Pre-defined gene co-expression modules in rheumatoid arthritis transition towards molecular health following anti-TNF

Megan Sutcliffe1, Nisha Nair1,2, James Oliver1,2

  • 1Versus Arthritis Centre for Genetics and Genomics, Division of Musculoskeletal Sciences, The University of Manchester.

Abstract

Insights

Researchers validated gene expression changes in rheumatoid arthritis (RA) patients treated with TNF inhibitors (TNFi). While some gene modules shifted towards a disease-free state, these changes were not exclusive to TNFi therapy.

Area of Science:

  • Immunology
  • Genomics
  • Rheumatology

Background:

  • Rheumatoid arthritis (RA) lacks reliable biomarkers to predict treatment response to TNF inhibitors (TNFi).
  • Gene co-expression modules have been previously reported to change in response to TNFi therapy in RA patients.
  • Understanding these molecular changes is crucial for personalized medicine in RA.

Purpose of the Study:

  • To replicate previously reported changes in gene co-expression modules in RA patients treated with TNFi.
  • To determine if observed module expression changes are specific to TNFi therapy.
  • To assess if module expression transitions towards a disease-free state in patients responding to treatment.

Main Methods:

  • Analysis of published whole-blood transcriptomic data from RA patients treated with adalimumab (a TNFi) or methotrexate.
  • Assessment of treatment response using EULAR criteria at 3 or 6 months.
  • Application of linear mixed models to evaluate transitions in module expression towards a disease-free state.

Main Results:

  • Replication of published findings for 25 out of 27 gene co-expression modules in the adalimumab cohort.
  • Six modules transitioned towards a disease-free state by 3 months, independent of clinical response.
  • One module (M3.2), linked to inflammation and TNF biology, correlated with adalimumab response; similar, but less pronounced, patterns were seen with methotrexate.

Conclusions:

  • Independent validation of module expression changes in response to RA therapy.
  • Observed molecular effects are not specific to TNFi, suggesting broader mechanisms.
  • Further research is needed to explore specific modules for molecular classification of therapeutic response in RA.

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