Early Treatment Of Multiple Sclerosis Research Articles

A New Study Adds Support for Early Treatment in Multiple Sclerosis

A New Study Adds Support for Early Treatment in Multiple Sclerosis

Association between early treatment of multiple sclerosis and patient-reported outcomes: a nationwide observational cohort study

BackgroundTiming of disease-modifying therapy affects clinical disability in multiple sclerosis, but it is not known whether patient reported outcomes are also affected. This study investigates the relationship between treatment timing...

The Brave New World of Early Treatment of Multiple Sclerosis: Using the Molecular Biomarkers CXCL13 and Neurofilament Light to Optimize Immunotherapy.

Multiple sclerosis (MS) is a highly heterogeneous disease involving a combination of inflammation, demyelination, and CNS injury. It is the leading cause of non-traumatic neurological disability in younger people. There is no cure, but treatments in the form of immunomodulatory drugs (IMDs) are available. Experience over the last 30 years has shown that IMDs, also sometimes called disease-modifying therapies, are effective in downregulating neuroinflammatory activity. However, there are a number of negatives in IMD therapy, including potential for significant side-effects and adverse events, uncertainty about long-term benefits regarding disability outcomes, and very high and increasing financial costs. The two dozen currently available FDA-approved IMDs also are heterogeneous with respect to efficacy and safety, especially long-term safety, and determining an IMD treatment strategy is therefore challenging for the clinician. Decisions about optimal therapy have been particularly difficult in early MS, at the time of the initial clinical demyelinating event (ICDE), at a time when early, aggressive treatment would best be initiated on patients destined to have a highly inflammatory course. However, given the fact that the majority of ICDE patients have a more benign course, aggressive immunosuppression, with its attendant risks, should not be administered to this group, and should only be reserved for patients with a more neuroinflammatory course, a decision that can only be made in retrospect, months to years after the ICDE. This quandary of moderate vs. aggressive therapy facing clinicians would best be resolved by the use of biomarkers that are predictive of future neuroinflammation. Unfortunately, biomarkers, especially molecular biomarkers, have not thus far been particularly useful in assisting clinicians in predicting the likelihood of future neuroinflammation, and thus guiding therapy. However, the last decade has seen the emergence of two highly promising molecular biomarkers to guide therapy in early MS: the CXCL13 index and neurofilament light. This paper will review the immunological and neuroscientific underpinnings of these biomarkers and the data supporting their use in early MS and will propose how they will likely be used to maximize benefit and minimize risk of IMDs in MS patients.

Sustained-release hot melt extrudates of the weak acid TMP-001: A case study using PBB modelling

Over the last 30 years, hot melt extrusion has become a leading technology in the manufacture of amorphous drug delivery systems. Mostly applied as an ‘enabling formulation’ for poorly soluble compounds, application in the design of sustained-release formulations increasingly attracts the attention of the pharmaceutical industry.The drug candidate TMP-001 is currently under evaluation for the early treatment of Multiple Sclerosis. Although this weak acid falls into class II of the Biopharmaceutics Classification System, the compound exhibits high solubility in the upper intestine resulting in high peroral bioavailability. In the present studies, four different formulation prototypes varying in their sustained-release behavior were developed, using L-arginine as a pore-forming agent in concentrations ranging between 0 and 20%. Initially, biorelevant release testing was applied to assess the dissolution behavior of the prototypes. For these formulations, a total drug release of 44.7%, 64.6%, 75%, and 90.5% was achieved in FaSSIF-v2 after 24 h. Two candidates were selected for further characterization considering the crystal structure and the physical stability of the amorphous state of TMP-001 in the formulations together with the release behavior in Level II biorelevant media. Our findings indicate L-arginine as a valuable excipient in the formulation of hot melt extrudates, as its presence led to a considerable stabilization of the amorphous state and favorably impacted the milling process and release behavior of TMP-001. To properly evaluate the proposed formulations and the importance of colonic dissolution and absorption on the overall bioavailability, a physiologically-based biopharmaceutics model was used.

The long-term impact of early treatment of multiple sclerosis on the risk of disability pension

ObjectiveThe objective of this retrospective, observational study was to estimate the long-term impact of early treatment of multiple sclerosis (MS) on the risk of disability pension.MethodsOur cohort comprised patients with MS in Sweden, identified in a nationwide disease-specific register (the Swedish Multiple Sclerosis Registry), who started treatment with a disease-modifying drug (DMD) between January 1, 2002, and December 31, 2012. We analyzed the association between time from onset of MS to treatment initiation and full-time disability pension using survival analysis.ResultsOur sample comprised 2477 patients. Unadjusted Kaplan–Meier failure functions showed that patients who started treatment within six months after onset had a lower risk of disability pension across follow-up compared with patients initiating therapy after 12 months. Outcomes from the univariate Cox proportional hazards model showed that time from onset to treatment initiation (in years) was significantly associated with disability pension (HR 1.03, p < 0.001). Outcomes from the multivariable Cox proportional hazards model showed that patients who started treatment within 6 months after onset had, on average, a 36% lower risk (HR 0.74, p = 0.010) of full-time disability pension during follow-up compared with patients starting treatment after 18 months when controlling for age, sex, marital status, university education, and prevalent comorbidities.ConclusionsWe show that early treatment with DMDs of MS is associated with a significantly reduced risk of disability pension. Our findings highlight the potential long-term benefits of early treatment of MS and should be helpful to inform ongoing discussion on the optimum medical management of the disease.

Eleven-Year Outcomes in the Early Treatment of MS

The BENEFIT trial was a 2-year, randomized, placebo-controlled, multicenter, manufacturer-funded study to evaluate interferon β-1b (IFN) for the prevention of a second clinical relapse in patients with an initial demyelinating event and abnormal brain magentic resonance imaging indicating possible multiple sclerosis (MS). Placebo recipients (delayed-treatment group) were provided the option to receive IFN open-label upon having a second clinical event or after completion of 2 years of follow-up. Of the original 468 randomized patients, 278 (59%) …

Free kappa light chains in cerebrospinal fluid as a biomarker to assess risk conversion to multiple sclerosis.

BackgroundMultiple sclerosis (MS) initiates with a first attack or clinically isolated syndrome (CIS). The importance of an early treatment in MS leads to the search, as soon as possible, for novel biomarkers which can predict conversion from CIS to MS.ObjectiveThe purpose of this study was to assess the predictive value of the kappa index ( index), using kappa free light light chains (FLCs) in cerebrospinal fluid (CSF), for the conversion of CIS patients to MS, and compare its accuracy with other parameters used in clinical practice.MethodsFLC levels were analysed in CSF from 176 patients: 70 as control group, 77 CIS, and 29 relapsing–remitting MS. FLC levels were quantified by nephelometry.Results Index sensitivity and specificity (93.1%; 95.7%) was higher than those from the immunoglobulin G (IgG) index (75.9%; 94.3%), and lower than those from oligoclonal IgG bands (OCGBs) (96.5%; 98.6%). The optimal cut-off for index was 10.62. Most of the CIS patients with index >10.62 presented OCGBs, IgG index >0.56 and fulfilled magnetic resonance imaging (MRI) criteria.ConclusionCIS patients above index cut-off of 10.62 present 7.34-fold risk of conversion to MS than CIS below this value. The index correlated with positive OCGBs, IgG index above 0.56 and MRI criteria.

Review of the pharmacoeconomics of early treatment of multiple sclerosis using interferon beta

Multiple sclerosis (MS) is a common neurological disease with increasing incidence and prevalence. Onset of disease is most frequently in young adulthood when productivity is usually highest; it is of chronic nature and, in the majority of patients, it will result in accumulation of disability. Due to loss of productivity in patients and caregivers as well as high expenses for medical treatment, MS is considered a disease with high economic burden for patients and society. Several drugs have been approved for treatment of MS. While treatment ameliorates the course of the disease, it is very costly; therefore, pharmacoeconomics, evaluating costs and effects of disease-modifying treatment in MS, has become an important issue. Here, we review the economic impact and treatment strategies of MS and discuss recent studies on pharmacoeconomics of early treatment with interferon beta.

Long-Term Cost-Effectiveness Model of Interferon Beta-1b in the Early Treatment of Multiple Sclerosis in the United States

BackgroundMultiple sclerosis (MS) is a potentially debilitating autoimmune disease that affects the brain and spinal cord. Disease-modifying therapies have been shown to slow disease progression but were not believed to prolong the survival of patients with MS. The recent 21-Year Long-Term Follow-Up (21Y-LTF) study found a significant survival advantage for patients receiving early treatment with interferon beta (IFNβ)-1b compared with placebo (no early treatment). ObjectivesThe aim of this study was to conduct cost-effectiveness analyses estimating the long-term benefit of early treatment with IFNβ-1b among MS patients from a US societal perspective. MethodsA Markov model was developed to simulate the experience of patients with MS from the 21Y-LTF study over a lifetime. Patients were randomized to receive either IFNβ-1b or placebo for up to 5 years and then receive a variety of MS treatments (including no treatment) thereafter. Survival data reported from the 21Y-LTF study were incorporated into the model. The model assumes that patients' MS was managed in similar ways for both groups during the uncontrolled phase of the 21Y-LTF study (ie, survival difference between the 2 groups is the result of early use of IFNβ-1b). Health outcomes were life-years and quality-adjusted life-years (QALYs). Costs included treatments, direct disease management, informal care, and lost productivities and were reported in 2011 US dollars. ResultsIn the modeled placebo group, the median age at death was predicted to be 63.7 years, and the median survival time from disease onset was 36.7 years. Early treatment with IFNβ-1b reduced the lost health benefits by 2.8 life-years and 1.9 QALYs, respectively, after discounting. Total discounted cost for IFNβ-1b–treated patients was $86,223 higher than that of patients receiving placebo. The incremental cost-effectiveness ratio was $46,357 per QALY gained and $30,967 per life-year gained. Sensitivity analyses indicate the robustness of the model's results. ConclusionsTreatment with IFNβ-1b during the earlier disease phase of patients with MS significantly increased patient life-years and QALYs. IFNβ-1b is likely to be a cost-effective intervention for MS.

Long term benefit of multiple sclerosis treatment: an investigation using a novel data collection technique

Background: The Knowledge Program (KP) is an initiative to collect self-reported patient data and objective clinician assessments electronically at each outpatient clinical encounter. Available outcomes include the EuroQoL-5D (EQ5D), Patient Health Questionnaire-9 (PHQ9), Multiple Sclerosis Performance Scales (MSPS), and the timed 25-foot walk (T25FW). Objective: This study was designed to use the KP to investigate the long-term benefits of early treatment (ET) in multiple sclerosis (MS). Methods: The KP was queried for patients with relapsing–remitting MS or secondary progressive MS who were ≥5 years from symptom onset. ET was defined as treatment with an approved agent for ≥3 of the first five years after symptom onset. Propensity scores for ET were calculated based on early clinical characteristics. Patients were divided into propensity score quintiles and linear regression models were constructed to determine the treatment effect sizes and confidence intervals. Results: From the 1082 patients that met entry criteria, 453 patients (41.9%) received ET. Those patients receiving ET showed significantly better scores on the EQ5D index, PHQ9, and MSPS, but only in the upper three propensity quintiles. For the T25FW, ET did not result in significantly better times in any quintile. Conclusions: These results suggest that ET of MS is beneficial but the effect appears modest.

Cost-Effectiveness Analysis of Interferon Beta-1b for the Treatment of Patients With a First Clinical Event Suggestive of Multiple Sclerosis

ObjectivesTo assess, from a Swedish societal perspective, the cost effectiveness of interferon β-1b (IFNB-1b) after an initial clinical event suggestive of multiple sclerosis (MS) (ie, early treatment) compared with treatment after onset of clinically definite MS (CDMS) (ie, delayed treatment). MethodsA Markov model was developed, using patient level data from the BENEFIT trial and published literature, to estimate health outcomes and costs associated with IFNB-1b for hypothetical cohorts of patients after an initial clinical event suggestive of MS. Health states were defined by Kurtzke Expanded Disability Status Scale (EDSS) scores. Model outcomes included quality-adjusted life years (QALYs), total costs (including both direct and indirect costs), and incremental cost-effectiveness ratios. Sensitivity analyses were performed on key model parameters to assess the robustness of model results. ResultsIn the base case scenario, early IFNB-1b treatment was economically dominant (ie, less costly and more effective) versus delayed IFNB-1b treatment when QALYs were used as the effectiveness metric. Sensitivity analyses showed that the cost-effectiveness results were sensitive to model time horizon. Compared with the delayed treatment strategy, early treatment of MS was also associated with delayed EDSS progressions, prolonged time to CDMS diagnosis, and a reduction in frequency of relapse. ConclusionEarly treatment with IFNB-1b for a first clinical event suggestive of MS was found to improve patient outcomes while controlling costs.

Early treatment in multiple sclerosis

There is now a consensus that early treatment of patients with relapsing-remitting multiple sclerosis is desirable, mainly because early treatment may delay the accumulation of disability, but also because disease-modifying treatments seem to be more effective when started early in the course of the disease. In particular, all current first-line disease-modifying treatments have also been shown to be effective in treating clinically isolated syndrome. The evidence for this comes from extensive experience in randomised controlled Phase III clinical trials. While many patients presenting a clinically isolated syndrome are at high risk of experiencing a second attack, early treatment with all disease-modifying treatments has been shown to delay conversion to clinically definite multiple sclerosis when compared to late treatment. Some of these trials have completed five years of follow-up. While the evidence for early intervention is stronger than ever, it is worthwhile to consider its relevance to everyday clinical practice. In particular, it is important to determine which patients are the best candidates for early therapy and to evaluate the anticipated risks and benefits of choosing a given therapy for a given patient.

Potential Health Care Cost Savings Associated With Early Treatment of Multiple Sclerosis Using Disease-Modifying Therapy

Background Clinical trials have shown that treatment with disease-modifying therapies (DMTs), such as interferon, at the time of clinically isolated syndrome can delay the onset of multiple sclerosis (MS). Objectives The objective of this study was to assess health care utilization and expenditures associated with treating patients early with DMTs rather than delaying until patients meet the full diagnostic criteria of MS. Methods A retrospective study used insurance claims data (2000–2008) of enrolled patients before documented MS (1 inpatient or 2 outpatient claims with International Classification of Diseases, 9th Revision, Clinical Modification 340 coding). Treatment cohorts were early DMT (DMT claim before the first documented MS; N = 227) and delayed DMT (DMT started after documented MS; N = 3724). Comparisons during 1 year of follow-up were adjusted for confounding using multivariate methods. Results Adjusted annual per-patient expenditures (including patient out of pocket) for early versus delayed were as follows: total ($28,280 vs $29,102; P = 0.44), excluding DMT cost ($15,214 vs $17,630; P < 0.01), and MS-related ($9365 vs $13,661; P < 0.01). Hospitalizations were 10.1% versus 16.5% (adjusted odds ratio [OR] = 0.51; 95% CI, 0.32–0.81). Conclusions Analysis indicated that early DMT treatment was associated with fewer hospitalizations than delayed treatment, and there was no statistically significant difference in annual health care expenditures. This suggests that the drug costs of early therapy were offset by savings in other medical expenditures.

Early Treatment of Multiple Sclerosis

Early Treatment of Multiple Sclerosis

The role of glatiramer acetate in the early treatment of multiple sclerosis

The treatment of the underlying disease process causing multiple sclerosis has continued to evolve since the initial approval of interferon-beta-1b in 1993. Current emphasis is on early treatment, including treatment after a single clinical attack (clinically isolated syndrome). The assessment of which disease modifying medication to use as initial therapy has continued to remain a combination of science and the art of medicine. Equally important are the assessment of treatment failure and the subsequent choice of medication change. This article will present scientific information, as well as information about clinical decision making, about these choices, with emphasis on the changing role of glatiramer acetate in this process.

Early treatment of multiple sclerosis to prevent neurologic damage

Multiple sclerosis (MS) involves ongoing accumulating CNS damage. Precisely which environmental factors trigger onset and progression of the disease are not known. However, clinical trials indicate benefits from early use of disease-modifying therapies (DMTs). All the completed clinically isolated syndrome trials (CHAMPS, ETOMS, BENEFIT, PRECISE) reported significant suppression of subsequent relapse and MRI lesion formation from use of DMT at the first relapse. This article reviews data on early treatment. Such an approach requires the ability to recognize clinically isolated syndrome features that indicate a diagnosis of MS.

Pharmacological Treatment of Early Multiple Sclerosis

Currently, six medications are approved by the US FDA for the treatment of relapsing forms of multiple sclerosis (MS). In contrast, no pharmacological agent has proved to be effective in patients with secondary-progressive MS without relapses, or in patients with primary-progressive MS. One of the principal issues concerning an optimal pharmacotherapy for relapsing forms of MS is the optimal time of treatment initiation. There is now an almost universal consensus among MS experts that many patients will benefit from early therapy. However, several formidable challenges exist in identifying individuals who will benefit versus those who will do well without intervention. How do we define early MS and what clinical and paraclinical markers may be useful in defining the timing and nature of therapy? Do patients with a benign form of MS require therapy or are they exposed unnecessarily to adverse effects of our currently available medications? How do we identify disease progression and treatment failures? This review discusses these issues and outlines the evidence for application of 'early' treatment in patients with relapsing forms of MS.

Early treatment

Class I clinical trials demonstrated that immunomodulatory treatments (interferon-beta and glatiramer acetate) reduce the disease activity and the accumulation of disability in relapsing-remitting multiple sclerosis (MS). Moreover, interferon-beta-1b had similar positive effects also in secondary progressive MS. The magnitude of these clinical effects was modest, but the reduction of inflammatory activity, as revealed by magnetic resonance imaging, was marked. There is converging evidence from new pathological studies and from new magnetic resonance techniques, characterised by an increased pathological specificity, that already in the early phases of the disease the inflammatory activity determines irreversible axonal damage. Moreover, the amount of inflammatory activity at clinical presentation of the disease has some value for predicting long-term disability. Taken together, these data indicate that patients may benefit from early treatment; the positive results of three double-blind placebo-controlled clinical trials (Early Treatment of Multiple Sclerosis and Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study and BENEFIT) support this conclusion.

Patient Perspectives on Disease-Modifying Therapy in Multiple Sclerosis

The purpose of this study was to understand factors contributing to the decision-making processes of individuals with multiple sclerosis (MS) regarding the use of disease-modifying therapy (DMT). Semi-structured qualitative interviews were conducted with 18 individuals with MS. Qualitative interviews revealed two major themes: opting for and opting out of DMT. Participants indicated that stable health, predictability, and perceived control were reasons to be on DMT. They also indicated that taking DMT is not without personal cost, both financial and psychological (eg, denial, fear, and uncertainty). Fear of needles and side effects, not feeling “sick enough,” the costs of medication versus benefits, and discouragement from physicians were given as reasons for opting out of DMT. Participants also reported that restarting DMT after they had stopped was difficult, especially if they felt better when not using DMT. Early treatment of MS with DMT, especially for those with relapsing-remitting MS, is strongly supported by published findings. Although participants in our study revealed significant barriers to initiating and adhering to DMT, recent advances in clinical practice and improved coverage for treatment costs should reduce these barriers.

History of modern multiple sclerosis therapy

Although the earliest recorded description of multiple sclerosis (MS) dates back to the 14(th) century, it was not until the latter years of the 20(th) that treatments for this disabling condition were found. However, the "road to success" has not been without hurdles. Trials with both interferon alpha and gamma proved unsuccessful, as did treatment with oral myelin, cladribine, sulfasalazine and inhibitors of tumour necrosis factor. In 1993, interferon beta-1b (IFNbeta-1b) became the first therapy proven to be effective in altering the natural history of relapsing-remitting MS (RRMS). This was followed by successful trials with IFNbeta-1a and glatiramer acetate. In 1998, a European trial showed IFNbeta-1b to be also beneficial in the treatment of secondary progressive MS (SPMS). A similar trial in North America failed to reach its primary endpoint but was effective across secondary endpoints, highlighting how different methodology and patient populations can lead to inconsistent results and, thus, making comparisons across trials difficult. The trend for early intervention in MS with IFNbeta was recently supported by the CHAMPS (Controlled High-risk Avonex MultiPle Sclerosis) and ETOMS (Early Treatment of Multiple Sclerosis) studies using once-weekly IFNbeta-1a. Both trials demonstrated delayed conversion to clinically definite MS in patients with a clinically isolated syndrome and magnetic resonance imaging (MRI) findings suggestive of MS. Two directly comparative trials of high- (250 microg IFNbeta-1b or 44 microg IFNbeta-1a) and low-dose (30 microg IFNbeta-1a) IFNbeta (INCOMIN [INdependent COMparison of INterferons] and EVIDENCE [EVidence of Interferon Dose-response: European North American Comparative Efficacy]) support the superior efficacy of the higher dose and/or more frequent administration for treating RRMS. Since MS entered the treatment era in 1993, therapies for RRMS, SPMS and, more recently, progressive- relapsing MS have been developed. There is now a much better understanding of the pathogenesis of the disease, but new and improved therapeutic approaches are still needed.