Rapid Improvement In Health-Related Quality Of Life In Gouty Arthritis Patients Treated With Canakinumab (Acz885) Compared To Triamcinolone Acetonide

Background : Canakinumab, a fully human anti-IL-1b antibody has been shown to control inflammation in gouty arthritis. This study evaluated changes in health-related quality of life (HRQoL) in patients treated with canakinumab or triamcinolone acetonide (TA).Methods : An 8-wk, dose-ranging, active controlled, single-blind study in patients (_18 to _80 years) with acute gouty arthritis flare, refractory to or contraindicated to NSAlDs and/or colchicine, were randomized to canakinumab 10, 25, 50, 90, 150mg sc or TA 40mg im. HRQoL was assessed using patient reported outcomes evaluating PCS and MCS, and subscale scores of SF-36_ [acute version 2]) and functional disability (HAQ-DI_).Results : In canakinumab 150mg group, the most severe impairment at baseline was reported for physical functioning and bodily pain; levels of 41.5 and 36.0, respectively, which improved in 7 days to 80.0 and 72.2 (mean increases of 39.0 and 35.6) and at 8 wks improved to 86.1 and 86.6 (mean increases of 44.6 and 50.6); these were higher than levels seen in the general US population. TA group, showed less improvement in 7 days (mean increases of 23.3 and 21.3 for physical function and bodily pain). Functional disability scores, measured by the HAQ-DI_ decreased in both treatment groups (Table 1).Conclusions : Gouty arthritis patients treated with canakinumab showed a rapid improvement in physical and mental well-being based on SF-36_ scores. In contrast to the TA group, patients treated with canakinumab showed improvement in 7 days in physical function and bodily pain approaching levels of the general population.Disclosure statement : U.A., A.F., V.M., D.R., P.S. and K.S. are employees and shareholders of Novartis Pharma AG. A.P. has received research support from Novartis Pharma AG. N.S. has received research support and consultancy fees from Novartis Pharmaceuticals Corporation, has served on advisory boards for Novartis, Takeda, Savient, URL Pharma and EnzymeRx, and is/has been a member of a speakers' bureau for Takeda. A.S. has received consultation fees from Novartis Pharma AG, Abbott, Bristol-Myers Squibb, Essex, Pfizer, MSD, Roche, UCB and Wyeth. All other authors have declared no conflicts of interest.

Nonlinear analysis of human physical activity patterns in health and disease.

The reliable and objective assessment of chronic disease state has been and still is a very significant challenge in clinical medicine. An essential feature of human behavior related to the health status, the functional capacity, and the quality of life is the physical activity during daily life. A common way to assess physical activity is to measure the quantity of body movement. Since human activity is controlled by various factors both extrinsic and intrinsic to the body, quantitative parameters only provide a partial assessment and do not allow for a clear distinction between normal and abnormal activity. In this paper, we propose a methodology for the analysis of human activity pattern based on the definition of different physical activity time series with the appropriate analysis methods. The temporal pattern of postures, movements, and transitions between postures was quantified using fractal analysis and symbolic dynamics statistics. The derived nonlinear metrics were able to discriminate patterns of daily activity generated from healthy and chronic pain states.

Lymphoid stroma in health and disease

Summary Secondary lymphoid organs (SLOB), such as lymph nodes and spleen, are the sites where primary immune responses are initiated. T lymphocytes patrol through the blood and SLOs on the search for pathogens which are presented to them as antigens by dendritic cells. Stromal cells in the Tzone - so called T zone fibroblastic reticular cells (TRCs) -are critical in organizing the migration of T cells and dendritic cells by producing the chemoattractants CCL19 and CCL21 and by forming a network which T cells use as a guidance system. They also form a system of small channels or conduits that allow rapid transport of small antigen molecules or cytokines from the subcapsular sinus to high endothelial venules. The phenotype and function of TRCs have otherwise remained largely unknown. We found a critical role for lymph node access in CD4+ and CD8+ T cell homeostasis and identified TRCs within these organs as the major source of interleukin-7 (IL-7). IL-7 is an essential survival factor for naïve T lymphocytes of which the cellular source in the periphery had been poorly defined. In vitro, TRC were able to prevent the death of naïve T but not of B lymphocytes by secreting IL-7 and the CCR7 ligand CCL 19. Using gene-targeted mice, we show anon-redundant function of CCL19 in T cell homeostasis. The data suggest that TRCs regulate T cell numbers by providing a limited reservoir of survival factors for which T cells have to compete. They help to maintain a diverse T cell repertoire granting full immunocompetence. To determine whether TRCs also play a role in pathology, we characterized so-called tertiary lymphoid organs (TLOs) that often develop at sites of chronic inflammation. We show that TLOs resemble lymph nodes or Peyer's patches not only with regard to lymphoid cells. TLOs formed extensive TRC networks and a functional conduit system in all three marine inflammation models tested. In one model we dissected the cells and signals leading to the formation of these structures. We showed that they critically depend on the presence of lymphotoxin and lymphoid tissue inducer cells. TRCs in TLOs also produce CCL19, GCL21 and possibly IL-7 which are all involved in the development of TLOs. Stromal cells therefore play a central role in the onset and perpetuation of chronic inflammatory diseases and could be an interesting target for therapy. Résumé Le système immunitaire est la défense de notre corps contre toutes sortes d'infections et de tumeurs. II est constitué de différentes populations de lymphocytes qui patrouillent constamment le corps à la recherche de pathogène. Parmi eux, les lymphocytes T et B passent régulièrement dans les organes lymphoïdes secondaires (SLO) qui sont les sites d'initiation de la réponse immunitaire. Les lymphocytes T sont recrutés du sang aux SLO où ils cherchent leur antigène respectif présenté par des cellules dendritiques. Des cellules stromales dans la zone T -nommées fibroblastic reticular cells' (TRC) -sécrètent des chimiokines CCL19 et CCL21 et ainsi facilitent les rencontres entre lymphocytes T et cellules dendritiques. De plus, elles forment un réseau que les lymphocytes T utilisent comme système de guidage. Ce réseau forme des petits canaux (ou conduits) qui permettent le transport rapide, d'antigène soluble ou de cytokines, de la lymphe aux veinules à endothelium épais (HEV). Le phénotype ainsi que les autres fonctions des TRCs demeurent encore à ce jour inconnus. Nous avons trouvé que l'accès des lymphocytes T CD4+ et CD8+ aux ganglions joue un rôle central pour l'homéostasie. Interleukin-7 (IL-7) est un facteur de survie essentiel pour les lymphocytes T naïfs dont la source cellulaire dans la périphérie était mal définie. Nous avons identifié les TRCs dans les ganglions comme source principale d'interleukin-7 (IL-7). In vitro, les TRCs étaient capable de prévenir la mort des lymphocytes T mais pas celle de lymphocytes B grâce à la sécrétion d'IL-7 et de CCL19. En utilisant des souris déficientes du gène CCL19, nous avons observé que l'homéostasie des lymphocytes T dépend aussi de CCL19 in vivo. Les données suggèrent que les TRCs aident à maintenir un répertoire large et diversifié de cellules T et ainsi l'immunocompétence. Pour déterminer si les TRCs pourraient jouer un rote également dans la pathologie, nous avons caractérisé des organes lymphoïdes tertiaires (TLOs) souvent associés avec l'inflammation chronique. Les TLOs ressemblent à des ganglions ou des plaques de Peyer pas seulement en ce qui concerne la présence de lymphocytes. Nous avons constaté que les TLOs forment des réseaux de TRC et un système fonctionnel de conduits. La formation de ces structures est fortement diminuée dans l'absence du signal lymphotoxin ou des cellules connues comme ymphoid tissue-inducer tells: Les TRCs dans les TLOs produisent les chimiokines CCL19, CCL21 et possiblement aussi IL-7 qui sont impliquées dans le développement des TLOs. Les cellules stromales jouent donc un rôle central dans l'initation et la perpétuation des maladies inflamatoires chroniques et pourraient être une cible intéressante pour la thérapie.

Rapid Improvement in Health-Related Quality of Life (HRQoL) in Gouty Arthritis Patients Treated with Canakinumab (ACZ885) Compared to Triamcinolone Acetonide

Background: Gouty arthritis is a painful inflammatory disease with a significant impact on patients' HRQoL. In gouty arthritis, the inflammatory response is initiated by interleukin-1b (IL-1b) release, due to activation of the NALP3 inflammasome by MSU crystals. Canakinumab, a fully human anti-IL-1b antibody has a long half-life and has been shown to control inflammation in gouty arthritis. This study evaluated changes in HRQoL in gouty arthritis patients following treatment with canakinumab or triamcinolone acetonide (TA).Methods: This was an 8-week, dose-ranging, multi-center, active controlled, single-blind study. Patients (>=18 to <=80 years) experiencing an acute gouty arthritis flare, refractory to or contraindicated to NSAlDs and/or colchicine, were randomized to canakinumab 10, 25, 50, 90, 150 mg sc or TA 40 mg im. HRQoL was assessed as an exploratory endpoint at baseline and different pre-specified time-points using patient reported outcomes evaluating general mental and physical component summary scores and subscale scores of SF-36® (acute version 2) and functional disability (HAQ-DI©). We report HRQoL results for canakinumab 150 mg, the dose that was selected for the Phase III studies.Results: Baseline assessments showed a major impact on the HRQoL during acute gouty arthritis. Compared to TA, canakinumab 150 mg showed greater improvements in SF-36® physical and mental component summary and subscale scores at 7 days post-dose.In the canakinumab 150 mg group, the most severe impairment at baseline was reported for physical functioning and bodily pain; levels of 41.5 and 36.0, respectively, which improved within 7 days to 80.0 and 72.2 (mean increases of 39.0 and 35.6) approaching levels of the general US population (84.2 and 75.2). 8 weeks post-dose patients reached levels of 86.1 and 86.6 (mean increases of 44.6 and 50.6 for physical functioning and bodily pain, respectively) and these were higher than levels seen in the general US population. This was in contrast to patients treated with TA, who showed less improvement within 7 days (mean increases of 23.3 and 21.3 for physical function and bodily pain, respectively). None of the scores reached levels of the general US population 8 weeks post-dose. Functional disability scores, as measured by the HAQ-DI© decreased in both treatment groupsConclusions: All canakinumab doses showed a rapid improvement in physical and mental well-being of gouty arthritis patients based on SF-36® scores, in particular the 150 mg dose. In contrast to the TA group, patients treated with canakinumab showed improvement within 7 days in physical function and bodily pain approaching levels of the general population. The 150 mg dose of canakinumab was selected for further development in Phase III studies.

La Generation Sandwich en Suisse Romande: mieux comprendre les facteurs associés avec la santé perçue afin de mieux agir en promotion de la santé [Sandwich Generation in Roman Switzerland : a better understanding of factors linked with perceived health for better acting in health promotion].

The so-called < Sandwich Generation > (SG) is characterized by concurrent and competing professional, familial, and informal caregiving workloads. These stressors pose potential health risks. However, the current knowledge about SG characteristics and perceived state of health are insufficient to allow occupational health nurses to develop evidence-based interventions designed for health promotion. We aimed to describe this population and examine the relationships between these coexisting workloads and their perceived health. This study is based on a descriptive, correlational design. Employees of a Swiss public administration completed an electronic questionnaire. Of 844 respondents, 23 % are SG members. Ages of frailed parents or parents-in-law, co-residence with the latters, children still living at home predict that employees could be members of the SG. Perceived physical health status of SG members is rated better than mental health status. The heterogeneity of SG is reflected in three clusters. Finally, physical health score is the only that differs from the other health scores adjusting for clusters and sex. This study provides a foundation for developing preventive interventions targeting the SG.

Impact of phenotype definition on genome-wide association signals: empirical evaluation in human immunodeficiency virus type 1 infection.

Discussion on improving the power of genome-wide association studies to identify candidate variants and genes is generally centered on issues of maximizing sample size; less attention is given to the role of phenotype definition and ascertainment. The authors used genome-wide data from patients infected with human immunodeficiency virus type 1 (HIV-1) to assess whether differences in type of population (622 seroconverters vs. 636 seroprevalent subjects) or the number of measurements available for defining the phenotype resulted in differences in the effect sizes of associations between single nucleotide polymorphisms and the phenotype, HIV-1 viral load at set point. The effect estimate for the top 100 single nucleotide polymorphisms was 0.092 (95% confidence interval: 0.074, 0.110) log(10) viral load (log(10) copies of HIV-1 per mL of blood) greater in seroconverters than in seroprevalent subjects. The difference was even larger when the authors focused on chromosome 6 variants (0.153 log(10) viral load) or on variants that achieved genome-wide significance (0.232 log(10) viral load). The estimates of the genetic effects tended to be slightly larger when more viral load measurements were available, particularly among seroconverters and for variants that achieved genome-wide significance. Differences in phenotype definition and ascertainment may affect the estimated magnitude of genetic effects and should be considered in optimizing power for discovering new associations.

Official positions of the International Society for Clinical Densitometry (ISCD) on DXA evaluation in children and adolescents.

Dual-energy X-ray absorptiometry (DXA) is the most widely used technical instrument for evaluating bone mineral content (BMC) and density (BMD) in patients of all ages. However, its use in pediatric patients, during growth and development, poses a much more complex problem in terms of both the technical aspects and the interpretation of the results. For the adults population, there is a well-defined term of reference: the peak value of BMD attained by young healthy subjects at the end of skeletal growth. During childhood and adolescence, the comparison can be made only with healthy subjects of the same age, sex and ethnicity, but the situation is compounded by the wide individual variation in the process of skeletal growth (pubertal development, hormone action, body size and bone size). The International Society for Clinical Densitometry (ISCD) organized a Pediatric Position Development Conference to discuss the specific problems of bone densitometry in growing subjects (9-19 years of age) and to provide essential recommendations for its clinical use.

Trabecular bone score (TBS) as a new complementary approach for osteoporosis evaluation in clinical practice.

Trabecular bone score (TBS) is a recently-developed analytical tool that performs novel grey-level texture measurements on lumbar spine dual X-ray absorptiometry (DXA) images, and thereby captures information relating to trabecular microarchitecture. In order for TBS to usefully add to bone mineral density (BMD) and clinical risk factors in osteoporosis risk stratification, it must be independently associated with fracture risk, readily obtainable, and ideally, present a risk which is amenable to osteoporosis treatment. This paper summarizes a review of the scientific literature performed by a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis. Low TBS is consistently associated with an increase in both prevalent and incident fractures that is partly independent of both clinical risk factors and areal BMD (aBMD) at the lumbar spine and proximal femur. More recently, TBS has been shown to have predictive value for fracture independent of fracture probabilities using the FRAX® algorithm. Although TBS changes with osteoporosis treatment, the magnitude is less than that of aBMD of the spine, and it is not clear how change in TBS relates to fracture risk reduction. TBS may also have a role in the assessment of fracture risk in some causes of secondary osteoporosis (e.g., diabetes, hyperparathyroidism and glucocorticoid-induced osteoporosis). In conclusion, there is a role for TBS in fracture risk assessment in combination with both aBMD and FRAX.