SynthesisClinical rheumatology2026
Age-stratified treatment response in rheumatoid arthritis: a systematic review, meta-analysis, and integrated genetic and single-cell evidence implicating IL6R/TYK2 signaling.
Synthesis in Clinical rheumatology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundLate-onset rheumatoid arthritis (LORA, onset ≥ 60 years, a threshold commonly adopted based on accelerated immunosenescence at this age) represents a growing clinical challenge as population's age, yet therapeutic outcomes in this subgroup remain inadequately characterized. Whether age-related immunological alterations influence treatment response and which molecular pathways underpin potential differences remain unclear.
methodsWe conducted a systematic review and meta-analysis following PRISMA guidelines, searching PubMed, Scopus, and Web of Science through 30 September 2025. Studies comparing LORA and young-onset RA (YORA, onset < 60 years) patients receiving DMARDs were eligible. Random-effects models estimated pooled effect sizes for disease activity, remission rates, and drug retention. Two-sample Mendelian randomization (MR) assessed causal relationships between genetically proxied plasma IL6 receptor (sIL6R) and TYK2 levels and RA risk using published GWAS summary statistics. Single-cell RNA sequencing data from RA joint tissues (GSE299518; cartilage, meniscus, synovium) were analyzed to map drug target expression and intercellular communication networks.
resultsTwelve studies (n>5000 patients) met inclusion criteria. Post-treatment DAS28 scores were higher in LORA than YORA (MD = 0.26, 95% CI = 0.11-0.41, I
conclusionsLORA patients exhibit diminished remission rates under current therapeutic regimens despite comparable drug survival. Genetic and single-cell evidence converge on IL6R and TYK2 pathways as mechanistically relevant targets, providing a rationale for age-stratified therapeutic optimization in RA. Key Points • This study evaluates the efficacy and safety of treatments for LORA using meta-analysis, Mendelian randomization, and single-cell RNA sequencing. • LORA patients show different treatment outcomes, particularly in biologic retention rates and clinical remission, compared to YORA patients. • Genetic markers, especially in the IL6R and TYK2 pathways, were identified as key modifiers of drug response in LORA. • The findings highlight the need for personalized treatment strategies for elderly rheumatoid arthritis patients based on genetic and immune system profiles.
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