Treatment Of Progressive Multiple Sclerosis Research Articles

Relapses During High-Dose Biotin Treatment in Progressive Multiple Sclerosis: a Case-Crossover and Propensity Score-Adjusted Prospective Cohort.

High-dose biotin (HDB) is a therapy used in non-active progressive multiple sclerosis (PMS). Some reports have suggested that HDB treatment may be associated with an increased risk of relapse. We evaluate the relationship between exposure to HDB for treating PMS and the risk of relapse. We screened for PMS patients prospectively registered in a French regional cohort being part of the OFSEP national registry. In a case-crossover design among patients who received HDB, we first compared number of relapses before and after initiation of HDB. Second, time to the first clinical relapse was compared between patients who received HDB (biotin group) and a control group using a Cox survival analysis after a propensity score (PS) matching (1:1) and inverse probability of treatment weighting (IPTW) method. In the 42 PMS patients who received HDB, the number of relapses was statistically and clinically significant higher after biotin initiation than before biotin initiation (incident rate ratio [IRR] 7.4, 95% confidence interval [CI] 3.5-15.9, p < 0.0001). With the PS matching method, the risk of relapse was significantly higher in the biotin group compared to the control group (hazard ratio [HR] 4.3, 95% CI 1.4-13.3, p = 0.01). The IPTW method with 440 control patients revealed consistent results (HR 5.1, 95% CI 2.3-11.3, p < 0.0001). In our non-randomized study, HDB treatment for PMS was associated with an increased risk of relapse. The follow-up of PMS patients initiating HDB should include careful assessment of clinical and radiological activity to monitor the potential pro-inflammatory effect of biotin.

The window of opportunity for treatment of progressive multiple sclerosis.

Based on the knowledge of disease mechanisms in the progressive course of multiple sclerosis and the experience from randomized clinical trials, we assessed the timing of disease-modifying therapy in patients with progressive multiple sclerosis to define the optimal window of opportunity for treatment of progressive multiple sclerosis. In progressive multiple sclerosis both small molecules that cross the blood--brain barrier (siponimod) and monoclonal antibodies (ocrelizumab) have shown therapeutic efficacy and have been approved for treatment of progressive multiple sclerosis. However, the majority of phase II and phase III trials in progressive forms of multiple sclerosis have been negative, probably owing to either late start of treatment or use of drugs that are ineffective for treatment of progressive multiple sclerosis. Results from phase II and III trials suggest that the window of opportunity for treatment of progressive multiple sclerosis with anti-inflammatory drugs is predominantly in the early phase of the progressive disease course when patients have lower age, shorter duration of progressive multiple sclerosis, and more pronounced clinical and MRI inflammatory activity. Ongoing trials of neuroprotective drugs may widen the window of opportunity by expanding targeted pathophysiologies.

Treatment of autoimmune encephalomyelitis with a histone deacetylase inhibitor.

We have previously shown that treatment of female NOD mice with a potent nonselective histone deacetylase inhibitor attenuated experimental autoimmune encephalomyelitis, a model for progressive multiple sclerosis. Herein we show that immunization with the MOG35-55 peptide induced prolonged upregulation of genes encoding interleukin 17A (IL-17A), aryl hydrocarbon receptor, and histone deacetylase 11 in the spinal cord whereas the subunits of IL-27, IL-27p28 and IL-27ebi3 were significantly increased in secondary lymphoid organs after a lag period. Interestingly, the nitric oxide synthase gene was prominently expressed in both of these anatomic compartments following immunization. Treatment with the histone modifier repressed the transcription of all of these genes induced by immunization. Moreover, the drug suppressed the steady-state levels of the migration inhibitory factor and CD274 genes in both the spinal cord and peripheral lymphoid tissues. At the same time, the CD39 gene was downregulated only in secondary lymphoid organs. Paradoxically, the epigenetic drug enhanced the expression of Declin-1 in the spinal cord, suggesting a protective role in neuronal disease. Immunization profoundly enhanced transcription of the chemokine CCL2 in the secondary lymphoid tissues without a corresponding increase in the translation of CCL2 protein. Histone hyperacetylation neither altered the transcription of CCL2 nor its cognate receptor CCR2 in the central nervous system and peripheral lymphoid tissues. Surprisingly, the drug did not exert modulatory influence on most other immune response-related genes previously implicated in encephalomyelitis. Nevertheless, our data uncover several potential molecular targets for the intervention of experimental autoimmune encephalomyelitis that have implications for the treatment of progressive multiple sclerosis.

Diagnosis and management of secondary-progressive multiple sclerosis: time for change.

Identifying the transition of relapsing-remitting multiple sclerosis (MS) to the secondary-progressive MS form remains a clinical challenge due to the gradual nature of the transition, superimposed relapses, the heterogeneous course of disease among patients and the absence of validated biomarkers and diagnostic tools. The uncertainty associated with the transition makes clinical care challenging for both patients and physicians. The emergence of new disease-modifying treatments for progressive MS and the increasing emphasis of nonpharmacological strategies mark a new era in the treatment of progressive MS. This article summarizes challenges in diagnosis and management, discusses novel treatment strategies and highlights the importance of establishing a clear diagnosis and instituting an interdisciplinary management plan in the care of patients with progressive MS.

Preserved brain functional plasticity after upper limb task-oriented rehabilitation in progressive multiple sclerosis.

Limited research has been dedicated to upper limb (UL) rehabilitation in progressive multiple sclerosis (PMS). The objective in this pilot study was to investigate the effect of task-oriented UL rehabilitation in PMS and to perform explorative analyses of the magnetic resonance imaging (MRI) correlates of changes in motor performance. Twenty-six PMS patients with mild UL impairment were prospectively enrolled and randomized into two groups: an active treatment group (ATG, n=13) and a passive treatment group (PTG, n=13). At baseline and after training, patients underwent MRI scans with structural and functional imaging and were evaluated with the action research arm test, the nine-hole peg test, the ABILHAND scale and the modified fatigue impact scale (MFIS). Measures of motor finger performance were obtained by engineered glove measuring. After rehabilitation, the ATG improved in several finger motor tasks (0.001≤P≤0.03, 0.72≤Cohen's d≤1.22) and showed reduced MFIS scores compared with the PTG (P=0.03). The ATG showed increased functional connectivity within the cerebellar and thalamic resting state networks compared with the PTG (P<0.05). Correlations were found between several measures of motor improvement and thalamic and sensorimotor networks (0.87≤r≤0.93, 0.001≤P≤0.03). No changes in cerebral volumes and diffusion tensor imaging derived measures were detected. Progressive multiple sclerosis patients with mild UL dysfunction benefit from task-oriented UL rehabilitation, which seems to be more efficient than simple passive mobilization. Despite a high burden of disability and brain damage, functional adaptive capacities seem to be preserved, thus providing a rationale for the use of rehabilitative treatments in late PMS.

Diagnosis and Management of Progressive Multiple Sclerosis.

Multiple sclerosis is a chronic autoimmune disease of the central nervous system that results in varying degrees of disability. Progressive multiple sclerosis, characterized by a steady increase in neurological disability independently of relapses, can occur from onset (primary progressive) or after a relapsing–remitting course (secondary progressive). As opposed to active inflammation seen in the relapsing–remitting phases of the disease, the gradual worsening of disability in progressive multiple sclerosis results from complex immune mechanisms and neurodegeneration. A few anti-inflammatory disease-modifying therapies with a modest but significant effect on measures of disease progression have been approved for the treatment of progressive multiple sclerosis. The treatment effect of anti-inflammatory agents is particularly observed in the subgroup of patients with younger age and evidence of disease activity. For this reason, a significant effort is underway to develop molecules with the potential to induce myelin repair or halt the degenerative process. Appropriate trial methodology and the development of clinically meaningful disability outcome measures along with imaging and biological biomarkers of progression have a significant impact on the ability to measure the efficacy of potential medications that may reverse disease progression. In this issue, we will review current evidence on the physiopathology, diagnosis, measurement of disability, and treatment of progressive multiple sclerosis.

The effect of interferon-β therapy on brain-derived neurotrophic factor serum concentration in relapsing— remitting multiple sclerosis: a randomized clinical trial

Introduction: Beta interferon (IFN-β) is known as the first-line therapy in relapsing-remitting multiple sclerosis (RRMS). Recent studies have shown different effects of IFN-β on brain-derived neurotrophic factor (BDNF) serum levels. Given the known role of BDNF in the restoration and conservation of the nervous system, this study was designed to investigate the possible effect of this drug through stimulating BDNF production. Objectives: Impressible treatments for progressive multiple sclerosis (MS) are still being sought. Individual response to existing treatments for MS varies significantly among patients while the risk of serious adverse events remains an issue, especially for the novel drugs. Patients and Methods: In this clinical trial, 96 patients newly diagnosed with RRMS were studied within three months, in 3 groups of 32 subjects. Each group received one of the foregoing drugs (Avonex, Rebif and Betaferon). BDNF levels were compared between different groups at the end. Results: BDNF serum concentration in all groups was significantly different (P&lt;0.001) compared to baseline after 3 months. And comparison between groups showed a significant difference between the groups receiving Betaferon (IFN-β1b) (P=0.001) and Rebif (P=0.002) compared to the other groups. Avonex compared with either control or Betaferon (IFN-β1b) and Rebif groups showed no significant difference. Also the correlation between the mean changes in expanded disability status scale (EDSS) and BDNF was not observed (r = -0.189, P=0.065). Conclusions: Significant difference in BDNF levels were observed between groups.

Factors influencing balance improvement in multiple sclerosis rehabilitation: A pragmatic multicentric trial

Treatment for progressive multiple sclerosis (pMS) is a key area of research. To date, whether MS type and the rehabilitation setting are associated with worse or better response to rehabilitation is unclear. We aimed to understand the association between balance and MS type, in/outpatient treatment and specificity of the intervention. We assessed 150 people with MS before and after in/outpatient rehabilitation. The Berg Balance Scale (BBS) was used to discriminate between responders (≥+3-point improvement in BBS score; a clinically meaningful improvement) and non-responders to specific or non-specific balance rehabilitation. Factors associated with balance were analyzed by univariate and multivariable logistic regression analyses, estimating odds ratios (ORs) and 95% confidence intervals (CIs). Balance improved after rehabilitation: median (quartile 1 [Q1]-Q3) BBS score pre- and post-rehabilitation of 49 (45-53) and 52 (47-55) (P<0.001). Univariate logistic analysis revealed a clinically meaningful improvement in balance associated with pMS (OR 2.21 [95% CI 1.09-4.05]), inpatient therapy (0.41 [0.19-0.84]), using a walking aid (1.68 [1.06-2.69]), and low baseline BBS score (0.86 [0.81-0.92]). On multivariable analysis, probability of improvement was similar for participants with pMS and the relapsing-remitting form but was associated with low baseline BBS score and specific treatment (OR 0.81 [95% CI 0.74-0.89] and 5.66 [1.79-21.5]). A clinically meaningful improvement in balance was more likely when MS individuals with moderate to high disability had specific exercises targeting balance, but MS type did not influence the outcome.

Effect of MD1003 (high dose Pharmaceutical grade Biotin) in the Treatment of Progressive MS: Long-term Safety Data at 48 Months of Follow-up (P3.2-043)

Effect of MD1003 (high dose Pharmaceutical grade Biotin) in the Treatment of Progressive MS: Long-term Safety Data at 48 Months of Follow-up (P3.2-043)

Effect of MD1003 (high dose Pharmaceutical grade Biotin) in the Treatment of Progressive MS: Earlier Treatment Results in Lower Disability Over 48 Months (P3.2-063)

Effect of MD1003 (high dose Pharmaceutical grade Biotin) in the Treatment of Progressive MS: Earlier Treatment Results in Lower Disability Over 48 Months (P3.2-063)

Progressive multiple sclerosis: latest therapeutic developments and future directions.

Multiple sclerosis (MS) is a chronic inflammatory condition of the central nervous system leading to demyelination and neurodegeneration. While the initial presentation is mostly characterized by a relapsing–remitting disease, patients often progress naturally after 10–15 years to a secondary-progressive disease course. Another 10–15% present with an initial, primary-progressive MS course. Pathogenic mechanisms possibly driving progression include continued compartmentalized inflammation by T- and B-lymphocytes and cells of innate immunity, oxidative stress, iron accumulation, and consecutive mitochondrial damage, altogether leading to neurodegeneration with accumulation of disability. Increasing knowledge about pathogenic mechanisms involved in progressive MS helps to design more specific and precise therapeutic approaches. Successful examples are the B-cell targeting monoclonal antibody ocrelizumab, effective in primary progressive MS, and the sphingosine-1-receptor modulator siponimod, effective in active forms of secondary-progressive MS. Apart from that, other medications such as the B-cell targeted antibody ofatumumab, cladribine due to T- and B-cell depletion, and other sphingosine-1-receptor modulators such as ozanimod and ponesimod are under development. Moreover, some therapeutic approaches in preclinical stages are under development. In this review, we will summarize the newest therapeutic development in the field of progressive MS of the last 3 years, and shed light on auspicious substances with similar mechanisms and new developments in the therapeutic pipeline, presumably supporting a bright future for progressive MS treatment.

Therapeutic Advances and Challenges in the Treatment of Progressive Multiple Sclerosis.

Despite the fact that majority of patients with multiple sclerosis (MS) have relapsing-remitting disease, many transition to secondary progressive disease (SPMS) over time. This transition is thought to be related to neurodegenerative processes increasingly predominating over inflammatory processes as the driving forces of disability. However, some patients initially present with primary progressive disease (PPMS) that is characterized by a gradual accumulation of neurological symptoms and subsequent disability accumulation. The treatment of both PPMS and SPMS, collectively referred to as progressive MS, has proven quite challenging due to the multifactorial and poorly understood pathophysiology of multiple sclerosis in general, specifically that of progressive disease. The purpose of this article is to discuss important clinical and pathophysiologic differences between relapsing and progressive forms of MS, review previous notable trials of drugs in progressive MS, examine current literature regarding recent and promising progressive MS treatments, and discuss future considerations for progressive MS therapeutics and management. Specifically, the current evidence regarding treatment of progressive MS with ocrelizumab, simvastatin, ibudilast, alpha-lipoic acid, high-dose biotin, siponimod, and cell-based therapies are discussed.

Phase 2 Trial of Ibudilast in Progressive Multiple Sclerosis

BackgroundThere are limited treatments for progressive multiple sclerosis. Ibudilast inhibits several cyclic nucleotide phosphodiesterases, macrophage migration inhibitory factor, and toll-like receptor 4 and can cross the blood–brain barrier, with potential salutary effects in progressive multiple sclerosis.MethodsWe enrolled patients with primary or secondary progressive multiple sclerosis in a phase 2 randomized trial of oral ibudilast (≤100 mg daily) or placebo for 96 weeks. The primary efficacy end point was the rate of brain atrophy, as measured by the brain parenchymal fraction (brain size relative to the volume of the outer surface contour of the brain). Major secondary end points included the change in the pyramidal tracts on diffusion tensor imaging, the magnetization transfer ratio in normal-appearing brain tissue, the thickness of the retinal nerve-fiber layer, and cortical atrophy, all measures of tissue damage in multiple sclerosis.ResultsOf 255 patients who underwent randomization, 129 were assigned to ibudilast and 126 to placebo. A total of 53% of the patients in the ibudilast group and 52% of those in the placebo group had primary progressive disease; the others had secondary progressive disease. The rate of change in the brain parenchymal fraction was −0.0010 per year with ibudilast and −0.0019 per year with placebo (difference, 0.0009; 95% confidence interval, 0.00004 to 0.0017; P=0.04), which represents approximately 2.5 ml less brain-tissue loss with ibudilast over a period of 96 weeks. Adverse events with ibudilast included gastrointestinal symptoms, headache, and depression.ConclusionsIn a phase 2 trial involving patients with progressive multiple sclerosis, ibudilast was associated with slower progression of brain atrophy than placebo but was associated with higher rates of gastrointestinal side effects, headache, and depression. (Funded by the National Institute of Neurological Disorders and Stroke and others; NN102/SPRINT-MS ClinicalTrials.gov number, NCT01982942.)

Over three decades study populations in progressive multiple sclerosis have become older and more disabled, but have lower on-trial progression rates: A systematic review and meta-analysis of 43 randomised placebo-controlled trials

Background: Progression is the major driver of disability and cost in multiple sclerosis (MS). However, the search for treatments in progressive multiple sclerosis (PMS) has not mirrored the success in relapsing MS. Objectives: To assess changes in PMS trials over time. Methods: PubMed, MEDLINE and Embase were searched to identify randomised, double-blind, placebo-controlled trials in PMS. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used, study quality was assessed and trends were examined by regression. Results: Placebo groups of 43 studies published between 1988 and 2018 were included. The mean age at trial entry increased by 9.8 years per decade (95% confidence interval (CI): [2.7; 4.9]; p < 0.001). Mean baseline Expanded Disability Status Scale (EDSS) scores increased by 0.36 points (95% CI: [0.09; 0.62]; p = 0.009) and disease durations at baseline were prolonged by 1.8 years (95% CI: [0.7; 2.9]; p = 0.003) per decade. The trials became larger, specifically placebo groups increased by about 222 patients (95% CI: [36; 409]; p = 0.021) and 88 patients (95% CI: [12; 165]; p = 0.025) per decade for primary progressive multiple sclerosis (PPMS) and secondary progressive multiple sclerosis (SPMS), respectively. The proportion of patients on placebo experiencing disability progression within 24 months decreased by 7.6 percentage points (95% CI: [1.2; 14.1]; p = 0.022) per year. Conclusion: Over three decades, PMS trial populations changed and are now older, with a longer disease duration and more disability, with lower on-trial progression rates.

P.031 A qualitative study of patient perspectives regarding the role of the neurologist in advanced Multiple Sclerosis

Background: With few evidence-based disease-modifying therapies being available for patients with progressive multiple sclerosis (PMS), how can neurologists best care for their patients? Little is known about the perspectives of patients with respect to the role they would like their neurologist to play in their care. We hereby report an update to our abstract presented at the Canadian Neurological Sciences Federation’s annual congress in 2016. Methods: Patients with PMS having an Expanded Disability Status Scale (EDSS) score of 6 or more were invited to participate. Semi-structured interviews were conducted with patients and their caregivers, and written questionnaires were completed by all participants. Collected data was subjected to thematic coding. Results: We have now interviewed a total of 18 patients (compared to 10 in 2016) and have reached thematic saturation. The majority of patients identified the neurologist as a useful figure in their care. Three main reasons were identified: (1) The neurologist provides information about new research and therapies (2) The neurologist educates patients about their disease and available services (3) The neurologist is viewed as an important supportive figure. Conclusions: Despite a lack of disease-modifying treatments for progressive multiple sclerosis, patients with PMS view the neurologist as an essential provider of care.

CSF inflammatory biomarkers responsive to treatment in progressive multiple sclerosis capture residual inflammation associated with axonal damage

Background: Development of treatments for progressive multiple sclerosis (MS) is challenged by the lack of sensitive and treatment-responsive biomarkers of intrathecal inflammation. Objective: To validate the responsiveness of cerebrospinal fluid (CSF) inflammatory biomarkers to treatment with natalizumab and methylprednisolone in progressive MS and to examine the relationship between CSF inflammatory and tissue damage biomarkers. Methods: CSF samples from two open-label phase II trials of natalizumab and methylprednisolone in primary and secondary progressive MS. CSF concentrations of 20 inflammatory biomarkers and CSF biomarkers of axonal damage (neurofilament light chain (NFL)) and demyelination were analysed using electrochemiluminescent assay and enzyme-linked immunosorbent assay (ELISA). Results: In all, 17 natalizumab- and 23 methylprednisolone-treated patients had paired CSF samples. CSF sCD27 displayed superior standardised response means and highly significant decreases during both natalizumab and methylprednisolone treatment; however, post-treatment levels remained above healthy donor reference levels. Correlation analyses of CSF inflammatory biomarkers and NFL before, during and after treatment demonstrated that CSF sCD27 consistently correlates with NFL. Conclusion: These findings validate CSF sCD27 as a responsive and sensitive biomarker of intrathecal inflammation in progressive MS, capturing residual inflammation after treatment. Importantly, CSF sCD27 correlates with NFL, consistent with residual inflammation after anti-inflammatory treatment being associated with axonal damage.

Effective treatment of progressive MS remains elusive

Effective treatment of progressive MS remains elusive

New Highlights in the Treatment of Progressive Multiple Sclerosis

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system. Most patients have a relapsing-remitting disease type, for which medicines are mostly dedicated. Clinical course of some patients will transition to secondary progressive multiple sclerosis and small portion of patients is classified as primary progressive multiple sclerosis from the beginning. The treatment of progressive multiple sclerosis has been limited for a long time, however, for a few years attention has been paid to the need for new disease modifying drugs that would focus on the treatment of progressive multiple sclerosis. The breakthrough was ocrelizumab, which is the first medicine registered in the treatment of primary progressive multiple sclerosis, while siponimod is planned to be approved soon in the treatment of secondary progressive multiple sclerosis. Numerous studies are currently underway on new substances with anti-inflammatory, neuroprotective or remyelinating effects such as high-dose biotin, ibudilast, simvastatin, alpha lipoic acid or clemastine. The first research results are very promising nevertheless, more accurate drug research is needed.

Systematic screening of generic drugs for progressive multiple sclerosis identifies clomipramine as a promising therapeutic

The treatment of progressive multiple sclerosis (MS) is unsatisfactory. One reason is that the drivers of disease, which include iron-mediated neurotoxicity, lymphocyte activity, and oxidative stress, are not simultaneously targeted. Here we present a systematic screen to identify generic, orally available medications that target features of progressive MS. Of 249 medications that cross the blood–brain barrier, 35 prevent iron-mediated neurotoxicity in culture. Of these, several antipsychotics and antidepressants strongly reduce T-cell proliferation and oxidative stress. We focus on the antidepressant clomipramine and found that it additionally inhibits B-lymphocyte activity. In mice with experimental autoimmune encephalomyelitis, a model of MS, clomipramine ameliorates clinical signs of acute and chronic phases. Histologically, clomipramine reduces inflammation and microglial activation, and preserves axonal integrity. In summary, we present a systematic approach to identify generic medications for progressive multiple sclerosis with the potential to advance rapidly into clinical trials, and we highlight clomipramine for further development.

Suppression of Inflammatory Demyelinaton and Axon Degeneration through Inhibiting Kv3 Channels.

The development of neuroprotective and repair strategies for treating progressive multiple sclerosis (MS) requires new insights into axonal injury. 4-aminopyridine (4-AP), a blocker of voltage-gated K+ (Kv) channels, is used in symptomatic treatment of progressive MS, but the underlying mechanism remains unclear. Here we report that deleting Kv3.1—the channel with the highest 4-AP sensitivity—reduces clinical signs in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS. In Kv3.1 knockout (KO) mice, EAE lesions in sensory and motor tracts of spinal cord were markedly reduced, and radial astroglia were activated with increased expression of brain derived neurotrophic factor (BDNF). Kv3.3/Kv3.1 and activated BDNF receptors were upregulated in demyelinating axons in EAE and MS lesions. In spinal cord myelin coculture, BDNF treatment promoted myelination, and neuronal firing via altering channel expression. Therefore, suppressing Kv3.1 alters neural circuit activity, which may enhance BNDF signaling and hence protect axons from inflammatory insults.