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They identify molecular signatures strongly associated with the presence and severity of RA-ILD and provide insight into unexplored disease pathways." /> <link rel="canonical" href="https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/" /> <meta property="og:locale" content="en_US" /> <meta property="og:type" content="article" /> <meta property="og:title" content="Therapeutic Targets for RA Patients With Interstitial Lung Disease" /> <meta property="og:description" content="Brigham researchers recently completed the first proteomic analysis in patients with rheumatoid arthritis and interstitial lung disease (RA-ILD). They identify molecular signatures strongly associated with the presence and severity of RA-ILD and provide insight into unexplored disease pathways." /> <meta property="og:url" content="https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/" /> <meta property="og:site_name" content="Brigham On a Mission" /> <meta property="article:publisher" content="https://www.facebook.com/BrighamandWomensHospital" /> <meta property="article:published_time" content="2022-11-25T05:00:46+00:00" /> <meta property="article:modified_time" content="2023-03-08T14:10:28+00:00" /> <meta property="og:image" content="https://www.brighamhealthonamission.org/wp-content/uploads/2023/03/doctor-at-appointment-in.jpg" /> <meta property="og:image:width" content="300" /> <meta property="og:image:height" content="225" /> <meta property="og:image:type" content="image/jpeg" /> <meta name="author" content="Faith Reidenbach" /> <meta name="twitter:card" content="summary_large_image" /> <meta name="twitter:creator" content="@BrighamWomens" /> <meta name="twitter:site" content="@BrighamWomens" /> <meta name="twitter:label1" content="Written by" /> <meta name="twitter:data1" content="Faith Reidenbach" /> <meta name="twitter:label2" content="Est. reading time" /> <meta name="twitter:data2" content="3 minutes" /> <script type="application/ld+json" class="yoast-schema-graph">{"@context":"https://schema.org","@graph":[{"@type":"Article","@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/#article","isPartOf":{"@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/"},"author":{"name":"Faith Reidenbach","@id":"https://www.brighamhealthonamission.org/#/schema/person/4b9967d6f8b443d2bfc1f5771e91574c"},"headline":"Proteomics Data Suggest Diagnostic, Therapeutic Targets for RA Patients With Interstitial Lung Disease","datePublished":"2022-11-25T05:00:46+00:00","dateModified":"2023-03-08T14:10:28+00:00","mainEntityOfPage":{"@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/"},"wordCount":557,"commentCount":0,"publisher":{"@id":"https://www.brighamhealthonamission.org/#organization"},"image":{"@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/#primaryimage"},"thumbnailUrl":"https://www.brighamhealthonamission.org/wp-content/uploads/2023/03/doctor-at-appointment-in.jpg","articleSection":["Pulmonology","Rheumatology"],"inLanguage":"en-US","potentialAction":[{"@type":"CommentAction","name":"Comment","target":["https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/#respond"]}]},{"@type":"WebPage","@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/","url":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/","name":"Therapeutic Targets for RA Patients With Interstitial Lung Disease","isPartOf":{"@id":"https://www.brighamhealthonamission.org/#website"},"primaryImageOfPage":{"@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/#primaryimage"},"image":{"@id":"https://www.brighamhealthonamission.org/2022/11/25/proteomics-data-suggest-diagnostic-therapeutic-targets-for-ra-patients-with-interstitial-lung-disease/#primaryimage"},"thumbnailUrl":"https://www.brighamhealthonamission.org/wp-content/uploads/2023/03/doctor-at-appointment-in.jpg","datePublished":"2022-11-25T05:00:46+00:00","dateModified":"2023-03-08T14:10:28+00:00","description":"Brigham researchers recently completed the first proteomic analysis in patients with rheumatoid arthritis and interstitial lung disease (RA-ILD). 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format-standard has-post-thumbnail hentry category-pulmonology category-rheumatology"> <header class="entry-header"> <h1 class="entry-title textcenter-xs">Proteomics Data Suggest Diagnostic, Therapeutic Targets for RA Patients With Interstitial Lung Disease</h1> <div class="entry-thumbnail"> <img width="300" height="225" src="https://www.brighamhealthonamission.org/wp-content/uploads/2023/03/doctor-at-appointment-in.jpg" class="attachment-full size-full wp-post-image" alt="Doctor examing ct scan images of lungs at desk, lung disease concept" decoding="async" fetchpriority="high" /> </div> </header> <div class="entry-content"> <p>About 40% of patients with rheumatoid arthritis have varying degrees of interstitial lung disease (RA-ILD), as published in <a href="https://journal.chestnet.org/article/S0012-3692%2815%2948746-X/fulltext" target="_blank" rel="noopener noreferrer"><em>Chest</em></a>, but the latter frequently goes undetected until the advanced stages.</p> <p><a href="https://connects.catalyst.harvard.edu/Profiles/display/Person/187735" target="_blank" rel="noopener noreferrer">Yunju Jeong, PhD</a>, a research fellow, and <a title="Tracy J. Doyle, MD, Profile" href="https://physiciandirectory.brighamandwomens.org/Details/376/tracy-doyle-pulmonary_and_critical_care-boston" target="_blank" rel="noopener noreferrer">Tracy J. Doyle, MD</a>, a physician in the <a title="The Brigham's Division of Pulmonary and Critical Care Medicine" href="https://www.brighamandwomens.org/medicine/pulmonary-and-critical-care-medicine" target="_blank" rel="noopener noreferrer">Division of Pulmonary and Critical Care Medicine</a> at Brigham and Women’s Hospital, collaborated with <a target="_blank" href="https://physiciandirectory.brighamandwomens.org/details/134/paul-dellaripa-rheumatology-boston-chestnut_hill-foxborough" title="Paul F. Dellaripa, MD, Profile" rel="noopener noreferrer">Paul F. Dellaripa, MD</a>, and others in the Brigham’s <a target="_blank" href="https://www.brighamandwomens.org/medicine/rheumatology-inflammation-immunity" title="The Brigham's Division of Rheumatology, Inflammation and Immunity" rel="noopener noreferrer">Division of Rheumatology, Inflammation and Immunity</a> to complete the first proteomic analysis in RA-ILD, simultaneously analyzing over a thousand molecular markers and mapping groups of proteins to common biological pathways. In <a title="Serum proteomic profiling of rheumatoid arthritis鈥搃nterstitial lung disease with a comparison to idiopathic pulmonary fibrosis" href="https://thorax.bmj.com/content/77/10/1041" target="_blank" rel="noopener noreferrer"><em>Thorax</em></a>, they identify molecular signatures strongly associated with the presence and severity of RA-ILD, and they provide insight into unexplored disease pathways.</p> <h2>Methods</h2> <p>The team quantified 1,321 proteins in serum from:</p> <ul> <li>39 subjects who had RA-ILD</li> <li>36 subjects who had RA without ILD (RA-noILD)</li> <li>42 subjects with idiopathic pulmonary fibrosis (IPF)</li> <li>42 healthy control (HC) subjects</li> </ul> <p>Subjects in the latter two groups were matched by age, gender, and smoking history to those in the RA-ILD group.</p> <h2>Differential Expression</h2> <p>The SomaScan assay (Somalogic, Boulder, CO) revealed:</p> <ul> <li>234 proteins differentially expressed between RA-ILD and RA-noILD</li> <li>98 proteins differentially expressed between IPF and HC</li> <li>25 proteins differentially expressed in both the RA-ILD to RA-noILD comparison and the IPF to HC comparisons</li> <li>16 proteins overexpressed in both RA-ILD and IPF, perhaps reflecting shared disease mechanisms</li> </ul> <h2>Hierarchical Clustering</h2> <p>The team further explored the top five proteins differentially expressed between RA-ILD and RA-noILD. Independent of gender, age, and smoking, two proteins were associated with percent predicted carbon monoxide diffusing capacity (P<0.00001 for both):</p> <ul> <li>PIANP (paired immunoglobulin-like type two receptor-associated neural protein), which is moderately expressed in respiratory epithelial cells and appears to be necessary for regulation of tissue damage in response to neutrophil-mediated inflammation鈥攎ean difference, 1.34; fold change, 2.53</li> </ul> <ul> <li>SLPI (secretory leukocyte peptidase inhibitor), a major defense against the destruction of lung tissue by neutrophil elastase鈥攎ean difference, 1.36; fold change, 2.57</li> </ul> <p>Neither protein was associated with percent predicted forced vital capacity or percent predicted total lung capacity.</p> <h2>Important Gene Sets in RA-ILD vs. RA-noILD</h2> <p>Gene set enrichment analysis detected 50 significantly enriched functional groups in RA-ILD compared with RA-noILD. Some of the strongest associations with RA-ILD were:</p> <ul> <li>Signaling receptor binding鈥攏ormalized enrichment score (NES), 3.06 (adjusted P=0.0077)</li> <li>G protein鈥揷oupled receptor binding鈥擭ES, 2.70 (P=0.0077)</li> <li>Negative regulation of proteolysis鈥擭ES, 2.62 (P=0.0113)</li> <li>Extracellular matrix鈥擭ES, 2.61 (P=0.0077)</li> <li>Cell鈥揷ell signaling鈥擭ES, 2.56 (P=0.0077)</li> </ul> <p>The leading-edge proteins driving these gene sets in RA-ILD included several proteins implicated in pulmonary fibrosis:</p> <ul> <li>The cytokines CCL18 and interleukin-17</li> <li>The chemokines CXCL12 and CCL5</li> <li>Fibroblast growth factor family members FGF4 and FGF7</li> <li>Galectin-3, which helps regulate myofibroblast proliferation, fibrogenesis, and tissue repair</li> </ul> <p>Based on encouraging results from human and mouse studies, some of those proteins are already considered new therapeutic targets for IPF or RA-ILD.</p> <h2>Important Gene Sets in Fibrotic vs. Nonfibrotic RA-ILD</h2> <p>Gene set enrichment analysis also demonstrated enrichment of fibrotic RA-ILD for extracellular matrix and receptor signaling compared with nonfibrotic RA-ILD. The leading-edge gene sets driving this enrichment included proteins, such as matrix metalloproteinase-7 and galectin-3, that were also enriched in the comparison of all RA-ILD with RA-noILD.</p> <p>This finding suggests differences between the pathogenesis of fibrotic and nonfibrotic ILD subtypes. 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