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.

Comparative Study of the Effectiveness of Vedolizumab Versus Ustekinumab After Anti-TNF Failure in Crohn's Disease (Versus-CD): Data from the ENEIDA Registry.

BACKGROUND: Both vedolizumab and ustekinumab are approved for the management of Crohn's disease [CD]. Data on which one would be the most beneficial option when anti-tumour necrosis factor [anti-TNF] agents fail are limited. AIMS: To compare the durability, effectiveness, and safety of vedolizumab and ustekinumab after anti-TNF failure or intolerance in CD. METHODS: CD patients from the ENEIDA registry who received vedolizumab or ustekinumab after anti-TNF failure or intolerance were included. Durability and effectiveness were evaluated in both the short and the long term. Effectiveness was defined according to the Harvey-Bradshaw index [HBI]. The safety profile was compared between the two treatments. The propensity score was calculated by the inverse probability weighting method to balance confounder factors. RESULTS: A total of 835 patients from 30 centres were included, 207 treated with vedolizumab and 628 with ustekinumab. Dose intensification was performed in 295 patients. Vedolizumab [vs ustekinumab] was associated with a higher risk of treatment discontinuation (hazard ratio [HR] 2.55, 95% confidence interval [CI]: 2.02-3.21), adjusted by corticosteroids at baseline [HR 1.27; 95% CI: 1.00-1.62], moderate-severe activity in HBI [HR 1.79; 95% CI: 1.20-2.48], and high levels of C-reactive protein at baseline [HR 1.06; 95% CI: 1.02-1.10]. The inverse probability weighting method confirmed these results. Clinical response, remission, and corticosteroid-free clinical remission were higher with ustekinumab than with vedolizumab. Both drugs had a low risk of adverse events with no differences between them. CONCLUSION: In CD patients who have failed anti-TNF agents, ustekinumab seems to be superior to vedolizumab in terms of durability and effectiveness in clinical practice. The safety profile is good and similar for both treatments.

Serum and Urine Metabolomic Profiling of Newly Diagnosed Treatment-Naïve Inflammatory Bowel Disease Patients.

BACKGROUND AND AIMS: Inflammatory bowel disease (IBD) is a prevalent chronic noncurable disease associated with profound metabolic changes. The discovery of novel molecular indicators for unraveling IBD etiopathogenesis and the diagnosis and prognosis of IBD is therefore pivotal. We sought to determine the distinctive metabolic signatures from the different IBD subgroups before treatment initiation. METHODS: Serum and urine samples from newly diagnosed treatment-naïve IBD patients and age and sex-matched healthy control (HC) individuals were investigated using proton nuclear magnetic resonance spectroscopy. Metabolic differences were identified based on univariate and multivariate statistical analyses. RESULTS: A total of 137 Crohn's disease patients, 202 ulcerative colitis patients, and 338 HC individuals were included. In the IBD cohort, several distinguishable metabolites were detected within each subgroup comparison. Most of the differences revealed alterations in energy and amino acid metabolism in IBD patients, with an increased demand of the body for energy mainly through the ketone bodies. As compared with HC individuals, differences in metabolites were more marked and numerous in Crohn's disease than in ulcerative colitis patients, and in serum than in urine. In addition, clustering analysis revealed 3 distinct patient profiles with notable differences among them based on the analysis of their clinical, anthropometric, and metabolomic variables. However, relevant phenotypical differences were not found among these 3 clusters. CONCLUSIONS: This study highlights the molecular alterations present within the different subgroups of newly diagnosed treatment-naïve IBD patients. The metabolomic profile of these patients may provide further understanding of pathogenic mechanisms of IBD subgroups. Serum metabotype seemed to be especially sensitive to the onset of IBD.

Long-Term Real-World Effectiveness and Safety of Ustekinumab in Crohn's Disease Patients: The SUSTAIN Study.

BACKGROUND: Large real-world-evidence studies are required to confirm the durability of response, effectiveness, and safety of ustekinumab in Crohn's disease (CD) patients in real-world clinical practice. METHODS: A retrospective, multicentre study was conducted in Spain in patients with active CD who had received ≥1 intravenous dose of ustekinumab for ≥6 months. Primary outcome was ustekinumab retention rate; secondary outcomes were to identify predictive factors for drug retention, short-term remission (week 16), loss of response and predictive factors for short-term efficacy and loss of response, and ustekinumab safety. RESULTS: A total of 463 patients were included. Mean baseline Harvey-Bradshaw Index was 8.4. A total of 447 (96.5%) patients had received prior biologic therapy, 141 (30.5%) of whom had received ≥3 agents. In addition, 35.2% received concomitant immunosuppressants, and 47.1% had ≥1 abdominal surgery. At week 16, 56% had remission, 70% had response, and 26.1% required dose escalation or intensification; of these, 24.8% did not subsequently reduce dose. After a median follow-up of 15 months, 356 (77%) patients continued treatment. The incidence rate of ustekinumab discontinuation was 18% per patient-year of follow-up. Previous intestinal surgery and concomitant steroid treatment were associated with higher risk of ustekinumab discontinuation, while a maintenance schedule every 12 weeks had a lower risk; neither concomitant immunosuppressants nor the number of previous biologics were associated with ustekinumab discontinuation risk. Fifty adverse events were reported in 39 (8.4%) patients; 4 of them were severe (2 infections, 1 malignancy, and 1 fever). CONCLUSIONS: Ustekinumab is effective and safe as short- and long-term treatment in a refractory cohort of CD patients in real-world clinical practice.

This large retrospective study demonstrated the short- and long-term effectiveness and safety of ustekinumab in patients with Crohn's disease in real-world clinical practice, including those with refractory disease.

Usefulness of peripheral blood monocyte count to predict relapse in patients with inflammatory bowel disease: a prospective longitudinal cohort study.

BACKGROUND: monocytes play an important role in the pathogenesis of inflammatory bowel disease but data are scarce regarding activity biomarkers, above all in patients under biologic therapies. OBJECTIVE: the aim of this study was to evaluate the value of monocyte measurements in predicting flares in inflammatory bowel disease patients under maintenance treatment with anti-TNF. METHODS: a prospective, observational cohort study was designed. Relapse was defined as a Harvey-Bradshaw score > 4 in Crohn's disease, and a partial Mayo score ≥ 2 in ulcerative colitis. Monocyte concentration was quantified at 4-month intervals for twelve months. A total of 95 consecutive patients were included. Median age was 42 years, 50.5 % were female, and 75 % had Crohn's disease. RESULTS: sixteen months after inclusion, 65 (68.4 %) patients remained in clinical remission. Mean monocyte count preceding a relapse was 563 (standard deviation: 144) compared to 405 (standard deviation: 177) in patients who remained in remission. Final monocyte count was significantly different between relapse and remission in Crohn's disease (0.82; 95 % CI: 0.71-0.90; p < 0.005). According to the multivariate analysis, only monocytes and fecal calprotectin were related to more relapses. CONCLUSION: in conclusion, in inflammatory bowel disease patients under anti-TNF therapy, repeat monocyte counts could help monitor patients, at least in Crohn's disease.

Radon exposure and inflammatory bowel disease in a radon prone area.

INTRODUCTION: inflammatory bowel disease (IBD) is a multifactorial pathology with an increasing incidence. There is no study that has assessed a possible relationship with very high residential radon exposure in the study area. The aim of the study was to analyze if residential radon concentration is associated with a higher incidence of IBD. MATERIAL AND METHODS: an ecological study was performed. All incident cases of inflammatory bowel disease in the area of Santiago de Compostela were included between January and December 2017. Radon levels at a municipal level were correlated with demographic factors and type of IBD. RESULTS: ninety-six patients were included, 63 (65.6 %) with ulcerative colitis, 29 (30.25) with Crohn's disease and four (4.2 %) with indeterminate colitis. The incidence rate per 100,000 inhabitants-year was 21.6 cases. There were no statistically significant differences in the type of disease developed regarding radon levels (p > 0.05). No correlation between radon levels and the cumulative incidence of inflammatory bowel disease at the municipal level was observed (Spearman's rho = 0.13, p-value 0.5). CONCLUSION: in the area of Santiago de Compostela, there is a higher incidence of IBD in comparison with previous studies using western countries as reference. However, there was no correlation with the municipal average radon concentration and incidence of IBD or any of its types in this study.

Managing ulcerative colitis after surgery.

Management of ulcerative colitis after surgery suggested by guidelines (total proctocolectomy with ileal-pouch anal anastomosis) is a big challenge for physicians because patients who believed that their disease had been cured started experiencing very uncomfortable symptoms repeatedly. A high number of patients develop episodes of pouchitis, which is a non-specific inflammation of the pouch whose etiology is unknown. Antibiotics are the elective treatment for acute pouchitis, but regarding chronic pouchitis, this condition is very complicated to treat due to the absence of well-designed specific studies for this group of patients. Antibiotics, budesonide, and biological therapies are some of the recommended drugs for these patients, but despite their use, some need a permanent ileostomy.

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.

Effectiveness of ustekinumab dose escalation in Crohn's disease patients with insufficient response to standard-dose subcutaneous maintenance therapy.

BACKGROUND: Ustekinumab is effective in Crohn's disease. However, a substantial proportion of patients will not respond or lose response to ustekinumab. The current evidence to support the effectiveness of dose-optimisation for ustekinumab nonresponse is limited. AIM: To assess the effectiveness of dose escalation of ustekinumab. METHODS: This was a multicentre retrospective cohort study. We included active Crohn's disease patients who received a standard-dose intravenous induction and at least one subcutaneous ustekinumab 90 mg dose. All enrolled patients received dose escalation by either shortening the interval between the doses to every 4 or 6 weeks, intravenous reinduction or a combination of strategies. The primary outcome of the study was clinical response at week 16 after dose escalation. RESULTS: A total of 142 patients (22 centres/14 countries) were included. The patients were dose-escalated after a median treatment duration of 30 weeks. At week 16 from escalation, 73/142 (51.4%) responded to treatment, including 55/142 (38.7%) in clinical remission. Corticosteroid-free remission was achieved in 6/34 (17.6%) patients on corticosteroids at the time of escalation; 118/142 (83%) continued treatment beyond week 16. Follow-up data beyond week 16 were available for 74/118 (62.7%) patients. On the last follow-up, 51/98 (52%) patients with available data responded to treatment, including 41/98 (42%) in clinical remission. CONCLUSIONS: Intensification of ustekinumab maintenance dosage was effective in over 50% of the patients. This strategy should be considered in patients who are nonresponsive to every 8 weeks ustekinumab maintenance dosing.

Pouchitis: Treatment dilemmas at different stages of the disease.

Pouchitis is a frequent complication in ulcerative colitis patients after proctocolectomy with ileal pouch-anal anastomosis. It is an unspecific inflammation of the pouch with unknown aetiology. First-line treatment for acute and chronic pouchitis is antibiotics. Some cases of severe chronic refractory pouchitis may benefit from biological treatment. Anti-tumour necrosis factor should be recommended as the first option, leaving the new biologicals for multirefractory patients. Permanent ileostomy may be an option in severe cases, after failure of medical treatment. Prophylaxis therapy with a probiotic mixture is recommended after the first episode of pouchitis, whereas it is not clear whether probiotics are useful for all patients after surgery. Here, we present a case report and review the treatment options in different forms of pouchitis.

High primary antibiotic resistance of Helicobacter Pylori strains isolated from dyspeptic patients: A prevalence cross-sectional study in Spain.

BACKGROUND: The rate of H. pylori resistance to different antibiotics is increasing and determines the selection of eradication therapy. The aim of this study was to determine the resistance patterns of H. pylori strains in our area. METHODS: Biopsies from gastric corpus for microbiological culture and antibiotic resistance were obtained in patients undergoing upper gastrointestinal endoscopy for dyspepsia. Selective Agar Pylori for isolation of the bacteria and Agar Mueller-Hinton supplemented with blood to test the sensitivity to antibiotics were used. Presence of H. pylori was confirmed using direct observation with phase-contrast microscopy and/or smears stained with acridine orange. In vitro bacterial susceptibility to amoxicillin, clarithromycin, rifampicin, tetracycline, metronidazole, and levofloxacin was tested using diffusion MIC test strips. Minimum inhibitory concentration values were determined based on the 6th version of the EUCAST (European Committee on Antimicrobial Susceptibility Testing) Clinical Breakpoint (2016). RESULTS: Two hundred and seventeen patients were included (58.1% female, median age 64 years, range 25-92). H. pylori was identified in 108 patients (49.8%); culture and antibiogram were completed in 77 of them (71.3% of H. pylori-positive patients). The resistance rates were as follows: levofloxacin 38.7%, rifampicin 33.3%, metronidazole 27% and clarithromycin 22.4%. No case of amoxicillin or tetracycline resistance was identified. Dual clarithromycin-metronidazole resistance was observed in 10% of strains, whereas multiple drug-resistant was observed in 14.2%. CONCLUSIONS: Resistance rate of H. pylori to antibiotics is high in the northwest of Spain. The high resistance to levofloxacin and clarithromycin advises against their wide empirical use of these antibiotics in eradication regimens.