Steroid-Free Deep Remission at One Year Does Not Prevent Crohn's Disease Progression: Long-Term Data From the TAILORIX Trial.

BACKGROUND & AIMS: Crohn's disease (CD) patients included in the Tailored Treatment With Infliximab for Active Crohn's Disease (TAILORIX) trial started infliximab in combination with an immunosuppressant for 1 year. The aim of the present study was to determine the long-term disease course beyond the study period. METHODS: We compared the outcomes of patients who did or did not reach the primary end point of the TAILORIX trial, defined as sustained corticosteroid-free clinical remission from weeks 22 through 54, with no ulcers on ileocolonoscopy at week 54. The primary outcome of this follow-up study was the progression-free survival of CD defined by anal or major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. RESULTS: The 95 patients (median disease duration, 4.5 mo; interquartile range, 1.0-56.6 mo) analyzed, including 45 (47%) who achieved the primary end point, were followed up for a median duration of 64.2 months (interquartile range, 57.6-69.9 mo) after the end of the study period. There was no significant difference in CD progression-free survival at 1, 3, and 5 years between patients who achieved the TAILORIX primary end point and patients who did not (P = .64). No difference was observed between both groups for each component of CD progression: anal surgery, major abdominal surgery, CD-related hospitalization, or the need for a new systemic CD treatment. CONCLUSIONS: Achieving a sustained clinical remission off steroids with complete endoscopic remission in this cohort of 95 patients with early CD was not associated with less disease progression. Prospective trials to define the therapeutic goals that change the natural history of CD and prevent complications are needed.

Increasing Infliximab Dose Based on Symptoms, Biomarkers, and Serum Drug Concentrations Does Not Increase Clinical, Endoscopic, and Corticosteroid-Free Remission in Patients With Active Luminal Crohn's Disease.

BACKGROUND & AIMS: A combination of infliximab and immunomodulators is the most efficacious treatment for Crohn's disease (CD). Patients have the best outcomes when their serum concentrations of these drugs are above a determined therapeutic threshold. We performed a prospective, randomized trial to determine whether therapeutic drug monitoring (TDM) to maintain serum levels of infliximab above 3 µg/mL produced higher rates of clinical and endoscopic remission than adapting dose based only on symptoms. METHODS: We performed a double-blind trial in which 122 biologic-naïve adult patients with active CD (71 female, median age 29.8 years) received induction treatment with infliximab in combination with an immunosuppressant, from July 2012 through September 2015 at 27 centers in Europe. At week 14 of treatment, patients were randomly assigned (1:1:1) to 3 infliximab maintenance groups: dose increases (2 maximum) in steps of 2.5 mg/kg based on clinical symptoms and biomarker analysis and/or serum infliximab concentrations (dose intensification strategy [DIS]1 group); dose increase from 5 to 10 mg/kg based on the same criteria (DIS2 group); dose increase to 10 mg/kg based on clinical symptoms alone (controls). Patients' CD activity index scores, levels of C-reactive protein, fecal levels of calprotectin, and serum concentrations of infliximab were determined at baseline and at weeks 2, 4, 6, 12, and 14 of treatment, and then every 4 weeks thereafter until week 54. The primary endpoint was sustained corticosteroid-free clinical remission (CD activity index <150) from weeks 22 through 54 with no ulcers at week 54. RESULTS: The primary endpoint was reached by 15 (33%) of 45 patients in the DIS1 group, 10 (27%) of 37 patients in the DIS2 group, and 16 (40%) of 40 patients in the control group (P = .50). CONCLUSIONS: In a prospective randomized exploratory trial of patients with active CD, we found increasing dose of infliximab based on a combination of symptoms, biomarkers, and serum drug concentrations does not lead to corticosteroid-free clinical remission in a larger proportion of patients than increasing dose based on symptoms alone. EUDRACT NUMBER: 2011-003038-14.

Is Crohn's Disease a Rightly Used Eponym?

In 1932 Burrill B. Crohn, a gastroenterologist at Mount Sinai Hospital in New York City, described, together with two surgical colleagues, a series of 14 patients with an inflammatory condition of the terminal ileum. All patients were operated on by Dr Albert Berg, the Chief Surgeon of the hospital, whose name did not appear on the initial publication. The 'new' disease was called 'regional ileitis', but was rapidly referred to as 'Crohn's disease'. From earlier accounts and publications it has become clear that the condition had already existed for many centuries and was 'discovered' several times before 1932, most notably by Giovanni Morgagni in 1769, Antoni Lesniowski in 1903 and Thomas K. Dalziel in 1913. 'Crohn's disease' might reasonably be known by another eponym. Nevertheless, the 1932 publication of Crohn was pivotal, as were his later contributions to the knowledge of 'his' disease. Therefore the worldwide use of the eponym is rightly to be continued. Present researchers and clinicians with an interest in inflammatory bowel disease [IBD] might learn from the complicated story summarised in this contribution. Apart from an interesting historical overview, there are some lessons for today: the importance of thorough clinical observation and pattern recognition, the need for communication between colleagues and multidisciplinary approaches, and the need for broad access to valuable data, past or present, regardless of the journal or language of publication. It should ultimately bring us some humility, despite great achievements in treating this chronic disease, which defies all our efforts yet to find a cure.

Early combined immunosuppression or conventional management in patients with newly diagnosed Crohn's disease: an open randomised trial.

BACKGROUND: Most patients who have active Crohn's disease are treated initially with corticosteroids. Although this approach usually controls symptoms, many patients become resistant to or dependent on corticosteroids, and long exposure is associated with an increased risk of mortality. We aimed to compare the effectiveness of early use of combined immunosuppression with conventional management in patients with active Crohn's disease who had not previously received glucocorticoids, antimetabolites, or infliximab. METHODS: We did a 2-year open-label randomised trial at 18 centres in Belgium, Holland, and Germany between May, 2001, and January, 2004. We randomly assigned 133 patients to either early combined immunosuppression or conventional treatment. The 67 patients assigned to combined immunosuppression received three infusions of infliximab (5 mg/kg of bodyweight) at weeks 0, 2, and 6, with azathioprine. We gave additional treatment with infliximab and, if necessary, corticosteroids, to control disease activity. 66 patients assigned to conventional management received corticosteroids, followed, in sequence, by azathioprine and infliximab. The primary outcome measures were remission without corticosteroids and without bowel resection at weeks 26 and 52. Analysis was by modified intention to treat. This trial was registered with ClinicalTrials.gov, number NCT00554710. FINDINGS: Four patients (two in each group) did not receive treatment as per protocol. At week 26, 39 (60.0%) of 65 patients in the combined immunosuppression group were in remission without corticosteroids and without surgical resection, compared with 23 (35.9%) of 64 controls, for an absolute difference of 24.1% (95% CI 7.3-40.8, p=0.0062). Corresponding rates at week 52 were 40/65 (61.5%) and 27/64 (42.2%) (absolute difference 19.3%, 95% CI 2.4-36.3, p=0.0278). 20 of the 65 patients (30.8%) in the early combined immunosuppression group had serious adverse events, compared with 19 of 64 (25.3%) controls (p=1.0). INTERPRETATION: Combined immunosuppression was more effective than conventional management for induction of remission and reduction of corticosteroid use in patients who had been recently diagnosed with Crohn's disease. Initiation of more intensive treatment early in the course of the disease could result in better outcomes.

Early Mucosal Healing Predicts Favorable Outcomes in Patients With Moderate to Severe Ulcerative Colitis Treated With Golimumab: Data From the Real-life BE-SMART Cohort.

Background: Golimumab (GOL) is registered for moderate to severely active ulcerative colitis (UC). Data on the use of GOL in daily clinical practice are limited. Currently, it is unclear which factors are predictive of a favorable outcome. The goals of this study were to evaluate the mid-term outcome of GOL (week 26) in patients with moderate to severe UC and to determine predictors of favorable outcome. Methods: Patients included in the SMART study (NCT02155335) were evaluated for their mid-term outcome. Demographic data, disease characteristics, and medical history were recorded retrospectively. Data on disease activity based on total Mayo score, previous and concomitant medication, GOL dosing, mucosal healing (Mayo 0 or 1), adverse events (colectomy, hospitalization), and biomarkers (C-reactive protein, fecal calprotectin, hemoglobin, and albumin) were collected at baseline and weeks 2, 6, 14, 26, and 52. GOL was dosed at 200 and 100 mg at weeks 0 and 2, respectively, and 50 mg (<80 kg body weight) or 100 mg (≥80 kg body weight) every 4 weeks thereafter. The primary end point was steroid-free GOL continuation at week 26. Results: From the 91 evaluable patients (42% female; median age, 42 years; median disease duration, 5 years), 4% were active smokers, 25% had extensive colitis, and 38% had an endoscopic Mayo score of 3 at baseline. The median (interquartile range [IQR]) baseline Mayo score was 9 (8-10). Although 75% of patients had previously failed immunomodulators (IMMs), the majority (87%) were anti-tumor necrosis factor (TNF) naïve. GOL was started in combination with IMM in 40% and steroids in 64%. The median (IQR) duration of GOL therapy during follow-up was 35.7 (11.4-105.7) weeks. Twenty-six weeks after GOL induction, 37 patients (41%) were steroid-free and still on GOL, of whom 8 (21.6%) required GOL dose optimization. Short-term mucosal healing (STMH) at week 14 was evaluated in 60% of the patients. Considering the whole cohort, only 40% achieved STMH. No predictors could be retained of short-term treatment outcome. In multivariate analysis, STMH was predictive of steroid-free GOL continuation at week 26 (odds ratio [OR], 5.56; 95% confidence interval [CI], 1.90-16.29; P = 0.002) and week 52 (OR, 9.38; 95% CI, 2.68-32.84; P < 0.001). In patients continuing GOL after week 14, STMH was predictive of intervention-free survival (OR, 2.05; 95% CI, 1.09-3.86; P = 0.026) and discontinuation-free survival (OR, 3.47; 95% CI, 1.58-7.58; P = 0.002). During follow-up, 78% needed an intervention, 68% discontinued GOL, and 3 patients needed a colectomy. Conclusions: Real-life data confirm the moderate effectiveness of GOL on the mid-term in active UC, but therapeutic interventions are frequently needed. Short-term mucosal healing predicts a favorable outcome. 10.1093/ibd/izy219_video1izy219.video15798038438001.

Long-term Clinical Effectiveness of Ustekinumab in Patients with Crohn's Disease Who Failed Biologic Therapies: A National Cohort Study.

BACKGROUND: Ustekinumab [UST] was recently approved in Europe for the treatment of moderate to severe Crohn's disease [CD]. Long-term real-world data are currently scarce for CD patients previously exposed to several biologics. METHODS: This is an observational, national, retrospective multicentre study. Patients received intravenous UST ~6 mg/kg at baseline, with 90 mg subcutaneously thereafter every 8 weeks. Response and remission rates were assessed at Weeks 8, 16, and 52. RESULTS: Data from 152 patients were analysed. All patients were exposed to at least one anti-TNFα agent, with 69.7% were exposed to even two anti-TNFα and vedolizumab. After 1 year, 42.1% and 25.7% of patients had experienced clinical response and clinical remission, respectively, and 38.8% and 24.3% had achieved steroid-free clinical response and remission, respectively; 38.8% of patients discontinued therapy during the 12 months of follow-up. Colonic location was predictive of clinical response at 1 year, and low body mass index [BMI] at baseline was a negative predictor of clinical remission. Resolution of arthralgia was associated with clinical response over time. De novo arthralgia was reported by 17.9% of patients at Week 8 and 13.5% of patients at Week 52. No impact of UST on arthralgia was observed in patients with concomitant ankylosing spondylitis [n = 17]. Others adverse events were reported in 7.2% of patients. CONCLUSIONS: This real-world cohort study confirms the effectiveness of UST in CD patients previously exposed to several biologics. Ustekinumab was well tolerated with respect to adverse events. PODCAST: This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.

Preference for a prefilled syringe or an auto-injection device for delivering golimumab in patients with moderate-to-severe ulcerative colitis: a randomized crossover study.

PURPOSE: Simponi® (golimumab, MSD) is a fully human monoclonal antibody against tumor necrosis factor alpha administered subcutaneously using an autoinjector or a prefilled syringe. This study examined preference for administration of golimumab by autoinjector or prefilled syringe in patients with moderate-to-severe ulcerative colitis (UC). PATIENTS AND METHODS: This was a multicenter, open-label, randomized crossover trial (EudraCT no 2014-000656-29). Patients with moderate-to-severe UC were randomized 1:1 to receive 2 subcutaneous injections of 50 mg golimumab with the autoinjector followed by 2 injections of 50 mg with the prefilled syringe or the same 4 injections administered in the opposite order. Patients assessed preference, ease of use, and discomfort immediately after the injections and 2 weeks later. RESULTS: Ninety-one patients were included (median age=42.7 years [range, 19.7-93.7]; 58% male). The autoinjector was preferred by 76.9% of patients immediately after injections and by 71.4% 2 weeks later. The autoinjector was more often considered extremely easy or easy to use (94.5%) than the prefilled syringe (73.6%). Moderate discomfort or worse was reported by more patients when using the prefilled syringe (20.9%) than when using the autoinjector (5.5%), and severe discomfort or discomfort preventing injection of future doses was reported by 8.8% for the pre-filled syringe but not at all when using the autoinjector. A favorable or extremely favorable overall impression was reported by 89.0% for the autoinjector and 72.5% for the prefilled syringe. CONCLUSION: Most patients with moderate-to-severe UC preferred to self-administer golimumab with the autoinjector over a prefilled syringe.

Consecutive fecal calprotectin measurements to predict relapse in patients with ulcerative colitis receiving infliximab maintenance therapy.

BACKGROUND: This study examined whether fecal calprotectin can be used in daily practice as a marker to monitor patients with ulcerative colitis (UC) receiving infliximab maintenance therapy. METHODS: This prospective multicenter study enrolled adult patients with UC in clinical remission under infliximab maintenance therapy. Fecal calprotectin levels were measured every 4 weeks. Sigmoidoscopies were performed at inclusion and at study end. Relapse was defined as a clinical need for change in treatment or an endoscopic Mayo subscore of ≥2 at week 52. Sustained deep remission was defined as a partial Mayo score <3 at all points and an endoscopic Mayo score 0 at week 52. RESULTS: Full analysis was possible for 87 of 113 included patients with UC (77%). Of these patients, 30 (34.4%) were considered to be in sustained deep remission and 13 (14.9%) to have relapsed. Calprotectin levels in patients with sustained deep remission remained very low (median < 40 mg/kg at all time points). Patients who flared had significantly higher calprotectin levels (median > 300 mg/kg) already 3 months before the flare. Further receiver operator curve analysis suggested that a calprotectin level >300 mg/kg had a reasonable sensitivity (58.3%) and specificity (93.3%) to model flare. Two consecutive calprotectin measurements of >300 mg/kg with 1-month interval were identified as the best predictor of flare (61.5% sensitivity and 100% specificity). CONCLUSIONS: Fecal calprotectin can be used in daily practice to monitor patients with UC receiving infliximab maintenance therapy. Two consecutive measurements >300 mg/kg is more specific than a single measurement for predicting relapse.