The STAR Study: a real-world, international, observational study of the safety and tolerability of, and adherence to, serum-free subcutaneous interferon ß-1a in patients with relapsing multiple sclerosis.

BACKGROUND: Adverse reactions, particularly injection site reactions (ISRs), are common reasons for nonadherence to injectable multiple sclerosis (MS) treatments. Adherence to MS treatment is important to ensure good treatment outcomes. OBJECTIVE: The aim of this study was to assess the local tolerability of subcutaneous (SC) serum-free interferon (IFN) ß-1a in patients with relapsing MS over 1 year in a real-life, international setting. The study also assessed safety, disease activity, and adherence. METHODS: This was a prospective, international, multicenter, observational study of 251 patients with relapsing-remitting MS treated with SC serum-free IFN ß-1a 44 µg or 22 µg 3 times weekly for 12 months or until early discontinuation. The primary end point was the proportion of patients with ISRs. Secondary end points included proportion of patients with adverse events (AEs); annualized relapse rate (ARR); proportion of patients remaining relapse-free; and adherence to treatment. RESULTS: During the observation period, 27.5% (69 of 251) of patients experienced nonserious ISRs, which was consistent with the incidence reported in clinical studies. Five patients discontinued treatment and 2 patients suspended treatment because of ISRs. Mean age was 35.8 years; patients were predominantly white (94.8%), and two thirds (66.1%) were female. The overall incidence of AEs was 63.7% (160 of 251), and overall safety and tolerability were assessed as excellent, very good, or good in >85% of patients. More than 70% of patients remained relapse-free, and the mean ARR was 0.4. More than 90% of patients had very good or good adherence to treatment; a significantly greater proportion of these were relapse-free at 12 months compared with those with fair or poor adherence (77.6% vs 50.0%; P = 0.0107), and their ARR was significantly lower (0.3 vs 0.9; P = 0.0055). Patients with fair or poor adherence had 4.6 times higher odds of experiencing a relapse than those with very good or good adherence. CONCLUSIONS: The incidence of ISRs and the overall safety profile in this observational study, in an international population in a real-life setting, confirm the good local tolerability of SC serum-free IFN ß-1a reported in clinical studies. The association between good adherence and a lower ARR underlines the importance of good adherence. The good local and general tolerability of SC IFN ß-1a may help ensure a high level of adherence, which is associated with better clinical outcomes. ClinicalTrials.gov identifier: NCT01080027.

CD44 variant isoforms control experimental autoimmune encephalomyelitis by affecting the lifespan of the pathogenic T cells.

CD44 variant (CD44(v)) isoforms play important roles in the development of autoimmune disorders, including colitis and arthritis, but their role in multiple sclerosis (MS) has been explored only to a limited extent. We determined the functional relevance of CD44(v) isoforms in MS and its animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation of CD44(v7) and CD44(v10) isoforms significantly reduced the clinical EAE burden, as well as the number of inflammatory infiltrates. CD44(v7) and CD44(v10) expression on both memory T and antigen-presenting cells, participated in the development of adoptive transfer EAE. Significantly reduced mRNA expression of Th1 signature genes was detected in the brains of CD44(v10-/-) mice compared with those of CD44(WT) mice. Furthermore, forkhead transcription factor 3 (Foxp3), Bcl-2, and inducible nitric oxide synthase (iNOS) levels were reduced in CD44(v10-/-) brains, whereas active caspase-3 was elevated. Brain-infiltrating CD4(hi)CD44(v10+) T cells preceded EAE onset and paralleled disease severity in wild-type but not in CD44(v7-/-) and CD44(v10-/-) mice. CD44(v7) and CD44(v10) expression contributed to EAE by increasing the longevity of autoreactive CD4(hi)panCD44(hi) T cells. Accordingly, the absence of CD44(v7) and CD44(v10) led to increased apoptosis in the inflammatory infiltrates and reduced Th1 responses, resulting in marked disease reduction. Although absent in noninflamed human brains, we detected CD44(v3), CD44(v7), and CD44(v10) isoforms on glial cells and on perivascular infiltrating cells of MS lesions. We conclude that CD44(v7) and CD44(v10), expressed on autoreactive CD4(hi)panCD44(hi) T cells, are critically involved in the pathogenesis of classic EAE by increasing their life span. Targeting these short CD44(v) isoform regions may reduce inflammatory processes and clinical symptoms in MS.

Efficacy of vitamin D3 as add-on therapy in patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon ß-1a: a Phase II, multicenter, double-blind, randomized, placebo-controlled trial.

Recent studies have demonstrated the immunomodulatory properties of vitamin D, and vitamin D deficiency may be a risk factor for the development of MS. The risk of developing MS has, in fact, been associated with rising latitudes, past exposure to sun and serum vitamin D status. Serum 25-hydroxyvitamin D [25(OH)D] levels have also been associated with relapses and disability progression. The identification of risk factors, such as vitamin D deficiency, in MS may provide an opportunity to improve current treatment strategies, through combination therapy with established MS treatments. Accordingly, vitamin D may play a role in MS therapy. Small clinical studies of vitamin D supplementation in patients with MS have reported positive immunomodulatory effects, reduced relapse rates and a reduction in the number of gadolinium-enhancing lesions. However, large randomized clinical trials of vitamin D supplementation in patients with MS are lacking. SOLAR (Supplementation of VigantOL(®) oil versus placebo as Add-on in patients with relapsing-remitting multiple sclerosis receiving Rebif(®) treatment) is a 96-week, three-arm, multicenter, double-blind, randomized, placebo-controlled, Phase II trial (NCT01285401). SOLAR will evaluate the efficacy of vitamin D(3) as add-on therapy to subcutaneous interferon beta-1a in patients with RRMS. Recruitment began in February 2011 and is aimed to take place over 1 calendar year due to the potential influence of seasonal differences in 25(OH)D levels.