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OBJECTIVE: This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013-2021). Disease cohorts were divided by age at diagnosis (years): children (65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease-specific and non-disease-specific damage scores built from VDI and AVID items. RESULTS: Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3-ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P

OBJECTIVE: To study the prevalence, risk and clinical associations of hypothyroidism among several forms of vasculitis. METHODS: Patients with GCA, Takayasus arteritis (TAK), PAN and the three forms of ANCA-associated vasculitis [AAV; granulomatosis with polyangiitis (GPA), microscopic polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA)] enrolled in a prospective, multicentre, longitudinal study were included. RESULTS: The study included data on 2085 patients [63% female, 90% White] with a mean age of 54.6 years (s.d. 17.2). Diagnoses were GCA (20%), TAK (11%), PAN (5%), GPA (42%), microscopic polyangiitis (8%) and EGPA (14%). Hypothyroidism was present in 217 patients (10%) (83% female), with a mean age 59.8 years (s.d. 14.5). Age- and sex-adjusted risk of hypothyroidism was GCA, odds ratio (OR) 0.61 (95% CI 0.41, 0.90); TAK, OR 0.57 (95% CI 0.31, 1.03); PAN, OR 0.59 (95% CI 0.25, 1.38); GPA, OR 1.51 (95% CI 1.12, 2.05); microscopic polyangiitis, OR 1.81 (95% CI 1.18, 2.80) and EGPA, OR 0.82 (95% CI 0.52, 1.30). Among patients with AAV, age- and sex-adjusted risk of hypothyroidism was higher with positive MPO-ANCA [OR 1.89 (95% CI 1.39, 2.76)]. The clinical manifestations of vasculitis were similar in patients with and without hypothyroidism, except transient ischaemic attacks, which were more frequently observed in patients with GCA and hypothyroidism (12% vs 2%; P = 0.001). CONCLUSIONS: Differences in the risk of hypothyroidism among vasculitides may be due to genetic susceptibilities or immune responses. This study confirms an association of hypothyroidism with MPO-ANCA.

BackgroundWomen with rare diseases, such as osteogenesis imperfecta, may consider pregnancy, although data regarding outcomes, specific risks, and management strategies are lacking.ObjectiveThe Brittle Bone Disorders Consortium of the National Institute of Health Rare Diseases Clinical Research Network established an Osteogenesis Imperfecta Pregnancy Registry to collect and evaluate pregnancy, maternal, and neonatal outcomes in women with osteogenesis imperfecta.Study designThis was a cross-sectional, survey-based study. Appropriate participants of the Brittle Bone Disorders Consortium Contact Registry were invited to participate in the study. Self-reported information regarding pregnancy characteristics and maternal and neonatal outcomes of women with osteogenesis imperfecta was compared with that of the general population, referenced by literature-based standards. Furthermore, compared with the general population, cohorts of women and fetuses with osteogenesis imperfecta were evaluated to determine whether the presence of osteogenesis imperfecta conveyed an increase in antepartum, intrapartum, and postpartum complications and an increase in adverse neonatal outcomes.ResultsHere, a total 132 participants completed the survey. Compared with the general population, women with osteogenesis imperfecta had higher rates of diabetes in pregnancy (13.3% vs 7%; 95% confidence interval, 7.0-19.6; P=.049), cesarean delivery (68.5% vs 32.7%; 95% confidence interval, 59.9-77.1; P

A three-arm, randomized, double-masked, placebo-controlled phase 2b trial performed by the Type 1 Diabetes TrialNet Study Group previously demonstrated that low-dose anti-thymocyte globulin (ATG) (2.5 mg/kg) preserved β-cell function and reduced HbA1c for 1 year in new-onset type 1 diabetes. Subjects (N = 89) were randomized to 1) ATG and pegylated granulocyte colony-stimulating factor (GCSF), 2) ATG alone, or 3) placebo. Herein, we report 2-year area under the curve (AUC) C-peptide and HbA1c, prespecified secondary end points, and potential immunologic correlates. The 2-year mean mixed-meal tolerance test-stimulated AUC C-peptide, analyzed by ANCOVA adjusting for baseline C-peptide, age, and sex (n = 82) with significance defined as one-sided P < 0.025, was significantly higher in subjects treated with ATG versus placebo (P = 0.00005) but not ATG/GCSF versus placebo (P = 0.032). HbA1c was significantly reduced at 2 years in subjects treated with ATG (P = 0.011) and ATG/GCSF (P = 0.022) versus placebo. Flow cytometry analyses demonstrated reduced circulating CD4:CD8 ratio, increased regulatory T-cell:conventional CD4 T-cell ratios, and increased PD-1+CD4+ T cells following low-dose ATG and ATG/GCSF. Low-dose ATG partially preserved β-cell function and reduced HbA1c 2 years after therapy in new-onset type 1 diabetes. Future studies should determine whether low-dose ATG might prevent or delay the onset of type 1 diabetes.

OBJECTIVES: To evaluate large-vessel (LV) abnormalities on serial imaging in patients with giant cell arteritis (GCA) and discern predictors of new lesions. METHODS: Clinical and imaging data from patients with GCA (including subjects diagnosed by LV imaging) enrolled in a prospective, multicenter, longitudinal study and/or a randomized clinical trial were included. New arterial lesions were defined as a lesion in a previously unaffected artery. RESULTS: The study included 187 patients with GCA, 146 (78%) female, mean (±SD) age at diagnosis 68.5 ± 8.5 years; 39% diagnosed by LV imaging. At least one arterial lesion was present in 123 (66%) on the first study. The most frequently affected arteries were subclavian (42%), axillary (32%), and thoracic aorta (20%). In 106 patients (57%) with serial imaging, new arterial lesions were noted in 41 patients (39%), all of whom had a baseline abnormality, over a mean (±SD) follow-up of 4.39 (2.22) years. New abnormalities were observed in 33% patients by year 2; clinical features of active disease were present at only 50% of these cases. There were no differences in age, sex, temporal artery biopsy positivity, or disease activity in patients with or without new lesions. CONCLUSIONS: In this cohort of patients with GCA, LV abnormalities on first imaging were common. Development of new arterial lesions occurred in patients with arterial abnormalities at first imaging, often in the absence of symptoms of active disease. Arterial imaging should be considered in all patients with GCA at diagnosis and serial imaging at least in patients with baseline abnormalities.

PurposeOsteogenesis imperfecta (OI) predisposes people to recurrent fractures, bone deformities, and short stature. There is a lack of large-scale systematic studies that have investigated growth parameters in OI.MethodsUsing data from the Linked Clinical Research Centers, we compared height, growth velocity, weight, and body mass index (BMI) in 552 individuals with OI. Height, weight, and BMI were plotted on Centers for Disease Control and Prevention normative curves.ResultsIn children, the median z-scores for height in OI types I, III, and IV were -0.66, -6.91, and -2.79, respectively. Growth velocity was diminished in OI types III and IV. The median z-score for weight in children with OI type III was -4.55. The median z-scores for BMI in children with OI types I, III, and IV were 0.10, 0.91, and 0.67, respectively. Generalized linear model analyses demonstrated that the height z-score was positively correlated with the severity of the OI subtype (P

Pulmonary complications are a significant cause for morbidity and mortality in osteogenesis imperfecta (OI). However, to date, there have been few studies that have systematically evaluated pulmonary function in individuals with OI. We analyzed spirometry measurements, including forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1 ), in a large cohort of individuals with OI (n = 217) enrolled in a multicenter, observational study. We show that individuals with the more severe form of the disease, OI type III, have significantly reduced FVC and FEV1 which do not follow the expected trends of the normal population. We also show that "normalization" of FVC and FEV1 using general population data to generate percent predicted values underestimates the pulmonary involvement in OI. Within each subtype of OI, we used linear mixed models to find potential correlations between FEV1 and FVC with the clinical variables including mobility, bisphosphonate use, and scoliosis. Our results are an important step in understanding the extent of pulmonary involvement in individuals with OI and for developing pulmonary endpoints for use in the routine patient care as well as in the investigation of new therapies.

Background: The TrialNet Oral Insulin (OI) prevention trial showed no overall treatment effect, using the diagnosis of type 1 diabetes as an endpoint. A significant delay in onset was only found in a high‐risk stratum (termed secondary stratum 1) of participants with low first‐phase insulin release (FPIR). Methods: Since trials with an endpoint of type 1 diabetes take years to complete, in this post hoc analysis, we assessed whether a novel combination of glucose and C‐peptide markers could identify a therapeutic benefit after 1 year of follow‐up (trial participants followed for a median 2.7 years). Results: Participants were relatives with multiple islet autoantibodies and low FPIR (n = 40). Glucose rose, and C‐peptide declined in the placebo group, whereas glucose rose minimally, and C‐peptide increased in the OI group. When glucose and C‐peptide were plotted on two‐dimensional grids using 30–120‐min oral glucose tolerance test (OGTT) time points, changes in ratios of their central points (centroid ratio) differed between groups (p = 0.037 adjusted for age, BMI, and baseline C‐peptide and glucose). Conclusions: These findings support a favorable early effect of OI on combined glucose and C‐peptide endpoints in high‐risk individuals, indicating metabolic benefit. With further study, these measures may allow for shorter trials compared to the standard endpoint of type 1 diabetes diagnosis. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To evaluate damage and variables associated with damage in GCA. METHODS: Patients with GCA enrolled in a prospective, multicentre, longitudinal study were included. Per-protocol assessments were made with the Vasculitis Damage Index and the Large-Vessel Vasculitis Index of Damage. RESULTS: The study included 204 patients: 156 women (76%), mean age at diagnosis 71.3 years (s.d. 8.3), mean follow-up of 3.5 years (s.d. 1.9). One or more damage item was present in 54% at baseline and 79% at the last follow-up on the Vasculitis Damage Index, and 60% at baseline and 82% at the last follow-up on the Large-Vessel Vasculitis Index of Damage. The most frequently observed damage items were large-artery complications (29% cohort) and ocular (22%). Among 117 patients with new damage, most new items were ocular (63 patients), cardiac/vascular (48) and musculoskeletal (34). Of these, treatment-associated items were frequently observed, including cataracts (46 patients), osteoporosis (22) and weight gain (22). Disease-associated new damage included ischaemic optic neuropathy (3 patients), limb claudication (13), arterial occlusions (10) and damage requiring vascular intervention (10). In univariate analysis, the risk of damage increased 22% for every additional year of disease duration [odds ratio (OR) 1.22 (95% CI 1.04, 1.45)]. In 94 patients enrolled within ⩽90 days of diagnosis of GCA, the risk of new damage at the last follow-up decreased 30% for each additional relapse [OR 0.70 (95% CI 0.51, 0.97)]. CONCLUSIONS: Large-artery complications and ocular manifestations are the most commonly occurring items of damage in GCA. Most new damage is associated with treatment. These findings emphasize the cumulative burden of disease in GCA.

OBJECTIVE: The antineutrophil cytoplasmic antibody-associated vasculitides (AAV) are multiorgan diseases. Patients with AAV report impairment in their health-related quality of life (HRQOL) and have different priorities regarding disease assessment compared with physicians. The Outcome Measures in Rheumatology (OMERACT) Vasculitis Working Group previously received endorsement for a core set of domains in AAV. Two approaches to measure patient-reported outcomes (PRO) were presented at OMERACT 2016. METHODS: A novel 5-step tool was used to facilitate assessment of the instruments by delegates: the OMERACT Filter 2.0 Instrument Selection Algorithm, with a red-amber-green checklist of questions, including (1) good match with domain (face and content validity), (2) feasibility, (3) do numeric scores make sense (construct validity)?, (4) overall ratings of discrimination, and (5) can individual thresholds of meaning be defined? Delegates gave an overall endorsement. Three generic Patient-Reported Outcomes Measurement Information System (PROMIS) instruments (fatigue, physical functioning, and pain interference) and a disease-specific PRO, the AAV-PRO (6 domains related to symptoms and HRQOL), were presented. RESULTS: OMERACT delegates endorsed the use of the PROMIS instruments for fatigue, physical functioning, and pain interference (87.6% overall endorsement) and the disease-specific AAV-PRO instrument (89.4% overall endorsement). CONCLUSION: The OMERACT Vasculitis Working Group gained endorsement by OMERACT for use of the PROMIS and the AAV-PRO in clinical trials of vasculitis. These instruments are complementary to each other. The PROMIS and the AAV-PRO need further work to assess their utility in longitudinal settings, including their ability to discriminate between treatments of varying efficacy in the setting of a randomized controlled trial.

Context Metabolic measures are frequently used to predict type 1 diabetes (T1D) and to understand effects of disease-modifying therapies. Objective Compare metabolic endpoints for their ability to detect preventive treatment effects and predict T1D. Methods Six-month changes in metabolic endpoints were assessed for (1) detecting treatment effects by comparing placebo and treatment arms from the randomized controlled teplizumab prevention trial, a multicenter clinical trial investigating 14-day intravenous teplizumab infusion and (2) predicting T1D in the TrialNet Pathway to Prevention natural history study. For each metabolic measure, t-Values from t tests for detecting a treatment effect were compared with chi-square values from proportional hazards regression for predicting T1D. Participants in the teplizumab prevention trial and participants in the Pathway to Prevention study selected with the same inclusion criteria used for the teplizumab trial were studied. Results Six-month changes in glucose-based endpoints predicted diabetes better than C-peptide–based endpoints, yet the latter were better at detecting a teplizumab effect. Combined measures of glucose and C-peptide were more balanced than measures of glucose alone or C-peptide alone for predicting diabetes and detecting a teplizumab effect. Conclusion The capacity of a metabolic endpoint to detect a treatment effect does not necessarily correspond to its accuracy for predicting T1D. However, combined glucose and C-peptide endpoints appear to be effective for both predicting diabetes and detecting a response to immunotherapy. These findings suggest that combined glucose and C-peptide endpoints should be incorporated into the design of future T1D prevention trials. [ABSTRACT FROM AUTHOR]

Objective: We describe the demographics, clinical features, disease course, and survival of polyarteritis nodosa (PAN) through an international collaboration (GLOBAL‐PAN). Methods: Patients with PAN were recruited between 1990 and 2020 from observational cohorts of nine countries across Europe, Japan, and North America. Eligibility was retrospectively defined using the European Medicines Agency classification algorithm. Patients with PAN related to hepatitis B virus (n = 12) and two monogenic diseases mimicking PAN, deficiency of adenosine deaminase 2 enzyme (n = 16) or familial Mediterranean fever (n = 11), were excluded. Data regarding organ involvement, relapse, disease‐related damage, and survival were analyzed. Results: Three hundred fifty‐eight patients (female:male ratio 174:184), including those with systemic PAN (sPAN, n = 282) and cutaneous PAN (n = 76), were included. Twenty‐five were pediatric onset. Mean ± SD age at diagnosis was 44.3 ± 18.1 years. Constitutional symptoms (71.5%), cutaneous involvement (70.5%), musculoskeletal findings (69.1%), and neurologic features (48.0%) were common manifestations. Among patients with sPAN, gastrointestinal involvement and proteinuria over 400 mg/day were reported in 52.2% and 11.2%, respectively. During a median (interquartile range) 59.6 (99.5) months of follow‐up, relapse occurred in 48.5% of patients. One, 5‐ and 10‐year survival rates for sPAN were 97.1%, 94.0%, and 89.0%, respectively. Predictors of death for sPAN included age ≥65 years at diagnosis, serum creatinine at diagnosis >140 μmol/L, gastrointestinal manifestations, and central nervous system (CNS) involvement. Conclusion: The spectrum of PAN remains a complex, multifaceted disease. Relapse is common. Age ≥65 years and serum creatinine >140 μmol/L at diagnosis, as well as gastrointestinal and CNS involvement, are independent predictors of death in sPAN. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Mixed-meal tolerance test–stimulated area under the curve (AUC) C-peptide at 12–24 months represents the primary end point for nearly all intervention trials seeking to preserve β-cell function in recent-onset type 1 diabetes. We hypothesized that participant benefit might be detected earlier and predict outcomes at 12 months posttherapy. Such findings would support shorter trials to establish initial efficacy. RESEARCH DESIGN AND METHODS: We examined data from six Type 1 Diabetes TrialNet immunotherapy randomized controlled trials in a post hoc analysis and included additional stimulated metabolic indices beyond C-peptide AUC. We partitioned the analysis into successful and unsuccessful trials and analyzed the data both in the aggregate as well as individually for each trial. RESULTS: Among trials meeting their primary end point, we identified a treatment effect at 3 and 6 months when using C-peptide AUC (P = 0.030 and P < 0.001, respectively) as a dynamic measure (i.e., change from baseline). Importantly, no such difference was seen in the unsuccessful trials. The use of C-peptide AUC as a 6-month dynamic measure not only detected treatment efficacy but also suggested long-term C-peptide preservation (R 2 for 12-month C-peptide AUC adjusted for age and baseline value was 0.80, P < 0.001), and this finding supported the concept of smaller trial sizes down to 54 participants. CONCLUSIONS: Early dynamic measures can identify a treatment effect among successful immune therapies in type 1 diabetes trials with good long-term prediction and practical sample size over a 6-month period. While external validation of these findings is required, strong rationale and data exist in support of shortening early-phase clinical trials. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To evaluate the performance of the Birmingham Vasculitis Activity Score (BVAS) in the assessment of disease activity in giant cell arteritis (GCA). METHODS: Patients with GCA enrolled in a prospective, multicenter, longitudinal study with symptoms of active vasculitis during any visit were included. Spearmans rank correlation was used to explore the association of the BVAS with other measures of disease activity. RESULTS: During a mean (SD) followup of 2.3 (1.6) years, symptoms of active GCA were present in 236 visits in 136 subjects (100 female, 74%). Median (range) BVAS1 (new/worse symptoms) was 1 (0-10) and median (range) BVAS2 (persistent symptoms) was 0 (0-5). Median (range) physicians global assessment (PGA) was 4 (0-9) for disease activity in the past 28 days and 2 (0-9) for activity on the day of the visit. Important ischemic manifestations of active vasculitis not recorded by the BVAS included tongue/jaw claudication (27%), upper extremity claudication (15%), lower extremity claudication (5%), carotidynia (7%), and ischemic retinopathy (5%). During 25 visits (11%) with active disease, all symptoms of active vasculitis were placed in the Other category yet still resulted in a BVAS1 and BVAS2 of 0. BVAS1 moderately correlated with PGA for the past 28 days (Spearmans correlation 0.50) and physician-rated disease activity for the past 28 days (Spearmans correlation 0.46). CONCLUSION: The BVAS has limited utility in GCA. Patients with active GCA can have a BVAS of 0. Many important ischemic symptoms attributable to active vasculitis are not included in the composite score.

Abstract Background All spinocerebellar ataxias (SCAs) are rare diseases. SCA1, 2, 3 and 6 are the four most common SCAs, all caused by expanded polyglutamine-coding CAG repeats. Their pathomechanisms are becoming increasingly clear and well-designed clinical trials will be needed. Methods To characterize the clinical manifestations of spinocerebellar ataxia (SCA) 1, 2, 3 and 6 and their natural histories in the United States (US), we conducted a prospective multicenter study utilized a protocol identical to the European consortium study, using the Scale for the Assessment and Rating of Ataxia (SARA) score as the primary outcome, with follow-ups every 6 months up to 2 years. Results We enrolled 345 patients (60 SCA1, 75 SCA2, 138 SCA3 and 72 SCA6) at 12 US centers. SCA6 patients had a significantly later onset, and SCA2 patients showed greater upper-body ataxia than patients with the remaining SCAs. The annual increase of SARA score was greater in SCA1 patients (mean ± SE: 1.61 ± 0.41) than in SCA2 (0.71 ± 0.31), SCA3 (0.65 ± 0.24) and SCA6 (0.87 ± 0.28) patients (p = 0.049). The functional stage also worsened faster in SCA1 than in SCA2, 3 and 6 (p = 0.002). Conclusions The proportions of different SCA patients in US differ from those in the European consortium study, but as in the European patients, SCA1 progress faster than those with SCA2, 3 and 6. Later onset in SCA6 and greater upper body ataxia in SCA2 were noted. We conclude that progression rates of these SCAs were comparable between US and Europe cohorts, suggesting the feasibility of international collaborative clinical studies.

[West J Emerg Med. 2012;13(4):362.]

Objective: This study examined the relationship between age at diagnosis and disease characteristics and damage in patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV). Methods: Analysis of a prospective longitudinal cohort of patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), and eosinophilic GPA (EGPA) in the Vasculitis Clinical Research Consortium (2013–2021). Disease cohorts were divided by age at diagnosis (years): children (<18), young adults (18–40), middle‐aged adults (41–65), and older adults (>65). Data included demographics, ANCA type, clinical characteristics, Vasculitis Damage Index (VDI) scores, ANCA Vasculitis Index of Damage (AVID) scores, and novel disease‐specific and non‐disease‐specific damage scores built from VDI and AVID items. Results: Analysis included data from 1020 patients with GPA/MPA and 357 with EGPA. Female predominance in GPA/MPA decreased with age at diagnosis. AAV in childhood was more often GPA and proteinase 3‐ANCA positive. Children with GPA/MPA experienced more subglottic stenosis and alveolar hemorrhage; children and young adults with EGPA experienced more alveolar hemorrhage, need for intubation, and gastrointestinal involvement. Older adults (GPA/MPA) had more neurologic manifestations. After adjusting for disease duration, medications, tobacco, and ANCA, all damage scores increased with age at diagnosis for GPA/MPA (P < 0.001) except the disease‐specific damage score, which did not differ (P = 0.44). For EGPA, VDI scores increased with age at diagnosis (P < 0.009), whereas all other scores were not significantly different. Conclusion: Age at diagnosis is associated with clinical characteristics in AAV. Although VDI and AVID scores increase with age at diagnosis, this is driven by non‐disease‐specific damage items. [ABSTRACT FROM AUTHOR]

Objectives ANCA-associated vasculitis (AAV) is a group of multisystem diseases that can have several ocular manifestations. There are published data on ocular manifestations of granulomatosis with polyangiitis (GPA), but few for eosinophilic granulomatosis with polyangiitis (EGPA) or microscopic polyangiitis (MPA). There is little information concerning chronicity, complications, and association with other cranial manifestations of AAV. Methods This study retrospectively analysed longitudinal multicentre cohorts of individuals with AAV followed between 2006 and 2022. Data included diagnosis, demographics, cranial manifestations of disease, presence of manifestations at onset of disease and/or follow-up, and ocular complications of disease. Univariate and multivariable logistic regression analysis assessed associations across disease manifestations. Results Data from 1441 patients were analysed, including 395 with EGPA, 876 with GPA, and 170 with MPA. Ocular manifestations were seen within 23.1% of patients: 39 (9.9%) with EGPA, 287 (32.7%) with GPA, and 12 (7.1%) with MPA at any time in the disease course. There were more ocular manifestations at onset (n  = 224) than during follow-up (n  = 120). The most common disease-related manifestations were conjunctivitis/episcleritis and scleritis. In multivariable analysis, dacryocystitis, lacrimal duct obstruction, and retro-orbital disease were associated with sinonasal manifestations of GPA; ocular manifestations were associated with hearing loss in MPA. The most common ocular complications and/or damage seen were cataracts (n  = 168) and visual impairment (n  = 195). Conclusion Ocular manifestations occur in all forms of AAV, especially in GPA. Clinicians should be mindful of the wide spectrum of ocular disease in AAV, caused by active vasculitis, disease-associated damage, and toxicities of therapy. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Metabolic zones were developed to characterize heterogeneity of individuals with islet autoantibodies. RESEARCH DESIGN AND METHODS: Baseline 2-h oral glucose tolerance test data from 6,620 TrialNet Pathway to Prevention Study (TNPTP) autoantibody-positive participants (relatives of individuals with type 1 diabetes) were used to form 25 zones from five area under the curve glucose (AUCGLU) rows and five area under the curve C-peptide (AUCPEP) columns. Zone phenotypes were developed from demographic, metabolic, autoantibody, HLA, and risk data. RESULTS: As AUCGLU increased, changes of glucose and C-peptide response curves (from mean glucose and mean C-peptide values at 30, 60, 90, and 120 min) were similar within the five AUCPEP columns. Among the zones, 5-year risk for type 1 diabetes was highly correlated with islet antigen 2 antibody prevalence (r = 0.96, P < 0.001). Disease risk decreased markedly in the highest AUCGLU row as AUCPEP increased (0.88–0.41; P < 0.001 from lowest AUCPEP column to highest AUCPEP column). AUCGLU correlated appreciably less with Index60 (an indicator of insulin secretion) in the highest AUCPEP column (r = 0.33) than in other columns (r ≥ 0.78). AUCGLU was positively related to "fasting glucose × fasting insulin" and to "fasting glucose × fasting C-peptide" (indicators of insulin resistance) before and after adjustments for Index60 (P < 0.001). CONCLUSIONS: Phenotypes of 25 zones formed from AUCGLU and AUCPEP were used to gain insights into type 1 diabetes heterogeneity. Zones were used to examine GCRC changes with increasing AUCGLU, associations between risk and autoantibody prevalence, the dependence of glucose as a predictor of risk according to C-peptide, and glucose heterogeneity from contributions of insulin secretion and insulin resistance. [ABSTRACT FROM AUTHOR]