Koji Kamikozuru

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 Crohns 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. (Inflamm Bowel Dis 2012)

Placebo controlled evaluation of Xilei San, a herbal preparation in patients with intractable ulcerative proctitis

Background and Aim:  Topical mesalamine or corticosteroid has shown efficacy in patients with ulcerative proctitis, but patients often become refractory to these interventions. Xilei San is a herbal preparation with evidence of anti‐inflammatory effects. We evaluated the efficacy of topical Xilei San in ulcerative proctitis patients.

The CD4+CD28null and the regulatory CD4+CD25High T-cell phenotypes in patients with ulcerative colitis during active and quiescent disease, and following colectomy

The CD4+CD25High T-cell phenotype has an essential immunoregulatory role, while the CD4+CD28null T-cell reflects immune pathology. We investigated the profiles of the CD4+CD25High and the CD4+CD28null T-cell phenotypes in patients with ulcerative colitis (UC) during active and quiescent phases as well as following colectomy. Fifty-nine UC patients, 34 active (UCa) and 25 quiescent (UCq) together with 19 healthy controls (HC) were included. Ten of 34 UCa patients underwent colectomy due to unremitting UC (UCo). Immunohistochemical phenotypic of the peripheral blood lymphocytes bearing CD4, CD25 or CD28 was done for analyzes by a multiparameter fluorescence activated cell sorting technique. The expression of the CD4+CD25High phenotype was higher in UCq (P<0.01) or UCo (P<0.01) group vs UCa group. Further, the expression of the CD4+CD28null phenotype in UCa or UCo group was higher than in the HC group (P<0.05). However, the expression of the CD4+CD28null phenotype up to 12 months after colectomy was not significantly different from the levels in the same patients during acute phase. Our impression is that a high CD4+CD25High T-cell reflects alleviation of inflammation, while the expression of the CD4+CD28null T-cell phenotype is an etiologic feature in UC patients, and is maintained after removing the affected colon.

Selective depletion of peripheral granulocyte/monocyte enhances the efficacy of scheduled maintenance infliximab in Crohn's disease.

Background: This is the first report on a case of Crohns disease (CD), who was successfully maintained with a combination of infliximab (IFX) and selective depletion of granulocytes/monocytes by adsorption (GMA). Case: A 33‐year‐old female with CD activity index (CDAI) 294.2 responded to iv IFX (5mg/kg) administered at weeks 0, 2, and 6 in combination with 3000 mg/day oral 5‐aminosalicylic acid (5‐ASA; CDAI = 118). Then IFX at 8 week intervals was given as maintenance therapy. Two weeks before the 5th scheduled IFX, the patient worsened with an increase in stool frequency and a rise in CDAI. GMA was administered at weeks 5, 6, and 7 after her 6th iv IFX. Her CDAI decreased from 166.2 to 126.3 and 111.9 before 2nd and 3rd GMA sessions. She received her 7th iv IFX while the CDAI was 83.6. GMA course was repeated before 8th and 9th IFX. The patient remained in stable clinical and endoscopic remission without experiencing any serious side effect. After achieving mucosal healing, the patient decided to cease IFX therapy while continuing with GMA. Conclusions: IFX appears to induce and maintain remission of CD, but it may lose its efficacy after repeated administration. GMA is safe and by selectively depleting elevated/activated leukocytes may be a useful adjunct for IFX efficacy. J. Clin. Apheresis, 2010.

Looking for predictive factors of clinical response to adsorptive granulocyte and monocyte apheresis in patients with ulcerative colitis: markers of response to GMA

BackgroundAdsorptive granulocyte and monocyte apheresis (GMA) with an Adacolumn in patients with ulcerative colitis (UC) has been applied as a non-pharmacological treatment strategy, but the efficacy has been encouraging as well as discouraging, depending on patients’ demography at entry. In this study, we looked for predictive factors for clinical response to GMA in patients with UC.MethodsIn a retrospective setting, 43 outpatients who had been treated with GMA for active UC were evaluated. Patients were divided into remission group and non-remission group based on Lichtiger’s clinical activity index (CAI) before and after 10, once a week GMA sessions. The efficacy was analysed in relation to patients’ demographic variables. To determine predictive factors that closely related to the response to GMA, receiver operating characteristic (ROC) curve, and multiple logistic regression analyses were applied.ResultsAfter 10 GMA sessions, the overall clinical remission rate (CAI < 4) was 53.5%. Multiple logistic regression and ROC analyses showed that the interval between relapse and the first GMA session was a significant and independent predictive factor for clinical response to GMA (P = 0.016); the clinical response was better in patients who received GMA immediately after a relapse and vice versa. Likewise, univariate analyses showed that, the duration of UC (P = 0.036) and the cumulative prednisolone (PSL) dose (P = 0.006) before the first GMA session were significantly greater in the GMA non-responder group as compared with the responder group. Additionally, a lower white blood cell (WBC) count at first GMA session was related to clinical response to GMA (P = 0.032).ConclusionsIn this study, patients with a short duration of UC and low cumulative PSL dose seemed to respond well to GMA. However, we found that the best responders were patients who received GMA immediately after a clinical relapse. Additionally, GMA was effective in patients with low WBC count at the first GMA session. The findings of this study should spare medical cost and reduce morbidity time for many patients, relevant for decision making in clinical settings.

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 Crohns 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)‐β1 (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‐β1 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.

Prospective postsurgical capsule endoscopy in patients with Crohn’s disease

AIM To clarify the usefulness of postsurgical capsule endoscopy (CE) in the diagnosis of recurrent small bowel lesions of Crohns disease (CD). METHODS This prospective study included 19 patients who underwent ileocolectomy or partial ileal resection for CD. CE was performed 2-3 wk after surgery to check for the presence/absence and severity of lesions remaining in the small bowel, and for any recurrence at the anastomosed area. CE was repeated 6-8 mo after surgery and the findings were compared with those obtained shortly after surgery. The Lewis score (LS) was used to evaluate any inflammatory changes of the small bowel. RESULTS One patient was excluded from analysis because of insufficient endoscopy data at the initial CE. The total LS shortly after surgery was 428.3 on average (median, 174; range, 8-4264), and was ≥ 135 (active stage) in 78% (14 of 18) of the patients. When the remaining unresected small bowel was divided into 3 equal portions according to the transition time (proximal, middle, and distal tertiles), the mean LS was 286.6, 83.0, and 146.7, respectively, without any significant difference. Ulcerous lesions in the anastomosed area were observed in 83% of all patients. In 38% of the 13 patients who could undergo CE again after 6-8 mo, the total LS was higher by ≥ 100 than that recorded shortly after surgery, thus indicating a diagnosis of endoscopic progressive recurrence. CONCLUSION Our pilot study suggests that CE can be used to objectively evaluate the postoperative recurrence of small bowel lesions after surgery for CD.

Crohn's disease complicated by hepatitis B virus successfully treated with the use of adsorptive depletion of myeloid lineage leucocytes to suppress inflammatory cytokine profile

BACKGROUND AIMS In patients with inflammatory bowel disease infected with hepatitis B virus (HBV), immunosuppressive therapy required to suppress active inflammatory bowel disease may promote HBV reactivation. METHODS A 27-year-old corticosteroid-naive woman with Crohns disease (CD) activity index of 249.8 complicated by HBV infection was offered Entecavir to control HBV reactivation during immunosuppressive therapy for CD. The patient refused Entecavir, fearing that it might adversely affect her pregnancy outcome. Instead, we applied intensive granulocyte/monocyte adsorptive apheresis (GMA) at two sessions per week to deplete inflammatory cytokine-producing leucocytes as an immunosuppressive therapy in this case. RESULTS GMA induced stable remission (CD activity index, I 105) and endoscopic improvement without HBV reactivation or safety concern. Furthermore, CD remission was paralleled by suppression of tumor necrosis factor and interleukin as measured in serum samples. CONCLUSIONS Immunosuppressive therapy required to treat an active CD potentially can promote HBV reactivation and worsen liver function. In this study involving a CD case complicated by chronic HBV infection, intensive GMA as a non-pharmacologic treatment intervention was associated with clinical remission and endoscopic improvement without HBV reactivation. Furthermore, GMA was well-tolerated and was without any safety concern. However, suppression of tumor necrosis and interleukin-6by GMA in this clinical setting is potentially very interesting.

Cytapheresis as a Non-Pharmacological Therapy for Inflammatory Bowel Disease.

Although inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn’s disease (CD), is a chronic recurrent disease with unknown etiology. Recent immunological studies suggest close relation to autoimmune status featured by antibodies against colonic epithelial cells. For patients with IBD, 5-aminosalycilates are often used in case of mild disease, and cortico - steroids are standard therapy for moderate-to-severe disease. However, we often encounter patients who are resistant to or dependent of conventional therapy, which are likely to lead to future problems in quality of life due to adverse effects of drugs used, especially cortico - steroids. Extracorporeal leukocyte removal therapy (cytapheresis) is one of the adjunctive therapies for IBD patients refractory to steroids. By removing circulating activated leukocytes, especially granulocytes and lymphocytes, impaired immune response is suppressed. In the present article recently published studies are reviewed in order to reflect the current state of the art in the use of cytapheresis for treating IBD, especially UC and CD. Although there are only few randomized controlled trials, clinical experience so far suggests that cytapheresis has superior efficiency than conventional therapies in steroid-resistant moderate-to-severe UC. Moreover, cytapheresis features its safety characteristic compared with other conventional medications for severe UC, cytapheresis is regarded as safe treatment regimen.

NUDT15, FTO, and RUNX1 genetic variants and thiopurine intolerance among Japanese patients with inflammatory bowel diseases.

Background/Aims Recent genome-wide analyses have provided strong evidence concerning adverse events caused by thiopurine drugs such as azathioprine (AZA) and 6-mercaptopurine. The strong associations identified between NUDT15 p.Arg139Cys and thiopurine-induced leukopenia and severe hair loss have been studied and confirmed over the last 2 years. However, other coding variants, including NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, and FTO p.Ala134Thr, and a noncoding variation in RUNX1 (rs2834826) remain to be examined in detail in this respect. Therefore, we investigated the correlation between these adverse events and the 5 recently identified variants mentioned above among Japanese patients with inflammatory bowel diseases (IBD). Methods One hundred sixty thiopurine-treated patients with IBD were enrolled. Genotyping was performed using TaqMan SNP Genotyping Assays or Sanger sequencing. Results None of the 5 variants were associated with gastrointestinal intolerance to AZA. However, NUDT15 p.Arg139Cys was significantly associated with the interval between initiation and discontinuation of AZA among patients with gastrointestinal intolerance. This variant was strongly associated with early (<8 weeks) and late (≥8 weeks) leukopenia and severe hair loss. Moreover, it correlated with the interval between initiation of thiopurine therapy and leukopenia occurrence, and average thiopurine dose. NUDT15 p.Val18_Val19insGlyVal, NUDT15 p.Val18Ile, FTO p.Ala134Thr, and RUNX1 rs2834826 exhibited no significant relationship with the adverse events examined. Conclusions Of the 5 variants investigated, NUDT15 p.Arg139Cys had the strongest impact on thiopurine-induced leukopenia and severe hair loss; therefore, its genotyping should be prioritized over that of other variants in efforts to predict these adverse events in Japanese patients with IBD.