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Abstract: Interleukin-6 (IL-6) is a cytokine that can facilitate autoimmune phenomena, amplify acute inflammation and promote the evolution into a chronic inflammatory state. In addition, it is a major promoter of bone resorption in pathological conditions. In particular, IL-6 has a pivotal role in synovitis, bone erosions and in the systemic features of inflammation. This cytokine specifically binds to IL-6 receptor (IL-6R), forming the IL-6/IL-6R complex that binds to gp130, a membrane-bound protein, which is involved in non-ligand-binding signal transduction. Targeting IL-6R in both animal models of arthritis and in rheumatoid arthritis patients with a humanized anti IL-6R monoclonal antibody (tocilizumab) effectively controls local and systemic inflammatory manifestations and blocks cartilage and bone destruction. Given the pleiotropic function of IL-6 it can be anticipated that other inflammatory diseases and bone metabolic conditions might benefit from selective IL-6 signaling inhibition. [Copyright &y& Elsevier]

La connectivite mixte (CM) ou syndrome de Sharp est une maladie auto-immune rare caractérisée par un phénomène de Raynaud, une positivité des anticorps anti-U1RNP et différentes manifestations cliniques qui recoupent celles d'autres connectivites [1]. Certains patients peuvent développer une pneumopathie interstitielle diffuse (PID). Toutefois, la pneumopathie interstitielle diffuse associée à la CM (PID-CM) est mal connue et de présentation très hétérogène [2]. Cette complication est à l'origine d'une augmentation du risque de décès [3]. L'objectif de cette étude était de comparer les deux populations de patients suivis pour une CM avec et sans PID et d'identifier des facteurs associés à cette complication et ceux prédictifs d'aggravation de la PID. Étude observationnelle rétrospective multicentrique internationale (11 centres universitaires) de patients suivis pour une CM. Pour être inclus, les patients devaient répondre à l'un des trois critères de classification couramment utilisés dans la CM [4]. La PID a été définie selon la présence d'anomalies scannographiques typiques. Les patients ont été divisés en deux groupes : patients avec et sans PID appariés selon un ratio 1 :1 en fonction de la durée d'évolution de la maladie ± 2 ans. 290 patients ont été inclus. L'âge moyen au diagnostic de CM était 39,7 ± 14,8 ans et 183 (63,1 %) étaient des femmes. Dans le sous-groupe de patients PID-CM la durée moyenne de la maladie jusqu'au diagnostic de PID était 4,5 ± 7,4 ans, la capacité vitale forcée (CVF %) moyenne était de 80,4 ± 20,2 %, la capacité de diffusion du monoxyde de carbone (DLCO %) était 62,2 ± 17,9 % ; l'étendue scannographique moyenne des lésions de PID était 11,0 ± 11,3 %. Le profil scannographique le plus fréquent était celui d'une pneumopathie interstitielle non spécifique (PINS) chez 100 patients (70,0 %). À l'inclusion, les facteurs suivants étaient associés à la présence d'une PID : sclérose cutanée limitée (p = 0,02), CVF < 80 % (p < 0,0001), DLCO < 80 % (p < 0,0001), positivité des anticorps anti-SSA (p = 0,03) et présence d'une cryoglobulinémie (p = 0,04). Pour la partie longitudinale, 29 (20,0 %) patients ont présenté une aggravation des épreuves fonctionnelles respiratoires (EFR) (perte de 10 % de la CVF ou ≥ et/ou 15 % de la DLCO) au cours du suivi. Nous n'avons pas identifié de facteur associé à l'aggravation pulmonaire interstitielle. Concernant les traitements, nous avons observé aucun cas d'aggravation de la PID chez les patients traités par mycophénolate mofétil (MMF) (vs. 22 aggravations chez les patients non traités par MMF (p = 0,11). Dans cette large série internationale de patients suivis pour une CM, nous avons identifié des facteurs associés à la présence d'une PID : une sclérose cutanée limitée, la présence d'anticorps anti-SSA et d'une cryoglobulinémie. Les acteurs predictfs de progression sont en cours d'analyses complémentaires. [ABSTRACT FROM AUTHOR]

Abstract: Materials with a cellular structure are common in nature and an example of natural solid foam is trabecular bone. As for other materials, the microstructural features of cellular solids affect their mechanical response. The aim of this work is to study how the trabecular bone microarchitecture affects the mechanical properties of two types of bone and compare the results with models existing on the literature for solid cellular materials. In spite of several works which make a more medical analysis, this type of materials-science approach is rare. Two types of trabecular bone were studied, namely from male and female patients with osteoporotic (fragility) fractures and patients with coxarthrosis, that were submitted to total hip arthroplasty. Each sample was first analyzed with micro-computed tomography, micro‑CT, for structural assessment. Several parameters used to characterize the three-dimensional structure of trabecular bone were obtained, including the bone volume fraction. Cylinder samples were also tested under uniaxial compression and the Young’s modulus and the ultimate stress were determined. No statistical differences between the two bone groups in respect to the structural and mechanical properties were found. The structural parameters that correlate better with the mechanical properties are different for each bone assembly, being the trabecular separation on the coxarthrosis group and the trabecular number on the osteoporotic group. However, both trabecular separation and trabecular number are strongly correlated with the bone volume fraction, i.e., to the bone relative density. The existing models of Gibson and Ashby were adapted to the relationship between stiffness and strength with the bone volume fraction. In both bone groups, the Young’s modulus is reduced with the decrease of the bone volume fraction following a quadratic law as happens in bending dominated open-cell foams. The ultimate strength is related to the bone volume fraction by a relationship with an exponent between 1 and 2, which indicates that during cell collapse, there is a mixture of two mechanisms: elastic buckling and brittle crushing. [Copyright &y& Elsevier]

Abstract: We have previously reported an increase in interleukin (IL)-1β and IL-17 levels, and a continuous activation of caspase-1 in early rheumatoid arthritis (RA) patients. These results suggest that drugs targeting IL-1β regulatory pathways, in addition to tumor necrosis factor (TNF), may constitute promising therapeutic agents in early RA. We have recently used a THP-1 macrophage-like cell line to screen 2320 compounds for those that down-regulate both IL-1β and TNF secretion. Celastrol was one of the most promising therapeutic candidates identified in that study. Our main goal in the present work was to investigate whether administration of celastrol is able to attenuate inflammation in a rat model of adjuvant-induced arthritis (AIA). Moreover, since IL-1β is known to play a role in the polarization of Th17 cells, we also investigate whether administration of digoxin, a specific inhibitor of Th17 cells polarization, is able to attenuate inflammation in the same rat model. We found that celastrol administration significantly suppressed joint inflammation. The histological and immunohistochemical evaluation revealed that celastrol-treated rats had a normal joint structure with complete abrogation of the inflammatory infiltrate and cellular proliferation. In contrast, we observed that digoxin administration significantly ameliorated inflammation but only if administrated in the early phase of disease course (after 4days of disease induction), and it was not efficient at inhibiting the infiltration of immune cells within the joint and in preventing damage. Thus, our results suggest that celastrol has significant anti-inflammatory and anti-proliferative properties and can constitute a potential anti-inflammatory drug with therapeutic efficacy in the treatment of immune-mediated inflammatory diseases such as RA. Furthermore, we find that early inhibition of Th17 cells polarization ameliorates arthritis but it is not as effective as celastrol. [Copyright &y& Elsevier]

Abstract: The development of consistent procedures with the inclusion of patient-specific data is essential in the computational modeling of biological processes, in order to achieve clinical relevant data. In this work, these issues are addressed with the development of a methodology that combines the gold standard technique for bone mineral density measurement and osteoporosis diagnosis, Dual energy X-ray absorptiometry (DXA), with a computational model for bone remodeling simulation. The DXA results were divided in three samples constituted from proximal femur DXA exams of patients in different stages of bone mineral density (normal, osteopenia and osteoporosis). These results were quantitatively compared with computational model results. A correlation study was performed between femoral neck T-score and a parameter from the model to ascertain the hypothesis of adjusting the model accordingly to biological variables. The results evidenced the predictive ability of the computational model in the estimation of femoral neck bone mineral content (BMC), with a maximum relative error of 3.92%. On the other hand, a strong correlation (R=−0.862) was found between the variables in study and a mathematical relationship was obtained to estimate the range of values for a model parameter that leads to biological relevant results. The methodology developed and the results obtained represent a solid and reliable basis to further studies on bone quality, ensuring the validity of the computational model in the simulation of bone remodeling process. [ABSTRACT FROM AUTHOR]

Abstract: Rheumatoid arthritis is the most common inflammatory joint disease. The etiopathogenesis of this condition has been classically explained by a T cell-driven process. However, recent studies have highlighted the possible contribution of neutrophils for the early phases of RA physiopathology. These cells are phagocytic leukocytes that play crucial roles in the acute defense against pathogens while modulating the function of other immune cells and contributing to the perpetuation of an initial inflammatory response. The herein article reviews recent progresses in the understanding of the immunopathology of RA with a special emphasis on the role of neutrophils. [Copyright &y& Elsevier]

Abstract: Inflammatory diseases, such as rheumatoid arthritis (RA), influence the bone remodelling process and increase the risk of fracture. Bone can be viewed as a composite material comprising of two phases: the organic phase, constituted predominantly by collagen type I, and the mineral phase, composed primarily by calcium phosphate, in the form of mineral crystals. The mineral component confers bone with strength and stiffness while the organic phase is responsible for bone toughness and ductility and acts as a scaffold for the mineralisation process. The efficacy of bone as a structural material depends on the balance between these different bone components and their biomechanical properties. The main determinants of mechanical properties of bone are the amount of mineral, the collagen content, the orientation of the collagen fibers and minerals and the accumulation of microcracks in the bone matrix. In a mice model of arthritis mechanical testing has shown that arthritic femurs have a significantly lower Young''s modulus, yield stress and work until ultimate stress. This evidence suggests that one of the major explanations for the increased fracture risk in RA is related to the changes on bone components induced by inflammation that result in compromised biomechanical properties. [Copyright &y& Elsevier]

Biologic therapy has been successfully adopted for the treatment of patients with ankylosing spondylitis (AS). This analysis indicates that secukinumab is the most cost-effective treatment option for biologic-experienced AS patients in Portugal. [Extracted from the article]

Biologic therapy has been successfully adopted for the treatment of patients with ankylosing spondylitis (AS). This analysis indicates that secukinumab is the most cost-effective treatment option for biologic-naive AS patients in Portugal. [Extracted from the article]