Background Children and adults with the lysosomal storage diseases mucopolysaccharidosis (MPS) types I, II and VI live shortened lives permeated by chronic pain and physical disability. Current treatments do not alleviate these problems. Thus there is a critical need to understand the mechanism of chronic pain and disability in MPS in order to improve the way we treat patients. A potential target is inflammation. Hypothesis We hypothesized that excessive inflammation mediated by the tumor necrosis factor-α (TNF-α) inflammatory pathway is the fundamental cause of much of the chronic pain and physical disability in MPS. Methods 55 patients with MPS I, II, or VI were enrolled over the course of a 5-year prospective longitudinal natural history study and evaluated annually for 2–5 years. 51 healthy controls were enrolled in a separate cross-sectional study of bone and energy metabolism. TNF-α was measured by ELISA. Pain and physical disability were measured by the Children's Health Questionnaire – Parent Form 50 (CHQ-PF50). Differences in log-transformed TNF-α levels and associations with CHQ domains were evaluated using a linear mixed effects model with random intercept. Results TNF-α levels were measured in 48 MPS (age: 5–17 years; 35% female) and 51 controls (age: 8–17 years; 53% female). Among MPS, 22 (46%) were treated with hematopoietic cell transplantation (HCT) alone, 24 (50%) with enzyme replacement therapy (ERT) alone, and 2 (4%) with both HCT and ERT. TNF-α levels are higher in MPS compared to healthy controls (p < 0.001). Higher TNF-α levels are associated with increased pain and decreased physical function, social limitations due to physical health, and physical summary score (all p < 0.05). TNF-α levels were not significantly associated with the general health score. TNF-α levels did not change significantly over time in MPS. Conclusions Higher TNF-α levels are implicated in the pain and decreased physical function present in individuals with MPS despite treatment with ERT and/or HCT, suggesting that TNF-a inhibition could potentially be a useful adjunctive therapy. Further investigation into the role of TNF-α inhibition in MPS to decrease pain and improve physical function is indicated.
Bibliographical noteFunding Information:
This project was supported by grant number K23AR057789 (LEP) from the National Institute of Arthritis and Musculoskeletal and Skin Diseases , U54NS065768 (CBW) from the National Institute of Neurological Disorders and Stroke , and by UL1TR000114 and UL1RR024131 from the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) to the University of Minnesota and to the Children's Hospital and Research Center, Oakland, respectively, Clinical and Translational Science Institutes (CTSI). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the CTSI or the NIH. Comparison data on healthy children were obtained from a project funded by the Irvine McQuarrie Research Scholar Award (LEP).