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Bone Marrow Transplantation (2003) 32, S57–S59& 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 Hematopoietic stem cell transplantation for severe Crohn’s disease Division of Immunotherapy, Northwestern University Medical Center, Chicago, IL, USA corticosteroids that are broad-spectrum anti-inflammatoryagents;2–9 cytokine suppression or stimulation that work on It is clear that some patients with severe Crohn’s disease the expression of inflammation rather than at the patho- (CD) fail to respond favorably to the standard treatment, genesis of the inflammation;10–12 and antibiotics, such as including antibody to Tumor Necrosis Factor alpha metronidazole and quinolones that may perhaps decrease (TNFa). We have embarked on a unique therapy for this exposure to responsible antigens.13 None of these therapies group of patients, intense immune suppression followed by gets at the fundamental nature of the inflammatory process.
Standard therapies suppress until a spontaneous remission (HSCT). The response to this approach in our first four patients has been excellent, with there being no significant Although there are little data on CD mortality, it is clear untoward event from the transplantation and with each that CD has a mortality in and of itself, supported by one patient entering clinical remission in terms of the Crohn’s of the largest series of CD which reported a 6% mortality Disease Activity Index off all therapy for CD and no rate.14,15 In a selected series such as patients with severe and diarrhea or abdominal pain. However, some evidence of refractory disease, the mortality rate is probably higher, minor laboratory abnormalities and slight inflammation perhaps in the 10% range.Serious morbidity accompanies of the colon on colonoscopic evaluation persist up to 1 Crohn’s disease including fistulae, abscesses, eye, skin joint year post-transplant. It is suggested that HSCTshould be and hepatic problems, the need for recurrent surgery and considered a reasonable option for patients who have eventual short bowel syndrome necessitating home par- failed standard CD therapy, although long-term follow-up enteral nutrition and its complications, and abdominal pain will be necessary to confirm the duration of the induced with resultant drug addiction.15–17 Support for HSCT comes from reported patients who had undergone either Bone Marrow Transplantation (2003) 32, S57–S59.
allogeneic or autologous HSCT and had incidental CD.18–21 Crohn’s disease; autologous stem cell trans- plantation; hematopoietic stem cell transplantation Candidates for HSCT must have failed prednisone,azathioprine, azulfidine, metronidazole, and remicade Approximately 4 years ago, Northwestern University (TNF inhibitor) with failure defined as a Crohn’s Disease opened a protocol for hematopoietic stem cell transplanta- Activity Index (CDAI) greater than 250 on a scale of 0 to tion (HSCT) in severe Crohn’s disease (CD).Although the 400 (Table 1).22 We have found the CDAI to be an proposal was approved by the FDA and local Institutional imperfect assessment of CD morbidity and are in the Review Board, the first suitable candidate underwent this process of evaluating the Craig Crohn’s Severity Score procedure 1 year ago.Since then, three additional patients (Table 2) for future trials.As an example of the type of have undergone this treatment.The response has been candidate, our first patient, a 22-year-old female had excellent, with the patients rapidly going into clinical continuous disease for 10 years, with up to 25 bowel remission, although the two longest-duration patients still movements daily, requiring an ileo colonic resection at one have superficial ulcerations seen on colonoscopy.
point.She had been on total parenteral nutrition for 2 While CD is an immune-mediated disease, it is not at all years.She was also addicted to narcotics, receiving 3 mg/h clear that autoimmunity is the underlying pathogenesis.It intravenous hydromorphone.Her CDAI was 305.She had may, instead, be an unbalanced reaction towards gut flora.
severe colitis and ileitis on both colonoscopy and small Standard therapy for CD includes: five-aminosalicylic acid products that are anti-inflammatory and work locally;1 Peripheral blood stem cells are mobilized with cyclo- phosphamide 2.0 g/m2 and G-CSF 10 mg/kg/day and en-riched via an Isolex cell separator.Conditioning iscyclophosphamide 200 mg/kg and antithymocyte globulin Correspondence: Dr RK Burt, Division of Immunotherapy, North- (ATG 90 mg/1 kg & ATG 5.5 mg/kg). Post-transplant western University Medical Centre, Chicago, IL 60611, USA.E-mail:[email protected] evaluation includes CDAI, Inflammatory Disease Bowel iritis, erythema nodosum, pyodermagangrenosa, aphthous ulcerations,anal fissure, anal fistula, anal abscess, From Best et al22: CDAIo150=remission; >450=severely ill.
Questionnaire, colonoscopy, small bowel radiographs, CRP, sedimentation rate, albumin, weight, and anti-Saccharomyces Four patients have completed HSCT.One of these subjects is 1 year, one is 11 months, one is 2 months andthe final is 2 weeks post-transplantation.The only toxicity in these patients was culture-negative fever for 24 to 48 hours.23 Abdominal pain and diarrhea resolved for themost part during the hospitalization.In all patients, the CDAI and the severity index have normalized despite withdrawal of all therapy for CD.However, some of the colonoscopies show persistent but asymptomatic mild inflammation.While the depth of this remission and how long this remission will last remains uncertain, it is reasonable to consider HSCT in patients with severe CD so long as these patients have failed standard therapy.
1 Rao SS, Cann PA, Holdsworth CD.Clinical experience of the tolerance of mesalazine and olsalazine in patients intolerant ofsulfasalazine. Scand J Gastroenterol 1987; 22: 332–336.
newly diagnosed Crohn’s disease. Gastroenterology 2000; 119: 2 Summers RW, Switz DM, Sessions Jr JT et al.National Cooperative Crohn’s Disease Study: Results of drug treatment.
7 Brynshov J, Freund L, Rasmussen SN et al.A place- Gastroenterology 1979; 77: 847–869.
bo-controlled, double-blind, randomized trial of cyclosporine 3 Bar-Meir S, Chowers Y, Lavy A et al.Budesonide versus therapy in active chronic Crohn’s disease. N Engl J Med 1989; prednisone in the treatment of active Crohn’s disease.
Gastroenterology 1998; 115: 835–840.
8 Kozarek RA, Patterson DJ, Gelfand MD et al.Methotrexate 4 Willoughby JM, Becket J, Kumar PJ, Dawson JM.Controlled induces clinical and histologic remission in patients with trial of azathioprine in Crohn’s disease. Lancet 1971; 2: refractory inflammatory bowel disease. Ann Intern Med 1989; 5 Present DH, Korelitz BI, Wisch N et al.Treatment of Crohn’s 9 Neurath MF, Wanitschke R, Peters M et al.Randomized trial disease with 6-mercaptopurine.A long-term, randomized, of mycophenolate mofetil versus azathioprine for treatment of double-blind study. N Engl J Med 1980; 302: 981–987.
chronic active Crohn’s disease. Gut 1999; 44: 625–628.
6 Markowitz J, Grancher K, Kohn N et al.A multicenter trial 10 Targan S, Hanauer SB, van Deventer SJH et al.A short-term study of chimeric monoclonal antibody cA2 to tumor necrosis factor a for Crohn’s disease. N Engl J Med 1997; 337: 11 Present DP, Rutgeerts P, Targan S et al.Infliximab for the 18 Lopez-Cubera SO, Sullivan KM, McDonald GB.Course treatment of fistulas in patients with Crohn’s disease. N Engl J of Crohn’s disease after allogeneic bone marrow transplant- ation. Gastroenterology 1998; 114: 433–440.
12 Fedorak RN, Gangl A, Elson CO et al.Recombinant human 19 Drakos PE, Nagler A, Or R.Case of Crohn’s disease in interleukin 10 in the treatment of patients with mild to bone marrow transplantation. Am J Hematol 1993; 43: moderately active Crohn’s disease. Gastroenterology 2000; 119: 20 Kashyap A, Foreman SJ.Autologous bone marrow trans- 13 Bernstein LH, Frank MS, Brant LJ, Boley SJ.Healing of plantation for non-Hodgkin’s lymphoma resulting in long term perineal Crohn’s disease with metronidazole. Gastroenterology remission of coincidental Crohn’s disease. Br J Haematol 1998; 14 Farmer RG, Hawk WA, Turnbull RB.Clinical patterns 21 Castro J, Benich HI, Smith HL.Prolonged clinical remission in in Crohn’s disease: a statistical study of 615 cases. Gastro- patients with inflammatory bowel disease after high dose chemotherapy and autologous bone marrow stem cell trans- 15 Farmer RG, Whelan G, Fazio VW.Long-term follow-up of patients with Crohn’s disease.Relationship of the clinical 22 Best WR, Becktel JM, Singleton JW, Kern F.Development of pattern and prognosis. Gastroenterology 1985; 88: 1818–1827.
a Crohn’s disease activity index.National Cooperative Crohn’s 16 Lapidus A, Bernell O, Hellers G, Lofberg R.Clinical course of Disease Study. Gastroenterology 1976; 70: 843–850.
colorectal Crohn’s disease: a 35 -year follow-up study of 507 23 Burt RK, Traynor AE, Oyama Y, Craig R.High-dose patients. Gastroenterology 1998; 114: 1151–1160.
immune suppression and autologous hematopoietic stem cell 17 Loftus EV, Silverstein MD, Sandborn WJ et al.Crohn’s transplantation in refractory Crohn’s Disease. Blood 2003; 101: disease in Olmsted county, Minnesota, 1940–1993: incidence,

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