Leukocytapheresis Therapy for Severe Ulcerative Colitis

Abstract: Severe attacks of ulcerative colitis are medical emergencies, and surgical treatment is indicated when glucocorticoid therapy is not effective. We have carried out an open clinical study of patients with severe attacks of ulcerative colitis to find out whether leukocytapheresis (LCAP) therapy can improve their outcomes. Nine patients were enrolled in this study. Seven of the nine patients had failed to respond to an intensive intravenous regimen before LCAP. LCAP was performed once a week for 4–5 weeks as intensive therapy using a leukocyte apheresis filter. Six of the 9 patients had an overall improvement after intensive therapy. Three patients reached the remission stage. The percentages of HLA-DR+, HLA-DR+ CD3+, HLA-DR+ CD4+, and HLA-DR+ CD8+ cells in the peripheral blood were higher in the responders than in the nonresponders, but there were no significant differences. In conclusion, LCAP therapy is useful for patients with severe attacks of ulcerative colitis, even those patients who failed to respond to glucocorticoid therapy.     

Predictive Factors of Response to Leukocytapheresis Therapy for Ulcerative Colitis

Abstract. Leukocytapheresis (LCAP) using a leukocyte removal filter was performed for 8 patients with moderate to severe ulcerative colitis (UC). Significant clinical improvement was attained in 5 of 8 patients (62.5%). All of them had been suffering from moderately active colitis and Received corticosteroid therapy. On the other hand, 3 patients with severely active disease and treated with little or no corticosteroid were resistant to LCAP. This result indicates that LCAP is an effective treatment for steroid-resistant cases of UC when combined with steroid therapy. LCAP alone, however, seems to have little efficacy for severely active UC.     

Leukocytapheresis with Leukocyte Removal Filter as New Therapy for Ulcerative Colitis

Abstract: Leukocytapheresis (LCAP) with a leukocyte removal filter column was administered for 45 patients with ulcerative colitis (UC). We evaluated changes in the leukocyte count and the differential percentages during LCAP. Cytokine production was assessed from each patient's peripheral mononuclear cells or monocytes. Flow cytometry was performed to assess the removal rates of activated cells and adhesion molecule positive cells by LCAP. Clinical improvement was recognized in 35 of 45 patients during intensive LCAP therapy, and it continued throughout maintenance therapy in 32 patients (71.1%). The leukocyte count was decreased to about 40% during the first 30 min, but it increased to approximately 170% at 20 min after the completion of LCAP. The concentration of tumor necrosis factor (TNF)α before LCAP in the effective group was higher than it was in either the ineffective group or the control group. Its level decreased to near normal range after LCAP. In the effective group, the concentrations of interleukin (1L)-1β, IL-2, interferon (IFN)γ, and IL-8 were near the normal upper limits before LCAP; however, they had decreased after LCAP. The concentration of IL-4 increased after LCAP. In the ineffective group, in contrast, the concentrations had been at or near normal before the initial LCAP treatment. Flow cytometry study revealed that LCAP could remove the activated cells and adhesion molecule positive cells more effectively. The clinical improvement and the changes observed before and after LCAP therapy suggest that LCAP is able to intervene in the causal mechanism(s) of UC.     

Ratio of Platelet Reduction is an Early Predictive Factor for the Effectiveness of Leukocytapheresis for Ulcerative Colitis Patients

Abstract: Leukocytapheresis is effective for ulcerative colitis (UC), and both peripheral leukocyte and platelet counts decrease during apheresis. While leukocyte counts increase and overshoot after finishing the apheresis procedure, platelet reduction continues even after apheresis. The aim of this study is to elucidate the impact of the overshoot of leukocyte and continuous platelet reduction on the efficacy of leukocytapheresis for UC. Leukocyte and platelet counts before and one hour after each leukocytapheresis session of 43 UC cases were examined (31 entered remission, but 12 did not). The correlation between the efficacy of leukocytapheresis and leukocyte overshoot or platelet reduction was examined. The average increase ratio of leukocytes in the initial five sessions of the responders was not significantly different from that of the non-responders (95% vs. 92%, P = 0.28). In contrast, the average decrease ratio of platelets in the initial five sessions of the responders was significantly higher than that of the non-responders (34% vs. 27%, P = 0.0041). Moreover, the platelet reduction at the third and fourth apheresis sessions in the responders was remarkably greater than that in the non-responders (33% vs. 20%, P = 0.0018). The efficiency of platelet reduction could be a predictive factor for the efficacy of leukocytapheresis.     

Feasibility of Five Days of Consecutive Leukocytapheresis for the Treatment of Ulcerative Colitis: A Preliminary Study

Abstract: Leukocytapheresis (LCAP) has been applied for the treatment of steroid refractory ulcerative colitis (UC). A standard protocol employs one or two sessions of LCAP per week. Our aim was to determine whether five consecutive LCAP sessions can be performed safely and effectively for UC patients. Six patients with moderately active UC were enrolled. The patients received five days of consecutive LCAP in which the processing volume of blood was limited to 1500 mL per session. The hemoglobin levels in each patient gradually decreased, and the platelet count by the fifth session reached half of the value before the first session. The clinical activity index in two patients improved daily, and they went into remission with an improvement in the colonic endoscopic appearance after one week. This preliminary study showed that five consecutive LCAP sessions are safe and feasible for active UC patients. The therapeutic efficacy and suitable patients for this treatment protocol should be confirmed by further studies.     

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.     

Predictors of Clinical Response to Systemic Steroids in Active Ulcerative Colitis

Although systemic steroids remain as the gold standard for the treatment of acute moderate to severe active ulcerative colitis (UC), 15–57% of patients do not achieve clinical remission. We sought to identify clinical, biological, or radiologic predictive factors of response to steroid treatment in acute UC attacks. The medical records of 39 consecutive patients admitted for an acute attack of UC and treated with systemic steroids, were reviewed. Epidemiologic, demographic, and clinical data at baseline and clinical data 3 days after starting steroid treatment were registered. Treatment failure was defined as the need of IV cyclosporine or colectomy before hospital discharge. Twenty-four patients (62%) responded to systemic steroids. Thirteen out of the 15 nonresponders, were treated with IV cyclosporine, avoiding colectomy in 7 cases (54%). More than six bowel movements per day at the third day of treatment, blood in stools in the third day of therapy, extensive UC, and the presence of malnutrition were associated with steroid treatment failure, but only blood in stools (P=.04), and more than six movements per day (P=.012) after 3 days of treatment, were found to be independent predictive factors of steroid refractoriness. In conclusion, clinical evaluation 3 days after starting systemic steroids seems to be the best tool to assess short-term prognosis.     

Effective Maintenance Leukocytapheresis for Patients with Steroid Dependent or Resistant Ulcerative Colitis

Abstract: We prospectively examined the effect of leukocytapheresis (LA) on the maintenance of remission in 7 patients with ulcerative colitis (UC) who were initially refractory to corticosteroid therapy (steroid resistant or steroid dependent). The patients with refractory UC had been in remission due to LA (induction LA) in combination with the steroid therapy. They were then treated with LA once or twice a month for the purpose of maintaining remission (maintenance LA). The maintenance LA was performed by either a centrifuge method in 5 patients or a polyester adsorbent column method in 2 patients. Steroid dosage was gradually tapered as little as possible without recurrence based on clinical and/or colonoscopical judgments. Four patients were maintained in remission without steroids over 12 months. Recurrence was observed in 3 patients at 3, 3, and 6 months after the beginning of the maintenance LA, respectively. Two of the 3 patients were again conducted to remission by the second induction LA and maintained in remission by the second maintenance LA. Two patients finally underwent total colectomy because of recurrence of UC in a severe form. It is concluded that the maintenance LA therapy might be effective in some patients with steroid dependent or resistant UC for the maintenance of remission without steroids.     

Safety and Tolerability of Nafamostat Mesilate and Heparin as Anticoagulants in Leukocytapheresis for Ulcerative Colitis: Post Hoc Analysis of a Large‐Scale,Prospective, Observational Study

Nafamostat mesilate is the first anticoagulant of choice for leukocytapheresis (LCAP) with a Cellsorba E column for treating ulcerative colitis (UC). However, because of complications, mainly due to allergy to nafamostat mesilate, heparin may be used as a substitute. To evaluate the safety and tolerability of nafamostat mesilate and heparin as anticoagulants in LCAP for UC, we conducted post hoc analysis of data from a large‐scale, prospective, observational study of LCAP, which was conducted at 116 medical facilities in Japan between May 2010 and December 2012. Of 832 patients included in this analysis, nafamostat mesilate and heparin were used in 676 (81.3%) and 113 (13.6%), respectively. There were no significant differences in the incidence of adverse reactions (8.6% vs. 7.1%) and intrafilter pressure increases (12.7% vs. 16.8%) between the nafamostat mesilate and heparin groups. Adverse reactions of hemorrhage or blood pressure decreases associated with heparin use were not observed. There were no significant differences in rates of clinical remission (69.1% vs. 68.1%) and mucosal healing (62.9% vs. 63.6%) between the nafamostat mesilate and heparin groups. Thus, the safety and tolerability were comparable in the nafamostat mesilate and heparin groups, indicating that both nafamostat mesilate and heparin can be well tolerated as anticoagulants in LCAP for UC.     

A Case Report: First Case of Filtration Leukocytapheresis for a Patient of Aortitis Syndrome Associated with Ulcerative Colitis

Abstract: An 18‐year‐old woman was treated with leukocytapheresis (LCAP) for her combined ulcerative colitis (UC) and aortitis syndrome (AS). Because a close relationship between these two diseases has been suspected based on their etiological and/or pathological findings, we had hypothesized that LCAP, which has satisfactory effects on inflammatory bowel disease such as UC and Crohn's disease might be effective for both her UC and her AS. After informed consent, LCAP therapy was performed once a week for a total of 7 times. Endoscopic remission of the UC was observed. Even though there were no significant improvements in her subjective symptoms of AS such as side‐neck pain and dizziness, objective evidence of improvement was obtained when the patient's condition was compared before and after LCAP by angiography, angio‐magnetic resonance imaging, and the plethysmogram of her fingertips. These results suggest that LCAP may be valuable as a new adjunct therapy for AS.     

A Retrospective Search for Predictors of Clinical Response to Selective Granulocyte and Monocyte Apheresis in Patients With Ulcerative Colitis

Recently, selective granulocytapheresis (Adacolumn) has appeared as a new treatment for patients with inflammatory bowel disease. This study sought to determine predictors of response to this new nonpharmacologic mode of therapy by retrospectively evaluating 28 patients who received granulocytapheresis after experiencing active ulcerative colitis (UC). Between April 2000 and March 2004, 28 consecutive patients received granulocytapheresis for active UC with the Adacolumn, which is filled with cellulose acetate beads as the column leukocytapheresis carriers; the carriers adsorb granulocytes, monocytes/macrophages, and a small fraction of lymphocytes (FcγR and complement receptors bearing leukocytes). Each patient could receive up to 10 Adacolumn sessions, at 2 sessions per week. In 2004, clinical response was retrospectively evaluated. Seven days after the last Adacolumn session, 20 of 28 patients had remission (colitis activity index [CAI] ≤4) including all 8 patients who had their first UC episode. The mean duration of UC in the 8 first episode cases was 3.4 months compared with 40.2 months for all 28 patients and 65.4 months for the 8 nonresponders. The response to Adacolumn was independent of basal CAI. The 8 nonresponders were given conventional medication (CM) or cyclosporine (CsA) if the former failed. Two responded to CM, 3 to CsA, and 3 underwent colectomy. First UC episode and short disease duration appear good predictors of response to granulocytapheresis. Selective granulocytapheresis might be an effective first-line treatment.     

溃疡性结肠炎的并发症

溃疡性结肠炎是慢性复发性疾病,其并发症直接影响该病的预后。本文以1993年全国慢性非感染肠道疾病学术研讨对本病会制定的诊断标准,对北京协和医院1974年1月至1995年1月溃疡性结肠炎住院和门诊病人483例进行了分析,着重探讨并发症的种类与疾病严重程度的关系以及对预后的影响。本组病人并发症的发生率为6.2％(30/483)。重症患者并发症的发生率为24.3％。并发症的种类,按其发生频率的多少依次排列如下:严重电解质紊乱(9.01％)、肠梗阻(8.11％)、人出血、菌群失调,肠穿孔(各3.60％)、败血症(2.70％)、肠瘘、癌变(各1.80％).中毒性肠扩张(0.90％)。本组溃疡性结肠炎早期并发症,除电解质紊乱外尚有大出血、中毒性肠扩张、败血症多见,随病程迁延则以肠梗阻、肠瘘、肠穿孔和癌变为主。并发症多发生于重度活动期(24.3％);其中病变累及全结肠为82％,左半结肠仅为18％。住院病人中该病病死率为6.08％,并发症组为23.08％,高于无并发症组(2％)。因此,对溃疡性结肠炎的并发症,要提请广大临床医师注意:需早期诊断,积极治疗,以减少病死率。     

溃疡性结肠炎的并发症

目的:探讨溃疡性结肠炎并发症的种类与疾病严重程度的关系以及对预后的影响.方法:以1993年全国慢性非感染肠道疾病学术研讨会制定的对本病的诊断标准,分析了北京协和医院1974年1月至1995年1月溃疡性结肠炎住院和门诊病人483例.结果:本组病人并发症的发生率为6.2%(30/483).重症患者并发症的发生率为24.3%.并发症的种类按其发生频率的多少依次为:严重的电解质紊乱(9.01%)、肠梗阻(8.11%)、大出血、菌群失调、肠穿孔(各3.6%)、败血症(2.70%)、肠瘘、癌变(各1.80%)、中毒性肠扩张(0.90%).本组溃疡性结肠炎早期并发症,除电解质紊乱外尚有大出血、中毒性肠扩张、败血症多见,随病程迁延则以肠梗阻、肠瘘、肠穿孔和癌变为主.并发症多发生于重度活动期(24.3%);其中病变累及全结肠为82%,左半结肠仅为18%.住院病人中该病病死率为6.08%,并发症组为23.08%,高于无并发症组(2%).结论:溃疡性结肠炎的并发症需早期诊断,积极治疗以减少病死率.     

Meta-Analysis of the Placebo Response in Ulcerative Colitis

Purpose The placebo response rate in randomized controlled trials (RCTs) in ulcerative colitis (UC) varies from 0 to 76%. The aims of this study were to quantify the pooled placebo response rate and identify the factors affecting it. Methods We performed a meta-analysis of 110 RCTs carried out between 1955 and 2005 and published in English. Regression analysis was used to identify factors significantly modifying placebo response. Results The pooled placebo remission rate was 23% (95%CI: 18.4–28%) and the pooled placebo improvement rate was 32.1% (95%CI: 28.1–36.3%). Multivariate analysis showed that the country where the study was performed (P = 0.025 for placebo remission and P = 0.0083 for placebo response rates) significantly influenced the placebo remission and response rates. Conclusion Placebo remission and response rates in RCTs of UC are highly variable and are significantly influenced by the country in which the RCT is performed.     

缺血性结肠炎与溃疡性结肠炎临床表现及内镜特点的对比分析

目的 比较缺血性结肠炎(IC)与溃疡性结肠炎(UC)临床及内镜表现的差异,研究对两者的鉴别以利对其的诊断和治疗.方法 回顾分析2007年1月～2010年8月诊断为IC 30例和UC 40例患者的资料,重点分析两者在年龄分布、性别构成、病程、基础疾患、临床和内镜表现及病理诊断的异同点.结果 IC组和UC组在年龄分布、病...     

Preoperative Steroid-Related Complications in Japanese Pediatric Patients With Ulcerative Colitis

Purpose This study was designed to clarify a limit for steroid therapy in patients with ulcerative colitis through analyzing the preoperative major steroid-related complications and to define when alternative therapies, including surgery, should be performed in pediatric ulcerative colitis patients. Methods The medical records of 28 pediatric and 57 adult patients with ulcerative colitis who underwent total proctocolectomy and ileal J-pouch-anal anastomosis were reviewed. The relationship between the preoperative dose of glucocorticoids and major steroid-related complications, as well as the surgery variables, was evaluated. Results Significantly higher incidences of growth retardation, osteoporosis, glaucoma, and cataracts were noted in pediatric patients than in adult patients. In pediatric patients, major steroid-related complications occurred at a significantly lower preoperative total dosage of glucocorticoids/body weight (mg/kg) or preoperative total dosage of glucocorticoids/body surface area (mg/m²) than in adult patients. A similar surgical procedure was performed in both pediatric and adult patients. The presence of major steroid-related complications can lower a patient's long-term quality of life. Conclusions Evidence-based guidelines for the recommended dose ofglucocorticoids according to body weight or body surface area are needed. To allow patients to feel well and maintain a good quality of life, early introduction of alternative treatments, including surgery, should be considered.     

Lower Prevalence of Diverticulosis in Patients with Ulcerative Colitis

Purpose Colonic diverticulosis is characterized by abnormal thickening of the bowel wall, associated with luminal overpressure and increase of sigmoid contractility. However, patients with ulcerative colitis show chronic inflammatory alterations determining a reduction of both bowel wall muscle tone and contractility. Thus, we could presume ulcerative colitis and colonic diverticulosis as two pathophysiologically and mutually excluding diseases. This study was designed to evaluate the prevalence of colonic diverticulosis in patients with ulcerative colitis compared with a control endoscopic population. Methods We prospectively analyzed the prevalence of colonic diverticulosis in 85 patients, older than aged 45 years, with known ulcerative colitis compared with that in 85 age/gender-matched patients without colitis. All patients underwent pancolonoscopy with ulcerative colitis and colonic diverticulosis diagnosis made by endoscopy and histopathology. The patients with ulcerative colitis also were divided in three subgroups according to the age at diagnosis (<30 years, 30–45 years, >45 years) and extension of disease (sigmoiditis, left colitis, extensive colitis). Results Colonic diverticulosis was present in 7 of 85 patients with and in 24 patients without ulcerative colitis (8.2 vs. 28.2 percent; P < 0.001; relative risk, 3.4; 95 percent confidence interval, 1.56–7.52). All seven patients with both diseases were diagnosed with ulcerative colitis when older than age 45 years. No differences were found between the two groups in terms of extension of diverticula. Conclusions Patients with ulcerative colitis show a significantly lower prevalence of colonic diverticulosis, with this finding probably reflecting the motor alterations caused by chronic bowel wall inflammation. In the patients affected by ulcerative colitis with late onset of the disease, the reduced prevalence of colonic diverticulosis is not evident.     

昆明市379例溃疡性结肠炎患者治疗分析

目的 回顾性调查昆明市近10年来溃疡性结肠炎(UC)住院病例的资料,以进一步了解昆明市UC患者的治疗状况.方法 选取昆明市1998年1月～2007年3月期间7家大型综合医院379例住院的炎症性肠病患者作为调查对象.诊断均符合2007年中华医学会消化病学分会的UC诊治标准,分析UC患者的治疗状况.结果 379例UC患者有...     

Leukocytapheresis Using a Leukocyte Removal Filter

Abstract: Leukocytapheresis (LCAP) long has been investigated with a leukocyte removal filter for the treatment of various kinds of autoimmune related and inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, and so on. A lot of patients with such diseases have been reported to respond to LCAP. Asahi Medical Co. has developed the leukocyte removal filter Cellsorba and an extracorporeal treatment unit Plasauto LC so that the LCAP technique can be performed easily with a high performance filter, easy attachment of the blood circuit tubing set, and automatic operation. Cellsorba E has been listed as a medical device reimbursed by Japanese national health insurance to be used in LCAP for active ulcerative colitis since October 2001. Although the effective mechanism of LCAP is still controversial, the removal of activated leukocyte from the peripheral blood and the reaction by blood contacting materials in Cellsorba can be triggers of the immunomodulation for the treatment of immune disorder. This review introduces the development of LCAP technologies and several reports on therapeutic results.