Juvenile idiopathic arthritis (JIA) is the most common paediatric rheumatological disorder and is classified by subtype according to International League of Associations for Rheumatology criteria. Depending on the number of joints affected, presence of extra-articular manifestations, systemic symptoms, serology and genetic factors, JIA is divided into oligoarticular, polyarticular, systemic, psoriatic, enthesitis-related and undifferentiated arthritis. This review provides an overview of advances in understanding of JIA pathogenesis focusing on aetiology, histopathology, immunological changes associated with disease activity, and best treatment options. Greater understanding of JIA as a collective of complex inflammatory diseases is discussed within the context of therapeutic interventions, including traditional non-biologic and up-to-date biologic disease-modifying anti-rheumatic drugs. Whilst the advent of advanced therapeutics has improved clinical outcomes, a considerable number of patients remain unresponsive to treatment, emphasising the need for further understanding of disease progression and remission to support stratification of patients to treatment pathways.
BackgroundOsteoarthritis (OA) is the most common chronic progressive musculoskeletal system disease affecting more than 500 million people globally, which represents the formidable public health challenge. Currently osteoarthritis treatment includes acetaminophen, NSAIDs and/or opioids, intra-articular corticosteroid injections. Some guidelines also recommended chondroitin and glucosamine sulfate, suggested that they may be effective and reduce functional impairment. However, despite of the huge amount of data on the problem of OA, there is still no effective treatment that slows down the progression of the disease. Recently appeared monoclonal antibodies against nerve growth factor (NGF) as well as fibroblast growth factor (FGF)-18 may be the promising tool for clinical improvement of OAObjectivesTo evaluate the safety and efficacy of anti-NGF and FGF-18 on patients with osteoarthritis by a systematic review.MethodsIn the current study the search process was conducted in PubMed using the following strategy: “FGF-18” or “anti-NGF” and “OA”, “monoclonal antibody” + “osteoarthritis”. All articles published in the format of Case Reports, Clinical Study, Clinical Trial Protocol, Clinical Trial, Multicenter Study were reviewed. Clinical outcomes were assessed using clinical scores, included the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Pain and Physical Function score, Patient’s Global Assessment of OA (PGA-OA), adverse events (AEs); cartilage repair and total femorotibial joint cartilage thickness were assessed using magnetic resonance imaging.ResultsBased on our search 23 publication were included in the study after omitting repetitions. Among 23 studies, 16 used anti-NGF monoclonal antibodies (Tanezumab, Fasinumab, Fulranumab), and 7 used recombinant human FGF-18 (Sprifermin). The total of 6679 patients were analysed in these articles.In the pooled analysis NGF inhibitors demonstrated statistically significant improvements compared with placebo in WOMAC Pain and Physical Function score (all studies revealed significantly better clinical outcomes in the anti-NGF group). After treatment with FGF-18 (Sprifermin) there was also improvement in WOMAC scores though not statistically significant. However, FGF-18 therapy was associated with the reductions in loss of total and lateral femorotibial cartilage thickness. Moreover, it does not only significantly reduce cartilage loss but also increase cartilage thickness. In terms of cartilage repair, 5 of 7 studies reported improvement in total femorotibial joint cartilage thickness.The AEs of FGF-18 or anti-NGF therapies were not serious, however they may affect the compliance and satisfaction of patients and clinicians. The proportion of patients with adverse events in anti-NGF treatment group was higher than that in FGF-18. The following conditions were reported in anti-NGF: abnormal peripheral sensation such as hypoesthesia (7.43%), paraesthesia (9.15%), hyperesthesia (0.36%), peripheral neuropathy and sensory disturbance (0.35%); arthralgia (15%), back pain (15.06%), pain in extremity (10%), headache (9.11%), upper respiratory tract infection (10.65%), diarrhoea (11.95%), sinusitis or nasopharyngitis (10.13%). The difference in AEs between sprifermin and placebo groups was found insignificant, most frequently reported event was arthralgia.ConclusionIn recent years significant progress has been achieved in search for pathogenetic therapy of OA. Based on the results of current research findings, NGF inhibitors relieved pain and enhance joint function and may be considered as the most effective for functional improvement. FGF-18 decrease the cartilage loss and may improve cartilage thickness. However, further clinical longitudinal studies characterised the risk-benefit are needed to establish their safety and efficacy.Disclosure of InterestsNone declared
Introduction. Fetal cell transplantation is a promising biomedical approach for disease treatment; however, the use of fetal cell therapy is still experimental. This research was deemed a necessity to provide evidence-based research for the application of cell transplantation as a treatment method. The aim of this study was to evaluate the effect of fetal nerve cell transplantation in rat survivors (and non-survivors) after clinical death by mechanical asphyxia.Methods. 68 white laboratory rats were divided into two groups of identical age and sex: a control group of 12-month adult male rats (n = 26) and an experimental group (n = 42). Rats were fixed under ether anesthesia. We then blocked the oral and nasal regions with cotton wool soaked in saline solution. A four-minute clinical death though acute mechanical asphyxia was simulated by applying the method of N. Shim. After the 4-minute clinical death, we resuscitated the rats using external cardiac massage and artifical respiration. Suspension of the fetal nerve cells was injected intraperitoneally at 1mm3 per 25g at the time of cardiac activity restoration. Lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) levels were examined in the homogenate cerebral cortex of reanimated animals. We recorded the survival rate during the post-resuscitation period and analyzed the integrative brain functions using anxiety-phobic status and latent inhibition.Results. After fetal nerve cell transplantation, the enzymatic reactions in the experimental group became normal with a significant decrease in LDH and an increase in CPK levels compared to the control group. In the control group, 10 rats died and 16 lived (62% survival rate), while 7 rats died and 35 lived (83% survival rate) in the experimental group during the first 7 days. Rats that did not receive the treatment tended to die sooner than those in the experimental group. As a result of transplantation, the anxiety level in the experimental group was less than in the control group. Moreover, cell therapy improved the reflexes in the experimental animals. Conclusions. The study revealed the positive neuroprotective effect of the fetal nerve cells on the recovery in the early post-resuscitation period. This was confirmed by the normalization of enzymatic reactions, improvement reflective activity, and increase in the survival rate of the resuscitated animals in the group treated with fetal nerve cell transplantation. These findings warrant future research on the mechanisms associated with reflex improvement.
Background:Juvenile idiopathic arthritis (JIA) is a well-known chronic rheumatic disease of childhood characterised by progressive joint destruction and severe systemic complications.Immune cells are known to trigger the pathophysiological cascade in JIA, but there is little information regarding the contribution made by Mesenchymal stem cells (MSCs). These cells are able to modulate the immune response and decrease the level of pro-inflammatory cytokines. With addition of regenerative property it makes MSCs potential candidates for clinical application as immunosuppressants in treatment of autoimmune diseases.Objectives:To investigate MSCs proliferation, viability and immunomodulatory function in JIA and healthy children.Methods:MSCs were separated from peripheral blood (PB) and synovial fluid (SF) of JIA patients and healthy controls. Cell proliferation rate was counted by Population doublings per day (PDD) during 9 days, in the last of which alamarBlue™ assays were performed to assess cell viability. Due to measure senescence MSCs were stained with SA-β-galactosidase. Immunofluorescence was used to examine the expression of p16, p21, p53. Oxidative stress was measured with DCFH-DA. Cell cycle analysis was evaluated with Propidium Iodide and analysed by Accuri® C6 Flow Cytometer.Commercially-available bone marrow mesenchymal stem cells (BM-MSCs) were treated with graded concentrations of pro-inflammatory cytokines (0.1-100 ng/ml) with following examination of cell viability. Mixed lymphocyte reactions (MLR) were performed to measure MSC immunomodulatory abilityin vitro.Results:The growth kinetics of JIA-MSCs were different from healthy controls. JIA-MSCs divided slowly and appeared disorganised with large cytoplasm and loads of outgrowth. They demonstrated a decrease in cell proliferation (negative PDD) and metabolic activity. Difference in growth kinetics and metabolic activity were found inside the JIA PB group with some evidence of response following biological treatment. Thus, PB-MSCs from patients treated with TNFi and anti-IL6 medications had notably higher cell proliferation and metabolic activity against JIA patients received other therapy. Considering this difference, it was hypothesised that cytokines obtained in a high amount in PB and SF of JIA patients may influence MSCs viability. To prove this BM-MSCs were treated with cytokines and demonstrated a dose-dependent decrease in metabolic activity significantly after TNFα and IL1, no significantly after treatment with IL6. Both BM-MSCs treated with cytokines and JIA-MSCs displayed high level of reactive oxygen species.Cell cycle analysis revealed that JIA-MSCs were arrested in G0/G1 phase with low number of mitotic cells. In addition, the number of senescence-associated SA-β-gal-positive cells was notably higher in JIA-MSCs. Furthermore, JIA-MSCs expressed high level of immunofluorescence for p16, p21 and p53 which played an important role in regulating the senescence progress of MSCs.Results of MLR showed the ability of BM-MSCs to decrease the percentage of activated T-helpers, T-suppressors, B-cells and natural killers proliferation, while JIA-MSCs lost this property.Conclusion:Taken together current research has demonstrated that under the influence of proinflammatory cytokines JIA-MSCs suffered from oxidative stress and disruption of metabolic activity acquire senescent morphology, shorten of telomere length, arrest in G0 phase of cell cycle and finally loss of immune regulation. We are continuing our research to determine the mechanisms that are responsible for the impaired phenotype with the aim of identifying new therapeutic strategies for the treatment of JIA.Disclosure of Interests: :None declared
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