Precision Genetics Can Predict Methotrexate Non-Responders Save

Investigators from Glasgow and Oxford have identified changes in genomic architecture, represented by a chromosome conformation signature (CCS), that can predict nonresponse to methotrexate in early rheumatoid arthritis (RA) patients.

Recognizing that studies show 35–59% of RA patients do not achieve clinically meaningful responses after starting MTX, they sought to identify a pattern of genetic changes in 59 early RA patients that would predict poor responses to MTX therapy.

Background research suggests that external (epigenetic) perturbations may lead to changes in 3-dimensional structure and the functional regulation of gene activity. Episwitch was used to identify changes in chromosomal conformation signature between two states (disease vs. non-disease, pre-treatment vs. post-treatment). Their results were developed in one cohort and validated in a separate cohort.

Using patients from an early or undifferentiated RA (SERA) study, they identified a 5-marker CCS that could descriminate MTX responders and non-responders at baseline in a cohort of 59 early RA patients.

This genetic "signature" had a negative predictive value of 90% for MTX response. When tested on an independent validation cohort of 19 early RA patients, the signature similary had a high negative predictive value and a 90% sensitivity for identifying MTX non-responders.

Their CCS consisted of chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. This CCS signature points to a central role in the IL-17/IL-23 axis, with the two most informative long-range chromatin interactions predicting MTX-NR coming from IL-17A and CXCL13 loci.

The authors note that while there are many well-known predictors of RA disease activty, these do not correlate well with treatment responses.

These data demonstrate the ability to predict, a priori, nonresponse to MTX early in the course of the disease. This and other precision tools are desperately needed and require further study.