CFTR Modulators Rescue the Activity of CFTR in Colonoids Expressing the Complex Allele p.[R74W;V201M;D1270N]/dele22_24.

An Italian, 46-year-old female patient carrying the complex allele p.[R74W;V201M;D1270N] in trans with CFTR dele22_24 was diagnosed at the Cystic Fibrosis (CF) Center of Verona as being affected by CF-pancreatic sufficient (CF-PS) in 2021. The variant V201M has unknown significance, while both of the other variants of this complex allele have variable clinical consequences, according to the CFTR2 database, with reported clinical benefits for treatment with ivacaftor + tezacaftor and ivacaftor + tezacaftor + elexacaftor in patients carrying the R74W-D1270N complex allele, which are currently approved (in USA, not yet in Italy). She was previously followed up by pneumologists in northern Italy because of frequent bronchitis, hemoptysis, recurrent rhinitis, Pseudomonas aeruginosa lung colonization, bronchiectasis/atelectasis, bronchial arterial embolization and moderately compromised lung function (FEV1: 62%). Following a sweat test with borderline results, she was referred to the Verona CF Center where she presented abnormal values in both optical beta-adrenergic sweat tests and intestinal current measurement (ICM). These results were consistent with a diagnosis of CF. CFTR function analyses were also performed in vitro by forskolin-induced swelling (FIS) assay and short-circuit currents (Isc) in the monolayers of the rectal organoids. Both of these assays showed significantly increased CFTR activity following treatment with the CFTR modulators. Western-blot analysis revealed increased fully glycosylated CFTR protein after treatment with correctors, in line with the functional analysis. Interestingly, tezacaftor, together with elexacaftor, rescued the total organoid area under steady-state conditions, even in the absence of the CFTR agonist forskolin. In conclusion, in ex vivo and in vitro assays, we measured a residual function that was significantly enhanced by in vitro incubation with CFTR modulators, especially by ivacaftor + tezacaftor + elexacaftor, suggesting this combination as a potentially optimal treatment for this case.

Factors influencing the presence of potentially explosive gases during colonoscopy: Results of the SATISFACTION study.

This study tested the hypothesis that bowel preparation with mannitol should not affect the colonic concentration of H2 and CH4 . Therefore, the SATISFACTION study, an international, multicenter, randomized, parallel-group phase II-III study investigated this issue. The phase II dose-finding part of the study evaluated H2 , CH4 , and O2 concentrations in 179 patients randomized to treatment with 50 g, 100 g, or 150 g mannitol. Phase III of the study compared the presence of intestinal gases in 680 patients randomized (1:1) to receive mannitol 100 g in single dose or a standard split-dose 2 L polyethylene glycol (PEG)-Asc preparation (2 L PEG-Asc). Phase II results showed that mannitol did not influence the concentration of intestinal gases. During phase III, no patient in either group had H2 or CH4 concentrations above the critical thresholds. In patients with H2 and/or CH4 levels above detectable concentrations, the mean values were below the risk thresholds by at least one order of magnitude. The results also highlighted the effectiveness of standard washing and insufflation maneuvers in removing residual intestinal gases. In conclusion, bowel cleansing with mannitol was safe as the concentrations of H2 and CH4 were the same as those found in patients prepared with 2 L PEG-Asc. In both groups, the concentrations of gases were influenced more by the degree of cleansing achieved and the insufflation and washing maneuvers performed than by the preparation used for bowel cleansing. The trial protocol was registered with ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT04759885) and with EudraCT (eudract_number: 2019-002856-18).

A non-invasive combined strategy to improve the appropriateness of upper gastrointestinal endoscopy.

Background and aim Increasing the appropriateness of upper gastrointestinal endoscopy (UGIE) improves the quality of care while containing costs. The aim of this study was to improve the appropriateness of UGIE through a process involving evaluation of prescriptions and the use of a non-invasive alternative. Materials and methods A senior endoscopist evaluated the appropriateness of all outpatient referrals for UGIE and established the proper timing. Referrals were either accepted and programmed, canceled, or substituted by a non-invasive evaluation of gastric function, determining serum levels of gastrin-17 (G17), Pepsinogen I (PGI) and II (PGII), and antibodies against Helicobacter pylori. Results A total of 5102 requests for UGIE examinations were evaluated; 540 (10.4%) were inappropriate and had been prescribed for: gastroesophageal reflux disease (n=307), surveillance with erroneous timing (n=113), dyspepsia (n=66), other indications (n=20), and absence of written indication (n=34). Gastric function was evaluated in 282/540 patients; findings included normal values in 94 patients without proton-pump inhibitor therapy (PPI) and in 48 on PPI, active H pylori infection in 56, previous H pylori infection in 30, GERD in n=50, and atrophic gastritis in n=4. UGIE was performed in the latter 4 cases.  Within 2 years (range 1-22 months) of the initial refusal, 105/504 patients underwent UGIE, with normal endoscopic findings in 71/105 (67.5%), and with no cases of cancer. Conclusions This strategy, based on a strict control of prescriptions, is effective to increase the appropriateness while containing public health costs. The use of gastric function testing improves patient selection for UGIE endoscopy.

Isolation and Sequencing of the First Case of Symptomatic MDR Salmonella enterica Subsp. Enterica ST40 in Human in Italy, July 2020.

Strains of drug-resistant nontyphoidal Salmonella spp. are emerging in livestock worldwide. We describe the first case of symptomatic multidrug-resistant (MDR) Salmonella enterica subsp. enterica in human and the genetic mechanisms at the basis of its antibiotic resistance. To control outbreaks, rapid identification and sequencing are necessary. Proactive research and notification are needed to evaluate the routes of transmission from livestock to humans and risk-management strategies of MDR Salmonella strains.

Posterior Reversible Encephalopathy Syndrome After Azathioprine Administration in Severe Ulcerative Colitis.

Posterior reversible encephalopathy syndrome is a rare syndrome characterized by brain edema and neurological symptoms, often resulting from several drugs. Treatment is based on discontinuation, and diagnosis is thus essential. Only 13 cases of posterior reversible encephalopathy syndrome have been reported in inflammatory bowel diseases, and we present the first after azathioprine in adults. A 56-year-old patient with active ulcerative colitis was found unconscious 5 days after the institution of azathioprine. Right-sided hemiplegia was found after the patient regained consciousness. Magnetic resonance imaging showed altered signal associated with diffusion restriction in the occipital lobe and cerebral vasogenic edema. Complete regression of neurological signs occurred after azathioprine discontinuation.

The PROSIT Cohort of Infliximab Biosimilar in IBD: A Prolonged Follow-up on the Effectiveness and Safety Across Italy.

BACKGROUND: We report a prospective, nationwide cohort evaluating the safety and effectiveness of CT-P13. METHODS: A structured database was used to record serious adverse events (SAEs), clinical remission/response, inflammatory biomarkers (CRP and calprotectin), and endoscopic findings. RESULTS: Eight hundred ten patients with inflammatory bowel disease (IBD) (452 Crohn's disease [CD]) were enrolled. Four hundred fifty-nine patients were naïve to anti-TNFα (group A), 196 had a previous exposure (group B), and the remaining 155 were switched to CT-P13 (group C). All patients were included in the safety evaluation with a mean follow-up of 345 ± 215 days and a total number of 6501 infusions. One hundred fifty-four SAEs were reported (19%), leading to cessation of the biosimilar in 103 subjects (12.7%). Infusion reactions were 71, leading to cessation of the biosimilar in 53 subjects (6.5%), being significantly more frequent in patients pre-exposed to anti-TNFα (P = 0.017). The efficacy of therapy was calculated in 754 IBD patients, with a mean follow-up of 329 ± 202 days. Forty-eight patients had a primary failure (6.4%), and 188 (25.6%) lost response during follow-up. Six hundred twenty-eight (364 CD) and 360 IBD patients (222 CD) completed the follow-up at 6 and 12 months, respectively. At 12 months, patients without loss of response were 71%, 64%. and 82% in groups A, B, and C, respectively (log rank P = 0.01). Clinical/endoscopic scores and inflammatory biomarkers dropped significantly in CD and UC patients (P = 0.01 and P < 0.0001) compared with baseline. CONCLUSIONS: In this large prospective cohort, no further signals of difference in safety and effectiveness of CT-P13 in IBD has been observed.

Clinical efficacy and safety of golimumab in biologically experienced and naive patients with active ulcerative colitis: A real-life experience from two Italian IBD centers.

OBJECTIVE: To evaluate the efficacy and safety of golimumab in biological naive and experienced patients with moderately to severely active ulcerative colitis (UC) treated at two Italian IBD centers. METHODS: We retrospectively reviewed our prospectively maintained UC database from March 2015 to March 2017. Patients received golimumab 200 mg at week 0, 100 mg at week 2, then 50 mg or 100 mg every 4 weeks. Follow-up was recorded at 12 and 24 weeks and in March 2017, with a median follow-up of 64 weeks. The main outcomes evaluated were clinical remission (CR) and adverse event rates. RESULTS: Of the 59 patients (44% naive and 56% experienced), CR rate was 47% at 12-week follow-up, 55% (among the 49 patients on treatment) at 24-week follow-up and 49% (among 35 patients on treatment) at the last follow-up visit. Median treatment duration was 52 weeks (interquartile range 30-64 weeks) among patients treated for >6 months. Overall, 10 (17%) patients experienced adverse events, of whom 50% discontinued treatment. The most frequent adverse events were infections. Biological naive and experienced patients did not differ in terms of CR and adverse event rates. CONCLUSIONS: Our real-life experience showed that CR decreased over time and was achieved by almost one-third of the cohort at the last follow-up visit. Golimumab showed an overall favorable safety profile and the results were not different between biological naive and experienced patients. Future research is needed to confirm our results and to identify criteria to select patients most likely to respond.

Azathioprine Maintenance Therapy to Prevent Relapses in Autoimmune Pancreatitis.

OBJECTIVES: Steroids are used to induce remission in autoimmune pancreatitis (AIP). Low-dosage steroid therapy or immunosuppressant (IMs) has been proposed as maintenance therapy to prevent AIP relapse. Few and conflicting data have been published on the efficacy of azathioprine (AZA) in preventing AIP relapse. The aim of this study was to evaluate the indication and efficacy of AZA as maintenance therapy to prevent disease relapse in AIP. METHODS: Patients suffering from AIP diagnosed according to the ICDC in type 1, type 2, and not otherwise specified (NOS) were divided in those treated with AZA (AZA+ group) as maintenance therapy and not treated with maintenance therapy (AZA- group). Exclusion criteria were: previous pancreatic surgery, other autoimmune diseases as indication for AZA treatment, and use of IMs different from AZA. Drug safety, clinical and instrumental outcome of AZA+ patients were evaluated. RESULTS: A total of 23 patients (18 Males and 5 Females, mean age 54±11 years) in AZA+ group and 97 (58 Males and 39 Females, mean age 45±18 years) in AZA- group were compared. In AZA+ group, patients were significantly older (P=0.043), type 1 AIP was more frequently diagnosed (87 vs. 51%, P=0.006), sIgG4 higher (758±625 vs. 311±409 mg/dl, P<0.001), other organ involvement (OOI) more frequently observed (83 vs. 48%, P=0.002), with higher frequency of relapse before AZA treatment (78 vs. 14%, P<0.001). Three patients in AZA+ group required drug discontinuation because of adverse events. Twenty patients were therefore evaluated for outcome. Six out of 20 patients (30%) relapsed after 24±15 months (5 in pancreas and 1 on biliary tract). They were retreated with steroids and continued AZA. Two out of 6 patients (33%) had a second relapse,after respectively 11 months (in pancreas and kidney) and 22 months (in kidney). CONCLUSIONS: AZA is an effective and safe treatment to prevent AIP relapses.

The PROSIT-BIO Cohort: A Prospective Observational Study of Patients with Inflammatory Bowel Disease Treated with Infliximab Biosimilar.

BACKGROUND: Few data are available on the safety and efficacy of infliximab biosimilar CT-P13 in patients with ulcerative colitis and Crohn's disease. METHODS: A prospective, multicenter, cohort study using a structured database. RESULTS: Consecutive patients (313 Crohn's disease and 234 ulcerative colitis) were enrolled from 31 referral centers; 311 patients were naive to anti-tumor necrosis factor alpha, 139 had a previous exposure to biologics, and the remaining 97 were switched to CT-P13 after a mean of 18 ± 14 infusions of infliximab. The mean follow-up was 4.3 ± 2.8 months, and the total follow-up time was 195 patient-years. After 2061 infusions, 66 serious adverse events were reported (12.1%), 38 (6.9%) of them were infusion-related reactions. The biosimilar had to be stopped in 29 (5.3%) cases for severe infusion reactions (8 naive, 19 previous exposed, and 2 switch), and in further 16 patients (2.9%) for other serious adverse events. Infusion reactions were significantly more frequent in patients pre-exposed to infliximab than to other anti-tumor necrosis factor alpha (incidence rate ratio = 2.82, 95% CI: 1.05-7.9). The efficacy of the biosimilar was evaluated in 434 patients who received treatment for at least 8 weeks, using time-to-event methods for censored observations: 35 patients were primary failures (8.1%). After further 8, 16, and 24 weeks, the efficacy estimations were 95.7%, 86.4%, and 73.7% for naive, 97.2%, 85.2%, and 62.2% for pre-exposed, and 94.5%, 90.8%, and 78.9% for switch, respectively (log-rank P = 0.64). CONCLUSIONS: Although no direct comparison was performed, preliminary data on efficacy and safety of CT-P13 were in line with those of infliximab.

Fecal elastase-1 is useful in the detection of steatorrhea in patients with pancreatic diseases but not after pancreatic resection.

BACKGROUND: Fecal elastase-1(FE-1) has been suggested as an alternative to steatorrhea quantification to evaluate pancreatic insufficiency, but its diagnostic performance has not been compared with steatorrhea in chronic pancreatitis or after pancreatic resection. METHODS: The relationship between steatorrhea and FE-1 was studied in patients with chronic pancreatic disorders or pancreatic resection. Student's t test and ANOVA were used for statistical analysis, accepting 0.05 as limit for significance. RESULTS: Eighty-two patients were studied (42 non-operated; 40 previously submitted to pancreatic resection). Fat output was higher in operated than non-operated patients (29.2 ± 3.1 vs 9.9 ± 2.2 g/day, p < 0.001) FE-1 was more severely reduced in operated patients (202 ± 32.3 µg/g in non operated vs 68.6 ± 18.2 in operated patients; p < 0.001). Steatorrhea was significantly more severe in operated patients across different levels of FE-1. The relationship between FE-1 and steatorrhea was described by a power regression model, with a regression line significantly different in operated and non-operated patients (p < 0.001). A steatorrhea of 7 g (upper limit of normal range) was calculated by this regression line when FE-1 is 15 µg/g in non-operated, but as high as 225 µg/g in operated patients. CONCLUSION: FE-1 is useful to identify pancreatic insufficiency. Steatorrhea is anticipated in non-operated patients only when FE-1 is below the limit for a confident measurement of our assay. In operated patients, steatorrhea may be present even if FE-1 is only slightly reduced, that suggests a role for non pancreatic factors. FE1 is not useful to identify operated patients at risk of malabsorption.