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#Post#: 1721--------------------------------------------------
Induction of new autoimmune diseases after alemtuzumab therapy f
or MS: Learning from adversity
By: agate Date: June 13, 2017, 12:40 am
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An editorial in JAMA Neurology, June 12, 2017, seems to be
trying to find something positive about the diseases like PML
that crop up as a result of some of the MS disease-modifying
drugs:
[quote]Induction of New Autoimmune Diseases After Alemtuzumab
Therapy for Multiple Sclerosis: Learning from Adversity
Lawrence Steinman, MD1
1Department of Neurology and Neurological Sciences, Stanford
University, Stanford, California
We all learn from adversity. In pharmaceutical development, this
adage is manifest in helping to define the risk part of the
risk-benefit profile for a potential therapeutic agent. We refer
to serious adverse events (SAEs) in the standard vocabulary of
those engaged in clinical trials. Serious adverse events are
described in detail in the package insert for an approved
pharmaceutical. In this issue of JAMA Neurology, Baker and
colleagues1 describe a potential mechanism that provides
insights into this SAE of the multiple sclerosis (MS) treatment
alemtuzumab. Baker et al explain how alemtuzumab might trigger
new autoimmune disease as the immune system reconstitutes itself
after administration.
Two of the major approved therapies for MS, natalizumab and
alemtuzumab, have SAEs.1- 3 In the case of natalizumab,
progressive multifocal leukoencephalopathy (PML) appeared in 3
patients, 3 months after it was approved in 2005.3 When
natalizumab is given monthly for more than 24 doses, the
incidence of PML is 1 in 75 or higher4 in patients who are
seropositive for the JC virus. With alemtuzumab, one-quarter of
treated individuals develop a new autoimmune disease, subsequent
to treatment of their MS.1,2 The insights gained from studying
this adverse effect of alemtuzumab,1 as well as those learned
from the study of PML after therapy with natalizumab,3,4 teach
us important lessons about physiology.
In the development of new therapies, adverse effects of drugs
are unique opportunities to study physiology under a selective
pressure imposed through the fruits of medical science. For
example, although immune surveillance of the brain was a topic
that experts theorized and debated, the unfortunate development
of PML after long-term use of natalizumab for more than 1 or 2
years illuminated this previously controversial notion. The SAE
from natalizumab provided evidence that “immune surveillance” of
the brain is ongoing. If one impeded T cell, B cell, and
macrophage homing to the brain for longer than 2 years with
natalizumab targeting α4 integrin, then the incidence of
PML reached approximately 1% of those exposed.3,4 One of the
implications of this serious complication with its disturbingly
high frequency was that indeed immune surveillance of the brain
is routine and provides real protection. Impairing immune
surveillance resulted in a serious infectious disease.
Learning a lesson from this adverse event with natalizumab
provided a further benefit. Researchers developed the diagnostic
test to predict the risk for PML and to allow selection of
patients relatively free of risk: the JC virus antibody test.3
Thus, an adverse event gave insights into normal physiology and
allowed the first predictive test approved by the US Food and
Drug Administration to mitigate the serious risk of an effective
therapeutic.
Alemtuzumab is a humanized monoclonal directed to a cell surface
molecule known as CD52 present on T and B cells.1 Profound
depletion of T and B cells occurs when a course of alemtuzumab
is given.1 T and B cells represent a variety of cell populations
with nuanced functions, including those that carry out so-called
effector functions, such as the killing of cellular targets, and
those that engage in regulatory or suppressive functions,
thereby restraining the immune responses mediated by T and B
cells.5
Baker et al1 analyzed how T and B cell populations returned
after a course of therapy with alemtuzumab. T and B cells were
largely depleted, meaning 90% or more were deleted.1 However,
the B cells repopulated much more rapidly than the T cells. Of
note, a regulatory T-cell population returned much more slowly
than the B cells. The reconstitution of the B-cell population
without adequate regulatory control from T cells is a strategic
hypothesis that Baker et al1 have raised to explain how
autoimmunity arises so often following alemtuzumab.
The implications of this hypothesis might obviously go far
beyond these adverse effects seen with alemtuzumab in MS. The
hypothesis may provide considerable insight into how autoimmune
diseases arise in general. A generalization of this hypothesis
might be that B-cell development without adequate T-cell
regulatory control is a critical factor in the development of
autoimmune disease. This generalization might apply to some of
those most common autoimmune conditions, including Graves
disease, Hashimoto thyroiditis, and some of the rarer conditions
such as idiopathic thrombocytopenic purpura seen with
alemtuzumab therapy.1
If this hypothesis gains traction—and it indeed has precedent
from other studies—it would be yet another example of how SAEs,
even from approved therapies, help to inform us of how the
immune system functions in health and in disease. Autoimmune
diseases in general may arise from B-cell development without
adequate control from regulatory T cells. That concept, applied
broadly, would be a significant advance in understanding
autoimmunity.
Gratitude is extended to Baker and coauthors1 for those careful
measurements of immune cell repopulation after a successful
therapy for MS and for their astute interpretation of the data,
all emanating from an unwanted SAE. Their observations may
kindle further advances in understanding how autoimmunity
arises.[/quote]
[References omitted]
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