Comparison of dimethyl fumarate and interferon outcomes in an MS cohort.

BACKGROUND: To compare the effectiveness of dimethyl fumarate (DMF) with subcutaneous interferon beta-1a (IFNß-1a) in controlling disease activity in patients with relapsing-remitting Multiple Sclerosis (MS). METHODS: Clinical and imaging data from patients treated with either IFNß-1a or DMF for at least one year were reviewed. The proportion of patients with at least one clinical relapse within 3-15 months after treatment onset, the proportion of patients with new T2 or gadolinium-enhancing lesions, and the proportion of subjects who achieved no evidence of disease activity (NEDA) status were assessed. RESULTS: Three hundred sixteen (98 on IFNß-1a, 218 on DMF) subjects were included. Baseline demographics were comparable between groups except for age, disease duration, and the number of previous treatments being higher and relapse rate in the prior year being lower in the DMF-treated group. The proportion of patients having a clinical relapse (24.5% vs. 9.6%; OR = 3.04; P < 0.001) or a new MRI lesion (28.6% vs. 8.7%; OR = 4.19, P < 0.001) at 15 months were higher on IFNß-1a. 79.9% of the patients achieved NEDA status at 15 months on DMF (vs. 51.1% for IFNß-1a; OR = 0.26, P < 0.001). Further adjustment for demographics, disease characteristics, treatment and relapse history, and subgroup analyses confirmed these findings. CONCLUSION: DMF was associated with less clinical and radiological disease activity compared to IFNß-1a.

A possible case of serum sickness after ocrelizumab infusion.

A 41-year-old female diagnosed with multiple sclerosis began ocrelizumab treatment. She received her first treatment course without significant complication. After receiving the first maintenance dose 6 months later, she developed weakness, myalgias, gastrointestinal symptoms, headache, and intermittent fever persisting for 4 weeks. A working diagnosis of serum sickness was determined after excluding other probable entities. She received 3 days of 1 g methylprednisolone intravenously and five plasma exchanges, experiencing gradual improvement. Serum sickness has occurred with monoclonal antibodies including rituximab. This case of possible ocrelizumab-associated serum sickness suggests that clinicians should remain vigilant about this possibility with this medication.

Prospective growth and developmental outcomes in infants born to mothers with multiple sclerosis.

BACKGROUND: The importance of supporting pregnancy-related decisions in multiple sclerosis (MS) patients has increasingly been recognized and hence the need for prospective data on pregnancy and pediatric outcomes in this patient population. OBJECTIVE: To assess prospective growth and developmental outcomes of infants born to mothers with multiple sclerosis (IMS). METHODS: PREG-MS is a prospective multicenter cohort study in New England, United States. We followed 65 women with MS and their infants with up to 12 months consistent pediatric follow-up. Pediatric, neurologic, and demographic information was obtained via structured telephone interviews and validated with medical records. RESULTS: No differences in infant weights and lengths with World Health Organization (WHO) 50th percentile standards were observed (p > 0.05). However, larger head circumference (HC) measurements than WHO standards were reported in cohort infants (p < 0.05). There was no association between HC and markers of maternal MS activity, demographic, or social factors. No irreversible pediatric developmental abnormalities were observed. CONCLUSION: This first prospective study on pediatric anthropometry in IMS suggests a possible increase in HC compared to WHO standards without an increase in irreversible developmental abnormalities. The observations are exploratory and require confirmation with larger prospective studies in diverse groups of MS patients.

A probiotic modulates the microbiome and immunity in multiple sclerosis.

OBJECTIVE: Effect of a probiotic on the gut microbiome and peripheral immune function in healthy controls and relapsing-remitting multiple sclerosis (MS) patients. METHODS: MS patients (N = 9) and controls (N = 13) were orally administered a probiotic containing Lactobacillus, Bifidobacterium, and Streptococcus twice-daily for two months. Blood and stool specimens were collected at baseline, after completion of the 2-month treatment, and 3 months after discontinuation of therapy. Frozen peripheral blood mononuclear cells (PBMCs) were used for immune cell profiling. Stool samples were used for 16S rRNA profiling and metabolomics. RESULTS: Probiotic administration increased the abundance of several taxa known to be depleted in MS such as Lactobacillus. We found that probiotic use decreased the abundance of taxa previously associated with dysbiosis in MS, including Akkermansia and Blautia. Predictive metagenomic analysis revealed a decrease in the abundance of several KEGG (Kyoto Encyclopedia of Genes and Genomes) pathways associated with altered gut microbiota function in MS patients, such as methane metabolism, following probiotic supplementation. At the immune level, probiotic administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of inflammatory monocytes, decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes, as well as decreased human leukocyte antigen (HLA) D related MFI on dendritic cells. Probiotic administration was also associated with decreased expression of MS risk allele HLA-DQA1 in controls. Probiotic-induced increase in abundance of Lactobacillus and Bifidobacterium was associated with decreased expression of MS risk allele HLA.DPB1 in controls. INTERPRETATION: Our results suggest that probiotics could have a synergistic effect with current MS therapies. Ann Neurol 2018.

Investigation of probiotics in multiple sclerosis.

None of the disease-modifying therapies (DMTs) currently being used for the management of multiple sclerosis (MS) are 100% effective. In addition, side effects associated with the use of these DMTs have limited the practice of combination therapy. Hence, there is a need for safe immunomodulatory agents to fine-tune the management of MS. The gut microbiome plays an important role in autoimmunity, and several studies have reported alterations in the gut microbiome of MS patients. Studies in animal model of MS have identified members of the gut commensal microflora that exacerbate or ameliorate neuroinflammation. Probiotics represent an oral, non-toxic immunomodulatory agent that could be used in combination with current MS therapy. We designed a pilot study to investigate the effect of VSL3 on the gut microbiome and peripheral immune system function in healthy controls and MS patients. VSL3 administration was associated with increased abundance of many taxa with enriched taxa predominated by Lactobacillus, Streptococcus, and Bifidobacterium species. At the immune level, VSL3 administration induced an anti-inflammatory peripheral immune response characterized by decreased frequency of intermediate monocytes (CD14highCD16low), decreased mean fluorescence intensity (MFI) of CD80 on classical monocytes as well as decreased human leukocyte antigen-antigen D related (HLA-DR) MFI on dendritic cells.

Neurological Complications of Acute and Chronic Sinusitis.

PURPOSE OF REVIEW: Acute and chronic sinusitis can give rise to a wide array of intracranial and orbital complications. These complications include brain abscess, subdural empyema, epidural abscess, meningitis, venous sinus thrombosis, frontal bone osteomyelitis, and orbital cellulitis and abscess. Despite numerous medical advances, these complications carry a risk of mortality and significant morbidity. RECENT FINDINGS: Recent studies have shown improvement in both the mortality and the morbidity associated with the neurologic complications of acute and chronic sinusitis. However, there are still a large portion of patients with long-term sequelae, and the literature reports a morbidity rate of approximately 30%. The most common post-treatment morbidities include permanent changes in vision, seizures, and hemiparesis. Although the overall incidence of neurologic complications from a sinogenic source are rare, the potential long-term complications can be devastating making prompt diagnosis and treatment vital to improving outcomes.

A longitudinal uncontrolled study of cerebral gray matter volume in patients receiving natalizumab for multiple sclerosis.

OBJECTIVE: Brain atrophy in multiple sclerosis (MS) selectively affects gray matter (GM), which is highly relevant to disability and cognitive impairment. We assessed cerebral GM volume (GMV) during one year of natalizumab therapy. DESIGN/METHODS: Patients with relapsing-remitting (n = 18) or progressive (n = 2) MS had MRI ∼1 year apart during natalizumab treatment. At baseline, patients were on natalizumab for (mean ± SD) 16.6 ± 10.9 months with age 38.5 ± 7.4 and disease duration 9.7 ± 4.3 years. RESULTS: At baseline, GMV was 664.0 ± 56.4 ml, Expanded Disability Status Scale (EDSS) score was 2.3 ± 2.0, timed 25-foot walk (T25FW) was 6.1±3.4 s; two patients (10%) had gadolinium (Gd)-enhancing lesions. At follow-up, GMV was 663.9 ± 60.2 mL; EDSS was 2.6 ± 2.1 and T25FW was 5.9 ± 2.9 s. One patient had a mild clinical relapse during the observation period (0.052 annualized relapse rate for the entire cohort). No patients had Gd-enhancing lesions at follow-up. Linear mixed-effect models showed no significant change in annualized GMV [estimated mean change per year 0.338 mL, 95% confidence interval -9.66, 10.34, p = 0.94)], GM fraction (p = 0.92), whole brain parenchymal fraction (p = 0.64), T2 lesion load (p = 0.64), EDSS (p = 0.26) or T25FW (p = 0.79). CONCLUSIONS: This pilot study shows no GM atrophy during one year of natalizumab MS therapy. We also did not detect any loss of whole brain volume or progression of cerebral T2 hyperintense lesion volume during the observation period. These MRI results paralleled the lack of clinical worsening.

Sample size requirements for one-year treatment effects using deep gray matter volume from 3T MRI in progressive forms of multiple sclerosis.

OBJECTIVE: The subcortical deep gray matter (DGM) develops selective, progressive, and clinically relevant atrophy in progressive forms of multiple sclerosis (PMS). This patient population is the target of active neurotherapeutic development, requiring the availability of outcome measures. We tested a fully automated MRI analysis pipeline to assess DGM atrophy in PMS. DESIGN/METHODS: Consistent 3D T1-weighted high-resolution 3T brain MRI was obtained over one year in 19 consecutive patients with PMS [15 secondary progressive, 4 primary progressive, 53% women, age (mean±SD) 50.8±8.0 years, Expanded Disability Status Scale (median, range) 5.0, 2.0-6.5)]. DGM segmentation applied the fully automated FSL-FIRST pipeline ( http://fsl.fmrib.ox.ac.uk ). Total DGM volume was the sum of the caudate, putamen, globus pallidus, and thalamus. On-study change was calculated using a random-effects linear regression model. RESULTS: We detected one-year decreases in raw [mean (95% confidence interval): -0.749 ml (-1.455, -0.043), p = 0.039] and annualized [-0.754 ml/year (-1.492, -0.016), p = 0.046] total DGM volumes. A treatment trial for an intervention that would show a 50% reduction in DGM brain atrophy would require a sample size of 123 patients for a single-arm study (one-year run-in followed by one-year on-treatment). For a two-arm placebo-controlled one-year study, 242 patients would be required per arm. The use of DGM fraction required more patients. The thalamus, putamen, and globus pallidus, showed smaller effect sizes in their on-study changes than the total DGM; however, for the caudate, the effect sizes were somewhat larger. CONCLUSIONS: DGM atrophy may prove efficient as a short-term outcome for proof-of-concept neurotherapeutic trials in PMS.

A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity.

OBJECTIVE: A proportion of multiple sclerosis (MS) patients experience disease activity despite treatment. The early identification of the most effective drug is critical to impact long-term outcome and to move toward a personalized approach. The aim of the present study is to identify biomarkers for further clinical development and to yield insights into the pathophysiology of disease activity. METHODS: We performed a genome-wide association study in interferon-ß (IFNß)-treated MS patients followed by validation in 3 independent cohorts. The role of the validated variant was examined in several RNA data sets, and the function of the presumed target gene was explored using an RNA interference approach in primary T cells in vitro. RESULTS: We found an association between rs9828519(G) and nonresponse to IFNß (pdiscovery = 4.43 × 10(-8)) and confirmed it in a meta-analysis across 3 replication data sets (preplication = 7.78 × 10(-4)). Only 1 gene is found in the linkage disequilibrium block containing rs9828519: SLC9A9. Exploring the function of this gene, we see that SLC9A9 mRNA expression is diminished in MS subjects who are more likely to have relapses. Moreover, SLC9A9 knockdown in T cells in vitro leads an increase in expression of IFNγ, which is a proinflammatory molecule. INTERPRETATION: This study identifies and validates the role of rs9828519, an intronic variant in SLC9A9, in IFNß-treated subjects, demonstrating a successful pharmacogenetic screen in MS. Functional characterization suggests that SLC9A9, an Na(+) -H(+) exchanger found in endosomes, appears to influence the differentiation of T cells to a proinflammatory fate and may have a broader role in MS disease activity, outside of IFNß treatment.

Management of rhinosinusitis during pregnancy: systematic review and expert panel recommendations.

BACKGROUND: Management of rhinosinusitis during pregnancy requires special considerations. OBJECTIVES: 1. Conduct a systematic literature review for acute and chronic rhinosinusitis (CRS) management during pregnancy. 2. Make evidence-based recommendations. METHODS: The systematic review was conducted using MEDLINE and EMBASE databases and relevant search terms. Title, abstract and full manuscript review were conducted by two authors independently. A multispecialty panel with expertise in management of Rhinological disorders, Allergy-Immunology, and Obstetrics-Gynecology was invited to review the systematic review. Recommendations were sought on use of following for CRS management during pregnancy: oral corticosteroids; antibiotics; leukotrienes; topical corticosteroid spray/irrigations/drops; aspirin desensitization; elective surgery for CRS with polyps prior to planned pregnancy; vaginal birth versus planned Caesarian for skull base erosions/ prior CSF rhinorrhea. RESULTS: Eighty-eight manuscripts underwent full review after screening 3052 abstracts. No relevant level 1, 2, or 3 studies were found. Expert panel recommendations for rhinosinusitis management during pregnancy included continuing nasal corticosteroid sprays for CRS maintenance, using pregnancy-safe antibiotics for acute rhinosinusitis and CRS exacerbations, and discontinuing aspirin desensitization for aspirin exacerbated respiratory disease. The manuscript presents detailed recommendations. CONCLUSIONS: The lack of evidence pertinent to managing rhinosinusitis during pregnancy warrants future trials. Expert recommendations constitute the current best available evidence.

Eosinophilic fasciitis-like disorder developing in the setting of multiple sclerosis therapy.

IMPORTANCE: Dimethyl fumarate received FDA approval in March 2013 for treatment of multiple sclerosis and has had a rapid uptake in the field due in large part to a favorable safety profile. Side effects of dimethyl fumarate include flushing, gastrointestinal discomfort, and peripheral eosinophilia. We report a case of eosinophilic fasciitis-like disorder occurring in the setting of oral dimethyl fumarate therapy. Eosinophilic fasciitis is rare and may be related to the peripheral eosinophilia known to occur with this medication. OBSERVATIONS: We present a case of a 36-year-old male treated with oral dimethyl fumarate for 16 weeks who developed a bilateral eosinophilic fasciitis-like disorder of the thighs. Magnetic resonance imaging revealed a fluid collection in the fascial plane and histopathologic examination revealed an inflammatory infiltrate with dermal and subcutaneous edema and sclerosis consistent with eosinophilic fasciitis. We discuss studies reporting peripheral eosinophilia with fumaric acid medications as well as the literature exploring possible mechanisms. CONCLUSIONS: With the anticipated widespread use of dimethyl fumarate for multiple sclerosis patients, it is important for practitioners to recognize the symptoms of eosinophilic fasciitis and be aware of a possible association of oral dimethyl fumarate treatment with the development of an eosinophilic fasciitis-like disorder.

Diagnosis and Management of Orbital Fat Exposure During Endoscopic Sinus Surgery.

BACKGROUND: The orbital complication rate during endoscopic sinus surgery (ESS) is <1%. Orbital fat exposure during ESS can herald orbital complications including orbital hematoma, extraocular muscle trauma, optic nerve injury, or blindness. The objective of this study was to evaluate the current consensus regarding diagnosis and management of orbital fat exposure during ESS. METHODS: A 24-point survey focused on orbital fat exposure during ESS was distributed to American Rhinologic Society members. Also, a retrospective review of 25 cases of orbital fat exposure drawn from the principal investigator's 30-year experience was performed. RESULTS: Over 10 000 surgical cases of the principal investigator were reviewed. Twenty-five patients had orbital fat exposure. Five developed minor complications while 2 were major (ie, temporary vision changes). Two hundred thirty-six surgeons responded to the survey; 93% had encountered orbital fat during ESS; 88% of surgeons identify orbital fat by either its appearance endoscopically or the "bulb press" test. Almost every responding surgeon will cautiously avoid further manipulation in the area of orbital fat exposure. Nearly half will immediately curtail the extent of surgery. Surgeons do not significantly change postoperative management. Considerations regarding observation in postanesthesia care unit, close follow-up, and strict nose blowing precautions are common. CONCLUSION: Orbital fat exposure during ESS is a rarely discussed, but clinically important. Orbital fat exposure can be a harbinger for major orbital complications that should be recognized by endoscopic appearance and confirmed with the bulb press test. Caution with "no further manipulation" of orbital fat is the guiding principle for intraoperative management, while postoperative management is generally expectant.Level 4 Evidence.

Secondary hypogammaglobulinemia in patients with multiple sclerosis on anti-CD20 therapy: Pathogenesis, risk of infection, and disease management.

Hypogammaglobulinemia is characterized by reduced serum immunoglobulin levels. Secondary hypogammaglobulinemia is of considerable interest to the practicing physician because it is a potential complication of some medications and may predispose patients to serious infections. Patients with multiple sclerosis (MS) treated with B-cell-depleting anti-CD20 therapies are particularly at risk of developing hypogammaglobulinemia. Among these patients, hypogammaglobulinemia has been associated with an increased risk of infections. The mechanism by which hypogammaglobulinemia arises with anti-CD20 therapies (ocrelizumab, ofatumumab, ublituximab, rituximab) remains unclear and does not appear to be simply due to the reduction in circulating B-cell levels. Further, despite the association between anti-CD20 therapies, hypogammaglobulinemia, and infections, there is currently no generally accepted monitoring and treatment approach among clinicians treating patients with MS. Here, we review the literature and discuss possible mechanisms of secondary hypogammaglobulinemia in patients with MS, hypogammaglobulinemia results in MS anti-CD20 therapy clinical trials, the risk of infection for patients with hypogammaglobulinemia, and possible strategies for disease management. We also include a suggested best-practice approach to specifically address secondary hypogammaglobulinemia in patients with MS treated with anti-CD20 therapies.

Humoral immune response to COVID-19 mRNA vaccines in patients with relapsing multiple sclerosis treated with ofatumumab.

BACKGROUND: There are limited data available regarding the impact of ofatumumab, an anti-CD20 B-cell-depleting monoclonal antibody for relapsing multiple sclerosis (RMS), on vaccination response. The study objective was to assess humoral immune response (HIR) to non-live coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination in patients with RMS treated with ofatumumab. METHODS: This was an open-label, single-arm, multicenter, prospective pilot study of patients with RMS aged 18-55 years who received 2 or 3 doses of a COVID-19 mRNA vaccine after ≥1 month of subcutaneous ofatumumab (20 mg/month) treatment. The primary endpoint was the proportion of patients achieving HIR, as defined by local laboratory severe acute respiratory syndrome coronavirus-2 qualitative immunoglobulin G assays. Assay No. 1 was ≥14 days after the second or third vaccine dose. Assay No. 2 was 90 days thereafter. RESULTS: Of the 26 patients enrolled (median [range] age: 42 [27-54] years; median [range] ofatumumab treatment duration: 237 [50-364] days), HIR was achieved by 53.9% (14/26; 95% CI: 33.4 - 73.4%) at Assay No. 1 and 50.0% (13/26; 95% CI: 29.9 - 70.1%) at Assay No. 2. Patients who received 3 vaccine doses had higher HIR rates (Assay No. 1: 70.0% [7/10]; Assay No. 2: 77.8% [7/9]) than those who received 2 doses (Assay No. 1: 46.7% [7/15]; Assay No. 2: 42.9% [6/14]). Of patients aged <40 years without previous anti-CD20 therapy, HIR was achieved by 90.0% (9/10) at Assay No. 1 and 75.0% (6/8) at Assay No. 2. No serious adverse events were reported. CONCLUSION: Patients with RMS treated with ofatumumab can mount HIRs following COVID-19 vaccination. A plain language summary, infographic and a short video summarizing the key results are provided in supplementary material. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov: NCT04847596 (https://clinicaltrials.gov/ct2/show/NCT04847596).

Obstructing encephaloceles presenting as chronic rhinosinusitis: lessons learned from a case series.

We present a unique anatomic cause of encephalocele, and describe appropriate diagnosis. Two patients underwent stereotactic image-guided sinus surgery for presumed chronic rhinosinusitis with intraoperative findings of a sinus encephalocele. The first patient underwent a conservative 2-stage management that included an initial cerebrospinal fluid (CSF) leak repair followed by encephalocele resection. The second patient underwent a 1-stage encephalocele resection and CSF leak repair with a septal graft. The sinus surgeon needs to consider the possibility of encephalocele when the ethmoid, sphenoid, or, rarely, frontal sinuses present with an isolated opacification that does not improve with conservative medical therapy.

Review of Phase III Clinical Trials Outcomes in Patients with Secondary Progressive Multiple Sclerosis.

OBJECTIVE: Few satisfyingly effective treatments exist for patients with Secondary Progressive Multiple Sclerosis (SPMS). Our goal in conducting this review is to highlight clinical outcomes and study design, which may be applied to future phase III clinical trials for patients with SPMS. METHODS: A review of the available literature of phase III clinical trials since 1990 that specifically studied patients with SPMS. PubMed and ClinicalTrials.org were searched using appropriate terms. RESULTS: Expanded Disability Status Scale (EDSS) was most often used as an outcome measure, with time to confirmed disability progression at three months being used most often. Components of the Multiple Sclerosis Functional Composite (MSFC) were the next most frequent primary outcome measure used. Patient Reported Outcomes (PROs) were frequently used as secondary outcome measures with specific PROs more successful than others. MRI measures related to brain parenchymal volume have recently started to be used in phase III clinical trials. CONCLUSIONS: Some successful trials may have been related to patient selection for less inflammatory disease, which confounds the comparison between successful trials. Time to confirmed disability at three months or changes in composite MSFC are reasonable primary outcome measures to use in future SPMS trials with a suggestion that the MSFC may be more sensitive to progressive disease changes. PROs and MRI measures following brain parenchymal volume are reasonable secondary outcome measures to incorporate into future phase III trials in SPMS.

Effectiveness and safety of dimethyl fumarate in progressive multiple sclerosis.

BACKGROUND: There is limited data analyzing the safety and effectiveness of dimethyl fumarate (DMF) in the progressive multiple sclerosis (PMS) population. OBJECTIVE: To analyze the safety and effectiveness of DMF in patients with PMS. METHODS: We used Cox proportional hazards models to compare the time to confirmed worsening and improvement on the Expanded Disability Status Scale (EDSS) and timed 25-foot walk (T25FW) between patients treated with DMF and glatiramer acetate (GA) for at least one year. RESULTS: We included 46 patients treated with DMF and 42 patients treated with GA. The safety and tolerability of GA and DMF were consistent with established profiles. There was no difference in confirmed EDSS progression. A trend towards reduced T25FW was seen in the DMF compared to GA after adjustment (HR = 0.86; 95% CI:0.37, 1.98; p = 0.72 and HR = 0.60; 95% CI:0.27, 1.34; p = 0.21, respectively). CONCLUSION: Dimethyl fumarate showed a trend towards reduction in T25FW but no evidence of clinically significant impact on EDSS. The small sample precluded definitive determination.

A method for evaluating treatment switching criteria in multiple sclerosis.

BACKGROUND AND OBJECTIVE: We investigated a method to evaluate a treatment switching approach, namely treatment change after one multiple sclerosis (MS) relapse. METHODS: Patients who experienced a relapse while on a first-line disease-modifying therapy, glatiramer acetate, were identified. Based on their subsequent course, patients were divided into two groups: those who changed treatment and those who did not. Patients were allowed to change to any other treatment. Subsequent annualized relapse rate and time to next relapse were compared in the two groups. Since patients were not randomized to treatment group, negative binomial and Cox regression models were used to control for several potential clinical confounders, including relapse severity, relapse duration, age, disease duration and presence of previous/combination therapy. In addition, an inverse probability of treatment weighting model was used to control for confounding. Several secondary analyses investigated patient subgroups. RESULTS: Statistical modeling showed that there was no significant difference between groups in terms of relapse rate (rate ratio; 95% CI = 0.68; 0.35, 1.31) and time to next relapse (hazard ratio; 95% CI = 0.61; 0.30, 1.25). All secondary analyses confirmed these results. In addition, no significant difference in time to sustained progression on the Expanded Disability Status Scale was observed (p > 0.05). Our approach allowed investigation of the choice to change treatment after a relapse. CONCLUSIONS: Our results showed that a single relapse may not be sufficient to indicate treatment failure. Although clinical confounders were addressed in our modeling, unmeasured confounders, particularly the presence of magnetic resonance imaging activity, may have biased our conclusion.

An argument for broad use of high efficacy treatments in early multiple sclerosis.

Two different treatment paradigms are most often used in multiple sclerosis (MS). An escalation or induction approach is considered when treating a patient early in the disease course. An escalator prioritizes safety, whereas an inducer would favor efficacy. Our understanding of MS pathophysiology has evolved with novel in vivo and in vitro observations. The treatment landscape has also shifted significantly with the approval of over 10 new medications over the past decade alone. Here, we re-examine the treatment approach in light of these recent developments. We believe that recent work suggests that early prediction of the disease course is fraught, the amount of damage to the brain that MS causes is underappreciated, and its impact on patient function oftentimes is underestimated. These concerns, coupled with the recent availability of agents that allow a better therapeutic effect without compromising safety, lead us to believe that initiating higher efficacy treatments early is the best way to achieve the best possible long-term outcomes for people with MS.

Teriflunomide Safety and Efficacy in Advanced Progressive Multiple Sclerosis.

OBJECTIVES: To explore the safety and efficacy profile of teriflunomide in progressive multiple sclerosis. METHODS: We conducted a single-center retrospective observational analysis of a progressive multiple sclerosis population, assessing safety and efficacy in patients treated at least one year with teriflunomide or glatiramer acetate. Sustained progression of expanded disability status scale and sustained worsening of timed 25-foot walk were compared using a Cox proportional hazards model. RESULTS: Teriflunomide group (n = 29) mean characteristics: age = 58 years (SD ± 7.6), disease duration = 16.7 years (SD ± 9.5), expanded disability status score = 5.9 (SD ± 1.3), and follow - up = 32.4 months (SD ± 13.6). Glatiramer acetate group (n = 30) mean characteristics: age = 52.4 years (SD ± 11.3), disease duration = 15.1 years (SD ± 10.4), expanded disability status score = 5.7 (SD ± 1.6), and follow - up = 46.9 months (SD ± 43.9). Both treatments were well tolerated without serious side effects. After adjustment for age, sex, and baseline expanded disability status score, sustained expanded disability status score progression did not differ between groups (hazard ratio = 1.17; 95% confidence interval: 0.45, 3.08; p = 0.75). Sustained timed 25-foot walk worsening after adjustment also did not differ (hazard ratio = 0.56; 95% confidence interval: 0.2, 1.53; p = 0.26). CONCLUSION: In an advanced progressive multiple sclerosis population, no substantial differences in tolerability, safety, sustained EDSS progression, or sustained T25FW worsening over time were observed between glatiramer acetate and teriflunomide-treated groups. The small sample precluded definitive determination.