Objective
To assess the efficacy and safety of combination therapy with chondroitin sulfate (CS) and glucosamine sulfate (GS) compared to placebo in patients with symptomatic knee osteoarthritis ...(OA).
Methods
A multicenter, randomized, double‐blind, placebo‐controlled study was performed in 164 patients with Kellgren/Lawrence grade 2 or grade 3 radiographic knee OA and moderate‐to‐severe knee pain (mean ± SD global pain score 62.1 ± 11.3 mm on a 100‐mm visual analog scale VAS). Patients were randomized to receive either combined treatment with CS (1,200 mg) plus GS (1,500 mg) or placebo in a single oral daily dose for 6 months. The mean change from baseline in the VAS global pain score was set as the primary end point. Secondary outcomes included the mean change in the investigator's global assessment of disease activity, total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), pain and function subscale scores on the WOMAC, responder rates based on the Outcome Measures in Rheumatology (OMERACT)–Osteoarthritis Research Society International (OARSI) 2004 response criteria, and rescue medication use. Adverse events were also recorded. A Data and Safety Monitoring Board was instituted to ensure patient safety and data accuracy.
Results
Intriguingly, in the modified intent‐to‐treat (mITT) population, CS/GS combination therapy was inferior to placebo in the reduction of joint pain (mean ± SD change in VAS global pain score over 6 months −11.8 ± 2.4 mm 19% reduction in patients receiving CS plus GS versus −20.5 ± 2.4 mm 33% reduction in patients receiving placebo; peak between‐group difference in global pain score at 6 months 8.7 mm 14.2%, P < 0.03), but no between‐group differences were seen in the per‐protocol completers. Both placebo treatment and CS/GS combination treatment improved to a similar extent the total WOMAC score as well as the pain and function WOMAC subscale scores, both in the mITT population and in the per‐protocol completers. Neither the OMERACT–OARSI responder rate nor the frequency of rescue medication use differed between the treatment groups. Severe adverse events were uncommon and equally distributed.
Conclusion
The results of this trial demonstrate a lack of superiority of CS/GS combination therapy over placebo in terms of reducing joint pain and functional impairment in patients with symptomatic knee OA over 6 months. Further research might fully elucidate the suitability of CS/GS combination therapy in patients with OA.
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Osteoarthritis (OA) is a chronic joint disease characterized by cartilage degradation, osteophyte formation, subchondral bone sclerosis, and synovitis. Systemic factors such as ...obesity and the components of the metabolic syndrome seem to contribute to its progression. Breakdown of cartilage ensues from an altered balance between mechanical overload and its absorption by this tissue. There is in this context a status of persistent local inflammation by means of the chronic activation of innate immunity. A broad variety of danger-associated molecular patterns inside OA joint are able to activate pattern recognition receptors, mainly TLR (toll-like receptor) 2 and 4, which are overexpressed in the OA cartilage. Chronic activation of innate immune responses in chondrocytes results in a robust production of pro-inflammatory cytokines and chemokines, as well as of tissue-destructive enzymes, downstream of NF-κB and MAPK (mitogen activated protein kinase) dependent pathways. Besides, the toxic effects of an excess of glucose and/or fatty acids, which share the same pro-inflammatory intracellular signalling pathways, may add fuel to the fire. Not only high concentrations of glucose can render cells prone to inflammation, but also AGEs (advanced glycation end products) are integrated into the TLR signalling network through their own innate immune receptors. Considering these mechanisms, we argue for the control of both primary inflammation and proteolytic catabolism as a preventive strategy in OA, instead of focusing treatment on the enhancement of anabolic responses. Even though this approach would not return to normal already degraded cartilage, it nonetheless might avoid damage extension to the surrounding tissue.
PurposeThe aim of this study was to describe the cellular infiltrate in aqueous and vitreous samples of patients with uveitis analysed by multiparametric flow cytometry.MethodsThis is a retrospective ...analysis of aqueous and vitreous samples analysed by flow cytometry for diagnostic purposes, in cases of masquerade syndromes and infectious and non-infectious uveitis. Data collected included demographics, anatomical classification of uveitis, phenotypic diagnosis, anterior chamber cells grading, vitreous haze and time of follow-up since presentation to sample obtained.ResultsThirty-one samples (17 aqueous and 14 vitreous fluids) from 31 patients, 18 men, were analysed. The mean age at the time of sample collection was 60.23±17.03 years. The most frequent anatomical classification was panuveitis (14 of 31). T cells accounted for the main cellular component in the majority of the samples (10 of 13 aqueous samples; 7 of 14 in vitreous samples). CD4:CD8 ratios ranged from 0.21 to 16.3 in the case of aqueous samples and from 0.5 to 9.7 in the case of vitreous samples.DiscussionFlow cytometry analysis of aqueous and vitreous samples from patients with uveitis could provide insight into the pathogenesis of human uveitis and help develop accurate animal models which better mimic human disease.
Besides its primary function in locomotion, skeletal muscle (SKM), which represents up to half of human's weight, also plays a fundamental homeostatic role. Through the secretion of soluble peptides, ...or myokines, SKM interacts with major organs involved in metabolic processes. In turn, metabolic cues from these organs are received by muscle cells, which adapt their response accordingly. This is done through an intricate intracellular signaling network characterized by the cross-talking between anabolic and catabolic pathways. A fine regulation of the network is required to protect the organism from an excessive energy expenditure. Systemic inflammation evokes a catabolic reaction in SKM known as sarcopenia. In turn this response comprises several mechanisms, which vary depending on the nature of the insult and its magnitude. In this regard, aging, chronic inflammatory systemic diseases, osteoarthritis and idiopathic inflammatory myopathies can lead to muscle loss. Interestingly, sarcopenia may persist despite remission of chronic inflammation, an issue which warrants further research. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) system stands as a major participant in muscle loss during systemic inflammation, while it is also a well-recognized orchestrator of muscle cell turnover. Herein we summarize current knowledge about models of sarcopenia, their triggers and major mediators and their effect on both protein and cell growth yields. Also, the dual action of the JAK/STAT pathway in muscle mass changes is discussed. We highlight the need to unravel the precise contribution of this system to sarcopenia in order to design targeted therapeutic strategies.
To describe a retrospective review of HIV patients with noninfectious uveitis. Data collected included: demographics, anatomic classification and phenotypic diagnosis of the uveitis, systemic ...immune-mediated disorders (IMD), time from HIV diagnosis to uveitis, CD4 count, viral load, treatment and complications of treatment and time of follow-up.
Twenty patients (18 males) were included. The time lag between HIV diagnosis and the onset of uveitis was 9 ± 8.5 years. Mean CD4 count was 670 ± 294 cells/ml. Viral load was undetectable in 14 out of 18 cases. In 6 patients IMD was diagnosed prior to or concurring with the uveitis diagnosis. The use of immunosuppressive therapies was necessary in 6 patients (including biologics in 4 cases). The mean follow-up was 42.2 months.
noninfectious uveitis could be the first manifestation of IMD in patients with well-controlled HIV infection. Immunosuppression appeared to be a safe therapeutic option in our cohort of patients.
Unexpected Bone Formation Produced by RANKL Blockade Portal-Núñez, Sergio; Mediero, Aranzazu; Esbrit, Pedro ...
Trends in endocrinology and metabolism,
October 2017, 2017-10-00, 20171001, Letnik:
28, Številka:
10
Journal Article
Recenzirano
Denosumab (Dmab) is a humanized monoclonal antibody that blocks RANKL (receptor activator for nuclear factor κB ligand), thereby exerting a potent bone antiresorptive action. Dmab treatment leads to ...a dramatic and sustained increase in bone mass through mechanisms that are currently under debate. It is also a matter of controversy whether this potent action of Dmab could lead to intrabone dystrophic mineralization. Recent research has uncovered a possible anabolic role of Dmab involving RANKL-dependent reverse signaling in osteoblasts, and that bone marrow adipocytes can modulate osteoclastogenesis through the production of RANKL. We comment here on potential pathways which might account for the anabolic action of Dmab. The impact of this proposed mechanism needs to be addressed in further research.
Dmab is a monoclonal antibody raised against RANKL – the principal contributor to osteoclastogenesis – which exhibits a potent antiresorptive action and reduces fracture risk in patients with OP. However, its mechanism of action is not totally understood.
The dramatic and sustained increase in bone density of patients treated with Dmab suggests that unique bone-forming mechanisms could be elicited by the compound.
Owing to its efficient blockade of bone remodeling, Dmab could promote exaggerated secondary mineralization at pre-existing collagen fibers, thus leading to intrabone dystrophic ossification.
Binding of Dmab to RANKL expressed at the osteoblast surface could lead to osteoblast differentiation. Binding could thus alter bone biomechanical properties, inducing a stochastic bone-modeling process. Upon Dmab withdrawal, these sites might undergo rapid remodeling, making them vulnerable. This may explain the increased incidence of fractures following Dmab discontinuation.
Marrow adipocytes regulate osteoclastogenesis through RANKL that is under parathormone control/regulation. Inhibition of this additional source of RANKL by Dmab might contribute to its actions on bone.
Turning resorption blockade into a bone-forming process is an unexpected outcome of Dmab.
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