Scheduled infliximab monotherapy to prevent recurrence of Crohn's disease following ileocolic or ileal resection: a 3-year prospective randomized open trial.

BACKGROUND: Infliximab (IFX) is effective for remission induction and maintenance of Crohn's disease (CD). This trial assessed the efficacy of scheduled maintenance IFX monotherapy to prevent postoperative CD recurrence. METHODS: Thirty-one CD patients who had ileocolic resection within the past 4 weeks were randomly assigned to scheduled IFX at 5 mg/kg intravenously every 8 weeks for 36 months (n = 15) or without IFX (control, n = 16). All patients were treated without immunomodulator or corticosteroid following surgery. The primary and secondary endpoints were remission rates at 12 and 36 months, defined as CD Activity Index (CDAI) ≤150, an International Organization for the Study of Inflammatory Bowel Disease (IOIBD) score <2, and C-reactive protein (CRP) <0.3 mg/dL. Additionally, endoscopic recurrences at 12 and 36 months were evaluated. RESULTS: At 12 and 36 months, 100%, and 93.3% of patients in the IFX group were in remission (IOIBD <2), respectively vs. 68.8% and 56.3% in the control arm (P < 0.03). Similarly, 86.7% and 86.7% of patients in the IFX group maintained serological remission (CRP <0.3 mg/dL) vs. 37.5% and 37.5% in the control arm (P < 0.02). Further, the IFX group achieved higher endoscopic remission at 12 months, 78.6% vs. 18.8% (P = 0.004). However, in the Kaplan-Meier survival analysis the CDAI scores between the two arms were not significantly different either at 12 or at 36 months. No adverse event (AE) was observed. CONCLUSIONS: An early intervention with IFX monotherapy should prevent clinical, serological, and endoscopic CD recurrence following ileocolic resection. Thiopurine naivety and eliminating the initial loading dose of IFX might minimize serious AEs.

Optimal apheresis treatment volume for the efficacy and safety of leukocytapheresis with Cellsorba in patients with active ulcerative colitis.

BACKGROUND: Leukocytapheresis (LCAP) is used as an adjunct therapy for patients with active ulcerative colitis (UC). Although, LCAP is routinely performed at 3,000 mL per session, we were interested to see that if this can be replaced with bodyweight (BW) adjusted volume. METHODS: In an open label prospective trial, the clinical response to BW adjusted LCAP (BWA-LCAP) was evaluated in 14 patients with active UC. Fourteen demography matched UC patients who had been treated with the routine 3,000 mL LCAP were randomly sampled from our database as a control group. All patients were given 10 weekly LCAP sessions. In the BWA-LCAP group, the processed blood volume (PBV) was set at 30 mL/kg × BW/session. Baseline demographic measures were not significantly different between the two groups. RESULTS: The average PBV in the BWA-LCAP group was 1971.0 ± 330.0 mL, range 1,020-2,460. In both groups, the average UC clinical disease activity index, the endoscopic index, and the concomitant prednisolone dosage were significantly and equally reduced during the course of 10 LCAP. Accordingly, at the end of the trial, no significant difference was seen in any outcome measure between the two groups. However, a significantly higher incidence of adverse event (AE) was observed in the routine 3,000 mL LCAP group as compared with the BWA-LCAP group (P < 0.01). CONCLUSIONS: The outcomes of this investigation showed that the therapeutic efficacy of LCAP based on 30 mL/kg × BW is similar to the routine 3,000 mL per session LCAP. However, BWA-LCAP should be favored if one is to see the full potential of LCAP without AE.

Relevance of the processed blood volume per granulocyte and monocyte apheresis session to its clinical efficacy in patients with ulcerative colitis.

Granulocyte/monocyte adsorption (GMA) has been introduced as an adjunct intervention for active ulcerative colitis (UC) patients. The processed blood volume (PV) per GMA session is an important factor for its efficacy because depletion of elevated/activated myeloid leukocytes is its main action. Hitherto, this aspect of GMA has been largely ignored. Thirty-three patients were enrolled for remission induction therapy with five weekly GMA sessions at a standard PV of 1800 mL, regardless of patients' bodyweight (BW). The patients were divided into three groups: high (H)BW (≥ 65 kg, n = 11), 50 kg ≤ medium (M)BW < 65 kg (n = 12), and low (L)BW (≤ 50 kg, n = 10). UC clinical activity index (CAI) was according to Lichtiger, and the clinical efficacies were evaluated at both one week post 3(rd) GMA (Week 4) and one week post 5(th) GMA (Week 6). The average BW was 70.9 ± 6.2 kg in HBW, 55.8 ± 4.5 kg in MBW, and 46.8 ± 1.2 kg in LBW, indicating the mean PV/BW in the three groups being 25.6 ± 2.12, 32.5 ± 2.50, and 38.7 ± 1.0 (mL/kg, P < 0.05), respectively. The LBW group consisted of female patients only. Significant improvements of CAI were seen before treatment at either Week 4 or Week 6 in all groups. A significantly higher remission rate was achieved in the LBW (80.0%) vs. MBW (33.3%) or HBW (27.3%) at Week 6 (P < 0.03). According to this GMA evaluation, the lower-limit of optimum PV/kg should be higher than 38.7 mL/kg for its potential clinical efficacy to be significantly greater than the routine GMA method. Additional BW-oriented GMA studies in larger and gender controlled cohorts of patients should strengthen our findings.

Immunoregulatory effects of adsorptive granulocyte and monocyte apheresis in patients with drug refractory Crohn's disease.

In Japan, adsorptive granulocyte/monocyte apheresis (GMA) is an approved treatment option in patients with active Crohn's disease (CD). However, there is inadequate knowledge regarding the mechanism(s) of therapeutic effects of this non-pharmacologic treatment strategy. Further, recently we have been interested in the regulatory T-cell (Treg) profile which has an essential immunoregulatory function. Thirteen CD patients were treated with a single GMA session. The mean CD activity index (CDAI) and duration of CD were 218.5 and 9.8 years, respectively. Eight healthy volunteers participated as a control group. From CD patients, whole blood was taken immediately before and after the GMA session directly from the GMA column inflow and outflow lines. Broad spectrum serum key cytokines and chemokines were measured by suspension-array and ELISA. At baseline, almost all assayed inflammatory cytokines were significantly elevated in CD patients. Treg-associated cytokines including IL-10 (P < 0.02) and transforming growth factor (TGF)-ß1 (P < 0.03), were higher in the GMA column outflow vs. inflow. In contrast, the Th1/Th2 balance, defined as IFN-γ/IL-10 was lower during hemofiltration (P = 0.05), potentially due to an elevated IL-10 (P < 0.02) because an elevation of pro-inflammatory IFN-γ (Th1) was not observed at the GMA column outflow. A single GMA session had a significant impact on the Treg profile. Treg-related cytokines like IL-10 and TGF-ß1 in the blood returning to the patients from the GMA column outflow were elevated, while pro-inflammatory cytokines like IFN-γ were not. This action of GMA is potentially very interesting in patients with immune disorders, like CD patients.

Infliximab therapy impacts the peripheral immune system of immunomodulator and corticosteroid naïve patients with Crohn's disease.

BACKGROUND/AIMS: Infliximab (IFX), an antibody to tumor necrosis factor, (TNF)-α has efficacy in treating Crohn's disease (CD). However, knowledge of the potential effects of IFX on patients' immune profiles is lacking. The purpose of this study was to reveal the immunological effects of IFX. METHODS: Twenty-two patients with a CD activity index (CDAI) of 194.2±92.9 and an average duration of disease of 3.26 months and 21 healthy controls were included. Patients were to have their first IFX remission induction therapy with 3 infusions (5 mg/kg) at weeks 0, 2, and 6. Oral 5-aminosalicylic acid was the only ongoing medication in the patient population. Blood samples at baseline, 12 hours after the first infusion and at week 14 were labeled with anti-CD4/CD25 antibodies for immunohistochemical measurement of regulatory T-cells (Treg). Serum cytokines and chemokines were measured by suspension array and ELISA. RESULTS: CDAI significantly decreased prior to the second IFX infusion (p<0.001). Clinical remission rates were 77.3% and 91% by the second and third infusions, respectively. At baseline, interleukin (IL)-6 (p<0.03), IL-8 (p<0.03), IL-10 (p=0.050), IL-13 (p<0.01), transforming growth factor-ß1 (p<0.01), and 'regulated on activation, normal T cell expressed and secreted' (RANTES) (p<0.01) were elevated in patients. After the initial IFX infusion, TNF-α (p<0.04), IL-6 (p<0.03), interferon (IFN)-γ (p<0.04), IFN-γ-inducible protein-10 (p<0.01), monocyte chemoattractant protein-1 (p<0.01), macrophage inflammatory protein-1ß (p<0.01), and RANTES (p<0.01) were decreased. IFX infusion was associated with an increase in Treg (p<0.01) and a decrease in the Th1 (IFN-γ)/Th2 (IL-4) ratio (p<0.03). CONCLUSIONS: IFX use was associated with restoration of the Th1/Th2 balance after a single infusion and seemed to promote induction of naïve Th0 lymphocytes to Treg. This knowledge should have clinical relevance.

Mechanism of carcinogenesis in familial tumors.

It is thought that malignant tumors occur through interactions of multiple environmental factors and a personal genetic factor. A normal somatic cell having an intrinsic function is able to acquire the characteristics of a malignant cell under the influence of many factors. A small percentage of all tumors have obvious familial aggregation. These entities are called familial cancer. The familial cancer syndrome is well defined for colorectal cancer, breast cancer, endocrine neoplasia, and so on. Traits of familial tumors are sequentially inherited by offspring through gametes in a Mendelian fashion, most commonly in an autosomal-dominant manner. Carcinogenesis requires multiple genetic events. A patient with a familial tumor is ahead of an individual without any germline mutation in the carcinogenesis process. In such a situation, patients frequently suffer from multiple malignant tumors at a young age. It is well known that three major genes are closely related to the cell cycle and tumorigenesis. These gene types are protooncogenes, tumor suppressor genes, and DNA mismatch repair genes. Proto-oncogenes function to accelerate cells during the G1 or growth phase of the cell cycle. Tumor suppressor genes act as blocks against cell growth and proliferation. Inactivation of tumor suppressor genes requires alterations in both alleles. These phenomena are known as Knudson's two-hits theory. However, DNA mismatch repair genes are known as caretaker genes and correct mismatch pair generation during DNA replication. Germline mutation of DNA mismatch repair genes causes hereditary nonpolyposis colorectal cancer. The tumor phenotype from patients with hereditary nonpolyposis colorectal cancer is demonstrated to be microsatellite instability positive.

IL18 polymorphism is associated with an increased risk of 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.