Response to: 'Correspondence on 'Long-term efficacy and safety of canakinumab in patients with colchicine-resistant familial Mediterranean fever: results from the randomised phase III CLUSTER trial'' by Satis<i>et al</i>

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Efficacy and safety of tocilizumab for polyarticular-course juvenile idiopathic arthritis in the open-label two-year extension of a phase III trial

Objective. To report the 2-year efficacy and safety of tocilizumab (TCZ) in patients with polyarticular-course juvenile idiopathic arthritis (JIA). Methods. Patients ages 2–17 years with active polyarticular-course JIA, in whom treatment with methotrexate was unsuccessful, received 16 weeks of open-label intravenous TCZ in part 1 (once every 4 weeks: 8 mg/kg or 10 mg/kg for body weight [BW] 1 of the remaining JIA CRVs by >30%) at week 16 were randomly assigned (1:1) to receive TCZ or placebo in part 2. Patients remained in part 2 until either week 40 or the occurrence of JIA flare. Upon starting part 3, all patients received open-label TCZ. At week 104 of the study, efficacy was assessed using JIA-ACR50/70/90 response rates (defined as 50%, 70%, or 90% improvement, respectively), achievement of inactive disease, and the Juvenile Arthritis Disease Activity Score in 71 joints (JADAS-71). Safety was assessed in the all-exposure population per 100 patient-years of exposure. Results. Overall, 188 patients entered part 1, 166 patients entered part 2, and 160 patients entered part 3. By week 104, among the 188 patients in the modified intent-to-treat group who received TCZ, JIA-ACR50/70/90 response rates were 80.3%/77.1%/59.6%, respectively, the median JADAS-71 score decreased from 3.6 at week 40 to 0.7 at week 104, 51.1% of patients had achieved inactive disease, and 31 of 66 patients who had been receiving glucocorticoids discontinued them. Adverse event (AE) and serious AE rates were 406.5 per 100 patient-years and 11.1 per 100 patient-years, respectively. The infection rate was 151.4 per 100 patient-years, and the serious infection rate was 5.2 per 100 patient-years. Conclusion. Patients treated with TCZ for polyarticular-course JIA showed high-level disease control for up to 2 years. The TCZ safety profile was consistent with that previously reported

Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome.

BACKGROUND: The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in the setting of primary hemophagocytic lymphohistiocytosis. OBJECTIVE: We sought to investigate the pathogenic role of IFN-γ and the therapeutic efficacy of IFN-γ neutralization in an animal model of MAS. METHODS: We used an MAS model established in mice transgenic for human IL-6 (IL-6TG mice) challenged with LPS (MAS mice). Levels of IFN-γ and IFN-γ-inducible chemokines were evaluated by using real-time PCR in the liver and spleen and by means of ELISA in plasma. IFN-γ neutralization was achieved by using the anti-IFN-γ antibody XMG1.2 in vivo. RESULTS: Mice with MAS showed a significant upregulation of the IFN-γ pathway, as demonstrated by increased mRNA levels of Ifng and higher levels of phospho-signal transducer and activator of transcription 1 in the liver and spleen and increased expression of the IFN-γ-inducible chemokines Cxcl9 and Cxcl10 in the liver and spleen, as well as in plasma. A marked increase in Il12a and Il12b expression was also found in livers and spleens of mice with MAS. In addition, mice with MAS had a significant increase in numbers of liver CD68+ macrophages. Mice with MAS treated with an anti-IFN-γ antibody showed a significant improvement in survival and body weight recovery associated with a significant amelioration of ferritin, fibrinogen, and alanine aminotransferase levels. In mice with MAS, treatment with the anti-IFN-γ antibody significantly decreased circulating levels of CXCL9, CXCL10, and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in serum levels of proinflammatory cytokines and ferritin. CONCLUSION: These results provide evidence for a pathogenic role of IFN-γ in the setting of MAS

Increased levels of interleukin-6 exacerbate the dystrophic phenotype in mdx mice

Duchenne muscular dystrophy (DMD) is characterized by progressive lethal muscle degeneration and chronic inflammatory response. The mdx mouse strain has served as the animal model for human DMD. However, while DMD patients undergo extensive necrosis, the affected muscles of adult mdx mice rapidly regenerates and regains structural and functional integrity. The basis for the mild effects observed in mice compared with the lethal consequences in humans remains unknown. In this study, we provide evidence that interleukin-6 (IL-6) is causally linked to the pathogenesis of muscular dystrophy. We report that forced expression of IL-6, in the adult mdx mice, recapitulates the severe phenotypic characteristics of DMD in humans. Increased levels of IL-6 exacerbate the dystrophic muscle phenotype, sustaining inflammatory response and repeated cycles of muscle degeneration and regeneration, leading to exhaustion of satellite cells. The mdx/IL6 mouse closely approximates the human disease and more faithfully recapitulates the disease progression in humans. This study promises to significantly advance our understanding of the pathogenic mechanisms that lead to DMD

c-Src and IL-6 inhibit osteoblast differentiation and integrate IGFBP5 signalling

Interleukin-6 (IL-6) and c-Src impair osteoblast maturation in vitro and in vivo. Given the similar effects of these factors, they are likely to establish a functional loop to maintain osteoblasts in a less mature status. Here we describe a pathway whereby c-Src stimulates IL-6 expression through the STAT3 factor, which, in response to IL-6 induces insulin-like growth factor 5 (IGFBP5), a c-Src activating factor that amplifies this loop only in immature osteoblasts. In contrast, in mature osteoblasts, IGFBP5 is enhanced by Runx2, but is no longer able to stimulate c-Src activation, as this tyrosine kinase at this stage is downregulated. We find that the IGFBP5 produced by osteoblasts stimulates osteoclastogenesis and bone resorption, acting as an osteoblast-osteoclast coupling factor. Finally, we demonstrate that the integrated actions of c-Src, IL-6 and IGFBP5 also have a role in vivo. We conclude that this pathway is relevant for bone metabolism, both in physiological and in pathological conditions

ProNGF-p75NTR axis plays a proinflammatory role in inflamed joints. A novel pathogenic mechanism in chronic arthritis

To identify the role of mature nerve growth factor (mNGF), its immature form proNGF and their receptors in arthritis inflammatio

Variable Clinical Phenotypes and Relation of Interferon Signature with Disease Activity in ADA2 Deficiency

Objective.An upregulation of type I interferon (IFN) stimulated genes [IFN score (IS)] was described in patients with adenosine deaminase 2 deficiency (DADA2). We describe the clinical course of 5 such patients and the role of IS as a marker of disease activity and severity.Methods.Expression levels of IS were determined by quantitative real-time PCR.Results.Five white patients were identified as carrying CECR1 mutations. The IS before treatment was elevated in 4 out of 5 patients and decreased after treatment.Conclusion.Our data confirm the high variability of DADA2 and suggest type I IS as a biomarker of disease activity