Novel Parenchymal Lung Disease Prevalent in Systemic Juvenile Idiopathic Arthritis

Investigators analyzed the characteristic traits and risk factors of parenchymal lung disease, which has been increasingly associated with systemic juvenile idiopathic arthritis.

Study data published in the Annals of the Rheumatic Diseases outline several candidate indicators of parenchymal lung disease (LD) in systemic juvenile idiopathic arthritis (sJIA).

Investigators conducted a multicenter retrospective study of 61 patients with sJIA and parenchymal LD, which was diagnosed by chest computed tomography (CT) scans and/or lung tissue histopathology. Researchers collected data of patients with LD from pediatric rheumatology registries, and they abstracted comparator data from patients with sJIA but without LD from the same networks. Demographics, medical history, and clinical features at sJIA onset and at LD diagnosis were included. Investigators performed centralized analyses of data from chest CT scans of 58 patients, histopathology of 36 patients, and whole exome sequence of 20 patients.

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The study cohort comprised 45 patients with sJIA and 16 patients with sJIA-like disease. Median time to LD diagnosis after sJIA onset was 1.6 years (interquartile range [IQR], 0.8-3.3 years). Clinical features associated with LD included acute clubbing (61%), pruritic and nonevanescent rashes (56%), eosinophilia (37%), and unexplained severe abdominal pain (16%). Anaphylaxis to tocilizumab occurred in 38% of patients with LD, compared with just 0.6% of the comparators. Ferritin levels in the patient group with sJIA and LD vs the control group were substantially elevated 12 months before LD diagnosis.

In addition, significant lymphopenia (absolute lymphocyte count, <60%) was found before LD diagnosis in 42% of patients, excluding those with LD at sJIA onset. According to chest CT data, LD was associated with septal thickening involving the periphery of multiple lobes (60%). The most common histopathologic feature of LD was pulmonary arterial hypertension (64%), followed by interstitial LD (28%) and pulmonary alveolar proteinosis (PAP; 20%). Patients with LD also presented with atypical features of PAP/endogenous lipoid pneumonia (ELP), lymphoplasmacytic inflammation (71%) and mild to moderate pulmonary arterial wall thickening (55%).

Data from whole exome sequencing did not indicate any novel risk factors for LD, although trisomy 21 and young age at sJIA onset increased LD risk. Exposure to interleukin (IL)-1 and IL-6 inhibitors in patients (n=46) was associated with several LD features, including acute clubbing, digital erythema, unexplained abdominal pain, peripheral eosinophilia, certain CT patterns, and PAP/ELP pathology. The severity of sJIA was comparable among patients exposed and unexposed to inhibitors, suggesting that inhibitors may promote LD. Median time from IL-1 or IL-6 inhibitor exposure to LD diagnosis was 1.2 years (IQR, 0.7-2.0 years). Parenchymal LD had a high fatality rate, and survival was significantly lower in the LD cohort than in the comparator cohort.

These data identify several potential risk factors for LD in patients with sJIA. Inhibitor exposure may increase the risk for LD, independent of sJIA severity. According to the pathology data, investigators hypothesized that LD may be related to macrophage dysfunction. In fact, among 61 patients, LD detection was associated with macrophage activation syndrome in 23.

Further research is necessary to investigate the molecular mechanisms of LD and parse out appropriate intervention strategies.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures


Saper VE, Chen G, Deutsch GH, et al. Emergent high fatality lung disease in systemic juvenile arthritis [published online September 27, 2019]. Ann Rheum Dis. doi:10.1136/annrheumdis-2019-216040