Sphingosine 1-phosphate receptor (S1PR) modulators possess a unique mechanism of action in the treatment of multiple sclerosis (MS). Subtype 1 of the S1PR is expressed on the surface of lymphocytes and is important in regulating egression from lymph nodes. The S1PR modulators indirectly antagonize the receptor's function leading to sequestration of lymphocytes in the lymph nodes. Fingolimod was the first S1PR modulator to receive regulatory approval for relapsing-remitting MS after 2 phase III trials demonstrated potent efficacy, safety, and tolerability. Fingolimod can cause undesirable effects as a result of its interaction with other S1PR subtypes, which are expressed in diverse tissues, including cardiac myocytes. As such, agents that more selectively target subtype 1 of the S1PR are of interest and are at various stages of development. These include ponesimod (ACT128800), siponimod (BAF312), ozanimod (RPC1063), ceralifimod (ONO-4641), GSK2018682, and MT-1303. Data from phase II trials and early results from phase III studies have been promising and will be presented in this review. Of special interest are results from the EXPAND study of siponimod, which suggest a potential role for S1PR modulators in secondary progressive MS.

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This 3-year longitudinal study revealed that all comorbidities tested except hyperlipidemia impacted clinical outcomes and a cumulative effect with multiple comorbidities was observed. Consideration of comorbid conditions is essential in MS patient care.

Most patients over age 60, who discontinued DMT, remained off DMT. This study provides real-world data that may guide clinicians considering discontinuing DMT.

References 30 (max is 30) * > 0•5% patients per system organ class and > 1% patients per preferred term (MedDRA Version 19•1 System Organ Class Preferred Term; MedDRA = Medical Dictionary for Regulatory Activities) TEAE = Treatment Emergent Adverse Event * Based on Safety population; MD1003 n=331 and placebo n=311. ^ T2 imaging analysis at M6 is M0-M6 and at M15 is M6-M15. DMT = disease modifying treatment; Gd+ = gadolinium enhanced; MRI = Magnetic Resonance Imaging

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Peroxisome proliferator-activated receptor gamma (PPARγ) agonists have antineoplastic effects on gliomas in cell lines and animal models. In a retrospective chart review, we assessed the influence of PPARγ agonists on the odds of having a high grade glioma. We reviewed patients with a diagnosis of anaplastic astrocytoma and glioblastoma multiforme (GBM) between 1999 and 2008. Patients with hip fractures served as the control group. Multivariable unconditional logistic regression models were used to calculate the odds of diabetic hip fracture patients using a PPARγ agonist at time of diagnosis as compared to diabetic glioma patients. In addition, survival analysis was performed for all GBM patients. We identified 1602 hip fracture patients and 302 high grade glioma patients, 15 and 16% were diabetics, respectively. PPARγ agonists were used by 20% of diabetic hip fracture patients and by 6% of high grade glioma patients (chi-square P-value = 0.02) with an odds ratio of 4.081 (95% CI: 1.119-14.881). In addition, there was no difference in survival for diabetic patients with GBM compared to non-diabetic patients with GBM. The prevalence of PPARγ agonist use was lower in the diabetic high grade glioma group when compared to diabetic hip fracture patients. These findings suggest that diabetic high grade glioma patients are not given PPARγ agonists as often as diabetic hip fracture patients even though these drugs are considered standard of care and should be equally distributed throughout both groups. This indicates a possible anti-neoplastic effect of PPARγ agonists in gliomas.