Search

Our patients' phenotypes are a mix of features found in both DADA2 and ALPS. It has been reported that patients with pathogenic variants in I FAS i will have 100% cellular and laboratory penetrance; however, only 25-45% of patients will express a clinical phenotype highlighting the variable expressivity seen in ALPS [[2]]. 1Hematologic, immunologic, and genetic findings in patients with variants in ADA2 and FAS causing DADA2 and ALPS. [Extracted from the article]

Objectives: Families that contain multiple siblings affected with childhood onset of systemic lupus erythematosus (SLE) likely have strong genetic predispositions. We performed whole exome sequencing (WES) to identify familial rare risk variants and to assess their effects in lupus.Methods: Sanger sequencing validated the two ultra-rare, predicted pathogenic risk variants discovered by WES and identified additional variants in 562 additional patients with SLE. Effects of a splice site variant and a frameshift variant were assessed using a Minigene assay and CRISPR/Cas9-mediated knock-in (KI) mice, respectively.Results: The two familial ultra-rare, predicted loss-of-function (LOF) SAT1 variants exhibited X-linked recessive Mendelian inheritance in two unrelated African-American families. Each LOF variant was transmitted from the heterozygous unaffected mother to her two sons with childhood-onset SLE. The p.Asp40Tyr variant affected a splice donor site causing deleterious transcripts. The young hemizygous male and homozygous female Sat1p.Glu92Leufs*6 KI mice spontaneously developed splenomegaly, enlarged glomeruli with leucocyte infiltration, proteinuria and elevated expression of type I interferon-inducible genes. SAT1 is highly expressed in neutrophils and encodes spermidine/spermine-N1-acetyltransferase 1 (SSAT1), a rate-limiting enzyme in polyamine catabolism. Young male KI mice exhibited neutrophil defects and decreased proportions of Foxp3 +CD4+ T-cell subsets. Circulating neutrophil counts and proportions of Foxp3 +CD4+ T cells correlated with decreased plasma levels of spermine in treatment-naive, incipient SLE patients.Conclusions: We identified two novel SAT1 LOF variants, showed the ability of the frameshift variant to confer murine lupus, highlighted the pathogenic role of dysregulated polyamine catabolism and identified SAT1 LOF variants as new monogenic causes for SLE. [ABSTRACT FROM AUTHOR]

Objective: The Effects of Youngsters' Eyesight on Quality of Life (EYE‐Q) questionnaire measures vision‐related functioning (VRF) and vision‐related quality of life (VRQoL) in children with uveitis. Our aim was to revise the alpha version of the EYE‐Q to refine VRF and VRQoL subscales and to assess the validity of the EYE‐Q. Methods: Children with juvenile idiopathic arthritis (JIA), JIA‐associated uveitis, and other noninfectious uveitis were enrolled. Patients and parents completed the EYE‐Q, Pediatric Quality of Life Inventory (overall quality of life), and Childhood Health Assessment Questionnaire (physical functioning). The development site completed the alpha version of the EYE‐Q, and the composite sites completed the beta version. We compared item‐subscale correlations, internal consistency, and construct and discriminant validity among the different versions. Results: Of the 644 patients enrolled, 61.6% completed the alpha version, and 38.4% the beta version of the EYE‐Q. Mean ± SD patient age was 11.1 ± 4.2 years, and 70% were female. Fewer White patients (73.5%) completed the alpha version compared to the beta version (86.2%; P < 0.001). With the exception of patient‐reported VRF, both versions had similar item‐subscale correlations. Version comparisons on scale internal consistencies indicated significant differences for parent‐ and patient‐reported VRF, but each scale had a Cronbach's α of >0.80 beta. When data were combined, the EYE‐Q showed significant differences between JIA‐only and uveitis patients on all parent and patient scores, except for patient‐reported VRF. Conclusion: The EYE‐Q appears to be a valid measure of VRF and VRQoL in pediatric uveitis. Our results suggest it may be used as an outcome measure in multicenter pediatric uveitis studies. [ABSTRACT FROM AUTHOR]

As newer treatment modalities become available for patients with severe lupus nephritis, it becomes increasingly important to identify patients at risk for renal failure. In this study, the records of 90 children presenting with systemic lupus erythematosus over a 13-year period were reviewed. Nineteen were lost to follow-up prior to completion of the study. Of the 71 remaining children, 16 (22%) progressed to chronic renal failure. Persistent hypertension lasting greater than 4 months, anemia, abnormalities of the urinalysis, and elevated serum creatinine level were significantly associated with progression to renal failure. Sex, race, age, abnormalities of creatinine clearance, and 24-hour urine protein collection were not associated with progression to renal failure. Renal biopsies were obtained in 45 children. Biopsies were initially classified according to World Health Organization criteria. Diffuse proliferative glomerulonephritis was significantly associated with progression to renal failure. The 45 biopsies available were reviewed by one of the authors and categorized by activity and chronicity indices. Both the active lesions of fibrinoid necrosis, synechiae, tubular casts, and vasculitic lesions and the chronic lesion of glomerular sclerosis correlated with progression to renal failure. Of the 16 children who progressed to renal failure, 2 had cadaver kidney transplants and are well 5 years posttransplant; 4 had fulminant lupus and died within 1 month of commencing dialysis; 10 began chronic dialysis. Five of the 10 children on chronic dialysis died from sepsis. These data suggest that children with systemic lupus erythematosus who undergo dialysis do poorly. This alters the risk-to-benefit ratio of newer, more aggressive treatment protocols which should be considered in children whose clinical, laboratory, and renal biopsy findings suggest eventual progression to renal failure. Pediatrics 1992;89:240-246; lupus nephritis, renal failure, prognosis.

Objective: To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA).Methods: The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples.Results: The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample.Conclusion: The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA. [ABSTRACT FROM AUTHOR]

Background: No large population-based studies have been done on systemic lupus erythematosus (SLE) mortality trends in the United States.Objective: To identify secular trends and population characteristics associated with SLE mortality.Design: Population-based study using a national mortality database and census data.Setting: United States.Participants: All U.S. residents, 1968 through 2013.Measurements: Joinpoint trend analysis of annual age-standardized mortality rates (ASMRs) for SLE and non-SLE causes by sex, race/ethnicity, and geographic region; multiple logistic regression analysis to determine independent associations of demographic variables and period with SLE mortality.Results: There were 50 249 SLE deaths and 100 851 288 non-SLE deaths from 1968 through 2013. Over this period, the SLE ASMR decreased less than the non-SLE ASMR, with a 34.6% cumulative increase in the ratio of the former to the latter. The non-SLE ASMR decreased every year starting in 1968, whereas the SLE ASMR decreased between 1968 and 1975, increased between 1975 and 1999, and decreased thereafter. Similar patterns were seen in both sexes, among black persons, and in the South. However, statistically significant increases in the SLE ASMR did not occur among white persons over the 46-year period. Females, black persons, and residents of the South had higher SLE ASMRs and larger cumulative increases in the ratio of the SLE to the non-SLE ASMR (31.4%, 62.5%, and 58.6%, respectively) than males, other racial/ethnic groups, and residents of other regions, respectively. Multiple logistic regression showed independent associations of sex, race, and region with SLE mortality risk and revealed significant racial/ethnic differences in associations of SLE mortality with sex and region.Limitations: Underreporting of SLE on death certificates may have resulted in underestimates of SLE ASMRs. Accuracy of coding on death certificates is difficult to ascertain.Conclusion: Rates of SLE mortality have decreased since 1968 but remain high relative to non-SLE mortality, and significant sex, racial, and regional disparities persist.Primary Funding Source: None. [ABSTRACT FROM AUTHOR]

Objective. The importance of hypomethylation in SLE is well recognized; however, the significance of hypermethylation has not been well characterized. We screened hypermethylated marks in SLE and investigated their possible implications. Methods. DNA methylation marks were screened in SLE whole-blood DNA by microarray, and two marks (CD3Z and VHL hypermethylations) were confirmed by a methylation single-base extension method in two independent ethnic cohorts consisting of 207 SLE patients and 151 controls. The correlation with clinical manifestations and the genetic influence on those epigenetic marks were analysed. Results. Two epigenetic marks, CD3Z and VHL hypermethylation, were significantly correlated with SLE: CD3Z hypermethylation (odds ratio = 7.76; P = 1.71 x 10-13) and VHL hypermethylation (odds ratio = 3.77; P = 3.20 x10-8), and the increased CD3Z methylation was correlated with downregulation of the CD3ς-chain in SLE T cells. In addition, less genetic influence on CD3Z methylation relative to VHL methylation was found in analyses of longitudinal and twin samples. Furthermore, a higher CD3Z methylation level was significantly correlated with a higher SLE disease activity index and more severe clinical manifestations, such as proteinuria, haemolytic anaemia and thrombocytopenia, whereas VHL hypermethylation was not. Conclusion. CD3Z hypermethylation is an SLE risk factor that can be modified by environmental factors and is associated with more severe SLE clinical manifestations, which are related to deranged T cell function by downregulating the CD3ς-chain. [ABSTRACT FROM AUTHOR]

Objective The American College of Rheumatology (ACR) and the Association of Rheumatology Health Professionals (ARHP) Annual Scientific Meeting is an important forum for early dissemination of novel ideas. However, unlike published studies in peer-reviewed journals, reviewers select abstracts based solely on a general summary of the research. Analyses of the scientific impact and the publication record of the ACR/ARHP Annual Meeting have not been previously described. This study characterizes publication trends and outcomes associated with abstracts presented at the ACR/ARHP Annual Scientific Meeting. Methods We identified all abstracts accepted for oral or poster presentation at the 2006 ACR/ARHP Annual Scientific Meeting. Using a defined search algorithm, we conducted a manual PubMed search for each accepted abstract, which was repeated by a custom computerized search, and analyzed the resulting journal title, impact factor, and time to publication. Results A total of 2,149 abstracts were analyzed. The overall publication ratio was 59.1%. The mean ± SD time from abstract presentation to publication was 18.2 ± 15.2 months with a mean ± SD impact factor of 5.61 ± 4.20. Overall, studies presented in oral format were significantly more likely to be published than poster presentations ( P < 0.0001). The average time to publication was significantly shorter for basic science studies than clinical research studies ( P < 0.0001). The average journal impact factor of published studies presented in oral format was significantly higher than those presented as posters ( P < 0.0001). Conclusion These results reflect high research productivity with a publication ratio of approximately 60% for abstracts presented at the 2006 Annual Scientific Meeting. [ABSTRACT FROM AUTHOR]

The article presents a study on the importance of plasmin immunization in the production of immunoglobulin G (IgG) anticardiopolin (aCL) antibodies in patients with antiphospolipid syndrome (APS). It uses two mouse models that were immunized with Freund's complete adjuvant. Results show that BALB/cJ mice only develop IgG antiplasmin, while MRL/MpJ mice had produced IgG antiplasmin and IgG aCL antibodies. It concludes that plasmin immunization can produce prothrombotic aCL in susceptible people.

We studied a 14 year-old boy with partial DiGeorge syndrome (DGS), status post complete repair of Tetralogy of Fallot, who developed antiphospholipid syndrome (APS) and type III mixed cryoglobulinemia. He presented with recurrent fever and dyspnea upon exertion secondary to right pulmonary embolus on chest computed tomography (CT). Coagulation studies revealed homozygous methylene tetrahydrofolate reductase 677TT mutations, elevated cardiolipin IgM antibodies, and elevated β2-glycoprotein I IgM antibodies. Infectious work-up revealed only positive anti-streptolysin O (ASO) and anti-DNAse B titers. Autoimmune studies showed strongly positive anti-platelet IgM, elevated rheumatoid factor (RF), and positive cryocrit. Renal biopsy for evaluation of proteinuria and hematuria showed diffuse proliferative glomerulonephritis (DPGN) with membranoproliferative features consistent with cryoglobulinemia. Immunofixation showed polyclonal bands. Our patient was treated successfully with antibiotics, prednisone, and mycophenolate mofetil (MMF). This is the first report of a patient with partial DGS presenting with APS and type III mixed cryoglobulinemia possibly due to Streptococcal infection. [ABSTRACT FROM AUTHOR]

Abstract. To evaluate whether the onset of systemic lupus erythematosus in the first decade of life was associated with a unique pattern of racial preponderance, sexual preponderance, genetic predisposition, or disease expression, the medical records of 23 children with systemic lupus erythematosus prior to their tenth birthdays were compared with the medical records of 82 children in whom lupus was diagnosed between their tenth and 20th birthdays. No statistically significant differences in sex distribution, racial (ethnic) background, family history, mode of onset, morbidity, or mortality rates were found between the two age groups. The frequently held view that children with early-onset lupus do worse probably relates to the fact that even though they survive as long as children with the older-onset disease, they die younger because they have the onset of their lupus at a younger age. [ABSTRACT FROM AUTHOR]