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N ENGL J MED 10.1056/NEJMe058123
The
new england journal
of
medicine
1
editorial
Patients at Risk
Jeffrey M. Drazen, M.D.
In clinical trials, the term “patients at risk” refers
to the altruistic people who volunteer to participate
in studies of novel treatments. In this issue of
the
Journal,
three reports
1-3
provide details about
patients who were participating in trials involving
experimental treatment with natalizumab for either
multiple sclerosis or Crohn’s disease and who
were affected by progressive multifocal leukoencephalopathy
(PML). PML is a rapidly progressive,
often fatal demyelinating brain disorder caused
by infection of the central nervous system with JC
virus
4
; it usually occurs in patients with diminished
T-cell function. These events remind us once again
of the true meaning of being a “patient at risk.”
The clinical story is intriguing. Natalizumab
(Tysabri) is a humanized monoclonal antibody to
the T-cell adhesion molecule known as
a
4
integrin;
patients given the antibody have suppressed T-cell
function. The agent was approved by the Food and
Drug Administration for the treatment of multiple
sclerosis in November 2004, but the manufacturer,
Biogen Idec, has been conducting continuing clinical
tests with the agent to clarify its role in the treatment
of a number of medical conditions. In February
of this year, two cases of PML in patients with
multiple sclerosis were diagnosed among those at
risk in these ongoing trials. Biogen Idec then put
a halt to the sales and testing of the drug. In this issue
of the
Journal,
Kleinschmidt-DeMasters and
Tyler
1
and
Langer-Gould et al.
2
provide the medical
details of these cases of PML in patients with multiple
sclerosis.
Once they were on high alert, investigators in
Belgium revisited a case of what had originally been
considered to be a fatal astrocytoma in a patient
participating in a clinical trial of natalizumab for
the treatment of Crohn’s disease. As detailed by
Van Assche and colleagues,
3
they quickly discovered
that the patient had actually died from PML.
These investigators provide strong evidence, based
on a detailed chronology of recovery of JC virus
from the blood, of a temporal association between
treatment with natalizumab and PML.
Given these data, the association between treatment
with natalizumab and the occurrence of PML
seems clear. What we do not know is the magnitude
of the risk of PML per year of exposure. It is our
understanding that Biogen Idec has examined as
many of the patients who received the drug as possible
for evidence of virus in the blood or for imaging
findings consistent with PML to determine
whether there is a reservoir of subclinical cases.
Here is where close surveillance for further active
or subclinical cases of PML becomes so important.
These data are needed to set provisional bounds on
the risk of acquiring PML. With this knowledge, a
reasonable assessment of the risk of this complication
versus the treatment benefit can be made. In
the case of natalizumab, there is a dilemma. On the
one hand, it appears to be a promising therapy for
multiple sclerosis and has raised the hopes of patients
with this debilitating condition; on the other,
the complication of PML can be fatal.
The bottom line is sobering. If we are to advance
the art of medicine, we need patients who are willing
to volunteer to be subjects in clinical trials. Despite
the obstacles presented by adverse outcomes,
clinical research must proceed if new therapies are
to be developed. We always need to remember that
these patients are “at risk.” We need to be sure that
research is carried out in a responsible manner and
that patients who volunteer to participate are treated
in an open, honest, and fair fashion; from what
is currently on the public record, Biogen appears to
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org on June 9, 2005 . For personal use only. No other uses without permission.

The
new england journal
of
medicine
2
N ENGL J MED 10.1056/NEJMe058123
have honored this trust. Patients and their families
expect no less, and we must always deliver on that
expectation.
1.
Kleinschmidt-DeMasters BK, Tyler KL. Progressive multifocal
leukoencephalopathy complicating treatment with natalizumab
and interferon beta-1a for multiple sclerosis. N Engl J Med 2005;
353.
2.
Langer-Gould A, Atlas SW, Bollen AW, Pelletier D. Progressive
multifocal leukoencephalopathy in a patient treated with natalizumab.
N Engl J Med 2005;353.
3.
Van Assche G, Van Ranst M, Sciot R, et al. Progressive multifocal
leukoencephalopathy after natalizumab therapy for Crohn’s disease.
N Engl J Med 2005;353.
4.
Berger JR, Koralnik IJ. Progressive multifocal leukoencephalopathy
and natalizumab. N Engl J Med 2005;353.
Copyright © 2005 Massachusetts Medical Society.
Copyright © 2005 Massachusetts Medical Society. All rights reserved.
Downloaded from www.nejm.org on June 9, 2005 . For personal use only. No other uses without permission.