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BackgroundGastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors’ (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients’ survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.MethodsThis is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan–Meier curves and log-rank test were used to estimate unadjusted survival durations. The Cox proportional hazards model was used to evaluate survival predictors; irAEs were included as time-dependent variables.ResultsA total of 346 patients were included, 173 patients had GI-irAEs; 124 (72%) received immunosuppression. In multivariate Cox regression, ECOG 2–3 (HR 2.57, 95%CI 1.44–4.57; P < 0.01), LDH ≥ 618 IU/L (HR 2.20, 95% CI 1.47–3.29; P < 0.01), stage M1c (HR 2.21, 95% CI 1.35–3.60; P < 0.01) were associated with worse OS rates. Any grade GI-irAEs (HR 0.53, 95% CI 0.36–0.78; P < 0.01) was associated with improved OS rates. Immunosuppressive treatment did not affect OS (P = 0.15). High-grade diarrhea was associated with improved OS (P = 0.04). Patients who developed GI-irAEs had longer PFS durations on Cox model (HR 0.56, 95% CI 0.41–0.76; P < 0.01).ConclusionGI-irAEs are associated with improved OS and PFS in patients with metastatic melanoma. Furthermore, higher grades of diarrhea are associated with even better patients’ OS rates.

Cigarette smoking is an important environmental factor affecting inflammatory bowel disease. The role of smoking has not been rigorously studied in microscopic colitis (MC). The aim of this study was to compare the association of cigarette smoking in individuals with MC compared to a control population without MC.MethodsWe reviewed the records of patients with a clinical and histologic diagnosis of collagenous colitis (CC) or lymphocytic colitis (LC). Clinical history, including alcohol and smoking status at the time of diagnosis of MC, were reviewed. In this case–control study, age- and gender-matched patients without diarrhea presenting for outpatient colonoscopy served as the control population.ResultsWe analyzed a total of 340 patients with MC: 124 with CC and 216 with LC. Overall, any smoking status (former or current) was associated with MC (odds ratio [OR] 2.12, 95% confidence interval [CI]: 1.56–2.88). This risk was more prominent in current smokers (adjusted OR 5.36, 3.81, and 4.37 for CC, LC, and all MC, respectively, 95% CI all greater than 1). The association of smoking was not significantly affected by gender or average alcohol consumption.ConclusionsIn our study population, cigarette smoking is a risk factor for the development of both forms of microscopic colitis. There were no significant differences between LC and CC, and current smoking and the development of microscopic colitis affected men and women similarly. We feel that these data are sufficient to discuss the potential risks of tobacco use in patients with microscopic colitis.

Whether current smoking worsens the clinical course of microscopic colitis (MC) is unknown. The aim was to evaluate the impact of smoking on the clinical course of MC.MethodsOne hundred and eighty-four patients (72% women; age, 62.4 ± 1.1 years) with MC (118 collagenous colitis (CC) and 66 lymphocytic colitis (LC) were evaluated (39 of them were current smokers). In all the patients, smoking habits and clinical data at presentation, response to therapy, and clinical relapses during follow-up were prospectively recorded. Risk factors for clinical relapse were studied in 160 patients after a mean follow-up of 28 ± 1 months. Cox regression analysis was used to adjust for confounding variables.ResultsAge at diarrhea onset was 63.0 ± 1.4 years in nonsmokers and 50.4 ± 2.1 years in current smokers (P < 0.001). There was no significant influence of smoking habit on either clinical symptoms at diagnosis or clinical remission rate. Clinical relapse rate was 25.5% for CC and 29.6% for LC, with the mean relapse-free time 28.8 months (95% confidence interval, 26.3–31.4) for CC and 26.9 months (95% confidence interval, 26–30.3) for LC (P = 0.5). Multivariate analysis showed that age at diagnosis (<50 years versus others; adjusted hazard ratio, 2.8; 95% confidence interval, 1.3–6; P = 0.01) was associated with risk of relapse of CC but not LC. Current smoking was not an independent risk factor for either CC or LC relapse.ConclusionsActive smokers developed MC more than a decade before nonsmokers. Age at diagnosis, but not smoking, was an independent risk factor of relapse in patients with CC.

Previous studies suggest an increase in the incidence rate of microscopic colitis in recent decades. The aim was to evaluate changes in the population-based incidence rate of microscopic colitis and its subtypes over time in Terrassa, Spain.MethodsThis was a prospective study during the period 2004–2008, with a comparison of data from the period 1993–1997. The catchment area was a mixed rural-urban type, with nearly 290,000 inhabitants. All patients with nonbloody chronic diarrhea referred for a diagnostic colonoscopy were included. Multiple biopsy specimen samples were obtained when the macroscopic appearance of the colonic mucosa was normal to rule out microscopic colitis. Crude and adjusted incidence rates based on either the year of diagnosis or the date of onset of symptoms were calculated.ResultsForty patients with collagenous colitis (CC) and 32 with lymphocytic colitis (LC) were identified. The mean annual incidence of CC and LC based on the year of onset of symptoms was 2.6/105 inhabitants (95% confidence interval [CI], 1.9–3.3), and 2.2/105 inhabitants (95% CI, 1.5–3.0), respectively. Incidence rates for CC based on the year of onset of symptoms were significantly higher in the period 2004–2008 than in 1993–1997 (2.6 versus 1.1/105; P = 0.012). The increase in CC incidence was more marked in women (P = 0.047) than in men (P = 0.19).ConclusionsThe annual incidence of CC in Terrassa increased over time, mainly in women. Nevertheless, the rates were much lower than those observed in northern Europe, suggesting that there is a north–south difference in the incidence of microscopic colitis. (Inflamm Bowel Dis 2011;)

Specific nutrients or foods have been inconsistently associated with ulcerative colitis (UC) or Crohn's disease (CD) risks. Thus, we investigated associations between diet as a whole, as dietary patterns, and UC and CD risks.MethodsWithin the prospective EPIC (European Prospective Investigation into Cancer) study, we set up a nested matched case–control study among 366,351 participants with inflammatory bowel disease data, including 256 incident cases of UC and 117 of CD, and 4 matched controls per case. Dietary intake was recorded at baseline from validated food frequency questionnaires. Incidence rate ratios of developing UC and CD were calculated for quintiles of the Mediterranean diet score and a posteriori dietary patterns produced by factor analysis.ResultsNo dietary pattern was associated with either UC or CD risks. However, when excluding cases occurring within the first 2 years after dietary assessment, there was a positive association between a “high sugar and soft drinks” pattern and UC risk (incidence rate ratios for the fifth versus first quintile, 1.68 [1.00–2.82]; Ptrend = 0.02). When considering the foods most associated with the pattern, high consumers of sugar and soft drinks were at higher UC risk only if they had low vegetables intakes.ConclusionsA diet imbalance with high consumption of sugar and soft drinks and low consumption of vegetables was associated with UC risk. Further studies are needed to investigate whether microbiota alterations or other mechanisms mediate this association.

Fecal microbiota transplant is a promising therapy for ulcerative colitis. Parameters maximizing effectiveness and tolerability are not yet clear, and it is not known how import the transmission of donor microbes to patients is. Here (clinicaltrails.gov: NCT03006809) we have tested the effects of antibiotic pretreatment and compared two modes of maintenance dose delivery, capsules versus enema, in a randomized, pilot, open-label, 2 × 2 factorial design with 22 patients analyzed with mild to moderate UC. Clinically, the treatment was well-tolerated with favorable safety profile. Of patients who received antibiotic pretreatment, 6 of 11 experienced remission after 6 weeks of treatment, versus 2 of 11 non-pretreated patients (log odds ratio: 1.69, 95% confidence interval: −0.25 to 3.62). No significant differences were found between maintenance dosing via capsules versus enema. In exploratory analyses, microbiome turnover at both the species and strain levels was extensive and significantly more pronounced in the pretreated patients. Associations were also revealed between taxonomic turnover and changes in the composition of primary and secondary bile acids. Together these findings suggest that antibiotic pretreatment contributes to microbiome engraftment and possibly clinical effectiveness, and validate longitudinal strain tracking as a powerful way to monitor the dynamics and impact of microbiota transfer.

In the intestinal epithelium, the aberrant regulation of cell/cell junctions leads to intestinal barrier defects, which may promote the onset and enhance the severity of inflammatory bowel disease (IBD). However, it remains unclear how the coordinated behaviour of cytoskeletal network may contribute to cell junctional dynamics. In this report, we identified ACF7, a crosslinker of microtubules and F-actin, as an essential player in this process. Loss of ACF7 leads to aberrant microtubule organization, tight junction stabilization and impaired wound closure in vitro . With the mouse genetics approach, we show that ablation of ACF7 inhibits intestinal wound healing and greatly increases susceptibility to experimental colitis in mice. ACF7 level is also correlated with development and progression of ulcerative colitis (UC) in human patients. Together, our results reveal an important molecular mechanism whereby coordinated cytoskeletal dynamics contributes to cell adhesion regulation during intestinal wound repair and the development of IBD. The cytoskeleton plays a key role in cell/cell junction formation, but how the coordinated behaviour of the cytoskeleton contributes is not known. Here the authors show that actin-microtubule crosslinker ACF7 plays a key role in tight junction stabilization and wound healing in intestinal epithelium.

Inflammatory bowel disease (IBD) patients often experience disease flare-ups during international air travel. We aimed to identify risk factors associated with IBD flare-up during international air travel. Patients with scheduled international air travel were enrolled in the study from the Seoul National University Bundang Hospital IBD clinic. Flight information and clinical data were collected via questionnaires and personal interviews, and risk factors associated with IBD flares were determined. Between May 2018 and February 2020, 94 patients were prospectively enrolled in the study (mean age, 33.0 years; males, 53.2%; mean disease duration, 56.7 months), including 56 (59.6%) with ulcerative colitis and 38 (40.4%) with Crohn's disease. Of the 94 patients enrolled, 15 (16.0%) experienced an IBD flare-up and 79 (84.0%) remained in remission throughout travel. Logistic regression analysis revealed that high fecal calprotectin levels before travel (odds ratio [OR]: 1.001, 95% confidence interval [CI]: 1.000-1.001, p = 0.016), the presence of a comorbidity (OR: 6.334, 95% CI: 1.129-35.526, p = 0.036), and history of emergency room visit (OR: 5.283, 95% CI: 1.085-25.724, p = 0.039) were positively associated with disease flare-up. The previous and current use of immunomodulators and biologics, time of flight, altitude, number countries visited, travel duration, objective of visit, and previous medical consultations were not associated with disease flare-up. Elevated fecal calprotectin levels, history of emergency room visits, and the presence of a comorbidity predicted IBD flare-up during international air travel.

Abstract Background Psychiatric comorbidity might modify the disease course adversely in patients with inflammatory bowel disease (IBD). Treatment options include antidepressants, which, apart from improving mood, have anti-inflammatory properties that might modify the disease course. This nationwide study aimed to examine the influence of antidepressants on the disease course among patients with ulcerative colitis (UC) and Crohn's disease (CD). Methods Patients registered with an incident diagnosis of CD or UC in the Danish National Patient Register (2000-2017) were included. Information on antidepressant use and proxy measures of disease activity (health care and drug utilization) was extracted from national population registers. Poisson regression was performed to estimate disease activity rates by antidepressant use adjusted for confounders. Furthermore, the analyses were performed stratified by IBD subtype and type of antidepressants. Results A total of 42,890 patients were included (UC: 69.5%; CD: 30.5%). When adjusted for confounders, a lower incidence rate of disease activity was found among antidepressant users compared with nonusers in both CD (incidence rate ratio [IRR], 0.75; 95% confidence interval [CI], 0.68-0.82) and UC (IRR, 0.90; 95% CI, 0.84-0.95) patients. Further, markedly lower rates of disease activity were found among CD (IRR, 0.51; 95% CI, 0.43-0.62) and UC (IRR, 0.67; 95% CI, 0.59-0.75) patients with no use of antidepressants before IBD onset. Conclusions In this nationwide study, antidepressant use was found to be beneficial on the disease course among patients with UC and CD, particularly in patients with no use of antidepressants before IBD onset. Randomized controlled trials are warranted to investigate the potential of antidepressants being an adjunct treatment to conventional IBD therapy.

Treatment of advanced melanoma patients with ipilimumab results in improved survival. However, only about 20% of treated patients experience long-term benefit. Combining treatment of ipilimumab with other drugs may improve immune activation and potentially enhance clinical efficacy. The aims of the phase II clinical trial reported here were to investigate tolerability and efficacy of a combined immunotherapeutic strategy comprising standard systemic ipilimumab at 3 mg/kg four times at 3-week intervals and intratumorally injected IL-2 at 9 MIU daily twice weekly for four weeks in pretreated melanoma patients with distant metastasis. The primary endpoint was the disease control rate according to immune-related response criteria at week 12; tolerability according to Common Terminology Criteria for Adverse Events criteria was secondary endpoint. No objective responses were observed in the 15 enrolled patients. Three patients had stable disease 12 weeks after starting treatment, yielding a disease control rate of 20%. Tolerability of this combination treatment was acceptable. Observed adverse events were those expected from the respective monotherapies. Autoimmune colitis was observed in two patients. Grade III/IV adverse events were observed in 40% of patients, and no treatment-related deaths occurred. Thus, this combined immunotherapy is associated with adverse events similar to those associated with the respective monotherapies. However, this study does not provide any evidence of improved efficacy of the combination over ipilimumab alone.