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Peer-reviewedCC BYJournal of neuroinflammation

Characteristic central nervous system fingerprints and related molecular signatures in difficult-to-treat rheumatoid arthritis.

  • Lilla Gunkl-Tóth1,2,3
  • Gergely Orsi4,5
  • Noémi Császár-Nagy6,7
  • Lili Duzsik6
  • Gábor Mátay6
  • Krisztina Csókási8
  • Gábor Sütő9
  • Gábor Kumánovics10
  • Szabolcs Takács11
  • Zoltán Vidnyánszky12
  • József Kun2,13,14
  • Krisztina Takács-Lovász2
5 more authors
  • Anett Pintér1
  • Panna Királyhidi1,15
  • Georg Schett16
  • György Nagy17,18,19
  • Zsuzsanna Helyes20,21,22
22 affiliations
  1. 1Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary.
  2. 2Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary.
  3. 3HUN-REN-PTE Chronic Pain Research Group, Pécs, Hungary.
  4. 4HUN-REN-PTE Clinical Neuroscience MR Research Group, Pécs, Hungary.
  5. 5Department of Neurology, Medical School, University of Pécs, Pécs, Hungary.
  6. 6Psychosomatic Outpatient Clinic, Budapest, Hungary.
  7. 7Ludovika University of Public Service, Budapest, Hungary.
  8. 8Institute of Psychology, Faculty of Humanities and Social Sciences, University of Pécs, Pécs, Hungary.
  9. 9Second Department of Medicine and Nephrology-Diabetes Centre, University of Pécs, Pécs, Hungary.
  10. 10Department of Rheumatology, Immunology and Musculoskeletal Rehabilitation, Medical School, University of Pécs, Pécs, Hungary.
  11. 11Institute of Psychology, Department of General Psychology and Methodology Faculty of Humanities and Social Sciences, Károli Gáspár University of the Reformed Church in Hungary, Budapest, Hungary.
  12. 12Brain Imaging Centre, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
  13. 13Hungarian Centre for Genomics and Bioinformatics, Szentágothai Research Centre, University of Pécs, Pécs, Hungary.
  14. 14National Laboratory for Drug Research and Development, Budapest, Hungary.
  15. 15Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary.
  16. 16Department of Internal Medicine 3 - Rheumatology and Clinical Immunology, Friedrich-Alexander-University (FAU) Erlangen-Nürnberg and Universitätsklinikum Erlangen, Erlangen, Germany.
  17. 17Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary. [email protected].
  18. 18Department of Genetics, Cell and Immunobiology, Semmelweis University, Budapest, Hungary. [email protected].
  19. 19Heart and Vascular Centre, Semmelweis University, Budapest, Hungary. [email protected].
  20. 20Department of Pharmacology and Pharmacotherapy, Medical School, University of Pécs, Pécs, Hungary. [email protected].
  21. 21HUN-REN-PTE Chronic Pain Research Group, Pécs, Hungary. [email protected].
  22. 22National Laboratory for Drug Research and Development, Budapest, Hungary. [email protected].
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Abstract

Background

Despite guideline-recommended treatment, approximately 30% of rheumatoid arthritis (RA) patients remain symptomatic and are classified as difficult-to-treat (D2T), representing an unmet clinical need. D2T RA is a heterogeneous state potentially involving differences across several biological and psychological levels, but the exact underlying mechanisms remain unclear. To capture this complexity, our multimodal cross-sectional study aimed to characterize the contributing factors of the D2T state with a multimodal approach.Methods

31 D2T RA (defined by EULAR, 2021), 18 non-D2T RA patients, and 32 healthy controls (HCs) were included. All participants underwent a clinical assessment, psychological analysis (in-depth interviews, the Rorschach test, and questionnaires), two resting-state functional MRI (fMRI) scans with standardized heat pain stimulation in between, and peripheral blood transcriptomic analysis.Results

The activity and connectivity of brain regions, especially the somatosensory cortex and the posterior cingulate cortex, one of the main hubs of the default mode network (DMN), showed significant alterations in D2T RA. Furthermore, acute pain stimulation influenced connectivity patterns of D2T patients differently compared to non-D2T patients and HCs. These results are in line with the psychological profiles of D2T patients characterized by cognitive, coping, and emotional dysregulations as well as altered pain processing. Transcriptomic analysis identified mediators, pathways, and signaling mechanisms such as neuregulin 1 (NRG1) and type I interferon signaling associated with neuroinflammation and synaptic plasticity.Conclusion

Our findings identify central nervous system (CNS) alterations as a meaningful contributor to the D2T RA phenotype, helping to explain persistent symptom burden beyond inflammation. These characteristic neuroimmune signatures support multidisciplinary, personalized interventions that target CNS processes alongside inflammation control to improve outcomes.

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Cite

BibTeXRIS
BibTeX
@article{gunkltoth2026characteristic,
  title = {{Characteristic central nervous system fingerprints and related molecular signatures in difficult-to-treat rheumatoid arthritis.}},
  author = {Lilla Gunkl-Tóth and Gergely Orsi and Noémi Császár-Nagy and Lili Duzsik and Gábor Mátay and Krisztina Csókási and Gábor Sütő and Gábor Kumánovics and Szabolcs Takács and Zoltán Vidnyánszky and József Kun and Krisztina Takács-Lovász and Anett Pintér and Panna Királyhidi and Georg Schett and György Nagy and Zsuzsanna Helyes},
  journal = {Journal of neuroinflammation},
  year = {2026},
  month = aug,
  doi = {10.1186/s12974-026-03992-z},
  url = {https://europepmc.org/article/MED/42958501},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Characteristic central nervous system fingerprints and related molecular signatures in difficult-to-treat rheumatoid arthritis.
AU  - Lilla Gunkl-Tóth
AU  - Gergely Orsi
AU  - Noémi Császár-Nagy
AU  - Lili Duzsik
AU  - Gábor Mátay
AU  - Krisztina Csókási
AU  - Gábor Sütő
AU  - Gábor Kumánovics
AU  - Szabolcs Takács
AU  - Zoltán Vidnyánszky
AU  - József Kun
AU  - Krisztina Takács-Lovász
AU  - Anett Pintér
AU  - Panna Királyhidi
AU  - Georg Schett
AU  - György Nagy
AU  - Zsuzsanna Helyes
PY  - 2026
DA  - 2026/08/03
JO  - Journal of neuroinflammation
DO  - 10.1186/s12974-026-03992-z
UR  - https://europepmc.org/article/MED/42958501
AB  - Background  Despite guideline-recommended treatment, approximately 30% of rheumatoid arthritis (RA) patients remain symptomatic and are classified as difficult-to-treat (D2T), representing an unmet clinical need. D2T RA is a heterogeneous state potentially involving differences across several biological and psychological levels, but the exact underlying mechanisms remain unclear. To capture this complexity, our multimodal cross-sectional study aimed to characterize the contributing factors of the D2T state with a multimodal approach.Methods  31 D2T RA (defined by EULAR, 2021), 18 non-D2T RA patients, and 32 healthy controls (HCs) were included. All participants underwent a clinical assessment, psychological analysis (in-depth interviews, the Rorschach test, and questionnaires), two resting-state functional MRI (fMRI) scans with standardized heat pain stimulation in between, and peripheral blood transcriptomic analysis.Results  The activity and connectivity of brain regions, especially the somatosensory cortex and the posterior cingulate cortex, one of the main hubs of the default mode network (DMN), showed significant alterations in D2T RA. Furthermore, acute pain stimulation influenced connectivity patterns of D2T patients differently compared to non-D2T patients and HCs. These results are in line with the psychological profiles of D2T patients characterized by cognitive, coping, and emotional dysregulations as well as altered pain processing. Transcriptomic analysis identified mediators, pathways, and signaling mechanisms such as neuregulin 1 (NRG1) and type I interferon signaling associated with neuroinflammation and synaptic plasticity.Conclusion  Our findings identify central nervous system (CNS) alterations as a meaningful contributor to the D2T RA phenotype, helping to explain persistent symptom burden beyond inflammation. These characteristic neuroimmune signatures support multidisciplinary, personalized interventions that target CNS processes alongside inflammation control to improve outcomes.
SN  - 1742-2094
ER  -