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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)-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.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 × 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.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-β, nor IFN-β antibodies could be detected. Neutralizing antibody titers against AAV5 raised post-dose.Conclusion: Single 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.Trial Registration: NCT02727764. [ABSTRACT FROM AUTHOR]

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-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/m2, 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. [ABSTRACT FROM AUTHOR]

Objective: To investigate determinants of decrease and increase in joint pain in symptomatic finger osteoarthritis (OA) on magnetic resonance (MR) imaging over 2 years.Design: Eighty-five patients (81.2% women, mean age 59.2 years) with primary hand OA (89.4% fulfilling American College of Rheumatology (ACR) classification criteria) from a rheumatology outpatient clinic received contrast-enhanced MR imaging (1.5T) and physical examination of the right interphalangeal finger joints 2-5 at baseline and at follow-up 2 years later. MR images were scored paired in unknown time order, following the Hand OA MRI scoring system (HOAMRIS). Joint pain upon palpation was assessed by research nurses. Odds ratios (ORs; 95% confidence intervals) were estimated on joint level (n = 680), using generalized estimating equations (GEE) to account for the within patient effects. Additional adjustments were made for change in MR-defined osteophytes, synovitis, and bone marrow lesions (BMLs).Results: Of 116 painful joints at baseline, at follow-up: 76 had less pain, 21 less synovitis, and 13 less BMLs. A decrease in synovitis (OR = 5.9; 1.12─31.0), but not in BMLs (OR = 0.39; 0.10─1.50), was associated with less pain. Of 678 joints without maximum baseline pain, at follow-up: 115 had increased pain, 132 increased synovitis, 96 increased BMLs, and 44 increased osteophytes. Increased synovitis (OR = 1.81; 1.11─2.94), osteophytes (OR = 2.75; 1.59─4.8), but not BMLs (OR = 1.14; 0.81─1.60), was associated with increased pain. Through stratification it became apparent that BMLs were mainly acting as effect modifier of the synovitis-pain association.Conclusion: Decrease in MR-defined synovitis is associated with reduced joint pain, identifying synovitis as a possible target for treatment of finger OA. [ABSTRACT FROM AUTHOR]

Summary Objective To investigate the construct validity of the new thumb base OA magnetic resonance imaging (MRI) scoring system (TOMS) by comparing TOMS scores with radiographic scores in patients with primary hand OA. Design In 200 patients (83.5% women, mean (SD) age 61.0 (8.4) years), postero-anterior radiographs and MR scans (1.5 T) of the right first carpometacarpal (CMC-1) and scaphotrapeziotrapezoid (STT) joints, were scored using the OARSI atlas and TOMS, respectively. The distributions of the TOMS scores (specified in results section) were stratified for the OARSI scores of corresponding radiographic features and investigated using boxplots and non-parametric tests. Furthermore, Spearman's rank or Phi correlation coefficients (ρ / φ) were calculated. Results For all features, especially for erosions and osteophytes, the prevalence found with MRI was higher than with radiography. TOMS osteophyte and cartilage loss scores differed statistically significant between corresponding OARSI scores in CMC-1 (0 vs 1; 1 vs 2). TOMS scores were positively correlated with radiographic scores in CMC-1 for osteophytes (coefficient [95% confidence interval], ρ = 0.75 [0.69; 0.81]), cartilage loss/joint space narrowing (ρ = 0.70 [0.62; 0.76]), subchondral bone defects (SBDs)/erosion-cyst (ρ = 0.41 [0.29; 0.52]), bone marrow lesions (BMLs)/subchondral sclerosis (ρ = 0.65 [0.56; 0.73]) and subluxation (φ = 0.65 [0.57; 0.73]); and in STT for osteophytes (ρ = 0.30 [0.17; 0.42]) and cartilage loss/joint space narrowing (ρ = 0.53 [0.42; 0.62]). Conclusions In patients with hand OA, TOMS scores positively correlated with radiographic scores, indicating good construct validity. However, the prevalence of features on MR images was higher compared to radiographs, suggesting that TOMS might be more sensitive than radiography. The clinical meaning of these extra MR detected cases is currently still unknown. [ABSTRACT FROM AUTHOR]

Objective: Osteoarthritis in thumb base joints (first carpometacarpal (CMC-1), scaphotrapeziotrapezoid (STT)) is prevalent and disabling, yet focussed studies are scarce. Our aim was to investigate associations between ultrasonographic and magnetic resonance imaging (MRI) inflammatory features, radiographic osteophytes, and thumb base pain in hand osteoarthritis patients.Design: Cross-sectional analyses were performed in cohorts with MRI (n = 202) and ultrasound measurements (n = 87). Pain upon thumb base palpation was assessed. Radiographs were scored for CMC-1/STT osteophytes. Synovial thickening, effusion and power Doppler signal in CMC-1 joints were assessed with ultrasound. MRIs were scored for synovitis and bone marrow lesions (BMLs) in CMC-1 and STT joints using OMERACT-TOMS. Associations between ultrasound/MRI features, osteophytes, and thumb base pain were assessed. Interaction between MRI features and osteophytes was explored.Results: In 289 patients (mean age 60.2, 83% women) 139/376 thumb bases were painful. Osteophyte presence was associated with pain (MRI cohort: odds ratio (OR) 5.1 (2.7-9.8)). Ultrasound features were present in 25-33% of CMC-1 joints, though no associations were seen with pain. MRI-synovitis and BMLs grade ≥2 were scored in 25% and 43% of thumb bases, and positively associated with pain (OR 3.6 (95% CI 1.7-7.6) and 3.0 (1.6-5.5)). Associations attenuated after adjustment for osteophyte presence. Combined presence of osteophytes and MRI-synovitis had an additive effect.Conclusions: Ultrasonographic and MRI inflammatory features were often present in the thumb base. Osteophytes were more strongly associated with thumb base pain than inflammatory features, in contrast to findings in finger OA studies, supporting thumb base osteoarthritis as a distinct phenotype. [ABSTRACT FROM AUTHOR]

Objective: Subchondral bone abnormalities (SBAs) on magnetic resonance imaging (MRI) are observed frequently and associated with disease course in various musculoskeletal disorders. This review aims to map the existing knowledge of their underlying histological features, and to identify needs for future research.Design: We conducted a systematic review following PRISMA guidelines until September 2017, including all studies correlating histological features to on MRI defined SBAs in patients with osteoarthritis (OA), rheumatoid arthritis (RA), spondyloarthritis (SpA) and degenerative disc disease (DDD). Two authors independently retrieved articles and assessed study quality.Results: A total of 21 studies (466 patients) correlated histological features to SBAs in OA (n = 13), RA (n = 3), ankylosing spondylitis (AS) (n = 1) and DDD (n = 4). Reported changes in OA were substitution of normal subchondral bone with fibrosis and necrosis, and increased bone remodeling. In contrast, in RA, AS or DDD fibrosis was not reported and SBAs correlated to an increase in inflammatory cell number. In DDD necrosis was observed. Similar to OA, increased bone remodeling was shown in RA and DDD. The risk of bias assessment showed a lack in described patient criteria, blinding and/or adequate topographic correlation in approximately half of studies. There was heterogeneity regarding the investigated histological features between the different disorders.Conclusions: Current studies suggest that SBAs correlate to various histological features, including fibrosis, cell death, inflammation and bone remodeling. In the majority of studies most quality criteria were not met. Future studies should aim for high quality research, and consistency in investigated features between different disorders. [ABSTRACT FROM AUTHOR]

Objective: To determine the association between bone marrow lesions (BMLs) and (teno)synovitis as assessed on magnetic resonance (MR) imaging in patients with pain in hand osteoarthritis (OA).Methods: In 105 consecutive primary hand OA patients (83% women, mean age 59 years), who were diagnosed by rheumatologists and included in the HOSTAS (Hand OSTeoArthritis in Secondary care) cohort, contrast enhanced MR imaging of right distal and proximal interphalangeal joints were obtained. In 92 patients joint site specific pain upon palpation was assessed within 3 weeks of magnetic resonance imaging (MRI) examination. MR features were scored (0-3) following the Oslo hand OA score: BMLs, synovitis, cysts, flexor tenosynovitis (FTS). Additionally, extensor tendon inflammation (ETI) (0-3) was scored. Odds ratios (OR, 95% confidence interval (CI)) were calculated using generalized estimating equations for MR features with joint pain, adjusted for putative confounders. Stratified analyses were performed to investigate interaction.Results: BMLs, synovitis, cysts, FTS and ETI were demonstrated in 56%, 90%, 22%, 16% and 30% of patients, respectively. BMLs (grade 2/3 vs 0: 3.5 (1.6-7.7)) and synovitis (3 vs 0: OR 3.6 (95% CI 1.9-6.6)) were severity-dependent associated with joint pain, but FTS and ETI were not. Stratified analyses showed that BMLs did not associate with pain in the absence of synovitis, whereas synovitis was associated with pain in the absence of BMLs. Interaction was seen between BMLs and synovitis grade 2 or 3.Conclusion: In hand OA patients severe synovitis is associated with joint pain, which is worsened when BMLs co-occur, suggesting synovitis as primary target of treatment. [ABSTRACT FROM AUTHOR]

Summary: Objective: To investigate if the amount of fat mass (FM) or skeletal muscle mass (SMM) is more strongly associated with knee osteoarthritis (OA), in both men and women. Methods: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45–65 years, including 5313 participants (53% female, median body mass index (BMI) 29.9 kg/m2). FM (kg), fat percentage, SMM (kg) and skeletal muscle (SM) percentage were estimated using bioelectrical impedance analysis (BIA). Clinical OA was defined following the ACR criteria. Structural OA was defined based on magnetic resonance imaging (MRI) in 1142 participants. Logistic regression analyses were used to examine the associations of all body composition measures with clinical and structural knee OA per standard deviation (SD), stratified by sex and adjusted for age and height. Results: Clinical or structural OA was present in 25% and 14% of women and 12% and 13% of men, respectively. FM and fat percentage were positively associated with clinical knee OA in men and women. SMM was positively associated, while the SM percentage was negatively associated with clinical OA in both men and women. The FM/SMM ratio was positively associated with clinical OA. All determinants showed even stronger ORs for structural knee OA. In men, SMM was more strongly associated with knee OA as compared to FM whereas in women, FM was most strongly associated. Conclusion: Especially a high FM/SMM ratio seems to be unfavorable in knee OA. In men, SMM is most strongly associated with knee OA whereas in women FM seems to be of most importance. [Copyright &y& Elsevier]

Summary: Objective: To study inflammatory ultrasound (US) features and pain over a 3-month period in hand osteoarthritis (HOA). Design: In 25 consecutive HOA patients (mean age 60 years, 76% female), fulfilling the American College of Rheumatology (ACR) criteria, visual analogue scale (VAS) pain scores were collected at baseline and 3 months. In 750 [all first carpometacarpal (CMC), metacarpalphalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) and first interphalangeal (IP)] joints, pain was assessed upon palpation and synovial thickening, effusion and power Doppler signal (PDS) were scored with standardized methods by US. Associations between inflammatory features and painful joints were analysed using generalized estimated equations to account for patient effects, adjusting for confounders, and presented as odds ratios (ORs) with 95% confidence intervals (95%CI). Results: Inflammatory US features were seen in (nearly) all patients. The median number (range) of inflammatory joints per patient did not change over time: 9 (0–16) to 9 (2–18). In 18.7% of joints inflammatory features were present at both time points; in 20.5% inflammatory features occurred only at baseline or follow-up. Pain decreased over time: median VAS pain 49–39 mm; median number of painful joints 8–3. Synovial thickening, effusion and PDS were associated with pain upon palpation both at baseline and follow-up: OR 2.9 (1.4, 5.7), 2.7 (1.7, 4.3), 3.6 (2.1, 6.3) and 7.3 (3.2, 16.5), 3.3 (2.3, 4.7), 4.1 (2.1, 7.9). respectively. Conclusions: In HOA inflammatory US features are stable over time at patient level, but vary on joint level. Pain diminished after 3 months, while associations between painful joints and inflammation seem to increase, emphasizing the multifactorial aetiology of pain. [Copyright &y& Elsevier]

Summary: Objective: Although a few consistent osteoarthritis (OA) susceptibility genes have been identified, little is known on OA progression. Since OA progression is clinically the most relevant phenotype, we investigate the association between asporin (ASPN), bone morphogenetic protein 5 (BMP5) and growth differentiation factor 5 (GDF5) polymorphisms and progression of hand OA. Methods: Single-nucleotide polymorphisms (SNPs) ASPN rs13301537, BMP5 rs373444 and GDF5 rs143383 were genotyped in 251 hand OA patients from the Genetics osteoARthritis and Progression (GARP) study and 725 controls. In a case–control comparison we assessed the association between these SNPs and radiographic progression of hand OA over 6 years, which was based on change in osteophytes or joint space narrowing (JSN), above the smallest detectable change. SNPs with suggestive evidence for association were further analysed for their effect on progression over 2 years, and for the mean change in osteophytes and JSN. Results: The minor allele of ASPN SNP rs13301537 was associated with hand OA progression over 6 years (odds ratio (OR) (95% CI) 1.49 (1.06–2.07); P = 0.020). The mean change in osteophytes and JSN was higher in carriers of the minor allele compared to homozygous carriers of the common allele with mean difference of 0.73 (95% CI – 0.07–1.56; P = 0.073) and 0.82 (95% CI 0.12–1.52; P = 0.022), respectively. An association with similar effect size was found between ASPN SNP rs13301537 and 2-year progression, and the mean change in osteophytes and JSN was significantly higher in homozygotes. Conclusion: ASPN is associated with hand OA progression. This gives insight in the pathogenesis of hand OA progression and identified a potential target for therapeutic approaches. [ABSTRACT FROM AUTHOR]

Objective: To investigate the construct validity of the new thumb base OA magnetic resonance imaging (MRI) scoring system (TOMS) by comparing TOMS scores with radiographic scores in patients with primary hand OA.Design: In 200 patients (83.5% women, mean (SD) age 61.0 (8.4) years), postero-anterior radiographs and MR scans (1.5 T) of the right first carpometacarpal (CMC-1) and scaphotrapeziotrapezoid (STT) joints, were scored using the OARSI atlas and TOMS, respectively. The distributions of the TOMS scores (specified in results section) were stratified for the OARSI scores of corresponding radiographic features and investigated using boxplots and non-parametric tests. Furthermore, Spearman's rank or Phi correlation coefficients (ρ/φ) were calculated.Results: For all features, especially for erosions and osteophytes, the prevalence found with MRI was higher than with radiography. TOMS osteophyte and cartilage loss scores differed statistically significant between corresponding OARSI scores in CMC-1 (0 vs 1; 1 vs 2). TOMS scores were positively correlated with radiographic scores in CMC-1 for osteophytes (coefficient [95% confidence interval], ρ = 0.75 [0.69; 0.81]), cartilage loss/joint space narrowing (ρ = 0.70 [0.62; 0.76]), subchondral bone defects (SBDs)/erosion-cyst (ρ = 0.41 [0.29; 0.52]), bone marrow lesions (BMLs)/subchondral sclerosis (ρ = 0.65 [0.56; 0.73]) and subluxation (φ = 0.65 [0.57; 0.73]); and in STT for osteophytes (ρ = 0.30 [0.17; 0.42]) and cartilage loss/joint space narrowing (ρ = 0.53 [0.42; 0.62]).Conclusions: In patients with hand OA, TOMS scores positively correlated with radiographic scores, indicating good construct validity. However, the prevalence of features on MR images was higher compared to radiographs, suggesting that TOMS might be more sensitive than radiography. The clinical meaning of these extra MR detected cases is currently still unknown. [ABSTRACT FROM AUTHOR]