结缔组织病相关间质性肺疾病危险因素及发病机制研究进展

doi:10.16150/j.1671-2870.2024.02.015

摘要/Abstract

摘要：

结缔组织病相关间质性肺疾病（connective tissue disease-associated interstitial lung disease, CTD-ILD）是一组由结缔组织病引起的肺部疾病，发病率为10%~50%，死亡率高达20%。CTD-ILD的临床表现和影像学特征异质性大，其发病原因尚不完全清楚，了解其危险因素及发病机制对于疾病的诊断、治疗及预后管理至关重要。CTD-ILD的危险因素多样。遗传因素中，CTD-ILD患者的端粒相关基因（包括TERT、RTEL1、PARN和SFTPC）突变率是正常人的3倍，携带MUC5B启动子突变的患者发病风险可能增加至正常人的2倍以上，TOLLIP和HLA-DRB1基因突变也与CTD-ILD患者的疾病易感性增加有关。治疗CTD的药物也可能增加ILD的发病风险。合并感染的患者出现重症CTD-ILD风险更高（OR值为1.34~2.73），死亡风险也更高（OR值为1.2~4.3）。约三分之一的CTD-ILD患者合并胃食管反流病。长期吸烟和暴露于空气污染的环境中均可诱发CTD-ILD。CTD-ILD的发病机制涉及免疫系统的异常，主要表现为自身抗体产生（如系统性硬化症相关抗体和肌炎特异性抗体等）、免疫细胞（如中性粒细胞、自然杀伤细胞、Th2和Th17等）功能异常以及细胞因子（如TNF-α、TGF-β、IL-6和IL-8等）大量释放，可见于50%以上的CTD-ILD患者中。CTD-ILD的危险因素及发病机制复杂，构建CTD-ILD的风险预测模型，可以更精准地识别高风险个体，为疾病的预防和治疗提供新策略，从而改善患者的长期预后。

关键词: 结缔组织病, 间质性肺疾病, 危险因素, 发病机制

Abstract:

Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a group of lung diseases caused by connective tissue diseases, with an incidence ranging from 10% to 50% and a mortality rate as high as 20%. The clinical manifestations and imaging features are heterogeneous. However, its pathogenesis is not fully understood. Exploring the risk factors and pathogenesis is crucial for the diagnosis, treatment and prognosis management of CTD-ILD. The risk factors for CTD-ILD are diverse. Firstly,genetic factors play an important role in pathogenesis. Mutation rate of telomere-related genes (including TERT, RTEL1, PARN, and SFTPC) in CTD-ILD patients is three times as high as that of general population. The risk of developing CTD-ILD in patients with the mutation in MUC5B promoter is more than twice that of normal people. The mutations in the TOLLIP and HLA-DRB1 are also associated with increased disease susceptibility. In addition, medications used to treat CTD may also increase the risk of developing ILD. Approximately one-third of CTD-ILD patients also suffer from gastroesophageal reflux disease. Chronic smoking and exposure to air pollution may also increase the incidence of CTD-ILD. CTD-ILD patients with infections have a higher risk of severe outcomes (OR 1.34-2.73) and increased mortality risk (OR 1.2-4.3). The pathogenesis of CTD-ILD involves the abnormality of the immune system, which is mainly manifested in the production of autoantibodies (such as systemic sclerosis-related antibodies and myositis-specific antibodies), the dysfunction of immune cells (such as neutrophils, natural killer cells, Th2 and Th17) and the extensive release of cytokines (such as TNF-α, TGF-β, IL-6 and IL-8), which exist in more than 50% of CTD-ILD patients. The risk factors and pathogenesis of CTD-ILD are complex. Risk prediction model based on these factors may help identify high-risk individuals accurately, which can provide new strategies for the prevention and treatment of the disease, improve the long-term prognosis of patients.

Key words: Connective tissue disease, Interstitial lung disease, Risk factors, Pathogenesis

中图分类号:

邵新淋, 朱雪梅, 曹华. 结缔组织病相关间质性肺疾病危险因素及发病机制研究进展[J]. 诊断学理论与实践, 2024, 23(02): 202-209.

SHAO Xinlin, ZHU Xuemei, CAO Hua. Advances in research on the risk factors and pathogenesis of connective tissue disease-associated interstitial lung disease[J]. Journal of Diagnostics Concepts & Practice, 2024, 23(02): 202-209.

图/表 2

参考文献 58

[1]	JOY G M, ARBIV O A, WONG C K, et al. Prevalence, imaging patterns and risk factors of interstitial lung di-sease in connective tissue disease: a systematic review and meta-analysis[J]. Eur Respir Rev, 2023, 32(167):220210.
[2]	OLIVEIRA R P, RIBEIRO R, MELO L, et al. Connective tissue disease-associated interstitial lung disease[J]. Pulmonology, 2022, 28(2):113-118.
[3]	ZHANG Y, WANG J. Cellular and molecular mechanisms in idiopathic pulmonary fibrosis[J]. Adv Respir Med, 2023, 91(1):26-48. doi: 10.3390/arm91010005 pmid: 36825939
[4]	WALSH S M, WORRELL J C, FABRE A, et al. Novel differences in gene expression and functional capabilities of myofibroblast populations in idiopathic pulmonary fibrosis[J]. Am J Physiol Lung Cell Mol Physiol, 2018, 315(5):L697-l710.
[5]	SPAGNOLO P, DISTLER O, RYERSON C J, et al. Mechanisms of progressive fibrosis in connective tissue disease (CTD)-associated interstitial lung diseases (ILDs)[J]. Ann Rheum Dis, 2021, 80(2):143-150. doi: 10.1136/annrheumdis-2020-217230 pmid: 33037004
[6]	LIU S, CHUNG M P, LEY B, et al. Peripheral blood leucocyte telomere length is associated with progression of interstitial lung disease in systemic sclerosis[J]. Thorax, 2021, 76(12):1186-1192. doi: 10.1136/thoraxjnl-2020-215918 pmid: 34272332
[7]	JUGE P A, BORIE R, KANNENGIESSER C, et al. Shared genetic predisposition in rheumatoid arthritis-interstitial lung disease and familial pulmonary fibrosis[J]. Eur Respir J, 2017, 49(5):1602314
[8]	SPARKS J A. Towards clinical significance of the MUC5B promoter variant and risk of rheumatoid arthritis-associated interstitial lung disease[J]. Ann Rheum Dis, 2021, 80(12):1503-1504.
[9]	WENG L, LIU W, WANG L, et al. Serum MUC5AC protein levels are correlated with the development and seve-rity of connective tissue disease-associated pulmonary interstitial lesions[J]. Front Immunol, 2022, 13:987723.
[10]	WHEELER A M, BAKER J F, POOLE J A, et al. Genetic, social, and environmental risk factors in rheumatoid arthritis-associated interstitial lung disease[J]. Semin Arthritis Rheum, 2022, 57:152098.
[11]	SHIRAI Y, HONDA S, IKARI K, et al. Association of the RPA3-UMAD1 locus with interstitial lung diseases complicated with rheumatoid arthritis in Japanese[J]. Ann Rheum Dis, 2020, 79(10):1305-1309.
[12]	徐莉莉, 洪赟晢, 李智慧, 等. 特发性肺纤维化预后标志物的研究进展[J]. 中国全科医学, 2023, 26(3):372-379.
	XU L L, HONG Y Z, LI Z H, et al. Prognostic biomarkers in idiopathic pulmonary fibrosis: a recent review[J]. Chin Gen Pract, 2023, 26(3):372-379.
[13]	MOTAMEDI M, FERRARA G, YACYSHYN E, et al. Skin disorders and interstitial lung disease: Part I-Scree-ning, diagnosis, and therapeutic principles[J]. J Am Acad Dermatol, 2023, 88(4):751-764.
[14]	NEWTON C A, OLDHAM J M, LEY B, et al. Telomere length and genetic variant associations with interstitial lung disease progression and survival[J]. Eur Respir J, 2019, 53(4):1801641.
[15]	SONG S T, KIM S S, KIM J Y, et al. Association of Single Nucleotide Polymorphisms of PADI4 and HLA-DRB1 Alleles with Susceptibility to Rheumatoid Arthritis-Related Lung Diseases[J]. Lung, 2016, 194(5):745-753. doi: 10.1007/s00408-016-9916-x pmid: 27372294
[16]	SIMEÓN C P, FONOLLOSA V, TOLOSA C, et al. Association of HLA class II genes with systexmic sclerosis in Spanish patients[J]. J Rheumatol, 2009, 36(12):2733-2736.
[17]	ODANI T, YASUDA S, OTA Y, et al. Up-regulated expression of HLA-DRB5 transcripts and high frequency of the HLA-DRB5*01:05 allele in scleroderma patients with interstitial lung disease[J]. Rheumatology (Oxford), 2012, 51(10):1765-1774. pmid: 22723597
[18]	WANG J, GUO X, YI L, et al. Association of HLA-DPB1 with scleroderma and its clinical features in Chinese population[J]. PLoS One, 2014, 9(1):e87363.
[19]	CHINOY H, SALWAY F, FERTIG N, et al. In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class Ⅱ haplotype, rather than by myositis subtype[J]. Arthritis Res Ther, 2006, 8(1):R13.
[20]	GONO T, KAWAGUCHI Y, KUWANA M, et al. Brief report: Association of HLA-DRB10101/0405 with susceptibility to anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis in the Japanese population[J]. Arthritis Rheum, 2012, 64(11):3736-3740.
[21]	SPAGNOLO P, BONNIAUD P, ROSSI G, et al. Drug-induced interstitial lung disease[J]. Eur Respir J, 2022, 60(4):24.
[22]	ATZENI F, GERARDI M C, BARILARO G, et al. Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review[J]. Expert Rev Clin Immunol, 2018, 14(1):69-82.
[23]	LIANG J, CAO H, KE Y, et al. Acute exacerbation of interstitial lung disease in adult patients with idiopathic inflammatory myopathies: a retrospective case-control study[J]. Front Med (Lausanne), 2020, 7:12.
[24]	RICCI A, PAGLIUCA A, VERMI M, et al. The role of lung colonization in connective tissue disease-associated interstitial lung disease[J]. Microorganisms, 2021, 9(5):932.
[25]	ZHANG H, YUE J, HOU X, et al. Rapidly progressive interstitial lung disease combined with pneumocystis jiro-veci pneumonia in a patient with single anti-TIF-1γ antibody positive dermatomyositis in the context of an underlying tumor[J]. BMC Pulm Med, 2023, 23(1):248.
[26]	中国研究型医院学会呼吸病学专业委员会. 新型冠状病毒感染背景下间质性肺疾病患者临床管理中国专家共识(2023年版)[J]. 中华结核和呼吸杂志, 2023, 46(12):1204-1218.
	Respiratory Council of Chinese Research Hospital Association. [Expert consensus on the management of interstitial lung disease during the COVID-19 epidemic][J]. Zhonghua Jie He He Hu Xi Za Zhi, 2023, 46(12):1204-1218.
[27]	MCFARLANE I M, ZHAZ S Y, BHAMRA M S, et al. Assessment of interstitial lung disease among black rheumatoid arthritis patients[J]. Clin Rheumatol, 2019, 38(12):3413-3424. doi: 10.1007/s10067-019-04760-6 pmid: 31471819
[28]	AKIYAMA M, KANEKO Y. Pathogenesis, clinical features, and treatment strategy for rheumatoid arthritis-associated interstitial lung disease[J]. Autoimmun Rev, 2022, 21(5):103056.
[29]	KIM H, CHO S K, SONG Y J, et al. Clinical characteristics of rheumatoid arthritis patients with interstitial lung disease: baseline data of a single-center prospective cohort[J]. Arthritis Res Ther, 2023, 25(1):43. doi: 10.1186/s13075-023-03024-8 pmid: 36932433
[30]	LE TALLEC E, BOURG C, BOUZILLÉ G, et al. Prognostic value and predictors of the alteration of the diffusing capacity of the lungs for carbon monoxide in systemic lupus erythematosus[J]. Rheumatology (Oxford), 2023,kead558.
[31]	MATHAI S C, DANOFF S K. Management of interstitial lung disease associated with connective tissue disease[J]. BMJ, 2016, 352:h6819.
[32]	CHEN H H, YONG Y M, LIN C H, et al. Air pollutants and development of interstitial lung disease in patients with connective tissue disease: a population-based case-control study in Taiwan[J]. BMJ Open, 2020, 10(12):e041405.
[33]	JEE A S, ADELSTEIN S, BLEASEL J, et al. Role of autoantibodies in the diagnosis of connective- tissue disease ILD (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF)[J]. J Clin Med, 2017, 6(5):51.
[34]	WANG R, ZHAO Y, QI F, et al. Analysis of the clinical features of antisynthetase syndrome: a retrospective cohort study in China[J]. Clin Rheumatol, 2023, 42(3):703-709.
[35]	FUKAMATSU H, HIRAI Y, MIYAKE T, et al. Clinical manifestations of skin, lung and muscle diseases in dermatomyositis positive for anti-aminoacyl tRNA synthetase antibodies[J]. J Dermatol, 2019, 46(10):886-897.
[36]	ZHANG M, YIN J, ZHANG X. Factors associated with interstitial lung disease in patients with rheumatoid arthritis: A systematic review and meta-analysis[J]. PLoS One, 2023, 18(6):e0286191.
[37]	WANG Y, HOU Z, QIU M, et al. Risk factors for primary Sjögren syndrome-associated interstitial lung disease[J]. J Thorac Dis, 2018, 10(4):2108-2117. doi: 10.21037/jtd.2018.03.120 pmid: 29850114
[38]	BUVRY C, CASSAGNES L, TEKATH M, et al. Anti-Ro52 antibodies are a risk factor for interstitial lung di-sease in primary Sjögren syndrome[J]. Respir Med, 2020, 163:105895.
[39]	GAO H, ZHANG X W, HE J, et al. Prevalence, risk factors, and prognosis of interstitial lung disease in a large cohort of Chinese primary Sjögren syndrome patients: A case-control study[J]. Medicine (Baltimore), 2018, 97(24):e11003.
[40]	HUANG Y, QIU Y, XIE Z, et al. Risk factors and prognosis of interstitial lung disease for primary Sjögren syndrome patients: A retrospective case-control study[J]. Clin Rheumatol, 2023, 42(11):3033-3041.
[41]	ENOMOTO N, EGASHIRA R, TABATA K, et al. Analysis of systemic lupus erythematosus-related interstitial pneumonia: a retrospective multicentre study[J]. Sci Rep, 2019, 9(1):7355. doi: 10.1038/s41598-019-43782-7 pmid: 31089189
[42]	HUO R, HUANG X, YANG Y, et al. Potential of resveratrol in the treatment of interstitial lung disease[J]. Front Pharmacol, 2023, 14:1139460.
[43]	CERRO CHIANG G, PARIMON T. Understanding interstitial lung diseases associated with connective tissue di-sease (ctd-ild): genetics, cellular pathophysiology, and biologic drivers[J]. Int J Mol Sci, 2023, 24(3):2405.
[44]	XU L, ZHANG Y, DAI Q, et al. Scorpion venom polypeptide governs alveolar macrophage M1/M2 polarization to alleviate pulmonary fibrosis[J]. Tissue Cell, 2022, 79:101939.
[45]	皮定南. M2型巨噬细胞在肺纤维化中的相关研究进展[J]. 中国临床新医学, 2023, 16(3):291-294.
	PI D N. Advances in the related research of M2 macrophages in pulmonary fibrosis[J]. Chin J New Clin Med, 2023, 16(3):291-294.
[46]	D’ALESSANDRO M, CONTICINI E, BERGANTINI L, et al. Neutrophil extracellular traps in anca-associated vasculitis and interstitial lung disease: a scoping review[J]. Life (Basel), 2022, 12(2):317.
[47]	RUTA V M, MAN A M, ALEXESCU T G, et al. Neutrophil-to-lymphocyte ratio and systemic immune-inflammation index-biomarkers in interstitial lung disease[J]. Medicina (Kaunas), 2020, 56(8):381.
[48]	LAI N L, JIA W, WANG X, et al. Risk factors and changes of peripheral NK and T cells in pulmonary interstitial fibrosis of patients with rheumatoid arthritis[J]. Can Respir J, 2019, 2019:7262065.
[49]	XING N S, FAN G Z, YAN F, et al. Safety and efficacy of rituximab in connective tissue disease-associated interstitial lung disease: A systematic review and meta-analysis[J]. Int Immunopharmacol, 2021, 95:107524.
[50]	SHIMIZU T, NAGAFUCHI Y, HARADA H, et al. Decreased peripheral blood memory B cells are associated with the presence of interstitial lung disease in rheumatoid arthritis: a case-control study[J]. Mod Rheumatol, 2021, 31(1):127-132.
[51]	PELLICANO C, VANTAGGIO L, COLALILLO A, et al. Type 2 cytokines and scleroderma interstitial lung disease[J]. Clin Exp Med, 2023, 23(7):3517-3525. doi: 10.1007/s10238-023-01125-x pmid: 37392249
[52]	ZHANG J, WANG D, WANG L, et al. Profibrotic effect of IL-17A and elevated IL-17RA in idiopathic pulmonary fibrosis and rheumatoid arthritis-associated lung disease support a direct role for IL-17A/IL-17RA in human fibrotic interstitial lung disease[J]. Am J Physiol Lung Cell Mol Physiol, 2019, 316(3):L487-L497.
[53]	ZHU W, WANG Y, LIU C, et al. Connective tissue di-sease-related interstitial lung disease is alleviated by tripterine through inhibition of the PI3K/Akt, apoptosis, and TNF-α signalling pathways[J]. Front Pharmacol, 2022, 13:990760.
[54]	MA C, MENG K, SHI S, et al. Clinical significance of interleukin-6, total bilirubin, CD3 + CD4 + T cells counts in the acute exacerbation of connective tissue disease-associated interstitial lung disease: a cross-sectional study[J]. Eur J Med Res, 2023, 28(1):393. doi: 10.1186/s40001-023-01384-0 pmid: 37773193
[55]	ZHAO W, YUE X, LIU K, et al. The status of pulmonary fibrosis in systemic sclerosis is associated with IRF5, STAT4, IRAK1, and CTGF polymorphisms[J]. Rheumatol Int, 2017, 37(8):1303-1310. doi: 10.1007/s00296-017-3722-5 pmid: 28434122
[56]	LIU Y, HU M, FAN G, et al. Effect of Baricitinib on the epithelial-mesenchymal transition of alveolar epithelial cells induced by IL-6[J]. Int Immunopharmacol, 2022, 110:109044.
[57]	FIELDS A, POTEL K N, CABUHAL R, et al. Mediators of systemic sclerosis-associated interstitial lung disease (SSc-ILD): systematic review and meta-analyses[J]. Thorax, 2023, 78(8):799-807.
[58]	MAKINO K, MAKINO T, STAWSKI L, et al. Blockade of PDGF Receptors by Crenolanib Has Therapeutic Effect in Patient Fibroblasts and in Preclinical Models of Systemic Sclerosis[J]. J Invest Dermatol, 2017, 137(8):1671-1681.

疾病	易感基因
RA-ILD	端粒相关基因^[7] MUC5B^[10] RPA3-UMAD1^[11] TOLLIP^[10,14] HLA-DRB1^[15]
SSc-ILD	端粒相关基因^[6] MUC5B^[9] HLA-DRB111^[16]、HLA-DRB501:05^[17]、HLA-DPB103:01*^[18]
PM/DM-ILD	MUC5B^[9] HLA-DRB103-DQA105-DQB102^[19]、HLA-DRB10101/0405*^[20]