Methotrexate’s effect on cells and adalimumab immunogenicity in axial spondyloarthritis: A mathematical study
Abstract
Axial spondyloarthritis is a chronic inflammatory disease impacting the spine and joints. Tumour necrosis factor inhibitors, like adalimumab, are used to treat severe cases, but up to 25% of patients discontinue due to reduced effectiveness, often from emergence of anti-drug antibodies. Methotrexate, while ineffective alone in treatment, has shown potential in reducing the formation of anti-drug antibodies to the therapeutic compound, but its mechanism of action on the immune response remains unclear. The objective of the study is to develop a mathematical model that describes the impact of methotrexate in reducing the immunogenicity of adalimumab in axial spondyloarthritis. Based on mathematical models established in the literature, we formulate a system of ordinary differential equations to describe the temporal dynamics of the immune cells (T and B lymphocytes), the therapeutic compounds in the study (adalimumab and methotrexate), and TNFα. The data used to calibrate the model are sourced from previously published in vitro experiments and a clinical trial which involved 110 patients who received adalimumab alone or adalimumab in combination with methotrexate, from whom adalimumab concentration, lymphocyte counts, and antibody titres collected along five visits during the course of treatment. A computational model is used to generate virtual patient cohorts reflecting the original data and to simulate immunogenic responses to adalimumab. Simulations across 31 scenarios for the mechanism whereby methotrexate acts on the immune cell subsets, predict that methotrexate likely reduces immunogenicity by increasing apoptosis of activated T cells. Author summary: We present a mathematical model that describes the impact of the disease-modifying drug methotrexate in suppressing immunogenicity of the tumour necrosis factor inhibitor adalimumab by describing the temporal dynamics of the immune response based on a study of patients with axial spondyloarthtitis. We study computationally 31 scenarios for the possible mechanism of action on different immune cell subsets via generated virtual patient cohorts reflecting the available data. Our simulations predict that methotrexate likely reduces immunogenicity by suppressing activated T cells. Our model’s predictions can help guide further experimental work to illuminate methotrexate’s mechanism of action in chronic inflammatory diseases, and improve quality of life for patients whose treatment is often interrupted due to development of anti-drug antibodies.
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BibTeX
@article{sottile2026methotrexates,
title = {{Methotrexate’s effect on cells and adalimumab immunogenicity in axial spondyloarthritis: A mathematical study}},
author = {Sara Sottile and Conception Paul and Rachel Audo and Theo Rispens and Denis Mulleman and Peter Rashkov},
journal = {PLoS Computational Biology},
year = {2026},
month = sep,
doi = {10.1371/journal.pcbi.1014740},
url = {https://hal.science/hal-05758085v1},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Methotrexate’s effect on cells and adalimumab immunogenicity in axial spondyloarthritis: A mathematical study
AU - Sara Sottile
AU - Conception Paul
AU - Rachel Audo
AU - Theo Rispens
AU - Denis Mulleman
AU - Peter Rashkov
PY - 2026
DA - 2026/09/21
JO - PLoS Computational Biology
DO - 10.1371/journal.pcbi.1014740
UR - https://hal.science/hal-05758085v1
AB - Axial spondyloarthritis is a chronic inflammatory disease impacting the spine and joints. Tumour necrosis factor inhibitors, like adalimumab, are used to treat severe cases, but up to 25% of patients discontinue due to reduced effectiveness, often from emergence of anti-drug antibodies. Methotrexate, while ineffective alone in treatment, has shown potential in reducing the formation of anti-drug antibodies to the therapeutic compound, but its mechanism of action on the immune response remains unclear. The objective of the study is to develop a mathematical model that describes the impact of methotrexate in reducing the immunogenicity of adalimumab in axial spondyloarthritis. Based on mathematical models established in the literature, we formulate a system of ordinary differential equations to describe the temporal dynamics of the immune cells (T and B lymphocytes), the therapeutic compounds in the study (adalimumab and methotrexate), and TNFα. The data used to calibrate the model are sourced from previously published in vitro experiments and a clinical trial which involved 110 patients who received adalimumab alone or adalimumab in combination with methotrexate, from whom adalimumab concentration, lymphocyte counts, and antibody titres collected along five visits during the course of treatment. A computational model is used to generate virtual patient cohorts reflecting the original data and to simulate immunogenic responses to adalimumab. Simulations across 31 scenarios for the mechanism whereby methotrexate acts on the immune cell subsets, predict that methotrexate likely reduces immunogenicity by increasing apoptosis of activated T cells. Author summary: We present a mathematical model that describes the impact of the disease-modifying drug methotrexate in suppressing immunogenicity of the tumour necrosis factor inhibitor adalimumab by describing the temporal dynamics of the immune response based on a study of patients with axial spondyloarthtitis. We study computationally 31 scenarios for the possible mechanism of action on different immune cell subsets via generated virtual patient cohorts reflecting the available data. Our simulations predict that methotrexate likely reduces immunogenicity by suppressing activated T cells. Our model’s predictions can help guide further experimental work to illuminate methotrexate’s mechanism of action in chronic inflammatory diseases, and improve quality of life for patients whose treatment is often interrupted due to development of anti-drug antibodies.
SN - 1553-734X
SN - 1553-7358
ER -