Lung Involvement in Systemic Juvenile Idiopathic Arthritis: A Narrative Review

Abstract

Systemic juvenile idiopathic arthritis associated with lung disorders (sJIA-LD) is a subtype of sJIA characterized by the presence of chronic life-threatening pulmonary disorders, such as pulmonary hypertension, interstitial lung disease, pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, which were exceptionally rare before 2013. Clinically, these children show a striking dissociation between the relatively mild clinical manifestations (tachypnoea, clubbing and chronic cough) and the severity of the pulmonary inflammatory process. Our review describes sJIA-LD as having a reported prevalence of approximately 6.8%, with a mortality rate of between 37% and 68%. It is often associated with an early onset (<2 years of age), macrophage activation syndrome and high interleukin (IL)-18 circulating levels. Other risk factors may be trisomy 21 and a predisposition to adverse reactions to biological drugs. The most popular hypothesis is that the increase in the number of sJIA-LD cases can be attributed to the increased use of IL-1 and IL-6 blockers. Two possible explanations have been proposed, named the “DRESS hypothesis” and the “cytokine plasticity hypothesis”. Lung ultrasounds and the intercellular-adhesion-molecule-5 assay seem to be promising tools for the early diagnosis of sJIA-LD, although high resolution computed tomography remains the gold standard. In this review, we also summarize the treatment options for sJIA-LD, focusing on JAK inhibitors.

Keywords: DRESS; anti-IL-1; anti-IL-6; cytokine plasticity hypothesis; digital clubbing; sJIA-LD; systemic juvenile idiopathic arthritis and lung disease; tocilizumab.

Figure 1

The proposed underlying mechanism of lung involvement in children with systemic juvenile idiopathic arthritis. [*] In cells exposed to interleukin (IL)-2 e IL-12, IL- 18 enhances the synthesis of interferon (IFN) γ, which promotes Th1 differentiation. In particular circumstances, it can trigger a vicious cycle leading to a cytokine storm that favors the development of macrophage activation syndrome. [**] Overexpression of IFN-γ and Th1 cytokines can lead in some murine models to the development of pulmonary alveolar proteinosis.