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Background Anemia is a common extraintestinal manifestation of inflammatory bowel disease (IBD), with a 6% to 74% prevalence and a negative impact on patient survival and quality of life, although the prevalence is apparently declining due to improved disease treatment. We aimed to investigate the prevalence, pathogenesis, and clinical correlates of anemia in Italian patients with IBD. Methods A multicenter, prospective, observational study, involving 28 Italian gastroenterology centers, was conducted to investigate the epidemiology and consequences of IBD-associated anemia. Clinical and laboratory data of anemic patients were obtained at study enrolment. Results Anemia was diagnosed in 737 of 5416 adult IBD outpatients (prevalence 13.6%); females were more commonly affected than males (odds ratio, 1.5; 95% confidence interval [CI], 1.2–1.7) and had more severe anemia. In the majority of cases, anemia was due to iron deficiency (62.5% of cases; 95% CI, 58.3%–66.6%), either isolated or in association with inflammation and/or vitamin deficiencies; anemia of inflammation accounted for only 8.3% of cases. More severe anemia was associated with increasing fatigue and worse quality of life. Only 68.9% of anemic patients with iron deficiency (95% CI, 63.4%–73.8%) and 34.6% of those with vitamin deficiencies (95% CI, 26.2%–44.2%) were properly treated with supplementation therapy. Conclusions In Italy, the prevalence of IBD-associated anemia is lower than previously reported. Anemia of IBD is most commonly due to iron deficiency and contributes to fatigue and poor quality of life, but remains untreated in a large proportion of patients with iron and/or vitamin deficiencies. This study is registered at clinicaltrials.gov as NCT02872376.

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).

Background Azathioprine (AZA) and thiopurine are widely used for induction and maintenance of remission in steroid dependent patients with inflammatory bowel disease (IBD). Methods Aim of this study has been to investigate its efficacy and safety in maintaining steroid-free remission in steroid dependent IBD patients seven year after the institution of treatment. Data from consecutive IBD outpatients referred in our Institution, between 1985-2016, were reviewed and all patients treated with AZA were included in this retrospective study. AZA was administered at the recommended dose of 2-2.5 mg/kg. Results Out of 2802 consecutive IBD outpatients visited in the index period, AZA was prescribed to 433 patients, 236 (54.5%) were affected by Crohn's disease (CD) and 197 (45.5%) by ulcerative colitis (UC). One hundred and seventy-nine patients with a follow-up < 84 months were excluded from the study. Two hundred and fifty-four patients were evaluated, 141 (55.5%) with CD and 113 (44.5%) with UC. One hundred and thirty-nine (54.7%) were male and 115 (45.3%) female (average age of 35.62 ± 14.20 SD years, range 14-74 y.). Seven year after the institution of treatment, 127 (50%) patients still were in steroid-free remission (83 CD vs 44 UC, 58.8% and 38.9%, respectively, p = 0.0024), 71 (27.9%) had a relapse requiring retreatment with steroids (29 CD vs 42 UC, 20.6% and 37.2%, respectively, p = 0.0047), 56 (22.1%) discontinued the treatment due to side effects (29 CD vs 27 UC, 20.6% and 23.9%, respectively). Loss of response from 1st to 7th year of follow-up was low, about 20%. Conclusions Seven year after the onset of treatment 50% of patients did not require further steroid courses. After the first year loss of response was low in six subsequent years. In the present series the maintenance of steroid-free remission was significantly higher in CD than in UC patients. The occurrence of side effects leading to the withdrawal of AZA treatment has been low. Key messages An important therapeutic moment of IBD is mantaining remission in steroid dipendent patients. AZA can be a viable and inexpensive alternative to treath these patients.

Background Small intestinal bacterial overgrowth (SIBO) has been reported with varying prevalence, depending upon the criteria used for diagnosis. Lactulose and glucose breath tests are the most used in clinical settings. Early rises of hydrogen excretion during a lactose breath test suggest SIBO, but the finding could result from accelerated mouth-to-caecum transit time. Aims Defining the prevalence of early hydrogen peaks during lactose breath tests and assessing the proportion of patients affected by SIBO. Methods An early (≤ 60′) hydrogen excretion peak was observed in 120/663 patients with positive lactose hydrogen breath test. Eighty-one of them underwent a 50 g-9sample-glucose hydrogen breath test to diagnose SIBO. Results The glucose breath test proved positive in 11/81 (13.6%) patients. The positivity rate was 18.2% (2/11) in those with the first peak detected at 30′ and 12.8% (9/70) in those with the peak occurring at 60′. Conclusions Early hydrogen excretion peaks are rarely associated with SIBO. The low positive predictive value indicates that the finding does not help identifying patients at high risk for this condition. Indirectly, the present data support the opinion that the prevalence of SIBO diagnosed by standard lactulose breath tests is much lower than reported, and the reliability of the test is low.

Background Clinical severity and intestinal lesions of Crohn’s disease (CD) usually progress over time and require a step up adjustment of the therapy either to prevent or to treat complications. The aim of the study was to develop a simple risk scoring system to assess in individual CD patients the risk of disease progression and the need for more intensive treatment and monitoring. Methods Prospective cohort study (January 2002–September 2014) including 160 CD patients (93 female, median age 31 years; disease behavior (B)1 25%, B2 55.6%, B3 19.4%; location (L)1 61%, L3 31.9%, L2 6%; L4 0.6%; perianal disease 28.8%) seen at 6–12-month interval. Median follow-up 7.9 years (IQR: 4.3–10.5 years). Poisson models were used to evaluate predictors, at each clinical assessment, of having the following outcomes at the subsequent clinical assessment a) use of steroids; b) start of azathioprine; c) start of anti-TNF-α drugs; d) need of surgery. For each outcome 32 variables, including demographic and clinical characteristics of patients and assessment of CD intestinal lesions and complications, were evaluated as potential predictors. The predictors included in the model were chosen by a backward selection. Risk scores were calculated taking for each predictor the integer part of the Poisson model parameter. Results Considering 1464 clinical assessments 12 independent risk factors were identified, CD lesions, age at diagnosis 50, presence of inflammatory markers, no previous surgery or presence of termino-terminal anastomosis, current use of corticosteroid, no corticosteroid at first flare-up. Six of these predicted steroids use (score 0–9), three to start azathioprine (score 0–4); three to start anti-TNF-α drugs (score 0–4); six need of surgery (score 0–11). The predicted percentage risk to be treated with surgery within one year since the referral assessment varied from 1 to 28%; with azathioprine from 3 to 13%; with anti-TNF-α drugs from 2 to 15%. Conclusions These scores may provide a useful clinical tool for clinicians in the prognostic assessment and treatment adjustment of Crohn’s disease in any individual patient.

OBJECTIVE Inadequate sun exposure impairs vitamin D activity and favors low bone density, especially in patients at increased risk for osteoporosis, such as those affected by inflammatory bowel disease (IBD). In this study, sun exposure was investigated in a large series of patients with IBD in a Mediterranean country, Italy, where this risk is considered less likely to occur than in higher latitudes. METHODS This is a case-control study of 292 patients with IBD [132 with Crohn's disease (CD) and 160 with ulcerative colitis (UC)], 80 diseased and 540 healthy controls, conducted via a validated questionnaire to quantify sunlight exposure. Data were also compared with controls matched by age and gender. RESULTS In total 78 of the 292 patients with IBD had low, 169 had moderate and 45 had high exposure to sunlight, significantly differing from controls (P < 0.001). The 132 patients with CD were more likely to have abnormal levels of sunlight exposure (49 low, 72 moderate and 11 high) than those with UC (29 low, 97 moderate and 34 high) (P < 0.001). The controls were significantly more exposed to sunlight than both men and women with IBD (P < 0.001 and 0.004, respectively). CONCLUSIONS IBD patients are significantly less exposed to sunlight than matched controls in Italy, often to an extent that may impair vitamin D activation. Increasing responsible sunlight exposure, thus promoting adequate vitamin D concentrations, may prove beneficial in IBD, in geographical areas in which this risk factor is not generally taken into consideration.

Background The appropriate maintenance treatment for patients with acute severe ulcerative colitis (ASUC) responsive to intravenous steroids (IVS) is still a matter of debate. Although major Guidelines consider thiopurine maintenance an option in this setting, the long-term benefit of early immunomodulator (IMMs) initiation is not well established. The aim of our study was to explore the long-term outcome of patients with ASUC responsive to IVS who received different maintenance strategies Methods In a multicenter retrospective study, all patients with ASUC hospitalized between January 2005 and December 2017 in 14 Italian IBD referral centres were reviewed. Thiopurine and biologic-naïve patients experiencing their first acute severe attack and who responded to IVS were included in the study. Maintenance treatment was prescribed by attending physicians according to their clinical judgment. The main outcomes were recurrent flares requiring escalation of therapy, new hospitalization, and long-term colectomy rate. The Kaplan-Meier survival method was used to estimate the cumulative probability of a course without the main outcomes. Differences between curves were tested using the log-rank test. A propensity score matching analysis was performed to establish comparable groups of patients who received different maintenance treatment Results Overall 372 patients were reviewed. Of these, 141 met the inclusion criteria (males 61.7%, median age 34.5 (IQR 23–50). After response to IVS, 82 patients (58.1%) received maintenance treatment with aminosalicylates, 42 (29.8%) received IMMs and 17 (12.1%) were maintained with scheduled infliximab (IFX) + thiopurines. After a median follow-up of 48 (IQR 25–90) months, 94 patients (68.8%) experienced a flare requiring escalation of therapy, 51 (36.1%) required new hospitalization and 18 (12.8%) underwent colectomy. After 12, 36 and 60 months after the acute attack, the cumulative probability of a course without escalation of therapy was 59.6%, 33.3% and 23.1%; the cumulative probability of a hospitalization-free course was 83.9%, 67.4% and 59.5%; the cumulative probability of a colectomy-free course was 96.3%, 90.2%, and 88.9%. No differences were observed between patients receiving aminosalicylates, IMMs or IFX as maintenance treatment (log-rank test: p= 0.39; p = 0.41; p = 0.11 respectively). After a propensity score matching analysis, no significant difference in main outcomes was observed between patients maintained with aminosalicylates or IMMs/IFX Conclusion IMM-naïve ASUC patients responsive IVS remain at risk of relapse requiring escalation of therapy. Early IMMs introduction after the acute attack did not reduce the risk of escalation of therapy, hospitalization or colectomy

Ulcerative colitis (UC) is a chronic inflammatory disease rarely arising during gestation. Because the available information is based on case reports or small retrospective studies, diagnosis may be difficult and treatment is still controversial. A case of toxic megacolon developing in late pregnancy associated to a sudden fetal decompensation is described. Diagnostic and clinical topics of acute UC onset in pregnancy are debated.A primipara, 34 years old, 33/0 weeks of gestation, was admitted with a diagnosis of preterm labor, associated to acute bloody diarrhea (up to 10 daily motions) and cramping abdominal pain. A diagnosis of new-onset early-stage UC was made by sigmoidoscopy. An intensive care regimen including hydrocortisone, antibiotics and parenteral nutrition was immediately started. Magnetic resonance imaging of maternal abdomen, fostered by the worsening patient conditions, evidenced dilatation of the entire colon and a severely hampered of fetal muscular tone.Toxic megacolon complicated by superimposed Clostridium difficile infection was associated to a sudden fetal decompensation diagnosed by chance during maternal abdominal magnetic resonance imaging. An emergency cesarean section was mandatory. According to a senior surgeon's decision, total colectomy was not immediately performed following cesarean section with reference to the absence of colonic perforation. We obtained a good short-term maternal outcome and an uncomplicated neonatal course. Counseling of those patients must be focused on timely and multidisciplinary intervention in order to improve the course of maternal disease and to prevent fetal distress.

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.

To identify differences between two cohorts of adult and pediatric patients affected by Crohn’s disease (CD), with regard to lesion location in the small intestine and colon-rectum, lesion activity, and prevalence of perianal disease (PD), using MRI as the main diagnostic tool. We retrospectively reviewed 350 consecutive MRI examinations performed between 2013 and 2016 in outpatients or inpatients with histologically proven CD, monitored by the Gastroenterology and Pediatric Units of our Hospital. The magnetic resonance enterography (MRE) protocol for adult and pediatric CD patients routinely includes evaluation of nine different intestinal segments (from jejunum to rectum) and of the anal canal. Intestinal activity was also calculated using a validated score. Perianal disease (PD) was staged. Fisher’s exact test was used and the odds ratio (OR) was calculated. Two hundred and nineteen out of 350 MRI studies (118 adults and 101 children) were included. The prevalence of PD was 34.6% in children and 16.1% in adults (OR = 2.8; p = 0.0017). Pediatric patients showed more frequent rectal involvement (29.7% vs 13.5%, OR = 2.7; p = 0.0045) and higher risk of PD in the presence of rectal disease (p = 0.043; OR = 4.5). In pediatric patients with severe colorectal disease, the prevalence of PD was twofold (86.7% vs 40%; p = 0.072). Using the clinical Montreal classification for lesion location, no significant differences emerged between the two patient populations. MRI showed a significantly higher prevalence of rectal involvement and perianal disease in the pediatric population. These results may have a relevant clinical impact and deserve further investigation. • To our knowledge, this is the largest morphological comparative study available in the literature using MRI as the main diagnostic tool to compare adult patients and children with Crohn’s disease. • Our study showed significant differences between adults and children: a higher prevalence of rectal and perianal fistulous disease (PD) in pediatric patients and an increased prevalence of PD in the presence of severe colon-rectum involvement. • The association of rectal and perianal disease implies a poorer clinical prognosis and a higher risk of disabling complications in pediatric patients.

Hypovitaminosis D is prevalent in inflammatory bowel disease (IBD) and may be associated with disease activity.This study evaluated vitamin D (VitD) status in an Italian cohort of IBD patients, not taking VitD supplementation. We investigated risk factors for VitD deficiency and its correlation with disease activity.VitD levels were measured in 300 consecutive outpatients (42% with Crohn's Disease (CD) and 58% with ulcerative colitis (UC), 56% male) from a tertiary referral center. Data from the IBD cohort were compared with those of 234 healthy controls, matched by sex, age, and the month in which VitD levels were measured.The mean VitD level in IBD patients was significantly lower than in controls (18.9 ng/ml vs. 25 ng/ml, p 0.001) when accounting for gender, age, and season. VitD deficiency was present in 62% of IBD patients. Risk factors for deficiency were: age40 and ≥60 years, winter, previous surgery, C-reactive protein (CRP) ≥0.5 mg/dl, and erythrocyte sedimentation rate ≥20 mm/h. In multivariate analysis, VitD levels were negatively influenced by disease location and CRP in UC.Although VitD deficiency was more prevalent than expected in healthy controls living in a Mediterranean country not at high risk of hypovitaminosis D, it was more common and severe in IBD patients. This study also found an association between VitD status and disease activity.

The MARS-5 (Medication Adherence Report Scale) was developed in English. The aim of this project was to analyse the MARS-5I (© Prof Rob Horne) psychometric properties and to identify whether its Italian translation is suitable for assessing medication adherence in Crohn Disease (CD) Italian patients. The MARS was translated and linguistically validated in Italian. The MARS-5I was used for evaluating medication adherence in the SOLE study, conducted in Italy on 552 subjects with CD. In order to un-bias the questionnaire results from the effects of treatment change and/or effectiveness, the analyses were performed on the 277 patients whose disease activity remained stable, selected among the 371 patients who maintained the same treatment between two consecutive visits. Internal consistency was high (Cronbach's alpha of 0.86). Pearson's correlation coefficient was 0.50 (p0.001) and 0.86 (p0.001- outliers removed), indicating satisfactory test-retest. MARS 5I scores were not correlated with Treatment Satisfaction Questionnaire for Medication but a small and statistically significant correlation was shown with physician-evaluated medication adherence, indicating convergent validity. MARS-5I, the Italian translation of the English MARS, showed satisfactory internal consistency and test-retest, and a low but statistically significant convergent validity. We confirmed the utility of this tool in patients with CD.

Inadequate sun exposure impairs vitamin D activity and favors low bone density, especially in patients at increased risk for osteoporosis, such as those affected by inflammatory bowel disease (IBD). In this study, sun exposure was investigated in a large series of patients with IBD in a Mediterranean country, Italy, where this risk is considered less likely to occur than in higher latitudes.This is a case-control study of 292 patients with IBD [132 with Crohn's disease (CD) and 160 with ulcerative colitis (UC)], 80 diseased and 540 healthy controls, conducted via a validated questionnaire to quantify sunlight exposure. Data were also compared with controls matched by age and gender.In total 78 of the 292 patients with IBD had low, 169 had moderate and 45 had high exposure to sunlight, significantly differing from controls (P0.001). The 132 patients with CD were more likely to have abnormal levels of sunlight exposure (49 low, 72 moderate and 11 high) than those with UC (29 low, 97 moderate and 34 high) (P0.001). The controls were significantly more exposed to sunlight than both men and women with IBD (P0.001 and 0.004, respectively).IBD patients are significantly less exposed to sunlight than matched controls in Italy, often to an extent that may impair vitamin D activation. Increasing responsible sunlight exposure, thus promoting adequate vitamin D concentrations, may prove beneficial in IBD, in geographical areas in which this risk factor is not generally taken into consideration.

Granulocyte-monocyte apheresis is a relatively new therapy that has been proposed, sometimes with controversial results, for the treatment of inflammatory bowel disease, particularly ulcerative colitis. The aim of the present study was to perform a thorough review of the literature on the application of this type of treatment in ulcerative colitis and discuss the results, in order to provide an opinion on its use which is shared by the involved experts. The review of the literature was performed by searching PubMed with appropriate key words. The results obtained suggest that the major role for this treatment at this moment is for those patients with steroid dependency or with major contraindications to use of steroids. However, promising, albeit very preliminary, results have also been observed in steroid-naive subjects, and this is of particular interest in consideration of the safety profile of this therapeutic method. As such, the Adacolumn may prove useful in specific subgroups of patients. Future phenotypic, genotypic, and molecular characterization of patients with inflammatory bowel disease might prove useful in defining better those subjects who might benefit most from this treatment modality.

Background About 20% of ulcerative colitis patients will experience a severe attack during the course of the disease. Intensive treatment, early surgery and, more recently, “rescue therapies” improved prognosis. Aims To evaluate in-hospital colectomy and mortality rates for severe ulcerative colitis over 40 years in two referral centres. Methods All in-patients with severe ulcerative colitis from 1976 to 2010 were considered. 159 patients were assigned to 4 cohorts: cohort 1 n = 34 (1976–1980); cohort 2 n = 29 (1986–1990); cohort 3 n = 45 (1996–2000); cohort 4 n = 51 (2006–2010). Results The colectomy rate was 64.7%, 62.0%, 44.4% and 9.8%, respectively, in the four cohorts ( p p = 0.04). Infliximab was used only in cohort 4 (17 patients). Conclusions A significant reduction of colectomy and mortality rates in severe ulcerative colitis was observed in the last 40 years. Better management of patients, reduced attitude to operate severe ulcerative colitis, as well as the use of Infliximab in the last cohort, all could have contributed to the improved outcome.

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Inflammatory bowel disease characteristically affects young adults in their reproductive ages. Thus the medication used for the treatment of active disease should not compromise fertility and, also, should not have teratogenic effect on baby. A lot of data are available about effects of steroids, antibiotics, and mesalazine but no data are available about safety and efficacy of granulocyte-monocyte-apheresis (GMA) during pregnancy. In this case report, the 37 year-old pregnant woman with chronically active and steroid dependent ulcerative colitis (UC), at risk of abortion, refused more aggressive pharmacological therapeutic options and gave the informed consent to GMA. To minimize symptoms and the risk of severe clinical relapse, a maintenance GMA treatment was performed throughout pregnancy. The course of pregnancy was uneventful with no side effects; the mother and the baby were all healthy and well at the delivery.

Background: Diagnosis of lactose intolerance is based on a “positive” H2 breath test associated with abdominal symptoms. The present study established to what extent the occurrence of symptoms during a “negative” H2 breath test may result from a “nocebo effect” instead of lack of sensitivity of the procedure. Methods: Between 2005 and 2007, 636 outpatients performed a standard 4-h 25 g lactose tolerance test. The test was positive in 254, negative in 325, and 57 patients were H2 “non-producers”. Twenty-seven patients reporting symptoms despite a negative H2 breath test underwent a “sham” breath test following ingestion of 1 g of glucose. Fifty-four patients presenting with documented lactose intolerance were used as controls. Results: Twelve out of 27 patients (44.4%), and unexpectedly also 14 (25.9%) controls presented abdominal symptoms during the sham test. The difference between the two groups was not significant (P < 0.15) OR 2.28; C.I. 0.77–6.78. Conclusion: In most instances, symptoms reported by patients during a negative lactose H2BT cannot be attributed to a false-negative test. Instead, a non-organic component, resulting from negative expectations (“nocebo effect”) is likely implicated. Moreover, also in patients diagnosed as lactose intolerant, the need for restricting the primary source of dietary calcium should be critically reconsidered. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

BACKGROUND: The hydrogen breath test (H2BT) is the most widely used procedure in the diagnostic workup of lactose malabsorption and lactose intolerance.AIM: To establish whether a simplified two-or three-sample test may reduce time, costs and staff resources without reducing the sensitivity of the procedure.PATIENTS AND METHODS: Data from 1112 patients (292 men, 820 women) with a positive 4 h, nine-sample H2BT were retrospectively analyzed. Patients were stratified according to the degree of lactose malabsorption, the occurrence and type of symptoms. Loss of sensitivity in the procedure was evaluated taking into account two-sample tests (0 min and 120 min or 0 min and 210 min) or three-sample tests (0 min, 120 min and 180 min or 0 min, 120 min and 210 min).RESULTS: Using a two-sample test (0 min and 120 min or 0 min and 210 min) the false-negative rate was 33.4% and 22.7%, respectively. With a three-sample test (0 min, 120 min and 180 min or 0 min, 120 min or 210 min), lactose malabsorption was diagnosed in 91.2% (1014 of 1112) patients and in 96.1% (1068 of 1112) patients, respectively. Of 594 patients with abdominal symptoms, 158 (26.6%) and 73 (12.2%) would have false-negative results with 0 min and 120 min or 0 min and 210 min two-sample tests, respectively. The three-sample tests, 0 min, 120 min and 180 min or 0 min, 120 min and 210 min, have a false-negative rate of 5.9% and 2.1%, respectively.CONCLUSIONS: A three-sample H2BT is time-and cost-sparing without significant loss of sensitivity for the diagnosis both of lactose malabsorption and lactose intolerance.

Summary Aim: To determine the efficacy of infliximab in the treatment of chronic refractory pouchitis complicated by fistulae following ileal pouch-anal anastomosis for ulcerative colitis. Methods: This open study included seven patients (four females, three males) with chronic refractory pouchitis complicated by fistulae. Pouchitis was diagnosed by clinical, endoscopic and histological criteria. The sites of the fistulae were as follows: pouch-bladder in one, vaginal in three, perianal in two, and both vaginal and perianal in one. Extra-intestinal manifestations (erythema nodosum, arthralgia) were present in four patients. Crohn's disease was carefully excluded in all patients after re-evaluation of the history, re-examination of the original proctocolectomy specimen and examination of the proximal small bowel. All patients had been treated with antibiotics and three with steroids. Patients received infliximab, 5 mg/kg, at 0, 2 and 6 weeks. Azathioprine (2.5 mg/kg) was also started for all patients as bridge therapy. Clinical response was classified as complete, partial or no response. Fistulae closure was classified as complete (cessation of fistulae drainage and total closure of all fistulae), partial (a reduction in the number, size, drainage or discomfort associated with fistulae) or no closure. The pouchitis disease activity index and quality of life were also used as outcome measures. Results: Clinically, all patients improved. At the 10-week follow-up, six of the seven patients had a complete clinical response, and five had complete fistulae closure. At the 10-week follow-up, the median pouchitis disease activity index decreased from 12 (baseline) (range, 10–15) to 5 (range, 3–8); the median quality of life decreased from 37 points (range, 33–40) to 14 (range, 9–18). Erythema nodosum and arthralgia showed complete remission soon after the first infusion of infliximab. Conclusions: These preliminary results indicate that infliximab may be recommended for the treatment of refractory pouchitis complicated by fistulae following ileal pouch-anal anastomosis for ulcerative colitis.

Background The treatment of distal ulcerative colitis, refractory to conventional 5-ASA/steroid treatment, is still a matter of debate. The present study aimed at confirming, with adequate statistical power, previous data indicating the usefulness of topical butyrate and 5-ASA in the treatment of this condition. Design Double-blind, placebo-controlled, multicentre study. A total of 51 patients with distal (

OBJECTIVES: In previous retrospective studies in patients with severe ulcerative colitis (UC), small bowel distension was found to characterize a subgroup of patients at higher risk for both toxic megacolon (TMC) and multiple organ dysfunction syndrome (MODS). In this study we prospectively evaluated the prevalence of GI distension and its relationship to clinical outcome in patients with severe UC. METHODS: Of 109 consecutive inpatients with acute UC (admitted to the GI Unit of the University of Rome during the period 1995–2000), 45 had severe colitis. Routine blood tests and acid-base balance and plain abdominal film evaluations were performed upon admission and repeated every 1–3 days. The gas content of the stomach and small and large intestines was evaluated on plain abdominal films. All patients were submitted to the standard Oxford intensive medical regimen; clinical improvement, occurrence of major complications, need for surgery, and mortality were evaluated. Statistical analysis was carried out using Student’s t, χ2, Fisher’s exact, Mann-Whitney, and Wilcoxon rank sum tests, when appropriate. RESULTS: Of 45 patients with severe UC, 24 (53%) had GI distension. Three of these 24 patients had TMC on admission (all underwent surgery and survived), 21 showed increased GI gas content (four developed TMC 1–4 days after the detection of GI distension and were operated on, two developed MODS and died, and eight did not improve but were submitted to surgery and survived). None of the 21 patients with normal GI gas content had complications; all survived (five did not improve and required surgery). CONCLUSIONS: In severe UC, persistent GI distension characterized a subgroup of patients with poor response to medical therapy and at higher risk for TMC and of need for surgery. The development of MODS was the most important predicting factor for fatal outcome.

Background The burden of inflammatory bowel diseases, including Crohn's disease and ulcerative colitis, has never been estimated in Italy using administrative data sources. Our objective was to measure the occurrence of inflammatory bowel diseases in the Lazio region (Italy) using administrative data and to test the sensitivity of the Crohn's disease case-finding algorithm with respect to clinical diagnosis. Methods We conducted a population-based cross-sectional study identifying prevalent and incident cases. We estimated occurrence rates of inflammatory bowel diseases using hospital discharges or activation of copayment exemptions. Sensitivity was calculated from 2358 subjects with clinical diagnosis of Crohn's disease. Results Exemptions identified more than 20% of the cases. Prevalence rates (per 100,000) on December 31, 2009 for males and females were 177 and 144 for ulcerative colitis and 91 and 81 for Crohn's disease, respectively. The incidence rates during the years 2008–2009 were 14.5 and 12.2 for ulcerative colitis and 7.4 and 6.5 for Crohn's disease for males and females, respectively. The sensitivity of the administrative sources was 82.2%. Conclusions Health and population data sources allow the estimation of inflammatory bowel diseases occurrence. The age-specific peaks of diagnosis were consistent with those reported in other studies. Sensitivity may be affected by temporal changes in the quality of the data sources.

To investigate prevalence, type and time of onset of extraintestinal manifestations (EIMs) in a series of Italian inflammatory bowel disease (IBD) patients.Data of 811 IBD consecutive patients, first referred to our Centre from 2000 to 2011, were retrospectively evaluated.Eight hundred and eleven IBD patients (437 M, 374 F) were studied: 595 ulcerative colitis (UC) (73.4%) and 216 Crohn's disease (CD) (26.6%). Among these, 329 (40.6%) showed EIMs: 210 UC (35.3%) and 119 CD (55.1%) (P0.0001). Considering the time of the diagnosis of IBD, 37 EIMs (11.2%) were developed before, 229 (69.6%) after and 63 (19.2%) were simultaneous. The type of EIM were as follows: 240 musculoskeletal (29.6%), in 72 CD patients and in 168 UC (P0.0001); 47 mucocutaneous (5.8%), in 26 CD and in 21 UC (P = 0.0049); 26 ocular (3.2%), in 16 CD and in 10 UC (CD 7.4% vs UC 1.7%, P = 0.0093); 6 hepatobiliary (0.8%); 10 endocrinological (1.2%). In particular, with regards to the involvement of the musculoskeletal system, arthritis Type 1 was found in 41 CD (19%) and in 61 UC (10.2%) (P = 0.0012) and Type 2 in 25 CD (11.6%) and in 100 UC (16.8%) (P = 0.0012).Mucocutaneous manifestations, arthritis Type 1 and uveitis were significantly more frequent in CD than UC. The complications of the musculoskeletal system were the mostly observed ones, often with symptoms more severe than intestinal ones, confirming the need for close cooperation with rheumatologists.

Introduction : The incidence of endoscopic recurrence (ER) in Crohn's disease following curative resection is up to 75% at 1 year. Endoscopy is the most sensitive method to detect the earliest mucosal changes and the severe ER at 1 year seems to predict a clinical relapse. Methods : The aim of this prospective study was to evaluate the incidence of early ER 6 months after curative resection. Secondary outcome was to evaluate the role of 5-aminosalicylic acid (5-ASA) in the prevention of ER at 6 months. A total of 170 patients were included in the study. They were carried-out from the evaluation of the appearance of ER during a trial performed to assess the role of azathioprine vs. 5-ASA as early treatment of severe ER. All the patients started 5-ASA treatment 2 weeks after surgery. Results : Six months after surgery ER was observed in 105 patients (62%). The endoscopic score was reported as severe in 78.1% of them (82 out of 105). At univariable analysis only ileo-colonic disease influenced the final outcome associating to a lower risk of severe ER (p = 0.04; OR 0.52, 95% CI 0.277–0.974). Conclusion: In this prospective Italian multicenter IG-IBD study a great proportion of ER occur within 6 months from ileo-colonic resection, with a significant rate of severe ER. Furthermore this study confirms the marginal role of 5-ASA in the prevention of ER. This suggests that post-surgical endoscopic evaluation should be performed at 6 months instead of 1 year to allow an adequate early treatment.

Background. The relationship between lactose malabsorption, irritable bowel syndrome and development of intestinal symptoms is unclear, especially when the ingested dose of milk is small. Thus, the role of hydrogen breath testing in the diagnostic work-up of patients with nonspecific intestinal symptoms is still debated. Aims. To establish the relationship between lactose malabsorption, severe self-reported milk intolerance, irritable bowel syndrome and related symptoms. Methods. The prevalence of lactose malabsorption was prospectively assessed by means of a hydrogen breath test in 839 patients (503 with irritable bowel syndrome, based on the Rome criteria, regularly consuming milk, and 336 subjects who identified themself as milk intolerant, after an oral load of 25 g lactose). The test was considered “positive” when a hydrogen peak exceeding 20 ppm over baseline values was observed in two or more samples. Attempts were also made to establish whether the predominant presenting symptom (diarrhoea, constipation, alternating diarrhoea and constipation, pain and gaseousness) might be helpful in predicting the outcome of the breath test. Results. The prevalence of a positive breath test was comparable in the two groups (337 patients with irritable bowel syndrome (66.9%) vs 240 patients with milk intolerance (71.4%)). The same holds true for the first peak of hydrogen excretion, total hydrogen output and prevalence of symptoms during, and in the four hours after, the test. The predominant presenting symptom was not useful for predicting outcome of the test either in regular milk users or in milk intolerant subjects. Conclusions. The almost identical results of the lactose breath test of patients with irritable bowel syndrome and subjects with self-reported milk intolerance suggests that the two conditions overlap to such an extent that the clinical approach should be the same. A lactose breath test should always be included in the diagnostic work-up for irritable bowel syndrome, as fermentation of malabsorbed lactose is likely responsible for triggering symptoms. Conversely, lactase deficiency is probably irrelevant in most subjects not affected by irritable bowel syndrome, within a moderate milk consumption.

Therapeutic apheresis, a novel approach for immunodisorders, has been used in the last decade for the treatment of ulcerative colitis with promising result, and represents an alternative to conventional pharmacological therapy. Selective apheresis is aimed at reducing the number of circulating lymphocytes, interfering with recruitment and activation of mucosal granulocytes and macrophages, reducing cytokine and chemokine production which are thought to contribute to induction and perpetuation of inflammation. The article briefly reports indications, treatment schedule and clinical results of leukocytapheresis in ulcerative colitis. Available data for the two selective adsorption devices so far approved for clinical use (granulocyte-monocyte apheresis- Adacolumn- and leukocytapheresis-Cellsorba) are partially conflicting, and the number of controlled studies too small to draw definitive conclusions. Nonetheless apheresis definitely appears to be an effective non-conventional tool for the treatment of steroid refractory and steroid dependent UC patients with moderately active disease. The excellent safety profile of the procedure makes this approach attractive, both in adult and in pediatric patients, more so in those refractory to conventional drug therapy, who are presently treated with immunosuppressive and biological therapies.

Background: Hydrogen breath tests are widely used in clinical practice. For a correct evaluation of data, low basal H2 excretion is required, thus, 12-hour fasting is usually prescribed. An additional reduction in the intake of complex carbohydrates in the preceding 24 h is suggested in some centers. The issue, however, has never been directly investigated. Aim: The aim of the present study was to analyze the effect of the pretest diet on the basal H2 excretion and the number of subjects excluded from the test due to high basal H2 excretion. Methods: Two cohorts of 500 consecutive patients undergoing a lactose tolerance test in the years 1997–1998 (when 12-hour fasting was required) and in 2007–2008 (when a low-carbohydrate diet in the preceding 24 h was also prescribed) were retrospectively reviewed. Results: The mean basal H2 excretion was significantly lower (p < 0.0001) in the low-carbohydrate diet group (2.46 ± 6.8 vs. 4.73 ± 3.3 ppm). In 1997–1998, 46/500 patients (9.2%) were excluded from the test due to basal H2 values as compared to 7/500 (1.4%) in the period 2007–2008. Discussion: To the best of our knowledge, ours is the first study to provide objective data on the advantage offered by reducing the intake of complex carbohydrates before H2 breath tests.

Summary Background No available therapy has, as yet, proven effective to treat acute radiation proctitis (ARP) following radiation therapy for malignant pelvic disease. We assessed whether sodium butyrate enemas, at a dose of 80 mmol/L (80 mL/24 h), might offer effective treatment for this condition. Methods 20 patients presenting with ARP after completing a cycle of 35-52 Gy external-beam radiation therapy for pelvic malignant disease, were treated for 3 weeks with topical sodium butyrate and saline enemas according to a randomised, double-blind, crossover protocol. Clinical, endoscopic, and histololical findings were assessed at enrolment, at week 3, and then at the end of the study. Data were analysed by two-tailed t test for paired data (continuous variables) and a logistic-regression model with variable multiple response for ordered categorical data. Findings Topical butyrate, but not saline, led to remission of symptoms (clinical score from 8·2 [SE 1·6] to 1·5 [0·7] vs 7·9 [1·8] to 8·1 [3·4]). When the treatment regimen was switched, eight out of nine of the previously placebo-treated patients went into remission, whereas three patients relapsed when switched to saline. The advantage of butyrate over placebo, expressed as CI, odds ratio, and p value was significant for almost all the clinical, endoscopic and histological factors taken into consideration. Interpretation Topical sodium butyrate, unlike other therapeutic regimens used so far, proved effective in the treatment of ARP.

Butyrate represents the main source of energy for colonic epithelial cells; however, its availabilty/utilization is impaired in ulcerative colitis (UC). In the present randomized, double-blind, placebo-controlled pilot study, the safety and efficacy of colonic targeted oral sodium butyrate tablets, coated with a pH-dependent soluble polymer, have been evaluated in ulcerative colitis. Thirty patients with mild to moderate colitis underwent a six-week course of oral sodium butyrate (4 g/day) plus oral mesalazine (2.4 g/day), (Group A) or of oral mesalazine plus placebo (Group B). Clinical, endoscopic, and histologic data were collected at the beginning and the end of the study. Twenty-five patients completed the study (12 in group A, 13 in group B). No untoward side effects were reported. In group A, seven patients underwent remission and four improved; in Group B the numbers were 5 and 5, respectively. After treatment, all clinical parameters had significantly improved in both treatment arms compared to pretreatment findings. The UC disease activity index (UCDAI) score decreased from 7.27 ± 2.02 to 2.58 ± 2.19 (P < 0.05) in the combined treatment group and from 6.07 ± 1.60 to 3.46 ± 1.98 (P < 0.05) in group B. The endoscopic and histologic scores also significantly improved after treatment in both groups (P < 0.05). The difference between the two treatment arms was not significant, but a significantly better improvement vs baseline values (P < 0.05) was observed in the combined treatment group vs the mesalazine group, when considering both the clinical index (Δ9.58 ± 4.19 vs 5.92 ± 3.48) and the UCDAI score (Δ4.67 ± 2.19 vs 2.54 ± 2.18). A more favorable trend, although not significant, was observed for all individual parameters in group A. In conclusion, results of the present pilot study indicate that oral butyrate is safe and well tolerated. These data also suggest that oral butyrate may improve the efficacy of oral mesalazine in active ulcerative colitis and prompt the need of a large scale investigation to confirm the present findings.

SUMMARYThis study was performed in order to assess the cytotoxic activity, both natural (NK) and antibody-dependent (ADCC), of PBMC from 38 IBD patients and correlate it with their clinical features. Cytotoxicity assays were performed using sensitive target cells for NK and ADCC activities. In some experiments, highly purified NK cells, obtained both by Percoll density gradient and by co-culturing non-adherent PBMC with RPMI 8866 feeder cells, were used as effector cells. Furthermore, we evaluated NK cell parameters such as number, surface expression of adhesion molecules (CD11a/CD18, CD49d and CD54) and response to different stimuli. We observed a decreased NK cytotoxicity of PBMC from IBD patients, both in ulcerative colitis (UC) and Crohn's disease (CD), independently of the clinical activity of disease. In contrast, the ADCC lytic activity was within normal range. The lower NK cytotoxic activity observed in our IBD patients cannot be related to a decreased number of NK cells, surface expression of adhesion molecules, defective response to IL-2 and maturative defect. Decreased NK activity was induced in PBMC of controls when serum of patients was added and this was unrelated to monocyte-derived modulating factor(s). Our data show a decreased natural killing by fresh PBMC from IBD patients. This lower activity seems to be unrelated to a primary NK cell defect, since purified NK cells exhibited normal levels of killing. It might be hypothesized that serum factors, possibly derived from lymphocytes, with inhibitory properties on NK activity, might be functionally active in the blood of IBD patients, thus modulating NK activity.

Background & aims: Osteopenia and increased risk for fractures in IBD result from several factors. Aim of the study: To investigate the dietary intake of calcium in IBD patients. Methods: A 22-item quantitative validated frequency food questionnaire was used for quantifying dietary calcium in relation to gender and age, in 187 IBD patients, 420 normal- and 276 diseased controls. Statistical analysis: Mann–Whitney, chi-square- and T-tests. Results: The mean calcium intake was 991.0 ± 536.0 (105.8% Recommended Daily Allowances) and 867.6 ± 562.7 SD mg/day (93.8% RDA) in healthy and diseased controls, and 837.8 ± 482.0 SD mg/day (92.7% RDA) in IBD, P < 0.001. Calcium intake was high in celiac disease (1165.7 ± 798.8 SD mg/day, 120% RDA), and non-significantly lower in ulcerative colitis than in Crohn's disease (798.7 ± 544.1 SD mg/day vs 881.9 ± 433.0). CD and UC females, but not males, had a mean calcium intake well under RDA. In all study groups the intake was lower in patients believing that consumption of lactose-containing food induced symptoms, versus those who did not (105.8% vs 114.3% RDA in normal controls; 100.4% vs 87.6% RDA in IBD). Conclusions: Diet in IBD patients contained significantly less calcium than in healthy controls. Gender and age, more than diagnosis, are central in determining inadequate calcium intake, more so in IBD. Self-reported lactose intolerance, leading to dietary restrictions, is the single major determinant of low calcium intake. Inadequate calcium intake is present in one third of IBD patients and represents a reversible risk factor for osteoporosis, suggesting the need for tailored nutritional advice in IBD. * Abbreviations : BMD : bone mass density Ca : calcium CD : Crohn's disease FFQ : food frequency questionnaire IBD : inflammatory bowel diseases RANKL–OPG : receptor activator of nuclear factor kappa-B ligand–osteoprotegerin RDA : recommended dietary allowance UC : ulcerative colitis

Anti-tumor necrosis factor alpha antibodies have been used with increasing frequency despite the number of reported adverse effects. Further new information is still emerging. Here we report the case of a 71-years-old patient affected by Crohn's disease and HCV-positive who developed Guillain-Barrè syndrome after four injections of fully human anti-tumor necrosis factor alpha antibodies (adalimumab). Indication for the treatment was severe clinical recurrence of Crohn's disease following intestinal resection. Guillain-Barrè syndrome was treated by intravenous immunoglobulins, and methylprednisolone and plasmapheresis were started with a progressive partial resolution of neurological symptoms. To date, Crohn's disease was maintained in clinical remission with low dose steroid therapy.

To identify factors predicting the clinical response of ulcerative colitis patients to granulocyte-monocyte apheresis (GMA).Sixty-nine ulcerative colitis patients (39 F, 30 M) dependent upon/refractory to steroids were treated with GMA. Steroid dependency, clinical activity index (CAI), C reactive protein (CRP) level, erythrocyte sedimentation rate (ESR), values at baseline, use of immunosuppressant, duration of disease, and age and extent of disease were considered for statistical analysis as predictive factors of clinical response. Univariate and multivariate logistic regression models were used.In the univariate analysis, CAI (P = 0.039) and ESR (P = 0.017) levels at baseline were singled out as predictive of clinical remission. In the multivariate analysis steroid dependency [Odds ratio (OR) = 0.390, 95% Confidence interval (CI): 0.176-0.865, Wald 5.361, P = 0.0160] and low CAI levels at baseline (4CAI7) (OR = 0.770, 95% CI: 0.425-1.394, Wald 3.747, P = 0.028) proved to be effective as factors predicting clinical response.GMA may be a valid therapeutic option for steroid-dependent ulcerative colitis patients with mild-moderate disease and its clinical efficacy seems to persist for 12 mo.

In 109 Crohn’s disease (CD) patients, the median FC for the histology scores; 0, 1, 2, 3 were; 85, 175, 644 and 4144, respectively (graph). The corresponding medians for CRP were; 8, 10, 14 and 100. There were highly significant FC differences between the different histology groups (c2 = 62.5, p 6 were 72% and 43%. Conclusions: In IBD, FC was strongly predictive of histological disease and with a FC cut off level of ~250mg/g gave high levels of sensitivity and moderate specificity for predicting moderate to severe disease. FC showed greater accuracy in CD than in UC and also performed better than CRP. This study highlights the importance of FC as a valuable, non-invasive marker for measuring disease activity in IBD, and may be predictive of disease remission and relapse.