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Aims/hypothesisOur aim was to study the association between serum 25-hydroxyvitamin D (25OHD) concentration and islet autoimmunity and type 1 diabetes in children with an increased genetic risk of type 1 diabetes.MethodsSerum samples for 25OHD measurements were obtained in the Trial to Reduce IDDM in the Genetically at Risk (TRIGR) ancillary study (Divia) from children in 15 countries. Case children (n = 244) were defined as having positivity for at least two out of four diabetes-associated autoantibodies measured at any one sample. For each case child, two control children were selected matched for country and date of birth (±1 year) (n = 488). Of the case children, 144 developed type 1 diabetes. Serum 25OHD was measured repeatedly in infancy and childhood and was compared according to age at the first seroconversion (at 6, 12 and 18 months prior to and at seroconversion) and calendar age (0, 6, 12 and 18 months).ResultsIn children with islet autoimmunity, mean serum 25OHD concentration was lower 18 months prior to the age of first seroconversion of the case children compared with the control children (57.7 vs 64.8 nmol/l, p = 0.007). In children with type 1 diabetes (n = 144), mean serum 25OHD concentration was lower 18 months prior to the age of the first seroconversion (58.0 vs 65.0 nmol/l, p = 0.018) and at the calendar age of 12 months (70.1 vs 75.9 nmol/l, p = 0.031) than in their control counterparts. Analyses were adjusted for month of sample collection, human leucocyte antigen genotype, maternal type 1 diabetes and sex.Conclusions/interpretationThe results suggest that early postnatal vitamin D may confer protection against the development of type 1 diabetes.Trial registrationClinicalTrials.gov NCT00179777

Zellweger spectrum disorder (ZSD) is a rare, debilitating genetic disorder of peroxisome biogenesis that affects multiple organ systems and presents with broad clinical heterogeneity. Although severe, intermediate, and mild forms of ZSD have been described, these designations are often arbitrary, presenting difficulty in understanding individual prognosis and treatment effectiveness. The purpose of this study is to conduct a scoping review and meta-analysis of existing literature and a medical chart review to determine if characterization of clinical findings can predict severity in ZSD. Our PubMed search for articles describing severity, clinical findings, and survival in ZSD resulted in 107 studies (representing 307 patients) that were included in the review and meta-analysis. We also collected and analyzed these same parameters from medical records of 136 ZSD individuals from our natural history study. Common clinical findings that were significantly different across severity categories included seizures, hypotonia, reduced mobility, feeding difficulties, renal cysts, adrenal insufficiency, hearing and vision loss, and a shortened lifespan. Our primary data analysis also revealed significant differences across severity categories in failure to thrive, gastroesophageal reflux, bone fractures, global developmental delay, verbal communication difficulties, and cardiac abnormalities. Univariable multinomial logistic modeling analysis of clinical findings and very long chain fatty acid (VLCFA) hexacosanoic acid (C26:0) levels showed that the number of clinical findings present among seizures, abnormal EEG, renal cysts, and cardiac abnormalities, as well as plasma C26:0 fatty acid levels could differentiate severity categories. We report the largest characterization of clinical findings in relation to overall disease severity in ZSD. This information will be useful in determining appropriate outcomes for specific subjects in clinical trials for ZSD.

Objectives To compare patterns of arteriographic lesions of the aorta and primary branches in patients with Takayasu's arteritis (TAK) and giant cell arteritis (GCA). Methods Patients were selected from two North American cohorts of TAK and GCA. The frequency of arteriographic lesions was calculated for 15 large arteries. Cluster analysis was used to derive patterns of arterial disease in TAK versus GCA and in patients categorised by age at disease onset. Using latent class analysis, computer derived classification models based upon patterns of arterial disease were compared with traditional classification. Results Arteriographic lesions were identified in 145 patients with TAK and 62 patients with GCA. Cluster analysis demonstrated that arterial involvement was contiguous in the aorta and usually symmetric in paired branch vessels for TAK and GCA. There was significantly more left carotid (p=0.03) and mesenteric (p=0.02) artery disease in TAK and more left and right axillary (p<0.01) artery disease in GCA. Subclavian disease clustered asymmetrically in TAK and in patients ≤55 years at disease onset and clustered symmetrically in GCA and patients >55 years at disease onset. Computer derived classification models distinguished TAK from GCA in two subgroups, defining 26% and 18% of the study sample; however, 56% of patients were classified into a subgroup that did not strongly differentiate between TAK and GCA. Conclusions Strong similarities and subtle differences in the distribution of arterial disease were observed between TAK and GCA. These findings suggest that TAK and GCA may exist on a spectrum within the same disease.

Objective To assess markers of neutrophil activation such as calprotectin and N-formyl methionine (fMET) in anti-neutrophil cytoplasmic autoantibody-associated vasculitis (AAV) and large-vessel vasculitis (LVV). Methods Levels of fMET, and calprotectin, were measured in the plasma of healthy controls ( n =30) and patients with AAV (granulomatosis with polyangiitis (GPA, n =123), microscopic polyangiitis (MPA, n =61)), and LVV (Takayasu’s arteritis (TAK, n =58), giant cell arteritis (GCA, n =68)), at times of remission or flare. Disease activity was assessed by physician global assessment. In vitro neutrophil activation assays were performed in the presence or absence of formyl peptide receptor 1 (FPR1) inhibitor cyclosporine H. Results Levels of calprotectin, and fMET were elevated in patients with vasculitis as compared to healthy individuals. Levels of fMET correlated with markers of systemic inflammation: C-reactive protein ( r =0.82, p <0.0001), and erythrocyte sedimentation rate ( r =0.235, p <0.0001). The neutrophil activation marker, calprotectin was not associated with disease activity. Circulating levels of fMET were associated with neutrophil activation ( p <0.01) and were able to induce de novo neutrophil activation via FPR1-mediated signaling. Conclusion Circulating fMET appears to propagate neutrophil activation in AAV and LVV. Inhibition of fMET-mediated FPR1 signaling could be a novel therapeutic intervention for systemic vasculitides.

Background Patient reported outcome (PRO) information is crucial for establishing better patient-provider communication, improving shared decision-making between clinicians and patients, assessing patient responses to therapeutic interventions, and increasing satisfaction with care. We used the Brittle Bones Disease Consortium (BBDC) Contact Registry for People with OI, managed by the Rare Disease Clinical Research Network (RDCRN) to (1) to evaluate the construct validity of the Patient-Reported Outcome Measurement Information System® (PROMIS®) to record important components of the disease experience among individuals with OI; and (2) explore the feasibility of using a registry to recruit individuals with OI to report on health status. Our long-term goal is to enhance communication of health and disease management findings back to the OI community, especially those who do not have access to major OI clinical centers. Results We demonstrated the construct validity of PROMIS instruments in OI. Our results confirm that the scores from most domains differ significantly from the general US population: individuals with OI have worse symptom burden and functioning. We found no excessive floor or ceiling effects. Our study demonstrates that the BBDC Contact Registry can be used to recruit participants for online health status surveys. However, there are numerous challenges that must be addressed: lack of self-knowledge of OI type, under-representation of men, limited ethnic diversity, and imperfect questionnaire completion rates. Conclusion Our pilot study demonstrated the feasibility of using a contact registry to recruit respondents from the OI community and to obtain analyzable PROMIS data regarding disease experience. Because the results differ from the general population and avoid excessive floor and ceiling effects, PROMIS instruments can be used to assess response to therapeutic interventions in individuals with OI. Future directions will include (1) development and validation of an OI-specific patient-based classification system that aggregates persons with similar clinical characteristics and risks for complications to identify treatment needs; and (2) integrating these PRO tools into routine patient care and research studies.

OBJECTIVE: There is limited information from large-scale prospective studies regarding the prediction of type 1 diabetes by specific types of pancreatic islet autoantibodies, either alone or in combination. Thus, we studied the extent to which specific autoantibodies are predictive of type 1 diabetes. RESEARCH DESIGN AND METHODS: Two cohorts were derived from the first screening for islet cell autoantibodies (ICAs) in the Diabetes Prevention Trial-Type 1 (DPT-1). Autoantibodies to GAD 65 (GAD65), insulinoma-associated antigen-2 (ICA512), and insulin (micro-IAA [mIAA]) were also measured. Participants were followed for the occurrence of type 1 diabetes. One cohort (Questionnaire) included those who did not enter the DPT-1 trials, but responded to questionnaires (n = 28,507, 2.4% ICA⁺). The other cohort (Trials) included DPT-1 participants (n = 528, 83.3% ICA⁺). RESULTS: In both cohorts autoantibody number was highly predictive of type 1 diabetes (P < 0.001). The Questionnaire cohort was used to assess prediction according to the type of autoantibody. As single autoantibodies, ICA (3.9%), GAD65 (4.4%), and ICA512 (4.6%) were similarly predictive of type 1 diabetes in proportional hazards models (P < 0.001 for all). However, no subjects with mIAA as single autoantibodies developed type 1 diabetes. As second autoantibodies, all except mIAA added significantly (P < 0.001) to the prediction of type 1 diabetes. Within the positive range, GAD65 and ICA autoantibody titers were predictive of type 1 diabetes. CONCLUSIONS: The data indicate that the number of autoantibodies is predictive of type 1 diabetes. However, mIAA is less predictive of type 1 diabetes than other autoantibodies. Autoantibody number, type of autoantibody, and autoantibody titer must be carefully considered in planning prevention trials for type 1 diabetes.

Both nuclear receptor subfamily 2 group F member 1 (NR2F1) and microRNAs (miRNAs) have been shown to play critical roles in the developing and functional inner ear. Based on previous studies suggesting interplay between NR2F1 and miRNAs, we investigated the coregulation between NR2F1 and miRNAs to better understand the regulatory mechanisms of inner ear development and functional maturation. Using a bioinformatic approach, we identified 11 potential miRNAs that might coregulate target genes with NR2F1 and analyzed their targets and potential roles in physiology and disease. We selected 6 miRNAs to analyze using quantitative real-time (qRT) -PCR and found that miR-140 is significantly down-regulated by 4.5-fold (P=0.004) in the inner ear of NR2F1 knockout (Nr2f1(-/-)) mice compared to wild-type littermates but is unchanged in the brain. Based on this, we performed chromatin-immunoprecipitation followed by qRT-PCR and confirmed that NR2F1 directly binds and regulates both miR-140 and Klf9 in vivo. Furthermore, we performed luciferase reporter assay and showed that miR-140 mimic directly regulates KLF9-3'UTR, thereby establishing and validating an example coregulatory network involving NR2F1, miR-140, and Klf9. We have described and experimentally validated a novel tissue-dependent coregulatory network for NR2F1, miR-140, and Klf9 in the inner ear and we propose the existence of many such coregulatory networks important for both inner ear development and function.

Previous studies suggest a role for eotaxin-3, TARC/CCL17 and IgG4 in newly-diagnosed patients with eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss) with highly active disease. The role of these biomarkers in relapsing disease is unclear. Serum levels of TARC/CCL17, eotaxin-3, IgG4, and IgG4/IgG ratio were determined in serum samples from a longitudinal cohort of patients with EGPA (105 visits of 25 patients). Epidemiological, clinical and laboratory data were available for all visits. At the first visit, 80% of patients were using glucocorticoids and 68% additional immunosuppressive drugs. Disease flares were seen at 18 visits. The median BVAS and BVAS/WG scores at time of relapse were 4 and 2, respectively. None of the biomarkers tested were useful to discriminate between active disease and remission. Patients treated with prednisone had lower eotaxin-3 and eosinophil levels compared to patients not taking glucocorticoids irrespective of disease activity. Use of immunosuppressive agents was not associated with biomarker levels. Serum levels of TARC/CCL17, eotaxin-3, IgG4, and IgG4/IgG ratio do not clearly differentiate active and inactive disease in established EGPA. Defining biomarkers in EGPA remains a challenge especially during times of glucocorticoid use.

Objective To describe clinical manifestations and outcomes in patients with eosinophilic granulomatosis with polyangiitis (EGPA) in North America. Methods Analysis of patients aged 18 years or older who fulfilled the 1990 American College of Rheumatology Classification Criteria for EGPA enrolled in the Vasculitis Clinical Research Consortium from 2003 to 2019. Main clinical characteristics, treatments, outcomes, and accumulated damage were studied. Results The cohort included 354 patients; 59% female; age at diagnosis of 50.0 (±14) years; 39% were antineutrophil cytoplasm antibody (ANCA) positive. Time from diagnosis to last follow‐up was 7.0 (±6.2) years; 49.4% had one or more relapse. Patients positive for ANCA more commonly had neurological and kidney involvement when compared with patients negative for ANCA, who had more cardiac and lung manifestations. At last study visit, only 35 (12.6%) patients had been off all therapy for more than 2 years during their follow‐up. The overall mortality rate was 4.0% and did not differ by ANCA status or cyclophosphamide use. Scores on the Vasculitis Damage Index (VDI) for 134 patients with two or more visits and more than 1 year of follow‐up increased from 1.7 (±1.8) at enrollment (3.7 [±5.1] years after diagnosis) to 3.35 (±2.1) at last follow‐up (7.5 [±5.8] years after diagnosis), mainly represented by chronic asthma (67.5%), peripheral neuropathy (49.6%), and chronic sinusitis (31.3%). Longer duration of glucocorticoid use and relapse were associated with higher VDI scores. Conclusion This analysis describes the many clinical manifestations and varied outcomes of EGPA and highlights the ongoing need to attain more sustained, long‐term remission to limit the accrual of disease‐related damage.

Urea cycle disorders often present as devastating metabolic conditions, resulting in high mortality and significant neuropsychological damage, despite treatment. The Urea Cycle Disorders Longitudinal Study is a natural history study that collects data from regular clinical follow-up and neuropsychological testing. This report examines links between biochemical markers (ammonia, glutamine, arginine, citrulline) and primary neuropsychological endpoints in three distal disorders, argininosuccinic acid synthetase deficiency (ASD or citrullinemia type I), argininosuccinic acid lyase deficiency (ASA or ALD), and arginase deficiency (ARGD). Laboratory results and test scores from neuropsychological evaluations were assessed in 145 study participants, ages 3 years and older, with ASD ( n  = 64), ASA ( n  = 65) and ARGD ( n  = 16). Mean full scale IQ was below the population mean of 100 ± 15 for all groups: (ASD = 79 ± 24; ASA = 71 ± 21; ARGD = 65 ± 19). The greatest deficits were noted in visual performance and motor skills for all groups. While ammonia levels remain prominent as prognostic biomarkers, other biomarkers may be equally valuable as correlates of neuropsychological functioning. Cumulative exposure to the biomarkers included in the study proved to be highly sensitive indicators of neuropsychological outcomes, even when below the cut-off levels generally considered toxic. Blood levels of biomarkers obtained on the day of neuropsychological evaluations were not correlated with measures of functioning for any disorder in any domain. The importance of cumulative exposure supports early identification and confirms the need for well-controlled management of all biochemical abnormalities (and not just ammonia) that occur in urea cycle disorders.