Risk of tuberculosis among Alabama children and adolescents treated with tumor necrosis factor inhibitors: a retrospective study

Abstract Background Tumor Necrosis Factor inhibitors (TNFi) have dramatically improved the outlook for patients with inflammatory arthritides and bowel disease (IBD), but are associated with increased infection risks, including tuberculosis (TB). Pediatric inflammatory diseases are uncommon, and the risk of TB in children taking TNFi remains unclear. The objective of this study was to report the incidence of TB disease among TNFi recipients at a single pediatric medical center serving most of Alabama compared to that of the general population of Alabama children. Methods Instances of TNFi usage among patients under age 20 years from July 1, 2007 through April 17, 2015 were captured from electronic health records at Children’s of Alabama (CoA), which has the only pediatric rheumatology clinic in Alabama, and where a substantial number of children in Alabama with inflammatory bowel disease receive care., and reports of TB cases were obtained from the Alabama Department of Public Health (ADPH). Incidence was expressed as TB cases/10,000 person-years, using population estimates from the Alabama Center for Health Statistics. Results 1033 Alabama patients at CoA who were residents of Alabama were identified who received TNFi for a total of 1564 person-years. One adolescent on TNFi developed severe extrapulmonary TB (incidence density = 6.4 per 10,000; 95% CI 0.9–45.4 per 10,000). Sixty-three cases occurred in persons not on TNFi (incidence density = 0.064 per 10,000; 95% CI 0.050–0.082 per 10,000). Conclusions One case of TB disease among TNFi-exposed children was identified for 1564 person-years in Alabama residents. Although rare, this is higher than expected relative to the general rate of TB in Alabama. Thus, continued diagnostic vigilance for TB in children taking TNFi is required. Trial registration number Not applicable

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry

Objective: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. Data Source: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. Study Design: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. Principal Findings: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. Conclusions: A quality improvement based approach to data quality monitoring and improvement is feasible and effective

Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn\u27s Disease: A Pragmatic Randomized Trial

BACKGROUND & AIMS: Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn\u27s disease therapy; however, nonresponse and loss of response are common. As combination therapy with methotrexate may improve response, we performed a multicenter, randomized, double-blind, placebo-controlled pragmatic trial to compare tumor necrosis factor inhibitors with oral methotrexate to tumor necrosis factor inhibitor monotherapy. METHODS: Patients with pediatric Crohn\u27s disease initiating infliximab or adalimumab were randomized in 1:1 allocation to methotrexate or placebo and followed for 12-36 months. The primary outcome was a composite indicator of treatment failure. Secondary outcomes included anti-drug antibodies and patient-reported outcomes of pain interference and fatigue. Adverse events (AEs) and serious AEs (SAEs) were collected. RESULTS: Of 297 participants (mean age, 13.9 years, 35% were female), 156 were assigned to methotrexate (110 infliximab initiators and 46 adalimumab initiators) and 141 to placebo (102 infliximab initiators and 39 adalimumab initiators). In the overall population, time to treatment failure did not differ by study arm (hazard ratio, 0.69; 95% CI, 0.45-1.05). Among infliximab initiators, there were no differences between combination and monotherapy (hazard ratio, 0.93; 95% CI, 0.55-1.56). Among adalimumab initiators, combination therapy was associated with longer time to treatment failure (hazard ratio, 0.40; 95% CI, 0.19-0.81). A trend toward lower anti-drug antibody development in the combination therapy arm was not significant (infliximab: odds ratio, 0.72; 95% CI, 0.49-1.07; adalimumab: odds ratio, 0.71; 95% CI, 0.24-2.07). No differences in patient-reported outcomes were observed. Combination therapy resulted in more AEs but fewer SAEs. CONCLUSIONS: Among adalimumab but not infliximab initiators, patients with pediatric Crohn\u27s disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. CLINICALTRIALS: gov, Number: NCT02772965

Implementing a Novel Quality Improvement-Based Approach to Data Quality Monitoring and Enhancement in a Multipurpose Clinical Registry

Objective: To implement a quality improvement based system to measure and improve data quality in an observational clinical registry to support a Learning Healthcare System. Data Source: ImproveCareNow Network registry, which as of September 2019 contained data from 314,250 visits of 43,305 pediatric Inflammatory Bowel Disease (IBD) patients at 109 participating care centers. Study Design: The impact of data quality improvement support to care centers was evaluated using statistical process control methodology. Data quality measures were defined, performance feedback of those measures using statistical process control charts was implemented, and reports that identified data items not following data quality checks were developed to enable centers to monitor and improve the quality of their data. Principal Findings: There was a pattern of improvement across measures of data quality. The proportion of visits with complete critical data increased from 72 percent to 82 percent. The percent of registered patients improved from 59 percent to 83 percent. Of three additional measures of data consistency and timeliness, one improved performance from 42 percent to 63 percent. Performance declined on one measure due to changes in network documentation practices and maturation. There was variation among care centers in data quality. Conclusions: A quality improvement based approach to data quality monitoring and improvement is feasible and effective

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease.

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease

Whole-genome sequencing of African Americans implicates differential genetic architecture in inflammatory bowel disease

Whether or not populations diverge with respect to the genetic contribution to risk of specific complex diseases is relevant to understanding the evolution of susceptibility and origins of health disparities. Here, we describe a large-scale whole-genome sequencing study of inflammatory bowel disease encompassing 1,774 affected individuals and 1,644 healthy control Americans with African ancestry (African Americans). Although no new loci for inflammatory bowel disease are discovered at genome-wide significance levels, we identify numerous instances of differential effect sizes in combination with divergent allele frequencies. For example, the major effect at PTGER4 fine maps to a single credible interval of 22 SNPs corresponding to one of four independent associations at the locus in European ancestry individuals but with an elevated odds ratio for Crohn disease in African Americans. A rare variant aggregate analysis implicates Ca2+-binding neuro-immunomodulator CALB2 in ulcerative colitis. Highly significant overall overlap of common variant risk for inflammatory bowel disease susceptibility between individuals with African and European ancestries was observed, with 41 of 241 previously known lead variants replicated and overall correlations in effect sizes of 0.68 for combined inflammatory bowel disease. Nevertheless, subtle differences influence the performance of polygenic risk scores, and we show that ancestry-appropriate weights significantly improve polygenic prediction in the highest percentiles of risk. The median amount of variance explained per locus remains the same in African and European cohorts, providing evidence for compensation of effect sizes as allele frequencies diverge, as expected under a highly polygenic model of disease