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Background and Study Aims: The infliximab biosimilar CT-P13 was the first biosimilar drug targeting tumor necrosis factor-α. However, its efficacy and safety in real-world clinical situations have remained insufficient. Therefore, we aimed to verify the efficacy and safety of CT-P13 in bio-naïve patients with Crohn's disease., Patients and Methods: This retrospective multicenter study compared the remission rate at week 54 between patients with Crohn's disease who were treated with originator infliximab or CT-P13. Endoscopic and laboratory findings were assessed in both groups. A total of 184 (156 originator and 28 CT-P13) patients were analyzed. Of these, 138 originator users and 19 biosimilar users completed 54-week administration., Results: The clinical remission rates in patients taking originator infliximab of CT-P13 at week 54 were 92.5 % and 100 %, respectively. The endoscopic scores of each group significantly decreased from baseline at week 54 in both groups, and the mucosal healing rate at week 54 was 53 % and 64 %, respectively. Laboratory data including C-reactive protein, serum albumin, and hemoglobin significantly improved from baseline to week 14 and 54 in both groups. Adverse events were observed more frequently in the CT-P13 group (25 % vs. 4.5 %, p = 0.0015), but severe adverse events were rare in both groups., Conclusion: The efficacy and safety of CT-P13 were comparable with those of originator infliximab in bio-naïve patients with Crohn's disease evaluated by clinical, endoscopic, and laboratory findings. This study establishes the needed groundwork for the development of a strategy for treatment with biologics in patients with Crohn's disease., Competing Interests: Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Pan-Arab Association of Gastroenterology. Published by Elsevier B.V. All rights reserved.)

Many molecular targeted agents, including biologics, have emerged for inflammatory bowel diseases (IBD), but their high prices have prevented their widespread use. This study aimed to reveal the changes in patient characteristics and the therapeutic strategies of IBD before and after the implementation of biologics in Japan, where the unique health insurance system allows patients with IBD and physicians to select drugs with minimum patient expenses. The analysis was performed using a prospective cohort, including IBD expert and nonexpert hospitals in Japan. In this study, patients were classified into two groups according to the year of diagnosis based on infliximab implementation as the prebiologic and biologic era groups. The characteristics of therapeutic strategies in both groups were evaluated using association analysis. This study analyzed 542 ulcerative colitis (UC) and 186 Crohn's disease (CD). The biologic era included 53.3% of patients with UC and 76.2% with CD, respectively. The age of UC (33.9 years vs. 38.8 years, P < 0.001) or CD diagnosis (24.3 years vs. 31.9 years, P < 0.001) was significantly higher in the biologic era group. The association analysis of patients with multiple drug usage histories revealed that patients in the prebiologic era group selected anti-tumor necrosis factor (TNF)-α agents, whereas those in the biologic era group preferred biologic agents with different mechanisms other than anti-TNF-α. In conclusion, this study demonstrated that both patient characteristics and treatment preferences in IBD have changed before and after biologic implementation., (© 2023. Springer Nature Limited.)

Aims: We investigated Crohn's Disease (CD) patients with carcinomas in the intestinal tract to emphasize the difficulty in establishing a diagnosis, as well as show the importance of establishing formal guidelines for screening and surveillance of cancers associated with perianal CD., Methodology: We studied 504 CD patients treated in our department with surgical intervention., Results: In 9 of the patients, carcinomas developed in relation to CD, 7 of whom had cancer of the lower rectum and anus with severe anorectal CD lesions. Five of 6 patients with advanced carcinoma in the anorectal region were treated using preoperative chemoradiation therapy and all 7 with anorectal carcinomas underwent an abdominoperineal resection. Two patients with a carcinoma of the fistula in the ileo-rectum or ileo-sigmoid colon were treated by a partial resection of the small and large bowel with the fistula. Mucinous cell type carcinomas were present in 6 patients, while signet ring cell type was found in 2 patients and poorly differentiated adenocarcinoma in 1. Three died prior to the follow-up examination., Conclusions: There was an increased incidence of carcinoma in the intestinal tracts of patients with CD. It is important to establish a surveillance program for CD patients, especially those complicated with severe anorectal CD lesions.

Objectives: Anal fistulas are common in individuals with Crohn's disease (CD). We sought to evaluate the efficacy of oral spherical adsorptive carbon (AST-120) (Kremezin; Kureha Corporation, Tokyo, Japan) for the treatment of intractable anal fistulas in patients with CD., Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, patients with CD and at least one active anal fistula under treatment were assigned to receive either AST-120 or placebo for 8 wk. Improvement was defined as a reduction of 50% or more from baseline in the number of draining fistulas observed at both 4 and 8 wk. Remission was defined by closure of all draining fistulas at both 4 and 8 wk. The Perianal Disease Activity Index (PDAI) and Crohn's Disease Activity Index (CDAI) were also assessed., Results: In total, 62 patients were randomized, of whom 57 received AST-120 (N = 27) or placebo (N = 30). The improvement rate in the AST-120 group (37.0%) was significantly greater than that in the placebo group (10.0%) (P= 0.025). The corresponding remission rates were 29.6% and 6.7%, respectively (P= 0.035). PDAI significantly improved at both 4 and 8 wk with AST-120, compared to placebo (P= 0.004 and P= 0.005, respectively). CDAI was also significantly improved at both 4 and 8 wk in the AST-120 group, compared to the placebo group (P= 0.007 and P= 0.001, respectively). AST-120 treatment was well tolerated and no life-threatening adverse events were observed., Conclusion: AST-120 is useful for the control of intractable anal fistulas in CD patients.

Objectives: There is no clear evidence that dietary proteins aggravate Crohn's disease (CD). We aimed to clarify the antibody response to dietary proteins in CD., Methods: Antibody to porcine pancreatic amylase (PPA) a protease-resistant dietary protein (anti-PPA), was examined in CD patients (N = 104), ulcerative colitis (UC) patients (N = 85), and healthy controls (N = 83), and its relationship with the clinical characteristics of CD was investigated. Antibodies to casein and ovalbumin, anti-Saccharomyces cerevisiae antibodies (ASCA), and antibodies to I2 from Pseudomonas fluorescens (anti-I2) were also examined., Results: Thirty-eight percent (39/104) of the CD patients expressed anti-PPA antibodies, and this percentage was significantly higher as compared with the control group (5%, 4/83) and the UC group (9%, 8/85) (P < 0.001). A significantly higher level of anti-PPA antibodies was detected in patients with "small bowel disease-dominant" CD than in those with "colitis-dominant" CD (P < 0.05). Antibodies to casein and ovalbumin were not specifically expressed in CD patients. As ASCA was detected in 33% and anti-I2 in 46% of the CD patients, 72% of the CD patients were found positive for at least one of the three antibodies including anti-PPA antibodies., Conclusions: CD patients showed a specific antibody response to PPA, as compared with UC patients and controls. There was a significantly higher level of anti-PPA antibody in patients with "small bowel disease-dominant" CD, suggesting that dietary proteins could play a role in the inflammatory response in CD patients with small bowel disease. Anti-PPA antibodies combined with ASCA/anti-I2 may be useful for the diagnosis of CD.

To evaluate the role of dietary factors in the etiology of inflammatory bowel disease (IBD), we conducted a multicenter hospital-based case-control study in a Japanese population. Cases were IBD patients aged 15 to 34 years [ulcerative colitis (UC) 111 patients; Crohn's disease (CD) 128 patients] within 3 years after diagnosis in 13 hospitals. One control subject was recruited for each case who was matched for sex, age, and hospital. A semiquantitative food frequency questionnaire was used to estimate preillness intakes of food groups and nutrients. All the available control subjects (n = 219) were pooled, and unconditional logistic models were applied to calculate odds ratios (ORs). In the food groups, a higher consumption of sweets was positively associated with UC risk [OR for the highest versus lowest quartile, 2.86; 95% confidence interval (CI), 1.24 to 6.57], whereas the consumption of sugars and sweeteners (OR, 2.12; 95% CI, 1.08 to 4.17), sweets (OR, 2.83; 95% CI, 1.38 to 5.83), fats and oils (OR, 2.64; 95% CI, 1.29 to 5.39), and fish and shellfish (OR, 2.41; 95% CI, 1.18-4.89) were positively associated with CD risk. In respect to nutrients, the intake of vitamin C (OR, 0.45; 95% CI, 0.21 to 0.99) was negatively related to UC risk, while the intake of total fat (OR, 2.86; 95% CI, 1.39 to 5.90), monounsaturated fatty acids (OR, 2.49; 95% CI, 1.23 to 5.03) and polyunsaturated fatty acids (OR, 2.31; 95% CI, 1.12 to 4.79), vitamin E (OR, 3.23; 95% CI, 1.45 to 7.17), and n-3 (OR, 3.24; 95% CI, 1.52 to 6.88) and n-6 fatty acids (OR, 2.57; 95% CI, 1.24 to 5.32) was positively associated with CD risk. Although this study suffers from the shortcoming of recall bias, which is inherent in most retrospective studies (prospective studies are warranted to confirm the associations between diet and IBD risk), the present findings suggest the importance of dietary factors for IBD prevention.

Background: Active Crohn's disease (CD) is often associated with elevated levels of platelets, granulocytes, and monocytes that are activated and resistant to apoptosis. The level of neutrophils in the intestinal mucosa has been quantitatively related to the severity of intestinal inflammation in CD. We postulated that patients with CD that is refractory to conventional medications might respond to a reduction of granulocytes and monocytes by adsorptive apheresis., Methods: Twenty-one patients with a CD activity index (CDAI) of 200-399 and unresponsive to standard medication, which included nutritional intervention, received granulocyte and monocyte adsorptive apheresis (GCAP) as an adjunct to their ongoing medication. GCAP was performed with an Adacolumn, which adsorbs granulocytes, monocytes, and a small fraction of lymphocytes (FcgammaR and complement receptor-bearing leucocytes). Patients received one GCAP session/week for 5 consecutive weeks. CDAI, International Organization for the Study of Inflammatory Bowel Disease (IOIBD), and IBD questionnaire (IBDQ) scores were evaluated., Results: During the initial conventional/nutritional therapy, no significant improvement was seen in any patient. However, at week 7 of GCAP therapy, significant improvements in CDAI, IOIBD, and IBDQ scores were observed. The CDAI, IOIBD, and IBDQ scores before GCAP were 275.6+/-54.2, 3.4+/-1.4, and 152+/-22, respectively. The corresponding values after GCAP were 214.8+/-89.2 (P=0.0005), 2.54+/-1.5 (P=0.0224), and 165+/-29 (P=0.0327), respectively., Conclusions: GCAP could be effective for inducing remission and improving quality of life in patients with active CD that is refractory to conventional therapy.

Background/aims: Enteral nutrition is the currently established primary therapy for Crohn's disease in Japan. We examined the effects of postoperative nutritional therapy in patients with perforating type and non-perforating type Crohn's disease., Methodology: We retrospectively reviewed the records for 218 patients who underwent surgical interventions for Crohn's disease in our hospital between January 1, 1974 and September 30, 2001. They were divided into four groups: 92 patients in the non-perforating type (NP type) + Elemental Diet (ED) group had received ED therapy and nutritional education, 22 patients in the NP type + NoED group had not received ED therapy or nutritional education, 88 patients in the perforating type (P type) + ED group and 16 patients in P type + NoED group. We evaluated the incidence of reoperation rate for each group., Results: Patients with a postoperative ED therapy demonstrated a significant decrease in the incidence of second resection. The incidence of second resection in the NP type + ED group was significantly lower than that of the other groups. The NP type + NoED group and the P type + ED group followed similar courses., Conclusions: In patients with Crohn's disease postoperative ED therapy and nutritional education is effective in reducing the incidence of second resection. It appears that postoperative ED therapy and nutritional education is more important in patients with P type Crohn's disease.

Background & Aims: Interleukin-6 (IL-6) regulates immune response and inflammation. We carried out a pilot placebo-controlled study to investigate the efficacy, pharmacokinetics, and safety of MRA, a humanized monoclonal antibody to IL-6 receptor, in patients with active Crohn's disease., Methods: Thirty-six patients with active Crohn's disease (Crohn's Disease Activity Index [CDAI] > or =150) were randomly assigned to receive biweekly intravenous infusion of either placebo, MRA, or MRA/placebo alternately for 12 weeks at a dose of 8 mg/kg. The study's primary end point was a clinical response rate that was defined as a reduction of CDAI > or =70., Results: At the final evaluation, 80% of the patients (8 of 10) given biweekly MRA had a clinical response as compared with 31% of the placebo-treated patients (4 of 13; P = 0.019). Twenty percent of the patients (2 of 10) on this regimen went into remission (CDAI <150), as compared with 0% of the placebo-treated patients (0 of 13). The clinical response rate of the every-4-week regimen was 42% (5 of 12). The serum concentrations of MRA were detected at 2 weeks after every infusion, at which time acute phase responses were completely suppressed; however, they were not suppressed at 4 weeks. Endoscopic and histologic examination showed no difference between MRA and placebo groups. The incidence of adverse events was similar in all the groups., Conclusions: This is the first clinical trial of humanized anti-IL-6 receptor monoclonal antibody in Crohn's disease. A biweekly 8 mg/kg infusion of MRA was well tolerated, normalized the acute-phase responses, and suggests a clinical effect in active Crohn's disease.

Six patients with active Crohn's disease (CD) unresponsive to conventional medications (CM) were treated with Monocyte-granulocytapheresis (M-GCAP). CD patients who scored 200-400 points in Crohn's disease activity index (CDAI) in spite of receiving CM, including enteral nutrition, for at least 2 weeks were enrolled in our double series trial. Each series had 5 weekly M-GCAP and 2 follow-up weeks, and each M-GCAP treated 1,800 ml of patient's peripheral blood. After the 1st series, patients who decreased more than 50 points on the CDAI were deemed responders and enrolled in the second series. Patients with a CDAI score less than 150 points were considered in remission. The patients' quality of life was evaluated using an index (IBDQ) before and after the 1st series. The CDAI was significantly decreased comparing before and after the 1st series (258.2 +/- 36.2 vs. 166.5 +/- 16.6; P < 0.02). 50% of patients (3/6) responded to the therapy, and one case (16.7%) could be induced to remission. Significant removal was revealed only for white blood cells (25.6 +/- 16.9%; P < 0.05), especially granulocytes (29.5 +/- 22.5%; P < 0.05). A statistically significant improvement of IBDQ was revealed in the responders' group (162.3 +/- 17.2 vs. 189.3 +/- 11.5; P < 0.03). M-GCAP could be an effective adjunctive therapy for active CD patients unresponsive to CM allowing them to maintain a high QOL. However, it might be difficult to improve patients who could not be induced to remission after the 1st series by applying another series.

Objectives: Although an elemental diet has been established as the primary treatment for patients with Crohn's disease, the influence of dietary fat on the elemental diet remains unclear. We have designed the first randomized, controlled trial for elemental diets containing different fat percentages in patients with active Crohn's disease., Methods: Each patient was randomized to receive one of three dose levels of fat in an elemental diet (Elental) for 4 weeks: 10 patients received low fat (3.06 g/day), 10 patients received medium fat (16.56 g/day) and eight patients received high fat (30.06 g/day). The additional fat was composed of long-chain fatty acids. All patients were evaluated using the International Organization of Inflammatory Bowel Disease rating, plus C-reactive protein level and erythrocyte sedimentation rate, which were measured at weekly intervals., Results: Although the International Organization of Inflammatory Bowel Disease rating, C-reactive protein level and erythrocyte sedimentation rate in the low-fat group decreased, the values in the medium- and high-fat groups fluctuated during the study. The remission rate after 4 weeks in each group was 80%, 40% and 25% for patients in the low-, medium- and high-fat groups, respectively., Conclusions: When the fat consisted of long-chain triglycerides, a high amount of this fat in the elemental diet formula decreased its therapeutic effect against active Crohn's disease.

Background: The etiology of inflammatory bowel disease, which includes ulcerative colitis and Crohn's disease, has not yet been made clear. However, inflammatory bowel disease is recognized as a multifactorial disease, and innate genetic factors might contribute to the pathogenesis. Cytokine genes are thought to be important in inflammatory bowel disease. Recently, interleukin 18, cloned as a novel proinflammatory cytokine, has been implicated in inflammatory bowel disease, especially Crohn's disease., Methods: To identify germline mutations in patients with inflammatory bowel disease, the entire coding region of IL18 was examined using a DNA sequencing procedure., Results: No functional mutations were found, but a novel single nucleotide polymorphism (SNP) was identified as TCA/TCC at codon 35. In patients with Crohn's disease, the frequency of TCC allele carriers was significantly higher than in healthy controls (chi2 = 9.35, P = 0.002229, OR = 2.58, 95% CI = 1.39-4.80). Also, the magnitude of the association was more remarkable in females (chi2 = 16.36, P = 0.000052, OR = 8.17, 95% CI = 2.73-24.41). The TCC allele at codon 35 of IL18 may increase the risk for Crohn's disease, especially in females., Conclusions: IL18 is probably one of several genes that determine susceptibility to Crohn's disease.

Background & Aims: Previous studies have linked Crohn's disease (CD) to the pericentromeric region of chromosome 16 (IBD1). Three independent studies of Western populations have recently shown that 3 variants of NOD2, a gene located at 16q12, are associated with susceptibility to CD. Here, we have evaluated the 3 NOD2 variants in Japanese patients to determine whether the gene is also associated with susceptibility to CD in a non-Western population., Methods: Blood samples were obtained from 350 patients with CD, 272 patients with ulcerative colitis, and 292 healthy controls at 3 hospitals in Japan. DNA was sequenced in the region of the 3 NOD2 variants (C2104T in exon 4, G2722C in exon 8, and 3020insC in exon 11) by genomic polymerase chain reaction followed by direct sequencing., Results: Among the subjects in our 3 study groups, including patients with CD, patients with ulcerative colitis, and healthy controls, none had common NOD2 variants that have been associated with CD in white patients., Conclusions: These results indicate that genetic variation, which may predispose some human populations to CD, may not be present in other populations and specifically that common variants in NOD2 found in white patients with CD are not associated with CD in the Japanese population.

The importance of tumor necrosis factor (TNF)-alpha and the TNF receptor gene polymorphisms in the etipathogenesis of inflammatory bowel disease (IBD) has not been elucidated. DNA from peripheral blood samples was obtained from 124 patients with Crohn's disease (CD), 106 patients with ulcerative colitis (UC), and 111 unrelated healthy controls. We examined two single nucleotide polymorphisms (SNPs) of the TNF-alpha gene, TNF (-308 G/A and -238 G/A), an SNP of the TNF receptor superfamily member 1A gene, TNFRSF1A(also known as TNFR1), at codon 12 in exon 1 (CCA/CCG), and two SNPs of the 1B gene, TNFRSF1B (also known as TNFR2), (1466 A/G and 1493 C/T). There was a difference in the carrier frequency for haplotype AG (-308 A, -238 G) between UC patients and the controls (OR=4.76, 95% CI=1.53-14.74, P<0.01). We found a significant difference in carrier frequency for haplotype AT (1466 A, 1493 T) of the TNFRSF1B gene between CD patients and the controls (OR=2.13, 95% CI=1.08-4.21, P<0.05). The significance proved to be greater in CD patients with both internal and external fistula (OR=4.8, 95% CI=1.73-13.33, P<0.01), and in those who were poor responders ( n=22) to our treatments, which consisted of nutritional therapy, medical therapy and surgical therapy (OR=9.24, 95% CI=3.37-25.36, P<0.001). This study suggests that one of the genes responsible for UC may be the TNF gene, or an adjacent gene, and that TNFRSF1B gene polymorphisms contribute greatly to the increased onset risk of CD and to the disease behavior.