Pulito-Cueto Verónica, Atienza-Mateo Belén, Batista-Liz Joao C, Sebastián Mora-Gil María, Mora-Cuesta Víctor M, Iturbe-Fernández David, Izquierdo Cuervo Sheila, Aguirre Portilla Carolina, Blanco Ricardo, López-Mejías Raquel
Immunopathology Group, Marqués de Valdecilla University Hospital-IDIVAL, Santander, Spain.
Department of Rheumatology, Hospital Universitario Marqués de Valdecilla, Santander, Spain.
Mol Med. 2025 Feb 20;31(1):70. doi: 10.1186/s10020-025-01128-2.
BACKGROUND: Lack of understanding of interstitial lung disease (ILD) associated with systemic sclerosis (SSc) and rheumatoid arthritis (RA) hinders the early and accurate identification of these devastating diseases. Current clinical tools limitations highlight the need to complement them with accessible and non-invasive methods. Accordingly, we focused on identifying useful matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) as new biomarkers with clinical value in the diagnosis and prognosis of RA-ILD and SSc-ILD. METHODS: Peripheral blood was collected from patients with RA-ILD (n = 49) and SSc-ILD (n = 38); as well as with RA-ILD (n = 25), SSc-ILD (n = 20) and idiopathic pulmonary fibrosis (IPF) (n = 39). MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, TIMP-1, and TIMP-2 serum levels were measured using xMAP Technology. RESULTS: Concerning early connective tissue disease (CTD)-ILD diagnosis, increased MMP-7, MMP-9, MMP-10, and MMP-12 levels were found in RA-ILD and SSc-ILD patients in relation to RA-ILD and SSc-ILD patients, respectively. RA-ILD patients showed higher MMP-2 levels and lower TIMP-1 levels than RA-ILD patients. Interestingly, a reliable utility for identifying ILD in CTD was confirmed for the MMP-2, MMP-7, MMP-9, MMP-10, MMP-12, and TIMP-1 combination in RA and MMP-7, MMP-9, MMP-10, and MMP-12 combinatorial signature in SSc. Regarding accurate CTD-ILD diagnosis, RA-ILD and SSc-ILD patients showed lower MMP-7 and MMP-10 levels than IPF patients. Lower MMP-9 and TIMP-1 levels and higher MMP-3 levels were found in RA-ILD compared to IPF. Remarkably, effectively better differentiation between CTD-ILD and IPF was confirmed for a 5-biomarker signature consisting of MMP-3, MMP-7, MMP-9, MMP-10, and TIMP-1 in RA as well as for the MMP-7 and MMP-10 combination in SSc. Finally, in RA-ILD patients, higher MMP-10 levels were associated with worse pulmonary function, increased MMP-2 levels were related to the treatment with conventional synthetic disease-modifying anti-rheumatic drugs, and decreased TIMP-1 levels were linked with positivity rheumatoid factor status. CONCLUSIONS: MMPs and TIMPs form combinatorial biomarker signatures with clinical value for non-invasive, early, and accurate diagnosis of RA-ILD and SSc-ILD, constituting promising screening tools in clinical practice.
背景：对与系统性硬化症（SSc）和类风湿关节炎（RA）相关的间质性肺疾病（ILD）缺乏了解，阻碍了对这些破坏性疾病的早期准确识别。当前临床工具的局限性凸显了用可及且非侵入性方法对其进行补充的必要性。因此，我们专注于鉴定有用的基质金属蛋白酶（MMPs）及其组织抑制剂（TIMPs），作为在RA-ILD和SSc-ILD的诊断和预后中具有临床价值的新型生物标志物。 方法：采集RA-ILD患者（n = 49）和SSc-ILD患者（n = 38）的外周血；以及RA-ILD患者（n = 25）、SSc-ILD患者（n = 20）和特发性肺纤维化（IPF）患者（n = 39）的外周血。使用xMAP技术检测MMP-1、MMP-2、MMP-3、MMP-7、MMP-9、MMP-10、MMP-12、TIMP-1和TIMP-2的血清水平。 结果：关于早期结缔组织病（CTD）-ILD诊断，与RA-ILD和SSc-ILD患者相比，RA-ILD和SSc-ILD患者中MMP-7、MMP-9、MMP-10和MMP-12水平升高。RA-ILD患者的MMP-2水平高于RA-ILD患者，TIMP-1水平低于RA-ILD患者。有趣的是，在RA中，MMP-2、MMP-7、MMP-9、MMP-10、MMP-12和TIMP-1的组合以及在SSc中MMP-7、MMP-9、MMP-10和MMP-12的组合特征被证实对识别CTD中的ILD具有可靠效用。关于准确的CTD-ILD诊断，RA-ILD和SSc-ILD患者的MMP-7和MMP-10水平低于IPF患者。与IPF相比，RA-ILD患者的MMP-9和TIMP-1水平较低，MMP-3水平较高。值得注意的是，在RA中由MMP-3、MMP-7、MMP-9、MMP-10和TIMP-1组成的5种生物标志物特征以及在SSc中MMP-7和MMP-10的组合被证实在CTD-ILD和IPF之间具有更好的鉴别效果。最后，在RA-ILD患者中，较高的MMP-10水平与较差的肺功能相关，较高的MMP-2水平与使用传统合成抗风湿药物治疗有关，较低的TIMP-1水平与类风湿因子阳性状态有关。 结论：MMPs和TIMPs形成具有临床价值的组合生物标志物特征，可用于RA-ILD和SSc-ILD的非侵入性、早期和准确诊断，是临床实践中有前景的筛查工具。
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