Disease Course, Treatments, and Outcomes of Children With Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease

Abstract

Objective: Systemic juvenile idiopathic arthritis-associated lung disease (SJIA-LD) is a life-threatening disease complication. Key questions remain regarding clinical course and optimal treatment approaches. The objectives of the study were to detail management strategies after SJIA-LD detection, characterize overall disease courses, and measure long-term outcomes.

Methods: This was a prospective cohort study. Clinical data were abstracted from the electronic medical record, including current clinical status and changes since diagnosis. Serum biomarkers were determined and correlated with presence of LD.

Results: We enrolled 41 patients with SJIA-LD, 85% with at least one episode of macrophage activation syndrome and 41% with adverse reactions to a biologic. Although 93% of patients were alive at last follow-up (median 2.9 years), 37% progressed to requiring chronic oxygen or other ventilator support, and 65% of patients had abnormal overnight oximetry studies, which changed over time. Eighty-four percent of patients carried the HLA-DRB1*15 haplotype, significantly more than patients without LD. Patients with SJIA-LD also showed markedly elevated serum interleukin-18 (IL-18), variable C-X-C motif chemokine ligand 9 (CXCL9), and significantly elevated matrix metalloproteinase 7. Treatment strategies showed variable use of anti-IL-1/6 biologics and addition of other immunomodulatory treatments and lung-directed therapies. We found a broad range of current clinical status independent of time from diagnosis or continued biologic treatment. Multidomain measures of change showed imaging features were the least likely to improve with time.

Conclusion: Patients with SJIA-LD had highly varied courses, with lower mortality than previously reported but frequent hypoxia and requirement for respiratory support. Treatment strategies were highly varied, highlighting an urgent need for focused clinical trials.

Figure 1.

Serum biomarkers levels in patients with SJIA-LD. (A) Initial serum IL-18 level for a convenience sample of patients with SJIA with various disease activity (n = 82) compared with patients with SJIA-LD (n = 34) is shown. Upper limit of normal is 540 pg/ml. (B) Initial serum CXCL9 level for patients with SJIA (n = 93) and patients with SJIA-LD (n = 22) is shown. Upper limit of normal is 67 pg/ml. (C) Serum levels of MMP7 as determined by specific ELISA in control children (n = 15), patients with SJIA without LD (n = 30), and patients with SJIA-LD (n = 15) are shown. ****P < 0.001 vs SJIA without LD. (D) Serum levels of CCL11 (eotaxin-1) as determined by specific ELISA in control children (n = 15), patients with SJIA without LD (n = 30), and patients with SJIA-LD (n = 15) are shown. CCL11, C-C motif chemokine ligand 11; CXCL9, C-X-C motif chemokine ligand 9; ELISA, enzyme-linked immunosorbent assay; IL-18, interleukin-18; LD, lung disease; MMP7, matrix metalloproteinase 7; SJIA, systemic juvenile idiopathic arthritis.

Figure 2.

Medication use by patients with SJIA-LD before and after LD diagnosis, separated into (A) medications routinely used for SJIA, (B) other immunomodulatory therapy, and (C) treatments for pulmonary disease and prophylaxis. *P < 0.05, **P < 0.01, ***P < 0.001 compared with pre-LD diagnosis. IVIG, intravenous immunoglobulin; LABA, long-acting beta agonist; LD, lung disease; MMF, mycophenolate mofetil; SABA, short-acting beta agonist; SJIA, systemic juvenile idiopathic arthritis; TMP/SMIX, trimethoprim-sulfamethoxazole.

Figure 3.

Survival curves of patients with SJIA-LD. (A) Overall survival of patients with SJIA-LD (median follow-up 2.9 years) is shown. (B) Survival free of supplemental oxygen for patients with SJIA-LD after LD diagnosis is shown. LD, lung disease; SJIA, systemic juvenile idiopathic arthritis.

Figure 4.

Current clinical status of patients with SJIA-LD. (A) Distribution of PGALD scores at last follow-up for patients with SJIA-LD is shown. (B) Correlation between PGALD score at last follow-up and peak serum IL-18 level is shown. (C) Change in clinical status from LD diagnosis to last follow-up in four cardinal clinical domains (chi-square, P = 0.001) is shown. (D) Hierarchical clustering of patterns of clinical change for patients with SJIA-LD is shown. IL-18, interleukin-18; LD, lung disease; PGALD, Physician Global Assessment of Lung Disease; SJIA, systemic juvenile idiopathic arthritis; SLD, SJIA Lung Disease.

Figure 5.

Variability in imaging progression in patients with SJIA-LD. For patient 1, baseline chest CT demonstrated extensive parenchymal pulmonary opacities with interstitial thickening. Repeat imaging showed an overall similar pattern with development of small cysts suggesting fibrosis despite stopping all anticytokine therapy. Patient 2 at baseline demonstrated extensive bilateral ground-glass opacities and interlobular septal thickening. Follow-up study 2 years later showed progression of findings, including more dependent consolidation despite treatment with multiple biologic and nonbiologic agents. CT, computed tomography; LD, lung disease; SJIA, systemic juvenile idiopathic arthritis.