Hydroxychloroquine works in synergy with oral methotrexate, promoting the increase in erythrocyte mean corpuscular volume, which could serve as a fellow biomarker of therapy response in patients with rheumatoid arthritis (RA).

This retrospective observational study was conducted to examine if hydroxychloroquine increased erythrocyte mean corpuscular volume (MCV) initiated by methotrexate therapy and if it is linked with better clinical efficacy in people with RA.

Biologically-naïve, early rheumatoid arthritis patients who started methotrexate orally were included. Thereafter, the baseline characteristics, disease activity score- erythrocyte sedimentation rate (DAS28-ESR) and MCV per month were studied. Conventional and machine-learning statistical methods were applied to the group of 655 patients (Cohort 1), and results were authenticated using Cohort 2 (225 patients).

At six months, hydroxychloroquine used along with methotrexate increased the probability of response described in this study as clinical remission or low disease activity by up to two times. There was an elevated MCV from two months following the combination therapy. The increase in MCV at three months corresponded to the simultaneous decrease in the DAS28-ESR in the prediction of clinical response at six months.

Overall, five routes of change in MCV over six months from the baseline were recognized. Compared to just methotrexate, the odds ratio of response to combination therapy was 16.2, categorized within the MCV elevation greater than 5fL class in the majority of patients.

The results provide a mechanistic view into the clinical advantage of hydroxychloroquine when used with methotrexate, which could work as a companion biomarker of therapy response.