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Objectives <p>Interstitial lung disease (ILD) is a serious extra-articular complication of rheumatoid arthritis (RA) and a leading cause of mortality. This meta-analysis aims to comprehensively evaluate the diagnostic utility and clinical relevance of tumor-associated biomarkers in patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD).</p> Methods <p>A systematic literature search was conducted in PubMed, EMBASE, Web of Science, CBM, Wan-Fang, and CNKI databases from inception to April 1, 2025. We included case-control and cohort studies that compared tumor marker levels between RA-ILD and RA-non-ILD patients, following the PICOS framework. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Pooled effect sizes were calculated as standardized mean differences (SMD) with 95% confidence intervals (CI) using random-effects models. Diagnostic accuracy was evaluated using summary receiver operating characteristic (ROC) curves.</p> Results <p>Thirty-six studies comprising 7300 RA patients were included. Compared to RA-non-ILD patients, those with RA-ILD showed significantly elevated levels of CA125 (SMD = 1.10, 95%CI 0.47–1.72), CA199 (SMD = 0.90, 95%CI 0.56–1.23), CA153 (SMD = 1.70, 95%CI 1.16–2.23), CEA (SMD = 0.58, 95%CI 0.24–0.92), KL-6 (SMD = 1.68, 95%CI 1.22–2.14), NSE (SMD = 0.32, 95%CI 0.16–0.48), and HE4 (SMD = 1.87, 95%CI 1.60–2.14). After adjustment for publication bias using trim-and-fill analysis, CYFRA21-1 was also significantly elevated (SMD = 0.48, 95%CI 0.06–0.89). For distinguishing RA-ILD, KL-6 demonstrated the highest diagnostic accuracy (AUC = 0.964), followed by CYFRA21-1 (AUC = 0.906).</p> Conclusion <p>Our findings, which are primarily based on evidence from Chinese cohorts, support the utility of CA125, CA199, CA153, CEA, KL-6, NSE, HE4, and CYFRA21-1 as biomarkers for RA-ILD. The superior diagnostic performance of KL-6 and CYFRA21-1 suggests their potential clinical utility as part of a multi-marker panel discriminating RA-ILD from RA-non-ILD and risk stratification, offering a complementary approach to imaging for identifying this high-risk RA complication.</p> Registration number <p>PROSPERO CRD42022362487.</p>

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Tumor markers in rheumatoid arthritis -associated interstitial lung disease: a systematic review and meta-analysis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月23日

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  • Zeng Qiaoqian,
  • Wu Qing,
  • Li Bowen,
  • Wei Qijiao,
  • Wang Na

摘要

Objectives

Interstitial lung disease (ILD) is a serious extra-articular complication of rheumatoid arthritis (RA) and a leading cause of mortality. This meta-analysis aims to comprehensively evaluate the diagnostic utility and clinical relevance of tumor-associated biomarkers in patients with Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD).

Methods

A systematic literature search was conducted in PubMed, EMBASE, Web of Science, CBM, Wan-Fang, and CNKI databases from inception to April 1, 2025. We included case-control and cohort studies that compared tumor marker levels between RA-ILD and RA-non-ILD patients, following the PICOS framework. Study quality was assessed using the Newcastle-Ottawa Scale (NOS). Pooled effect sizes were calculated as standardized mean differences (SMD) with 95% confidence intervals (CI) using random-effects models. Diagnostic accuracy was evaluated using summary receiver operating characteristic (ROC) curves.

Results

Thirty-six studies comprising 7300 RA patients were included. Compared to RA-non-ILD patients, those with RA-ILD showed significantly elevated levels of CA125 (SMD = 1.10, 95%CI 0.47–1.72), CA199 (SMD = 0.90, 95%CI 0.56–1.23), CA153 (SMD = 1.70, 95%CI 1.16–2.23), CEA (SMD = 0.58, 95%CI 0.24–0.92), KL-6 (SMD = 1.68, 95%CI 1.22–2.14), NSE (SMD = 0.32, 95%CI 0.16–0.48), and HE4 (SMD = 1.87, 95%CI 1.60–2.14). After adjustment for publication bias using trim-and-fill analysis, CYFRA21-1 was also significantly elevated (SMD = 0.48, 95%CI 0.06–0.89). For distinguishing RA-ILD, KL-6 demonstrated the highest diagnostic accuracy (AUC = 0.964), followed by CYFRA21-1 (AUC = 0.906).

Conclusion

Our findings, which are primarily based on evidence from Chinese cohorts, support the utility of CA125, CA199, CA153, CEA, KL-6, NSE, HE4, and CYFRA21-1 as biomarkers for RA-ILD. The superior diagnostic performance of KL-6 and CYFRA21-1 suggests their potential clinical utility as part of a multi-marker panel discriminating RA-ILD from RA-non-ILD and risk stratification, offering a complementary approach to imaging for identifying this high-risk RA complication.

Registration number

PROSPERO CRD42022362487.