Withdrawal of infliximab or concomitant immunosuppressant therapy in patients with Crohn's disease on combination therapy (SPARE): a multicentre, open-label, randomised controlled trial.

BACKGROUND: The combination of infliximab and immunosuppressant therapy is a standard management strategy for patients with Crohn's disease. Concerns regarding the implications of long-term combination therapy provided the rationale for a formal clinical trial of treatment de-escalation. Our aim was to compare the relapse rate and the time spent in remission over 2 years between patients continuing combination therapy and those stopping infliximab or immunosuppressant therapy. METHODS: This multicentre, open-label, randomised controlled trial was performed in 64 hospitals in seven countries in Europe and Australia. Adult patients with Crohn's disease in steroid-free clinical remission for more than 6 months, on combination therapy of infliximab and immunosuppressant therapy for at least 8 months were randomly assigned (1:1:1) to either continue combination therapy (combination group), discontinue infliximab (infliximab withdrawal group), or discontinue immunosuppressant therapy (immunosuppressant withdrawal group). Randomisation was stratified according to disease duration before start of first anti-TNF treatment (≤2 or >2 years), failure of immunosuppressant therapy before start of infliximab, and presence of ulcers at baseline endoscopy. The patient number and group of each stratum were assigned by a central online randomisation website. Treatment was optimised or resumed in case of relapse in all groups. Participants, those assessing outcomes, and those analysing the data were not masked to group assignment. The coprimary endpoints were the relapse rate (superiority analysis) and time in remission over 2 years (non-inferiority analysis, non-inferiority margin 35 days). Analyses were done on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02177071, and with EU Clinical Trials Register, EUDRACT 2014-002311-41. The trial was completed in April, 2021. FINDINGS: Between Nov 2, 2015, and April 24, 2019, 254 patients were screened. Of these, 211 were randomised and 207 were included in the final analysis (n=67 in the combination group, n=71 in the infliximab withdrawal group, and n=69 in the immunosuppressant withdrawal group). 39 patients had a relapse (eight [12%] of 67 in the combination group, 25 [35%] of 71 in the infliximab withdrawal group, six [9%] of 69 in the immunosuppressant withdrawal group). 2-year relapse rates were 14% (95% CI 4-23) in the combination group, 36% (24-47) in the infliximab withdrawal group, and 10% (2-18) in the immunosuppressant withdrawal group (hazard ratio [HR] 3·45 [95% CI 1·56-7·69], p=0·003, for infliximab withdrawal vs combination, and 4·76 [1·92-11·11], p=0·0004, for infliximab withdrawal vs immunosuppressant withdrawal). Of 28 patients who had a relapse and were retreated or optimised according to protocol, remission was achieved in 25 patients (one of two in the combination group, 22 of 23 in the infliximab withdrawal group, and two of three in the immunosuppressant withdrawal group). The mean time spent in remission over 2 years was 698 days (95% CI 668-727) in the combination group, 684 days (651-717) in the infliximab withdrawal group, and 706 days (682-730) in the immunosuppressant withdrawal group. The difference in restricted mean survival time in remission was -14 days (95% CI -56 to 27) between the infliximab withdrawal group and the combination group and -22 days (-62 to 16) between the infliximab withdrawal group and the immunosuppressant withdrawal group. The 95% CIs contained the non-inferiority threshold (-35 days). We recorded 31 serious adverse events, in 20 patients, with no difference in frequency between groups. The most frequent serious adverse events were infections (four in the combination group, two in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group) and Crohn's disease exacerbation (three in the combination group, four in the infliximab withdrawal group, and one in the immunosuppressant withdrawal group). No death nor malignancy was recorded. INTERPRETATION: In patients with Crohn's disease in sustained steroid-free remission under combination therapy with infliximab and immunosuppressant therapy, withdrawal of infliximab should only be considered after careful assessment of risks and benefits for each patient, whereas withdrawal of immunosuppressant therapy could generally represent a preferable strategy when considering treatment de-escalation. FUNDING: European Union's Horizon 2020

Optimization of biologics to reduce treatment failure in inflammatory bowel diseases

International audienceModerate to severe inflammatory bowel disease patients can fail to respond to conventional therapy and/or to biologic treatment. In the era of TNFα antagonists and other non-anti-TNF biologic drugs, it is important to review the literature on biologic treatment failure, which could be defined as primary non-response, secondary loss of response and intolerance. Therapeutic drug monitoring (TDM), that is, drug trough level and antidrug antibodies, should enable to determine the mechanisms of treatment failure and to optimize drug efficacy. There is a consensus on reactive TDM at the time of loss of response. Proactive TDM could be of interest during induction and/or maintenance, but randomized controlled trials are required

Changes in the Lemann Index values during the First Years of Crohn's Disease.

International audienceStricturing or penetrating lesions develop over time in most patients with Crohn's disease. The Lémann Index indicates the degree of digestive damage at a given time in 1 individual. We tracked changes in Lémann Index scores in an inception cohort of patients and looked for factors associated with digestive damage. We studied 221 patients diagnosed with Crohn's disease from 2004 through 2011 who received 2 or 3 serial morphological evaluations over a period of 2-10 y. We collected cross-sectional images and had them reviewed by a gastroenterologist and a radiologist; Lémann index scores were calculated. A value of 2 was chosen as the cut-off for substantial transparietal damage. Factors associated with score >2 at last evaluation and progression of index scores were identified using univariate analysis and logistic regression analyses. Median index Lémann Index scores were 2.3 (intra-quartile range [IQR], 1.2-3.9) at first evaluation, 3.5 (IQR, 1.2-8.6) 2-5 y after diagnosis, and 8.3 (IQR, 1.2-12.1) 5-10 y after diagnosis. Index scores increased significantly at each stage compared with initial or previous values (P2.0. The only early factor that predicted later damage was first index value. Intestinal resection, time, and percentage of time elapsed with a clinically active disease were associated with progressing damage. Based on an analysis of patients with Crohn's disease using the Lémann Index, nearly two thirds have substantial mucosal damage 2-10 y after diagnosis. High Lémann index scores at first evaluation, time, persistent clinical activity, and intestinal resection are associated with damage

Adipose-Derived Stem Cells in the Treatment of Perianal Fistulas in Crohn’s Disease: Rationale, Clinical Results and Perspectives

International audienceBetween 20 to 25% of Crohn’s disease (CD) patients suffer from perianal fistulas, a marker of disease severity. Seton drainage combined with anti-TNFα can result in closure of the fistula in 70 to 75% of patients. For the remaining 25% of patients there is room for in situ injection of autologous or allogenic mesenchymal stem cells such as adipose-derived stem/stromal cells (ADSCs). ADSCs exert their effects on tissues and effector cells through paracrine phenomena, including the secretome and extracellular vesicles. They display anti-inflammatory, anti-apoptotic, pro-angiogenic, proliferative, and immunomodulatory properties, and a homing within the damaged tissue. They also have immuno-evasive properties allowing a clinical allogeneic approach. Numerous clinical trials have been conducted that demonstrate a complete cure rate of anoperineal fistulas in CD ranging from 46 to 90% of cases after in situ injection of autologous or allogenic ADSCs. A pivotal phase III-controlled trial using allogenic ADSCs (Alofisel®) demonstrated that prolonged clinical and radiological remission can be obtained in nearly 60% of cases with a good safety profile. Future studies should be conducted for a better knowledge of the local effect of ADSCs as well as for a standardization in terms of the number of injections and associated procedures

Incidence and Risk Factors of Cancer in the Anal Transitional Zone and Ileal Pouch following Surgery for Ulcerative Colitis and Familial Adenomatous Polyposis

International audienceProctocolectomy with ileal pouch-anal anastomosis is the intervention of choice for ulcerative colitis and familial adenomatous polyposis requiring surgery. One of the long-term complications is pouch cancer, having a poor prognosis. The risk of high-grade dysplasia and cancer in the anal transitional zone and ileal pouch after 20 years is estimated to be 2 to 4.5% and 3 to 10% in ulcerative colitis and familial polyposis, respectively. The risk factors for ulcerative colitis are the presence of pre-operative dysplasia or cancer, disease duration > 10 years and severe villous atrophy. For familial polyposis, the risk factors are the number of pre-operative polyps > 1000, surgery with stapled anastomosis and the duration of follow-up. In the case of ulcerative colitis, a pouchoscopy should be performed annually if one of the following is present: dysplasia and cancer at surgery, primary sclerosing cholangitis, villous atrophy and active pouchitis (every 5 years without any of these factors). In the case of familial polyposis, endoscopy is recommended every year including chromoendoscopy. Even if anal transitional zone and ileal pouch cancers seldom occur following proctectomy for ulcerative colitis and familial adenomatous polyposis, the high mortality rate associated with this complication warrants endoscopic monitoring

Iron Deficiency in Patients with Inflammatory Bowel Diseases: A Prospective Multicenter Cross-Sectional Study

International audienceBackground Iron deficiency (ID) is a frequent condition in patients with inflammatory bowel disease (IBD). Aim Our aim was to investigate the prevalence of ID in patients with IBD. Methods This was a prospective multicenter cross-sectional study conducted in 21 gastroenterology departments in France between January and March 2020. All adult patients with confirmed IBD who were admitted to the hospital were eligible for inclusion. ID was defined as ferritinemia <= 100 mu g/L in patients with signs of inflammation (C-reactive protein (CRP) >= 5 mg/L) or ferritinemia < 30 mu g/L in the absence of inflammation. Results In total, 1036 IBD (685 Crohn's disease and 351 ulcerative colitis) patients (52.1% women) with a mean age of 41.8 +/- 15.5 years were recruited. Approximately half of the patients (504, 51.1%) were in disease remission at the time of enrollment. Systematic monitoring of iron status was performed in 12/21 (57%) participating centers, including measurements of ferritin (12/12, 100%), hemoglobin (11/12, 92%), transferrin saturation (TSAT) (6/12, 50.0%), and serum iron (5/12, 42%). About one-fifth of the patients had been treated with intravenous iron (218, 21.0%), whereas only a small percentage received oral iron (36, 3.5%). ID occurred in 97 patients (23.7% CI 95% 19.8-28.1). Patients with moderate/severe IBD activity (OR: 3.66; CI 95% 24.4-61.2; p = 0.007) or concomitant anemia (OR: 3.66; CI 95% 1.97-6.78; p < 0.001) had an increased likelihood of having ID. Conclusion Patients with moderate/severe IBD activity or concomitant anemia are at increased risk of ID. Early detection and management of ID in patients with IBD is recommended

Preoperative Predictors of Neoplasia in Patients Undergoing Small Bowel Resection for Complicated Crohn’s Disease: A Multicentre Case-Control Study

Crohn’s disease (CD) is associated with an increased risk of small bowel neoplasia (SBN). We aimed to assess preoperative predictors of SBN in CD patients. We conducted a retrospective case-control study including CD patients who underwent surgery: cases were diagnosed with SBN on histopathological analysis and controls had no neoplasia. Preoperative cross-sectional imaging was reviewed by a panel of blinded expert radiologists. Fifty cases were matched to one hundred and fifty consecutive controls. In multivariable analysis, predictors of SBN were age ≥ 50 years (OR = 28, 95% CI = 5.05–206), median CD duration ≥ 17.5 years (OR = 4.25, 95% CI = 1.33–14.3), and surgery for stricture (OR = 5.84, 95% CI = 1.27–35.4). The predictors of small bowel adenocarcinoma were age ≥ 50 years (OR = 5.14, 95% CI = 2.12–12.7), CD duration ≥ 15 years (OR = 5.65, 95% CI = 2.33–14.3), and digestive wall thickening > 8 mm (OR = 3.79, 95% CI = 1.45–11.3). A predictive score based on the aforementioned factors was constructed. Almost 73.7% of patients with a high score had SBA. Old age, long small bowel CD duration, and stricture predicted the presence of SBN, particularly adenocarcinoma when patients have digestive wall thickening > 8 mm on preoperative imaging

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

Effectiveness and safety of ustekinumab 90 mg every 4 weeks in Crohn's disease

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