Differential DNA methylation correlates with response to methotrexate in rheumatoid arthritis.

Darren Plant,Anne Barton,John D Isaacs,Kimme L Hyrich,Ann W Morgan,Anthony G Wilson,Nisha Nair,Suzanne M Verstappen

doi:10.1093/rheumatology/kez411

Abstract

ObjectivesIdentifying blood-based biomarkers that predict treatment response in RA is a clinical priority. We investigated differential DNA methylation as a candidate biomarker of response for the first-line drug used in RA, MTX.MethodsDNA methylation was measured in DNA samples from individuals recruited to the Rheumatoid Arthritis Medication Study. Differentially methylated positions were compared between whole blood samples collected at baseline and at 4 weeks from patients who, by 6 months, had a good (n = 34) or poor response (n = 34) to MTX using linear modelling, adjusting for gender, age, cell composition, baseline 28-joint disease activity score (DAS28) and smoking status. Analyses also compared methylation with changes in DAS28 and changes in swollen joint count and tender joint count, and changes in CRP over the initial 6 months after MTX commencement. Differentially methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study.ResultsIn the discovery group, two CpG sites showed methylation changes at 4 weeks associated with clinical EULAR response by 6 months. Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP. Of the 12 CpGs, four showed replicated association in an independent dataset of samples from the Rheumatoid Arthritis Medication Study.ConclusionThese data represent an advance on current practice by contributing to a personalized medicine strategy allowing an escalation or change in therapy as early as 4 weeks.

Highlights

Multiple studies have shown that patients with RA who receive prompt and efficacious treatment resulting in sustained remission are less likely to experience long-term disability and premature mortality [13]
Methylated positions showing significant differences with any response parameter were tested using pyrosequencing in an independent group of 100 patients from the Rheumatoid Arthritis Medication Study
Significant changes in methylation for three differentially methylated positions associated with change in tender joint counts, three with change in swollen joint count and a further four with change in CRP

Summary

Introduction

Multiple studies have shown that patients with RA who receive prompt and efficacious treatment resulting in sustained remission are less likely to experience long-term disability and premature mortality [13]. A clinical decision regarding response to MTX is generally made at 6 months following treatment initiation. During that time, prolonged inflammation can cause lasting disability in patients who are nonresponsive to treatment. It is imperative to identify earlier biomarkers of response so that patients CLINICAL SCIENCE.

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