Juvenile idiopathic arthritis associated with a mutation in GATA3.

BACKGROUND: GATA3 is a transcription factor that is important during development and plays a role in differentiation and activity of immune cells, particularly T cells. Abnormal T cell function is found in autoimmune arthritis. We present the first known case of autoimmune arthritis associated with a novel GATA3 mutation. METHODS: Whole exome sequencing of the proband was performed on a clinical basis. Peripheral blood mononuclear cells (PBMCs) were collected from the proband, healthy sibling, and parent. cDNA prepared from RNA was analyzed with polymerase chain reaction and Sanger sequencing. Intracellular proteins were assessed by immunoblot of PBMC homogenates. GATA3 in vitro activity was measured in HeLa cell cultures expressing a mammalian expression vector containing GATA3 or mutants generated by site-directed mutagenesis. GATA3 transcriptional activity was examined using a luciferase reporter assay system. T helper cell ex vivo function was evaluated by stimulating PBMCs to differentiate into effector T cells along Th0, Th1, Th2, and Th17 lineages, and re-stimulating effector cells to secrete cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay. RESULTS: The proband is the first known case of autoimmune arthritis associated with a mutation in GATA3. The proband M401VfsX106 protein is expressed and has a dominant negative function on GATA3 transcriptional activity. The proband PBMCs have markedly increased differentiation along the Th1 and Th17 pathways, with decreased differentiation along the Th2 pathway. Unexpectedly, Th0 cells from the proband express high levels of IFNγ. CONCLUSIONS: Our research presents the first known case of autoimmune arthritis associated with a mutation in GATA3. This work expands the phenotypic spectrum of GATA3 mutations. It reveals the novel insight that decreased and altered GATA3 activity coincides with autoimmune arthritis. This work suggests that modulation of GATA3 may be a therapeutic approach for patients with autoimmune arthritis.

Controlled follow-up study of physical and psychosocial functioning of adolescents with juvenile primary fibromyalgia syndrome.

OBJECTIVES: Currently, there are no prospective studies exploring the prognosis of patients with juvenile primary FM syndrome (JPFS) or their physical, emotional and social outcomes as they enter the early adult years. The primary objective of this study was to assess long-term outcomes of a paediatric sample of clinically referred JPFS patients and their matched healthy controls. METHODS: Participants were 48 youths (current mean age = 19 years) diagnosed with JPFS in childhood or adolescence and 43 healthy controls matched in age, gender and race. The average length of follow-up was 3.67 years (range 2-6 years). Participants completed online (web-based) self-report questionnaires about current pain and physical symptoms, health status, anxiety, depressive symptoms and current and past treatments. RESULTS: Results showed that 62.5% of participants in the JPFS group continued to experience widespread pain and 60.4% reported having all the cardinal features of FM syndrome (including widespread pain, poor sleep and fatigue) at follow-up. The JPFS group reported significantly lower scores on all measures of health status and physical functioning compared with healthy controls and significantly greater symptoms of anxiety and depression. CONCLUSION: The results of this controlled follow-up study demonstrate that symptoms of FM appear to be chronic in a majority of clinically referred JPFS patients and the associated physical and emotional impairment can also be persistent. Implications for treatment and the need for further prospective longitudinal studies are discussed.

Anxiety, mood, and behavioral disorders among pediatric patients with juvenile fibromyalgia syndrome.

BACKGROUND: Mood and anxiety disorders are common psychiatric conditions among adult patients with fibromyalgia syndrome, but little is known about whether psychiatric disorders are prevalent among pediatric patients with fibromyalgia. OBJECTIVE: The primary objective of this study was to assess the prevalence of mood, anxiety, and behavioral disorders in a clinical sample of children and adolescents with juvenile primary fibromyalgia syndrome (JPFS) and assess the relationship between psychiatric disorders and JPFS symptom severity. METHODS: Standardized psychiatric interviews were conducted with children and their parents/primary caregivers, and measures of symptom severity including pain intensity and physician global ratings were obtained for 76 children and adolescents diagnosed with JPFS (ages 11 to 18 y) in pediatric rheumatology clinics at 4 hospitals in the Midwest. RESULTS: A total of 67.1% of patients had at least 1 current and 71.5% had at least 1 lifetime DSM-IV (Diagnostic and Statistical Manual of Mental Disorders-fourth edition) psychiatric diagnosis. The most frequent psychiatric diagnosis was anxiety disorder (57.5% of JPFS patients). Although mood difficulties were also common, the presence of major depression was lower than has been reported for adults with fibromyalgia syndrome. Physicians' global assessment of functioning was significantly lower for patients with a current anxiety disorder. There were no significant differences in pain severity among patients with and without anxiety, mood, or behavioral disorders. DISCUSSION: There seems to be a high prevalence of anxiety disorders in patients with JPFS, and presence of anxiety disorder is associated with poorer physician-rated functioning. Future research should explore whether early anxiety symptoms are predictive of long-term functioning.