Long-term Crohn's Disease Research Articles

Therapeutic sequencing in inflammatory bowel disease: Determining the optimal position of vedolizumab for long-term Crohn's disease control using real-world evidence.

Several biologics are available for the treatment of moderate to severe Crohn's disease, but data to optimize their use are scarce. Vedolizumab (VDZ) is a gut-selective anti-lymphocyte trafficking monoclonal antibody that was approved in 2014 for the treatment of moderate to severe Crohn's disease. Based on real-world evidence, a model was developed to examine the effect of VDZ's position in the treatment sequence on clinical outcomes. The aim of this study was to develop a model using real-world data to investigate how the positioning of VDZ in a sequence of biologic therapies for CD affects clinical effectiveness outcomes of quality-adjusted life-years (QALYS), patient-reported disease activity, and surgery rates. A semi-Markov sequential model was developed to identify the optimal position of VDZ in a treatment sequence that included corticosteroids (CS), two biologics, and best supportive care (BSC). Using real-world data, three sequences were compared: VDZ as first (position), second, and last biologic (with anti-tumor necrosis factor alpha agents adalimumab (ADA) and infliximab (IFX) and the anti-interleukin-12 and -23 agent ustekinumab (UST) as alternative biologic treatments). Published real-world evidence informed model inputs. Vedolizumab sequences were compared and ranked based on QALYS, patient-reported outcomes from Crohn's disease activity index scores, or proportion of patients undergoing surgery by the 10-year time horizon for model simulation. Sensitivity analyses were used to evaluate the impact of model input uncertainty. Vedolizumab as the first biologic was the optimal position for this treatment according to all criteria, including yielding the highest QALYs (5.09) versus VDZ in second (4.97) and third (4.96) biologic sequence positions in sequences containing CS, anti-TNFα (aggregated data), UST, and BSC; 1780/2000 (89%) probabilistic simulations. In sequences containing ADA, VDZ, and UST biologics, ADA and VDZ in the first-line biologic position yielded QALYs of 5.09 versus 5.07, respectively. Adalimumab as the first biologic was best for clinical remission. This simulation model using real-world evidence indicates that positioning VDZ or ADA as the first biologic is likely to lead to improved long-term patient outcomes when compared to administering these treatments later or starting with IFX monotherapy.

Within-network brain connectivity in Crohn's disease patients with gadolinium deposition in the cerebellum.

Patients with Crohn's disease (CD) undergo multiple gadolinium-based contrast agent injections across their lifespan to enhance signal intensity of the intestinal wall and differentiate active from quiescent inflammatory disease. Thus, CD patients are prone to gadolinium accumulation in the brain and represent a non-neurological population to explore gadolinium-related brain toxicity. Possible effects are expected to be greater on the cerebellar network due to the high propensity of the dentate nucleus to accumulate gadolinium. Herein, we provide a whole-brain network analysis of resting-state fMRI dynamics in long-term quiescent CD patients with normal renal function and MRI evidence of gadolinium deposition in the brain. Fifteen patients with CD and 16 healthy age- and gender-matched controls were enrolled in this study. Relevant resting-state networks (RSNs) were identified using independent component analysis (ICA) from functional magnetic resonance imaging data. An unpaired two-sample t test (with age and sex as nuisance variables) was used to investigate between different RSNs. Clusters were determined by using threshold-free cluster enhancement and a family-wise error corrected cluster significance threshold of p < 0.05. Patients showed significantly decreased resting-state functional connectivity (p < 0.05, FWE corrected) of several regions of the right frontoparietal (FPR) and the dorsal attention (DAN) RSNs. No differences between the two groups were found in the functional connectivity maps of all the other RSNs, including the cerebellar network. Our findings suggest a non-significant impact of gadolinium deposition on within-network cerebellar functional connectivity of long-term quiescent CD patients.

Assessment of Bowel Inflammation and Strictures by Magnetic Resonance Enterography in Long-term Crohn's Disease.

Crohns disease [CD] is a chronic inflammation in the gut that often progresses to fibrosis. Magnetic resonance enterography [MRE] is an important diagnostic tool in evaluating CD. We aimed to assess the prevalence of inflammation and stricturing disease in patients with long-term CD, and to investigate associations with clinical factors. We performed a follow-up analysis of a population-based cohort of 237 CD patients in south-eastern Norway 20 years after diagnosis; 95 patients were examined with MRE, and the magnetic enterographic global score [MEGS] was calculated. We assessed inflammation and strictures during the follow-up. Association of the MEGS and bowel strictures with clinical variables was examined by univariate regression analysis. Of the 237 patients, 62 [65.3%] had active inflammation mostly affecting the terminal ileum; 35 [36.8%] had substantial inflammation according to MEGS, which associated with inflammatory biomarkers during the follow-up; and 25 [26.3%] had stricturing disease that associated with age (odds ratio [OR] = 0.92), initial use of systemic steroids [OR = 3.36], and inflammatory biomarkers. Most patients with strictures were treated with surgery without recurrence [n = 24, 42.1%] and seven [21.2%] strictures in the terminal ileum healed without surgery. Twenty years after the diagnosis, the majority of patients had active inflammation, often complicated by stricturing disease. Most patients with strictures were treated with surgery without recurrence, and some strictures resolved over time. Inflammatory biomarkers, extensive and complicated disease type, and use of systemic medication associated with both inflammation and stricturing disease.

Efficacy and tolerability of certolizumab pegol in Crohn's disease in clinical practice.

To assess the efficacy and tolerance of certolizumab pegol (CP) in patients with Crohn's disease (CD) treated in the Department of inflammatory bowel diseases of the A.S. Loginov Moscow Clinical Research Center and to determine the predictors of response to therapy. All patients with CD who had received the treatment of CP were observed prospectively for at least 6 months or until the date of discontinuation of the drug. The effectiveness of the study was assessed response to therapy by the 6th week, maintaining the clinical response (6th and 26th weeks), the dynamics of endoscopic parameters by the 10th and 54th week of therapy, long-term maintenance of remission, healing fistula. Used univariant and multivariate analyses of predictors of response to treatment. The study included 39 patients: 12 (30.7%) men and 27 (69.3%) female, the average duration of observation was 104 weeks. The interdepartmental range was in the range from 28 to 158 weeks. Clinical improvement occurred in 38 out of 39 (97.4 %) patients with CD. Comparative analysis of response to treatment with CP have bionaive patients previously treated with another inhibitor of TNF-α. In the group of bionaive response to therapy in a month, 6 months and at the end of the observation period occurred at 100.0%, 95.0% and 95.0%, respectively. In the group of patients previously treated with GSI, the response rate was about 94.4 %, 88.9 % and 77.7% week 54 endoscopic response and endoscopic remission was maintained in 46,2% and 30,1% patients, complete healing of the mucosa on the background of maintenance therapy, CP, was preserved in 20.5% of patients with Crohn's disease. In the group of patients with perianal lesions (n=13) complete closure of all fistulas was observed in 5 (38.6 %) patients, partial response was observed in 4 patients (30,7%) patients, in 4 (30.7 %) closure of fistulas occurred. The frequency of adverse events was 0 cases (0.0%). The dose escalation was required in 3 patients (7,7%) patients with CD. Dose escalation in our study required patients with high initial CDAI and previous inefficiencies of the other two inhibitors of TNF-α. Reliable predictors of secondary loss of response and need for dose escalation of the drug has been the continued level of CRP &gt;5 mg/l after 2 weeks initiation of therapy CP and smoking. The obtained results demonstrate the efficacy and tolerability profile of CP appropriate for long-term CD therapy in real clinical practice.

Fourteen-Year Anti-TNF Therapy in Crohn's Disease Patients: Clinical Characteristics and Predictive Factors.

Crohn's disease (CD) is an intractable disease that requires long-term treatment. Tumor necrosis factor (TNF) inhibitors have strong efficacy and are widely used for CD treatment. However, a loss of response is one of the issues in long-term TNF therapy. To identify the factors affecting the efficacy of long-term CD treatment with TNF inhibitors, we conducted a retrospective study of treatment outcomes and clinical factors using clinical data over a 14-year period. Clinical characteristics and factors for surgery, hospitalization, and TNF inhibitor treatment discontinuation were examined in 219 biologic-naïve patients who were treated with TNF inhibitors at our hospital before October 2014. Treatment persistence rates with no hospitalization, surgery, or dose escalation were 60.7, 25.9, and 17.3% for 1, 5, and 10years, respectively; these rates did not differ between infliximab (IFX) and adalimumab. In patients receiving IFX dose escalation, 1- and 5-year persistence rates were approximately 90.4 and 65.1%, respectively. Previous surgery (OR=1.45, P=0.043) was identified as a risk factor for surgery, male sex (OR=0.70, P=0.044) and previous surgery (OR=1.51, P=0.03) were risk factors for hospitalization, and perianal fistula (OR=1.39, P=0.049) was the risk factor for TNF inhibitor treatment discontinuation. The durability of anti-TNF therapy in CD patients remains a problem, and treatment optimization that includes dose escalation should be carefully examined depending on patient characteristics and the timing of optimization.

Examining Patient Decision-Making Surrounding Biologic Therapies in Inflammatory Bowel Disease: Insights from a Conjoint Analysis Survey

Introduction: Recent drug approvals have increased the availability of biologic therapies for inflammatory bowel disease (IBD). The growing number of biologics has made it increasingly difficult for patients to navigate treatment options and to ultimately select the most appropriate therapy. In this study, we examined patient decision-making surrounding IBD biologic therapies using conjoint analysis, a form of tradeoff analysis that determines how respondents make complex decisions by presenting them with competing product profiles. Methods: We performed a conjoint analysis survey that quantified the relative importance of 9 biologic therapy attributes (see Figure) in the decision-making process. We partnered with a survey research firm to recruit IBD patients to complete the survey. The conjoint analysis software determined each individual's preferences by calculating importance factors called partworth utilities for each biologic therapy attribute (higher part-worth utility=more important factor in decision-making process). We also conducted regression analyses to determine if patient demographics and IBD characteristics (e.g. type of IBD, severity, etc.) predicted importance of tested attributes. Results: 274 and 269 patients with ulcerative colitis (UC) and Crohn's disease (CD), respectively, completed the conjoint survey (Table). The primary determinants of decision-making differed between UC and CD patients as shown in the Figure. In regression analyses, demographic and IBD characteristics largely did not predict part-worth utility scores for the tested attributes; the main exception was IBD type. When compared to UC patients, those with CD were significantly more likely to attribute more importance to short-term improvement rates, risk of serious infection, and tolerability of side effects in the decision-making process (all p < .01). Conversely, those with UC were more likely to value mode of administration, long-term remission rates, and rash vs. CD patients (all p < .01). No differences were seen between UC and CD patients for lymphoma risk, fatigue, or mechanism of action (all p>.05). Conclusion: The determinants of decision-making surrounding IBD biologic therapies varied considerably between those with UC and CD. Moreover, patient demographics and IBD characteristics poorly predicted decision-making. This suggests the benefit of tailored decision tools to support patient choice of IBD therapy, which may be accessed either online or via mobile devices.Table 1: Study population demographics.Figure 1

Su1197 Recurrence and Long Term Evolution of Small Bowel (SB) Lesions After Curative Ileo-Colon Resection in Crohn's Disease (CD) Patients: A Prospective Follow-up Study

Previous radiological and endoscopic studies limiting their assessment to luminal alterations and/or upper GI and terminal ileum, and performed at patients or investigators' discretion could not provide a systematic prospective evolution of long-term CD SB lesions .Small intestine contrast ultrasonography (SICUS) is as accurate as (a) endoscopy to assess in operated patients the presence and severity of CD recurrence (1) and (b) surgery to assess the presence and extension of SB CD lesions (2). Aim. To assess, by means of SICUS in CD patients submitted to curative ileo-colonic resection and treated with immunosuppressive or biological therapy, the onset and long-term evolution of SB CD lesions in comparison to no, or mesalazine, therapy (not treated patients). Subjects and Methods. Follow-up (FU) visits and SICUS were carried out 6-12 monthly for 65±35.3 months in 60 operated patients (M 36, age at diagnosis 34.5±14 yrs); non treated patients 36/60. SICUS was performed after the ingestion of 375 ml of macrogol contrast solution as previously described (1). Results. Neo-terminal ileal recurrent lesions occurred in 48/60 (80%) patients at 20±21.8 months after surgery. No recurrence was detected in 9/36 of non treated patients (FU 54±38.5 months, range 12-120). Non-treated and treated patients did not differ in terms of median age at diagnosis (33 vs 31.5 yrs), extension of ileo-colonic resection (40 vs 25.5 cm) and time interval between surgery and first visit (6 vs 6.5 months). Median length of FU was longer in treated vs not-treated patients (69 vs 42 months, p=0.03). In not-treated patients recurrent lesions occurred in 16/27 after ≤ 12 months with a mean extension of 8.3±9.4 cm (last FU extension 12±10.4 cm), in 3/27 after ≤ 24 months with a mean extension of 19.8±19.8 cm (last FU extension 28±33 cm), in 1/27 after ≤ 36 months with an extension of 4 cm (last FU extension 4 cm), in 2/27 after ≤ 48 months with a mean extension of 4.8±2 cm (last FU extension 10.5±6.5 cm) and in 5/27 after . 48 months with a mean extension of 2.3±2.5 cm (last FU extension 4.5±2.3 cm). In treated patients recurrent lesions occurred in 15/21 after ≤ 12 months with a mean extension of 9±7 cm (last FU extension 8.5±9.5 cm), in 1/21 after ≤ 24 months with a extension of 10 cm (last FU extension 0.5 cm), in 2/21 after ≤ 36 months with a mean extension of 6.5±0.7 cm (last FU extension 18±7 cm), in 3/21 after ≤ 48 months with a mean extension of 1.4±1.3 cm (last FU extension 4.2±6.8 cm). Conclusions. SB CD recurrence occurred in 80% of the operated patients, more than 50% within the first year. An early recurrence of CD lesions appears to be associated with a greater extension compared to a later recurrence and immunosuppressive and biological therapies appear to delay the evolution of CD SB lesions. 1) Pallotta N et al BMC gastroenterology 2010;2) Pallotta N et al IBD 2012

Factors affecting outcomes in Crohn's disease over 15 years

Crohn's disease (CD) progression is marked by the occurrence of stricturing complications or intestinal and perianal penetrating complications, typically requiring surgery.1 ,2 We previously reported three factors at the time...