variance in radiographic knee and hand OA severity, respectively. Lipids were not associated with knee pain or function. Lipidomics accounted for 12% and 6% of variance in hand pain and function, respectively. The investigated OA severity outcomes were associated with the lipidomic fraction of bound and free arachidonic acid, bound palmitoleic acid, oleic acid, linoleic acid and docosapentaenoic acid. Conclusions: Within the APPROACH cohort lipidomics explained a minor portion of the variation in OA severity, which was most evident for the outcome hand pain. Our results suggest that eicosanoids may be involved in OA severity. (c) 2022 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. Show less
ObjectivesTo investigate how ANP32A, previously linked to the antioxidant response, regulates Wnt signaling as unraveled by transcriptome analysis of Anp32a-deficient mouse articular cartilage, and... Show moreObjectivesTo investigate how ANP32A, previously linked to the antioxidant response, regulates Wnt signaling as unraveled by transcriptome analysis of Anp32a-deficient mouse articular cartilage, and its implications for osteoarthritis (OA) and diseases beyond the joint.MethodsAnp32a knockdown chondrogenic ATDC5 cells were cultured in micromasses. Wnt target genes, differentiation markers and matrix deposition were quantified. Wnt target genes were determined in articular cartilage from Anp32a-deficient mice and primary human articular chondrocytes upon ANP32A silencing, using qPCR, luciferase assays and immunohistochemistry. Co-immunoprecipitation, immunofluorescence and chromatin-immunoprecipitation quantitative PCR probed the molecular mechanism via which ANP32A regulates Wnt signaling. Anp32a-deficient mice were subjected to the destabilization of the medial meniscus (DMM) OA model and treated with a Wnt inhibitor and an antioxidant. Severity of OA was assessed by cartilage damage and osteophyte formation. Human Protein Atlas data analysis identified additional organs where ANP32A may regulate Wnt signaling. Wnt target genes were determined in heart and hippocampus from Anp32a-deficient mice, and cardiac hypertrophy and fibrosis quantified.ResultsAnp32a loss triggered Wnt signaling hyper-activation in articular cartilage. Mechanistically, ANP32A inhibited target gene expression via histone acetylation masking. Wnt antagonist treatment reduced OA severity in Anp32a-deficient mice by preventing osteophyte formation but not cartilage degradation, contrasting with antioxidant treatment. Dual therapy ameliorated more OA features than individual treatments. Anp32a-deficient mice also showed Wnt hyper-activation in the heart, potentially explaining the cardiac hypertrophy phenotype found.ConclusionsANP32A is a novel translationally relevant repressor of Wnt signaling impacting osteoarthritis and cardiac disease. Show less
Hall, M.; Esch, M. van der; Hinman, R.S.; Peat, G.; Zwart, A. de; Quicke, J.G.; ... ; Bennell, K.L. 2022
Hip and knee osteoarthritis (OA) are leading causes of global disability. Most research to date has focused on the knee, with results often extrapolated to the hip, and this extends to treatment... Show moreHip and knee osteoarthritis (OA) are leading causes of global disability. Most research to date has focused on the knee, with results often extrapolated to the hip, and this extends to treatment recommendations in clinical guidelines. Extrapolating results from research on knee OA may limit our understanding of disease characteristics specific to hip OA, thereby constraining development and implementation of effective treatments. This review highlights differences between hip and knee OA with respect to prevalence, prognosis, epigenetics, pathophysiology, anatomical and biomechanical factors, clinical presentation, pain and non-surgical treatment recommendations and management. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Objective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)... Show moreObjective: Inflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-beta, under the transcriptional control of nuclear factor kappa-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.Methods: In this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 x 10(12)-1.2 x 10(13) genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-beta immune responses were evaluated. A data review committee provided safety recommendations.Results: Four patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-beta, nor IFN-beta antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.Conclusion: Single IA doses of 0.6 x 10(12) or 1.2 x 10(12) ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. (C) 2021 Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. Show less
ObjectiveInflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β,... Show moreObjectiveInflammatory hand arthritis (IHA) results in impaired function. Local gene therapy with ART-I02, a recombinant adeno-associated virus (AAV) serotype 5 vector expressing interferon (IFN)-β, under the transcriptional control of nuclear factor κ-B responsive promoter, was preclinically shown to have favorable effects. This study aimed to investigate the safety and tolerability of local gene therapy with ART-I02 in patients with IHA.MethodsIn this first-in-human, dose-escalating, cohort study, 12 IHA patients were to receive a single intra-articular (IA) injection of ART-I02 ranging 0.3 × 1012-1.2 × 1013 genome copies in an affected hand joint. Adverse events (AEs), routine safety laboratory and the clinical course of disease were periodically evaluated. Baseline- and follow-up contrast enhanced magnetic resonance images (MRIs), shedding of viral vectors in bodily fluids, and AAV5 and IFN-β immune responses were evaluated. A data review committee provided safety recommendations.ResultsFour patients were enrolled. Long-lasting local AEs were observed in 3 patients upon IA injection of ART-I02. The AEs were moderate in severity and could be treated conservative. Given the duration of the AEs and their possible or probable relation to ART-I02, no additional patients were enrolled. No systemic treatment emergent AEs were observed. The MRIs reflected the AEs by (peri)arthritis. No T-cell response against AAV5 or IFN-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.ConclusionSingle IA doses of 0.6 × 1012 or 1.2 × 1012 ART-I02 vector genomes were administered without systemic side effects or serious AEs. However, local tolerability was insufficient for continuation. Show less
Terpstra, S.E.S.; Velde, J.H.P.M. van der; Mutsert, R. de; Schiphof, D.; Reijnierse, M.; Rosendaal, F.R.; ... ; Loef, M. 2021
Objective: To investigate if knee osteoarthritis (OA) is associated with lower physical activity in the general middle-aged Dutch population, and if physical activity is associated with patient... Show moreObjective: To investigate if knee osteoarthritis (OA) is associated with lower physical activity in the general middle-aged Dutch population, and if physical activity is associated with patient-reported outcomes in knee OA. Design: Clinical knee OA was defined in the Netherlands Epidemiology of Obesity population using the ACR criteria, and structural knee OA on MRI. We assessed knee pain and function with the Knee Injury and Osteoarthritis Score (KOOS), health-related quality of life (HRQoL) with the Short Form-36, and physical activity (in Metabolic Equivalent of Task (MET) hours) with the Short Questionnaire to Assess Health-enhancing physical activity. We analysed the associations of knee OA with physical activity, and of physical activity with knee pain, function, and HRQoL in knee OA with linear regression adjusted for potential confounders. Results: Clinical knee OA was present in 14% of 6,212 participants, (mean age 56 years, mean BMI 27 kg/m(2), 55% women, 24% having any comorbidity) and structural knee OA in 12%. Clinical knee OA was associated with 9.60 (95% CI 3.70; 15.50) MET hours per week more physical activity, vs no clinical knee OA. Structural knee OA was associated with 3.97 (-7.82; 15.76) MET hours per week more physical activity, vs no structural knee OA. In clinical knee OA, physical activity was not associated with knee pain, function or HRQoL. Conclusions: Knee OA was not associated with lower physical activity, and in knee OA physical activity was not associated with patient-reported outcomes. Future research should indicate the optimal treatment advice regarding physical activity for individual knee OA patients. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Houtman, E.; Almeida, R.C. de; Tuerlings, M.; Suchiman, H.E.D.; Broekhuis, D.; Nelissen, R.G.H.H.; ... ; Meulenbelt, I. 2021
Objective: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human... Show moreObjective: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. Methods: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1b; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. Results: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. Discussion & conclusions: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in carti-lage. The determined direct negative effect of warfarin on human explant cultures functionally un-derscores the previously found association between vitamin K deficiency and OA. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Objective: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of... Show moreObjective: Autoantibodies (AutoAbs) have been observed in osteoarthritis (OA) with broad antigenicity, although their prevalence and role remain unclear. Post-translational modification (PTMs) of proteins (oxidation, carbamylation, citrullination) is associated with synovitis and can lead to AutoAb development. Given the prevalence of synovitis, we explored whether AutoAbs to PTM-antigens are common in OA compared with rheumatoid arthritis (RA). Methods: Serum (n = 895) was obtained from healthy controls, OA and RA patients; and arthritic synovial fluid (SF, n = 290). ELISAs were used to quantify anti-citrullinated peptide (ACPA), anti-carbamylated protein (anti-CarP), anti-oxidized collagen (anti-ROS-CI/CII) antibodies.Results: In sera, positivity for PTM-antigens AutoAbs was observed at a lower frequency in OA with 64.1% (95%CI: 57.2-70.1%) more ACPA+ and 29.8% (21.0-37.3%) more anti-CarP + patients in RA (both P < 0.0001). Levels of ACPA, anti-CarP were also lower in OA (P < 0.0001). Anti-ROS-CII positivity was lower in OA compared to RA (16.6%, 4.8-28.6%) less frequent, P = 0.033) but not anti-native-CII. There was no impact of age/gender on AutoAbs associations with diseases either looking at positivity or levels. In SF, OA patients were often ACPA+ (45.9%) although less frequently than in RA (P = 0.004). Anti-CarP were rarely observed (<5% all samples). All collagen AutoAbs were more frequent in RA compared to OA (all P < 0.010) but only levels of anti-CII and anti-ROS-CII were significantly higher in they RA (P < 0.050).Conclusion: Although the frequency of AutoAbs for PTM proteins were lower in OA sera compared to RA, a higher proportion of OA SF were positive. The relative retention of AutoAbs in the OA joint requires further investigation.(c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Loef, M.; Kroon, F.P.B.; Bohringer, S.; Roos, E.M.; Rosendaal, F.R.; Kloppenburg, M. 2020
Objective: To improve the interpretation of the Knee injury and Osteoarthritis Outcome Score (KOOS) in individual patients, we explored associations with age, sex, BMI, history of knee injury and... Show moreObjective: To improve the interpretation of the Knee injury and Osteoarthritis Outcome Score (KOOS) in individual patients, we explored associations with age, sex, BMI, history of knee injury and presence of clinical knee osteoarthritis, and developed percentile curves.Methods: We used cross-sectional data of middle-aged individuals from the population-based Netherlands Epidemiology of Obesity (NEO) study. Clinical knee osteoarthritis was defined using the ACR classification criteria. KOOS scores were handled according to the manual (zero = extreme problems, 100 = no problems). Patient characteristics associated with KOOS were explored using ordered logistic regression, and sex and body mass index (BMI)-specific percentile curves were developed using quantile regression with fractional polynomials. The curves were applied as a benchmark for comparison of KOOS scores of participants with knee osteoarthritis and comorbidities.Results: The population consisted of 6,643 participants (56% women, mean (SD) age 56(6) years). Population-based KOOS subscale scores (median; interquartile range) near optimum: pain (100;94-100), symptoms (96;86-100), ADL function (100;96-100), sport/recreation function (100;80-100), quality of life (100;75-100). Worse KOOS scores were observed in women and in participants with higher BMI. Clinical knee osteoarthritis was defined in 15% of participants, and was, in comparison to other patient characteristics, associated with the highest odds of worse KOOS scores. Furthermore, presence of any comorbidity and cardiovascular disease specifically, was associated with worse KOOS scores, particularly in women.Conclusions: In the middle-aged Dutch population KOOS scores were generally good, but worse in women and with higher BMI. These percentile curves may be used as benchmarks in research and clinical practice. (c) 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Objective: Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce... Show moreObjective: Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce extracellular-matrix molecules. How inflammatory mediators reach chondrocytes is incompletely understood. Previous studies have shown that chondrocytes express mRNA encoding complement proteins such as C1q, suggesting local protein production, which has not been demonstrated conclusively. The aim of this study is to explore C1q production at the protein level by chondrocytes.Design: We analysed protein expression of C1q in freshly isolated and cultured human articular chondrocytes using Western blot, ELISA and flow cytometry. We examined changes in mRNA expression of collagen, MMP-1 and various complement genes upon stimulation with pro-inflammatory cytokines or C1q. mRNA expression of C1 genes was determined in articular mouse chondrocytes.Results: Primary human articular chondrocytes express genes encoding C1q, C1QA, C1QB, C1QC, and secrete C1q to the extracellular medium. Stimulation of chondrocytes with pro-inflammatory cytokines upregulated C1QA, C1QB, C1QC mRNA expression, although this was not confirmed at the protein level. Extracellular C1q bound to the chondrocyte surface dose dependently. In a pilot study, binding of C1q to chondrocytes resulted in changes in the expression of collagens with a decrease in collagen type 2 and an increase in type 10. Mouse articular chondrocytes also expressed C1QA, C1QB, C1QC, C1R and C1S at the mRNA level.Conclusions: C1q protein can be expressed and secreted by human articular chondrocytes and is able to bind to chondrocytes influencing the relative collagen expression. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Over the past year many studies and clinical trials have been published in the osteoarthritis (OA) field. This review is based on systematic literature review covering the period May 1st, 2018 to... Show moreOver the past year many studies and clinical trials have been published in the osteoarthritis (OA) field. This review is based on systematic literature review covering the period May 1st, 2018 to April 19th , 2019; the final selection of articles was subjective. Specifically those articles considered to be presenting novel insights and of potential importance for clinical practice, are discussed.Further evidence has emerged that OA is a serious disease with increasing impact worldwide. Our understanding of development of pain in OA has increased. Detailed studies investigating widely used pharmacological treatments have shown the benefits to be limited, whereas the risks seem higher than expected, suggesting further studies and reconsideration of currently used guidelines. Promising new pharmacological treatments have been developed and published, however subsequent studies are warranted. While waiting for new treatment modalities to appear joint replacement is an effective alternative; new data have become available on how long they might last. (C) 2020 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. Show less
Loef, M.; Ioan-Facsinay, A.; Mook-Kanamori, D.O.; Dijk, K.W. van; Mutsert, R. de; Kloppenburg, M.; Rosendaal, F.R. 2020
Objective: To investigate the association of postprandial and fasting plasma saturated fatty acid (SFAs), monounsaturated fatty acid (MUFAs) and polyunsaturated fatty acid (PUFAs) concentrations... Show moreObjective: To investigate the association of postprandial and fasting plasma saturated fatty acid (SFAs), monounsaturated fatty acid (MUFAs) and polyunsaturated fatty acid (PUFAs) concentrations with hand and knee osteoarthritis (OA).Design: In the population-based NEO study clinical hand and knee OA were defined by the ACR classification criteria. Structural knee OA was defined on MRI. Hand and knee pain was determined by Australian/Canadian Hand Osteoarthritis Index (AUSCAN) and KOOS, respectively. Plasma was sampled fasted and 150 min after a standardized meal, and subsequently analysed using a nuclear magnetic resonance platform. Logistic regression analyses were used to investigate the association of total fatty acid, SFA, MUFA, total PUFA, omega-3 PUFA and omega-6 PUFA concentrations with clinical hand and knee OA, structural knee OA and hand and knee pain. Fatty acid concentrations were standardized (mean 0, SD 1). Analyses were stratified by sex and corrected for age, education, ethnicity and total body fat percentage.Results: Of the 5,328 participants (mean age 56 years, 58% women) 7% was classified with hand OA, 10% with knee OA and 4% with concurrent hand and knee OA. In men, postprandial SFAs (OR (95% CI)) 1.23 (1.00; 1.50), total PUFAs 1.26 (1.00; 1.58) and omega-3 PUFAs 1.24 (1.01; 1.52) were associated with hand OA. SFAs and PUFAs were associated with structural, but not clinical knee OA. Association of fasting fatty acid concentrations were weaker than postprandial concentrations.Conclusion: Plasma postprandial SFA and PUFA levels were positively associated with clinical hand and structural knee OA in men, but not in women. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
Kroon, F.P.B.; Veenbrink, A.I.; Mutsert, R. de; Visser, A.W.; Dijk, K.W. van; Cessie, S. le; ... ; Kloppenburg, M. 2019
OBJECTIVE:Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce... Show moreOBJECTIVE:Inflammation and innate immune responses may contribute to development and progression of Osteoarthritis (OA). Chondrocytes are the sole cell type of the articular cartilage and produce extracellular-matrix molecules. How inflammatory mediators reach chondrocytes is incompletely understood. Previous studies have shown that chondrocytes express mRNA encoding complement proteins such as C1q, suggesting local protein production, which has not been demonstrated conclusively. The aim of this study is to explore C1q production at the protein level by chondrocytes.DESIGN:We analysed protein expression of C1q in freshly isolated and cultured human articular chondrocytes using Western blot, ELISA and flow cytometry. We examined changes in mRNA expression of collagen, MMP-1 and various complement genes upon stimulation with pro-inflammatory cytokines or C1q. mRNA expression of C1 genes was determined in articular mouse chondrocytes.RESULTS:Primary human articular chondrocytes express genes encoding C1q, C1QA, C1QB, C1QC, and secrete C1q to the extracellular medium. Stimulation of chondrocytes with pro-inflammatory cytokines upregulated C1QA, C1QB, C1QC mRNA expression, although this was not confirmed at the protein level. Extracellular C1q bound to the chondrocyte surface dose dependently. In a pilot study, binding of C1q to chondrocytes resulted in changes in the expression of collagens with a decrease in collagen type 2 and an increase in type 10. Mouse articular chondrocytes also expressed C1QA, C1QB, C1QC, C1R and C1S at the mRNA level.CONCLUSIONS:C1q protein can be expressed and secreted by human articular chondrocytes and is able to bind to chondrocytes influencing the relative collagen expression. Show less
Eyles, J.P.; Hunter, D.J.; Bennell, K.L.; Dziedzic, K.S.; Hinman, R.S.; Esch, M. van der; ... ; Joint Effort Initiative 2019
Objective: The Joint Effort Initiative was endorsed by Osteoarthritis Research Society International (OARSI) in 2018 as a collaboration between international researchers and clinicians with an... Show moreObjective: The Joint Effort Initiative was endorsed by Osteoarthritis Research Society International (OARSI) in 2018 as a collaboration between international researchers and clinicians with an interest in the implementation of osteoarthritis management programs (OAMPs). This study aimed to identify and prioritise activities for future work of the Joint Effort Initiative.Design: A survey was emailed to delegates of the 2018 OARSI World Congress attending a pre-conference workshop or with a known interest in OAMPs (n = 115). Delegates were asked about the most important issues regarding OAMP implementation. The top 20 issues were synthesised into 17 action statements, and respondents were invited to participate in a priority ranking exercise to determine the order of importance of the statements.Results: Survey respondents (n = 51, 44%) were most commonly female (71%), with an allied health background (57%), affiliated with universities (73%) from Oceania (37%), and Europe/UK (45%). The five highest ranked action statements were:i) Establish guidelines for the implementation of different OAMP models to ensure consistency of delivery and adherence to international best practice.ii) Develop and assess training and education programs for health care professionals (HCPs) delivering OAMPs.iii) Develop and evaluate the implementation and outcomes of novel models of OAMPs.iv) Develop and assess core skill sets and resources for HCPs delivering OA care.v) Develop a framework for enhancing the quality of care provided by OAMPs.Conclusion: Prioritising statements will bring focus to the future work of the Joint Effort Initiative in the future and provide a basis for longer-term actions. (C) 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved. Show less
