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interferon beta 1a [keywords]
- Smokers run increased risk of developing anti-natalizumab antibodies. [JOURNAL ARTICLE]
- Mult Scler 2013 Dec 5.
Smoking may contribute to the induction of neutralizing antibodies to interferon β-1a.In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis.This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals.Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2-4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5-5.1).The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.
- Effects of Bacille Calmette-Guerin after the first demyelinating event in the CNS. [JOURNAL ARTICLE]
- Neurology 2013 Dec 4.
To evaluate Bacille Calmette-Guérin (BCG) effects after clinically isolated syndromes (CIS).In a double-blind, placebo-controlled trial, participants were randomly assigned to receive BCG or placebo and monitored monthly with brain MRI (6 scans). Both groups then entered a preplanned phase with IM interferon-β-1a for 12 months. From month 18 onward, the patients took the disease-modifying therapies (DMTs) that their neurologist considered indicated in an open-label extension phase lasting up to 60 months.Of 82 randomized subjects, 73 completed the study (33 vaccinated and 40 placebo). During the initial 6 months, the number of cumulative lesions was significantly lower in vaccinated people. The relative risks were 0.541 (95% confidence interval [CI] 0.308-0.956; p = 0.03) for gadolinium-enhancing lesions (the primary endpoint), 0.364 (95% CI 0.207-0.639; p = 0.001) for new and enlarging T2-hyperintense lesions, and 0.149 (95% CI 0.046-0.416; p = 0.001) for new T1-hypointense lesions. The number of total T1-hypointense lesions was lower in the BCG group at months 6, 12, and 18: mean changes from baseline were -0.09 ± 0.72 vs 0.75 ± 1.81 (p = 0.01), 0.0 ± 0.83 vs 0.88 ± 2.21 (p = 0.08), and -0.21 ± 1.03 vs 1.00 ± 2.49 (p = 0.02). After 60 months, the cumulative probability of clinically definite multiple sclerosis was lower in the BCG + DMT arm (hazard ratio = 0.52, 95% CI 0.27-0.99; p < 0.05), and more vaccinated people remained DMT-free (odds ratio = 0.20, 95% CI 0.04-0.93; p = 0.04).Early BCG may benefit CIS and affect its long-term course.BCG, as compared to placebo, was associated with significantly reduced development of gadolinium-enhancing lesions in people with CIS for a 6-month period before starting immunomodulating therapy (Class I evidence).
- Efficacy of subcutaneous interferon β-1a on MRI outcomes in a randomised controlled trial of patients with clinically isolated syndromes. [JOURNAL ARTICLE]
- J Neurol Neurosurg Psychiatry 2013 Nov 29.
The REbif FLEXible dosing in early MS (REFLEX) study compared several brain MRI outcomes in patients presenting with clinically isolated syndromes suggestive of multiple sclerosis and treated with two dose-frequencies of subcutaneous interferon (IFN) β-1a or placebo.Patients were randomised (1:1:1) to IFN β-1a, 44 µg subcutaneously three times a week or once a week, or placebo three times a week for up to 24 months. MRI scans were performed every 3 months, or every 6 months if the patient developed clinically definite multiple sclerosis. End points analysed included: number of combined unique active lesions per patient per scan; numbers and volumes of new T2, T1 hypointense and gadolinium-enhancing (Gd+) lesions per patient per scan; and brain volume.517 patients were randomised (intent-to-treat population: subcutaneous IFN β-1a three times a week, n=171; subcutaneous IFN β-1a once a week, n=175; placebo, n=171). Combined unique active lesions were lower in patients treated with subcutaneous IFN β-1a versus placebo (mean (SD) lesions per patient per scan: three times a week 0.6 (1.15); once a week 1.23 (4.26); placebo 2.70 (5.23); reduction versus placebo: three times a week 81%; once a week 63%; p<0.001) and with three times a week versus once a week (48% reduction; p=0.002). The mean numbers of new T2, T1 hypointense and Gd+ lesions were all significantly lower in the two active treatment arms compared with placebo (p≤0.004 for three times a week or once a week) and in the three times a week group compared with once a week (p≤0.012).Both subcutaneous IFN β-1a 44 µg regimens improved MRI outcomes versus placebo, with the three times a week regimen having a more pronounced effect than once a week dosing.clinicaltrial.gov identifier, NCT00404352.
- Current evaluation of alemtuzumab in multiple sclerosis. [JOURNAL ARTICLE]
- Expert Opin Biol Ther 2013 Dec 2.
Introduction: Alemtuzumab is a humanized IgG1 kappa monoclonal antibody approved for treatment of B-cell chronic lymphocytic leukemia. This cytolytic antibody is directed against CD52 and depletes lymphocytes, with monocytes, macrophages, natural killer cells and a subpopulation of granulocytes being affected to a much lesser degree. Alemtuzumab is currently under review to treat relapsing multiple sclerosis (MS) in the United States, based on positive Phase II and Phase III trials in both treatment-naïve and treated relapsing MS patients. There was excellent efficacy in suppressing both clinical and neuroimaging disease activities. In these trials, the comparator arm was not placebo, but high dose frequently dosed subcutaneous interferon beta 1a. Alemtuzumab has recently been approved by the European authorities for active relapsing MS, in essence as a first-line agent. It produces long-standing effects, consistent with an induction agent. Efficacy will have to be weighed against risk of adverse effects, which include autoimmune disorders and infection. Alemtuzumab joins an increasingly crowded market, and will add to the complexity of treating MS. Areas covered: This review will discuss alemtuzumab as a therapy for MS, reviewing PubMed for clinical trials, publications and presentations at international meetings. It will focus on a United States market perspective. Expert opinion: Alemtuzumab offers induction strategy for very active relapsing MS patients who have failed conventional therapy, and possibly selected treatment-naive patients. Alemtuzumab use is likely to be restricted to specialized MS centers, with long-term monitoring to determine the true risk for adverse effects.
- Alemtuzumab-Related Thyroid Dysfunction in a Phase 2 Trial of Patients with Relapsing-Remitting Multiple Sclerosis. [JOURNAL ARTICLE]
- J Clin Endocrinol Metab 2013 Oct 29.
Context:Alemtuzumab, an anti-CD52 monoclonal antibody, increased risk of thyroid dysfunction in CAMMS223, a phase 2 trial in relapsing-remitting multiple sclerosis (RRMS).Objective:Detailed description of thyroid dysfunction in CAMMS223.Design:RRMS patients (n=334) were randomized 1:1:1 to 44 mcg subcutaneous interferon beta-1a (SC IFNB-1a, Rebif®) or annual courses of 12 or 24 mg intravenous alemtuzumab. Thyroid function tests (TSH, free T3, free T4) and thyrotropin-binding inhibitory immunoglobulin (TBII) were assessed at screening, month 1, and quarterly thereafter; anti-thyroid peroxidase antibodies were assessed at screening and every 6 months. Thyroid dysfunction episodes were categorized post hoc by an endocrinologist.Results:During median follow-up of 57.3 months, 34% of alemtuzumab and 6.5% of SC IFNB-1a patients had thyroid dysfunction (p<0.0001). Ten percent of alemtuzumab and 3% of SC IFNB-1a patients had >1 episode of thyroid dysfunction. With alemtuzumab, Graves' hyperthyroidism occurred in 22%, hypothyroidism in 7%, and subacute thyroiditis in 4%. Of patients with overt Graves' hyperthyroidism, 23% spontaneously became euthyroid and an additional 15% spontaneously developed hypothyroidism. Of patients with overt hypothyroidism, 74% were TBII-positive. Annual incidence of first episode of thyroid dysfunction increased each year through year 3, then decreased each subsequent study year.Conclusions:Thyroid dysfunction was more common with alemtuzumab than with SC IFNB-1a. There were few serious episodes. Regular monitoring facilitated early detection. Unique features of this population included high prevalence of Graves' hyperthyroidism, multiple episodes of thyroid dysfunction in individual patients, spontaneous hypothyroidism following overt Graves' hyperthyroidism, and a high prevalence of TBII-positive overt hypothyroidism.
- Current and Future Therapies for Multiple Sclerosis. [REVIEW]
- Scientifica (Cairo) 2013.:249101.
With the introduction of interferon- β 1b in 1993 as the first FDA-approved treatment for multiple sclerosis, the era of treatment of this incurable disease began, and its natural course was permanently changed. Currently, seven different treatments for patients with multiple sclerosis with different mechanisms of action and dissimilar side effect profiles exist. These medications include interferon- β 1a intramuscular (Avonex), interferon- β 1a subcutaneous (Rebif), interferon- β 1b subcutaneous (Betaseron/Extavia), glatiramer acetate (Copaxone), natalizumab (Tysabri), fingolimod (Gilenya), teriflunomide (Aubagio), and mitoxantrone (Novantrone). In addition, a large number of clinical trials are being conducted to assess the safety and efficacy of various experimental agents in patients with multiple sclerosis, including alemtuzumab, dimethyl fumarate, laquinimod, rituximab, daclizumab, and cladribine. In this paper, the author presents a concise and comprehensive review of present and potential treatments for this incurable disease.
- Teriflunomide for the treatment of relapsing multiple sclerosis: a review of clinical data. [Journal Article]
- Ann Pharmacother 2013 Sep; 47(9):1153-60.
To review the pharmacology and clinical data for teriflunomide in relapsing multiple sclerosis (MS).A literature search from 1966 to May 2013 using PubMed/MEDLINE, Web of Science, International Pharmaceutical Abstracts, Academic Search Premiere, Science Citation Index, and the national clinical trials registry was performed using the terms teriflunomide, HMR1726, and A771726. All articles containing human clinical trial data and relevant pharmacologic information were reviewed.Phase 2 and phase 3 clinical trials for teriflunomide were evaluated. All peer-reviewed articles with clinically relevant information were reviewed. Priority for inclusion was placed on randomized controlled trials.Three phase 2 and three phase 3 clinical trials have evaluated teriflunomide as monotherapy or as adjunctive therapy in approximately 3000 patients with relapsing forms of MS. The phase 3 studies used annualized relapse rate, magnetic resonance imaging changes, and Expanded Disability Status Scale scores as outcome measures. One additional Phase 3 clinical study is ongoing. The annualized relapse rates and magnetic resonance imaging findings were improved compared to those with placebo and similar to or improved compared with those with subcutaneously administered interferon-β-1a 44 µg thrice weekly. Durability of response is supported by open-label extension studies. Common adverse events include increased liver function enzymes, alopecia, diarrhea, influenza, nausea, and paresthesias. Treatment discontinuation was not common and occurred in approximately 10% of patients in phase 3 studies.Teriflunomide is an effective and safe oral treatment option for relapsing MS. It can be used as monotherapy or added to an interferon or glatiramer acetate. It reduces the rate of relapse and may slow disease progression. The advantages of this drug are the convenience of oral administration and good tolerability. The disadvantage is the lack of long-term safety data and data about the benefit of combination therapy.
- Teriflunomide: a review of its use in relapsing multiple sclerosis. [Journal Article]
- CNS Drugs 2013 Dec; 27(12):1103-23.
Teriflunomide (Aubagio™) is the main active metabolite of leflunomide, an established disease-modifying anti-rheumatic drug. Teriflunomide is an inhibitor of de novo pyrimidine synthesis, reducing lymphocyte proliferation, amongst other immunomodulatory effects; autoimmunity is believed to be one of the potential mechanisms of disease for multiple sclerosis. Teriflunomide is considered cytostatic but not cytotoxic: it does not affect resting or slowly dividing lymphocytes. This article reviews the available pharmacological properties of oral teriflunomide and its clinical efficacy and tolerability in patients with relapsing multiple sclerosis. While both the 7 and the 14 mg/day dosages are discussed, the 7 mg/day dosage is not approved in the EU. Both dosages are approved in the USA. In phase III trials, teriflunomide 7 or 14 mg/day was consistently demonstrated to be more effective than placebo and as effective as interferon beta-1a in the prevention of relapses in patients with relapsing forms of multiple sclerosis; moreover, teriflunomide 14 mg/day was also consistently shown to be more effective than placebo in prevention of disability progression. Teriflunomide was generally well tolerated in these patients. Long-term, extension data were generally similar to those observed in the shorter-term trials. Teriflunomide is associated with increased liver enzyme levels, and is contraindicated in pregnant patients because of a potential risk of teratogenicity. As an oral treatment, it offers an alternative to the traditional, parenteral, disease-modifying therapies; however, further investigation into the efficacy and/or tolerability differences between teriflunomide and other available oral drugs would be of great use in the placement of this drug. At present, given the relatively limited long-term data, it is difficult to draw definite conclusions with regard to safety; however, as teriflunomide is the main active metabolite of leflunomide, long-term safety data can be extrapolated from the large amount of post-approval data available regarding its parent drug. Oral teriflunomide is a valuable addition to available treatment options for patients with relapsing multiple sclerosis, in particular those patients who prefer an oral drug.
- Assessment of structural and functıonal vısual outcomes ın relapsıng remıttıng multıple sclerosıs wıth vısual evoked potentıals and optıcal coherence tomography. [Journal Article]
- J Neurol Sci 2013 Dec 15; 335(1-2):182-5.
The purpose of this study is to consider the clinical utility of optical coherence tomography (OCT) and find a correlation with VEP. Effects of different disease modifying treatments (DMT) were further evaluated by measuring OCT parameters and whether a correlation exists between the RNFL thickness, disease duration and expanded disability status scale (EDSS) were also assessed. 13 patients were on interferon beta-1a (IFN), 14 patients were receiving glatiramer acetate (GA), 19 patients were not being treated with any DMT and 21 healthy controls were included the study. During OCT examination, retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness was found to be lower in all MS groups but macular volume (MV) was lower only in GA group than controls. Although, P100 latencies were longer than controls in all MS groups, there was no statistically significant difference between IFN and w/o DMT groups. Patients with ON history, P100 latencies were found significantly longer than those without ON. VEP amplitudes were found lower with ON history patients than those without ON, however this was not statistically significant. EDSS strongly correlated with P100 latency, RNLF, GCC but no correlation was observed with VEP amplitude and MV. Our results show that RNFL, GCC and MV were all decreased in MS patients with or without DMT comparing to controls and it is more prominent in eyes with ON. Further follow-up studies are warranted to understand the pathophysiology of CNS axonal degeneration and involvement of optic nerves.