Chromosome conformation signatures define predictive markers of inadequate response to methotrexate in early rheumatoid arthritis

• Published in: Journal of translational medicine Vol. 16; no. 1; pp. 18 - 11
• Main Authors: Carini, Claudio, Hunter, Ewan, Ramadass, Aroul S, Green, Jayne, Akoulitchev, Alexandre, McInnes, Iain B, Goodyear, Carl S
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 29-01-2018; BioMed Central; BMC
• Subjects: Arthritis, Rheumatoid - drug therapy; Biomarkers - metabolism; Care and treatment; Chromosomes, Human - chemistry; Cohort Studies; DMARDs (synthetic); Dosage and administration; Early rheumatoid arthritis; Gene expression; Genetic aspects; Humans; Logistic Models; Methotrexate; Methotrexate (MTX); Methotrexate - pharmacology; Methotrexate - therapeutic use; Precision medicine drug response biomarkers; Quantitative trait loci; Quantitative Trait Loci - genetics; Reproducibility of Results; Rheumatoid arthritis; DMARDs (synthetic); Methotrexate (MTX); Rheumatoid arthritis; Chromatin conformation signatures (CCS); Methotrexate; Early rheumatoid arthritis; Expression quantitative trait loci (eQTL); Precision medicine drug response biomarkers
• ISSN: 1479-5876; 1479-5876
• DOI: 10.1186/s12967-018-1387-9

There 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).
We 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.
We 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.
Here 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.