甲泼尼龙冲击治疗对复发缓解型多发性硬化患者血清中IL-23及IL-17A水平的影响

目的 分析甲泼尼龙冲击治疗对复发缓解型多发性硬化患者血清中IL-23及IL-17A水平的影响,为临床治疗复发缓解型多发性硬化提供参考.方法 选取我院2013年1月至2016年6月收治的52例复发缓解型多发性硬化患者作为观察组,并给予甲泼尼龙冲击治疗,选取同期于我院进行健康体检的52例志愿者作为对照组,比较两组阳性检出率、血清和脑脊液IL-23和IL-17A水平.结果 观察组治疗前血清中IL-23、IL-17A阳性检出率高于对照组,差异有统计学意义(P＜0.05).治疗前观察组血清和脑脊液IL-23和IL-17A水平均高于对照组,差异有统计学意义(P＜0.05);观察组治疗后血清和脑脊液IL-23和IL-17A水平均低于治疗前,差异有统计学意义(P＜0.05).结论 复发缓解型多发性硬化患者血清和脑脊液IL-23及IL-17A呈高表达状态,这可能与其发病有关,甲泼尼龙冲击治疗可有效降低IL-23和IL-17A水平.     

The clinical importance of neutralizing antibodies in relapsing-remitting multiple sclerosis

ABSTRACT

Background: Neutralizing antibodies (NAbs) develop in patients receiving interferon beta (IFN-β) for multiple sclerosis (MS). Debate continues concerning the relevance of NAb development on treatment efficacy.

Objective: To determine the incidence and clinical importance of NAbs in patients with relapsing-remitting MS (RRMS).

Methods: A comprehensive literature review was conducted using PubMed (accessed from 1983 to June 2005), Cochrane MS Group trials register (accessed June 2005), MEDLINE (accessed 1983 to June 2005), and Toxnet (accessed June 2005) databases. NAb-induced changes in clinical efficacy and disease progression were evaluated according to the clinical guidelines established by the American Academy of Neurology.

Results: Currently, there is no standardized assay to comparatively assess NAbs among different treatments. NAbs develop independent of age, sex, disease duration and progression index at the onset of treatment. The occurrence of NAbs varies from 2–45% depending on the treatment initiated. NAb+ patients demonstrate accelerated disease progression as confirmed by an approximate 1‐point increase in the Expanded Disability Status Scale score. The odds of relapse during a NAb+ period are between 1.51 and 1.58 (?p < 0.03) with the time to first relapse being shortened by an average of 244 days after 12 months of IFN‐β therapy. NAb+ patients experience an approximately four-fold increase (?p = 0.009) in the median number of active T2 magnetic resonance imaging (MRI) lesions compared to NAb-negative patients (1.4 vs. 0.3 respectively, p < 0.01).

Conclusion: The induction of NAbs in IFN‐β treated patients reduce clinical effect and accelerate disease progression.     

Pharmacokinetics and pharmacodynamics of peginterferon beta-1a in patients with relapsingremitting multiple sclerosis in the randomized ADVANCE study

AimsTo evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) of subcutaneous peginterferon beta-1a in patients with relapsing-remitting multiple sclerosis (RRMS) in the phase 3 ADVANCE study (n = 1512).MethodsDuring year 1, patients were randomized (1:1:1) to placebo or peginterferon beta-1a 125 μg every 2 or 4 weeks. After year 1, patients randomized to placebo were re-randomized to 125 μg peginterferon beta-1a administered every 2 weeks or every 4 weeks for year 2. Patients randomized to peginterferon beta-1a in year 1 remained on the same dosing regimen in year 2. Intensive blood samples for PK and PD (neopterin elevation; a biomarker of pharmacological activity induced by interferon beta-1a) measurements were collected from 44 patients pre-dosing and at intervals over 240 h post-dosing at weeks 4 and 24. Sparse samples were collected from all patients after each dosing at weeks 4, 12, 24, 56 and 84.ResultsThe PK profile of peginterferon beta-1a did not change over time or between dosing regimens. No accumulation was observed. Peak serum concentrations were reached 1–1.5 days post-dosing, with a mono-phasic decline and a median half-life of approximately 2–3 days. Dosing every 2 weeks provided approximately two-fold greater monthly cumulative area under the curve than every 4 weeks. Neopterin elevation was sustained for 10−14 days following each dose, indicating doubled cumulative duration of pharmacological activity for dosing every 2 weeks vs. every 4 weeks.ConclusionsThese PK/PD profiles potentially explain the enhanced efficacy of dosing every 2 weeks in patients with RRMS.     

PRISMS: the story of a pivotal clinical trial series in multiple sclerosis

Abstract

Background:

The PRISMS (Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis) study was initiated in 1994, at which time there were few disease-modifying drugs for multiple sclerosis (MS). The PRISMS series of studies has since provided up to 8 years of clinical, magnetic resonance imaging (MRI), safety, and immunogenicity data on the use of subcutaneous (sc) interferon (IFN) beta-1a in patients with relapsing–remitting MS. This review is the first collation of all these data in one article, with a look ahead to the next generation of studies involving the new formulation of sc IFN beta-1a.     

Polypharmacy among patients with multiple sclerosis: a qualitative systematic review

ABSTRACT

Objectives: The consequences of polypharmacy (intake of ≥ 5 drugs) are diverse, including drug interactions, rising costs and side effects. Risk groups for polypharmacy are multimorbid and chronically ill people, such as patients with multiple sclerosis (MS). MS is the most common neuroimmunological disease in young adults worldwide. We aimed to provide a systematic overview of the current research status regarding frequency and predictors of polypharmacy in MS patients.

Methods: A systematic literature search in the databases PubMed, Cochrane Library and Scopus was carried out according to the PRISMA guidelines. English and German original research articles were included.

Results: Seven studies fulfilled the inclusion criteria of this review, while the research objectives and methods were very heterogenous. The polypharmacy rates in these studies ranged from 15% to 59%. Polypharmacy correlated with comorbidities, increased disability, cognitive deficits, increased hospitalization, higher relapse rate and lower quality of life.

Conclusions: In MS patients, polypharmacy is common and closely associated with health issues. There is a great need for research in this area, especially regarding longitudinal changes in drug utilization. Effective networks between physicians and pharmacists are needed to optimize medication management for patients and to achieve the best possible therapy results.     

Results from the single-use autoinjector for self-administration of subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis (MOSAIC) study

Background: Patients with multiple sclerosis (MS) often receive long-term injectable therapy, and difficulties associated with self-injection can affect treatment adherence and efficacy.

Objective: The objective of this study was to evaluate an investigational, ready-to-use, single-use autoinjector for self-injection of subcutaneous (sc) interferon beta-1a (IFNβ-1a).

Methods: In this multicenter, open-label, single-arm study, patients with relapsing MS who were receiving IFNβ-1a sc 44 μg three times weekly for ≥ 12 weeks continued therapy using a single-use autoinjector and completed a user trial questionnaire at baseline and weeks 6 and 12. The primary endpoint was the proportion of patients rating the autoinjector as easy or very easy to use at week 12.

Results: At 12 weeks, 86% of 109 patients included in the intent-to-treat population rated the autoinjector easy or very easy to use (95% confidence interval, 80% ? 93%), and the most important perceived benefit was its overall convenience. The majority (74%) of patients reported the device as somewhat or extremely convenient to use, and most (83%) agreed or strongly agreed that the device made injections simple.

Conclusion: The single-use autoinjector was well received and supported by favorable ratings for simplified injections and convenience. The results suggest that the device may improve overall injection experience in patients with relapsing MS.     

Effect of natalizumab on oxidative damage biomarkers in relapsing-remitting multiple sclerosis

BackgroundNatalizumab is a monoclonal antibody used to treat multiple sclerosis. This study sought to determine whether the protective action of natalizumab involved a reduction in oxidative damage.MethodsTwenty-two multiple sclerosis patients fulfilling the revised McDonald criteria were assigned to treatment with 300 mg natalizumab intravenously once monthly (infusion every 4 weeks) in accordance with Spanish guidelines. Carbonylated proteins, 8-hydroxy-2’-deoxyguanosine, total glutathione, reduced glutathione, superoxide dismutase, glutathione peroxidase, and myeloperoxidase levels were measured at baseline and after 14 months’ treatment, and the antioxidant gap was calculated.ResultsNatalizumab prompted a drop in oxidative-damage biomarker levels, together with a reduction both in myeloperoxidase levels and in the myeloperoxidase/neutrophil granulocyte ratio. Interestingly, natalizumab induced nuclear translocation of Nrf2 and a fall in serum vascular cell adhesion molecule-1 levels.ConclusionThese findings suggest that natalizumab has a beneficial effect on oxidative damage found in MS patients.     

High-dose,high-frequency recombinant interferon beta-1a in the treatment of multiple sclerosis

Background: There is at present no cure for multiple sclerosis (MS), and existing therapies are designed primarily to prevent lesion formation, decrease the rate and severity of relapses and delay the resulting disability by reducing levels of inflammation. Objective: The aim of this review was to assess the treatment of relapsing MS with particular focus on subcutaneous (sc) interferon (IFN) beta-1a. Method: The literature on IFN beta-1a therapy of MS was reviewed based on a PubMed search (English-language publications from 1990) including its pharmacodynamics and pharmacokinetics, clinical efficacy in relapsing MS as shown in placebo-controlled studies and in comparative trials, efficacy in secondary progressive MS, safety and tolerability, and the impact of neutralizing antibodies. Conclusion: The literature suggests that high-dose, high-frequency sc IFN beta-1a offers an effective option for treating patients with relapsing MS, with proven long-term safety and tolerability, and has a favourable benefit-to-risk ratio compared with other forms of IFN beta.     

Overview and safety of fingolimod hydrochloride use in patients with multiple sclerosis

Introduction: Fingolimod (Gilenya®, FTY720) is an oral sphingosine-1-phosphate analogue that was approved by the FDA in 2010 for the treatment of relapsing forms of multiple sclerosis (MS). Fingolimod’s mechanism of action is primarily related to lymphocyte sequestration in primary and secondary lymphoid tissues. Phase III trials demonstrated a reduction in annualized relapse rate and MRI progression in fingolimod-treated subjects compared with both placebo and IFN-β-treated subjects. Frequent adverse effects include fatigue, gastrointestinal disturbance, headache and upper respiratory tract infection. More serious, but rare, adverse events associated with fingolimod include atrioventricular block, symptomatic bradycardia, herpetic viral infections and macular edema.

Areas covered: We discuss the mechanism of action, pharmacokinetics, clinical efficacy and safety profile of fingolimod in patients with relapsing MS.

Expert opinion: Fingolimod is an effective treatment for relapsing MS and its oral route of administration may be preferred by some. Fingolimod is generally well tolerated but requires diligence in patient selection and monitoring. Additional information is needed regarding risk of infection, malignancy and rebound disease with long-term use of fingolimod.     

Long-term adherence of patients with relapsing-remitting multiple sclerosis to subcutaneous self-injections of interferon β-1a using an electronic device: the RIVER study

ABSTRACT

Objectives: The BRIDGE study has previously shown a high short-term (12 weeks) adherence rate (>85%) of patients with relapsing-remitting multiple sclerosis (RRMS) to subcutaneous self-injections of interferon β-1a using an electronic auto-injection device (RebiSmart®). The primary goal of the RIVER study was to investigate in a real-life setting the long-term adherence to the use of RebiSmart among patients enrolled in the parent BRIDGE study.

Methods: The RIVER study was designed as a real-life extension study of the BRIDGE trial. RRMS patients who completed BRIDGE and still had an indication for treatment were included. Data were collected prospectively through the RebiSmart device, and analyzed retrospectively. Long term adherence (administration of ≥ 80% of injections) to and safety of RebiSmart were assessed. The expected follow-up period ranged from 19 to 26 months.

Results: A total of 57 RRMS patients participated in the follow-up study. The mean observation period was 20.5 ± 5.7 months. The overall adherence to the use of RebiSmart in the entire study cohort was 79.8% (median = 85.2%, range = 16–100%). There were 36 patients (63.2%) who completed at least 80% of the scheduled injections. No statistically significant differences were found between adherent and non-adherent patients in terms of age, sex, duration of the observation period, and occurrence of relapses. No serious treatment-related adverse events occurred.

Conclusions: This study showed a high level of long-term adherence to the use of RebiSmart, with 63.2% of participants meeting the criterion for adherence to treatment.     

Pharmacoeconomic considerations of multiple sclerosis therapy with the new disease-modifying agents

Multiple sclerosis (MS) represents the second most common cause of neurological disability in young adults. The introduction of treatments that can change the natural course of the disease has focused attention on the economic burden of MS. There have been fears that the newly approved treatments for MS will ruin healthcare systems. Other published economic evaluations stress that the economic burden of a disease should be seen in a global perspective and that new treatments offer an opportunity to reduce the burden of the disease in the long-term. This paper reviews a number of key health economic studies in MS, which reveal the burden of MS on society and the cost-effectiveness of the new disease-modifying drugs, and highlight some unresolved issues. All relevant costs, including indirect costs and costs of informal care, should be taken into account for a global estimation of the cost/benefit balance. Further rigorous economic evaluations, focusing on the comparison of different available alternatives, are necessary. A major task will be the collection of data on the impact of the new disease-modifying therapies in reducing disability progression over the long-term, outside clinical trials. Gathering this kind of information is of critical importance in order to improve the precision of cost-effectiveness estimates in the future.     

Interferon-β1b in the treatment of multiple sclerosis

Ever since IFN-β_1b was first approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the US and Europe, other disease-modifying drugs have become available. Phase III clinical trials have shown the efficacy of IFN-β_1b in the treatment of RRMS and secondary progressive MS in that it can reduce the annual relapse rate as well as magnetic resonance imaging parameters of activity and progression. There is mounting evidence that the best time to initiate treatment is early in the course of the disease, and available data suggest that efficacy is sustained for at least 5 years. IFN-β_1b is safe and well tolerated, although there are adverse events such as the flu-like complex and skin reactions. In the face of a proportion of RRMS patients experiencing a poor response to the drug, other therapeutic approaches need to be considered.     

Treatment of cognitive impairment in patients with multiple sclerosis

Introduction: Identifying and treating cognitive impairment in patients with multiple sclerosis (MS) is increasingly recognized as a crucial step in selecting the most appropriate treatment for the individual. Currently, the neuropsychological tests used to assess patients are time-consuming and require specialist training to administer; consequently, cognitive impairment in MS is underdiagnosed. Many treatments are available for MS, including disease-modifying drugs (DMDs) and symptomatic therapies, but what are their effects on cognitive performance?

Areas covered: This article will review published studies describing the cognitive effects of DMDs and symptomatic treatments for MS.

Expert opinion: Some DMDs may improve cognitive performance in patients with MS. None of the symptomatic drug treatments reviewed showed positive effects on cognitive performance, with the possible exception of L-amphetamine, which may improve memory in patients with existing deficits, and methylphenidate, on which more data are needed. Cognitive rehabilitation can improve cognitive performance, but experience with these techniques is limited. Treatment for patients with MS and cognitive impairment should, therefore, include a DMD in combination with a pharmacological or perhaps non-pharmacological cognitive-enhancement strategy. However, the methods used to diagnose cognitive impairment, and to assess the effect of treatment on function over time and need to be refined.     

大剂量甲泼尼龙与免疫球蛋白治疗多发性硬化急性期的疗效观察

目的 评价大剂量甲泼尼龙和免疫球蛋白冲击治疗急性期多发性硬化(MS)的临床疗效.方法 对2002～2007年分别采用大剂量甲泼尼龙、免疫球蛋白以及两者联合冲击治疗67例复发一缓解型急性期MS患者进行回顾性分析.按主要的治疗方法分为甲泼尼龙(MPS)组、免疫球蛋白(IG)组及甲泼尼龙加免疫球蛋白(MPS IG)组,以治疗前后3组患者Kurtzke神经功能障碍量表(EDSS)平均评分的变化反映疗效,比较以上3种治疗急性期MS的疗法的疗效.结果 治疗7d时有效率MPS组为69.2%.IG组为85%,MPS IG组为85.7%,IG组和MPS IG组明显高于MPS组(P均＜0.05);治疗30d时有效率Mrs组为96.1%,IG组为100%,MPS IG组为95.2%.3组之间有效率无统计学差异(P＞0.05).IG组和MPS IG组住院治疗后第7d时EDSS评分降低明显(P＜0.01).且优于MPS组(P均＜0.05);治疗30d时3组治疗前后比较有非常显著的差异(P均＜0.01),MPS IG组与IG组、MPs组比较EDSS评分无明显差异(P＞0.05).结论 大剂量甲泼尼龙和免疫球蛋白均对急性期复发一缓解型MS有效.其中免疫球蛋白能较快起效,但二者合用并没有比单用表现出更好的疗效.     

Single-use autoinjector for peginterferon-β1a treatment of relapsing-remitting multiple sclerosis: safety,tolerability and patient evaluation data from the Phase IIIb ATTAIN study

Objectives: A sub-study to evaluate safety, tolerability, ease-of-use and patient satisfaction with a single-use autoinjector administering subcutaneous peginterferon-β_1a (a pegylated interferon-β_1a in clinical development) in a subset of relapsing-remitting multiple sclerosis (MS) patients participating in ATTAIN, a long-term dose-frequency blinded extension of the Phase III randomized ADVANCE study.

Methods: Over 8 weeks, patients self-administered peginterferon-β_1a 125 µg or placebo every 2 weeks (two injections via manual pre-filled syringe [PFS]; two injections via single-use autoinjector). Primary end points were incidence of adverse events (AEs), patient assessment of injection pain score (10-point Visual Analog Scale), and clinician assessment of injection site reactions (ISRs). Secondary objectives included patient assessment of ease-of-use and satisfaction with the autoinjector and evaluation of autoinjector training materials.

Results: In 39 patients, the safety profile of peginterferon-β_1a was similar when delivered via autoinjector or PFS; AEs were mostly mild or moderate in severity. Clinicians and patients reported a similar tolerability profile using both PFS and autoinjector, and pain scores were low (< 1), with no reports of clinician-assessed ISRs after administration with the autoinjector. Patients perceived the single-use autoinjector to be easy to use and convenient; overall patient satisfaction with the autoinjector and accompanying training materials was high.

Conclusion: The safety and tolerability profile of peginterferon-β_1a delivered via autoinjector was similar to delivery via PFS. Patients found the autoinjector easy to use and convenient; this device may simplify the injection process for MS patients who require long-term therapy, thereby potentially improving patient’s quality of life and adherence.     

Characteristics associated with drug-induced liver injury from interferon beta in multiple sclerosis patients

Objective: To identify and characterize drug-induced liver injury (DILI) associated with IFN-β in multiple sclerosis (MS) using recommended criteria.

Methods: This retrospective, mixed methods design included a cohort of IFN-β exposed MS patients from British Columbia (BC), Canada and a series of DILI cases from other Canadian provinces and two adverse drug reaction (ADR) networks (USA and Sweden). Associations between sex, age and IFN-β product, and DILI were explored in BC cohort using Cox proportional hazard analyses. Characteristics, including the time to DILI, were compared between sites.

Results: In BC, 18/942 (1.9%) of IFN-β exposed MS patients met criteria for DILI, with a trend toward an increased risk for women and those exposed to IFN-β-1a SC (44 mcg 3 × weekly) (adjusted Hazard Ratios: 3.15;95% CI:0.72 – 13.72, p = 0.13 and 6.26;95%CI:0.78 – 50.39, p = 0.08, respectively). Twenty-four additional cases were identified from other sites; the median time to DILI was comparable between BC and other Canadian cases (105 and 90 days, respectively), but longer for the ADR network cases (590 days, p = 0.006).

Conclusions: Approximately 1 in 50 IFN-β exposed patients developed DILI in BC, Canada. Identification of DILI cases from diverse sources highlighted that this reaction occurs even after years of exposure.     

Factors associated with early initiation of disease-modifying drug treatment in newly-diagnosed patients with multiple sclerosis

Objective: To examine the time to first disease-modifying drug (DMD) treatment and to identify factors associated with early DMD initiation in newly-diagnosed patients with MS.

Methods: This retrospective cohort study included newly-diagnosed patients with MS from a US administrative claims database, aged 18–65 years, with a first MS diagnosis (ICD-9-CM code: 340.xx) between January 1, 2007 and June 30, 2013 (index date), continuous eligibility for 12 months pre- and 24 months post-index, and initiated DMD treatment within 2 years. Time to first DMD within 24 months post-index was evaluated. A logistic regression model predicted earlier initiation of DMD treatment (within 60 days of MS diagnosis).

Results: In total, 37.4% of patients initiated DMD treatment within 2 years of MS diagnosis and were included in the primary analysis (n?=?7,124). Mean (standard deviation [SD]) time from MS diagnosis to first DMD was 112.6 (148.3) days (median?=?51); 30.7% received first DMD in <30 days, 55.1% in <60 days, and 18.5% not until ≥180 days after diagnosis. Logistic regression found that younger age; not living in the Northeast; diagnoses of balance disorders, numbness, and optical neuritis; the absence of musculoskeletal diagnoses; and a neurologist visit or MRI within 90 days before diagnosis were associated with DMD initiation within 60 days.

Conclusions: In this population of patients initiating DMD treatment within 2 years of MS diagnosis, mean time to first DMD was 112.6 days. Identifying factors associated with delayed treatment may provide better understanding of the reasons for delay, leading to improved disease management.     

Good results for early treatment of clinically isolated syndrome prior to multiple sclerosis with interferon beta-1b and glatiramer group

The first sign of developing multiple sclerosis is a clinically isolated syndrome that resembles a multiple sclerosis relapse. Objective/methods: The objective was to review the clinical trials of two medicines in clinically isolated syndromes (interferon β and glatiramer acetate) to determine whether they prevent progression to definite multiple sclerosis. In the BENEFIT trial, after 2 years, 45% of subjects in the placebo group developed clinically definite multiple sclerosis; the rate was lower in the interferon β-1b group. All subjects were then offered interferon β-1b, and the original interferon β-1b group became the early-treatment group and the placebo group became the delayed-treatment group. After 5 years, the number of subjects with clinical definite multiple sclerosis remained lower in the early-treatment than in the late-treatment group. In the PreCISe trial, after 2 years, the time for 25% of the subjects to convert to definite multiple sclerosis was prolonged in the glatiramer group. Interferon β-1b and glatiramer acetate slow the progression of clinically isolated syndromes to definite multiple sclerosis. However, it is not known whether this early treatment slows the progression to the physical disabilities experienced in multiple sclerosis.     

Macular oedema and changes in macular thickness in multiple sclerosis patients treated with fingolimod

Macular oedema is a known side effect to fingolimod, but changes in specific areas of the retina are only sparsely described. Our aim was to investigate the prevalence of macular oedema and characterize macular changes after initiation of fingolimod based on routine ophthalmological examinations in all consecutive patients treated at our hospital. We evaluated macular thickness change from baseline to 3‐4 months after initiation of treatment. Central retinal thickness, total macular volume, total macular thickness, average thickness and inner‐/outer macular thickness were automatically measured using optical coherence tomography (OCT). A total of 190 eyes completed the study, and none of those developed visible macular oedema. All macular areas showed a small, but statistically significant increase in thickness. Total macular volume increased by a mean of 0.05 mm³ (P = <.001). Mean best‐corrected visual acuity only changed by .03 (P = .074). We observed a minimal change in macular thickness and no clinically relevant affection on visual acuity after 3‐4 months of fingolimod treatment. Thus, our results do not underpin the need for routine screening for macular oedema in asymptomatic MS patients without diabetes or uveitis receiving 0.5 mg fingolimod daily.