Treating MS: getting to know the two birds in the bush

Current therapies for immune-mediated diseases, such as rheumatoid arthritis and MS, could represent the proverbial bird in the hand — a known entity, yet limited in potential. Emerging biologic therapeutics for these diseases carry with them the potential for known as well as unknown adverse effects. Alemtuzumab, a biologic that depletes leukocytes, shows great promise for the treatment of MS. However, a significant number of patients develop autoimmunity after treatment, raising the level of caution for the use of this drug. In this issue of the JCI, Jones et al. describe a link between IL-21 levels and alemtuzumab-associated autoimmunity (see the related article beginning on page 2052). They show that proliferation of lymphocytes in those patients with autoimmunity is higher than in those without autoimmunity and suggest that the lymphopenia-driven proliferation of T cells, in combination with higher IL-21 levels, results in autoimmunity. This study helps inspire new enthusiasm for making a grab for the proverbial two birds in the bush — representing undiscovered therapies — with greater confidence.

MS is an immune-mediated disease characterized by inflammatory areas of demyelination in the brain and spinal cord. Patients typically experience episodes of neurologic disability (termed relapsing-remitting MS [RR-MS]), which often evolves into unrelenting disability progression. MS is at the forefront of diseases being treated with biologic therapeutics that modulate the immune system. Given the limited reduction of relapses and disability induced by current treatments, these emerging therapies are highly anticipated. However, caution must be exercised, as current MS therapies are on the whole safe and well tolerated.

Among the monoclonal antibodies that have had significant promise is alemtuzumab (also known as Campath-H1). Alemtuzumab targets the leukocyte antigen, CD52, which is ubiquitously expressed on T and B lymphocytes, monocytes, and macrophages. A single treatment causes profound leukopenia. In preliminary clinical trials, alemtuzumab has shown much greater efficacy in the treatment of RR-MS than that of a currently approved drug, IFN-β1a (1). While it may have greater efficacy in the treatment of MS, a major concern with alemtuzumab is the not-infrequent adverse effect of autoimmunity. Notable among the adverse events in early trials were autoimmune thyroiditis and idiopathic thrombocytopenic purpura (ITP) (1). One patient enrolled in the study cited above in fact died from ITP. While the trial resumed after safety measures were implemented, it is of particular importance to understand why some MS patients succumb to autoimmune disease after alemtuzumab treatment, while others do not, in order to gain maximal benefit from this potential therapeutic.

It has long been recognized that autoimmunity develops in patients who develop significant leukopenia (2). This led Jones et al., authors of the related study in this issue of the JCI (3), to consider the factors that predispose to autoimmunity in the setting of lymphopenia/leukopenia. Experimentally, the association between lymphopenia and autoimmunity was clarified by Sarvetnick and colleagues using the diabetes-prone mouse strain, NOD (4). They demonstrated that NOD mice are lymphopenic and that correction of lymphocyte numbers prevented immune-mediated damage of the pancreas. Lymphopenia was associated with a deficit in the pro-survival proteins Bcl-2 and Bcl-XL; a striking association between IL-21 and IL-21 receptor levels and autoimmune diabetes was also reported. Given the role of IL-21 in homeostatic proliferation, elevated IL-21 levels likely promote T cell proliferation and favor the expansion of self-reactive lymphocytes. Further work by others has extended this observation to show that IL-21 is critical for autoantibody production in a mouse model for lupus (5). Thus, IL-21 provides a mechanistic link between lymphopenia and autoimmune diseases in mice.

RR-MS patients treated with alemtuzumab are optimal subjects for the study of whether autoimmunity observed following the induction of lymphopenia is a result of IL-21–driven lymphocyte expansion. Typically, lymphocyte numbers do not recover until 6–12 months after alemtuzumab administration, and the percentage of patients experiencing autoimmune disease is around 30% (3). In their current study, Jones et al. examined RR-MS patients enrolled in two separate alemtuzumab trials and found that lymphocytes reemerging after alemtuzumab treatment not only had a greater tendency to proliferate, but also exhibited higher degrees of apoptosis (3). These features were more frequent in patients with autoimmune disease (defined as persistent autoantibodies or clinical disease with or without autoantibodies) 9 months after treatment with alemtuzumab, compared with patients without autoimmune disease after treatment. Jones et al. also report that in an overlapping cohort of patients, serum IL-21 levels were more than 2-fold higher in patients with thyroid autoantibodies than in those with no serologic evidence of autoimmunity. These results fit nicely with our understanding of the process by which lymphopenia drives autoimmunity in mice.

Jones and colleagues took a further step in defining the risk for developing autoimmune disease after alemtuzumab treatment (3). They asked whether the predisposition for developing autoimmunity following lymphopenia induction could be identified prior to treatment. Interestingly, the difference in serum IL-21 levels was found even before alemtuzumab administration. In fact, serum levels of IL-21 were used to generate a sensitivity of 66% and specificity of 67% in predicting the development of autoimmunity after alemtuzumab administration. Can this predisposition to higher IL-21 levels, and accompanying autoimmunity after alemtuzumab treatment, be explained genetically? The authors examined this possibility by looking at several SNPs within the IL21 gene. They found that in a small group of subjects, a higher percentage of those carrying a risk allele developed autoimmunity. While there was only a trend toward statistical significance, this strategy represents a major advance in defining the predisposition toward complications arising from alemtuzumab therapy, based on a defined immunologic mechanism.

The report by Jones et al. (3) heralds a new era of medicine in which genetic analysis of patients can be used to tailor treatments that may otherwise have unacceptable adverse effects. A clear example of the utility of this approach is the recent clinical practice of screening patients prior to initiation of anticoagulation therapy with warfarin. To anticipate the rate of warfarin metabolism, allelic differences in the cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) and vitamin K epoxide reductase complex, subunit 1 (VKORC1) genes can be used to predict dosing requirements, helping prevent the under- or overdosing of anticoagulant that can lead to disastrous consequences (6). Genetic predisposition toward benefiting from disease-specific treatment is also under intense scrutiny. For example, in rheumatoid arthritis, genetic analysis has been performed, with the goal of predicting who will respond well to treatment with anti-TNF molecules (7). From limited studies, no genetic basis for treatment response has been clearly demonstrated, although some studies suggest that alleles within the MHC complex may influence response to anti-TNF therapy in rheumatoid arthritis (7). Overall, employing drugs more effectively based on the genetic makeup of each patient — a pharmacogenomic approach — appears to be on the horizon.

Jones et al. raise several questions as a result of their study (3). First, why do some forms of autoimmunity predominate after lymphopenia-induced proliferation? In alemtuzumab trials, a vast majority of affected patients develop autoimmune thyroiditis (1). This could be due in part to the high prevalence of this condition (clinically as well as subclinically) in the general population. Alternatively, factors that are suppressive for the development of other autoimmune diseases may contribute to organ-specific autoimmunity. In their study, Jones et al. purposely excluded patients who developed transient autoantibody elevation from the “autoimmunity” group. Perhaps other mechanisms are employed in patients that transiently develop autoantibodies, suppressing the emergence of disease. It should be noted that a major concern with alemtuzumab treatment is the handful of patients who develop ITP. Certainly ITP is more critical clinically than thyroiditis, and it will be important to determine whether IL-21 levels are also associated with antiplatelet antibodies, even if this is clinically not evident.

Second, is the benefit from alemtuzumab treatment in MS related to IL-21 levels? IL-21 has been identified as a critical regulator of Th17 lineage commitment (8). These proinflammatory CD4⁺ T cells, characterized by their production of IL-17, are thought to play a crucial role in MS and its experimental models (9, 10). If IL-21 levels are higher in some patients with RR-MS, it could be posited that the result of alemtuzumab treatment would be less effective in disease suppression, as greater proportions of Th17 cells would emerge upon lymphocyte recovery. The authors note by means of personal communication that there was no relationship between the development of autoimmunity in MS patients treated with alemtuzumab and the degree of disease suppression. However, whether or not patients with higher IL-21 levels and autoimmunity respond less favorably to alemtuzumab needs further exploration.

A third question — less biologic, yet broader — is how to deal with the changing landscape of risk/benefit analysis in the use of biologic therapeutics. Current MS therapeutics (e.g., IFN-β1a and glatiramer acetate) are considered relatively safe. Faced with several deaths resulting from progressive multifocal leukoencephalopathy after natalizumab treatment (11), the MS community had to make a large adjustment to how therapies with far greater risks are used. Again, addressing the potentially fatal adverse reaction of ITP after treatment with alemtuzumab inspires a long hard look at the bird in the hand, namely the current immunomodulatory agents used to treat MS. Armed with a greater degree of knowledge, on behalf of the patient, as to who will optimally respond to treatment, it may be easier to embrace the potential benefit of reducing disease burden, rather than fearing a complication that is not likely to occur. Clearly, pharmacogenomic profiling will aid greatly in this pursuit. Thus, instead of being content with one bird in the hand, perhaps we can begin to see the value of reaching for two birds in the bush.

The authors were supported by grants from the National Multiple Sclerosis Society. G.F. Wu is the recipient of a KO8 award from the National Institute of Neurological Disorders and Stroke, National Institutes of Health.

Address correspondence to: Terri M. Laufer, Division of Rheumatology, University of Pennsylvania, BRB II/III Room 753, 421 Curie Boulevard, Philadelphia, Pennsylvania 19104-6100, USA. Phone: (215) 573-2955; Fax: (215) 573-7599; E-mail: tlaufer@mail.med.upenn.edu.

Conflict of interest: The authors have declared that no conflict of interest exists.

Nonstandard abbreviations used: ITP, idiopathic thrombocytopenic purpura; RR-MS, relapsing-remitting MS.

Reference information: J. Clin. Invest.119:1852–1853 (2009). doi:10.1172/JCI39963

See the related article at IL-21 drives secondary autoimmunity in patients with multiple sclerosis, following therapeutic lymphocyte depletion with alemtuzumab (Campath-1H).

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