Sphingosine-1-Phosphate: Its Pharmacological Regulation and the Treatment of Multiple Sclerosis: A Review Article.

Sphingosine-1-phosphate (S1P), via its G-protein-coupled receptors, is a signaling molecule with important regulatory properties on numerous, widely varied cell types. Five S1P receptors (S1PR1-5) have been identified, each with effects determined by their unique G-protein-driven downstream pathways. The discovery that lymphocyte egress from peripheral lymphoid organs is promoted by S1P via S1PR-1 stimulation led to the development of pharmacological agents which are S1PR antagonists. These agents promote lymphocyte sequestration and reduce lymphocyte-driven inflammatory damage of the central nervous system (CNS) in animal models, encouraging their examination of efficacy in the treatment of multiple sclerosis (MS). Preclinical research has also demonstrated direct protective effects of S1PR antagonists within the CNS, by modulation of S1PRs, particularly S1PR-1 and S1PR-5, and possibly S1PR-2, independent of effects upon lymphocytes. Three of these agents, fingolimod, siponimod and ozanimod have been approved, and ponesimod has been submitted for regulatory approval. In patients with MS, these agents reduce relapse risk, sustained disability progression, magnetic resonance imaging markers of disease activity, and whole brain and/or cortical and deep gray matter atrophy. Future opportunities in the development of more selective and intracellular S1PR-driven downstream pathway modulators may expand the breadth of agents to treat MS

Youth Football Injuries: A Prospective Cohort

Background: There are approximately 2.8 million youth football players between the ages of 7 and 14 years in the United States. Rates of injury in this population are poorly described. Recent studies have reported injury rates between 2.3% and 30.4% per season and between 8.5 and 43 per 1000 exposures. Hypothesis: Youth flag football has a lower injury rate than youth tackle football. The concussion rates in flag football are lower than in tackle football. Study Design: Cohort study; Level of evidence, 3. Methods: Three large youth (grades 2-7) football leagues with a total of 3794 players were enrolled. Research personnel partnered with the leagues to provide electronic attendance and injury reporting systems. Researchers had access to deidentified player data and injury information. Injury rates for both the tackle and flag leagues were calculated and compared using Poisson regression with a log link. The probability an injury was severe and an injury resulted in a concussion were modeled using logistic regression. For these 2 responses, best subset model selection was performed, and the model with the minimum Akaike information criterion value was chosen as best. Kaplan-Meier curves were examined to compare time loss due to injury for various subgroups of the population. Finally, time loss was modeled using Cox proportional hazards regression models. Results: A total of 46,416 exposures and 128 injuries were reported. The mean age at injury was 10.64 years. The hazard ratio for tackle football (compared with flag football) was 0.45 (95% CI, 0.25-0.80; P = .0065). The rate of severe injuries per exposure for tackle football was 1.1 (95% CI, 0.33-3.4; P = .93) times that of the flag league. The rate for concussions in tackle football per exposure was 0.51 (95% CI, 0.16-1.7; P = .27) times that of the flag league. Conclusions: Injury is more likely to occur in youth flag football than in youth tackle football. Severe injuries and concussions were not significantly different between leagues. Concussion was more likely to occur during games than during practice. Players in the sixth or seventh grade were more likely to suffer a concussion than were younger players

Reducing return of disease activity in patients with relapsing multiple sclerosis transitioned from natalizumab to teriflunomide: 12-month interim results of teriflunomide therapy.

Background: Natalizumab is an effective treatment for relapsing multiple sclerosis. Return of disease activity upon natalizumab discontinuance creates the need for follow-up therapeutic strategies. Objective: To assess the efficacy of teriflunomide following natalizumab discontinuance in relapsing multiple sclerosis patients. Methods: Clinically stable relapsing multiple sclerosis patients completing 12 or more consecutive months of natalizumab, testing positive for anti-John Cunningham virus antibody, started teriflunomide 14 mg/day, 28 ± 7 days after their final natalizumab infusion. Physical examination, Expanded Disability Status Scale, laboratory assessments, and brain magnetic resonance imaging were performed at screening and multiple follow-up visits. Results: Fifty-five patients were enrolled in the study. The proportion of patients relapse-free was 0.94, restricted mean time to first gadolinium-enhancing lesion was 10.9 months and time to 3-month sustained disability worsening was 11.8 months. The mean number of new or enlarging T2 lesions per patient at 12 months was 0.42. Exploratory analyses revealed an annualized relapse rate of 0.08, and a proportion of patients with no evidence of disease activity of 0.68. Forty-seven patients (85.5%) reported adverse events, 95% of which were mild to moderate. Conclusions: Teriflunomide therapy initiated without natalizumab washout resulted in a low rate of return of disease activity. Clinicians may consider this a worthwhile strategy when transitioning clinically stable patients off natalizumab to another therapy.ClinicalTrials.gov Identifier: NCT01970410

Utilization, safety, and tolerability of ocrelizumab: year 2 data from the Providence Ocrelizumab Registry

Background: Ocrelizumab (OCR), a humanized anti-CD20 monoclonal antibody, was approved in the US in 2017 for the treatment of relapsing MS (RMS) and primary progressive MS (PPMS). The Providence OCR Registry was established to monitor long-term treatment and safety outcomes. Objective: To evaluate OCR treatment outcomes using real-world data from a diverse, community-based MS population. Methods: Adult MS patients who have been prescribed OCR were eligible. Chart reviews at OCR start date and then every 6 months were done by a trained RN. Expanded Disability Status Scale (EDSS) scores were determined by the treating provider on the start date and then yearly. Results: Of the 308 patients enrolled from March 2017 to March 2019, 72.6% were female; mean (SD) age was 51.9 (12.0) years; 76.3% had RMS, 14.3% had SPMS, and 9.4% had PPMS. Median baseline EDSS [interquartile range (IQR)] was 3.0 [2.0, 4.0], 6.5 [6.0, 7.5], and 6.5 [5.8, 7.1] respectively. The RMS cohort had an annualized relapse rate (ARR) of 0.34 prior to starting OCR. Among all patients who had \u3e 1 dose of OCR (n=262), ARR was 0.10 with two patients having two relapses. Median EDSS scores at 12 months were 3.0 [2.0, 5.0] (n=98) for RMS patients, 6.5 [5.5, 7.5] (n=23) for SPMS, and 6.5 [5.0, 7.5] (n=13) for PPMS. Infusion reactions occurred in 33.6% of patients during dose one, becoming less frequent with subsequent doses (15.1%). Respiratory infections occurred in 32.1% of patients followed by urinary tract infections (UTI) (25.3%). Of the 22 hospitalizations that have occurred, 9 were due to infection, majority due to UTIs (89.9%) with four patients developing sepsis. Eighteen (81.8%) of these patients were 55 years or older. Twenty-two (7.1%) patients have stopped OCR with a median time to discontinuation [IQR] of 7.0 [4.6, 11.1] months; eleven patients stopped due to side effects, three patients stopped due to a relapse, and three patients died one each due to urosepsis, suicide, and respiratory distress. No significant changes in Beck Depression Inventory (BDI) or Modified Fatigue Impact Scale (MFIS) from baseline to 6 months including patients transitioning from natalizumab (n=12). Discussion: Our study showed that OCR was effective in controlling relapse and disability worsening and reported similar rates of infusion reactions compared to earlier phase III clinical trials. Although only a small percentage of patients have stopped OCR, infections resulting in hospitalization are a concern, especially in older patients

Three-year clinical outcomes of relapsing multiple sclerosis patients treated with dimethyl fumarate in a United States community health center.

BACKGROUND: Following approval of dimethyl fumarate (DMF), we established a registry of relapsing multiple sclerosis (RMS) patients taking DMF at our community MS center. OBJECTIVE: To track DMF patients\u27 tolerability, disease progression, and lymphopenia. METHODS: Patients prescribed DMF for RMS from March 2013 to March 2016 were prospectively enrolled ( N = 412). Baseline data, clinical relapses, magnetic resonance imaging (MRI) activity, discontinuation, and lymphocyte counts were captured through chart review. RESULTS: The mean age of patients starting DMF was 49.4 ± 12.0 years and 70% transitioned from a previous disease-modifying therapy (DMT). Of the patients, 38% discontinued DMF, 76% of whom discontinued due to side effects. Clinical relapse and MRI activity were low. Comparing patients who transitioned from interferon-β (IFN), glatiramer acetate (GA), or natalizumab (NTZ), patients previously on NTZ had higher rates of relapse than those previously on GA (annualized relapse rate p = 0.039, percent relapse p = 0.021). Grade III lymphopenia developed in 11% of patients. Lymphopenia was associated with older age ( p \u3c 0.001) and longer disease duration ( p \u3c 0.001). CONCLUSION: Given the high rates of lymphopenia and discontinuation, it has become our clinical practice to more closely scrutinize older patients and those with a longer disease duration who are potential candidates for initiating DMF therapy

Youth Football Injuries: A Prospective Cohort

BACKGROUND: There are approximately 2.8 million youth football players between the ages of 7 and 14 years in the United States. Rates of injury in this population are poorly described. Recent studies have reported injury rates between 2.3% and 30.4% per season and between 8.5 and 43 per 1000 exposures. HYPOTHESIS: Youth flag football has a lower injury rate than youth tackle football. The concussion rates in flag football are lower than in tackle football. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Three large youth (grades 2-7) football leagues with a total of 3794 players were enrolled. Research personnel partnered with the leagues to provide electronic attendance and injury reporting systems. Researchers had access to deidentified player data and injury information. Injury rates for both the tackle and flag leagues were calculated and compared using Poisson regression with a log link. The probability an injury was severe and an injury resulted in a concussion were modeled using logistic regression. For these 2 responses, best subset model selection was performed, and the model with the minimum Akaike information criterion value was chosen as best. Kaplan-Meier curves were examined to compare time loss due to injury for various subgroups of the population. Finally, time loss was modeled using Cox proportional hazards regression models. RESULTS: A total of 46,416 exposures and 128 injuries were reported. The mean age at injury was 10.64 years. The hazard ratio for tackle football (compared with flag football) was 0.45 (95% CI, 0.25-0.80; P = .0065). The rate of severe injuries per exposure for tackle football was 1.1 (95% CI, 0.33-3.4; P = .93) times that of the flag league. The rate for concussions in tackle football per exposure was 0.51 (95% CI, 0.16-1.7; P = .27) times that of the flag league. CONCLUSION: Injury is more likely to occur in youth flag football than in youth tackle football. Severe injuries and concussions were not significantly different between leagues. Concussion was more likely to occur during games than during practice. Players in the sixth or seventh grade were more likely to suffer a concussion than were younger players