5 Questions About Interstitial Lung Disease in Systemic JIA

Interstitial lung disease—also known as diffuse parenchymal lung disease—is increasingly found in children with systemic juvenile idiopathic arthritis (JIA). The reason behind the rising prevalence of the lung disease in systemic JIA remains unknown.

In a recent study,¹ Vivian Saper, MD, clinical researcher and adjunct clinical professor at the Stanford University School of Medicine, and colleagues sought to investigate the characteristics and risk factors of parenchymal lung disease in systemic JIA after several children seen at Stanford Children’s Health–Lucile Packard Children’s Hospital Stanford, developed lung disease in the context of systemic JIA.

Results of their multicenter cases series of 61 children suggested the following: Parenchymal lung disease is associated with a group of unusual clinical characteristics, and the lung pathology is an unusual variant of pulmonary alveolar proteinosis (PAP). This pathology which is not typically associated with connective tissue disease, suggests lung macrophage overload or dysfunction. The constellation of clinical features and unusual lung pathology was associated with IL-1/IL-6 inhibitor exposure, although causality cannot be assumed. PAP was observed in 4 children without exposure or the unusual features, suggesting inhibitor exposure may promote this rare pathologic process.  

Rheumatology Consultant caught up with Dr Saper and Elizabeth Mellins, MD, a senior coauthor of the study, about the research.

RHEUM CON: What surprised you the most about the study findings?

Vivian Saper: I was surprised to see an eerie repetition in the occurrence of 4 features preceding lung disease detection in a substantial subset of the cases. The sequence included an elevation in serum ferritin level, appearance of an often intensely pruritic nonevanescent rash (atypical for systemic JIA), impressive peripheral eosinophilia, and profound lymphopenia. This sequence was observed in children who were exposed to cytokine inhibition. However, the paucity of cases who developed lung disease without these drug exposures is a caveat of our study, as are the limitations inherent to a retrospective study. Further research is needed to investigate a relationship to drug exposure.

RHEUM CON: What are the clinical implications of the study, and how can rheumatologists apply them to practice?

VS: Lung disease appears difficult to recognize until it is advanced. Appreciating risk factors and prodromal features may improve detection. For example, the lung disease cohort was enriched for children with sJIA onset at a young age, although lung disease occurrence is not limited to these children. The following features should raise suspicion: escape from control with current medications and occurrence of macrophage activation syndrome (MAS) while receiving treatment with a cytokine inhibitor. Careful attention to other medication-related adverse events including delayed drug hypersensitivity is warranted. If drug hypersensitivity is present, the recommendation is to withdraw the implicated medication, turning to alternative immunosuppression as indicated. Pneumocystis pneumonia complicated some cases of systemic JIA in our study, so prophylaxis is advised, especially if lymphopenia is present or steroids are a part of treatment.

RHEUM CON: What are characteristics of parenchymal lung disease in this patient population that a rheumatologist may not recognize? 

VS: With the lack of significant respiratory symptoms, lung disease was often first indicated by the appearance of acute clubbing with the unusual element of erythematous digital tips. The lung histopathology is a variant of pulmonary alveolar proteinosis/endogenous lipoid pneumonia (PAP/ELP); this was unexpected, as PAP/ELP is not part of any known connective tissue-related lung disease.

Elizabeth Mellins: Also striking in our study was the significant number of children with trisomy 21 (10%) and the frequent occurrence of anaphylactic reactions to tocilizumab—38% of children experienced this after being exposed to tocilizumab. This is a dramatic finding, because this number is significant compared with the less than 1% in the clinical trial of this medication in children with systemic JIA.²

RHEUM CON: How can a rheumatologist approach management of parenchymal lung disease in systemic JIA?

VS: The detection of lung disease is often accompanied by MAS. Management decisions must be individualized according to the activity of systemic JIA with consideration of the lung manifestations. Coordinating care together with a pediatric pulmonologist is advised.

RHEUM CON: What are the next steps of your research?

EM: Studies are needed to determine the incidence and clinical spectrum of this disease and the underlying mechanism(s) of its development. Those studies will require large collaborative efforts. Fortunately, such efforts are currently being discussed in the international pediatric rheumatology community, and the research networks needed for such studies exist.  

References:

1. Saper VE, Chen G, Deutsch GH, et al; Childhood Arthritis and Rheumatology Research Alliance Registry Investigators. Emergent high fatality lung disease in systemic juvenile arthritis. Ann Rheum Dis. 2019;78(12):1722-173 doi:10.1136/annrheumdis-2019-216040.
2. De Benedetti F, Brunner HI, Ruperto N, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385-2395. doi:10.1056/NEJMoa1112802.

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