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Emerging Therapies

Michael D. Kornberg and Peter A. Calabresi

INTRODUCTION

The pace of therapeutics discovery in MS over the past several decades has been remarkable, producing 15 Food and Drug Administration (FDA)-approved disease-modifying therapies. As a whole, these agents substantially impact the disease, not only reducing relapses and short-term disability but also, as increasing evidence indicates, delaying or preventing long-term disability (1–4). Nonetheless, currently available therapies target the peripheral immune system and, with the exceptions of ocrelizumab and mitoxantrone, carry exclusive indications for relapsing forms of MS. These traditional immunologic therapies have largely failed in progressive MS, with the rare successes likely related to patient selection (i.e., younger patients with radiologically active disease) rather than specific targeting of the mechanisms underlying progression.

Although improvements may still be made in the traditional immunologic approach (e.g., development of targeted therapies with more favorable efficacy/risk profiles than present drugs), the next generation of therapeutics will focus largely on mechanisms relevant to progressive MS, with a goal of arresting progression and restoring function. This includes targeting the compartmentalized inflammation that characterizes progressive MS (consisting of diffuse macrophage/microglial activation and leptomeningeal inflammation), as well as strategies to prevent neurodegeneration and induce remyelination. Although more work is needed to elucidate the pathogenesis of progression and to improve the outcome measures used to assess efficacy, many promising agents already exist within the therapeutic pipeline. This chapter reviews some of the most promising therapies and strategies in development, organized as follows: immunologic, neuroprotective, and remyelinating/reparative therapies.

EMERGING IMMUNOLOGIC THERAPIES

Immunologic therapies in the most advanced stages of development are still largely targeted at relapsing–remitting MS (RRMS), with a goal either of providing additional high-efficacy options for aggressive disease or eliminating off-target effects to increase safety/tolerability (see Table 16.1). Agents selectively targeting compartmentalized inflammation (either adaptive immune cells that have migrated to the CNS or innate immune resident CNS cells) remain farther from the clinic.

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151Autologous Hematopoietic Stem Cell Transplant

The rationale underlying autologous hematopoietic stem cell transplant (aHSCT) is to “reset” the immune system and remove autoreactive immune cells by first treating with high-potency immunosuppression to produce chemical immunoablation. The immune system is then repopulated using hematopoietic stem cells derived from the patient, avoiding the complications of allogeneic transplant. Given the serious risks associated with immunoablation, this approach has primarily been studied in patients with very aggressive MS that have failed multiple other therapies. Most of the trials to date have been small, open-label, single-arm studies that differ both in the immunoablative regimen used and the transplant protocol. Nonetheless, several analyses and two phase 2 studies have likely set the stage for a larger, randomized trial comparing aHSCT to other aggressive treatments.

A meta-analysis evaluated 15 studies of aHSCT in MS patients published between 1995 and 2016, including 764 transplanted patients (5). The pooled rate of progression (defined as a sustained increase in Expanded Disability Status Scale [EDSS] score) was 23.3% at 5 years posttransplant, in the absence of ongoing disease modifying therapy. One lesson from this analysis was that younger patients with RRMS see greater benefit, with a pooled 2-year progression rate of 24.8% versus 7.8% in studies including a low versus high proportion of RRMS patients, respectively. Concurrently, a large, retrospective cohort study examined outcomes from 281 patients who underwent aHSCT at 25 different centers from 1995 to 2006 (6). Overall progression-free survival at 5 years was 46%, but again this was greater for patients with relapsing (73%) versus progressive (33%) MS. Building on these lessons, a phase 2 trial of high-intensity immunoablation and aHSCT in 24 MS patients with highly active disease found 69.6% of patients without disease activity or progression after 3 years (7). The effect on new disease activity was profound, as none of the patients experienced clinical or MRI relapse after a median of 6.7 and maximum of 13 years follow-up. Another phase 2 trial, the HALT-MS study, evaluated 24 highly active RRMS patients undergoing aHSCT (8). Progression-free, clinical relapse-free, and MRI activity-free survival were 91.3%, 86.9%, and 86.3%, respectively, after median follow-up of 62 months. Although promising, it must be emphasized that these were open-label studies with careful patient selection, generally excluding patients with significant comorbid conditions.

As mentioned, safety has been a major concern with aHSCT, as immunoablation necessarily leads to cytopenias and therefore a risk of serious infections and other complications. In the meta-analysis and retrospective cohort study described earlier, pooled treatment-related mortality was 2.1% and 2.8%, respectively (5,6). Factors associated with higher mortality have been identified, including progressive disease and higher EDSS score, suggesting that younger patients with RRMS fare better. Notably, mortality with aHSCT appears to have decreased over time, likely driven by greater experience and better patient selection. In fact, only one treatment-related death has been reported among the 349 patients undergoing aHSCT since 2005 (5). As such, further phase 3 studies may reveal aHSCT as a viable strategy in aggressive MS.

Cladribine

Cladribine (2-chlorodeoxyadenosine), currently FDA approved to treat hairy cell leukemia, has been under development as an oral agent for MS. A purine analog that disrupts DNA metabolism and causes apoptosis, cladribine preferentially depletes T and B lymphocytes because of their high levels of the enzyme necessary for its incorporation into DNA (9). It has a unique dosing regimen among oral agents: two to four short courses (daily treatment for 4–5 consecutive days) in the first year, followed by two short courses during the second year.

Cladribine has been tested in two placebo-controlled phase 3 trials. In the CLARITY study, cumulative doses of 3.5 and 5.25 mg/kg were tested in relapsing MS patients, producing 57.6% and 54.5% reductions in annualized relapse rate (ARR) versus placebo, respectively (10). The risk of 3-month disability progression decreased from 20.6% in the placebo group to 14.3% (33% relative reduction) and 15.1% (31% relative reduction) in the 3.5 and 5.25 mg/kg groups, respectively, with concomitant reductions in brain atrophy rate. Intriguingly, results from a 2-year extension study showed that the effect on ARR is durable even after discontinuation of the drug (11). In the ORACLE MS trial, cladribine was compared to placebo in patients with clinically isolated syndrome (CIS) (12). The risk reduction in time to conversion to clinically definite MS was 67% for the 3.5 mg/kg dose and 62% for the 5.25 mg/kg dose.

The primary safety concern with cladribine is lymphopenia, predictably from its mechanism of action. Lymphocyte counts nadir shortly after each course of treatment, with slow recovery over weeks to months. In CLARITY, 25.8% and 45% of patients experienced grade 3 or 4 lymphopenia at nadir in the 3.5 and 5.25 mg/kg groups, respectively, with persistent lymphopenia at 96 weeks in 21.6% and 31.5% of patients (10). Neutropenia and thrombocytopenia occurred rarely. In CLARITY, there was also concern for increased cancer risk, with 1.1% of cladribine-treated patients developing a malignancy versus none on placebo. This risk was not observed in ORACLE MS; however, a subsequent meta-analysis of cladribine studies found no increased risk of cancer (13).

Although cladribine was approved for use in RRMS in Russia and Australia in 2010, such approval was denied by the European Union in 2010 and by the FDA in 2011. However, with additional safety data from extension studies and a changing landscape of risk/benefit calculations in MS therapeutics, efforts to seek approval have been renewed. The dosing regimen has advantages over some other high-potency treatments, and head-to-head comparisons and longer term safety data may still demonstrate a role for this therapy in aggressive MS.

152Selective Sphingosine 1-Phosphate Receptor Modulators

Sphingosine 1-phosphate (S1P) receptors are G protein–coupled receptors comprised of five subtypes (S1P_1–5), with S1P₁ expressed on lymphocytes and controlling egress from peripheral lymph nodes (14). S1P receptor modulators act by causing degradation of S1P₁ and “trapping” lymphocytes in the periphery. Fingolimod, a nonselective S1P receptor modulator, was FDA approved for RRMS in 2010. Despite good efficacy, it has a long half-life (6–9 days) and broad side effect profile owing to off-target effects, including potentially dangerous cardiac risks (14,15). As a result, selective S1P receptor modulators are being developed in hopes of limiting side effects while maintaining efficacy.

Furthest along in development are siponimod (targeting S1P₁ and S1P₅) and the S1P₁-selective agents ponesimod and ozanimod. Siponimod and ponesimod have both shown efficacy in clinical and MRI measures of RRMS in phase 2 studies (16–18), and results released from two phase 3 studies of ozanimod in RRMS describe reduced ARR and brain atrophy progression rates compared with intramuscular interferon beta-1a (19,20). The phase 3 EXPAND trial evaluated siponimod 2 mg daily in secondary progressive MS (SPMS) and showed a 21% decreased risk of 3-month confirmed disability versus placebo (21). Although S1P₅ expressed by CNS cells, including oligodendrocytes, has been cited as a potential target in progressive MS, the benefit in EXPAND was greatest for younger patients with active disease—suggesting prevention of inflammatory disease activity as the most relevant mechanism.

Although the selective S1P receptor modulators all have shorter half-lives (and therefore a quicker washout period) than fingolimod, it remains to be seen whether their side effect profiles are truly superior. These agents caused variable degrees of bradycardia and cardiac conduction block in phase 2 trials (unsurprisingly given that S1P₁ is expressed on atrial myocytes), as well as other side effects seen with fingolimod, such as macular edema and dyspnea (14).

Laquinimod

Laquinimod is an oral quinoline 3-carboxamide derivative with broad immune effects on multiple cell types, including CNS-resident astrocytes and microglia (22). Although studies to date have shown only a modest effect on ARR in RRMS, recent interest in laquinimod stems from a disproportionate impact on measures of disease progression, with animal data suggesting it may target the compartmentalized inflammation that drives neurodegeneration in progressive MS.

In the MS animal model experimental autoimmune encephalomyelitis (EAE), laquinimod prevents formation of meningeal B-cell aggregates (23). In humans, similar leptomeningeal clusters become more frequent in progressive MS and are closely associated with cortical atrophy. In the phase 3 ALLEGRO trial, 0.6 mg/d laquinimod produced a modest 23% reduction in ARR versus placebo, but disability progression and brain atrophy were disproportionately reduced by 36% and 33%, respectively (24). In a second placebo-controlled phase 3 trial, the BRAVO study, 0.6 mg/d laquinimod produced a nonsignificant 18% reduction in ARR but again showed a significant reduction (28%) in brain volume loss (25). An additional placebo-controlled phase 3 trial, CONCERTO, is examining time to disease progression as a primary outcome in RRMS, although initial results released by the sponsors showed no significant effect on this measure (26). A phase 2 trial (ARPEGGIO, NCT02284568) is currently underway in primary progressive MS (PPMS).

Although an increased incidence of cardiovascular events led to discontinuation of the high-dose arms in CONCERTO and ARPEGGIO (1.2 and 1.5 mg/d, respectively), no such events have been reported at the 0.6 mg/d dose in any of the trials (27). Otherwise, the overall safety profile of laquinimod appears favorable, with no increased risk of infection or neoplasm. Dose-dependent increases in liver enzymes were observed but typically were asymptomatic and reversible without withdrawing therapy (22).

Future Directions

Compartmentalized inflammation—chronic activation of innate immune cells and leptomeningeal inflammation—persists in progressive MS and correlates with measures of neurodegeneration, providing a potential immunologic target in this stage of disease. Nonetheless, more work is needed to determine its causality in neuro-axonal injury, as well as how to modulate it pharmacologically and reliably measure it in vivo. Truly “smart” therapies that selectively deplete autoreactive lymphocytes or induce tolerance to myelin-derived antigens likewise remain far from the clinic, although promising approaches are in development. For instance, immunization with autologous Epstein–Barr virus (EBV)-specific T cells (given the postulated role of chronic EBV infection in MS) has produced encouraging phase 1 results (28), as have strategies to induce tolerance via transdermal or peripheral blood mononuclear cell-coupled application of myelin peptides (29,30). Finally, as part of the move toward more precise “personalized” medicine, ongoing research seeks to identify immunologic biomarkers that can predict which therapies are most likely to work for individual patients—such that treatment choices can be tailored for each patient.

EMERGING NEUROPROTECTIVE THERAPIES

Although classically considered a demyelinating disease, neurodegeneration is nearly universal in MS (particularly in progressive MS) and correlates more closely with disability than other pathological and clinical features (31). Neuroprotective therapies thus represent a major goal of current research efforts. Neuro-axonal loss likely results 153from a combination of inflammation-induced injury and the consequences of chronic demyelination. A number of early-stage therapies are being developed based on the current understanding of mechanisms driving neurodegeneration, the most advanced of which are discussed in the following sections and Table 16.2.

Biotin

The rationale for evaluating high-dose biotin, otherwise known as vitamin B₇, in MS is based on its role as a cofactor for four essential carboxylase enzymes. One of these enzymes is critical for fatty acid synthesis in oligodendrocytes, and the other three produce intermediates of the Krebs cycle—part of the energy-producing pathway in mitochondria. Accumulating evidence points to energy failure, and mitochondrial dysfunction in particular, as a driver of axonal degeneration in MS. By augmenting mitochondrial function and stimulating fatty acid synthesis, biotin might protect axons and stimulate myelin repair, respectively.

Based on encouraging data from an initial pilot study (32), a small, phase 3 trial of high-dose, pharmaceutical-grade biotin (called MD1003) was conducted in 154 patients with primary or secondary progressive MS with an EDSS score of 4.5 to 7 (the MS-SPI study) (33). MD1003 100 mg three times daily was evaluated versus placebo, with a daring primary endpoint of the proportion of patients experiencing improved disability at month 9, confirmed at month 12. This endpoint was met by 12.6% of the 103 MD1003-treated patients and none of the 51 placebo-treated patients. As a secondary endpoint, the proportion of patients experiencing EDSS progression at month 9 was 4.2% in the MD1003 arm versus 13.6% in the placebo arm, which did not reach statistical significance. Aside from its small size, there were several other methodological weaknesses of the study, such as imbalance in baseline EDSS scores between the two groups and the absence of distinct treating and evaluating physicians. Nonetheless, the data are positive, and a larger phase 3 trial (SPI2, NCT02936037) is currently underway.

154Overall, treatment with MD1003 was safe and well tolerated. A concern that arose is the interference of high-dose biotin with biotin-based clinical laboratory tests. These include standard thyroid function tests, and some patients in MS-SPI had false-positive results indicating hyperthyroidism (33). Because many clinical laboratory tests (including emergent tests such as cardiac enzyme levels) employ a biotinstreptavidin system, the potential for interference extends beyond thyroid testing. Practitioners must be aware of this problem, and patients should be counseled to stop biotin supplementation 72 hours before planned blood testing.

Sodium Channel Blockers

Demyelinated axons must redistribute sodium channels to previously myelinated segments in order to maintain the ability to propagate action potentials. This requires increased energy levels to maintain the electrochemical gradient across axonal membranes, ultimately contributing to energy failure and the influx of cytotoxic calcium ions. As such, sodium channel blockers have stirred interest as a potential strategy for neuroprotection in MS, particularly because many are already in clinical use for other conditions such as epilepsy. After initial success in preclinical animal models (34,35), there has been encouraging preliminary data in humans, with several trials ongoing.

A phase 2 study evaluated whether the voltage-gated sodium channel blocker and antiepileptic phenytoin can produce neuroprotection in acute optic neuritis (ON) (36). Patients presenting within 2 weeks of onset were randomized to phenytoin versus placebo and treated for 3 months, with a primary outcome of retinal nerve fiber layer (RNFL) thickness (a measure of optic nerve degeneration) in the affected eye at 6 months, adjusted for RNFL thickness of the unaffected eye at baseline. Treatment with phenytoin produced a 30% reduction in the extent of RNFL loss versus placebo. No significant effect was observed on visual acuity or visual evoked potential (VEP) latency, although the study was not powered to observe such an effect. Another antiepileptic sodium channel blocker with encouraging preclinical data, oxcarbazepine, is currently being tested in a phase 2 trial (PROXIMUS, NCT02104661) in which the primary outcome is levels of neurofilament light (a marker of neuronal damage) in cerebrospinal fluid (CSF). Finally, the acid-sensing ion channel blocker amiloride, currently used in hypertension and congestive heart failure, decreased the rate of brain volume loss and other MRI markers of neurodegeneration in a pilot study of 14 patients with PPMS (37). Phase 2 studies of amiloride as a neuroprotectant in acute ON (38) (ACTION, NCT01802489) and SPMS (MS-SMART, NCT01910259) have been planned or are underway.

It is worth mentioning that, in addition to providing neuroprotection, sodium channel blockers may also have anti-inflammatory actions on macrophages/microglia, confounding their mechanism of action to some degree (39,40).

Statins

Cholesterol-lowering HMG-CoA reductase inhibitors, commonly referred to as statins, are among the most widely used drugs in medicine. Beyond their specific impact on serum cholesterol levels, however, they exhibit wide-ranging anti-inflammatory and neuroprotective properties and thus have been investigated in progressive MS (41). Supported by preclinical data and a small study showing improved outcomes in ON (42), the phase 2 MS-STAT study evaluated high-dose simvastatin (80 mg daily) in SPMS, with a primary outcome of annualized whole-brain atrophy rate (43). In this 24-month study, simvastatin reduced the annualized atrophy rate by 43%. Although not a primary outcome measure, statistically significant benefits were also shown for EDSS progression and the patient-reported Multiple Sclerosis Impact Scale (MSIS)-29. Based on these encouraging results, a large, phase 3 study of simvastatin 80 mg daily is being planned in patients with SPMS (44) (MS-STAT2).

Future Directions

In addition to the therapies described earlier, a number of other candidates are currently being investigated in clinical trials as neuroprotective agents in MS. Included among these are erythropoietin (45) (NCT01962571), ibudilast (NCT01982942), and idebenone (NCT01854359). Although this work is promising, successful identification and evaluation of potential neuroprotective therapies in the future will require advances in two domains.

First, a better understanding of the mechanisms underlying neuro-axonal injury is needed to identify rational targets for drug design. In this regard, progress in basic/preclinical research has identified mechanisms of injury with potential relevance in MS. For instance, in models of MS, defects in axonal transport and autophagy (the cellular mechanism for clearing damaged cell components) lead to accumulation of damaged axonal mitochondria (46,47). Recent advances in understanding the mechanisms of autophagy in axons and why it fails in disease therefore hold promise in MS (48). Similarly, preclinical research has demonstrated that injured axons execute an active program of self-destruction culminating in depletion of the critical metabolite NAD⁺ (49,50). Supplementation with NAD⁺ precursors or mutations that increase NAD⁺ levels lead to axonal preservation in EAE (51), suggesting the components of this pathway as therapeutic targets. Finally, preclinical studies have identified the complement 155components C1q and C3 as potential neuroprotective targets in MS. Increased expression of these proteins at synapses leads to microglia-mediated synaptic loss (52), and secretion of C1q by aberrantly activated microglia generates neurotoxic astrocytes that actively kill neurons and oligodendrocytes (53).

A second domain requiring progress is the methods available to measure both neurodegeneration and clinical progression in MS, in order to effectively evaluate therapies in clinical trials. Especially important is the development of validated biomarkers with high predictive value that can be used to screen therapies in small, phase 2 trials before committing to larger studies. Thus far, the acute ON paradigm shows potential, as do measures derived from optical coherence tomography, which not only reflect neurodegeneration from prior optic nerve injury but also correlate with brain atrophy and clinical progression (54).

EMERGING REMYELINATING/REPARATIVE THERAPIES

Finally, a third major goal of therapeutics development in MS is to develop strategies for repairing damage and restoring function. Much effort has focused on inducing remyelination of existing lesions, both to restore function and to prevent further degeneration of demyelinated axons. De novo myelination (and remyelination) is mediated by oligodendrocyte precursor cells (OPCs), which are widely distributed, self-renewing cells that are rapidly recruited to areas of myelin injury, where they differentiate into myelinating oligodendrocytes (55). Although OPCs are abundant in adult human brains and present in the majority of chronic MS lesions, remyelination in MS frequently fails, particularly in late-stage and progressive MS patients (56). This failure likely results from a combination of factors, such as inhibitory/toxic components of the lesion environment and the lack of receptive axons. Exciting progress has been made over the last decades to understand and overcome these obstacles. Although remyelinating therapies remain far removed from the clinic, several promising strategies have been identified (see Table 16.3).

Opicinumab

LINGO-1 is a protein expressed by CNS oligodendrocytes and neurons that acts as a negative regulator of oligodendrocyte differentiation and remyelination (57). Opicinumab (also known as BIIB033) is a human monoclonal antibody that antagonizes LINGO-1 and enhances remyelination in preclinical models (58). Much excitement has surrounded the therapeutic potential of opicinumab in MS, and phase 2 trials have been completed in patients with ON and active MS. Although the results of these trials have been mixed, thereby tempering some of this enthusiasm, enough suggestion of benefit exists to pursue larger phase 3 studies.

The RENEW study evaluated opicinumab 100 mg/kg, dosed every 4 weeks for a total of six doses, versus placebo in patients experiencing a first episode of ON, with a primary endpoint of VEP latency at 24 weeks but followed up to 32 weeks (59). In a possibly under-powered study, nonsignificant trends toward improved VEP latency were seen at 24 and 32 weeks in an intention-to-treat analysis, with statistically significant improvement in VEP latency (but not visual acuity) at 32 weeks in a prespecified per-protocol analysis. The SYNERGY trial evaluated four doses of opicinumab (3, 10, 30, and 100 mg/kg), given every 4 weeks for 19 doses, in patients with active RRMS or SPMS, with a primary endpoint of improvement on composite disability scores (60,61). Although the reported results failed to show a linear dose response, the two intermediate doses (10 and 30 mg/kg) led to an increased percentage of improvement responders (65.6% and 68.8%, respectively vs. 51.6% for placebo). These doses may be pursued further in phase 3 trials.

Agents Identified From Cell-Based Screens

One strategy for identifying remyelinating therapies has been to screen existing drugs for their ability to induce OPC differentiation into myelinating oligodendrocytes in vitro, followed by subsequent validation in in vivo models. Using such methods, several promising agents have been identified, including miconazole, clobetasol, and the anti-muscarinics clemastine and benzatropine (62,63). Results released from a phase 2 study of clemastine in MS patients with chronic optic neuropathy demonstrated an improvement in VEP latency with drug treatment, providing proof of principle for the approach and impetus for further clinical trials (64).

Cell-Based Therapies

Another strategy under investigation involves infusion of nonhematopoietic cells to induce remyelination and tissue repair, with two particular cell-based therapies garnering the most interest thus far. The first involves direct injection of neural stem cells or OPCs into the CNS, with a phase 1 safety trial of this approach planned in SPMS patients (65). Although this strategy induces myelination in genetically hypomyelinating animal models, its potential in MS is less clear, since OPCs are abundant in adult human brains but fail to migrate into lesions or differentiate into mature oligodendrocytes when present. A second therapy under investigation involves injection (either intravenous or intrathecal) of mesenchymal stem cells (MSCs), which are pluripotent cells derived from a variety of sources with immunomodulatory and repair-promoting properties in animal models (66). Phase 1 safety trials have been completed in MS patients (67,68) with a phase 2 study currently underway (MESEMS, NCT01854957). Although not designed to evaluate for a treatment effect, a phase 1 study showed no evidence of change in disease activity or neurologic function after MSC infusion (68).

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Future Directions

Analogous to neuroprotective therapies, further development of remyelinating/reparative therapies will require addressing two main challenges: (a) an incomplete understanding of the mechanisms of remyelination failure and (b) better clinical trial paradigms. With regard to the latter, the most sensitive approach for evaluating efficacy in phase 2 trials remains uncertain, as does the length of treatment necessary to observe an effect.

Regarding the mechanisms of remyelination failure, future research will identify additional factors that either impede or promote OPC migration and differentiation. Some potential therapeutic targets have already been identified but have yet to advance beyond the preclinical stage. For instance, the inflammatory cytokine interferon gamma and astrocyte-derived hyaluronans have both been shown to inhibit OPC differentiation and myelination within inflammatory lesions (69,70). Conversely, immunoregulatory “M2” macrophages/microglia have been demonstrated to promote remyelination both by phagocytosing myelin debris and by secreting pro-regenerative factors (71), and regulatory T lymphocytes directly induce oligodendrocyte differentiation (72). Therapeutic strategies based on these findings hold promise for the future.

CONCLUSIONS

In addition to producing more targeted immunologic therapies with improved safety and efficacy, the future of MS therapeutics lies in halting progression and restoring function. Although obstacles remain, the pace of progress has been rapid and many promising approaches are already in development—giving hope that the next several decades will continue to see great strides in the fight against this debilitating disease.

 

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