Inhibition of Co-Stimulation in Rheumatoid Arthritis (ICoSRA)
Research type
Research Study
Full title
Inhibition of Co-Stimulation in Rheumatoid Arthritis
IRAS ID
156923
Contact name
Iain McInnes
Contact email
Sponsor organisation
NHS Greater Glasgow and Clyde
Eudract number
2014-004419-35
Duration of Study in the UK
1 years, 6 months, 1 days
Research summary
Summary of Research
Rheumatoid arthritis (RA) is a chronic inflammatory immune-mediated arthritis which leads to pain, swelling and destruction of joints. RA affects more than 500,000 subjects in the UK and incurs significant health and economic cost. Most patients require potent immune suppressing drugs such as methotrexate, which help reduce pain and stiffness, and protect the joints against damage. However, many patients do not respond or are unable to tolerate methotrexate. In these patients, biologic drugs such as abatacept are used to try to control the arthritis.
Abatacept is designed to target and inhibit a specific molecule involved in “costimulation” of the inflammatory signal that is thought to be important in RA. While abatacept has been shown to be effective in trials and clinical practice, the exact mechanism of action of abatacept in RA has not been fully elucidated. Understanding these actions is likely to inform both the use of abatacept in RA and lead to increased understanding of inflammation in humans with implications for further therapies. This six month prospective open-label study, therefore, aims to investigate the effects of inhibiting co-stimulation on a variety of important inflammatory cell types and processes in humans with RA.
25 participants with RA who have bad prognostic genetic markers (ACPA and HLA-DR4) and who were scheduled to receive subcutaneous abatacept as part of their standard clinical treatment will be recruited. Consenting participants will followed for a total of 24 weeks during which time they will have additional venous blood and urine samples taken to investigate the effects of abatacept on their immune cells and system. The primary endpoint of the study is the characterisation of the immune response following costimulatory modulation in RA patients at 12 weeks. Secondary endpoints include change in immunological response and its association with clinical outcome measures up to 24 weeks.
Summary of Results
The ICoSRA study was aimed at using Abatacept (CTLA4 and IgG1 Fc fusion protein) as a clinical molecular probe to evaluate the effect of inhibiting co-stimulation on the immune response in rheumatoid arthritis. The primary objective was based on determining the extent of antigen-specific T cell responses pre- and post-treatment with abatacept. This analysis via MHC tetramer staining combined with a flow cytometric readout is still in progress. With the expectation that results will be available in Q4 of 2022. In addition to the primary objective, a number of exploratory objectives were also undertaken. The first of these was the determination of the transcriptomic profiles of CD4 T cells and dendritic cells pre- and post-treatment was determined. This revealed two discrete differential signatures in both CD4 T cell and dendritic cell compartments. Notably, one of the dendritic associated signals included changes in the CTLA-4 transcript. Further bioinformatic analysis is underway to investigate the signatures and understand the influence these transcriptional programmes have on the immunological compartments. The second exploratory objective revolved around the flow cytometric characterisation of the circulating immunological compartment pre- and post-treatment. This analysis has revealed that treatment with abatacept results in modulation of immunological checkpoint receptors in the monocyte compartment. For instance, we observed an increase in PDL1 in non-classical monocytes versus a decrease in PDL2 in intermediate monocytes. Suggesting that even within one myeloid compartment, treatment can have discrete and opposing effects on different populations that are known to have different roles in driving inflammatory responses. Interestingly, it was not just the innate immune compartment that was affected by treatment, as we also observed significant changes in the CD4 T cell compartment. In brief, treatment resulted in a decrease of Th17 and Th17.1 CD4 T cells, and an increase in Th1 CD4 T cells. Further characterisation of these populations revealed that CD4 T cells had a decreased activation state (i.e., lower expression of CD25) and altered co-stimulation receptor expression (i.e., decreased ICOS and PD1). Taken together this suggest that treatment has a direct impact on the composition of the CD4 T Cell compartment and how it can response to immunological signals. Further analysis is underway to correlate these immunological changes with clinical parameters. Finally, studies were also undertaken to evaluate the impact of treatment on anti-modified protein antibodies (AMPA; hallmark feature of RA). In short, treatment with Abatacept did not affect the overall level of circulating IgA, IgG or IGM AMPAs.
REC name
West of Scotland REC 1
REC reference
15/WS/0010
Date of REC Opinion
18 Mar 2015
REC opinion
Further Information Favourable Opinion