Diagnosis and Management of Progressive Multiple Sclerosis
Abstract
:1. Introduction
2. Pathogenesis
3. Diagnostic Criteria and Disease Course Definitions
4. Disability Outcome Measures
5. Measuring Disease Progression
6. Treatment
6.1. Anti-Inflammatory Disease-Modifying Therapies
6.1.1. Approved Therapies
6.1.2. Therapies with Negative or Weak Effect in Progressive MS
6.2. Remyelination and Neuroprotection in Progressive MS
6.3. Symptomatic Management
7. Challenges in Progressive MS Treatment and Research
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Therapy | Potential Mechanism of Action | Trials | Primary Endpoint | Results |
---|---|---|---|---|
Remyelination strategies | ||||
Clemastine fumarate | First-generation anti-histamine, promotes remyelination and oligodendrocyte differentiation via anti-muscarinic effect [123,124] | ReBUILD [125] | Shortening of P100 latency delay on visual-evoked potentials at 150 days | Improvement in P100 latency of 1.7 ms/eye (95% CI 0.5 to 2.9, p = 0.0048) with clemastine |
Opicinumab | Anti-LINGO-1 antibody, promotes remyelination and oligodendrocyte differentiation via blocking of inhibitory adhesion molecule [126,127] | RENEW [128] (in acute unilateral optic neuritis) | 24-week change in optic nerve conduction latency using full-field visual evoked potential | Non-significant trend towards improvement in the intention-to-treat analysis, modest but significant benefit at week 32 in the per-protocol analysis |
SYNERGY [129,130] (in RRMS and SPMS with active disease) | Percentage of participants with ≥3 month confirmed improvement of composite endpoint (EDSS, T25FW, 9HPT, PASAT) over 72 weeks | Benefit seen in those receiving the 30 mg/kg dose. | ||
Neuroprotection strategies | ||||
Ibudilast | Phosphodiesterase-inhibitor, inhibits macrophage migration inhibitory factor, and toll-like receptor 4 [131] | SPRINT-MS [132] | Progression of whole brain atrophy over 96 weeks | 48% slowing in the rate of atrophy progression with ibudilast compared to placebo |
Simvastatin | HMG-CoA reductase inhibitor, inhibit MHCII-restricted antigen presentation, shifts cytokine production from a pro- to an anti-inflammatory response, decreases T-cell proliferation [133] | MS-STAT [134] | Progression of whole-brain atrophy, change in EDSS and total MS Impact Scale-29 at 24 months | Decrease in annualized rate of whole brain atrophy compared to placebo, benefit on EDSS and MS Impact Scale-29 as well |
Lipoic acid | Endogenous antioxidant, various potential mechanisms, including free radical scavenging, oxidative damage repair, downregulation of inflammatory cytokines, T-cell migration in CNS inhibition [135,136] | Spain et al. [137]. | Annual percent change of brain volume | 68% reduction in the rate of brain atrophy compared to placebo over 24 months |
Phenytoin | Selective sodium-channel inhibitor, reverses sodium influx, which drives calcium influx via reverse operation of the sodium/calcium exchanger after axonal injury [138] | Raftopoulos et al. [139]. | RNFL thickness in the affected eye | 30% reduction in the extent of RNFL loss with phenytoin compared with placebo at 6 months |
Mesenchymal stem cells * | Pluripotent non-hematopoietic precursor cells (isolated from bone marrow or adipose tissue), release of soluble trophic factors that promote intrinsic tissue repair mechanisms [140] | Multiple small clinical trials and open label studies using variable route of administration and dosing regimens [141,142,143,144,145,146,147,148,149] | Variable endpoints depending on trial | Good safety and tolerability, efficacy not yet established [150] |
Phase II randomized, double-blind trial, MESEMS (NCT01854957) [151] | Safety, reduction in the total number of contrast-gadolinium enhancing lesions | Ongoing | ||
Open-label study, MSC-NTF Cells (NCT03799718) | Safety, T25FW change from baseline, changes in neurotrophic factors | Ongoing | ||
High-dose biotin (MD 1003) * | Essential co-factor for five carboxylases involved in fatty acid synthesis and energy production, promotes remyelination, and reduces axonal hypoxia [152] | Sedel et al. (pilot study) [153] | Shortening of P100 latency on visual-evoked potentials | Improvement or normalization of P100 latency |
Tourbah et al. (randomized, double-blind placebo-controlled trial) [154] | Proportion of patients with disability reversal on EDSS or T25FW at month 9, confirmed at month 12 | 2.6% of treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005) | ||
Birnbaum et al. (open-label study of compound medication, not MD 1003) [155] | EDSS worsening or improvement while on treatment (3 to 12 months) | No benefits observed |
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Macaron, G.; Ontaneda, D. Diagnosis and Management of Progressive Multiple Sclerosis. Biomedicines 2019, 7, 56. https://doi.org/10.3390/biomedicines7030056
Macaron G, Ontaneda D. Diagnosis and Management of Progressive Multiple Sclerosis. Biomedicines. 2019; 7(3):56. https://doi.org/10.3390/biomedicines7030056
Chicago/Turabian StyleMacaron, Gabrielle, and Daniel Ontaneda. 2019. "Diagnosis and Management of Progressive Multiple Sclerosis" Biomedicines 7, no. 3: 56. https://doi.org/10.3390/biomedicines7030056