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Crohn’s disease (CD) is an immune-mediated condition characterized by the transmural inflammation of the gut tissue, associated with progressive bowel damage often leading to surgical intervention. As operative resection of the damaged segment is not curative, a majority of patients undergoing intestinal resections for complicated CD present disease recurrence within 3 years after the intervention. Postoperative recurrence can be defined as endoscopic, clinical, radiological or surgical. Endoscopic recurrence rates within 1 year exceed 60% and the severity, according to the Rutgeerts’ score, is associated with worse prognosis and can predict clinical recurrence (in up to 1/3 of the patients). Most importantly, about 50% of patients will undergo a reoperation after 10 years of their first intestinal resection. Therefore, the prevention of postoperative recurrence in CD remains a challenge in clinical practice and should be properly managed. We aim to summarize the most recent data on the definition, risk factors, assessment and treatment of postoperative CD recurrence.

Background The nocebo effect is a negative effect of a pharmacological or nonpharmacological medical treatment that is induced by patients' expectations, and that is unrelated to the physiological action of the treatment. The nocebo effect can negatively affect treatment outcomes. Aim To develop evidence-based consensus recommendations for the prevention and management of the nocebo effect in biosimilar-treated patients with IBD. Methods The "NOCE-BIO Consensus Group" was composed of 19 members from five European countries, and with different fields of expertise. A literature review on the nocebo effect, with specific focus on information about its prevention and management in biosimilar-treated IBD patients, was performed. Preliminary statements were formulated and voted on during a consensus group meeting held in Milan, Italy, in July 2018. A statement was accepted if >75% of participants voted 4 ("agree") or 5 ("strongly agree") on a scale of 1-5. Results Consensus was reached on 11 recommendation statements. Seven statements reached consensus after one voting round and four statements reached consensus after two voting rounds. All statements were supported by very low-quality level of evidence. The panel agreed that patient-health-care provider relationship is a key driver of acceptance of biosimilars, which limits the risk of negative bias and the nocebo effect. Lack of knowledge among patients and health-care providers about the effectiveness and safety of biosimilars should be minimized. Education about biosimilars needs to be tailored to the individual patient, and positive framing is recommended. Conclusions The nocebo effect is under-recognised in the era of biosimilars, although it may negatively impact on the cost-savings of biosimilars. Future research should focus on the magnitude, the risk factors, the impact, and the management of the nocebo effect in biosimilars-treated IBD patients.

Therapeutic drug and immunogenicity monitoring (TDIM) is increasingly proposed to guide therapy with biologics, characterised by high inter-individual variability of their blood levels, to permit objective decisions for the management of non-responders and reduce unnecessary interventions with these expensive treatments. However, TDIM has not yet entered clinical practice partly because of uncertainties regarding the accuracy and precision of enzyme-linked immunosorbent assays (ELISA). Here we report the characterisation of a novel surface plasmon resonance (SPR)-based TDIM, applied to the measurement of serum concentrations of infliximab, an antibody against tumour necrosis factor α (anti-TNFα), and anti-infliximab antibodies. SPR has the obvious advantages of directly detecting and measuring serum antibodies in minutes, avoiding the long incubation/separation/washing/detection steps of the methods proposed so far, reducing complexity and variability. Moreover, drug and anti-drug antibodies can be measured simultaneously. This new method was validated for sensitivity and reproducibility, and showed cost-effectiveness over commercial ELISA kits. This method may be applied to other biotherapeutics. These data pave the way for the development of SPR-based point-of-care devices for rapid on-site analysis.

Background and aims The role of new psychological factors such as psychopathological patterns and defense mechanisms in the care of inflammatory bowel disease (IBD) has been poorly investigated. We aimed to assess the psychological characteristics and defense mechanisms of IBD patients. Methods This was a single-center, observational, cross-sectional study. Consecutive adult IBD patients were enrolled and stratified according to disease activity. Sociodemographic and clinical data were collected, and validated questionnaires (Symptom Checklist-90-R [SCL-90-R]) for psychological distress, Defense Mechanism Inventory (DMI) for psychological defense mechanisms, and Inflammatory Bowel Disease Questionnaire (IBDQ) for quality of life (QoL) were administered. Results Two hundred one patients were enrolled: 101 in remission and 100 with active disease. The mean score for IBDQ was below the cutoff level (156.8 ± 37.8), with a significantly greater impairment of QoL in subjects with flares (136.5 vs 177.5, P < 0.001). Lower scores were associated with female gender. No patients had psychological scores above the cutoff for normality. Statistically higher SCL-90-R scores were found in active patients for obsessive-compulsive disorder (P = 0.026), depression (P = 0.013), anxiety (P = 0.013), phobic anxiety (P = 0.002), psychoticism (P = 0.007), global severity index (GSI) (P = 0.005) and positive symptom total (PST) (P = 0.001). A significantly increased probability of higher global indexes was associated with Crohn’s disease and disease flares. None of the defensive Defense Mechanism Inventory (DMI) styles resulted above the cutoff in our cohort. Conclusions Further data are needed to demonstrate the potential key role of psychological intervention in the therapeutic strategies utilized for IBD patients, and the identification of specific psychological patterns based on the patients profile is necessary to optimize psychological intervention.

The high cost of biological drugs for patients with inflammatory bowel disease (IBD) considerably impacts on health-care budgets. Since the patent of biological products expired, cheaper biosimilars have entered the market. Available data coming from real-world cohorts and clinical trials indicate that the efficacy and safety of biosimilars is comparable to that of the originator drugs. Treating IBD patients with a biosimilar may be complicated by the risk of the nocebo effect, a negative effect of a pharmacological or non-pharmacological treatment, induced by patients's expectations and unrelated to the physiological action of the treatment. The nocebo effect can negatively affect treatment outcomes and hamper the cost-savings of biosimilars. Reducing the nocebo effect requires a multidisciplinary effort of all health-care providers in charge of biosimilar-treated IBD patients. The aim of the review is to reflect the key messages of an international workshop on this topic, including viewpoints from the perspective of physicians, nurses, psychologists, pharmacists and patients.

Background The comparative accuracy of bowel ultrasound [US] versus magnetic resonance enterography [MRE] in combination with colonoscopy [CS] in assessing Crohn's disease [CD] and influencing the decision-making process is unknown. Methods Consecutive ileo-colonic CD patients seen in a tertiary referral centre were prospectively assessed by MRE, CS, and bowel US, within 1 week. Sensitivity, specificity, accuracy, positive predictive value [PPV], and negative predictive value [NPV] of bowel US in assessing localisation, enhancement [presence of vascularisation at Power Doppler], active disease [presence of ulcers at colonoscopy], strictures, fistulas, and abscesses were calculated using CS + MRE findings together as a reference standard. Two blinded inflammatory bowel disease [IBD] specialists reviewed MRE and bowel US findings and were asked to decide the therapeutic strategy [continue versus change therapy]. Kappa agreement with clinical decision was calculated. Results Sixty CD patients [36 with endoscopic disease activity, 28 with complications] were enrolled. For localisation, sensitivity, specificity, accuracy, PPV, and NPV of bowel US were 88%, 96%, 91%, 96%, and 85%, respectively; for enhancement, 87%, 92%, 89%, 93%, and 86%; for activity, 92%, 100%, 96%, 100%, and 94%; for strictures, 75%, 86%, 81%, 78%, and 83%; for fistulas, 100%, 98%, 98%, 66%, and 100%; for abscesses, 100%, 96%, 96%, 33%, and 100%. The concordance of management of CD patients based on bowel US or MRE findings, alone, compared with clinical decision, was 0.768 and 0.767, respectively [p

Background Infliximab (IFX) biosimilars CT-P13 and SB2 have comparable efficacy, safety, and immunogenicity to the originator Remicade (RMC). However, concerns about cross-switching patients between the 3 brands were raised in the absence of cross reactivity data between them. We aimed to determine whether antibodies to infliximab (ATI) in inflammatory bowel disease (IBD) patients cross-react with RMC, CT-P13, and SB2. Methods Based on previous ATI status, samples from 34 patients participating in the BIOSIM01 study (13 RMC, 9 CT-P13, and 12 switchers) were selected. Patients were treated with either RMC only, or CT-P13 only, or with RMC switched to CT-P13. Additionally, 28 IFX-naive patients were assayed as controls. In total, 180 samples were analyzed. ATI trough levels were measured in parallel with 3 different bridging Enzyme Linked Immunosorbent Assays constructed using the 3 drugs. Spearman's coefficient and percentages of agreement were used to study the correlation between each assay. Results In total, 76 samples out of 152 IFX-treated patient samples were ATI-positive (30 RMC, 14 CT-P13, and 32 switchers). All resulted ATI-positive when either CT-P13 or SB2 bridging assays were used. The overall percentage of agreement was 100% when compared either with CT-P13 or SB2 assays. No significant differences were found among ATI levels and coefficients (Spearman's 0.98 to 1.0, P < 0.0001). Conclusions ATI of RMC-treated, CT-P13-treated or RMC to CT-P13 switched patients show full cross-reactivity with CT-P13 and SB2. Findings suggest that immunodominant epitopes in the reference and CT-P13 drugs are equally present in SB2. Data support full interchangeability between biosimilars in regard to immunogenicity.

A considerable percentage of patients with ulcerative colitis (UC) do not respond to therapies, including anti-tumor necrosis factor (TNF) drugs and vedolizumab, or lose response over time. Hence the continuing need to find new therapeutic strategies and novel drugs to control this chronic debilitating disease. Increased levels of interleukin (IL)-23 and T helper (Th) 17 cell cytokines have been found in intestinal mucosa, plasma, and serum of patients with inflammatory bowel disease (IBD). IL23-blocking has been shown to reduce the severity of inflammation in experimental colitis. Lastly, ustekinumab, a monoclonal antibody (mAb) to the p40 subunit of IL-12 and IL-23, has showed good efficacy and safety profile in patients with Crohn's disease (CD). This review aims to discuss the available data on IL-23 and Th17 cell pathways in UC, in order to define the role of IL-23 as possible target for the treatment of UC.

Introduction: Inflammatory bowel diseases (IBD), which include Crohn's disease and ulcerative colitis, are lifetime chronic inflammatory disorders. Over the past few decades, new therapeutic approaches, including early and more effective intervention with immunomodulators and biological agents, increased the possibility of a favorable modification of the natural history of IBD. Despite this progress, there is still a need to explore new therapeutic options.Area covered: Here, we review the literature about the role of therapeutic sphingolipids in inflammatory bowel disease patients.Expert opinion: Despite the great increase of treatment options in the last 20 years, many patients still do not respond to the induction therapy (primary non-responders) or lose response over time (secondary responders). Small-molecule drugs are a promising group of drugs with low molecular weight, an oral route of administration, and low immunogenicity offering several advantages when compared to biologics such as anti-TNFs and anti-integrins. Sphingosine-1-phosphate (S1P) receptor modulators are some among the new small molecules currently under clinical investigation for the treatment of IBD.

Intestinal fibrosis, driven by chronic inflammation in Crohn’s disease, can be defined as an excessive accumulation of extracellular matrix in the affected gut segment ultimately leading to an impaired wound healing and cumulative tissue damage, possibly resulting in organ dysfunction, formation of stenotic lesions and necessity of surgical intervention. Despite continuous advances in developing novel treatment modalities targeting different pathways to control chronic gut inflammation in CD, no effective anti-fibrotic agents have been released, to date. Thus, a better understanding of the molecular and cellular mechanisms underlying intestinal fibrosis is key to move this area of investigation forward.

Introduction: Biosimilars represent great potential in cost saving and re-investment opportunities in healthcare and allow patients greater access to effective mAbs. Infliximab biosimilars are succ...

Introduction: Biosimilars present a considerable potential to reduce costs related to clinical management allowing health-care providers to reinvest this money, leading to a wider access to an effective biological treatment with monoclonal antibodies (mAb). Infliximab biosimilars have already been incorporated in daily clinical practice and are currently used in all indications for which the reference product (RP) was approved. Areas covered: In the next few years, also adalimumab biosimilars will become available for the treatment of inflammatory bowel disease (IBD). In fact, several of them (ABP501, BI 695501, GP2017, and SB5) have been approved by the European Medicines Agency (EMA) with the same indications of the reference product (Humira ®). Initial preclinical data proved a strong similarity between all biosimilars and the RP. Moreover, phase 3 studies in rheumatoid arthritis and psoriasis showed no differences in terms of efficacy, safety, and immunogenicity. Data on IBD patients are urgently needed. Expert opinion: Biosimilars of adalimumab showed equivalent clinical efficacy to the RP in other immunemediated diseases. However, defining the ideal patient’s profile to receive or to be switched to a biosimilar, choosing one biosimilar vs. another, or cross-switching among biosimilars, will become the next challenge in IBD.

Crohn's disease (CD) is an immune-mediated inflammatory bowel disease, in which inflammation is driven by a complex interaction between the microbiota, immune cells, genes and mediators. New mechanisms of action and several cytokines have been identified as factors involved in the inflammatory process in CD, and many new molecules have been developed to treat this complex disease. New agents have been developed that target leukocyte trafficking, block or adhesion molecules for example, as well as the development of antibodies against classic inflammatory cytokines or therapies directed against IL-12/23 and Janus kinases. The development of selective mechanisms of action and targeting of different cytokines or inflammatory mediators for each patient presents the biggest challenge for the future in CD therapy. Such agents are currently at different phases of development. We aim to review the current literature data on a targeted approach in CD, which could be promising alternative approach for CD patients in the near future.

BACKGROUND Inflammatory bowel diseases [IBD] are characterised by significant quality of life [QoL] impairment, as well as illness perception. Assessing illness perception may help in optimising the management of IBD patients. METHODS In this single-centre, observational, transversal study, consecutive adult IBD patients were enrolled and stratified according to disease activity [active/remission]. The Revised Illness Perception Questionnaire [IPQ-R], based on identity, opinions, and causes of their disease was administered to all patients. Comparison within IPQ-R parameters was done between clinically active patients and those in remission. RESULTS A total of 201 patients were enrolled (Crohn's disease [CD] = 47%). The most frequently reported IBD-related symptoms were fatigue [86.9%], loss of strength [83.3%], pain [80%], and weight loss [68.2%]. Active patients reported significantly more frequently fatigue [p = 0.005], sore eyes [p = 0.046], and sleep difficulties [p = 0.001], and reported more symptoms than controls [p = 0.023]. Overall, the patients considered stress [84.1%], altered immunity [69.32%], family problems [49.4%], and emotional status [40.9%] as the main causes of IBD. Work overload was more frequently considered as a disease cause in active patients than in those in remission [p = 0.002]. Smoking, family history, and previous inadequate therapies were considered as a relevant risk factor for illness by only 20% of patients. Active IBD patients had more negative thoughts on prognosis [p = 0.001] and more negative emotions [p < 0.0001]. Patients in remission were significantly more convinced about treatment control [p = 0.007] and had clearer understanding of illness [p = 0.009]. CONCLUSIONS Illness perception is impaired in IBD patients. Adequate educational and psychological support may be helpful in the optimal management of IBD patients.

Janus kinase inhibitors are small molecules, orally administered, under development for the treatment of ulcerative colitis. These molecules reduce the immune response, blocking the signal transduction of multiple cytokines implicated in the activation of inflammation. Currently multiple JAK inhibitors are being evaluated in clinical trials. The aim of this review is to examine the efficacy and the safety of the JAK inhibitors being tested and to discuss the available data on the use of these drugs in moderate-to-severe ulcerative colitis, in order to understand how these new molecules can fit into the therapeutic algorithm of patients with ulcerative colitis.

There has been considerable literature on sexual issues in women with inflammatory bowel disease (IBD), but relatively little attention has been paid to these aspects in men. To review the available literature and to provide the best management of sexual and reproductive issues in male patients with IBD. The scientific literature on sexual and reproductive issues in men with IBD was reviewed. Several factors, including surgical and medication treatments, disease activity, lifestyle, and psychological factors, may play a role in the development of infertility and sexual dysfunction and may negatively impact pregnancy outcomes. Proctocolectomy with ileal pouch-anal anastomosis increases the risk of erectile and ejaculatory dysfunction by up to 26%. A treatment with sildenafil can be effective. Sperm banking should be advised to young men with IBD before surgery. Both sulfasalazine and methotrexate may be responsible for reversible sexual dysfunction and infertility. Furthermore, sulfasalazine should be switched to mesalazine at least 4 months before conception because of a higher risk of congenital malformations in pregnancies fathered by men treated with this drug. Psychotropic drugs, frequently used in IBD, may cause sexual dysfunction up to 80%. Last but not the least, voluntary childlessness occurs frequently, mainly because of concerns about medication safety in pregnancy and fear of transmitting disease. Accurate counseling, and where necessary, psychological support can decrease any misperceptions and fears. Close collaboration between the gastroenterologist and the patient is recommended for the best management of these relevant, neglected aspects in men with IBD.

INTRODUCTION Gut-specific homing is mainly mediated by the expression of MAdCAM-1 on endothelial cells. An increase in MAdCAM-1 expression has been shown in patients with inflammatory bowel disease (IBD). Areas covered: PF-00547659 is a fully human monoclonal antibody (mAb) toward MAdCAM-1 on endothelial cells, blocking its binding with the α4β7 integrin on leukocytes. This review discusses the available data on effectiveness and safety of PF-00547659 in IBD. Expert opinion: A phase II study in moderate-to-severe ulcerative colitis (UC) patients, both naive and previously exposed to anti-tumor necrosis factors, showed that PF-00547659 was superior to placebo for induction of remission, response, and mucosal healing at week 12. In contrast, preliminary results in a similar study in Crohn's disease (CD) did not show a superiority of PF-00547659, suggesting that PF-00547659 may have limited impact over CD outcomes. However, the time frame needed to evaluate clinical effectiveness of PF-00547659 may be longer in CD patients, given its transmural characteristic. In addition, it should be taken into consideration the possibility of incorporating new tools and more objective parameters in disease assessment that are proven to better correlate with inflammation. Future randomized-controlled trials are needed to confirm the efficacy of PF-00547659 in CD.

Background Colonoscopy [CS] is the standard for assessing disease activity in ulcerative colitis [UC], although invasive and poorly tolerated. Bowel ultrasound [BUS] may be a valid alternative in UC patients; however, the comparative accuracy between BUS and CS is unknown. Methods Consecutive patients with UC were prospectively assessed by CS and BUS. Colonic wall thickening [CWT >3 mm], colonic wall flow at power Doppler [CWF], colonic wall pattern [CWP], and presence of lymph nodes evaluated at BUS were compared with CS. The endoscopic activity was assessed according to the Mayo endoscopic sub-score [0–3]. All BUS investigations were performed by two independent gastroenterologists and the kappa statistic for agreement was calculated. Ultrasonography-based criteria (Humanitas Ultrasound Criteria [HUC]) were developed. Results A total of 53 UC patients [56% with left-sided colitis, 19% with pancolitis] were prospectively enrolled. Of these, 22 patients had mucosal healing [Mayo endoscopic sub-score 0–1] and 31 patients were in endoscopic activity. CWT, CWF, hypoechogenic CWP and the presence of lymph nodes significantly correlated with endoscopic activity [p < 0.05]. CWT [p = 0.01] and CWF [p = 0.09] were independent predictors for endoscopic activity. The HUC developed are: [i] the presence of a CWF and CWT > 3 mm; or [ii] the absence of a CWF and CWT > 4.43 mm. They showed high accuracy for the detection of disease activity [sensitivity 0.71, specificity 1.00]. The interobserver agreement for BUS was excellent [kappa 0.86]. Conclusions BUS is a non-invasive, easy-to-use tool to manage UC patients in clinical practice. HUC were very accurate in assessing disease activity in UC patients.

BACKGROUND. The urea Breath-test is a widely-used method to detect the presence of Helicobacter pylori (HP) infection. Recently, new technologies were introduced, to obtain an immediate test result by continuous breath samples analysis after labeled urea intake. The total test duration is shorter than 20 minutes. METHODS. The study compared two diagnostic methods requiring the administration of EXPIROBACTER (R) (Sofar SpA, Trezzano Rosa, Milan, Italy) 100 mg as a source of labeled urea. Subjects with clinical indication to urea breath test for H. pylori were enrolled. This study was designed to directly compare the accuracy of urea breath test performed with both the classic method and BreathID (R) (Exalenz Bioscience, Inc., Manasquan, NJ, USA). Each patient simultaneously underwent to both tests, to measure the concordance between the results (positive or negative test), minimizing the risks of differences related to the intra- and inter-individual variability. RESULTS. Forty-six subjects were enrolled. Forty-one patients (91.1%) were found negative with both methods and 5 (10.1%) were positive for H. pylori infection in both tests. Correlation between the two methods was excellent(kappa=1.00). BreathID (R) was significantly preferred by patients, with a 7.83 (95% CI: 3.35 to 12.30, P=0.001) difference in mean patient satisfaction, measured by a Visual Analogue Scale (VAS). No adverse event was observed. CONCLUSIONS. Correlation between the two methods was excellent. Moreover, the patient satisfaction, measured by VAS, showed a significantly greater acceptance of BreathID (R) method. This study support the use of a product containing C-13-urea 100 mg and citric acid for immediate determination of HP infection by urea breath test performed with BreathID (R)

Adaptive immunity in intestinal inflammation may play a key role in the pathogenesis of Crohn's disease. In particular, interleukin (IL)-23 may be a key mediator in chronic intestinal inflammation by inducing the differentiation of naïve CD4 + T cells into Th17, with the production of several pro-inflammatory cytokines. Furthermore, IL-23 induces interferon-γ (IFN- γ) production from activated T cells, a critical cytokine in innate and adaptive immunity against infections. Areas covered: We aim to review the available data from literature regarding the role of IL-23, with a more specific focus on the recent progresses in the therapeutic modulation of this cytokine. Expert commentary: Increased knowledge regarding the role of IL-23 has allowed for the development of effective therapeutic progresses by blocking the IL-23 mediated pathways. Primary or secondary loss of response to anti-TNF therapies in Crohn's disease patients during the first year is widely described in literature: the development of new drugs, with alternative mechanisms of action, is thus a key point to consider for the optimal management of these subjects. Drugs blocking the IL-12/23 pathway showed a good efficacy and safety profile in immune-mediated diseases Further studies are necessary regarding the role of the single blockade of IL-23.

The use of complementary and alternative medicine is wide-spread not only in Eastern countries, but also in the Western world. Despite the increasing evidence on the harmful effects induced by several naturopathic/homeopathic products, patients seem to appreciate these remedies, in particular because they consider them to be absolutely safe. This same phenomenon is common among inflammatory bowel disease (IBD) patients. As a result there is a significant request for scientific data to evaluate both the efficacy and safety of these remedies, and to support the use of such medications as adjuvant treatments to biological and synthetic drugs. We aimed to review the current evidence on efficacy and safety of some natural products that are believed to be effective in inflammatory bowel disease. Further perspectives for the clinical use of herbal products and strategies for improving knowledge about herbal products in IBD are also discussed.

Antiadhesion molecules are effective and safe in patients with ulcerative colitis (UC). Etrolizumab, a monoclonal antibody targeting both α4β7 and αEβ7, represents a promising therapy for patients with UC, since this novel mechanism of action may be effective in blocking leukocyte recruitment both at the vascular and at the mucosal level. Preliminary studies show that etrolizumab is effective in inducing clinical response and remission, and mucosal healing. Moreover, new predictors of response have recently been identified, opening the way to a tailored therapeutic approach. This review of the literature aims to present and discuss the most recent evidence on etrolizumab in UC, focusing on the clinical implications of the use of etrolizumab in UC.