Academic Journal
Geroscience insights into difficult-to-treat rheumatoid arthritis: the role of unhealthy aging, comorbidity, and therapeutic complexity.
| Τίτλος: | Geroscience insights into difficult-to-treat rheumatoid arthritis: the role of unhealthy aging, comorbidity, and therapeutic complexity. |
|---|---|
| Συγγραφείς: | Lehoczki A; Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.; Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary.; Doctoral College, Health Sciences Division, Semmelweis University, Budapest, Hungary., Ungvari Z; Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary., Szappanos Á; Heart and Vascular Center, Semmelweis University, Budapest, Hungary.; Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary., Fekete M; Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.; Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary., Gunkl-Tóth L; Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary.; Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.; HUN-REN Chronic Pain Research Group, Pécs, Hungary., Nagy G; Heart and Vascular Center, Semmelweis University, Budapest, Hungary. nagy.gyorgy2@semmelweis.hu.; Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary. nagy.gyorgy2@semmelweis.hu.; Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary. nagy.gyorgy2@semmelweis.hu. |
| Πηγή: | GeroScience [Geroscience] 2026 Apr; Vol. 48 (2), pp. 2153-2177. Date of Electronic Publication: 2025 Dec 27. |
| Τύπος έκδοσης: | Journal Article; Review; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Springer International Publishing Country of Publication: Switzerland NLM ID: 101686284 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2509-2723 (Electronic) Linking ISSN: 25092723 NLM ISO Abbreviation: Geroscience Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Cham : Springer International Publishing, [2017]- |
| Ιατρικοί όροι (MeSH): | Arthritis, Rheumatoid*/immunology , Arthritis, Rheumatoid*/drug therapy , Arthritis, Rheumatoid*/therapy , Arthritis, Rheumatoid*/epidemiology , Aging*/immunology , Geroscience*, Antirheumatic Agents/therapeutic use ; Humans ; Comorbidity ; Aged ; Immunosenescence |
| Περίληψη: | Difficult-to-treat rheumatoid arthritis (D2T RA) is an emerging challenge in aging populations, where disease persistence and therapeutic failure often reflect not only autoimmune dysregulation but also the cumulative effects of age-related biological changes across multiple organ systems. This review reframes D2T RA through the lens of geroscience, highlighting how immunosenescence, inflammaging, and organ system vulnerability converge to create a treatment-resistant disease phenotype. Age-associated alterations in adaptive and innate immunity-such as diminished T cell diversity, impaired regulatory function, expansion of age-associated B cells, and heightened inflammasome activation-closely intersect with the immunopathogenesis of RA. The potential contribution of clonal hematopoiesis of indeterminate potential (CHIP) to systemic inflammation and myeloid dysfunction is also discussed as a novel mechanistic link. In parallel, aging of the musculoskeletal system magnifies joint damage, sarcopenia, and pain sensitization. Furthermore, advancing age is also accompanied by multimorbidity, polypharmacy, and frailty, which in turn constrain therapeutic options and increase the risk of adverse events. We argue that D2T RA in the elderly should not be viewed in isolation, but as part of a broader syndemic of age-related diseases driven by shared inflammatory and metabolic pathways. This perspective calls for a shift toward integrated, individualized care strategies that balance efficacy, safety, and quality of life. Future directions include the development of age-adapted treatment guidelines, expanded inclusion of older adults in clinical trials, and the application of artificial intelligence and machine learning to predict high-risk trajectories and personalize management. A geroscience-informed approach offers the conceptual foundation to meet the growing complexity of RA care in aging populations. (© 2025. The Author(s).) |
| Competing Interests: | Declarations. Ethics approval and consent to participate: N/A. Consent for publication: N/A. Competing interests: Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience. All other authors declare no competing interests. |
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| Grant Information: | TKP2021-NKTA-47 Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; TKP2021-EGA-29 Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; National Cardiovascular Laboratory Program (RRF-2.3.1-21-2022-00003) Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; the EKÖP-2024-9 New National Excellence Program of the Ministry for Culture Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; Innovation Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; 101004093/ EUniWell/EAC-A02-2019 / EAC-A02-2019-1 European University for Well-Being |
| Contributed Indexing: | Keywords: Age-related immune dysfunction; Aging; Biological aging; Difficult-to-treat rheumatoid arthritis; Elderly-onset rheumatoid arthritis; Frailty; Immunosenescence; Inflammaging; Multimorbidity; Personalized therapeutics; Polypharmacy; Precision medicine; Therapeutic resistance; Unhealthy aging |
| Substance Nomenclature: | 0 (Antirheumatic Agents) |
| Entry Date(s): | Date Created: 20251226 Date Completed: 20260309 Latest Revision: 20260926 |
| Update Code: | 20260926 |
| PubMed Central ID: | PMC12972182 |
| DOI: | 10.1007/s11357-025-02049-y |
| PMID: | 41454175 |
| Βάση Δεδομένων: | MEDLINE |
| FullText | Text: Availability: 0 CustomLinks: – Url: https://dx.doi.org/doi:10.1007/s11357-025-02049-y Name: EDS - Springer Nature Journals (s7799221) Category: fullText Text: View record at Springer – Url: https://resolver.ebsco.com/c/fiv2js/result?sid=EBSCO:cmedm&genre=article&issn=25092723&ISBN=&volume=48&issue=2&date=20260401&spage=2153&pages=2153-2177&title=GeroScience&atitle=Geroscience%20insights%20into%20difficult-to-treat%20rheumatoid%20arthritis%3A%20the%20role%20of%20unhealthy%20aging%2C%20comorbidity%2C%20and%20therapeutic%20complexity.&aulast=Lehoczki%20A&id=DOI:10.1007/s11357-025-02049-y Name: Full Text Finder (for New FTF UI) (ns324271) Category: fullText Text: Full Text Finder MouseOverText: Full Text Finder |
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| Items | – Name: Title Label: Title Group: Ti Data: Geroscience insights into difficult-to-treat rheumatoid arthritis: the role of unhealthy aging, comorbidity, and therapeutic complexity. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AU" term="%22Lehoczki+A%22">Lehoczki A</searchLink>; Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.; Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary.; Doctoral College, Health Sciences Division, Semmelweis University, Budapest, Hungary.<br /><searchLink fieldCode="AU" term="%22Ungvari+Z%22">Ungvari Z</searchLink>; Vascular Cognitive Impairment, Neurodegeneration, and Healthy Brain Aging Program, Department of Neurosurgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.; International Training Program in Geroscience, Doctoral College/Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.<br /><searchLink fieldCode="AU" term="%22Szappanos+Á%22">Szappanos Á</searchLink>; Heart and Vascular Center, Semmelweis University, Budapest, Hungary.; Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary.<br /><searchLink fieldCode="AU" term="%22Fekete+M%22">Fekete M</searchLink>; Institute of Preventive Medicine and Public Health, Semmelweis University, Budapest, Hungary.; Fodor Center for Prevention and Healthy Aging, Semmelweis University, Budapest, Hungary.<br /><searchLink fieldCode="AU" term="%22Gunkl-Tóth+L%22">Gunkl-Tóth L</searchLink>; Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary.; Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, Pécs, Hungary.; HUN-REN Chronic Pain Research Group, Pécs, Hungary.<br /><searchLink fieldCode="AU" term="%22Nagy+G%22">Nagy G</searchLink>; Heart and Vascular Center, Semmelweis University, Budapest, Hungary. nagy.gyorgy2@semmelweis.hu.; Department of Rheumatology and Immunology, Semmelweis University, Budapest, Hungary. nagy.gyorgy2@semmelweis.hu.; Department of Genetics, Cell- and Immunobiology, Semmelweis University, Budapest, Hungary. nagy.gyorgy2@semmelweis.hu. – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22101686284%22">GeroScience</searchLink> [Geroscience] 2026 Apr; Vol. 48 (2), pp. 2153-2177. <i>Date of Electronic Publication: </i>2025 Dec 27. – Name: TypePub Label: Publication Type Group: TypPub Data: Journal Article; Review; Research Support, Non-U.S. Gov't – Name: Language Label: Language Group: Lang Data: English – Name: TitleSource Label: Journal Info Group: Src Data: <i>Publisher: </i><searchLink fieldCode="PB" term="%22Springer+International+Publishing%22">Springer International Publishing </searchLink><i>Country of Publication: </i>Switzerland <i>NLM ID: </i>101686284 <i>Publication Model: </i>Print-Electronic <i>Cited Medium: </i>Internet <i>ISSN: </i>2509-2723 (Electronic) <i>Linking ISSN: </i><searchLink fieldCode="IS" term="%2225092723%22">25092723 </searchLink><i>NLM ISO Abbreviation: </i>Geroscience <i>Subsets: </i>MEDLINE – Name: PublisherInfo Label: Imprint Name(s) Group: PubInfo Data: <i>Original Publication</i>: Cham : Springer International Publishing, [2017]- – Name: SubjectMESH Label: MeSH Terms Group: Su Data: <searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid%22">Arthritis, Rheumatoid*</searchLink>/<searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid%22">Arthritis, Rheumatoid*</searchLink>/<searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid+drug+therapy%22">drug therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid%22">Arthritis, Rheumatoid*</searchLink>/<searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid+therapy%22">therapy</searchLink> <br /><searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid%22">Arthritis, Rheumatoid*</searchLink>/<searchLink fieldCode="MM" term="%22Arthritis%2C+Rheumatoid+epidemiology%22">epidemiology</searchLink> <br /><searchLink fieldCode="MM" term="%22Aging%22">Aging*</searchLink>/<searchLink fieldCode="MM" term="%22Aging+immunology%22">immunology</searchLink> <br /><searchLink fieldCode="MM" term="%22Geroscience%22">Geroscience*</searchLink><br /><searchLink fieldCode="MH" term="%22Antirheumatic+Agents%22">Antirheumatic Agents</searchLink>/<searchLink fieldCode="MH" term="%22Antirheumatic+Agents+therapeutic+use%22">therapeutic use</searchLink> ; <searchLink fieldCode="MH" term="%22Humans%22">Humans</searchLink> ; <searchLink fieldCode="MH" term="%22Comorbidity%22">Comorbidity</searchLink> ; <searchLink fieldCode="MH" term="%22Aged%22">Aged</searchLink> ; <searchLink fieldCode="MH" term="%22Immunosenescence%22">Immunosenescence</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: Difficult-to-treat rheumatoid arthritis (D2T RA) is an emerging challenge in aging populations, where disease persistence and therapeutic failure often reflect not only autoimmune dysregulation but also the cumulative effects of age-related biological changes across multiple organ systems. This review reframes D2T RA through the lens of geroscience, highlighting how immunosenescence, inflammaging, and organ system vulnerability converge to create a treatment-resistant disease phenotype. Age-associated alterations in adaptive and innate immunity-such as diminished T cell diversity, impaired regulatory function, expansion of age-associated B cells, and heightened inflammasome activation-closely intersect with the immunopathogenesis of RA. The potential contribution of clonal hematopoiesis of indeterminate potential (CHIP) to systemic inflammation and myeloid dysfunction is also discussed as a novel mechanistic link. In parallel, aging of the musculoskeletal system magnifies joint damage, sarcopenia, and pain sensitization. Furthermore, advancing age is also accompanied by multimorbidity, polypharmacy, and frailty, which in turn constrain therapeutic options and increase the risk of adverse events. We argue that D2T RA in the elderly should not be viewed in isolation, but as part of a broader syndemic of age-related diseases driven by shared inflammatory and metabolic pathways. This perspective calls for a shift toward integrated, individualized care strategies that balance efficacy, safety, and quality of life. Future directions include the development of age-adapted treatment guidelines, expanded inclusion of older adults in clinical trials, and the application of artificial intelligence and machine learning to predict high-risk trajectories and personalize management. A geroscience-informed approach offers the conceptual foundation to meet the growing complexity of RA care in aging populations.<br /> (© 2025. The Author(s).) – Name: Abstract Label: Competing Interests Group: Ab Data: Declarations.  Ethics approval and consent to participate: N/A.  Consent for publication: N/A. Competing interests: Dr. Zoltan Ungvari serves as Editor-in-Chief for GeroScience. 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(PMID: <searchLink fieldCode="PM" term="%2218501101%22">18501101)</searchLink> – Name: GrantInfo Label: Grant Information Group: Grant Data: TKP2021-NKTA-47 Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; TKP2021-EGA-29 Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; National Cardiovascular Laboratory Program (RRF-2.3.1-21-2022-00003) Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; the EKÖP-2024-9 New National Excellence Program of the Ministry for Culture Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; Innovation Nemzeti Kutatási, Fejlesztési és Innovaciós Alap; 101004093/ EUniWell/EAC-A02-2019 / EAC-A02-2019-1 European University for Well-Being – Name: SubjectMinor Label: Contributed Indexing Group: Data: <i>Keywords: </i>Age-related immune dysfunction; Aging; Biological aging; Difficult-to-treat rheumatoid arthritis; Elderly-onset rheumatoid arthritis; Frailty; Immunosenescence; Inflammaging; Multimorbidity; Personalized therapeutics; Polypharmacy; Precision medicine; Therapeutic resistance; Unhealthy aging – Name: NumberCAS Label: Substance Nomenclature Group: ID Data: 0 (Antirheumatic Agents) – Name: DateEntry Label: Entry Date(s) Group: Date Data: <i>Date Created: </i>20251226 <i>Date Completed: </i>20260309 <i>Latest Revision: </i>20260926 – Name: DateUpdate Label: Update Code Group: Date Data: 20260926 – Name: PubmedCentralID Label: PubMed Central ID Group: ID Data: PMC12972182 – Name: DOI Label: DOI Group: ID Data: 10.1007/s11357-025-02049-y – Name: AN Label: PMID Group: ID Data: 41454175 |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1007/s11357-025-02049-y Languages: – Code: eng Text: English PhysicalDescription: Pagination: StartPage: 2153 Subjects: – SubjectFull: Antirheumatic Agents therapeutic use Type: general – SubjectFull: Humans Type: general – SubjectFull: Comorbidity Type: general – SubjectFull: Aged Type: general – SubjectFull: Immunosenescence Type: general – SubjectFull: Arthritis, Rheumatoid immunology Type: general – SubjectFull: Arthritis, Rheumatoid drug therapy Type: general – SubjectFull: Arthritis, Rheumatoid therapy Type: general – SubjectFull: Arthritis, Rheumatoid epidemiology Type: general – SubjectFull: Aging immunology Type: general – SubjectFull: Geroscience Type: general Titles: – TitleFull: Geroscience insights into difficult-to-treat rheumatoid arthritis: the role of unhealthy aging, comorbidity, and therapeutic complexity. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Lehoczki A – PersonEntity: Name: NameFull: Ungvari Z – PersonEntity: Name: NameFull: Szappanos Á – PersonEntity: Name: NameFull: Fekete M – PersonEntity: Name: NameFull: Gunkl-Tóth L – PersonEntity: Name: NameFull: Nagy G IsPartOfRelationships: – BibEntity: Dates: – D: 01 M: 04 Text: 2026 Apr Type: published Y: 2026 Identifiers: – Type: issn-electronic Value: 2509-2723 Numbering: – Type: volume Value: 48 – Type: issue Value: 2 Titles: – TitleFull: GeroScience Type: main |
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