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Novel Immunomodulatory Therapies for Respiratory Pathologies

ABSTRACT: The respiratory tract is constantly exposed to environmental aggressions including allergens, infections, and pollution. The immune system is pivotal to fight potential invaders and prevent the establishment of infections in the respiratory tract; however, excessive, misplaced or altered immune responses contribute to increase tissue damage, impair lung function, and exacerbate respiratory diseases. Indeed, asthma, chronic obstructive pulmonary disease (COPD) and cystic fibrosis are respiratory diseases that have uncontrolled inflammation as a unifying severity factor. In addition, the acute inflammatory responses in pneumonia must be controlled to avoid progression to acute respiratory distress syndrome, which can be lethal. In this regard, immunomodulatory therapies are promising pharmacological strategies to treat important respiratory pathologies. Understanding the pathogenesis of respiratory disorders have paved the way for the development of cytokine-directed therapies, allosteric or non-allosteric inhibitors of inflammatory receptors and enzymes, agonists of resolution of inflammation and other anti-inflammatory compounds. A multitude of studies have evaluated the safety, pharmacokinetics, and pharmacodynamics of several molecules that target inflammation in the respiratory tract, yet only few have been translated to clinical use. This article will summarize important aspects of asthma, COPD, cystic fibrosis, and pneumonia focusing on the role of immune responses in disease development and novel immunomodulatory therapies.

SUBMITTER: Tavares L

PROVIDER: S-EPMC8238403 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundIn the INBUILD trial in patients with chronic fibrosing interstitial lung diseases (ILDs) and a progressive phenotype, nintedanib reduced the rate of ILD progression with adverse events that were manageable for most patients. We investigated the potential impact of immunomodulatory therapies on the efficacy and safety of nintedanib.MethodsSubjects with fibrosing ILDs other than idiopathic pulmonary fibrosis, who had shown progression of ILD within the prior 24 months despite management in clinical practice, were randomized to receive nintedanib or placebo. Certain immunomodulatory therapies were restricted for the first 6 months. We analyzed post-hoc the rate of decline in forced vital capacity (FVC) over 52 weeks in subgroups by glucocorticoid use at baseline and in analyses excluding subjects or FVC measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies.ResultsOf 663 subjects, 361 (54.4%) were taking glucocorticoids at baseline (353 at a dose of ≤ 20 mg/day). In the placebo group, the adjusted rate of decline in FVC (mL/year) over 52 weeks was numerically greater in subjects taking than not taking glucocorticoids at baseline (- 206.4 [SE 20.2] vs - 165.8 [21.9]). The difference between the nintedanib and placebo groups was 133.3 (95% CI 76.6, 190.0) mL/year in subjects taking glucocorticoids at baseline and 76.1 (15.0, 137.2) mL/year in subjects who were not (interaction P = 0.18). The effect of nintedanib on reducing the rate of FVC decline in analyses excluding subjects or measurements taken after initiation of restricted immunomodulatory or antifibrotic therapies was similar to the primary analysis. The adverse event profile of nintedanib was similar between subjects who did and did not use prohibited or restricted therapies at baseline or during treatment with trial drug.ConclusionsIn patients with progressive fibrosing ILDs, the effect of nintedanib on reducing FVC decline was not influenced by the use of immunomodulatory therapies. Nintedanib can be used in combination with immunomodulatory therapies in patients with progressive fibrosing ILDs. Trial registration ClinicalTrials.gov, NCT02999178. Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178.

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Novel Immunomodulatory Therapies for Respiratory Pathologies

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