P17 Prediction of response of methotrexate in patients with rheumatoid arthritis using serum lipidomics
Authors: Maciejewski Mateusz , Sands Caroline , Nair Nisha , Ling Stephanie , Verstappen Suzanne , Hyrich Kimme , RAMS MATURA , Barton Anne , Ziemek Daniel , Lewis Matthew , Plant Darren 
Published: April 2020

Abstract

Background
For patients with rheumatoid arthritis (RA), introduction of early, effective therapy has consistently been shown to improve long-term outcomes. Low-dose methotrexate (MTX) is commonly prescribed as first-line treatment for RA. However, MTX is not effective for a large minority of patients and there is currently no way to determine ahead of therapy which patients are most likely to benefit. Metabolomics and lipidomics are emerging approaches for studying patient stratification in RA and have the potential to identify disease processes that underpin treatment outcomes. Here we apply state-of-the-art machine learning algorithms to predict MTX treatment response, by testing serum lipid levels measured at two time-points (pre-treatment and following 4 weeks on drug) to predict MTX response by 6 months.

Methods
This study included patients from the Rheumatoid Arthritis Medication Study (RAMS), a UK multi-centre one-year prospective observational study investigating predictors of response to MTX in patients with RA. Since 2008, patients who are about to start MTX for the first time are asked to provide demographic and clinical data, as well as blood samples to permit DNA, RNA and serum-based biomarker studies. Patients about to commence MTX treatment were followed longitudinally and those categorised as good or non-responders following 6 months on-drug using EULAR response criteria were analysed. Serum lipid levels were measured at pre-treatment and following 4 weeks on drug using ultra-performance liquid chromatography tailored for complex lipid analysis, coupled to mass spectrometry. State-of-the-art supervised machine learning methods were then applied to predict EULAR response at 6 months. Models including lipid levels were compared to models including clinical covariates (including: MTX start dose, steroid use at inclusion, BMI, number of swollen joints, number of tender joints, CRP levels, patients’ assessment of their overall wellbeing, gender, age-at-inclusion, age-at-onset, disease duration, HAQ score and pre-treatment smoking habits).

Results
Following quality control, 3,366 features (1,060 in negatively-charged mode and 2,306 in positive mode) were available for analysis at pre-treatment and 4 weeks from 100 RA patients categorised as good (GR, n = 50) or poor (NR, n = 50) responders to MTX following 6 months on drug. The best model performance for the classifier including clinical covariates was observed using L1/L2-regularised logistic regression (ROC AUC 0.68 ± 0.02). However, the clinical covariate model outperformed the classifier including lipid levels when either pre- or on-treatment time-points were investigated (ROC AUC 0.61 ± 0.02).

Conclusion
These data do not support the utility of early treatment lipidomic monitoring in routine clinical practice in patients started on MTX for their RA.

Disclosures
M. Maciejewski: Shareholder/stock ownership; owns stock or stock options in Pfizer. C. Sands None. N. Nair None. S. Ling None. S. Verstappen None. K. Hyrich None. A. Barton None. D. Ziemek Shareholder/stock ownership; owns stock or stock options in Pfizer. M. Lewis None. D. Plant None.