Stem Cell-Based Therapies for Osteoarthritis: From Pre-Clinical to Clinical Applications

Although many surgical and pharmaceutical interventions are currently available for treating osteoarthritis (OA), restoration of normal cartilage function remains inefficient. In fact, because of the absence of vasculature within the articular cartilage (AC), the self-potential for regeneration is very poor. Recently, researchers and clinicians have been focusing on alternative methods for cartilage preservation and repair. It has been shown that AC contains a population of stem cells or progenitor cells, similar to those found in many other adult tissues that are thought to be involved in the maintenance of tissue homeostasis. In the present chapter, we review the current status of stem cells potential in the treatment of early OA and discuss the possible origin of these cells and the role they might have in cartilage repair. We also review the recent progress in the field of chondroprogenitors in cartilage

Image processing for porous media characterization

International audienceIn digital image processing, skeletonization is a valuable technique for the characterization of complex 3D porous media, such as bone, stone and soils. 3D thinning algorithms are usually used to extract one-voxel wide skeleton from 3D porous objects while preserving the topological information. Models based on simplified skeletons have been shown to be efficient in retrieving morphological information from large scale disordered objects at a local level. In this paper, we present a series of 3D skeleton-based image processing techniques for evaluating the micro-architecture of large scale disordered porous media. The proposed hybrid skeleton method combines curve and surface thinning methods with the help of an enhanced shape classification algorithm. Results on two different porous objects demonstrate the ability of the hybrid skeleton method to provide significant topological and morphological information

Long-Term Safety and Tolerability of Apremilast Versus Placebo in Psoriatic Arthritis: A Pooled Safety Analysis of Three Phase III, Randomized, Controlled Trials.

OBJECTIVE: Psoriatic arthritis (PsA) requires long-term treatment, yet safety concerns and monitoring requirements make maintenance a challenge. This analysis of pooled Psoriatic Arthritis Long-term Assessment of Clinical Efficacy (PALACE) 1, 2, and 3 data describes 3-year apremilast safety and tolerability in PsA. METHODS: Patients with active PsA were randomized (1:1:1) to placebo, apremilast 30 mg twice daily, or apremilast 20 mg twice daily. Placebo patients were re-randomized to apremilast 30 mg twice daily or 20 mg twice daily at week 16 (early escape) or 24. Double-blind treatment continued to week 52; patients could continue apremilast during an open-label, long-term treatment phase. RESULTS: In total, 1493 patients received at least one dose of study medication and were included in the safety population (placebo: n = 495; apremilast 30 mg: n = 497; apremilast 20 mg: n = 501). Among patients receiving apremilast, 53.2% (767/1441) completed 3 years of treatment. Greater rates of adverse events (AEs) were reported with apremilast (61.1%; exposure-adjusted incidence rate [EAIR]/100 patient-years, 265.1) versus placebo (47.5%; EAIR/100 patient-years, 200.7) in the placebo-controlled period. During weeks 0 to ≤52, the most common AEs occurring in apremilast-exposed patients were diarrhea (13.9%; EAIR/100 patient-years, 18.6), nausea (12.3%; EAIR/100 patient-years, 16.0), headache (9.4%; EAIR/100 patient-years, 12.1), upper respiratory tract infection (9.1%; EAIR/100 patient-years, 11.5), and nasopharyngitis (6.2%; EAIR/100 patient-years, 7.7). Most AEs were mild/moderate with apremilast exposure ≤156 weeks. Rates of depression remained low (EAIR/100 patient-years, 1.8). Major adverse cardiac events (EAIR/100 patient-years, 0.5), malignancies (EAIR/100 patient-years, 0.9), and serious opportunistic infections (EAIR/100 patient-years, 0.0) were infrequent over the 3-year exposure period. Discontinuation rates due to AEs were low ( CONCLUSION: Apremilast demonstrated a favorable safety profile and was well tolerated up to 156 weeks

Interim 2-year analysis from SERENA: A real-world study in patients with psoriatic arthritis or ankylosing spondylitis treated with secukinumab

Introduction: Sustained improvement of high degree in clinical outcomes have been demonstrated in phase 3 trials with secukinumab in both psoriatic arthritis (PsA) and ankylosing spondylitis (AS). The objective of the SERENA study was to evaluate the effectiveness, retention rates, and safety of secukinumab in patients with PsA and AS. Methods: SERENA is an ongoing, longitudinal, real-world observational study involving patients with moderate-to-severe psoriasis, PsA, or AS. Patients had received at least 16 weeks of secukinumab treatment before recruitment to the study. Retention rate was defined as percentage of patients who continued secukinumab treatment over the course of study. Effectiveness of secukinumab in AS and PsA cohorts was assessed using descriptive statistics. Results: The current interim analysis included 1004 patients with PsA or AS. Overall secukinumab retention rates at 2 years after enrolment were 74.9 and 78.9% in patients with PsA and AS, respectively. At baseline and at 2 years, swollen joint count [3.3 (5.8) vs. 2.9 (5.8)], tender joint count [6.3 (9.4) vs. 5.6 (7.2)] in patients with PsA and BASDAI scores [3.2 (2.3) vs. 2.9 (2.3)] in patients with AS, suggest sustained effectiveness for patients remaining on secukinumab for at least 2 years after enrolment. A total of 73 patients had treatment interruption; 78% of these patients reinitiated secukinumab without a loading dose. No new or unexpected safety signals were reported. Conclusions: After more than 2 years since initiation, secukinumab demonstrated high retention rates and favorable safety profile as well as sustained effectiveness in patients who continued secukinumab treatment

Secukinumab use in patients with moderate to severe psoriasis, psoriatic arthritis and ankylosing spondylitis in real-world setting in Europe: Baseline data from SERENA study

INTRODUCTION: Secukinumab, a fully human monoclonal antibody that directly inhibits interleukin-17A, has demonstrated robust efficacy in the treatment of moderate to severe psoriasis (PsO), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with a rapid onset of action, sustained long-term clinical responses and a consistently favourable safety profile across phase 3 trials. Here, we report the clinical data at enrolment from SERENA, designed to investigate the real-world use of secukinumab across all three indications. METHODS: SERENA is an ongoing, longitudinal, observational study conducted at 438 sites across Europe in patients with moderate to severe plaque PsO, active PsA or active AS. Patients should have received at least 16 weeks of secukinumab treatment before enrolment in the study. RESULTS: Overall 2800 patients were included in the safety set; patients with PsA (N = 541) were older than patients with PsO (N = 1799) and patients with AS (N = 460); patients with PsO had a higher mean body weight than patients with PsA and patients with AS; and patients with PsO and patients with AS were predominantly male. Time since diagnosis was longer in patients with PsO compared with patients with PsA and patients with AS, and about 40% of patients were either current or former smokers. The proportion of obese patients (body mass index ≥ 30 kg/m2) was similar across indications. Patients were treated with secukinumab for a mean duration of 1 year prior to enrolment (range 0.89-1.04). The percentages of patients with prior biologics exposure were 31.5% PsO, 59.7% PsA and 55% AS. The percentages of patients prescribed secukinumab monotherapy were 75% (n = 1349) in PsO, 48.2% (n = 261) in PsA and 48.9% (n = 225) in AS groups. CONCLUSION: Baseline demographics of the study population are consistent with existing literature. This large observational study across all secukinumab indications will provide valuable information on the long-term effectiveness and safety of secukinumab in the real-world setting

Treatment of psoriatic arthritis in a phase 3 randomised, placebo-controlled trial with apremilast, an oral phosphodiesterase 4 inhibitor

Objectives: Apremilast, an oral phosphodiesterase 4 inhibitor, regulates inflammatory mediators. Psoriatic Arthritis Long-term Assessment of Clinical Efficacy 1 (PALACE 1) compared apremilast with placebo in patients with active psoriatic arthritis despite prior traditional disease-modifying antirheumatic drug (DMARD) and/or biologic therapy. Methods: In the 24-week, placebo-controlled phase of PALACE 1, patients (N=504) were randomised (1:1:1) to placebo, apremilast 20 mg twice a day (BID) or apremilast 30 mg BID. At week 16, patients without ≥20% reduction in swollen and tender joint counts were required to be re-randomised equally to either apremilast dose if initially randomised to placebo or remained on their initial apremilast dose. Patients on background concurrent DMARDs continued stable doses (methotrexate, leflunomide and/or sulfasalazine). Primary outcome was the proportion of patients achieving 20% improvement in modified American College of Rheumatology response criteria (ACR20) at week 16. Results: At week 16, significantly more apremilast 20 mg BID (31%) and 30 mg BID (40%) patients achieved ACR20 versus placebo (19%) (p<0.001). Significant improvements in key secondary measures (physical function, psoriasis) were evident with both apremilast doses versus placebo. Across outcome measures, the 30-mg group generally had higher and more consistent response rates, although statistical comparison was not conducted. The most common adverse events were gastrointestinal and generally occurred early, were self-limiting and infrequently led to discontinuation. No imbalance in major adverse cardiac events, serious or opportunistic infections, malignancies or laboratory abnormalities was observed. Conclusions: Apremilast was effective in the treatment of psoriatic arthritis, improving signs and symptoms and physical function. Apremilast demonstrated an acceptable safety profile and was generally well tolerated. Clinical trial registration number NCT01172938

Efficacy and Safety of Ixekizumab in the Treatment of Radiographic Axial Spondyloarthritis:Sixteen-Week Results From a Phase III Randomized, Double-Blind, Placebo-Controlled Trial in Patients With Prior Inadequate Response to or Intolerance of Tumor Necrosis Factor Inhibitors

Objective: To investigate the efficacy and safety of ixekizumab in patients with active radiographic axial spondyloarthritis (SpA) and prior inadequate response to or intolerance of 1 or 2 tumor necrosis factor inhibitors (TNFi). Methods: In this phase III randomized, double-blind, placebo-controlled trial, adult patients with an inadequate response to or intolerance of 1 or 2 TNFi and an established diagnosis of axial SpA (according to the Assessment of SpondyloArthritis international Society [ASAS] criteria for radiographic axial SpA, with radiographic sacroiliitis defined according to the modified New York criteria and ≥1 feature of SpA) were recruited and randomized 1:1:1 to receive placebo or 80-mg subcutaneous ixekizumab every 2 weeks (IXEQ2W) or 4 weeks (IXEQ4W), with an 80-mg or 160-mg starting dose. The primary end point was 40% improvement in disease activity according to the ASAS criteria (ASAS40) at week 16. Secondary outcomes and safety were also assessed. Results: A total of 316 patients were randomized to receive placebo (n = 104), IXEQ2W (n = 98), or IXEQ4W (n = 114). At week 16, significantly higher proportions of IXEQ2W patients (n = 30 [30.6%]; P = 0.003) or IXEQ4W patients (n = 29 [25.4%]; P = 0.017) had achieved an ASAS40 response versus the placebo group (n = 13 [12.5%]), with statistically significant differences reported as early as week 1 with ixekizumab treatment. Statistically significant improvements in disease activity, function, quality of life, and spinal magnetic resonance imaging–evident inflammation were observed after 16 weeks of ixekizumab treatment versus placebo. Treatment-emergent adverse events (AEs) with ixekizumab treatment were more frequent than with placebo. Serious AEs were similar across treatment arms. One death was reported (IXEQ2W group). Conclusion: Ixekizumab treatment for 16 weeks in patients with active radiographic axial SpA and previous inadequate response to or intolerance of 1 or 2 TNFi yields rapid and significant improvements in the signs and symptoms of radiographic axial SpA versus placebo

Specific and combined effects of zoledronic acid and physical exercice in ovariectomized rats

L’objectif de ce travail était d’examiner chez la rate adulte ovariectomisée les effets osseux et sur le métabolisme lipidique de l’acide zolécronique et de l’exercice physique. Dans une première étude, les effets individuels et combinés de l’acide zolédronique 20 µg/kg une injection unique et de l’exercice physique (course dur tapis roulant pendant 12 semaines) ont été examinés sur la densité osseuse au corps entier et au fémur, l’analyse de la microarchitecture trabéculaires, les propriétés biomécaniques et le remodelage osseux. Les résultats montrent globalement que l’acide zolédronique prévient la dégradation microarchitecturale et l’hyperresorption induite par l’ovariectomie, que l’exercice physique maintient partiellement les propriétés biomécaniques et agit sur le remodelage osseux en augmentant la formation osseuse mais qu’aucun bénéfice additionnel ou synergique n’est trouvé sur le squelette osseux de la combinaison des deux interventions. La deuxième étude s’est intéressée aux effets sur le profil lipidique de l’action spécifique et combinée des deux interventions ci-dessus mentionnées. Si l’acide zolédronique et l’exercice de course sur tapis roulant modifient les taux de cholestérol total et de HDL cholestérol dans le sens d’une amélioration du risque d’athérosclérose, leurs effets associés ne sont pas synergiques et ont eu un effet paradoxal inverse possiblement expliqué par un effet pro-inflammatoire de la combinaison des deux interventions.The aim of this study was to investigate in mature ovariectomized rats the effects on bone tissue and on the lipids metabolism of zoledronic acid and physical exercise. In this first study, the individual and combined effects of zoledronic acid (20 µg/kg a single injection) and physical exercise (treadmill running exercise during twelve week) have been examined on whole body and femur bone mineral density, on trabecular microarchitecture analysis, on bone strength parameters and on bone turnover. Results showned globally that zoledronic acid prevented the trabecular microarchitectural changes and the increase in resorption induced by ovariectomy. Treadmill running exercise particully maintained the bone strength and exerted its action by an increase in bone formation. However we dit not found any additive or synergistic effect of the two interventions combined on the rat skeletal status. The second study aimed to assess the specific and combined effects of zoledronic acid and treadmill running exercise on the lipid profile in this model of ovariectomized mature rats. If both zoledronic acid and treadmill running exercise modified total cholesterol and HDL cholesterol with an improvement of the atherosclerosis risk, their combined effects were not synergistic and furthermore they produced a paradoxical inverse effect possibly explained by a pro-inflammatory effect of the two interventions combined

Prise en charge de l'ostéoporose cortico-induite au CHR d'Orléans

POITIERS-BU Médecine pharmacie (861942103) / SudocSudocFranceF

Osteoporosis assessment using Multilayer Perceptron neural networks

The objective of this paper is to investigate the effectiveness of a Multilayer Perceptron (MLP) to discriminate subjects with and without osteoporosis using a set of five parameters characterizing the quality of the bone structure. These parameters include Age, Bone mineral content (BMC), Bone mineral density (BMD), fractal Hurst exponent (Hmean) and coocurrence texture feature (CoEn). The purpose of the study is to detect the potential usefulness of the combination of different features to increase the classification rate of 2 populations composed of osteporotic patients and control subjects. k-fold Cross Validation (CV) was used in order to assess the accuracy and reliability of the neural network validation. Compared to other methods MLP-based analysis provides an accurate and reliable platform for osteoporosis prediction. Moreover, the results show that the combination of the five features provides better performance in terms of discrimination of the subject