Differential effects of mesalazine formulations on thiopurine metabolism through thiopurine S-methyltransferase inhibition.

BACKGROUND AND AIM: Thiopurines are often used in combination with mesalazine for the treatment of ulcerative colitis (UC). Mesalazine formulations are delivered to the digestive tract by various delivery systems and absorbed as 5-aminosalicylic acid (5-ASA). 5-ASA is known to inhibit thiopurine S-methyltransferase (TPMT) activity and to affect thiopurine metabolism. There have been no studies comparing TPMT inhibition by multimatrix mesalazine (MMX) with other formulations. We investigated the difference in TPMT inhibition by different mesalazine formulations and prospectively confirmed the clinical relevance. METHODS: Plasma concentrations of 5-ASA, N-acetyl-5-aminosalicylic acid (N-Ac-5-ASA), and TPMT activities were measured in UC patients receiving various mesalazine formulations (time-dependent or pH-dependent mesalazine or MMX) as monotherapy. Patients already on both time-dependent or pH-dependent mesalazine and thiopurines switched their mesalazine to MMX, examining 6-thioguanine nucleotide (6-TGN) and 6-methylmercaptopurine (6-MMP) 0 and 8 weeks after switching. Clinical relapse after switching was also monitored for 24 weeks. RESULTS: Plasma 5-ASA and N-Ac-5-ASA levels were significantly higher in patients receiving time-dependent mesalazine (n = 12) compared with pH-dependent mesalazine (n = 12) and MMX (n = 15), accompanied by greater TPMT inhibition. Prospective switching from time-dependent mesalazine to MMX decreased 6-TGN levels, increased those of 6-MMP, and increased 6-MMP/6-TGN ratios. Furthermore, this resulted in significantly more relapses than switching from pH-dependent mesalazine to MMX. CONCLUSIONS: Time-dependent mesalazine has higher plasma 5-ASA and N-Ac-5-ASA levels and greater TPMT inhibition than MMX. Therefore, switching from time-dependent mesalazine to MMX may lead to an increase of 6-MMP/6-TGN, which may reduce the clinical effectiveness of thiopurines, warranting close monitoring after switch.

MEFV Gene-Related Enterocolitis Account for Some Cases Diagnosed as Inflammatory Bowel Disease Unclassified.

BACKGROUND AND AIMS: Familial mediterranean fever (FMF), an autoinflammatory disease, is characterized by periodic fever and serositis. An MEFV gene mutation has been identified as the cause of FMF. Recently, patients with MEFV gene mutations and chronic gastrointestinal mucosal inflammation mimicking inflammatory bowel disease (IBD) have been reported. In this retrospective study, we analyzed the clinical characteristics of patients with IBD unclassified (IBDU) with MEFV gene mutations. METHODS: MEFV gene analysis was performed on 8 patients with IBDU among 710 patients with IBD who had been treated at Kyorin University Hospital from April 2016 to December 2018. Clinical manifestations, endoscopic findings, and serological markers were also analyzed. RESULTS: The average of the 8 patients with IBDU (3 men, 5 women) was 32.7 ± 6.4 years (range 26-76 years). Their symptoms comprised diarrhea (n = 8, 100%), hematochezia (n = 3, 37.5%), abdominal pain (n = 3, 37.5%), high fever (n = 2, 16.5%), and other periodic symptoms (n = 2, 16.5%). MEFV gene mutation was confirmed in 4/8 of these patients. Colonoscopy showed various mucosal lesions, rectal sparing, right side dominant colitis, pseudopolyposis, and granular protrusions. Colchicine was administered to 5 of the 8 patients (4 with and 1 without MEFV mutation) who were resistant to conventional treatment for ulcerative colitis. Clinical and endoscopic improvement was observed in all of 5 patients treated with colchicine. CONCLUSIONS: Some patients diagnosed as having IBDU have enterocolitis related to MEFV gene mutation and respond to colchicine therapy.

Community-acquired fulminant colitis caused by binary toxin-producing Clostridium difficile in Japan.

We report a case of community-acquired fulminant colitis caused by Clostridium difficile in Japan. A 46-year-old woman was diagnosed with severe infectious enterocolitis and was admitted at another hospital. The stool culture was positive for toxigenic C. difficile. Since the patient presented with fulminant C. difficile infection (CDI) with toxic megacolon, respiratory insufficiency, and circulatory failure, she was transferred to Kyorin University Hospital for intensive care. Intubation and antibiotic therapy were performed. The general condition improved with conservative treatment, and she was discharged without sequelae. While the recovered isolate was toxin A and B-positive and binary toxin-positive, it was identified as polymerase chain reaction (PCR) ribotype ts0592 and slpA sequence type ts0592. The isolate was different from PCR ribotype 027 epidemic in Europe and North America. In Japan, binary toxin-producing strains are rare and have not caused an epidemic to date. Furthermore, there are few data on community-acquired CDI in Japan. In this case, a non-elderly woman with no major risk factors such as antibiotic use, administration of proton pump inhibitor and history of gastrointestinal surgery developed community-acquired fulminant CDI caused by the binary toxin-positive strain, and ICU treatment was required. Further studies focusing on the role of binary toxin-positive C. difficile in the severity of community-acquired CDI are necessary.

Evaluation of the drug-induced lymphocyte stimulation test for diagnosing mesalazine allergy.

BACKGROUND/AIMS: Mesalazine is an effective drug for treating ulcerative colitis (UC), but causes allergic symptoms in a few cases. Therefore, the objective of this study was to evaluate the usefulness of the drug-induced lymphocyte stimulation test (DLST) for the diagnosis of mesalazine allergy. METHODS: Patients with UC treated with mesalazine with or without a history of associated adverse events (AEs) were enrolled at Kyorin University Hospital from July 2016 to April 2017. RESULTS: The DLST was performed in 104 patients with UC, of which 24 had a history of AEs due to mesalazine treatment. The control value of DLST was 337.4±296.3 counts per minute (cpm) in the AE+ group and 408.0±371.9 cpm in the AE- group. The measured value of DLST was 578.8±424.7 cpm in the AE+ group and 476.5±471.8 cpm in the AE- group. The stimulation index (SI) was 243.9%±291.1% in the AE+ group and 119.8%±53.0% in the AE- group. The SI value and DLST positivity were significantly higher in the AE+ group than in the AE- group (P=0.030 and P=0.029, respectively). The test sensitivity and specificity were 0.240 and 0.805, respectively, and the false-positive and false-negative rate was 0.195 and 0.760, respectively. CONCLUSIONS: The DLST for mesalazine showed low sensitivity and high specificity, suggesting that it may be useful for the definitive diagnosis of allergy to mesalazine.

An HIV-infected Patient with Confirmed Overlapping Complications of Severe Amebic Colitis and CMV Enteritis.

We herein report a case of simultaneous amebic colitis and cytomegalovirus (CMV) enteritis in an HIV-infected patient. The patient was a 40-year-old man who developed bloody stool and diarrhea. We diagnosed him with severe amebic colitis associated with HIV infection and administered metronidazole. While his symptoms began to improve, the patient then developed CMV enteritis. We administered ganciclovir, and his symptoms improved. However, despite control of the infection, stenosis of the descending colon caused intestinal obstruction, and colostomy was performed. This case shows the importance of considering the possibility of simultaneous infection when gastrointestinal symptoms appear in people infected with HIV.

A Caucasian American patient with celiac disease diagnosed in Japan and successfully treated with a gluten-free diet.

We report the case of a 33-year-old Caucasian American man diagnosed with celiac disease in Japan. He presented to a community hospital because of chronic watery diarrhea and weight loss for 6 months. The laboratory data showed low serum albumin and serum cholesterol. A colonoscopy was normal. He was referred to our hospital for further work-up. Serum tissue transglutaminase immunoglobulin A (IgA) and endomysial antibody were positive. The HLA type was DQ2. Esophagogastroduodenoscopy (EGD) revealed nodular and mosaic-patterned mucosa from the bulb to the second part of the duodenum. The histopathological findings were consistent with Marsh type 3c of the modified Marsh classification for celiac disease. The patient was instructed to follow a gluten-free diet (GFD). Six months after the initiation of the GFD, his symptom and the levels of serum albumin and cholesterol were improved, and the serum tissue transglutaminase IgA and endomysial antibody became negative. However, EGD showed little improvement. Capsule endoscopy also revealed mosaic-patterned mucosa, nodular mucosa, and scalloping of the folds of the duodenum and proximal small intestine. There was no definite improvement in histopathological findings. Collectively, the GFD was effective in this patient with celiac disease, but it should be maintained to achieve endoscopic and histopathologic healing.