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Inflammatory Bowel Disease Surgery

Developments in Non-pharmacological Treatment for Inflammatory Bowel Disease

a report by

F r i d r i k T h o r S i g u r b j o r n s s o n and I n g v a r B j a r n a s o n

King's College Hospital Foundation Trust, London

Ulcerative colitis (UC) and Crohn's disease can be recognised by periods of clinical quiescence interrupted by clinical relapses that are characterised by escalating inflammation in the colon or the full length of the gastrointestinal tract, respectively. The severity of the clinical relapse is variable, but most patients require hospitalisation at some stage of their disease and many require surgery. The relapse impacts significantly on patient quality of life and employment. A key hypothesis for the relapsing­remitting nature of inflammatory bowel disease (IBD) is the suggestion that the causes of the disease and the clinical relapse are determined by distinctively different pathogenic mechanisms that are nevertheless functionally interdependent. Hence, the cause of IBD can be viewed as the collective outcome of complex multiple genetic and environmental factors leading to the phenotype of Crohn's disease and UC. Under these circumstances the intestinal mucosa is in a state of vastly heightened immune activation, determined by the cells that underlie adaptive or acquired immunity. When the balance between luminal aggressors and mucosal defence is tilted to the advantage of the former, there is an exaggerated inflammatory response in terms of massive polymorphonuclear cell migration to the intestine. This inflammation causes the common relapse symptoms (tiredness, diarrhoea, urgency, bleeding, abdominal pain, etc.), and may well underlie the serious complications of the disease (perforation, strictures, fistulae, megacolon, etc.). The goal of medical management of UC and Crohn's disease is first to induce remission of active disease and then to maintain this non-symptomatic status. This is achieved by administration of drugs that interfere with the inflammatory process. Targeted treatment of active IBD involves the administration of 5-aminosalicylic acid (5-ASA) preparations, corticosteroids, tumour necrosis factor (TNF) antibodies (and other biologicals), immunosuppressants (cyclosporine, tacrolimus, etc.) and, in the case of Crohn's disease, elemental diets and cessation of smoking. Maintenance of remission is conventionally attempted with the use of 5-ASA and azathioprine. These treatments are effective in most patients, but there is ongoing concern about the side

effects of medical treatment. These range from renal problems and pancreatitis (5-ASA) to hypertension, diabetes mellitus, osteoporosis, cushingoid appearances (corticosteroids) and overwhelming infections (biologicals and immunosuppressants) that may be lethal. An alternative strategy is to remove mechanically the inflammatory mediators, the cells that produce them or the main effector cells (neutrophils) from the circulation in the hope that this interferes with the vicious cycle whereby the inflammation is self-perpetuating.1 If successful, such non-pharmacological treatment might be expected to be associated with an improved safety profile. This is increasingly becoming of major interest to the informed patient. Apheresis Non-pharmacological treatment ­ namely apheresis (`take away') ­ for IBD is in its infancy, although it has been widely used by haematologists and oncologists. The technology involves passing the patient's blood through an apparatus that `selectively' removes a constituent of the blood (by centrifugation or absorption onto beads coated with an absorbent material) and returns the remainder to the circulation. White cell apheresis (predominantly polymorphonuclear cells) has been tried in IBD using two separate instruments: Cellsorba (leukocytapheresis ­ LCAP) and Adacolum (granulocytapheresis ­ GCAP). The former is a column containing nonwoven fabric of polyester that preferentially traps leukocytes from whole blood through filtration and adhesion. It removes granulo- and monocytes, lymphocytes and platelets with around 100%, 30­90% and 84% efficacy, respectively.2 Adacolumn, on the other hand, is a column filled with cellulose acetate beads, each 2mm in diameter. This device adsorbs mainly granulo- and monocytes (65 and 55% efficacy, respectively), as well as a small fraction of lymphocytes.3 Efficacy The efficacy of LCAP and GCAP in the treatment of active UC and Crohn's disease has been assessed in groups that have different therapeutic complexities. It should be emphasised that a wide range of definitions has

Fridrik Thor Sigurbjornsson is a final-year medical student at the University of Iceland who spent three months with Professor Bjarnason in London reviewing the efficacy of Adacolumn in inflammatory bowel disease.

been used to define therapeutic response, i.e. different laboratory and clinical outcome scores that define clinical remission, improvement or worsening. First-line Treatment A few studies have been performed on the efficacy of apheresis for steroidnaïve patients with moderate or severe disease. Hanai et al.4 found that GCAP induced remission in seven of eight patients (88%) with severe UC at week six. Suzuki et al.5 reported similar results with GCAP, inducing remission in 17 of 20 patients (85%) with moderate to severe UC. These were sustained remissions, with 60 and 50% of patients remaining in remission at eight months and 12 months, respectively. A third study compared the efficacy of LCAP with prednisolone.6 Eight of nine patients with UC improved (three of whom achieved remission) on LCAP, a similar result to that of prednisolone, where seven of 20 (35%) achieved clinical

Ingvar Bjarnason, who works at King's College Hospital, has a long-standing research interest in inflammatory bowel disease (IBD). He was instrumental in the introduction of elemental diets for the treatment of Crohn's disease. Professor Bjarneson has developed a number of non-invasive tests for assessing disease activity in IBD and has a special interest in the genetic aspects of IBD and their inter-relationship with spondylarthropathy, especially ankylosing spondylitis. E: [email protected]



Adacolumn GMA (Granulocyte Monocyte Adsorption) apheresis is providing a rare combination of efficacy and safety in IBD treatment. Adacolumn can induce remission, and at the same time minimise steroid requirement and side effects ­ and thereby maximise your patient's quality of life.This is exemplified by a Scandinavian study where more than 40 % of IBD-patients achieved clinical remission and half of the steroid dependent patients could cease their steroid use.1 For more detailed information on Adacolumn, visit

1. Ljung,T et al. Scand J Gastroenterol, 2007; 42(2): 221-227.

A gentle revolution in IBD therapy

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remission. Collectively, it is suggested that both GCAP and LCAP provide effective non-pharmacological therapy in UC patients who are on 5-ASA only. However, the strength of these conclusions is tempered by the relatively small number of patients studied and lack of controls in two of the three studies. No reports have specifically addressed the effect of apheresis in steroid-naïve patients with Crohn's disease. Steroid-refractory/Steroid-dependent Disease The efficacy of white cell apheresis as treatment for IBD has been investigated to a greater extent in steroid-refractory/steroid-dependent patients, all using Adacolumn. The results are summarised in Table 1. It will be appreciated that the above trials represent a heterogeneous group of patients with regard to length of treatment, other treatments, location and severity of disease, etc. An in-depth analysis of these studies is beyond the scope of this paper. Nevertheless, these studies support GCAP as a treatment for IBD, especially for patients with UC. Furthermore, not only did patients who achieved remission during the trial period maintain this nonsymptomatic status for a considerably long (albeit variable) time, but many patients improved after apheresis had stopped. However, the overwhelming drawback of these studies is that they largely lack a control group. Other White Cell Apheresis Studies in Inflammatory Bowel Disease A large proportion of studies published on the efficacy and safety of leukocytapheresis focus on other clinical conditions than those described above (see Table 2). The study by Sawada et al.16 is of particular interest, as it compared the efficacy of LCAP with that of prednisolone in a group of 83 patients with moderately severe UC. In the prednisolone group, steroid

dosage was increased to 30­80mg/day. LCAP therapy was carried out in five weekly sessions. Patients in the LCAP group who responded received additional apheresis sessions every four weeks for 43 weeks after LCAP therapy. LCAP yielded remission rates of 47% and an overall improvement rate of 70%. Corresponding numbers in the prednisolone group were 33 and 38%. Remission was maintained in 37 and 40% of responding LCAP and prednisolone-treated patients, respectively, followed up for 43 weeks. Another important but rather complicated trial1 was a placebo-controlled (sham apheresis) prospective multicentre study involving 19 patients with active UC who were unresponsive to steroid treatment.21 Patients received five weekly sessions, then two sessions in the next four weeks. Nine patients received sham apheresis. Two weeks prior to and after the start of LCAP treatment, patients received prednisolone 15­40mg/day depending on disease activity. Clinical improvement in the treated group was 80% compared with 33% in the sham group. These are landmark `proof-ofconcept' studies as they show that LCAP treatment is equally or more effective than steroid therapy or placebo in inducing remission. However, a large multicentre sham-controlled study in moderately active UC in Europe and the US (not published) is purported not to have shown a significant difference between apheresis and sham. The reasons for these apparent discrepancies are unknown and difficult to analyse until the results of the trial are published in full. Adverse Effects One of the most attractive features of leukocytapheresis is that it avoids the administration of foreign substances that unavoidably carry the risk of side effects. The safety and tolerability of the therapy were investigated in nearly all the studies involving over 250 patients covered in this review. There is



Inflammatory Bowel Disease Surgery

number destined to the intestine, thereby allowing the mucosa to heal. However, current understanding on neutrophil function is that these are `non-specific' effector cells that migrate to areas of damage by virtue of the

IBD UC Number of Patients 53 11 31 11 20 35 52 13 25 21 44 10 Improved (%) 58 64 87 82 60 37 75 77 92 52 64 70 Remission (%) 21 55 81 73 45 43 48 62 92 29 41 70 Reference 7 8 4 9 10 11 12 13 14 15 12 13

Table 1: White Cell Apheresis in Steroid-refractory/ Steroid-dependent Disease

presence of chemo-attractants. Furthermore, the reduction in circulating neutrophil number is transient (lasting a few hours at best) only after each apheresis session. The finding that apheresis alters T-cell subsets is therefore interesting.23 There are some studies assessing alterations in serological parameters of inflammation and/or alterations in pro- and anti-inflammatory parameters.1,20 Most of the changes (C-reactive protein, erythrocyte sedimentation rate, complement levels, faecal calprotectin, TNF, interleukin 1, 6 and 8, L-selectins, integrins, etc.) do not necessarily give mechanistic details of the mode of action of the apheresis procedures. Therefore, the changes in pro- and anti-inflammatory mediators could simply be the result of a downgrading of the inflammatory response due to separate action rather than a specific action on the cytokines, adhesion molecules, etc. As is often the case, elucidation of the mechanism of action is best carried out in experimental animals where it may be possible to assess the specificity and importance of each of these observations. Conclusion The authors suggest that the published literature provides an optimistic promise for the efficacy of apheresis in the treatment of UC. The outstanding problem is that the studies have mostly been observational and lack adequate controls. The cost of the treatment and need for adequate facilities is equally as problematic as with the new biologicals. The availability of skilled and enthusiastic apheresis staff is of paramount importance for success of treatment. The overwhelming interest in and enthusiasm for the non-pharmaological treatment of IBD are due to the fact that it avoids the systematic toxicity of drug treatment. In the past, these side effects were problematic, but with the new biologicals we are seeing for the first time significant mortality with medical treatment. The precise positioning of white cell apheresis (first-, second- or third-line treatment) requires further study. In the future we are likely to see different kinds of apheresis applied to patients with IBD such as centrifugal leukocytapheresis,24 T-cell apheresis25 and, perhaps, more selective apheresis of pro-inflammatory molecules.


Table 2: White Cell Apheresis in Inflammatory Bowel Disease

Disease UC Number 43* 13 31 60 10 30 10* 6* 10 Improved (%) 70 62 84 83 86 87 80 67 60 Remission (%) 47 62 84 28 64 70 80 67 60 Reference 16 17 18 19 10 20 21 21 22


* LCAP treatment, the others being GCAP. UC = ulcerative colitis.

an overwhelming consensus that adverse events are uncommon and, when present (usually in fewer than 10% of patients), are almost always minor such as nausea, mild headache and/or fever, skin rash, urinary tract infection and fatigue. Possible Mode of Action The original idea was that neutrophils and polymorphs are the driving force for the clinical relapse of disease and that their removal might limit the


2. 3.






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Active and Refractory Ulcerative Colitis, Medical Tribune Inc, 2002;259­370. Tomomasa T, Kobayashi A, Kaneko H, et al., Granulocyte adsorptive apheresis for pediatric patients with ulcerative colitis, Dig Dis Sci, 2003;48:750­54. Naganuma M, Funakoshi S, Sakuraba A, et al., Granulocytapheresis is useful as an alternative therapy in patients with steroid-refractory or -dependent ulcerative colitis, Inflamm Bowel Dis, 2004;10:251­7. Kruis W, Dignass A, Steinhagen-Thiessen E, et al., Open label trial of granulocyte apheresis suggests therapeutic efficacy in chronically active steroid refractory ulcerative colitis, World J Gastroenterol, 2005. Ljung T, Thomsen OO, Vatn M, et al., Granulocyte, monocyte/macrophage apheresis for inflammatory bowel disease: the first 100 patients treated in Scandinavia, Scand J Gastroenterol, 2007;42:221­7. Domenech E, Hinojosa J, Esteve-Comas M, et al., Granulocyteaphaeresis in steroid-dependent inflammatory bowel disease: a prospective, open, pilot study, Aliment Pharmacol Ther, 2004;20:1347­52. Honma T, Sugimura K, Asakura H, et al., Leukocytapheresis is effective in inducing but not in maintaining remission in ulcerative colitis, J Clin Gastroenterol, 2005;39:886­90. Fukuda Y, Matsui T, Suzuki Y, et al., Adsorptive granulocyte and monocyte apheresis for refractory Crohn's disease: An open multicenter prospective study, J Gastroenterol, 2004;39:1158­64. Sawada K, Therapeutic cytapheresis for ulcerative colitis, Medical Tribune Inc, 2002;133­49. Suzuki Y, Efficacy of Granulocyte Adsorption Apheresis with G-1









Column in the Treatment of Patients with Active Ulcerative Colitis, Medical Tribune Inc, 2002. Hanai H, Watanabe F, Yamada M, et al., Adsorptive granulocyte and monocyte apheresis versus prednisolone in patients with corticosteroid-dependent moderately severe ulcerative colitis, Digestion, 2004;70:33­44. Kanke K, Nakano M, Hiraishi H, Terano A, Clinical evaluation of granulocyte/monocyte apheresis therapy for active ulcerative colitis, Dig Liver Dis, 2004;36:811­17. Yamamoto T, Umegae S, Kitagawa T, et al., Granulocyte and monocyte adsorptive apheresis in the treatment of active distal ulcerative colitis: A prospective, pilot study, Aliment Pharmacol Ther, 2004;20:783­92. Sawada K, Kusugami K, Suzuki Y, 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;100:1362­9. D'Ovidio V, Aratari A, Viscido A, et al., Mucosal features and granulocyte-monocyte-apheresis in steroid-dependent/refractory ulcerative colitis, Dig Liver Dis, 2006;38:389­94. Andoh A, Tsujikawa T, Inatomi O, et al., Leukocytapheresis therapy modulates circulating T cell subsets in patients with ulcerative colitis, Ther Apher Dial, 2005;9:270­76. Okada H, Takenaka R, Hiraoka S, et al., Centrifugal leukocytapheresis therapy for ulcerative colitis without concurrent corticosteroid administration, Ther Apher Dial, 2006;10:242­6. Bicks RO, Groshart KD, The current status of T-lymphocyte apheresis (TLA) treatment of Crohn's disease, J Clin Gastroenterol, 1989;11:136­8.





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