Abstract
BackgroundThere is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to first-line disease-modifying anti-rheumatic drugs (DMARD). We explored whether differences in genomic architecture represented by a chromosome conformation signature (CCS) in blood taken from early RA patients before methotrexate (MTX) treatment could assist in identifying non-response to DMARD and, whether there is an association between such a signature and RA specific expression quantitative trait loci (eQTL).MethodsWe looked for the presence of a CCS in blood from early RA patients commencing MTX using chromosome conformation capture by EpiSwitch™. Using blood samples from MTX responders, non-responders and healthy controls, a custom designed biomarker discovery array was refined to a 5-marker CCS that could discriminate between responders and non-responders to MTX. We cross-validated the predictive power of the CCS by generating 150 randomized groups of 59 early RA patients (30 responders and 29 non-responders) before MTX treatment. The CCS was validated using a blinded, independent cohort of 19 early RA patients (9 responders and 10 non-responders). Last, the loci of the CCS markers were mapped to RA-specific eQTL.ResultsWe identified a 5-marker CCS that could identify, at baseline, responders and non-responders to MTX. The CCS consisted of binary chromosome conformations in the genomic regions of IFNAR1, IL-21R, IL-23, CXCL13 and IL-17A. When tested on a cohort of 59 RA patients, the CCS provided a negative predictive value of 90.0% for MTX response. When tested on a blinded independent validation cohort of 19 early RA patients, the signature demonstrated a true negative response rate of 86 and a 90% sensitivity for detection of non-responders to MTX. Only conformations in responders mapped to RA-specific eQTL.ConclusionsHere we demonstrate that detection of a CCS in blood in early RA is able to predict inadequate response to MTX with a high degree of accuracy. Our results provide a proof of principle that a priori stratification of response to MTX is possible, offering a mechanism to provide alternative treatments for non-responders to MTX earlier in the course of the disease.
Highlights
There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to firstline disease-modifying anti-rheumatic drugs (DMARD)
A total of 86 early RA patients and 34 healthy controls (HC) were included. 67 were used to develop the chromosome conformation signature (CCS), and an independent, blinded cohort of 19 patients used in validation (Fig. 1)
We identified a 5-marker panel consisting of chromosomal conformations in the genomic loci of IFNAR1, IL-21R, IL-23, IL-17A, and CXCL13 that could identify R and NR to MTX with 90% sensitivity in an independent blinded validation cohort
Summary
There is a pressing need in rheumatoid arthritis (RA) to identify patients who will not respond to firstline disease-modifying anti-rheumatic drugs (DMARD). The diagnosis of RA prompts early initiation of methotrexate (MTX), the first choice of disease modifying anti-rheumatic drug (DMARD) as recommended by European League against Rheumatism (EULAR) and American College of Rheumatology (ACR) ‘treat-to-target’ strategy (target being remission or low disease activity). This approach has substantially improved outcomes in the last decade [4,5,6]. Several attempts have been made to develop diagnostics able to predict MTX-response [16,17,18,19,20,21,22,23] (Additional file 1: Table S1) most studies have failed
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