Immunomodulation in paediatric inflammatory interstitial lung diseases: towards mechanism-based targeted therapies, a focus on the anti-cytokines.

Abstract

Childhood interstitial lung diseases (chILDs) associated with inflammatory diseases represent a heterogeneous group of rare conditions. To date, therapeutic approaches predominantly rely on broad-spectrum immunosuppressive agents, often independently of the underlying mechanism. During the last ten years, next generation sequencing techniques allowed the identification of monogenic auto-inflammatory diseases with the subsequent development of mechanism-based targeted immunomodulatory therapies. Among these emerging therapies, anti-cytokine agents occupy an increasingly prominent role in inflammatory chILDs. Janus kinase (JAK) inhibitors have emerged as a promising strategy, with initial efficacy demonstrated in monogenic type I interferonopathies involving the lung, such as STING-associated vasculopathy with onset in infancy (SAVI) and COPA syndrome. Their therapeutic scope has subsequently expanded to include disorders driven by type II interferon signalling, notably systemic juvenile idiopathic arthritis-associated lung disease and refractory pulmonary granulomatosis. In juvenile dermatomyositis with anti-melanoma differentiation-associated gene 5 (MDA5) antibodies, JAK inhibitors address refractory rapidly progressive interstitial lung disease. Further anti-cytokine therapies include tocilizumab (anti-interleukin-6) for juvenile systemic sclerosis-associated interstitial lung disease, anti-interleukin-1β/18 combinations (MAS-825), and anti-tumour necrosis factor-alpha. Whilst evidence remains predominantly limited to case reports and small series, these mechanism-based approaches represent a paradigm shift towards personalised medicine in chILDs. Understanding disease-specific pathophysiology-from interferon activity assessment to genomic sequencing-is essential for optimal therapeutic targeting. Multicentre collaborations are needed to evaluate long-term efficacy and safety of these targeted interventions.