Rheumatic and musculoskeletal diseases (RMDs) are a diverse range of conditions that primarily affect joints, leading to pain, functional impairment and disability. Increasing evidence highlights the critical role of complex interactions among leukocytes, such as T cells, dendritic cells, neutrophils, and monocytes in the pathogenesis of certain RMDs

Telomeres are specialized structures located at the terminal portions of linear chromosomes that protect genomic integrity and stability. Leukocyte telomere length (LTL) has been associated with the rate of biological ageing and the onset or severity of various age-related diseases, including cancer, cardiovascular disease, obesity and immune-mediated disorders5. In recent years, a growing body of evidence has suggested a potential link between telomere length (TL) and the pathogenesis of rheumatic and musculoskeletal diseases (RMDs), including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), psoriatic arthritis (PsA), osteoarthritis (OA), and systemic sclerosis (SSc). However, the nature of this association remains controversial and appears to be disease-specific. 

To better elucidate the role of LTL in the development of RMDs and to identify potential therapeutic targets, we analyzed data from the UK Biobank to investigate whether LTL is associated with the incidence of RMDs.

This multicenter, community-based cohort study utilized data from the United Kingdom Biobank, which recruited more than 500,000 participants from March 2006 to December 2010, with longitudinal follow-up. Cox proportional hazards model was used to assess the relationship between LTL and the risk of RMDs. Models were adjusted for age, sex, ethnicity, body mass index, smoking status, alcohol consumption. Townsend deprivation index and white blood cell count. Kaplan–Meier survival curves were plotted to  illustrate the incidence of RMDs among participants stratified by baseline LTL.

A total of 81,907 participants with missing data for LTL were excluded from the final analysis. Compared with participants who remained free of RMDs (controls), those who developed RMDs during the follow-up period tended to be older, had a higher average BMI, exhibited shorter LTL, and included a higher proportion of females and individuals of White ethnicity. Additionally, a notably higher prevalence of current smoking was observed in the RMD group. These differences in baseline characteristics highlight potential demographic, anthropometric, and lifestyle factors associated with the subsequent development of RMDs in this large prospective cohort.

In the prospective analysis, after adjustment for age, sex, ethnicity, BMI, smoking status, alcohol consumption and Townsend deprivation index, shorter LTL was significantly associated with an increased risk of AAV (HR 0.825, 95% CI 0.718–0.949; P < 0.05), gout (HR 0.944, 95% CI 0.922–0.965; P < 0.05) , OA (HR 0.966, 95% CI 0.957–0.976; P < 0.05), PBC (HR 0.836, 95% CI 0.740–0.944; P < 0.05), RA (HR 0.960, 95% CI 0.935–0.985; P < 0.05), SpA (HR 0.939, 95% CI 0.903–0.977; P < 0.05) and pSS (HR 0.890, 95% CI 0.826–0.958; P < 0.05) . These hazard ratios indicate that longer LTL confers a protective effect against the development of these two conditions. 

Kaplan-Meier Survival Curves for Incident RMDs by LTL Quartiles

We further plotted Kaplan-Meier curves for RMDs that exhibited an inverse dose-response relationship with LTL. The protective effect was especially strong and statistically significant across all higher quartiles (Q2, Q3, and Q4) for AAV, gout, OA, RA, and primary Sjögren’s syndrome (pSS). For other conditions, the pattern showed greater variablity. In PBC, a meaningful risk reduction was observed only in Q3, but not in Q2 or Q4. In SSc, significance protection appearedin Q2 and Q3, but not in the longest quartile (Q4). For SpA, reduced risk was evident in Q2 and Q4, but absent in Q3.

Taken together, these findings indicate that longer leukocyte telomere length is associated with a decreased incidence of several rheumatic and musculoskeletal diseases. However, the magnitude, statistical significance, and linearity of this protective relationship vary across specific disease,  pointing to possible variations in the underlying biological processses or disease-specific mechanisms connecting telomere length to RMD development. 

This study demonstrated identified significant associations between shortened LTL and an increased risk of several RMDs. These findings suggest that LTL may serve as a potential biomarker for certain RMDs and highlight its possible involvement in their pathogenesis. Further research is warranted to elucidate the underlying mechanisms and to explore the clinical utility of LTL, which holds promise for advancing the prevention, early detection, and treatment of these conditions.