Negative Feedback Regulation of T Cells via Interleukin-2 and FOXP3 Reciprocity

As interleukin-2 (IL2) is central to the clonal expansion of antigen-selected T cells, we investigated the relationship between IL2 and the negative regulatory transcription factor FOXP3. We found IL2 to be responsible for T cell antigen receptor (TCR)-activated FOXP3 expression by both CD4+ and CD8+ human T cells, and as anticipated, FOXP3 expression restricted TCR-stimulated IL2 expression. However, no evidence could be found that FOXP3+ cells actively suppress IL2 expression by FOXP3- cells. These data are consistent with an IL2/FOXP3-dependent negative feedback loop that normally regulates the T cell immune response. It follows that a defect in this negative feedback loop as a result of a deficiency of either IL2 or FOXP3 will lead to a hyperproliferative autoimmune syndrome, without the necessity of invoking an active suppressive function for FOXP3+ T cells

Health-related quality-of-life improvements during 98 weeks of infliximab therapy in patients with plaque-type psoriasis in real-world practice

Purpose: We evaluated the effect of plaque-type psoriasis on health-related quality of life (HRQoL) of patients who received infliximab (IFX) in real-world clinical settings. Methods: REALITY was a prospective, observational, open-label study of the efficacy and safety of up to 98 weeks of IFX (5 mg/kg infused at weeks 0, 2, 6, and every 8 weeks thereafter) in patients with moderate-to-severe plaque-type psoriasis. Patients with ≥25 % Psoriasis Area Severity Index (PASI) improvement (PASI 25) at week 50 were eligible for the Extended Treatment Phase (treatment to week 98). Inclusion criteria were diagnosis of plaque-type psoriasis, age ≥18 years, decision to start IFX, and patient consent. Key secondary efficacy outcomes included the Dermatologic Life Quality Index (DLQI; mean DLQI scores, attainment of DLQI 0/1), which was analyzed over 98 weeks. Post hoc analyses examined improvement in DLQI and the relationship between PASI and DLQI. Results: In the Treatment Phase, patients (n = 516, 66.0 % men, mean age 46.4 years) had a mean baseline PASI of 18.1. Mean DLQI improved from 12.7 at baseline to 4.7 [mean change (95 % CI); −8.0 (−8.9, −7.1)] at week 50; 64.0 % (229/358) of patients improved by ≥5 DLQI points. At week 50 (n = 362), 37.6 % (95 % CI; 32.7, 42.7) achieved a DLQI of 0. In the Extended Treatment Phase, patients (n = 167, 68.3 % men, mean age 46.6 years) had a mean baseline PASI of 20.4. Mean DLQI improved from 12.3 at baseline to 2.8 at week 98 [mean change (95 % CI); −9.4 (−10.8, −8.0)]; 68.6 % (96/140) of patients improved by ≥5 DLQI points. At week 98 (n = 141), 47.5 % (95 % CI; 39.4, 55.7) achieved a DLQI of 0. Conclusions: Patients with plaque-type psoriasis who received treatment with IFX for 50 weeks or up to 98 weeks reported substantial HRQoL improvement. © 2016, Springer International Publishing Switzerland

A Randomized, Clinical Trial to Assess the Relative Efficacy and Tolerability of Two Doses of Etoricoxib in Patients with Ankylosing Spondylitis

Pathophysiology and treatment of rheumatic disease

CC-90001, a c-Jun N-Terminal kinase (JNK) inhibitor, in patients with pulmonary fibrosis: Design of a phase 2, randomised, placebo-controlled trial

Introduction Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal interstitial lung disease (ILD); other ILDs have a progressive, fibrotic phenotype (PF-ILD). Antifibrotic agents can slow but not stop disease progression in patients with IPF or PF-ILD. c-Jun N-Terminal kinases (JNKs) are stress-Activated protein kinases implicated in the underlying mechanisms of fibrosis, including epithelial cell death, inflammation and polarisation of profibrotic macrophages, fibroblast activation and collagen production. CC-90001, an orally administered (PO), one time per day, JNK inhibitor, is being evaluated in IPF and PF-ILD. Methods and analysis This is a phase 2, randomised, double-blind, placebo-controlled study evaluating efficacy and safety of CC-90001 in patients with IPF (main study) and patients with PF-ILD (substudy). Both include an 8-week screening period, a 24-week treatment period, up to an 80-week active-Treatment extension and a 4-week post-Treatment follow-up. Patients with IPF (n=165) will be randomised 1:1:1 to receive 200 mg or 400 mg CC-90001 or placebo administered PO one time per day; up to 25 patients/arm will be permitted concomitant pirfenidone use. Forty-five patients in the PF-ILD substudy will be randomised 2:1 to receive 400 mg CC-90001 or placebo. The primary endpoint is change in per cent predicted forced vital capacity from baseline to Week 24 in patients with IPF. Ethics and dissemination This study will be conducted in accordance with Good Clinical Practice guidelines, Declaration of Helsinki principles and local ethical and legal requirements. Results will be reported in a peer-reviewed publication. Trial registration number NCT03142191