Caudal type homeobox 2 expression induced by leukocytapheresis might be associated with mucosal healing in ulcerative colitis.

BACKGROUND AND AIM: Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. Although the goal of UC therapy has recently been to target mucosal healing, the molecular mechanism of mucosal healing remains unknown. In this study, we aimed to elucidate the molecular dynamics related to the proliferation and differentiation of intestinal epithelial cells during cytapheresis therapy in a short duration. METHODS: Endoscopy was performed in 26 patients with UC in multicentre hospitals, and biopsy specimens were collected from the rectum before and within two weeks after leukocytapheresis (LCAP). The expression of representative proteins in intestinal epithelial cells and pathological findings was compared before and after LCAP. RESULTS: The expression of caudal type homeobox 2 (CDX2) and a hes family bHLH transcription factor 1(HES1) markedly increased after LCAP. Patients with endoscopic improvement after LCAP showed the expression of CDX2 before LCAP. Moreover, the number of goblet cells significantly increased after LCAP. Patients without endoscopic improvement after LCAP did not show the expression of CDX2 before LCAP. However, the expression of CDX2 markedly increased after LCAP. CONCLUSION: This study suggests that cytapheresis might induce CDX2 expression without affecting the cell proliferation, thus resulting in mucosal healing with goblet cell restoration.

Factors associated with treatment outcome, and long-term prognosis of patients with ulcerative colitis undergoing selective depletion of myeloid lineage leucocytes: a prospective multicenter study.

BACKGROUND: Patients with ulcerative colitis (UC) have elevated/activated myeloid lineage leucocytes and may respond favorably to adsorptive granulocyte/monocyte apheresis (GMA). However, there are patients who respond well to GMA, and patients who do not benefit. Therefore, predictive factors of GMA efficacy need to be defined. METHODS: In a prospective multicenter setting, 200 UC patients at 32 institutes received one GMA session per week over 10 weeks. Patients who achieved remission were followed for 12 months. The Clinical Activity Index (CAI) ≤3 meant remission, and response meant CAI decreased by ≥3. Quality of life was evaluated by the Inflammatory Bowel Disease Questionnaire (IBDQ). RESULTS: After final GMA, remission, response and no response rates were 67.0%, 15.0% and 18%, respectively. The remission group had a significant decrease in myeloid leucocytes and platelets. Corticosteroid dose decreased (P < 0.001); 49 of 97 patients on corticosteroids became steroid-free. Baseline CAI was lower in the remission group versus non-remission (P < 0.01), whereas IBDQ was higher in the remission group versus non-remission (P < 0.05). After 12 months, 52 of 134 patients had maintained remission. Disease duration was longer in the relapsed group versus maintained remission group (P = 0.041). Male gender, first UC episode and corticosteroid responder were significant factors for maintaining remission, whereas corticosteroid dependent UC was associating with relapse. DISCUSSION: Selective myeloid leucocyte depletion was effective for remission induction and improving patients' quality of life. Baseline demographics such as disease activity level, duration and corticosteroid dependency appear to predict response to GMA. Additionally, patients with a first UC episode who were drug naive responded well to GMA and achieved a favorable long-term disease course by avoiding pharmacologics from an early stage of their inflammatory bowel disease. These findings should help to end unnecessary use of medical resources by targeting GMA to patients who may respond well.

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 Crohn's 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.

Multicenter prospective study for clinical and endoscopic efficacies of leukocytapheresis therapy in patients with ulcerative colitis.

OBJECTIVE: This study aimed to assess the efficacy and tolerability of leukocytapheresis (LCAP) and to investigate predictive factors for mucosal healing and a sustained clinical response in steroid-free and steroid-refractory patients with ulcerative colitis (UC). MATERIAL AND METHODS: Thirty-one steroid-free or steroid-refractory patients with active UC were enrolled. Five or ten consecutive sessions of LCAP were performed in each patient. The efficacy and tolerability was then evaluated at weeks 3 and 6. Endoscopic examination was performed at week 6 to evaluate the mucosal healing, and the sustained cumulative response rate was evaluated at 12 months. RESULTS: At week 6, the mean Mayo clinical activity score had decreased significantly from 8.0 to 4.6 in the steroid-free patients and from 8.3 to 3.9 in the steroid-refractory patients. Rachmilewitz's endoscopic index had also decreased significantly from 9.1 to 6.1 in the steroid-free patients and from 10.0 to 5.7 in the steroid-refractory patients. Forty-seven percent of the steroid-free patients and 33% of the steroid-refractory patients achieved mucosal healing. The peripheral platelet counts had decreased significantly at weeks 3 and 6 in the mucosal healing group, compared with the non-mucosal healing group. The patients with a more than 15% platelet reduction had a significantly higher cumulative response rate, compared with the patients without a platelet reduction (p = 0.015). CONCLUSIONS: LCAP is beneficial for the induction of mucosal healing in steroid-free and steroid-refractory patients with UC. The degree of platelet reduction during LCAP might be a predictive marker for mucosal healing and a sustained clinical response.

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

BACKGROUND: Adsorptive 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. METHODS: In 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. RESULTS: After 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). CONCLUSIONS: In 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.

Current status and future perspectives of leukocytapheresis for inflammatory bowel disease.

Ulcerative colitis (UC) and Crohn's disease (CD) comprise the idiopathic inflammatory bowel diseases (IBD) of the gut. The etiology of IBD is poorly understood, but an autoimmune disturbance has been suggested to play an important role in this incurable disease. Extracorporeal leukocytapheresis (CAP) is an additional adjunct for IBD patients refractory to other conventional therapies, including steroids. The primary aim of CAP should be to suppress such unwanted immunological response by removing circulating inflammatory cells from the blood stream. The first decade has been passed since CAP was approved by Japanese social health insurance policy. It is therefore now an appropriate opportunity to upgrade and summarize our current understandings and/or future perspectives of this unique non-pharmacological and non-surgical strategy for IBD patients. According to several clinical and basic research reports, an early introduction of CAP should produce higher efficacy as compared with CAP applied sometime after a clinical relapse. Likewise, CAP therapy adjusted to patients' body-weight as well as two treatment sessions per week (intensive regimen) should benefit the efficacy rate. The etiology of IBD is not fully elucidated yet. As a result, the major therapeutic strategies in the Western world have been immunosuppressive therapy, including biologics. CAP is an unusual treatment modality for IBD because it seems to have both effectiveness and safety, which should generally be balanced in this type of illness. We now have to develop future strategies with and without combining biologics to improve the quality of life of IBD patients.

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. METHODS: In a double blind setting, 30 patients with intractable ulcerative proctitis despite ≥ 4 weeks of topical mesalamine or corticosteroid were randomly assigned to True (n = 15) and placebo (n = 15). Patients in True received suppository Xilei San (0.1 g/dose per day of Xilei San), the other 15 received placebo suppository. The initial efficacy was evaluated on day 14. Primary endpoint of the trial was avoiding relapse during 180 days, relapse meant recurrence of active disease. Riley's index was applied for endoscopic and histological evaluations, while patients' quality of life was evaluated by an inflammatory bowel disease questionnaire. RESULTS: On day 14, the number of patients who achieved remission, clinical activity index ≤ 4 in True was significantly higher versus placebo (P < 0.04). Likewise, at day 180, an 81.8% of patients in True were without relapse versus 16.7% in placebo (P < 0.001). Further, significant endoscopic (P < 0.01), histological (P < 0.02) and inflammatory bowel disease questionnaire (P < 0.04) improvements were observed in True, but not in placebo. CONCLUSIONS: This is the first controlled investigation showing significant clinical and endoscopic efficacy for Xilei San in patients with intractable ulcerative proctitis. Topical Xilei San was well tolerated, and was without safety concerns.

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.

GC/MS-based profiling of amino acids and TCA cycle-related molecules in ulcerative colitis.

OBJECTIVE: The roles that amino acids play in immunity and inflammation are well defined, and the relationship between inflammatory bowel disease (IBD) and certain amino acids has recently attracted attention. In this study, the levels of amino acids and trichloroacetic acid (TCA) cycle-related molecules in the colonic tissues and sera of patients with ulcerative colitis (UC) were profiled by gas chromatography/mass spectrometry (GC/MS), with the aim of evaluating whether the clinical state induced by UC leads to variations in the amino acid profile. MATERIALS AND METHODS: Colonic biopsy samples from 22 UC patients were used, as well as serum samples from UC patients (n = 13), Crohn's disease (CD) patients (n = 21), and healthy volunteers (n = 17). RESULTS: In the GC/MS-based profiling of amino acids and TCA cycle-related molecules, lower levels of 16 amino acids and 5 TCA cycle-related molecules were observed in the colonic lesion tissues of the UC patients, and the serum profiles of amino acids and TCA cycle-related molecules of the UC patients were different from those of the CD patients and healthy volunteers. CONCLUSIONS: Our study raises the possibility that GC/MS-based profiling of amino acids and TCA cycle-related molecules is a useful early diagnostic tool for UC.

Effect and safety of granulocyte-monocyte adsorption apheresis for patients with ulcerative colitis positive for cytomegalovirus in comparison with immunosuppressants.

BACKGROUND: Cytomegalovirus (CMV) infection exacerbates ulcerative colitis (UC) refractory to immunosuppressive therapies (IMT). However, the underlying UC remained active in some UC patients, despite the fact that CMV-DNA in colonic mucosa became negative after antiviral therapy. Therefore, new therapeutic strategies for UC patients concomitant with CMV infection in mucosa are required. AIMS: The aim of this study was to evaluate the effect and safety of granulocyte-monocyte adsorption apheresis (GMA) in UC patients positive for CMV infection after antiviral therapy. METHODS: From October 2003 to December 2008, 64 patients with UC refractory to IMT, including steroids and immunomodulators, were enrolled in this retrospective, observational, multicenter study, which was reviewed and approved by the Institutional Review Board of Kyoto University. CMV infection was investigated by 3 methods (histologic examination, CMV antigenemia, and polymerase chain reaction). We investigated the clinical outcomes of GMA and IMT after 2 weeks of treatment with ganciclovir. RESULTS: Thirty-one (48.4%) of 64 patients with UC refractory to IMT were positive for CMV. Of the 31 patients, 4 (12.9%) underwent colectomy. Twenty-seven patients (87.1%) underwent antiviral therapy. Of those 27 patients, 7 achieved remission following antiviral therapy alone. Of the remaining 20 patients who did not achieve remission despite the disappearance of CMV-DNA, 11 and 9 patients were treated with additional GMA (GMA group) and IMT (IMT group), respectively. Of 11 patients (GMA group), 9 achieved remission and 2 underwent colectomy. Out of the remaining 9 patients (IMT group), 4 achieved remission and 5 underwent colectomy. CMV-DNA was not detected in 11 patients after GMA, but it was detected again in all 5 patients of the IMT group who underwent colectomy. The total colectomy rate in UC patients positive for CMV was 35.5% (11/31). In addition, colectomy-free survival in the CMV relapse (+) group was estimated to be 12.9% at 65 months, while that in the CMV relapse (-) group was estimated to be 100% at 60 months. CONCLUSION: The colectomy ratio tends to be high in refractory UC patients with recurrent CMV reactivation or infection. Therefore, GMA might be a safe and effective treatment for UC patients positive for CMV because it does not induce CMV reactivation.

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.

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 Crohn's 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.

An open-label prospective randomized multicenter study shows very rapid remission of ulcerative colitis by intensive granulocyte and monocyte adsorptive apheresis as compared with routine weekly treatment.

OBJECTIVES: Granulocyte and monocyte adsorptive apheresis (GMA) has shown efficacy in patients with active ulcerative colitis (UC). However, with routine weekly treatment, it may take several weeks to achieve remission, and to date, the efficacy of a more frequent treatment schedule remains unknown. The aim of this study was to assess the clinical efficacy and safety of intensive GMA treatment in patients with active UC. METHODS: This was an open-label, prospective, randomized multicenter study to compare an intensive, two GMA sessions per week, with the routine, one GMA session per week. A total of 163 patients with mild-to-moderately active UC were randomly assigned to routine weekly treatment or intensive treatment. The maximum number of sessions of GMA permitted was 10. However, when patients achieved remission, GMA was discontinued. Remission rate at the end of the study, time to remission, and adverse events were assessed in both groups. RESULTS: Of the 163 patients, 149 were available for efficacy analysis as per protocol, 76 were in weekly GMA, and 73 were in intensive GMA. At the end of the study period, clinical remission was achieved in 41 of 76 patients (54.0%) in weekly GMA and in 52 of 73 patients (71.2%) in intensive GMA (P=0.029). The mean time to remission was 28.1+/-16.9 days in the weekly GMA treatment group and 14.9+/-9.5 days in the intensive GMA group (P<0.0001). Intensive GMA was well tolerated without GMA-related serious adverse side effects. CONCLUSIONS: Intensive GMA in patients with active UC seems to be more efficacious than weekly treatment, and significantly reduced the patients' morbidity time without increasing the incidence of side effects.

Hyperthermic stimulation of blood increases the immunological effects of granulocyte and monocyte adsorption in vitro: relevance to extracorporeal immunomodulation.

Extracorporeal granulocyte and monocyte/macrophage adsorption (GMA) using an adacolumn filled with cellulose acetate beads as GMA carriers selectively depletes excess and activated myeloid leucocytes from the circulation and has been used as a non-pharmacologic adjunct therapy in patients with inflammatory bowel disease (IBD). In this study we applied hyperthermic stimulation of blood during exposure to the GMA carriers with the aim of enhancing the release of anti-inflammatory substances from leucocytes. In blood from patients with Crohn's disease (CD) and healthy controls (HC), incubation with the carriers was associated with a striking increase in the release of interleukin-1 receptor antagonist (IL-1ra, a powerful anti-inflammatory cytokine) independent of hyperthermic stimulation, while in the blood from both CD and HC, the release of heat shock protein70 (Hsp70, a cytoprotective protein) was increased by two fold. The present data indicate that hyperthermic stimulation of blood at 43 degrees C or exposure to cellulose acetate carriers is a simple strategy to generate substances of therapeutic potential from blood, especially in patients with IBD. These observations are very interesting in the context of extracorporeal immunomodulation in patients with immune pathology.

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

SUMMARY: 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 corticosteroids 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 corticosteroids. 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.

Therapeutic leukocytapheresis for inflammatory bowel disease.

The inference that granulocytes and monocytes/macrophages (GM) are part of the immunopathogenesis of inflammatory bowel disease (IBD) and hence should be targets of therapy stems from observations of elevated, and activated GM in patients with IBD. The Adacolumn can selectively deplete GM by adsorption (GMA) and in patients with IBD, GMA has been associated with significant clinical efficacy together with sustained suppression of inflammatory cytokine profiles. Additionally, GMA depleted proinflammatory CD14(+)CD16(+) monocytes and was followed by an increase in CD4(+) T lymphocytes including the regulatory CD4(+)CD25(high+)Foxp3 phenotype. Hence, GMA could be a non-pharmacologic therapy for IBD with potential to spare steroids and other unsafe pharmacologic preparations.

Role of leukocytapheresis in the management of inflammatory bowel disease.

Ulcerative colitis (UC) together with Crohn's disease (CD) constitute idiopathic inflammatory bowel diseases (IBD) of the gut. The etiology of IBD is poorly understood, but autoimmune-disturbance has been suggested to play an important role in this incurable disease. Extracorporeal leukocyte removal therapy (ELRT) is the latest adjunct for IBD patient refractory to steroids, and it aims at suppressing immunological response by removing circulating leukocytes, especially granulocytes, from the blood stream. The present paper reviews the latest evidences in order to propose the current status of ELRT in the therapeutic strategy for IBD, especially for UC and CD. Clinical experience so far suggests that ELRT has superior efficiency as a non-pharmacological immuno-modulative therapy for steroid resistant UC patients before submission to colectomy. Moreover, ELRT has been proven to be a safe therapy compared with other current medications for severe UC.

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

BACKGROUND: Leukocytapheresis (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. METHODS: Fourteen 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. RESULTS: Clinical 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. CONCLUSIONS: These 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.

Poorly controlled ulcerative colitis treated by colectomy during remission induced by extracorporeal leukocyte removal therapy.

Both monocyte-granulocytapheresis (M-GCAP) and leukocytapheresis (LCAP) are categorized as extracorporeal leukocyte removal therapies (ECCTs). These therapies have been recognized as efficient adjuncts for patients of steroid-resistant ulcerative colitis (UC). This study aimed to consider the adaptation and the limitation of these new therapies from the clinical standpoint based on a case of UC showing strong resistance to high-dose continuous steroid injection therapy. The patient successfully underwent a scheduled colectomy while maintaining remission after applying M-GCAP and LCAP independently. Surgical therapy was chosen because of a deep ulcer in the patient's sigmoid colon, which was assumed to constitute a future risk for perforation. This case suggests that combining ECCT with steroid therapy can maintain such poorly controlled and high-risk UC patients safely for the scheduled colectomy while improving the prognosis by reducing the dosage of steroid efficiently prior to operation.

Detection of specific IgE antibodies to nafamostat mesilate as an indication of possible adverse effects of leukocytapheresis using nafamostat mesilate as anticoagulant.

The aim was to determine whether adverse effects of leukocytapheresis (LCAP) are related to nafamostat mesilate (NM) as an anticoagulant. Anti-NM IgE were detected in inflammatory bowel disease (IBD) patients who were administrated LCAP in our institute. Forty-nine patients (ulcerative colitis (UC)/Crohn's disease (CD): 30/19) were evaluated. Anti-NM IgE was measured by the ELISA method. Total IgE level and eosinophil count was tested concurrently. We retrospectively checked the presence of allergic symptoms and medications used concurrently with LCAP. Anti-NM IgE were present in six symptomatic patients (6/49; 12.2%) whose adverse effects were highly suspected to be from NM. However, 21 patients showed anti NM IgE-negative, in spite of the fact that their adverse effects were also highly suspected to be from NM. Through the detection of anti-NM IgE alone we could not estimate the relevance of NM as an anticoagulant to the adverse effects of LCAP.