{
  "abstract": "Introduction Systemic sclerosis (SSc) is a rare autoimmune disease characterized by inflammation and fibrosis of the skin and other organs, and there is a significant unmet need for new treatments. Gastrointestinal (GI) manifestations are the most common complication of SSc, affecting up to 90% of patients with SSc. Nerandomilast is an oral, preferential inhibitor of phosphodiesterase 4B (PDE4B) and a potential treatment for idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. In vitro, nerandomilast has shown antifibrotic and immunomodulatory properties, suggesting potential benefits in SSc by targeting both fibrosis and inflammation.Material and Methods We investigated the antifibrotic and immunomodulatory properties of nerandomilast in vitro across multiple human cell types relevant to SSc pathology. These included normal and SSc patient-derived dermal fibroblasts, keratinocytes, macrophages, peripheral blood mononuclear cells (PBMCs), CD4+ T cells, normal primary intestinal fibroblasts and smooth muscle cells. Cells were stimulated with profibrotic or proinflammatory cytokines and then treated with nerandomilast. Investigations included cell proliferation, fibrosis-associated protein expression, cytokine secretion, interferon (IFN) responses and T-cell activation.Results Nerandomilast reduced SSc patient dermal fibroblast proliferation and IGFBP-3, sICAM-1 and PAI-1 expression, and significantly decreased the levels of α-smooth muscle actin in fibroblasts. The effect of nerandomilast alone was greater compared with mycophenolate mofetil (MMF) alone, a common SSc treatment. In combination with MMF, nerandomilast had similar or greater effects on proliferation and expression of fibrosis markers, except on sICAM-1. Antiproliferative and antifibrotic effects of nerandomilast were observed on normal fibroblasts. Nerandomilast reduced Col1α1 expression in normal human keratinocytes and tumor necrosis factor (TNF)-α secretion from PBMCs, suppressed TNF-α and interleukin-6 secretion from human macrophages, and attenuated type I and type II IFN responses. Nerandomilast dose-dependently suppressed IFN-γ release from CD4+ T cells, indicating potent inhibition of T-cell activation. In GI cell models, nerandomilast reduced proliferation of intestinal fibroblasts and smooth muscle cells, and decreased α-smooth muscle actin in smooth muscle cells and Col1α1 expression in fibroblasts, consistent with antifibrotic activity.Conclusions Nerandomilast demonstrated significant antifibrotic and immunomodulatory properties on cell types relevant to SSc in vitro, as well as significant antifibrotic effects on intestinal cells relevant to GI pathology. These findings support further investigation of PDE4B inhibition as a targeted therapeutic approach in SSc.",
  "authors": [
    {
      "affiliations": [
        "Department of Life Scienssces, Albstadt-Sigmaringen University of Applied Sciences, Sigmaringen, Germany"
      ],
      "name": "Daniel Schniertshauer"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "David Ebenezer"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Daniela Schloesser"
    },
    {
      "affiliations": [
        "Inflammation Medicine, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Barbara Kistler"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Chang Zeng"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Leslie Amador"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Chantelle Simone-Roach"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Kristen Hall"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "LeeAnne Daley"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Jochen Schmitz"
    },
    {
      "affiliations": [
        "Inflammation Medicine, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Kremena Simitchieva"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riß, Germany"
      ],
      "name": "Peter Nickolaus"
    },
    {
      "affiliations": [
        "Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany"
      ],
      "name": "Christian Hesslinger"
    },
    {
      "affiliations": [
        "Department of Life Scienssces, Albstadt-Sigmaringen University of Applied Sciences, Sigmaringen, Germany"
      ],
      "name": "Jörg Bergemann"
    },
    {
      "affiliations": [
        "Immunology & Respiratory Disease Research, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, Connecticut, USA"
      ],
      "name": "Karim Christian El Kasmi"
    }
  ],
  "title": "P.095 Antifibrotic and immunomodulatory properties of the PDE4B inhibitor nerandomilast in cell models relevant to systemic sclerosis, including intestinal fibrosis",
  "uid": "6ceb7f6a-b2ce-5727-ac4b-f5e0bb1e839c"
}