Gionata Fiorino

Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE): Determining Therapeutic Goals for Treat-to-Target.

OBJECTIVES:The Selecting Therapeutic Targets in Inflammatory Bowel Disease (STRIDE) program was initiated by the International Organization for the Study of Inflammatory Bowel Diseases (IOIBD). It examined potential treatment targets for inflammatory bowel disease (IBD) to be used for a “treat-to-target” clinical management strategy using an evidence-based expert consensus process.METHODS:A Steering Committee of 28 IBD specialists developed recommendations based on a systematic literature review and expert opinion. Consensus was gained if ≥75% of participants scored the recommendation as 7–10 on a 10-point rating scale (where 10=agree completely).RESULTS:The group agreed upon 12 recommendations for ulcerative colitis (UC) and Crohn’s disease (CD). The agreed target for UC was clinical/patient-reported outcome (PRO) remission (defined as resolution of rectal bleeding and diarrhea/altered bowel habit) and endoscopic remission (defined as a Mayo endoscopic subscore of 0–1). Histological remission was considered as an adjunctive goal. Clinical/PRO remission was also agreed upon as a target for CD and defined as resolution of abdominal pain and diarrhea/altered bowel habit; and endoscopic remission, defined as resolution of ulceration at ileocolonoscopy, or resolution of findings of inflammation on cross-sectional imaging in patients who cannot be adequately assessed with ileocolonoscopy. Biomarker remission (normal C-reactive protein (CRP) and calprotectin) was considered as an adjunctive target.CONCLUSIONS:Evidence- and consensus-based recommendations for selecting the goals for treat-to-target strategies in patients with IBD are made available. Prospective studies are needed to determine how these targets will change disease course and patients’ quality of life.

3rd European Evidence-based Consensus on the Diagnosis and Management of Crohn’s Disease 2016: Part 1: Diagnosis and Medical Management

This paper is the first in a series of two publications relating to the European Crohn’s and Colitis Organisation [ECCO] evidence-based consensus on the diagnosis and management of Crohn’s disease and concerns the methodology of the consensus process, and the classification, diagnosis and medical management of active and quiescent Crohn’s disease. Surgical management as well as special situations including management of perianal Crohn’s disease of this ECCO Consensus are covered in a subsequent second paper [Gionchetti et al JCC 2016].

Prospective comparison of computed tomography enterography and magnetic resonance enterography for assessment of disease activity and complications in ileocolonic Crohn's disease

Background: Studies comparing magnetic resonance enterography (MRE) and computerized tomography enterography (CTE) for Crohns disease (CD) are scarce. Methods: The aim of this study was to prospectively compare the sensitivity, specificity, and accuracy of abdominal MRE and CTE to assess disease activity and complications (fistulas, strictures) in ileocolonic CD. A total of 44 patients (23 male; 21 female; mean age 44) with ileocolonic CD underwent both MR and CT in a short time interval (mean 5 days). A 16‐slice CT with intravenous contrast and an MRI with oral and paramagnetic intravenous contrast were performed. Ileocolonoscopy was used as the reference standard. Sensitivity values of CT and MR for detection of extraenteric signs of disease were compared with the McNemar test, with results of imaging studies, surgery, and physical examination as reference standards. Results: No significant differences in sensitivity, specificity, and accuracy were observed between MRE and CTE regarding the following parameters at the patient level: localization of CD (P = 1.0), bowel wall thickening (P = 1.0), bowel wall enhancement (P = 1.0), enteroenteric fistulas (P = 0.08), detection of abdominal nodes (P = 1.0), and perivisceral fat enhancement (P = 0.31). MR was significantly superior compared to CT in detecting strictures (P = 0.04). Per segment analysis showed that MRE was significantly superior to CTE in detecting ileal wall enhancement (P = 0.02). Conclusions: MR and CT are equally accurate to assess disease activity and bowel damage in CD. MR may be superior to CT in detecting intestinal strictures and ileal wall enhancement. MR may represent an alternative technique to CT in assessing ileocolonic CD. (Inflamm Bowel Dis 2010)

Development of the Lémann Index to Assess Digestive Tract Damage in Patients With Crohn's Disease

BACKGROUND & AIMS There is a need for a scoring system that provides a comprehensive assessment of structural bowel damage, including stricturing lesions, penetrating lesions, and surgical resection, for measuring disease progression. We developed the Lémann Index and assessed its ability to measure cumulative structural bowel damage in patients with Crohns disease (CD). METHODS We performed a prospective, multicenter, international, cross-sectional study of patients with CD evaluated at 24 centers in 15 countries. Inclusions were stratified based on CD location and duration. All patients underwent clinical examination and abdominal magnetic resonance imaging analyses. Upper endoscopy, colonoscopy, and pelvic magnetic resonance imaging analyses were performed according to suspected disease locations. The digestive tract was divided into 4 organs and subsequently into segments. For each segment, investigators collected information on previous operations, predefined strictures, and/or penetrating lesions of maximal severity (grades 1-3), and then provided damage evaluations ranging from 0.0 (no lesion) to 10.0 (complete resection). Overall level of organ damage was calculated from the average of segmental damage. Investigators provided a global damage evaluation (from 0.0 to 10.0) using calculated organ damage evaluations. Predicted organ indexes and Lémann Index were constructed using a multiple linear mixed model, showing the best fit with investigator organ and global damage evaluations, respectively. An internal cross-validation was performed using bootstrap methods. RESULTS Data from 138 patients (24, 115, 92, and 59 with upper tract, small bowel, colon/rectum, and anus CD location, respectively) were analyzed. According to validation, the unbiased correlation coefficients between predicted indexes and investigator damage evaluations were 0.85, 0.98, 0.90, 0.82 for upper tract, small bowel, colon/rectum, anus, respectively, and 0.84 overall. CONCLUSIONS In a cross-sectional study, we assessed the ability of the Lémann Index to measure cumulative structural bowel damage in patients with CD. Provided further successful validation and good sensitivity to change, the index should be used to evaluate progression of CD and efficacy of treatment.

Biological Agents for Moderately to Severely Active Ulcerative Colitis: A Systematic Review and Network Meta-analysis

Ulcerative colitis (UC) is an idiopathic, remitting and relapsing, chronic inflammatory bowel disease. It is characterized by mucosal ulceration, rectal bleeding, diarrhea, abdominal cramps, urgency or tenesmus, fever, malaise, weight loss and fatigue, depending on the extent and severity of the disease. Worldwide, the estimated incidence of UC ranges from 1.2 to 20.3 cases per 100000 person-years and its prevalence ranges from 7.6 to 246.0 per 100000 persons (14). Pharmacologic management of UC aims at reducing inflammation and maintaining remission of symptoms and includes sulfasalazine, 5-aminosalicylates (mesalamine, olsalazine, and balsalazide), glucocorticoids, and immunosuppressants (azathioprine, 6-mercaptopurine, and cyclosporine) (5, 6). Despite progress, treatment options for moderately to severely active UC remain limited because conventional therapies inadequately control the disease in a substantial proportion of patients and often lead to adverse events (AEs). However, a series of biological agents have recently received regulatory approval or are under scrutiny; in 2013, those included the monoclonal antibodies adalimumab, golimumab, infliximab, and vedolizumab. Evidence on comparative effectiveness and harms of those treatments would be very useful to inform clinical decision making. We conducted a systematic review of randomized, controlled trials (RCTs) assessing biological agents as induction or maintenance therapy for moderately to severely active UC in adults to address this issue. We assessed their comparative clinical efficacy and harm using the method of multiple-treatment meta-analysis, also known as network meta-analysis or mixed-treatment comparison (710), based on the available evidence from RCTs. We aimed to compare the different treatment options and provide a clinically useful summary that can be used to support optimal decision making. Methods Our study protocol (11) was registered on PROSPERO (CRD42013005459). We followed standard methods for conducting and reporting systematic reviews and network meta-analyses (12, 13). Data Sources and Searches We systematically searched MEDLINE and EMBASE databases from inception to 31 December 2013. Search terms included biologic(al) agent(s), biologic(s), adalimumab, golimumab, infliximab, or vedolizumab, combined with ulcerative colitis. The search was limited to RCTs and humans. Language or age restrictions were not imposed. We also searched the Cochrane Library for any recent systematic review on the subject, the ClinicalTrials.gov database for completed but unpublished studies, and the European Medicines Agency and U.S. Food and Drug Administration Web sites to obtain details on study characteristics or outcomes if these data were missing or unclearly presented in the original articles. Study Selection The titles and abstracts of identified published articles were scanned to exclude irrelevant studies. The full text of the selected articles was retrieved and read. The bibliographies of the articles and of reviews and meta-analyses were scanned. We further asked field experts to provide additional evidence. Studies were eligible for inclusion if they were randomized, placebo-controlled or head-to-head trials assessing the efficacy or harm of biological agents for the treatment of adult patients with moderately to severely active UC. We considered only biological agents that were market-authorized by either the U.S. Food and Drug Administration or European Medicines Agency, as well as agents under review for the new drug application (United States) or marketing authorisation application (European Union). We defined moderately to severely active UC as a Mayo Clinic score (MCS) of 6 to 12 points, with an endoscopic subscore of 2 or 3. An MCS is a composite activity index ranging from 0 to 12, with higher scores indicating more severe disease activity. It is calculated as the sum of 4 items: stool frequency, rectal bleeding, endoscopic findings, and physicians global assessment (14). Randomized, controlled trials were eligible for inclusion in the network regardless of country, phase (2 or 3), or support. Data Extraction and Quality Assessment Two reviewers abstracted the data independently. The following information was collected from each study: publication data; trials acronym and identifier; first authors last name; geographic location of study; year of publication; study design; number of participants and population characteristics; and interventions variables, including drug, dose, and administration. We extracted data specific for patients who were naive to treatment with biological agents because the relative efficacy of biological agents should not be assessed by pooling patients for whom standard therapies were unsuccessful with patients for whom biological agents were unsuccessful (15, 16). Different doses of the same treatment were treated as separate interventions, and for biological agents that received regulatory approval, only data for dose and administration as approved in the respective summary of product characteristics were considered. The outcome measures were the odds ratios (ORs) for clinical response (primary outcome), clinical remission, and mucosal healing at the end of induction and at completion of each trials maintenance phase, calculated in accordance with the intention-to-treat principle (that is, total number of randomly assigned participants, regardless of how the original study investigators analyzed the data). Clinical response was defined as a decrease from baseline in the MCS of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point, or an absolute rectal bleeding subscore of 0 or 1. Clinical remission was defined as an MCS of 2 points or lower, with no individual subscore exceeding 1 point. Mucosal healing was defined as an absolute subscore for endoscopy of 0 or 1. We also examined the occurrence of serious adverse events (SAEs), which are defined as any untoward medical occurrence that results in death, requires hospital admission or prolongation of an existing hospital stay, causes persistent or significant disability or incapacity, or is life-threatening (17); the AEs leading to discontinuation of the study drug; the total number of AEs; the total number of infectious AEs; the number of serious infections; tuberculosis; and congestive heart failure. Reviewers assessed the risk of bias in the results of included studies by using the Cochrane Collaborations tool (18), which addresses the following key domains: sequence generation, allocation concealment, blinding of participants and personnel, incomplete outcome data, selective outcome reporting, and other sources of bias. These items are considered as key domains for risk-of-bias assessment and reclassified as adequate (low risk of bias), inadequate (high risk of bias), or unclear. Studies with adequate procedures in all domains are considered to have a low risk of bias, ones with inadequate procedures in 1 or more domains are considered to have a high risk of bias, and those with unclear procedures in 1 or more domains are considered to have unclear risk of bias. Disagreements among reviewers were discussed and agreement was reached by consensus. Data Synthesis and Analysis We conducted the network meta-analysis within a Bayesian framework using Markov chain Monte Carlo methods in WinBUGS (Medical Research Council Biostatistics Unit, Cambridge, United Kingdom) (19). Analysis was based on noninformative priors for relative-effect parameters (flat normal with mean of 0 and precision of 0.001) and between-study SD (a flat uniform distribution between 0 and 2). Convergence and lack of autocorrelation were checked and confirmed after a 5000-simulation burn-in phase without any thinning and using 4 chains with different initial values. Then, a burn-in phase of 20000 iterations was used, followed by 50000 iterations to estimate parameters. We did sensitivity analyses by setting the prior on the heterogeneity equal to a uniform (0, 100) and on the precision parameter equal to a (0.001, 0.001) to check the robustness of the model to different sets of priors. Model choice was based on the deviance information criterion, and a lower deviance information criterion by 5 or more units suggested a better model fit. We report estimates only for the default model because we did not find differences in model fit according to deviance information criterion. We used the resulting ORs and 95% credible intervals (CrIs), the Bayesian equivalent to CIs, to assess treatment effects. We also calculated fixed-effects ORs and 95% CIs (frequentist approach). Given that each pairwise comparison included a limited number of RCTs, we could not formally assess statistical heterogeneity and publication bias. Role of the Funding Source This study was funded by the Centro Ricerca e Cura delle Malattie Infiammatorie Croniche Intestinali, IRCCS Istituto Clinico Humanitas. The funding source had no role in the design of the study; the collection, analysis, and interpretation of the data; or the decision to submit the manuscript for publication. Results Figure 1 summarizes the search and selection of evidence. We identified 6 publications (2025) reporting the results of 7 trials (ACT [Active Ulcerative Colitis Trial] 1, ACT 2, ULTRA [Ulcerative Colitis Long-Term Remission and Maintenance With Adalimumab] 1, ULTRA 2, PURSUIT-SC [Program of Ulcerative Colitis Research Studies Utilizing an Investigational TreatmentSubcutaneous], PURSUIT-M [Program of Ulcerative Colitis Research Studies Utilizing an Investigational TreatmentMaintenance], and GEMINI 1). One additional study, the NCT00853099 trial, was initially identified through ClinicalTrials.gov (26) and later in full-text publication (27). In total, 8 trials met the eligibility criteria, none of which were head-to-head comparisons of biological agents. Figure 1. Summ

European Evidence-based Consensus: Inflammatory Bowel Disease and Malignancies

The global prevalence of cancer is increasing, largely as more patients are living into old age. Therefore, gastroenterologists caring for patients with inflammatory bowel disease [IBD] increasingly are managing patients with cancer, or a previous history of cancer. This often requires joint management with the patient’s oncologist, enabling case-by-case decision-making based on the characteristics and expected evolution of the index cancer. Previously, no European guidelines existed describing the impact of IBD on malignancy. For this reason, the European Crohn’s and Colitis Organisation [ECCO] Guidelines Committee [GuiCom] decided to elaborate a set of Consensus Statements on optimal risk/benefit strategies for treating IBD patients with cancer or a history of cancer. The development of clinical practice guidelines is expensive and time consuming, and it is the Committee’s hope that these statements will facilitate and accelerate future efforts to elaborate formal guidelines, providing useful information on areas for which evidence is lacking and where controlled studies are needed. The strategy used to produce the Consensus Statements involved five steps: 1. Two members of Guicom [VA and RE] identified four main topics that needed to be addressed: a] IBD and solid tumours; b] IBD and skin and haematological malignancies; c] malignancy related to therapy: risk and prevention; and d] management of IBD patients with a history of malignancy. During 2014, calls for participation in the drafting of consensus statements were issued to ECCO members, and selected oncologists known for their expertise and active research in the field were invited to join the Consensus. Participants were selected by the Committee, and four working groups were created, each composed of a chairperson [LE, RE, LB, and VA], two ECCO members including young members [Y-ECCO], and one or two experienced oncologists. The chairmen and their groups elaborated relevant questions on topics dealing with current practice and/or areas …

Review article: causative factors and the clinical management of patients with Crohn’s disease who lose response to anti‐TNF‐α therapy

Aliment Pharmacol Ther 2011; 34: 1–10

Paradoxical immune-mediated inflammation in inflammatory bowel disease patients receiving anti-TNF-α agents.

Reports of autoimmune diseases, including psoriasis- and dermatitis-like skin reactions with anti-tumor necrosis factor-α (TNF-α), are increasing, likely a reflection of the growing use of these agents. This paradoxical phenomenon can no longer be considered rare, with some studies providing incidence estimates of greater than 10%. This paradoxical inflammation has been reported in patients receiving treatment with anti-TNF-α agents for a variety of inflammatory conditions, including inflammatory bowel disease, psoriasis and rheumatoid arthritis and appears to be a class effect. Moreover, there have recently been reports of autoimmune arthralgia occurring in patients receiving anti-TNF-α agents. Further studies are necessary to determine the true incidence of this phenomenon and to identify those patients most likely to be at risk.

The efficacy of shortening the dosing interval to once every six weeks in Crohn's patients losing response to maintenance dose of infliximab.

Aliment Pharmacol Ther 2011; 33: 349–357

Effects of immunosuppression on immune response to pneumococcal vaccine in inflammatory bowel disease: a prospective study.

Background: Since immunomodulators and antitumor necrosis factor (TNF) agents are increasingly used to treat inflammatory bowel disease (IBD), it is recommended to administer antipneumococcal vaccination to prevent opportunistic pneumonia. There is some evidence that concomitant immunosuppression may impair the immune response to vaccination. We aimed to evaluate the response rates to pneumococcal vaccination in four different treatment groups (mesalamine, azathioprine, infliximab, infliximab plus azathioprine). Methods: In all, 96 patients with IBD (54 with Crohns disease; 42 with ulcerative colitis) were administered a 23‐valent polysaccharide pneumococcal vaccine (PSV‐23). The levels of antipneumococcal antibodies were measured prior to and at least 3 weeks after vaccination. Response rates and risk factors for impaired immunosuppression were investigated. Patients on mesalamine were used as a control group. Results: Patients administered infliximab or the combination immunosuppressive therapy had significantly lower response rates to vaccination (57.6% and 62.5%, respectively) compared with the group on mesalamine (88.6%; P < 0.05 for both comparisons). Azathioprine alone did not influence the response rate to vaccination (78.9%; P = 0.43 vs. mesalamine group). Mean antibody titers after vaccination were significantly lower in patients under infliximab or combined immunosuppression than controls (P < 0.05). Immunosuppression with infliximab or combination therapy significantly decreased the likelihood of responding to vaccination (odds ratio [OR] = 0.17, 95% confidence interval [CI] 0.04–0.64, P = 0.009, and OR = 0.21, 95% CI 0.05–0.91, P = 0.038, respectively). Pneumococcal vaccination was generally safe and well tolerated. Conclusions: Anti‐TNF therapy alone or in combination with azathioprine impairs the response to pneumococcal vaccination in patients with IBD. All patients with IBD should therefore be vaccinated before starting anti‐TNF therapy. (Inflamm Bowel Dis 2012;)