Emergent high fatality lung disease in systemic juvenile arthritis

Abstract

ObjectiveTo investigate the characteristics and risk factors of a novel parenchymal lung disease (LD), increasingly detected in systemic juvenile idiopathic arthritis (sJIA).MethodsIn a multicentre retrospective study, 61 cases were investigated using physician-reported clinical information and centralised analyses of radiological, pathological and genetic data.ResultsLD was associated with distinctive features, including acute erythematous clubbing and a high frequency of anaphylactic reactions to the interleukin (IL)-6 inhibitor, tocilizumab. Serum ferritin elevation and/or significant lymphopaenia preceded LD detection. The most prevalent chest CT pattern was septal thickening, involving the periphery of multiple lobes ± ground-glass opacities. The predominant pathology (23 of 36) was pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia (PAP/ELP), with atypical features including regional involvement and concomitant vascular changes. Apparent severe delayed drug hypersensitivity occurred in some cases. The 5-year survival was 42%. Whole exome sequencing (20 of 61) did not identify a novel monogenic defect or likely causal PAP-related or macrophage activation syndrome (MAS)-related mutations. Trisomy 21 and young sJIA onset increased LD risk. Exposure to IL-1 and IL-6 inhibitors (46 of 61) was associated with multiple LD features. By several indicators, severity of sJIA was comparable in drug-exposed subjects and published sJIA cohorts. MAS at sJIA onset was increased in the drug-exposed, but was not associated with LD features.ConclusionsA rare, life-threatening lung disease in sJIA is defined by a constellation of unusual clinical characteristics. The pathology, a PAP/ELP variant, suggests macrophage dysfunction. Inhibitor exposure may promote LD, independent of sJIA severity, in a small subset of treated patients. Treatment/prevention strategies are needed.

Storm Warning: Lung Disease in Systemic Juvenile Idiopathic Arthritis

“…Intriguingly, almost 50% of patients had experienced an adverse reaction to a biologic drug, most characteristically an allergic-type reaction to tocilizumab, an otherwise quite uncommon event. These findings are echoed in the still-unpublished larger series, which includes 9 patients who were also described in the study by Schulert and colleagues, although in the larger series an extrapolated mortality of >50% at 5 years has been observed, as well as features such as lymphopenia and a striking overrepresentation of patients with trisomy 21 (8). Considering only referrals within the Cincinnati catchment area, Schulert et al provide the first estimate of the prevalence of LD in systemic JIA patients, 5 of 74 (or almost 7%), making SJIA-LD a complication that we should have noticed years ago if present at this frequency.…”

“…In 2013, Kimura and colleagues observed that some patients with systemic JIA developed life-threatening pulmonary complications of a kind unfamiliar to practitioners who had treated this disease for decades (7). A recent case series identified 61 additional cases (8). In this issue of Arthritis & Rheumatology, Schulert and coworkers report yet more patients matching this case description and provide the first detailed mechanistic look at systemic JIA with lung disease, designated SJIA-LD (9).…”

“…The SJIA-LD case series is discussed in more detail in a recent article by Saper et al (see ref. 8).…”

SARS-CoV-2 Inflammatory Syndrome. Clinical Features and Rationale for Immunological Treatment

“…Thus, it resembles the inflammatory syndromes that may complicate anti-phospholipid antibody syndrome (APS), namely the catastrophic anti-phospholipid syndrome (CAPs), characterized by disseminated intravascular microthrombosis [29]; or, the systemic CLLS characterized by altered capillary wall permeability [30]. Besides CAPs and CLLS, the SARS-CoV-2 inflammation, leading to ARDS, shares pathogenic mechanisms and clinical-radiological aspects with other auto-immune/-inflammatory diseases, such as juvenile idiopathic arthritis and its adult form [31][32][33] and Kawasaki disease [34]. Systemic CLLS has also been observed in Kawasaki disease [35].…”

Successful treatment of plasma exchange for refractory systemic juvenile idiopathic arthritis complicated with macrophage activation syndrome and severe lung disease

“…We read with great interest the recent article by Saper et al 1 describing high mortality of systemic juvenile idiopathic arthritis (sJIA) patients affected by parenchymal lung disease (LD). LD with sJIA has also been associated with macrophage activation syndrome (MAS).…”