Studies on the differentiation of inflammatory and regulatory T-cells

Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve T$_R$$_e$$_g$ and T$_h$17 dysregulation. Thus, understanding how vitamin D modifies CD4$^+$ T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH)$_2$D$_3$, the active form of vitamin D, upon human CD4$^+$ T-cell differentiation. 1,25(OH)$_2$D$_3$, acted directly upon human CD4$^+$ T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFN$_y$ and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH)$_2$D$_3$-treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH)$_2$D$_3$reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH)$_2$D$_3$modified immunity. Furthermore, pro-regulatory effects of 1,25(OH)$_2$D$_3$were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH)$_2$D$_3$ was observed, supporting ability of 1,25(OH)$_2$D$_3$to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D$_3$to drive 1,25(OH)$_2$D$_3$-modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH)$_2$D$_3$in serum. Whether dysregulation of the T$_R$$_e$$_g$/T17 balance or response to 1,25(OH)$_2$D$_3$ was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH)$_2$D$_3$ were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH)$_2$D$_3$might be useful in the treatment of synovitis.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Post-intervention Status in Patients With Refractory Myasthenia Gravis Treated With Eculizumab During REGAIN and Its Open-Label Extension

OBJECTIVE: To evaluate whether eculizumab helps patients with anti-acetylcholine receptor-positive (AChR+) refractory generalized myasthenia gravis (gMG) achieve the Myasthenia Gravis Foundation of America (MGFA) post-intervention status of minimal manifestations (MM), we assessed patients' status throughout REGAIN (Safety and Efficacy of Eculizumab in AChR+ Refractory Generalized Myasthenia Gravis) and its open-label extension. METHODS: Patients who completed the REGAIN randomized controlled trial and continued into the open-label extension were included in this tertiary endpoint analysis. Patients were assessed for the MGFA post-intervention status of improved, unchanged, worse, MM, and pharmacologic remission at defined time points during REGAIN and through week 130 of the open-label study. RESULTS: A total of 117 patients completed REGAIN and continued into the open-label study (eculizumab/eculizumab: 56; placebo/eculizumab: 61). At week 26 of REGAIN, more eculizumab-treated patients than placebo-treated patients achieved a status of improved (60.7% vs 41.7%) or MM (25.0% vs 13.3%; common OR: 2.3; 95% CI: 1.1-4.5). After 130 weeks of eculizumab treatment, 88.0% of patients achieved improved status and 57.3% of patients achieved MM status. The safety profile of eculizumab was consistent with its known profile and no new safety signals were detected. CONCLUSION: Eculizumab led to rapid and sustained achievement of MM in patients with AChR+ refractory gMG. These findings support the use of eculizumab in this previously difficult-to-treat patient population. CLINICALTRIALSGOV IDENTIFIER: REGAIN, NCT01997229; REGAIN open-label extension, NCT02301624. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, after 26 weeks of eculizumab treatment, 25.0% of adults with AChR+ refractory gMG achieved MM, compared with 13.3% who received placebo

Minimal Symptom Expression' in Patients With Acetylcholine Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis Treated With Eculizumab

The efficacy and tolerability of eculizumab were assessed in REGAIN, a 26-week, phase 3, randomized, double-blind, placebo-controlled study in anti-acetylcholine receptor antibody-positive (AChR+) refractory generalized myasthenia gravis (gMG), and its open-label extension

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Studies on the differentiation of inflammatory and regulatory T-cells

Low vitamin D is associated with an increased risk of autoimmune diseases, whose pathology might involve T$_R$$_e$$_g$ and T$_h$17 dysregulation. Thus, understanding how vitamin D modifies CD4$^+$ T-cell responses holds therapeutic potential. I therefore investigated the effect of 1,25(OH)$_2$D$_3$, the active form of vitamin D, upon human CD4$^+$ T-cell differentiation. 1,25(OH)$_2$D$_3$, acted directly upon human CD4$^+$ T-cells, suppressing inflammatory cytokines (IL-17, IL-21, IFN$_y$ and IL-22) whilst enhancing regulatory markers (CTLA-4, CD25, FoxP3 and IL-10). Consistently, 1,25(OH)$_2$D$_3$-treated T-cells suppressed division of naive T-cells stimulated by dendritic cells (DCs). Strong up-regulation of CTLA-4 by 1,25(OH)$_2$D$_3$reduced B7 expression by DCs, suggesting that enhanced CTLA-4 could be important mechanistically in 1,25(OH)$_2$D$_3$modified immunity. Furthermore, pro-regulatory effects of 1,25(OH)$_2$D$_3$were maintained under inflammatory conditions and modest suppression of established IL-17 by 1,25(OH)$_2$D$_3$ was observed, supporting ability of 1,25(OH)$_2$D$_3$to control T-cell phenotype at inflammatory sites. DCs could also efficiently convert 25(OH)D$_3$to drive 1,25(OH)$_2$D$_3$-modified T-cell responses, which might be important in-vivo, given the low level of 1,25(OH)$_2$D$_3$in serum. Whether dysregulation of the T$_R$$_e$$_g$/T17 balance or response to 1,25(OH)$_2$D$_3$ was associated with disease outcome in early synovitis patients was also studied. Although the TReg/T17 ratio did not stratify with outcome, T-cell responses to 1,25(OH)$_2$D$_3$ were observed in all patients, suggesting that their VDR signalling is intact and that 1,25(OH)$_2$D$_3$might be useful in the treatment of synovitis

[TEMPORARILY RENAMED] Immunomodulatory therapy in children with paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS, MIS-C; RECOVERY): a randomised, controlled, open-label, platform trial

BackgroundPaediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 (PIMS-TS), also known as multisystem inflammatory syndrome in children (MIS-C) emerged in April, 2020. The paediatric comparisons within the RECOVERY trial aimed to assess the effect of intravenous immunoglobulin or corticosteroids compared with usual care on duration of hospital stay for children with PIMS-TS and to compare tocilizumab (anti-IL-6 receptor monoclonal antibody) or anakinra (anti-IL-1 receptor antagonist) with usual care for those with inflammation refractory to initial treatment.MethodsWe did this randomised, controlled, open-label, platform trial in 51 hospitals in the UK. Eligible patients were younger than 18 years and had been admitted to hospital for PIMS-TS. In the first randomisation, patients were randomly assigned (1:1:1) to usual care (no additional treatments), usual care plus methylprednisolone (10mg/kg per day for 3 consecutive days), or usual care plus intravenous immunoglobulin (a single dose of 2 g/kg). If further anti-inflammatory treatment was considered necessary, children aged at least 1 year could be considered for a second randomisation, in which patients were randomly assigned (1:2:2) to usual care, intravenous tocilizumab (12 mg/kg in patients 99%). Mean duration of hospital stay was 8·5 days (SD 1·2) in children assigned to anakinra (difference from usual care –1·4 days, 95% CrI –4·3 to 1·8; posterior probability 84%). Two persistent coronary artery aneurysms were reported among patients assigned to usual care in the first randomisation. There were few cardiac arrythmias, bleeding, or thrombotic events in any group. Two children died; neither was considered related to study treatment.InterpretationModerate evidence suggests that, compared with usual care, first-line intravenous methylprednisolone reduces duration of hospital stay for children with PIMS-TS. Good evidence suggests that second-line tocilizumab reduces duration of hospital stay for children with inflammation refractory to initial treatment. Neither intravenous immunoglobulin nor anakinra had any effect on duration of hospital stay compared with usual care.FundingMedical Research Council and National Institute of Health Research

Long-term efficacy and safety of eculizumab in Japanese patients with generalized myasthenia gravis: A subgroup analysis of the REGAIN open-label extension study

The terminal complement inhibitor eculizumab was shown to improve myasthenia gravis-related symptoms in the 26-week, phase 3, randomized, double-blind, placebo-controlled REGAIN study (NCT01997229). In this 52-week sub-analysis of the open-label extension of REGAIN (NCT02301624), eculizumab's efficacy and safety were assessed in 11 Japanese and 88 Caucasian patients with anti-acetylcholine receptor antibody-positive refractory generalized myasthenia gravis. For patients who had received placebo during REGAIN, treatment with open-label eculizumab resulted in generally similar outcomes in the Japanese and Caucasian populations. Rapid improvements were maintained for 52 weeks, assessed by change in score from open-label extension baseline to week 52 (mean [standard error]) using the following scales (in Japanese and Caucasian patients, respectively): Myasthenia Gravis Activities of Daily Living (−2.4 [1.34] and − 3.3 [0.65]); Quantitative Myasthenia Gravis (−2.9 [1.98] and − 4.3 [0.79]); Myasthenia Gravis Composite (−4.5 [2.63] and − 4.9 [1.19]); and Myasthenia Gravis Quality of Life 15-item questionnaire (−8.6 [5.68] and − 6.5 [1.93]). Overall, the safety of eculizumab was consistent with its known safety profile. In this interim sub-analysis, the efficacy and safety of eculizumab in Japanese and Caucasian patients were generally similar, and consistent with the overall REGAIN population

Consistent improvement with eculizumab across muscle groups in myasthenia gravis

Objective: To assess whether eculizumab, a terminal complement inhibitor, improves patient- and physician-reported outcomes (evaluated using the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale, respectively) in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis across four domains, representing ocular, bulbar, respiratory, and limb/gross motor muscle groups. Methods: Patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis were randomized 1:1 to receive either placebo or eculizumab during the REGAIN study (NCT01997229). Patients who completed REGAIN were eligible to continue into the open-label extension trial (NCT02301624) for up to 4 years. The four domain scores of each of the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale recorded throughout REGAIN and through 130 weeks of the open-label extension were analyzed. Results: Of the 125 patients who participated in REGAIN, 117 enrolled in the open-label extension; 61 had received placebo and 56 had received eculizumab during REGAIN. Patients experienced rapid improvements in total scores and all four domain scores of both the myasthenia gravis activities of daily living profile and the quantitative myasthenia gravis scale with eculizumab treatment. These improvements were sustained through 130 weeks of the open-label extension. Interpretation: Eculizumab treatment elicits rapid and sustained improvements in muscle strength across ocular, bulbar, respiratory, and limb/gross motor muscle groups and in associated daily activities in patients with refractory anti-acetylcholine receptor antibody-positive generalized myasthenia gravis

Long-term safety and efficacy of eculizumab in generalized myasthenia gravis

Introduction: Eculizumab is effective and well tolerated in patients with antiacetylcholine receptor antibody-positive refractory generalized myasthenia gravis (gMG; REGAIN; NCT01997229). We report an interim analysis of an open-label extension of REGAIN, evaluating eculizumab's long-term safety and efficacy. Methods: Eculizumab (1,200 mg every 2 weeks for 22.7 months [median]) was administered to 117 patients. Results: The safety profile of eculizumab was consistent with REGAIN; no cases of meningococcal infection were reported during the interim analysis period. Myasthenia gravis exacerbation rate was reduced by 75% from the year before REGAIN (P < 0.0001). Improvements with eculizumab in activities of daily living, muscle strength, functional ability, and quality of life in REGAIN were maintained through 3 years; 56% of patients achieved minimal manifestations or pharmacological remission. Patients who had received placebo during REGAIN experienced rapid and sustained improvements during open-label eculizumab (P < 0.0001). Discussion: These findings provide evidence for the long-term safety and sustained efficacy of eculizumab for refractory gMG. Muscle Nerve 2019