Multiple sclerosis and vitamin D: a review and recommendations.

A relationship between vitamin D and several diseases, including multiple sclerosis (MS), has recently received interest in the scientific community. Vitamin D appears to have important actions beyond endocrine function, particularly for the immune system. Risk of development of MS, as well as disease severity, has been associated with vitamin D in a variety of studies. There remains a need for prospective studies to further establish this relationship. Given the current evidence of the potential benefits of vitamin D, it appears to be reasonable and safe to consider vitamin D supplementation at dosing adequate to achieve normal levels in patients with MS and clinically isolated syndrome.

Synthetic Peptide dendrimers block the development and expression of experimental allergic encephalomyelitis.

Multiple Ag peptides (MAPs) containing eight proteolipid protein (PLP)(139-151) peptides arranged around a dendrimeric branched lysine core were used to influence the expression and development of relapsing experimental allergic encephalomyelitis (EAE) in SJL mice. The PLP(139-151) MAPs were very efficient agents in preventing the development of clinical disease when administered after immunization with the PLP(139-151) monomeric encephalitogenic peptide in CFA. The treatment effect with these MAPs was peptide specific; irrelevant multimeric peptides such as guinea pig myelin basic protein GPBP(72-84) MAP (a dendrimeric octamer composed of the 72-84 peptide) and PLP(178-191) MAP (a dendrimeric octamer composed of the PLP(178-191) peptide) had no treatment effect on PLP(139-151)-induced EAE. PLP(139-151) MAP treatment initiated after clinical signs of paralysis also altered the subsequent course of EAE; it limited developing signs of paralysis and effectively limited the severity and number of disease relapses in MAP-treated mice over a 60-day observation period. PLP(139-151) MAP therapy initiated before disease onset acts to limit the numbers of Th17 and IFN-gamma-producing cells that enter into the CNS. However, Foxp3(+) cells entered the CNS in numbers equivalent for nontreated and PLP(139-151) MAP-treated animals. The net effect of PLP(139-151) MAP treatment dramatically increases the ratio of Foxp3(+) cells to Th17 and IFN-gamma-producing cells in the CNS of PLP(139-151) MAP-treated animals.

Practices of US health insurance companies concerning MS therapies interfere with shared decision-making and harm patients.

The US Food and Drug Administration has registered 13 multiple sclerosis (MS) disease-modifying therapies (DMTs). The medications are not interchangeable as they vary in route of administration, efficacy, and safety profile. Selecting the appropriate MS DMT for individual patients requires shared decision-making between patients and neurologists. To reduce costs, insurance companies acting through pharmacy benefit companies restrict access to MS DMTs through tiered coverage and other regulations. We discuss how policies established by insurance companies that limit access to MS DMTs interfere with the process of shared decision-making and harm patients. We present potential actions that neurologists can take to change how insurance companies manage MS DMTs.

The contemporary spectrum of multiple sclerosis misdiagnosis: A multicenter study.

OBJECTIVE: To characterize patients misdiagnosed with multiple sclerosis (MS). METHODS: Neurologists at 4 academic MS centers submitted data on patients determined to have been misdiagnosed with MS. RESULTS: Of 110 misdiagnosed patients, 51 (46%) were classified as "definite" and 59 (54%) "probable" misdiagnoses according to study definitions. Alternate diagnoses included migraine alone or in combination with other diagnoses 24 (22%), fibromyalgia 16 (15%), nonspecific or nonlocalizing neurologic symptoms with abnormal MRI 13 (12%), conversion or psychogenic disorders 12 (11%), and neuromyelitis optica spectrum disorder 7 (6%). Duration of misdiagnosis was 10 years or longer in 36 (33%) and an earlier opportunity to make a correct diagnosis was identified for 79 patients (72%). Seventy-seven (70%) received disease-modifying therapy and 34 (31%) experienced unnecessary morbidity because of misdiagnosis. Four (4%) participated in a research study of an MS therapy. Leading factors contributing to misdiagnosis were consideration of symptoms atypical for demyelinating disease, lack of corroborative objective evidence of a CNS lesion as satisfying criteria for MS attacks, and overreliance on MRI abnormalities in patients with nonspecific neurologic symptoms. CONCLUSIONS: Misdiagnosis of MS leads to unnecessary and potentially harmful risks to patients. Misinterpretation and misapplication of MS clinical and radiographic diagnostic criteria are important contemporary contributors to misdiagnosis.

The cost of multiple sclerosis drugs in the US and the pharmaceutical industry: Too big to fail?

OBJECTIVE: To examine the pricing trajectories in the United States of disease-modifying therapies (DMT) for multiple sclerosis (MS) over the last 20 years and assess the influences on rising prices. METHODS: We estimated the trend in annual drug costs for 9 DMTs using published drug pricing data from 1993 to 2013. We compared changes in DMT costs to general and prescription drug inflation during the same period. We also compared the cost trajectories for first-generation MS DMTs interferon (IFN)-ß-1b, IFN-ß-1a IM, and glatiramer acetate with contemporaneously approved biologic tumor necrosis factor (TNF) inhibitors. RESULTS: First-generation DMTs, originally costing $8,000 to $11,000, now cost about $60,000 per year. Costs for these agents have increased annually at rates 5 to 7 times higher than prescription drug inflation. Newer DMTs commonly entered the market with a cost 25%-60% higher than existing DMTs. Significant increases in the cost trajectory of the first-generation DMTs occurred following the Food and Drug Administration approvals of IFN-ß-1a SC (2002) and natalizumab (reintroduced 2006) and remained high following introduction of fingolimod (2010). Similar changes did not occur with TNF inhibitor biologics during these time intervals. DMT costs in the United States currently are 2 to 3 times higher than in other comparable countries. CONCLUSIONS: MS DMT costs have accelerated at rates well beyond inflation and substantially above rates observed for drugs in a similar biologic class. There is an urgent need for clinicians, payers, and manufacturers in the United States to confront the soaring costs of DMTs.

Eluding anaphylaxis allows peptide-specific prevention of the relapsing stage of experimental autoimmune encephalomyelitis.

We have used a peptide derived from Acanthamoeba castellanii (ACA) to treat the relapsing phase of EAE that develops in SJL mice following immunization with the PLP 139-151 peptide. The native sequence of the ACA 81-95 peptide that shares key residues with the PLP 139-151 peptide is weakly encephalitogenic in SJL mice but is not recognized by antiserum from SJL mice immunized with PLP 139-151. A single amino acid change to the ACA 81-95 peptide sequence significantly enhanced its encephalitogenicity. When administered to SJL mice as a nonlinear peptide octamer, the modified ACA peptide prevented relapsing episodes of EAE in SJL mice previously immunized with the PLP 139-151 encephalitogenic peptide.

Access to multiple sclerosis specialty care.

BACKGROUND: Health care providers recommend an annual visit to a multiple sclerosis specialty care provider. OBJECTIVE: To examine potential barriers to the implementation of this recommendation in the Veterans Health Administration. DESIGN: Observational cohort study. SETTING: Veterans Health Administration. PARTICIPANTS: Participants were drawn from the Veterans Affairs Multiple Sclerosis National Data Repository and were included if they had an outpatient visit in 2007 and were alive in 2008 (N = 14,723). MAIN OUTCOME MEASUREMENTS: Specialty care visit, receipt of medical services. RESULTS: A total of 9643 (65.5%) participants had a specialty care visit in 2007. Veterans who were service connected, had greater medical comorbidity, and who lived in urban settings were more likely to have received a specialty care visit. Veterans who were older and had to travel greater distances to a center were less likely to have a specialty care visit. CONCLUSIONS: Access to care in rural areas and areas at a greater distance from a major medical center represent notable barriers to rehabilitation and other multiple sclerosis-related care.

Targeting T cells responsive to the priming epitope prevent the relapsing phase of experimental autoimmune encephalomyelitis.

Upon recovery from the initial episode of experimental autoimmune encephalomyelitis (EAE), virtually all SJL mice develop relapsing/remitting episodes of disease. These relapses may occur due to the reactivation of memory T cells initially stimulated as part of the disease-inducing protocol or naïve T-cell populations stimulated by distinct encephalitogens derived from the inflammatory disease process (epitope spread). We have used encephalitogen-specific non-linear peptide octamers to modify the course of relapsing EAE (rEAE) in SJL mice immunized with an oliogodendrocyte-specific protein peptide (OSP 55-71). Our studies show that the peptide-octamers, which target the T cells stimulated by the priming encephalitogen, but not other candidate encephalitogens, prevent rEAE.

Exploring educational needs of multiple sclerosis care providers: Results of a care-provider survey.

Our objective was to survey experienced multiple sclerosis (MS) care providers, determine their ongoing professional educational needs, and develop future education programs. We asked providers across a variety of disciplines to identify the areas in which clinical consultation and continuing medical education (CME) would most improve their ability to provide care to individuals with MS; their preferred education modalities; and their confidence in providing care related to disease-modifying agents (DMAs), fatigue, depression, spasticity, and bladder management. At a national meeting of MS professionals, 152 MS care providers completed a self-report survey that was designed for this cross-sectional cohort study. Areas of greatest interest for clinical consultation and CME were identical and included cognition, fatigue, DMA use, spasticity, pain, sex, diagnosis of MS, and depression. Participants expressed a preference for live and interactive CME modalities. Confidence in providing specific disease-related care sometimes differed between Veterans Health Administration (VHA) and non-VHA providers. The results indicate that clinical consultations and CME should be targeted to the topics of greatest interest identified by providers and delivered in a live or interactive modality whenever possible.

Correlations of Perceived Deficits Questionnaire of Multiple Sclerosis Quality of Life Inventory with Beck Depression Inventory and neuropsychological tests.

The Perceived Deficits Questionnaire (PDQ) is a part of the Multiple Sclerosis (MS) Quality of Life Inventory that assesses self-perceived cognitive difficulties. We used baseline data from 49 MS subjects participating in a clinical trial to evaluate the correlation of the PDQ with two measures of cognitive impairment, the Paced Auditory Serial Addition Test (PASAT) and the California Verbal Learning Test, 2nd edition (CVLT-II), total score, and one measure of depression, the Beck Depression Inventory-Amended (BDI-IA). The PDQ correlated significantly (r = 0.42; 95% confidence interval [CI], 0.15 to 0.62; p = 0.003) with the BDI-IA scores but not with either the PASAT (r = -0.22; 95% CI, -0.48 to 0.06; p = 0.2) or the CVLT-II total (r = -0.17; 95% CI, -0.43 to 0.12; p = 0.25). A subset of 38 of these subjects who scored worse than 0.5 standard deviation below the mean on the PASAT or CVLT-II received a more extensive neuropsychological battery of tests. No significant correlations were found between any of these tests and the PDQ. These results suggest that self-perceived cognitive dysfunction relates more to depression than to objective cognitive dysfunction.

Functional assay for human CD4+CD25+ Treg cells reveals an age-dependent loss of suppressive activity.

CD4+CD25+ regulatory T cells (Treg cells) prevent T cell-mediated autoimmune diseases in rodents. To develop a functional Treg assay for human blood cells, we used FACS- or bead-sorted CD4+CD25+ T cells from healthy donors to inhibit anti-CD3/CD28 activation of CD4+CD25- indicator T cells. The data clearly demonstrated classical Treg suppression of CD4+CD25- indicator cells by both CD4+CD25(+high) and CD4+CD25(+low) T cells obtained by FACS or magnetic bead sorting. Suppressive activity was found in either CD45RO- (naive) or CD45RO+ (memory) subpopulations, was independent of the TCR signal strength, required cell-cell contact, and was reversible by interleukin-2 (IL-2). Of general interest is that a wider sampling of 27 healthy donors revealed an age- but not gender-dependent loss of suppressive activity in the CD4+CD25+ population. The presence or absence of suppressive activity in CD4+CD25+ T cells from a given donor could be demonstrated consistently over time, and lack of suppression was not due to method of sorting, strength of signal, or sensitivity of indicator cells. Phenotypic markers did not differ on CD4+CD25+ T cells tested ex vivo from suppressive vs. nonsuppressive donors, although, upon activation in vitro, suppressive CD4+CD25+ T cells had significantly higher expression of both CTLA-4 and GITR than CD4+CD25- T cells from the same donors. Moreover, antibody neutralization of CTLA-4, GITR, IL-10, or IL-17 completely reversed Treg-induced suppression. Our results are highly consistent with those reported for murine Treg cells and are the first to demonstrate that suppressive activity of human CD4+CD25+ T cells declines with age.