Infliximab desensitization in patients with inflammatory bowel diseases: a safe therapeutic alternative.

BACKGROUND: Hypersensitivity reactions (HSR) to the administration of infliximab (IFX) in Inflammatory Bowel Diseases (IBD) patients are not rare and usually lead to drug discontinuation. We report data on safety and effectiveness of desensitization to IFX in patients with previous HSR. METHODS: We conducted a retrospective monocentric observational study. Patients for whom a desensitization protocol to IFX was realized after a previous HSR were included. Anti-drug antibodies (ADA) and IFX trough levels at both inclusion and six months after desensitization were collected. Clinical outcomes, including recurrence of HSR were evaluated. RESULTS: From 2005 to 2020, 27 patients (Crohn's Disease: 26 (96%) were included). Desensitization after HSR was performed after a median time of 10.4 months (2.9-33.1). Nineteen (70%) patients received immunosuppressants at time of desensitization. Eight (30%) patients presented HSR at first (n = 2), second (n = 4) or third (n = 2) IFX perfusion after desensitization. None led to intensive care unit transfer or death. Thirteen (48%) had clinical response at 6 months and 8 (29%) were still under IFX treatment two years after desensitization. IFX trough levels and ADA were available for 14 patients at time of desensitization. Most patients (12 out of 14) had ADA at a high level. At 6 months, among the 7 patients with long term response to IFX, 4 presented a decrease of ADA titers and 2 had a significant trough level of IFX. CONCLUSION: IFX desensitization in patients with IBD is a safe therapeutic alternative and represents a potential option for patients refractory to multiple biologics.What is already known? Hypersensitivity reactions to the administration of infliximab is frequent. Occurrence of hypersensitivity reaction, either immediate or delayed, usually leads to permanent drug discontinuation.What is new here? Infliximab desensitization is well tolerated with no hypersensitivity reaction recurrence in 70% of patients. Clinical success at 6 months was of 48% and around a third of patients remained under infliximab therapy two years after desensitization. Antidrug antibodies decreased and infliximab trough levels increased in these patients showing the impact of desensitization on immunogenicity.How can this study help patient care? Infliximab desensitization represents a potential option for patients refractory to multiple biologics who presented hypersensitivity reaction to the drug.

Autologous organoid co-culture model reveals T cell-driven epithelial cell death in Crohn's Disease.

Lympho-epithelial interactions between intestinal T resident memory cells (Trm) and the epithelium have been associated with inflammatory bowel disease (IBD) activity. We developed ex vivo autologous organoid-mucosal T cell cocultures to functionally assess lymphoepithelial interactions in Crohn's Disease (CD) patients compared to controls. We demonstrate the direct epithelial cell death induced by autologous mucosal T cells in CD patients but not in controls. These findings were positively correlated with T cell infiltration of the organoids. This potential was inhibited by limiting lympho-epithelial interactions through CD103 and NKG2D blocking antibodies. These data directly demonstrate for the first time the direct deleterious effect of mucosal T cells on the epithelium of CD patients. Such ex-vivo models are promising techniques to unravel the pathophysiology of these diseases and the potential mode of action of current and future therapies.

Microcirculatory changes in the liver of patients with refractory ascites and their relationship with diabetes and alcohol.

OBJECTIVES: The determinants of refractory ascites have not been fully characterized. The aims of this study were to assess liver histopathological alterations associated with refractory ascites and their relationship with comorbidities. METHODS: Consecutive patients with cirrhosis who underwent liver transplantation were retrospectively included. Patients' characteristics at the time of listing were analysed. The native livers were reviewed and lesions associated with refractory ascites were examined. RESULTS: Out of the 89 patients included, 30 had refractory ascites and 59 did not (including 35 without ascites and 24 with diuretic-sensitive ascites). Patients with and without refractory ascites had a similar amount of fibrous tissue and features of fatty liver disease. By contrast, microvascular changes, namely sinusoidal dilatation (P < 0.001), diffuse perisinusoidal fibrosis (P = 0.001), hepatic venous thromboses (P = 0.004) and vascular proliferation (P = 0.01) were more frequently observed in the livers of patients with refractory ascites. Diabetes (57% vs. 31%, P = 0.02) and alcohol as a causal factor for cirrhosis (80% vs. 42%, P = 0.001) were more frequent in patients with refractory ascites than in those without. By multivariate analysis, refractory ascites was independently associated with diabetes mellitus [odds ratio (OR) (95% confidence interval, CI) 6.15 (1.47-25.71); P = 0.01], alcohol as a causal factor for cirrhosis [OR (95% CI) 4.63 (1.07-20.02); P = 0.04], higher Model For End Stage Liver Diseases [OR (95% CI) 1.21 (1.05-1.38); P = 0.008] and lower serum sodium [OR (95% CI) 0.87 (0.78-0.98); P = 0.03]. CONCLUSION: Liver microcirculatory changes are associated with refractory ascites. Diabetes and alcohol may explain refractory ascites by causing microangiopathy.

Safety of Hydrocortisone Premedication Discontinuation in Patients with Inflammatory Bowel Disease on Maintenance Therapy with Infliximab: a Prospective Clinical and Pharmacological Study.

BACKGROUND: Hydrocortisone premedication reduces the risk of antibodies to infliximab [ATIs] formation in patients receiving infliximab [IFX] therapy for inflammatory bowel disease [IBD]. AIM: We aimed to determine the safety of hydrocortisone premedication withdrawal in IBD patients with sustained clinical response on maintenance therapy with IFX. METHODS: We performed an observational prospective pharmacoclinical study in a tertiary referral centre, including all consecutive IBD outpatients with no previous IFX infusion reaction and in clinical remission on maintenance IFX [alone or in combination therapy] for at least 6 months. This cohort was followed for 1 year after discontinuation of hydrocortisone premedication. RESULTS: Among the 268 IBD outpatients, 95 patients met the inclusion criteria [mean age 38 years; 64% male; 80% Crohn's disease; 45% combination therapy]. The median IFX duration was 5 years [0.54-14] with a mean infused dose of 533 mg [200-1000] and a mean interval duration of 7.9 weeks [4-10]. None of the patients developed permanent ATIs or infusion-related reaction at 1 year. Four patients developed transient ATIs without loss of clinical response. There was no significant variation of infliximab serum trough levels [5.5 µg/mL vs 5.9 µg/mL] measured at the time of the three IFX infusions before and after hydrocortisone withdrawal. Loss of response rate to IFX was 18% at 1 year. CONCLUSIONS: Hydrocortisone discontinuation is safe in IBD patients with sustained clinical remission on maintenance therapy with IFX. Our data suggest that routine premedication with hydrocortisone is unnecessary in patients in prolonged remission under IFX maintenance therapy.

Negative Screening Does Not Rule Out the Risk of Tuberculosis in Patients with Inflammatory Bowel Disease Undergoing Anti-TNF Treatment: A Descriptive Study on the GETAID Cohort.

AIM: to describe the characteristics of incident cases of tuberculosis [TB] despite negative TB screening tests, in patients with inflammatory bowel disease [IBD] undergoing anti-TNF treatment, and to identify the risk factors involved. METHODS: A retrospective descriptive study was conducted at GETAID centers on all IBD patients undergoing anti-TNF treatment who developed TB even though their initial screening test results were negative. The following data were collected using a standardized anonymous questionnaire: IBD, and TB characteristics and evolution, initial screening methods and results, and time before anti-TNF treatment was restarted. RESULTS: A total of 44 IBD patients [including 23 men; median age 37 years] were identified at 20 French and Swiss centers at which TB screening was performed [before starting anti-TNF treatment] based on Tuberculin Skin Tests [n = 25], Interferon Gamma Release Assays [n = 12], or both [n = 7]. The median interval from the start of anti-TNF treatment to TB diagnosis was 14.5 months (interquartile range [IQR] 25-75: 4.9-43.3). Pulmonary TB involvement was observed in 25 [57%] patients, and 40 [91%] had at least one extrapulmonary location. One TB patient died as the result of cardiac tamponade. Mycobacterium tuberculosis exposure was thought to be a possible cause of TB in 14 cases [32%]: 7 patients [including 6 health care workers] were exposed to occupational risks, and 7 had travelled to endemic countries. Biotherapy was restarted on 27 patients after a median period of 11.2 months [IQR 25-75: 4.4-15.2] after TB diagnosis without any recurrence of the infection. CONCLUSION: Tuberculosis can occur in IBD patients undergoing anti-TNF treatment, even if their initial screening results were negative. In the present population, TB was mostly extrapulmonary and disseminated. TB screening tests should be repeated on people exposed to occupational risks and/or travelers to endemic countries. Restarting anti-TNF treatment seems to be safe.

Certolizumab pegol - A new therapeutic option for refractory disseminated pyoderma gangrenosum associated with Crohn's disease.

Systemic steroids, in association or not with cyclosporin, are indicated for the treatment of large or widespread Pyoderma gangrenosum (PG). We report the case of a 27-year-old woman with a 15-year history of severe Crohn's disease, who developed a severe and disseminated PG, refractory to multiple lines of treatment. Infliximab and adalimumab were contraindicated, either because of allergy or of ineffectiveness on Crohn's disease. The addition of certolizumab pegol to the baseline treatment, associating systemic steroids and tacrolimus, finally allowed the complete healing of PG. Oral prednisone was stopped and tacrolimus was decreased, without any cutaneous or digestive relapse. Certolizumab pegol could be an alternative therapy in the treatment of PG in case of intolerance or ineffectiveness of the other anti-tumor necrosis factor (anti-TNF) therapies.

Endoscopic and clinical recurrences after laparoscopic or open ileocolic resection in Crohn's disease.

BACKGROUND: After ileocolic resection in Crohn's disease, studies concerning the influence of the laparoscopic or open approach on clinical and endoscopic recurrences are scarce. PATIENTS AND METHODS: In a prospective database, we identified all patients operated on between 2004 and 2012 for primary ileocolic resection in Crohn's disease, with at least 6 months of follow-up. The rates of endoscopic recurrence during the first postoperative year and the clinical recurrence at any time during follow-up were measured and compared after the laparoscopic or open approach. RESULTS: Sixty-two patients (mean±standard deviation age, 33.5±12.7 years; 35 females) were operated on through laparoscopy (n=28) or laparotomy (n=34). Medical treatment, evolution and phenotype of disease, and postoperative course were comparable in both groups. Mean±standard deviation follow-up was 3.5±1.9 years. Ileocolonoscopy was available in 46 (74.2%) patients. Normal endoscopy or minor recurrence (i0 or i1 grade) was significantly more frequent after laparoscopy (14/24 [58.3%]) versus laparotomy (5/22 [22.7%]) (P=.019). Clinical recurrence was comparable at 1 year (P=.116) and at the end of follow-up (P=.799) after laparoscopy (28.6% and 50%, respectively) or laparotomy (11.8% and 55.9%, respectively). CONCLUSIONS: After resection, normal or minor endoscopic lesions (i0 or i1 grade) were more frequent after laparoscopy than after laparotomy. However, clinical recurrence was similar after both techniques.

Tailored treatment according to early post-surgery colonoscopy reduces clinical recurrence in Crohn's disease: a retrospective study.

BACKGROUND: After intestinal resection for Crohn's disease, the severity of endoscopic recurrence in the first year following surgery is predictive of clinical outcome. Aim of the study was to assess the impact on clinical recurrence of tailored therapy based on endoscopic findings in the first year following surgery for Crohn's disease. METHODS: All patients who underwent an intestinal resection for Crohn's disease between 1995 and 2005 at Saint-Louis Hospital were retrospectively included. Time-to-clinical recurrence was compared in two groups: patients who had systematic ileocolonoscopy 6-12 months after intestinal surgery with tailored treatment according to the severity of endoscopic lesions (group C) and patients without systematic endoscopic evaluation (group NC). RESULTS: 132 patients (group C=90, group NC=42) were included. Probabilities of clinical recurrence were significantly lower in group C (21% and 26% at 3 and 5 years, respectively) compared with group NC (31% and 52% at 3 and 5 years respectively, p=0.01). CONCLUSION: Tailored treatment according to endoscopic assessment after ileocolonic resection is significantly associated with reduced clinical recurrence rate.

Cephalic duodenopancreatectomy for hyperalgic duodenal Crohn's disease fistulized in the pancreatic gland.

Upper gastrointestinal (GI) tract involvement in adult Crohn's disease (CD) is rare and severe complications unusual. Stenosis has been reported, but gastroduodenal fistulae are seldom detected during surgery and most of the fistulae are cologastric or ileogastric. In complicated gastroduodenal CD, medical treatments are often effective and surgery is only considered in exceptional cases. We here report the unusual case of a 23-year-old patient with upper GI CD presenting a hyperalgic giant ulcer of the bulb fistulized in the pancreatic gland. The failure of steroids and two lines of combined treatment led us to a salvage surgical option. Abdominal exploration showed a plate stomach with an inflammatory bulboduodenal block. Cephalic duodenopancreatectomy and cholecystectomy were performed; histological analysis reported large fissuring pylorus ulceration with micro abscesses reaching the pancreas and the presence of non-caseating granulomas. Six months after the surgery, the patient had stopped antalgic treatment and did not have residual abdominal pain. He had gained 11 kg in weight and had no diarrhea with pancreatic enzymes. To our knowledge, we report the first case of an upper GI and fistulizing CD patient heavily treated with steroids and combined immunosuppressant agents requiring salvage cephalic duodenopancreatectomy.

Trough levels and antibodies to infliximab may not predict response to intensification of infliximab therapy in patients with inflammatory bowel disease.

BACKGROUND: Infliximab is effective for the treatment of refractory inflammatory bowel disease (IBD). Nevertheless, up to 40% of patients lose response to infliximab over time. The aim was to assess the clinical value of measuring infliximab trough levels and antibodies to infliximab (ATI) concentrations in IBD patients who lost response to infliximab therapy. METHODS: We retrospectively studied records of IBD patients who lost response to infliximab therapy. We first assessed clinical responses of different therapeutic strategies that were applied when patients lost response to infliximab and then we looked at the correlation between clinical response and infliximab trough levels and ATI concentrations. RESULTS: Seventy-six IBD patients were included. 31/76 patients (41%) continued infliximab therapy without any modification, 39 patients (51%) had an intensification of infliximab therapy, five patients (7%) had switched to adalimumab therapy, and one patient (1%) underwent surgery. Clinical response was observed in 27 patients (69%) with an intensification of infliximab therapy. There was no significant difference in mean infliximab trough level at inclusion in patients who responded to intensification of infliximab therapy (3.3 ± 4.1 µg/mL) as compared with patients who did not respond (2.3 ± 2.2 µg/mL, P = 0.85). In all, 16/76 patients (22.4%) presented detectable ATI in the serum. Ten ATI-positive patients had an intensification of infliximab therapy and six (60%) demonstrated a clinical response. After intensification of infliximab therapy the ATI concentration decreased in five patients. CONCLUSIONS: In patients with IBD who lose response to infliximab, clinical improvement may occur upon intensification of infliximab therapy, irrespective of infliximab serum concentration or presence of ATI.

Crohn's disease recurrence after total proctocolectomy with definitive ileostomy.

BACKGROUND: Total proctocolectomy with definitive ileostomy is the ultimate treatment for refractory colonic Crohn's disease (CD). Aim of the study was to report the outcome of Crohn's disease patients after total proctocolectomy with definitive ileostomy. PATIENTS AND METHODS: Between 1990 and 2005, 55 patients underwent total proctocolectomy with definitive ileostomy for Crohn's disease in our institution. None of them received preventive post-operative treatment. We studied clinical recurrence, need for immunosuppressants (IS), anti-TNF therapy and re-operation in this retrospective cohort. RESULTS: Median follow-up was 5.4 years. Probabilities of clinical Crohn's disease recurrence were 4%, 27% and 39% at 1, 5 and 8 years, respectively. In multivariate analysis, clinical recurrence rate was significantly higher for patients with penetrating disease behaviour (RR 1.7 IC95% [1.5-19], p=0.05) and absence of perianal disease (RR=1.6, IC95% [1.4-10]; p=0.01). Clinical recurrences were located in terminal ileum in all cases and treated medically in 9 of 16 patients including IS or anti TNF agents in 7 cases. Probabilities of treatment with immunosuppressants or anti-TNF therapy were 4%, 15% and 15% at 1, 5 and 8 years, respectively. Nearly one third of the patients (29%) underwent surgery for mechanical complications (N=11) and/or CD recurrence (N=7). Probabilities of reoperation for Crohn's disease recurrence were 0%, 10% and 18% at 1, 5 and 8 years, respectively. CONCLUSION: Recurrence after total proctocolectomy with definitive ileostomy for Crohn's disease is not uncommon, and in our series often required immunosuppressants or surgical procedure.