Selective Adhesion-Molecule Therapy and Inflammatory Bowel Disease
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《新英格兰医药杂志》
To the Editor: In his editorial, Podolsky (Nov. 3 issue)1 suggests that monitoring with the use of magnetic resonance imaging (MRI) may be helpful in the care of patients with Crohn's disease who are receiving natalizumab therapy and are at risk for progressive multifocal leukoencephalopathy (PML). This is not an ideal approach. The long-term safety and efficacy of natalizumab are relatively unknown, and there is a lack of clarity regarding the optimal duration of treatment beyond the trial period. In an experimental model of inflammatory colitis, long-term treatment with anti– integrin antibodies resulted in disease exacerbation,2 indicating that the prolonged blockade of adhesion molecules is therapeutically unhelpful.
Patients with inflammatory bowel disease have an increased risk of central nervous system demyelination. There is an association of Crohn's disease with multiple sclerosis,3,4 and in one study, late multiple sclerosis developed in patients with Crohn's disease despite prolonged immunosuppression.5 The monitoring of patients with the use of MRI may not reliably distinguish multiple sclerosis from early PML. It is also likely that the use of other forms of immunosuppression increases the risk of PML in patients receiving natalizumab therapy.6
The future use of natalizumab should be limited to the subjects of a closely monitored research protocol. We must raise the bar of safety before approving any new treatment that targets a young population and carries a risk of death.
Abhijit Chaudhuri, D.M., M.D., Ph.D.
Essex Centre for Neurological Sciences
Romford RM7 0BE, United Kingdom
chaudhuria@gmail.com
References
Podolsky DK. Selective adhesion-molecule therapy and inflammatory bowel disease -- a tale of Janus? N Engl J Med 2005;353:1965-1968.
Bjursten M, Bland PW, Willen R, Hornquist EH. Long-term treatment with alpha-4 integrin antibodies aggravates colitis in G-alphai2-deficient mice. Eur J Immunol 2005;35:2274-2283.
Minuk GY, Lewkonia RM. Possible familial association of multiple sclerosis and inflammatory bowel disease. N Engl J Med 1986;314:586-586.
Gupta G, Gelfand JM, Lewis JD. Increased risk of demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129:819-826.
Constantinescu CS, Whiteley A, Blumhardt LD. Long term azathioprine fails to prevent onset of multiple sclerosis: report of two cases. Mult Scler 2000;6:362-363.
Chaudhuri A. Natalizumab for multiple sclerosis: lessons in clinical trial. BMJ (in press).
Dr. Podolsky replies: Dr. Chaudhuri raises a number of important issues, which were touched on within the editorial. It is indeed important that any new medication be closely scrutinized before ultimate regulatory approval, and natalizumab should certainly be no exception. However, the risks of adverse effects must be kept in perspective, lest patients be deprived of all needed new therapies. With regard to the frequency of reported serious complications associated with natalizumab in patients with Crohn's disease, in the aggregate they actually appear to be less frequent than those associated with a number of approved treatments.
The presence of multiple sclerosis in patients with inflammatory bowel disease would certainly provide a potentially confounding influence, and I would agree that natalizumab, if it were approved for this indication, should not be used in the small number of patients with both conditions — in order to avoid masking the development of PML.
Finally, although the single report of a potentially paradoxical effect of long-term adhesion blockade is interesting, it would be unfortunate to place undue emphasis on this limited study of a mouse model of uncertain relevance when the human model (patients with actual inflammatory bowel disease) has not shown a comparable effect.
Daniel K. Podolsky, M.D.
Massachusetts General Hospital
Boston, MA 02114
Patients with inflammatory bowel disease have an increased risk of central nervous system demyelination. There is an association of Crohn's disease with multiple sclerosis,3,4 and in one study, late multiple sclerosis developed in patients with Crohn's disease despite prolonged immunosuppression.5 The monitoring of patients with the use of MRI may not reliably distinguish multiple sclerosis from early PML. It is also likely that the use of other forms of immunosuppression increases the risk of PML in patients receiving natalizumab therapy.6
The future use of natalizumab should be limited to the subjects of a closely monitored research protocol. We must raise the bar of safety before approving any new treatment that targets a young population and carries a risk of death.
Abhijit Chaudhuri, D.M., M.D., Ph.D.
Essex Centre for Neurological Sciences
Romford RM7 0BE, United Kingdom
chaudhuria@gmail.com
References
Podolsky DK. Selective adhesion-molecule therapy and inflammatory bowel disease -- a tale of Janus? N Engl J Med 2005;353:1965-1968.
Bjursten M, Bland PW, Willen R, Hornquist EH. Long-term treatment with alpha-4 integrin antibodies aggravates colitis in G-alphai2-deficient mice. Eur J Immunol 2005;35:2274-2283.
Minuk GY, Lewkonia RM. Possible familial association of multiple sclerosis and inflammatory bowel disease. N Engl J Med 1986;314:586-586.
Gupta G, Gelfand JM, Lewis JD. Increased risk of demyelinating diseases in patients with inflammatory bowel disease. Gastroenterology 2005;129:819-826.
Constantinescu CS, Whiteley A, Blumhardt LD. Long term azathioprine fails to prevent onset of multiple sclerosis: report of two cases. Mult Scler 2000;6:362-363.
Chaudhuri A. Natalizumab for multiple sclerosis: lessons in clinical trial. BMJ (in press).
Dr. Podolsky replies: Dr. Chaudhuri raises a number of important issues, which were touched on within the editorial. It is indeed important that any new medication be closely scrutinized before ultimate regulatory approval, and natalizumab should certainly be no exception. However, the risks of adverse effects must be kept in perspective, lest patients be deprived of all needed new therapies. With regard to the frequency of reported serious complications associated with natalizumab in patients with Crohn's disease, in the aggregate they actually appear to be less frequent than those associated with a number of approved treatments.
The presence of multiple sclerosis in patients with inflammatory bowel disease would certainly provide a potentially confounding influence, and I would agree that natalizumab, if it were approved for this indication, should not be used in the small number of patients with both conditions — in order to avoid masking the development of PML.
Finally, although the single report of a potentially paradoxical effect of long-term adhesion blockade is interesting, it would be unfortunate to place undue emphasis on this limited study of a mouse model of uncertain relevance when the human model (patients with actual inflammatory bowel disease) has not shown a comparable effect.
Daniel K. Podolsky, M.D.
Massachusetts General Hospital
Boston, MA 02114