Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Sung Hae Chang¹, Yong-Beom Park², Gregory C McDermott³, Misti L Paudel³, Keigo Hayashi⁴, You-Jung Ha⁵, Jeong Seok Lee⁶, Min Uk Kim⁷, Chan Ho Park⁸, Ji-Won Kim⁹, Jang Woo Ha², Sang Wan Chung¹⁰, Sung Won Lee¹¹, Eun Ha Kang⁵, Yeon Ah Lee¹⁰, Jung-Yoon Choe⁹, Eun Young Lee¹², Jeffrey A Sparks¹³

Affiliations

¹ S.H. Chang, MD, PhD, MPH, Soonchunhyang University, Division of Rheumatology, Department of Internal Medicine, Cheonan, South Korea, and Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA, and Soonchunhyang University Cheonan Hospital, Division of Rheumatology, Department of Internal Medicine, Cheonan, South Korea.
² Y.B. Park, MD, PhD, J.W. Ha, MD, PhD, Yonsei University College of Medicine, Division of Rheumatology, Department of Internal Medicine, Seoul, South Korea.
³ G.C. McDermott, MD, MPH, M.L. Paudel, MPH, PhD, J.A. Sparks, MD, MMSc, Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA.
⁴ K. Hayashi, MD, MPH, Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA, and Okayama University Graduate School of Medicine, Okayama, Japan.
⁵ Y.J. Ha, MD, PhD, E.H. Kang, MD, PhD, MPH, Seoul National University Bundang Hospital, Division of Rheumatology, Department of Internal Medicine, Seongnam, South Korea.
⁶ J.S. Lee, MD, PhD, Korea Advanced Institute of Science and Technology, KAIST, Graduate School of Medical Science and Engineering, Daejeon, South Korea.
⁷ M.U. Kim, MD, SMG-SNU Boramae Medical Center, Department of Radiology, Seoul, South Korea.
⁸ C.H. Park, MD, Soonchunhyang University College of Medicine, Department of Radiology, Cheonan, South Korea.
⁹ J.W. Kim, MD, PhD, J.Y. Choe, MD, PhD, Catholic University of Daegu School of Medicine, Division of Rheumatology, Department of Internal Medicine, Daegu, South Korea.
¹⁰ S.W. Chung, MD, PhD, Y.A. Lee, MD, PhD, Kyung Hee University Hospital, Division of Rheumatology, Department of Internal Medicine, Seoul, South Korea.
¹¹ S.W. Lee, MD, Soonchunhyang University Cheonan Hospital, Division of Rheumatology, Department of Internal Medicine, Cheonan, South Korea.
¹² E.Y. Lee, MD, PhD, Seoul National University College of Medicine, Division of Rheumatology, Department of Internal Medicine, Seoul, South Korea. jsparks@bwh.harvard.edu elee@snu.ac.kr.
¹³ G.C. McDermott, MD, MPH, M.L. Paudel, MPH, PhD, J.A. Sparks, MD, MMSc, Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA; jsparks@bwh.harvard.edu elee@snu.ac.kr.

PMID: 39814449
PMCID: PMC11961329 (available on 2026-04-01)
DOI: 10.3899/jrheum.2024-0713

Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Sung Hae Chang et al. J Rheumatol. 2025.

. 2025 Apr 1;52(4):323-333.

doi: 10.3899/jrheum.2024-0713.

Authors

Affiliations

¹ S.H. Chang, MD, PhD, MPH, Soonchunhyang University, Division of Rheumatology, Department of Internal Medicine, Cheonan, South Korea, and Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA, and Soonchunhyang University Cheonan Hospital, Division of Rheumatology, Department of Internal Medicine, Cheonan, South Korea.
² Y.B. Park, MD, PhD, J.W. Ha, MD, PhD, Yonsei University College of Medicine, Division of Rheumatology, Department of Internal Medicine, Seoul, South Korea.
³ G.C. McDermott, MD, MPH, M.L. Paudel, MPH, PhD, J.A. Sparks, MD, MMSc, Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA.
⁴ K. Hayashi, MD, MPH, Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA, and Okayama University Graduate School of Medicine, Okayama, Japan.
⁵ Y.J. Ha, MD, PhD, E.H. Kang, MD, PhD, MPH, Seoul National University Bundang Hospital, Division of Rheumatology, Department of Internal Medicine, Seongnam, South Korea.
⁶ J.S. Lee, MD, PhD, Korea Advanced Institute of Science and Technology, KAIST, Graduate School of Medical Science and Engineering, Daejeon, South Korea.
⁷ M.U. Kim, MD, SMG-SNU Boramae Medical Center, Department of Radiology, Seoul, South Korea.
⁸ C.H. Park, MD, Soonchunhyang University College of Medicine, Department of Radiology, Cheonan, South Korea.
⁹ J.W. Kim, MD, PhD, J.Y. Choe, MD, PhD, Catholic University of Daegu School of Medicine, Division of Rheumatology, Department of Internal Medicine, Daegu, South Korea.
¹⁰ S.W. Chung, MD, PhD, Y.A. Lee, MD, PhD, Kyung Hee University Hospital, Division of Rheumatology, Department of Internal Medicine, Seoul, South Korea.
¹¹ S.W. Lee, MD, Soonchunhyang University Cheonan Hospital, Division of Rheumatology, Department of Internal Medicine, Cheonan, South Korea.
¹² E.Y. Lee, MD, PhD, Seoul National University College of Medicine, Division of Rheumatology, Department of Internal Medicine, Seoul, South Korea. jsparks@bwh.harvard.edu elee@snu.ac.kr.
¹³ G.C. McDermott, MD, MPH, M.L. Paudel, MPH, PhD, J.A. Sparks, MD, MMSc, Brigham and Women's Hospital, Division of Rheumatology, Inflammation, and Immunity and Harvard Medical School, Boston, Massachusetts, USA; jsparks@bwh.harvard.edu elee@snu.ac.kr.

PMID: 39814449
PMCID: PMC11961329 (available on 2026-04-01)
DOI: 10.3899/jrheum.2024-0713

Abstract

Objective: To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression.

Methods: In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF). Associations between biomarkers and RA-ILD progression were analyzed using multivariable Cox regression, adjusting for potential confounders.

Results: We analyzed 136 patients with RA-ILD (mean age 66.5 yrs, 30% male, 60.3% with usual interstitial pneumonia pattern). During a median 3.0 years of follow-up, 47 patients (34.6%) experienced progression. Higher baseline KL-6 and hSP-D levels were associated with higher risk of ILD progression (multivariable hazard ratios [HRs] 1.37 [95% CI 1.03-1.82] and 1.51 [95% CI 1.09-2.08], respectively), whereas only the highest quartile of MMP-7 showed an increased risk (multivariable HR 2.60 [95% CI 1.07-6.33]). Increasing levels of serum KL-6 at 1 year showed the strongest association with progression (∆KL-6: multivariable HR 2.00 [95% CI 1.29-3.11]), additionally adjusting for baseline biomarker levels.

Conclusion: In this first prospective study to apply PPF criteria to RA-ILD, 34.6% progressed over 3 years. Higher baseline KL-6 and hSP-D were associated with progression. In follow-up, greater change in KL-6 was associated with progression. Serial measurement of pulmonary damage biomarkers may predict RA-ILD progression and may be helpful in monitoring patients and treatment decisions.

Keywords: biological markers; disease progression; interstitial lung diseases; mucin-1; pulmonary surfactant-associated protein D; rheumatoid arthritis.

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Conflict of interest statement

Conflict of Interest

Other authors report no competing interests.

References

1. Hyldgaard C, Hilberg O, Pedersen AB, et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality. Ann Rheum Dis 2017;76:1700–6. - PubMed
1. Bongartz T, Nannini C, Medina-Velasquez YF, et al. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: A population-based study. Arthritis Rheumatol 2010;62:1583–91. - PMC - PubMed
1. Juge PA, Wemeau L, Ottaviani S, et al. Increased mortality in patients with RA-associated interstitial lung disease: data from a French administrative healthcare database. RMD Open 2023;9:e003491. - PMC - PubMed
1. Lee JK, Ahn Y, Noh HN, et al. Clinical effect of progressive pulmonary fibrosis on patients with connective tissue disease-associated interstitial lung disease: a single center retrospective cohort study. Clin Exp Med 2023;23:4797–807. - PMC - PubMed
1. Kakutani T, Hashimoto A, Tominaga A, et al. Related factors, increased mortality and causes of death in patients with rheumatoid arthritis-associated interstitial lung disease. Mod Rheumatol 2020;30:458–64. - PubMed

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Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Affiliations

Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

Miscellaneous