Efficacy and safety of biological treatment for inflammatory bowel disease in elderly patients: Results from a GETECCU cohort.

INTRODUCTION: Biological therapies used for the treatment of inflammatory bowel disease (IBD) have shown to be effective and safe, although these results were obtained from studies involving mostly a young population, who are generally included in clinical trials. The aim of our study was to determine the efficacy and safety of the different biological treatments in the elderly population. METHODS: Multicenter study was carried out in the GETECCU group. Patients diagnosed with IBD and aged over 65 years at the time of initiating biological therapy (infliximab, adalimumab, golimumab, ustekinumab or vedolizumab) were retrospectively included. Among the patients included, clinical response was assessed after drug induction (12 weeks of treatment) and at 52 weeks. Patients' colonoscopy data in week 52 were assessment, where available. Regarding complications, development of oncological events during follow-up and infectious processes occurring during biological treatment were collected (excluding bowel infection by cytomegalovirus). RESULTS: A total of 1090 patients were included. After induction, at approximately 12-14 weeks of treatment, 419 patients (39.6%) were in clinical remission, 502 patients (47.4%) had responded without remission and 137 patients (12.9%) had no response. At 52 weeks of treatment 442 patients (57.1%) had achieved clinical remission, 249 patients had responded without remission (32.2%) and 53 patients had no response to the treatment (6.8%). Before 52 weeks, 129 patients (14.8%) had discontinued treatment due to inefficacy, this being significantly higher (p<0.0001) for Golimumab - 9 patients (37.5%) - compared to the other biological treatments analyzed. With respect to tumor development, an oncological event was observed in 74 patients (6.9%): 30 patients (8%) on infliximab, 23 (7.14%) on adalimumab, 3 (11.1%) on golimumab, 10 (6.4%) on ustekinumab, and 8 (3.8%) on vedolizumab. The incidence was significantly lower (p=0.04) for the vedolizumab group compared to other treatments. As regards infections, these occurred in 160 patients during treatment (14.9%), with no differences between the different biologicals used (p=0.61): 61 patients (19.4%) on infliximab, 39 (12.5%) on adalimumab, 5 (17.8%) on golimumab, 22 (14.1%) on ustekinumab, and 34 (16.5%) on vedolizumab. CONCLUSIONS: Biological drug therapies have response rates in elderly patients similar to those described in the general population, Golimumab was the drug that was discontinued most frequently due to inefficacy. In our experience, tumor development was more frequent in patients who used anti-TNF therapies compared to other targets, although its incidence was generally low and that this is in line with younger patients based on previous literature.

Comparison of original and biosimilar infliximab (CTP-13) in biologic-naïve patients with Crohn's disease and ulcerative colitis: a retrospective, multicenter real-life study in Spain.

PURPOSE: biosimilar infliximab (CTP-13) has been recently approved for the treatment of several immune-mediated inflammatory disorders, including inflammatory bowel disease (IBD). Comparative studies between this biosimilar and original infliximab in the real clinical practice are scarce. The objective of this study was to compare short and long-term safety and efficacy of original (O) and biosimilar infliximab (B-IFX) in biologic-naïve, IBD patients in the real life clinical practice. METHODS: a retrospective, multicentric study was performed in five Spanish hospitals. Consecutive IBD, biologic-naïve patients from an historic cohort who initiated O-IFX from January 2013 were compared with biologic-naïve patients, who started treatment with B-IFX since its approval in January 2015. The evaluation of efficacy was assessed after the induction phase, at week 14 and week 54 of treatment. Time to dose escalation or treatment persistence of both O-IFX and B-IFX was also considered. The appearance of serious adverse events was recorded. RESULTS: two hundred and thirty-nine IBD biologic-naïve patients who started with O-IFX or B-IFX were included: 153 patients were diagnosed with Crohn's disease (95 treated with O- and 58 treated with B-IFX) and 86 with ulcerative colitis (40 received O- and 46 received B-IFX). At weeks 14 and 54, both O-IFX and B-IFX groups reached a similar clinical response and remission rates. Time to dose escalation, treatment persistence and safety profile were comparable between both groups. CONCLUSIONS: this long-term real-life experience provides additional evidence of the similarity of O- and B-IFX CTP-13 in terms of efficacy and safety in IBD patients.

Cases report: severe colonic bleeding in ulcerative colitis is refractory to selective transcatheter arterial embolization.

BACKGROUND: Severe haemorrhage is an uncommon but life-threatening complication of ulcerative colitis (UC). Superselective transcatheter embolization has shown to be an effective and safe therapeutic modality in patients with lower gastrointestinal bleeding of various aetiologies; nevertheless, its role in UC-related acute bleeding is unknown. CASES PRESENTATION: Efficacy and safety of selective transcatheter arterial embolization in three consecutive UC patients diagnosed with massive haemorrhage admitted in a tertiary institution are reported. In all patients computed tomography scan showed active arterial haemorrhage from ascendant or sigmoid colon; subsequent arteriography demonstrated active arterial bleeding from colic branches of the superior or inferior mesenteric arteries, and selective transcatheter embolization was performed with immediate technical success in all three cases. Nevertheless, rebleeding requiring subtotal colectomy occurred between 5 h and 6 days after the procedure. CONCLUSIONS: Transcatheter arterial embolization is not an effective therapeutic approach in UC patients with severe, acute colonic haemorrhage. Colectomy should not be delayed in this setting.

Familial low phospholipid-associated cholelithiasis resulting from an autosomal dominant ABCB4 mutation.

Low phospholipid-associated cholelithiasis (LPAC) syndrome is characterized by early intrahepatic and symptomatic gallstones leading to cholangitis, acute pancreatitis and biliary colic. It has been associated with loss of function variants in the ABCB4 gene. ABCB4 encodes for a phospholipid translocator at the canalicular membrane of the hepatocyte, which "flops" phosphatidylcholine into bile. The autosomal recessive form is the most common, although autosomal dominant forms have also been described. We report the first family with autosomal dominant LPAC syndrome due to heterozygosity of the loss of function mutation c.2932T>C in ABCB4, identified by targeted next generation sequencing.

Lipid Profile in Inflammatory Bowel Disease Patients on Anti-TNFα Therapy.

BACKGROUND: Previous studies analyzing lipid profile in small cohorts of patients with rheumatic and inflammatory bowel diseases (IBD) treated with TNFα blockers showed conflicting results. We aim to evaluate the effect of anti-TNFα monoclonal antibodies, infliximab and adalimumab, on lipid profile in IBD patients followed up to 3 years. METHODS: Clinical charts of 128 consecutive IBD patients, who received at least three doses of infliximab or two doses of adalimumab, and with a clinical follow-up of at least 1 year, were retrospectively reviewed. Lipid profiles (total, HDL and LDL cholesterol, and triglycerides) before beginning the treatment and after 1 and 3 years of follow-up were collected. Multiple linear regression analysis was performed considering total cholesterol difference at basal time, 1 and 3 years as a dependent variable. RESULTS: There was not a statistically significant difference between pre- and post-treatment lipid profiles. However, the subgroup with normal-range total cholesterol level before anti-TNFα treatment (n = 82) showed a significant increase in total cholesterol after 1 and 3 years, and a significant increase in LDL cholesterol after 3 years. The subgroup with basal normal-range triglycerides showed a significant increase after 1 and 3 years of follow-up. Atherogenic index resulted significantly increased after 3 years of anti-TNFα treatment. Multivariate analysis showed no influence of age, gender, type of IBD, body mass index, or the presence of two or more cardiovascular risk factors. CONCLUSIONS: No significant changes in lipid profile of IBD patients on anti-TNFα therapy were observed after 1 and 3 years of treatment.

The potential usefulness of human leukocyte antigen typing for celiac disease screening: A systematic review and meta-analysis.

BACKGROUND AND AIM: The presence of specific human leukocyte antigen-DQ2 and DQ8 seems to be necessary for celiac disease development, but the real contribution of its typing for screening is still uncertain. We aim to conduct a systematic review and meta-analysis of the diagnostic performance of human leukocyte antigen typing tests for celiac disease screening. METHODS: Systematic review of published studies assessing accuracy of human leukocyte antigen DQ2 and DQ8 typing for the detection of celiac disease were selected. MEDLINE and EMBASE were searched from 1st January 2004 until 31st December 2013. Two independent researchers carried out selection and classification of studies, data extraction and analysis. Meta-analysis combining sensitivities, specificities and likelihood ratios of HLA-DQ2 and DQ8 for the diagnosis of celiac disease were carried out. RESULTS: 6 studies including 1303 individuals were finally evaluated. Pooled sensitivity was 98% (95% confidence interval: 97-99). Overall specificity was 45% (95% confidence interval: 41-48). Regarding specificity, studies were heterogeneous and a subgroup analysis was done according to the type of population included. Overall negative likelihood ratio was 0.05 (0.03-0.09). CONCLUSIONS: Due to its great sensitivity and low negative likelihood ratio, human leukocyte antigen-DQ2/DQ8 typing would be an appropriate test for ruling out celiac disease in the general population suffering related symptoms, and even more in at risk population.

Effectiveness and safety of azathioprine for inflammatory pouch disorders: results from the RESERVO study of GETECCU.

Background: The usefulness of thiopurines has been poorly explored in pouchitis and other pouch disorders. Objective: To evaluate the effectiveness and safety of azathioprine as maintenance therapy in inflammatory pouch disorders. Design: This was a retrospective and multicentre study. Methods: We included patients diagnosed with inflammatory pouch disorders treated with azathioprine in monotherapy. Effectiveness was evaluated at 1 year and in the long term based on normalization of stool frequency, absence of pain, faecal urgency or fistula discharge (clinical remission), or any improvement in these symptoms (clinical response). Endoscopic response was evaluated using the Pouchitis Disease Activity Index (PDAI). Results: In all, 63 patients were included [54% males; median age, 49 (28-77) years]. The therapy was used to treat pouchitis (n = 37) or Crohn's disease of the pouch (n = 26). The rate of clinical response, remission and non-response at 12 months were 52%, 30% and 18%, respectively. After a median follow-up of 23 months (interquartile range 11-55), 19 patients (30%) were in clinical remission, and 45 (66%) stopped therapy. Endoscopic changes were evaluated in 19 cases. PDAI score decreased from 3 (range 2-4) to 1 (range 0-3). In all, 21 patients (33%) presented adverse events and 16 (25%) needed to stop therapy. Conclusion: Azathioprine may be effective in the long term for the treatment of inflammatory pouch disorders and could be included as a therapeutic option.

Akkermansia deficiency and mucin depletion are implicated in intestinal barrier dysfunction as earlier event in the development of inflammation in interleukin-10-deficient mice.

Background: Dysbiosis and mucin depletion are related with intestinal barrier dysfunction and seems to be an early pathophysiological event in inflammatory bowel disease (IBD). The objective of this work is to study these parameters in the natural history of colitis in IL-10 deficient mice (IL-10-/-). Methods: Wild type (WT) and IL-10-/-. mice were followed until sacrifice at 3, 5, 10, 20, 57, and 70 weeks. Body weight, colonic weight/length ratio and in vivo intestinal permeability were registered. Expression of inflammatory and adhesion molecules in the colon was explored by qPCR as Mucin-2 (MUC-2) and molecules involved in goblet cell maturation Interleukin-18 (IL-18) and WAP Four-Disulfide Core Domain 2 (WFDC2), the endoplasmic reticulum stress markers X-box-binding protein (Xbp-1) and Reticulon-4B (RTN-4B). Bacterial composition in feces and colonic mucosa was determined by massive sequencing of the V3-V4 regions of 16S rDNA gene. Results: IL-10-/- mice showed histological inflammation at weeks 20 and 57, but most notably the intestinal permeability was significantly higher from week 10. Concordantly, the number of goblet cells and expression of MUC-2, IL-18, WFDC2 and Xbp-1 were significantly lower in KO from week 10. Nevertheless, no significant differences were found in the mRNA expression of MUC-2 or Xbp-1 between both groups-derived colon organoids. Significant bacterial differences began at week 5, being the Akkermansia deficiency in KO the most relevant result. Conclusion: Gut microbiota alterations and mucin depletion are associated with early intestinal barrier dysfunction and precede overt gut inflammation in this animal model of IBD.

Liver X Receptor Exerts Anti-Inflammatory Effects in Colonic Epithelial Cells via ABCA1 and Its Expression Is Decreased in Human and Experimental Inflammatory Bowel Disease.

BACKGROUND: Liver X receptor (LXR) exerts anti-inflammatory effects in macrophages. The aim of this study was to explore the expression and function of LXR in the colonic epithelium under inflammatory conditions. METHODS: The expression of LXR was explored by Western blot and immunohistochemistry in colonic biopsies from patients diagnosed with inflammatory bowel disease (IBD) and control patients. In addition, LXR and its target gene expression were analyzed in the colon from interleukin (IL)-10-deficient (IL-10-/-) and wild-type mice. Caco-2 cells were pretreated with the synthetic LXR agonist GW3965 and further challenged with IL-1ß, the expression of IL-8 and chemokine (C-C motif) ligand (CCL)-28 chemokines, the activation of mitogen-activated protein (MAP) kinases, and the nuclear translocation of the p65 subunit of nuclear factor kappa B was evaluated. Glibenclamide was used as an ABCA1 antagonist. RESULTS: We found that LXR expression was downregulated in colonic samples from patients with IBD and IL-10-/- mice. The nuclear positivity of LXR inversely correlated with ulcerative colitis histologic activity. Colonic IL-1ß mRNA levels negatively correlated with both LXRα and LXRß in the colon of IL-10-/- mice, where a decreased mRNA expression of the LXR target genes ABCA1 and FAS was shown. In addition, IL-1ß decreased the expression of the LXR target gene ABCA1 in cultured intestinal epithelial cells. The synthetic LXR agonist GW3965 led to a decreased nuclear positivity of the p65 subunit of nuclear factor kappa B, a phosphorylation ratio of the p44-42 MAP kinase, and the expression of CCL-28 and IL-8 in IL-1ß-stimulated Caco-2 cells. The pharmacological inhibition of ABCA1 increased the phosphorylation of p44-42 after GW3965 treatment and IL-1ß stimulation. CONCLUSIONS: The LXR-ABCA1 pathway exerts anti-inflammatory effects in intestinal epithelial cells and is impaired in the colonic mucosa of patients with IBD and IL-10-/- mice.

Impact of Biological Agents on Postsurgical Complications in Inflammatory Bowel Disease: A Multicentre Study of Geteccu.

BACKGROUND: The impact of biologics on the risk of postoperative complications (PC) in inflammatory bowel disease (IBD) is still an ongoing debate. This lack of evidence is more relevant for ustekinumab and vedolizumab. AIMS: To evaluate the impact of biologics on the risk of PC. METHODS: A retrospective study was performed in 37 centres. Patients treated with biologics within 12 weeks before surgery were considered "exposed". The impact of the exposure on the risk of 30-day PC and the risk of infections was assessed by logistic regression and propensity score-matched analysis. RESULTS: A total of 1535 surgeries were performed on 1370 patients. Of them, 711 surgeries were conducted in the exposed cohort (584 anti-TNF, 58 vedolizumab and 69 ustekinumab). In the multivariate analysis, male gender (OR: 1.5; 95% CI: 1.2-2.0), urgent surgery (OR: 1.6; 95% CI: 1.2-2.2), laparotomy approach (OR: 1.5; 95% CI: 1.1-1.9) and severe anaemia (OR: 1.8; 95% CI: 1.3-2.6) had higher risk of PC, while academic hospitals had significantly lower risk. Exposure to biologics (either anti-TNF, vedolizumab or ustekinumab) did not increase the risk of PC (OR: 1.2; 95% CI: 0.97-1.58), although it could be a risk factor for postoperative infections (OR 1.5; 95% CI: 1.03-2.27). CONCLUSIONS: Preoperative administration of biologics does not seem to be a risk factor for overall PC, although it may be so for postoperative infections.

Metabolic bone disease in patients diagnosed with inflammatory bowel disease from Spain.

BACKGROUND: The objective of this study was to analyse the prevalence of metabolic bone disease (MBD) in a cohort of Southern European patients with inflammatory bowel disease (IBD) and to identify associated risk factors in this population. METHODS: We conducted a retrospective, both cross-sectional and longitudinal study of MBD, assessed by dual energy X-ray absorptiometry (DXA), among patients diagnosed with IBD and previously recognized risk factors for this complication from two referral Spanish institutions. RESULTS: A total of 612 patients (58.6% diagnosed with Crohn's disease) were included. Mean (SD) age was 44.9 (14.7) years; 71.7% of patients received at least one tapered dosage of corticosteroids before first DXA. MBD and osteoporosis were diagnosed in 66.4% and 21.4% of patients, respectively. At baseline, male gender, menopause and ulcerative colitis were found as independent risks factors for osteoporosis, whereas age, more than three IBD-related hospitalizations and previous steroid treatment were found as independent risks factors for MBD. A total of 261 patients had at least a second DXA and were included in the longitudinal study; median follow up was 56.4 months. Logistic regression model identified menopause, ulcerative colitis and baseline lumbar DXA T-score value, but not steroid treatment, as risk factors for worsening ⩾1 SD in follow-up DXA T-score. According to guidelines, all patients under treatment with corticosteroids received calcium and vitamin D supplements. CONCLUSION: MBD is a frequent complication in south-European IBD patients. Routine evaluation of bone density when risk factors are present, as well as calcium plus D vitamin prophylaxis in patients under corticosteroid treatment should be recommended.

Weber-Christian disease with ileocolonic involvement successfully treated with infliximab.

Weber-Christian disease (WCD) is an inflammatory disease whose main histological feature is lobular panniculitis of adipose tissue. The location of panniculitis determines the clinical presentation, being the subcutaneous adipose tissue the most frequent one, followed by liver, spleen, bone marrow and mesenteric adipose tissue. Systemic corticosteroids are first line treatment, but other options should be considered if systemic symptoms are observed or in case of refractory clinical situation. We report herein a case with WCD showing orbital, mesenteric and ileocolonic involvement, which required surgical treatment and also developed postoperative recurrence. Symptoms were resolved by administration of thalidomide and, afterwards, infliximab. To our knowledge, this is the first report of Weber-Christian disease with luminal ileocolonic involvement, treated with infliximab.

Listeria monocytogenes infection in inflammatory bowel disease patients: case series and review of the literature.

BACKGROUND: Listeria monocytogenes (LM) is a gram-positive intracellular bacillus that in immunodeficient patients, children, geriatric patients, pregnant women, and even in healthy individuals can cause central nervous system infection, bacteremia, and other clinical manifestations, becoming a relevant pathogen. MATERIALS AND METHODS: From the Microbiology Service data of 'Gregorio Marañón' Hospital, we selected all positive biological sample cultures for LM from inflammatory bowel disease (IBD) patients, from January 1986 until January 2011. These cases were included in an SPSS database, analyzing several basal clinical characteristics and factors related to the infection. RESULTS: Three patients diagnosed with IBD had positive cultures for LM during this period. All of them were male, and also all of them had a diagnosis of Crohn's disease. Every patient had a corticosteroid cumulated dose of more than 400 mg (equivalency in methylprednisolone doses), adding anti-tumor necrosis factor-α treatment (certolizumab) in one patient. Prior colonoscopy with biopsy was performed in two patients. Clinical presentation of the infection was bacteremia in two patients, accompanied by central nervous system infection in one patient. One patient had isolated meningoencephalitis. Despite correct empiric treatment, one patient died from a cause related to the infection, that is, rombencephalitis. Increased incidence of LM bacteremia was found in IBD patients, compared with the general population (12.2 bacteremias/100 000 IBD patient-years, compared with 1.6 bacteremias/100 000 person-years), with an odds ratio of 7.4. CONCLUSION: IBD patients may be at risk for more frequent and serious LM infection compared with the general population.