Citations

AbstractBackgroundAn association between inflammatory bowel disease (IBD) and obesity has been observed. Little is known about the effect of weight loss on IBD course. Our aim was to determine the impact of bariatric surgery on long-term clinical course of obese patients with IBD, either Crohn's disease (CD) or ulcerative colitis (UC).MethodsPatients with IBD who underwent bariatric surgery subsequent to IBD diagnosis were identified from 2 tertiary IBD centers. Complications after bariatric surgery were recorded. Patients were matched 1:1 for age, sex, IBD subtype, phenotype, and location to patients with IBD who did not undergo bariatric surgery. Controls started follow-up at a time point in their disease similar to the disease duration in the matched case at the time of bariatric surgery. Inflammatory bowel disease medication usage and disease-related complications (need for corticosteroids, hospitalizations, and surgeries) among cases and controls were compared.ResultsForty-seven patients met inclusion criteria. Appropriate matches were found for 25 cases. Median follow-up among cases (after bariatric surgery) and controls was 7.69 and 7.89 years, respectively. Median decrease in body mass index after bariatric surgery was 12.2. Rescue corticosteroid usage and IBD-related surgeries were numerically less common in cases than controls (24% vs 52%; odds ratio [OR], 0.36; 95% confidence interval [CI], 0.08–1.23; 12% vs 28%; OR, 0.2; 95% CI, 0.004–1.79). Two cases and 1 control were able to discontinue biologics during follow-up.ConclusionsInflammatory bowel disease patients with weight loss after bariatric surgery had fewer IBD-related complications compared with matched controls. This observation requires validation in a prospective study design.

Abstract Background A meta-analysis by our group has shown an elevated risk of lymphoma with thiopurine therapy for IBD (Kandiel 2005 Gut). It summed referral data and population (pop) data, but the risk of lymphoma in referral centers may be skewed higher due to referral bias (Ang 2006 PMID 16531538). Since a previous meta-analysis presented in 2012 (Kotlyar 2012, DDW), there have been two large population based studies published (Pasternak 2013 Am J of Epidemiol, Abbas 2013 Gastroenterology). The latter study reported on a nationwide database of patients from the Veterans Affairs (VA) Hospitals from the United States. Aims Calculate the standard incidence rate of lymphoma in pts exposed to AZA/6-MP in population cohort studies and contrast these results to referral center studies. Methods We searched MEDLINE and the Cochrane Database for: “lymphoproliferative and thiopurines”; and “azathioprine and lymphoma”. Included citations were IBD cohort studies, evaluated cancer as an outcome, and pts. received AZA and/or 6-MP. Additionally a comprehensive search of the literature and abstracts from international meetings (2005-2013) was done. In our study additional data were extracted from the Spanish collaborative registry ENEIDA. Pooled standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were estimated. CIs assumed a Poisson distribution. To examine for heterogeneity, the deviance statistic from Poisson regression models was examined. Results There were 507 citations, and fifteen citations were included. Two studies (Korelitz and Kinlen) were obtained from Kandiel 2005, and Lewis 2001 was replaced by Armstrong 2010 as data were of the GPRD database. In referral studies (n=7), the SIR = 6.47 (95% CI: 3.77-10.36). In pop studies (n=8), the SIR = 2.27 (95% CI: 1.76-2.88). Overall the SIR was = 2.61 (95% CI: 2.08-3.23). Data from referral centers did not show significant heterogeneity (p=0.052), while pop studies did show significant heterogeneity (p=0.003). Results between referral and pop centers showed a significant difference (p<0.01). Conclusion Pts with IBD who are treated with thiopurines have approximately a 3-fold increased risk of lymphoma as compared to the general pop. The SIR of referral studies were seen to be significantly higher than those of population based studies, consistent with possible referral bias. Also, the addition of two population based studies have added 58,349 person-years of follow-up to our analysis.With a total of 84 lymphomas observed, and with total pt-years being 184,085, this study shows 2,191 pt-yrs per lymphoma in the exposed group. Meta-analysis of Standardized Incidence Ratios (SIR) Disclosures: Lewis: Pfizer: Consultancy; Centocor: Consultancy; Allos: Research Funding; Shire: Consultancy; Takeda: Research Funding; Amgen: Research Funding; Millenium: Consultancy; AstraZeneca: Consultancy; GlaxoSmithKline: Consultancy; Dark Canyon Labs: Consultancy; Roche Pharma AG: Consultancy. Beaugerie:Ferring : Speakers Bureau; Schering-Plough: Speakers Bureau; Merck : Speakers Bureau. Loftus:Pfizer: Consultancy; Genentech: Research Funding; Braintree: Research Funding; Abbott: Consultancy, Research Funding; UCB: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Shire: Membership on an entity’s Board of Directors or advisory committees; Centocor: Research Funding; Takeda: Research Funding; Amgen: Research Funding. Lichtenstein:Abbott: Research Funding; BristolMyers: Consultancy; Centocor: Consultancy, Research Funding; Elan: Research Funding; Ferring: Consultancy; MilleniumResearch: Consultancy; Procter and Gamble: Consultancy, Research Funding; Prometheus: Consultancy, Research Funding; Salix: Consultancy, Research Funding; Warner-Chilcotte: Consultancy, Research Funding; Schering-Plough: Consultancy; Shire: Consultancy, Research Funding; Wyeth: Consultancy; UCB: Consultancy.

INTRODUCTION: Histologic remission is associated with superior long-term clinical outcomes in ulcerative colitis (UC). VARSITY, the first head-to-head comparison of biologic agents in UC (NCT02497469; EudraCT 2015-000939-33), showed superior clinical remission and endoscopic improvement at Week 52 with vedolizumab (VDZ), a gut-selective, humanized, α 4 β 7 integrin monoclonal antibody, vs adalimumab (ADA), a systemic, human, anti-tumor necrosis factor (anti-TNF) monoclonal antibody. 1 Both VDZ and ADA were generally safe and well-tolerated. 1 This analysis compared histologic improvements with VDZ vs ADA in VARSITY. METHODS: Patients with moderately to severely active UC were randomized 1:1 to active VDZ intravenous (IV) infusions (300 mg)/placebo subcutaneous (SC) injections or placebo IV/active ADA SC (160/80/40 mg). Prespecified histologic exploratory endpoints included histologic remission (Geboes score < 2 or Robarts Histopathology Index [RHI] score < 3) and minimal histologic disease activity (Geboes score < 3.2 or RHI score < 5) at Week 14 and Week 52. Histologic remission was also assessed based on previous anti-TNF use. RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Median (range) duration of exposure was 477 (127, 630) days for VDZ and 420 (71, 454) days for ADA. Mean (standard deviation) baseline histologic disease activity was similar between groups (Geboes: VDZ, 15.0 [4.92]; ADA, 15.1 [5.03]; RHI: VDZ, 19.5 [8.74]; ADA, 19.6 [8.89]). Histologic remission induced by VDZ at Week 52 was greater than with ADA in the overall (Geboes or RHI), anti-TNF naïve (Geboes or RHI), and anti-TNF failure (RHI only) groups (Table 1). Histologic remission at Week 14 favored VDZ over ADA, with larger differentiation when using RHI (Table 1). VDZ also outperformed ADA in achieving minimal histologic disease activity at Weeks 14 and 52 (Table 1). CONCLUSION: VARSITY showed that use of VDZ, compared with ADA, achieved higher rates of histologic remission and minimal histologic disease activity at Weeks 14 and 52 in patients with moderately to severely active UC. These data support the use of VDZ over ADA in UC.

INTRODUCTION: Patients with inflammatory bowel disease (IBD) are at significantly increased risk for Clostridium difficile infection (CDI). CDI in IBD is associated with increased in-hospital mortality, IBD treatment failure, re-hospitalization and high CDI recurrence rates. The existing literature on predictors of these adverse outcomes is limited. We evaluated four potentially modifiable novel risk factors (BMI, statin use, opioid use, and antidepressant use) on the risk and outcomes of CDI in patients with IBD. METHODS: CDI disease severity and other clinical outcomes, including colon surgery, CDI recurrence, CDI-related hospitalization, IBD exacerbations, and mortality were abstracted using the electronic medical record. Additionally, variables including BMI, statin use, opioid use, and antidepressant use at the time of CDI were abstracted from records for patients with IBD and CDI from 2008 and 2013. Statistical analysis comprised of descriptive statistics and univariate and multivariate logistic regression analyses. RESULTS: There were 137 patients with IBD and CDI included in this study: 70 with ulcerative colitis (51%), 63 with Crohn's disease (46%), and 4 with indeterminate colitis (3%). The median age was 46 years, and 55% were female. On multivariate analysis controlling for age, 43% of patients in the overweight BMI category had severe or severe complicated CDI, compared to 22% of patients in the underweight/normal BMI (OR, 2.85, P = 0.02) and 19% in the obese category (OR, 3.95, P = 0.04). Statin use was associated with severe or severe complicated CDI when controlling for age and BMI (OR, 5.66, P = 0.01). On multivariate analysis controlling for age and CDI severity, there was no association between statin use and post-CDI IBD exacerbations. Opioid and antidepressant use were not associated with CDI disease severity or IBD exacerbations. BMI category, statin use, opioid use, and antidepressant use were not associated with colon surgery, CDI recurrence, CDI-related hospitalizations, or mortality at 1 year. CONCLUSION: An overweight BMI and statin use were associated with severe or severe complicated CDI. There was no association between statin use and IBD exacerbations following CDI. Opioid and antidepressant use were not associated with disease severity or frequency of IBD exacerbations following CDI. Further studies are needed to better understand how these results could impact management of patients with IBD to improve clinical outcomes and potentially reduce the risk of CDI.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety in patients (pts) with UC was evaluated in an 8-week induction Phase (P) 2 study (NCT00787202), 1 2 8-week induction P3 studies (OCTAVE Induction 1 & 2; NCT01465763 & NCT01458951), 2 a 52-week maintenance P3 study (NCT01458574), and an ongoing, open-label, long-term extension (OLE) study (OCTAVE Open, NCT01470612). 3 We present updated infections data (Sep 2018) from the tofacitinib UC clinical program. 4,5 METHODS: Pts receiving placebo, tofacitinib 5 or 10 mg twice daily (BID) were analyzed as Induction (P2 & P3, n = 1220), Maintenance (P3, N = 592), and Overall (pts in P2, P3 & OLE receiving tofacitinib 5 or 10 mg BID, N = 1157 [Sep 2018]) Cohorts. Proportions and incidence rates (IRs; pts with events per 100 pt-years [PY] of exposure) were evaluated for infections of special interest (incl. serious infections [SIs], opportunistic infections [OIs; independently adjudicated], and herpes zoster [HZ]). RESULTS: A total of 1157 pts received ≥1 dose of tofacitinib 5 or 10 mg BID (83% predominantly 10 mg BID [avg. daily dose ≥15 mg]), with 2403.6 PY of exposure (median 623 days, up to 6.1 years of treatment). The Table 1 shows infection IRs by Cohort. In the Overall Cohort, nasopharyngitis was the most frequent infection. For SIs, the Overall Cohort “Tofacitinib All” IR (1.75 [95% CI 1.27, 2.36]) was similar to the Maintenance Cohort IRs for tofacitinib 5 and 10 mg BID. No SIs resulted in death. OIs were infrequent (28 pts) and most were HZ (24 pts; IR 0.99 [95% CI 0.63, 1.47]), mostly cutaneous. Not all HZ events were OIs; 83 pts overall had HZ events (IR 3.57 [95% CI 2.84, 4.43]; 6 serious). CONCLUSION: In induction, SIs and OIs occurred with tofacitinib but not with placebo. Overall, SIs were generally infrequent and Overall Cohort IRs did not suggest increased risk with longer tofacitinib treatment vs the Maintenance Cohort. Non-HZ OIs were rare. SI incidence was similar in the UC and rheumatoid arthritis programs (incl. increased HZ risk) 6 and to other UC therapies incl. biologics. 7

INTRODUCTION: VARSITY is the first head-to-head trial comparing the efficacy and safety of 2 biologic therapies, vedolizumab (VDZ) and adalimumab (ADA), in patients with moderately to severely active ulcerative colitis (UC). We previously reported significantly higher rates of clinical remission (31.3% vs 22.5%; P = 0.0061) and endoscopic improvement (39.7% vs 27.7%; P = 0.0005) at Week (Wk) 52 with VDZ vs ADA. 1 METHODS: VARSITY was a phase 3b, randomized, double-blind, double-dummy, active-controlled study (NCT02497469; EudraCT 2015-000939-33). Here we report the predefined, exploratory endpoints of early clinical response and clinical remission (defined in the Table 1) within the first 14 wks, as well as durable clinical remission (patients in clinical remission at Wk 14 and Wk 52). RESULTS: A total of 769 patients received ≥1 dose of VDZ (n = 383) or ADA (n = 386). Baseline characteristics were comparable between the 2 groups. A trend for separation in clinical response started to emerge at Wk 6 favoring VDZ vs ADA. Clinical response at Wk 14 favored VDZ vs ADA (257 [67.1%] vs 177 [45.9%]; treatment difference 21.2%). More patients achieved clinical remission at Wk 14 on VDZ vs ADA (102 [26.6%] vs 82 [21.2%]; treatment difference 5.3%). Patients on VDZ achieved higher rates of durable clinical remission (70 [18.3%] vs 46 [11.9%]); laboratory results correlated with these findings. Post hoc analyses showed a larger mean (standard deviation) change of C-reactive protein (CRP) from baseline to Wk 14 (−32.88 [155.77] nmol/L VDZ vs −3.35 [260.81] nmol/L ADA) and to Wk 52 (−50.87 [174.76] nmol/L VDZ vs −37.21 [169.17] nmol/L ADA) in favor of VDZ. Greater mean declines in fecal calprotectin (FCP) levels were seen in patients on VDZ compared with ADA (Wk 14: −1,551.3 [6,236.70] mg/kg VDZ vs −1,167.6 [4,647.67] mg/kg ADA; Wk 52: −2,187.3 [7,440.42] mg/kg VDZ vs −1,846.6 [4,560.55] mg/kg ADA). CONCLUSION: Patients on VDZ had numerically higher rates of both clinical response and clinical remission by Wk 14 compared with ADA. Patients on VDZ also achieved higher rates of durable clinical remission compared with ADA. CRP and FCP results correlated with these findings. These data on early clinical response and clinical remission, as well as durable remission, further support the use of VDZ over ADA in patients with moderately to severely active UC.

INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of ulcerative colitis (UC). Tofacitinib safety and efficacy were demonstrated in patients (pts) with moderate to severe UC in 3 Phase 3 studies, 1 and are being evaluated in an ongoing, open-label, long-term extension (OLE) study. 2 METHODS: We present updated safety and efficacy data from the OCTAVE Open OLE study (NCT01470612; Sep 2018; database not locked) 2 in completers/treatment failures in OCTAVE Sustain (NCT01458574) or non-responders in OCTAVE Induction 1/2 (NCT01465763/NCT01458951). Week (Wk) 8 data (OCTAVE Induction 1/2) and Wk 52 (completers) or early-termination data (OCTAVE Sustain) determined eligibility. Pts in remission (total Mayo score ≤2, no individual subscore >1, rectal bleeding subscore 0) at Wk 52 of OCTAVE Sustain (central read) received tofacitinib 5 mg twice daily (BID) in the OLE study; all others received 10 mg BID. At Month 2, all pts had endoscopy, and induction non-responders with no clinical response were withdrawn. Incidence rates (IRs; unique pts with events per 100 pt-years [PY]) for adverse events (AEs) of special interest were calculated. Efficacy endpoints were derived from Mayo score (local read). RESULTS: Of 944 pts receiving ≥1 tofacitinib dose (for up to 5.5 years), 175 (18.5%) and 769 (81.5%) received 5 and 10 mg BID, respectively (454 and 1550 PY, respectively). 337 (35.7%) pts discontinued due to insufficient clinical response and 78 (8.3%) due to AEs excl. worsening UC. The most frequent AE class was infections and infestations (52.1%). The most frequent AEs were nasopharyngitis (20.3%) and worsening UC (19.5%). IRs (95% CI) for “Tofacitinib All” were: serious infections 1.61 (1.10, 2.27); herpes zoster (all) 3.35 (2.58, 4.27); major adverse cardiovascular events 0.15 (0.03, 0.44); malignancies excl. non-melanoma skin cancer (NMSC) 0.85 (0.50, 1.36); and NMSC 0.81 (0.46, 1.32), with no clustering of malignancy type. Table 1 shows AEs and IRs by dose. No new safety risks were identified. Table 2 shows efficacy data at Month 36. CONCLUSION: In pts with UC in the OLE study, no new safety risks emerged at 5.5 years vs earlier OLE analyses 2 or with tofacitinib in rheumatoid arthritis. Efficacy data continue to support long-term efficacy of tofacitinib 5 or 10 mg BID up to 36 months beyond OCTAVE Sustain.

INTRODUCTION: An unmet need exists to find effective therapy in more severe ulcerative colitis (UC) patients, especially those who have failed multiple therapies. The efficacy and safety of upadacitinib, a selective Janus Kinase 1 inhibitor, has been assessed in an 8-week double-blind, placebo-controlled, dose-ranging, phase 2b induction study in adult patients with moderately-to-severely active UC (U-ACHIEVE). 1,2 METHODS: In U-ACHIEVE, adult patients with moderately-to-severely active UC as determined by the Adapted Mayo Score (5-9 points and centrally-read endoscopy subscore 2-3) were randomized to receive extended-release upadacitinib 7.5, 15, 30, 45 mg once daily (QD) or placebo for 8 weeks. In the current sub-analysis, the efficacy of upadacitinib in more severe and/or more refractory patient populations was assessed. Patients who at baseline had failed ≥2 prior biologic agents, had pancolitis, and/or an Adapted Mayo score >7, were included. Pairwise comparisons between upadacitinib doses and placebo for the primary endpoint, clinical remission per Adapted Mayo Score at Week 8 (defined as stool frequency subscore ≤1, rectal bleeding subscore = 0, and endoscopic subscore ≤1) and secondary endpoints were conducted using the Fisher's Exact test and no multiplicity adjustments were applied. Non-responder imputation was utilized for missing values. RESULTS: At baseline, 142 (56.8% of the total study population) patients had failed ≥2 prior biologics, 135 (54.0%) patients had pancolitis, and 90 (36.0%) patients had an Adapted Mayo score >7. The proportions of patients achieving endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were significantly higher (nominal P -value < 0.05) with upadacitinib doses ≥30 mg QD versus the placebo group in patients who failed ≥2 biologics or had pancolitis at baseline (Table 1). Trends of higher proportions of patients achieving clinical remission per Adapted Mayo score, endoscopic improvement, clinical response per Adapted Mayo score, and clinical response per Partial Mayo score were observed with all upadacitinib groups versus placebo in all the sub-analyses. CONCLUSION: In this dose-ranging induction study, upadacitinib demonstrated greater efficacy compared to placebo with dose response in the more severe and refractory population; significantly greater efficacy was demonstrated with upadacitinib at doses ≥30 mg QD for most of the endpoints evaluated.

INTRODUCTION: There are multiple assays for infliximab (IFX) trough level (IFX-TL) and antibody (ATI) measurement. The aims of this study are to examine the correlation and outcomes of IFX-TL and ATI measured with liquid chromatography-tandem mass spectrometry (LC-MS/MS) and electrochemiluminescence (ECLIA) in inflammatory bowel disease (IBD) patients. METHODS: This was a prospective study of IFX-treated IBD patients undergoing drug monitoring with an ECLIA panel (Esoterix Laboratories). Residual serum samples were used to simultaneously quantify IFX-TL via LC-MS/MS and ATI via an in-house ECLIA (iECLIA) (Mayo Clinic). Both LC-MS/MS and iECLIA have been previously validated. Primary outcomes: IFX-TL and ATI comparison between the two assays. Secondary outcomes: association of IFX-TL and ATI with clinical remission, mucosal healing (MH) (absence of ulcers in Crohn's disease and Mayo endoscopic score ≤1 for ulcerative colitis) and normal serum C-reactive protein (CRP ≤8 mg/L). RESULTS: A total of 151 patients were included (median age 32 years (12-84), 45.7% female) (Table 1). Median IFX-TL was 7 mcg/mL (IQR: 1.3, 19.4) and 6 mcg/mL (IQR: 0.9, 20) via LC-MS/MS and ECLIA, respectively (Spearman correlation coefficient r = 0.975). Median IFX-TL via LC-MS/MS was not significantly different between patients in clinical remission, response and no response (5.7 vs. 8.4 vs. 2.3 mcg/mL, respectively; P = 0.46), but significantly higher in patients who had a normal CRP (11.1 vs. 1.4 mcg/mL; P < 0.001) and in those who achieved MH (13.1 mcg/mL vs. 3.9 mcg/mL; P = 0.01). ATI was detected in 13/142 (9.2%) via iECLIA and 39/151 (25.8%) via ECLIA. The frequency of ATI detection via iECLIA was lower in patients in clinical remission or response than no response (7.3% vs. 9.3% vs. 15.4%; P = 0.68). On the contrary, the frequency of ATI detection via ECLIA was higher in patients with clinical remission (35.7%) than response (18.7%) and comparable to patients who had no clinical response (40%) ( P = 0.05) (Table 2). The frequency of ATI was not significantly different between patients who did and did not achieve MH or had normal CRP using both assays (Table 2). CONCLUSION: IFX-TL was comparable between LC-MS/MS and ECLIA assays. IFX-TL correlated with MH and normal CRP but not clinical remission. Frequency of ATI detection was not significantly associated with outcomes via both methods. ATI detected via iECLIA showed a trend towards correlation with clinical outcomes compared to ECLIA.

INTRODUCTION: Combination immunomodulator (IMM) with infliximab (IFX) has been shown to be superior to IFX monotherapy therapy in the management of inflammatory bowel disease (IBD). It is unclear if this is related to IMM solely or higher IFX trough level (IFX-TL). The aims of this study are to examine the correlation of IFX-TL with clinical outcomes of IBD patients and to evaluate whether IFX-TL or combination IMM therapy correlate best with mucosal healing (MH). METHODS: This is a retrospective study of consecutive IFX treated IBD patients undergoing drug monitoring with liquid chromatography-tandem mass spectrometry (LC-MS/MS). IMM included either thiopurines or methotrexate. Primary analyses included: comparing IFX-TL with clinical remission, MH (absence of mucosal ulcers in Crohn's disease (CD) and Mayo endoscopic score ≤1 for ulcerative colitis (UC)) and normal c-reactive protein (CRP ≤8 mg/L). Secondary analyses included determining an IFX-TL cut off to achieve MH and evaluating the predictors of MH (IMM vs. IFX-TL). RESULTS: A total of 151 patients were included (67% CD, 24% UC, 6% indeterminate colitis, 3% pouchitis) (Table 1). The median IFX-TL was 7 mcg/mL (IQR: 1.3, 19.4). The distribution of IFX-TL was not significantly different between patients in clinical remission, response and no response (median: 5.7 vs. 8.4 vs. 2.3 mcg/mL, respectively; P = 0.46). The median IFX-TL was significantly higher in patients who had a normal CRP (11.1 vs. 1.4 mcg/mL; P < 0.001) and in those who achieved MH (13.1 mcg/mL vs. 3.9 mcg/mL; P = 0.01). An IFX-TL ≥7.5 mcg/mL predicted MH with a sensitivity of 67% and specificity of 64% (AUC = 0.67; Figure 1). Combination therapy was associated with higher IFX-TL (median: 15.8 vs. 4.6 mcg/mL; P < 0.001). In a multivariable model to predict MH based on IFX-TL (continuously), combination therapy (yes vs no), dosing frequency (≥8 vs <8 weeks), and albumin (<3.5 vs ≥3.5), higher IFX-TL was associated with higher likelihood of MH (OR for 5-mcg/mL increase: 1.18, 95% CI 1.01-1.39; P = 0.04). In this model, IMM combination was not significant (OR: 0.79, P = 0.66), neither was dosing frequency (OR: 1.44, P = 0.48). Low albumin showed lower likelihood of MH, but this was not statistically significant (OR 0.14, 95% CI: 0.02-1.16, P = 0.07). CONCLUSION: IFX-TL was associated with normal CRP and MH but not clinical remission in this cohort of IBD patients. IFX-TL and not combination IMM therapy was independently associated with MH.