Gain-of-function human UNC93B1 variants cause systemic lupus erythematosus and chilblain lupus.

UNC93B1 is a transmembrane domain protein mediating the signaling of endosomal Toll-like receptors (TLRs). We report five families harboring rare missense substitutions (I317M, G325C, L330R, R466S, and R525P) in UNC93B1 causing systemic lupus erythematosus (SLE) or chilblain lupus (CBL) as either autosomal dominant or autosomal recessive traits. As for a D34A mutation causing murine lupus, we recorded a gain of TLR7 and, to a lesser extent, TLR8 activity with the I317M (in vitro) and G325C (in vitro and ex vivo) variants in the context of SLE. Contrastingly, in three families segregating CBL, the L330R, R466S, and R525P variants were isomorphic with respect to TLR7 activity in vitro and, for R525P, ex vivo. Rather, these variants demonstrated a gain of TLR8 activity. We observed enhanced interaction of the G325C, L330R, and R466S variants with TLR8, but not the R525P substitution, indicating different disease mechanisms. Overall, these observations suggest that UNC93B1 mutations cause monogenic SLE or CBL due to differentially enhanced TLR7 and TLR8 signaling.

How to use autoantibodies in suspected paediatric rheumatic disease.

Autoantibodies can be an important indicator of paediatric rheumatic disease and useful in establishing a diagnosis. However, autoantibodies may be requested in cases where the patient does not have clinical features strongly suggestive of a rheumatic disease. This can lead to further unnecessary investigations, specialist referral and undue anxiety for the family. The aim of this article is to provide guidance for when it is appropriate to request autoantibodies, which ones to perform and how to interpret the results.

Foot orthoses in children with juvenile idiopathic arthritis: a randomised controlled trial.

INTRODUCTION: There is limited evidence supporting the podiatric treatment of children with juvenile idiopathic arthritis (JIA). This multicentre randomised controlled trial aimed to determine whether preformed foot orthoses (FOs) impacted on pain and quality of life (QoL) in children with JIA. METHODS: Eligible children were randomised to receive either 'fitted' FOs with customised chair-side corrections or 'control' FOs made without corrections. Changes in pain and QoL were measured using a visual analogue scale and Paediatric Quality of Life questionnaire, respectively. JIA children were assessed at baseline, 3 months and 6 months. RESULTS: 60 children were recruited. 179 out of a possible 180 assessments (99.4%) were completed. A statistically significant greater difference in pain reduction (baseline - 6 months) was seen between the two groups favouring fitted FOs (p=0.029). The reduction in pain in the fitted FOs group was clinically important (8 mm). Significant differences in QoL favouring fitted FOs were also identified as measured by the children and independently by their parents/carers. CONCLUSIONS: Fitted FOs may reduce pain and improve QoL in selected children with JIA. TRIAL REGISTRATION NUMBER: NCT02001844.

Suppression of the Nrf2-dependent antioxidant response by glucocorticoids and 11ß-HSD1-mediated glucocorticoid activation in hepatic cells.

BACKGROUND: Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is a key transcription factor regulating a plethora of detoxifying enzymes and antioxidant genes involved in drug metabolism and defence against oxidative stress. The glucocorticoid receptor (GR) is a ligand-induced transcription factor involved in the regulation of energy supply for metabolic needs to cope with various stressors. GR activity is controlled by glucocorticoids, which are synthesized in the adrenal glands and regenerated mainly in the liver from inactive cortisone by 11ß-hydroxysteroid dehydrogenase-1 (11ß-HSD1). METHODS AND PRINCIPAL FINDINGS: Using transfected HEK-293 cells and hepatic H4IIE cells we show that glucocorticoids, activated by 11ß-HSD1 and acting through GR, suppress the Nrf2-dependent antioxidant response. The expression of the marker genes NQO1, HMOX1 and GST2A was suppressed upon treatment of 11ß-HSD1 expressing cells with cortisone, an effect that was reversed by 11ß-HSD1 inhibitors. Furthermore, our results demonstrate that elevated glucocorticoids lowered the ability of cells to detoxify H(2)O(2). Moreover, a comparison of gene expression in male and female rats revealed an opposite sexual dimorphism with an inverse relationship between 11ß-HSD1 and Nrf2 target gene expression. CONCLUSIONS: The results demonstrate a suppression of the cellular antioxidant defence capacity by glucocorticoids and suggest that elevated 11ß-HSD1 activity may lead to impaired Nrf2-dependent antioxidant response. The gender-specific differences in hepatic expression levels of 11ß-HSD1 and Nrf2 target genes and the impact of pharmacological inhibition of 11ß-HSD1 on improving cellular capacity to cope with oxidative stress warrants further studies in vivo.

Access to care for children and young people diagnosed with localized scleroderma or juvenile SSc in the UK.

OBJECTIVES: To describe pathways of care and referral to paediatric rheumatology from onset of first symptom (noticed by the patient or their family) to diagnosis for children and young people diagnosed with localized scleroderma (LS) or juvenile SSc (jSSc). METHODS: Retrospective case note audit of patients under paediatric rheumatology care who presented during January 2005-January 2010. Data included disease subtype, sex, age at key points in the referral pathway and health care professional (HCP) contact. All patient and HCP data were pseudo-anonymized in accordance with good clinical practice. RESULTS: Data were from eight UK centres that saw 89 cases: 62 females, 26 males; 73 LS, 16 jSSc. Median time from first symptom to first HCP review was 4 (range 0-72) months (LS) and 1 (range 0-50) month (jSSc). Median time from first symptom to paediatric rheumatology review was 15 (range 1-103) months (LS) and 7 (range 0-50) months (jSSc). Median time from first HCP review to first paediatric rheumatology review was 11 (range 0-103) months (LS) and 2 (range 0-10) months. First HCP seen (74%) was usually a general practitioner. The referring HCP to paediatric rheumatology was usually a dermatologist (56%) for LS. Median time from first symptom to diagnosis was 13 (range 1-102) months (LS) and 8 (range 1-50) months (jSSc). CONCLUSION: A prolonged interval occurs from first symptom to definitive diagnosis, which may adversely affect outcome. There is a need to raise awareness of this rare diagnosis and facilitate earlier recognition.