Harmful Effects and Potential Benefits of Anti-Tumor Necrosis Factor (TNF)-α on the Liver.

Anti-tumor necrosis factor (TNF)-α agents represent an effective treatment for chronic inflammatory diseases. However, some concerns about their potentially undesirable effects on liver function have been reported. On the other hand, evidence of their therapeutic effects on certain liver diseases is accumulating. Many data showed the safety of anti-TNF-α in patients with chronic hepatitis B and C and in liver transplanted patients even if a strict follow-up and prophylaxis are recommended in well-defined subgroups. On the other side, anti-TNF-α-induced liver injury is not a rare event. However, it is often reversible after anti-TNF-α withdrawal. Anti-TNF-α agents have been tested in advanced stages of severe alcoholic hepatitis and non-alcoholic fatty liver disease. Limited data on the efficacy of anti-TNF-α in patients with autoimmune hepatitis and primary biliary cholangitis are also available. In this review, we explored the hepatic safety concerns in patients receiving anti-TNF-α agents with and without pre-existent hepatic diseases. In addition, the available evidence on their potential benefits in the treatment of specific hepatic diseases is discussed.

Discontinuation of Anti-Tumour Necrosis Factor Therapy in Patients with Perianal Fistulizing Crohn's Disease: Individual Participant Data Meta-Analysis of 309 Patients from 12 Studies.

BACKGROUND: The risk of relapse after anti-tumour necrosis factor [TNF] therapy discontinuation in Crohn's disease patients with perianal fistulas [pCD] is unclear. We aimed to assess this risk. METHODS: A systematic literature search was conducted to identify cohort studies on the incidence of relapse following anti-TNF discontinuation in pCD patients. Individual participant data were requested from the original study cohorts. Inclusion criteria were age ≥16 years, pCD as a (co)indication for start of anti-TNF therapy, more than three doses, and remission of luminal and pCD at anti-TNF discontinuation. The primary outcome was the cumulative incidence of CD relapse using Kaplan-Meier estimates. Secondary outcomes included response to re-treatment and risk factors associated with relapse as assessed by Cox regression analysis. RESULTS: In total, 309 patients from 12 studies in ten countries were included. The median duration of anti-TNF treatment was 14 months [interquartile range 5.8-32.5]. Most patients were treated for pCD without active luminal disease [89%], received first-line anti-TNF therapy [87%], and continued immunomodulatory therapy following anti-TNF discontinuation [78%]. The overall cumulative incidence of relapse was 36% (95% confidence interval [CI] 25-48%) and 42% [95% CI 32-53%] at 1 and 2 years after anti-TNF discontinuation, respectively. Risk factors for relapse included smoking (hazard ratio [HR] 1.5 [1.0, 2.1]) and history of proctitis (HR 1.7 [1.1, 2.5]). The overall re-treatment response rate was 82%. CONCLUSIONS: This individual participant data meta-analysis, on predominantly patients with pCD without active luminal disease and first-line anti-TNF therapy, shows that over half of patients remain in remission 2 years after anti-TNF discontinuation. Therefore, anti-TNF discontinuation may be considered in this subgroup.

Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome.

Mutations of forkhead box p3 (FOXP3), the master gene for naturally occurring regulatory T cells (nTregs), are responsible for the impaired function of nTregs, resulting in an autoimmune disease known as the immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. The relevance of other peripheral tolerance mechanisms, such as the presence and function of type 1 regulatory T (Tr1) cells, the major adaptive IL-10-producing Treg subset, in patients with IPEX syndrome remains to be clarified. FOXP3(mutated) Tr1-polarized cells, differentiated in vitro from CD4(+) T cells of four IPEX patients, were enriched in IL-10(+) IL-4(-) IFN-γ(+) T cells, a cytokine production profile specific for Tr1 cells, and expressed low levels of FOXP3 and high levels of Granzyme-B. IPEX Tr1 cells were hypoproliferative and suppressive, thus indicating that FOXP3 mutations did not impair their function. Furthermore, we isolated Tr1 cell clones from the peripheral blood of one FOXP3(null) patient, demonstrating that Tr1 cells are present in vivo and they can be expanded in vitro in the absence of WT FOXP3. Overall, our results (i) show that functional Tr1 cells differentiate independently of FOXP3, (ii) confirm that human Tr1 and nTregs are distinct T-cell lineages, and (iii) suggest that under favorable conditions Tr1 cells could exert regulatory functions in IPEX patients.

Ileal Crohn disease: mural microvascularity quantified with contrast-enhanced US correlates with disease activity.

PURPOSE: To quantitatively assess microvascular activation in the thickened ileal walls of patients with Crohn disease (CD) by using contrast-enhanced ultrasonography (US) and evaluate its correlation with widely used indexes of CD activity. MATERIALS AND METHODS: This prospective study was approved by the ethics committee, and written informed consent was obtained from all patients. The authors examined 54 consecutively enrolled patients (mean age, 35.29 years; age range, 18-69 years; 39 men, 15 women) with endoscopically confirmed CD of the terminal ileum. Ileal wall segments thicker than 3 mm were examined with low-mechanical-index contrast-enhanced US and a second-generation US contrast agent. The authors analyzed software-plotted time-enhancement intensity curves to determine the maximum peak intensity (MPI) and wash-in slope coefficient (ß) and evaluated their correlation with (a) the composite index of CD activity (CICDA), (b) the CD activity index (CDAI), and (c) the simplified endoscopic score for CD (SES-CD, evaluated in 37 patients) for the terminal ileum. Statistical analysis was performed with the Mann-Whitney test, Spearman rank test, and receiver operating characteristic (ROC) analysis. RESULTS: MPI and ß coefficients were significantly increased in the 36 patients with a CICDA indicative of active disease (P<.0001 for both), the 33 patients with a CDAI of at least 150 (P<.032 and P<.0074, respectively), and the 26 patients with an SES-CD of at least 1 (P<.0001 and P<.002, respectively). ROC analysis revealed accurate identification (compared with CICDA) of active CD with an MPI threshold of 24 video intensity (VI) (sensitivity, 97%; specificity, 83%) and a ß coefficient of 4.5 VI/sec (sensitivity, 86%; specificity, 83%). CONCLUSION: Contrast-enhanced US of the ileal wall is a promising method for objective, reproducible assessment of disease activity in patients with ileal CD.

Ileal Crohn's disease: CEUS determination of activity.

Transabdominal ultrasound is currently accepted as a clinical first-line tool in the assessment of Crohn's disease activity. During recent years, great improvements have been achieved in ultrasound examination with the introduction of high-frequency transducers, ultrasonographic microbubble contrast agents, and dedicated contrast-specific ultrasound software. Therefore, contrast-enhanced ultrasonography (CEUS) is emerging as one of the most important imaging techniques in the diagnosis and follow-up of patients with ileal Crohn's disease. It is non-invasive and non-ionizing, easily repeatable, well-tolerated by patients and has significant diagnostic accuracy. Moreover, the possibility to monitor response to therapies, describing, and quantifying contrast enhancement behavior by specific software, represents an interesting aspect of its utilization, considering the still open questions about the correct use of immunosuppressive and biological agents. The aim of our review is to provide an updated overview of the role of CEUS in the patients who have an ileal localization of Crohn's disease, defining its qualitative and quantitative features.

[Predictors of clinical response in patients with ulcerative colitis treated with granulocyte-monocyte apheresis: analysis of the apheresis registry data]. / Predittori di risposta clinica in pazienti affetti da colite ulcerosa trattati con granulocito-monocito aferesi: analisi dei dati del registro aferesi.

We analyzed predictors of clinical response after a cycle of granulocytemonocyte apheresis in 173 patients with ulcerative colitis. Hemoglobin levels independently predicted good clinical outcome.

Glucagon-like peptide-2 analogues for Crohn's disease patients with short bowel syndrome and intestinal failure.

Short bowel syndrome (SBS) with intestinal failure (IF) is a rare but severe complication of Crohn's disease (CD), which is the most frequent benign condition that leads to SBS after repeated surgical resections, even in the era of biologics and small molecules. Glucagon-like peptide-2 analogues have been deeply studied recently for the treatment of SBS-IF. These drugs have a significant intestinotrophic effect and the potential to reduce the chronic dependence of SBS-IF patients on parenteral support or nutrition. Teduglutide has been approved for the treatment of SBS-IF, and apraglutide is currently in clinical development. The use of these drugs was examined with a focus on their use in CD patients.

Incident Colorectal Cancer in Inflammatory Bowel Disease.

Colorectal cancer (CRC) risk is increased in Inflammatory Bowel Disease (IBD) and surveillance needs to be tailored according to individual risk. The open issues include the role of the characteristics of IBD and CRC in determining the long-term outcome. These issues were assessed in our multicenter study, including a cohort of 56 IBD patients with incident CRC. The clinical and histopathological features of IBD patients and of CRC were recorded. Incident CRC in IBD occurred at a young age (≤40 years) in 25% of patients (median age 55.5 (22-76)). Mucinous signet-ring carcinoma was detected in 6 out of the 56 (10.7%) patients, including 4 with Ulcerative Colitis (UC) and 2 with Crohn's disease (CD). CRC was more frequently diagnosed by colonoscopy in UC (85.4% vs. 50%; p = 0.01) and by imaging in Crohn's Disease CD (5.8% vs. 31.8%; p = 0.02). At onset, CRC-related symptoms occurred in 29 (51.9%) IBD patients. The time interval from the diagnosis of IBD to CRC was shorter in UC and CD patients with >40 years (p = 0.002; p = 0.01). CRC-related death occurred in 10 (29.4%) UC and in 6 (27.2%) CD patients (p = 0.89), with a short time interval from CRC to death (UC vs. CD: 6.5 (1-68) vs. 14.5 (8-40); p = 0.85; IBD: 12 months (1-68)). CRC occurring at a young age, a short time interval from the diagnosis of IBD to CRC-related death in the elderly, CRC-symptoms often mimicking IBD relapse and the observed high mortality rate may support the need of closer surveillance intervals in subgroups of patients.

Comparison of performances of infliximab biosimilars CT-P13 versus SB2 in the treatment of inflammatory bowel diseases: a real-life multicenter, observational study in Italy.

BACKGROUND: To compare the performances of Infliximab (IFX) biosimilar CT-P13 and SB2 in the treatment of Inflammatory Bowel Diseases (IBD) outpatients in Italy. RESEARCH DESIGN AND METHODS: Three hundred and eighty IBD outpatients were retrospectively evaluated. The primary endpoint was to compare the two IFX biosimilars in terms of reaching and maintenance of remission at any timepoint. RESULTS: 197 patients with Ulcerative Colitis (UC) and 183 patients with Crohn's Disease (CD) treated with CT-P13 or SB2 and having a median (IQR) follow-up of 12 (6-36) months were compared: 230 (60.5%) were naïve to anti-TNFα, 20 (5.26%) were switched from IFX originator or from IFX CT-P13 to IFX SB2. Clinical remission was achieved in 133 (67.5%) UC patients and in 164 (89.6%) CD patients (p < 0.000), with no differences between CT-P13 and SB2 in the rate of remission in UC (p = 0.667) and CD (p = 0.286). Clinical response, steroid-free remission, rate of surgery, mucosal healing (MH) in UC, switching from IFX originator or from other biosimilar, and safety were similar. Higher MH rate was obtained in CD patients treated with CT-P13 (p = 0.004). CONCLUSION: This first comparative study found that both IFX biosimilars CT-P13 and SB2 are effective and safe in managing IBD outpatients.

Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.

BACKGROUND & AIMS: Few data are available on effects of biologic therapies in patients more than 65 years old with inflammatory bowel disease (IBD). We evaluated the risk and benefits of therapy with tumor necrosis factor (TNF) inhibitors in these patients. METHODS: We collected data from patients with IBD treated with infliximab (n = 2475) and adalimumab (n = 604) from 2000 to 2009 at 16 tertiary centers. Ninety-five patients (3%) were more than 65 years old (52 men; 37 with ulcerative colitis and 58 with Crohn's disease; 78 treated with infliximab and 17 with adalimumab). The control group comprised 190 patients 65 years old or younger who were treated with both biologics and 190 patients older than 65 years who were treated with other drugs. The primary end points were severe infection, cancer, or death. RESULTS: Among patients more than 65 years old who received infliximab and adalimumab, 11% developed severe infections, 3% developed neoplasms, and 10% died. No variable was associated with severe infection or death. Among control patients more than 65 years old, 0.5% developed severe infections, 2% developed cancer, and 2% died. Among control patients less than 65 years old, 2.6% developed severe infections, none developed tumors, and 1% died. CONCLUSIONS: Patients older than 65 years treated with TNF inhibitors for IBD have a high rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics. The effects of anti-TNF agents in older patients with IBD should be more thoroughly investigated, because these patients have higher mortality related to hospitalization than younger patients.

Anti-TNF-alpha therapies do not increase early postoperative complications in patients with inflammatory bowel disease. An Italian single-center experience.

PURPOSE: The impact of preoperative use of TNF-alpha inhibitors on postoperative complications in patients with inflammatory bowel disease (IBD) undergoing abdominal surgery is controversial. The aim of this study was to evaluate the 30-day postoperative outcomes for IBD patients treated with these drugs prior to surgery. METHODS: We analyzed retrospectively the incidence of short-term postoperative complications. Statistical analyses were performed to reveal the independent variables that influenced postoperative complications and the role of preoperative medical therapy with anti-TNF drugs within 12 weeks prior to surgery. RESULTS: One hundred fourteen patients (76 with Crohn's disease (CD) and 38 ulcerative colitis (UC)) underwent abdominal surgery for IBD. Fifty-four patients were treated with anti-TNF-alpha within 12 weeks prior to surgery (anti-TNF group). Postoperative mortality and morbidity were 0% and 21%, respectively. The infection rate was 15%. A significantly higher incidence of postoperative complications was found in patients treated with high-dose steroids (58% vs. 17%; p = 0.003) after univariate analysis. The infection rate was significantly higher in patients treated with high-dose corticosteroids (50% vs. 11%; p = 0.002) and concomitant anti-TNF-alpha (60% vs. 13%; p = 0.023). Multivariate analysis revealed that only therapy with high-dose corticosteroids was significantly associated with cumulative (p = 0.017) and infective postoperative complications (p = 0.046). No significant differences were found between the anti-TNF group and the control group. CONCLUSION: High-dose corticosteroids increased the risk of short-term postoperative cumulative and infective complications. Anti-TNF drugs within 12 weeks prior to abdominal surgery in patients with IBD did not appear to increase the rate of postoperative complications.

Predictors and Early Markers of Response to Biological Therapies in Inflammatory Bowel Diseases.

Inflammatory bowel diseases (IBD) are chronic conditions that primarily affect the gastrointestinal tract, with a complex pathogenesis; they are characterized by a significant heterogeneity of clinical presentations and of inflammatory pathways that sustain intestinal damage. After the introduction of the first biological therapies, the pipeline of therapies for IBD has been constantly expanding, and a significant number of new molecules is expected in the next few years. Evidence from clinical trials and real-life experiences has taught us that up to 40% of patients do not respond to a specific drug. Unfortunately, to date, clinicians lack a valid tool that can predict each patient's response to therapies and that could help them in choosing what drug to administer. Several candidate biomarkers have been investigated so far, with conflicting results: clinical, genetic, immunological, pharmacokinetic and microbial markers have been tested, but no ideal marker has been identified so far. Based on recent evidence, multiparametric models seemingly hold the greatest potential for predicting response to therapy. In this narrative review, we aim to summarize the current knowledge on predictors and early markers of response to biological therapies in IBD.

Transition of inflammatory bowel disease patients from pediatric to adult care: an observational study on a joint-visits approach.

BACKGROUND: Transition from pediatric to adult care of patients affected by Inflammatory Bowel Disease (IBD) is a critical step that needs specific care and multidisciplinary involvement. The aim of our study was to evaluate the outcome of the transition process of a cohort of IBD patients, exploring their readiness and the possible impact on quality of life. METHODS: This observational study followed transitioned IBD patients from pediatric to adult care. Transition was carried-out through combined visits, jointly performed by the pediatrician and the adult gastroenterologist. Clinical data were collected before and after transition. A subgroup of patients was submitted to an anonymous online questionnaire of 38 items based on the validated questionnaires TRAQ and SIBDQ within the first 6 months from the beginning of the transition process. RESULTS: Eighty-two patients with IBD were enrolled, with a mean age at transition of 20.2±2.7 years. Before transition, 40.2% of patients already had major surgery and 64.6% started biologics. At transition, 24% of patients were in moderate to severe active phase of their disease and 40% of them had already been treated with ≥ 2 biologics. The mean score of the TRAQ questionnaires collected is 3.4±1.5 and the mean score of SIBDQ is 53.9±9.8. A significant association was found between a TRAQ mean score > 3 and a SIBDQ > 50 (p=0.0129). Overall, 75% of patients had a positive opinion of the transition model adopted. CONCLUSIONS: A strong association has been found between TRAQ and SIBDQ questionnaires, showing how transition readiness has a direct impact on the quality of life of the young adult with IBD.

Novel trends with biologics in inflammatory bowel disease: sequential and combined approaches.

Inflammatory bowel disease (IBD) management has changed dramatically over the past 20 years, after the introduction of targeted biological therapies. However, the impact of these new drugs in changing the natural history of disease is still under debate. Recent evidence seems to suggest that the extent of their efficacy might be, at least partially, dependent on the timing of their introduction and on the subsequent management strategy. In this complex landscape, the potential role for a more dynamic approach with treatments based on sequencing and combining targeted therapies has been explored only minimally so far. In this review, we aim to explore the potential biological rationale behind the use of sequential and combination therapies in IBD, to summarise the current knowledge on this topic and to propose a management algorithm that combines these notions.

Serum triiodothyronine-to-thyroxine (T3/T4) ratio predicts therapeutic outcome to biological therapies in elderly IBD patients.

INTRODUCTION: Rates of elderly patients with inflammatory bowel diseases (IBDs) are increasing, and biomarkers are needed to optimise their therapies. Serum triiodothyronine-to-thyroxine (T3/T4) ratio has been correlated with geriatric patient frailty. AIM: To assess the suitability of T3/T4 ratio as a response marker to biologics in elderly patients with IBD. METHODS: Patients with IBD over 60 years old were enrolled, when starting biological therapy. Therapeutic outcome was assessed after 54 weeks of treatment as mucosal healing (Mayo endoscopic score < 2 for ulcerative colitis; ulcer disappearance for Crohn's disease) and clinical remission (Partial Mayo Score < 2 for ulcerative colitis; Harvey-Bradshaw Index < 5 for Crohn's disease). T3/T4 ratio was evaluated at baseline, and its association with therapeutic outcomes was tested by multivariable logistic regression and receiver operating characteristic (ROC). RESULTS: We enrolled 80 patients; 44 achieved clinical remission and 36 mucosal healing. Baseline T3/T4 ratio was higher in patients with mucosal healing, as compared with those without mucosal healing (P < 0.0001), regardless of the disease type or biological drug (OR 6.4 [2.9-14.3] for each T3/T4 unit increase, P < 0.0001). A cut point of 3.3 was identified as the optimal threshold of baseline T3/T4 ratio for predicting mucosal healing, providing 78% sensitivity and 89% specificity (area under the ROC curve 0.88 [0.79-0.94]; positive and negative likelihood ratios 6.8 [2.9-15.9] and 0.3 [0.1-0.5] respectively). CONCLUSIONS: T3/T4 ratio seems a reliable tool for predicting therapeutic outcome of biological therapy in elderly patients with IBD. If validated, the assessment of this parameter before starting biological treatment might be suggested.

Switching from IFX originator to biosimilar CT-P13 does not impact effectiveness,safety and immunogenicity in a large cohort of IBD patients.

BACKGROUND: Switching from IFX originator to CT-P13 is safe; however, little data on immunogenicity exists. RESEARCH DESIGN AND METHODS: Consecutive IBD patients on IFX originator were switched to CT-P13 and followed-up for 12 months. Clinical activity, infliximab trough levels (ITLs), anti-drug antibodies (ATIs), and adverse events were recorded at predefined timepoints (baseline, second CT-P13 infusion, 6 and 12 months). The outcomes investigated were immunogenicity, pharmacokinetics, effectiveness and safety. RESULTS: 119 patients were switched to CT-P13 after a median time with IFX of 5.8 years. No changes in mean ITLs were observed. ATIs were detected in 30 patients (25.2%): 14 before and 16 after switch. Mean persistent ATIs were significantly higher compared to mean transient ones (109.74 ng/mL ±84.70 vs 18.22 ng/mL ±11.37, p < 0.001), with significantly lower ITLs associated (mean 0.32 µg/mL ±0.6 vs 3.08 µg/mL ±3.22, p < 0.001). A significant decrease of patients in steroid-fee clinical remission was observed after the switch (p = 0.004), with subsequent improvement at 6 months (p = 0.005). Eighteen patients (15.1%) discontinued IFX, only 6 (5%) for loss of response. CONCLUSIONS: Switching from infliximab originator to CT-P13 seems safe and effective, without differences in immunogenicity. A temporary reduction of clinical benefit after switching could be potentially explained by a 'nocebo-effect response'.

Magnesium Absorption in Intestinal Cells: Evidence of Cross-Talk between EGF and TRPM6 and Novel Implications for Cetuximab Therapy.

Hypomagnesemia is very commonly observed in cancer patients, most frequently in association with therapy with cetuximab (CTX), a monoclonal antibody targeting the epithelial growth factor receptor (EGFR). CTX-induced hypomagnesemia has been ascribed to renal magnesium (Mg) wasting. Here, we sought to clarify whether CTX may also influence intestinal Mg absorption and if Mg supplementation may interfere with CTX activity. We used human colon carcinoma CaCo-2 cells as an in vitro model to study the mechanisms underlying Mg transport and CTX activity. Our findings demonstrate that TRPM6 is the key channel that mediates Mg influx in intestinal cells and that EGF stimulates such influx; consequently, CTX downregulates TRPM6-mediated Mg influx by interfering with EGF signaling. Moreover, we show that Mg supplementation does not modify either the CTX IC50 or CTX-dependent inhibition of ERK1/2 phosphorylation. Our results suggest that reduced Mg absorption in the intestine may contribute to the severe hypomagnesemia that occurs in CTX-treated patients, and Mg supplementation may represent a safe and effective nutritional intervention to restore Mg status without impairing the CTX efficacy.

TRPM7 is overexpressed in human IBD-related and sporadic colorectal cancer and correlates with tumor grade.

BACKGROUND: Inflammatory bowel disease (IBD) predisposes to colorectal cancer (CRC) with some specific features that distinguish it from sporadic CRC. Magnesium (Mg) homeostasis is severely compromised in IBD patients, which may affect both inflammation and tumor development. Efficient transcellular Mg transport in intestinal cells depends on the transient receptor potential melastatin (TRPM) channels type 6 and 7, but their expression has never been investigated in the context of IBD-related CRC. AIMS: We sought to study the expression pattern of TRPM6 and TRPM7 in CRC, and to compare IBD-related cases to sporadic cases. METHODS: TRPM6 and TRPM7 protein expression was evaluated by immunohistochemistry in surgical specimens from 16 IBD and 13 NON-IBD CRC patients. RESULTS: TRPM7 expression was higher in tumor tissue than in the adjacent non-neoplastic tissue in both IBD and NON-IBD patients. Overall, adenocarcinomas showed a higher TRPM7 expression than adenomas. TRPM7 expression also positively correlated with tumor grade. Conversely, TRPM6 expression was higher in tumor tissues in both IBD and NON-IBD CRC, but it did not correlate with tumor stage or grade. CONCLUSIONS: We report a possible participation of TRPM6 and 7 in both IBD-related and sporadic CRC and suggest that TRPM7 might serve as a marker of malignant transformation and lack of differentiation.

Dual Targeted Therapy: a possible option for the management of refractory Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Dual Targeted Therapy (DTT) has been proposed as a novel therapeutic strategy for the management of complicated patients with Inflammatory Bowel Diseases (IBD). Our aim was to investigate the safety and effectiveness of this approach in a real-life setting. METHODS: We retrospectively extracted data from IBD patients receiving DTT in Italian IBD referral centres. Baseline characteristics, clinical activity of intestinal and extraintestinal disease and C-reactive proteins levels were recorded. All adverse events were reported. Clinical effectiveness, biochemical remission and safety of DTT were investigated. RESULTS: Sixteen patients were identified; indications for DTT were: "active IBD" or "active EIM" despite ongoing biological therapy. The most commonly used DTT were: vedolizumab + ustekinumab (3 patients) and vedolizumab + adalimumab (3 patients). Clinical response of intestinal or extraintestinal symptoms, according to the indication for DTT, was reported by all patients by the end of the induction. Four patients discontinued DTT during follow-up. Three patients experienced an adverse event; no serious adverse event was reported. CONCLUSIONS: DTT seems to be an effective and safe treatment and may represent an appealing therapeutic strategy for the management of complicated IBD patients.

Impact of COVID-19 pandemic on the daily management of biotechnological therapy in inflammatory bowel disease patients: Reorganisational response in a high-volume Italian inflammatory bowel disease centre.

The coronavirus disease 2019 (COVID-19) pandemic is having a major clinical as well as organisational impact on the national health-care system in Italy, particularly in high-volume hospitals which are usually active for many essential clinical needs, including inflammatory bowel disease (IBD). Here, we report major clinical and organisational challenges at a high-volume Italian IBD centre one month after the start of the Italian government's restrictions due to the COVID-19 pandemic. All routine follow-up IBD visits of patients in remission were cancelled or rescheduled for 8-12 weeks' time. However, access to the hospital for therapy or for unstable/relapsing patients was not considered postponable. Everyone attending the centre (e.g. physicians, nurses, administrative personnel and patients) were advised to respect the general recommended rules for hand hygiene and social distancing, to disclose if they had a fever or cough or flu-like symptoms and to wear a surgical mask and gloves. At the entrance of the therapy area, a control station was set up in order to double-check all patients with a clinical interview and conduct thermal scanning. A total of 1451 IBD patients under biotechnological or experimental therapy actively followed in the CEMAD IBD centre were included in the study. About 65% of patients maintained their appointment schedules without major problems, while in 20% of cases planned infusions were delayed because of the patient's decision or practical issues. About 10% of patients receiving subcutaneous therapy were allowed to collect their medicine without a follow-up visit. Finally, 10% of patients living outside the Lazio region requested access to their therapy at a local centre closer to their home. At present, five patients have been found to be positive for SARS-CoV-2 infection but with minimal symptoms, 22 are in 'quarantine' for contact considered to be 'at risk' for the infection. Up to now, none of them has experienced significant symptoms. This study represents the first observational detailed report about short-term impact of the COVID-19 pandemic on patient organisation and management in a high-volume IBD centre.