Faculty Bibliography

INTRODUCTION: Utilizing recently-developed inflammatory bowel disease (IBD)-specific scales, we aimed to correlate sexual dysfunction (SD) with clinical and psychosocial IBD metrics, and track SD longitudinally, specifically in patients initiating biologic therapies.
METHOD(S): We surveyed Crohn's disease (CD) and ulcerative colitis (UC) patients starting a biologic agent (anti-TNF, anti-integrin, or anti-IL12/23) at induction of therapy and 60 days after. Surveys included the IBD- Female and Male Sexual Dysfunction Scales (IBD-FSDS and MSDS), the PROMIS Brief Sexual Function and Satisfaction Profile, as well as disease activity indices [Harvey-Bradshaw index (HBI), partial Mayo score], and scales for depression [Patient Health Questionnaire-9 (PHQ-9)], quality of life (QoL) [Short IBD Questionnaire (SIBDQ)], functional disability [IBD-Disability Index (IBDDI)], and illness perception [Brief Illness Perception Questionnaire (BIPQ)]. We reviewed baseline colonoscopies [simple endoscopic score (SES) and Mayo endoscopic subscore (MES)], biomarkers of inflammation (ESR, CRP, calprotectin), comorbidities, and IBD history.
RESULT(S): 61 patients (35 males and 26 females) completed survey 1 and 35 completed survey 2. The mean age was 34 years, 59% had CD, 41% had UC, and 38% were non-white. At induction, there was a high degree of SD as measured by the MSDS and FSDS (mean MSDS 9, FSDS 15). Initial SD scores were strongly correlated with PROMIS scores (r = 0.82, P < 0.001) and MES (r = 0.74, P < 0.001), and moderately correlated with the HBI (r = 0.48, P = 0.003) and Mayo score (0.46, P = 0.03). SD also correlated with the SIBDQ (r = 0.54, P < 0.001), PHQ-9 (r = 0.41, P < 0.001), IBDDI (r = 0.46, P < 0.001), and with domains of the BIPQ assessing illness effect on emotions and wellbeing (r = 0.58, P < 0.001; r = 0.50, P < 0.001). SD did not correlate with baseline biomarkers of inflammation (Table 2). FSDS scores improved from survey 1 to 2 (mean 18.2 to 11.3, P = 0.01). MSDS scores also numerically improved (10.1 to 8.5), but did not reach significance (Table 3). HBI, SCCAI and pMayo scores improved with a clinically significant response seen in 22% of patients.
CONCLUSION(S): In this prospective observational cohort, SD scores correlated with depression, QoL metrics, and disease activity, but did not correlate with biomarkers of inflammation. There was a moderate improvement in disease activity and SD scores after induction therapy with biologics, but a degree of SD persisted. Further studies must track this effect during maintenance therapy

INTRODUCTION: Fecal microbiota transplant (FMT) is an effective treatment for recurrent Clostridioides difficile infection (rCDI), but its precise mechanism remains unknown (1-2). Recent studies suggest that the restoration of gut bacteria, which carry necessary enzymes to convert primary bile acids (PBAs) to secondary bile acids (SBAs), may play a key role in rCDI risk (3, Figure 1). For example, in vitro studies have demonstrated that PBAs stimulate C. difficile spore germination and that deoxycholic acid, a SBA, inhibits toxin-producing C. difficile (4). As normal fecal bile acid pools consist predominantly of SBAs, we hypothesize that a contributor of rCDI risk is the decrease in SBAs from enteric bacteria loss following antibiotic use (5-8).We present the first case enrolled in our clinical trial using ursodeoxycholic acid (UDCA), a SBA, as an adjunct treatment to prevent future rCDI. CASE DESCRIPTION/METHODS: An otherwise healthy 46-year-old man presented with S. aureusbacteremia secondary to septic knee arthritis. While on an extended course of cefazolin, he developed profuse, watery diarrhea and stool C. difficile toxin PCR was positive. He was then treated with intravenous metronidazole for one week and oral vancomycin for two weeks, with resolution of symptoms. Six weeks later, CDI recurred and was successfully treated with oral vancomycin for two weeks, in conjunction with concurrent UDCA 300 mg twice daily for eight weeks. Stool samples were collected at two-week intervals and fecal bile acid compositions were assessed via liquid chromatography - mass spectrometry. Fecal bile acid analyses demonstrated a shift towards protective SBAs by the end of the 8-week course of ursodiol (Figure 2). This profile of increased SBAs remained consistent despite subsequent retreatment with cefazolin at 5 months for recurrent septic arthritis. The patient has been without rCDI now for almost 2 years. DISCUSSION: The findings in this case are consistent with our hypothesis that increasing SBAs through adjunct treatment with UDCA can be effective in breaking the rCDI cycle. While some CDI patients have adequate enteric bacteria to produce SBAs after antibiotic treatment, others may have a delayed normalization of their gut microbiome, and may therefore require ?bridge therapy? with supplementary SBAs (e.g., UDCA) until their endogenous microbial community is restored. Treatment and analysis of additional patients with rCDI in this clinical trial are in progress. (Figure Presented)

OBJECTIVES/OBJECTIVE:The gut microbiome is believed to play a role in the susceptibility to and treatment of Clostridium difficile infections (CDIs). It is, however, unknown whether the gut microbiome is also affected by asymptomatic C difficile colonization. Our study aimed to evaluate the fecal microbiome of children based on C difficile colonization, and CDI risk factors, including antibiotic use and comorbid inflammatory bowel disease (IBD). METHODS:Subjects with IBD and non-IBD controls were prospectively enrolled from pediatric clinics for a biobanking project (n = 113). A fecal sample was collected from each subject for research purposes only and was evaluated for asymptomatic toxigenic C difficile colonization. Fecal microbiome composition was determined by 16S rRNA sequencing. RESULTS:We found reduced bacterial diversity and altered microbiome composition in subjects with C difficile colonization, concurrent antibiotic use, and/or concomitant IBD (all P < 0.05). Accounting for antibiotic use and IBD status, children colonized with C difficile had significant enrichment in taxa from the genera Ruminococcus, Eggerthella, and Clostridium. Children without C difficile had increased relative abundances of Faecalibacterium and Rikenellaceae. Imputed metagenomic functions of those colonized were enriched for genes in oxidative phosphorylation and beta-lactam resistance, whereas in the subjects without C difficile, several functions in translation and metabolism were over-represented. CONCLUSIONS:In children, C difficile colonization, or factors that predispose to colonization such as antibiotic use and IBD status were associated with decreased gut bacterial diversity and altered microbiome composition. Averting such microbiome alterations may be a method to prevent or treat CDI.

Background and Aims/UNASSIGNED:This review is the first to evaluate the burden of ulcerative colitis [UC] on patients' quality of life by synthesizing data from studies comparing scores from the SF-36® Health Survey, a generic measure assessing eight quality-of-life domains, between UC patients and matched reference samples. Methods/UNASSIGNED:A systematic review of the published literature identified articles reporting SF-36 domains or physical and mental component summary scores [PCS, MCS] from UC and reference samples. Burden of disease for each SF-36 domain was then summarized across studies by comparing weighted mean differences in scores between patient and reference samples with minimally important difference thresholds. Results/UNASSIGNED:Thirty articles met pre-specified inclusion criteria. SF-36 scores were extracted from five samples of patients with active disease, 11 samples with a mixture of disease activity, five samples of patients in clinical remission, and 13 samples of patients following proctocolectomy with ileostomy or ileal pouch-anal anastomosis, along with respective reference samples. Clinically meaningful burden was observed in samples with active or mixed disease activity [deficits: PCS = 5.6, MCS = 5.5] on all SF-36 domains except Physical Functioning. No burden was observed in samples in remission or post-surgical patients [deficits: PCS = 0.8, MCS = 0.4] except for the General Health perception domain. Conclusions/UNASSIGNED:Patients with active UC experience a clinically meaningful burden of disease across most aspects of quality of life. Patients with inactive UC exhibit negligible disease burden and are comparable to the general population on most quality-of-life outcomes. Thus, treatments which effectively induce and maintain remission may restore physical and mental health status.

BACKGROUND:Case series suggest a possible association between bariatric surgery and incident IBD. AIM/OBJECTIVE:The aim of this study was to evaluate the association between bariatric surgery and new-onset IBD. METHODS:We first conducted a multi-institutional case series of patients with a history of IBD and bariatric surgery. We next conducted a matched case-control study using medical and pharmacy claims from 2008 to 2012 in a US national database from Source Healthcare Analytics LLC. Bariatric surgery was defined by ICD-9 or CPT code. Bariatric surgery was evaluated as recent (code in database timeframe), past (past history V code) or no history. Conditional logistic regression was used to estimate odds ratios (OR) and 95% CI for new-onset IBD, CD and UC. RESULTS:A total of 15 cases of IBD (10 CD, 4 UC, 1 IBD, type unclassified) with a prior history of bariatric surgery were identified. Most cases were women, had Roux-en-Y surgery years prior to diagnosis and few IBD-related complications. A total of 8980 cases and 43 059 controls were included in our database analysis. Adjusting for confounders, a past history of bariatric surgery was associated with an increased risk of new-onset IBD (OR 1.93, 95% CI 1.34-2.79). However, patients who had recent bariatric surgery did not appear to be at shorter term risk of IBD (OR 0.94, 95% CI 0.58-1.52). CONCLUSION/CONCLUSIONS:New-onset IBD was significantly associated with a past history of bariatric surgery. This potential association needs to be confirmed in future prospective studies.

PURPOSE: To conduct a systematic literature review of the reliability, construct validity, and responsiveness of the SF-36(R) Health Survey (SF-36) in patients with ulcerative colitis (UC). METHODS: We performed a systematic search of electronic medical databases to identify published peer-reviewed studies which reported scores from the eight scales and/or two summary measures of the SF-36 collected from adult patients with UC. Study findings relevant to reliability, construct validity, and responsiveness were reviewed. RESULTS: Data were extracted and summarized from 43 articles meeting inclusion criteria. Convergent validity was supported by findings that 83% (197/236) of correlations between SF-36 scales and measures of disease symptoms, disease activity, and functioning exceeded the prespecified threshold (r >/= |0.40|). Known-groups validity was supported by findings of clinically meaningful differences in SF-36 scores between subgroups of patients when classified by disease activity (i.e., active versus inactive), symptom status, and comorbidity status. Responsiveness was supported by findings of clinically meaningful changes in SF-36 scores following treatment in non-comparative trials, and by meaningfully larger improvements in SF-36 scores in treatment arms relative to controls in randomized controlled trials. The sole study of SF-36 reliability found evidence supporting internal consistency (Cronbach's alpha >/= 0.70) for all SF-36 scales and test-retest reliability (intraclass correlation coefficient >/=0.70) for six of eight scales. CONCLUSIONS: Evidence from this systematic literature review indicates that the SF-36 is reliable, valid, and responsive when used with UC patients, supporting the inclusion of the SF-36 as an endpoint in clinical trials for this patient population.

Introduction: Tofacitinib is an oral, small molecule Janus kinase inhibitor being investigated for moderately to severely active ulcerative colitis (UC). We performed a systematic literature review (SLR) and network meta-analysis (NMA) to compare the efficacy and safety of tofacitinib to available tumour necrosis factor inhibitors (TNFi) and integrin receptor antagonists for induction therapy of adults with moderately to severely active UC. Aims & Methods: Using indexing and free-text terms, searches were conducted in the EMBASE, MEDLINE, CENTRAL, DARE and CINAHL databases to identify RCTs published as of January 2015. Proceedings of relevant conferences from 2012-2014 were also reviewed. Comparators of interest were infliximab, golimumab, adalimumab and vedolizumab. Two reviewers independently assessed studies for inclusion, and extracted and validated the study/patient data. Fixed- and random-effects Bayesian NMAs were conducted to compare efficacy outcomes and rates of adverse events (AEs) at 6-12 weeks in the overall population (TNFi-naive or exposed) and by prior TNFi exposure. Results: Twelve induction trials were identified from the SLR (ACT 1 & 2, EUCALYPTUS, GEMINI-I, PURSUIT SC, TOFACITINIB PHASE 2, Feagan 2005, 1 Probert 2003, 2 UC-SUCCESS, ULTRA 1, ULTRA 2, Suzuki 20143) and included in the NMA. Unpublished data from tofacitinib Phase 3 induction trials (OCTAVE 1 & 2) were also used in the analysis. Fixed-effects NMA showed that tofacitinib 10mg twice daily (BID) is associated with a higher rate of mucosal healing vs adalimumab 160/80/40mg in the overall population (odds ratio [OR] 1.82 [95% credible interval (CrI) 1.06, 3.14]), and vs vedolizumab 300mg (OR 3.71 [95% CrI 1.37, 10.64]) and etrolizumab 300mg (OR 12.09 [95% CrI 1.68, 122.73]) in TNFi-exposed patients. A higher rate of clinical remission was seen with tofacitinib 10mg BID vs adalimumab in TNFi-exposed patients (OR 11.93 [95% CrI 1.84, 154.78]). AE rates were similar between tofacitinib 10mg BID and comparators in the overall andTNFi-naive populations when analysed individually, but tofacitinib 10mg BID was found to be associated with a higher rate of disaggregated AEs ("any AE") than etrolizumab 300mg in the overall population (OR 2.78 [95% CrI 1.08, 7.41]). There were no statistically conclusive differences in the rates of specific AEs between tofacitinib 10mg BID and comparators. Conclusion: This NMA suggests that tofacitinib may be more effective as induction therapy in moderately to severely active UC than adalimumab and vedolizumab in TNFi-exposed patients, and is associated with a higher rate of mucosal healing than adalimumab in the overall population. Rates of specific safety events were similar between tofacitinib and other treatments

BACKGROUND: Inflammatory bowel diseases (IBD) are believed to be driven by dysregulated interactions between the host and the gut microbiota. Our goal is to characterize and infer relationships between mucosal T cells, the host tissue environment, and microbial communities in patients with IBD who will serve as basis for mechanistic studies on human IBD. METHODS: We characterized mucosal CD4 T cells using flow cytometry, along with matching mucosal global gene expression and microbial communities data from 35 pinch biopsy samples from patients with IBD. We analyzed these data sets using an integrated framework to identify predictors of inflammatory states and then reproduced some of the putative relationships formed among these predictors by analyzing data from the pediatric RISK cohort. RESULTS: We identified 26 predictors from our combined data set that were effective in distinguishing between regions of the intestine undergoing active inflammation and regions that were normal. Network analysis on these 26 predictors revealed SAA1 as the most connected node linking the abundance of the genus Bacteroides with the production of IL17 and IL22 by CD4 T cells. These SAA1-linked microbial and transcriptome interactions were further reproduced with data from the pediatric IBD RISK cohort. CONCLUSIONS: This study identifies expression of SAA1 as an important link between mucosal T cells, microbial communities, and their tissue environment in patients with IBD. A combination of T cell effector function data, gene expression and microbial profiling can distinguish between intestinal inflammatory states in IBD regardless of disease types.