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Abstract Background Increased levels of cytokines, including interleukin-6 (IL-6), reflect inflammation and have been shown to be predictive of therapeutic responses, fatigue, pain, and depression in patients with rheumatoid arthritis (RA), but limited data exist on associations between IL-6 levels and health-related quality of life (HRQoL). This post hoc analysis of MONARCH phase III randomized controlled trial data evaluated the potential of baseline IL-6 levels to differentially predict HRQoL improvements with sarilumab, a fully human monoclonal antibody directed against both soluble and membrane-bound IL-6 receptor α (anti-IL-6Rα) versus adalimumab, a tumor necrosis factor α inhibitor, both approved for treatment of active RA. Methods Baseline serum IL-6 levels in 300/369 randomized patients were categorized into low (1.6–7.1 pg/mL), medium (7.2–39.5 pg/mL), and high (39.6–692.3 pg/mL) tertiles. HRQoL was measured at baseline and week (W)24 and W52 by Short Form 36 (SF-36) physical/mental component summary (PCS/MCS) and domain scores, Functional Assessment of Chronic Illness Therapy -fatigue, and duration of morning stiffness visual analog scale (AM-stiffness VAS). Linear regression of changes from baseline in HRQoL (IL-6 tertile, treatment, region as a stratification factor, and IL-6 tertile-by-treatment interaction as fixed effects) assessed predictivity of baseline IL-6 levels, with low tertile as reference. Pairwise comparisons of improvements between treatment groups were performed by tertile; least squares mean differences and 95% CIs were calculated. Similar analyses evaluated W24 patient-level response on minimum clinically important differences (MCID). Results At baseline, patients with high versus medium or low IL-6 levels (n = 100, respectively) reported worse (nominal p

Abstract Background The interleukin-6 receptor inhibitor sarilumab demonstrated efficacy in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or as monotherapy in patients with moderately to severely active rheumatoid arthritis (RA) with an inadequate response (IR) or intolerant (INT) to methotrexate (MTX) or tumour necrosis factor (TNF)-α inhibitors. This analysis investigated the efficacy and safety of sarilumab in patient subgroups. Methods Data were included from phase III studies: two placebo-controlled studies of subcutaneous sarilumab 150/200 mg every 2 weeks (q2w) either + MTX in MTX-IR patients (52 weeks) or + csDMARDs in TNF-IR/INT patients (24 weeks), and a monotherapy study of sarilumab 200 mg q2w vs. adalimumab 40 mg q2w in MTX-IR/INT patients (24 weeks). Prespecified and post hoc subgroups included patient demographics, disease characteristics, and prior treatments. Prespecified and post hoc endpoints included clinical, radiographic, and physical function measures, and p values are considered nominal. Safety was assessed during double-blind treatment. Results The superiority of sarilumab (either as monotherapy vs. adalimumab or in combination with csDMARDs vs. placebo + csDMARDs) across clinical endpoints was generally consistent across subgroups defined by patient demographics, disease characteristics, and prior treatments, demonstrating the benefit of sarilumab treatment for a wide range of patient types. Interaction p values of

Abstract Background Interleukin-6 (IL-6) is a pleiotropic cytokine that plays a key role in the pathogenesis of rheumatoid arthritis. Sarilumab is a human monoclonal antibody that binds membrane-bound and soluble IL-6 receptor-α to inhibit IL-6 signalling. The aim of this study was to compare the effects of sarilumab and adalimumab (a tumour necrosis factor alpha inhibitor) monotherapy on levels of circulating biomarkers associated with the acute-phase response, bone remodelling, atherothrombosis, anaemia of chronic disease and markers purported to reflect synovial lymphoid and myeloid cell infiltrates, as well as the potential of these biomarkers to differentially predict clinical and patient-reported outcomes with sarilumab vs. adalimumab. Methods In this post hoc analysis, serum samples were analysed at baseline and prespecified post-treatment timepoints up to week 24 in adults with moderate-to-severe active rheumatoid arthritis intolerant of or inadequate responders to methotrexate from the MONARCH trial (NCT02332590). Results Greater reductions in C-reactive protein (CRP; − 94.0% vs. –24.0%), serum amyloid A (SAA; − 83.2% vs. –17.4%), total receptor activator of nuclear factor-κB ligand (RANKL; − 18.3% vs. 10.5%) and lipoprotein (a) (− 41.0% vs. –2.8%) were observed at week 24 with sarilumab vs. adalimumab, respectively (adjusted p

Abstract Background The phase III MONARCH randomized controlled trial (NCT02332590) demonstrated that in patients with rheumatoid arthritis (RA), sarilumab (anti-interleukin-6 receptor monoclonal antibody) monotherapy is superior to adalimumab monotherapy in reducing disease activity and signs and symptoms of RA, as well as in improving physical function, with similar rates of adverse and serious adverse events. We report the effects of sarilumab versus adalimumab on patient-reported outcomes (PROs). Methods Patients with active RA intolerant of, or inadequate responders to, methotrexate were randomized to sarilumab 200 mg plus placebo every 2 weeks (q2w; n = 184) or adalimumab 40 mg plus placebo q2w (n = 185). Dose escalation to weekly administration of adalimumab or matching placebo was permitted at week 16. PROs assessed at baseline and weeks 12 and 24 included patient global assessment of disease activity (PtGA), pain and morning stiffness visual analogue scales (VASs), Health Assessment Questionnaire Disability Index (HAQ-DI), 36-item Short Form Health Survey (SF-36), Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F), Rheumatoid Arthritis Impact of Disease (RAID), and rheumatoid arthritis-specific Work Productivity Survey (WPS-RA). Between-group differences in least-squares mean (LSM) changes from baseline were analyzed. p

The mechanisms of texture development were examined for BaTiO3 and a (K,Na,Li)(Nb,Ta)O3 solid solution made by the templated grain growth method, and compared with the mechanism in Bi0.5(Na,K)0.5TiO3. The dominant mechanism was different in each material; grain boundary migration in BaTiO3, solid state spreading in Bi0.5(Na,K)0.5TiO3, and abnormal grain growth in the (K,Na,Li)(Nb,Ta)O3 solid solution. The factor determining the dominant mechanism is the degree of smoothness of surface structure at an atomic level.

To compare the mechanisms underlying mechanical responses to ephedrine and Ephedra herb, a main component of Kakkon-to, in isolated male and female rabbit urinary bladder and urethral strips, responses of isolated strips to the agents were recorded in organ bath systems. Ephedrine and Ephedra herb relaxed the female urinary bladder to the similar extent. These relaxations are reversed to contractions by timolol. In the presence of timolol, ephedrine produced less contraction of urethral strips in the female than those in the male; this contraction was abolished by prazosin. Ephedra herb contracted the female urethra less than that of the male, and the contraction was stronger than that by ephedrine. The contraction caused by Ephedra herb in strips treated with timolol was significantly inhibited by prazosin. The prazosin-resistant contraction of the female urethra was greater than that of the male. Quinacrine, a phospholipase A2 inhibitor, indomethacin, and AA861, a 5-lipoxygenase inhibitor, inhibited the contraction. The contraction was inhibited by ZK 158252, a leukotriene (LT) B4-receptor antagonist. These findings suggest that Ephedra herb contracts the urethra via arachidonic acid metabolites together with α1-adrenoceptor stimulation. The metabolites produced by 5-lipoxygenase may stimulate LTB4, but not CysLt1, receptors. These contractile components induced by Ephedra herb and Kakkon-to might be effective for the treatment of stress urinary incontinence. Keywords:: stress urinary incontinence, Ephedra herb, ephedrine, urethral contraction, arachidonic acid metabolite