Project 1:
Title: A mechanistic mathematical model to describe the effect of methotrexate in reducing immunogenicity of adalimumab in axial spondyloarthritis. An ancillary analysis on the clinical trial Effect of the Combination of Methotrexate and Adalimumab on Reduction of Immunization in Ankylosing Spondylitis (CoMARIS).
Material & methods: cytokines, lymphocytes phenotyping, anti-drug antibodies at consecutive time points in a subset of 20 subjects with or without methotrexate in combination with adalimumab; statistical analysis; compartmental model defined as a system of ordinary differential equations, which describe the changes in the levels of the immune cell populations and cytokine abundance over time.
Location: Institute of Mathematics and Informatics University of Sofia, BG (on-site) /CNRS UPR 4301, University of Tours, FR (on remote)
Skills required: computational biology, statistics, applied mathematics (calculus, differential equations, numerical optimisation), quantitative systems pharmacology modelling
Duration: 1 month (the STSM must be completed before September 30th 2024)
Reference:
- Ducourau E et al. Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial. RMD Open. 2020 Jan;6(1):e001047.
https://doi.org/10.1136/rmdopen-2019-001047
- Rogers KV et al. A dynamic quantitative systems pharmacology model of inflammatory bowel disease. Clin Transl Sci (2021) 14, 239–248 (2-part paper)
https://doi.org/10.1111/cts.12849
https://doi.org/10.1111/cts.12850
- Chen X et al. A mechanistic, multiscale mathematical model of immunogenicity for therapeutic proteins. CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e133-e134 (2 part paper)
https://doi.org/10.1038/psp.2014.30
https://doi.org/10.1038/psp.2014.31
Contact:
– Peter Rashkov (Sofia): p.rashkov@math.bas.bg
– Denis Mulleman (Tours): denis.mulleman@univ-tours.fr
Project 2:
Title: An interim analysis of a biomarker-guided therapeutic drug monitoring trial
Material & methods: BIOTIPRA is a feasibility study investigating pro-active therapeutic drug monitoring of adalimumab treated rheumatoid arthritis patients. The study measures drug and anti-drug antibody levels and records outcome measures. The proposed short-term scientific mission offers opportunities for health economic analysis, bDMARD laboratory measurement and clinical trial outcome analysis in a subset of 50 subjects.
Location: The Centre for Musculoskeletal Research, The University of Manchester, United Kingdom
Skills required: bio-statistics or health economic analysis
Duration: 1 month (the STSM must be completed before September 30th 2024)
Reference:
Contact:
– James Bluett: james.bluett@manchester.ac.uk
Project 3:
Title: Investigating the Relationship between Methotrexate Adherence and Biologic Response in Rheumatoid Arthritis Patients
Methotrexate is one of the first-line DMARDs in rheumatology and co-prescription with biologic DMARDs reduces the development of anti-drug antibodies. This project aims to explore the impact of methotrexate (MTX) biochemical adherence on biologic response in rheumatoid arthritis (RA) patients initiating biologic therapy. Utilizing data from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), serum samples were analyzed using High-Performance Liquid Chromatography coupled with Selected Reaction Monitoring Mass Spectrometry (HPLC-SRM-MS) to measure MTX levels and adherence. Statistical analysis will assess the relationship between MTX adherence, development of anti-drug antibodies and biologic response, with the aim of optimizing treatment strategies and improving patient outcomes in RA management.
Material & methods: Serum samples were collected from RA patients initiating biologic therapy at baseline, 3, and 6 months. Methotrexate (MTX) adherence was assessed using HPLC-SRM-MS, with adherence categorized based on predefined cutoffs. Statistical analysis will explore the associations between MTX adherence, development of anti-drug antibodies and biologic response. The proposed short-term scientific mission offers opportunities for biostatistical analysis.
Location: The Centre for Musculoskeletal Research, The University of Manchester, United Kingdom
Skills required: Statistical analysis, data management, biostatistics, longitudinal modelling.
Duration: 1 month (the STSM must be completed before September 30th 2024)
Reference:
Bluett J, Riba-Garcia I, Verstappen SMM, Wendling T, Ogungbenro K, Unwin RD, Barton A. Development and validation of a methotrexate adherence assay. Ann Rheum Dis. 2019 Sep;78(9):1192-1197. doi: 10.1136/annrheumdis-2019-215446. Epub 2019 Jun 5. PMID: 31167761; PMCID: PMC6788879.
Gavan SP, Jani M, Bluett J, Payne K, Barton A. Therapeutic monitoring of TNF inhibitors for rheumatoid arthritis: evidence required following NICE’s recommendations. Rheumatol Adv Pract. 2020 Jun 22;4(2):rkaa023. doi: 10.1093/rap/rkaa023. PMID: 32914047; PMCID: PMC7474855.
Jani M, Chinoy H, Warren RB, Griffiths CE, Plant D, Fu B, Morgan AW, Wilson AG, Isaacs JD, Hyrich K, Barton A; Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate Collaborators. Clinical utility of random anti-tumor necrosis factor drug-level testing and measurement of antidrug antibodies on the long-term treatment response in rheumatoid arthritis. Arthritis Rheumatol. 2015 May;67(8):2011-9. doi: 10.1002/art.39169. Erratum in: Arthritis Rheumatol. 2015 Nov;67(11):3096. PMID: 26109489; PMCID: PMC4843946.
Contact: James Bluett: james.bluett@manchester.ac.uk
Project 4:
Title: The role of methotrexate metabolites in reducing immunogenicity of adalimumab in axial spondyloarthritis: An ancillary analysis on the clinical trial Effect of the Combination of Methotrexate and Adalimumab on Reduction of Immunization in Ankylosing Spondylitis (CoMARIS).
Material & methods: Red blood cells (RBC) Methotrexate polyglutamates (MTXPG) levels (up to 5 glutamic residues) in patients allocated to the adalimumab/MTX arm at week 12 and W26. Anti-drug antibodies (ADA) and adalimumab concentrations at 5 consecutive time points in 110 patients included in the CoMARIS trial. The objective of the STSM is to analyse the relationship between MTXPG levels, ADA emergence and adalimumab concentration overtime. This work is a collaboration with T Dervieux, Exagen, Vista, California, USA
Location: CNRS UPR 4301, anomedicines and Nanoprobes department, University of Tours, F
Skills required: Statistics, manuscript writing
Duration: 1 month (the STSM must be completed before September 30th 2024)
Reference:
- Ducourau E et al. Methotrexate effect on immunogenicity and long-term maintenance of adalimumab in axial spondyloarthritis: a multicentric randomised trial. RMD Open. 2020 Jan;6(1):e001047.
- Dervieux T, Kremer JM, Weinblatt ME. Ann Rheum Dis 2019;78:1285–1286.
Contact: denis.mulleman@univ-tours.fr