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Updated: Feb 28, 2026

An Adoptive Transfer Model of Rheumatoid Arthritis in Mice
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Pathogenic Drivers of Difficult-to-Treat Rheumatoid Arthritis: Synovium and Beyond

András Miklós Dorgó1, Lilla Gunkl-Tóth1,2,3, György Nagy1,4,5

  • 1Department of Rheumatology and Immunology, Semmelweis University, 1023 Budapest, Hungary.

International Journal of Molecular Sciences
|February 27, 2026
PubMed

Insights

Difficult-to-treat rheumatoid arthritis (RA) involves complex factors beyond standard treatments. Understanding genetic, immune, and environmental influences is key to identifying new therapies for refractory RA.

Area of Science:

  • Rheumatology
  • Immunology
  • Genetics

Background:

  • Difficult-to-treat rheumatoid arthritis (D2T RA) presents persistent symptoms despite various therapies.
  • This condition poses a significant clinical challenge, impacting a substantial patient subset.

Purpose of the Study:

  • To provide a comprehensive review of molecular and cellular mechanisms underlying D2T RA.
  • To explore factors contributing to therapeutic resistance in rheumatoid arthritis.

Main Methods:

  • Narrative review synthesizing evidence on genetic, epigenetic, and immune factors.
  • Examination of synovial signatures, stromal cell pathways, and central determinants.
  • Inclusion of comorbid, environmental, and treatment-related factors.

Main Results:

  • D2T RA is influenced by a complex interplay of genetic, epigenetic, autoantibody, and immune cell factors.
  • Synovial and stromal cell pathways may drive chronicity independently of traditional targets.
  • Peripheral and central determinants, comorbidities, and environmental factors impact outcomes.

Conclusions:

  • A multifaceted approach is needed to understand and treat D2T RA.
  • Better patient stratification and novel therapeutic targets can be identified by integrating diverse biological and clinical data.
  • Addressing complex factors is crucial for managing refractory rheumatoid arthritis.
Keywords:
D2Tb/tsDMARDscomorbiditydifficult-to-treatinefficacypainpathogenesisrheumatoid arthritistreatment failure

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