Browsing by Author "Kugathasan, Subra"

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    Analysis of Using the Total White Blood Cell Count to Define Severe New-onset Ulcerative Colitis in Children
    (Wolters Kluwer, 2020-09) Mack, David R.; Saul, Bradley; Boyle, Brendan; Griffiths, Anne; Sauer, Cary; Markowitz, James; LeLeiko, Neal; Keljo, David; Rosh, Joel R.; Baker, Susan S.; Steiner, Steve; Heyman, Melvin B.; Patel, Ashish S.; Baldassano, Robert; Noe, Joshua; Rufo, Paul; Kugathasan, Subra; Walters, Thomas; Marquis, Alison; Thomas, Sonia M.; Denson, Lee; Hyams, Jeffrey; Pediatrics, School of Medicine
    Objectives: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. Methods: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis). Results: Mean age was 12.7 years; 49.6% (n = 212) were girls, and 83% (n = 351) were Caucasian. Severe total Mayo score was present in 28% (n = 120), mean PUCAI score was 49.8 ± 20.1, and 33% (n = 142) had severe mucosal disease with extensive involvement in 82% (n = 353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%. Conclusions: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.
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    Association of Baseline Luminal Narrowing With Ileal Microbial Shifts and Gene Expression Programs and Subsequent Transmural Healing in Pediatric Crohn Disease
    (Oxford University Press, 2021) Ta, Allison D.; Ollberding, Nicholas J.; Karns, Rebekah; Haberman, Yael; Alazraki, Adina L.; Hercules, David; Baldassano, Robert; Markowitz, James; Heyman, Melvin B.; Kim, Sandra; Kirschner, Barbara; Shapiro, Jason M.; Noe, Joshua; Oliva-Hemker, Maria; Otley, Anthony; Pfefferkorn, Marian; Kellermayer, Richard; Snapper, Scott; Rabizadeh, Shervin; Xavier, Ramnik; Dubinsky, Marla; Hyams, Jeffrey; Kugathasan, Subra; Jegga, Anil G.; Dillman, Jonathan R.; Denson, Lee A.; Pediatrics, School of Medicine
    Background: Transmural healing (TH) is associated with better long-term outcomes in Crohn disease (CD), whereas pretreatment ileal gene signatures encoding myeloid inflammatory responses and extracellular matrix production are associated with stricturing. We aimed to develop a predictive model for ileal TH and to identify ileal genes and microbes associated with baseline luminal narrowing (LN), a precursor to strictures. Materials and methods: Baseline small bowel imaging obtained in the RISK pediatric CD cohort study was graded for LN. Ileal gene expression was determined by RNASeq, and the ileal microbial community composition was characterized using 16S rRNA amplicon sequencing. Clinical, demographic, radiologic, and genomic variables were tested for association with baseline LN and future TH. Results: After controlling for ileal location, baseline ileal LN (odds ratio [OR], 0.3; 95% confidence interval [CI], 0.1-0.8), increasing serum albumin (OR, 4; 95% CI, 1.3-12.3), and anti-Saccharomyces cerevisiae antibodies IgG serology (OR, 0.97; 95% CI, 0.95-1) were associated with subsequent TH. A multivariable regression model including these factors had excellent discriminant power for TH (area under the curve, 0.86; positive predictive value, 80%; negative predictive value, 87%). Patients with baseline LN exhibited increased Enterobacteriaceae and inflammatory and extracellular matrix gene signatures, coupled with reduced levels of butyrate-producing commensals and a respiratory electron transport gene signature. Taxa including Lachnospiraceae and the genus Roseburia were associated with increased respiratory and decreased inflammatory gene signatures, and Aggregatibacter and Blautia bacteria were associated with reduced extracellular matrix gene expression. Conclusions: Pediatric patients with CD with LN at diagnosis are less likely to achieve TH. The association between specific microbiota, wound healing gene programs, and LN may suggest future therapeutic targets.
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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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    Compositional and Temporal Changes in the Gut Microbiome of Pediatric Ulcerative Colitis Patients Are Linked to Disease Course
    (Elsevier, 2018-10-10) Schirmer, Melanie; Denson, Lee; Vlamakis, Hera; Franzosa, Eric A.; Thomas, Sonia; Gotman, Nathan M.; Rufo, Paul; Baker, Susan S.; Sauer, Cary; Markowitz, James; Pfefferkorn, Marian; Oliva-Hemker, Maria; Rosh, Joel; Otley, Anthony; Boyle, Brendan; Mack, David; Baldassano, Robert; Keljo, David; LeLeiko, Neal; Heyman, Melvin; Griffiths, Anne; Patel, Ashish S.; Noe, Joshua; Kugathasan, Subra; Walters, Thomas; Huttenhower, Curtis; Hyams, Jeffrey; Xavier, Ramnik J.; Medicine, School of Medicine
    Evaluating progression risk and determining optimal therapy for ulcerative colitis (UC) is challenging as many patients exhibit incomplete responses to treatment. As part of the PROTECT (Predicting Response to Standardized Colitis Therapy) Study, we evaluated the role of the gut microbiome in disease course for 405 pediatric, new-onset, treatment-naive UC patients. Patients were monitored for 1 year upon treatment initiation, and microbial taxonomic composition was analyzed from fecal samples and rectal biopsies. Depletion of core gut microbes and expansion of bacteria typical of the oral cavity were associated with baseline disease severity. Remission and refractory disease were linked to species-specific temporal changes that may be implicative of therapy efficacy, and a pronounced increase in microbiome variability was observed prior to colectomy. Finally, microbial associations with disease-associated serological markers suggest host-microbial interactions in UC. These insights will help improve existing treatments and develop therapeutic approaches guiding optimal medical care
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    Serologic, but Not Genetic, Markers Are Associated With Impaired Anthropometrics at Diagnosis of Pediatric Crohn's Disease
    (Wolters Kluwer, 2019-11) Naramore, Sara K.; Bennett, William E., Jr.; Jiang, Guanglong; Kugathasan, Subra; Denson, Lee A.; Hyams, Jeffrey S.; Steiner, Steven J.; Pediatrics, School of Medicine
    Objectives: Children with Crohn's disease may present with malnutrition and linear growth impairment, which can be secondary to insufficient caloric intake, chronic inflammation, malabsorption, and suppression of growth-promoting hormones. We evaluated clinical, serologic, and genetic data to determine risk factors for impaired anthropometrics in Crohn's disease at diagnosis. Methods: Our study evaluated 772 children newly diagnosed with Crohn's disease, inflammatory phenotype, enrolled in the RISK Stratification Project to determine the factors associated with anthropometric impairment. Data were collected on demographics, growth parameters, disease location, serologic and immunologic markers, and disease severity. We performed a genome-wide association study of genetic polymorphisms associated with inflammatory bowel disease. Regression analysis determined associations between anthropometrics and clinical, serologic, and genetic variables. Results: There were 59 (7%) children with height z score <−2, 126 (14%) with a weight z score <−2, and 156 (17%) with a body mass index z score <−2. Linear growth impairment was associated with hypoalbuminemia (P = 0.0052), elevated granulocyte-macrophage colony stimulating factor autoantibodies (P = 0.0110), and elevated CBir antibodies against flagellin (P = 0.0117). Poor weight gain was associated with female sex (P = 0.0401), hypoalbuminemia (P = 0.0162), and thrombocytosis (P = 0.0081). Malnutrition was associated with hypoalbuminemia (P = 0.0061) and thrombocytosis (P = 0.0011). Children with moderate or severe disease had lower weight (P = 0.02 and P = 1.16×10−6, respectively) and body mass index z scores (P = 2.7 × 10−3 and P = 1.01 × 10−6, respectively) than children with quiescent and mild disease. There was no association between age of diagnosis, Tanner stage, or disease location and having impaired anthropometrics. There was no genome-wide association between the genetic polymorphisms and the serologic variables and anthropometric measurements. Conclusions: This is the largest study evaluating growth in treatment-naïve children with Crohn's disease, inflammatory phenotype. It is the first study to use genome-wide sequencing to assess for genetic determinants of growth impairment. Granulocyte-macrophage colony stimulating factor autoantibodies and CBir antibodies are more likely to be elevated in children with growth impairment. Future investigations should evaluate the relationship between genetic polymorphisms, pathologic immune responses, and the biological pathways regulating growth.
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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.