TY - JOUR

T1 - Identification of heterogenous treatment response trajectories to anti-IL6 receptor treatment in rheumatoid arthritis

AU - Blair, J. P. M.

AU - Bay-Jensen, A. -C.

AU - Tang, M. H.

AU - Frederiksen, P.

AU - Bager, C.

AU - Karsdal, M.

AU - Brunak, S.

PY - 2020

Y1 - 2020

N2 - Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed crosssectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p <0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p <0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.

AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease with fluctuating course of progression. Despite substantial improvement in treatments in recent years, treatment response is still not guaranteed. The aim of this study was to identify variation in Disease Activity Score 28 (DAS28) of RA patients in response to Tocilizumab, and to investigate both molecular and clinical factors influencing response. Clinical and biochemical data for 485 RA patients receiving Tocilizumab in combination with methotrexate were extracted from the LITHE phase III clinical study (NCT00106535), and post-hoc analysis conducted. Latent class mixed models were used to identify statistically distinct trajectories of DAS28 after the initiation of treatment. Biomarker measurements were then analysed crosssectionally and temporally, to characterise patients by serological biomarkers and clinical factors. We identified three distinct trajectories of drug response: class 1 (n = 85, 17.5%), class 2 (n = 338, 69.7%) and class 3 (n = 62, 12.8%). All groups started with high DAS28 on average (DAS28 > 5.1). Class 1 showed the least reduction in DAS28, with significantly more patients seeking escape therapy (p <0.001). Class 3 showed significantly higher rates of improvement in DAS28, with 58.1% achieving ACR response levels compared to 2.4% in class 1 (p <0.0001). Biomarkers of inflammation, MMP-3, CRP, C1M, showed greater reduction in class 3 compared to the other classes. Identification of more homogenous patient sub-populations of drug response may allow for more targeted therapeutic treatment regimens and a better understanding of disease aetiology.

KW - TOCILIZUMAB

KW - BIOMARKERS

KW - METHOTREXATE

KW - CARTILAGE

KW - BONE

U2 - 10.1038/s41598-020-70942-x

DO - 10.1038/s41598-020-70942-x

M3 - Journal article

C2 - 32811969

VL - 10

JO - Scientific Reports

JF - Scientific Reports

SN - 2045-2322

IS - 1

M1 - 13975

ER -