Use, Durability, and Risks for Discontinuation of Initial and Subsequent Biologics in a Large Pediatric-Onset IBD Cohort.

BACKGROUND: Biologic medications are recommended for treatment of moderately-to-severely active Crohn disease (CD) or ulcerative colitis (UC) in children. However, many patients require sequential biologic treatment because of nonresponse or loss of response to the initial biologic. METHODS: We analyzed pediatric inflammatory bowel disease (IBD) data from the ImproveCareNow Network registry between May 2006 and September 2016, including time to biologic initiation, choice of first subsequent biologics, biologic durability, and reasons for discontinuation. RESULTS: Of 17,649 patients with IBD [CD: 12,410 (70%); UC: 5239 (30%)], 7585 (43%) were treated with a biologic agent before age 18 (CD: 50%; UC: 25%). Biologic treatment was more likely for CD than UC (odds ratio, 3.0; 95% CI: 2.8-3.2; P < 0.0001). First biologic agents for all patients were anti-tumor necrosis factor agents (88% infliximab, 12% adalimumab). Probability of remaining on the first biologic was significantly higher in CD than UC ( P < 0.0001). First biologics were discontinued because of loss of response (39%), intolerance (23%), and nonresponse (19%). In univariate analysis, factors associated with discontinuation of first and/or second biologics in CD include colonic-only disease, corticosteroid use, upper gastrointestinal tract involvement, and clinical and biochemical markers of severe disease. Biologic durability improved with later induction date. CONCLUSIONS: Treatment with biologic medications is common in pediatric IBD. Patients with CD are more likely to receive biologics, receive biologics earlier in disease course, and remain on the first biologic longer than patients with UC. Multiple factors may predict biologic durability in children with IBD.

Belatacept for Simultaneous Calcineurin Inhibitor and Chronic Corticosteroid Immunosuppression Avoidance: Two-Year Results of a Prospective, Randomized Multicenter Trial.

BACKGROUND AND OBJECTIVES: Immunosuppressive therapy in kidney transplantation is associated with numerous toxicities. CD28-mediated T-cell costimulation blockade using belatacept may reduce long-term nephrotoxicity, compared with calcineurin inhibitor-based immunosuppression. The efficacy and safety of simultaneous calcineurin inhibitor avoidance and rapid steroid withdrawal were tested in a randomized, prospective, multicenter study. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study reports the 2-year results of a randomized clinical trial of 316 recipients of a new kidney transplant. All kidney transplants were performed using rapid steroid withdrawal immunosuppression. Recipients were randomized in a 1:1:1 ratio to receive belatacept with alemtuzumab induction, belatacept with rabbit anti-thymocyte globulin (rATG) induction, or tacrolimus with rATG induction. The composite end point consisted of death, kidney allograft loss, or an eGFR of <45 ml/min per 1.73 m2 at 2 years. RESULTS: The composite end point was observed for 11 of 107 (10%) participants assigned to belatacept/alemtuzumab, 13 of 104 (13%) participants assigned to belatacept/rATG, and 21 of 105 (21%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.99; for belatacept/rATG versus tacrolimus/rATG, P=0.66). Patient and graft survival rates were similar between all groups. An eGFR of <45 ml/min per 1.73 m2 was observed for nine of 107 (8%) participants assigned to belatacept/alemtuzuab, eight of 104 (8%) participants assigned to belatacept/rATG, and 20 of 105 (19%) participants assigned to tacrolimus/rATG (P<0.05 for each belatacept group versus tacrolimus/rATG). Biopsy sample-proven acute rejection was observed for 20 of 107 (19%) participants assigned to belatacept/alemtuzuab, 26 of 104 (25%) participants assigned to belatacept/rATG, and seven of 105 (7%) participants assigned to tacrolimus/rATG (for belatacept/alemtuzumab versus tacrolimus/rATG, P=0.006; for belatacept/rATG versus tacrolimus/rATG, P<0.001). Gastrointestinal and neurologic adverse events were less frequent with belatacept versus calcineurin-based immunosuppression. CONCLUSIONS: Overall 2-year outcomes were similar when comparing maintenance immunosuppression using belatacept versus tacrolimus, and each protocol involved rapid steroid withdrawal. The incidence of an eGFR of <45 ml/min per 1.73 m2 was significantly lower with belatacept compared with tacrolimus, but the incidence of biopsy sample-proven acute rejection significantly higher. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Belatacept Early Steroid Withdrawal Trial, NCT01729494.

Belatacept-based immunosuppression with simultaneous calcineurin inhibitor avoidance and early corticosteroid withdrawal: A prospective, randomized multicenter trial.

Simultaneous calcineurin inhibitor avoidance (CNIA) and early corticosteroid withdrawal (ESW) have not been achieved primarily due to excessive acute rejection. This trial compared 2 belatacept-based CNIA/ESW regimens with a tacrolimus-based ESW regimen. Kidney transplant recipients were randomized to receive alemtuzumab/belatacept, rabbit anti-thymocyte globulin (rATG)/belatacept, or rATG/tacrolimus. The combinatorial primary endpoint consisted of patient death, renal allograft loss, or a Modification of Diet in Renal Disease-calculated eGFR of <45 mL/min/1.73 m2 at 12 months. Results are reported by treatment group (alemtuzumab/belatacept, rATG/belatacept, and rATG/tacrolimus). Superiority was not observed at 1 year for the primary endpoint (9/107 [8.4%], 15/104 [14.4%], and 14/105 [13.3%], respectively; P = NS) for either belatacept-based regimen. Differences were not observed for secondary endpoints (death, death-censored graft loss, or estimated glomerular filtration rates < 45 mL/min/1.73 m2 ). Differences were observed in biopsy-proved acute cellular rejection (10.3%, 18.3%, and 1.9%, respectively) (P < .001), but not in antibody-mediated rejection, mixed acute rejection, or de novo donor-specific anti-HLA antibodies. Neurologic and electrolyte abnormality adverse events were less frequent under belatacept. Belatacept-based CNIA/ESW regimens did not prove to be superior for the primary or secondary endpoints. Belatacept-treated patients demonstrated an increase in biopsy-proved acute cellular rejection and reduced neurologic and metabolic adverse events. These results demonstrate that simultaneous CNIA/ESW is feasible without excessive acute rejection.

Impaired cerebral autoregulation in preoperative newborn infants with congenital heart disease.

OBJECTIVES: To characterize cerebral autoregulation (CA) in preoperative newborn infants with congenital heart disease (CHD). METHODS: This was a prospective, pilot study of term newborns with CHD who required intensive care. Continuous mean arterial blood pressure (MAP), cerebral tissue oxygen saturation (SCTO2) via near-infrared spectroscopy, and arterial oxygen saturation (SaO2) were collected. Significant low-frequency coherence between MAP and SCTO2 was used to define impaired CA in 20-minute epochs. Cerebral fractional tissue oxygen extraction (FTOE) = (SaO2 - SCTO2)/SaO2 was calculated. Spearman's and rank bi-serial correlations and logistic linear models accounting for multiple measures were used to identify associations with impaired CA and coherence. RESULTS: Twenty-four term neonates were evaluated for 23.4 ± 1.8 hours starting the first day of life. Periods of SaO2 variability >5% were excluded, leaving 63 ± 10 epochs per subject, 1515 total for analysis. All subjects demonstrated periods of abnormal CA, mean 15.3% ± 12.8% of time studied. Significant associations with impaired CA per epoch included greater FTOE (P = .02) and lack of sedation (P = .02), and associations with coherence included greater FTOE (P = .03), lack of sedation (P = .03), lower MAP (P = .006), and lower hemoglobin (P = .02). CONCLUSIONS: Term newborns with CHD display time-varying CA abnormalities. Associations seen between abnormal CA and greater FTOE, lack of sedation, and lower hemoglobin suggest that impaired oxygen delivery and increased cerebral metabolic demand may overwhelm autoregulatory capacity in these infants. Further studies are needed to determine the significance of impaired CA in this population.

Digoxin Use Is Associated With Reduced Interstage Mortality in Patients With No History of Arrhythmia After Stage I Palliation for Single Ventricle Heart Disease.

BACKGROUND: Interstage mortality (IM) remains significant after stage 1 palliation (S1P) for single-ventricle heart disease (SVD), with many deaths sudden and unexpected. We sought to determine whether digoxin use post-S1P is associated with reduced IM, utilizing the multicenter database of the National Pediatric Cardiology Quality Improvement Collaborative (NPCQIC). METHODS AND RESULTS: From June 2008 to July 2013, 816 infants discharged after S1P from 50 surgical sites completed the interstage to stage II palliation, transplant, or IM. Arrhythmia during S1P hospitalization or discharge on antiarrhythmic medications were exclusions (n=270); 2 patients were lost to follow-up. Two analyses were performed: (1) propensity-score adjusted logistic regression with IM as outcome and (2) retrospective cohort analysis for patients discharged on digoxin versus not, matched for surgical site and other established IM risk factors. Of 544 study patients, 119 (21.9%) were discharged on digoxin. Logistic regression analysis with propensity score, site-size group, and digoxin use as predictor variables showed an increased risk of IM in those not discharged on digoxin (odds ratio, 8.6; lower confidence limit, 1.9; upper confidence limit, 38.3; P<0.01). The retrospective cohort analysis for 60 patients on digoxin (matched for site of care, type of S1P, post-S1P ECMO use, genetic syndrome, discharge feeding route, ventricular function, tricuspid regurgitation, and aortic arch gradient) showed 0% IM in the digoxin at discharge group and an estimated IM difference between the 2 groups of 9% (P=0.04). CONCLUSIONS: Among SVD infants in the NPCQIC database discharged post-S1P with no history of arrhythmia, use of digoxin at discharge was associated with reduced IM.

Molecular diagnosis of eosinophilic esophagitis by gene expression profiling.

BACKGROUND & AIMS: Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Here we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), which is currently diagnosed by histology and clinical symptoms. METHODS: We developed an EoE diagnostic panel (EDP) comprising a 96-gene quantitative polymerase chain reaction array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14) and subsequently vetted the EDP using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed, paraffin-embedded tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. RESULTS: The EDP identified adult and pediatric patients with EoE with approximately 96% sensitivity and approximately 98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with formalin-fixed, paraffin-embedded tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse after treatment. CONCLUSIONS: We developed a molecular diagnostic test (referred to as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.

Meta-analysis of function after secondary shoulder surgery in neonatal brachial plexus palsy.

BACKGROUND: Shoulder internal rotation contracture, active abduction, and external rotation deficits are common secondary problems in neonatal brachial plexus palsy (NBPP). Soft tissue shoulder operations are often utilized for treatment. The objective was to conduct a meta-analysis and systematic review analyzing the clinical outcomes of NBPP treated with a secondary soft-tissue shoulder operation. METHODS: A literature search identified studies of NBPP treated with a soft-tissue shoulder operation. A meta-analysis evaluated success rates for the aggregate Mallet score (≥ 4 point increase), global abduction score (≥ 1 point increase), and external rotation score (≥ 1 point increase) using the Mallet scale. Subgroup analysis was performed to assess these success rates when the author chose arthroscopic release technique versus open release technique with or without tendon transfer. RESULTS: Data from 17 studies and 405 patients were pooled for meta-analysis. The success rate for the global abduction score was significantly higher for the open technique (67.4%) relative to the arthroscopic technique (27.7%, P<0.0001). The success rates for the global abduction score were significantly different among sexes (P=0.01). The success rate for external rotation was not significantly different between the open (71.4%) and arthroscopic techniques (74.1%, P=0.86). No other variable was found to have significant impact on the external rotation outcomes. The success rate for the aggregate Mallet score was 57.9% for the open technique, a nonsignificant increase relative to the arthroscopic technique (53.5%, P=0.63). Data suggest a correlation between increasing age at the time of surgery and a decreasing likelihood of success with regards to aggregate Mallet with an odds ratio of 0.98 (P=0.04). CONCLUSIONS: Overall, the secondary soft-tissue shoulder operation is an effective treatment for improving shoulder function in NBPP in appropriately selected patients. The open technique had significantly higher success rates in improving global abduction. There were no significant differences in the success rates for improvement in the external rotation or aggregate Mallet score among these surgical techniques.

PedsQL eosinophilic esophagitis module: feasibility, reliability, and validity.

OBJECTIVE: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammatory condition with a paucity of information on health-related quality of life (HRQOL). The objective of the study was to report on the measurement properties of the PedsQL EoE Module. METHODS: The PedsQL EoE Module was completed in a multisite study by 196 pediatric patients with EoE and 262 parents of patients with EoE. RESULTS: The PedsQL EoE Module scales evidenced excellent feasibility (0.6%-3.1% missing), excellent group comparison reliability across total scale scores (patient α 0.93; parent proxy α 0.94), good reliability for the 7 individual scales (patient α 0.75-0.87; parent proxy α 0.81-0.92), excellent test-retest reliability (patient intraclass correlation coefficient 0.88; parent intraclass correlation coefficient 0.82), demonstrated no floor effects and low ceiling effects, and demonstrated a high percentage of scaling success for most scales. Intercorrelations with the PedsQL Generic Core Scales were in the medium (0.30) to large (0.50) range. PedsQL EoE Module scores were worse among patients with active histologic disease (≥ 5 eos/hpf) compared with those in remission (patient self-report: 63.3 vs 69.9 [P < 0.05]; parent proxy report: 65.1 vs 72.3 [P < 0.01]), and those treated with dietary restrictions compared with those with no restrictions (patient self-report: 61.6 vs 74.3 [P < 0.01]; parent proxy report: 65.5 vs 74.7 [P < 0.01]). CONCLUSIONS: The results demonstrate excellent measurement properties of the PedsQL EoE Module. Patients with active histologic disease and those treated with dietary restrictions demonstrated worse PedsQL scores. The PedsQL EoE Module may be used in the evaluation of pediatric EoE disease-specific HRQOL in clinical research and practice.

Comparative dietary therapy effectiveness in remission of pediatric eosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis is a chronic, immune-mediated inflammatory disorder that responds to dietary therapy; however, data evaluating the effectiveness of dietary therapeutic strategies are limited. OBJECTIVE: This study compared the effectiveness of 3 frequently prescribed dietary therapies (elemental, 6-food elimination, and skin prick and atopy patch-directed elimination diets) and assessed the remission predictability of skin tests and their utility in directing dietary planning. METHODS: A retrospective cohort of proton-pump inhibitor-unresponsive, non-glucocorticoid-treated patients with eosinophilic esophagitis who had 2 consecutive endoscopic biopsy specimens associated with dietary intervention was identified. Biopsy histology and remissions (<15 eosinophils/high-power field) after dietary therapy and food reintroductions were evaluated. RESULTS: Ninety-eight of 513 patients met the eligibility criteria. Of these 98 patients, 50% (n= 49), 27% (n= 26), and 23% (n= 23) received elemental, 6-food elimination, and directed diets, respectively. Remission occurred in 96%, 81%, and 65% of patients on elemental, 6-food elimination, and directed diets, respectively. The odds of postdiet remission versus nonremission were 5.6-fold higher (P= .05) on elemental versus 6-food elimination diets and 12.5-fold higher (P= .003) on elemental versus directed diets and were not significantly different (P= .22) on 6-food elimination versus directed diets. After 116 single-food reintroductions, the negative predictive value of skin testing for remission was 40% to 67% (milk, 40%; egg, 56%; soy, 64%; and wheat, 67%). CONCLUSION: All 3 dietary therapies are effective; however, an elemental diet is superior at inducing histologic remission compared with 6-food elimination and skin test-directed diets. Notably, an empiric 6-food elimination diet is as effective as a skin test-directed diet. The negative predictive values of foods most commonly reintroduced in single-food challenges are not sufficient to support the development of dietary advancement plans solely based on skin test results.

Soy isoflavone phase II metabolism differs between rodents and humans: implications for the effect on breast cancer risk.

BACKGROUND: Human and animal studies have produced conflicting results with regard to the effect of soy isoflavones on breast cancer risk. This may be due to differences in isoflavone metabolism. OBJECTIVE: The objective of this study was to determine whether soy isoflavone phase II metabolism differs between humans and rodents. DESIGN: Circulating total and unconjugated isoflavone concentrations were determined by mass spectrometry in plasma samples from 7 separate studies: 1) in Sprague-Dawley rats and in 3 strains of mice fed commercial soy-containing diets; 2) in Sprague-Dawley rats gavaged with genistein; 3) in healthy adults who consumed single servings of soy nuts, soy milk, and tempeh; 4) in healthy adults subchronically given soy milk; 5) in healthy women orally administered 50 mg genistein; 6) in healthy women orally administered 20 mg pure S-(-)equol; and 7) in 6-mo-old infants fed soy infant formula and later, at age 3 y, a soy germ isoflavone supplement. RESULTS: The proportion of unconjugated genistein in plasma from adults and infants who consumed different soy foods, pure genistein, or an isoflavone supplement was <1% in steady state and <2% at peak concentrations. By contrast, rodents fed soy-containing diets conjugate isoflavones less efficiently. The plasma percentages of unconjugated genistein concentrations in Sprague-Dawley rats and C57BL/6, nude, and transgenic AngptL4B6 mice were 4.0 ± 0.6%, 4.6 ± 0.6%, 11.6 ± 0%, and 30.1 ± 4.3%, respectively, which represent 20, 23, 58, and 150 times that in humans. CONCLUSION: The markedly higher circulating concentrations of biologically active (unconjugated) genistein in certain strains of mice cast doubt on the value of the use of these rodents for gaining insight into the effects of isoflavones in humans, especially with regard to the effects on breast tissue.

Long-term outcomes in pediatric-onset esophageal eosinophilia.

BACKGROUND: Pediatric eosinophilic esophagitis (EoE) is a newly recognized antigen-induced form of chronic esophagitis (CE). OBJECTIVE: Characterization of long-term clinical outcomes in patients with pediatric EoE is needed. METHODS: From histologic review of 3817 pediatric esophageal biopsy specimens from 1982-1999, we conducted a nested case-control study of patients with retrospectively identified histologic eosinophilic esophagitis (rEoE) and CE, as well as an age-matched control cohort. Participants were asked to complete validated health-related outcome questionnaires. RESULTS: At an average of 15 years after initial endoscopy, both cohorts (42/198 patients with rEoE and 67/468 patients with CE, as well as 100 age-matched control subjects) completed questionnaires. Compared with control subjects, quality of life was significantly decreased among patients with rEoE (P < .001) and patients with CE (P < .001). Rates of dysphagia (patients with rEoE, 49%; patients with CE, 37%; control subjects, 6%) and food impaction (patients with rEoE, 40%; patients with CE, 14%; control subjects, 3%) were significantly increased in the rEoE cohort compared with those seen in control subjects (P < .001 and P < .001, respectively). Increased esophageal eosinophil counts (odds ratio [OR], 1.6; 95% CI, 1.1-2.5; P < .05) during childhood were predictive of dysphagia during early adulthood. Food allergy (OR, 2.7; 95% CI, 1.2-6.0; P < .01), allergic rhinitis (OR, 3.5; 95% CI, 1.8-6.8; P < .001), and asthma (OR, 2.1; 95% CI, 1.04-4.3; P = .04) were associated with dysphagia. Food impaction was more common among patients with reported food allergy than among those without (OR, 3.1; 95% CI, 1.2-7.8; P = .02). CONCLUSIONS: Esophageal eosinophilia is associated with reduced quality of life and persistent symptoms 15 years after presentation. Increased esophageal eosinophil counts and the occurrence of food allergy and atopy in childhood increase the rate of dysphagia in young adulthood.

Identification, epidemiology, and chronicity of pediatric esophageal eosinophilia, 1982-1999.

BACKGROUND: Eosinophilic esophagitis (EE) is now a commonly encountered disorder that was rarely diagnosed a decade ago. OBJECTIVE: We aimed to determine the epidemiologic and histologic features of retrospective pediatric esophageal eosinophilia before the first case of EE at our institution was recognized. METHODS: Esophageal biopsy specimens obtained between 1982 and 1999 with reflux esophagitis were re-examined and reorganized into 2 groups based on peak esophageal eosinophil number (<15 eosinophils per high-powered field [hpf] and > or =15 eosinophils/hpf). The epidemiology and histology of the entire cohort and a population-based cohort were evaluated. RESULTS: Eight hundred seven biopsy specimens from 666 patients were re-examined; 198 patients had 15 eosinophils/hpf or greater. Among a population-based cohort of patients with 15 eosinophils/hpf or greater, there was a modest increase in incidence (P < .001; incidence rate ratio, 1.18; 95% CI, 1.09-1.28). After correcting for a 40-fold increase in the number of endoscopies during this time period, the proportion of biopsy specimens with 15 eosinophils/hpf or greater did not change (0.08 in 1982 vs 0.08 in 1996 [peak]; P = .9; incidence rate ratio, 1.02; 95% CI, 0.73-1.44). Patients who had as few as 5 eosinophils/hpf were more likely to have persistent esophageal eosinophilia on repeat esophagogastroduodenoscopy, evidence of basal layer hyperplasia, and lamina propria fibrosis compared with patients with less than 5 eosinophils/hpf (P < .001). CONCLUSIONS: Esophageal eosinophilia at levels consistent with EE was present among 30% of patients given diagnoses of reflux esophagitis, and the incidence of esophageal eosinophilia did not change over time. Patients with 5 eosinophils/hpf or greater had evidence of other histologic abnormalities and were likely to have persistent esophageal eosinophilia.

Effect of mild and moderate hepatic impairment on azimilide pharmacokinetics following single dose oral administration.

Azimilide dihydrochloride (75-125 mg/day) is currently being developed for use in prolonging the time to recurrence of atrial fibrillation/flutter and for reducing the frequency of shocks in patients with an implantable cardioverting defibrillator. This study investigated the influence of mild and moderate hepatic impairment on azimilide pharmacokinetics. Six subjects each with mild and moderate hepatic impairment (Child-Pugh grades A and B, respectively) were age, weight, smoking status, and gender-matched to a healthy subject (total N = 24). Each subject was administered a single, oral dose of 100 mg azimilide dihydrochloride following an overnight fast. Blood/plasma and urine samples were collected up to 28 days and over 9 days, respectively, and analyzed using HPLC with MS/MS or UV detection. For azimilide, most parameters in subjects with mild to moderate hepatic impairment were within 25% of those observed in matched healthy subjects, with no statistically significant differences observed. For F-1292 (major metabolite in plasma), a significant decrease in AUC was observed in subjects with moderate hepatic impairment, secondary to an increase in renal clearance (CL(r)). Based on these results, no a priori dosage adjustment is required in subjects with mild to moderate hepatic impairment.