Objective: To update and expand upon prior Osteoarthritis Research Society International (OARSI) guidelines by developing patient-focused treatment recommendations for individuals with Knee, Hip, and Polyarticular osteoarthritis (OA) that are derived from expert consensus and based on objective review of high-quality meta-analytic data. Methods: We sought evidence for 60 unique interventions. A systematic search of all relevant databases was conducted from inception through July 2018. After abstract and full-text screening by two independent reviewers, eligible studies were matched to PICO questions. Data were extracted and metaanalyses were conducted using RevMan software. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Evidence Profiles were compiled using the GRADEpro web application. Voting for Core Treatments took place first. Four subsequent voting sessions took place via anonymous online survey, during which Panel members were tasked with voting to produce recommendations for all joint locations and comorbidity classes. We designated non-Core treatments to Level 1A, 1B, 2, 3, 4A, 4B, or 5, based on the percentage of votes in favor, in addition to the strength of the recommendation.

Chondrocytes in OA cartilage demonstrated morphologic changes that are characteristic features of apoptosis. This mechanism of cell death plays an important role in the pathogenesis of OA and could be targeted for new treatment strategies.

Osteoarthritis (OA) is the most common chronic joint disease in the elderly population, causing significant pain and disability. Because the cardinal feature of OA is a progressive loss of articular cartilage, a great portion of the research endeavour into the pathogenesis of OA has been focused on the regulation of matrix synthesis and degradation. The phenotypic stability and survival of the chondrocytes are essential for the maintenance of a proper cartilage matrix. This has lead to the long-standing assumption that cell death is a central feature in OA cartilage degeneration. The important role of apoptosis in OA has been demonstrated in in vitro and in vivo models. However, it should be noted that the relative contribution of apoptotic cell death in the pathogenesis of OA is still difficult to assess because of the chronic nature of the disease process. Therefore, the apoptosis of chondrocytes seems to be a potential target for therapeutic interventions in OA. The death receptor, mitochondrial and endoplasmic reticulum pathways are the major cellular pathways of apoptosis. Of all these elements involved in the apoptosis of chondrocytes, caspase inhibition has been studied with the most detail. Other molecules with the capacity to modulate mitochondria function, phosphatase (PP-1A/B) activity and pro-apoptosis stimuli (NO, prostaglandins, cytokines, ROS) could be excellent targets to block apoptosis of chondrocytes. Finally, the regulation of the natural inhibitors of apoptosis (c-FLIP, BAR, ARC and HC-gp39) could complement the other strategies to reduce cartilage degradation.

NaSH and GYY4137 show anti-inflammatory and anti-catabolic properties when added to IL1β activated osteoarthritic CHs. Supplementation with exogenous H2S sources can regulate the expression of relevant genes in OA pathogenesis and progression, counteracting IL1β pro-inflammatory signals that lead to cartilage destruction in part by reducing NFκB activation.

These results confirm that TNF-alpha and IL-1beta regulate apoptosis differently in this human chondrocyte model and that the differing effects of these cytokines are PGE2-independent. Indomethacin potentiates the effect of IL-1 on cell death and this may explain the reported effect of indomethacin on the progression of joint destruction.

ILA, a gene induced by lymphocyte activation, is a member of the human nerve growth factor tumor necrosis factor receptor family and the human homologue of murine 4–1BB. The present study analyzed the role of ILA in the regulation of human peripheral blood T-lymphocyte function. Antibodies raised against different fusion proteins recognized ILA on activated lymphocytes. These antibodies significantly increased anti- CD3--induced T-lymphocyte proliferation. When anti-CD3--stimulated cells were incubated on ILA-expressing CHO cells, proliferation was inhibited. CHO cells transfected with a control construct and not expressing ILA did not reduce T-cell proliferation. A purified fusion protein containing the extracellular domain of ILA and the constant domain of human IgG (ILA-IgG) also inhibited lymphocyte proliferation. Results obtained by 3H-thymidine incorporation were confirmed by cell cycle analysis that showed a decrease in the number of lymphocytes in S phase. Lymphocyte morphology in cultures with ILA-expressing CHO cells was suggestive of apoptosis. Flow cytometry on propidium iodide-stained cells showed a time-dependent increase in the number of hypodiploid apoptotic cells when lymphocytes were cultured on ILA-expressing CHO cells. Internucleosomal DNA cleavage was seen in these cultures, but not in the presence of ILA-negative CHO cells. Studies on the mechanism by which ILA regulates T-cell function showed that ILA-IgG inhibited anti-CD3-induced T-cell proliferation when presented in immobilized but not in soluble form. These results suggest that ILA may act by cross- linking its ligand and thereby inhibit T-cell proliferation.

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Aim: To determine whether hyaluronan (HA) delays and/or reduces the knee replacement surgery (KRS) in patients with osteoarthritis (OA). Material and Methods: A prospective, single-center, double-blind, randomized, placebo-controlled, pilot clinical trial with two treatment groups [HA (Adant ®) treatment group and placebo treatment group] was conducted. The intra-articular treatments (HA or placebo) consisted of two cycles of five weekly injections with a 24-week interval between each cycle. The efficacy variable was determined by change in pain, articular mobility and functional capacity as measured by WOMAC. All efficacy variables have been analyzed for the intention-to-treat population. Results: 52 patients (10M/42F) were enrolled in the study (HA group: 26; placebo group: 26). Time until KRS in the HA group subjects (368.8 days) was longer than that in the placebo group (253.9 days). The change in the WOMAC stiffness subscale at 24 weeks, compared to the baseline score, was-22.4 in the HA group and-2.2 in the placebo group (p = 0.081). The change in the physical function WOMAC subscale, compared to the baseline score, was statistically significant at 24 weeks (HA group =-24.7 placebo group =-4.4 p = 0.019). Similar results were found in the change in the total WOMAC index score (HA group =-23.9 vs placebo group =-5.6 p = 0.044). Conclusion: The use of intra-articular HA to treat OA patients on the waiting list for KRS does not delay surgery. However, it could improve the physical condition of patients while they are waiting by surgery.