Inflammatory bowel disease (IBD), which includes Crohn's disease (CD) and ulcerative colitis (UC), is a complex, immune-mediated, disorder which leads to several gastrointestinal and systemic manifestations determining a poor quality of life, disability, and other negative health outcomes. Our knowledge of this condition has greatly improved over the last few decades, and a comprehensive management should take into account both biological (i.e., disease-related, patient-related) and non-biological (i.e., socioeconomic, cultural, environmental, behavioral) factors which contribute to the disease phenotype. From this point of view, the so called 4P medicine framework, including personalization, prediction, prevention, and participation could be useful for tailoring ad hoc interventions in IBD patients. In this review, we discuss the cutting-edge issues regarding personalization in special settings (i.e., pregnancy, oncology, infectious diseases), patient participation (i.e., how to communicate, disability, tackling stigma and resilience, quality of care), disease prediction (i.e., faecal markers, response to treatments), and prevention (i.e., dysplasia through endoscopy, infections through vaccinations, and post-surgical recurrence). Finally, we provide an outlook discussing the unmet needs for implementing this conceptual framework in clinical practice.

BACKGROUND:Disease heterogeneity, according to the age at onset, has been reported in Crohn's disease (CD).OBJECTIVE:This study aimed to compare natural history in CD patients diagnosed ≤17 (early onset (EO)) versus ≥60 (late onset (LO)) years old.METHODS:EO CD and LO CD patients referred to two Italian inflammatory bowel disease (IBD) centres were included. Relevant data comprised sex, current smoking, disease location and behaviour, IBD family history, extra-intestinal manifestations and use of medical/surgical therapy during the follow-up period.RESULTS:Among 2321 CD patients, 160 met the inclusion criteria: 92 in the EO and 68 in the LO group (mean follow-up 11.7 ± 7.7 years). Family history of IBD was more frequent in EO compared to LO CD (26% vs. 4%; p < 0.0001). Ileocolonic, upper gastrointestinal and perianal involvement occurred more frequently in EO compared to LO CD (56% vs. 21%, p < 0.0001; 17% vs. 3%, p < 0.01; and 38% vs. 19%, p < 0.01, respectively). Progression to complicated disease occurred more frequently in EO CD (40% vs. 10% p < 0.005), with an increased use of corticosteroids and anti-tumour necrosis factor alpha agents within 10 years since diagnosis (81% vs. 58%, p = 0.004, and 36% vs. 16%, p = 0.01, respectively), while the cumulative probability of surgery did not differ between the two groups.CONCLUSIONS:Patients with EO CD are more likely to develop a more aggressive disease with perianal involvement and a greater use of drug treatment compared to those with LO CD, without carrying an increased need for surgery.

OBJECTIVE:The recurrence of Crohn's Disease after ileo-colonic resection is a crucial issue. Severe endoscopic lesions increase the risk of developing early symptoms. Prevention and treatment of post-operative Endoscopic Recurrence (ER) have been studied with conflicting results. We compare effi cacy of azathioprine (AZA) vs. high-dose 5-aminosalicylic acid (5-ASA) in preventing clinical recurrence and treating severe post-operative ER.PATIENTS AND METHODS:We performed a 1-year multicenter randomized double-blind double-dummy trial. Primary end-points were endoscopic improvement and therapeutic failure (clinical recurrence or drug discontinuation due to lack of efficacy or adverse events) 12 months after randomization. We also performed a post-trial analysis on symptomatic and endoscopic outcomes 10 years after the beginning of the trial, with a median follow-up of 60 months.RESULTS:Therapeutic failure occurred in 8 patients (17.4%) within 12 months from randomization, with no significant difference between patients treated with 5-ASA (20.8%, 5 patients) and those with AZA (13.6%, 3 patients). Therapeutic failure was due to clinical recurrence in the 5-ASA group and to adverse events in the AZA group. Endoscopic improvement at 12 months was observed in 8 patients, 2 (11.8%) in the 5-ASA group and 6 (30%) in the AZA group. No serious adverse event was recorded. At the post-trial analysis (median follow-up 60 months), 47.8% (22/46) of patients experienced clinical recurrence: 54.2% (13/24) in the 5-ASA group and 40.9% (9/22) in the AZA group, p=0.546. Patients treated with AZA had lower risk of drug escalation. Clinical recurrence was associated with smoking (p=0.031) and previous surgery (p=0.003).CONCLUSIONS:Our trial indicates that there was no difference in terms of treatment failure between 5-ASA and AZA in patients with severe ER. The main limit of AZA is its less favorable safety profile.

More than 70% of patients with Crohn's disease (CD) require surgery at least once during the course of their disease. Unfortunately endoscopic recurrence (ER) is up to 100% at 5 years with a risk of six-month severe ER (≥ i2) around 50% as showed in a previous Italian study. As well know symptomatic recurrence is strongly related to the severity of ER and ECCO guideline recommended prophylactic treatment after ileocolonic resection despite effectiveness of immunosuppressants remain debated. We performed a multi-centre randomised double-blind double-dummy trial to assess the role of azathioprine (AZA) vs. high dose of mesalamine (5-ASA) as treatment of early severe POR (Rutgeerts’ score ≥ i2) and as prophylaxis for clinical relapse (eligible patients and treatment allocation are showed in Table 1). Table 1 Primary outcomes: endoscopic improvement and clinical relapse after 12 months from randomisation. Post-trial analysis: data on clinical and endoscopic outcomes up to 10 years from T0. According to inclusion/exclusion criteria 46 patients were randomised (characteristics of screened patients are showed in Table 1): 65% males, overall median age at diagnosis and at surgery of 29.5 and 36.5 years, respectively. At the final analysis 17% of patients experienced a clinical relapse within 12 months from randomisation without differences between AZA and 5-ASA groups. Considering POR after 12 months of treatment no significant improvement were observed from T0 in both groups (p = ns). At the post-trial analysis, 53% of patients experienced a clinical relapse without differences between those previously treated with AZA or 5-ASA (p = ns). Smoking and previous surgery at T0 were risk factors for clinical relapse (p = 0.031 and 0.003). No significant AE were recorded. This multi-centre RCT does not show efficacy of AZA or 5-ASA in the treatment of severe POR or as prophylaxis for clinical relapse. In the post-trial analysis, in those with POR at 6-month from surgery, risk factors for severe CD (smoking and multiple surgery) could help to identify patients with worse prognosis to start biological therapy.

Background: Disease phenotype and outcome of late-onset Crohn’s disease are still poorly defined. Methods: In this Italian nationwide multicentre retrospective study, patients diagnosed ≥65 years (late-onset) were compared with young adult-onset with 16–39 years and adult-onset Crohn’s disease 40–64 years. Data were collected for 3 years following diagnosis. Results: A total of 631 patients (late-onset 153, adult-onset 161, young adult-onset 317) were included. Colonic disease was more frequent in late-onset (P < 0005), stenosing behaviour was more frequent than in adult-onset (P < 0003), but fistulising disease was uncommon. Surgery rates were not different between the three age groups. Systemic steroids were prescribed more frequently in young adult-onset in the first year, but low bioavailability steroids were used more frequently in late-onset in the first 2 years after diagnosis (P < 0.036, P < 0.041, respectively). The use of immunomodulators and anti-TNF’s even in patients with more complicated disease, that is, B2 or B3 behaviour (Montreal classification), remained significantly inferior (P < 0.0001) in late-onset compared to young adult-onset. Age at diagnosis, Charlson comorbidity index, and steroid used in the first year were negatively associated with the use of immunomodulators and biologics. Comorbidities, related medications and hospitalizations were more frequent in late-onset. Polypharmacy was present in 56% of elderly Crohn’s disease patients. Conclusion: Thirty-two percent of late-onset Crohn’s disease presented with complicated disease behaviour. Despite a comparable use of steroids and surgery, immunomodulators and biologics were used in a small number of patients.

BACKGROUND:No data are available on the variability in the clinical management of ulcerative colitis (UC) patients by Italian gastroenterologists. Therefore, improving the standards of UC care as provided by the National Welfare Clinical Path (PDTA), in accordance with the European Crohn's and Colitis Organization (ECCO) guidelines for UC, is not easy.AIMS:To assess the management of UC by Italian gastroenterologists in a real-life setting taking into account its variability.METHODS:This prospective, cross-sectional, observational study included IBD-specialized gastroenterologists (GSIBDs) and general gastroenterologists (GGs) working in Italian public hospital units. Consecutive patients with an UC flare were enrolled and the medical treatment evaluated. For each center, the physician in charge of the study (16 GSIBDs and 10 GGs) was administered two electronic questionnaires.RESULTS:Among 26 units, 573 UC patients were enrolled. Good adherence to the European guidelines was reported; GSIBDs reported greater adherence than GGs with a higher prescription of rectal and combination therapy in mild to moderate distal disease and a higher rate of hospitalization in severe UC.CONCLUSION:The management of UC by Italian gastroenterologists in clinical practice is good according to the ECCO consensus recommendations, though some discrepancies are present between GSIBDs and GGs.

Background: The comparison of effectiveness and safety of anti-tumor necrosis factor-alpha agents for the treatment of inflammatory bowel disease (IBD) is relevant for clinical practice and stakeholders. Objective: The objective of this study was to compare the risk of abdominal surgery, steroid utilization, and hospitalization for infection in Crohn's disease (CD) or ulcerative colitis (UC) patients newly treated with infliximab (IFX) or adalimumab (ADA). Methods: A retrospective population-based cohort study was performed using health information systems data from Lazio region, Italy. Patients with CD or UC diagnosis were enrolled at first prescription of IFX or ADA during 2008-2014 (index date). Only new drug users were followed for 2 years from the index date. IFX versus ADA adjusted hazard ratios were calculated applying "intention-to-treat" approach, controlling for several characteristics and stratifying the analysis on steroid use according to previous drug utilization. Sensitivity analyses were performed according to "as-treated" approach, adjusting for propensity score, censoring at switching or discontinuation, and evaluating different lengths of follow-up periods. Results: We enrolled 1,432 IBD patients (42% and 83% exposed to IFX for CD and UC, respectively). In both diseases, treatment effects did not differ in any outcome considered, and sensitivity analyses confirmed the results from the main analysis. Conclusion: In our population-based cohort study, effectiveness and safety data in new users of ADA or IFX with CD or UC were comparable for the outcomes we tested.

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-TNFa 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.

The two main forms of intestinal bowel disease, namely ulcerative colitis and Crohn’s disease, are not curable but can be controlled by various medical therapies. The Italian Group for the Study of Inflammatory Bowel Disease (IG-IBD) has prepared clinical practice guidelines to help physicians prescribe corticosteroids and immunosuppressive drugs for these patients. The guidelines consider therapies that induce remission in patients with active disease as well as treatment regimens that maintain remission. These guidelines complement already existing guidelines from IG-IBD on the use of biological drugs in patients with inflammatory bowel diseases.

Background: Therapeutic drug monitoring (TDM) of infliximab for inflammatory bowel disease (IBD) is being increasingly proposed, particularly for managing the loss of response (LOR), as an alternative to empirical dose adjustment. Our aim was to verify in a prospective multicenter cohort the usefulness and cost-effectiveness of applying an algorithm based on TDM, modified from Steenholdt C. et al. 2014. Methods: We recruited consecutive IBD patients, experiencing a LOR to infliximab while on maintenance therapy from at least 4 months, for which the assay of infliximab trough levels (ITL) and of antibodies to infliximab (ATI) was available for subsequent therapeutic decisions. We compared this cohort with a retrospective one composed of patients for which a serum sample was collected at the time of LOR diagnosis although the clinical decisions were made blinded to ITL and ATI results. We evaluated the clinical outcome after 12 weeks, also in term of direct costs for anti-TNF therapy, verifying the agreement with an algorithm considering a therapeutic ITL cut-off of 3 ug/ml. ITL and ATI were assayed by ELISA technique (Lisa Tracker-Duo® Infliximab, Theradiag, Marne-la-Vallée, France). Results: Ninety-six patients were evaluable in the prospective cohort, and they were compared with 52 retrospectively studied. The two cohorts were similar in characteristics and distribution of TDM results. In the prospective cohort, however, we observed that less optimizations (infliximab dose increase and/or interval decrease) were performed compared to the retrospective one (45% versus 71%, p=0.003). In parallel, more patients were shifted to adalimumab in the prospective cohort than in the retrospective one (25% versus 4%, p=0.001). No difference was detected among the two cohorts in terms of clinical efficacy of the therapeutic modifications: the percentage of patients achieving a clinical response at 12 weeks were 52% and 54%, respectively. However, we estimated a cost saving of up to 98.872 Euros if the algorithm was correctly applied to the retrospective cohort, avoiding unjustified dose optimizations in 28 cases, with a global cost for TDM of 4.160 Euros for the whole retrospective cohort. Conclusions: In our IBD population, applying TDM for infliximab LOR management resulted in 26% less drug dose optimizations, without loss of efficacy as compared to empirical treatment adjustment. TDM use in LOR management appears to be cost-effective, allowing a more rational use of infliximab without unjustified dose intensification.

Background: The Infliximab biosimilar CT-P13 has been used since March 2015 in Italy. We report here a prolonged follow-up of a prospective, nationwide, multicentre, observational cohort (PROSIT) evaluating the safety, and clinical/endoscopic efficacy. Methods: A structured data base has been used to record relevant serious adverse events (SAEs), clinical efficacy (partial Mayo [PM] and Harvey-Bradshaw Index [HBI]), inflammatory markers (CRP and calprotectin [calpro]) and endoscopic findings (endoscopic Mayo [EM] and Simple Endoscopic Score for Crohn's Disease [SES-CD]). Results: Results 680 consecutive patients (373 CD, 307 UC) have been included from academic (n=13) and non-academic (n=12) referral centers. Age at the disease onset was 30.5±13.9 years in CD and 33.7±13.3 years for UC. 400 patients were naïve to anti-TNFα (192 CD, 208 UC), 171 patients (115 CD, 56 UC) had a previous exposure to one or more biologics, whereas the remaining 109 patients (66 CD, 43 UC) were switched after a mean of 18±10 previous infusions of infliximab (range 3–72). All patients were included in the safety evaluation. A total number of over 4,000 infusions were recorded; 92 SAEs (13.5%) were reported, leading to stop biosimilar in 73 patients (10.7%). IRs were 46, leading to stop biosimilar in 38 subjects (5.6%), and were significantly more frequent in patients pre-exposed to anti-TNFα (p<0.02). Primary failure was recorded in 55/680 patients (8.1%). The efficacy of therapy was calculated following the induction regimen or at least two infusions after switching in 601 patients with a mean follow-up of 32 weeks (range 8–83). As a whole 274 patients were in remission (45.6%), 186 were considered responders (30.9%) and 62 lost the response (10.3%). The remaining patients were failure or stopped the therapy. 377 patients (222 CD) and 150 patients (89 CD) completed the follow-up of 6 and 12 months, respectively. After 1 year of CT-P13 therapy, HBI, SES-CD, CRP, and Calpro significantly (p<0.01) dropped in CD patients (7.1±3.4 vs 3.2±2; 10.1±42 vs 3±2.6; 1.9±1.7 mg/dl vs 0.9±0.8; 565±485 mg/kg vs 126±133 respectively), compared to baseline. Similarly, in UC patients PM, EM, CRP, and Calpro (6.1±2.3 vs 1.9±1.8; 2.1±0.6 vs 1.3±0.8; 3±2 mg/dl vs 0.9±0.7; 759±516 mg/kg vs 72±65, respectively) were significantly reduced (p<0.001). A deep remission was achieved in 57% and 50% of CD and UC patients in whom all information were available, respectively. Conclusions: This is one of the largest prospective cohort of patients with IBD treated with CT-P13. After a more prologed follow-up, no further signals of difference in safety and clinical efficacy has been observed.

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 quaLità 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 < 0.05 for all). 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: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohn's disease.Methods: A prospective, multicenter, cohort study using a structured database.Results: Consecutive patients (313 Crohn's disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti-tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 6 14 infusions of infliximab. The mean follow-up was 4.3 6 +/- 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti-tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05-7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64).Conclusions: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

ObjectiveNeutralising pro-inflammatory interleukin-6 (IL-6) may effectively treat Crohn’s disease (CD). Effects of PF-04236921, an anti-IL-6 antibody, in adults with CD are reported.DesignParallel-group, dose-ranging, double-blind trial with 4-week screening and 12-week treatment periods. After induction, patients entered 28-week follow-up or 48-week open-label extension (OLE) with 28-week follow-up. Adults with confirmed CD and inadequate response to anti-tumour necrosis factor (TNF) therapy were included. Induction study: 249 patients randomised 1:1:1:1 to placebo, PF-04236921 10, 50 or 200 mg by subcutaneous injection on days 1 and 28. OLE study: PF-04236921 50 mg every 8 weeks up to six doses followed by 28-week follow-up.Results247 patients were randomised and received treatment in the induction study. The 200 mg dose was discontinued due to safety findings in another study (NCT01405196) and was not included in the primary efficacy analysis. Crohn’s Disease Activity Index (CDAI)-70 response rates with PF-04236921 50 mg were significantly greater than placebo at weeks 8 (49.3% vs 30.6%, P<0.05) and 12 (47.4% vs 28.6%, P<0.05) and met the primary end point. Week 12 CDAI remission rates with PF-04236921 50 mg and placebo were 27.4% and 10.9%, respectively (16.5% difference; P<0.05). 191 subjects received treatment in the OLE. Common treatment-emergent and serious adverse events in both studies included worsening CD, abdominal pain and nasopharyngitis.ConclusionsPF-04236921 50 mg induced clinical response and remission in refractory patients with moderate-to-severe CD following failure of anti-TNF therapy. GI abscess and perforation were observed, a specific focus of attention during future clinical development.Trial registration numberNCT01287897 and NCT01345318.

BACKGROUND AND AIMS:Inflammatory bowel disease [IBD] patients are still under-diagnosed or diagnosed with serious delay. We examined whether diagnostic delay [DD] in IBD has changed over the last 60 years, and explored the risk factors of longer DD. METHODS:In total, 3392 IBD patients recorded in the registry of four IBD Italian centres were divided according to the year of diagnosis into a historical cohort [HC: 1955-84] and modern cohort [MC: 1985-2014]. DD, i.e. time lapse between onset of symptoms indicative of IBD and definitive diagnosis, was divided into four sub-periods [0-6, 7-12, 13-24, >24 months], which were correlated with age and disease location/behaviour at diagnosis. RESULTS:Median DD in IBD was 3.0 months, it was significantly [P < 0.0001] higher in Crohn's disease [CD] [7.1 months] than in ulcerative colitis [UC] [2.0 months], and did not differ either between the HC and the MC or over the last three decades. However, the proportion of patients with a DD>24 months was significantly [P < 0.0001] higher in the HC [26.0%] than in the MC [18.2%], and the same trend was evident over the last three decades [1985-94: 19.9%; 1995-2004: 16.4%; 2005-14: 13.9%; P = 0.04]. At logistic regression analysis, age at diagnosis >40 years (CD: odds ratio 1.73, 95% confidence interval [CI] 1.31-2.28, P < 0.0001; UC: 1.41, 95% CI 1.02-1.96, P = 0.04) and complicated disease at CD diagnosis [1.39, 95% CI 1.06-1.82, P = 0.02] were independently associated with a DD>24 months. CONCLUSIONS:DD duration has not changed over the last 60 years in Italy, but the number of IBD patients with a longer DD significantly decreased. Older age at diagnosis and a complicated disease at CD diagnosis are risk factors for longer DD.

Biological therapies are an important step in the management of Inflammatory Bowel Diseases. In consideration of high cost and safety issues there is the need to have clear recommendations for their use. Despite the American Gastroenterological Association and the European Crohn's and Colitis Organisation have published exhaustive Inflammatory Bowel Disease guidelines, national guidelines may be necessary as cultural values, economical and legal issues may differ between countries. For these reasons the Italian Society of Gastroenterology and the Italian Group for the study of Inflammatory Bowel Disease have decided to elaborate the Italian guidelines on the use of biologics in Inflammatory Bowel Disease. The following items have been chosen: definitions of active, inactive, steroid dependent and resistant disease; measures of activity; anti-tumor necrosis factor alpha therapy use in active steroid dependent and refractory luminal Crohn's Disease, in fistulising Crohn's Disease, in steroid dependent and resistant active Ulcerative Colitis; risk of cancer; risk of infections during anti-tumor necrosis factor alpha therapy; special situations. These guidelines are based on evidence from relevant medical literature and clinical experience of a national working group.