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Leukocytapheresis in Inflammatory Bowel Disease (Primarily Ulcerative Colitis)

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SBU Assessment

Presents a comprehensive, systematic assessment of available scientific evidence for effects on health, social welfare or disability. Full assessments include economic, social and ethical impact analyses. Assessment teams include professional practitioners and academics. Before publication the report is reviewed by external experts, and scientific conclusions approved by the SBU Board of Directors.

Published: Report no: 2009-02 https://www.sbu.se/200902e

Summary and Conclusions

SBU’s appraisal of the evidence

Ulcerative colitis and Crohn’s disease are the most common chronic inflammatory bowel diseases. Leukocytapheresis is a method aimed at ameliorating symptoms in patients with moderately severe to severe inflammatory bowel disease.

  • Few studies of sufficient quality address leukocytapheresis in the treatment of inflammatory bowel disease. No randomized studies were found on Crohn’s disease. Hence, well-designed studies of sufficient size are urgently needed to determine the effectiveness of leukocytapheresis in treating inflammatory bowel disease.
  • Contradictory scientific evidence* makes it impossible to establish whether the treatment results of leukocytapheresis are superior to conventional pharmacotherapy with corticosteroids or sham apheresis in treating moderately severe to severe ulcerative colitis. Studies that compare apheresis with steroid treatment suggest that the treatments yield comparable results.
  • Compared to steroid treatment, apheresis has fewer and milder adverse effects during the treatment period. Knowledge is lacking concerning the potential adverse effects of leukocytapheresis in the long term, but it is well documented that long-term treatment with corticosteroids carries a substantial risk for adverse effects.
  • Apheresis treatment is more expensive than conventional pharmacotherapy1. The scientific evidence is insufficient* to determine the cost-effectiveness of the method. 

Footnote

1 Does not include treatment with so-called biological/immunomodulating drugs (eg, infliximab).

* Criteria for Evidence Grading SBU’s Conclusions
Evidence Grade 1 – Strong Scientific Evidence. The conclusion is corroborated by at least two independent studies with high quality, or a good systematic overview.
Evidence Grade 2 – Moderately Strong Scientific Evidence. The conclusion is corroborated by one study with high quality, and at least two studies with medium quality.
Evidence Grade 3 – Limited Scientific Evidence. The conclusion is corroborated by at least two studies with medium quality.
Insufficient Scientific Evidence – No conclusions can be drawn when there are not any studies that meet the criteria for quality.
Contradictory Scientific Evidence – No conclusions can be drawn when there are studies with the same quality whose findings contradict each other.

Technology and target group

Approximately 1% of the Swedish population has ulcerative colitis or Crohn’s disease. In ulcerative colitis the rectum and often part or all of the colon are inflamed. Common symptoms include blood in feces, diarrhea, and urgency and increased frequency of bowel movements. In Crohn’s disease, inflammation is usually localized in the small intestine and colon, but it can affect the entire gastrointestinal tract. Crohn’s disease in the colon causes symptoms similar to ulcerative colitis, but substantial weight loss is more usual. A common feature of both diseases is that they often present as recurring episodes of acute attacks followed by periods that are relatively or even completely symptom-free.

Conventional treatment of acute episodes aims to make patients symptom free and usually includes cortisone medication (corticosteroids). This method, however, often involves substantial adverse effects. Surgical treatment is an option and involves removal of the inflamed parts of the intestine, mainly in severe cases. In Crohn’s disease, surgery seldom yields a permanent cure, and the disease often reappears in other parts of the gastrointestinal tract.

Leukocytapheresis aims to reduce the number of white blood cells (leukocytes) to dampen the inflammatory reaction. Different apheresis techniques remove different types of white blood cells. The two most common techniques involve drawing blood via a venous catheter, pumping it through a cylinder (column) containing cellulose acetate beads (Adacolumn) or a filter of nonwoven polyester fibers (Cellsorba), thereafter returning it to the circulatory system. As blood passes through the system, leukocytes adhere to the beads or filter. Treatment takes one hour and is usually repeated once per week for 5 weeks. The biochemical mechanisms concerning how leukocytapheresis affects the course of disease remain largely unknown.

Leukocytapheresis involves mainly adult patients. The aim of treatment is to ameliorate symptoms in acute, severe attacks of the disease, or in moderately severe to severe chronic, active disease where satisfactory effects have not been achieved from corticosteroids or other immuno­suppressive therapy. The target group also includes patients who have developed steroid dependence, ie, disease recurs if steroid dosage is reduced. The number of patients who could be candidates for treatment is difficult to estimate.

Primary questions

  • Is leukocytapheresis an effective complement to, or replacement for, treatment with corticosteroids to relieve symptoms from acute episodes of ulcerative colitis and Crohn’s disease? Could leukocytapheresis be an option when immunosuppressive treatment has not had effects, or has been discontinued due to adverse effects?
  • What does treatment cost? Is it cost-effective?

Patient benefit

The assessment includes 7 randomized controlled trials that compared leukocytapheresis with pharmacotherapy or sham apheresis. One of these trials was judged to be of high quality, and the others were of medium quality. The trials included only patients with ulcerative colitis. Five of the trials used Adacolumn and two used Cellsorba.

Results were contradictory as regards the endpoints of clinical remission (symptom free), clinical improvement, and endoscopic improvement. Hence, it cannot be established with certainty whether leukocytapheresis in moderately severe or severe ulcerative colitis leads to a better treatment result than conventional pharmacotherapy with corticosteroids or sham apheresis. Studies that compared leukocytapheresis with steroid treatment alone reported treatment effects of similar size in both groups. The only study judged to be of high quality compared leukocytapheresis with sham treatment, but showed no advantage for leukocytapheresis.

Treatment of acute episodes always aims to help patients become completely free from symptoms (achieve clinical remission) with as few adverse effects as possible. To date, the adverse effects reported to be associated with leukocytapheresis, eg, headache, nausea, and fatigue, are generally mild and transitory.

The included studies differ as regards, eg, the drugs used and the severity of disease at the outset of the study. Furthermore, the studies included two methods (Adacolumn and Cellsorba), and different evaluation systems were used to assess treatment effects. This affects the comparability of the studies and raises some uncertainty about the overall assessment. Given these disparities, the prerequisites do not exist to conduct a meta-analysis of the studies’ results. However, most of the studies included in the assessment suggest that treatment with leukocytapheresis yields a result comparable to pharmacotherapy, but with fewer and milder side effects. Knowledge is lacking concerning the possible adverse effects of apheresis treatment in the long term.

Considering the current level of knowledge, it is essential to conduct well-designed and sufficiently large studies to establish the effectiveness of the method.

Economic aspects

The average cost per patient and round of leukocytapheresis treatment, using Adacolumn, can be estimated at approximately 100 000 Swedish kronor (SEK). In 2007, approximately 1250 treatments were provided for 180 patients. Using Cellsorba, the corresponding cost would be approximately SEK 80 000. To date, however, Cellsorba has been used primarily in a research context. Scientific evidence is insufficient to assess the method’s cost-effectiveness.


This summary is based on a report prepared by SBU in collaboration with Clas Göran Axelsson, MD, PhD, Örebro University Hospital, Örebro and Gunnar Järnerot, MD, Professor Emeritus, Örebro University Hospital, Örebro. It has been reviewed by Åke Danielsson, MD, Professor, Umeå University/Norrland’s University Hospital, Umeå and Stefan Lindgren, MD, Professor, Malmö University Hospital, Malmö. Project manager: Johan Wallin, SBU.

The complete report is available in Swedish.

SBU Alert is a service provided by SBU in collaboration with the Medical Products Agency, the National Board of Health and Welfare, and the Swedish Association of Local Authorities and Regions.

References

  1. Hildebrand H, Finkel Y, Grahnquist L, Lindholm J, Ekbom A, Askling J. Changing pattern of paediatric inflammatory bowel disease in northern Stockholm 1990-2001. Gut 2003;52(10):1432-4.
  2. Lapidus A. Crohn’s disease in Stockholm County during 1990-2001: an epidemiological update. World J Gastroenterol 2006;12(1):75-81.
  3. Edwards FC, Truelove SC. The course and prognosis of ulcerative colitis. Gut 1963;4:299-315.
  4. Tysk C, Lindberg E, Järnerot G, Flodérus-Myrhed B. Ulcerative colitis and Crohn’s disease in an unselected population of monozygotic and dizygotic twins. A study of heritability and the influence of smoking. Gut 1988;29(7):990-6.
  5. Lindberg E, Tysk C, Andersson K, Järnerot G. Smoking and inflammatory bowel disease. A case control study. Gut 1988;29(3):352-7.
  6. Sartor RB. Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Pract Gastroenterol Hepatol 2006;3(7):390-407.
  7. Lügering N, Kucharzik T, Stoll R, Domschke W. Current concept of the role of monocytes/macrophages in inflammatory bowel disease – balance of proinflammatory and immunosuppressive mediators. Ital J Gastroenterol Hepatol 1998;30(3):338-44.
  8. Sandborn WJ. Preliminary data on the use of apheresis in inflammatory bowel disease. Inflamm Bowel Dis 2006;12 Suppl 1:S15-21.
  9. Shimoyama T, Sawada K, Hiwatashi N, Sawada T, Matsueda K, Munakata A et al. Safety and efficacy of granulocyte and monocyte adsorption apheresis in patients with active ulcerative colitis: a multicenter study. J Clin Apher 2001;16(1):1-9.
  10. Shimoyama T, Sawada K, Tanaka Y, Saito A, Munakata T, Toyota N. Granulocyte and monocyte apheresis in patients with active ulcerative colitis. Japanese J Apheresis 1999;18:117-31.
  11. Shibata H, Kuriyama T, Yamawaki N. Cellsorba. Ther Apher Dial 2003;7(1):44-7.
  12. Yamaji K, Yang K, Tsuda H, Hashimoto H. Fluctuations in the peripheral blood leukocyte and platelet counts in leukocytapheresis in healthy volunteers. Ther Apher 2002;6(6):402-12.
  13. Kashiwagi N, Sugimura K, Koiwai H, Yamamoto H, Yoshikawa T, Saniabadi AR et al. Immunomodulatory effects of granulocyte and monocyte adsorption apheresis as a treatment for patients with ulcerative colitis. Dig Dis Sci 2002;47(6):1334-41.
  14. Andoh A, Tsujikawa T, Inatomi O, Deguchi Y, Sasaki M, Obata H et al. Leukocytapheresis therapy modulates circulating t cell subsets in patients with ulcerative colitis. Ther Apher Dial 2005;9(3):270-6.
  15. Hiraishi K, Takeda Y, Shiobara N, Shibusawa H, Jimma F, Kashiwagi N et al. Studies on the mechanisms of leukocyte adhesion to cellulose acetate beads: an in vitro model to assess the efficacy of cellulose acetate carrier-based granulocyte and monocyte adsorptive apheresis. Ther Apher Dial 2003;7(3):334-40.
  16. Saniabadi AR, Hanai H, Suzuki Y, Ohmori T, Sawada K, Yoshimura N et al. Adacolumn for selective leukocytapheresis as a non-pharmacological treatment for patients with disorders of the immune system: an adjunct or an alternative to drug therapy? J Clin Apher 2005;20(3):171-84.
  17. Danese S, Angelucci E, Stefanelli T, Omodei P, Luigiano C, Finazzi S et al. Cytapheresis in inflammatory bowel diseases: current evidence and perspectives. Digestion 2008;77(2):96-107.
  18. Hanai H. Positions of selective leukocytapheresis in the medical therapy of ulcerative colitis. World J Gastroenterol 2006;12(47):7568-77.
  19. Hanai H, Iida T, Yamada M, Sato Y, Takeuchi K, Tanaka T et al. Effects of adacolumn selective leukocytapheresis on plasma cytokines during active disease in patients with active ulcerative colitis. World J Gastroenterol 2006;12(21):3393-9.
  20. Järnerot G, Rolny P, Sandberg-Gertzén H. Intensive intravenous treatment of ulcerative colitis. Gastroenterology 1985;89(5):1005-13.
  21. Järnerot G, Hertervig E, Friis-Liby I, Blomquist L, Karlén P, Grännö C et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: a randomized, placebo-controlled study. Gastroenterology 2005;128(7):1805-11.
  22. Gustavsson A, Halfvarson J, Magnuson A, Sandberg-Gertzén H, Tysk C, Järnerot G. Long-term colectomy rate after intensive intravenous corticosteroid therapy for ulcerative colitis prior to the immunosuppressive treatment era. Am J Gastroenterol 2007;102(11):2513-9.
  23. Sands BE, Sandborn WJ, Feagan B, Löfberg R, Hibi T, Wang T et al. A randomized, double-blind, sham-controlled study of granulocyte/monocyte apheresis for active ulcerative colitis. Gastroenterology 2008;135(2):400-9.
  24. Hanai H, Watanabe F, Yamada M, Sato Y, Takeuchi K, Iida T et al. Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis. Digestion 2004;70(1):36-44.
  25. Bresci G, Parisi G, Mazzoni A, Scatena F, Capria A. Treatment of patients with acute ulcerative colitis: conventional corticosteroid therapy (MP) versus granulocytapheresis (GMA): a pilot study. Dig Liver Dis 2007;39(5):430-4.
  26. Sawada K, Muto T, Shimoyama T, Satomi M, Sawada T, Nagawa H et al. Multicenter randomized controlled trial for the treatment of ulcerative colitis with a leukocytapheresis column. Curr Pharm Des 2003;9(4):307-21.
  27. Sawada K, Kusugami K, Suzuki Y, Bamba T, Munakata A, Hibi T et al. Leukocytapheresis in ulcerative colitis: results of a multicenter double-blind prospective case-control study with sham apheresis as placebo treatment. Am J Gastroenterol 2005;100(6):1362-9.
  28. Hanai H, Iida T, Takeuchi K, Watanabe F, Maruyama Y, Kageoka M et al. Intensive granulocyte and monocyte adsorption versus intravenous prednisolone in patients with severe ulcerative colitis: an unblinded randomised multi-centre controlled study. Dig Liver Dis 2008;40(6):433-40.
  29. Emmrich J, Petermann S, Nowak D, Beutner I, Brock P, Klingel R et al. Leukocytapheresis (LCAP) in the management of chronic active ulcerative colitis – results of a randomized pilot trial. Dig Dis Sci 2007;52(9):2044-53.
  30. Maiden L, Takeuchi K, Baur R, Bjarnason I, O’Donohue J, Forgacs I et al. Selective white cell apheresis reduces relapse rates in patients with IBD at significant risk of clinical relapse. Inflamm Bowel Dis 2008;14(10):1413-8.
  31. Lerebours E, Bussel A, Modigliani R, Bastit D, Florent C, Rabian C et al. Treatment of Crohn’s disease by lymphocyte apheresis: a randomized controlled trial. Groupe d’Etudes Thérapeutiques des Affections Inflammatoires Digestives. Gastroenterology 1994;107(2):357-61.
  32. Ricart E, Esteve M, Andreu M, Casellas F, Monfort D, Sans M et al. Evaluation of 5 versus 10 granulocyteaphaeresis sessions in steroid-dependent ulcerative colitis: a pilot, prospective, multicenter, randomized study. World J Gastroenterol 2007;13(15):2193-7.
  33. Sakata Y, Iwakiri R, Amemori S, Yamaguchi K, Fujise T, Otani H et al. Comparison of the efficacy of granulocyte and monocyte/macrophage adsorptive apheresis and leukocytapheresis in active ulcerative colitis patients: a prospective randomized study. Eur J Gastroenterol Hepatol 2008;20(7):629-33.
  34. Kanke K, Nakano M, Hiraishi H, Terano A. Clinical evaluation of granulocyte/monocyte apheresis therapy for active ulcerative colitis. Dig Liver Dis 2004;36(12):811-7.
  35. Rachmilewitz D. Coated mesalazine (5-aminosalicylic acid) versus sulphasalazine in the treatment of active ulcerative colitis: a randomised trial. BMJ 1989;298(6666):82-6.
  36. Schroeder KW, Tremaine WJ, Ilstrup DM. Coated oral 5-aminosalicylic acid therapy for mildly to moderately active ulcerative colitis. A randomized study. N Engl J Med 1987;317(26):1625-9.
  37. Ljung T, Thomsen OØ, Vatn M, Karlén P, Karlsen LN, Tysk C et al. Granulocyte, monocyte/macrophage apheresis for inflammatory bowel disease: the first 100 patients treated in Scandinavia. Scand J Gastroenterol 2007;42(2):221-7.
  38. Ruuska T, Lähdeaho ML, Sutas Y, Ashorn M, Grönlund J. Leucocyte apheresis in the treatment of paediatric ulcerative colitis. Scand J Gastroenterol 2007;42(11):1390-1.
  39. Tomomasa T, Kobayashi A, Kaneko H, Mika S, Maisawa S, Chino Y et al. Granulocyte adsorptive apheresis for pediatric patients with ulcerative colitis. Dig Dis Sci 2003;48(4):750-4.
  40. Martín de Carpi J, Vilar P, Prieto G, García Novo MD, Ribes C, Varea V. Safety and efficacy of granulocyte and monocyte adsorption apheresis in paediatric inflammatory bowel disease: a prospective pilot study. J Pediatr Gastroenterol Nutr 2008;46(4):386-91.
  41. Panés J, Guilera M, Ginard D, Hinojosa J, González-Carro P, González-Lara V et al. Treatment cost of ulcerative colitis: Is apheresis with Adacolumn cost-effective? Dig Liver Dis 2007;39(7):617-25.
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