Treat-to-target and sequencing therapies in Crohn's disease.

Crohn's disease (CD) is a chronic immune-mediated inflammatory condition which can negatively impact a patient's quality of life. The traditional management strategy for CD has focused on symptomatic control, however, this approach fails to prevent organ damage and to change the progressive course of this disease. Thus, the field has moved towards a treat-to-target strategy that includes identifying individualized objective targets, choosing a therapy based on individual factors that include disease severity and risk, closely monitoring disease activity at predefined time points, and optimizing therapies as needed. Due to the increasing number of therapies approved for CD, this review explores the various factors which should be considered in the sequencing of treatment options together with using the treat-to-target framework to control disease activity early in its course and provide holistic patient care.

Objective disease activity assessment and therapeutic drug monitoring prior to biologic therapy changes in routine inflammatory bowel disease clinical practice: TARGET-IBD.

BACKGROUND: Inflammatory bowel disease (IBD) treatment paradigms recommend objective disease activity assessment and reactive therapeutic drug monitoring (TDM) prior to changes in biologic therapy. We aimed to describe objective marker and TDM assessment in routine clinical practice prior to biologic therapeutic changes in adult IBD patients. METHODS: TARGET-IBD is a prospective longitudinal cohort of over 2100 IBD patients receiving usual care at 34 US academic or community centers enrolled between June 2017 and October 2019 who received biologic therapy and had a dose change or biologic discontinuation for lack of efficacy. Objective markers of disease activity within 12 weeks prior included fecal calprotectin, C-reactive protein (CRP), endoscopy, computed tomography (CT) and magnetic resonance imaging (MRI). TDM data for infliximab or adalimumab was obtained. RESULTS: 525 patients (71.4% Crohn's disease [CD], 28.6% ulcerative colitis [UC]) receiving biologic therapy underwent dose change (55.6%) or discontinuation (44.4%) for lack of efficacy. The majority were Caucasian (85.7%), 18-39 years old (52.2%), privately insured (81.5%), and at academic centers (73.7%). For dose changes, 67.5% had at least one objective disease activity assessment or TDM in the 12 weeks prior (CD 67.9%, UC 66.2%; P = 0.79). The most common objective marker was CRP in both CD (39.1%) and UC (54.5%). CRP and calprotectin were used significantly more in UC (P = 0.02 and P = 0.03). TDM was obtained in 30.7% (28.8% UC, 31.4% CD; P = 0.72) prior to dose change. For biologic discontinuation, 79.4% patients underwent objective assessment or TDM prior. In CD, CRP (46.3%) was most common, and CT (P = 0.03) and MRI (P < 0.001) were significantly more frequent than in UC. TDM was performed in 40.1% of patients (43.5% UC, 38.0% CD, P = 0.49) prior to discontinuation. Among all participants with dose change or discontinuation, endoscopy was performed in 29.3% with CD and 31.3% with UC. Academic care setting was associated with objective assessment before therapy change (OR 1.59, 95% CI 1.01-2.50). CONCLUSION: Nearly one-third of patients undergoing a biologic dose change or discontinuation do not undergo objective disease activity assessment or TDM. Assessment choice differs by disease. Future studies assessing the impact of such practices on long-term outcomes are needed.

Ustekinumab is more effective than azathioprine to prevent endoscopic postoperative recurrence in Crohn's disease.

BACKGROUND: Preventing postoperative recurrence (POR) is a major concern in Crohn's disease (CD). While azathioprine is an option, no data is available on ustekinumab efficacy in this situation. AIMS: We compared the effectiveness of ustekinumab versus azathioprine in preventing endoscopic POR in CD. METHODS: We retrospectively collected data from all consecutive CD patients treated with ustekinumab after intestinal resection in 9 centers. The control group (azathioprine alone) was composed of patients who participated in a randomized controlled trial conducted in the same centers comparing azathioprine alone or in combination with curcumin. Propensity score analyses (inversed probability of treatment weighting = IPTW) were applied to compare the two groups. The primary endpoint was endoscopic POR (Rutgeerts' index ≥ i2) at 6 months. RESULTS: Overall, 32 patients were included in the ustekinumab group and 31 in the azathioprine group. The propensity score analysis was adjusted on the main risk factors (smoking, fistulizing phenotype, prior bowel resection, resection length >30 cm and ≥2 biologics before surgery) and thiopurines or ustekinumab exposure prior to surgery making the two arms comparable (∣d∣ < 0.2). After IPTW, the rate of endoscopic POR at 6 months was lower in patients treated with ustekinumab compared to azathioprine (28.0% vs. 54.5%, p = 0.029). After IPTW, the rates of i2b-endoscopic POR (Rutgeerts' index ≥ i2b) and severe endoscopic POR (Rutgeerts' index ≥ i3) were 20.8% versus 42.5% (p = 0.066) and 16.9% versus 27.9% (p = 0.24), in the ustekinumab and azathioprine groups, respectively. CONCLUSION: Ustekinumab seemed to be more effective than azathioprine in preventing POR in this cohort of CD patients.

Sustained long-term benefits of patient support program participation in immune-mediated diseases: improved medication-taking behavior and lower risk of a hospital visit.

BACKGROUND: Patient support programs (PSPs) improve medication-taking behavior in the first 12 months of treatment for patients with immune-mediated diseases, but it is unknown if these benefits are sustained. As immune-mediated diseases continue to increase in prevalence and economic burden, understanding the potential value of PSPs in helping patients adhere to their long-term treatment plan and avoid costly hospital visits is crucial. Launched nationally in 2015, HUMIRA Complete (a PSP for adalimumab patients) provides an opportunity to study long-term effects of PSP participation, including the impact on medication-taking behavior and hospital visits. OBJECTIVE: To evaluate the sustained relationship between PSP participation, long-term medication-taking behavior, and hospital visits. METHODS: A longitudinal, retrospective matched-cohort study was conducted of patients initiating adalimumab between January 2015 and February 2016 with or without enrolling in the PSP, using patient-level data from the HUMIRA Complete PSP linked with Symphony Health claims. The sample included adult, commercially insured patients diagnosed with an indicated disease who were biologic-naive and had data available for ≥ 6 months before and ≥ 12 months after initiating adalimumab. Adherence (proportion of days covered) and hospital visits were assessed at 12, 24, and 36 months for patients with sufficient follow-up data. Multivariable generalized models estimated differences between cohorts, controlling for baseline characteristics and hospital visits. Duration of persistence and time to a hospital visit were compared using Kaplan-Meier analyses. Hazard ratios were estimated using multivariable Cox proportional hazards models. RESULTS: The matched cohort included 2,268 patients (1,134 per cohort), and patient attrition was similar across cohorts. The PSP cohort consistently demonstrated higher adalimumab adherence than the non-PSP cohort at 12 (64.8% vs. 50.1%, P < 0.0001; 29% greater), 24 (49.4% vs. 38.4%; P < 0.0001; 29% greater), and 36 (39.4% vs. 35.1%; P = 0.02; 12% greater) months. PSP participation was associated with a 30% lower hazard of discontinuation (P < 0.0001), and median duration of persistence was 4.8 months longer for the PSP cohort (13.2 vs. 8.4 months; P < 0.0001). The PSP cohort had lower rates of hospital visits at 12 (30% vs. 37%; P < 0.001; 19% lower), 24 (44% vs. 53%; P = 0.01; 17% lower), and 36 (55% vs. 65%; P < 0.01; 16% lower) months, and PSP participation was associated with a 25% lower hazard of a hospital visit (P < 0.0001). Median time to a hospital visit was 10.8 months longer for the PSP cohort (32.7 vs. 21.9 months; P < 0.0001). Findings were consistent across therapeutic areas: hazard of a hospital visit was 28%, 27%, and 37% lower for rheumatology, gastroenterology, and dermatology patients participating in the PSP (all P < 0.05). CONCLUSIONS: Patients with immune-mediated diseases receiving adalimumab and utilizing this PSP had improved long-term medication-taking behavior and lower risk of hospital visits, demonstrating the potential of PSPs to improve patient outcomes and lower the burden to the health care system. DISCLOSURES: Design, study conduct, and financial support for the study were provided by AbbVie Inc., which participated in the interpretation of data, review, and approval of the manuscript. Fendrick has received personal fees from Merck, AstraZeneca, Trizetto, Amgen, Lilly, AbbVie, Johnson & Johnson, and Sanofi; grants from the National Pharmaceutical Council, PhRMA, the Gary and Mary West Health Foundation, the states of New York and Michigan, the Laura and John Arnold Foundation, the Robert Wood Johnson Foundation, and the Agency for Healthcare Research and Quality; and equity in Zansors, Sempre Health, Wellth, and V-BID Health. Brixner has received consulting fees from AbbVie, Novartis, Xcenda, Elevar Therapeutics, Sanofi, UCB Pharma, and the Millcreek Outcomes Group. Rubin has received consulting fees from AbbVie, Abgenomics, Allergan Inc., Amgen, Celgene Corporation, Forward Pharma, Genentech/Roche, Janssen Pharmaceuticals, Merck & Co., Miraca Life Sciences, Mitsubishi Tanabe Pharma Development America, Napo Pharmaceuticals, Pfizer, Salix Pharmaceuticals Inc., Samsung Bioepis, Sandoz Pharmaceuticals, Shire, Takeda, and Target Pharmaceuticals; and research support from AbbVie, Genentech/Roche, Janssen Pharmaceuticals, Prometheus Laboratories, Shire, Takeda, and UCB Pharma. Mease has received grant/research support from AbbVie, Amgen, BMS, Celgene, Janssen, Lilly, Merck, Novartis, Pfizer, SUN Pharma, and UCB; consulting fees from AbbVie, Amgen, BMS, Boehringer Ingelheim, Celgene, Galapagos, Genentech, Gilead, GlaxoSmithKline, Janssen, Lilly, Novartis, Pfizer, SUN Pharma, and UCB; and has served on the speakers bureau for AbbVie, Amgen, Celgene, Janssen, Lilly, Novartis, Pfizer, and UCB. Liu has no financial conflict of interest. Davis is an employee of Medicus Economics, which received payment from AbbVie to participate in this research. Mittal is an employee and stockholder of AbbVie. This study used a cohort of patients previously described in Brixner D, Rubin DT, Mease P, et al. Patient support program increased medication adherence with lower total health care costs despite increased drug spending. J Manag Care Spec Pharm. 2019 Jul;25(7):770-79 (doi: 10.18553/jmcp.2019.18443). As such, the sample selection and select baseline characteristics and 12-month outcomes have been published previously; however, the hospital visit outcomes and the longer-term medication-taking behavior outcomes have not been previously published or presented.

Emerging treatment options for extraintestinal manifestations in IBD.

Extraintestinal manifestations (EIMs) are frequently observed in IBDs and contribute considerably to morbidity and mortality. They have long been considered a difficult to treat entity due to limited therapy options, but the increasing use of anti-tumour necrosis factors has dramatically changed the therapeutic approach to EIM in recent years. Newly emerging therapies such as JAK inhibitors and anti-interleukin 12/23 will further shape the available armamentarium. Clinicians dealing with EIMs in everyday IBD practice may be puzzled by the numerous available biological agents and small molecules, their efficacy for EIMs and their potential off-label indications. Current guidelines on EIMs in IBD do not include treatment algorithms to help practitioners in the treatment decision-making process. Herein, we summarise knowledge on emerging biological treatment options and small molecules for EIMs, highlight current research gaps, provide therapeutic algorithms for EIM management and shed light on future strategies in the context of IBD-related EIMs.

Cost-effectiveness analysis of a fecal microbiota transplant center for treating recurrent C.difficile infection.

OBJECTIVE: We assessed the cost-effectiveness of establishing a fecal microbial transplant (FMT) unit in Canada for the treatment of recurrent CDI. DESIGN: We performed a cost-effectiveness analysis to determine the number of patients with recurrent CDI needed to treat (NNT) annually to make establishing a FMT unit cost-effective. We compared treating patients for their second recurrence of CDI with FMT in a jurisdiction with a FMT unit, compared to being treated with antibiotics; then sent to a medical center with FMT available for the third recurrence. We used a willingness to pay threshold of $50,000 per quality-adjusted-life-year gained. RESULTS: The minimum annual NNT was 15 for FMT via colonoscopy, 17 for FMT via capsule, and 44 for FMT via enema compared with vancomycin, and 16, 18, and 47 compared with fidaxomicin, respectively. A medical center's minimum catchment area when establishing a FMT unit would have to be 56,849 if using FMT via colonoscopy, or 64,429 if using capsules. CONCLUSION: We report the minimum number of patients requiring treatment annually with FMT to achieve cost-effectiveness, when including start-up and ongoing costs. FMT is cost-effective in Canada in populations with a sufficient number of eligible patients, ranging from 15 to 47 depending on the FMT modality used. This is crucial for medical jurisdictions making decisions about establishing a FMT unit for the treatment of recurrent CDI. The cost-effectiveness can be generalized in other countries.

Abnormal Pouchogram Predicts Pouch Failure Even in Asymptomatic Patients.

BACKGROUND: Anastomotic complications after restorative total proctocolectomy with IPAA for ulcerative colitis alter functional outcomes and quality of life and may lead to pouch failure. Routine contrast enema of the pouch assesses anastomotic integrity before ileostomy reversal, but its clinical use is challenged. OBJECTIVE: The purpose of this research was to assess the relationship among preoperative clinical characteristics, abnormal pouchography, and long-term pouch complications. DESIGN: This was a retrospective chart review. SETTINGS: The study was conducted at a tertiary care center between 2000 and 2010. PATIENTS: Ulcerative colitis patients with IPAA undergoing pouchography before ileostomy closure were included. MAIN OUTCOME MEASURES: Patient demographics, incidence of pouch-related complications, and findings on pouchogram were recorded. Primary outcome was pouch failure, defined as excision or permanent diversion of the ileoanal pouch. Independent predictors of pouch failure were determined by multivariate regression. RESULTS: A total of 262 patients with ulcerative colitis were included. Contrast extravasation was seen in 27 patients (10.3%): 14 (51.9%) were clinically asymptomatic at the time of pouchogram. Six (22.2%) of 27 patients with extravasation developed pouch failure despite normalization of the pouchogram before ileostomy closure. Forty patients (15.3%) were found to have pouch-anal anastomotic stenosis; only 1 developed pouch failure. Pre-IPAA serum albumin and hemoglobin levels were inversely associated with contrast extravasation (serum albumin: OR = 0.42; hemoglobin: OR = 0.77; p < 0.05). Contrast extravasation was associated with delayed takedown operation (average = 67 d), increased risk (OR = 5.25; p < 0.01), and shorter time (median = 32.0 vs 72.5 mo; HR = 5.88; p < 0.05) to pouch failure, as well as increased risk of pouch-related complications (p < 0.05). LIMITATIONS: The study was limited by its retrospective nature and small number of patients who developed pouch failure. CONCLUSIONS: Pouchography before ileostomy takedown is useful in identifying patients with ulcerative colitis at risk for postoperative complications. Radiologic resolution of IPAA-related leak does not reliably predict healing; caution is warranted in this subgroup. See Video Abstract at http://links.lww.com/DCR/A818.

The Role of Cannabis in the Management of Inflammatory Bowel Disease: A Review of Clinical, Scientific, and Regulatory Information.

There is significant interest among patients and providers in using cannabis (marijuana) and its derivatives to treat a number of chronic illnesses, including inflammatory bowel disease. Despite the Schedule I classification of cannabis by the federal government, state governments have sought ways to make cannabis available for specific medical conditions, and some states have legalized cannabis outright. This white paper summarizes the preclinical data, clinical data, safety data, and the regulatory landscape as they apply to medical cannabis use in inflammatory bowel disease. Animal models of cannabinoid chemistry and physiology give evidence of anti-inflammatory, antidiarrheal, and nociceptive-limiting properties. Human studies have found benefit in controlling symptoms and improving quality of life, but no studies have established true disease modification given the absent improvement in biomarker profiles or endoscopic healing. Finally, this review describes the legal, regulatory, and practical hurdles to studying the risks and benefits of medical cannabis in the United States. 10.1093/ibd/izy319_video1 izy319.video1 5852852028001.

Vedolizumab as Induction and Maintenance for Inflammatory Bowel Disease: 12-month Effectiveness and Safety.

Background: Vedolizumab is approved for moderate to severe Crohn's disease (CD) and ulcerative colitis (UC). We present prospective, 1-year data of the real-world effectiveness and safety of vedolizumab in inflammatory bowel disease. Methods: Consecutive patients receiving vedolizumab for treatment of UC or CD with at least 14 weeks of follow-up, regardless of outcome, were included. Patients had clinical activity scores (Harvey-Bradshaw Index [HBI] or Simple Clinical Colitis Activity Index [SCCAI]) and inflammatory markers prospectively measured at baseline and weeks 14, 30, and 52. Clinical response was defined as a reduction ≥3 in HBI or SCCAI, clinical remission as HBI ≤4 or SCCAI ≤2, steroid-free remission as clinical remission without the need for corticosteroids, and mucosal healing (assessed at 6 months) as a Mayo endoscopic subscore of 0 or 1 or CD-SES <3. Results: A total of 132 patients were included: 61 (45%) male, 94 (71%) with CD, 42 (29%) with UC; 22% and 34% of CD and UC patients, respectively, achieved steroid-free remission by week 14. This increased to 31% in CD patients and plateaued at 35% in UC patients at 12 months. Increasing remission rates to 6 months were seen in patients with CD, but minimal improvements after 3 months of therapy occurred in those with UC. Mucosal healing was achieved in 52% of UC and 30% of CD patients. Most adverse events were minor; 74% remained on vedolizumab at 12 months. Conclusions: In this real-world study, vedolizumab demonstrated similar efficacy and safety seen in pivotal trials, with sustained clinical response in the majority of patients. Similar rates of response were seen in UC and CD patients. 10.1093/ibd/izx067_video1izx067_Video5754037470001.

Indicators of suboptimal biologic therapy over time in patients with ulcerative colitis and Crohn's disease in the United States.

This study assessed the occurrence of indicators for suboptimal biologic therapy among ulcerative colitis (UC) and Crohn's disease (CD) patients over time in the United States (US). Data from a large US claims database (2005-2013) were used to retrospectively identify patients with diagnosed with either UC or CD who were new biologic users. Indicators of suboptimal biologic therapy included: dose escalation during the maintenance phase, discontinuation of the initial biologic, switch to another biologic within 90 days following the last day of supply of the initial biologic, augmentation with a non-biologic systemic therapy, UC- or CD-related surgery, UC- or CD-related urgent care, and development of fistula (for CD only). Kaplan-Meier analyses were used. A total of 1,699 UC and 4,569 CD patients were included. Among UC patients, 51.1% and 90.9% experienced ≥1 indicator of suboptimal biologic therapy within 6 months and 36 months of biologic therapy initiation, respectively. Among CD patients, 54.3% and 91.4% experienced ≥1 indicator of suboptimal biologic therapy within 6 and 36 months of biologic therapy initiation, respectively. For both UC and CD patients, the most frequent indicators of suboptimal biologic therapy were discontinuation, dose escalation and augmentation. In conclusion, this study found that the occurrence of suboptimal biologic therapy is common among patients with UC and CD, with approximately 90% of patients experiencing at least one indicator of suboptimal biologic therapy within 36 months of biologic treatment initiation.

Patient perceptions of fecal microbiota transplantation for ulcerative colitis.

BACKGROUND: Fecal microbiota transplantation (FMT), the delivery of stool from a healthy prescreened donor to an individual with disease, is gaining increasing recognition as a potential treatment for inflammatory bowel diseases. Our objective was to describe patient interest in and social concerns around FMT. METHODS: We conducted a survey of adults with ulcerative colitis (UC) seen in outpatient clinic at the University of Chicago IBD Center. All English-speaking patients ≥18 years of age were eligible. Subjects completed a written survey in clinic. Ninety-five participants, median age 39 years, 53% female, were enrolled in the study. RESULTS: Forty-four percent and 49% reported excellent or good/satisfactory medical management of their UC, respectively. Forty-six percent participants were willing to undergo FMT as a treatment of UC, 43% were unsure, and 11% were unwilling to undergo FMT. Subjects who had been hospitalized were more willing to undergo FMT, 54% versus 34%, P = 0.035. Primary concerns included the following: adequate screening for infections (41%), cleanliness (24%), and potential to worsen UC (18%); 21% reported no specific concerns. For donor selection, an equal number of participants (46%) preferred whomever their doctor recommended or family member/spouse. CONCLUSIONS: In our center despite reporting satisfactory to excellent disease control with their treatments, the vast majority of patients with UC are interested in or willing to consider FMT. Proof of safety and effectiveness, and failure of other medical therapies are key issues in considering FMT. Strong interest in this as-yet unproven therapy warrants attention and is a pressing priority for clinical research and education.

Secondary gastrointestinal cancer in childhood cancer survivors: a cohort study.

BACKGROUND: Childhood cancer survivors develop gastrointestinal cancer more frequently and at a younger age than the general population, but the risk factors have not been well-characterized. OBJECTIVE: To determine the risk and associated risk factors for gastrointestinal subsequent malignant neoplasms (SMNs) in childhood cancer survivors. DESIGN: Retrospective cohort study. SETTING: The Childhood Cancer Survivor Study, a multicenter study of childhood cancer survivors diagnosed between 1970 and 1986. PATIENTS: 14 358 survivors of cancer diagnosed when they were younger than 21 years of age who survived for 5 or more years after the initial diagnosis. MEASUREMENTS: Standardized incidence ratios (SIRs) for gastrointestinal SMNs were calculated by using age-specific population data. Multivariate Cox regression models identified associations between risk factors and gastrointestinal SMN development. RESULTS: At median follow-up of 22.8 years (range, 5.5 to 30.2 years), 45 cases of gastrointestinal cancer were identified. The risk for gastrointestinal SMNs was 4.6-fold higher in childhood cancer survivors than in the general population (95% CI, 3.4 to 6.1). The SIR for colorectal cancer was 4.2 (CI, 2.8 to 6.3). The highest risk for gastrointestinal SMNs was associated with abdominal radiation (SIR, 11.2 [CI, 7.6 to 16.4]). However, survivors not exposed to radiation had a significantly increased risk (SIR, 2.4 [CI, 1.4 to 3.9]). In addition to abdominal radiation, high-dose procarbazine (relative risk, 3.2 [CI, 1.1 to 9.4]) and platinum drugs (relative risk, 7.6 [CI, 2.3 to 25.5]) independently increased the risk for gastrointestinal SMNs. LIMITATION: This cohort has not yet attained an age at which risk for gastrointestinal cancer is greatest. CONCLUSION: Childhood cancer survivors, particularly those exposed to abdominal radiation, are at increased risk for gastrointestinal SMNs. These findings suggest that surveillance of at-risk childhood cancer survivors should begin at a younger age than that recommended for the general population. PRIMARY FUNDING SOURCE: National Cancer Institute.

Prospective comparison of patient experience with colon imaging tests.

PURPOSE: Patient experience varies with the currently available colon imaging tests, including air contrast barium enema, computed tomographic colonography, and colonoscopy. We examined differences in patient experience with colon imaging tests and whether they varied with gender, age, and race. SUBJECTS AND METHODS: Patients with fecal occult blood, hematochezia, iron-deficiency anemia, or a family history of colon cancer underwent air contrast barium enema followed 7 to 14 days later by computed tomographic colonography and colonoscopy. Validated patient experience questionnaires that measured the experience for each test and a separate questionnaire that obtained an overall summary measure were administered after testing. Eleven patient experiences including pain, embarrassment, difficulty with bowel preparation, and satisfaction with tests were examined. RESULTS: A total of 614 subjects completed all 3 imaging tests. The test most patients were willing to repeat was colonoscopy; it also was reported to be the least painful procedure. Patients were least satisfied with air contrast barium enema, and fewer would undergo air contrast barium enema compared with computed tomographic colonography or colonoscopy. There were limited racial and gender differences in perceptions of the tests. Younger adults perceived air contrast barium enema to be more painful than older adults. CONCLUSION: Taking into account a wide variety of patient experience measures, patients preferred colonoscopy to air contrast barium enema and computed tomographic colonography. This finding has important implications for physicians considering different colon imaging tests.