Background Response to anti-TNF therapy is highly variable in patients with rheumatoid arthritis (RA). Predictors of treatment response have been identified, but their ability to predict response in individual patients is poor (1). MicroRNAs (miRNAs) have been suggested to influence susceptibility to RA and disease severity (2).
Objectives To identify predictive miRNAs associated with treatment response in 180 patients with RA (disease duration <6 months), who participated in the OPERA Study, a prospective, double-blind, placebo-controlled study (3).
Methods Patients received methotrexate 7.5 mg weekly (increased to 20 mg/week within two months) in combination with adalimumab (n=89)/placebo-adalimumab (n=91) 40 mg subcutaneously every other week. If swollen joints were present, they were injected with triamcinolone. Treatment response after 1 year was assessed according to EULAR response (good vs. moderate/poor), DAS28(CRP) remission, and ACR/EULAR Boolean remission criteria. MiRNAs were purified from pretreatment whole blood. Expressions of miRNAs were determined using TaqMan® Human MicroRNA LDA, A Card v2.0 (Applied Biosystems). Raw Cycle threshold (Ct) values of each miRNA were pre-processed using quantile normalization. Interaction between miRNAs and treatment was tested for each miRNA, and potential predictive miRNAs (p-values<0.05) were identified. Potential predictive miRNAs were then included in a multivariate model with treatment response as the dependent variable and subsequently backwards eliminated using the Bayesian Information Criterion. All effects were reported for a Ct inter-quartile range increase.
Results In the adalimumab-group/placebo-group 82%/74% achieved EULAR good response, 74%/49% achieved DAS28(CRP) remission, and 48%/30% EULAR/ACR Boolean remission. After backwards elimination a low expression of miR-22 in the adalimumab group was associated with response using EULAR response (OR: 12.18, 95% CI: 2.30-140.45, p=0.01) and DAS28(CRP) remission (OR: 44.74, 95% CI: 5.99-736.18, p=0.001) as outcome parameters. Similarly, high expressions of miR-23b (OR: 0.48, 95% CI: 0.24-0.86, p=0.03) and miR-758 (OR: 0.20, 95% CI: 0.03-0.86, p=0.05) in the adalimumab group were associated with response using DAS28(CRP) remission as outcome parameter. A high expression of miR-629 in the adalimumab group (OR: 0.45, 95% CI: 0.23-0.82, p=0.01) was associated with response using ACR/EULAR remission.
Conclusions We identified several miRNAs in whole blood from patients with early RA associated with treatment response to adalimumab. Validation studies are needed to assess the utility of these miRNAs as predictive biomarkers in patients with RA.
Prajapati R et al. Pharmacogenomics 2011;12:1571-85.
Trenkmann M et al. Clin Rev Allergy Immunol 2010;39:10-9.
Hørslev-Petersen K et al. Arthritis Rheum 2011; 63 (Supplement 10): 394.
Disclosure of Interest S. B. Krintel: None Declared, C. Dehlendorff: None Declared, M. Hetland: None Declared, K. Hørslev-Petersen: None Declared, K. Andersen: None Declared, P. Junker: None Declared, J. Pødenphant: None Declared, T. Ellingsen: None Declared, P. Ahlqvist: None Declared, H. Lindegaard Consultant for: MSD, Merck, Roche, A. Linauskas: None Declared, A. Schlemmer: None Declared, M. Dam: None Declared, I. Hansen: None Declared, H. C. Horn: None Declared, A. Jørgensen: None Declared, J. Raun: None Declared, C. Ammitzbøll: None Declared, M. Østergaard: None Declared, K. Stengaard-Pedersen: None Declared, J. Johansen: None Declared