IL-17 receptor and its functional significance in psoriatic arthritis

To delineate the functional significance of IL-17 Receptor (IL-17RA) and characterize the IL-17 producing T cell (Th17) subpopulation in psoriatic arthritis (PsA). Mononuclear cells from blood and synovial fluid (SF) were obtained from PsA (n=20), rheumatoid arthritis (RA, n=20) and osteoarthritis (OA, n=20) patients. Synoviocytes (FLS) were isolated from the synovium of RA (n=5), PsA (n=5) and OA (n=5) patients. IL-17RA expression in FLS was identified by western blotting (WB) and flowcytometry. T lymphocytes derived from the SF of these patients were studied to identify and phenotype the Th17 cells. The functional significance of IL-17RA was determined by evaluating its regulatory role on the production of proinflammatory cytokines and endopeptidase. IL-17RA expression was found to be significantly higher in FLS of RA (15.7%±4.9) and PsA (4.5%±0.9) in comparison to OA (1.14%±0.9). Western blot analyses showed that the relative intensity (RI) of IL-17RA protein was higher in RA and PsA compared to OA (Fisher exact, P<0.01). A significant enrichment of IL-17-producing CD4+T cells (7.9%±2.8) was observed in the SF of PsA patients compared to that of OA patients (P<.001). Compared to OA-FLS, recombinant IL-17 induced higher levels of IL-6, IL-8, and MMP-3 production in PsA-FLS. Blockage of IL-17RA with an anti-IL-17RA antibody inhibited the production of IL-6, IL-8, and MMP-3. This is the first report to demonstrate the functional significance of IL-17RA in PsA. Results of this study support the hypothesis that IL-17RA blocking antibodies have the potential to be a therapeutic option for psoriatic arthriti

Wavelets for Density-Functional Theory and Post-Density-Functional-Theory Calculations

We give a fairly comprehensive review of wavelets and of their application to density-functional theory (DFT) and to our recent application of a wavelet-based version of linear-response time-dependent DFT (LR-TD-DFT). Our intended audience is quantum chemists and theoretical solid-state and chemical physicists. Wavelets are a Fourier-transform-like approach which developed primarily in the latter half of the last century and which was rapidly adapted by engineers in the 1990s because of its advantages compared to standard Fourier transform techniques for multiresolution problems with complicated boundary conditions. High performance computing wavelet codes now also exist for DFT applications in quantum chemistry and solid-state physics, notably the BigDFT code described in this chapter. After briefly describing the basic equations of DFT and LR-TD-DFT, we discuss how they are solved in BigDFT and present new results on the small test molecule carbon monoxide to show how BigDFT results compare against those obtained with the quantum chemistry gaussian-type orbital (GTO) based code deMon2k. In general, the two programs give essentially the same orbital energies, but the wavelet basis of BigDFT converges to the basis set limit much more rapidly than does the GTO basis set of deMon2k. Wavelet-based LR-TD-DFT is still in its infancy, but our calculations confirm the feasibility of implementing LR-TD-DFT in a wavelet-based code.Comment: 45 pages, 10 figures, book chapter in Theoretical and Computational Methods in Modern Density Functional Theory, Editor: A.K. Ro

A randomized, controlled trial of interferon-β-1a (Avonex(®)) in patients with rheumatoid arthritis: a pilot study [ISRCTN03626626]

The objective of this study was to evaluate the safety and possible efficacy of IFN-β-1a for the treatment of patients with rheumatoid arthritis (RA). Twenty-two patients with active RA were enrolled in a phase II randomized, double-blind, placebo-controlled trial of 30 μg IFN-β-1a by weekly self-injection for 24 weeks. The primary outcome of the study was safety. Secondary outcomes included the proportion of patients achieving an American College of Rheumatology (ACR) 20 response at 24 weeks. There were no significant differences in adverse events reported in the two groups. Fewer than 20% of patients in each arm of the study achieved an ACR 20 response at 24 weeks (P = 0.71). Sixty-nine percent of patients receiving IFN-β and 67% receiving placebo terminated the study early, most of them secondary to a perceived lack of efficacy. Overall, IFN-β-1a had a safety profile similar to that of placebo. There were no significant differences in the proportion of patients achieving an ACR 20 response between the two groups

Wavelet-Based Linear-Response Time-Dependent Density-Functional Theory

Linear-response time-dependent (TD) density-functional theory (DFT) has been implemented in the pseudopotential wavelet-based electronic structure program BigDFT and results are compared against those obtained with the all-electron Gaussian-type orbital program deMon2k for the calculation of electronic absorption spectra of N2 using the TD local density approximation (LDA). The two programs give comparable excitation energies and absorption spectra once suitably extensive basis sets are used. Convergence of LDA density orbitals and orbital energies to the basis-set limit is significantly faster for BigDFT than for deMon2k. However the number of virtual orbitals used in TD-DFT calculations is a parameter in BigDFT, while all virtual orbitals are included in TD-DFT calculations in deMon2k. As a reality check, we report the x-ray crystal structure and the measured and calculated absorption spectrum (excitation energies and oscillator strengths) of the small organic molecule N-cyclohexyl-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-amine

Daubechies wavelets as a basis set for density functional pseudopotential calculations

Daubechies wavelets are a powerful systematic basis set for electronic structure calculations because they are orthogonal and localized both in real and Fourier space. We describe in detail how this basis set can be used to obtain a highly efficient and accurate method for density functional electronic structure calculations. An implementation of this method is available in the ABINIT free software package. This code shows high systematic convergence properties, very good performances and an excellent efficiency for parallel calculations.Comment: 15 pages, 11 figure

A plain language summary of what clinical studies can tell us about the safety of evobrutinib – a potential treatment for multiple sclerosis

Immunology; Rheumatology; Systemic lupus erythematosusInmunología; Reumatología; Lupus eritematoso sistémicoImmunologia; Reumatologia; Lupus eritematós sistèmicWhat is this summary about?: This summary explains the findings from a recent investigation that combined the results of over 1000 people from three clinical studies to understand the safety of evobrutinib. Evobrutinib is an oral medication (taken by mouth), being researched as a potential treatment for multiple sclerosis (MS). This medication was also investigated in rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Over 1000 people have taken evobrutinib as part of three separate phase 2 clinical studies. These studies looked at how much of the drug should be taken, how safe the drug is, and how well it might work for treating a certain medical condition. What were the results?: Evobrutinib was well-tolerated by participants in all three studies. The number of side effects reported by participants taking the medication was very similar to those reported by participants taking the placebo (a 'dummy' treatment without a real drug). The most common side effects in clinical studies were urinary tract infections, headache, swelling of the nose and throat, diarrhoea and blood markers of potential liver damage (these returned to normal once the treatment was stopped). What do the results mean?: The safety data from all three clinical studies are encouraging and can be used to inform further research into using evobrutinib in MS.X Montalban has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS. D Wallace has received consultant fees from Amgen, Celgene, Eli Lilly, EMD Serono Research & Development Institute, Inc., Billerica, MA, USA (an affiliate of Merck KGaA), Janssen and Merck. MC Genovese is an employee of and has financial interests in Gilead. D Tomic is an employee of Ares Trading SA, Eysins, Switzerland, an affiliate of Merck KGaA, and received stock or an ownership interest from Novartis. D Parsons-Rich was an employee of EMD Serono Research & Development Institute, Inc., Billerica, MA, USA, an affiliate of Merck KGaA, at the time of the study, and is currently an employee of and has received stock from Pfizer. C Le Bolay and H Guehring are employees of Merck Healthcare KGaA, Darmstadt, Germany. A Kao is an employee of and received stock or an ownership interest from EMD Serono Inc., Billerica, MA, USA, a healthcare business of Merck KGaA. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported by Merck (CrossRef Funder ID: 10.13039/100009945). This summary was prepared by Lumanity on behalf of, and funded by, Merck KGaA, Darmstadt, Germany

Antibody response to pneumococcal and influenza vaccination in patients with rheumatoid arthritis receiving abatacept

Background Patients with rheumatoid arthritis (RA), including those treated with biologics, are at increased risk of some vaccine-preventable infections. We evaluated the antibody response to standard 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 2011–2012 trivalent seasonal influenza vaccine in adults with RA receiving subcutaneous (SC) abatacept and background disease-modifying anti-rheumatic drugs (DMARDs). Methods Two multicenter, open-label sub-studies enrolled patients from the ACQUIRE (pneumococcal and influenza) and ATTUNE (pneumococcal) studies at any point during their SC abatacept treatment cycle following completion of ≥3 months’ SC abatacept. All patients received fixed-dose abatacept 125 mg/week with background DMARDs. A pre-vaccination blood sample was taken, and after 28 ± 3 days a final post- vaccination sample was collected. The primary endpoint was the proportion of patients achieving an immunologic response to the vaccine at Day 28 among patients without a protective antibody level to the vaccine antigens at baseline (pneumococcal: defined as ≥2-fold increase in post-vaccination titers to ≥3 of 5 antigens and protective antibody level of ≥1.6 μg/mL to ≥3 of 5 antigens; influenza: defined as ≥4-fold increase in post-vaccination titers to ≥2 of 3 antigens and protective antibody level of ≥1:40 to ≥2 of 3 antigens). Safety and tolerability were evaluated throughout the sub-studies. Results Pre- and post-vaccination titers were available for 113/125 and 186/191 enrolled patients receiving the PPSV23 and influenza vaccine, respectively. Among vaccinated patients, 47/113 pneumococcal and 121/186 influenza patients were without protective antibody levels at baseline. Among patients with available data, 73.9 % (34/46) and 61.3 % (73/119) met the primary endpoint and achieved an immunologic response to PPSV23 or influenza vaccine, respectively. In patients with pre- and post-vaccination data available, 83.9 % in the pneumococcal study demonstrated protective antibody levels with PPSV23 (titer ≥1.6 μg/mL to ≥3 of 5 antigens), and 81.2 % in the influenza study achieved protective antibody levels (titer ≥1:40 to ≥2 of 3 antigens) at Day 28 post-vaccination. Vaccines were well tolerated with SC abatacept with background DMARDs. Conclusions In these sub-studies, patients with RA receiving SC abatacept and background DMARDs were able to mount an appropriate immune response to pneumococcal and influenza vaccines. Trial registration NCT00559585 (registered 15 November 2007) and NCT00663702 (registered 18 April 2008)

Secukinumab in active rheumatoid arthritis after anti-TNFα therapy : a randomized, double-blind placebo-controlled phase 3 study

Introduction: 'REASSURE' (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors). Methods: A total of 637 patients were randomized (1: 1: 1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire-Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year. Results: The primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups. Conclusion: Secukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA

Secukinumab in active rheumatoid arthritis after anti-TNFα therapy : a randomized, double-blind placebo-controlled phase 3 study

Introduction: 'REASSURE' (NCT01377012), a phase 3 study, evaluated the efficacy and safety of secukinumab in patients with active rheumatoid arthritis (RA) who had an inadequate response to, or intolerance of, tumor necrosis factor inhibitors (TNF-inhibitors). Methods: A total of 637 patients were randomized (1: 1: 1) to receive intravenous secukinumab 10 mg/kg (baseline, weeks 2 and 4) followed by subcutaneous secukinumab 150 mg or 75 mg every 4 weeks (starting from week 8) or placebo at the same dosing schedule. The primary endpoint was the American College of Rheumatology 20% improvement criteria (ACR20) at week 24. Other predefined hierarchical endpoints included Health Assessment Questionnaire-Disability Index, van der Heijde modified total Sharp score (vdH-mTSS) at week 24, and major clinical response (MCR; continuous 6 month period of ACR70 response) at 1 year. Results: The primary efficacy endpoint was met with both secukinumab dose groups: ACR20 response rate at week 24 was 35.2% for both secukinumab dose groups (P = 0.0009) vs 19.6% for placebo. The improvements in secondary endpoints were greater in the secukinumab dose groups vs placebo but did not meet statistical significance. The overall safety profile was similar across all treatment groups. Conclusion: Secukinumab demonstrated efficacy in reducing disease activity over placebo as measured by ACR20 in patients with active RA who had an inadequate response to TNF-inhibitors. Secukinumab demonstrated a safety profile similar to other biologics currently approved for RA