Aranzazu Jauregui-Amezaga

Accuracy of Magnetic Resonance Enterography in Assessing Response to Therapy and Mucosal Healing in Patients With Crohn's Disease

BACKGROUND & AIMS We assessed the accuracy of magnetic resonance enterography (MRE) in monitoring response to therapy in patients with Crohns disease (CD) using ileocolonoscopy as a reference standard. METHODS We performed a prospective multicenter study of 48 patients with active CD and ulcers in at least one ileocolonic segment. All patients underwent ileocolonoscopy and MRE at baseline and 12 weeks after completing treatment with corticosteroids (CS) or anti-tumor necrosis factor agents. Disease activity was quantified using Crohns Disease Endoscopic Index of Severity (CDEIS) and Magnetic Resonance Index of Activity (MaRIA). The primary analysis was to determine the accuracy of MRE in identification of healing, defined as the disappearance of ulcers in endoscopy examination. Additional analyses established the accuracy of MRE in determining endoscopic remission (a CDEIS score <3.5) and change in severity based on consideration of all segments. RESULTS MRE determined ulcer healing with 90% accuracy and endoscopic remission with 83% accuracy. The mean CDEIS and MaRIA scores significantly changed at week 12 in segments with ulcer healing, based on endoscopic examination (CDEIS: 21.28 ± 9.10 at baseline vs 2.73 ± 4.12 at 12 weeks; P < .001 and MaRIA: 18.86 ± 9.50 at baseline vs 8.73 ± 5.88 at 12 weeks; P < .001). The MaRIA score accurately detected changes in lesion severity (Guyatt score: 1.2 and standardized effect size: 1.07). MRE was as reliable as endoscopy in assessing healing; no significant changes in CDEIS or MaRIA scores were observed in segments with persistent ulcers, based on endoscopic examination (CDEIS: 26.43 ± 9.06 at baseline vs 20.77 ± 9.13 at 12 weeks; P = .18 and MaRIA: 22.13 ± 8.42 at baseline vs 20.77 ± 9.17 at 12 weeks; P = .42). The magnitude of change in CDEIS scores correlated with those in MaRIA scores (r = 0.51; P < .001). CONCLUSIONS MRE evaluates ulcer healing with a high level of accuracy when ileocolonoscopy is used as the reference standard. The MaRIA is a valid, responsive, and reliable index assessing response to therapy in patients with CD.

Characterization of inflammation and fibrosis in Crohn's disease lesions by magnetic resonance imaging.

Objectives:Measurement of the component of fibrosis in Crohn’s disease (CD) may have important therapeutic implications. The aim of this study was to characterize the Magnetic Resonance Imaging (MRI) findings that are differentially associated with the presence of fibrosis and those associated with inflammatory activity, using the pathological analysis of surgically resected intestinal lesions as reference standard.Methods:MRI studies with identical imaging protocol of 41 CD patients who underwent elective bowel resection within 4 months before surgery were reviewed. MRI evaluated wall thickening, edema, ulcers, signal intensity at submucosa at 70 s and 7 min after gadolinium injection, stenosis, and pattern of enhancement in each phase of the dynamic study and changes on this pattern over time. Pathological inflammatory and fibrosis scores were classified into three grades of severity.Results:In all, 44 segments from 41 patients were analyzed. The pathological intensity of inflammation was associated with the following MRI parameters: hypersignal on T2 (P=0.02), mucosal enhancement (P=0.03), ulcerations (P=0.01), and blurred margins (P=0.05). The degree of fibrosis correlated with the percentage of enhancement gain (P<0.01), the pattern of enhancement at 7 min (P<0.01), and the presence of stenosis (P=0.05). Using percentage of enhancement gain, MRI is able to discriminate between mild–moderate and severe fibrosis deposition with a sensitivity of 0.94 and a specificity of 0.89.Conclusions:MRI is accurate for detecting the presence of severe fibrosis in CD lesions on the basis of the enhancement pattern.

Risk of developing tuberculosis under anti-TNF treatment despite latent infection screening

BACKGROUND In patients treated with TNF-antagonists, incident cases of tuberculosis (TB) after a negative screening have been reported, leading to the suggestion that improved TB testing is necessary. AIM The aim of the current study is to establish the incidence of TB and its characteristics in patients with inflammatory bowel disease (IBD) under TNF antagonists to design improved prevention strategies. METHODS IBD patients from a single center treated with anti-TNF therapy between January 2000 and September 2011 were identified through a database that prospectively records clinical data, treatments and adverse events. RESULTS During the study period 423 patients received anti-TNF therapy. Screening for latent TB infection (LTBI) previous to anti-TNF treatment was positive in 30 patients (6.96%). Seven patients (1.65%) developed TB while under anti-TNF treatment. Six patients (five under immunosuppressant treatment) had a negative LTBI screening. TST was positive in one patient not receiving immunosuppressants, and was treated with isoniazid before starting anti-TNF therapy. In 4 patients TB was diagnosed within the first 16 weeks after starting anti-TNF therapy. Three cases had pulmonary TB and 4 extrapulmonary disease. CONCLUSIONS In the IBD population under study, incidence of TB infection associated with anti-TNF therapy is higher than that reported in controlled trials and occurs early after treatment initiation. False negative results of LTBI despite appropriate measures may occur, suggesting that more effective screening strategies are needed.

Intraperitoneal Administration of Autologous Tolerogenic Dendritic Cells for Refractory Crohn's Disease: A Phase I Study.

BACKGROUND AND AIMS Ex vivo-generated autologous tolerogenic dendritic cells [tolDCs] can restore immune tolerance in experimental colitis. The aim of this study was to determine the safety and tolerability of administration of autologous tolDCs in refractory Crohns disease [CD] patients. METHODS A phase-I, single-centre, sequential-cohorts, dose-range study was designed. Stable tolDCs were generated ex vivo from monocytes following a previously developed protocol, and administered by sonography-guided intraperitoneal injection. Six sequential refractory-CD cohorts were established: the first three cohorts received a single intraperitoneal injection of tolDCs at escalating doses [2 x 10(6)/5 x 10(6)/10 x 10(6)]; and the last three cohorts received three biweekly intraperitoneal injections at same escalating doses. Safety was sequentially evaluated. Patients were assessed from week 0 to 12 and followed up for 1-year period for safety. RESULTS Nine patients were included. No adverse effects were detected during tolDC injection or follow-up. Three patients withdrew from the study due to CD worsening. Crohns Disease Activity Index [CDAI] decreased from 274 [60] {mean (standard deviation [SD])} to 222 [113] [p = 0.3]; one [11%] patient reached clinical remission [CDAI < 150] and two [22%] clinical response [CDAI decrease ≥ 100]. Crohns Disease Endoscopic Index of Severity [CDEIS] decreased from 18 [5] to 13 [8] [p = 0.4]; lesions improved markedly in three patients [33%]. Quality of life (inflammatory bowel disease questionnaire [IBDQ]) changed from 125 [27] to 131 [38] [p = 0.7]; remission [IBDQ at Week 12 ≥ 170] was reached in one [11%] case and response [IBDQ score increase ≥ 16] in two [22%]. CONCLUSIONS Intraperitoneal administration of autologous tolDCs appears safe and feasible in refractory CD patients. Further studies should be developed to test clinical benefit, determine the optimal administration route and dose, and monitor the immune responses; See [www.eudract.ema.europa.eu, EudraCT number 2007-003469-42; www.aemps.gob.es number PEI 08-049].

Tuberculosis in Anti-Tumour Necrosis Factor-treated Inflammatory Bowel Disease Patients After the Implementation of Preventive Measures: Compliance With Recommendations and Safety of Retreatment

BACKGROUND AND AIMS Despite having adopted preventive measures, tuberculosis (TB) may still occur in patients with inflammatory bowel disease (IBD) treated with anti-tumour necrosis factor (anti-TNF). Data on the causes and characteristics of TB cases in this scenario are lacking. Our aim was to describe the characteristics of TB in anti-TNF-treated IBD patients after the publication of the Spanish TB prevention guidelines in IBD patients and to evaluate the safety of restarting anti-TNF after a TB diagnosis. METHODS In this multicentre, retrospective, descriptive study, TB cases from Spanish hospitals were collected. Continuous variables were reported as mean and standard deviation or median and interquartile range. Categorical variables were described as absolute and relative frequencies and their confidence intervals when necessary. RESULTS We collected 50 TB cases in anti-TNF-treated IBD patients, 60% male, median age 37.3 years (interquartile range [IQR] 30.4-47). Median latency between anti-TNF initiation and first TB symptoms was 155.5 days (IQR 88-301); 34% of TB cases were disseminated and 26% extrapulmonary. In 30 patients (60%), TB cases developed despite compliance with recommended preventive measures; *not performing 2-step TST (tuberculin skin test) was the main failure in compliance with recommendations. In 17 patients (34%) anti-TNF was restarted after a median of 13 months (IQR 7.1-17.3) and there were no cases of TB reactivation. CONCLUSIONS Tuberculosis could still occur in anti-TNF-treated IBD patients despite compliance with recommended preventive measures. A significant number of cases developed when these recommendations were not followed. Restarting anti-TNF treatment in these patients seems to be safe.

Cell Therapies for IBD: What Works?

The inflammatory response in patients with inflammatory bowel disease is a complex self-amplifying process with multiple cellular and molecular pathways controlling activation and shut-off of the process. Available therapeutic interventions with drugs that have a very selective action, such as anti-tumor necrosis factor antibodies, or broader effects such as corticosteroids still leave a significant proportion of patients with Crohns disease and ulcerative colitis insufficiently treated. Cellular therapies are emerging as promising new approaches to treat inflammatory bowel diseases and in particular Crohns disease. Experimental and clinical data are the origin of the increasing utilization of cell therapies for severe immune-mediated diseases including inflammatory bowel disease. The types of cell therapies for these diseases can be divided into two different areas: hematopoietic stem cell therapies, and selected/conditioned immune cell therapy, the latter including mesenchymal stem cells and T-regulatory cells-based therapies.

Autologous Haematopoietic Stem Cell Transplantation for Refractory Crohn’s Disease: Efficacy in a Single-Centre Cohort

Background Haematopoietic stem cell transplantation [HSCT] is considered a therapeutic option for patients with severe Crohns disease [CD] unresponsive to currently available therapies. Methods Autologous HSCT was considered for CD patients with active disease, unresponsive or intolerant to approved medications and unsuitable for surgery. After HSCT, patients were closely followed up every 6 weeks during the first 2 years and every 6 months thereafter up to 5 years. Colonoscopy and/or magnetic resonance imaging were performed at Months 6, 12, 24, and 48 after HSCT. Results From December 1, 2007 to December 31, 2015, 37 CD patients were assessed for HSCT. Of these, 35 patients [13 within the ASTIC trial] underwent mobilisation. Six patients did not complete the transplant for various reasons and 29 patients were finally transplanted. Patients were followed up during a median of 12 months [6-60]. At 6 months, 70% of patients achieved drug-free clinical remission (Crohns Disease Index of Severity [CDAI] < 150). The proportion of patients in drug-free remission (CDAI < 150, Simple Endoscopic activity Score [SES]-CD < 7] was 61% at 1 year, 52% at 2 years, 47% at 3 years, 39% at 4 years, and 15% at 5 years. Patients who relapsed were re-treated and 80% regained clinical remission. Six out of the 29 [21%] required surgery. One patient died due to systemic cytomegalovirus infection 2 months after transplant. Conclusions HSCT is a salvage therapy for patients with extensive and refractory CD. Although relapse occurs in a majority of patients within 5 years after transplant, drug responsiveness is regained and clinical remission achieved in 80% of cases.

Long-lasting Remission Induced by Syngeneic Haematopoietic Stem Cell Transplantation in a Patient with Refractory Crohn's Disease.

BACKGROUND AND AIMS Autologous haematopoietic stem cell transplantation (HSCT) is considered a salvage therapy for patients with refractory immune-mediated diseases. Syngeneic HSCT may be an alternative to autologous HSCT, with potential advantages in terms of safety and efficacy. METHODS A patient with severe Crohns disease refractory to available medical therapies underwent a syngeneic HSCT from her identical twin sister. Cyclophosphamide and rabbit anti-thymocyte globulin were administered for conditioning. RESULTS After transplant, the patient presented successful engraftment, complete haematological and immunological reconstitution, and no severe complications. The patient achieved complete remission after transplant which is sustained 4 years after transplantation without any active treatment for Crohns disease. CONCLUSIONS Patients with refractory immune-mediated diseases who have an identical disease-free twin may benefit from a syngeneic HSCT.

Corrigendum: Characterization of inflammation and fibrosis in Crohn's disease lesions by magnetic resonance imaging.

Corrigendum: Characterization of Inflammation and Fibrosis in Crohn’s Disease Lesions by Magnetic Resonance Imaging

Mo1176 Autologous Hematopoietic Stem Cell Transplantation in Refractory Crohn's Disease: Feasibility and Toxicity

G A A b st ra ct s diagnosis of cancer was 10 (range 1-38). IMM used after the diagnosis of cancer included thiopurines in 12 (AZA n= 8 ; 6MP n4), anti-TNFs in 3 (ADA n=.2; local IFX n=1). Among the 15 IBD patients treated with IMM after the diagnosis of neoplasia, cancer involved: thyroid (n=4), skin (n=2; 1 basal cell carcinoma, 1 spinal cell carcinoma); breast (n=2), colon (n=2), prostatic cancer (n=2) lymphoma (HL n=1), seminoma (n=1), carcinoid of the appendix (n=1). The time interval between the diagnosis of cancer and IMM was 6 yrs (range 1-26). After a median follow up from the diagnosis of cancer of 10 yrs (range 3-30), none of the 15 IBD patients treated with IMM after the diagnosis of cancer showed recurrence of cancer, or had a cancer-related death. Death was observed in 1 CD patient, due to cirrhosis. CONCLUSIONS. In a preliminary retrospective study, treating IBD patients with thiopurines or anti-TNFs after a diagnosis of cancer currently appeared not to determine a recurrence of the neoplastic disease. Larger prospective longitudinal studies are needed to further address this open issue in IBD.