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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<jats:sup>+<\/jats:sup> and SSc-ILD<jats:sup>+<\/jats:sup>.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>Peripheral blood was collected from patients with RA-ILD<jats:sup>+<\/jats:sup> (<jats:italic>n<\/jats:italic>\u2009=\u200949) and SSc-ILD<jats:sup>+<\/jats:sup> (<jats:italic>n<\/jats:italic>\u2009=\u200938); as well as with RA-ILD<jats:sup>-<\/jats:sup> (<jats:italic>n<\/jats:italic>\u2009=\u200925), SSc-ILD<jats:sup>-<\/jats:sup> (<jats:italic>n<\/jats:italic>\u2009=\u200920) and idiopathic pulmonary fibrosis (IPF) (<jats:italic>n<\/jats:italic>\u2009=\u200939). 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Concerning early connective tissue disease (CTD)-ILD<jats:sup>+<\/jats:sup> diagnosis, increased MMP-7, MMP-9, MMP-10, and MMP-12 levels were found in RA-ILD<jats:sup>+<\/jats:sup> and SSc-ILD<jats:sup>+<\/jats:sup> patients in relation to RA-ILD<jats:sup>-<\/jats:sup> and SSc-ILD<jats:sup>-<\/jats:sup> patients, respectively. RA-ILD<jats:sup>+<\/jats:sup> patients showed higher MMP-2 levels and lower TIMP-1 levels than RA-ILD<jats:sup>-<\/jats:sup> 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<jats:sup>+<\/jats:sup> diagnosis, RA-ILD<jats:sup>+<\/jats:sup> and SSc-ILD<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> compared to IPF. Remarkably, effectively better differentiation between CTD-ILD<jats:sup>+<\/jats:sup> 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<jats:sup>+<\/jats:sup> 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.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>MMPs and TIMPs form combinatorial biomarker signatures with clinical value for non-invasive, early, and accurate diagnosis of RA-ILD<jats:sup>+<\/jats:sup> and SSc-ILD<jats:sup>+<\/jats:sup>, constituting promising screening tools in clinical practice.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s10020-025-01128-2","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T19:11:46Z","timestamp":1740078706000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Matrix metalloproteinases and their tissue inhibitors as upcoming biomarker signatures of connective tissue diseases-related interstitial lung disease: towards an earlier and accurate diagnosis"],"prefix":"10.1186","volume":"31","author":[{"given":"Ver\u00f3nica","family":"Pulito-Cueto","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bel\u00e9n","family":"Atienza-Mateo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joao C.","family":"Batista-Liz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Sebasti\u00e1n Mora-Gil","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"V\u00edctor M.","family":"Mora-Cuesta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Iturbe-Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila","family":"Izquierdo Cuervo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Aguirre Portilla","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ricardo","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"L\u00f3pez-Mej\u00edas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,2,20]]},"reference":[{"key":"1128_CR7","doi-asserted-by":"publisher","first-page":"86","DOI":"10.1007\/s13665-022-00290-w","volume":"11","author":"S Ahmed","year":"2022","unstructured":"Ahmed S, Handa R. 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