Effects of Fatty Acid Metabolites on Adipocytes Britening: Role of Thromboxane A2.

Obesity is a complex disease highly related to diet and lifestyle and is associated with low amount of thermogenic adipocytes. Therapeutics that regulate brown adipocyte recruitment and activity represent interesting strategies to fight overweight and associated comorbidities. Recent studies suggest a role for several fatty acids and their metabolites, called lipokines, in the control of thermogenesis. The purpose of this work was to analyze the role of several lipokines in the control of brown/brite adipocyte formation. We used a validated human adipocyte model, human multipotent adipose-derived stem cell model (hMADS). In the absence of rosiglitazone, hMADS cells differentiate into white adipocytes, but convert into brite adipocytes upon rosiglitazone or prostacyclin 2 (PGI2) treatment. Gene expression was quantified using RT-qPCR and protein levels were assessed by Western blotting. We show here that lipokines such as 12,13-diHOME, 12-HEPE, 15dPGJ2 and 15dPGJ3 were not able to induce browning of white hMADS adipocytes. However, both fatty acid esters of hydroxy fatty acids (FAHFAs), 9-PAHPA and 9-PAHSA potentiated brown key marker UCP1 mRNA levels. Interestingly, CTA2, the stable analog of thromboxane A2 (TXA2), but not its inactive metabolite TXB2, inhibited the rosiglitazone and PGI2-induced browning of hMADS adipocytes. These results pinpoint TXA2 as a lipokine inhibiting brown adipocyte formation that is antagonized by PGI2. Our data open new horizons in the development of potential therapies based on the control of thromboxane A2/prostacyclin balance to combat obesity and associated metabolic disorders.

Impact of a Wearable Activity Tracker on Disease Flares in Spondyloarthritis: A Randomized Controlled Trial.

OBJECTIVE: To evaluate the impact of a wearable activity tracker used to encourage physical activity, on disease flares in patients with spondyloarthritis (SpA). METHODS: This randomized controlled trial involved randomizing 108 patients with SpA into tracker and nontracker groups. The participants were then subjected to assessments of disease activity, performance (6-minute walk test), and quality of life (QOL; 36-item Short Form Health Survey) at the 12th, 24th, and 36th week. The primary outcome was the change in the frequency of flare episodes (categorized as no flare, flare in ≤ 3 days, and flare in > 3 days) between baseline and 12 weeks. RESULTS: The results of the study showed that at the 12th week, the mean change (∆) of the number of flares improved in both groups: -0.32 (95% CI -0.66 to 0.02) and -0.38 (95% CI -0.68 to -0.09) in the tracker and nontracker group, respectively. However, the between-group differences were insignificant (P = 0.87). Performance scores improved in both groups at the 12th, 24th, and 36th week (all P < 0.01). The different dimensions of QOL also improved at the 12th week (P < 0.01). Conversely, moderate flares (P < 0.01) and performance (P < 0.01) improved over time; however, the influence over time of a wearable activity tracker was not significant (P = 0.29 and P = 0.66, respectively). CONCLUSION: The use of a wearable activity tracker did not affect the number of flares, performance, or QOL of patients with SpA. Nevertheless, this study confirmed the benefits of physical activity on flares, disease activity, QOL, and physical performance in patients with SpA. (Move Your Spondyl "Better Live Its Rheumatism With the Physical Activity"; ClinicalTrials.gov: NCT03458026).

Association of Baseline Cardiovascular Diseases with 5-Year Knee and Hip Osteoarthritis Progression in Non-Obese Patients: Data from the KHOALA Cohort.

We aimed to explore the relationship between comorbidities and the structural progression in symptomatic knee and/or hip osteoarthritis (OA) patients. We analyzed the 5-year outcome of non-obese participants (body mass index (BMI) < 30 kg/m2) from the KHOALA cohort having symptomatic hip and/or knee OA (Kellgren and Lawrence (KL) ≥ 2). The primary endpoint was radiological progression, defined as ΔKL ≥ 1 of the target joint at 5 years. The secondary outcome was the incidence of total knee or hip replacement over 5 years. Dichotomous logistic regression models assessed the relationship of comorbidities with KL progression and joint replacement while controlling for gender, age and BMI. Data from 384 non-obese participants were analyzed, 151 with hip OA and 254 with knee OA. At 5 years, cardiovascular diseases (CVD) were significantly associated with the 5-year KL change in both knee (OR = 2.56 (1.14-5.78), p = 0.02) and hip OA (OR = 3.45 (1.06-11.17), p = 0.04). No significant relationship was found between any type of comorbidities and knee or hip arthroplasty. This 5-year association between CVD and radiological progression of knee and hip OA in non-obese participants argue for an integrated management of CVD in knee and hip OA non-obese patients.

Methotrexate treatment in hand osteoarthritis refractory to usual treatments: A randomised, double-blind, placebo-controlled trial.

OBJECTIVE: To examine the effect of methotrexate (MTX) on pain and structural progression in symptomatic erosive hand osteoarthritis (HOA). METHODS: This 1-year prospective, single-centre, randomised, double-blind, placebo-controlled study (www.ClinicalTrial.gov, NCT01068405) followed up patients with symptomatic erosive HOA. Patients were randomised into two groups based on the drug that was administered: 10 mg methotrexate (MTX) per week or a placebo. The primary endpoint was the change in pain (determined using a visual analogue scale [VAS]) from baseline to 3 months. The secondary endpoints were pain VAS score at 12 months, clinical features (pain VAS score and function), radiographic features (the anatomical radiographic Verbruggen-Veys [VV] score and Gent University Score System), and magnetic resonance imaging (MRI) at 12 months. RESULTS: Sixty-four patients with HOA were randomised into either the placebo or MTX group. At 3 months, there was no significant difference in the mean decrease in the pain VAS score (mm) (MTX: 21.1 [standard deviation, 27.4], placebo: 11.7 [24.3]; p = 0.2). At 12 months, according to the VV score, erosive joints progressed significantly more to a remodelling phase in the MTX group than in the placebo group (27% vs 15%; p = 0.03). Joints with space loss appeared to be eroding less in the MTX group compared to the placebo group (8% vs 29%; p = 0.2). Synovitis on MRI at baseline could be associated with the erosive structural evolution of non-erosive joints (p = 0.02). CONCLUSIONS: Weekly doses of 10-mg MTX showed no superiority over the placebo in terms of pain relief at 3 or 12 months. CLINICAL TRIAL REGISTRATION NUMBER: This study was registered at www.ClinicalTrial.gov (NCT01068405).

Recommendations of the French Society of Rheumatology on pharmacological treatment of knee osteoarthritis.

OBJECTIVES: To establish recommendations for pharmacological treatment of knee osteoarthritis specific to France. METHODS: On behalf of the French Society of Rheumatology (SFR), a bibliography group analyzed the literature on the efficacy and safety of each pharmacological treatment for knee osteoarthritis. This group joined a multidisciplinary working group to draw up recommendations. Strength of recommendation and quality of evidence level were assigned to each recommendation. A review committee gave its level of agreement. RESULTS: Five general principles were established: 1) need to combine pharmacological and non-pharmacological treatments, 2) personalization of treatment, 3) symptomatic and/or functional aim of pharmacological treatments, 4) need to regularly re-assess the treatments and 5) discussion about arthroplasty if medical treatment fails. Six recommendations involved oral treatments: 1) paracetamol should not necessarily be prescribed systematically and/or continuously, 2) NSAIDs, possibly as first-line, 3) weak opioids, 4) strong opioids, 5) symptomatic slow-acting drugs of osteoarthritis, and 6) duloxetine (off-label use). Two recommendations involved topical agents (NSAIDs and capsaicin<1%). Three recommendations involved intra-articular treatments: corticosteroid or hyaluronic acid injections that can be proposed to patients. The experts did not draw a conclusion about the benefits of platelet-rich plasma injections. CONCLUSION: These are the first recommendations of the SFR on the pharmacological treatment of knee osteoarthritis.

Oxytocin Controls Chondrogenesis and Correlates with Osteoarthritis.

This study investigated the relationship of oxytocin (OT) to chondrogenesis and osteoarthritis (OA). Human bone marrow and multipotent adipose-derived stem cells were cultured in vitro in the absence or presence of OT and assayed for mRNA transcript expression along with histological and immunohistochemical analyses. To study the effects of OT in OA in vivo, a rat model and a human cohort of 63 men and 19 women with hand OA and healthy controls, respectively, were used. The baseline circulating OT, interleukin-6, leptin, and oestradiol levels were measured, and hand X-ray examinations were performed for each subject. OT induced increased aggrecan, collagen (Col) X, and cartilage oligomeric matrix protein mRNA transcript levels in vitro, and the immunolabelling experiments revealed a normalization of Sox9 and Col II protein expression levels. No histological differences in lesion severity were observed between rat OA groups. In the clinical study, a multivariate analysis adjusted for age, body mass index, and leptin levels revealed a significant association between OA and lower levels of OT (odds ratio = 0.77; p = 0.012). Serum OT levels are reduced in patients with hand OA, and OT showed a stimulatory effect on chondrogenesis. Thus, OT may contribute to the pathophysiology of OA.

MRI and serum biomarkers correlate with radiographic features in painful hand osteoarthritis.

OBJECTIVES: To explore the relationship between clinical findings, biologic biomarkers, conventional radiography and MRI in patients with painful hand OA. METHODS: The following patient baseline data from the DORA study (evaluating anti-TNF-α agents against painful hand OA) were used: clinical assessment (pain, swelling, stiffness and function: Dreiser functional hand index [FIHOA] and Cochin hand functional scale [CHFS]); measurement of biomarkers (cartilage oligomeric matrix protein (COMP), type IIA collagen N-propeptid (PIINP), hyaluronic acid (HA), ultrasensitive C-reactive protein (usCRP), tumour necrosis factor (TNF), interleukin (IL)-6, IL-1ß and urinary CTXII); radiological staging (Verbruggen, Kallman, Kellgren-Lawrence); anatomical evaluation by contrast-enhanced MRI of proximal and distal interphalangeal joints of dominant hand. Associations between clinical, biomarker and imaging findings were assessed using the Spearman correlation coefficient and test. RESULTS: 18 patients were recruited, and 144 joints studied. A correlation was found between clinical features (pain, FIHOA, CHFS) and the Verbruggen score (respectively: p=0.05, r=0.47; p=0.05, r=0.48; p=0.05, r=0.48). Serum IL-1 level was strongly associated with loss of function (FIHOA: p=0.02, r=-0.73; CHFS: p=0.01, r=-0.76) and radiological erosions (p=0.03, r=0.7) as with urinary CTX2. A significant association was found between MRI osteophytes and usCRP (p=0.0026). MRI and radiological features were significantly correlated except for synovitis and bone marrow lesions. CONCLUSIONS: MRI synovitis was not correlated with radiological scores, clinical or biologic markers of inflammation. There was a strong correlation between other MRI features and radiological scores. Serum IL-1 level was associated with structural damage and function.

Association between hip morphology and prevalence, clinical severity and progression of hip osteoarthritis over 3 years: The knee and hip osteoarthritis long-term assessment cohort results.

OBJECTIVE: To assess the effects of variations in hip morphology on prevalence, clinical severity and progression of hip osteoarthritis. METHODS: From 2007 to 2009, we conducted a study of 242 patients aged between 40 and 75 years with symptomatic lower limb osteoarthritis, as part of a population-based osteoarthritis cohort study in France. Standard radiographs of both hips were obtained at baseline and at three years. The progression of hip osteoarthritis was evaluated according to the radiological Kellgren-Lawrence score (KL) and clinical severity from the scores on a Visual Analogic Scale (VAS) for pain recorded yearly. Five measures were used to describe hip morphology: centre edge angle, acetabular index (AI), vertical centre anterior angle, acetabular depth and neck-shaft angle. RESULTS: Of the 484 hips studied, 205 (42%) showed osteoarthritis at baseline and 16 (11 right and 5 left) underwent joint replacement during the follow-up. AI was the morphological measure most consistently and strongly associated with radiographic osteoarthritis at baseline (odds-ratio=1.05, 95% CI: 1.01-1.08 per degree of angle change), clinical severity (correlation coefficient with VAS during 3 years=0.15, P=0.004), radiological progression (odds-ratio=1.05, 95% CI: 1.00-1.10 per degree) and joint replacement (hazard ratio=1.18, 95% CI: 1.07-1.29 per degree). CONCLUSIONS: Acetabular obliquity and especially AI is strongly, and likely causally, associated with the existence, severity and progression of hip osteoarthritis.

Oxytocin reverses osteoporosis in a sex-dependent manner.

The increase of life expectancy has led to the increase of age-related diseases such as osteoporosis. Osteoporosis is characterized by bone weakening promoting the occurrence of fractures with defective bone regeneration. Men aged over 50 have a prevalence for osteoporosis of 20%, which is related to a decline in sex hormones occurring during andropause or surgical orchidectomy. As we previously demonstrated in a mouse model for menopause in women that treatment with the neurohypophyseal peptide hormone oxytocin (OT) normalizes body weight and prevents the development of osteoporosis, herein we addressed the effects of OT in male osteoporosis. Thus, we treated orchidectomized mice, an animal model suitable for the study of male osteoporosis, for 8 weeks with OT and then analyzed trabecular and cortical bone parameters as well as fat mass using micro-computed tomography. Orchidectomized mice displayed severe bone loss, muscle atrophy accompanied by fat mass gain as expected in andropause. Interestingly, OT treatment in male mice normalized fat mass as it did in female mice. However, although OT treatment led to a normalization of bone parameters in ovariectomized mice, this did not happen in orchidectomized mice. Moreover, loss of muscle mass was not reversed in orchidectomized mice upon OT treatment. All of these observations indicate that OT acts on fat physiology in both sexes, but in a sex specific manner with regard to bone physiology.

The KHOALA cohort of knee and hip osteoarthritis in France.

OBJECTIVES: This study aimed to describe the prevalence of symptomatic knee and hip osteoarthritis (OA) and its course over time, as well as identify prognostic factors of OA course and determinants of costs and access to care in France in a patient cohort. METHODS: Subjects aged 40 to 75 years, with uni- or bilateral symptomatic hip and/or knee OA (ACR criteria), Kellgren and Lawrence (KL) stage 2 or greater, were recruited from a French national prevalence survey for the multicenter KHOALA cohort study. Data collected at baseline included sociodemographic and clinical data; WOMAC, IKS and Harris scores for pain and function; MAQ score for physical activity; functional comorbidity index; GHQ28 score for psychological status; and SF-36 (generic) and OAKHQOL (specific) scores for quality of life. Blood and urine samples were collected. RESULTS: Eight hundred and seventy-eight subjects were included, 222 with OA of the hip (mean age 61.2±8.8 years), 607 knee (mean age 62.0±8.5 years) and 49 both hip and knee (mean age 64.9±7.9 years). Mean body mass index was 26.9±4.5 for hip OA and 30.3±6.3 for knee OA. Hip and knee OA patients had 1.99 and 2.06 comorbidities, on average, respectively. Disease severity on X-rays for KL stages 2, 3 and 4 for hip OA was 69.8, 26.1 and 4.1%, respectively, and for knee OA, 44.5, 30.3, and 25.2%. As compared with population norms, age- and sex-standardized SF-36 scores were greatly decreased for both knee and hip OA in all dimensions, particularly physical and emotional dimensions. PERSPECTIVES: Patients will be followed up annually, alternately by mail and clinical visit. This cohort of representative patients with knee and hip OA will be an opportunity for future collaborative research.

Etanercept compared to intraarticular corticosteroid injection in rheumatoid arthritis: double-blind, randomized pilot study.

OBJECTIVE: To compare etanercept (anti-tumor necrosis factor-α) with intraarticular (IA) corticosteroid injections to treat rheumatoid arthritis (RA). METHODS: Patients with RA who had persistent monoarthritis received etanercept or IA corticosteroid injections. Efficacy was compared at Weeks 4 and 24. RESULTS: Thirty-four patients were included (8 dropped out). Mean age was 58.8 years. No difference between groups was found at Weeks 4 or 24, but both groups showed significant improvement at Weeks 4 and 24 compared to baseline. CONCLUSION: Etanercept and IA steroid injections resulted in significant improvement at Week 4 that persisted to Week 24. There was no significant difference in outcome between the groups.

Prevalence in two-phase surveys: accuracy of screening procedure and corrected estimates.

BACKGROUND: Two-phase surveys often are used to estimate prevalence, in particular when the disease is rare or the case ascertainment procedure difficult and/or costly. However, few authors of such surveys take into account the sensitivity error associated with the use of a screening procedure in the first phase and its imprecision in correcting the prevalence estimate and confidence interval. METHODS: Two examples of two-phase surveys of rheumatic diseases (hip and knee osteoarthritis, rheumatoid arthritis and spondyloarthropathies) are used to present methodological approaches to obtain corrected prevalence estimates. Two methods for assessing the accuracy of the screening procedure are described--two-phase pilot and case-control designs--that are best suited for frequent and rare diseases, respectively, and naive and corrected estimates of prevalence compared. RESULTS: When the sensitivity error is not taken into account, prevalence is underestimated, as is, especially, the width of its confidence interval. In our examples, the corrected confidence interval width increased up to 50% as compared with naïve one. CONCLUSIONS: The screening procedure accuracy should be thoroughly assessed in two-phase prevalence surveys and prevalence estimates and their confidence intervals corrected accordingly.

Drug Insight: choosing a drug treatment strategy for women with osteoporosis-an evidence--based clinical perspective.

Many randomized controlled trials (RCTs) have investigated drug treatment for women at high risk of fracture, with a reduction in fracture risk as their end point. There has also been progress in identifying women at the highest risk of fractures. The most important clinical determinant contributing to the clinical decision of initiating and choosing drug therapy for fracture prevention is a woman's fracture risk, which, in RCTs, was determined by menopausal state, age, bone mineral density, fracture history, fall risks and glucocorticoid use. Women with secondary osteoporosis were excluded, except in studies of glucocorticoid use. A second determinant of drug therapy is the evidence for fracture prevention in terms of spectrum (vertebral, nonvertebral and/or hip fractures), size and speed of effect. In the absence of head-to-head RCTs with fracture risk as the end point, however, the efficacy of antifracture drugs cannot be directly compared. Other determinants include the potential extraskeletal benefits and safety concerns of the drug, patient preferences and reimbursement issues.

Rheumatoid arthritis and spondyloarthropathies: geographical variations in prevalence in France.

OBJECTIVE: To determine geographical variation in the prevalence of rheumatoid arthritis (RA) and spondyloarthropathies (SpA) in France. METHODS: The survey sample was drawn from 7 areas of France. Households were randomly selected using the national telephone directory, and an individual within each household was randomly chosen by the next-birthday method. All cases of suspected RA and SpA were confirmed by the patient's rheumatologist or by clinical examination. Standardized estimates of prevalence were compared between regions and groups of regions. RESULTS: In total 15,219 anonymous telephone numbers were selected. An average response rate of 64% led to a total of 9395 respondents included in the study. The highest regional rates of RA were observed in the south (range 0.59-0.66%), and the lowest in the north (range 0.14-0.24%), with a national rate of 0.31% (95% CI 0.18-0.48%). Regional heterogeneity was observed for SpA, with the highest rates in Bretagne (0.47%) and the Sud-Est (0.53%) and a national rate of 0.30% (95% CI 0.17-0.46%). CONCLUSION: This study is the largest of its kind conducted in France. It shows inter-regional variations, mainly in RA, with a higher prevalence in the south of the country. The many potential reasons for the heterogeneity observed, including genetic and environmental factors, warrant further research.