Browsing by Author "Boyle, Brendan M."

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    Comparative Effectiveness of Anti-TNF in Combination With Low-Dose Methotrexate vs Anti-TNF Monotherapy in Pediatric Crohn's Disease: A Pragmatic Randomized Trial
    (Elsevier, 2023-07) Kappelman, Michael D.; Wohl, David A.; Herfarth, Hans H.; Firestine, Ann M.; Adler, Jeremy; Ammoury, Rana F.; Aronow, Jeanine E.; Bass, Dorsey M.; Bass, Julie A.; Benkov, Keith; Berenblum Tobi, Catalina; Boccieri, Margie E.; Boyle, Brendan M.; Brinkman, William B.; Cabera, Jose M.; Chun, Kelly; Colletti, Richard B.; Dodds, Cassandra M.; Dorsey, Jill M.; Ebach, Dawn R.; Entrena, Edurne; Forrest, Christopher B.; Galanko, Joseph A.; Grunow, John E.; Gulati, Ajay S.; Ivanova, Anastasia; Jester, Traci W.; Kaplan, Jess L.; Kugathasan, Subra; Kusek, Mark E.; Leibowitz, Ian H.; Linville, Tiffany M.; Lipstein, Ellen A.; Margolis, Peter A.; Minar, Phillip; Molle-Rios, Zarela; Moses, Jonathan; Olano, Kelly K.; Osaba, Lourdes; Palomo, Pablo J.; Pappa, Helen; Park, K. T.; Pashankar, Dinesh S.; Pitch, Lisa; Robinson, Michelle; Samson, Charles M.; Sandberg, Kelly C.; Schuchard, Julia R.; Seid, Michael; Shelly, Kimberly A.; Steiner, Steven J.; Strople, Jennifer A.; Sullivan, Jillian S.; Tung, Jeanne; Wali, Prateek; Zikry, Michael; Weinberger, Morris; Saeed, Shehzad A.; Bousvaros, Athos; Medicine, School of Medicine
    Background & Aims Tumor necrosis factor inhibitors, including infliximab and adalimumab, are a mainstay of pediatric Crohn’s 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’s 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’s disease treated with methotrexate combination therapy experienced a 2-fold reduction in treatment failure with a tolerable safety profile. ClinicalTrials.gov, Number: NCT02772965.
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    Stratification of risk of progression to colectomy in ulcerative colitis via measured and predicted gene expression
    (Elsevier, 2021) Mo, Angela; Nagpal, Sini; Gettler, Kyle; Haritunians, Talin; Giri, Mamta; Haberman, Yael; Karns, Rebekah; Prince, Jarod; Arafat, Dalia; Hsu, Nai-Yun; Chuang, Ling-Shiang; Argmann, Carmen; Kasarskis, Andrew; Suarez-Farinas, Mayte; Gotman, Nathan; Mengesha, Emebet; Venkateswaran, Suresh; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; LeLeiko, Neal S.; Heyman, Melvin B.; Griffiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Davis Thomas, Sonia; Aronow, Bruce J.; Walters, Thomas D.; McGovern, Dermot P.B.; Hyams, Jeffrey S.; Kugathasan, Subra; Cho, Judy H.; Denson, Lee A.; Gibson, Greg; Pediatrics, School of Medicine
    An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
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    Ulcerative colitis mucosal transcriptomes reveal mitochondriopathy and personalized mechanisms underlying disease severity and treatment response
    (Springer Nature, 2019-01-03) Haberman, Yael; Karns, Rebekah; Dexheimer, Phillip J.; Schirmer, Melanie; Somekh, Judith; Jurickova, Ingrid; Braun, Tzipi; Novak, Elizabeth; Bauman, Laura; Collins, Margaret H.; Mo, Angela; Rosen, Michael J.; Bonkowski, Erin; Gotman, Nathan; Marquis, Alison; Nistel, Mason; Rufo, Paul A.; Baker, Susan S.; Sauer, Cary G.; Markowitz, James; Pfefferkorn, Marian D.; Rosh, Joel R.; Boyle, Brendan M.; Mack, David R.; Baldassano, Robert N.; Shah, Sapana; Leleiko, Neal S.; Heyman, Melvin B.; Grifiths, Anne M.; Patel, Ashish S.; Noe, Joshua D.; Aronow, Bruce J.; Kugathasan, Subra; Walters, Thomas D.; Gibson, Greg; Thomas, Sonia Davis; Mollen, Kevin; Shen-Orr, Shai; Huttenhower, Curtis; Xavier, Ramnik J.; Hyams, Jeffrey S.; Denson, Lee A.; Pediatrics, School of Medicine
    Molecular mechanisms driving disease course and response to therapy in ulcerative colitis (UC) are not well understood. Here, we use RNAseq to define pre-treatment rectal gene expression, and fecal microbiota profiles, in 206 pediatric UC patients receiving standardised therapy. We validate our key findings in adult and paediatric UC cohorts of 408 participants. We observe a marked suppression of mitochondrial genes and function across cohorts in active UC, and that increasing disease severity is notable for enrichment of adenoma/adenocarcinoma and innate immune genes. A subset of severity genes improves prediction of corticosteroid-induced remission in the discovery cohort; this gene signature is also associated with response to anti-TNFα and anti-α4β7 integrin in adults. The severity and therapeutic response gene signatures were in turn associated with shifts in microbes previously implicated in mucosal homeostasis. Our data provide insights into UC pathogenesis, and may prioritise future therapies for nonresponders to current approaches.