Low Incidence of Inflammatory Bowel Disease Adverse Events in Adalimumab Clinical Trials Across Nine Different Diseases.

OBJECTIVE: Adalimumab is approved for treatment of Crohn's disease and ulcerative colitis. Thus, we postulated that exacerbation or new-onset of inflammatory bowel disease (IBD) would be rare events in patients treated with adalimumab for non-IBD indications. The objective was to evaluate the incidence of IBD adverse events (AEs) across adalimumab trials. METHODS: IBD AE rates in 75 adalimumab clinical trials in rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, pediatric enthesitis-related arthritis, uveitis, hidradenitis suppurativa, adult and pediatric psoriasis, psoriatic arthritis, nonpsoriatic arthritis peripheral spondyloarthritis (SpA), axial SpA, including nonradiographic axial SpA, and ankylosing spondylitis, were analyzed. Search terms for IBD AEs (new onset or worsening/flare) included IBD, ulcerative colitis, Crohn's disease, and ulcerative proctitis. RESULTS: This analysis included 24,114 patients, representing 36,508 patient-years of adalimumab exposure. The overall rate of IBD AEs in adalimumab-treated patients was 0.1 (95% confidence interval [95% CI] 0.1-0.2)/100 patient-years (41 events), ranging from no events (psoriatic arthritis, uveitis, and pediatric trials) to 0.8 (95% CI 0.2-2.2)/100 patient-years in peripheral SpA. The rate of IBD in axial SpA was 0.6 (95% CI 0.4-1.0)/100 patient-years. During placebo-controlled trials, the overall IBD rate was 0.1 (95% CI 0.0-0.3)/100 patient-years for adalimumab groups (3 events in 6,781 patients; 2,752 patient-years of exposure) and 0.1 (95% CI 0.0-0.4)/100 patient-years for placebo groups (1 event in 3,493 patients; 1,246 patient-years of exposure). IBD rates in axial SpA were 0.5 (95% CI 0.1-1.4)/100 patient-years for adalimumab and 0.6 (95% CI 0.0-3.1)/100 patient-years for placebo. CONCLUSION: The rates of IBD AEs in adalimumab clinical trials were generally low across the evaluated diseases, including axial SpA; all events occurred in adult patients.

Tolerance development in food protein-induced allergic proctocolitis: single centre experience

BACKGROUND: Food protein-induced allergic proctocolitis (FPIAP) is characterised by inflammation of the distal colon in response to one or more food proteins. It is a benign condition of bloody stools in a well-appearing infant, with usual onset between one and four weeks of age. OBJECTIVE: Our objective was to examine the clinical properties of patients with FPIAP, tolerance development time as well as the risk factors that affect tolerance development. METHODS: The clinical symptoms, offending factors, laboratory findings, methods used in the diagnosis and tolerance development for 77 patients followed in the Paediatric Allergy and Gastroenterology Clinics with the diagnosis of FPIAP during January 2010-January 2015 were examined in our retrospective cross-sectional study. RESULTS: The starting age of the symptoms was 3.3±4.7 months (0-36). Milk was found as the offending substance for 78% of the patients, milk and egg for 13% and egg for 5%. Mean tolerance development time of the patients was 14.7±11.9 months (3-66 months). Tolerance developed before the age of one year in 40% of the patients. Tolerance developed between the age of 1-2 years in 27%, between the age of 2-3 years in 9% and after the age of 3 years in 5% of the patients. CONCLUSIONS: Smaller onset age and onset of symptoms during breastfeeding were found associated with early tolerance development. In the majority of the patients, FPIAP resolves before the age of one year, however in some of the patients this duration may be much longer

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A case report of sevelamer-associated recto-sigmoid ulcers.

BACKGROUND: Optimal phosphorous control is an important aspect of the care of patients with end-stage renal disease, and phosphate binders are usually needed. CASE PRESENTATION: A 74-year-old woman with end-stage renal disease on maintenance hemodialysis presented to the emergency room with abdominal discomfort, rectal pain, and blood-tinged stools. Initial concern was for a rectal carcinoma, based on the symptoms and imaging in initial computerized tomography of the abdomen showing rectal wall thickening, and her clinical presentation. She had been treated with the phosphate binder sevelamer for two months. In this case report, we explore the unique features of sevelamer-associated recto-sigmoid ulcers which led to her symptoms. CONCLUSION: Sevelamer is widely used in chronic kidney disease and end-stage renal disease patients with hyperphosphatemia. It is a crosslinked polymeric amine that binds phosphates and bile acids; it is not systemically absorbed. To the authors' knowledge, this is the first reported case of recto-sigmoid ulcers associated with use of this phosphate binder. Nephrologists, pathologists, and gastroenterology sub-specialists should be aware of this recently-reported entity in patients on sevelamer with suggestive symptoms, as this medication is widely used in renal patients.

Glutaraldehyde-induced colitis: case reports and literature review.

Glutaraldehyde-induced colitis is an uncommon colitis in clinical practice. Because the involvement of colonic segment is determined by the endoscopic part where glutaraldehyde remains, a recent history of endoscopy and a demarcated involvement of colonic segment are the most characteristic signs of glutaraldehyde-induced colitis. The typical clinical scenario is acute onset of lower abdominal pain, fever, and bloody stool. Laboratory data usually show leukocytosis and elevated C-reactive protein. The endoscopic pictures of involved segments are compatible with acute colitis, including hyperemic, edematous, with or without multiple erosions. Acute ischemic colitis and infectious colitis should be differentiated at the outset of the disease. Stool pathogen tests are usually negative. Parenteral empiric antibiotic may be considered if severe transmural edema of the involved segment is observed in computed tomography. Conservative treatment, including bowel rest and parenteral hydration, is able to stabilize the condition in a week. Herein, we present two cases of acute proctocolitis caused by glutaraldehyde after uneventful colonoscopy.

Complications following formalin installation in the treatment of radiation induced proctitis.

Formalin installation has been safely and effectively used to treat refractory bleeding caused by radiation proctitis. This study evaluated the results of such treatment in terms of outcome and complications. All four patients who underwent formalin irrigation for transfusion-dependent radiation proctitis over a 15-month period were evaluated retrospectively. The procedure was performed under sedation in the operating room, with patients in the prone jack-knife position. A solution of 4% formalin was introduced in aliquots of 50 ml kept in contact with the mucosa for 30 s and then cleared away using saline irrigation; five to six aliquots were used in each session. In a fifth patient formalin-soaked gauze pads were applied directly to the injured mucosa. At a mean follow-up of 18 months (range 6-26) two patients had repeat episodes of bleeding, one underwent successful repeat irrigation, and the other refused further treatment. One patient suffered from severe anococcygeal pain and worsening of incontinence after the procedure. The pain was treated with lidocaine ointment and sitz baths with partial success. Another patient developed severe formalin-induced colitis 5 days after the procedure, which required intravenous antibiotics and hydration. Formalin installation may be effective in controlling refractory bleeding due to radiation induced proctitis. The procedure, however, is not risk free and may induce major complications such as acute colitis.

Protective effect of the tachykinin NK2 receptor antagonist nepadutant in acute rectocolitis induced by diluted acetic acid in guinea-pigs.

We have evaluated the potential protective activity of nepadutant, a selective tachykinin NK2 receptor antagonist, in a model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. The injury was quantified visually by using a macroscopic injury score, and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of nepadutant (0.3-10 mg/kg s.c., 1 h before acetic acid) markedly reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early phase of the injury. Single administration of nepadutant (3 mg/kg s.c.) reduced the macroscopic score and myeloperoxidase activity at the top (24 h) of inflammation. Repeated administration (3 mg/kg s.c. three times during 24 h) or co-administration of the tachykinin NK1 receptor antagonist MEN 11467 (3 mg/kg s.c.) did not enhance the antiulcer effect obtained with the single treatment with nepadutant. These data suggest the involvement of tachykinin NK2 receptors in the first phases of inflammation induced by acetic acid.

Effect of MEN 11467, a new tachykinin NK1 receptor antagonist, in acute rectocolitis induced by acetic acid in guinea-pigs.

The aim of this study was to evaluate the effect of MEN 11467 (1R,2S)-2-N[1(H)indol-3-yl-carbonyl]-1-N{N-(p-tolylacetyl)-N-(meth yl)-D-3(2-Naphthyl)alanyl}diaminocyclohexane), a new potent tachykinin NK1 receptor antagonist, in an experimental model of acute rectocolitis induced by an enema with 7.5% acetic acid in guinea-pigs. This effect was compared to that of mesalazine (5-amino-2-hydroxybenzoic acid). The injury was quantified visually by using a macroscopic injury score and histologically by using a necrosis score. In addition, changes in myeloperoxidase activity, a marker for neutrophil infiltration, and plasma protein extravasation were evaluated. The injury caused by 7.5% acetic acid was mild, affecting the superficial layers and producing a strong edema of the submucosa. A single administration of MEN 11467 (0.3-10 mg/kg s.c., I h before acetic acid) reduced the macroscopic damage and necrosis score and the increase in plasma protein extravasation induced by 7.5% acetic acid in the early acute phase of the injury (death at 2.5 h). Mesalazine (100 mg/kg p.o., 1 h before) reduced the macroscopic score but not the plasma protein extravasation. Repeated administration of MEN 11467 (1-3 mg/kg s.c., -1, +6 and +23 h after 7.5% acetic acid) reduced the macroscopic score and myeloperoxidase activity but not the plasma protein extravasation induced in the late phase of acute injury (death at 24 h). At this time mesalazine markedly reduced the macroscopic score, myeloperoxidase activity and plasma protein extravasation induced by 7.5% acetic acid. These results suggest a greater involvement of tachykinin NK1 receptors in the early phase than in the late phase of colonic inflammation in response to chemical injury.

Acute colitis caused by caustic products.

We report two cases of acute proctocolitis caused by rectal application of caustic products of domestic use. One 61-yr-old woman applied an ammonia solution enema; the other patient, a 63-yr-old woman, accidentally applied an enema containing lye. Both patients presented with intense anal pain, but the first patient also had abdominal pain with guarding, hematochezia, and leucocytosis. An acute proctocolitis was found at sigmoidoscopy in both patients. Only conservative and symptomatic measures were prescribed in both cases, and a clinical and endoscopic recovery was seen. In spite of persistent fibrosis in the lamina propria, no signs of stenosis were found.

Intolerance to protein hydrolysate infant formulas: an underrecognized cause of gastrointestinal symptoms in infants.

The purpose of this study was to determine the effectiveness of an amino acid-based infant formula in infants with continued symptoms suggestive of formula protein intolerance while they were receiving casein hydrolysate formula (CHF). Twenty-eight infants, 22 to 173 days of age, were enrolled; each had received CHF for an average of 40 days (10 to 173 days) and continued to have bloody stools, vomiting, diarrhea, irritability, or failure to gain weight, or a combination of these symptoms. Sigmoidoscopy with rectal biopsy was performed in all infants. The infants then received an amino acid-based infant formula, Neocate, for 2 weeks. After 2 weeks of treatment, 25 of the infants demonstrated resolution of their symptoms and underwent challenge with CHF. Of the 25 who were challenged, eight tolerated the CHF and the remainder had recurrence of their symptoms. The histologic features in these infants varied from eosinophilic infiltration to normal. We conclude that not all infants with apparent formula protein-induced colitis respond to CHF and that these infants may have resolution of their symptoms when fed an amino acid-based infant formula.

Outbreak of glutaraldehyde-induced proctocolitis.

BACKGROUND: An outbreak of hemorrhagic proctocolitis occurred after the introduction of 2% glutaraldehyde as a disinfectant for colonoscopes. An inadequate rinsing procedure was detected. Recent studies have pointed to glutaraldehyde as an irritant potentially capable of inducing colitis. This study aimed to measure retrospectively the occurrence of proctocolitis after colonoscopy in persons exposed to glutaraldehyde used as a disinfectant for colonoscopes, and to compare this rate with that in patients exposed to the previous cleaning procedure. METHODS: Colonoscopic procedures were randomly selected during the period when glutaraldehyde was used, as well as during the previous period, when a detergent was used. Patients were asked to respond to a questionnaire during a telephone interview, in search of symptoms compatible with proctocolitis after colonoscopy. RESULTS: Of the 400 colonoscopic procedures selected during each of the glutaraldehyde and the detergent periods, respectively 299 and 242 were evaluable. According to different nonexclusive definitions, we observed in the glutaraldehyde period higher frequencies of proctocolitis (at least five stools/day; 14/299 vs 3/242, p = 0.02), severe proctocolitis (> 10 stools/day; 10/299 vs 1/242, p = 0.04), and severe hemorrhagic proctocolitis (6/299 vs 0/242, p = 0.04). Younger age was associated with proctocolitis only during the glutaraldehyde period (p = 0.0008). No pathogen was demonstrated in the only two patients who had stool cultures. The median incubation after colonoscopy was 4 hours (range 0 to 24 hours) and the symptoms lasted 30 hours (range 6 to 216 hours). No patient had fever, and the illness resolved spontaneously in all cases. CONCLUSION: Inadequate rinsing of colonoscopes after immersion in glutaraldehyde may result in proctocolitis, presumably caused by direct action on the mucosa.

Experimental colitis alters visceromotor response to colorectal distension in awake rats.

The influence of intermittent colorectal distension (CRD) on proximal colonic motility and abdominal pain perception was investigated in awake rats equipped with intraparietal electrodes on the cecum, proximal colon, and abdomen, before and three days after rectocolitis induction by trinitrobenzene sulfonic acid (TNB)/ethanol. The normal myoelectrical activities of cecum and proximal colon [5.2 +/- 0.5 and 9.7 +/- 0.7 long spike bursts (LSB) per 5 min, respectively] were significantly (P < 0.05) and gradually decreased by control CRD, at diameters above 9 mm. At the maximum CRD diameter (13.7 mm), 1.6 +/- 0.6 cecal and 3.9 +/- 0.8 colonic spike bursts occurred per 5 min (respectively, 69 and 60% decreases). This upstream inhibition was accompanied by a significant (P < 0.05) and gradual increase in abdominal contractions (0.4 +/- 0.4 per 5 min in control vs 23.4 +/- 1.9 in response to 13.7 mm in diameter). Three days after TNB/ethanol, visceromotor and abdominal responses were significantly (P < 0.05) enhanced at the least CRD diameter of 9 mm (cecum: 3.1 +/- 0.4 after TNB vs 5.0 +/- 0.7 in control; proximal colon: 5.1 +/- 0.9 vs 9.3 +/- 2.2; abdomen: 7.7 +/- 1.5 vs 0.5 +/- 0.4). We conclude that in awake rats, CRD evokes both abdominal contractions in response to pain and inhibition of cecal and proximal colonic motility, which thresholds are both lowered by TNB-induced rectocolitis.