Author Topic: Induction of new autoimmune diseases after alemtuzumab therapy for MS: Learning from adversity  (Read 46 times)

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Offline agate

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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:

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.

[References omitted]
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SPMS, diagnosed 1980. Avonex 2001-2004. Copaxone 2007-2010.


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