Luca Pastorelli 1, Theresa T Pizarro, Fabio Cominelli, Maurizio Vecchi Expert Opin Emerg Drugs. 2009 Sep;14(3):505-21. doi: 10.1517/14728210903146882.
Tag : steroid-dependent
Section scientifique
Emerging drugs for the treatment of ulcerative colitis
Background: Ulcerative colitis (UC) is a chronic, relapsing inflammatory disorder of the colon for which the etiology is currently unknown. At present, strategies to treat UC are primarily targeted to control inflammation during active phases of disease as well as maintain remission during quiescence. As such, several unmet needs in the treatment of UC still remain. In recent years, basic research has led to the recognition of several key factors in the pathogenesis of UC, translating into the development of several novel therapeutic agents. Objective: The aim of this study is to review emerging therapies that may advance the treatment and improve the overall care of UC patients. Methods: An extensive literature search on published manuscripts and meeting proceedings has been performed to provide a comprehensive review of future drug therapies to treat UC. Results/conclusion: The translational application of new discoveries in the basic understanding of UC pathogenesis is continuing and critical for the development of novel treatment strategies. Design of novel biologic therapies to treat UC has the challenge of addressing potential safety issues, while more traditional drugs should be further developed to facilitate patient compliance to treat this chronic, debilitating disease.
Section scientifique
Clinical, endoscopic and histological remission in paediatric chronically active ulcerative colitis after prolonged treatment with selective granulocyte–monocyte adsorptive apheresis
Javier Martin-Carpi Martín-Carpi, Vicente Varea Journal of Crohn’s and Colitis, Volume 3, Issue 3, September 2009, Pages 216–217, https://doi.org/10.1016/j.crohns.2009.03.003
Treatment of paediatric ulcerative colitis (UC) unresponsive to conventional treatment constitutes a challenge. The finding of new secure, steroid-sparing and long acting treatments for these cases are mandatory. We report our experience with a long-term therapeutic strategy with Adacolumn in a chronically active paediatric UC patient (9 year-old boy) with the aim of achieving stabilization and ameliorating symptoms, permitting a successful switch to AZA monotherapy. These two aspects have been achieved without reappearance of rectal bleeding after oral mesalamine suppression. But the most interesting and promising finding is the confirmation of GMA apheresis effect on mucosal healing after prolonged treatment: maintenance treatment with Adacolumn has been effective in achieving a complete endoscopic and histological remission.
This case shows the utility of prolonged Adacolumn treatment in chronically active UC patients.
Section scientifique
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
Section scientifique
Cytapheresis in Inflammatory Bowel Diseases: Current Evidence and Perspectives
Silvio Danese 1, Erika Angelucci, Tommaso Stefanelli, Paolo Omodei, Carmelo Luigiano, Silvia Finazzi, Nico Pagano, Alessandro Repici, Maurizio Vecchi, Alberto Malesci, Digestion. 2008;77(2):96-107.
Ulcerative colitis and Crohn’s disease are inflammatory bowel diseases with a chronic relapsing course. Management of both conditions is far from being fully satisfactory. For this reason in the last decade a large number of biological therapies, targeting cytokines involved in intestinal inflammation, has been developed with various results in terms of efficacy, safety and costs. Activated granulocytes and monocytes represent the major sources of pro-inflammatory cytokines in the intestinal mucosa, playing a pivotal role in inducing and maintaining intestinal inflammation. Leukocytapheresis using an adsorptive carrier-based system (Adacolumn) or a removal filter column (Cellsorba) has been proposed as a feasible, safe and effective therapy for ulcerative colitis and Crohn’s disease. The objective of this paper is to provide an overview on the current knowledge about mechanisms of action, available clinical data and the possible future perspectives for the use of Adacolumn and Cellsorba in the management of inflammatory bowel diseases.
Section scientifique
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.
Section scientifique
Leucocyte apheresis in the treatment of paediatric ulcerative colitis
Tarja Ruuska, Marja-Leena Lähdeaho, Yelda Sutas, Merja Ashorn, Juhani Grönlund Scand J Gastroenterol 2007 Nov; 42(11):1390-1. doi: 10.1080/00365520701231116.
Recent studies show corticosteroid dependency in 45% of paediatric ulcerative colitis (UC) patients despite using other medicaments, including immunomodulators This patient group is problematic as corticosteroids have numerous side effects when used long term. New biological approaches have proved effective in the treatment of inflammatory bowel disease (IBD), but as the side effects can be severe, especially in young patients, their use is restricted in UC.
In UC, circulating activated granulocytes and macrophages/monocytes are increased and can infiltrate the bowel and cause tissue injury by producing inflammatory cytokines, being thus involved in the initiation and perpetuation of an inflammatory disorder. Periodic removal of activated granulocytes and monocytes/ macrophages with selective leucocyte apheresis (Adacolumn; JIMRO, Japan) is expected to reduce leucocyte-dependent tissue injury. Preliminary reports show promising results in the treatment of IBD, in children with corticosteroid-dependent or -resistant UC.
We design a pilot study where 11 children (7 corticosteroid-dependent, 3 corticosteroid-resistant and 1 refusing corticosteroids) were treated with apheresis and their data analysed. Treatment was given once a week, a total of 5-9 sessions. 8 out of the remaining 11 patients responded well to the treatment. Corticosteroids could be tapered-off either totally or to minimal doses in all cases. Treatment was well tolerated.
Section scientifique
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.
Section scientifique
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.
Section scientifique
Efficacy of Granulocyte Apheresis in Pediatric Patients With Ulcerative Colitis: A Pilot Study
Ikeda, Hitoshi; Ishimaru, Yuki; Takayasu, Hajime; Fujino, Junko; Kisaki, Yoshiyuki; Otani, Yushi; Yamagishi, Junko; Tahara, Kazunori. J Pediatr Gastroenterol Nutr 2006; 43:592-6. doi: 10.1097/01.mpg.0000237928.07729.79
Objectives: Granulocyte apheresis (GCAP), involving the removal of granulocytes from the blood, may improve clinical symptoms and facilitate a reduction in the dose of steroids in adult patients with ulcerative colitis. As a preliminary trial, GCAP was used to taper the dose of steroids in 4 pediatric patients with ulcerative colitis. Methods: Three males and 1 female ranging from 11 to 17 years old were treated with GCAP once per week for 5 consecutive weeks/course. The ages of patients at clinical onset ranged from 8 to 12 years and the length of time from the clinical onset to GCAP treatment ranged from 28 to 58 months (median, 38.5 months). Results: In 2 patients, symptoms and signs indicating disease activity improved after 2 courses of GCAP. Laboratory data and endoscopic findings also improved after treatment and the clinical efficacy was judged to be excellent in these patients. In 1 patient, GCAP improved laboratory and endoscopic hallmarks, but bloody stools persisted. Finally, the treatment was ineffective in the fourth patient who eventually underwent surgery. Conclusions: GCAP is effective in improving clinical symptoms and may play an important role in converting steroid therapy to other treatments in children with steroid-refractory or steroid-dependent ulcerative colitis.
Section scientifique
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
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