Academic Journal
Preferential phosphodiesterase inhibition as a novel strategy to modulate key pathways in systemic sclerosis.
| Τίτλος: | Preferential phosphodiesterase inhibition as a novel strategy to modulate key pathways in systemic sclerosis. |
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| Συγγραφείς: | Distler JHW; Department of Rheumatology, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany.; Hiller Research Center, University Hospital Düsseldorf, Heinrich Heine University, Düsseldorf, Germany., Frech T; Division of Rheumatology and Immunology, Department of Internal Medicine, Vanderbilt University Medical Center, Tennessee Valley Healthcare System Veterans Affairs Medical Center, Nashville, TN, United States., McMahan ZH; Division of Rheumatology, UTHealth Houston, Houston, TX, United States. |
| Πηγή: | Frontiers in immunology [Front Immunol] 2026 Oct 02; Vol. 17, pp. 1829186. Date of Electronic Publication: 2026 Oct 02 (Print Publication: 2026). |
| Τύπος έκδοσης: | Journal Article; Review |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Frontiers Research Foundation] Country of Publication: Switzerland NLM ID: 101560960 Publication Model: eCollection Cited Medium: Internet ISSN: 1664-3224 (Electronic) Linking ISSN: 16643224 NLM ISO Abbreviation: Front Immunol Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: [Lausanne : Frontiers Research Foundation] |
| Ιατρικοί όροι (MeSH): | Scleroderma, Systemic*/drug therapy , Scleroderma, Systemic*/metabolism , Phosphodiesterase 4 Inhibitors*/therapeutic use , Phosphodiesterase 4 Inhibitors*/pharmacology , Cyclic Nucleotide Phosphodiesterases, Type 4*/metabolism, Signal Transduction/drug effects ; Humans ; Animals |
| Περίληψη: | Systemic sclerosis (SSc) is a complex autoimmune disease marked by vasculopathy, immune dysregulation, and progressive fibrosis of the skin and internal organs. The high disease burden and impact on quality of life highlight the need for therapies that target underlying pathogenic mechanisms rather than merely treating organ-specific symptoms. Phosphodiesterases, including phosphodiesterase 4B (PDE4B), are key regulators of cellular function and inflammatory responses of several cell types central to SSc pathogenesis. Given PDE4B's broad effects, targeting it may provide benefits beyond organ-specific manifestations and improve current care. Selective PDE4B inhibition represents a novel therapeutic approach for SSc, with improved subtype selectivity compared with earlier pan-PDE4 inhibitors. Nerandomilast preferentially inhibits PDE4B (ninefold over PDE4D), potentially improving tolerability versus oral pan-PDE4 inhibitors by avoiding adverse events such as gastrointestinal intolerance. Preclinical findings in SSc-relevant mouse and cell models show that PDE4B inhibition modulates inflammatory cytokine secretion, smooth muscle cell tension, endothelial and epithelial barrier integrity, and extracellular matrix synthesis under oxidative stress; this suggests nerandomilast could attenuate immune dysregulation, fibrosis, and potentially impact vasculopathy. Two pivotal Phase III trials evaluated nerandomilast in patients with idiopathic pulmonary fibrosis (FIBRONEER™-IPF; NCT05321069) and progressive pulmonary fibrosis (FIBRONEER™-ILD; NCT05321082), the latter of which included patients with SSc-associated interstitial lung disease (SSc-ILD). The ongoing CONQUEST trial (NCT06195072) is investigating the efficacy and safety of various drugs, including nerandomilast, in patients with early active SSc-ILD. This perspective highlights the rationale for targeting PDE4B in SSc therapy and explores preclinical findings in SSc and clinical findings in SSc-ILD to date. (Copyright © 2026 Distler, Frech and McMahan.) |
| Competing Interests: | JHWD has received grants or holds contracts from: AbbVie, Agomab, Anamar, Argenx, ARXX, BMS, Boehringer Ingelheim, Candid, Cantargia, CSL Behring, Elli Lilly, ExoTherapeutics, GSK, Lassen, Kyverna, Mestag, Novartis, Otsuka, Sanofi-Aventis, RedX, Sulis, Spica, Tyra, and UCB; consulting fees from: AbbVie, Anamar, ARXX, AstraZeneca, Boehringer Ingelheim, Genentech/Roche, GSK, Novartis, Roche, UCB, and Xenas; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from: AbbVie, Anamar, ARXX/Caluna, AstraZeneca, Boehringer Ingelheim, Elli Lilly, Genentech/Roche, GSK, Merck, Novartis, and UCB; payment for expert testimony from: AbbVie, Anamar, ARXX/Caluna, AstraZeneca, Bayer Pharma, Boehringer Ingelheim, Cantargia, Genentech, Quell, Kyverna, Novartis, Prolium, Roche, and UCB; support for attending meetings and/or travel from: AbbVie and SOBI; and declares stock or stock options from: 4D Science and FibroCure. ZHM declares consultancy relationships with AbbVie, Aera Therapeutics, Allogene Therapeutics, Boehringer Ingelheim, and Prolium Biosciences. The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. |
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| Contributed Indexing: | Keywords: PDE4B; connective tissue disorder; phosphodiesterase inhibition; progressive fibrosis; systemic sclerosis |
| Substance Nomenclature: | 0 (Phosphodiesterase 4 Inhibitors) EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4) |
| Entry Date(s): | Date Created: 20261017 Date Completed: 20261017 Latest Revision: 20261019 |
| Update Code: | 20261020 |
| PubMed Central ID: | PMC13672333 |
| DOI: | 10.3389/fimmu.2026.1829186 |
| PMID: | 42890786 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1664-3224 |
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| DOI: | 10.3389/fimmu.2026.1829186 |