Yoko Yokoyama

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.

Multivariate Analysis for Factors Predicting Rapid Response of Leukocytapheresis in Patients With Steroid-resistant Ulcerative Colitis: A Multicenter Prospective Open-label Study

Leukocytapheresis (LCAP) has been advocated as a treatment for moderate to severe active ulcerative colitis (UC) in Japan. To clarify the predictive factors for a rapid response to LCAP treatment, we conducted a multicenter prospective open‐label study. A total of 105 patients with UC were analyzed. LCAP was performed using a Cellsorba EX column once a week for 5–10 sessions. The response was evaluated by the clinical activity index (CAI). When the CAI score decreased to less than half the pretreatment value or to less than 5 points within 3 weeks, the patient was considered to be a rapid responder. The average CAI significantly decreased from 11.7 to 4.2 (P < 0.01). Seventy‐four percent of the patients responded to the therapy, and 53% of these patients were rapid responders. The following significant factors correlated with the rapid LCAP response: (i) steroid resistance (P < 0.05), (ii) severe disease indicated by a CAI score greater than 11 (P = 0.05), (iii) disease duration of less than 1 year (P < 0.05), and (iv) C‐reactive protein levels before treatment (P < 0.01). These results suggest that the early initiation of LCAP is beneficial in patients with steroid‐resistant UC.

Activated platelets as a possible early marker to predict clinical efficacy of leukocytapheresis in severe ulcerative colitis patients

BackgroundLeukocytapheresis (LCAP) is an effective adjunct for patients with active ulcerative colitis (UC). Because LCAP may have the potential to remove and modulate not only leukocytes but also platelets, we evaluated the correlation between activated platelets and the therapeutic response to LCAP.MethodsFourteen patients with severe UC received weekly LCAP for 5 consecutive weeks. Their average clinical activity index (CAI) and endoscopic index (EI) were 9.6 ± 3.4 and 10.9 ± 1.0, respectively. Their peripheral blood was sampled before and after every LCAP and stained with fluorescent antibodies to the activation-dependent surface antigens of platelets (CD63, CD62-P) prior to flow cytometry. Endoscopic evaluations were performed after the last LCAP.ResultsClinical remission (CAI < 4) was induced in 50% of the patients (7/14) after 5 weeks, and there were no significant differences observed in clinical background between the responder group (RG) and the nonresponder group (NG). In the RG, the populations of CD63+ (P < 0.03) and CD62-P+ (P < 0.05) platelets were significantly decreased after the first LCAP, and their reduction ratio decreased gradually with repeated LCAP. A significant improvement of the EI score, especially mucosal damage, was achieved in RG (P < 0.04) but not in NG.ConclusionsThese results indicate that the therapeutic responses to LCAP were reflected in modulations of population and/or platelet functions, especially after the first session. The decrease of such activated platelets immediately after the first LCAP may be an early marker for predicting the response in patients with severe UC.

A large-scale, prospective, observational study of leukocytapheresis for ulcerative colitis: Treatment outcomes of 847 patients in clinical practice

BACKGROUND AND AIMS Leukocytapheresis is an extracorporeal therapy for ulcerative colitis. However, no large-scale study on leukocytapheresis has been reported. This large-scale, prospective, observational study aimed to evaluate the treatment outcomes of leukocytapheresis for active ulcerative colitis in clinical practice. METHODS Patients with active ulcerative colitis treated with leukocytapheresis using a Cellsorba E column between May 2010 and December 2012 were enrolled from 116 medical facilities in Japan. RESULTS A total of 847 patients were enrolled, and 623 were available for efficacy analysis. Out of 847 patients, 80.3% of the patients had moderate to severe disease activity, and 67.6% were steroid refractory. As concomitant medications, 5-aminosalicylic acids, corticosteroids, and thiopurines were administered to 94.8%, 63.8%, and 32.8% of the patients, respectively. In addition, infliximab and tacrolimus were concomitantly used in 5.8% and 12.3%, respectively. Intensive leukocytapheresis (≥4 leukocytapheresis sessions within the first 2 weeks) was used in >70% of the patients. Adverse events were seen in 10.3% (87/847), which were severe in only 5 patients (0.6%). Any concomitant medications did not increase the incidence of adverse events. Intensive leukocytapheresis was as safe as the conventional weekly procedure. The overall clinical remission rate was 68.9% (429/623), and the mucosal healing rate was 62.5% (145/232). Clinical remission was achieved more frequently and rapidly in the intensive group than in the weekly group. CONCLUSIONS This large-scale study indicates that leukocytapheresis, including intensive procedure, is a safe and effective therapeutic option for active ulcerative colitis.

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.

Adsorptive Granulocyte/Monocyte Apheresis for the Maintenance of Remission in Patients with Ulcerative Colitis: A Prospective Randomized, Double Blind, Sham-Controlled Clinical Trial

Background/Aims Weekly granulocyte/monocyte adsorption (GMA) to deplete elevated and activated leucocytes should serve as a non-pharmacological intervention to induce remission in patients with ulcerative colitis (UC). This trial assessed the efficacy of monthly GMA as a maintenance therapy to suppress UC relapse. Methods Thirty-three corticosteroid refractory patients with active UC received 10 weekly GMA sessions as a remission induction therapy. They were then randomized to receive one GMA session every 4 weeks (True, n=11), extracorporeal circulation without the GMA column every 4 weeks (Sham, n=11), or no additional intervention (Control, n=11). The primary endpoint was the rate of avoiding relapse (AR) over 48 weeks. Results At week 48, the AR rates in the True, Sham, and Control groups were 40.0%, 9.1%, and 18.2%, respectively. All patients were steroid-free, but no statistically significant difference was seen among the three arms. However, in patients who could taper their prednisolone dose to <20 mg/day during the remission induction therapy, the AR in the True group was better than in the Sham (p<0.03) or Control (p<0.05) groups. Conclusions Monthly GMA may potentially prevent UC relapse in patients who have achieved remission through weekly GMA, especially in patients on <20 mg/day PSL at the start of the maintenance therapy.

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.