Expression levels of serum Krebs von den Lungen-6 and interleukin 33 in rheumatoid arthritis patients and their clinical significance
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摘要:
目的 了解类风湿关节炎(RA)患者血清涎液化糖链抗原6(KL-6)和白细胞介素33(IL-33)的表达水平,探讨检测血清KL-6和IL-33对RA相关间质性肺病(RA-ILD)的诊断价值。 方法 选择2022年5月—2023年2月在蚌埠医学院第一附属医院和安徽理工大学第一附属医院风湿科住院并确诊为RA的患者88例,根据肺部CT有无间质性肺病(ILD)分为一般RA组(40例)和RA-ILD组(48例)。所有患者均检测与RA相关的血清学指标,如血清类风湿因子(RF)、红细胞沉降率(ESR)和抗环瓜氨酸肽抗体(抗CCP抗体)等。同时检测上述患者血清KL-6和IL-33水平,分析各项指标与ILD的相关性,通过受试者工作特征(ROC)曲线分析各指标对RA-ILD的诊断效能。 结果 RA-ILD组患者血清KL-6、IL-33水平显著升高;血清KL-6与ESR、CRP、D-二聚体呈正相关关系,血清IL-33与IgG、球蛋白呈正相关关系。经ROC曲线分析发现,各项指标(RF、ESR、CRP、D-二聚体、IgA、KL-6、IL-33)诊断RA-ILD的曲线下面积(AUC)分别为0.678、0.667、0.716、0.702、0.666、0.773和0.705。KL-6、IL-33联合检测诊断RA-ILD的AUC为0.816,均优于各项单独检测。 结论 联合检测RA患者血清KL-6和IL-33,对RA-ILD的早期诊断及病情严重性判断有较高的参考价值。 Abstract:Objective To understand the expression levels of serum Krebs von den Lungen-6 (KL-6) and interleukin 33 (IL-33) in patients with rheumatoid arthritis (RA), and to investigate the diagnostic value of detecting serum KL-6 and IL-33 in RA-associated interstitial lung disease (RA-ILD). Methods A total of 88 patients diagnosed with RA who were admitted to the Rheumatology Department of the First Affiliated Hospital of Bengbu Medical College and the First Affiliated Hospital of Anhui Hospital of Science and Technology from May 2022 to February 2023 were selected. They were divided into general RA group (40 cases) and RA-ILD group (48 cases) according to the presence of interstitial lung disease (ILD) on lung CT. Serological indicators of RA, such as serum rheumatoidfactors (RF), erythrocytesedimentationrate (ESR) and anticyclic citrullinated peptide antibody (anti-CCP) were found in all patients. At the same time, the levels of serum KL-6 and IL-33 in the above patients were determined, the correlation between each index and ILD was analyzed, and the diagnostic efficiency of each index for RA-ILD was analyzed by receiver operating characteristic (ROC) curve. Results Serum KL-6 and IL-33 levels were significantly increased in RA-ILD group; serum KL-6 was positively correlated with ESR, CRP, and D-dimer, and serum IL-33 was positively correlated with IgG and globulin. After ROC analysis, the area under the curve (AUC) of each index for diagnosing RA-ILD was RF (0.678), ESR (0.667), CRP (0.716), D-dimer (0.702), IgA (0.666), KL-6 (0.773) and IL-33 (0.705). The AUC of combined detection of KL-6 and IL-33 in diagnosing RA-ILD was 0.816, both of which were superior to individual detection. Conclusion The combined detection of serum KL-6 and IL-33 in RA patients has a high reference value for the early diagnosis of RA-ILD and the assessment of disease severity. -
表 1 2组RA患者关节表现情况比较[例(%)]
Table 1. Comparison of joint performance between two groups of RA patients [cases(%)]
组别 例数 多关节受累 寡关节受累 单关节受累 无关节压痛 一般RA组 40 23(57.5) 9(22.5) 2(5.0) 6(15.0) RA-ILD组 48 30(62.4) 9(18.8) 2(4.2) 7(14.6) 注:寡关节受累指受累关节数2~4个,多关节受累指受累关节数≥5个。2组关节表现情况比较,Z=0.496, P=0.620。 表 2 2组RA患者实验室检测结果比较
Table 2. Comparison of laboratory test results between two groups of RA patients
组别 例数 抗CCP抗体(%) RF [M(P25, P75),U/mL] ESR [M(P25, P75),mm/h] CRP [M(P25, P75),mg/L] D-二聚体[M(P25, P75),mg/L] IgA [M(P25, P75),g/L] 一般RA组 40 32.5(13/40) 101.14(32.24, 150.41) 28.5(14.0, 52.0) 5.0(0.0, 21.0) 0.60(0.30, 1.41) 2.46(1.69, 2.94) RA-ILD组 48 60.4(27/48) 148.61(110.02, 206.99) 41.5(30.0, 80.0) 26.5(4.0, 50.0) 1.44(0.72, 2.31) 3.12(2.16, 4.04) 统计量 6.816a 2.866b 2.697b 3.464b 3.549b 2.669b P值 0.009 0.004 0.007 0.001 <0.001 0.008 注:a为χ2值,b为Z值。 表 3 2组RA患者KL-6与IL-33水平比较[M(P25, P75)]
Table 3. Comparison of KL-6 and IL-33 levels between two groups of RA patients [M(P25, P75)]
组别 例数 KL-6(U/mL) IL-33(pg/mL) 一般RA组 40 204.70(140.85, 272.70) 18.88(6.04, 66.26) RA-ILD组 48 356.20(237.00,528.80) 85.89(26.81,182.92) Z值 10.267 6.480 P值 0.001 0.011 表 4 各项血清免疫学指标对RA-ILD的诊断效能
Table 4. Diagnostic efficacy of various serum immunologic indices for RA-ILD
项目 临界值 灵敏度(%) 特异度(%) 约登指数 AUC(95%CI) RF 97.05 U/mL 83.3 50.0 0.333 0.678(0.564~0.792) ESR 33.5 mm/h 72.9 60.0 0.329 0.667(0.554~0.781) CRP 34 mg/L 45.8 87.5 0.333 0.716(0.609~0.823) IgA 3.01 g/L 56.3 82.5 0.388 0.666(0.552~0.780) D-二聚体 0.605 mg/L 85.4 52.5 0.379 0.702(0.591~0.812) KL-6 300.95 U/mL 60.4 85.0 0.454 0.773(0.677~0.870) IL-33 81.17 pg/mL 54.2 82.5 0.367 0.705(0.596~0.814) KL-6和IL-33联合检测 81.9 97.4 0.793 0.816(0.730~0.901) -
[1] AKIYAMA M, KANEKO Y. Pathogenesis, clinical features, and treatment strategy for rheumatoid arthritis-associated interstitial lung disease[J]. Aut Rev, 2022, 21: 103056. DOI: 10.1016/j.autrev.2022.103056. [2] 梅永君, 费艳芳, 王健, 等. 类风湿关节炎相关自身抗体与并发间质性肺病的相关性研究[J]. 中华全科医学, 2020, 18(5): 720-722. doi: 10.16766/j.cnki.issn.1674-4152.001338MEI Y J, FEI Y F, WANG J, et al. Research on the correlation between rheumatoid arthritis-related autoantibodies and interstitial lung disease[J]. Chinese Journal of General Practice, 2020, 18(5): 720-722. doi: 10.16766/j.cnki.issn.1674-4152.001338 [3] HUANG S, DOYLE T J, HAMMER M M, et al. Rheumatoid arthritis-related lung disease detected on clinical chest computed tomography imaging: prevalence, risk factors, and impact on mortality[J]. Semin Arthritis Rheum, 2020, 50(6): 1216-1225. doi: 10.1016/j.semarthrit.2020.08.015 [4] WANG Y K, CHEN S Q, ZHENG S Y, et al. The role of lung ultrasound B-lines and serum KL-6 in the screening and follow-up of rheumatoid arthritis patients for an identification of interstitial lung disease: review of the literature, proposal for a preliminary algorithm, and clinical application to cases[J]. Arthritis Res Ther, 2021, 23: 212. doi: 10.1186/s13075-021-02586-9 [5] KELLY C, MATTESON E, ARINGER M, et al. effects of nintedanib in patients with progressive fibrosing interstitial lung disease associated with Rheumatoid Arthritis(RA-ILD)in the inbuild trial annals of the Rheumatic Diseases[J]. Scie Abst, 2021, 80: 69. [6] WELLS A U, FLAHERTY K R, BROWN K K, et al. Nintedanibin in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo controlled, parallel-group trial[J]. Lancet Respir Med, 2020, 8(20): 453-460. [7] MENA-V' A N, ROJAS-GIMENEZ M, ROMERO-BARCO C M, et al. Predictors of progression and mortality in patients with prevalent rheumatoid arthritis and interstitial lung disease: a prospe-ctive cohort study[J]. Clin Med, 2021, 10: 874. [8] IBRAHEIM M K, GOVINDU R R. Rheumatoidarthritis associated interstitial lung di-sease[J]. Am J Med Sci, 2020, 359(5): 312-313. doi: 10.1016/j.amjms.2019.12.010 [9] KIM H C, CHORI K H, JACOB J, et al. Prognostic role of blood KL-6 in rheuma-toid arthritis associated interstitial lung disease[J]. PLoS One, 2020, 15(3): e229997. DOI: 10.1371/journal.pone.0229997. [10] 吕程娜, 唐攀, 郭伦, 等. 血清标记物在类风湿关节炎相关间质性肺疾病中的作用[J]. 生命的化学, 2021, 41(1): 41-48.LYU C N, TANG P, GUO L, et al. Role of serum markers in rheumatoid arthritis-associated interstitial lung disease[J]. Chemistry of Life, 2021, 41(1): 41-48. [11] MANTOVANI A, DINARELLO C A, MOLGORA M, et al. Interleukin-1 and related cytokines in the regulation of inflammation and immunity[J]. Immunity, 2019, 50: 778-795. [12] CHEN Z, BOZEC A, RAMMING A, et al. Anti-inflammatory and immune-regulatory cytokines in rheumatoid arthritis[J]. Rheumatology, 2019, 15(3): 9-17. [13] ZHU X, ZHU J. CD4 T Helper cell subsets and related human immunological disorders[J]. J Molecu Sci, 2020, 21: 8011. [14] VERSACE A G, BITTO A, IOPPOLO C, et al. IL-13 and IL-33 serum levels are increased in systemic sclerosis patients with interstitial lung disease[J]. Front Med, 2022, 9: 825567. DOI: 10.3389/fmed.2022.825567. [15] WANG L, TANG J, YANG X, et al. TGF-β induces ST2 and programs ILC2 development[J]. Nat Commun, 2020, 11(1): 35. [16] ZHANG J J, QIU J X, ZHOU W Y, et al. Neuropilin-1 mediates lung tissue-specific control of ILC2 function in type 2 immunity[J]. Nat Immu, 2022, 23: 237-250. [17] MIKULS T R, AURAV R, THIELE G M, et al. The impact of airborn endotoxin exposure on rheumatoid arthritis-related joint damage, autoantigen expression, autoimmunity, and lung disease[J]. Inter Immun, 2021, 100: 108069. DOI: 10.1016/j.intimp.2021.108069.