Pre-defined Gene Co-expression Modules in Rheumatoid Arthritis Transition towards Molecular Health following Anti-TNF Therapy
Two prospectively followed RA patient cohorts were studied, in addition to 10 disease-free controls.
The first cohort (adalimumab cohort; n = 70) were recruited from UK centres to the Biologics in Rheumatoid Arthritis Genetics and Genomics Study Syndicate (BRAGGSS), previously described by Oliver et al. 
All selected patients were white adults with a clinician diagnosis of RA, and about to begin treatment with adalimumab for the first time for their RA symptoms. Patients were categorised as either good- or non-responders to treatment following 3-months of therapy using established EULAR response criteria. Good responders (n = 50) were patients who achieved a <2.6 Disease Activity Score of 28-joints (DAS28) (i.e. DAS28 clinical remission) and a DAS28 improvement of >1.2 at the 3-month follow-up. Non-responders (n = 20) were defined as patients that had a 3-month DAS28 score of >5.1 (i.e. high disease activity) and an improvement of <0.6. Non-responders were excluded from analysis if they reported non-adherence to treatment or if anti-drug antibodies were detected in their blood samples. Ethics was approved by the North West 6 Central Manchester South Research Ethics Committee (COREC 04/Q1403/37) and all patients provided written consent.
The second patient cohort (MTX cohort; n = 85) were recruited from the Rheumatoid Arthritis Medication Study (RAMS), a UK multicentre longitudinal observational study that enrols new-onset RA patients who are about to commence therapy with MTX. Response to treatment was assessed 6-months after treatment using the EULAR response criteria. Patients were then categorised as good (n = 42) or non-responders (n = 43) to MTX. RAMS was approved by the Central Manchester NHS Research Ethics Committee (reference 08/H1008/25) and all patients provided written informed consent.
The disease-free controls were recruited under the National Repository for Healthy Volunteers (NRHV) study within the Versus Arthritis Centre for Genetics and Genomics at the University of Manchester. Ethical approval was obtained (reference REC 99/8/84) and all volunteers gave written informed consent in compliance with Good Clinical Practice and the Declaration of Helsinki.
Summary demographic information on both patient cohorts and disease-free controls are provided in Supplementary Table 1.
Whole blood gene expression profiles were captured using the Affymetrix Human Transcriptome Array 2.0 (HTA) at pre-treatment and following 3-months of treatment with adalimumab, and using the Illumina HumanHT-12 v3 Array at pre-treatment and following 4-weeks of treatment with MTX, in the adalimumab cohort and MTX cohort respectively.
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