Diagnostic and prognostic role of serum kl-6 in rheumatoid arthritis-associated interstitial lung disease

Background Interstitial lung disease (ILD) is one of the leading causes of morbidity and premature mortality in rheumatoid arthritis (RA) patients. Some studies have shown that Krebs von den Lungen-6 (KL-6) may be a valuable biomarker for diagnosis and stratifying prognosis in Rheumatoid Arthritis-Associated Interstitial Lung Disease (RA-ILD). Objectives To evaluate the diagnostic and prognostic value of serum KL-6 in RA-ILD patients. Methods We conducted a retrospective study that included patients with RA (ACR/EULAR 2010 criteria) with available KL-6 data measured in blood serum at study enrolment. Patients were evaluated between February 2017 and October 2019 at a single center. ILD was diagnosed by high-resolution computed tomography (HRCT) and confirmed by a multidisciplinary committee. Serum KL-6 levels were measured by Lumipulse G KL-6 Kit (Fujirebio, Japan), using Chemiluminescent enzyme immunoassay (CLEIA). The reference value for KL-6 in healthy subjects was 118-627 U/mL. The inter-assay variation coefficient of the reagent was ≤ 4.4%. We performed a bivariate analysis according to the presence of ILD and high levels of KL-6. Mortality was assessed in December 2022 by medical chart review. Results A total of 166 patients were included (36 RA-ILD and 130 RA-non-ILD). Patient baseline characteristics were as follows: female gender 76.5%, mean age 62.9 ± 12.3 years, mean disease duration 9.1 ± 8.7 years, RF positive 66.3%, anti-CCP positive 85.5%, erosive disease 56.0%, and mean DAS28 3.0. The median follow-up period was 5 years (IQR 4.0–5.0). At baseline, patients with RA-ILD were older (69.9 ± 16.1 vs. 60.9 ± 12.3 years; p<0.001), were more frequently males (36.1% vs. 20.0%; p=0.044), had a longer disease duration (12.2 ± 1.3 vs. 8.3 ± 8.7 years; p=0.020), had higher RF titers (412.1 ± 120.5 vs. 165.6 ± 221.1; p<0.001), had a higher disease activity (DAS28 3.7 ± 0.2 vs. 2.8 ± 1.1; p<0.001), and higher mortality (33.3% vs. 9.2%; p<0.001). Among RA-ILD patients at baseline, the median FVC and DLco (% predicted value) were 79 (IQR 72.6–87.0) and 60 (IQR 49.0–70.4), respectively. Usual interstitial pneumonia (UIP) was the predominant pattern at HRCT in half of the patients (18/36). The mean serum KL-6 level at baseline was 513.1 ± 480.1 U/mL. KL-6 levels were abnormally elevated in 35 patients (21.0%). Serum levels of KL-6 in the RA-ILD group were significantly higher than those in the RA-non-ILD group (884.0 ± 134.6 vs. 410.4 ± 262.4 U/mL; p<0.001). Patients with high KL-6 had a higher prevalence of RA-ILD (54.3% vs. 13.0%; p<0.001) and UIP pattern at HRCT (22.9% vs. 7.6%; p<0.001), as well as higher mortality (34.3% vs. 9.2%; p<0.001) ( Table 1 ). During follow-up, 24 (14.5%) patients died, mainly due to respiratory infections (62.5%). The median time to death was 20 months (IQR 7.0–29.0). Conclusion Our results suggest that high KL-6 levels might be helpful as a biomarker for diagnosis and prognosis stratification in patients with RA-ILD, especially in patients with UIP pattern at HRCT. References [1]Kim HC, et al. PLoS One. 2020 [2]Avouac J, et al. PLoS One. 2020 Table 1. Baseline characteristics in patients with RA according to serum KL-6 status. Variable All population N=166 High KL-6 n=35 Normal KL-6 n=131 P Age, years 62.9 ± 12.3 68.0 ± 10.0 61.5 ± 12.5 0.005 Male gender 39 (23.5) 12 (34.3) 27 (20.6) 0.090 Ever smoking 86 (51.8) 18 (51.4) 68 (51.9) 0.871 RA duration, years 9.1 ± 8.7 10.7 ± 7.8 8.7 ± 8.9 0.250 RF, positive 110 (66.3) 25 (71.4) 85 (64.9) 0.467 RF, titer (IU) 219.1 ± 399.5 395.5 ± 685.0 172.0 ± 263.2 0.003 ACPA, positive 142 (85.5) 28 (80.0) 114 (87.0) 0.294 ACPA, titer (CU) 1201.6 ± 2107.4 1257.6 ± 1096.2 1186.7 ± 2306.8 0.860 DAS28-ESR 3.0 ± 1.2 3.3 ± 1.3 2.9 ± 1.2 0.094 GC, current 99 (59.6) 27 (77.1 ) 72 (55.0) 0.018 MTX, current 101 (69.8) 20 (57.1) 81 (61.8) 0.614 bDMARD, current 51 (30.7) 9 (25.7) 42 (32.1 ) 0.020 RA-ILD 36 (21.7) 19 (54.3 ) 17 (13) <0.001 UIP pattern (HRCT) 18 (18.8) 8 (22.9 ) 10 (7.6) <0.001 FVC, % predicted 79.7 ± 16.2 77.1 ± 15.7 82.8 ± 16.7 0.289 DLco, % predicted 63.0 ± 16.6 59.2 ± 17.3 67.9 ± 14.8 0.116 Mortality 24 (14.5) 12 (34.3 ) 12 (9.2) <0.001 Acknowledgements We want to thank all patients who have participated in the study. Funding: Hospital Clinic of Barcelona (Grant # 37 933) and the Spanish Ministry of Economy and Competitiveness (Grant # RTI2018-094120-B-I00). Disclosure of Interests Juan C. Sarmiento-Monroy: None declared, Albert Pérez-Isidro: None declared, Raul Castellanos Moreira Employee of: Bristol-Myers Squibb, Virginia Ruiz: None declared, Beatriz Frade-Sosa: None declared, Ana Azuaga: None declared, Julio Ramírez: None declared, Rosa Morlà: None declared, ANDRES PONCE FERNANDEZ: None declared, PATRICIA CORZO GARCIA: None declared, Sandra Myriam Farietta Varela: None declared, Anna Colmenero: None declared, Manuel Morales-Ruiz: None declared, Estíbaliz Ruiz-Ortiz: None declared, Odette Viñas: None declared, Fernanda Hernández-González: None declared, Jacobo Sellarés: None declared, Juan de Dios Cañete: None declared, Raimón Sanmartí: None declared, José A Gómez-Puerta: None declared.