Background/Purpose: The introduction of biologic drug therapies targeting specific components of the inflammatory response represents a huge advance in the treatment of rheumatoid arthritis (RA). Despite this, up to 40% of patients fail to respond well to these therapies. Ideally, clinicians would like to identify patients who are likely to respond to therapy as early as possible in the disease course, making identification of reliable biomarkers of response an important area of research. Recent studies suggest that epigenetic control of gene expression may be important in RA; we have therefore hypothesized that epigenetic changes such as aberrant DNA methylation patterns may provide useful biomarkers of response to biologics.

Objectives: To identify a DNA methylation signature indicative of response to TNF-blockade therapy in patients with RA.

Methods: Patients were recruited from the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS) longitudinal cohort. Patients (n=72) were selected based on having an extreme response phenotype after 3 months of treatment with etanercept; 36 were good responders defined as having an endpoint DAS28<2.6, and 36 were poor responders defined as having an improvement of <0.6 or between 0.6-1.2 with an endpoint DAS28 of >5.1. Whole blood DNA from each patient, sampled before initiation of etanercept therapy, was bisulfite converted and an epigenome wide association study was conducted using the HumanMethylation450 BeadChip (Illumina). A detection threshold was applied and probes with a detection p-value of greater than 0.01 were removed. Differentially methylated positions between responders and non responders were identified by linear regression following quantile normalisation.

Results: 4 CpG sites showed differences between responders and non-responders to etanercept passing a false discovery rate of 0.05 with a (p≤10^-7): cg04857395, cg16426293, cg03277049, cg14862806. While none of the 4 CpG sites mapped to obvious candidate genes, the most differentially methylated probe mapped to exon 7 of LRPAP1, which is highly expressed in mononuclear cells. Statistical adjustment for whole blood cell composition did not qualitatively alter the results. 

Conclusion: This is the first methylome wide investigation of treatment response to TNF blockade therapy in RA and, while further well powered studies are required, these preliminary data identify methylation biomarkers of response.

Acknowledgements: This work was supported by the innovative medicines initiative joint undertaking (IMI JU) funded project BeTheCure, (contract number 115142-2). The work was supported by the NIHR Manchester Musculoskeletal Biomedical Research Unit. We also acknowledge support from Arthritis Research UK.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/differential-methylation-related-to-response-to-etanercept-in-patients-with-rheumatoid-arthritis/