Corticosteroids and Mesalamine Versus Corticosteroids for Acute Severe Ulcerative Colitis: A Randomized Controlled Trial.

BACKGROUND & AIMS: Corticosteroids are the mainstay of treatment for hospitalized patients with acute severe ulcerative colitis (ASUC). However, whether the addition/continuation of mesalamine with corticosteroids during hospitalization is superior to corticosteroids alone is unknown. METHODS: This was a randomized controlled, investigator-blinded, clinical trial conducted in 10 centers in 7 countries. Patients hospitalized with ASUC (Lichtiger score ≥10) were eligible. Patients received corticosteroids alone or corticosteroid + mesalamine (4 g/day mesalamine) by a stratified randomization according to mesalamine use before admission. The primary outcome was the percentage of patients who responded to treatment by day 7, defined by a drop >3 points in the Lichtiger score and an absolute score <10 without the need for rescue medications or colectomy. RESULTS: Three hundred forty-six patients were screened, and 149 were included (70/149 female; median age, 41 years). Of these, 73 received corticosteroids + mesalamine, and 76 received corticosteroids alone. For the primary outcome, 53 of 73 patients (72.6%) receiving corticosteroids with mesalamine responded versus 58 of 76 patients (76.3%) on corticosteroids alone (odds ratio, 0.82; 95% confidence interval, 0.39-1.72; P = .60). There was no difference between groups in duration of hospitalization, C-reactive protein normalization rate, or colectomy rate up to day 90. The need for biologics among patients receiving combination of corticosteroids with mesalamine was numerically lower by day 30 (P = .11) and day 90 (P = .07). CONCLUSIONS: In this randomized controlled trial, combination of mesalamine with corticosteroids did not benefit hospitalized patients with ASUC more than corticosteroids alone. An exploratory signal for a reduced need for biologics at 90 days in the mesalamine group merits further evaluation. CLINICALTRIALS: gov ID: NCT01941589.

New-onset ulcerative colitis in pregnancy associated to toxic megacolon and sudden fetal decompensation: Case report and literature review.

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.

Febrile events in acute lymphoblastic leukemia: a prospective observational multicentric SEIFEM study (SEIFEM-2012/B ALL).

The purpose of the present study is to estimate the current incidence of febrile events (FEs) and infectious episodes in acute lymphoblastic leukemia (ALL) and evaluate the outcome. We analyzed data on all FEs in a cohort of patients affected by ALL admitted to 20 Italian hematologic centers during 21 months of observation from April 1, 2012 to December 31, 2013. Data about treatment phase, steroids, neutropenia, type and site of infection, and outcome of infection were collected. The population comprehended 271 ALL adult patients. Median age was 46 years old (range 19-75), M/F 1.1:1. We collected 179 FEs occurring during 395 different phases of treatment in 127 patients (45.3% incidence): remission induction treatment 53.1%, consolidation/maintenance 35.7%, treatment for a first or second relapse 44.3%, and refractory disease 85.7%. The incidence of FUO (fever of unknown origin) was 55/395 (13.9%). In the remaining cases, bacteria caused 92 FEs (23.2%), fungi 17 (4.3%), viruses 5 (1%). Mixed infections occurred in 10 cases mainly fungal+bacterial (9/10 cases). Neutropenia was mostly present at onset of FE (89.9% of FEs). Mortality rate was 11.7% (21/179) while 16 deaths occurred with evidence of infection (8.9%). Age > 60 years, neutropenia, poor performance status, steroids, refractory disease, and mixed infections significantly correlated with infection-related mortality. A statistically significant association with mortality was observed also for pulmonary localization and bacteremia. Our study describes the real-life epidemiological scenario of infections in ALL and identifies a subset of patients who are at higher risk for infection-related mortality.

Pre-chemotherapy risk factors for invasive fungal diseases: prospective analysis of 1,192 patients with newly diagnosed acute myeloid leukemia (SEIFEM 2010-a multicenter study).

Correct definition of the level of risk of invasive fungal infections is the first step in improving the targeting of preventive strategies. We investigated the potential relationship between pre-hospitalization exposure to sources of fungi and the development of invasive fungal infections in adult patients with newly diagnosed acute myeloid leukemia after their first course of chemotherapy. From January 2010 to April 2012, all consecutive acute myeloid leukemia patients in 33 Italian centers were prospectively registered. Upon first admission, information about possible pre-chemotherapy risk factors and environmental exposure was collected. We recorded data regarding comorbid conditions, employment, hygienic habits, working and living environment, personal habits, hobbies, and pets. All invasive fungal infections occurring within 30 days after the first course of chemotherapy were recorded. Of the 1,192 patients enrolled in this study, 881 received intensive chemotherapy and were included in the present analysis. Of these, 214 developed an invasive fungal infection, including 77 proven/probable cases (8.7%). Of these 77 cases, 54 were proven/probable invasive mold infections (6.1%) and 23 were proven yeast infections (2.6%). Upon univariate analysis, a significant association was found between invasive mold infections and age, performance status, diabetes, chronic obstructive pulmonary disease, smoking, cocaine use, job, hobbies, and a recent house renovation. Higher body weight resulted in a reduced risk of invasive mold infections. Multivariate analysis confirmed the role of performance status, job, body weight, chronic obstructive pulmonary disease, and house renovation. In conclusion, several hospital-independent variables could potentially influence the onset of invasive mold infections in patients with acute myeloid leukemia. Investigation of these factors upon first admission may help to define a patient's risk category and improve targeted prophylactic strategies. (Clinicaltrial.gov: NCT01315925)

Early hydrogen excretion peaks during breath tests. Small intestinal bacterial overgrowth or accelerated transit?

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.

Successful resolution of pneumonia developed in a patient affected by Crohn's disease, rheumatoid arthritis, myasthenia gravis and recurrent uveitis during concomitant treatment with tumour necrosis factor alpha inhibitors and conventional immunosuppressive drugs.

Tumour necrosis factor alpha inhibitors, both infliximab and adalimumab, have been approved for the treatment of both rheumatoid arthritis and Crohn's disease. A slight increase in the risk of infections in patients receiving immunosuppressants and/or biological agents has been reported. Here, we present the case of a 68-year-old woman affected by Crohn's disease, myasthenia gravis, recurrent uveitis and rheumatoid arthritis who developed pneumonia during concomitant treatment with biological agents and conventional immunosuppressive drugs.

The central role of psychopathology and its association with disease severity in inflammatory bowel disease and irritable bowel syndrome.

BACKGROUND: Biopsychosocial models for both organic and functional gastrointestinal (GI) disorders can be found in the literature. To clarify the role of psychopathological factors and their relationship with GI symptom severity, several studies have examined them in inflammatory bowel disease (IBD) - occasionally distinguishing between ulcerative colitis (UC) and Crohn's disease (CD) - and in irritable bowel syndrome (IBS), leading to unclear results. AIMS: We aimed to evaluate the psychopathological features of IBD and IBS patients in comparison with healthy individuals and assess the association with disease severity. MATERIALS AND METHODS: Sixty-nine IBD outpatients, of which 35 UC and 34 CD, and 75 IBS ones were consecutively recruited at the third level Gastroenterological Center of our University Hospital; 76 healthy controls were also recruited. The psychological status was assessed with the Symptom Checklist-90-Revised (SCL-90-R). RESULTS: IBD and IBS patients showed significantly higher scores on the SCL-90-R Global Severity Index (GSI) and subscales than controls (all p-values<0.001), and IBS patients showed significantly higher GSI, depression, and anxiety scores than IBD patients (all p-values<0.01). Psychopathology was comparable between UC and CD patients. In IBD and IBS patients the SCL-90-R GSI was significantly associated with disease severity (p<0.001). CONCLUSIONS: The presence of chronic bowel symptoms, either organic or functional, is linked to a greater severity of psychopathology compared to the general population, possibly as a consequence of higher loads of stress due to the symptoms affecting everyday life. In both IBD and IBS patients, greater disease severity and worse psychopathological functioning are related.

Predicting the Individual Risk of Acute Severe Colitis at Diagnosis.

BACKGROUND AND AIMS: Acute severe colitis [ASC] is associated with major morbidity. We aimed to develop and externally validate an index that predicted ASC within 3 years of diagnosis. METHODS: The development cohort included patients aged 16-89 years, diagnosed with ulcerative colitis [UC] in Oxford and followed for 3 years. Primary outcome was hospitalization for ASC, excluding patients admitted within 1 month of diagnosis. Multivariable logistic regression examined the adjusted association of seven risk factors with ASC. Backwards elimination produced a parsimonious model that was simplified to create an easy-to-use index. External validation occurred in separate cohorts from Cambridge, UK, and Uppsala, Sweden. RESULTS: The development cohort [Oxford] included 34/111 patients who developed ASC within a median 14 months [range 1-29]. The final model applied the sum of 1 point each for extensive disease, C-reactive protein [CRP] > 10mg/l, or haemoglobin < 12g/dl F or < 14g/dl M at diagnosis, to give a score from 0/3 to 3/3. This predicted a 70% risk of developing ASC within 3 years [score 3/3]. Validation cohorts included different proportions with ASC [Cambridge = 25/96; Uppsala = 18/298]. Of those scoring 3/3 at diagnosis, 18/18 [Cambridge] and 12/13 [Uppsala] subsequently developed ASC. Discriminant ability [c-index, where 1.0 = perfect discrimination] was 0.81 [Oxford], 0.95 [Cambridge], 0.97 [Uppsala]. Internal validation using bootstrapping showed good calibration, with similar predicted risk across all cohorts. A nomogram predicted individual risk. CONCLUSIONS: An index applied at diagnosis reliably predicts the risk of ASC within 3 years in different populations. Patients with a score 3/3 at diagnosis may merit early immunomodulator therapy.

Combination of corticosteroids and 5-aminosalicylates or corticosteroids alone for patients with moderate-severe active ulcerative colitis: A global survey of physicians' practice.

AIM: To examine treatment decisions of gastroenterologists regarding the choice of prescribing 5-aminosalycilates (5ASA) with corticosteroids (CS) versus corticosteroids alone for patients with active ulcerative colitis (UC). METHODS: A cross-sectional questionnaire exploring physicians' attitude toward 5ASA + CS combination therapy vs CS alone was developed and validated. The questionnaire was distributed to gastroenterology experts in twelve countries in five continents. Respondents' agreement with stated treatment choices were assessed by standardized Likert scale. Background professional characteristics of respondents were analyzed for correlation with responses. RESULTS: Six hundred and sixty-four questionnaires were distributed and 349 received (52.6% response rate). Of 340 eligible respondents, 221 (65%) would continue 5ASA in a patient hospitalized for intravenous CS treatment due to a moderate-severe UC flare, while 108 (32%) would stop the 5ASA (P < 0.001), and 11 (3%) are undecided. Similarly, 62% would continue 5ASA in an out-patient starting oral CS. However, only 140/340 (41%) would proactively start 5ASA in a hospitalized patient not receiving 5ASA before admission. Most (94%) physicians consider the safety profile of 5ASA as very good. Only 52% consider them inexpensive, 35% perceive them to be expensive and 12% are undecided. On multi-variable analysis, less years of practice and perception of a plausible additive mechanistic effect of 5ASA + CS were positively associated with the decision to continue 5ASA with CS. CONCLUSION: Despite the absence of data supporting its benefit, most gastroenterologists endorse combination of 5ASA + CS for patients with active moderate-to-severe UC. Randomized controlled trials are needed to assess if 5ASA confer any benefit for these patients.

Methotrexate in Crohn's disease: a new face for an old drug?

INTRODUCTION: Methotrexate is commonly used in rheumatoid arthritis but randomised controlled trials demonstrated its efficacy also in Crohn's disease. Methotrexate, although marginally used in clinical practice, is considered an appropriate immunomodulator particularly in patients refractory or intolerant to thiopurines. Areas covered: A literature search using 'methotrexate', 'Crohn's disease' and 'Inflammatory Bowel Disease' as key words, identified randomised controlled trials, meta-analyses and observational studies. The aim of this review is to summarise and critically discuss the available evidence concerning the efficacy and safety of methotrexate in the treatment of Crohn's disease. Expert commentary: Methotrexate is effective in inducing and maintaining remission in steroid-dependent CD at a dose of 25 mg/week and 15 mg/week, respectively. Data from observational studies suggest that methotrexate may be as efficacious as thiopurines with a similar safety profile. In specific clinical settings, (patients with a history of malignancy or young Epstein-Barr Virus-seronegative patients), methotrexate compete favourably with thiopurines.

Perception of Reproductive Health in Women with Inflammatory Bowel Disease.

INTRODUCTION AND AIMS: As inflammatory bowel diseases [IBD] affect female patients almost exclusively during their reproductive age, issues related to fertility, fecundity, pregnancy, delivery, and lactation are of utmost importance. Lack of education and misconceptions regarding the effect of disease and/or treatment on reproductive outcome may lead to voluntary childlessness and/or development of unwanted cervical pathologies which may impact tremendously on patients' welfare and quality of life. The aims of this study were to assess the perspectives of IBD patients on fertility, pregnancy and its outcomes, and lactation, as well as their awareness of human papillomavirus [HPV]-related pathologies and screening for cervical cancer. METHODS: This prospective study was performed across nine different Mediterranean IBD centres between 2014 and 2015 and included consecutive female IBD patients between the ages of 16 and 50 years. All patients responded to a questionnaire based on ECCO guidelines. RESULTS: A total of 348 IBD female patients with a mean age of 37.4 (standard deviation [SD] ± 2.1) years were recruited; 50% had a diagnosis of ulcerative colitis, 49.4% had Crohn`s disease, and 0.6% patients had a diagnosis of indeterminate colitis [IC]. A significant proportion of patients [ > 60%] were afraid that IBD may lead to a complicated pregnancy and that the disease itself and/or its medications can cause fetal harm. Patients had similar concerns that IBD can be transmitted to their offspring as well as with regard to breastfeeding. Counselling from health care professionals with regard to fertility, pregnancy, and lactation was associated positively with the highest number of pregnancies and inversely with the lowest number of patients who considered voluntary childlessness [p < 0.0001]. Patients with a higher level of education were more likely to get pregnant [p = 0.004]. There was a low uptake of the HPV vaccine. However, there was a reasonably good uptake of cervical cancer screening. CONCLUSION: Our study demonstrates that women with IBD have misperceptions about fertility, pregnancy, and health maintenance. We also show that education by physicians has a positive influence. We thus conclude that improved multidisciplinary approaches should be used to educate and implement European guidelines for women with IBD.

Association between the ulcerative colitis endoscopic index of severity (UCEIS) and outcomes in acute severe ulcerative colitis.

BACKGROUND: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) accounts for 86% of the variance between observers in the overall assessment of endoscopic severity, but has not been correlated with outcomes. METHODS: Consecutive cases of acute severe colitis (ASC) defined by Truelove and Witts (TW) criteria were retrospectively evaluated. Demographic details, number of TW criteria, prior medical therapy, UCEIS and inpatient medical therapy were recorded. Pre-specified (adverse) endpoints included rescue therapy, colectomy and readmission. RESULTS: Eighty-nine patients, 48 (54%) male, mean age 38 years, all received intravenous hydrocortisone 400mg/d (median 5 days [range 1-11]). Median follow-up was 14 months (2-33). Forty-eight (54%) were diagnosed the year prior to or at the time of admission. Thirty-six (40%) required rescue therapy (infliximab 25/36, ciclosporin 12/36, one receiving both). Twenty-one (24%) underwent colectomy on the index admission (9/21) or during follow-up (12/21). Median UCEIS score (possible range 0-8) was 5 (3-8). UCEIS was higher in patients requiring rescue therapy or colectomy (median score 6 [range 4-8] versus 5/8 [3-8], both p < 0.005). For UCEIS ≥5, 27/54 (50%) required rescue therapy, compared with 9/33 (27%) for UCEIS ≤4 (p = 0.037). When UCEIS was ≥5, 18/54 (33%) came to colectomy during follow-up, compared with 3/33 (9%) with UCEIS ≤4. Of 14 patients with UCEIS 7 or 8, 11/14 needed rescue therapy and 13/14 met any adverse endpoint. CONCLUSION: Endoscopic severity is associated with a worse outcome in ASC. When the UCEIS is ≥7 on admission, almost all patients will need treatment with infliximab or ciclosporin beyond steroids. This may mark a threshold for an early decision to use infliximab or ciclosporin.

Dose optimization is effective in ulcerative colitis patients losing response to infliximab: a collaborative multicentre retrospective study.

BACKGROUND: Subjects maintained on infliximab scheduled therapy for inflammatory bowel disease may require dose optimization due to secondary loss of response. There are limited data on infliximab dose optimization for ulcerative colitis. AIMS: To investigate dose optimization in ulcerative colitis patients with secondary loss of response. METHODS: This was a retrospective multicentre study. Primary outcome was rapid clinical response assessed at the next administration of infliximab after dose intensification. Secondary outcomes were rapid clinical remission, and clinical response, remission and colectomy rate by week 52. Doubling the dose (10mg/kg q8 weeks) vs. shortening the dose interval (5mg/kg every 6 or 4 weeks) were compared. RESULTS: Forty-one patients from eight centres were enrolled (15 for double dose and 26 for interval shortening). Rapid response was achieved in 37/41 patients (90.2%), while 19/41 (46.3%) achieved rapid clinical remission. At week 52, 28/41 patients were maintained in clinical remission, but 4 (9.8%) underwent colectomy. No difference was found between the two optimization strategies. Subjects achieving rapid clinical response had a significantly higher colectomy-free rate at week 52 (p=0.002). CONCLUSION: Dose optimization of infliximab was effective to restore clinical response or remission and to prevent colectomy in ulcerative colitis patients with secondary loss of response.

Leukocyte traffic control: a novel therapeutic strategy for inflammatory bowel disease--an update.

Adhesion molecules play a key role in the pathogenetic mechanisms of inflammatory bowel disease (IBD), both in Crohn's disease (CD) and ulcerative colitis (UC). In the last decade, some progress has been made in understanding their key role in leukocyte trafficking control in terms of basic research, but evidence of clinical efficacy is lacking. In the last 2 years, new molecules directed against integrins and integrin receptors have been developed and investigated in clinical trials, showing that anti-α4ß7 integrin agents can be effective and safe for the induction and maintenance of remission in active CD and UC. Preliminary data show that anti-MAdCAM, anti-ß7 and anti-integrin receptor agents are not all effective in IBD. Such results open new perspectives on clinical management of IBD, and new directions in understanding the role of adhesion molecules and leukocyte recruitment both in CD and UC.

The role of magnetic resonance imaging in detecting intestinal fibrosis in Crohn's disease.

One of the main challenges for clinicians dealing with Crohn's disease (CD) is to distinguish between inflammation and fibrosis, two sequential steps in the evolution of the intestinal disease. While inflammation is amenable to medical treatment, stricturing disease can only benefit from surgery. Magnetic resonance imaging (MRI) is a widely used tool in the diagnosis and assessment of CD. Recent data suggest that this technique might help in discriminating between fibrosis and inflammation and as such potentially guide medical decisions. In this review we will first highlight the main diagnostic techniques for CD. We will then briefly review the main mechanisms of fibrosis in this condition and the use of MRI in CD focusing on findings predictive of fibrosis and fibrotic evolution.

Biological therapy for ulcerative colitis: what is after anti-TNF.

Ulcerative Colitis (UC) is an idiopathic chronic inflammation. Its etiology is still largely unknown. Environmental and genetic factors in combination with the microbial flora or specific microorganisms are thought to trigger the gut inflammation, leading to the activation of the intestinal immune response. Immune and non-immune cells create a cross talk via the secretion of soluble mediators and expression of cell adhesion molecules, resulting in further cell activation. Mediators such as cytokines and chemokines play a key role in cell recruitment and polarization, intercellular signal amplification or activation and differentiation. Lack of balance between pro-inflammatory and anti-inflammatory cytokines is crucial in the pathogenesis of IBD. Conventional therapy of UC quite commonly fails to avoid complications or colectomy and the therapeutic armamentarium remains still limited. New therapeutic options, such as, biological therapy, gene therapy, hematopoietic stem cell transplantation, and leucoapheresis, have been investigated recently. Biological therapy is focused on different targets involved in the inflammatory process. Several new biological drugs have been introduced in the last decade or are under investigation for the treatment of IBD. They include anti TNF-α agents, anti adhesion molecules, anti IL-12/23, anti IL-6R and more. We review the recent advances in biological therapy for UC treatment beyond the anti-TNFs.