Efficacy and safety of the human anti-IL-1beta monoclonal antibody canakinumab in rheumatoid arthritis: results of a 12-week, phase II, dose-finding study

<p>Abstract</p> <p>Background</p> <p>Canakinumab is a fully human anti-interleukin IL-1beta monoclonal antibody, being investigated for the treatment of rheumatoid arthritis (RA). This multicenter, phase II, randomized, double-blind, placebo-controlled, parallel-group, dose-finding study investigated the efficacy and safety of canakinumab in patients with active RA despite ongoing therapy at stable doses of methotrexate.</p> <p>Methods</p> <p>Patients were randomized to receive one of four regimens, in addition to methotrexate, for 12 weeks: canakinumab 150 mg subcutaneously (SC) every 4 weeks (q4wk), canakinumab 300 mg SC (2 injections of 150 mg SC) every 2 weeks, a 600 mg intravenous loading dose of canakinumab followed by 300 mg SC every 2 weeks', or placebo SC every 2 weeks.</p> <p>Results</p> <p>Among 274 patients with evaluable efficacy data, the percentage of responders according to American College of Rheumatology 50 criteria (the primary endpoint, based on a 28-joint count) was significantly higher with canakinumab 150 mg SC q4wk than with placebo (26.5% vs. 11.4%, respectively; p = 0.028). Compared to placebo, this dosage of canakinumab was also associated with significantly more favorable responses at week 12 with respect to secondary endpoints including the Disease Activity Score 28, scores on the Health Assessment Questionnaire and Functional Assessment of Chronic Illness Therapy-Fatigue, swollen 28-joint count, and patient's and physician's global assessments of disease activity. No safety concerns were raised with canakinumab therapy, particularly with regard to infections. Few injection-site reactions occurred.</p> <p>Conclusion</p> <p>The addition of canakinumab 150 mg SC q4wk improves therapeutic responses among patients who have active RA despite stable treatment with methotrexate.</p> <p>Trial Registration</p> <p>(ClinicalTrials.gov identifier: <a href="http://www.clinicaltrials.gov/ct2/show/NCT00784628">NCT00784628</a>)</p

R-h-erythropoietin counteracts the inhibition of in vitro erythropoiesis by tumour necrosis factor alpha in patients with rheumatoid arthritis

Anaemia of chronic disease (ACD) is a common extra-articular manifestation of rheumatoid arthritis (RA). Tumour necrosis factor alpha (TNFα) plays an important role in the development of ACD. The objective of the present study was to assess inhibition of in vitro colony-forming unit erythrocyte (CFUe) and blast-forming unit erythrocyte (BFUe) growth by TNFα and to examine whether this suppression could be counteracted by adding increasing concentrations of recombinant human erythropoietin (EPO) (r-h-EPO) to bone marrow cultures of RA patients with ACD and without anaemia (controls). Bone marrow cells of RA patients with ACD and control patients were cultured. The cultures were incubated with increasing concentrations of r-h-EPO (0.25; 0.5; 1; 2 U/ml), each in combination with increasing quantities of TFNα (0; 50; 100; 200; 400 U/ml). CFUe and BFUe were assessed after 7 and 14 days, respectively. Dose-dependent inhibition of BFUe and CFUc by increasing concentrations of TNFα was observed in ACD and controls. Regarding CFUe (ACD patients) incubated with 0.25 U/ml EPO, 50 U/ml TNFα caused 28% suppression compared to cultures without TNFα. Increasing the concentration of r-h-EPO from 0.25 U/ml to 2 U/ml completely restored the number of CFUe. A similar pattern was observed in BFUe growth in both groups. These data demonstrated the suppressive effects of TNFα on erythropoiesis in vitro and that the suppresed erythropoiesis could be partly corrected by the addition of excess r-h-EPO to the cultures. No significant differences were observed between ACD and control RA patients. This in vitro model may help explain the clinical response to r-h-EPO therapy as documented in RA patients with ACD

Mesenchymal stem cells rescue cardiomyoblasts from cell death in an in vitro ischemia model via direct cell-to-cell connections

<p>Abstract</p> <p>Background</p> <p>Bone marrow derived mesenchymal stem cells (MSCs) are promising candidates for cell based therapies in myocardial infarction. However, the exact underlying cellular mechanisms are still not fully understood. Our aim was to explore the possible role of direct cell-to-cell interaction between ischemic H9c2 cardiomyoblasts and normal MSCs. Using an in vitro ischemia model of 150 minutes of oxygen glucose deprivation we investigated cell viability and cell interactions with confocal microscopy and flow cytometry.</p> <p>Results</p> <p>Our model revealed that adding normal MSCs to the ischemic cell population significantly decreased the ratio of dead H9c2 cells (H9c2 only: 0.85 ± 0.086 vs. H9c2+MSCs: 0.16 ± 0.035). This effect was dependent on direct cell-to-cell contact since co-cultivation with MSCs cultured in cell inserts did not exert the same beneficial effect (ratio of dead H9c2 cells: 0.90 ± 0.055). Confocal microscopy revealed that cardiomyoblasts and MSCs frequently formed 200-500 nm wide intercellular connections and cell fusion rarely occurred between these cells.</p> <p>Conclusion</p> <p>Based on these results we hypothesize that mesenchymal stem cells may reduce the number of dead cardiomyoblasts after ischemic damage via direct cell-to-cell interactions and intercellular tubular connections may play an important role in these processes.</p

Anti-Arthritic Effects of Magnolol in Human Interleukin 1β-Stimulated Fibroblast-Like Synoviocytes and in a Rat Arthritis Model

Fibroblast-like synoviocytes (FLS) play an important role in the pathologic processes of destructive arthritis by producing a number of catabolic cytokines and metalloproteinases (MMPs). The expression of these mediators is controlled at the transcriptional level. The purposes of this study were to evaluate the anti-arthritic effects of magnolol (5,5′-Diallyl-biphenyl-2,2′-diol), the major bioactive component of the bark of Magnolia officinalis, by examining its inhibitory effects on inflammatory mediator secretion and the NF-κB and AP-1 activation pathways and to investigate its therapeutic effects on the development of arthritis in a rat model. The in vitro anti-arthritic activity of magnolol was tested on interleukin (IL)-1β-stimulated FLS by measuring levels of IL-6, cyclooxygenase-2, prostaglandin E2, and matrix metalloproteinases (MMPs) by ELISA and RT-PCR. Further studies on how magnolol inhibits IL-1β-stimulated cytokine expression were performed using Western blots, reporter gene assay, electrophoretic mobility shift assay, and confocal microscope analysis. The in vivo anti-arthritic effects of magnolol were evaluated in a Mycobacterium butyricum-induced arthritis model in rats. Magnolol markedly inhibited IL-1β (10 ng/mL)-induced cytokine expression in a concentration-dependent manner (2.5–25 µg/mL). In clarifying the mechanisms involved, magnolol was found to inhibit the IL-1β-induced activation of the IKK/IκB/NF-κB and MAPKs pathways by suppressing the nuclear translocation and DNA binding activity of both transcription factors. In the animal model, magnolol (100 mg/kg) significantly inhibited paw swelling and reduced serum cytokine levels. Our results demonstrate that magnolol inhibits the development of arthritis, suggesting that it might provide a new therapeutic approach to inflammatory arthritis diseases

The Early Postnatal Nonhuman Primate Neocortex Contains Self-Renewing Multipotent Neural Progenitor Cells

The postnatal neocortex has traditionally been considered a non-neurogenic region, under non-pathological conditions. A few studies suggest, however, that a small subpopulation of neural cells born during postnatal life can differentiate into neurons that take up residence within the neocortex, implying that postnatal neurogenesis could occur in this region, albeit at a low level. Evidence to support this hypothesis remains controversial while the source of putative neural progenitors responsible for generating new neurons in the postnatal neocortex is unknown. Here we report the identification of self-renewing multipotent neural progenitor cells (NPCs) derived from the postnatal day 14 (PD14) marmoset monkey primary visual cortex (V1, striate cortex). While neuronal maturation within V1 is well advanced by PD14, we observed cells throughout this region that co-expressed Sox2 and Ki67, defining a population of resident proliferating progenitor cells. When cultured at low density in the presence of epidermal growth factor (EGF) and/or fibroblast growth factor 2 (FGF-2), dissociated V1 tissue gave rise to multipotent neurospheres that exhibited the ability to differentiate into neurons, oligodendrocytes and astrocytes. While the capacity to generate neurones and oligodendrocytes was not observed beyond the third passage, astrocyte-restricted neurospheres could be maintained for up to 6 passages. This study provides the first direct evidence for the existence of multipotent NPCs within the postnatal neocortex of the nonhuman primate. The potential contribution of neocortical NPCs to neural repair following injury raises exciting new possibilities for the field of regenerative medicine