Reduction of Dendritic Cells by Granulocyte and Monocyte Adsorption Apheresis in Patients with Ulcerative Colitis

The influence of the granulocyte/monocyte apheresis (GMCAP) on cell populations participating in mechanisms of tolerance, e.g. dendritic cells (DCs), is still not very clear. In a first step, we aimed to investigate changes in the DC population of patients suffering from ulcerative colitis (UC) (n = 13) compared to healthy subjects (n = 9). In a second step, we studied the changes in peripheral DCs in a small group of patients with active UC before and after Adacolumn apheresis (n = 7). For this purpose, plasmacytoid and myeloid DCs and their maturation markers CD40, CD80, and CD86 were measured using four-color flow cytometry in the peripheral blood. After apheresis, and in acute flare-ups, we identified a significantly lower number of lymphocytes, plasmacytoid, and myeloid DCs. In conclusion, the additional removal of peripheral DCs by GMCAP, which otherwise would contribute to the inflammatory process in the gut, may lead to a higher tolerogeneic status towards luminal antigens.     

Appendiceal Involvement in Patients with Ulcerative Colitis

Abstract: There have been few case reports of ulcerative colitis with appendiceal involvement because the appendix has generally received little attention in ulcerative colitis patients. We encountered an inflammatory appendiceal lesion in a patient with ulcerative colitis, which piqued our interest in endoscopic findings of the appendix in these patients. Subsequently, we carefully observed the appendiceal orifice during colonoscopy in patients with ulcerative colitis. From December 1994 to December 1996, 44 patients with ulcerative colitis underwent colonoscopy in Nagaoka Red Cross Hospital. Among these 44, there were three in whom it had not been possible to observe the cecum. During this period, we encountered inflammatory appendiceal lesions in eight cases. Therefore, 20% (8/41) of patients with ulcerative colitis undergoing colonoscopy had appendiceal involvement. Five of these eight patients showed a colonoscopically normal cecum, such that appendiceal involvement thought to be a colonoscopic skip lesion was seen in five (12%: 5/41). There was only one case who had an appendiceal lesion without a microscopically diseased cecum. Appendiceal involvement may be frequent in ulcerative colitis. We thus recommend that endoscopists meticulously examine the appendiceal orifice during colonoscopy in patients with ulcerative colitis.     

Relationship Between Fecal Calprotectin, Intestinal Inflammation, and Peripheral Blood Neutrophils in Patients with Active Ulcerative Colitis

Active ulcerative colitis (UC) is associated with elevated granulocytes and monocytes/macrophages (GM) which show activation behavior and increased survival time. Further, fecal calprotectin (a stable neutrophil protein) level parallels intestinal inflammation and can predict UC relapse. Since GM are major sources of inflammatory cytokines and chemokines, they are suspected to have roles in the initiation and perpetuation of UC. Our objective was to investigated relationships between peripheral blood (PB) neutrophils, calprotectin, and UC disease activity. Full PB and calprotectin were determined in 69 healthy controls and 31 patients with UC, then 7 randomly selected patients received GM adsorptive apheresis (GMA) with Adacolumn, 10 sessions of 60-min duration each. Patients with UC had higher neutrophil counts (P < 0.001), but lower lymphocyte counts (P < 0.001) compared with controls. Further, fecal calprotectin levels showed a correlation with UC clinical activity index (CAI; P < 0.001) and mucosal inflammation (P < 0.001). Following GMA, there were falls in neutrophils (P < 0.02), CAI (P < 0.02) and calprotectin (P < 0.02). In conclusion, GM appear to contribute to intestinal inflammation and UC activity and reduction of these cells by GMA should benefit patients with active UC. Further, the correlations among calprotectin, UC activities, and PB neutrophils should serve as the basis for preemptive actions to control this disease.     

Functional Alterations of the Microflora in Patients with Ulcerative Colitis

Benno P, Leijonmarck C-E, Monsen U, Uribe A, Midtvedt T. Functional alterations of the microflora in patients with ulcerative colitis. Scand J Gastroenterol 1993;28:839-844.

The aim of the study was to examine microflora-associated characteristics in patients with inactive ulcerative colitis, receiving sulphasalazine, in relation to the spread of the disease. The conversion of cholesterol to coprostanol, the production of urobilinogen, and the degradation of tryptic activity (FTA) and β-aspartylglycine were measured in faecal samples from patients with proctitis or left-sided or total ulcerative colitis and in age- and sex-matched controls. No significant differences in the results were observed in patients with various degrees of extension of inflammatory bowel disease. However, the coprostanol ratio and the urobilinogen level were lower and the FTA was higher in patients with colitis than in the controls (p < 0.05). Beta-aspartylglycine was not found in any faecal sample. The results indicate that patients with ulcerative colitis taking sulphasalazine have a microflora with abnormal metabolic characteristics.     

Granulocyte and Monocyte Adsorptive Apheresis for Ulcerative Colitis in a Patient with Low Bone Mineral Density Due to Fanconi-Bickel Syndrome

Systemic steroid is required for the exacerbation of ulcerative colitis (UC), although its administration should be avoided in patients with a low bone mineral density (BMD) exacerbated by side effects of steroids. We herein report the successful induction of remission in an UC case with a low BMD due to Fanconi-Bickel syndrome-or glycogen storage disease type XI-using granulocyte and monocyte adsorptive apheresis (GMA). For a 43-year-old woman with a BMD of 50% the young adult mean, GMA was performed 2 times a week for a total of 10 times. GMA might be a steroid-free treatment option for UC patients with a low BMD.     

Serum Transglutaminase Correlates with Endoscopic and Histopathologic Grading in Patients with Ulcerative Colitis

Factor XIIIa, a circulating form of transglutaminase, plays a key role in intestinal mucosal repair. We found that transglutaminase levels are decreased in serum of patients with inflammatory bowel diseases and demonstrated in a rat model of chronic colitis that serum transglutaminase is closely related to the severity of intestinal damage. We aimed, therefore, to correlate serum transglutaminase levels with standard endoscopic and histopathologic grading systems in patients affected by ulcerative colitis (UC). In 249 patients with UC, we assayed serum transglutaminase activity by a radioenzymatic method and measured clinical activity index (CAI) according to modified Rachmilewitz's criteria. In a subset of 82 patients undergoing colonoscopy, endoscopic and histologic indices were studied. Biopsy specimens were also taken from 28 patients to measure myeloperoxidase (MPO) as a marker of mucosa inflammation. Serum transglutaminase levels significantly correlated with the CAI scoring (r = –0.63; P < 0.01); likewise serum transglutaminase showed the best correlation with endoscopic (r = –0.71; P < 0.001) and histologic (r = –0.79; P < 0.001) scores. Myeloperoxidase activity was significantly higher in patients with active UC than those in remission (P < 0.01), showing a significant correlation with serum transglutaminase levels (r = –0.68; P < 0.01). Immunohistochemistry showed factor XIIIa localization in the extracellular matrix of damaged mucosa. In conclusion, these results suggest that transglutaminase assay can be useful in managing UC as a serological, noninvasive indicator of intestinal mucosal status.     

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.     

Granulocyte and Monocyte Adsorption Apheresis Therapy Modulates Monocyte-Derived Dendritic Cell Function in Patients With Ulcerative Colitis

The aim of this study was to elucidate the molecular mechanisms responsible for the therapeutic effects of granulocyte and monocyte adsorption apheresis (GMA). We investigated the alterations in circulating monocyte subsets and monocyte-derived dendritic cell (moDC) function after GMA therapy in ulcerative colitis (UC) patients. Eighteen patients with UC were enrolled: 14 patients were responders, and 4 patients were non-responders. Peripheral venous blood was obtained within 5 min before and 5 min after GMA therapy. Flow cytometric analysis for monocyte markers (CD14/CD16) was then performed. Monocyte-derived dendritic cells were obtained and alterations in their phenotype were analyzed by flow cytometry. Their function was also analyzed in a mixed lymphocyte reaction assay between allo-naïve T lymphocytes. Flow cytometric analysis for intracellular interferon (IFN)-γ (T-helper 1 cells) and interleukin (IL)-4 (T-helper 2 cells) was then performed for the stimulated T lymphocytes. In patients who responded to GMA, the average numbers of monocytes, especially CD16⁺ monocytes, were significantly decreased after therapy (P < 0.05). In responders, post-GMA moDCs expressed significantly lower CD80 and B7-DC, which are one of the stimulation and maturation markers of dendritic cells, compared to pre-GMA moDCs. CD83, CD86 and human leukocyte antigen-DR also showed a tendency to decrease. In responders, naïve T lymphocytes stimulated with post-GMA moDCs produced significantly less IFN-γ and IL-4 compared to those stimulated with pre-GMA moDCs. The results of our study show that some of the immunosuppressive effects of GMA therapy may be associated with the modulation of monocyte subsets and moDC function.     

Colorectal Carcinomas Following Ulcerative Colitis in Japanese Patients

Abstract: Colorectal carcinomas occuring following ulcerative colitis in Japanese patients discussed in the literature were analyzed in order to review their characteristics. 1) Of the 74 cases reported from 1962 to November 1989, 29 were males and 45 were females. The sex differences in Japanese ulcerative colitis were almost 1: 1, so females with colorectal carcinomas occured more often than males. 2) Male patients had a bimodal peak in their 30's and 40's, while female patients had the peak in their 40's and 50's. More colorectal carcinomas were found among younger people than in the general population. 3) Universal colitis was the most common type of colorectal cancer occuring following ulcerative colitis. 57 patients out of 74 were classified into this type. 4) The duration of the disease prior to the diagnosis of colorectal cancer was generally 10 years or longer. 5) The rectum was the commonest site of cancer, and was seen in 44 cases out of 74. Rectosigmoid colon carcinomas occurred in 61 of 74 cases. 6) Histologically, colonic malignancy associated with ulcerative colitis was an adenocarcinoma, displaying a wide spectrum of differentiation. Poorly differentiated (4 males and 6 females) and signet ring cell carcinoma (3 males and 5 females) were also reported. 7) The so-called type 4 tumor occurred in 3 males and 6 females out of a total of 74 cases. This type of tumor is usually rare in colorectal cancer. 8) Most of the patients with early carcinomas had suffered from ulcerative colitis for more than 15 years and the characteristics of their macroscopic appearance were protruded lesions. 9) Foci of dysplasia accompanied carcinoma in as many as 80% of the Japanese cases reported. (56 out of 74 cases) Based on these, we should take consideration that: 1) Patients with pancolitis lasting more than 10 years whose forms are chronically active or intermittently active should be recognized as a high-risk group. 2) Full colonoscopy every one or two years may be sufficient to find dysplasia as well as carcinoma even if the condition of disease is stable. 3) Protruded lesions should be biopsied to detect early cancer as well as dysplasia on colonoscopy. 4) A change in the disease condition, i. e. rectal bleeding, weight loss and a change of bowel habits should not be mistaken for an exacerbation of colitis and should be investigated without fail.     

Significance of Periappendiceal Inflammation in the Patients with Distal Ulcerative Colitis

Abstract: To study the clinical significance of periappendiceal inflammation in patients with distal ulcerative colitis, we reviewed sixteen patients who underwent total colono-scopy from January in 1995 to September in 1998 in our department, and compared the clinicopathological findings in the patients with and without this lesion. Four of sixteen patients (25%) had periappendiceal inflammation. The patients with periappendiceal inflammation tended to be younger and had a significantly shorter duration of disease. Two of the patients with periappendiceal inflammation were one-attack-only type and 2 cases were relapse-remitting type, while all the other cases without this inflammation were relapse-remitting type. The periappendiceal lesion was observed on initial colono-scopy in 3 of the 4 patients. Severity was mild in all patients with periappendiceal inflammation while 4 cases were moderate and 1 case was severe in the other patients. The periappendiceal lesion and main lesion of the patients with periappendiceal inflammation were histological grades 2 or 3, while the main lesion varied up to grades 4 or 5 in the other patients. These findings suggested that distal ulcerative colitis patients with periappendiceal inflammation may have a relatively mild disease course. In addition, periappendiceal inflammation was thought to develop in the early stage of the disease course. (Dig Endosc 1999; 11: 119–124)     

Primary Sclerosing Cholangitis in Patients with Ulcerative Colitis

The prevalence of primary sclerosing cholangitis (PSC) in patients with ulcerative colitis (UC) attending the Depts. of Medical and Surgical Gastroenterology, Aalborg Hospital, during a 12-year period, was determined. All patients with an alkaline phosphatase (ALP) value above the normal range were investigated. Of 305 patients with UC, 24 patients had elevated ALP values, and 11 of these (3.6% of the study population), 4 males and 7 females, were found to have PSC by direct cholangiography. In five patients the disease worsened (two patients died of cholangiocarcinoma), in four it was stationary, and in two patients the disease improved during a mean observation period of 6 years. No differences in location of disease, disease activity, or duration of disease were found between patients with UC and PSC and patients with UC without PSC. The ALP values were raised to a mean of 3.7 times the upper normal limit (observed range, 1.5-5.5 times the upper normal limit). Aspartate aminotransferase was moderately elevated in most patients, but no other abnormal biochemical liver test results were observed at onset. The results of our study indicate that PSC is the major cause of raised ALP values in patients with UC; thus cholangiography should be performed in UC patients with unexplained elevated ALP levels. A prognostic indicator is needed to predict the individual prognosis and to determine the optimal timing of liver transplantation.     

Clinical Response Is Associated with Elevated Plasma Interleukin-1 Receptor Antagonist During Selective Granulocyte and Monocyte Apheresis in Patients with Ulcerative Colitis

Depletion of granulocytes and monocytes (GM) by selective apheresis (GMA) with an Adacolumn exerts an anti-inflammatory effect in patients with ulcerative colitis (UC) or rheumatoid arthritis. However, the mechanism of the anti-inflammatory effect of GMA is not fully understood yet. We investigated the effect of GMA on the plasma concentration of interleukin-1 receptor antagonist (IL-1ra), a potent anti-inflammatory cytokine. Twenty-six patients with active UC received GMA at one session per week for 5 consecutive weeks. Clinical response was defined as Δclinical activity index (ΔCAI=CAI at entry – CAI at post)≥4, while clinical remission was defined as CAI≤4. Twenty-one of twenty-six patients (80.8%) responded to GMA. In the first session, plasma from responder patients showed a significant (P < 0.01) increase in IL-1ra in the Adacolumn outflow. In contrast, there was no change in IL-1ra in nonresponders. In conclusion, release of IL-1ra during GMA might be one mechanism of clinical efficacy associated with this therapy.     

Total Antioxidant Capacity of Colon in Patients with Chronic Ulcerative Colitis

It has been proposed that oxidative stress is involved in the pathophysiology of ulcerative colitis. We have reported the depletion of the nonenzymatic antioxidant, glutathione, in colon from active and inactive ulcerative colitis. The colon contains several biochemically linked antioxidant systems. We hypothesized that diminished total antioxidant capacity in active ulcerative colitis would be associated with increased colonic lipid peroxidation. This study was designed to determine total antioxidant capacity and lipid hydroperoxide levels using colon obtained at surgery from controls (N = 16; 4 females, 12 males; mean age 70 years), and active and inactive ulcerative colitis (N = 15; 3 females, 12 males; mean age 39). Total antioxidant capacity of control colon was higher in muscularis externa compared to the mucosal–submucosal layer (P < 0.05). There were no differences in colonic total antioxidant capacity or lipid hydroperoxide levels comparing control colon to inactive and active ulcerative colitis. The results did not support depletion of tissue total antioxidant capacity by free radicals. Depletion of glutathione in ulcerative colitis may be a specific disorder rather than a secondary defect attributable to global oxidative stress. Nonspecific antioxidant supplements appear unlikely to be beneficial in the treatment of ulcerative colitis.     

Efficacy and Safety of Adsorptive Granulocyte and Monocyte Apheresis in Elderly and Pregnant Patients With Ulcerative Colitis

In patients with active ulcerative colitis (UC), adsorptive granulocyte/monocyte apheresis (GMA) is expected to promote remission. We conducted a retrospective cohort study to evaluate the efficacy and safety of GMA in patients with active UC. Twenty‐one UC patients including five pregnant or lactating mothers and four elderly patients (aged >60 years) received up to 10 GMA sessions. UC severity was evaluated at baseline and after GMA therapy according to Lichtiger's Clinical Activity Index (CAI). We defined clinical remission as CAI ≤4. Overall, the median CAI score after GMA therapy had decreased from 9 to 4 (P < 0.001). The clinical remission rate was 62%, but in the elderly and pregnant or lactating mothers, the remission rates were 100% and 60%, respectively. No severe adverse effects were seen in this study. Our results may support GMA as an effective and safe treatment for active UC patients, including elderly patients and pregnant cases.     

Increased Protein Tyrosine Kinase Activity of the Colonic Mucosa in Ulcerative Colitis

The protein tyrosine kinase (PTK) activity was measured in the inflamed colonic mucosa of 12 patients with ulcerative colitis and in the normal colonic mucosa of 12 control patients with colon cancer. The specific PTK activity in the particulate fraction obtained from ulcerative colitis mucosa was significantly increased compared with that of normal mucosa (5.10 ± 0.60 pmol/min/mg versus 2.12 ± 0.44 pmol/ min/mg protein; p < 0.05). Inflamed ulcerative colitis mucosa also showed a significantly higher total PTK activity in the particulate fraction than normal mucosa (2.60 ± 0.42 pmol/min/g versus 0.91 ± 0.16 pmol/min/g tissue; p < 0.05). Mucosal samples from ulcerative colitis patients were divided into those with mild and those with severe inflammation on histologic examination (n - 6 each). The particulate PTK activity of severely inflamed mucosa was significantly higher than that of mildly inflamed mucosa (p < 0.05). These results suggest that colonic inflammation in ulcerative colitis is associated with alterations in cellular PTK activity.     

Prediction of Short-Term Outcome for Patients with Active Ulcerative Colitis

We report results of a retrospective chart review to evaluate factors predicting short-term outcome of patients with ulcerative colitis treated by corticosteroids. Between January 1992 and December 1997, we treated 71 patients with ulcerative colitis (44 with severe and 27 with moderately severe disease). Forty-nine patients were treated by conventional prednisolone therapy and 22 patients by steroid pulse therapy. There were no differences in clinical or endoscopic improvement between the two treatments. Clinical examination showed that 41 patients entered remission, 17 patients improved, and 13 patients did not respond. Endoscopically, 26 patients entered remission, 30 patients improved, and 15 patients did not respond. Extent of disease, type of disease (first attack, relapsing, or chronic active type), and endoscopic findings were factors useful in predicting short-term outcome of medical treatment.     

Elective Surgery for Ulcerative Colitis: Colectomy in 158 Patients

Chronic ulcerative colitis was treated by elective colectomy in 158 patients. Proctocolectomy and ileostomy was performed in 140 patients and colectomy and ileorectal anastomosis (CIRA) in 18 patients. The operative mortality was 2.5%. and postoperative complications, mostly infections, occurred in 38%. Within a 2-year postoperative period another 1.9% of the patients died, and late complications occurred in 18%. Colorectal carcinoma was present at the time of colectomy in 5.1% and developed some years later in another two patients primarily operated on with CIRA. Half of the cancer patients died of malignancy. Most extracolic complications, present in 25% of patients before colectomy, regressed or disappeared after operation. Half of the patients operated on with CIRA needed to have their rectum removed within a few years because of cancer or proctitis, and few of the rest had lasting relief of symptoms.     

HLA-DR Expression and Disease Activity in Ulcerative Colitis

In 12 patients with active ulcerative colitis (UC) the rectal epithelial cells were analyzed for HLA-DR antigens by an immunohistochemical technique. The clinical, rectoscopic, and histologic stages were also determined. The investigations were carried out at the beginning of the study and 2 weeks and 3 months later. The rectal epithelial cells were HLA-DR-positive in all patients at the first two examinations. After 3 months five patients had changed to an HLA-DR-negative stage, whereas the other seven patients remained HLA-DR-positive. Closer analyses showed that expression/nonexpression of HLA-DR antigens on rectal epithelial cells of patients with UC could not be predicted from the clinical, rectoscopic, or histologic findings. HLA-DR expression is normally restricted to immunocompetent cells. The presence of HLA-DR antigens on epithelial cells may be a consequence of immunological reactions. Whether HLA-DR-positive cells have a specific function is unknown.