Monday, 25 Mar 2019

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Precision Genetics Can Predict Methotrexate Non-Responders

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.


The author has no conflicts of interest to disclose related to this subject

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