A propensity score weighted comparison of vedolizumab and adalimumab in Crohn's disease.

BACKGROUND AND AIM: There are no head-to-head randomized controlled trials between biologics in Crohn's disease (CD). We aimed to perform a multicenter, real-life comparison of the effectiveness of vedolizumab (VDZ) and adalimumab (ADA) in CD. METHODS: Data of consecutive patients with CD treated with VDZ and ADA from January 2016 to April 2019 were extracted from the cohort of the Sicilian Network for Inflammatory Bowel Disease. The effectiveness was evaluated at 12, 52 weeks, and as failure-free survival at the end of follow up. Propensity score analysis was performed using the inverse probability of treatment weighting method. RESULTS: Five hundred eighty-five treatments (VDZ: n = 277; ADA: n = 308) were included (median follow-up: 56.0 weeks). After 12 weeks, a clinical response was achieved in 64.3% patients treated with VDZ and in 83.1% patients treated with ADA (odds ratio [OR] 0.65, 95% confidence interval [CI] 0.38-1.10, P = 0.107), while at 52 weeks, a clinical response was observed in 54.0% patients treated with VDZ and in 69.1% patients treated with ADA (OR 0.77, 95% CI 0.45-1.31, P = 0.336). Cox survival analysis weighted for propensity score showed no significant difference in the probability of failure-free survival between the two drugs (hazard ratio = 1.20, 95% CI 0.83-1.74, P = 0.340). Post-treatment endoscopic response and mucosal healing rates were similar between the two groups (endoscopic response: 35.3% for VDZ and 25.5% for ADA, P = 0.15; mucosal healing: 31.8% for VDZ and 33.8% for ADA, P = 0.85). CONCLUSIONS: In the first study comparing VDZ and ADA in CD via propensity score analysis, the drugs showed comparable effectiveness and a similar safety profile.

Physicians' Knowledge and Application of Immunization Strategies in Patients with Inflammatory Bowel Disease: A Survey of the Italian Group for the Study of Inflammatory Bowel Disease.

BACKGROUND: No data on European countries about knowledge and application of immunization strategies in patients with inflammatory bowel disease (IBD) are available. OBJECTIVES: We designed a questionnaire aimed at exploring these issues among Italian gastroenterologists dealing with adult and paediatric IBD. METHODS: An anonymous, 24-item, questionnaire was sent via e-mail to all members of the Italian Group for the study of Inflammatory Bowel Disease. Three sets of questions were formulated: (1) Characteristics of respondents; (2) General opinions on the role of vaccines in IBD patients; (3) Immunizations of IBD patients in clinical practice. RESULTS: Of the 455 total surveys sent, there were 198 respondents (response rate: 43.5%). The great majority of respondents (82.9%) reputed as "very important" to perform the vaccinations recommended by the guidelines in patients with IBD. The indication to immunization is given at the diagnosis of the disease by 55.6% of the respondents. The most frequently recommended vaccine in IBD patients is the annual flu vaccine, while the recommendation rate for the other vaccines is variable depending on the different pathogens. CONCLUSIONS: Efforts carried out by the scientific societies are required to increase the awareness of this relevant topic among physicians.

Lupus-like reactions in patients with inflammatory bowel disease treated with anti-TNFs are insidious adverse events: data from a large single-center cohort.

Objectives: Very few data on the incidence, predictors, and clinical outcomes of lupus-like reactions (LLRs) in patients with inflammatory bowel disease (IBD) treated with anti-TNFs have been reported. Materials and methods: All records of consecutive IBD patients who started a treatment with an anti-TNF from January 2006 to June 2018 were retrospectively reviewed. Patients were defined as having LLR by the presence of immunologic abnormalities (positivity for ANA and/or anti-ds-DNA), along with clinical features that included at least two of the following: arthralgia, fatigue, fever, cutaneous manifestations, or serositis, which had a clear temporal association with exposure to the anti-TNFs, and resolved without recurrence once the drug was discontinued. Results: 760 patients (1059 total treatments with anti-TNFs) were included. Participants contributed a total of 2863.5 person-years of follow-up, during which 16 cases of LLRs (2.1% of patients) were reported, accounting for an incidence rate of 5.6 per 1000 person-years. Female gender and being former smokers were more prevalent in the LLR group (75.0% versus 44.1%, p = .02; and 18.8% versus 5.4%, p = .037, respectively), with a hazard ratio of 4.40 (95% CI: 1.40-13.81; p = .011) and 4.87 (95% CI: 1.37-17.38; p = .015), respectively, at Cox regression analysis. All LLRs resolved following discontinuation of the drug after a mean of 8.1 ± 4.2 weeks. Ten patients required corticosteroids to control severe symptoms. Conclusions: In this large cohort of patients treated with anti-TNFs with long follow-up, LLRs were rare adverse events, more common in women and former smokers, occurring with nonspecific and insidious clinical features.

Psoriasis and Inflammatory Bowel Disease.

BACKGROUND: Inflammatory bowel disease (IBD) and psoriasis (PS) are associated conditions. The reason for this association lies in the sharing of predisposition genes and common immunological mechanisms. SUMMARY: This review will focus on the interplay between IBD and PS, with details on prevalence and phenotype of PS in IBD, genetics, pathogenetic pathways, and therapy. Key Messages: Microbiome seems relevant in both conditions: a reduction of beneficial bacteria has been observed. IBD and PS have in common some comorbidities like cardiovascular disease, similar risk of cancer and psychiatric problems. Many biological therapies such as anti-tumour necrosis factor (TNF) and anti-interleukin 23 are effective in both conditions, underlining the common immunological mechanisms. Paradoxical PS has been mainly observed after anti-TNF therapies, but preliminary reports show that it can also occur with other biologics. Genetic predisposition to this phenomenon has been reported.

Tolerability profile of thiopurines in inflammatory bowel disease: a prospective experience.

OBJECTIVES: The occurrence of thiopurine-related adverse events (AEs) may complicate the management of patients with inflammatory bowel disease (IBD). We aimed to evaluate the tolerability of thiopurines in a current IBD setting. MATERIALS AND METHODS: All consecutive patients who started a treatment with azathioprine (AZA) from January 2010 to March 2016 were entered in a prospectively maintained database, and the AEs which led to the permanent discontinuation of the drug were reported. RESULTS: Two hundred and fifty three patients were included. Median total follow-up was 32 months (range: 0.2-75 months). At the end of the study, AZA was discontinued in 160 patients (63.2%). The main reason leading to drug withdrawal was the occurrence of AEs (109/160 patients [68.1%]; cumulative incidence among the entire cohort: 43.1%). Overall, the most frequent AEs leading to treatment withdrawal were nausea (31/253 patients, 12.3%) and subjective symptoms, i.e., poorly defined side effects such as fatigue, headache and muscle pain (20/253 patients, 7.9%). Among the 109 AZA-intolerant patients, a switch to 6-mercaptopurine (6-MP) was performed in 44 cases (40.4%). At the end of follow-up, 6-MP was discontinued in 35/44 patients (79.5%), mostly due to AEs (29/35 patients, 82.8%). Azathioprine-induced hepatic and pancreatic toxicity was associated with male gender (p = .01 and p = .03, respectively), and occurrence of nausea with Crohn's disease (p = .04). CONCLUSIONS: Our real-life prospective cohort showed the higher cumulative incidence of thiopurine withdrawal due to AEs reported to date. Switching from AZA to 6-MP was often ineffective.

Advanced age is an independent risk factor for severe infections and mortality in patients given anti-tumor necrosis factor therapy for inflammatory bowel disease.

BACKGROUND & AIMS: Few data are available on effects of biologic therapies in patients more than 65 years old with inflammatory bowel disease (IBD). We evaluated the risk and benefits of therapy with tumor necrosis factor (TNF) inhibitors in these patients. METHODS: We collected data from patients with IBD treated with infliximab (n = 2475) and adalimumab (n = 604) from 2000 to 2009 at 16 tertiary centers. Ninety-five patients (3%) were more than 65 years old (52 men; 37 with ulcerative colitis and 58 with Crohn's disease; 78 treated with infliximab and 17 with adalimumab). The control group comprised 190 patients 65 years old or younger who were treated with both biologics and 190 patients older than 65 years who were treated with other drugs. The primary end points were severe infection, cancer, or death. RESULTS: Among patients more than 65 years old who received infliximab and adalimumab, 11% developed severe infections, 3% developed neoplasms, and 10% died. No variable was associated with severe infection or death. Among control patients more than 65 years old, 0.5% developed severe infections, 2% developed cancer, and 2% died. Among control patients less than 65 years old, 2.6% developed severe infections, none developed tumors, and 1% died. CONCLUSIONS: Patients older than 65 years treated with TNF inhibitors for IBD have a high rate of severe infections and mortality compared with younger patients or patients of the same age that did not receive these therapeutics. The effects of anti-TNF agents in older patients with IBD should be more thoroughly investigated, because these patients have higher mortality related to hospitalization than younger patients.

Over-expression of paneth cell-derived anti-microbial peptides in the gut of patients with ankylosing spondylitis and subclinical intestinal inflammation.

OBJECTIVES: Subclinical gut inflammation has been demonstrated in patients with AS. Altered expression of paneth cell (PC) anti-microbial peptides have been reported in the inflamed ileum of patients with Crohn's disease (CD). Here, we investigated the expression of PC-derived peptides in subclinical gut inflammation in AS. METHODS: Multiple adjacent mucosal biopsies from terminal ileum were obtained from 25 patients with AS, 30 CD and 15 healthy controls (HCs). Expression of human α-defensin 5 (HD-5), phospholipase A2 (PLA2), lysozyme and SOX-9 molecules was assessed by quantitative Taqman RT-PCR on mucosal samples. Immunohistochemistry with anti-human HD-5 antibody and genotyping of relevant NOD2 mutations was also performed. RESULTS: HD-5, PLA2 and lysozyme transcript levels were strongly increased in AS and CD with similar degrees of intestinal inflammation when compared with normal controls. Immunohistochemical evaluation showed a normal number of PCs in both AS patients with chronic gut inflammation and CD patients with less-inflamed ileal samples. Conversely, CD patients with higher degree of gut inflammation had a reduced number of PCs and low expression levels of HD-5. CONCLUSION: In this study, we provide evidence that over-expression of PC-derived anti-microbial peptides occurs in the ileum of AS patients with subclinical gut inflammation, likely representing an important early alteration of the mucosal innate immune component and intestinal host defence in AS.

An open-safety study of dual antiviral therapy in real-world patients with chronic hepatitis C.

PURPOSE: Treatment of patients with chronic hepatitis C with alpha-interferon and ribavirin usually produces adverse events within the first 3 months. We aimed to assess safety and predictors of discontinuation or dose modification of these drugs. METHODS: Observational study of 312 patients with predominantly genotype 1 chronic hepatitis C treated openly along 5 years in a clinical practice setting. RESULTS: Eighty-four percent of patients experienced at least one adverse event (853 events in total, 3.3 per patient on average). Incidence rate was higher during the first 90 days and decreased thereafter (<5%). Discontinuation rates at 30 and 90 days and at end of treatment were 2, 4 and 8%, respectively. Seventy percent of discontinuation cases were due to adverse events rather than to laboratory abnormalities. Serious adverse events were rare (<1%). Dose modifications were made in 158 patients (51%) on 237 occasions. After adjusting for covariates, older age was a predictor of early discontinuation, whereas HCV genotypes 1-4 and daily ribavirin dose of 1000 mg or more were predictors of dose modification. CONCLUSIONS: The majority of real-world patients with chronic hepatitis C tolerate acceptably dual therapy and very few discontinue it. Subjective decisions on dose reduction of either compound appears to have a major impact on adherence of patients. There is a need to better define, collect and analyse clinical features which may predict adverse events and safety-related decisions during therapy of chronic hepatitis C.

Effectiveness and safety of Ustekinumab for the treatment of Crohn's disease in real-life experiences: a meta-analysis of observational studies.

Background: The aim of this meta-analysis was to estimate the effectiveness and safety of Ustekinumab in Crohn's disease (CD) reported by observational studies.Research design and methods: PubMed/Medline and Embase were systematically searched through September 2019. Only real-life observational studies were included.Results: Thirteen studies comprising 1450 patients met the inclusion criteria. Ustekinumab was administered subcutaneously at induction among 7 studies, while in 6 studies the intravenous formulation was used. At induction (8-16 weeks), the pooled estimate rates of clinical response and remission were 56% (95% CI: 43-68%; range: 16-94%; I2 = 94%) and 34% (95% CI: 25-45%; range: 15-58%; I2 = 90%), respectively. The rate of clinical response was higher among studies which employed the subcutaneous compared with the intravenous induction (68% vs. 38%, p = 0.01). At maintenance, the pooled estimate rates of clinical response, clinical remission, endoscopic response, and endoscopic remission were 62% (95% CI: 50-73%; range: 42-89%; I2 = 89%), 40% (95% CI: 28-54%; range: 26-73%; I2 = 90%), 56% (95% CI: 37-73%; range: 20-77%; I2 = 87%), and 19% (95% CI: 11-30%; range: 7-31%; I2 = 67%), respectively.Conclusions: Ustekinumab is an effective treatment in patients with CD with a reassuring safety profile. The subcutaneous induction seems to be superior to the intravenous one.

Effectiveness and safety of biologics in pediatric inflammatory boweldisease: Real-life data from the Sicilian Network.

BACKGROUND: Biological therapies have modified the disease course of pediatric inflammatory bowel disease (IBD) and are routinely used in clinical practice. Our observational study aims to evaluate effectiveness and safety of biologics in IBD. METHOD: Clinical benefit and safety data of 93 children with IBD, receiving biologics (Infliximab - IFX, Adalimumab - ADA, Golimumab - GOL) from January 2013 to December 2017, were extracted from the cohort of the Sicilian Network of IBD. RESULTS: Among 87 children aged 7-17 years (63 Crohn's disease [CD], 24 Ulcerative colitis [UC]), 101 out of 108 biologic treatments were considered. Evaluation of 74 biologic treatments in CD patients at 26, 52, 104 weeks showed clinical benefit rates of 84.2%, 93.3%, 66.7% with IFX (n= 38) and 88.9%, 84.4%, 65.2% with ADA (n= 36). Biologic treatments (n=27) evaluated in the UC group at 26, 52, 104 weeks, led to clinical benefit rates of 85.7%, 83.3%, 50% in IFX subgroup (n=21) and 40%, 50%, 33% in the ADA subgroup (n=5), respectively. One patient treated with GOL showed 100% clinical benefit at 26 and 52 weeks. Overall adverse events (AEs) rate was 9.25%. Six younger children, <6 years, receiving 8 treatments (4 ADA, 4 IFX) presented a clinical remission rate of 75% at 12 weeks and 25% at 52 weeks. AEs rate was 25% in this group. CONCLUSION: Our data show that biologic therapy in children, even at a younger age, is effective in allowing long-term remission with a good safety profile.

A propensity score weighted comparison of Vedolizumab, Adalimumab, and Golimumab in patients with ulcerative colitis.

BACKGROUND: No real-life study on the comparative effectiveness of Vedolizumab (VDZ), Adalimumab (ADA), and Golimumab (GOL) in ulcerative colitis (UC) is currently available. AIMS: To compare the effectiveness of the three biologics in consecutive patients with UC. METHODS: A three-arms propensity score-adjusted analysis was performed using the Inverse Probability of Treatment Weighting method. RESULTS: 463 treatments (VDZ: n = 187; ADA: n = 168; GOL: n = 108) were included (median follow-up: 47.6 weeks). At 12 weeks (n = 463), a steroid-free remission was reported in 24.1% patients in the VDZ group, in 33.3% patients in the ADA group, and in 30.6% patients in the GOL group (p = n.s. for all comparisons). At 52 weeks (n = 377), a steroid-free remission was reported in 51.5% patients in the VDZ group, in 31.2% patients in the ADA group, and in 29.4% patients in the GOL group (p = 0.002 for VDZ vs. ADA, p = 0.001 for VDZ vs. GOL, p = n.s. for ADA vs. GOL). Cox survival analysis demonstrated that patients treated with VDZ had reduced probability of treatment discontinuation compared to those treated with ADA (HR: 0.42, 95% CI 0.28-0.64, p < 0.001) and GOL (HR: 0.30, 95% CI 0.19-0.46, p < 0.001), while patients treated with ADA had reduced risk of treatment discontinuation compared to those treated with GOL (HR: 0.71, 95% CI 0.50-1.00, p = 0.048). CONCLUSIONS: VDZ was superior to ADA and GOL at 52 weeks and as treatment persistence, while ADA showed a superior treatment persistence compared to GOL.

Persistence on Anti-Tumour Necrosis Factor Therapy in Older Patients with Inflammatory Bowel Disease Compared with Younger Patients: Data from the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD).

BACKGROUND AND OBJECTIVE: Older people with inflammatory bowel disease (IBD) appear to have a lower response to anti-tumour necrosis factor (TNF) therapy, with more frequent complications than younger patients. The objective of this study was to assess persistence on therapy and the safety of anti-TNF therapy in older patients (aged ≥ 60 years). METHODS: We retrospectively reviewed the database of the Sicilian Network for Inflammatory Bowel Diseases (SN-IBD), extracting data regarding IBD patients aged ≥ 60 years and controls < 60 years of age at their first course of anti-TNF treatment. Data concerning persistence on therapy over the first year of treatment (primary objective) together with data on reasons for treatment withdrawal, concomitant diseases and treatments were collected. RESULTS: We identified 114 anti-TNF-naϊve patients aged ≥ 60 years (median age 64 years, range 60-80 years; 47 males) compared with 330 younger controls aged < 60 years (median age 39 years, range 18-59 years; 57 males). Older patients with Crohn's disease (n = 73) showed a significantly lower persistence with every kind of anti-TNF therapy (whether analysed together [p < 0.001] or separately for intravenous and subcutaneous [SC] therapy) than younger controls, whereas older patients with ulcerative colitis (n = 41) showed a lower persistence when combining all kinds of anti-TNF treatment (p = 0.004) and for SC therapy. Secondary failures, infections, and neoplasias, but not primary failure, occurred more frequently in older IBD patients than in younger controls. CONCLUSION: Despite a comparable number of primary failures, older IBD patients treated for the first time with anti-TNF agents showed lower treatment persistence due to higher rates of secondary failure, adverse events, infections, and tumours than younger patients in the first year of follow-up. The reasons for this difference still remain unclear.

Meta-analysis of the placebo rates of clinical relapse and severe endoscopic recurrence in postoperative Crohn's disease.

BACKGROUNDS & AIMS: The benefit of therapy for prevention of postoperative recurrence of Crohn's disease (CD) is limited. Clinical relapse and severe endoscopic recurrence are the main outcomes in the evaluation of trials on prevention of recurrence. The aim of this meta-analysis was to focus on knowledge of the placebo rates of relapse and recurrence in postoperative CD and to identify factors influencing these rates. METHODS: We performed a meta-analysis of placebo-controlled, randomized clinical trials, evaluating therapies for postoperative maintenance of CD identified on MEDLINE from 1990 to 2006. Primary outcomes were clinical relapse and severe endoscopic recurrence. RESULTS: The pooled estimate of the placebo relapse rate was 23.7% (95% confidence interval [CI], 13-35; range 0-78). There was a statistically significant heterogeneity among studies (P < .0001). Heterogeneity in clinical relapse was present even if the trials were stratified according to the time of outcome. The pooled estimate of the severe endoscopic recurrence rate was 50.2% (95% CI, 28-73; range, 30-79). There was significant heterogeneity among the studies (P = .00038). This heterogeneity was less apparent in studies carried out within 12 months. The logistic analysis identified only duration of follow-up as a variable associated with different placebo relapse rates. No variable was identified as a predictor of a placebo endoscopic recurrence rate. CONCLUSIONS: There is significant heterogeneity among placebo rates in postoperative CD. No single design variable was identified that explained the heterogeneity in placebo outcomes for clinical or endoscopic recurrence.

Radiofrequency thermal ablation vs. percutaneous ethanol injection for small hepatocellular carcinoma in cirrhosis: meta-analysis of randomized controlled trials.

OBJECTIVES: Radiofrequency thermal ablation (RF) and percutaneous ethanol injection (PEI) have been employed in the treatment of small hepatocellular carcinoma (HCC) as curative treatments. The aim of the study was to review the available evidence comparing RF to PEI for small HCC. SEARCH STRATEGY: Cochrane, MEDLINE, CANCERLIT, and ENBASE databases were used. SELECTION CRITERIA: randomized clinical trials evaluating RF vs. PEI. Data were extracted from each randomized controlled trial (RCT). Primary outcomes were overall survival and local recurrence. Meta-analysis software was used and risk differences (RDs) and their 95% confidence intervals and Q-test for heterogeneity were calculated. RESULTS: Five RCTs were identified including 701 patients. The overall survival was significantly higher in patients treated with RF than in those treated with PEI (RD 0.116, 95% CI 0.173/0.060; heterogeneity not present). Local recurrence rate is significantly higher in patients treated with PEI than in those treated with RF. In the RF group the 1, 2, and 3 years cancer-free survival rates were significantly better than in the PEI-treated patients (respectively: RD 0.098-95% CI 0.006/0.189; heterogeneity P=0.57; RD 0.187, 95% CI 0.082/0.293; heterogeneity P=0.98; RD 0.210, 95% CI 0.095/0.325; heterogeneity P = 0.78). A small number of adverse events were reported in the two treatments. CONCLUSIONS: RF ablation is superior to PEI in the treatment of small HCC with respect to overall survival, 1, 2, and 3 years survival rates, 1, 2, and 3 cancer-free survival rates, and tumor response. RF shows a significantly smaller risk of local recurrence.