Concept: Interleukin-6 receptor
A high circulating concentration of interleukin 6 is associated with increased risk of coronary heart disease. Blockade of the interleukin-6 receptor (IL6R) with a monoclonal antibody (tocilizumab) licensed for treatment of rheumatoid arthritis reduces systemic and articular inflammation. However, whether IL6R blockade also reduces risk of coronary heart disease is unknown.
Persistent inflammation has been proposed to contribute to various stages in the pathogenesis of cardiovascular disease. Interleukin-6 receptor (IL6R) signalling propagates downstream inflammation cascades. To assess whether this pathway is causally relevant to coronary heart disease, we studied a functional genetic variant known to affect IL6R signalling.
Evidence from preclinical, epidemiological, and human studies indicates that inflammation, and in particular elevated IL-6 activity, may be related to clinical manifestations and pathophysiology of schizophrenia. Furthermore, studies in preclinical models suggest that decreasing IL-6 activity may mitigate or reverse some of these deficits. The purpose of this trial was to test whether an IL-6 receptor antibody, tocilizumab, would improve residual positive and negative symptoms and cognitive deficits in schizophrenia. We randomized 36 clinically stable, moderately symptomatic (ie, PANSS>60) individuals with schizophrenia to 3 monthly infusions of 8 mg/kg tocilizumab or placebo (normal saline). The primary outcome was effect at week 12 on the PANSS Total Score. Effects on the MATRICS, other PANSS subscales, CGI, and GAF were secondary outcomes. There were no observed treatment effects on any behavioral outcome measure. Baseline C-reactive protein (CRP) or cytokine levels did not predict treatment outcome, nor were there correlations between changes in these inflammatory markers and the measured outcomes. As expected, IL-6 and IL-8 increased, while CRP decreased, in the tocilizumab group compared to the placebo group. This study did not reveal any evidence that an IL-6 receptor antibody affects behavioral outcomes in schizophrenia. One potential explanation is the lack of capacity of this agent to penetrate the central nervous system. Additional trials of medications aimed at targeting cytokine overactivity that act directly on brain function and/or treatment in early stage psychosis populations are needed.Neuropsychopharmacology accepted article preview online, 01 November 2017. doi:10.1038/npp.2017.258.
& Aims: Innate lymphoid cells (ILC) are a heterogeneous group of mucosal inflammatory cells that participate in chronic intestinal inflammation. We investigated the role of interleukin 6 (IL6) in inducing activation of ILCs in mice and humans with chronic intestinal inflammation.
For clinical trials of therapeutic monoclonal antibodies (mAbs) to be successful, their efficacy needs to be adequately evaluated in preclinical experiments. However, in many cases it is difficult to evaluate the candidate mAbs using animal disease models because of lower cross-reactivity to the orthologous target molecules. In this study we have established a novel humanized Castleman’s disease mouse model, in which the endogenous interleukin-6 receptor gene is successfully replaced by human IL6R, and human IL6 is overexpressed. We have also demonstrated the therapeutic effects of an antibody that neutralizes human IL6R, tocilizumab, on the symptoms in this mouse model. Plasma levels of human soluble IL6R and human IL6 were elevated after 4-week treatment of tocilizumab in this mouse model similarly to the result previously reported in patients treated with tocilizumab. Our mouse model provides us with a novel means of evaluating the in vivo efficacy of human IL6R-specific therapeutic agents.
BACKGROUND: Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. METHODS: Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement. RESULTS: The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise. CONCLUSIONS: The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition.
Interleukin-6 (IL-6) is implicated in the pathogenesis of both systemic juvenile idiopathic arthritis (SJIA) and syndrome of inappropriate secretion of antidiuretic hormone (SIADH), but the 2 have not been previously described as occurring together. We report a case of a 6-year-old girl with symptoms of arthralgia, daily fevers, evanescent rash, lymphadenopathy, and laboratory evaluation showing elevated inflammatory markers, consistent with SJIA. At presentation, the patient had hyponatremia with a sodium level of 128 mEq/L. She had low serum osmolality with elevated urine osmolality, consistent with SIADH. Hyponatremia improved temporarily during times of fluid restriction as expected in SIADH, but did not resolve until SJIA was treated successfully with tocilizumab, an IL-6 receptor antibody that inhibits IL-6 activity. The positive response to treatment with tocilizumab supports the role of IL-6 in the pathogenesis of both SJIA and SIADH. Patients with SJIA should be monitored for SIADH to avoid complications of untreated hyponatremia.
Interleukin-6 (IL-6) transduces signals via phosphorylation of STAT3 (pSTAT3). Tocilizumab (TCZ) is an IL-6 receptor blocker, which, when administered intravenously every 4 weeks, efficiently ameliorates rheumatoid arthritis (RA). Since IL-6 signal strength varies among patients with RA, the intensity necessary for appropriate IL-6 signal inhibition by TCZ might vary between individuals. In a previous study, we have examined the clinical utility of increasing (dosing interval shortened to 3 weeks) and decreasing (interval extended to 5 weeks) the dose frequency of TCZ. However, there is currently no established method for accurately measuring the strength of IL-6 signal inhibition by TCZ among individual patients. We therefore sought to develop such an assay.
Inflammation is reported to play a crucial role in the pathogenesis of bipolar disorder (BD). Higher serum levels of soluble interleukin-6 receptor (sIL-6R), which forms a ligand-receptor complex with the potent proinflammatory cytokine IL-6, have been consistently observed in patients with BD. However, the effect of sIL-6R on neural structure and function remains unclear. This study investigated the association between serum sIL-6R levels and the structural and functional connectivity (FC) of the brain in patients with BD.
Treatment-resistant ophthalmoplegia (OP-MG) is not uncommon in individuals with African genetic ancestry and myasthenia gravis (MG). To identify OP-MG susceptibility genes, extended whole exome sequencing was performed using extreme phenotype sampling (11 OP-MG vs 4 control-MG) all with acetylcholine receptor-antibody positive MG. This approach identified 356 variants that were twice as frequent in OP-MG compared to control-MG individuals. After performing probability test estimates and filtering variants according to those ‘suggestive’ of association with OP-MG (p < 0.05), only three variants remained which were expressed in extraocular muscles. Validation in 25 OP-MG and 50 control-MG cases supported the association of DDX17delG (p = 0.014) and SPTLC3insACAC (p = 0.055) with OP-MG, but ST8SIA1delCCC could not be verified by Sanger sequencing. A parallel approach, using a semantic model informed by current knowledge of MG-pathways, identified an African-specific interleukin-6 receptor (IL6R) variant, IL6R c.*3043 T>C, that was more frequent in OP-MG compared to control-MG cases (p = 0.069) and population controls (p = 0.043). A weighted genetic risk score, derived from the odds ratios of association of these variants with OP-MG, correlated with the OP-MG phenotype as opposed to control MG. This unbiased approach implicates several potentially functional gene variants in the gangliosphingolipid and myogenesis pathways in the development of the OP-MG subphenotype.