Impact of upadacitinib induction and maintenance therapy on health-related quality of life, fatigue, and work productivity in patients with moderately-to-severely active Crohn's disease.

BACKGROUND AND AIMS: Quality of life in patients with active Crohn's disease may be significantly reduced. We evaluated the effects of upadacitinib induction and maintenance therapy on fatigue, quality of life, and work productivity in the phase 3 trials U-EXCEL, U-EXCEED, and U-ENDURE. METHODS: Clinical responders to upadacitinib 45 mg in U-EXCEL and U-EXCEED induction trials were re-randomized 1:1:1 to upadacitinib 30 mg, 15 mg, or placebo for 52 weeks of maintenance in U-ENDURE. Clinically meaningful improvements in Inflammatory Bowel Disease Questionnaire (IBDQ) response, IBDQ remission, Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue), and Work Productivity and Activity Impairment were evaluated. Percentages of patients achieving clinically meaningful improvements were assessed at induction Weeks 4 and 12 and maintenance Week 52. RESULTS: Analysis included 1021 and 502 patients assessed at induction and maintenance, respectively. In U-EXCEL, greater improvements (all p≤0.001) in IBDQ response (71.0% vs 50.2%), IBDQ remission (44.2% vs 23.7%), and FACIT-Fatigue (42.0% vs 27.0%) were observed in upadacitinib-treated patients versus placebo at Week 4. Improvements in IBDQ response, IBDQ remission, and FACIT-Fatigue were similar or greater at Week 12. Clinically meaningful improvement in overall work impairment (52.1% vs 38.1%, p≤0.05) was demonstrated at Week 12. Similar results were observed in U-EXCEED. Improvements were sustained through 52 weeks of upadacitinib maintenance treatment. CONCLUSIONS: In patients with active Crohn's disease, upadacitinib treatment relative to placebo significantly improved fatigue, quality of life, and work productivity as early as Week 4. These effects were sustained through 52 weeks of maintenance.

Efficacy and Safety of Dual Biologic Therapy in Patients With Inflammatory Bowel Disease: A Review of the Literature.

Using 2 or more treatment modalities to achieve a synergistic effect in patients with refractory inflammatory bowel disease (IBD) has been an area of focus for many years. This methodology, known as combination therapy, has been proposed for various therapeutic agents, most commonly biologics and immunomodulators. Although the mainstay of biologic therapy for IBD has traditionally focused on agents targeting tumor necrosis factor, the development of newer biologics with different targets, such as vedolizumab and ustekinumab, has introduced the possibility of concomitant dual biologic therapy. Dual biologic therapy has been proposed in the treatment algorithm for 2 types of patients with IBD: those with well-controlled luminal IBD and uncontrolled extraintestinal symptoms (secondary indications such as arthritis or psoriasis) and those with refractory, uncontrolled IBD. Thus far, the data on the efficacy and safety of dual biologic therapy as a treatment for Crohn's disease or ulcerative colitis remain quite limited. In fact, the overwhelming majority of the literature consists of case reports and case series. Given this paucity of high-level data, physicians have looked to larger studies on dual biologic therapy in other fields of medicine, such as rheumatology and dermatology. The goal of this article is to summarize the current literature on the use of dual biologics in IBD, address the potential adverse effects or risks associated with combination therapy, and highlight future directions in the use of this therapeutic modality.

Dramatic Deep and Durable Remission of Acute Fulminant Ulcerative Colitis Achieved with Cyclosporine in a Patient Who Failed the Induction Intravenous Phase of Cyclosporine.

Medical rescue therapy for patients with severe steroid-refractory ulcerative colitis (UC) consists of intravenous (IV) cyclosporine or infliximab and remains limited. Cyclosporine is used by fewer medical facilities due to comfort and need for close drug level monitoring, despite evidence that it can have dramatic benefits. In many tertiary centers it is accepted that after 3-7 days of treatment with IV cyclosporine without response, a patient will not respond to the therapy, and other modalities, namely surgery, should be considered. We present the case of a 36-year-old man with acute severe UC refractory to steroids and multiple biologics, who "failed" IV cyclosporine for 2 weeks, much longer than the usually accepted induction phase, and achieved remission with continuation of oral cyclosporine. This case demonstrates the possibility that continued therapy with cyclosporine for a longer duration than the currently accepted timeline can lead to remission and avoidance of colectomy in properly selected and monitored patients.

Risk of Early Colorectal Cancers Needs to Be Considered in Inflammatory Bowel Disease Care.

BACKGROUND: Current guidelines recommend starting colorectal cancer (CRC) surveillance 8-10 years after inflammatory bowel disease (IBD) onset. Recent studies report that the incidence of CRC within 8-10 years of IBD onset (i.e., early CRC) ranges from 12 to 42%. AIMS: To describe the current prevalence of early CRC in a tertiary care center IBD cohort with CRC and to identify associated risk factors. METHODS: We performed a single-center observational study of IBD patients diagnosed with CRC from 2005 to 2015. We compared characteristics of patients with early CRC (diagnosis of CRC within 8 years of initial IBD onset) to those with CRC diagnosed later in their IBD course. RESULTS: Ninety-three patients met inclusion criteria. Eleven (11.8%) patients developed CRC within 8 years of initial IBD onset. On multivariable logistic regression, age greater than 28 at IBD onset (adjusted OR 12.0; 95% CI 2.30, 62.75) and tobacco use (adjusted OR 8.52; 95% CI 1.38, 52.82) were significant predictors of early CRC. A validation cohort confirmed calibration and discrimination of the model. CONCLUSIONS: One out of every eight IBD patients with CRC developed their malignancy prior to the currently recommended timeframe for the initiation of surveillance colonoscopy. IBD onset at 28 years or older and tobacco use were identified as predictors of early CRC. Early CRC should be considered in discussions of cancer surveillance in this population. Prospective cohort studies are necessary to further analyze the impact of early CRC in IBD.

Delays in Initiating Post-operative Prophylactic Biologic Therapy Are Common Among Crohn's Disease Patients.

BACKGROUND: Studies have shown that prophylactic biologic therapy can reduce post-surgical Crohn's disease recurrence. AIMS: We aimed to identify the frequency of delay and risk factors associated with a delay in the initiation of prophylactic post-surgical biologic therapy in high-risk patients. METHODS: We performed a cohort study of Crohn's disease patients who underwent a bowel resection. We identified those at risk of recurrence and explored multiple characteristics for those with and without a delay post-operatively. RESULTS: A total of 84 patients were included in our analysis of which 69.0% had a greater than 4-week delay and 56.0% a greater than 8-week delay in post-surgical biologic prophylaxis. Publicly insured patients had a 100% delay in post-surgical prophylaxis initiation (p = 0.039, p = 0.003 at 4 and 8 weeks, respectively). Patients on a biologic pre-surgery were less likely to have a delay (p < 0.001) in post-operative prophylaxis. Care at an inflammatory bowel disease (IBD) center was associated with timely therapy when considering a post-operative immunomodulator or biologic strategy. CONCLUSIONS: There are a substantial number of delays in initiating post-operative prophylactic biologic therapy in high-risk patients. Identifying susceptible patients by insurance type or absence of pre-operative therapy can focus future improvement efforts. Additionally, consultation with IBD-specialized providers should be considered in peri-surgical IBD care.

Perianal Fistulas in Patients With Crohn's Disease, Part 1: Current Medical Management.

Despite significant advances in the treatment of luminal inflammatory bowel disease, the treatment of perianal fistulas remains a clinical challenge. Perianal fistulas are traditionally described using the Parks classification based on their relationship to the external and internal anal sphincters. Traditional therapy for perianal fistulas focuses on antibiotics such as metronidazole or ciprofloxacin. However, medical management has expanded over the years to include immunomodulators and, most recently, biologic agents. Newer techniques such as intrafistulous biologic injections are also being explored as potentially effective treatments for patients with fistulizing disease. Here, in the first of a 2-part series on perianal fistulas in patients with Crohn's disease, we discuss the anatomy and classification of perianal fistulas as well as current medical therapies, including antibiotics, immunomodulators, biologic agents, and novel therapeutic agents. The second part of the series will focus on the surgical modalities that are available for patients with perianal fistulas in addition to novel endoscopic techniques and future therapies that are being investigated for the treatment of fistulizing Crohn's disease.

Perianal Fistulas in Patients With Crohn's Disease, Part 2: Surgical, Endoscopic, and Future Therapies.

The treatment of perianal fistulas remains a clinical challenge despite the significant advances that have been made in the management of luminal inflammatory bowel disease. In combination with medical therapies, surgical management of perianal fistulas is important for both infection control and definitive repair. Older surgical techniques include the placement of draining and cutting setons and endorectal advancement flaps. Newer surgical techniques that utilize lasers and video-assisted technology are being studied to help patients with chronic, refractory perianal fistulas. In addition to surgical management, less-invasive endoscopic techniques, including endoscopic fistulotomy and endoscopic clipping, are being investigated. Looking forward, allogeneic and autologous adult mesenchymal stem cells are being evaluated to induce fistula healing and improve rates of fistula closure. Here, in the second of a 2-part series on perianal fistulas in patients with Crohn's disease, we discuss the current surgical management of perianal fistulas as well as newer endoscopic techniques and future therapies.

Risk Stratification for Prevention of Recurrence of Postoperative Crohn's Disease.

Although there have been significant advances in medical therapies to treat Crohn's disease, an estimated 50% of patients will require surgery within the first decade of disease duration. Of these patients, a substantial number will develop recurrent symptoms within the first postoperative year. To prevent disease recurrence, many physicians use postoperative prophylactic therapy. Randomized, controlled trials, although limited in number, have demonstrated that a prophylactic postoperative strategy is effective at reducing recurrence (both clinical and endoscopic) in high-risk patients. This article reviews the frequency of and risk factors for postoperative Crohn's disease recurrence and the current evidence in favor of postoperative Crohn's disease management strategies. Future studies must be conducted to establish a gold standard as to who should receive postoperative prophylaxis and which therapies and time course are ideal.

Premedication Use in Preventing Acute Infliximab Infusion Reactions in Patients with Inflammatory Bowel Disease: A Single Center Cohort Study.

BACKGROUND: Infliximab (IFX) is commonly used in patients with inflammatory bowel disease. One common side effect of IFX is an acute infusion reaction. Despite the lack of evidence supporting their use, clinicians use various premedications to prevent acute reactions. We evaluated the effectiveness of premedications in the prevention of acute IFX infusion reactions. METHODS: A retrospective cohort study was performed identifying patients with a diagnosis of inflammatory bowel disease who received IFX at our institution. Information about each IFX infusion was recorded, including the dose, infusion rate, use of premedications, and any reactions. Infusions were stratified into low and high risk. In the high- and low-risk groups, the relative risk was calculated for each premedication combination used in our institution. RESULTS: Seven hundred seventy-three patients were identified; 578 patients (7090 infusions) met inclusion criteria and were included for analysis. Nine hundred eighty-six high-risk infusions were isolated; 620 (62.8%) of these infusions were administered with premedications (diphenhydramine and/or hydrocortisone) and 53 (5.4%) reactions occurred. Six thousand one hundred four low-risk infusions were identified; 2253 (36.9%) of these infusions had premedications and 61 (1.0%) reactions occurred. In both groups, none of the premedications used resulted in a significantly lower reaction rate compared with no premedication use. CONCLUSIONS: In both the high- and low-risk cohorts in this study, premedication use was not effective in reducing the rate of acute IFX reactions. Given this, routine premedication use is not recommended without future randomized control trials to demonstrate efficacy.

Advances in the Diagnosis and Management of Colonic Dysplasia in Patients With Inflammatory Bowel Disease.

The prevalence of colorectal cancer (CRC) in inflammatory bowel disease (IBD) is estimated at 3.7%. Risk factors for CRC include more severe disease (as reflected by the extent of disease and the duration of poorly controlled disease), family history of CRC, pseudopolyps, primary sclerosing cholangitis, and male sex. In addition, both early and late onset of IBD have been shown to be risk factors in different studies. Most societal guidelines recommend initiation of surveillance colonoscopy at 8 to 10 years after IBD symptom onset, followed by subsequent surveillance in 1- to 2-year intervals. A recent paradigm shift has led to a focus on targeted biopsies using high-definition colonoscopy or chromoendoscopy rather than traditional white-light endoscopy, as most dysplasia has proven to be visible with these advances in technology. With this shift, endoscopic resection of focal dysplasia, rather than early recommendation for colectomy, has become commonplace. Future studies should focus on newer methods of dysplasia detection, along with comparative effectiveness trials, to determine the optimal approach. Individual risk stratification may also prove beneficial in determining optimal surveillance strategies and intervals.

IgA-coated E. coli enriched in Crohn's disease spondyloarthritis promote TH17-dependent inflammation.

Peripheral spondyloarthritis (SpA) is a common extraintestinal manifestation in patients with active inflammatory bowel disease (IBD) characterized by inflammatory enthesitis, dactylitis, or synovitis of nonaxial joints. However, a mechanistic understanding of the link between intestinal inflammation and SpA has yet to emerge. We evaluated and functionally characterized the fecal microbiome of IBD patients with or without peripheral SpA. Coupling the sorting of immunoglobulin A (IgA)-coated microbiota with 16S ribosomal RNA-based analysis (IgA-seq) revealed a selective enrichment in IgA-coated Escherichia coli in patients with Crohn's disease-associated SpA (CD-SpA) compared to CD alone. E. coli isolates from CD-SpA-derived IgA-coated bacteria were similar in genotype and phenotype to an adherent-invasive E. coli (AIEC) pathotype. In comparison to non-AIEC E. coli, colonization of germ-free mice with CD-SpA E. coli isolates induced T helper 17 cell (TH17) mucosal immunity, which required the virulence-associated metabolic enzyme propanediol dehydratase (pduC). Modeling the increase in mucosal and systemic TH17 immunity we observed in CD-SpA patients, colonization of interleukin-10-deficient or K/BxN mice with CD-SpA-derived E. coli lead to more severe colitis or inflammatory arthritis, respectively. Collectively, these data reveal the power of IgA-seq to identify immunoreactive resident pathosymbionts that link mucosal and systemic TH17-dependent inflammation and offer microbial and immunophenotype stratification of CD-SpA that may guide medical and biologic therapy.

The Cost-Effectiveness of Vedolizumab for Inflammatory Bowel Disease: A Review of the Current Literature.

The United States spends a greater share per gross domestic product on health care than any other developed country in the world. Cost-conscious, high-value care has an important role in the practice of medicine. Inflammatory bowel disease (IBD) affects 1.6 million people in the United States and is responsible for significant health care costs, with estimates as high as $31.6 billion annually, a large portion of which is attributable to the use of biologic therapies. As the number of therapeutic targets for IBD expands, gastroenterologists can anticipate the arrival of novel therapeutic agents on the market, and these may carry significant costs. Vedolizumab, a monoclonal antibody directed against the gut-selective integrin α4ß7, is a novel biologic agent approved for the treatment of Crohn's disease and ulcerative colitis. Cost-effectiveness is an area of research that aims to assess the added value (in terms of both cost and utility) of diagnostic or therapeutic interventions. This article reviews the current literature evaluating the cost-effectiveness of vedolizumab for the treatment of IBD.

Cerebral venous thrombosis in inflammatory bowel disease.

Cerebral venous thrombosis (CVT) is a rare but devastating complication of inflammatory bowel disease (IBD). Here we describe six IBD patients with cerebral venous thrombosis. The patients presented with hours to days of headache and were found to have venous thrombosis on imaging. Four of the six patients had ulcerative colitis and two had Crohn's disease. All six patients were treated with therapeutic anticoagulation. There were two deaths; one patient became comatose and died despite anticoagulation while the other recovered well from the sinus thrombosis but died after a bowel perforation 3 weeks later. This case series demonstrates the critical need for early recognition of neurological symptoms in patients with IBD during disease flares. It is important to recognize the clinical signs in order to start anticoagulation expeditiously and improve neurological outcomes.

Bone, inflammation, and inflammatory bowel disease.

Osteoporosis is a leading cause of morbidity in patients with inflammatory bowel disease (IBD). Bone loss is an early systemic process and occurs even before clinical disease manifests. Bone disease is attributed to vitamin D deficiency, steroid use, and/or systemic inflammation. In this review, we discuss the molecular pathways of bone loss mediated by inflammatory cytokines and other mediators. Further research will hopefully clarify the mechanisms of inflammation-induced bone loss in IBD and guide effective treatment modalities.

Chromoendoscopy-targeted biopsies are superior to standard colonoscopic surveillance for detecting dysplasia in inflammatory bowel disease patients: a prospective endoscopic trial.

OBJECTIVES: Patients with extensive, longstanding chronic ulcerative or Crohn's colitis face greater risks of developing colorectal cancer. Current standard surveillance relies on detecting dysplasia using random sampling at colonoscopy but may fail to detect dysplasia in many patients. Dye spraying techniques have been reported to aid in detecting otherwise subtle mucosal abnormalities in the setting of colitis. We prospectively compared dye-spray technique using methylene blue to standard colonoscopic surveillance in detecting dysplasia. METHODS: One hundred fifteen patients were referred to the Chromoendoscopy Study Group and prospectively screened for the study. One hundred two (64 M, 38 F) (79 UC 23 CC) patients meeting the inclusion criteria were enrolled. Following a standard bowel preparation, each patient was examined using standard office endoscopic equipment by three methods: (a) standard surveillance colonoscopy with four random biopsies every 10 cm (for a total of at least 32 samples); (b) a targeted biopsy protocol; and finally (c) methylene blue (0.01%) dye spray was segmentally applied throughout the colon and any pit-pattern abnormality or lesion rendered visible by the dye spray was targeted and biopsied. Each patient had a single examination, which included two passes of the colonoscope. Specimens were reviewed in a blinded fashion by a single gastrointestinal pathologist. The three methods were then compared with each patient serving as his or her own control. RESULTS: Targeted biopsies with dye spray revealed significantly more dysplasia (16 patients with low grade and 1 patient with high grade) than random biopsies (3 patients with low-grade dysplasia) (P= 0.001) and more than targeted nondye spray (8 patients with low-grade and 1 patient with high-grade dysplasia) (P= 0.057). Targeted biopsies with and without dye spray detected dysplasia in 20 patients compared with 3 using Method (a) (P= 0.0002, two-tailed exact McNemar's Test). There were no adverse events. CONCLUSIONS: Colonoscopic surveillance of chronic colitis patients using methylene blue dye-spray targeted biopsies results in improved dysplasia yield compared to conventional random and targeted biopsy methods. Accordingly, this technique warrants incorporation into clinical practice in this setting and consideration as a standard of care for these patients. The value of multiple random biopsies as a surveillance technique should be revisited.