Towards a mathematical model of the methotrexate effect on immunogenicity to adalimumab in axial spondyloarthritis

PeterRashkov

Institute of Mathematics and Informatics, Bulgarian Academy of Science, Sofia, Bulgaria

"Towards a mathematical model of the methotrexate effect on immunogenicity to adalimumab in axial spondyloarthritis"

Axial spondyloarthritis (SpA) is a chronic inflammatory disease impacting the joints in the axial skeleton (e.g. chest, spine, pelvis). Tumor necrosis factor inhibitors (TNFi), such as the monoclonal antibody adalimumab, are used to treat severe cases, but therapy is often discontinued due to loss of efficacy, not least resulting from immunogeniocity and development of anti-drug antibodies (ADA). The disease-modifying drug methotrexate (MTX) has shown potential in reducing the formation of ADA to various TNFi in rheumatoid arthritis (Krickaert et al, 2012), but little is known about its mode of action. We adapt a mechanistic mathematical model for immunogencity towards adalimumab based on Chen et al. 2014 to describe the impact of MTX in reducing immunogenicity, and parametrise it based on patient data from a multicentric randomised trial (Ducoureau et al, 2020). ODEs describe the pharmacokinetics and pharmacodynamics of the therapeutic compounds (adalimumab only or adalimumab and MTX, depending on patient cohort), the dynamics of T and B lymphocytes, antigen presenting cells, and some relevant cytokines for the disease. Due to the large size of this model, we employ several reduced models to estimate some of the parameter values. The model is used to simulate several scenarios in order to elucidate the most likely modes of action of MTX to reduce immunogenicity by comparing the simulated and measured ADA titres along 5 hospital visits. This is joint work with Sara Sottile (Bologna, Italy) and Denis Mulleman (Tours, France). This work is based upon work from COST Action ENOTTA (CA21147), supported by COST (European Cooperation in Science and Technology), and Contract KP-06-DKOST-13 of the Bulgarian Fund for Scientific Research.
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