# Insulin Predicts Methotrexate Response by Affecting the Transcription of Methotrexate Target Genes in the Treatment-Naive Rheumatoid Arthritis

## TL;DR

This study shows that insulin levels can predict how well rheumatoid arthritis patients will respond to methotrexate treatment.

## Contribution

The novel finding is that insulin affects methotrexate target gene transcription, offering a new predictive model for treatment response.

## Key findings

- 53.5% of methotrexate-treated patients responded to treatment.
- Insulin levels and RA classification score were strong predictors of methotrexate response.
- Insulin altered transcription of methotrexate target genes in immune cells, influencing treatment outcomes.

## Abstract

Methotrexate (MTX), the most common first-line treatment in rheumatoid arthritis, is often insufficient, with no model capable of predicting response. The RA classification criteria, including autoantibodies and inflammation, were applied to 257 patients with newly diagnosed inflammatory arthritis in the cohort study, estimating MTX response. A total of 172 patients received MTX as the first anti-rheumatic drug and response was recorded at 1 year follow-up. A multivariable logistic regression used variables distinct between MTX-responders and non-responders to build the predictive model of response. Overall, 53.5% of MTX treated patients responded. Non-responders were frequently autoantibody positive, and responders were older, had lower RA classification scores, frequent corticosteroid use, and high insulin levels at baseline. Inflammation parameters were comparable between the groups. In the multiple regression analysis, the RA classification score and age at the first visit were strong predictors of MTX response (AUC 0.697, p < 0.0001). Including blood levels of insulin and IFNg improved AUC to 0.782 (p < 0.0001), offering early discrimination between responders and non-responders with high accuracy. Cellular experiments showed that insulin could be used to estimate MTX response by demonstrating that insulin changed the transcription of MTX target genes in the folate metabolism after exposing CD4+ cells ex vivo, which could facilitate MTX response in immune cells.