{
  "abstract": "Objectives Methotrexate (MTX) effectively controls rheumatoid arthritis (RA) but often leads to side effects (SE) such as gastrointestinal (GI) issues, liver toxicity and bone marrow suppression. To develop clinically interpretable machine learning (ML) models that accurately predict MTX-related SE in patients with RA taking MTX. The aim was to enhance predictive accuracy and to identify patient-specific risk factors using explainable artificial intelligence (XAI), thereby enabling transparent clinical interpretation. We specifically sought to address the unmet need for individualised risk stratification using real-world, multicentre observational data.Design Retrospective case-control study.Setting Across 23 rheumatology clinics in South Korea, based on data from a nationwide multicentre cohort.Participants A total of 5077 patients with RA were initially enrolled from the Korean Observational Study Network for Arthritis. After excluding those with missing clinical, demographic or prescription data and those not receiving MTX, 2375 patients remained eligible. Among these, 1654 and 1218 patients were included in the overall SE and GI SE analysis groups, respectively, after 1:1 propensity score matching. All patients were aged ≥18 years and met the 1987 American College of Rheumatology classification criteria.Primary and secondary outcome measures The primary outcome was the presence of SE in patients with RA taking MTX, categorised into overall SE and GI SE, based on standardised patient questionnaires and clinical assessments. The secondary outcome was the identification of key predictors using SHapley Additive exPlanations (SHAP) to enhance the interpretability of ML predictions.Results Among six ML classifiers, extreme gradient boosting demonstrated the highest performance in predicting overall SE (area under the curve (AUC) 0.781, F1 score 0.672, area under the precision-recall curve (AUPRC) 0.757) and GI SE (AUC 0.701, F1 score 0.690, AUPRC 0.670). SHAP analysis identified key predictive features including age, physician visual analogue scale score, alanine aminotransferase, Health Assessment Questionnaire score, celecoxib use and drug adherence. Logistic regression confirmed statistical significance for multiple variables (eg, OR 4.63; 95% CI 1.41 to 20.90 for non-adherence >30 days; OR 1.45; 95% CI 1.14 to 1.85 for celecoxib use). DeLong’s test indicated that boosting models significantly outperformed support vector machine (p<0.001).Conclusions Interpretable ML models using real-world clinical data can accurately predict SE in patients with RA taking MTX. These models may facilitate early identification of high-risk individuals and inform personalised treatment strategies. Integration into clinical decision support systems could improve MTX safety monitoring. Further prospective validation in external cohorts is warranted.",
  "authors": [
    {
      "affiliations": [
        "Department of Medical Sciences, Kangwon National University, Chuncheon-si, The Republic of Korea"
      ],
      "name": "Junbeom Jang"
    },
    {
      "affiliations": [
        "Department of Internal Medicine, Kangwon National University, Chuncheon-si, Gangwon-do, The Republic of Korea"
      ],
      "name": "Woo Jin Kim"
    },
    {
      "affiliations": [
        "Next-Generation Information Center, Kangwon National University Hospital, Chuncheon-si, Gangwon, The Republic of Korea"
      ],
      "name": "Sang Won Park"
    },
    {
      "affiliations": [
        "Division of Rheumatology, Department of Internal Medicine, Kangwon National University Hospital, Chuncheon-si, Kangwon-do, The Republic of Korea"
      ],
      "name": "Ki Won Moon"
    }
  ],
  "title": "Development of explainable machine learning models to predict side effects in patients with rheumatoid arthritis taking methotrexate treatment: a nationwide multicentre cohort study",
  "uid": "4837b13a-50ad-5fbf-83b8-cf81df7f4594"
}