Background Late-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. Methods We 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. Results Twelve 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, I2 = 0.0%), indicating persistent disease activity. LORA patients achieved clinical remission less frequently with biologic/targeted synthetic DMARDs (RR = 0.36, 95% CI = 0.16–0.79). However, drug retention rates were equivalent between groups (HR = 0.98, 95% CI = 0.87–1.11). MR analysis demonstrated that genetically elevated sIL6R was associated with reduced RA risk (IVW OR = 0.92, 95% CI = 0.87–0.98, p = 0.006), with consistent estimates across sensitivity methods. TYK2 showed a concordant inverse association. Single-cell profiling of 13,979 cells identified inflammatory fibroblasts and macrophages as dominant IL6R/IL6ST/STAT3-expressing populations and principal nodes in IL6 and TNF signaling networks. Pseudotime analysis revealed progressive upregulation of IL6ST and STAT3 along fibroblast differentiation trajectories enriched in synovium. Conclusions LORA 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.<Table Float="No" ID="Taba"> <tgroup cols="2"> <colspec align="left" colname="c1" colnum="1" /> <colspec align="left" colname="c2" colnum="2" /> <tbody> <row> <entry align="left" nameend="c2" namest="c1"> 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. </entry> </row> </tbody> </tgroup> </Table> Graphical Abstract

Age-stratified treatment response in rheumatoid arthritis: a systematic review, meta-analysis, and integrated genetic and single-cell evidence implicating IL6R/TYK2 signaling

期刊论文
发表日期：

2026年3月18日

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Mingfeng Yang,
Fangyan Xu,
Bin Zhang,
Hui Pi

摘要

Background

Late-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.

Methods

We 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.

Results

Twelve 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, I² = 0.0%), indicating persistent disease activity. LORA patients achieved clinical remission less frequently with biologic/targeted synthetic DMARDs (RR = 0.36, 95% CI = 0.16–0.79). However, drug retention rates were equivalent between groups (HR = 0.98, 95% CI = 0.87–1.11). MR analysis demonstrated that genetically elevated sIL6R was associated with reduced RA risk (IVW OR = 0.92, 95% CI = 0.87–0.98, p = 0.006), with consistent estimates across sensitivity methods. TYK2 showed a concordant inverse association. Single-cell profiling of 13,979 cells identified inflammatory fibroblasts and macrophages as dominant IL6R/IL6ST/STAT3-expressing populations and principal nodes in IL6 and TNF signaling networks. Pseudotime analysis revealed progressive upregulation of IL6ST and STAT3 along fibroblast differentiation trajectories enriched in synovium.

Conclusions

LORA 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.

Graphical Abstract