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SARD-ILDs result in substantial morbidity and mortality, and there is a high medical need for effective therapies that target both fibrotic and inflammatory pathways in SARD-ILD. Phosphodiesterase 4 (PDE4) hydrolyses cyclic AMP, which regulates multiple pathways involved in inflammatory processes. PDE4 is overexpressed in peripheral blood monocytes from patients with inflammatory diseases. However, clinical data on pan-PDE4 inhibition in fibrotic conditions are lacking. The PDE4B subtype is highly expressed in the brain, lungs, heart, skeletal muscle and immune cells. As such, inhibition of PDE4B may be a novel approach for fibrosing ILDs such as idiopathic pulmonary fibrosis (IPF) and SARD-ILD. Preclinical data for PDE4B inhibition have provided initial evidence of both anti-inflammatory and antifibrotic activity, with reduced potential for gastrointestinal toxicity compared with pan-PDE4 inhibitors. In a proof-of-concept phase II trial in patients with IPF, nerandomilast (BI 1015550), the only PDE4B inhibitor currently in clinical development, prevented a decline in lung function over 12 weeks compared with placebo. The potential clinical benefit of PDE4B inhibition is now being investigated in the phase III setting, with two trials evaluating nerandomilast in patients with IPF (FIBRONEER-IPF) or with progressive pulmonary fibrosis other than IPF (FIBRONEER-ILD). Here, we review the preclinical and clinical data that provide rationale for PDE4B inhibition as a treatment strategy in patients with SARD-ILD.<\/jats:p>","DOI":"10.1136\/rmdopen-2024-004704","type":"journal-article","created":{"date-parts":[[2024,12,27]],"date-time":"2024-12-27T10:36:56Z","timestamp":1735295816000},"page":"e004704","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":20,"title":["Rationale for phosphodiesterase-4 inhibition as a treatment strategy for interstitial lung diseases associated with rheumatic diseases"],"prefix":"10.1136","volume":"10","clinical-trial-number":[{"clinical-trial-number":"nct05321069","registry":"10.18810\/clinical-trials-gov"},{"clinical-trial-number":"nct05321082","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4471-8375","authenticated-orcid":false,"given":"Martin","family":"Aringer","sequence":"first","affiliation":[{"name":"University Medical Center and Faculty of Medicine, TU Dresden, Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0546-8310","authenticated-orcid":false,"given":"Oliver","family":"Distler","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6467-7422","authenticated-orcid":false,"given":"Anna-Maria","family":"Hoffmann-Vold","sequence":"additional","affiliation":[{"name":"Department of Rheumatology, University Hospital Zurich, University of Zurich, Zurich, Switzerland"},{"name":"Oslo University Hospital, Oslo, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8352-6136","authenticated-orcid":false,"given":"Masataka","family":"Kuwana","sequence":"additional","affiliation":[{"name":"Nippon Medical School, Tokyo, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helmut","family":"Prosch","sequence":"additional","affiliation":[{"name":"Medical University of Vienna, Vienna, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth R","family":"Volkmann","sequence":"additional","affiliation":[{"name":"David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"239","published-online":{"date-parts":[[2024,12,23]]},"reference":[{"key":"2025090312401363000_10.4.e004704.1","doi-asserted-by":"publisher","DOI":"10.1183\/13993003.00150-2015"},{"key":"2025090312401363000_10.4.e004704.2","doi-asserted-by":"publisher","DOI":"10.3899\/jrheum.141182"},{"key":"2025090312401363000_10.4.e004704.3","unstructured":"American College of Rheumatology . 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