Data are represented as the approximate change in the number of T cells at different points after administration of 12 mg of alemtuzumab (blue dotted lines). A, Mean (SD) baseline level of CD4 T cells was 970/μL (380/μL) (includes 376 people with multiple sclerosis, ranging from 361 to 374 per time point). B, Mean (SD) baseline level of CD8 T cells was 500/μL (220/μL) (includes 376 people with multiple sclerosis, ranging from 361 to 374 per time point). C, Mean (SD) baseline level of naive CD4 (CD45RA+) T cells was 380/μL (200/μL) (includes 98 people with multiple sclerosis, ranging from 53 to 94 per time point). D, Mean (SD) baseline level of memory CD4 (CD45RO+) T cells was 650/μL (60/μL) (includes 98 people with multiple sclerosis, ranging from 43 to 94 per time point). E and F, Mean (SD) baseline levels of CD4 and CD8 (CD25intermediate/bright and CD127-/low) T regulatory cells were 650/μL (60/μL) (includes 98 people with multiple sclerosis, ranging from 43 to 94 per time point). To convert lymphocyte counts to ×109 per liter, multiply by 0.001.
Data are represented as the approximate change in the number of B cells at different points after administration of 12 mg of alemtuzumab (blue dotted lines). A, Mean (SD) baseline level of CD19 B cells was 270/μL (130/μL) (includes 376 people with multiple sclerosis, ranging from 361 to 374 per time point). B, Mean (SD) baseline level of immature B cells (CD19+, CD27−, IgD+, CD38+, and CD10+) was 10/μL (10/μL) (includes 98 people with multiple sclerosis, ranging from 41 to 94 per time point). C, Mean (SD) baseline level of mature/naive B cells (CD19+, CD27−, IgD+, CD38+, and CD10−) was 180/μL (160/μL) (includes 98 people with multiple sclerosis, ranging from 41 to 94 per time point). D, Mean (SD) baseline level of memory B cells (CD19+ and CD27+) was 270/μL (130/μL) (includes 98 people with multiple sclerosis, ranging from 42 to 94 per time point). To convert lymphocyte counts to ×109 per liter, multiply by 0.001.
Lymphocyte reconstitution after alemtuzumab administration leads to control of multiple sclerosis and secondary B-cell autoimmunity.
eFigure 1. Kinetics of the Production of Alemtuzumab-Specific–Binding and –Neutralizing Antibodies
eFigure 2. Reconstitution Kinetics of CD4 T Cells After 2 Cycles of Alemtuzumab
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Baker D, Herrod SS, Alvarez-Gonzalez C, Giovannoni G, Schmierer K. Interpreting Lymphocyte Reconstitution Data From the Pivotal Phase 3 Trials of Alemtuzumab. JAMA Neurol. 2017;74(8):961–969. doi:10.1001/jamaneurol.2017.0676
Are lymphocyte subset reconstitution kinetics associated with efficacy and adverse effects of alemtuzumab administration in multiple sclerosis?
Analysis of previously unpublished data from pivotal phase 3 trials in the regulatory submissions of alemtuzumab indicated that efficacy was associated with long-term depletion of memory T and B cells, whereas rapid hyperrepopulation of immature B cells in the relative absence of regulatory CD4 and CD8 T cells create the environment for the generation of secondary B-cell autoimmunity, including anti–drug antibodies.
Controlling this B-cell hyperrepopulation after alemtuzumab administration may limit the risk for secondary autoimmunity if administration can be performed safely.
Alemtuzumab, a CD52-depleting monoclonal antibody, effectively inhibits relapsing multiple sclerosis (MS) but is associated with a high incidence of secondary B-cell autoimmunities that limit use. These effects may be avoided through control of B-cell hyperproliferation.
To investigate whether the data describing the effect of alemtuzumab on lymphocyte subsets collected during the phase 3 trial program reveal mechanisms explaining efficacy and the risk for secondary autoimmunity with treatment of MS.
Design, Setting, and Participants
Lymphocyte reconstitution data from regulatory submissions of the pivotal Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I and II (CARE-MS I and II) trials were obtained from the European Medicines Agency via Freedom of Information requests. Data used in this study were reported from June 22 to October 12, 2016.
Main Outcomes and Measures
Tabulated data from T- and B-lymphocyte subset analysis and antidrug antibody responses were extracted from the supplied documents.
Alemtuzumab depleted CD4+ T cells by more than 95%, including regulatory cells (−80%) and CD8+ T cells (>80% depletion), which remained well below reference levels throughout the trials. However, although CD19+ B cells were initially also depleted (>85%), marked (180% increase) hyperrepopulation of immature B cells occurred with conversion to mature B cells over time. These lymphocyte kinetics were associated with rapid development of alemtuzumab-binding and -neutralizing antibodies and subsequent occurrence of secondary B-cell autoimmunity. Hyperrepopulation of B cells masked a marked, long-term depletion of CD19+ memory B cells that may underpin efficacy in MS.
Conclusions and Relevance
Although blockade of memory T and B cells may limit MS, rapid CD19+ B-cell subset repopulation in the absence of effective T-cell regulation has implications for the safety and efficacy of alemtuzumab. Controlling B-cell proliferation until T-cell regulation recovers may limit secondary autoimmunity, which does not occur with other B-cell–depleting agents.
Multiple sclerosis (MS) is a major, immune-mediated, demyelinating, neurodegenerative disease of the central nervous system and is the leading cause of nontraumatic disability in young adults. The phase 2 trial1 and pivotal licensing trials2,3 for alemtuzumab demonstrated that this CD52-depleting monoclonal antibody (mAb) is among the most potent disease-modifying treatments in relapsing MS.1-4 This drug can induce long-term remission after only a short course of treatment.4 However, use of alemtuzumab is limited because it induces a number of secondary B-cell autoimmunities in people with MS.1-4 Although these effects may occur rapidly after alemtuzumab infusion,5 the incidence typically peaks 2 to 3 years after treatment initiation and occurs in about 50% of people with MS within 5 to 7 years of treatment.4,6
Although efficacy in people with MS has been attributed to CD4 T-cell deletion and relative sparing of CD4 T regulatory cells,7-10 less attention has been paid to the reason for the generation of secondary autoimmunities occurring after alemtuzumab administration. Autoimmunity may be attributable to the relative lack of thymic repopulation that occurs after alemtuzumab treatment.11 However, preferential expansion of memory cells typically occurs after antibody-mediated T-cell depletion and is not associated with the development of B-cell autoimmunities.12,13
We hypothesized that B-cell dynamics are central to secondary autoimmunities and that repopulation kinetics14,15 may offer some clues on this aspect. However, the lymphocyte subset repopulation capacities observed in the pivotal phase 3 trials were only partially described2,3 and have remained unpublished, although based on meeting abstracts, data documenting B-cell issues were collected and analyzed many years ago.6-18 These data, coupled with recent animal studies using CD52-specific antibodies that indicated lower efficacy of B-cell depletion activity in lymphoid tissues19,20 and blockade of immune tolerance induction by CD52-depleting antibody,20 may shed light on potential adverse effect profiles of alemtuzumab.
After Freedom of Information requests to the European Medicines Agency in London, England, we received redacted copies of the regulatory submissions of the pivotal phase 3 trials Comparison of Alemtuzumab and Rebif Efficacy in Multiple Sclerosis I (CARE-MS I), which focused on drug-naive pwMS,2 and CARE-MS II, which focused on people with MS who had used beta interferons or glatiramer acetate.3 Primary data relating to leukocyte numbers were not part of the submission or were not received. The data presented herein only concern the 12-mg/d alemtuzumab dose used in clinical practice that was derived from the tabulated documents supplied. In some instances, the percentages reported (Figure 1 and Figure 2) are derived from analysis of the mean data values relating to absolute numbers and may thus have subtle differences from the actual individual percentage data if they had been available. Data used in this study were reported from June 22 to October 12, 2016. Although these trials were recruited following ethical approval of the trials and informed consent, as previously reported,2,3 no specific ethical approval was obtained or required to view and use these documents in the public domain. The details of participants were anonymous.
The pivotal phase 3 trials2,3 stated that B cells “recovered2/ repopulated3 within 6 months” whereas “T cells recovered2/reconstituted more2 slowly,2(p1825)3(p1835) approaching the lower limit of normal at 1 year after treatment.” The regulatory submission obtained from the European Medicines Agency showed that similar results were obtained after analysis of lymphocyte phenotyping data from the CARE-MS I and II studies (Table 1). These results found marked T-cell (Table 1 and Figure 1) and B-cell (Table 1 and Figure 2) depletion within 1 month after antibody administration and a less marked effect on natural killer cells (CD16+ and CD56+), followed by variable degrees of reconstitution of all lymphocyte subsets (Table 1).
A rapid (with 1 month) and marked (95.3% in CARE-MS I and II) depletion of peripheral blood CD4 T cells (Figure 1A) and depletion of CD8 cells of 85.4% in CARE-MS I and 83.7% in CARE-MS II (Figure 2B) were evident. Their numbers remained low and constituted a CD4 T-cell depletion of approximately 69.0% in CARE-MS I and 69.8% in CARE-MS II and a CD8 T-cell depletion of 47.2% in CARE-MS I and 46.4% in CARE-MS II 1 year after alemtuzumab treatment. This depletion was well below the lower reference limit (400/μL [to convert to ×109/L, multiply by 0.001])21 for the CD4+ T-cell population, and an average of about 35 months has been reported for CD4+ T-cell repopulation to reach the lower reference limit.8,21
Although CD4 memory cells may repopulate relatively faster than naive CD4 T cells after depletion,11,14 naive CD4 (CD45RA+) (Figure 1C) and memory CD4 (CD45RA-) T cells were substantially depleted. The depletion of CD4 T cells may account for the marked effect of alemtuzumab on inhibiting relapsing MS,7 as occurs in many animal models of MS.20
In contrast, CD8 T cells may contain pathogenic cells, based on the observation that CD8 T cells predominate in MS lesions.22 The depletion of immune cells by alemtuzumab was associated with a high level of infections (253 of 376 [67.3%] in CARE-MS I and 334 of 435 [76.8%] in CARE-MS II)2,3 and notably viral infections, including 130 of 811 of people with MS with herpes simplex virus infections (16%),2,3 which may be attributed at least in part to cytotoxic T-cell depletion. However, loss of CD8 T-cell activity has been associated with loss of immune tolerance induction in an experimental autoimmune model of MS.20 Therefore, the losses of CD4 T regulatory cells (CD4+, CD25intermediate/bright, and CD127-/low) (Figure 1E) and CD8 T regulatory cells (CD8+, CD25intermediate/bright, and CD127-/low) (Figure 1F) were of interest. This finding is perhaps surprising because the reported proportion of T regulatory cells in the CD4, CD25+, and CD127low population, which in other studies expresses FoxP3 and other regulatory cell-associated markers and exhibits T regulatory cell function,9,10 increased from 3.4% to 13.7% in CARE-MS I and from 3.8% to 12.5% in CARE-MS II,16,17 supporting the view that T regulatory cell function is enhanced after alemtuzumab administration.
However, the reality is that the absolute number of CD4 T regulatory cells remains dramatically reduced by 81% in CARE-MS I and 86.3% in CARE-MS II10,14 (Figure 1E), compared with baseline, consistent with less than 100 T regulatory cells/50 mL of blood reported previously.14 This loss may be marginal in the context of T-cell control of autoimmunity, because regulatory CD8 cells will repopulate faster than the pathogenic cells driving MS and thus will return in the presence of adequate levels of regulation to limit the reemergence of MS. However, significant loss of T regulatory cells occurs compared with B lymphocytes at a time when B cells are repopulating and hyperrepopulating (Figure 2). This feature may be crucial in the development of secondary autoimmunities.
Although CD19+ B cells reached reference levels within 6 months as reported,1-3 the substantial hyperpopulation of CD19+ B cells that occurred was ignored (Table 1). This finding is of interest because the secondary autoimmunities occurring after alemtuzumab treatment in people with MS, such as Goodpasture syndrome, Graves disease, hemolytic anemia, and idiopathic thrombocytopenic purpura, are antibody-mediated B-cell autoimmunities.4 Thus, although B-cell hyperresponsiveness has been reported,15 this aspect has become largely ignored and was surprisingly not reported in the phase 2 and 3 trial publications or supplementary data.1-3 CD20-specific antibodies and cladribine deplete B cells, inhibit relapsing MS, and do not induce CD19 B-cell hyperpopulation23,24 or secondary autoimmunity.25,26 However, autoimmunity sometimes occurs after hematopoietic stem cell therapy without alemtuzumab.27 This occurrence suggests that marked lymphocyte depletion in people with MS and B-cell recovery in the absence of T-cell regulation may be a key issue in the development of alemtuzumab-induced autoimmunity. The higher frequency of autoimmunities compared with hematopoietic stem cell therapy4,6,27 may relate to coordination of the T- and B-cell reconstitution kinetics.
The most informative aspect to understand the CD19 hyperpopulation (Figure 2A), which expanded to 35.3% above baseline in CARE-MS I and 26.8% above baseline in CARE-MS II (Table 1), was the B-cell subset analysis (Figure 2B-D). This analysis demonstrated that the CD19 B-cell hyperproliferation (Figure 2A) was a product of initial and substantial immature (CD19+, CD27-, IgD+, CD38+, and CD10+) B-cell repopulation (Figure 2B) of the blood (approximately 180% at baseline), as has been noted previously.15 This repopulation led to the subsequent maturation to naive (CD19+, CD27-, IgD+, CD38+, and CD10-) B cells, which were initially markedly depleted by alemtuzumab but repopulated to approximately 130% above baseline (Figure 2C). This effect was countered by the marked and long-lasting depletion of memory (CD19+ and CD27+) B cells (Figure 2D). Thus, marked changes in the B-cell compartment could affect the development of autoimmunities.
Although approximately 20% of people with MS have been reported to develop secondary autoimmunities during the alemtuzumab trials, including 68 of 376 (18.1%) in CARE-MS I and 69 of 435 (15.8%) in CARE-MS II,2,3 this proportion increased to 317 of 811 people with MS (39.1%) in the 5-year follow-up of the CARE-MS studies.6 This finding suggests that alemtuzumab was blocking immune tolerance induction, which was consistent with results of mouse studies using CD52-depleting antibodies.20 This finding was perhaps further indicated by the development of alemtuzumab-specific antibodies. Humanization is designed to reduce drug-specific antibody responses; compared with approximately 13% of people with MS developing a neutralizing response to chimeric CD20-specific mAb,28 humanized CD20-specific antibodies induce antiglobulin responses in less than 1% of cases.29 However, as reported herein, alemtuzumab-neutralizing antibody responses developed in approximately 81.2% of people with MS in CARE-MS I and 76.3% of people with MS in CARE-MS II.
No mention has been made of neutralizing antibodies in the pivotal trials,2,3 and the occurrence of binding antibodies received cursory attention to indicate that they occur in approximately 30% of people with MS before and 80% after the second cycle (Table 2). These findings ignored the fact that, despite its potential to deplete lymphocytes, alemtuzumab can induce T-cell immunity,30 and during the trials, 327 of 376 people with MS (87%) in CARE-MS I and 364 of 435 people with MS (83.7%) in CARE-MS II developed binding antibodies specific for alemtuzumab.5,31 Furthermore, of those people with MS who developed binding antibodies, 93.3% of CARE-MS I and 91.2% of CARE-MS II people with MS had neutralizing antibodies at some stage. A large proportion of people with MS developed an alemtuzumab-specific response within the first month after infusion (Table 2). This response was boosted by the second cycle of alemtuzumab treatment (eFigure 1 in the Supplement).
Although binding2,3 and, in abstract form, neutralizing5 antibodies are reported not to influence clinical, depletion, and repopulation efficacy and infusion reactions, it is inconceivable that the generation of binding and neutralizing antibodies remains ultimately without effect (eFigure 2 in the Supplement). Because infusion-related reactions occur in approximately 90% of people with MS as a consequence of lymphocyte depletion,2,3 the problem of antiglobulin responses may be masked by the corticosteroids, antihistamines, and acetaminophen (paracetamol) used to control infusion-related reactions,32 which can be serious in a small (approximately 3%) proportion of individuals.2,3 However, some people with MS fail to respond adequately to alemtuzumab, even after multiple treatment cycles.4 In such cases, one should establish whether alemtuzumab neutralization is the cause, and treatment can be switched as persistent neutralizing antibodies become problematic.32
Although a potential lack of immune tolerance induction may contribute to the generation of alemtuzumab-specific antibodies, this may reflect simple immunogenicity of the molecule.30 Alemtuzumab may deplete via antibody-dependent cellular cytotoxicity with a lesser effect through complement depletion.19 As such, B-cell depletion is notably limited in the lymphoid tissues, including bone marrow, compared with the peripheral blood in animals18 and possibly humans.5,33 This limitation may allow new autoimmune B-cell responses to be generated.5 In addition, rapid reactivation of the disease may be allowed,5,33 if pathogenic cells are sequestered in the bone marrow or lymph glands by previous treatments, such as fingolimod, and not sufficiently depleted owing to the relatively short serum half-life of alemtuzumab.33 This aspect may also allow drug-specific antibody responses to be generated, and these may develop within the few days required for the first cycle of alemtuzumab to be complete. Once generated, humoral immunologic memory can survive the immune-depleting effects because people with MS treated with alemtuzumab retain their ability to mount an antibody response against common viruses and recall antigens.34 In the future, reduction of immunogenicity may be feasible with further development of CD52-specific reagents.30
The immune system clearly controls relapsing MS, as shown by marked induction of no evident disease activity after hematopoietic stem cell therapy.27 However, although lymphopenia is a common feature of many immunotherapies, it is not necessarily associated with the development of secondary autoimmunity. Furthermore, the T- and B-cell depletions and reconstitutions by memory T cells and immature B-cell pools that occur after alemtuzumab treatment also occurred after CD4 T-cell13 and CD20 B-cell depletion24,35 treatments that did not cause secondary autoimmunities. We hypothesize the B-cell depletion and rapid repopulation in the absence of effective T-cell regulation in an individual with genetic susceptibility for autoimmunity are key factors in the development of autoimmunity. As such, alemtuzumab induces secondary autoimmunities in people with MS, who may be predisposed to develop other autoimmunities, including thyroid disease,36 whereas secondary autoimmunities are not a feature among patients receiving alemtuzumab for the treatment of cancer.37
During lymphopenia, some mechanisms that normally serve to maintain host tolerance are temporarily suspended.38 Peripheral T cells proliferate in response to self-antigens in lymphopenic hosts, but proliferation toward these same antigens is prevented when T-cell numbers are within reference limits. This process, termed homeostatic peripheral expansion, augments peripheral T-cell number and limits repertoire skewing during recovery from lymphopenia and predisposes lymphopenic hosts to autoimmune disease.38 An association of secondary autoimmunity after alemtuzumab has been suggested with lymphopenia and reduced thymic output, leading to homeostatic T-cell proliferation and chronically activated oligoclonal memory T cells.15 This finding has prompted the Keratinocyte Growth Factor to Prevent Autoimmunity After Alemtuzumab Treatment of Multiple Sclerosis (CAM-THY) trial.39 The development of secondary autoimmunity has also been suggested to be associated with the level of T-cell regulation and interleukin 21 (IL-21) production.38,40 Investigators40 have thought that driving cycles of T-cell expansion and apoptosis would increase the stochastic opportunities for T cells to encounter self-antigen.
However, we propose alternative B-cell–centric mechanisms to explain alemtuzumab-induced autoimmunity. Interleukin 21 influences B-cell function, notably regulatory B-cell function, and IL-21 signaling in B cells has been shown to be important in the development of antibody-induced autoimmunity.41 Furthermore, the lymphocyte repopulation data presented herein suggest that after alemtuzumab administration, a surge of immature B cells repopulates the blood, probably from the bone marrow,15 in the absence of effective T-cell regulation via CD4 T regulatory cells and CD8 regulatory/suppressor cells,20 which could allow escape of autoreactive B cells41 (Figure 3). Although suggested to be a potential reason for the generation of autoimmunity,37 CD4 T regulatory cell depletion has been dismissed as an issue,14,40 notably when T regulatory cells form a greater population of the regenerating CD4 T-cell pool.9,10,14 However, the absolute numbers of CD8 T cells and CD4 T regulatory cells are substantially reduced relative to B-cell numbers, at a time when rapid B-cell expansion is occurring and T-cell regulation may be limited, particularly if T regulatory cell function requires cell-cell contact for functional activity to occur. Because T regulatory cells can control the silencing of autoreactive immature B cells exiting the bone marrow as they mature into naive B cells,42,43 the conditions are clearly established to allow the escape of B-cell autoimmunity.38,41 Indeed, deficits related to diminished CD4 T regulatory cell function and increased immature B cells have been related to childhood and adult thyrombocytopenic purpuras, which is one of the adverse autoimmunities after alemtuzumab treatment.44,45
However, because the autoantibody production is likely to be CD4 T-cell dependent, autoimmunity will require T-cell help, and thus autoimmunity is unlikely to occur until CD4 T-cell numbers regenerate (Figure 3). This situation creates a delay between the time of B-cell hyperreactivity and the development of autoimmunity. This finding is consistent with the observation that autoimmunity peaks in the years 2 to 3 as CD4 T cells repopulate, with approximately 20% of people with MS developing thyroiditis compared with approximately 10% in years 2, 4, and 5 in the CARE-MS follow-up studies.6 Furthermore, if the generation of autoreactive B cells is the primary driver of autoimmunity, driving more diverse T cells to exit the thymus and potentially support autoreactive B cells, as examined in the CAM-THY trial,39 may be counterproductive, and we therefore await the results of the trial with great interest. Furthermore, in addition to silencing of the generation of autoreactive immature B cells, T-cell function controls germinal center activity and the generation of autoantibodies during antibody affinity maturation.46 Using this mechanism, primary antibodies directed against gut bacteria can increase their binding affinity for the bacterial target as the antibody response develops, to gain cross-reactivity with and stimulation of the thyroid hormone receptor that occurs in Graves disease.47 Therefore, the thyroid-related autoimmunity that is the major immunologic consequence of alemtuzumab treatment developing in 317 of 811 people with MS (39.1%) in the 5-year follow-up of the CARE-MS studies5 is of interest and consistent with the findings of other studies where 35 of 86 people (40.7%) developed thyroid issues.4 Furthermore, Graves hyperthyroidism was present in 22 of 35 people with MS (62.9%) compared with 13 of 35 (34.3%) with hypothyroidism.4 Therefore, molecular mimicry between microbiota and autoantigens48 and the discoordinated kinetics of T- and B-cell reconstitution may contribute to the generation of autoimmunity.
Although animal studies in MS clearly indicate that repopulation of T cells relates to return of disease activity20 and may occur in humans,6 this indication is clearly not absolutely related to the total number of detectable cells. Likewise, the analysis of generalized (CD4, CD8, and CD19) populations appears to have failed to provide definitive evidence of the precise mechanisms of relapse and autoimmunity.8 This failure is likely to require detection and monitoring of lymphocyte subsets, such as CD19+ and CD27+ or, more importantly, antigen-specific responses. This monitoring may be feasible because blood plasma samples must be taken and tested for autoimmunity, notably idiopathic thrombocytopenic purpura, for 4 years after the last infusion of alemtuzumab. Therefore, through analysis of cells that are discarded for blood testing, antigen-specific responses may be identified. This process should be feasible because (1) relapses, presumably due to responses to the autoantigen in MS, occur in approximately 50% to 60% of people within 2 years after treatment with alemtuzumab4; (2) approximately 48% of people develop secondary B-cell autoimmunities4; and (3) more than 80% of people produce drug-specific antibody responses. Additional studies are evidently needed.
Based on the immunophenotyping data, CD4 T cells and CD19+ and CD27+ B cells demonstrated long-term inhibition, and these subsets may harbor the pathogenic cells that control MS. Although most experts in the field believe T cells drive disease activity in people with MS, CD4 T-cell depletion is perceived to have failed to control MS after CD4 mAb-induced depletion.12 However, the 70% CD4 depletion targeted to maintain cell numbers greater than 250/µL in CD4-specific mAb trials12 was substantially less than the 95% CD4 T-cell depletion achieved with alemtuzumab, which provided a clear suppression of disease activity.2,3 Because some effects were seen on magnetic resonance imaging lesion loads after treatment with CD4 mAb administration after depletion of approximately 70% of CD4 T cells was achieved,12 this may be the minimum depletion required for disease inhibition. However, evaluating the association of cell numbers with disease activity after alemtuzumab treatment has not always proved to be informative7,8 and this is likely to remain an issue. Until the frequency of antigen-specific pathogenic cells relative to the disease activity can be reliably monitored, gauging the lymphocyte level required to control disease will not be possible. However, that persistent T-cell depletion sustained for over 2 years, as shown after alemtuzumab treatment, coupled with tolerization of pathogenic cells by the repopulating regulatory systems that regenerate at a faster rate than pathogenic cells, may underscore why repeated treatment is often not required and long-term remission is induced4 (Figure 3).
Although T cells are considered to drive disease in MS, most agents that inhibit relapsing MS target B cells. That levels of CD19+ and CD27+ cells remain low after alemtuzumab treatment suggests that this subset of B cells may be a key substrate of the mechanism by which alemtuzumab controls the disease. Similarly, CD19+ and CD27+ cells are targeted by CD20-specific mAb,24,35 and this approach appears to offer comparable benefit, at least on some outcomes.2,26 Although B-cell depletion has been argued to block antigen-presenting capacity to stimulate pathogenic T cells or make pathogenic antibodies, an alternative view could be that these therapeutic antibodies are actually deleting the B-cell reservoir of infectious agents, such as Epstein Barr virus, and possibly endogenous retroviruses that have consistently been implicated as etiologic factors in MS and other autoimmune diseases.49
Events occurring within the central nervous system or lymphoid tissues are not captured by analysis of the blood and may be key to understanding the pathogenesis. Importantly, the unavailability of the primary data makes it impossible to properly interrogate the results, notably to determine the significance, if any, of cell subset levels and neutralizing antibodies on safety and disease activity at the level of individuals.
We hypothesize that limiting B-cell reconstitution until T regulatory and suppressor cell function returns may limit B-cell autoimmunities after alemtuzumab treatment of people with MS. However, adding other B-cell–targeting therapy after alemtuzumab treatment may increase the risk for serious infections and cancers, thereby leading to worse outcomes compared with the development of B-cell autoimmune diseases, which are often manageable and nonfatal. Therefore, careful consideration is needed before such an approach is undertaken and should be formally tested to ensure patient safety.
Corresponding Author: Klaus Schmierer, PhD, FRCP, Centre for Neuroscience and Trauma, Blizard Institute, Queen Mary University of London, 4 Newark St, London E1 2AT, England (email@example.com).
Accepted for Publication: March 24, 2017.
Published Online: June 12, 2017. doi:10.1001/jamaneurol.2017.0676
Author Contributions: Drs Baker and Schmierer had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Baker, Giovanonni, Schmierer.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Baker, Herrod, Alvarez-Gonzalez.
Critical revision of the manuscript for important intellectual content: Baker, Giovanonni, Schmierer.
Statistical analysis: Herrod, Alvarez-Gonzalez.
Administrative, technical, or material support: Schmierer.
Study supervision: Baker, Giovanonni, Schmierer.
Conflict of Interest Disclosures: Dr Baker reports being a founder and consultant to Canbex Therapeutics and receiving research funds from Canbex Therapeutics, Sanofi-Genzyme, and Takeda in the past 3 years. Dr Giovannoni reports receiving fees for participation in the advisory board for AbbVie Biotherapeutics, Biogen, Canbex, Ironwood, Novartis, Merck, Inc, Merck Serono, Roche, Sanofi Genzyme, Synthon, Teva, and Vertex; speaker fees from AbbVie, Biogen, Bayer HealthCare, Genzyme, Merck Serono, Sanofi-Aventis, and Teva; and research support from Biogen, Genzyme, Ironwood, Merck, Inc, Merck Serono, and Novartis. Dr Schmierer reports being a principal investigator of trials sponsored by Novartis, Roche, Teva, and Medday; involved in trials sponsored by Biogen, Sanofi-Genzyme, BIAL, Cytokinetics, and Canbex; and receiving speaking honoraria for lecturing and advisory activity and/or meeting support from Biogen, Merck, Inc, Merck Serono, Novartis, Roche, Sanofi-Genzyme, and Teva. No other disclosures were reported.
Additional Contributions: We thank the European Medicines Agency for suppling the regulatory submissions.
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