Assessment of Long-Term Efficacy and Safety of Adalimumab in Patients with Ulcerative Colitis: Results from a 6-Year Real-World Clinical Practice.

BACKGROUND: Although evidence for the short- to medium-term efficacy of adalimumab in ulcerative colitis (UC) patients is emerging, there are a limited number of reports on the long-term efficacy of adalimumab. This study was to understand baseline demographic features, which potentially could be risk factors for relapse or colectomy following induction of remission by adalimumab in UC patients. Additionally, factors affecting long-term outcomes were to be identified. METHODS: Twenty-one patients with UC who had been treated with adalimumab were reviewed retrospectively. Comparative analyses were undertaken by factoring steroid withdrawal versus non-withdrawal, long-term remission versus relapse following remission, and requiring surgical intervention for UC versus surgery-free. RESULTS: Adalimumab treatment was associated with steroid tapering in steroid-dependent cases in the long term. Of the 14 patients in whom clinical remission was achieved, the cumulative nonrelapse survival rate at 350 weeks was 43.8% and the cumulative nonoperative survival rate was 85.7%. Risk factors for surgery included intolerance to salicylates (p = 0.005) and past treatment with tacrolimus (p = 0.023). CONCLUSIONS: Adalimumab treatment was associated with long-term efficacy in patients with mild UC - patients achieved a high cumulative nonoperative survival rate over a long period of time, beyond 6 years.

[Simultaneous occurrence of an ampullary neuroendocrine tumor and multiple duodenal/jejunal gastrointestinal stromal tumors in a patient with neurofibromatosis type 1].

A 60-year-old female visited our hospital because of the identification of two duodenal tumors on upper gastrointestinal endoscopy performed for the investigation of anemia. The oral ampullary tumor was proven to be a neuroendocrine tumor (NET) on endoscopic biopsy. However, biopsy was not performed for the anal submucosal tumor (SMT) in the third duodenal portion because the tumor was included in the planned resection area. Multiple dermal soft tumors and café-au-lait spots were noted;her mother and daughter showed the same symptoms. The patient was diagnosed with neurofibromatosis type 1 (NF1). Laparotomy revealed more than 10 nodules at the serosal surface of the duodenum and proximal jejunum. Pancreaticoduodenectomy was performed with an additional 30-cm length of the jejunum that included most of the protruding tumors. Pathologically, the ampullary tumor and the other duodenal/jejunal SMTs were NET G2 and gastrointestinal stromal tumors (GISTs), respectively. Here, we report the rare case of simultaneous occurrence of an ampullary NET and multiple duodenal/jejunal GISTs in a patient with NF1.

Adsorptive Depletion of Myeloid Lineage Leucocytes as Remission Induction Therapy in Patients with Ulcerative Colitis after Failure of First-Line Medications: Results from a Three-Year Real World, Clinical Practice.

BACKGROUND/AIMS: In patients with active ulcerative colitis (UC), pharmacologics, although initially effective in most patients, are associated with refractoriness, loss of response or unfavourable side effects as additional morbidity factors. Depletion of myeloid lineage leucocytes like the CD14(+)CD16(+) monocyte phenotype, which is a major source of tumour necrosis factor-α, by granulocyte/monocyte apheresis (GMA) if effective, is also known to be free from side effects. METHODS: In clinical practice setting, 77 consecutive patients with moderate to severe UC, who failed to respond to first-line medications received GMA with the Adacolumn as remission induction therapy. Patients who achieved remission were followed for 3 years. RESULTS: Among the 77 patients, 46.8% were corticosteroids-naïve, 26% corticosteroid-dependent and 27.3% corticosteroid-refractory. The overall clinical remission rate was 79.2%, and the overall mucosal healing (MH) rate according to the Mayo endoscopic subscore ≤1 was 58.5%. MH rates in corticosteroid-naïve, corticosteroid-dependent and corticosteroid-refractory subgroups were 70.8, 56.3, and 38.5%, respectively. The 3-year sustained clinical remission rates in corticosteroid-naïve, corticosteroid-dependent and corticosteroid-refractory subgroups were 83.3, 68.8, and 23.1%, respectively. CONCLUSION: Corticosteroid-naïve patients appeared to benefit the most from the Adacolumn GMA, and attain a favourable long-term clinical course. Accordingly, GMA should be a first-line therapy in this clinical setting.

An Increased Serum N-Terminal Telopeptide of Type I Collagen, a Biochemical Marker of Increased Bone Resorption, Is Associated with Infliximab Therapy in Patients with Crohn's Disease.

BACKGROUND: Osteopenia and osteoporosis are considered to be extra-intestinal manifestations of inflammatory bowel disease (IBD). Anti-tumor necrosis factor (TNF)-α biologics have been introduced as novel medications for an active IBD. However, it is still not well documented whether anti-TNF-α affects the frequency of bone loss or abnormality of bone mineral markers among patients with IBD. AIMS: This study was to investigate the biochemical basis of low bone mineral density (BMD) and increased turnover in IBD during infliximab (IFX) therapy. METHODS: Forty patients with Crohn's disease (CD), 80 patients with ulcerative colitis (UC), and 65 age- and gender-matched controls were included. BMD was measured with dual-energy X-ray absorptiometry, and vitamins K and D were measured as serum undercarboxylated osteocalcin (ucOC) and 1,25-(OH)2D, respectively. Bone formation and resorption were based on measuring bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx), respectively. RESULTS: Significantly lower BMD was found in patients with UC and CD as compared to controls (P < 0.05). BAP, 1,25-(OH)2D, ucOC, and NTx were significantly higher in CD patients, but not in UC patients as compared to controls (P < 0.05). Further, serum NTx level was significantly higher in CD patients who were receiving IFX as compared to CD patients who were not receiving IFX (P < 0.01). CONCLUSIONS: A lower BMD and higher bone metabolism markers were found in CD patients as compared to controls or UC patients. A significant increased serum level of NTx, a biochemical marker of increased bone resorption, was observed in CD patients during IFX therapy.

[Coexistence of lymphoid follicular proctitis and ulcerative colitis].

We describe a rare case of ulcerative colitis (UC) with lymphoid follicular proctitis (LFP) extending discontinuously from the rectum to the ascending colon. The patient was a 42-year-old female presenting with a positive fecal occult blood test. Colonoscopy revealed erosions and disappearance of vascular patterns in the ascending colon and lower rectum, together with circumferential, uniform, granular lesions in the lower rectum. Histological examinations of the rectal biopsy specimens revealed lymphoid follicles, hyperplasia, and infiltration of chronic inflammatory cells. We suspected rectal and segmental UC with LFP. Initially, the patient was managed conservatively because of the lack of symptoms; however, on developing mucoid stools and haematochezia, mesalazine administration was started. Her symptoms and endoscopic findings resolved completely. LFP is closely associated with UC. Therefore, while diagnosing and managing LFP, it is necessary to ascertain or rule out potential complications.

[A case of pneumatosis cystoides intestinalis associated with ulcerative colitis].

Pneumatosis cystoides intestinalis (PCI) is associated with various diseases, but rarely with inflammatory bowel disease. We describe a rare case of PCI associated with ulcerative colitis. The patient was a 30-year-old man with ulcerative colitis (UC), which was in remission under immunomodulator therapy. Colonoscopic examination around 2 years after a diagnosis of UC revealed multiple hemispherical submucosal tumors (SMT) in the ascending colon and hepatic flexure, with erosion and disappearance of vascular network patterns in the rectum. PCI was diagnosed from the result of colonoscopic examination and computed tomography, and had not changed on colonoscopic examination 2 months later, without any treatment.

Long-term prognosis of patients after endoscopic sphincterotomy for choledocholithiasis.

INTRODUCTION: The aims of the present study were to clarify the long-term prognosis of endoscopic sphincterotomy (EST) for choledocholithiasis and to evaluate the need for cholecystectomy after EST. METHODS: Between 1993 and 2007, 262 patients who underwent successful EST for choledocholithiasis were followed up for more than 6 months). Eighteen patients had previously undergone cholecystectomy (Group A), 129 had a calculous gallbladder (GB) and underwent cholecystectomy after EST (Group B), 46 had a calculous GB in situ (Group C), and 69 had an acalculous GB in situ (Group D). Late complications, including recurrence of choledocholithiasis, acute cholecystitis and biliary carcinoma, were evaluated. RESULTS: Of the 262 patients, late complications occurred in 34 patients (13.0%) and recurrence of choledocholithiasis occurred in 29 patients (11.1%). The rate of late complications was higher in Group C (23.9%) than in Group B (7.8%) (P < 0.001). The rate of recurrent choledocholithiasis was higher in Group C (17.4%) than in Group B (7.8%) (P < 0.05). Univariate analysis indicated that pneumobilia after EST was associated with the recurrence of choledocholithiasis (P < 0.001). Acute cholecystitis occurred in eight (7.0%) of 115 patients with intact GB. A gallbladder carcinoma was found after EST. Late complications were not serious and endoscopically or surgically manageable. CONCLUSIONS: EST for choledocholithiasis is safe and effective. Cholecystectomy after EST is recommended in patients with calculous GB, but is not necessary in patients with acalculous GB. Pneumobilia was associated with the recurrence of choledocholithiasis.

Adsorptive depletion of elevated proinflammatory CD14+CD16+DR++ monocytes in patients with inflammatory bowel disease.

BACKGROUND: In human blood, two monocyte populations exist, CD14(++)CD16(-) classical monocytes and CD14(+)CD16(+) proinflammatory monocytes, which account for about 10% of total monocytes, but can expand to promote inflammatory conditions. CD14(+)CD16(+) monocytes produce large amounts of inflammatory cytokines including TNF-alpha and IL-1. Adacolumn adsorptive carriers adsorb from the blood in the column most of the monocytes/macrophages and granulocytes and this has been associated with clinical efficacy in patients with active inflammatory bowel disease (IBD). This study was to investigate the CD14(+)CD16(+) monocyte profile in patients with IBD and the impact of Adacolumn on this proinflammatory phenotype. METHODS: A total of 58 patients with ulcerative colitis (UC, N = 37) or Crohn's disease (CD, N = 21) together with 11 healthy controls were included in this study. Peripheral blood CD14(+)CD16(+) monocytes were determined by three-color immunofluorescence and flow cytometry. RESULTS: The percentage of CD14(+)CD16(+) monocytes in patients with active CD was significantly (P= 0.0089) higher than the level in the control group, in patients with quiescent CD (P= 0.0419) or quiescent UC (P= 0.0063). Further, the percentage of CD14(+)CD16(+) monocytes in patients with active UC who were on prednisolone (PSL) was less than the level in those not on PSL (P < 0.0001), thus PSL might have a suppressive effect on CD14(+)CD16(+) monocytes. Patients with active IBD were each given up to 10 Adacolumn granulocye/monocyte adsorption (GMA) sessions over an 8-wk period. The percentage of CD14(+)CD16(+) monocytes decreased dramatically (P= 0.0077 in UC and P= 0.0117 in CD) compared with entry levels. CONCLUSIONS: A significant reduction in peripheral CD14(+)CD16(+) monocytes by GMA should mitigate the inflammatory drive and contribute to the clinical efficacy of this procedure. Reduction of CD14(+)CD16(+) monocytes by corticosteroids was also seen. Hence, corticosteroids should enhance the efficacy of GMA. This is the first report on CD14(+)CD16(+) monocytes being decreased by Adacolumn GMA in patients with IBD.

Serum pepsinogens as an early diagnostic marker of H. pylori eradication.

BACKGROUND/AIMS: Helicobacter pylori (H. pylori) eradication increases the serum pepsinogen I/ pepsinogen II ratio and the percentage change in pepsinogen I/pepsinogen II ratios is a useful marker of H. pylori eradication. We studied whether the pepsinogen method could be an early diagnostic marker of H. pylori eradication even in patients persistently treated with a proton pump inhibitor. METHODOLOGY: Sixty-two H. pylori-positive patients underwent H. pylori-eradication therapy, followed by treatment with a proton pump inhibitor to cure ulcers. Serum levels of pepsinogen I and pepsinogen II were measured before, at the end of, and at 4 weeks after the eradication therapy. The cut-off values of percentage changes in pepsinogen I/pepsinogen II ratios for the diagnosis of eradication of H. pylori were set in proportion to pepsinogen I/pepsinogen II ratios before eradication in accordance with a previous report. RESULTS: Using the results of 13C-urea breath test as the standard, the sensitivity, specificity and validity of the pepsinogen method were 100.0%, 89.8% and 90.3%, respectively, at 4 weeks after eradication therapy. CONCLUSION: The percentage change in serum pepsinogen I/pepsinogen II ratios is useful as an early diagnostic marker for judgment of H. pylori eradication irrespective of proton pump inhibitor treatment.

[Case of pancreatic mucosa-associated lymphoid tissue (MALT) lymphoma].

A 77-year-old woman underwent abdominal ultrasonic diagnosis in a screening test for diabetes mellitus. A 65 x 45 mm tumor with low echo level was revealed and located from the uncinate process of the pancreas to the body. Contrast-enhanced computed tomography demonstrated the pancreas had a low density area in the arterial phase and a comparable area in the equilibrium phase, compared with the parenchyma of the normal pancreas. Gallium-scintigraphy showed strong accumulation, consistent with the tumor. Mucosa-associated lymphoid tissue (MALT) lymphoma was diagnosed by endosonography-guided fine-needle aspiration biopsy (EUS-FNAB). Complete remission was achieved after radiation therapy.

[Retroperitoneal fibrosis and Castleman disease in two patients with high IgG4 levels].

With the cumulative increase in the number of autoimmune pancreatitis cases, the disease is now widely accepted as a symptom of IgG4-related systemic disease. We recently experienced two cases of retroperitoneal fibrosis and Castleman disease presenting high IgG4 levels without evident pancreatic lesions. Both patients were successfully treated with steroid therapy. It is necessary to acknowledge that retroperitoneal fibrosis and Castleman disease, with or without pancreatic lesions, may have aspects of IgG4-related systemic disease and that the measurement of serum IgG4 and tissue immunostaining for IgG4 should be considered for diagnosing and treating the conditions.

[A case of colonic obstruction due to post-operative stenosis of the colon and multiple enteroliths].

An 81-year-old man who had under gone two abdominal surgeries and temporary colostomy 30 years previously was admitted due to lower abdominal pain and vomiting. An abdominal X-ray film and abdominal CT scan showed intestinal distension and multiple calcareous deposits in the colon. Gastrografin enema examination revealed smooth stenosis at the sigmoid colon and many additional defects. Endoscopy could not be performed due to the stenosis. He did not agree to surgery. Seven months later, he was admitted again, due to colonic obstruction. Surgery was performed which revealed colonic obstruction as the source of post-operative stenosis of the sigmoid colon and multiple enteroliths. The stones consisted of a core and a hull and contained ammonium magnesium phosphate.

[A case of Castlemans disease (plasma cell type) in which autoimmune pancreatitis developed 6 years later].

In 1998 a 74-year-old man, he had a medical checkup and mediastinal and hilar lymph node hyperplasia were discovered. Since the lymph nodes showed a tendency to increase in size, mediastinal lymph node biopsy was performed in the following year. Castlemans disease was diagnosed, and he was followed up. In 2005, autoimmune pancreatitis (AIP) developed. At this time, the mediastinal lymph node that had been biopsied was stained with anti-IgG4 antibody. Further examinations on pancreatic lesions associated with Castlemans disease and AIP are necessary in relation to IgG4-related systemic diseases.

Effects of adacolumn selective leukocytapheresis on plasma cytokines during active disease in patients with active ulcerative colitis.

AIM: To investigate the relationship between ulcerative colitis (UC) clinical activity index (CAI) and circulating levels of IL-1ra, IL-10, IL-6 and IL-18. METHODS: Blood levels of IL-1ra, IL-10, IL-6 and IL-18 were measured in 31 patients with active UC, the mean CAI was 11.1, ranging from 5-25; and 12 healthy individuals as controls. Patients were given granulocyte and monocyte adsorptive apheresis (GMA) with Adacolumn. Leucocytes which bear the FcgammaR and complement receptors were adsorbed to the column leucocytapheresis carriers. Each patient could receive up to 11 GMA sessions over 8 wk. RESULTS: We found strong correlations between CAI and IL-10 (r = 0.827, P < 0.001), IL-6 (r = 0.785, P < 0.001) and IL-18 (r = 0.791, P < 0.001). IL-1ra was not correlated with CAI. Following GMA therapy, 24 of the 31 patients achieved remission and the levels of all 4 cytokines fell to the levels in healthy controls. Further, blood levels of IL-1ra and IL-10 increased at the column outflow and inflow at 60 min suggesting release from leucocytes that adhered to the carriers.

[Superior mesenteric arterial thrombosis complicating ulcerative colitis: A case report].

36-year-old men with ulcerative colitis was attacked by the colic. The thrombus in superior mesenteric artery was revealed by computed tomography. Because the effect of the thrombolysis under intrarterial angiography was insufficient, thrombectomy was enforced under the laparotomy in the same day. The arterial thrombosis is extremely rare in the complication of ulcerative colitis. The activity of ulcerative colitis as one of factors of the appearance of thrombus was suggested.

The Ulcerative Colitis Endoscopic Index of Severity More Accurately Reflects Clinical Outcomes and Long-term Prognosis than the Mayo Endoscopic Score.

BACKGROUND AND AIMS: The Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and the Mayo endoscopic score (Mayo ES) are used to evaluate ulcerative colitis (UC) severity. This study compared UCEIS and the Mayo ES for evaluating UC severity and outcomes in patients undergoing remission induction during routine clinical practice with the aim of predicting medium- to long-term prognosis. METHODS: Forty-one UC patients who received colonoscopy before and after tacrolimus remission induction therapy were included. An index of clinical activity and endoscopic findings scored by both the UCEIS and the Mayo ES were determined. Changes in UCEIS and Mayo ES before and after induction therapy were compared. RESULTS: The mean UCEIS improved from 6.2±0.9 to 3.4±2.1 (p < 0.001). Based on the UCEIS, a significant reduction was reached in both the response and the remission groups. In contrast, the Mayo ES did not reflect a significant change in the response group. The discrepancy appeared to be due to ulcers becoming smaller and shallower during the early stages of mucosal healing; the Mayo ES seems to miss these early changes. In other words, whereas the UCEIS indicates improvements when ulcers shrink, the Mayo ES does not distinguish deep ulcers from shallow ulcers and is 3 (severe UC) for both deep and shallow ulcers. Additionally, better UCEIS strata after induction therapy were associated with lower incidences of colectomy (p = 0.0001) or relapse (p = 0.0008). CONCLUSIONS: The UCEIS accurately reflects clinical outcomes and predicts the medium- to long-term prognosis in UC patients undergoing induction therapy. These findings should support decision-making in clinical practice settings.

Decrease of reactive-oxygen-producing granulocytes and release of IL-10 into the peripheral blood following leukocytapheresis in patients with active ulcerative colitis.

AIM: To investigate the clinical efficacy of leukocytapheresis (LCAP) in patients with active ulcerative colitis (UC), and to elucidate the mechanisms by determining the changes in the cytokine levels in the peripheral blood and of the functions of the peripheral blood leukocytes in these patients. METHODS: The subjects were 19 patients with active UC, with a mean clinical activity index (CAI) of 9.2. The LCAP was conducted using Cellsorba E. In each session of LCAP, 2-3 L of blood at the flow rate of 30-50 mL/min was processed. The treatment was carried out in approximately 1-h sessions, once a week, for 5-10 wk. Blood samples for determination of the cytokine levels were collected from the inflow side of the column (site of dehematization; at the start of LCAP) and outflow side of the column (at the end of LCAP). Blood samples for the determination of reactive-oxygen-producing cells were collected from the peripheral blood before and after LCAP. RESULTS: LCAP resulted in clinical improvement in all the 19 patients of UC recruited for this study. Remission (CAI: < or = 4) was noted in 15 (79%) of the 19 patients. The blood level of the pro-inflammatory cytokine IL-6 was found to be decreased following treatment by LCAP, and the level of the anti-inflammatory cytokine IL-10 at the outflow side of the LCAP column was found to be significantly elevated as compared to that at the inflow side of the column. The reactive-oxygen-producing granulocytes in the peripheral blood of UC patients was increased as compared to that in healthy persons and the increase was found to be decreased following treatment by LCAP. CONCLUSION: LCAP exerted a high therapeutic efficacy in patients with active UC. Our findings suggest that LCAP is associated with enhanced production of the inhibitory cytokine IL-10 to indirectly inhibit the functions of the inflammatory leukocytes, and that inflammation is also considerably attenuated by the direct removal of reactive-oxygen-producing neutrophils from the peripheral blood.

Tacrolimus for remission induction in ulcerative colitis: Mayo endoscopic subscore 0 and 1 predict long-term prognosis.

BACKGROUND: Tacrolimus has shown efficacy in patients with ulcerative colitis. AIMS: To evaluate the efficacy of tacrolimus as remission induction therapy and assess medium to long-term outcomes in patients who achieve remission. METHODS: Forty-four ulcerative colitis patients who were treated with tacrolimus in three institutes during 2009-2013 were retrospectively reviewed. Short-term efficacy was based on the clinical activity index and the Mayo endoscopic subscores. Clinical activity index≤4 meant clinical remission, while Mayo endoscopic subscore 0 or 1 meant mucosal healing. Medium to long-term prognosis was based on relapse free survival in relation to the Mayo endoscopic subscore and duration of tacrolimus therapy in patients who achieved remission. RESULTS: At 12 weeks, clinical remission was achieved in 29 of 44 patients (65.9%). Thirty-two patients received endoscopic evaluations, and mucosal healing rate was 43.8%. Among patients with clinical remission, mucosal healing rate was 60.9%. Relapse-free survival at 6, 12, and 24 months were 66%, 56%, and 50%, respectively, and was higher in patients on long-term tacrolimus (over 4 months, P=0.03), and patients with better endoscopic subscore (P=0.009). CONCLUSIONS: Mucosal healing observed within 12 weeks or after a longer duration of tacrolimus therapy was associated with significantly better remission maintenance time.

Effect of cytochrome P4502C19 genotypic differences on cure rates for gastroesophageal reflux disease by lansoprazole.

BACKGROUND AND OBJECTIVES: The acid-inhibitory effect of lansoprazole depends on differences in cytochrome P450 (CYP) 2C19 genotypes. We assessed whether therapeutic effects of lansoprazole on gastroesophageal reflux disease (GERD) depended on the CYP2C19 genotype status in relation to the grade of GERD. METHODS: A total of 65 patients with GERD (grades A-D) completed treatment with lansoprazole, by taking 30 mg orally once a day for 8 weeks. The CYP2C19 genotype status of patients was determined by polymerase chain reaction-restriction fragment length polymorphism analysis. Before and after treatment, esophageal endoscopy was performed. GERD was considered to be cured on the basis of endoscopic findings at the end of treatment. Plasma lansoprazole levels could be determined at 3 hours after the last 30-mg dose of lansoprazole in the 27 genotyped patients. RESULTS: Cure rates for GERD depended significantly on the CYP2C19 genotype status, as well as the grade of GERD before treatment. Cure rates in the homozygous extensive, heterozygous extensive, and poor metabolizer groups were 45.8%, 67.9%, and 84.6%, respectively. Cure rates in the groups with GERD grade A, grade B, and grade C or D were 85.0%, 60.0%, and 45.0%, respectively. The cure rate in patients with the homozygous extensive metabolizer genotype of CYP2C19 with a GERD grade of C or D was very low (16.7%). Plasma lansoprazole levels in patients with the homozygous extensive metabolizer genotype were the lowest of the 3 groups. CONCLUSIONS: CYP2C19 genotype status, as well as the grade of GERD before treatment, is one of the determinants for the success or failure of treatment of GERD with lansoprazole. The low cure rate in patients with the homozygous extensive metabolizer genotype appeared to be a result of these patients having the lowest plasma lansoprazole levels among the 3 genotype groups.