The role of leptin and adiponectin as mediators in the relationship between adiposity and hand and knee osteoarthritis.

OBJECTIVES: To investigate associations of leptin and adiponectin levels with knee and hand osteoarthritis, and explore whether these mediate the association between adiposity and osteoarthritis. METHODS: This is a cross-sectional analysis of baseline data from the population-based Netherlands Epidemiology of Obesity study. Adiposity was assessed with body mass index (BMI) and percentage total body fat (%TBF). Osteoarthritis, defined as hand or knee osteoarthritis, was determined using American College of Rheumatology criteria. Fasting serum adipokine levels were measured using immunoassays. Associations between adiposity and osteoarthritis were examined with logistic regression, adjusted for age, sex, ethnicity and education, and additionally for leptin and adiponectin as potential mediators. RESULTS: In 6408 participants (56% women, median age 56 years), prevalence of osteoarthritis was 22% (10% isolated knee and 8% isolated hand osteoarthritis). Leptin levels were positively associated with osteoarthritis, while adiponectin levels were not. Leptin partially mediated the association of adiposity with osteoarthritis (OR 1.40 (95%CI 1.30; 1.52) attenuated to 1.38 (1.24; 1.54) per 5 units BMI and OR 1.25 (1.17; 1.35) to 1.20 (1.10; 1.32) per 5 units %TBF, representing 4% and 17% mediation, respectively). Larger proportion mediation by leptin was found in knee (13%/27%) than in hand osteoarthritis (9%/18%). Sex-stratified analyses generally showed stronger associations between adiposity, leptin and osteoarthritis in women than in men. CONCLUSIONS: Serum leptin levels were associated with osteoarthritis, and partially mediated the association between adiposity and osteoarthritis, while adiponectin levels were not associated with osteoarthritis. These findings provide evidence for systemic effects of adipose tissue in osteoarthritis.

No association between impaired glucose metabolism and osteoarthritis.

OBJECTIVE: To investigate the association between markers of glucose metabolism and hand and knee osteoarthritis (OA). METHODS: This is a cross-sectional analysis of baseline measurements of the Netherlands Epidemiology of Obesity (NEO) study, a population-based prospective cohort study. Fasting glucose, insulin and glycated hemoglobulin A1c (HbA1c) concentrations were measured, Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) was calculated and clinical OA was defined following the American College of Rheumatology (ACR) criteria. After exclusion of participants on glucose-lowering drugs, odds ratios (ORs) with 95% confidence intervals (CIs) for either hand, knee or both hand and knee OA were calculated (no OA as reference), as a function of each marker of glucose metabolism, with logistic regression analyses. Models were adjusted for age, ethnicity, education, height, weight and total body fat, and stratified by sex. RESULTS: In 6197 participants (age 45-65 years, 56% women, mean body mass index (BMI) 26 kg/m(2)), prevalences of hand OA, knee OA or both were 7%, 10% or 4%, respectively. In men, the adjusted OR (95%CI) for hand OA was 1.18 (1.01-1.39) per standard deviation (SD) increase in plasma glucose (0.85 mmol/L). There were no further associations of glucose, HbA1c, insulin and HOMA-IR with the different types of OA, neither in men nor in women. CONCLUSION: An impaired glucose metabolism does not seem be related to OA. In men, an association was observed for fasting glucose concentrations and hand OA. Future studies should investigate the presence of sex differences in the pathogenesis of hand OA.

The relative contribution of mechanical stress and systemic processes in different types of osteoarthritis: the NEO study.

OBJECTIVE: To study the relative contribution of surrogates for mechanical stress and systemic processes with osteoarthritis (OA) in weight-bearing and non-weight-bearing joints. METHODS: The Netherlands Epidemiology of Obesity study is a population-based cohort including 6673 participants (range 45-65 years, 56% women, median body mass index 26 kg/m(2)). Weight (kg) and fat mass (kg) were measured, fat-free mass (kg) was calculated. The metabolic syndrome was defined following the Adult Treatment Panel III criteria. Knee and hand OA were defined according to the American College of Rheumatology clinical criteria.Logistic regression analyses were performed to associate surrogates for mechanical stress (such as weight, fat-free mass) and systemic processes (such as metabolic syndrome) with OA in knees alone, knees and hands or hands alone, adjusted for age, sex, height, smoking, education and ethnicity, and when appropriate for metabolic factors and weight. RESULTS: Knee, knee and hand, and hand OA were present in 10%, 4% and 8% of the participants, respectively. Knee OA was associated with weight and fat-free mass, adjusted for metabolic factors (OR 1.49 (95% CI 1.32 to 1.68) and 2.05 (1.60 to 2.62), respectively). Similar results were found for OA in knees and hands (OR 1.51 (95% CI 1.29 to 1.78) and 2.17 (95% CI 1.52 to 3.10) respectively). Hand OA was associated with the metabolic syndrome, adjusted for weight (OR 1.46 (95% CI 1.06 to 2.02)). CONCLUSIONS: In knee OA, whether or not in co-occurrence with hand OA, surrogates for mechanical stress are suggested to be the most important risk factors, whereas in hand OA alone, surrogates for systemic processes are the most important risk factors.

Radiographic scoring methods in hand osteoarthritis--a systematic literature search and descriptive review.

OBJECTIVE: This systematic literature review aimed to evaluate the use of conventional radiography (CR) in hand osteoarthritis (OA) and to assess the metric properties of the different radiographic scoring methods. DESIGN: Medical literature databases up to November 2013 were systematically reviewed for studies reporting on radiographic scoring of structural damage in hand OA. The use and metric properties of the scoring methods, including discrimination (reliability, sensitivity to change), feasibility and validity, were evaluated. RESULTS: Of the 48 included studies, 10 provided data on reliability, 11 on sensitivity to change, four on feasibility and 36 on validity of radiographic scoring methods. Thirteen different scoring methods have been used in studies evaluating radiographic hand OA. The number of examined joints differed extensively and the obtained scores were analyzed in various ways. The reliability of the assessed radiographic scoring methods was good for all evaluated scoring methods, for both cross-sectional and longitudinal radiographic scoring. The responsiveness to change was similar for all evaluated scoring methods. There were no major differences in feasibility between the evaluated scoring methods, although the evidence was limited. There was limited knowledge about the validity of radiographic OA findings compared with clinical nodules and deformities, whereas there was better evidence for an association between radiographic findings and symptoms and hand function. CONCLUSIONS: Several radiographic scoring methods are used in hand OA literature. To enhance comparability across studies in hand OA, consensus has to be reached on a preferred scoring method, the examined joints and the used presentation of data.

The role of fat mass and skeletal muscle mass in knee osteoarthritis is different for men and women: the NEO study.

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/m(2)). 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.

Degree of synovitis on MRI by comprehensive whole knee semi-quantitative scoring method correlates with histologic and macroscopic features of synovial tissue inflammation in knee osteoarthritis.

OBJECTIVE: To evaluate the association between synovitis on contrast enhanced (CE) MRI with microscopic and macroscopic features of synovial tissue inflammation. METHOD: Forty-one patients (mean age 60 years, 61% women) with symptomatic radiographic knee OA were studied: twenty underwent arthroscopy (macroscopic features were scored (0-4), synovial biopsies obtained), twenty-one underwent arthroplasty (synovial tissues were collected). After haematoxylin and eosin staining, the lining cell layer, synovial stroma and inflammatory infiltrate of synovial tissues were scored (0-3). T1-weighted CE-MRI's (3 T) were used to semi-quantitatively score synovitis at 11 sites (0-22) according to Guermazi et al. Spearman's rank correlations were calculated. RESULTS: The mean (SD) MRI synovitis score was 8.0 (3.7) and the total histology grade was 2.5 (1.6). Median (range) scores of macroscopic features were 2 (1-3) for neovascularization, 1 (0-3) for hyperplasia, 2 (0-4) for villi and 2 (0-3) for fibrin deposits. The MRI synovitis score was significantly correlated with total histology grade [r = 0.6], as well as with lining cell layer [r = 0.4], stroma [r = 0.3] and inflammatory infiltrate [r = 0.5] grades. Moreover, MRI synovitis score was also significantly correlated with macroscopic neovascularization [r = 0.6], hyperplasia [r = 0.6] and villi [r = 0.6], but not with fibrin [r = 0.3]. CONCLUSION: Synovitis severity on CE-MRI assessed by a new whole knee scoring system by Guermazi et al. is a valid, non-invasive method to determine synovitis as it is significantly correlated with both macroscopic and microscopic features of synovitis in knee OA patients.

Long-term immunogenicity after yellow fever vaccination in immunosuppressed and healthy individuals.

BACKGROUND: The live-attenuated yellow fever vaccine (YFV) is generally contraindicated in immunosuppressed patients. Our aim was to investigate if immunosuppressive therapy impairs the long-term protection against yellow fever virus in patients who had received YFV prior to the start of their immunosuppressive therapy. METHODS: Our study examined 35 healthy individuals and 40 immunosuppressed patients with autoimmune diseases or organ transplants. All individuals had received YFV prior to the onset of their immunosuppression. We analysed the long-term influence of the immunosuppressive therapy on the YFV protective immunity by measuring neutralising antibodies (NA) with the Plaque Reduction Neutralisation Test (PRNT). We assessed risk factors for a negative PRNT result (titre below 1: 10) and their influence on the magnitude of the NA. RESULTS: A median time interval of 21.1 years (interquartile range 14.4-31.3 years) after the YFV in all patients, a total of 35 immunosuppressed patients (88%) were seropositive (PRNT ≥ 1:10) compared to 31 patients (89%) in the control group. The geometric mean titres of NA did not differ between the groups. The duration of an underlying rheumatic disease was the only risk factor found for a lower magnitude of NA. An insufficient level of NA was found in nine subjects (12%) who had received a single dose of YFV (in one subject, the number of YFV doses was unknown). CONCLUSION: The use of an immunosuppressive drug started after the administration of the YFV did not affect long-term persistence of NA. A second dose of YFV may be necessary to secure long-term immunity.

Bakers' cyst and tibiofemoral abnormalities are more distinctive MRI features of symptomatic osteoarthritis than patellofemoral abnormalities.

OBJECTIVE: To investigate which structural MR abnormalities discriminate symptomatic knee osteoarthritis (OA), taking co-occurrence of abnormalities in all compartments into account. METHODS: The Netherlands Epidemiology of Obesity (NEO) study is a population-based cohort aged 45-65 years. In 1285 participants (median age 56 years, 55% women, median body mass index (BMI) 30 kg/m(2)), MRI of the right knee were obtained. Structural abnormalities (osteophytes, cartilage loss, bone marrow lesions (BMLs), subchondral cysts, meniscal abnormalities, effusion, Baker's cyst) at 9 patellofemoral and tibiofemoral locations were scored following the knee OA scoring system. Symptomatic OA in the imaged knee was defined following the American College of Rheumatology criteria. Logistic ridge regression analyses were used to investigate which structural abnormalities discriminate best between individuals with and without symptomatic OA, crude and adjusted for age, sex and BMI. RESULTS: Symptomatic knee OA was present in 177 individuals. Structural MR abnormalities were highly frequent both in individuals with OA and in those without. Baker's cysts showed the highest adjusted regression coefficient (0.293) for presence of symptomatic OA, followed by osteophytes and BMLs in the medial tibiofemoral compartment (0.185-0.279), osteophytes in the medial trochlear facet (0.262) and effusion (0.197). CONCLUSIONS: Baker's cysts discriminate best between individuals with and without symptomatic knee OA. Structural MR abnormalities, especially in the medial side of the tibiofemoral joint and effusion, add further in discriminating symptomatic OA. Baker's cysts may present as a target for treatment.

17D yellow fever vaccine elicits comparable long-term immune responses in healthy individuals and immune-compromised patients.

BACKGROUND: The 17D live attenuated yellow fever (YF) vaccine is contra-indicated in immune-compromised individuals and may elicit a suboptimal immunologic response. The aim of this study is to assess whether long-term immune responses against the YF vaccine are impaired in immune-compromised patients. MATERIALS AND METHODS: Fifteen patients using different immunosuppressive drugs and 30 healthy individuals vaccinated 0-22 years ago were included. The serological response was measured using the plaque reduction neutralization test (PRNT). CD8(+) and CD4(+) T-cell responses were measured following proliferation and re-stimulation with YFV peptide pools. Phenotypic characteristics and cytokine responses of CD8(+) T-cells were determined using class I tetramers. RESULTS: The geometric mean titre of neutralizing antibodies was not different between the groups (p = 0.77). The presence of YFV-specific CD4(+) and CD8(+) T-cell did not differ between patients and healthy individuals (15/15, 100.0% vs. 29/30, 96.7%, p = 0.475). Time since vaccination correlated negatively with the number of YFV-specific CD8(+) T-cells (r = -0.66, p = 0.0045). Percentages of early-differentiated memory cells increased (r = 0.67, p = 0.017) over time. CONCLUSION: These results imply that YF vaccination is effective despite certain immunosuppressive drug regimens. An early-differentiated memory-like phenotype persisted, which is associated with effective expansion upon re-encounter with antigen, suggesting a potent memory T-cell pool remains.

Characteristic Sizes of Life in the Oceans, from Bacteria to Whales.

The size of an individual organism is a key trait to characterize its physiology and feeding ecology. Size-based scaling laws may have a limited size range of validity or undergo a transition from one scaling exponent to another at some characteristic size. We collate and review data on size-based scaling laws for resource acquisition, mobility, sensory range, and progeny size for all pelagic marine life, from bacteria to whales. Further, we review and develop simple theoretical arguments for observed scaling laws and the characteristic sizes of a change or breakdown of power laws. We divide life in the ocean into seven major realms based on trophic strategy, physiology, and life history strategy. Such a categorization represents a move away from a taxonomically oriented description toward a trait-based description of life in the oceans. Finally, we discuss life forms that transgress the simple size-based rules and identify unanswered questions.

Association of pain in knee osteoarthritis with distinct patterns of synovitis.

OBJECTIVE: To determine possible patterns of synovitis on contrast-enhanced magnetic resonance imaging (CE-MRI) and its relation to pain and severity in patients with radiographic knee osteoarthritis (OA). METHODS: In total, 86 patients (mean age 62 years, 66% women, median body mass index 29 kg/m(2) ) with symptomatic knee OA (Kellgren/Lawrence radiographic score 3) were included. T1-weighted, gadolinium-chelate-enhanced MRI with fat suppression was used to semiquantitatively score the extent of synovitis at 11 knee sites (total score range 0-22). Self-reported pain was assessed with 3 standardized questionnaires. Principal components analysis (PCA) was used to investigate patterns (the location and severity) of synovitis. Subsequently, these patterns were assessed for associations with pain measures and radiographic severity in adjusted logistic regression models. RESULTS: Synovitis was observed in 86 patients and was found to be generally mild on CE-MRI (median total synovitis score 7, range 0-16). The median pain scores were 53 (range 0-96) on the visual analog scale for pain, 51.4 (range 2.8-97.2) on the Knee Injury and Osteoarthritis Outcome Score (KOOS) for pain, 35 (range 0-75) on the Intermittent and Constant Osteoarthritis Pain (ICOAP) score for constant pain, and 40.6 (range 0-87.5) on the ICOAP score for intermittent pain. PCA resulted in extraction of 3 components, explaining 53.4% of the variance. Component 1 was characterized by synovitis at 7 sites (mainly medial parapatellar involvement) and was associated with scores on the KOOS pain subscale and the ICOAP constant pain subscale. Component 2 was characterized by synovitis at 4 sites (mainly the site adjacent to the anterior cruciate ligament), but was not associated with pain measures or with radiographic severity. Component 3, characterized by synovitis at 3 sites (mainly at the loose body site), was associated with radiographic severity. CONCLUSION: Different patterns of synovitis in knee OA were observed. The pattern that included several patellar sites was associated with pain, whereas other patterns showed no association, suggesting that pain perception in patients with knee OA is a localized response.

Illness perceptions in patients with osteoarthritis: change over time and association with disability.

OBJECTIVE: To investigate changes in illness perceptions in patients with osteoarthritis (OA) and the association of those changes with disability, and to determine the predictive value of illness perceptions in disability. METHODS: Illness perceptions and disability were measured at baseline and after 6 years in 241 patients with OA at multiple sites (mean age 59.0 years, 82.2% women) using the revised Illness Perception Questionnaire (IPQ-R) and the Health Assessment Questionnaire (HAQ), respectively. Mean changes for each IPQ-R dimension were reported and related to progression of disability, defined as the highest quartile of HAQ score change. The predictive value of baseline illness perceptions in disability at 6 years (with high disability defined as the highest quartile of HAQ score) was assessed using logistic regression. RESULTS: Illness perceptions changed over time, and these changes were related to the progression of disability. Patients with progression of disability had an increase in symptoms attributed to OA, perceived consequences, perceived disease chronicity, negative emotions associated with OA and beliefs about immunity as causal factor, and a decrease in perceived control and understanding of OA compared with patients without progression of disability. Moreover, a higher number of symptoms attributed to OA, less perceived control, and more perceived consequences of OA at baseline were predictive of high disability after 6 years. CONCLUSION: Illness perceptions in patients with OA changed over time, and these changes were related to outcome. Moreover, illness perceptions were predictive of disability. This may imply that interventions aimed at changing illness perceptions can contribute to better functional outcome.