Alemtuzumab for Refractory Celiac Disease
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《新英格兰医药杂志》
To the Editor: Vivas et al. (June 8 issue)1 describe a patient with refractory celiac disease who had a response to treatment with alemtuzumab. It is not clear whether the percentage of aberrant intraepithelial lymphocytes decreased while the patient was receiving alemtuzumab, since only T cells are mentioned. However, the aberrant T-cell population (CD7+CD3–CD4–CD8– cytoplasmic CD3+) determines the risk of enteropathy-associated T-cell lymphoma. This population is distinct from the population of T cells.2,3
We report on a 66-year-old woman who had refractory celiac disease with progressively more aberrant intraepithelial lymphocytes despite treatment with alemtuzumab. The patient had been on a gluten-free diet and had undergone therapy with prednisone and cladribine. Duodenal biopsy showed persistent total villous atrophy. Flow cytometry of intraepithelial lymphocytes revealed that 60% were aberrant. The percentage of T cells was only 1%.
Alemtuzumab was started. Although we observed clinical improvement, villous atrophy persisted, and the percentage of aberrant intraepithelial lymphocytes increased to 91%. Moreover, skin lesions showing aberrant T cells developed. A case with similar disappointing results has been reported by Lundin et al.4
An explanation may be that intraepithelial lymphocytes are not effectively targeted by alemtuzumab, since in our patient all aberrant intraepithelial lymphocytes still expressed CD52 after treatment with the drug, whereas no CD52+ lymphocytes could be detected in peripheral blood.
Wieke H.M. Verbeek, M.D.
Chris J.J. Mulder, M.D., Ph.D.
Sonja Zweegman, M.D., Ph.D.
Vrije Universiteit Medical Center
1081 HV Amsterdam, the Netherlands
s.zweegman@vumc.nl
References
Vivas S, Ruiz de Morales JM, Ramos F, Suárez-Vilela D. Alemtuzumab for refractory celiac disease in a patient at risk for enteropathy-associated T-cell lymphoma. N Engl J Med 2006;354:2514-2515.
Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203-208.
Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:413-424.
Lundin KE, Farstad IN, Raki M, Benestad Y, Hoie O, Tjonnfjord G. Alemtuzumab treatment of refractory celiac disease type II. Gastroenterology 2006;130:Suppl 2:A-666.
The authors reply: We completely agree that an aberrant T-cell population is the basis for the diagnosis of refractory celiac disease and determines the risk of enteropathy-associated T-cell lymphoma.1 In our patient, flow cytometry of intraepithelial lymphocytes revealed that 70% were aberrant before therapy and 30% were aberrant after therapy. In contrast to the case described by Verbeek et al., we observed a greater decrease in the entire population of intraepithelial lymphocytes expressing CD52. This suggests that intraepithelial lymphocytes may have been effectively targeted by alemtuzumab. In our patient, the number of normal T cells was high — a hallmark of celiac disease.2 However, Verbeek et al. observed only 1% T cells. We speculate that a more advanced stage of disease with a greater expansion of abnormal lymphocytes may decrease the normal population of T cells.
Although ineffective targeting of aberrant mucosal cells is a possibility, disseminated clonal expansion3 could explain the lack of response in the patients treated by Verbeek et al. and Lundin et al.4 Multicenter trials should be performed to identify the role of alemtuzumab in this heterogeneous group of patients.
Santiago Vivas, M.D.
Jose María Ruiz de Morales, M.D.
Fernando Ramos, M.D.
Hospital de León
24071 León, Spain
References
Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203-208.
Collin P, Wahab PJ, Murray JA. Intraepithelial lymphocytes and coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:341-350.
Daum S, Weiss D, Hummel M, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut 2001;49:804-812.
Lundin KE, Farstad IN, Raki M, Benestad Y, Hoie O, Tjonnfjord G. Alemtuzumab treatment of refractory celiac disease type II. Gastroenterology 2006;130:Suppl 2:A-666.
We report on a 66-year-old woman who had refractory celiac disease with progressively more aberrant intraepithelial lymphocytes despite treatment with alemtuzumab. The patient had been on a gluten-free diet and had undergone therapy with prednisone and cladribine. Duodenal biopsy showed persistent total villous atrophy. Flow cytometry of intraepithelial lymphocytes revealed that 60% were aberrant. The percentage of T cells was only 1%.
Alemtuzumab was started. Although we observed clinical improvement, villous atrophy persisted, and the percentage of aberrant intraepithelial lymphocytes increased to 91%. Moreover, skin lesions showing aberrant T cells developed. A case with similar disappointing results has been reported by Lundin et al.4
An explanation may be that intraepithelial lymphocytes are not effectively targeted by alemtuzumab, since in our patient all aberrant intraepithelial lymphocytes still expressed CD52 after treatment with the drug, whereas no CD52+ lymphocytes could be detected in peripheral blood.
Wieke H.M. Verbeek, M.D.
Chris J.J. Mulder, M.D., Ph.D.
Sonja Zweegman, M.D., Ph.D.
Vrije Universiteit Medical Center
1081 HV Amsterdam, the Netherlands
s.zweegman@vumc.nl
References
Vivas S, Ruiz de Morales JM, Ramos F, Suárez-Vilela D. Alemtuzumab for refractory celiac disease in a patient at risk for enteropathy-associated T-cell lymphoma. N Engl J Med 2006;354:2514-2515.
Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203-208.
Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:413-424.
Lundin KE, Farstad IN, Raki M, Benestad Y, Hoie O, Tjonnfjord G. Alemtuzumab treatment of refractory celiac disease type II. Gastroenterology 2006;130:Suppl 2:A-666.
The authors reply: We completely agree that an aberrant T-cell population is the basis for the diagnosis of refractory celiac disease and determines the risk of enteropathy-associated T-cell lymphoma.1 In our patient, flow cytometry of intraepithelial lymphocytes revealed that 70% were aberrant before therapy and 30% were aberrant after therapy. In contrast to the case described by Verbeek et al., we observed a greater decrease in the entire population of intraepithelial lymphocytes expressing CD52. This suggests that intraepithelial lymphocytes may have been effectively targeted by alemtuzumab. In our patient, the number of normal T cells was high — a hallmark of celiac disease.2 However, Verbeek et al. observed only 1% T cells. We speculate that a more advanced stage of disease with a greater expansion of abnormal lymphocytes may decrease the normal population of T cells.
Although ineffective targeting of aberrant mucosal cells is a possibility, disseminated clonal expansion3 could explain the lack of response in the patients treated by Verbeek et al. and Lundin et al.4 Multicenter trials should be performed to identify the role of alemtuzumab in this heterogeneous group of patients.
Santiago Vivas, M.D.
Jose María Ruiz de Morales, M.D.
Fernando Ramos, M.D.
Hospital de León
24071 León, Spain
References
Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:203-208.
Collin P, Wahab PJ, Murray JA. Intraepithelial lymphocytes and coeliac disease. Best Pract Res Clin Gastroenterol 2005;19:341-350.
Daum S, Weiss D, Hummel M, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut 2001;49:804-812.
Lundin KE, Farstad IN, Raki M, Benestad Y, Hoie O, Tjonnfjord G. Alemtuzumab treatment of refractory celiac disease type II. Gastroenterology 2006;130:Suppl 2:A-666.