吡非尼酮联合免疫抑制剂治疗结缔组织病相关肺间质性病变的研究进展

摘要/Abstract

摘要：

结缔组织病（connective tissue disease，CTD）常累及全身各个器官，多种CTD如系统性硬化症（systemic sclerosis， SSc）、类风湿关节炎（rheumatoid arthritis， RA）、炎性肌病（idiopathic inflammatory myopathies， IIM）、系统性红斑狼疮（systemic lupus erythematosus， SLE）、干燥综合征（sjogren syndrome， SS）等易累及肺脏，表现为不同病理及影像学亚型，进展速度和预后有显著差异的肺间质病变（interstitial lung disease，ILD），且某些亚型死亡率较高。目前临床上多以糖皮质激素联合免疫抑制剂为一线治疗方案，但其使用时长、维持和减停标准未见明确指南，且部分患者对免疫治疗反应欠佳。另一方面，靶向抗纤维化及抗炎药物吡非尼酮（pirfenidone， PFD）在我国开始尝试应用于多种CTD-ILD患者，但其与免疫治疗的联合方案、桥接时机、使用时长值得探讨。本文将结合近年临床指南和学科进展，对国内外现有文献进行述评，总结PFD联合免疫抑制剂在常见CTD-ILD使用中的研究进展，为临床实践提供参考。

关键词:吡非尼酮,免疫抑制剂,肺间质病变,结缔组织病,系统性硬化症,类风湿关节炎,炎性肌病

Abstract:

Connective tissue disease （CTD） is a heterogeneous group of systemic disorders that can affect any organ system. Lung involvement is a rather common manifestation of CTD，such as systemic sclerosis， rheumatoid arthritis， inflammatory myopathy， systemic lupus erythematosus， Sjogren's syndrome， contributing to significant morbidity and mortality. There are different subtypes in pathology and imaging manifestations of interstitial lung disease （ILD） and they may present with subclinical features following a slow or acute progressively course，and turn into clinically significant rapid progression leading to mortality. At present， glucocorticoids combined with immunosuppressive agents are used as the first-line treatment without enough guidelines for their maintenance and decline strategy. Some patients have poor response to it due to their fibrosis progression. On the other hand， the targeted anti-fibrosis and anti-inflammatory drug， pirfenidone （PFD） has been tried to be applied in some kind of CTD-ILD， but their combination with immunotherapy， bridging time and service time are worth discussing. This article will summarize clinical guidelines and academic progress reports in recent years， review the existing literature at home and abroad， the articles of PFD combined with immunosuppressants in CTD-ILD to provide references for clinical decision.

Key words:pirfenidone,immunosuppressant,interstitial lung disease,connective tissue disease,systemic sclerosis,rheumatoid arthritis,inflammatory myopathy

王佳琦, 舒强. 吡非尼酮联合免疫抑制剂治疗结缔组织病相关肺间质性病变的研究进展[J]. betway必威登陆网址（betway.com ）学报, 2022, 43(4): 304-310.

Jiaqi WANG, Qiang SHU. Pirfenidone combined with immunosuppressive agents in the treatment of connective tissue disease-related pulmonary interstitial disease.[J]. Journal of Shandong First Medical Unversity & Shandong Academy of Medical Sciences, 2022, 43(4): 304-310.

参考文献67

1	Cottin V， Hirani NA， Hotchkin DL， et al. Presentation， diagnosis and clinical course of the spectrum of progressive-fibrosing interstitial lung diseases［J］. Eur Respir Rev， 2018， 27（150）： 180076.
2	Khanna D， Mittoo S， Aggarwal R， et al. Connective tissue disease-associated interstitial lung diseases （CTD-ILD）-report from OMERACT CTD-ILD working group［J］. J Rheumatol， 2015， 42（11）： 2168.
3	Baughman RP， Lower EE. Frequency of acute worsening events in fibrotic pulmonary sarcoidosis patients［J］. Respir Med， 2013， 107（12）： 2009.
4	Marie I， Hatron PY， Dominique S， et al. Short-term and long-term outcomes of interstitial lung disease in polymyositis and dermatomyositis： a series of 107 patients［J］. Arthritis Rheum， 2011， 63（11）： 3439.
5	Hoffmann-Vold AM， Aaløkken TM， Lund MB， et al. Predictive value of serial high-resolution computed tomography analyses and concurrent lung function tests in systemic sclerosis［J］. Arthritis Rheumatol， 2015， 67（8）： 2205.
6	Hisatomi K， Mukae H， Sakamoto N， et al. Pirfenidone inhibits TGF-β1-induced over-expression of collagen type Ⅰ and heat shock protein 47 in A549 cells［J］. BMC Pulm Med， 2012， 12： 24.
7	Shi Q， Liu XY， Bai YY， et al.In vitroeffects of pirfenidone on cardiac fibroblasts： proliferation， myofibroblast differentiation， migration and cytokine secretion［J］. Plos One， 2011， 6（11）： e28134.
8	Bizargity P， Liu KF， Wang LQ， et al. Inhibitory effects of pirfenidone on dendritic cells and lung allograft rejection［J］. Transplantation， 2012， 94（2）： 114.
9	Grattendick KJ， Nakashima JM， Feng L， et al. Effects of three anti-TNF-alpha drugs： etanercept， infliximab and pirfenidone on release of TNF-alpha in medium and TNF-alpha associated with the cellin vitro［J］. Int Immunopharmacol， 2008， 8（5）： 679.
10	Visner GA， Liu FZ， Bizargity P， et al. Pirfenidone inhibits T-cell activation， proliferation， cytokine and chemokine production， and host alloresponses［J］. Transplantation， 2009， 88（3）： 330.
11	Liu HZ， Drew P， Cheng YP， et al. Pirfenidone inhibits inflammatory responses and ameliorates allograft injury in a rat lung transplant model［J］. J Thorac Cardiovasc Surg， 2005， 130（3）： 852.
12	Taniguchi H， Ebina M， Kondoh Y， et al. Pirfenidone in idiopathic pulmonary fibrosis［J］. Eur Respir J， 2010， 35（4）： 821.
13	King TE Jr， Bradford WZ， Castro-Bernardini S， et al. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis［J］. N Engl J Med， 2014， 370（22）： 2083.
14	Miura Y， Saito T， Fujita K， et al. Clinical experience with pirfenidone in five patients with scleroderma-related interstitial lung disease［J］. Sarcoidosis Vasc Diffuse Lung Dis， 2014， 31（3）： 235.
15	邱明亮，姜楠，吴婵媛，等. 吡非尼酮治疗结缔组织病相关肺间质病变三例及文献复习［J］. 中华临床免疫和变态反应杂志， 2017， 11（1）： 6.
16	Perelas A， Silver RM， Arrossi AV， et al. Systemic sclerosis-associated interstitial lung disease［J］. Lancet Respir Med， 2020， 8（3）： 304.
17	Cappelli S， Bellando Randone S， Camiciottoli G， et al. Interstitial lung disease in systemic sclerosis： where do we stand？［J］. Eur Respir Rev， 2015， 24（137）： 411.
18	Qiu MH， Nian XY， Pang LL， et al. Prevalence and risk factors of systemic sclerosis-associated interstitial lung disease in East Asia： a systematic review and meta-analysis［J］. Int J Rheum Dis， 2021， 24（12）： 1449.
19	Panagopoulos P， Goules A， Hoffmann-Vold AM， et al. Natural history and screening of interstitial lung disease in systemic autoimmune rheumatic disorders［J］. Ther Adv Musculoskelet Dis， 2021， 13： 1759720X211037519.
20	Christmann RB， Wells AU， Capelozzi VL， et al. Gastroesophageal reflux incites interstitial lung disease in systemic sclerosis： clinical， radiologic， histopathologic， and treatment evidence［J］. Semin Arthritis Rheum， 2010， 40（3）： 241.
21	Jacquerie P， Henket M， André B， et al. Inflammatory profile of induced sputum composition in systemic sclerosis and comparison with healthy volunteers［J］. Sci Rep， 2021， 11（1）： 10679.
22	Mathai SK， Gulati M， Peng XY， et al. Circulating monocytes from systemic sclerosis patients with interstitial lung disease show an enhanced profibrotic phenotype［J］. Lab Invest， 2010， 90（6）： 812.
23	Schoenfeld SR， Castelino FV. Interstitial lung disease in scleroderma［J］. Rheum Dis Clin North Am， 2015， 41（2）： 237.
24	Silver KC， Silver RM. Management of systemic-sclerosis-associated interstitial lung disease［J］. Rheum Dis Clin North Am， 2015， 41（3）： 439.
25	Khanna D， Albera C， Fischer A， et al. An open-label， phase Ⅱ study of the safety and tolerability of pirfenidone in patients with scleroderma-associated interstitial lung disease： the LOTUSS trial［J］. J Rheumatol， 2016， 43（9）： 1672.
26	Elhai M， Boubaya M， Distler O， et al. Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice： a prospective cohort study［J］. Ann Rheum Dis， 2019， 78（7）： 979.
27	Sullivan KM， Goldmuntz EA， Keyes-Elstein L， et al. Myeloablative autologous stem-cell transplantation for severe scleroderma［J］. N Engl J Med， 2018， 378（1）： 35.
28	Pradère P， Tudorache I， Magnusson J， et al. Lung transplantation for scleroderma lung disease： an international， multicenter， observational cohort study［J］. J Heart Lung Transplant， 2018， 37（7）： 903.
29	Khanna D， Lin CJF， Furst DE， et al. Tocilizumab in systemic sclerosis： a randomised， double-blind， placebo-controlled， phase 3 trial［J］. Lancet Respir Med， 2020， 8（10）： 963.
30	Rodríguez-Castellanos M， Tlacuilo-Parra A， Sánchez-Enríquez S， et al. Pirfenidone gel in patients with localized scleroderma： a phase Ⅱ study［J］. Arthritis Res Ther， 2015， 16（6）： 510.
31	Acharya N， Sharma SK， Mishra D， et al. Efficacy and safety of pirfenidone in systemic sclerosis-related interstitial lung disease-a randomised controlled trial［J］. Rheumatol Int， 2020， 40（5）： 703.
32	Brito Y， Glassberg MK， Ascherman DP. Rheumatoid arthritis-associated interstitial lung disease： current concepts［J］. Curr Rheumatol Rep， 2017， 19（12）： 79.
33	Raimundo K， Solomon JJ， Olson AL， et al. Rheumatoid arthritis-interstitial lung disease in the United States： prevalence， incidence， and healthcare costs and mortality［J］. J Rheumatol， 2019， 46（4）： 360.
34	Spagnolo P， Lee JS， Sverzellati N， et al. The lung in rheumatoid arthritis： focus on interstitial lung disease［J］. Arthritis Rheumatol， 2018， 70（10）： 1544.
35	Hyldgaard C， Hilberg O， Pedersen AB， et al. A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease： comorbidity and mortality［J］. Ann Rheum Dis， 2017， 76（10）： 1700.
36	Castelino FV， Varga J. Interstitial lung disease in connective tissue diseases： evolving concepts of pathogenesis and management［J］. Arthritis Res Ther， 2010， 12（4）： 213.
37	Carrasco Cubero C， Chamizo Carmona E， Vela Casasempere P. Systematic review of the impact of drugs on diffuse interstitial lung disease associated with rheumatoid arthritis［J］. Reumatol Clin （Engl Ed）， 2021， 17（9）： 504.
38	Sparks JA， He XT， Huang J， et al. Rheumatoid arthritis disease activity predicting incident clinically apparent rheumatoid arthritis-associated interstitial lung disease： a prospective cohort study［J］. Arthritis Rheumatol， 2019， 71（9）： 1472.
39	Kelly CA， Saravanan V， Nisar M， et al. Rheumatoid arthritis-related interstitial lung disease： associations， prognostic factors and physiological and radiological characteristics-a large multicentre UK study［J］. Rheumatology（Oxford）， 2014， 53（9）： 1676.
40	Castellanos-Moreira R， Rodríguez-García SC， Gomara MJ， et al. Anti-carbamylated proteins antibody repertoire in rheumatoid arthritis： evidence of a new autoantibody linked to interstitial lung disease［J］. Ann Rheum Dis， 2020， 79（5）： 587.
41	Juge PA， Lee JS， Ebstein E， et al. MUC5B promoter variant and rheumatoid arthritis with interstitial lung disease［J］. N Engl J Med， 2018， 379（23）： 2209.
42	Kiely P， Busby AD， Nikiphorou E， et al. Is incident rheumatoid arthritis interstitial lung disease associated with methotrexate treatment？ Results from a multivariate analysis in the ERAS and ERAN inception cohorts［J］. BMJ Open， 2019， 9（5）： e028466.
43	Rojas-Serrano J， Herrera-Bringas D， Pérez-Román DI， et al. Rheumatoid arthritis-related interstitial lung disease （RA-ILD）： methotrexate and the severity of lung disease are associated to prognosis［J］. Clin Rheumatol， 2017， 36（7）： 1493.
44	Vicente-Rabaneda EF， Atienza-Mateo B， Blanco R， et al. Efficacy and safety of abatacept in interstitial lung disease of rheumatoid arthritis： a systematic literature review［J］. Autoimmun Rev， 2021， 20（6）： 102830.
45	Md Yusof MY， Kabia A， Darby M， et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease： 10 years' experience at a single centre［J］. Rheumatology（Oxford）， 2017， 56（8）： 1348.
46	Huang Y， Lin WJ， Chen Z， et al. Effect of tumor necrosis factor inhibitors on interstitial lung disease in rheumatoid arthritis： angel or demon？［J］. Drug Des Devel Ther， 2019， 13： 2111.
47	Gan DH， Cheng WX， Ke LQ， et al. Repurposing of pirfenidone （anti-pulmonary fibrosis drug） for treatment of rheumatoid arthritis［J］. Front Pharmacol， 2021， 12： 631891.
48	Wu CC， Lin HB， Zhang X. Inhibitory effects of pirfenidone on fibroblast to myofibroblast transition in rheumatoid arthritis-associated interstitial lung disease via the downregulation of activating transcription factor 3 （ATF3）［J］. Int Immunopharmacol， 2019， 74： 105700.
49	杨金良，郑学军，赵亚君，等. 吡非尼酮联合糖皮质激素治疗类风湿关节炎合并肺间质纤维化的效果及对血清KL-6、ACPA的影响［J］. 广东医学， 2018， 39（23）： 3552.
50	Solomon JJ， Danoff SK， Goldberg HJ， et al. The design and rationale of the trail1 trial： a randomized double-blind phase 2 clinical trial of pirfenidone in rheumatoid arthritis-associated interstitial lung disease［J］. Adv Ther， 2019， 36（11）： 3279.
51	Jablonski R， Bhorade S， Strek ME， et al. Recognition and management of myositis-associated rapidly progressive interstitial lung disease［J］. Chest， 2020， 158（1）： 252.
52	Hervier B， Uzunhan Y. Inflammatory myopathy-related interstitial lung disease： from pathophysiology to treatment［J］. Front Med（Lausanne）， 2019， 6： 326.
53	Mariampillai K， Granger B， Amelin D， et al. Development of a new classification system for idiopathic inflammatory myopathies based on clinical manifestations and myositis-specific autoantibodies［J］. JAMA Neurol， 2018， 75（12）： 1528.
54	Nombel A， Fabien N， Coutant F. Dermatomyositis with anti-MDA5 antibodies： bioclinical features， pathogenesis and emerging therapies［J］. Front Immunol， 2021， 12： 773352.
55	Soponkanaporn S， Deakin CT， Schutz PW， et al. Expression of myxovirus-resistance protein A： a possible marker of muscle disease activity and autoantibody specificities in juvenile dermatomyositis［J］. Neuropathol Appl Neurobiol， 2019， 45（4）： 410.
56	De Paepe B. Interferons as components of the complex web of reactions sustaining inflammation in idiopathic inflammatory myopathies［J］. Cytokine， 2015， 74（1）： 81.
57	Tsuji H， Nakashima R， Hosono Y， et al. Multicenter prospective study of the efficacy and safety of combined immunosuppressive therapy with high-dose glucocorticoid， tacrolimus， and cyclophosphamide in interstitial lung diseases accompanied by anti-melanoma differentiation-associated gene 5-positive dermatomyositis［J］. Arthritis Rheumatol， 2020， 72（3）： 488.
58	Romero-Bueno F， Diaz Del Campo P， Trallero-Araguás E， et al. Recommendations for the treatment of anti-melanoma differentiation-associated gene 5-positive dermatomyositis-associated rapidly progressive interstitial lung disease［J］. Semin Arthritis Rheum， 2020， 50（4）： 776.
59	Chen ZW， Wang XD， Ye S. Tofacitinib in amyopathic dermatomyositis-associated interstitial lung disease［J］. N Engl J Med， 2019， 381（3）： 291.
60	Kurasawa K， Arai S， Namiki Y， et al. Tofacitinib for refractory interstitial lung diseases in anti-melanoma differentiation-associated 5 gene antibody-positive dermatomyositis［J］. Rheumatology（Oxford）， 2018， 57（12）： 2114.
61	Scirocco C， Gubbiotti A， Sebastiani A， et al. Rituximab in antimelanoma differentiation-associated protein-5 dermatomyositis with interstitial lung disease［J］. Case Rep Rheumatol， 2020， 2020： 8145790.
62	Abe Y， Kusaoi M， Tada K， et al. Successful treatment of anti-MDA5 antibody-positive refractory interstitial lung disease with plasma exchange therapy［J］. Rheumatology（Oxford）， 2020， 59（4）： 767.
63	Koguchi-Yoshioka H， Okiyama N， Iwamoto K， et al. Intravenous immunoglobulin contributes to the control of antimelanoma differentiation-associated protein 5 antibody-associated dermatomyositis with palmar violaceous macules/papules［J］. Br J Dermatol， 2017， 177（5）： 1442.
64	Li T， Guo L， Chen ZW， et al. Pirfenidone in patients with rapidly progressive interstitial lung disease associated with clinically amyopathic dermatomyositis［J］. Sci Rep， 2016， 6： 33226.
65	Flores-Chávez A， Kostov B， Solans R， et al. Severe， life-threatening phenotype of primary Sjögren's syndrome： clinical characterisation and outcomes in 1580 patients （GEAS-SS Registry）［J］. Clin Exp Rheumatol， 2018， 36 Suppl 112（3）： 121.
66	Ghosh A， Das T， Ghosh A， et al. Evaluation of respiratory manifestations in systemic lupus erythematosus with special reference to pulmonary interstitial involvement［J］. J Indian Med Assoc， 2012， 110（2）： 109.
67	Shen LC， Yan QR， Chen AA. Efficacy of combination therapy with pirfenidone and low-dose cyclophosphamide for refractory interstitial lung disease associated with connective tissue disease： a case-series of seven patients［J］. Arch Rheumatol， 2020， 35（2）： 180.

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