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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 18  |  Issue : 3  |  Page : 196-199

Multiple sclerosis in 2020


1 Department of Neurology, Sir Ganga Ram Hospital, New Delhi, India
2 Department of Neurology, G B Pant Hospital, New Delhi, India

Date of Submission31-Jul-2021
Date of Decision23-Aug-2021
Date of Acceptance24-Aug-2021
Date of Web Publication18-Sep-2021

Correspondence Address:
Anshu Rohatgi
Senior Consultant Neurologist, Sir Ganga Ram Hospital, New Delhi
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/am.am_90_21

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  Abstract 


Recent developments in the management of multiple sclerosis (MS) are ushering in a new era in MS treatment. The novel therapeutic disease-modifying agents that have been recently approved for the treatment of MS are B-cell therapies and various sphingosine-1-phosphate inhibitors. The Bruton's tyrosine kinase inhibitor therapies provide a novel therapeutic approach in the treatment of MS. Numerous studies have demonstrated a high degree of efficacy with autologous hematopoietic stem cells. There are upcoming trials focusing on remyelination strategies in MS. In this yearly review, we will focus on all these latest developments which are leading to a promising change in the diagnosis, treatment, and prognosis of this disease.

Keywords: Autologous hematopoietic stem cell transplant, B-cell therapies, multiple sclerosis, neuroprotection


How to cite this article:
Rohatgi A, Pandita N. Multiple sclerosis in 2020. Apollo Med 2021;18:196-9

How to cite this URL:
Rohatgi A, Pandita N. Multiple sclerosis in 2020. Apollo Med [serial online] 2021 [cited 2021 Dec 6];18:196-9. Available from: https://www.apollomedicine.org/text.asp?2021/18/3/196/326243




  Introduction Top


The treatment, diagnosis, and prognosis of multiple sclerosis (MS) is undergoing a sea change over the last few years and 2020 despite the COVID pandemic was no different ushering in newer therapies and bringing hope to MS patients.

In this yearly review, we will take a bird's-eye view how the MS landscape changed in 2020.


  B-Cell Therapies Top


The novel therapeutic disease-modifying agents recently approved for the treatment of MS are anti-CD20 antibodies (ocrelizumab and ofatumumab). These affect the B-cells causing their apoptosis, thereby producing anti-inflammatory effects.

Ocrelizumab is a humanized anti-CD20 monoclonal antibody (from mouse) which binds to an overlapping epitope to that of rituximab and is used intravenously. Ocrelizumab specifically depletes B-cells and was approved by the Food and Drug Administration (FDA) in March 2017 for the treatment of MS, in particular those with active primary progressive MS (PPMS). The drug is given in initial dose of 300 mg followed by repeat dose after 2 weeks intravenously, and subsequent doses (600 mg) are given at every 6-month interval. Common adverse effects noted are infections such as upper respiratory tract infections and urinary tract infections. Serious side effects noted are hypogammaglobulinemia and neutropenia.[1]

Ofatumumab is a subcutaneous anti-CD20 monoclonal antibody, which selectively depletes B-cells (95% reductions in B-cells). It was approved in August 2020. Ofatumumab with monthly 20 mg subcutaneous dosing regimen demonstrated high efficacy and a favorable safety profile. Adverse effects reported with this drug were infections, neutropenia, infusion-related reaction, anemia, thrombocytopenia, cough, and pneumonia. Less common adverse effects were cholelithiasis, hypokalemia, angioedema, and urticaria. No cases of incidental neoplasm were observed in any of the patients who received the medication.[2],[3] This marks a paradigm shift in the use of CD20 therapy at home with once a month subcutaneous injection of ofatumumab.

One of the recent promising strategies in targeting of the B-cells in MS are the Bruton's tyrosine kinase (BTK) inhibitors (evobrutinib, tolebrutinib, and fenebrutinib). The idea of targeting BTK in autoimmunity flows from the success of CD20-directed antibodies, such as rituximab (now generic) and Ocrevus (ocrelizumab), as therapies for rheumatoid arthritis, MS, and other disorders marked by autoreactive B-cells. Yet, whereas anti-CD20 drugs completely wipe out all B-cells, leaving people prone to opportunistic infections, BTK inhibitors which block a critical enzyme involved in B-cell maturation may more selectively remove unwanted B-cells while leaving healthy ones alone. BTK acts as an early downstream amplification enzyme of the B-cell antigen receptor. BTK signaling influences antigen presentation on B-cells and is essential to the production of antibodies, pro-inflammatory cytokines and chemokines, and cell adhesion molecules. BTK is expressed in B-cells, macrophages, and myeloid cells but not in T-cells. BTK is involved in both adaptive and innate immune responses. It mediates signaling through B-cell receptor, Fcy receptor, and GM-CSF receptor.[4],[5] Evobrutinib was tested as a monotherapy for relapsing-remitting MS (RRMS). This was the first large, placebo-controlled trial of BTK inhibition as a monotherapy in MS. In this double-blind, randomized Phase II clinical trial, three doses of evobrutinib (25 mg once daily, 75 mg once daily, or 75 mg twice daily) were tested against placebo or dimethyl fumarate (DMF). A total number of 267 patients were enrolled in the study. The primary endpoint was the overall number of gadolinium (Gd)-enhancing lesions on T1-weighted magnetic resonance imaging (MRI) at weeks 12, 16, 20, and 24. The annualized relapse rate (ARR) and changes from baseline expanded disability status scale (EDSS) were secondary endpoints. The trial reported a reduction of total number of Gd+-lesions as well as ARR in 75 mg evobrutinib once or twice per day treated patients. However, statistical significance was only reached for the number of Gd+-lesions when comparing placebo and 75 mg evobrutinib once per day. There was no change in EDSS observed in this trial.[6] Of note, intermediate- and high-dose evobrutinib was associated with an elevation of liver aminotransferase levels. Currently, a Phase III trial, in which evobrutinib will be compared to an active comparator and placebo, is recruiting a total number of around 950 MS patients. The primary outcome measure is the ARR, while total number of new lesions, change in EDSS as well as safety concerns will be also addressed. However, evobrutinib is only the first compound to show a clinical benefit in RRMS.

Tolebrutinib is another BTK inhibitor being evaluated. In a Phase II study, participants with RRMS took one of four doses of tolebrutinib for 12 weeks either before or after taking placebo for 4 weeks. Compared to the placebo period, treatment with the highest dose of tolebrutinib resulted in an 85% relative reduction in new T1 lesions and an 89% relative reduction in T2 lesions.[7]

Fenebrutinib is an orally available inhibitor of BTK with potential antineoplastic activity. It is being evaluated in relapsing MS (RMS) and PPMS. Its Phase 3 trial is ongoing.[8]


  Sphingosine-1-Phosphate Inhibitors Top


Ponesimod is a selective sphingosine-1-phosphate receptor inhibitor. It was recently approved by FDA for the treatment of RRMS in March, 2021 based on the results of the OPTIMUM study.[9] The OPTIMUM study (NCT02425644) evaluated the efficacy and safety of oral ponesimod 20 mg versus teriflunomide 14 mg once daily in adult patients with RRMS. It was a multicenter, randomized, double-blind, parallel-group, active-controlled superiority study that enrolled patients with established diagnosis of MS, as per 2010 McDonald criteria, with a relapsing course from onset and EDSS score of 0.5–5.5 inclusive and recent clinical or MRI disease activity. Ponesimod had a significant effect on fatigue symptoms compared to teriflunomide as measured by Fatigue Symptoms and Impacts Questionnaire-RMS. There was a significant reduction in number of combined unique active lesions. The most common adverse effects included nasopharyngitis, headache, upper respiratory tract infections, and an increase in alanine aminotransferase.


  Autologous Hematopoietic Stem Cell Transplant Top


Autologous hematopoietic stem cell transplantation(AHSCT) may be a useful treatment option for people with RRMS.[10] When considering any therapeutic intervention, physicians and patients must weigh the prospective benefits versus the potential risks. For AHSCT, the risk lies in the possible consequences of immunoablation, most notably serious and sometimes unusual infections. The prospective benefit, on the other hand, is long-lasting freedom from MS disease activity. Numerous studies have demonstrated a high degree of efficacy and durability of outcome in patients with active relapsing forms of MS. Studies have included retrospective analyses, single-arm clinical trials, and two small randomized clinical trials, as well as an extensive meta-analysis and another extensive analysis of the European Blood and Marrow Transplant Registry. In particular, the meta-analysis by Sormani et al. described rates of no evidence of disease activity of 78%–83% at 2 years and 60%–68% at 5 years, substantially exceeding those seen with disease-modifying therapies (DMTs), which ranged from 13% to 46% at 2 years.[11]

On the risk side of the equation, AHSCT for MS has clearly become safer in recent years, likely because of selection of candidates better suited to the procedure and changes in immunoablation regimens. Data from the European Blood and Marrow Transplant Registry indicated an overall mortality rate of 2.0% for procedures performed between 1995 and 2016 (829 transplants) but only a 0.2% rate for those done between 2012 and 2016 (439 transplants). Furthermore, in contrast with serious adverse events in patients treated with DMTs, which are more likely to occur over time, most of the serious adverse events with AHSCT are likely to occur early during the period of immunoablation.

AHSCT may be a useful treatment option for people with RMS who demonstrate substantial breakthrough disease activity (i.e., new inflammatory central nervous system [CNS] lesions and/or clinical relapses) despite treatment with high-efficacy DMT or have contraindications to high-efficacy DMTs. The best candidates are likely people younger than 50 years with shorter durations of disease (<10 years). The procedure should only be performed at centers with substantial experience and expertise. Questions remain about the ideal protocol, particularly about the best conditioning regimen to be used to kill immune cells. Larger randomized controlled trials (RCTs) are needed to address the question of whether AHSCT has advantage. One such trial (Best Available Therapy Versus Autologous Hematopoietic Stem Cell Transplant for MS [BEAT-MS]) is currently in progress. BEAT-MS is a multicenter prospective rater-masked (blinded) RCT of 156 participants, comparing the treatment of autologous hematopoietic stem cell transplantation (AHSCT) to the treatment of what's known as “best available therapy” for treatment-resistant MS. Participants are randomized at a 1-1 ratio, and all participants are followed for 72 months post randomization. The study started during the end of 2019 and runs through the estimated primary completion date of December 2025. The final study completion is October 2028.[12]


  Radiologically Isolated Syndrome Top


Radiologically isolated syndrome (RIS) is defined by MRI findings meeting the McDonald criteria for MS in the brain and/or spinal cord in asymptomatic patients. Radiological progression occurs in approximately 66% of the patients with RIS, while 33%/5-year period will subsequently develop neurological symptoms.[13] The radiologically isolated syndrome consortium[14] had 277 patients and reported a cumulative probability of 51.2% of a clinical event at 10 years. Young age, spinal cord lesions, presence of oligoclonal bands in the CSF, and infratentorial lesions are the risk factors for a clinical event. The probability increases from 29% in those with single risk factor to 87% in those with all four risk factors. Currently, no treatment is indicated for RIS, however two trials are ongoing to examine this, they are TERIS and ARISE.[15],[16]


  Remyelination Strategies Top


Several trials are studying the role of promoting neuroprotection in MS by remyelination.[17] As we know, MS is an inflammatory autoimmune disease of the CNS with both inflammatory and degenerative aspects. Inflammatory demyelination leads to oligodendroglial loss, myelin sheath damage, and axonal injury since early stages. Remyelination mediated by resident Oligodendrocyte Precursor Cells (OPCs) which differentiate into myelin-replacing oligodendrocytes restores axonal conduction and contributes to clinical recovery. However, brain's overall regeneration and remyelination capacity is limited which is why there is broad consensus that pharmacologically improved remyelination might be very beneficial. Current approaches to remyelination are focused on blocking inhibitors of remyelination (anti-LINGO), improving clearance of myelin debris, increasing the number of OPCs (transplantation of human OPCs), and stimulating OPC differentiation (clemastine and GSK 239512). In the AFFINITY trial (pro-remyelinating trial),[18] opicinumab failed to show effect on disability in patients with RMS, ending the development of anti-Lingo-1 strategy. Bexarotene was also used for promoting remyelination in patients with RRMS.[19] Although the primary efficacy outcome was negative, and the drug was poorly tolerated, the secondary outcomes suggest that it promotes myelin repair.


  COVID 19 and Multiple Sclerosis Top


Amid all the advancement in the management of this disease, the year 2020 made all the neurologists reconsider the treatment guidelines in patients with MS, as undoubtedly, it was the year of the COVID-19 pandemic. MS per se does not predispose to COVID-19 infection. However, higher age, EDSS = 6 or more, and obesity are independent risk factors for COVID-19.[20] In MS Global Data Sharing Initiative,[21] clinician-reported data from 21 countries were aggregated into a dataset of 1540 patients. Characteristics such as admission to hospital, admission to intensive care unit (ICU), need for mechanical ventilation, and death were assessed in patients with confirmed or suspected COVID-19. Adjusted prevalence ratios were calculated adjusting for age, sex, MS type, and EDSS. Of 1540 patients, 476 (30.9%) with suspected and 776 (50.4%) with confirmed COVID-19 were included in the analysis. A total of 313 patients required hospital admission, 76 required ICU admission, 54 required ventilation, and 48 died. Pooled data showed that the anti-CD20 drugs were more likely to be associated with higher risks of hospitalization, ICU admission, and ventilation when compared with natalizumab or DMF.


  Conclusions Top


  • Early diagnosis and treatment is changing the disease outcome.
  • Newer therapies will hopefully play a vital role in management of patients with MS in coming future.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, et al. Ocrelizumab versus interferon beta-1a in relapsing multiple sclerosis. N Engl J Med 2017;376:221-34.  Back to cited text no. 1
    
2.
Bar-Or A, Grove RA, Austin DJ, Tolson JM, VanMeter SA, Lewis EW, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. Neurology 2018;90:e1805-14.  Back to cited text no. 2
    
3.
Byrd JC, Brown JR, O'Brien S, Barrientos JC, Kay NE, Reddy NM, et al. Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med 2014;371:213-23.  Back to cited text no. 3
    
4.
Kuehn HS, Swindle EJ, Kim MS, Beaven MA, Metcalfe DD, Gilfillan AM. The phosphoinositide 3-kinase-dependent activation of Btk is required for optimal eicosanoid production and generation of reactive oxygen species in antigen-stimulated mast cells. J Immunol 2008;181:7706-12.  Back to cited text no. 4
    
5.
Kim YY, Park KT, Jang SY, Lee KH, Byun JY, Suh KH, et al. HM71224, a selective Bruton's tyrosine kinase inhibitor, attenuates the development of murine lupus. Arthritis Res Ther 2017;19:211.  Back to cited text no. 5
    
6.
Montalban X, Arnold DL, Weber MS, Staikov I, Piasecka-Stryczynska K, Willmer J, et al. Placebo-controlled trial of an oral BTK inhibitor in multiple sclerosis. N Engl J Med 2019;380:2406-17.  Back to cited text no. 6
    
7.
ClinicalTrials.gov.Tolebrutinib, a Brain-penetrant Bruton s Tyrosine Kinase Inhibitor, for the Modulation of Chronically inflammed White Matter Lesions in Multiple Sclerosis- NCT04742400.  Back to cited text no. 7
    
8.
ClinicalTrials.gov. Study to Evaluate the Efficacy and Safety of Fenebrutinib Compared with Teriflunomide in Relapsing Multiple Sclerosis (RMS) (FENhance)- NCT04586023.  Back to cited text no. 8
    
9.
ClinicalTrials.gov. Oral Ponesimod versus Teriflunomide in Relapsing Multiple Sclerosis (OPTIMUM) – NCT02425644; 2015. Available from: https://clinicaltrials.gov/ct2/show/study/NCT02425644?term=ponesimod and cond=Multiple+Sclerosis and draw=2. [Last accessed on 2021 Jun 11].  Back to cited text no. 9
    
10.
Miller AE, Chitnis T, Cohen BA, Costello K, Sicotte NL, Stacom R, et al. Autologous hematopoietic stem cell transplant in multiple sclerosis: Recommendations of the National Multiple Sclerosis Society. JAMA Neurol 2021;78:241-6.  Back to cited text no. 10
    
11.
Sormani MP, Muraro PA, Schiavetti I, Signori A, Laroni A, Saccardi R, et al. Autologous hematopoietic stem cell transplantation in multiple sclerosis: A meta-analysis. Neurology 2017;88:2115-22.  Back to cited text no. 11
    
12.
ClinicalTrials.gov. Oral ponesimod versus teriflunomide in relapsing multiple sclerosis (OPTIMUM) - NCT02425644; 2015 [cited 2020 Mar]. Available from: https://clinicaltrials.gov/ct2/show/study/NCT02425644?term=ponesimod&cond=Multiple+Sclerosis&draw=2. [Last accessed on 2021 Jun 11].  Back to cited text no. 12
    
13.
Siva A. Asymptomatic MS. Clin Neurol Neurosurg 2013;115 Suppl 1:S1-5.  Back to cited text no. 13
    
14.
Lebrun-Frenay C, Kantarci O, Siva A, Sormani MP, Pelletier D, Okuda DT, et al. Radiologically isolated syndrome: 10-year risk estimate of a clinical event. Ann Neurol 2020;88:407-17.  Back to cited text no. 14
    
15.
ClinicalTrials.gov. Best available therapy versus autologous hematopoietic stem cell transplantation for multiple sclerosis (BEAT-MS). https://clinicaltrials.gov/ct2/show/NCT04047628?term=immune+tolerance+network&cond=Multiple+Sclerosis&draw=2&rank=6. [Last accessed on 2021 Jun 11].  Back to cited text no. 15
    
16.
ClinicalTrials.gov. Randomized, Double-blinded Study of Treatment: Teriflunomide, in Radioogically Isolated Syndrome (TERIS) - NCT03122652. [Last accessed on 2021 Jun 11].  Back to cited text no. 16
    
17.
Lubetzki C, Zalc B, Williams A, Stadelmann C, Stankoff B. Remyelination in multiple sclerosis: From basic science to clinical translation. Lancet Neurol 2020;19:678-88.  Back to cited text no. 17
    
18.
MacCannell D, Nestorov I. Model-based identification of flat dosing regimen for opicinumab. AFFINITY trial. ECTRIMS Online Library. 2019: P642.  Back to cited text no. 18
    
19.
Brown J, Cunniffe N, Prados F, Kanber B, Jones J, Needham E, Georgieva Z, et al. Safety and efficacy of bexarotene in people with relapsing-remitting multiple sclerosis. Lancet Neurol 2021; 20: 709-720. https://doi.org/10.17863/CAM.70696.  Back to cited text no. 19
    
20.
Louapre C, Collongues N, Stankoff B, Giannesini C, Papeix C, Bensa C, et al. Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA Neurol 2020;77:1079-88.  Back to cited text no. 20
    
21.
Peeters LM, Parciak T, Walton C, Geys L, Moreau Y, De Brouwer E, et al. COVID-19 in people with multiple sclerosis: A global data sharing initiative. Mult Scler 2020;26:1157-62.  Back to cited text no. 21
    




 

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  In this article
Abstract
Introduction
B-Cell Therapies
Sphingosine-1-Ph...
Autologous Hemat...
Radiologically I...
Remyelination St...
COVID 19 and Mul...
Conclusions
References

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