An investigation into the role of complement factor H in the retina

Age-related macular degeneration (AMD) is the leading cause of visual impairment in the UK. In 2005, the first publication of a genome-wide associated study identified a single nucleotide polymorphism in complement factor H (CFH) as a genetic risk factor for AMD. CFH is a secreted regulator of the alternative complement pathway and therefore key to controlling the inflammatory response. Prior to 2005, little was known about the role of CFH in the retina. This study addresses this question in order to understand how this protein could contribute towards AMD pathology. Initial experiments confirmed that retinal pigment epithelial (RPE) cells are capable of secreting detectable levels of CFH, and that RPE cells were able to enhance the secretion of CFH in response to inflammatory stimuli. The main focus of this study was to characterise the effect of loss of CFH on young and aged retina in Cfh-/- mice. Immunohistochemical studies revealed that signs of stress and re-distribution of complement proteins appear at one year of age. Genome-wide microarray analysis of the RPE and choroid or neuroretina, showed that loss of CFH has little effect on gene expression in young mice but that the impact of CFH loss increases with age. The largest group of genes to change were involved in antigen presentation and immunity suggesting that CFH has an important role in immune regulation in the eye. Analysis of visual function using electoretinograms revealed that dysfunction seen at two years was not present at one year, indicating that age-related gene expression changes are likely to be involved in the pathogenic process in these mice. This study reveals the importance of CFH in maintaining retinal health and good visual function with age

Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial

Background: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. Method: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. Finding: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227–29 056) in the suspend methotrexate group and 12 326 U/mL (10 538–14 418) in the continue methotrexate group with a geometric mean ratio (GMR) of 2·08 (95% CI 1·59–2·70; p<0·0001). No intervention-related serious adverse events occurred. Interpretation: 2-week interruption of methotrexate treatment in people with immune-mediated inflammatory diseases enhanced antibody responses after COVID-19 booster vaccination that were sustained at 12 weeks and 26 weeks. There was a temporary increase in inflammatory disease flares, mostly self-managed. The choice to suspend methotrexate should be individualised based on disease status and vulnerability to severe outcomes from COVID-19. Funding: National Institute for Health and Care Research