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Summary: Regulatory B (Breg) cells are potentially implicated in the pathogenesis of immune thrombocytopenia (ITP). We analysed a prospective cohort of newly diagnosed steroid naïve ITP patients enrolled in the multicentre FLIGHT trial and found that the numbers of Bregs in their peripheral blood were similar to healthy controls. In contrast, Breg numbers were significantly reduced in ITP patients treated with systemic immunosuppression (glucocorticoids or mycophenolate mofetil). We also demonstrate that glucocorticoid treatment impairs Breg interleukin‐10 production via an indirect T‐cell‐mediated mechanism. [ABSTRACT FROM AUTHOR]

Graves orbitopathy is both disabling and disfiguring. Medical therapies to reduce inflammation are widely used, but there is limited trial data beyond 18 months of follow-up. Methods: Three-year follow-up of a subset of the CIRTED trial (N = 68), which randomized patients to receive high-dose oral steroid with azathioprine/placebo and radiotherapy/sham radiotherapy. Results: Data were available at 3 years from 68 of 126 randomized subjects (54%). No additional benefit was seen at 3 years for patients randomized to azathioprine or radiotherapy with regard to a binary clinical composite outcome measure (BCCOM), modified European Group on Graves’ Orbitopathy score, or Ophthalmopathy Index. Clinical Activity Score (CAS), Ophthalmopathy Index, and Total Eye Score improved over 3 years (P < .001). However, quality of life at 3 years remained poor. Of 64 individuals with available surgical outcome data, 24 of 64 (37.5%) required surgical intervention. Disease duration of greater than 6 months before treatment was associated with increased need for surgery [odds ratio (OR) 16.8; 95% CI 2.95, 95.0; P = .001]. Higher baseline levels of CAS, Ophthalmopathy Index, and Total Eye Score but not early improvement in CAS were associated with increased requirement for surgery. Conclusion: In this long-term follow-up from a clinical trial, 3-year outcomes remained suboptimal with ongoing poor quality of life and high numbers requiring surgery. Importantly, reduction in CAS in the first year, a commonly used surrogate outcome measure, was not associated with improved long-term outcomes. [ABSTRACT FROM AUTHOR]

Summary: Immune thrombocytopenia (ITP) is thought to result from an aberrant adaptive autoimmune response, involving autoantibodies, B and T lymphocytes, directed at platelets and megakaryocytes. Previous reports have demonstrated skewed CD4+ T‐helper subset distribution and enhanced production of pro‐inflammatory cytokines such as interleukin 17A and interferon gamma. The role of monocytes (MCs) in ITP is less widely described, but innate immune cells have a role in shaping CD4+ T‐cell phenotypes. Glucocorticoids (GCs) are commonly used for first‐line ITP treatment and modulate a broad range of immune cells including T cells and MCs. Using multiparameter flow cytometry analysis, we demonstrate the expansion of intermediate MCs (CD14++CD16+) in untreated patients with newly diagnosed ITP, with these cells displaying a pro‐inflammatory phenotype, characterised by enhanced expression of CD64 and CD80. After 2 weeks of prednisolone treatment (1 mg/kg daily), the proportion of intermediate MCs reduced, with enhanced expression of the anti‐inflammatory markers CD206 and CD163. Healthy control MCs were distinctly different than MCs from patients with ITP before and after GC treatment. Furthermore, the GC‐induced phenotype was not observed in patients with chronic ITP receiving thrombopoietin receptor agonists. These data suggest a role of MCs in ITP pathogenesis and clinical response to GC therapy. [ABSTRACT FROM AUTHOR]

The specific pathogenesis of idiopathic nephrotic syndrome (NS) is poorly understood, and the role of immune mediators remains contentious. However, there is good evidence for the role of a circulating factor, and we recently postulated circulating proteases as candidate factors. Immunosuppressive therapy with glucocorticoids (GCs) and T cell inhibitors are widely used in the clinical treatment of NS. Given that T helper (CD4+) cells expressing IL-17A (so-called Th17 cells) have recently been reported to be resistant to GC treatment, and GC resistance remains a major challenge in the management of NS, we hypothesized that Th17 cells produce a circulating factor that is capable of signaling to the podocyte and inducing deleterious phenotypic changes. To test this, we generated human Th17 cells from healthy volunteers and added the supernatants from these T cell cultures to conditionally immortalized human podocytes in vitro. This demonstrated that podocytes treated with Th17 cell culture supernatant, as well as with patient disease plasma, showed significant stimulation of JNK and p38 MAPK pathways and an increase in motility, which was blocked using a JNK inhibitor. We have previously shown that nephrotic plasma elicits a podocyte response via protease-activated receptor-1 (PAR-1). Stimulation of PAR-1 inpodocytes elicited the same signaling response as Th17 cell culture supernatant treatment. Equally, protease inhibitors with Th17 cell culture treatment blocked the signaling response. This was not replicated by the reagents added to Th17 cell cultures or by IL-17A. Hence, we conclude that an undefined soluble mediator produced by Th17 cells mimics the deleterious effect of PAR-1 activation in vitro. Given the association between pathogenic subsets of Th17 cells and GC resistance, these observations have potential therapeutic relevance for patients with NS. [ABSTRACT FROM AUTHOR]

CD4+ T cell mediated uveitis is conventionally treated with systemic immunosuppressive agents, including corticosteroids and biologics targeting key inflammatory cytokines. However, their long-term utility is limited due to various side effects. Here, we investigated whether DNA methylation inhibitor zebularine can target CD4+ T cells and control intraocular inflammation. Our results showed that zebularine restrained the expression of inflammatory cytokines IFN-γ and IL-17 in both human and murine CD4+ T cells in vitro. Importantly, it also significantly alleviated intraocular inflammation and retinal tissue damage in the murine experimental autoimmune uveitis (EAU) model in vivo , suggesting that the DNA methylation inhibitor zebularine is a candidate new therapeutic agent for uveitis. [ABSTRACT FROM AUTHOR]

Aim To assess the efficacy of intravitreal ranibizumab for the treatment of new onset in ammatory choroidal neovascularisation (iCNV), including both uveitic and idiopathic CNVs. Methods Single-centre, open-label, non-randomised Phase IIb clinical trial. Patients fulfilling strict entry criteria of new onset iCNV were given monthly intravitreal ranibizumab injections for 3 months. Thereafter, re-treatment was based on evidence of persisting activity. All patients completed trial follow-up. Optical coherence tomography (OCT) and best-corrected visual acuity (BCVA) were performed at every visit. Fluorescein angiography was performed at baseline, months 4 and 12. Descriptive analysis and Wilcoxon non-parametric test were performed for analysis. Results 15 patients, 10 women with a mean age of 48.8 years (range 24-85 years) were included in the study. The mean number of injections was 4.33 (range 3-7). There was a statistically significant difference in the BCVA at month 4 (p=0.001) and at month 12 (p=0.001) compared with baseline. The mean gain in BCVA at month 4 compared with baseline was 20 ±15.36 letters (mean±SD), and at month 12 was 21 ±16.97 letters. There was a statistically significant difference in the mean central sub field thickness (CST) at baseline versus month 4 (p=0.003) and month 12 (p=0.001). Conclusion Patients gained vision (mean of 21 letters at 12 months) and showed reduced CST. These results support the continued use of ranibizumab in the treatment of iCNV. Trial registration number 2008-007476-19, results. [ABSTRACT FROM AUTHOR]