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Table of Contents
Vol. 25, No. 3, 2007
Issue release date: September 2007
Dig Dis 2007;25:230–236
(DOI:10.1159/000103891)

The Management of Complicated Celiac Disease

Al-toma A. · Verbeek W.H.M. · Mulder C.J.J.
Department of Gastroenterology, VU University Medical Center, Amsterdam, The Netherlands
email Corresponding Author

Abstract

Refractory celiac disease (RCD) is being defined as persisting or recurring villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (IELs) in spite of a strict gluten-free diet (GFD) for >12 months or when severe persisting symptoms necessitate intervention independent of the duration of the GFD. RCD may not respond primarily or secondarily to GFD. All other causes of malabsorption must be excluded and additional features supporting the diagnosis of CD must be looked for, including the presence of antibodies in the untreated state and the presence of celiac-related HLA-DQ markers. In contrast to patients with a high percentage of aberrant T-cells, patients with RCD I seem to profit from an immunosuppressive treatment. RCD II is usually resistant to medical therapies. Response to corticosteroid treatment does not exclude underlying enteropathy-associated T-cell lymphoma. Cladribine seems to have a role, although it is less than optimal in the treatment of these patients. It may be considered, however, as the only treatment thus far studied that showed significant reduction of aberrant T cells, seems to be well tolerated, and may have beneficial long-term effects in a subgroup of patients showing significant reduction of the aberrant T-cell population. Autologous stem cell transplantation (ASCT) seems promising in those patients with persisting high percentages of aberrant T cells. The first group of patients treated with ASCT showed improvement in the small intestinal histology, together with an impressive clinical improvement. However, it remains to be proven if this therapy delays or prevents lymphoma development.


 goto top of outline Key Words

  • Autologous stem cell transplantation
  • Gluten-free diet
  • Celiac disease
  • Non-responsive celiac disease
  • Refractory celiac disease, pathogenesis
  • Cladribine
  • Enteropathy-associated T-cell lymphoma

 goto top of outline Abstract

Refractory celiac disease (RCD) is being defined as persisting or recurring villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (IELs) in spite of a strict gluten-free diet (GFD) for >12 months or when severe persisting symptoms necessitate intervention independent of the duration of the GFD. RCD may not respond primarily or secondarily to GFD. All other causes of malabsorption must be excluded and additional features supporting the diagnosis of CD must be looked for, including the presence of antibodies in the untreated state and the presence of celiac-related HLA-DQ markers. In contrast to patients with a high percentage of aberrant T-cells, patients with RCD I seem to profit from an immunosuppressive treatment. RCD II is usually resistant to medical therapies. Response to corticosteroid treatment does not exclude underlying enteropathy-associated T-cell lymphoma. Cladribine seems to have a role, although it is less than optimal in the treatment of these patients. It may be considered, however, as the only treatment thus far studied that showed significant reduction of aberrant T cells, seems to be well tolerated, and may have beneficial long-term effects in a subgroup of patients showing significant reduction of the aberrant T-cell population. Autologous stem cell transplantation (ASCT) seems promising in those patients with persisting high percentages of aberrant T cells. The first group of patients treated with ASCT showed improvement in the small intestinal histology, together with an impressive clinical improvement. However, it remains to be proven if this therapy delays or prevents lymphoma development.

Copyright © 2007 S. Karger AG, Basel


 goto top of outline References
  1. Working Group of the United European Gastroenterology Week in Amsterdam: When is a coeliac a coeliac? Eur J Gastroenterol 2001;13:1123–1128.
  2. Schuppan D, Kelly CP, Krauss N: Monitoring non-responsive patients with celiac disease. Gastrointest Endosc Clin N Am 2006;16:593–603.
  3. Wahab PJ, Crusius JB, Meijer J, Wand Mulder CJJ: Gluten challenge in borderline gluten-sensitive enteropathy. Am J Gastroenterol 2001;96:1464–1469.
  4. Abdulkarim A, Burgart L, See J, Murray J: Etiology of non-responsive celiac disease: results of a systematic approach. Am J Gastroenterol 2002;97:2016–2021.
  5. Cellier C, Delabesse E, Helmer C, et al: Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203–208.
  6. Daum S, Cellier C, Mulder CJ: Refractory coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:413–424.
  7. Marsh MN: Gluten, major histocompatibility complex and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–354.
  8. Van Belzen MJ, Meijer JW, Sandkuijl LA, et al: A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003;125:1032–1041.
  9. Mazzarella G, Maglio M, Paparo F, et al: An immunodominant DQ8-restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients. Gut 2003;52:57–62.
  10. Karell K, Louka AS, Moodie SJ, et al: European genetics cluster on celiac disease. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003;64:469–477.
  11. Al-toma A, Goerres MS, Meijer JW, Pena AS, Crusius JB, Mulder CJ: Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol 2006;4:315–319.
  12. Vahedi K, Mascart F, Mary JY, et al: Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol 2003;98:1079–1087.
  13. Mulder CJ, Harkema IM, Meijer JW, De Boer NK: Microscopic colitis. Rom J Gastroenterol 2004;13:113–117.

    External Resources

  14. Chott A, Dragosics B, Radaszkiewicz T: Peripheral T-cell lymphomas of the intestine. Am J Pathol 1992;141:1361–1371.
  15. Daum S, Ullrich R, Heise W, et al: Intestinal non-Hodgkin’s lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal Non-Hodgkin’s Lymphoma. J Clin Oncol 2003;21:2740–2746.
  16. Schmitt-Gräff A, Hummel M, Zemlin M, et al: Intestinal T-cell lymphoma: a reassessment of cytomorphological features in relation to patterns of small bowel remodelling. Virchows Arch 1996;429:27–36.
  17. Tomei E, Diacinti D, Marini M, Mastropasqua M, Di Tola M, Sabbatella L, Picarelli A: Abdominal CT findings may suggest coeliac disease. Dig Liver Dis 2005;37:402–406.
  18. Hadithi M, Mallant M, Oudejans J, et al: 18F-FDG-PET-fluorodeoxyglucose positron emission tomography versus computed tomography for the detection of enteropathy-associated T-cell lymphoma in refractory celiac disease. J Nucl Med 2006;47:1622–1627.
  19. Yamamoto H, Sekine Y, Sato Y, et al: Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc 2001;53:216–220.
  20. Ell C, May A, Nachbar L, et al: Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study. Endoscopy 2005;37:613–616.
  21. Ashton-Key M, Diss T, Pan L, et al: Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy-associated T-cell lymphoma. Am J Pathol 1997;151:493–498.
  22. Verkarre V, Asnafi V, Lecomte T, et al: Refractory coeliac disease is a diffuse gastrointestinal disease. Gut 2003;52:205–211.
  23. Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, Spaenij L, Koning F: The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T-cell responses. Proc Natl Acad Sci USA 2003;100:12390–12395.
  24. Bagdi E, Diss TC, Munson P, Isaacson PG: Mucosal intraepithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population. Blood 1999;94:260–264.
  25. Blumberg RS, Yockey CE, Gross GG, Ebert EC, Balk SP: Human intestinal intraepithelial lymphocytes are derived from a limited number of T-cell clones that utilize multiple Vβ T-cell receptor genes. J Immunol 1993;150:5144–5153.
  26. Goerres MS, Meijer JW, Wahab PJ, et al: Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther 2003;18:487–494.
  27. Wahab P, Crusius J, Meijer J, et al: Cyclosporin in the treatment of adults with refractory coeliac disease – an open pilot study. Aliment Pharmacol Ther 2000;14:767–774.
  28. Gillet HR, Arnott IDR, McIntyre M, et al: Successful infliximab treatment for steroid-refractory celiac disease: a case report. Gastroenterology 2002;122:800–805.
  29. Maurino E, Niveloni S, Chernavsky A, et al: Azathioprine in refractory sprue: results from a prospective, open-label study. Am J Gastroenterol 2002;97:2595–2602.
  30. Turner SM, Moorghen M, Probert CS: Refractory coeliac disease: remission with infliximab and immunomodulators. Eur J Gastroenterol Hepatol 2005;17:667–691.
  31. Al-toma A, Goerres MS, Meijer JW, von Blomberg BM, Wahab PJ, Kerckhaert JA, Mulder CJ: Cladribine therapy in refractory celiac disease with aberrant T cells. Clin Gastroenterol Hepatol 2006;4:1322–1327.
  32. Al-toma A, Visser O, van Roessel HM, von Blomberg BME, Scholten PET, Ossenkoppele GJ, Huijgens PC, Mulder CJJ: Autologous hematopoietic stem cell transplantation in four celiacs with aberrant T cells. Blood 2007;109:2243–2249.

 goto top of outline Author Contacts

Prof. C.J.J. Mulder
University Medical Center, Department Gastroenterology
PO Box 7057, NL–1005 MB Amsterdam (The Netherlands)
Tel. +31 20 444 0613, Fax +31 20 444 0554
E-Mail cjmulder@vumc.nl


 goto top of outline Article Information

Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 32


 goto top of outline Publication Details

Digestive Diseases (Clinical Reviews)

Vol. 25, No. 3, Year 2007 (Cover Date: September 2007)

Journal Editor: Malfertheiner, P. (Magdeburg)
ISSN: 0257–2753 (print), 1421–9875 (Online)

For additional information: http://www.karger.com/DDI


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Refractory celiac disease (RCD) is being defined as persisting or recurring villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes (IELs) in spite of a strict gluten-free diet (GFD) for >12 months or when severe persisting symptoms necessitate intervention independent of the duration of the GFD. RCD may not respond primarily or secondarily to GFD. All other causes of malabsorption must be excluded and additional features supporting the diagnosis of CD must be looked for, including the presence of antibodies in the untreated state and the presence of celiac-related HLA-DQ markers. In contrast to patients with a high percentage of aberrant T-cells, patients with RCD I seem to profit from an immunosuppressive treatment. RCD II is usually resistant to medical therapies. Response to corticosteroid treatment does not exclude underlying enteropathy-associated T-cell lymphoma. Cladribine seems to have a role, although it is less than optimal in the treatment of these patients. It may be considered, however, as the only treatment thus far studied that showed significant reduction of aberrant T cells, seems to be well tolerated, and may have beneficial long-term effects in a subgroup of patients showing significant reduction of the aberrant T-cell population. Autologous stem cell transplantation (ASCT) seems promising in those patients with persisting high percentages of aberrant T cells. The first group of patients treated with ASCT showed improvement in the small intestinal histology, together with an impressive clinical improvement. However, it remains to be proven if this therapy delays or prevents lymphoma development.



 goto top of outline Author Contacts

Prof. C.J.J. Mulder
University Medical Center, Department Gastroenterology
PO Box 7057, NL–1005 MB Amsterdam (The Netherlands)
Tel. +31 20 444 0613, Fax +31 20 444 0554
E-Mail cjmulder@vumc.nl


 goto top of outline Article Information

Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 0, Number of References : 32


 goto top of outline Publication Details

Digestive Diseases (Clinical Reviews)

Vol. 25, No. 3, Year 2007 (Cover Date: September 2007)

Journal Editor: Malfertheiner, P. (Magdeburg)
ISSN: 0257–2753 (print), 1421–9875 (Online)

For additional information: http://www.karger.com/DDI


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Working Group of the United European Gastroenterology Week in Amsterdam: When is a coeliac a coeliac? Eur J Gastroenterol 2001;13:1123–1128.
  2. Schuppan D, Kelly CP, Krauss N: Monitoring non-responsive patients with celiac disease. Gastrointest Endosc Clin N Am 2006;16:593–603.
  3. Wahab PJ, Crusius JB, Meijer J, Wand Mulder CJJ: Gluten challenge in borderline gluten-sensitive enteropathy. Am J Gastroenterol 2001;96:1464–1469.
  4. Abdulkarim A, Burgart L, See J, Murray J: Etiology of non-responsive celiac disease: results of a systematic approach. Am J Gastroenterol 2002;97:2016–2021.
  5. Cellier C, Delabesse E, Helmer C, et al: Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203–208.
  6. Daum S, Cellier C, Mulder CJ: Refractory coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:413–424.
  7. Marsh MN: Gluten, major histocompatibility complex and the small intestine. A molecular and immunobiologic approach to the spectrum of gluten sensitivity (‘celiac sprue’). Gastroenterology 1992;102:330–354.
  8. Van Belzen MJ, Meijer JW, Sandkuijl LA, et al: A major non-HLA locus in celiac disease maps to chromosome 19. Gastroenterology 2003;125:1032–1041.
  9. Mazzarella G, Maglio M, Paparo F, et al: An immunodominant DQ8-restricted gliadin peptide activates small intestinal immune response in in vitro cultured mucosa from HLA-DQ8 positive but not HLA-DQ8 negative coeliac patients. Gut 2003;52:57–62.
  10. Karell K, Louka AS, Moodie SJ, et al: European genetics cluster on celiac disease. HLA types in celiac disease patients not carrying the DQA1*05-DQB1*02 (DQ2) heterodimer: results from the European Genetics Cluster on Celiac Disease. Hum Immunol 2003;64:469–477.
  11. Al-toma A, Goerres MS, Meijer JW, Pena AS, Crusius JB, Mulder CJ: Human leukocyte antigen-DQ2 homozygosity and the development of refractory celiac disease and enteropathy-associated T-cell lymphoma. Clin Gastroenterol Hepatol 2006;4:315–319.
  12. Vahedi K, Mascart F, Mary JY, et al: Reliability of antitransglutaminase antibodies as predictors of gluten-free diet compliance in adult celiac disease. Am J Gastroenterol 2003;98:1079–1087.
  13. Mulder CJ, Harkema IM, Meijer JW, De Boer NK: Microscopic colitis. Rom J Gastroenterol 2004;13:113–117.

    External Resources

  14. Chott A, Dragosics B, Radaszkiewicz T: Peripheral T-cell lymphomas of the intestine. Am J Pathol 1992;141:1361–1371.
  15. Daum S, Ullrich R, Heise W, et al: Intestinal non-Hodgkin’s lymphoma: a multicenter prospective clinical study from the German Study Group on Intestinal Non-Hodgkin’s Lymphoma. J Clin Oncol 2003;21:2740–2746.
  16. Schmitt-Gräff A, Hummel M, Zemlin M, et al: Intestinal T-cell lymphoma: a reassessment of cytomorphological features in relation to patterns of small bowel remodelling. Virchows Arch 1996;429:27–36.
  17. Tomei E, Diacinti D, Marini M, Mastropasqua M, Di Tola M, Sabbatella L, Picarelli A: Abdominal CT findings may suggest coeliac disease. Dig Liver Dis 2005;37:402–406.
  18. Hadithi M, Mallant M, Oudejans J, et al: 18F-FDG-PET-fluorodeoxyglucose positron emission tomography versus computed tomography for the detection of enteropathy-associated T-cell lymphoma in refractory celiac disease. J Nucl Med 2006;47:1622–1627.
  19. Yamamoto H, Sekine Y, Sato Y, et al: Total enteroscopy with a nonsurgical steerable double-balloon method. Gastrointest Endosc 2001;53:216–220.
  20. Ell C, May A, Nachbar L, et al: Push-and-pull enteroscopy in the small bowel using the double-balloon technique: results of a prospective European multicenter study. Endoscopy 2005;37:613–616.
  21. Ashton-Key M, Diss T, Pan L, et al: Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy-associated T-cell lymphoma. Am J Pathol 1997;151:493–498.
  22. Verkarre V, Asnafi V, Lecomte T, et al: Refractory coeliac disease is a diffuse gastrointestinal disease. Gut 2003;52:205–211.
  23. Vader W, Stepniak D, Kooy Y, Mearin L, Thompson A, van Rood JJ, Spaenij L, Koning F: The HLA-DQ2 gene dose effect in celiac disease is directly related to the magnitude and breadth of gluten-specific T-cell responses. Proc Natl Acad Sci USA 2003;100:12390–12395.
  24. Bagdi E, Diss TC, Munson P, Isaacson PG: Mucosal intraepithelial lymphocytes in enteropathy-associated T-cell lymphoma, ulcerative jejunitis, and refractory celiac disease constitute a neoplastic population. Blood 1999;94:260–264.
  25. Blumberg RS, Yockey CE, Gross GG, Ebert EC, Balk SP: Human intestinal intraepithelial lymphocytes are derived from a limited number of T-cell clones that utilize multiple Vβ T-cell receptor genes. J Immunol 1993;150:5144–5153.
  26. Goerres MS, Meijer JW, Wahab PJ, et al: Azathioprine and prednisone combination therapy in refractory coeliac disease. Aliment Pharmacol Ther 2003;18:487–494.
  27. Wahab P, Crusius J, Meijer J, et al: Cyclosporin in the treatment of adults with refractory coeliac disease – an open pilot study. Aliment Pharmacol Ther 2000;14:767–774.
  28. Gillet HR, Arnott IDR, McIntyre M, et al: Successful infliximab treatment for steroid-refractory celiac disease: a case report. Gastroenterology 2002;122:800–805.
  29. Maurino E, Niveloni S, Chernavsky A, et al: Azathioprine in refractory sprue: results from a prospective, open-label study. Am J Gastroenterol 2002;97:2595–2602.
  30. Turner SM, Moorghen M, Probert CS: Refractory coeliac disease: remission with infliximab and immunomodulators. Eur J Gastroenterol Hepatol 2005;17:667–691.
  31. Al-toma A, Goerres MS, Meijer JW, von Blomberg BM, Wahab PJ, Kerckhaert JA, Mulder CJ: Cladribine therapy in refractory celiac disease with aberrant T cells. Clin Gastroenterol Hepatol 2006;4:1322–1327.
  32. Al-toma A, Visser O, van Roessel HM, von Blomberg BME, Scholten PET, Ossenkoppele GJ, Huijgens PC, Mulder CJJ: Autologous hematopoietic stem cell transplantation in four celiacs with aberrant T cells. Blood 2007;109:2243–2249.