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<p>Subcutaneous methotrexate (SC-MTX) remains the first-line treatment for rheumatoid arthritis (RA) patients who have failed oral therapy, offering superior bioavailability and clinical efficacy. However, existing fixed-dosage protocols (7.5–25&#xa0;mg weekly) fail to account for individual patient variability, resulting in 30–40% treatment discontinuation due to inadequate response or adverse events. Through comprehensive pharmacokinetic–pharmacodynamic (PK/PD) modeling incorporating 35 differential equations, we analyzed the impact of varying dosage intervals (7–17&#xa0;days) and amounts (7–30&#xa0;mg) on disease activity parameters including DAS28, tender joint count (TJC), and swollen joint count (SJC). The analysis revealed significant oscillatory behavior in disease control with fixed dosing, demonstrating that 67% of patients require doses outside standard ranges for optimal outcomes. These findings emphasize the critical need for personalized optimal dosage strategies that adhere to clinical physician guidelines while adapting to individual patient responses. To address this challenge, we implemented an Active Disturbance Rejection Control (ADRC) framework that generates real-time optimal drug dosage guidelines by continuously monitoring disease activity and compensating for patient-specific disturbances. The ADRC-based optimization achieved remarkable clinical benefits: an 87% American College of Rheumatology 70% improvement criteria (ACR70) response rate compared to 62% with conventional protocols, 38.9% faster remission (22 vs. 36&#xa0;weeks), and 92% sustained remission rate while reducing cumulative MTX exposure by 26.8% (615&#xa0;mg vs. 840&#xa0;mg over 40&#xa0;weeks). This technology-enabled approach transforms RA management by providing physicians with personalized dosing guidelines that maximize therapeutic efficacy while minimizing toxicity, establishing a new paradigm for precision medicine in chronic disease management.</p>

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Precision medicine in rheumatoid arthritis: active disturbance rejection control-based personalized methotrexate dosing framework for enhanced therapeutic outcomes

  • 期刊论文

  • 发表日期：

    2026年5月8日

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  • K. Rajkumar,
  • S. Narayanan,
  • N. Sivakumaran

摘要

Subcutaneous methotrexate (SC-MTX) remains the first-line treatment for rheumatoid arthritis (RA) patients who have failed oral therapy, offering superior bioavailability and clinical efficacy. However, existing fixed-dosage protocols (7.5–25 mg weekly) fail to account for individual patient variability, resulting in 30–40% treatment discontinuation due to inadequate response or adverse events. Through comprehensive pharmacokinetic–pharmacodynamic (PK/PD) modeling incorporating 35 differential equations, we analyzed the impact of varying dosage intervals (7–17 days) and amounts (7–30 mg) on disease activity parameters including DAS28, tender joint count (TJC), and swollen joint count (SJC). The analysis revealed significant oscillatory behavior in disease control with fixed dosing, demonstrating that 67% of patients require doses outside standard ranges for optimal outcomes. These findings emphasize the critical need for personalized optimal dosage strategies that adhere to clinical physician guidelines while adapting to individual patient responses. To address this challenge, we implemented an Active Disturbance Rejection Control (ADRC) framework that generates real-time optimal drug dosage guidelines by continuously monitoring disease activity and compensating for patient-specific disturbances. The ADRC-based optimization achieved remarkable clinical benefits: an 87% American College of Rheumatology 70% improvement criteria (ACR70) response rate compared to 62% with conventional protocols, 38.9% faster remission (22 vs. 36 weeks), and 92% sustained remission rate while reducing cumulative MTX exposure by 26.8% (615 mg vs. 840 mg over 40 weeks). This technology-enabled approach transforms RA management by providing physicians with personalized dosing guidelines that maximize therapeutic efficacy while minimizing toxicity, establishing a new paradigm for precision medicine in chronic disease management.