INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #61

Seymour Katz, M.D., Series Editor , Apheresis Treatment in Pediatric Inflammatory Bowel Disease

Tarja Ruuska Vibeke Wewer

Selective leukocyte apheresis is a new type of non-pharmacological treatment of inflam- matory bowel disease. As an increased number of activated and / have an important role in relapses of inflammatory bowel diseases, removal of this excess is believed to attenuate the inflammatory process. Data on adult patients have shown this treatment to be efficacious and safe. Although stud- ies in pediatric patients remain scanty, preliminary results are promising and encour- aging to future research in the treatment of pediatric and Crohn’s disease. This task is demanding and new treatment options are urgently needed.

he number of young patients with inflammatory eases in childhood and youth is especially demanding bowel disease (IBD)—comprising Crohn’s dis- in that it involves patients whose growth and psy- Tease (CD) and ulcerative colitis (UC)—is increas- chosocial development is an ongoing process (3). The ing markedly in Western countries; during the last mainstay in the treatment of IBD is to ensure the nor- twenty years the incidence of patients has doubled in mal growth, reproductive health, education and psy- Scandinavia (1,2). Treatment of chronic bowel dis- chosocial well-being of the child. The usual treatment of IBD consists of 5-ASA or Tarja Ruuska, M.D., Department of Pediatrics, sulphasalazine as basic treatment; most patients, how- Tampere University Hospital, Tampere, Finland. ever, need additional treatments with corticosteroids Vibeke Wewer, M.D., Department of Pediatrics, and other immunosuppressants such as azathioprine, 6- Hvidovre University Hospital, Denmark. mercaptopurine, or methotrexate and biologic treat-

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #61

ments. In Crohn’s disease exclusive enteral treatment is removal of activated granulocytes and monocytes/ a viable option in many patients (4) but has not proved macrophages is assumed to reduce leukocyte-depen- effective in UC. Regardless of other treatments, almost dent tissue injury. Despite their removal, however, the half of IBD children are corticosteroid- dependent (5). number of these cells does not fall below the normal Although the initial response to infliximab in Crohn’s range in the peripheral blood as an influx of new gran- disease can be as good as 94%, the majority of patients, ulocytes into the circulation has been observed. These 66 %, remain dependent on maintenance therapy (6,7). new cells in the circulation are inactivated and imma- Surgery is the final option being necessary in 1/3 of ture and therefore not inflammatory (19). Crohn’s patients and in 24% of UC patients (8). Apheresis is a method of extracorporeal removing Side-effects are common: it is known that long- cells from the circulatory system. The use of columns term corticosteroid treatment can cause growth failure to remove specific components from whole blood has (9), impaired bone density (10), altered fat deposit, proved to attain more active modification of cellular lowered sugar tolerance and dermatological problems. than simple centrifugation. Selective Immunomodulators can affect the liver, kidneys and apheresis has been evaluated as a treatment of several bone-marrow and with prolonged use carry a possible autoimmune diseases including rheumatoid arthritis risk of lymphomas. An increased number of infections and IBD (20,21). At present two different apheresis such as abscesses, septicemia and tuberculosis has been systems are available: Cellsorba (Asahi Medical, noted in patients using biological treatments (11) and Tokyo, Japan) which uses polyester fibers, the filter hepatosplenic T-cell lymphomas have more recently removing granulocytes, monocytes, and been reported in connection with their use (12). some . The second method is Adacolumn Although the most severe side-effects are rare, they (JIMRO, Takasaki, Japan), which has a column of cel- must be carefully considered when treating children. lulose acetate beads. With Adacolumn, about 65% of Side-effects are also rather common after surgery, granulocytes and 55% of monocytes are adsorbed being seen in 31–36% of cases both shortly after while there is no significant change in the number of surgery but also in 10 years follow-up. As many as 75% lymphocytes or platelets. Most of the published of patients has at least one side-effect and 54% undergo apheresis studies have used this latter system. a reoperation (13). Very little is known to date regard- ing fertility in adulthood after UC surgery in childhood. Studies among operated women show female fecundity ADACOLUMN TECHNIQUE to be clearly reduced after UC surgery (14). Although GMA is used in children according to the same princi- UC itself does not affect fertility, pediatricians should ples as in adults. Adacolumn columns are of 335 ml keep this in mind when considering and timing an oper- capacity filled with 220 g of cellulose diacetate beads ation. New treatment options are thus clearly called for 2 mm in diameter. The column is placed in an extra- especially for children. corporeal setting. Blood from one antecubital vein is Granulocyte, monocyte apheresis has been used as flowed into the column at 30 ml/min and returned to a new therapeutic method for the treatment of chronic the patient via the antecubital vein on the other arm; inflammatory bowel disease. In IBD circulating acti- one treatment session lasts 60 min. Eighteen-gauge vated granulocytes and macrophages/ monocytes are cannules are best for cannulation to ensure sufficient increased to approximately twice the concentrations circulation. If children are anxious before the first seen in healthy individuals; in patients with severely treatment, this being mild sedative can be given orally active disease, the granulocyte concentrations are (midazolam, diazepam), this also being helpful in pre- about 3 times higher. These cells also have a prolonged venting venous spasms. Furthermore, if the child is life—span and infiltrate the bowel, causing tissue dehydrated, Ringer solution can be given 10–20 ml/kg injury by producing inflammatory , which before initiation of the treatment. We have noted that are involved in the initiation and perpetuation of this procedure improves the circulation and renders the an inflammatory disorder (15,16,17,18). Periodic GMA technically easier to conduct.

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INFLAMMATORY BOWEL DISEASE: A PRACTICAL APPROACH, SERIES #61

No minimum age for GMA is given, but the manu- side-effects from other treatments, refused conven- facturer had recommended a minimum weight of 30 kg. tional treatments, had poor growth or were hoped to achieve a better clinical condition before surgery (one child). All patients had moderate-to-severe disease, CLINICAL EXPERIENCE ON GMA 95% used 5-ASA/sulphasalazine, 84% azathioprine/ Most published studies reports concern adult patients. methotrexate, and 81% were on steroids. In a large Scandinavian study (22) of 100 adult Apheresis treatment was given once a week for 5 patients with IBD, 52 patients with UC, 44 with to 10 sessions. Patients were evaluated at the begin- Crohn’s disease and 4 with indeterminate colitis, were ning, at the end and three months after the end of GMA treated with GMA; 97% were either corticosteroid- treatment. Treatment response was evaluated in 3 dif- dependent or corticosteroid-refractory. Clinical remis- ferent ways: 1. using the severity index PUCAI for UC sion (defined as an absence/near absence of and PCDAI for Crohn’s disease, 2. tapering of corti- symptoms) was attained in 48% of UC patients and in costeroids and 3. clinical response at the end of treat- addition 27% evinced clinical response (improvement ment. Clinical response was raked complete if the of symptoms) to GMA treatment. In the Crohn’s group patient had <3 stools/day, there was no blood in the 41% attained remission and 23% gave partial stools and the child had no abdominal pain and pur- response. Tomomasa and coworkers (23) evaluated sued normal social activity. Response was partial when retrospectively 12 children with UC, mean age 12.2 there was regression in symptoms, the number of years; they received GMA treatment for 5–10 consec- stools was <5/d and blood was seen occasionally but utive weeks. In 8 patients clinical symptoms were alle- not daily. No response was defined when the patient viated after two GMA sessions. The steroid dose was showed no benefit from the treatment. tapered during GMA therapy by 50%. No serious In the UC group, the mean PUCAI points before adverse effects were noted. Four out of the 8 cases treatment were 38.8 (SD 21.8), at the end of treatment relapsed 3.5 (SD2.2) months after the last GMA ses- 10.1 (SD 5) (p = 0.001) and three months later 4.6 (SD sion, while the other 4 were in remission up to 22.8 6.2) (p = 0.002). Corticosteroids were tapered off alto- (SD 18.1) months. A study by de Carpi et al (24) and gether only in 4/19 UC children during the follow-up associates involved 5 children with UC and 4 with while a significant reduction of the corticosteroid dose Crohn’s disease; mean age 13 years 9 months and was seen, from 22.5 mg at the beginning to 15 mg after mean disease duration was 28 months. All UC patients the treatment and to 7.5 mg 3 months later in the were steroid-dependent and Crohn’s patients had been remainder. treated unsuccessfully with other therapies, including In the Crohn’s group, the mean PCDAI before enteral nutrition, steroids, immunomodulators and bio- treatment was 31.1 (SD 23.7), at the end of treatment logics. After 5 GMA sessions 4 out of 5 UC patients 23.2 (SD 23.5) (p = NS) and three months later 8.2 (SD and 1 of the 4 Crohn’s patients achieved remission and 8.1) (p = 0.025). The two children with IC had a base- steroids could be tapered off in 3 out of 5. After a one line mean PUCAI index of 50(SD 0), at the end 5 (SD year follow-up, 2 out of 4 UC patients were still in 0), and three months later 37.5 (SD10.6). Corticos- remission as was also the one Crohn’s patient. The teroid dosages were 12.5 mg-15 mg-5 mg in Crohn’s treatment proved to be safe and well tolerated. patients at the beginning, at the end and three months In Scandinavia GMA treatment has been used for after treatment. IBD in pediatric patients, and our data have been col- The clinical response data are shown in Table 1. lected from 3 countries: Denmark, Sweden and Fin- Treatment was well tolerated. Thirty percent of the land (25). We had altogether 37 patients, 22 with UC children had a headache after the treatment, this and 13 with Crohn’s disease and two with indetermi- resolving with one dose of paracetamol. Most com- nate colitis. The indication for GMA treatment was plained of tiredness the day after the apheresis. This, steroid dependency in 54% of cases. Twenty-four per however, had no effect on daily activities such as cent were steroid-resistant. The rest (22%) either had (continued on page 18)

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(continued from page 16)

Table 1. Clinical response to the leukocyte apheresis treatment

Complete response Partial response No response p* CD 3 (23%) 7 (54%) 3 (23%) <0.001 UC 16 (72%) 3 (14%) 3 (14%) <0.001 All 20 (54%) 10 (27%) 7 (19%) <0.001 *Pearson chi square test school attendance. None of the children considered the the conclusion being that GMA in the therapeutic man- treatment unpleasant or wished to discontinue. One agement of moderate-to-severe UC patients is cost- child had more than usual bleeding after the first two effective and ensures savings related to a reduction in apheresis sessions, this could possibly be due to rou- the adverse effects of corticosteroids and to the tinely given heparin during the treatment or to deterio- decreased number of surgical interventions required. ration of the UC. Her clinical condition subsequently Further research is needed to evaluate which improved rapidly. patients will benefit from this treatment and what will Relapses were seen during the follow-up in 14% in the optimal number of treatment sessions as well as of the UC group and 23% in the CD group. maintenance therapy. n

References CONCLUSION 1. Jakobsen C, Wewer V, Urne F, et al. Rising incidence in children not only Crohn’s disease, but also ulcerative colitis. A population In the retrospective analysis of GMA treatment in based epidemiological study from Eastern Denmark. J Crohn pediatric IBD patients, GMA showed good response Colitis 2008;2:152-157. 2. Turunen P, Kolho K-L, Auvinen A, et al. Incidence of inflamma- especially in the treatment of corticosteroid-dependent tory bowel disease in Finnish children 1987-2003. Inflamm Bowel and corticosteroid-resistant UC patients. Treatment Dis 2006;12:677-683. was also well tolerated and side-effects were mild. 3. Mamula P, Markowitz JE, Baldassano RN. Inflammatory bowel disease in early childhood and adolescence: special considera- As the cohort was particularly heterogeneous, we tions. Gastroenterol Clin North Am 2003;32:967-995. cannot draw conclusions from any sub- groups. Most 4. Ruuska T, Savilahti E, Mäki M, et al. Exclusive whole protein enteral diet versus prednisolone in the treatment of acute Crohn’s of the patients were corticosteroid-dependent, these disease in children. J Pediatr Gastroentrol Nutr 1994;19:175- being our most problematic group of patients to treat 180. 5. Wewer V, Riis L, Vind I, et al. Infliximab dependency in a and subject to various side-effects. The number of national cohort of children with Crohn’s disease. J Pediatr Gas- relapses after treatment was comparable to rates seen troenterol Nutr 2006;42:40-45. 6. Duricova D, Pedersen N, Lenicek M et al. Infliximab dependency with other treatments and is attributable to the chronic in children with Crohn’s disease. Alimeent Pharmal Ther relapsing nature of these diseases. The question of 2009;29:792-799. maintenance therapy with GMA in pediatric IBD must 7. Hyams JS, Lerer T, Griffiths A et al. Long-term outcome of infliximab maintenance therapy in children with Crohn’s disease. thus be considered. Inflamm Bowel Dis 2009;15:816-822. For the treatment procedure, it is advisable to have 8. Turunen P, Ashorn M, Auvinen A, et al. Long–term health out- comes in pediatric inflammatory bowel disease: a a well-trained pediatric nurse to perform it and skilled population–based study. Inflamm Bowel Dis 2009;15:56-62. doctor to insert the needle. When surroundings and 9. Saha MT, Ruuska T, Laippala P, et al. Growth of prepubertal children with inflammatory bowel disease. J Pediatr Gastroen- staff are understanding and reliable, the child relaxes trol Nutr 1998;26:310-314. and treatment goes smoothly. 10. Walther F, Fusch C, Radke M, et al. Osteoporosis in pediatric patients suffering from chronic inflammatory bowel disease with The cost of new treatment seems nowadays always and without steroid treatment. J Pediatr Gastroenterol Nutr to be too high. There is so far only one paper evaluat- 2006;43:42-51. ing the cost-effectiveness of GMA treatment (26). The 11. Kolho KL, Ruuska T, Savilahti E. Severe adverse reactions to infliximab therapy are common in young children with inflam- cost of traditional treatment and GMA were compared, matory bowel disease. Acta Paediatr 2007;96:128-130.

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12. Kosh JR, Oliva-Henker M. Infliximab use and hepatosplenic T 20. Hanai H, Watanabe F, Takeuchi K, et al. Leukocyte adsorptive cell lymphoma: questions to asked and lessons learned. J Pediatr apheresis for the treatment of active ulcerative colitis: a prospec- Gastroenterol Nutr 2007;44:165-167. tive, uncontrolled, pilot study. Clin Gastroenterol Hepatol 13. Pakarinen MP, Natunen J, Ashorn M, et al. Long term outcome 2003;1:28-35. of restorative proctocolectomy in children with ulcerative colitis. 21. Suzuki Y, Yoshimura N, Saniabadi AR, et al. Selective granulo- Pediatrics 2009;123:1377-1382. cyte and monocyte adsorptive apheresis as a first-line treatment 14. Hahnloser D, Pemerton JH, Wolff BG, et al. Pregnancy and deliv- for steroid naive patients with active ulcerative colitis: a prospec- ery before and after ileal pouch-anal anastomosis for inflamma- tive uncontrolled study. Dig Dis Sci 2004;4:565-571. tory bowel disease: immediate and long-term consequences and 22. Ljung T, Thomse O, Vatn M, et al. Granulocyte, monocyte/ outcomes. Dis Colon Rectum 2004;47:1127-35. apheresis for inflammatory bowel disease: The first 15. McCarthy DA, Ramptom DS, Liu Y-C. Peripheral blood neu- 100 patients treated in Scandinavia. Scand J Gastroenterol trophils in inflammatory bowel disease: morphological evidence 2007;42: 221-227. of in vivo activation in active disease. Clin Excp Immunol 23. Tomomasa T, Kobayashi A, Kaneko H, et al. Granulocyte 1991;86:489-493. adsorptive apheresis for pediatric patients with ulcerative colitis. 16. Bjarnason I, Macpherson A, Hollander D. Intestinal permeability. Dig Dis Sci 2003;48:750-754. An overview. Gastroenterology 1995;108:1566-1581. 24. de Carpi JM, Vilar P, Prieto G, Novo MDG, et al. Safety and Effi- 17. Mahida YR. The key role of macrophages in the immunopatho- cacy of Granulocyte and Monocyte Adsorption Apheresis in Pae- genesis of inflammatory bowel disease. Inflamm Bowel Dis diatric Inflammatory Bowel Disease: A Prospective Study. J 2000;6:21-33. Paediatr Gastroenterol Nutr 2008;46:1-7. 18. D’Arrigo C, Candal-Couto JJ, Greer M, et al. Human 25. Ruuska T, Wewer V, Lindgren F, Malmborg P, Lindquist M, Fc receptor–mediated adhesion under flow: a hollow fiber model Marthinsen L, Browadh L, Casswall T, Kalliomaki M, Grönlund of intravascular arrest. Clin Exp Immunol 1993;100:173-179. J. Granulocyte, Monocyte Adsorptive Apheresis in Paediatric 19. Saniabadi AR, Hanai H, Takeuchi K, et al. Adacolumn, an Inflammatory Bowel Disease: Results, Practical Issues and absorptive carrier based granulocyte and monocyte apheresis Future Perspectives. Inflamm Bowel Dis 2009;15:1049-1054. device for the treatment of inflammatory and refractory diseases 26. Panes J, Guiler M, Ginard D et al. Treatment of ulcerative colitis: associated with leukocytes. Ther Apheresis Dialysis 2003; is apheresis with Adacolumn cost-effective? Dig Liver Dis 7(1):48-59. 2007;39:617-625.

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