title: Elevated TNF-α is associated with pain and physical disability in mucopolysaccharidosis types I, II, and VI.
abstract: 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.
  
  
  OBJECTIVE
  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 2-5years. 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: 5-17years; 35% female) and 51 controls (age: 8-17years; 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.
authors.affiliation: David Geffen School of Medicine - UCLA, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, United States. Electronic address: lpolgreen@labiomed.org.
authors.forename: Lynda E
authors.initials: LE
authors.lastname: Polgreen
authors.affiliation: University of Minnesota, 2450 Riverside Ave, Minneapolis, MN 55454, United States.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Vehe
authors.affiliation: University of Minnesota, 717 Delaware Street SE, Minneapolis, MN 55414, United States.
authors.forename: Kyle
authors.initials: K
authors.lastname: Rudser
authors.affiliation: University of Minnesota, 2450 Riverside Ave, Minneapolis, MN 55454, United States; HealthPartners Institute for Education and Research, 3311 Old Shakopee Road E. Minneapolis, MN 55425, United States.
authors.forename: Alicia
authors.initials: A
authors.lastname: Kunin-Batson
authors.affiliation: University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55414, United States.
authors.forename: Jeanine Jarnes
authors.initials: JJ
authors.lastname: Utz
authors.affiliation: David Geffen School of Medicine - UCLA, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 W. Carson Street, Torrance, CA 90502, United States.
authors.forename: Patricia
authors.initials: P
authors.lastname: Dickson
authors.affiliation: University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55414, United States.
authors.forename: Elsa
authors.initials: E
authors.lastname: Shapiro
authors.affiliation: University of Minnesota, 420 Delaware Street SE, Minneapolis, MN 55414, United States.
authors.forename: Chester B
authors.initials: CB
authors.lastname: Whitley
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D006233:Persons with Disabilities; D018450:Disease Progression; D005260:Female; D006304:Health Status; D006801:Humans; D008297:Male; D009083:Mucopolysaccharidoses / Q000097:blood* / Q000150:complications* / Q000175:diagnosis / Q000628:therapy; D010146:Pain / Q000209:etiology*; D010147:Pain Measurement; D063868:Patient Outcome Assessment; D011446:Prospective Studies; D014409:Tumor Necrosis Factor-alpha / Q000097:blood*
chemical_list: D014409:Tumor Necrosis Factor-alpha
keywords: Bone; Inflammation; Joint; Mucopolysaccharidosis; TNF-α