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Background <p>Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting 1–2% of the global population, characterized by systemic inflammation and progressive joint damage. The disease’s complex pathophysiology involves multiple immunological cells, inflammatory cytokines, and non-immune components, limiting the effectiveness of single-target therapeutic approaches.</p> Objective <p>This review examines the limitations of single-target pathways in RA treatment and explores the advantages of multi-target therapeutic strategies in improving patient outcomes through simultaneous modulation of multiple inflammatory cascades.</p> Methods <p>A comprehensive review of single-target pathways (MAPK, JAK-STAT, PI3K/AKT/mTOR signalling) and multi-target approaches was conducted, including analysis of current pharmacological agents, mechanisms of action, and clinical applications.</p> Key findings <p>Single-target therapies demonstrate significant limitations including incomplete symptom control, compensatory mechanisms, and treatment resistance. Multi-target approaches address these shortcomings through dual cytokine inhibition (TNF-α/IL-17, IL-6/IL-1), JAK inhibitors with broad-spectrum activity, and combined T-cell/B-cell targeting strategies. Current therapeutic options include JAK inhibitors (tofacitinib, baricitinib, upadacitinib), TNF-α inhibitors, IL-6 inhibitors, and various DMARDs, each with distinct mechanisms and safety profiles.</p> Conclusions <p>Multi-target pharmaceutical approaches represent a significant advancement in RA management by addressing disease complexity through simultaneous pathway modulation. Integration with biomarker-driven precision medicine enables personalized treatment strategies. Despite improved outcomes, challenges remain regarding dosage optimization and long-term safety. Further clinical trials are essential to refine these therapeutic strategies and enhance their applicability across diverse patient populations, ultimately transforming RA management and improving quality of life.</p>

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Narrative review on the development of multi-target pharmacological agents for the management of rheumatoid arthritis

  • 期刊论文

  • 发表日期：

    2026年1月10日

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  • Yarava Dhanush,
  • Vakkalagadda Siva Ganesh

摘要

Background

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease affecting 1–2% of the global population, characterized by systemic inflammation and progressive joint damage. The disease’s complex pathophysiology involves multiple immunological cells, inflammatory cytokines, and non-immune components, limiting the effectiveness of single-target therapeutic approaches.

Objective

This review examines the limitations of single-target pathways in RA treatment and explores the advantages of multi-target therapeutic strategies in improving patient outcomes through simultaneous modulation of multiple inflammatory cascades.

Methods

A comprehensive review of single-target pathways (MAPK, JAK-STAT, PI3K/AKT/mTOR signalling) and multi-target approaches was conducted, including analysis of current pharmacological agents, mechanisms of action, and clinical applications.

Key findings

Single-target therapies demonstrate significant limitations including incomplete symptom control, compensatory mechanisms, and treatment resistance. Multi-target approaches address these shortcomings through dual cytokine inhibition (TNF-α/IL-17, IL-6/IL-1), JAK inhibitors with broad-spectrum activity, and combined T-cell/B-cell targeting strategies. Current therapeutic options include JAK inhibitors (tofacitinib, baricitinib, upadacitinib), TNF-α inhibitors, IL-6 inhibitors, and various DMARDs, each with distinct mechanisms and safety profiles.

Conclusions

Multi-target pharmaceutical approaches represent a significant advancement in RA management by addressing disease complexity through simultaneous pathway modulation. Integration with biomarker-driven precision medicine enables personalized treatment strategies. Despite improved outcomes, challenges remain regarding dosage optimization and long-term safety. Further clinical trials are essential to refine these therapeutic strategies and enhance their applicability across diverse patient populations, ultimately transforming RA management and improving quality of life.