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Therapeutic strategies targeting B-cells in multiple sclerosis
Autoimmunity Reviews, Volume 15, Issue 7, July 2016, Pages 714–718
Multiple sclerosis (MS) is a chronic inflammatory and demyelinating disease of the central nervous system (CNS) that traditionally has been considered to be mediated primarily by T-cells. Increasing evidence, however, suggests the fundamental role of B-cells in the pathogenesis of the disease. Recent strategies targeting B-cells in MS have demonstrated impressive and sometimes surprising results: B-cell depletion by monoclonal antibodies targeting the B-cell surface antigen CD20 (e.g. rituximab, ocrelizumab, ofatumumab) was shown to exert profound anti-inflammatory effect in MS with favorable risk–benefit ratio, with ocrelizumab demonstrating efficacy in both relapsing–remitting (RR) and primary-progressive (PP) MS in phase III clinical trials. Depletion of CD52 expressing T- and B-cells and monocytes by alemtuzumab resulted in impressive and durable suppression of disease activity in RRMS patients. On the other hand, strategies targeting B-cell cytokines such as atacicept resulted in increased disease activity. As our understanding of the biology of B-cells in MS is increasing, new compounds that target B-cells continue to be developed which promise to further expand the armamentarium of MS therapies and allow for more individualized therapy for patients with this complex disease.
Keywords: B-cells, Multiple sclerosis, CD20, Ocrelizumab.
1. Role of B-cells in multiple sclerosis
Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) that is characterized pathologically by inflammation, demyelination and axonal loss, and clinically by a variety of neurological signs and symptoms disseminated in time and space. MS has long been considered to be primarily a T-cell-mediated disease due to the observations of activated T lymphocytes in MS plaques, T-cell subset alterations in MS blood, and the fact that the animal model for MS, experimental autoimmune encephalomyelitis (EAE), can be passively transferred by myelin-reactive T cells. Although the intrathecal synthesis of oligoclonal immunoglobulins has been recognized for decades, B-cells and antibodies (Ab's) have been neglected in MS research due to their indispensible role in EAE and the lack of suitable technology to investigate them. Recent advances in flow cytometry and DNA sequencing methods unveiled the fundamental contribution of B-cells, plasma cells and their products in immune responses and their central role in the pathogenesis of MS as well as other immune-mediated disorders: plasmablasts and plasma cells can produce autoantibodies recognizing surface myelin antigens, which can be pathogenic and initiate an acute inflammatory cascade by complement activation. Antibodies can also induce tissue injury by binding to Fc receptors on macrophages, neutrophils and NK cells, and attack their targets via an antibody-dependent cell-mediated cytotoxic process. Autoreactive B-cells can function as effective and specific antigen-presenting cells (APC) and activate their cognate autoreactive T-cells through the trimolecular complex and costimulatory molecules. Such B-cell–T-cell interactions result in simultaneous expansion of antigen-specific B- and T-cells that enhance the immune response and promote disease. B-cells from MS patients show exaggerated pro-inflammatory response to activating stimuli and may contribute to abberant T-cell activation and autoimmunity through “bystander activation” by secreting pro-inflammatory cytokines. Regulatory B-cells (Bregs) secreting interleukin (IL)-10, which normally maintain homeostasis and protect from autoimmunity, are deficient in MS, and thus contribute to unchecked autoimmunity. Finally, lymphogenesis supported by B-cell cytokines and chemokines in the brain may promote ongoing local immune injury , , , and . The possible contribution of B-cells to MS pathogenesis is supported by observations of (I) pathologic heterogeneity of MS lesions (with pattern-II, antibody-mediated demyelination, being the most common one) ; (II) the formation of meningeal B-cell follicles in secondary-progressive MS , which is associated with early disease onset and severe cortical pathology ; (III) the presence of dominant B-cell clonotypes, compatible with an antigen-selection process as well as antibody-secreting plasmablasts and plasma cells in the CSF and lesions of MS patients (the numbers of which correlate with local IgG synthesis and the extent of CNS inflammation), along with immunoglobulins (predominantly IgG1) and B-cell cytokines ; and (IV) the beneficial effect of B-cell targeted therapies in MS.
2. Therapies targeting CD20
The CD20 molecule is expressed on most cells of the human B cell lineage, from pre-B and immature B cells through naïve and memory B cells, but not on stem cells, pro-B cells, or differentiated plasma cells . Several monoclonal antibodies (mAbs) targeting CD20 can deplete B-cells by mechanisms of complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and induction of B-cell apoptosis. Three such mAbs have been tested in MS: (I) rituximab (Rituxan, Genentech and BiogenIdec, RTX), a chimeric mAb approved for the treatment of B-cell lymphoma and rheumatoid arthritis (RA); (II) ocrelizumab (Roche/Genentech), a humanized mAb that binds to a different but overlapping epitope compared with rituximab and depletes B cells primarily through ADCC, rather than by a CDC mechanism, possibly with greater efficacy than rituximab; and (III) ofatumumab (Arzerra, Novartis Oncology), a fully human mAb with a very low immunogenic risk profile that binds to a completely distinct epitope, dissociates more slowly from the CD20 antigen, and exhibits pronounced CDC activity and relatively decreased ADCC. Ofatumumab is approved for the treatment of chronic lymphocytic leukemia refractory to fludarabine and alemtuzumab.
Rituximab was evaluated in a 48-week double-blind placebo-controlled phase II clinical trial in 106 patients with relapsing–remitting (RR) MS (Table 1) . Patients received a single course of 1000 mg rituximab or placebo administered intravenously on days 1 and 15. The mean number of T1 gadolinium-enhancing (Gd +) lesions on MRI scans (the study's primary endpoint) was reduced at 24 weeks by 91% compared to placebo (p < 0.001). The mean number of new Gd + lesions was reduced by 95% (p < 0.001). These results were sustained for 48 weeks (p < 0.001). There was a significant reduction in the proportion of patients with relapse at week 24 (14.5% vs. 34.3%, p = 0.02) and 48 (20.3% vs. 40.0%, p = 0.04). Infusion-associated adverse events, mostly mild to moderate in severity, were more frequent in the rituximab group and decreased in frequency and intensity from the first to the second infusion. No differences were observed in the incidence of serious adverse events or infections between rituximab- and placebo-treated groups, and no clinically significant opportunistic infections were reported. Human anti-chimeric antibodies (HACA) against rituximab found in 24.1% of the treated patients at week 48 were not associated with the type or severity of adverse events, or the efficacy measures throughout the study.
|Trial (Ref)||Phase||Drug||Mechanism||Design||Population||Sample Size||Duration||Main Results|
|HERMES (10)||II||Rituximab (chimeric mAb)||Anti-CD20||Randomized, double-blind, PBO-controlled||RRMS||110||6 months||91% ↓ in total CEL;
95% ↓ in new CEL
|OLYMPUS (11)||II/III||Rituximab (chimeric mAb)||Anti CD20||Randomized, double-blind, PBO-controlled||PPMS||439||24 months||No significant ↑ in time to CDP;
Less increase in T2 lesion volume load
|OPERA I + II (12)||III||Ocrelizumab (humanized mAb)||Anti CD20||Randomized, double-blind, IFNβ-1a controlled||RRMS||1656||24 months||46-47% ↓ in ARR;
40% ↓ in CDP (12 & 24 weeks);
94-95% ↓ in total CEL;
77-83% ↓ new/enlarging T2 lesions;
23.8% ↓ in brain volume loss;
|ORATORIO (13)||III||Ocrelizumab (humanized mAb)||Anti CD20||Randomized, double-blind, PBO-controlled||PPMS||732||30 months||24% ↓ in CDP (12 weeks)
25% ↓ in CDP (24 weeks);
Significant ↓ in T2 lesion volume load;
17.5% ↓ in brain volume loss
|Sorensen et al. (16)||II||Ofatumumab (human mAb)||Anti CD20||Randomized, double-blind, PBO-controlled||RRMS||38||6 months||> 99% ↓ in new T2 lesions;
Significant ↓ in new CEL, total CEL and new/enlarging T2 lesions
|? (18)||II||Tabalumab (human mAb)||Anti-BAFF||Randomized, double-blind, PBO-controlled||RRMS||245||49 weeks||No results available|
|ATAMS (21)||II||Atacicept||Blocking B-cell activation||Randomized, double-blind PBO –controlled||RRMS||255||9 months||Terminated due to increased clinical disease activity;
No change in CEL
|ATON (22)||II||Atacicept||Blocking B-cell activation||Randomized, double-blind PBO –controlled||Optic neuritis as CIS||80||9 months||Terminated|
|CARE-MS I (27)||III||Alemtuzumab (humanized mAb)||Anti CD52||Randomized, rater-blinded, IFNβ-1a controlled||Treatment-naïve RRMS||581||24 months||55% ↓ in ARR;
No difference in CDP;
54% ↓ in the risk of developing CEL;
34% ↓ in the risk of developing new/enlarging T2 lesions;
34% ↓ in the risk of developing new T1 lesions
41.7% ↓ in brain volume loss
|CARE-MS II (28)||III||Alemtuzumab (humanized mAb)||Anti CD52||Randomized, rater-blinded, IFNβ-1a controlled||Treatment-experienced RRMS||840||24 months||50% ↓ in ARR;
42% ↓ in CDP (24 weeks);
55% ↑ in sustained reduction in disability;
59% ↓ in the risk of developing CEL;
62% ↓ in the risk of developing new/enlarging T2 lesions;
63% ↓ in the risk of developing new T1 lesions
24% ↓ in brain volume loss
Abbreviations: ARR – annualized relapse rate; BAFF – B-cell activating factor; CDP – confirmed disability progression; CEL – contrast enhancing lesions; CIS – clinically isolated syndrome; IFNβ – interferon beta; mAb – monoclonal antibody; PBO – Placebo; RRMS – relapsing-remitting multiple sclerosis; PPMS – primary progressive multiple sclerosis.
In another phase II/III clinical trial, 439 primary-progressive (PP) MS patients were randomized at a 2:1 ratio to receive 4 courses of two 1000-mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (Table 1) . Although the time to confirmed disability progression (CDP) sustained for 12 weeks (the primary endpoint) did not reach statistical difference, rituximab patients had less increase in T2 volume load on MRI (p < 0.001). Subgroup analysis showed that time to CDP was delayed in patients aged < 51 and those with Gd + lesions in the rituximab group compared with placebo, suggesting a beneficial effect of B-cell depletion in younger PPMS patients with inflammatory activity. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. Serious infections occurred in 4.5% of rituximab and 1.0% of placebo patients. Experience with rituximab in other autoimmune diseases and malignancies raised concerns about serious bacterial, fungal or viral infections, including progressive multifocal leukoencephalopathy (PML) and the reactivation of hepatitis-B virus, as well as serious mucocutaneous reactions .
Despite these results, Roche and Genentech decided not to advance trials of rituximab in MS and opted instead to focus on ocrelizumab, a humanized anti-CD20 mAb with better biological properties and reduced immunogenicity.
Three phase III clinical trials with ocrelizumab in MS have been presented at the recent European Committee on Treatment and Research in Multiple Sclerosis (ECTRIMS) Congress in Barcelona:
OPERA I and II were two identical phase III, multicenter, randomized, double-blind, double-dummy, parallel-group trials that randomized (1:1) a total of 1656 relapsing patients to receive ocrelizumab 600 mg via intravenous infusion every 24 weeks or interferon (IFN)-β-1a 44 μg subcutaneously three times per week throughout a 96-week treatment period (Table 1) . The primary endpoint—annualized relapse rate at 96 weeks—showed a 46% to 47% reduction with ocrelizumab compared with IFN-β-1a (p < 0.0001). Both studies also showed a 40% reduction in 12- and 24-weeks confirmed disability progression, a 94% to 95% reduction in the number of Gd + lesions and a 77% to 83% reduction in the number of new/enlarging T2 hyperintense lesions on MRI. Brain volume loss was reduced by 23.8% with ocrelizumab vs. IFN-β-1a, and the number of patients with “no evidence of disease activity” (NEDA) increased from 25% with IFN-β-1a to 48% with ocrelizumab.
The ORATORIO trial randomized (2:1) 732 patients with PPMS who had an elevated cerebrospinal fluid IgG index or one or more oligoclonal bands to ocrelizumab (two infusions of 300 mg separated by 14 days every 24 weeks) or placebo for 120 weeks (Table 1) . Ocrelizumab significantly reduced CDP sustained for at least 12 weeks (primary endpoint) by 24% (p = 0.0321) and CDP sustained for at least 24 weeks (secondary endpoint) by 25% (p = 0.0365). Additional secondary end-points were also reached, including change in time to walk 25 ft from baseline (p = 0.04), change in T2 lesion volume from baseline (p < 0.0001) and rate of brain volume loss (p = 0.02).
The most common adverse event in all 3 studies was infusion-related reactions. Serious adverse events did not differ between groups, and there were no opportunistic infections or cases of PML. Six malignancies were reported in the OPERA trials (2 in IFN-β-1a arm and 4 in ocrelizumab arm), and 13 malignancies occurred in the ORATORIO trial: 2 (0.8%) in the placebo arm and 11 (2.3%) in the ocrelizumab arm. Four patients died in the ocrelizumab arm (pulmonary embolism, pneumonia, pancreas carcinoma, pneumonia aspiration) and one in the placebo arm (traffic accident) in the ORATORIO trial. In contrast to RA where the development of ocrelizumab has been terminated due to an increased rate of serious infections relative to placebo , no serious or opportunistic infections have been observed in MS trials, possibly due to the lower dose of ocrelizumab used in the latter and the use of other immunosuppressive drugs in the former. The drug's overall favorable safety profile may be related to the fact that ocrelizumab interferes with the immune system in a very narrow range, specifically targeting circulating B cells expressing the CD20 antigen. On the other hand, the excess number of malignancies in the ocrelizumab-treated patients may be worrisome, and long-term safety follow-up is needed.
These studies suggest that ocrelizumab may be a highly effective agent in RRMS but without the serious adverse effects seen with other, similarly potent agents, and that its benefit may also extend to PPMS. Although the effect on disease progression in the ORATORIO trial was modest, this was the first-ever phase III study to show a slowing of disability progression in PPMS. There is still need to look into post hoc and subgroup analyses, to see whether the effect on disability progression is related to the anti-inflammatory effect or which subgroups of patients may better respond to ocrelizumab as the ORATORIO trial was enriched with younger PPMS patients with relatively short disease duration, oligoclonal bands in the CSF and some inflammatory activity on MRI. Recent subgroup analysis, however, showed that ocrelizumab has efficacy in patients with and without T1 Gd + lesions at baseline .
The safety and efficacy of ofatumumab were evaluated in a phase II randomized, double-blind, placebo-controlled study in 38 patients with RRMS who were randomized to receive 2 ofatumumab infusions (100 mg, 300 mg or 700 mg) or placebo 2 weeks apart. At week 24, patients received alternate treatment (Table 1) . Ofatumumab was well-tolerated and produced no unexpected safety signals or dose-related safety concerns. Treatment was associated with profound selective reduction of B-cells. New T2 MRI lesion activity was suppressed by > 99% in the first 24 weeks after ofatumumab administration by all doses, and statistically significant reductions (p < 0.001) favoring ofatumumab were found in new T1 Gd + lesions, total enhancing T1 lesions and new and/or enlarging T2 lesions. No significant changes in expanded disability status scale (EDSS) scores or multiple sclerosis functional composite (MSFC) scores were detected in this small study that was not designed to assess clinical efficacy, and no increase in the number of serious adverse events was reported. Infusion-related reactions were common on the first infusion day but not observed on the second infusion day. A phase III clinical trial with ofatumumab in relapsing forms of MS is underway.
Collectively, these trials provide MRI and clinical evidence that selective CD20 + B-cell depletion is an effective and safe approach in the treatment of both relapsing and progressive forms of MS.
3. Therapies targeting B-cell cytokines
The maturation and survival of B-cells are dependent on two crucial cytokines: BAFF (B-cell activating factor, also known as BLyS, TALL1 and TNFSF13B, a member of the tumor necrosis factor (TNF) family) and APRIL (A ProlifeRation Inducing Ligand, also known as TALL2 and TNFSF13A), which are produced by neutrophils, monocytes and activated T cells . BAFF is also produced by astrocytes and is upregulated in MS lesions .
BAFF binds strongly to the BAFF receptor (BAFF-R, also known as TNFRSF13C) which is expressed on late stages of the B-cell lineage and is essential for B-cell survival and maturation. It also binds to TACI (transmembrane activator and cyclophilin ligand interactor, also known as TNFRSF13B, expressed mainly on memory B cells), Nogo-66 receptor (also known as RTN4R), and weakly to B-cell maturation antigen (BCMA; also known as TNFRSF17). Targeting BAFF or APRIL or their receptors can inhibit B-cell proliferation and survival and decrease the number of B-cells.
Tabalumab (LY2127399, Eli-Lilly) is a fully human IgG4 mAb targeting and neutralizing both soluble and membrane-bound BAFF. A phase II clinical trial investigating tabalumab in 245 patients with RRMS (ClinicalTrials.gov identifier: NCT00882999) (Table 1) started in April 2009 and was registered online as “completed” , but “canceled” in 2011 by investigators . It is unknown whether this study has been terminated due to safety issues, clinical inefficacy as has been observed in systemic lupus erythematosus (SLE) , or increased disease activity, as has been observed with another approach for targeting B-cells with atacicept.
Atacicept (TACI-Ig, EMD Serono) is a fusion protein comprised of the extracellular domain of the naturally occurring TACI receptor (a binding site for BAFF and APRIL) and the Fc domain of human immunoglobulin (which increases the stability of the molecule). Two clinical trials with atacicept—the ATAMS phase II study in 292 relapsing MS patients (ClinicalTrials.gov identifier: NCT00642902)  and the ATON phase II study in 80 patients with optic neuritis (ClinicalTrials.gov identifier: NCT00624468)  have been terminated due to increased disease activity in the atacicept treatment groups compared to placebo as expressed by MRI and relapse-related measures (Table 1) . Possible explanations for the differential effects of anti-CD20 mAbs and atacicept in MS may include a broad depleting pattern of the former, while atacicept has a significant impact on Bregs without sufficiently depleting pathogenic B-cell subsets , or the presence of the receptors for BAFF and APRIL also on T-cells . In addition, atacicept can reduce serum immunoglobulin and disrupt nonspecific Fc-receptor blockade, which could have a therapeutic benefit .
4. Targeting CD52 with alemtuzumab
Alemtuzumab is a humanized lytic mAb approved for the treatment of chronic lymphocytic leukemia that targets CD52, a cell-surface glycoprotein of unknown function present on > 95% of T and B cells, monocytes and some dendritic cells, and to a lesser degree, on natural killer (NK) cells and other leukocytes . Alemtuzumab primarily depletes circulating T and B lymphocytes for a long time via ADCC and CDC mechanisms. Following depletion, gradual homeostatic reconstitution of immune cells begins within weeks, with monocytes and B-cells being first (median recovery time to baseline level—1 and 3 months, respectively) and finally CD4 + T-cells (median recovery time to baseline level—61 months), leading to prolonged alteration of the immune repertoire. Alemtuzumab also alters the number and proportions of some lymphocyte subsets, leading to increased number of Treg cells and memory T- and B-lymphocytes, and increases the production of anti-inflammatory cytokines .
Two phase III single-blind rater-masked clinical trials—CARE-MS I in treatment-naïve RRMS patients  and CARE-MS II in treatment-experienced RRMS patients —compared IV alemtuzumab 12 mg/day for 5 consecutive days followed by a second 3-day course 1 year later to SC IFN-β-1a three times a week for 2 years (Table 1). Both trials recruited patients with recently diagnosed relapsing MS and used annualized relapse rate and sustained 6-month EDSS progression as co-primary endpoints. In CARE-MS I, alemtuzumab reduced the annualized relapse rate by 55% compared to IFN-β-1a, but showed no superiority in reducing disability progression (probably due to a very low rate of sustained progression—11% only over 2 years—in patients treated with IFN-β-1a). Fewer patients treated with alemtuzumab had new and enlarging T2 lesions, new or persisting gadolinium enhancing lesions or new T1-hypointense lesions on MRI scans, and more patients were free of clinical and MRI disease activity (39% vs. 27%). Alemtuzumab-treated patients had slower rates of brain volume loss (p < 0.0001). In CARE-MS II where 2 doses were used (12 mg and 24 mg), alemtuzumab reduced relapse rate by 50%, sustained accumulation of disability by 42%, and all MRI measures compared to IFN-β-1a. More alemtuzumab-treated patients were free of disease activity (32% vs. 14%), and their rate of brain volume loss was slower than IFN-β-1a-treated patients (p = 0.01). Moreover, alemtuzumab treatment increased the proportion of patients with sustained improvement in disability (29% vs. 13%) and improved the mean EDSS score at 2 years by 0.17 points compared to 0.24 points worsening in the IFN-β-1a group.
This robust and durable  clinical efficacy comes at a substantial price, especially the occurrence of secondary autoimmune diseases: 30%–40% of patients develop autoimmune thyroid disease (Graves' disease and hypothyroidism). Other autoimmune diseases that have occurred after alemtuzumab treatment include Immune thrombocytopenic purpura (ITP) in 1%, antiglomerular basement membrane disease (Goodpasture's syndrome) and single cases of autoimmune hemolytic anemia and autoimmune neutropenia. High blood levels of interleukin-21 were found to be associated with increased risk for this secondary autoimmunity and can serve as potential biomarkers . Earlier repopulation of the immune system by B-cells ahead of some regulatory T-cell subsets may explain these secondary autoimmunity phenomena. About 90% of patients experience infusion-associated reactions, mostly mild to moderate, but serious in 3%. Infections were more common with alemtuzumab, mostly upper respiratory tract infection, urinary tract infection and oral herpes. Although malignancy is a concern during long-term immunosuppression induced by the drug, it has not been more frequent in the alemtuzumab group in the trials. Three cases of papillary thyroid cancer in the phase III trials may represent incidental finding due to the close monitoring for thyroid disease, but another case of Burkitt's lymphoma may have been caused by alemtuzumab, and close long-term monitoring for malignancy is required after alemtuzumab treatment. A comprehensive risk-mitigation and monitoring program lasting at least 4 years after the last dose of alemtuzumab is required in order to select the appropriate patients and to detect and treat early the autoimmune adverse effects.
The involvement of B-cells in MS has been neglected for many years despite hints for their contribution to the immunopathogenesis and propagation of the disease. Only recently has interest increased in the role of B-cells in MS, triggered by several pathological and immunological observations, and by the impressive effect of rituximab on inflammatory outcomes in patients with RRMS . Advances in B-cell basic and clinical research helped to establish the important role of B-cells and the high efficacy of B-cell targeted therapies in MS. Clinical trials with monoclonal antibodies that target CD20 showed that B-cell depletion is highly effective in RRMS without significant compromise of the normal immune reactivity. For the first time, one of these mAbs, ocrelizumab, has also demonstrated efficacy in PPMS. Other B-cell depleting mAbs targeting CD19 (which is also expressed on plasmablasts and early but not mature plasma cells) are currently being developed for clinical trials, the most advanced one is MEDI-551 (MedImmune). Another mAb that targets both T- and B-cells via CD52, alemtuzumab, has also shown high and durable efficacy in RRMS. On the other hand, blocking the effect of trophic factors that act on later stages in B-cell development by atacicept has failed and even led to increased disease activity, highlighting the complex role of B cells and humoral immunity in MS. Future research into B-cell-targeted therapy should focus on compounds that also target specific plasma cells or do not affect Bregs. The high diversity and complexity of the human immune system with its pleiotropy of functions suggest that other immunomodulatory agents may also affect the number or function of certain B-cell populations. An example is glatiramer acetate (Copaxone, Teva) that can augment Bregs and anti-inflammatory cytokine secretion . Fingolimod or natalizumab may also impact B-cells in MS . The beneficial effects of B-cell-targeted therapies in MS and other immune-mediated disorders seem to be long-lasting  and their favorite risk–benefit ratio in MS grants them a prominent place in the expanding armamentarium of MS therapies.
- There is increasing evidence for the essential role of B-cells in the pathogenesis of MS.
- B-cell depletion with anti-CD20 mAbs results in a profound anti-inflammatory effect in MS.
- Ocrelizumab has demosntrated impressive efficacy in RRMS and, for the first time, modest efficacy in PPMS.
- The safety of anti-CD20 mAbs seems better in MS than in other autoimmune or malignant diseases.
- The increased disease activity observed with atacicept requires further research into the role of B-cell cytokines and their receptors in MS.
- B-cell-targeted therapies are a welcome addition to the management of MS.
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Department of Neurology, Barzilai University Medical Center, Ashkelon, Israel
Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer-Sheva, Israel
⁎ Department of Neurology, Barzilai Medical Center, 2 Hahistadrut St., Ashkelon 7830604, Israel. Tel.: + 972 8 674 5117; fax: + 972 8 674 5463.
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