Distinct cytokine and chemokine alterations in bronchoalveolar fluid from patients with systemic juvenile idiopathic arthritis associated lung disease (SJIA-LD).
Ivanna Romankevych, Alyssa Sproles, Thuy Do, Lexi Auld, Taskin Sabit, Richard Chhaing, Elizabeth Baker, Ashish Kumar, Bruce Trapnell, Brenna Carey, John J Brewington, Christopher Towe, Alexei Grom, Grant Schulert
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Abstract
Background: Lung disease associated with systemic juvenile idiopathic arthritis (SJIA-LD) remains poorly understood. Evaluation of bronchoalveolar lavage fluid (BALF) may better reflect disease pathogenesis. The objectives of our study were to measure levels of cytokines and chemokines in BALF and their associations with clinical features and treatment in patients with SJIA-LD.
Methods: Children with SJIA-LD undergoing clinically indicated diagnostic bronchoscopy were enrolled. Comparator BALF was collected from patients with other chronic inflammatory and non-inflammatory lung diseases. BALF was assayed for IL-6, 8 and 18, S100A8/9, S100A12, sCD25, CCL11, CCL17, CCL25, MMP7, and CXCL9.
Results: BALF was obtained from 21 patients with SJIA-LD and 54 comparator patients with other lung diseases. Compared to all controls, children with SJIA-LD had a significant elevation of IL-18 (median (IQR) 1406 (722.3-2812) vs 37.2 (25.3-70) pg/mL, p < 0.0001), S100A8/9 (4745.3 (3003-11506) vs. 1297.5 (260-7755) ng/mL, p = 0.02), sCD25 (31.6 (19-50.3) vs. 13.6 (8.6-37.3) pg/mL, p = 0.04), MMP-7 (18,466.7 (10,462.2-33,516.1) vs. 13.645 (8.6-37.3) pg/mL, p = 0.0384), and CCL17 (0 (0-63.1; p = 0.038) vs 0 (0-0) pg/mL. BALF IL-18 was significantly higher in children with SJIA-LD compared to all control subgroups (inflammatory and non-inflammatory airway disease, autoimmune pulmonary alveolar proteinosis, and poorly controlled asthma), in patients who were actively treated with anti-cytokine biologics (N = 9), and in patients who ultimately underwent hematopoietic stem cell transfer (N = 8). Patients receiving anti-cytokine biologics also had significant elevations in several other cytokines compared to patients without such treatments, while profiles in those treated with JAKi (N = 14) were largely similar. Linear regression analysis showed an association between BALF level of IL-18 and the number of immunosuppressive medications utilized (p = 0.0167), but not with O2 requirement, dose of anakinra or prednisone, plasma IL-18, ferritin, CRP or ESR.
Conclusions: Patients with SJIA-LD showed a distinct BALF cytokine profile, including significant IL-18, S100A8/9 protein, sCD25, and CCL-17 elevation. The level of IL-18 was higher in patients who required more immunosuppressive medications and were actively treated with anti-cytokine biologics. The relationship between BALF cytokine profiles and anti-cytokine biologics and JAK inhibitors is unclear and should be evaluated further.
期刊介绍：
Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.
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