Subject(s)
Antirheumatic Agents/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmune Diseases/genetics , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Macrophage Activation Syndrome/genetics , cdc42 GTP-Binding Protein/genetics , Child , Female , Humans , Infant , Inflammation/genetics , Interleukin-1beta/antagonists & inhibitors , MaleABSTRACT
BACKGROUND: Autoinflammatory diseases manifest inflammation without evidence of infection, high-titer autoantibodies, or autoreactive T cells. We report a disorder caused by mutations of IL1RN, which encodes the interleukin-1-receptor antagonist, with prominent involvement of skin and bone. METHODS: We studied nine children from six families who had neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis. Response to empirical treatment with the recombinant interleukin-1-receptor antagonist anakinra in the first patient prompted us to test for the presence of mutations and changes in proteins and their function in interleukin-1-pathway genes including IL1RN. RESULTS: We identified homozygous mutations of IL1RN in nine affected children, from one family from Newfoundland, Canada, three families from The Netherlands, and one consanguineous family from Lebanon. A nonconsanguineous patient from Puerto Rico was homozygous for a genomic deletion that includes IL1RN and five other interleukin-1-family members. At least three of the mutations are founder mutations; heterozygous carriers were asymptomatic, with no cytokine abnormalities in vitro. The IL1RN mutations resulted in a truncated protein that is not secreted, thereby rendering cells hyperresponsive to interleukin-1beta stimulation. Patients treated with anakinra responded rapidly. CONCLUSIONS: We propose the term deficiency of the interleukin-1-receptor antagonist, or DIRA, to denote this autosomal recessive autoinflammatory disease caused by mutations affecting IL1RN. The absence of interleukin-1-receptor antagonist allows unopposed action of interleukin-1, resulting in life-threatening systemic inflammation with skin and bone involvement. (ClinicalTrials.gov number, NCT00059748.)
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Autoimmune Diseases/genetics , Inflammation/immunology , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Receptors, Interleukin-1/antagonists & inhibitors , Autoimmune Diseases/drug therapy , Base Sequence , Child , Female , Genes, Recessive , Homozygote , Humans , Infant , Infant, Newborn , Inflammation/drug therapy , Inflammation/genetics , Interleukin 1 Receptor Antagonist Protein/deficiency , Interleukin 1 Receptor Antagonist Protein/genetics , Interleukin-1/genetics , Interleukin-1/physiology , Interleukin-1beta/antagonists & inhibitors , Male , Mutation , Pedigree , RNA, Messenger/metabolismABSTRACT
A number of studies have demonstrated that patients with autoimmune disease have lower levels of vitamin D prompting speculation that vitamin D might suppress inflammation and immune responses in children with juvenile idiopathic arthritis (JIA). The objective of this study was to compare vitamin D levels in children with JIA at disease onset with healthy children. We hypothesized that children and adolescents with JIA have lower vitamin D levels than healthy children and adolescents. Data from a Canadian cohort of children with new-onset JIA (n= 164, data collection 2007-2012) were compared to Canadian Health Measures Survey (CHMS) data (n=4027, data collection 2007-2011). We compared 25-hydroxy vitamin D (25(OH)D) concentrations with measures of inflammation, vitamin D supplement use, milk intake, and season of birth. Mean 25(OH)D level was significantly higher in patients with JIA (79 ± 3.1 nmol/L) than in healthy controls (68 ± 1.8 nmol/L P <.05). Patients with JIA more often used vitamin D containing supplements (50% vs. 7%; P <.05). The prevalence of 25(OH)D deficiency (<30 nmol/L) was 6% for both groups. Children with JIA with 25(OH)D deficiency or insufficiency (<50 nmol/L) had higher C-reactive protein levels. Children with JIA were more often born in the fall and winter compared to healthy children. In contrast to earlier studies, we found vitamin D levels in Canadian children with JIA were higher compared to healthy children and associated with more frequent use of vitamin D supplements. Among children with JIA, low vitamin D levels were associated with indicators of greater inflammation.
Subject(s)
Arthritis, Juvenile/blood , Dietary Supplements , Inflammation , Parturition , Seasons , Vitamin D Deficiency/blood , Vitamin D/blood , Animals , Arthritis, Juvenile/complications , Arthritis, Juvenile/immunology , Autoimmune Diseases , C-Reactive Protein/metabolism , Canada/epidemiology , Case-Control Studies , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant, Newborn , Inflammation/etiology , Inflammation/metabolism , Male , Milk , Vitamin D/analogs & derivatives , Vitamin D/therapeutic use , Vitamin D Deficiency/complications , Vitamin D Deficiency/drug therapy , Vitamin D Deficiency/immunologyABSTRACT
A symposium was convened April 2, 2005, by the Department of Pediatrics, University of British Columbia, Vancouver, Canada. The event was a tribute to Dr. Ross Petty on his retirement and in recognition of his contributions to the local and international community of pediatric rheumatology. Speakers were past and present fellows, local basic science and adult rheumatology colleagues, and pediatric rheumatologists from the Pacific North West.