Validation in the ESPOIR cohort of vitamin K-dependent protein S (PROS) as a potential biomarker capable of predicting response to the methotrexate/etanercept combination

Abstract

Background: To validate the ability of PROS (vitamin K-dependent protein S) and CO7 (complement component C7) to predict response to the methotrexate (MTX)/etanercept (ETA) combination in rheumatoid arthritis (RA) patients who received this therapeutic combination in a well-documented cohort.

Method: From the ESPOIR cohort, RA patients having received the MTX/ETA or MTX/adalimumab (ADA) combination as a first-line biologic treatment were included. Serum concentrations of PROS and CO7 were measured by ELISA prior to the initiation of ETA or ADA, at a time where the disease was active (DAS28 ESR > 3.2). The clinical efficacy (response/non-response) of both combinations has been evaluated after at least 6 months of treatment, according to the EULAR response criteria with some modifications.

Results: Thirty-two were treated by MTX/ETA; the numbers of responders and non-responders were 24 and 8, respectively. Thirty-three patients received the MTX/ADA combination; 27 and 5 patients were respectively responders and non-responders. While there were no differences for demographic, clinical, biological, and X-rays data, as well as for CO7, serum levels of PROS tended to be significantly higher in responders to the MTX/ETA combination (p = 0.08) while no difference was observed in the group receiving MTX/ADA. For PROS, the best concentration threshold to differentiate both groups was calculated at 40 μg/ml using ROC curve. The theranostic performances of PROS appeared better for the ETA/MTX combination. When considering the response to this combination, analysis of pooled data from ESPOIR and SATRAPE (initially used to validate PROS and CO7 as potential theranostic biomarkers) cohorts led to a higher theranostic value of PROS that became significant (p = 0.009).

Conclusion: PROS might be one candidate of a combination of biomarkers capable of predicting the response to MTX/ETA combination in RA patients refractory to MTX.

Trial registration: ClinicalTrials.gov identifiers: NCT03666091 and NCT00234234 .

Keywords: Adalimumab; Biomarker; CO7; Etanercept; PROS; Prediction; Response; Rheumatoid arthritis.

Conflict of interest statement

The authors declare that they have no competing interests.

© 2022. The Author(s).

Figures

Fig. 1

Schematic view of the study and populations of subgroups having received the different bDMARDs

Fig. 2

Protein levels for the different classes of patients. Serum PROS (a) or CO7 (b) concentrations in responders (n=24 for ETA/MTX and n=27 for ADA/MTX) and non-responders (n=8 for ETA/MTX and n=5 for ADA/MTX) prior to methotrexate/etanercept or methotrexate/adalimumab initiation in RA patients who have failed to methotrexate in the ESPOIR cohort

Fig. 3

Determination of concentration threshold for PROS using receiver operating characteristic (ROC) from data of the ESPOIR cohort prior to treatment with etanercept/methotrexate or adalimumab/methotrexate. a ROC curve averaging of PROS prior to MTX/ETA treatment (left) or MTX/ADA combination (right). Gray line corresponds to 95% confidence interval. Black arrow corresponds to our best threshold (40 μg/mL). b Table showing the different parameters resulting from ROC curve analysis for each drug combination (MTX/ETA or MTX/ADA)

Fig. 4

Determination of concentration threshold for PROS, CO7 and PROS + CO7 combination using receiver operating characteristic (ROC) from data of both cohorts prior to treatment with etanercept and methotrexate. a Serum PROS (left) or CO7 (right) concentrations in responders (n=33) and non-responders (n=15) prior to etanercept/methotrexate initiation in RA patients who have failed to methotrexate in the 2 cohorts. b ROC curve averaging of PROS (left), CO7 (middle) and PROS+ CO7 (right) prior to MTX/ETA treatment; gray line corresponds to 95% confidence interval. c Table showing the performances of PROS, CO7, and PROS + CO7 combination resulting from ROC curve analysis for prediction of response to MTX/ETA treatment