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. 2018 May 7;13(5):e0196793.
doi: 10.1371/journal.pone.0196793. eCollection 2018.

Validation Study of Genetic Biomarkers of Response to TNF Inhibitors in Rheumatoid Arthritis

Free PMC article

Validation Study of Genetic Biomarkers of Response to TNF Inhibitors in Rheumatoid Arthritis

Rosario Lopez-Rodriguez et al. PLoS One. .
Free PMC article


Genetic biomarkers are sought to personalize treatment of patients with rheumatoid arthritis (RA), given their variable response to TNF inhibitors (TNFi). However, no genetic biomaker is yet sufficiently validated. Here, we report a validation study of 18 previously reported genetic biomarkers, including 11 from GWAS of response to TNFi. The validation was attempted in 581 patients with RA that had not been treated with biologic antirheumatic drugs previously. Their response to TNFi was evaluated at 3, 6 and 12 months in two ways: change in the DAS28 measure of disease activity, and according to the EULAR criteria for response to antirheumatic drugs. Association of these parameters with the genotypes, obtained by PCR amplification followed by single-base extension, was tested with regression analysis. These analyses were adjusted for baseline DAS28, sex, and the specific TNFi. However, none of the proposed biomarkers was validated, as none showed association with response to TNFi in our study, even at the time of assessment and with the outcome that showed the most significant result in previous studies. These negative results are notable because this was the first independent validation study for 12 of the biomarkers, and because they indicate that prudence is needed in the interpretation of the proposed biomarkers of response to TNFi even when they are supported by very low p values. The results also emphasize the requirement of independent replication for validation, and the need to search protocols that could increase reproducibility of the biomarkers of response to TNFi.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

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Grant support

This work was supported by the Instituto de Salud Carlos III (Spain) through grants [PI14/01651 and RD16/0012/0014 to AG; and PI12/01909 to JJG-R]. These grants are partially financed by the European Regional Development Fund of the EU (FEDER). R. L.-R. was supported by Instituto de Salud Carlos III (Spain) through a Postdoctoral Contract “Sara Borrell” [CD14/00186]. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.