Real-life efficacy and safety of Ustekinumab as second- or third-line therapy in Crohn's disease: results from a large Italian cohort study.

OBJECTIVE: Ustekinumab (UST) is an anti-IL12/23 antibody for the treatment of Crohn's Disease (CD). The aim of this study was to compare the efficacy and safety of UST in a large population-based cohort of CD patients who failed previous treatment with other biologics. PATIENTS AND METHODS: 194 CD patients (108 males and 86 females, mean age 48 years (range 38-58 years) were retrospectively reviewed. 147 patients were already treated with anti-TNFα (75.8%), and 47 (24.2%) patients were already treated with anti-TNFα and vedolizumab. Concomitant treatment with steroids was present in 177 (91.2%) patients. RESULTS: At week 12, clinical remission was achieved in 146 (75.2%) patients. After a mean follow-up of 6 months, clinical remission was maintained in 135 (69.6%) patients; at that time, mucosal healing was assessed in 62 (31.9%) patients, and it was achieved in 33 (53.2) patients. Three (1.5%) patients were submitted to surgery. Steroid-free remission was achieved in 115 (59.3%) patients. Both serum C-Reactive Protein and Fecal Calprotectin (FC) levels were significantly reduced with respect to baseline levels during follow-up. A logistic regression, UST therapy as third-line therapy (after both anti-TNFα and vedolizumab), FC >200 µg/g, and HBI ≥8 were significantly associated with lack of remission. Adverse events occurred in 5 (2.6%) patients, and four of them required suspension of treatment. CONCLUSIONS: UST seemed to be really effective and safe in CD patients unresponsive to other biologic treatments, especially when used as second-line treatment.

Articular manifestations in inflammatory bowel disease patients: a prospective study.

BACKGROUND AND AIMS: Rheumatic manifestations are frequent in inflammatory bowel disease (IBD) and are associated with a wide range of clinical patterns. METHODS: Articular symptoms and signs were investigated by questionnaire in a cohort of 651 pts, mean age 42+/-14 years, followed at two referral hospitals over a 12-month period. RESULTS: 142 ulcerative colitis (UC) and 120 Crohn's disease (CD) patients referred articular pain during their IBD history: in 46% this was associated with active IBD, in 56% symptoms were intermittent and in 19% symptoms preceded IBD diagnosis. 62 pts (28 UC, 34 CD) complaining of articular symptoms at the time of the interview, were investigated by the rheumatologist: arthropathy was axial in 52%, oligoarticular in 16% and polyarticular in 23%. Oligoarthritis commonly involved the lower limbs and was more commonly associated with UC. The mean number of small joints involved was significantly higher in CD than in UC pts (9.9+/-8.2 vs. 5.6+/-4.3; p<0.01). Bone scintigraphy was abnormal in 70% of pts. CONCLUSIONS: Prevalence of self-reported articular symptoms in IBD patients exceeds 40% with 9.5% incidence during 1-year follow up. Symptoms predict entheropatic involvement of the locomotor system.

Zinc supplementation tightens "leaky gut" in Crohn's disease.

OBJECTIVES: Small intestinal permeability is often increased in patients with Crohn's disease and may be pathogenic for clinical relapses. No effective prophylactic treatment is available for these patients. The aim of this study was to ascertain whether zinc supplementation may improve intestinal permeability. METHODS: We studied 12 patients with quiescent Crohn's disease who had been in remission for at least 3 months and had increased intestinal permeability on two separate occasions within the last 2 months. Patients received oral zinc sulfate supplements (110 mg three times a day) for 8 weeks and were followed-up for 12 months thereafter to monitor relapses. RESULTS: We found that the lactulose/mannitol ratio was significantly higher before supplementation than after (0.041 +/- 0.003 versus 0.026 +/- 0.005). During follow-up, 10 patients had normal intestinal permeability and did not relapse; of the remaining two who had increased intestinal permeability, one relapsed. CONCLUSIONS: Our findings show that zinc supplementation can resolve permeability alterations in patients with Crohn's disease in remission. Improving intestinal barrier function may contribute to reduce the risk of relapse in Crohn's disease.

Reduced plasma antioxidant concentrations and increased oxidative DNA damage in inflammatory bowel disease.

BACKGROUND: Oxidative stress is believed to play a key role in the pathogenesis of inflammatory bowel disease (IBD)-related intestinal damage. Circulating antioxidants may have a role to play in preventing free radical-mediated tissue injury. METHODS: Plasma vitamin A, E and carotenoid concentrations, leukocytic genomic damage and 8-hydroxy-deoxy-guanosine (8-OHdG) concentration were determined in 46 ulcerative colitis (UC) patients, 37 Crohn disease (CD) patients and 386 controls. A 20 ml blood sample was taken from each subject for antioxidant and 8-OHdG measurements. A food frequency questionnaire was administered to a sample of subjects from each group to evaluate daily intake of dietary compounds. RESULTS: Antioxidant concentration was significantly reduced in IBD patients, particularly in those with active disease, with respect to controls (P < 0.0001). 8-OHdG concentrations were significantly increased in IBD patients compared to controls, independent of disease activity (P < 0.05). No correlation was found between antioxidant and 8-OHdG concentrations. Carotenoid concentrations were significantly reduced in malnourished IBD patients (0.89 +/- 0.14 micromol/l) compared to patients with normal or high body mass index (1.83 +/- 0.12 micromol/l; P < 0.05), independent of disease activity or extension. Protein, fruit and vegetable intakes of IBD patients were significantly lower than those of controls. CONCLUSIONS: Depletion of antioxidants is likely to be important in the pathophysiology of IBD: UC and CD patients show increased free radical peripheral leukocyte DNA damage and decreased plasma antioxidant defenses. These results indicate the necessity of further studies to establish whether optimal vitamin status may improve the clinical course of UC and CD.

Influence of disease site and activity on peripheral neutrophil function in inflammatory bowel disease.

Reactive oxygen species, released by phagocytes, are involved in tissue injury in inflammatory bowel diseases. The aim of our study was to evaluate peripheral neutrophil function in patients with ulcerative colitis (N = 66) and Crohn's disease (N = 62) with respect to disease activity and extent, using chemiluminometry after three stimuli. Twenty-seven healthy subjects were enrolled as controls. Neutrophils from ulcerative colitis and Crohn's disease patients had a significantly higher response than those from controls following phorbol myristate acetate (86.6 +/- 6.5, 173.8 +/- 11.9, 167.5 +/- 12.2 mV, P < 0.0001), formyl-methionyl-leucyl-phenylalanine (39.5 +/- 3.4, 41.3 +/- 2.7, 58.6 +/- 4.7 mV, P < 0.001), and zymosan (142.6 +/- 10.4, 223.7 +/- 8.9, 231.2 +/- 9.5 mV, P < 0.0001) administration. The increased response was observed during both active disease and remission. The highest chemiluminescence values were found in patients with active ulcerative pancolitis and ileal Crohn's disease. The activation of circulating neutrophils may indicate persistent intestinal inflammation or may be triggered by luminal factors even in the absence of symptoms.

Median pancreatectomy for tumors of the neck and body of the pancreas.

BACKGROUND: When enucleation is too risky because of possible damage of the main pancreatic duct, benign tumors located in the neck or body of the pancreas are usually removed by a left (spleno)-pancreatectomy or by a pancreatoduodenectomy. But standard pancreatic resection results in an important loss of normal pancreatic parenchyma and may cause impairment of exocrine and endocrine function. The aim of this study was to evaluate early and longterm results of median pancreatectomy, a limited resection of the midportion of the pancreas, in selected patients with benign or borderline tumors of the pancreas. STUDY DESIGN: Records of patients at Ospedale Busonera between November 1985 and September 1998 were reviewed. Ten patients with tumors of the neck or body of the pancreas underwent median pancreatectomy; the cephalic stump was sutured and the distal stump was anastomosed with a Roux-en-Y jejunal loop. Followup included clinical evaluation and routine laboratory tests: abdominal ultrasonography, exocrine and endocrine pancreatic function with fecal chymotrypsin, and an oral glucose tolerance test. RESULTS: Pathologic examination showed: insulinoma (n = 3), mucinous cystadenoma (n = 3), nonfunctioning endocrine tumor (n = 1), papillary-cystic neoplasm (n= 1), serous cystadenoma (n = 1), and intraductal mucinous tumor (n = 1). Operative mortality and morbidity were 0% and 40%, respectively; pancreatic fistula occurred in three patients. At mean followup of 62.7 months, no recurrence was found and no patient had exocrine insufficiency or glucose metabolism impairment. CONCLUSIONS: Median pancreatectomy is a safe and effective alternative to major pancreatic resection in selected patients with benign or low-malignant lesions of the pancreas. This procedure carries a surgical risk similar to that of the standard operation, but avoids extensive pancreatic resection and pancreatic function impairment.