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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.

Switching from IFX originator to CT-P13 is safe; however, little data on immunogenicity exists.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.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.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'.

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.

BACKGROUND AND AIMS: There is a need to evaluate the benefit-risk ratio of current therapies in inflammatory bowel disease (IBD) patients to provide the best quality of care. The primary objective of I-CARE (IBD Cancer and serious infections in Europe) was to assess prospectively safety concerns in IBD, with specific focus on the risk of cancer/lymphoma and serious infections in patients treated with anti-tumor necrosis factor and other biologic monotherapy as well as in combination with immunomodulators.METHODS: I-CARE was designed as a European prospective longitudinal observational multicenter cohort study to include patients with a diagnosis of Crohn's disease, ulcerative colitis, or IBD unclassified established at least 3 months prior to enrollment.RESULTS: A total of 10,206 patients were enrolled between March 2016 and April 2019, including 6169 (60.4%) patients with Crohn's disease, 3853 (37.8%) with ulcerative colitis, and 184 (1.8%) with a diagnosis of IBD unclassified. Thirty-two percent of patients were receiving azathioprine/thiopurines, 4.6% 6-mercaptopurine, and 3.2% methotrexate at study entry. At inclusion, 47.3% of patients were treated with an anti-tumor necrosis factor agent, 8.8% with vedolizumab, and 3.4% with ustekinumab. Roughly one-quarter of patients (26.8%) underwent prior IBD-related surgery. Sixty-six percent of patients had been previously treated with systemic steroids. Three percent of patients had a medical history of cancer prior to inclusion and 1.1% had a history of colonic, esophageal, or uterine cervix high-grade dysplasia.CONCLUSIONS: I-CARE is an ongoing investigator-initiated observational European prospective cohort study that will provide unique information on the long-term benefits and risks of biological therapies in IBD patients. (EudraCT, Number: 2014-004728-23; ClinicalTrials.gov, Number: NCT02377258).

To compare the performances of Infliximab (IFX) biosimilar CT-P13 and SB2 in the treatment of Inflammatory Bowel Diseases (IBD) outpatients in Italy.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.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).This first comparative study found that both IFX biosimilars CT-P13 and SB2 are effective and safe in managing IBD outpatients.

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.

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.

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.

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.

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.

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 here 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 extra-intestinal disease, and C-reactive protein 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 [three patients] and vedolizumab + adalimumab [three patients]. Clinical response of intestinal or extra-intestinal 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.

Interleukin (IL)-17 is a recognised pro-inflammatory cytokine of the IL23/17 pathway, involved in the pathogenesis of several chronic inflammatory diseases (CIDs), including psoriasis (PsO), psoria...

Background The risk of relapse after anti-tumour necrosis factor [TNF] therapy cessation in Crohn’s disease [CD] patients with perianal fistulas is unclear. We aimed to assess the risk of relapse after anti-TNF cessation in a large cohort and to identify risk factors. Methods A systemic literature search was conducted to identify cohort studies reporting on the incidence of relapse after cessation of anti-TNF therapy in CD patients. Individual patient data [IPD] were requested from the original study cohorts. Inclusion criteria for IPD-meta-analysis (IPD-MA) included age ³ 18 years, perianal fistulizing CD as indication for start of anti-TNF therapy, minimal treatment duration ³3 doses, and remission of luminal and perianal CD at cessation of anti-TNF therapy. Primary outcome was CD relapse [either perianal or luminal]. Perianal fistula relapse was defined as recurrence of draining perianal fistula related to previous or new fistula tracks, or abscess. Luminal relapse was defined as a clinical, biochemical, endoscopic, or radiological relapse requiring treatment or dose optimization of IBD medication or surgery. In a secondary analysis, risk factors associated with relapse were assessed using multivariate logistic regression analysis. Results A total of 307 patients from 12 studies in 9 countries were included in this IPD-MA. The median duration of anti-TNF treatment prior to therapy cessation was 14 months [IQR 6.1 – 29.9]. In 272/307 patients [89%] anti-TNF therapy was started for active perianal fistula and in 34 [11%] for both active perianal fistula and luminal CD. 169 patients [55%] developed a relapse [either perianal or luminal] after a median follow-up after cessation of 25 months [IQR 12 – 54]. Overall cumulative incidence of relapse was 31% and 43% at 1 and 2 years after anti-TNF cessation. Risk factor for CD relapse include upper GI involvement (L4) [HR 1.9], whereas older age [A3 vs A1, HR 0.48] and continuation of concomitant immunomodulators [HR 0.62] were protective factors. For a subgroup of patients with active perianal fistula and in luminal remission at start of anti-TNF, the cumulative incidence relapse rates were 25% and 43% at 1 and 2 years. No considerable differences in risk factors were found within this subgroup regarding risk of recurrence. Of the 179 patients who relapsed, 104 were retreated with anti-TNF with a response rate of 85%. Conclusion According to this IPD-MA, approximately two-thirds of CD patients with perianal fistula remain in remission with regard to fistulizing and luminal disease during 2 years after cessation of anti-TNF therapy. Further risk stratification based on perianal fistula characteristics is required.

BACKGROUND: Data from trials of vedolizumab for inflammatory bowel disease and from real-world studies suggest an exposure-response relationship, such that vedolizumab trough levels may predict clinical and endoscopic outcomes. OBJECTIVE: The purpose of this study was to evaluate in a prospective observational study the utility of an early vedolizumab trough level assay for predicting the first-year vedolizumab therapy outcome. METHODS: This prospective observational study included consecutive inflammatory bowel disease patients. We measured vedolizumab trough levels and anti-vedolizumab antibodies at weeks 6 and 14. Clinical outcome was assessed at weeks 6, 14, 22 and 54. The primary endpoint was the correlation between early vedolizumab trough levels and vedolizumab persistence over the first year of treatment, defined as the maintenance of vedolizumab therapy due to sustained clinical benefit. RESULTS: We included 101 patients initiating vedolizumab. A cut-off vedolizumab trough level of 16.55 µg/ml at week 14 predicted vedolizumab persistence within the first year of therapy, with 73.3% sensitivity and 59.4% specificity (p = 0.0009). Week 14 vedolizumab trough level was significantly higher in patients with clinical remission at weeks 14, 22 and 54; and in patients achieving mucosal healing within 54 weeks. CONCLUSION: High vedolizumab trough level at week 14 was associated with a higher probability of maintaining vedolizumab therapy over the first year due to sustained clinical benefit.

Background In a 6-year, multicenter, prospective nested case–control study, we aimed to evaluate risk factors for incident cancer in inflammatory bowel disease (IBD), when considering clinical characteristics of IBD and immunomodulator use. The secondary end point was to provide characterization of incident cancer types. Methods All incident cases of cancer occurring in IBD patients from December 2011–2017 were prospectively recorded in 16 Italian Group for the Study of Inflammatory Bowel Disease units. Each of the IBD patients with a new diagnosis of cancer was matched with 2 IBD patients without cancer, according to IBD phenotype (ulcerative colitis [UC] vs Crohn’s disease [CD]), age (±5 years), sex. Risk factors were assessed by multivariate logistic regression analysis. Results Cancer occurred in 403 IBD patients: 204 CD (CD cases), 199 UC (UC cases). The study population included 1209 patients (403 IBD cases, 806 IBD controls). Cancer (n = 403) more frequently involved the digestive system (DS; 32%), followed by skin (14.9%), urinary tract (9.7%), lung (6.9%), genital tract (6.5%), breast (5.5%), thyroid (1.9%), lymphoma (2.7%, only in CD), adenocarcinoma of the small bowel (SBA; 3.9%, 15 CD, 1 pouch in UC), other cancers (15.9%). Among cancers of the DS, colorectal cancer (CRC) more frequently occurred in UC (29% vs 17%; P < 0.005), whereas SBA more frequently occurred in CD (13% vs 6.3% P = 0.039). In CD, perforating (B3) vs non-stricturing non-perforating (B1) behavior represented the only risk factor for any cancer (odds ratio [OR], 2.33; 95% confidence interval [CI], 1.33–4.11). In CD, risk factors for extracolonic cancer (ECC) were a B3 vs B1 and a stricturing (B2) vs B1 behavior (OR, 2.95; 95% CI, 1.62–5.43; OR, 1.79; 95% CI, 1.09–2.98). In UC, risk factors for ECC and for overall cancer were abdominal surgery for UC (OR, 4.63; 95% CI, 2.62–8.42; OR, 3.34; 95% CI, 1.88–5.92) and extensive vs distal UC (OR, 1.73; 95% CI, 1.10–2.75; OR, 1.99; 95% CI, 1.16–3.47). Another risk factor for ECC was left-sided vs distal UC (OR, 1.68; 95% CI, 1.00–2.86). Inflammatory bowel disease duration was a risk factor for skin and urinary tract cancers. Conclusions Perforating CD, extensive UC, and abdominal surgery for UC were identified as risk factors for overall incident cancer and for ECC. The clinical characteristics associated with severe IBD may increase cancer risk.

Therapeutic drug monitoring (TDM) is a useful tool for decision-making process in patients with inflammatory bowel disease (IBD) treated with anti TNF-α drugs, especially when experiencing loss of response. Growing evidences support the existence of exposure-response relationship with vedolizumab, but the utility and the appropriate use of TDM in clinical practice is still under debate. In this review, we summarize all evidences supporting a TDM-guided approach for patients treated with vedolizumab, suggesting three potential scenarios: 1) early prediction of long-term outcomes; 2) verifying the best strategy in case of loss of response; 3) maximizing therapeutic efficacy during maintenance treatment. Vedolizumab through concentrations20 µg/mL at week 6 and12 µg/mL seem to be associated with more favorable outcomes. No comparative studies have been conducted so far to demonstrate the advantage of adopting a TDM-guided versus an empirical approach for managing primary or secondary nonresponses. The frequency of antibodies to vedolizumab detection is quite low (up to 4% in pivotal trials), suggesting, unlike of anti TNF-α agents, a low probability of experiencing an immune-mediated pharmacokinetic failure in clinical practice. Future prospective and controlled studies are warranted to establish the guidance on the use of a TDM-guided approach with vedolizumab in clinical practice.

The first infliximab biosimilar for the treatment of inflammatory bowel disease (IBD) was introduced in 2013, and today eight anti-TNF alpha biosimilars (three for infliximab and five for adalimumab) have been approved and licensed by the European Medicines Agency. Biosimilars present great potential in terms of cost saving and possible consequential reinvestment in the health care system. The increasing knowledge about the process of biosimilar development and use in IBD and the publication of many prospective clinical studies and real-life clinical experiences have progressively changed the point of view of IBD physicians. In the present position paper, the Italian Group for the Study of Inflammatory Bowel Disease present and discuss their updated statements and positions on this topic, with emphasis on the concepts of biosimilarity and extrapolation across indications, safety and immunogenicity, interchangeability and switching, automatic substitution, and, finally, patient education about biosimilars.

Background Roughly 50% of patients with IBD have symptoms of psychological distress (Mikocka-Walus et al. 2019) but only 15.2% receive attention for their mental health although the effect on disease severity can be profound. It is necessary to have an easy-to-administer psychological distress screening tool. The distress thermometer (DT) is a single-item distress screening scale with 11-likert response widely used in oncological patients. The aim of study was to determine whether the single-item DT compared favourably with IBD clinical indices and time consuming measures currently used to screen for distress. Methods Two hundered and twenty IBD patients (51.43% male) who were recruited in eight Italian hospitals completed the DT and identified the presence or absence of 34 problems using standardised problem list (PL). They completed the 14-item Hospital Anxiety and Depression Scale (HADS) and the 32-item Inflammatory Bowel Disease Questionnaire (IBDQ). Disease clinical indices have been collected for each patient (Mayo score, Harvey–Bradshaw Index–HBI, years of illness, and exacerbation in the last year). Using receiver operating characteristic (ROC) analyses validated the use of the DT in Italian IBD population. Results 47.6% reported anxiety and depression symptoms (HADS ≥15) and needs emotional care. Anxiety is much more associated (43.8%) than depressive problems (26.2%). Data are confirmed by responses to DT and PL: 44.5% of patients reported moderate–severe emotional distress (TD ≥ 5), 43.1% of patients report nervousness and worry, 27.1% reported depression. We observed a strong positive correlation between IBDQ and HADS (r = 0.74, p < 0.001) and DT (r = 0.58, p < 0.001), while there was a slightly smaller association with Mayo score (r = 0.46, p < 0.001) and HBI (r = 0.39, p < 0.001). There was not a statistical significant correlation between disease indices and the emotional distress as measured by HADS or DT. ROC analyses showed that a DT cutoff score of 5 or higher had optimal sensitivity (83%) and specificity (68%) relative to the HADS score as ‘gold’ standard. DT scores yielded area under the curve estimates relative to the HADS cutoff score indicative of good overall accuracy (AUC = 0.81–95% CI: 0.77–0.85). Conclusion Our study confirms that anxiety and depression symptoms are associated with IBD. This is the first study that demonstrated that DT is an easy-to-administer screening tool of psychosocial distress in IBD population. We propose that gastroenterologists use DT to identify patients with psychological distress: an early psychological support and a multidisclinar equipe can determinate a patient’s better disease course (Mawdsley et al. 2005). Our analyses indicated that using a DT’s cutoff of 5 to indicate high levels of distress.

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.

BACKGROUND We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn's disease [CD]) were enrolled. Four hundred fifty-nine patients were naive to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. CONCLUSIONS In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

BACKGROUND AND AIMS Empirical dose intensification and therapeutic drug monitoring [TDM] of infliximab [IFX] trough levels [ITLs] and antibody to infliximab [ATI] assays are recognized approaches for managing loss of response [LoR] in patients with inflammatory bowel disease [IBD]. The aim of the study was to compare these two interventions in a clinical setting, in terms of effectiveness and cost savings. METHODS Consecutive IBD patients experiencing LoR were clinically managed according to a TDM algorithm. A historical group of empirically treated patients, for whom sera for ITLs and ATI assays had been collected, served as the control group. Clinical outcomes 12 weeks after the therapeutic interventions were compared between the two groups. A cost-minimization analysis was performed to compare the economic impact of these two approaches. RESULTS Ninety-six patients were enrolled prospectively and compared with 52 controls. The two cohorts were similar in characteristics and in the distribution of TDM results. In the prospective cohort, however, we observed less IFX dose escalations compared with in the controls [45% versus 71%, p = 0.003]. Also, more patients were switched to a different anti-TNFα in the prospective cohort than in the control cohort [25% versus 4%, p = 0.001]. The percentages of patients achieving a clinical response at 12 weeks were 52% and 54% for the prospective and control groups, respectively. By cost analysis, we estimated a savings of 15% if the TDM algorithm was applied. CONCLUSIONS In our population, applying a TDM algorithm for LoR to IFX resulted in less dose escalations, without loss of efficacy, compared with empirical adjustment. In addition, the TDM approach was cost-effective.

Background Infliximab is effective as rescue therapy in severe corticosteroid-refractory ulcerative colitis. The optimal dose regimen and the long term benefits are not well defined. The aim of the present study was to evaluate short- and long-term colectomy rate in a cohort of patients with severe corticosteroid-refractory ulcerative colitis who received a three-dose infliximab induction regimen. Methods One hundred and thirteen patients admitted to 11 Italian IBD referral centres and treated with infliximab according to an intention to treat three-dose regimen were included. The co-primary endpoints were 3- and 12-month colectomy rate. The secondary end-points were the overall colectomy-free survival and the identification of predictors of colectomy. Results The 3- and 12-month colectomy rates were 18.6% (95%CI 11.8%–26.9%) and 25.6% (95%CI 17.9%–34.7%) respectively. High CRP values and severe endoscopic lesions were associated with the risk of colectomy: Risk Ratio (RR) = 2.15 (95%CI 1.05–4.36), and RR = 5.13 (95%CI 1.55–16.96), respectively. In patients escaping early colectomy, the probability of a colectomy-free course at 12, 24, 36 and 60 months was 91%, 85%, 81% and 73%, respectively. Endoscopic severity was the only predictor of long term colectomy (RR = 7.0; 95%CI 1.09–44.7). Adverse events occurred in 16 patients (14%); there was one death (0.88%) due to pulmonary abscess. Conclusions Infliximab is an effective and safe rescue therapy for severe corticosteroid-refractory ulcerative colitis. A three-dose induction regimen seems to be the treatment of choice for preventing early colectomy. Severe endoscopic lesions appear to be predictor of short- and long-term colectomy.

Inflammatory bowel disease (IBD) is commonly associated with peripheral inflammatory arthritis, and it has been estimated that as many as 12% of IBD patients report these manifestations. However, rheumatoid arthritis (RA) is rarely associated with ulcerative colitis (UC). Among all the biological agents available, nine have been currently approved for the treatment of RA. Conversely, only Infliximab and recently Adalimumab have been approved for UC. In particular, the efficacy of Adalimumab in UC has been demonstrated by both recent randomized controlled trials and real-life studies. Moreover, Adalimumab is a well-established treatment for RA. Herein, we describe a patient with RA and UC treated successfully with ADA.

Background and aims Perception of quality of care is important in the management of patients with chronic diseases, particularly inflammatory bowel disease. Aims and methods This longitudinal study aimed to investigate variations of the Quality of Care through the Patients' Eyes (QUOTE-IBD) questionnaire scores one year after the basal evaluation in the Studio Osservazionale quaLita cUre malatTIe crOniche intestiNali (SOLUTION-1) study. Results Of the cohort of 992 patients, 936 were evaluable. The QUOTE-IBD score overcame satisfactory levels of more than the 80%, overall and in all subdomains except for the “Continuity of Care” sub-dimension (mean, 8.3; standard deviation, 1.49), scored satisfactory only by 34% of the patients. No significant changes in satisfaction were recorded overall, or considering patients subgroups. Significant differences were found at the end of the follow-up between physicians’ and patients’ perceptions of quality of care, with the former over-rating their performance in “Continuity of Cares” and under-rating “Costs”, “Competence”, and “Accessibility” sub-domains of the score (p Conclusion Perceived quality of care in a large cohort of Italian patients with inflammatory bowel disease remains unchanged after one-year follow-up and was not significantly affected by disease activity or therapeutic interventions. Differences between physicians’ and patients’ perceptions of quality of care should be taken into account.

Background The prevalence rates of hepatitis B virus (HBV) and hepatitis C virus (HCV) in patients with inflammatory bowel disease (IBD) have been reported to be higher than rates of infection among the general population. Although several cases of HBV infection reactivation in IBD patients treated with anti-TNF-α agents have been described, no evidence exists that anti-TNF-α therapy exacerbates the course of HCV. The aims of this study were to assess the prevalence of HBV and HCV and the rate of HBV vaccination in a population of IBD patients; and to investigate the long-term effects of anti-TNF-α therapy in the subgroup with HBV or HCV infections. Methods 301 patients were studied. Prior to the initiation of anti-TNF-α therapy, serum samples were tested for HBsAg and anti-HBc, anti-HBs and anti-HCV antibodies. During the follow-up, HBsAg and anti-HBc positive patients underwent periodic blood testing for viral markers, HBV-DNA and liver function; anti-HCV positive patients were assessed for liver function and HCV-RNA. Results One patient was HBsAg positive (0.3%), and 22 (7.3%) tested positive for anti-HBc. Seventy-two patients (23.9%) had been vaccinated for HBV. Four patients tested positive for anti-HCV (1.3%). During anti-TNF-α therapy, none of the patients experienced HBV or HCV reactivation. Conclusions HBV and HCV infection rates were similar to infection rates among the general population. Less than one quarter of the patients had been vaccinated against HBV. Anti-TNF-α agents appear to be safe for patients with HBV infection; more data are needed for patients with HCV infection.

Anti TNF-α agents have become a significant advance in the management of ulcerative colitis, proving to induce, with rapid onset, clinical and endoscopic remission. However, there is still a considerable unmet medical need in ulcerative colitis. Areas covered: The aim of this review was to summarize the patterns of use and the effectiveness of anti TNF-α in ulcerative colitis, highlighting their current position in treatment algorithms. Moreover, we set out a five-year view hypothesizing different treatment strategies. Expert commentary: The rapid onset of action and the effectiveness in inducing mucosal healing are the most important pros of anti TNF-α, supporting present and future use. Conversely, the relevant risk of loss of response and the safety profile have raised several concerns. In the future, the advent of different molecular targeting therapies can improve the management of UC patients, evolving to individually tailored strategies.

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.

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.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.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.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.

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 1 IL-4(+) IFN-gamma(+) 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.