K Kamikozuru 1, K Fukunaga, S Hirota, N Hida, Y Ohda, K Yoshida, Y Yokoyama, K Tozawa, K Kawa, M Iimuro, K Nagase, A R Saniabadi, S Nakamura, H Miwa, T Matsumoto Clin Exp Immunol 2009 May;156(2):320-7. doi: 10.1111/j.1365-2249.2009.03904.x. Epub 2009 Mar 9.
Tag: Clinical remission
Scientific corner
The expression profile of functional regulatory T cells, CD4+CD25high+/forkhead box protein P3+, in patients with ulcerative colitis during active and quiescent disease
Regulatory T cells (T(reg)) have an essential role in maintaining immune tolerance in the gut. The functional CD4(+) T(reg) express the transcription factor forkhead box protein 3 (FoxP3) or a CD25(high) in humans. Further, depletion of elevated granulocytes/monocytes by extracorporeal adsorption (GMA) induces immunomodulation in patients with ulcerative colitis (UC). We investigated the impact of GMA on T(reg). Thirty-one UC patients, clinical activity index (CAI) 12.1 +/- 2.97, refractory to conventional medications including intravenous corticosteroid and 13 healthy controls (HC), were included. Patients received five GMA sessions over 5 weeks. Biopsies from the rectal mucosa and blood samples at baseline and post-GMA were immunostained with anti-CD4/FoxP3 and anti-CD4/CD25 antibodies for immunohistochemistry and flow cytometry. Following GMA, 22 of 31 patients achieved remission (CAI <or= 4, P < 0.01) and their endoscopic activity index decreased from 10.6 +/- 2.32 to 4.75 +/- 1.48 (P = 0.003). The circulating CD4(+)CD25(high+) T(reg) level was low and increased markedly in responders (P < 0.02). In the nine non-responders, the baseline CD4(+)CD25(high+) T(reg) level was about 50% of the level in the responders (P < 0.03) or in the HC (P < 0.01), and all nine had to undergo colectomy. Conversely, the number of CD4(+)/FoxP3(+) mucosal T(reg) in GMA responders decreased significantly after the fifth GMA session compared with the baseline level (P < 0.05). It is believed that the CD4(+) T(reg) has an essential role in the control of immune pathology in UC patients and a net influx of these cells from the circulation into the mucosa may proceed to suppress inflammation. GMA can impact the circulating as well as the mucosal levels of T(reg).
CD25highCD4+ Tcell / CD4+ / Clinical remission / endoscopic remission / FoxP3+ T cells / gma / immunology / mucosa / mucosal biopsy / peripheral / serum / Tregs / ulcerative colitis /
Scientific corner
Leukocytapheresis for the treatment of IBD
Fridrik Thor Sigurbjörnsson & Ingvar Bjarnason, Nature Clinical Practice Gastroenterology & Hepatology volume 5, pages509–516 (2008)
Leukocytapheresis is a controversial nonpharmacologic treatment for IBD, in which white blood cells–the effector cells of the inflammatory process–are mechanically removed from the circulation. Current controversy centers on the uncontrolled nature of the leukocytapheresis trials performed and their use of different outcome measures in patient groups that have very variable disease activity and severity. Nonetheless, the efficacy data obtained are generally quite consistent: an excellent response (remission >80%) has been achieved in corticosteroid-naïve patients with ulcerative colitis and an average remission rate of more than 50% has been achieved in patients who have steroid-dependent or refractory ulcerative colitis. Interestingly, the largest randomized, double-blind, sham-controlled study of granulocyte-monocyte apheresis in patients with moderate to severe ulcerative colitis failed to demonstrate efficacy for the induction of clinical remission or response. Regardless, leukocytapheresis seems to be remarkably safe. The precise positioning of leukocytapheresis in the treatment of ulcerative colitis is uncertain at present and will vary according to geography and patient preference for a safe, nonpharmacologic treatment. Further efficacy studies are required to assess what the optimal number and frequency of treatments is, in addition to the need for head-to-head comparisons with established drugs.
Enthusiasm for the use of leukocytapheresis in the treatment of patients with IBD (mainly ulcerative colitis) is fueled by the lack of serious adverse effects and tempered by the lack of conventional placebo-controlled data or head-to-head comparisons with potential competitors
Leukocytapheresis induces clinical remission in more than 80% of corticosteroid-naïve patients who have ulcerative colitis
Average remission rates are in excess of 50% in patients with moderate or severe ulcerative colitis and in patients with corticosteroid-dependent or corticosteroid-resistant ulcerative colitis
Data in Crohn’s disease are sparse and further studies are required
Leukocyte apheresis clearly has potential use in patients with ulcerative colitis, but to decide its precise positioning in treatment algorithms will require targeted studies
Scientific corner
Leukocytapheresis for the treatment of active pouchitis: a pilot study
Yasumi Araki 1, Keiichi Mitsuyama, Takaaki Nagae, Yuji Tou, Motonori Nakagawa, Yasue Iwatani, Masakazu Harada, Hiroyuki Ozasa, Michio Sata, Toshihiro Noake, J Gastroenterol. 2008;43(7):571-5.
Background: Pouchitis is a major long-term complication of ileal pouch-anal anastomosis for ulcerative colitis. The aim of this study is to investigate the efficacy of leukocytapheresis for the treatment of active pouchitis. Methods: Eight patients with active pouchitis received leukocytapheresis weekly for 5 weeks in an open-label treatment protocol together with baseline therapy. Results: Patients showed significant improvement in their pouchitis disease activity index scores, from 9.5 (range, 8-10) to 4.0 (range, 2-8) (P < 0.05). Six (75%) of the 8 treated patients achieved remission. No adverse events were observed. Conclusions: Leukocytapheresis therapy could be a new therapeutic strategy for patients with pouchitis after ileal pouch-anal anastomosis for ulcerative colitis. These encouraging results lead us to propose a randomized controlled trial.
Scientific corner
Leukocytapheresis in a girl with severe ulcerative colitis refractory to corticosteroids, infliximab, and cyclosporine A
Katalin Dittrich, Markus Richter, Wolfgang Rascher, Henrik Köhler Inflamm Bowel Dis 2008 Oct;14(10):1466-7. doi: 10.1002/ibd.20464.
Although medical therapy remains the first-line treatment for UC, colectomy may be required for patients with severe medically refractory disease. Leukocytapheresis (LCAP) has been reported as a new line of therapy in
patients with UC. Only 2 pediatric case series, not including patients on immunosuppressive therapy or biologicals, treated with granulocytapheresis have been reported. The patient reported by us is the youngest to the best of our knowledge in which this LCAP technique was used . She had severe colitis refractory to corticosteroids, infliximab and yclosporine A. We were able to avoid colectomy and the procedure was well tolerated.
Clinical remission / Corticosteroids / cyclosporine A / gma / Infliximab / intensive / Leukocytapheresis / pediatric / Safety / severe / steroid / ulcerative colitis /
Scientific corner
In patients with ulcerative colitis, adsorptive depletion of granulocytes and monocytes impacts mucosal level of neutrophils and clinically is most effective in steroid naïve patients
T Tanaka 1, H Okanobu, S Yoshimi, E Murakami, A Kogame, H Imagawa, Y Numata, Y Kuga, T Moriya, T Ohya, G Kajiyama
Background: The aetiology of ulcerative colitis is inadequately understood, and drug therapy has been empirical rather than based on sound understanding of disease aetiology. This has been a major factor for refractoriness and adverse drug effects as additional complications. However, ulcerative colitis by its very nature is exacerbated and perpetuated by inflammatory cytokines, which are released by peripheral granulocytes and monocytes as well. Additionally, active ulcerative colitis is often associated with elevated peripheral granulocytes and monocytes with activation behaviour and are found in vast numbers within the colonic mucosa. Hence, from the clinicopathologic viewpoint, granulocytes and monocytes are appropriate targets for therapy in ulcerative colitis. Based on this thinking, an Adacolumn has been developed for depleting excess granulocytes and monocytes by adsorption. Methods: By colonoscopy, biopsy and histology, we investigated the impact of granulocyte and monocyte adsorption (GMA) on the mucosal level of granulocytes and monocytes in patients with active ulcerative colitis. Forty-five patients (26 steroid naïve and 19 steroid-dependent), mean age 44.7 yr, were included. Twenty patients had total colitis and 25 had left-sided colitis. Each patient was given up to 11 GMA sessions over 12 weeks. No patient received additional medications within 4 weeks (steroid) to 8 weeks (other immunosuppressants) prior to entry or during the GMA course. Colonoscopy together with biopsy was done at entry and within 2 weeks after the last GMA session. Results: At entry, the mean clinical activity index was 12.6; range 10-16. A total of 400 colonic biopsies were examined, which revealed massive infiltration of the colonic mucosa by granulocytes, and GMA was associated with striking reduction of granulocytes in the mucosa. At week 12, 33 of 45 patients (73.3%, P<0.01) had achieved clinical remission (the mean clinical activity index <or= 4). Colonoscopy revealed that most non-responders had deep colonic ulcers and extensive loss of the mucosal tissue. The response rate in steroid naïve subgroup was 22 of 26 patients (84.6%, P<0.005) and in steroid-dependent was 11 of 19 (57.9%, P<0.05 and P=0.02154 for steroid naïve vs. steroid-dependent). Patients who achieved remission could continue with their salicylates. On average, remission was sustained for 7.8 months in all 33 responders. Conclusions: This is the first report showing a striking difference in clinical response to GMA between steroid naïve and steroid-dependent patients. Further, patients with deep colonic ulcers together with extensive loss of the mucosal tissue are not like to respond to GMA.
Scientific corner
Current pharmacologic treatment paradigms for inflammatory bowel disease and the potential role of granulocyte/monocyte apheresis
David Schwartz 1, John R Ferguson, Curr Med Res Opin . 2007 Nov;23(11):2715-28.
Background: A broad range of pharmacologic therapies are available to treat active inflammatory bowel disease (IBD), including 5-aminosalicylate preparations, corticosteroids, and immunosuppressants (e.g., azathio prine/6-mercaptopurine [AZA/6-MP] or methotrexate). Although these therapies are effective, up to 60% of patients are refractory or intolerant. Biologic therapies, such as the anti-TNF agent infliximab, offer promise but are not without controversy; despite many positive reports, steroid-refractory patients are less likely than other individuals to respond to infliximab. Effective, long-term therapies that do not add to the adverse-effects burden in patients with IBD are needed. Of these, granulocyte/monocyte apheresis (GMA) is one promising approach.
Scope: PubMed and relevant congresses databases were searched using the terms ‘granulocyte/monocyte apheresis,’ ‘GMA,’ ‘leukocytapheresis,’ ‘Adacolumn,’ and ‘Cellsorba.’ These studies were further selected to include only those focusing on IBD. A time frame of 2000-2006 was used.
Findings: Data from open-label trials show that patients with moderate-to-severe IBD refractory to conventional pharmacologic treatment achieved clinical response and/or remission after treatment with GMA. Furthermore, recent small open-label trials of GMA show increased rates of induction and maintenance of response/remission in steroid-naïve IBD patients.
Conclusions: The remission rates seen in these open-label clinical trials of GMA are consistent with those of currently available pharmacologic therapies for IBD. However, the majority of these trials enrolled only small numbers of patients, were largely open-label, and were of limited duration. These data must be confirmed in well-controlled, large-scale clinical trials
Scientific corner
Granulocytapheresis in inflammatory bowel disease Efficacy of an induction plus maintenance sessions protocol at 32 weeks
F J Fernández Pérez 1, F Rodríguez, C de Sola, N Fernández Moreno, F Vera, R Rivera, A Sánchez Cantos, Rev Esp Enferm Dig. 2007 Nov;99(11):628-35.
Introduction: Granulocytapheresis (GCAP) eliminates activated granulocytes-monocytes from peripheral blood, thus modifying the circulating pool of leukocytes and reducing intestinal inflammation. Objective: To evaluate the efficacy of GCAP in inflammatory bowel disease (IBD) using an induction and maintenance protocol. Material and method: A retrospective study including patients with active corticosteroid-dependent or refractory IBD. Induction included 5 sessions in ulcerative colitis (UC) and 7 sessions in Crohn’s disease (CD); one monthly session was used thereafter until week 32. Clinical activity indices and use of corticosteroids were monitored. Results: Eighteen patients were included (10 with UC, 8 with CD), 10 of them dependent on and 8 refractory to corticosteroids. Fourteen of them were refractory and a further 4 were intolerant to immunosuppressants (IS). Induction was not completed in 2 UC (severe relapses) and 1 CD (side-effects) patients. One UC and 3 CD patients withdrew during maintenance. Among patients who completed induction, response or remission was achieved in 87.5% of UC cases (2 and 5 patients) and 71.4% of CD cases (1 and 4 patients), respectively. At week 32 response-remission rates reached 75% in CU (3 and 3 patients) and 42.8% in CD (1 and 2 patients) cases, respectively. Corticosteroid withdrawal was possible in 14.2% of CD and in 62.5% of UC patients (25% in remission and 37.5% with response). There were two major side effects (thrombophlebitis and syncope). No colectomies were performed for UC patients who completed GCAP induction after a mean follow-up of 97.6 weeks (range: 72-128). Conclusions: Both UC and CD respond well to GCAP induction. At 32 weeks UC patients maintain similar response-remission rates (87.5 vs. 75%), whereas almost one-third of CD patients lose response. Granulocytapheresis is an alternative, steroid-sparing treatment modality to induce and maintain remission in UC, while good patient selection and a maintenance protocol not well defined yet are needed for CD.
Scientific corner
Evaluation of 5 versus 10 granulocyteaphaeresis sessions in steroid-dependent ulcerative colitis: A pilot, prospective, multicenter, randomized study
Elena Ricart, Maria Esteve, Montserrat Andreu, Francesc Casellas, David Monfort, Miquel Sans, Natalia Oudovenko, Raúl Lafuente, and Julián Panés World J Gastroenterol. 2007 Apr 21; 13(15): 2193–2197.Published online 2007 Apr 21. doi: 10.3748/wjg.v13.i15.2193
AIM: To evaluate the efficacy of 5 compared to 10 granulocyteaphaeresis sessions in patients with active steroid-dependent ulcerative colitis. METHODS: In this pilot, prospective, multicenter randomized trial, 20 patients with moderately active steroid-dependent ulcerative colitis were randomized to 5 or 10 granulocyteaphaeresis sessions. The primary objective was clinical remission at wk 17. Secondary measures included endoscopic remission and steroid consumption. RESULTS: Nine patients were randomized to 5 granulocyteaphaeresis sessions (group 1) and 11 patients to 10 granulocyteaphaeresis sessions (group 2). At wk 17, 37.5% of patients in group 1 and 45.45% of patients in group 2 were in clinical remission. Clinical remission was accompanied by endoscopic remission in all cases. Eighty-six percent of patients achieving remission were steroid-free at wk 17. Daily steroid requirements were significantly lower in group 2. Eighty-nine per cent of patients remained in remission during a one year follow-up. One serious adverse event, not related to the study therapy, was reported. CONCLUSION: Granulocyteaphaeresis is safe and effective for the treatment of steroid-dependent ulcerative colitis. In this population, increasing the number of aphaeresis sessions is not associated with higher remission rates, but affords a significant steroid-sparing effect.
Scientific corner
Leukocytapheresis in Patients with Moderate-Severe Steroid-Dependant Ulcerative Colitis: Clinical Response without Endoscopic Response
Irene Modesto, Daniela Scimeca, Ambrogio Orlando, Mario Cottone, Inflamm Bowel Dis 12 (10), October 2006
We report the results of an open prospective study of LCAP in moderate to severe steroid-dependent UC. LCAP is an effective procedure in obtaining discontinuation of steroids in 36% of patients with UC for at least 3 months. Overall 4 of 11(36%) patients could discontinue steroids within 3 months. No relevant side effects were observed. The procedure was well tolerated. In our series, there was no endoscopic response. Most of the patients obtained a clinical temporary response, but many relapsed
Scientific corner
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 (FcgammaR 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] < or =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.
Contact UsFor more information
Contact Us