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Peer-reviewedCC BY 4.0Frontiers in Immunology

Anti-Ro52/TRIM21 seropositivity in interstitial lung disease: effect modification by disease subtype and myositis-specific antibody context

  • Junfeng Su1,2
  • Yan Du3
  • Chen Zhu4
  • Haodong Zhou5
  • Huyan Wang6
  • Yinjun Du7
  • Qiyuan Wang8
  • Zexin Chen9
  • Hanjun Cao10
  • Man Huang1,2
  • Jing Xue3
10 affiliations
  1. 1Department of General Intensive Care Unit, the Second Affiliated Hospital of Zhejiang University School of Medicine
  2. 2Key Laboratory of Multiple Organ Failure (Zhejiang University), Ministry of Education
  3. 3Department of Rheumatology, the Second Affiliated Hospital of Zhejiang University School of Medicine
  4. 4Key Laboratory of Respiratory Disease of Zhejiang Province, Department of Pulmonary and Critical Care Medicine, the Second Affiliated Hospital of Zhejiang University School of Medicine
  5. 5Department of Pharmacy, the Second Affiliated Hospital of Zhejiang University School of Medicine
  6. 6Department of Rheumatology, the First Affiliated Hospital of Ningbo University
  7. 7Department of Rheumatology, Ningbo Yinzhou No.2 Hospital
  8. 8Department of Radiology, the Second Affiliated Hospital of Zhejiang University School of Medicine
  9. 9Department of Clinical Epidemiology & Biostatistics, the Second Affiliated Hospital of Zhejiang University School of Medicine
  10. 10Department of Critical Care Medicine, The First People’s Hospital of Jingdezhen
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Abstract

Background: Anti-Ro52/TRIM21 shows contradictory prognostic associations in interstitial lung disease (ILD), protective in some cohorts and adverse in others. We evaluated whether it acts as an independent predictor or a phenotypic marker and whether its effect is modified by disease subtype and myositis-specific antibodies.

Methods: We retrospectively identified 538 adults with radiologically confirmed interstitial lung disease (228 anti-Ro52-positive) from a 2010–2020 single-center cohort. Cox proportional-hazards models were sequentially adjusted for demographic, smoking, malignancy, and pulmonary-function covariates. Pre-specified effect modification by connective tissue disease (CTD) status and myositis-specific antibodies was assessed by likelihood-ratio interaction tests with false-discovery-rate correction. Robustness to missing data was supported by multiple imputation ( m = 20) and a missing-not-at-random (MNAR) tipping-point analysis.

Results: Ro52 positivity was associated with younger age, CTD predominance, and lower complement levels. Pre-specified effect modification was suggested: anti-Ro52 trended toward lower mortality in CTD-ILD (HR 0.73, 95% CI 0.49–1.07, P = 0.104) but did not independently increase mortality within the anti-MDA5-positive subgroup (HR 1.73, 95% CI 0.66–4.54). Instead, the adverse prognostic effect of anti-MDA5 was numerically greater among anti-Ro52-positive than Ro52-negative patients (MDA5 HR 10.57, 95% CI 3.60–31.03 vs. 2.56, 95% CI 0.97–6.74), although the formal interaction term did not reach statistical significance ( P = 0.055). The fully adjusted (Model 6) HR was 0.72 (95% CI 0.52–0.99; P = 0.045); further adjustment for CTD status (Model 7) attenuated the association to non-significance (HR 0.75, 95% CI 0.54–1.04, P = 0.091), and IPCW weighting and time-varying-age analyses were likewise non-significant; malignancy independently predicted mortality (HR 1.81, 95% CI 1.15–2.88; P = 0.012).

Conclusion: Anti-Ro52 is a context-dependent phenotypic marker of immune-mediated ILD, not a universal prognostic biomarker. Its prognostic association is heterogeneous across ILD phenotypes: it is not independently protective in CTD-ILD (adjusted HR 0.73, P = 0.104), whereas the adverse prognostic effect of anti-MDA5 was numerically greater among anti-Ro52-positive than Ro52-negative patients (MDA5 HR 10.57 vs. 2.56), although this interaction did not reach statistical significance ( P = 0.055); CTD-status adjustment similarly attenuated the Ro52 association (HR 0.75, P = 0.091). These findings support stratified prognostic models integrating Ro52 with autoantibody and disease-subtype context.

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Cite

BibTeXRIS
BibTeX
@article{su2026antiro52trim21,
  title = {{Anti-Ro52/TRIM21 seropositivity in interstitial lung disease: effect modification by disease subtype and myositis-specific antibody context}},
  author = {Junfeng Su and Yan Du and Chen Zhu and Haodong Zhou and Huyan Wang and Yinjun Du and Qiyuan Wang and Zexin Chen and Hanjun Cao and Man Huang and Jing Xue},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1960409},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960409/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Anti-Ro52/TRIM21 seropositivity in interstitial lung disease: effect modification by disease subtype and myositis-specific antibody context
AU  - Junfeng Su
AU  - Yan Du
AU  - Chen Zhu
AU  - Haodong Zhou
AU  - Huyan Wang
AU  - Yinjun Du
AU  - Qiyuan Wang
AU  - Zexin Chen
AU  - Hanjun Cao
AU  - Man Huang
AU  - Jing Xue
PY  - 2026
DA  - 2026/10/16
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1960409
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1960409/full
AB  - Background: Anti-Ro52/TRIM21 shows contradictory prognostic associations in interstitial lung disease (ILD), protective in some cohorts and adverse in others. We evaluated whether it acts as an independent predictor or a phenotypic marker and whether its effect is modified by disease subtype and myositis-specific antibodies.  Methods: We retrospectively identified 538 adults with radiologically confirmed interstitial lung disease (228 anti-Ro52-positive) from a 2010–2020 single-center cohort. Cox proportional-hazards models were sequentially adjusted for demographic, smoking, malignancy, and pulmonary-function covariates. Pre-specified effect modification by connective tissue disease (CTD) status and myositis-specific antibodies was assessed by likelihood-ratio interaction tests with false-discovery-rate correction. Robustness to missing data was supported by multiple imputation ( m = 20) and a missing-not-at-random (MNAR) tipping-point analysis.  Results: Ro52 positivity was associated with younger age, CTD predominance, and lower complement levels. Pre-specified effect modification was suggested: anti-Ro52 trended toward lower mortality in CTD-ILD (HR 0.73, 95% CI 0.49–1.07, P = 0.104) but did not independently increase mortality within the anti-MDA5-positive subgroup (HR 1.73, 95% CI 0.66–4.54). Instead, the adverse prognostic effect of anti-MDA5 was numerically greater among anti-Ro52-positive than Ro52-negative patients (MDA5 HR 10.57, 95% CI 3.60–31.03 vs. 2.56, 95% CI 0.97–6.74), although the formal interaction term did not reach statistical significance ( P = 0.055). The fully adjusted (Model 6) HR was 0.72 (95% CI 0.52–0.99; P = 0.045); further adjustment for CTD status (Model 7) attenuated the association to non-significance (HR 0.75, 95% CI 0.54–1.04, P = 0.091), and IPCW weighting and time-varying-age analyses were likewise non-significant; malignancy independently predicted mortality (HR 1.81, 95% CI 1.15–2.88; P = 0.012).  Conclusion: Anti-Ro52 is a context-dependent phenotypic marker of immune-mediated ILD, not a universal prognostic biomarker. Its prognostic association is heterogeneous across ILD phenotypes: it is not independently protective in CTD-ILD (adjusted HR 0.73, P = 0.104), whereas the adverse prognostic effect of anti-MDA5 was numerically greater among anti-Ro52-positive than Ro52-negative patients (MDA5 HR 10.57 vs. 2.56), although this interaction did not reach statistical significance ( P = 0.055); CTD-status adjustment similarly attenuated the Ro52 association (HR 0.75, P = 0.091). These findings support stratified prognostic models integrating Ro52 with autoantibody and disease-subtype context.
SN  - 1664-3224
ER  -