Long-term Treatment Of Multiple Sclerosis Research Articles

Interferons in COVID-19: missed opportunities to prove efficacy in clinical phase III trials?

Interferons were repeatedly used in the therapy of COVID-19 due to their antiviral effects. Three recently published randomized controlled clinical phase III trials (WHO SOLIDARITY, ACTT-3, and SPRINTER) missed their primary objectives, i.e., a significant therapeutic effect of interferons was not demonstrated in these studies. In only one randomized controlled phase III trial (TOGETHER), a significant reduction in the hospitalization rate was revealed. Our study analyzes these findings, gives possible explanations for the failure of interferons, provides a proposal on how these agents could be successfully used, and also highlights the limitations of their employment in COVID-19. Interferons are apparently beneficial only if the patients are in the early stage of this disease and when they are usually not hospitalized, i.e., if the patients do not require oxygen support and/or if corticosteroids are not yet indicated. Furthermore, a higher dosage than the one used in the long-term treatment of multiple sclerosis with interferon beta or of chronic viral hepatitis with interferon alpha or lambda should be employed to achieve a better therapeutic effect in COVID-19.

Quantitative electroencephalography supports diagnosis of natalizumab-associated progressive multifocal leukoencephalopathy.

Long-term treatment of multiple sclerosis with natalizumab (NTZ) carries the risk of a devastating complication in the form of an encephalopathy caused by a reactivation of a latent John Cunningham virus infection (progressive multifocal leucoencephalopathy, PML). Early diagnosis is associated with considerably better prognosis. Quantitative EEG as an objective, rater-independent technique provides high sensitivity (88%) and specificity (82%) for the diagnosis of NTZ-PML. Combination of diagnostic modalities addressing static morphological (brain MRI) as well as functional (EEG) pathologic changes may improve risk management programmes.

Monthly Pulse Adrenocorticotropic Hormone (ACTH) or Methylprednisolone Therapy for Long-Term Treatment of Multiple Sclerosis as an Add-On Therapy to beta-Interferons: Current Status of the Pilot Study (P04.147)

Objective: This pilot study is designed to evaluate the efficacy and safety of monthly adrenocorticotropic hormone (ACTH) treatment added to beta-interferon in breakthrough multiple sclerosis (MS) compared with monthly methylprednisolone (MP), the most commonly used therapy. Background ACTH gel is approved for treatment of MS relapses. There is mounting evidence that ACTH may have a variety of immune-modulating mechanisms relevant to the MS disease course. However, no clinical studies have evaluated ACTH pulse therapy for MS. Design/Methods: This single-center, examiner-blinded study enrolled MS patients receiving ongoing beta-interferon treatment with Expanded Disability Status Scale (EDSS) scores of 3.0-6.5 and ≥1 relapse or new T2 or Gadolinium-enhanced lesion within the previous year. Patients were randomly assigned to open-label ACTH (80 units intramuscularly once/day x 3 consecutive days) or MP (1 gram IV x 1 dose) monthly for 12 months, with assessments every 3 months. Outcomes include relapse rate (primary); EDSS, MS Functional Composite, and MS Quality of Life scores; MRI; bone density; and side effects. We report the current status of the study. Results: Of 26 patients enrolled (ACTH: n=14, mean±SD EDSS 4.4±1.4; MP: n=12, mean EDSS 4.7±1.4), 18 have ≥6 months of data (ACTH: n=10, MP: n=8). During 6 months of pulse therapy, there were 0 relapses in the ACTH group and 4 relapses (in 2 patients) in the MP group. Mean EDSS score at month 3 was 3.9±2.0 (p=0.028; n=12) for ACTH and 3.9±1.6 (p=0.058; n=10) for MP. EDSS at month 6 was 4.4±1.8 (p=0.075) for ACTH and 4.2±2.0 (p=0.401) for MP. Seventeen side effects were reported from 9 patients in the ACTH group and 13 side effects were reported by 6 patients in the MP group. Conclusions: These data suggest a potential role for ACTH pulse therapy in treating breakthrough MS. Supported by: Questcor Pharmaceuticals, Inc. Disclosure: Dr. Berkovich has received personal compensation for activities with Acorda Therapeutics, Bayer Pharmaceuticals Corporation, Biogen Idec, Teva Neuroscience and Questcor Inc. as a speaker. Dr. Berkovich has received research support from Questcor Inc. Dr. Amezcua has received personal compensation for activities with Bayer Pharmaceuticals Corporation, Biogen Idec, Teva Neuroscience, and Serono/Pfizer Inc. Dr. Fernandez has nothing to disclose. Dr. Subhani has nothing to disclose. Dr. Kravtsova has nothing to disclose.

Long-term treatment of multiple sclerosis with glatiramer acetate: Natural history of the subtypes of anti-glatiramer acetate antibodies and their correlation with clinical efficacy

A retrospective phase IV study was designed to evaluate the anti-GA antibody subtypes, test their in vitro neutralizing activity and correlate these parameters with the clinical efficacy, in long-term GA treatment of MS patients. Serum samples from 153 MS patients, 126 treated with GA for 2 to 15 years (mean 6.6 years) and 27 treated for < 2 years, were collected. Anti-myelin basic protein (MBP) and anti-GA antibodies were measured by specific ELISA. Neutralizing activity was determined by the capacity of the serum to inhibit the proliferation of GA-specific T-cells. Anti-GA antibodies were detected even after very long treatment periods, although at lower levels. Anti-MBP reactivity remained consistently negative. The IgG2 isotype of anti-GA antibodies and the multiple sclerosis severity scale (MSSS) was lower in the long-term treated patients P = 0.0003 and 0.016 respectively. The neutralizing activity of anti-GA antibodies was insignificant. Our results indicate that the clinical efficacy of GA treatment could be associated with a decrease in anti-GA IgG2 isotype in long-term GA-treated patients.

The long-term treatment of multiple sclerosis with corticoids.

The long-term treatment of multiple sclerosis with corticoids.

Mechanisms of action of disease-modifying agents and brain volume changes in multiple sclerosis

Disease-modifying agents (DMAs), including interferon beta (IFNbeta) and glatiramer acetate (GA), are the mainstays of long-term treatment of multiple sclerosis (MS). Other potent anti-inflammatory agents like natalizumab and different types of chemotherapeutics are increasingly being used for treatment of MS, particularly in patients with breakthrough disease activity. Brain volume (BV) loss occurs early in the disease process, accelerates over time, and may be only partially affected by DMA therapy. Low-dose, low frequency IFNbeta administered once weekly and GA appear to partially reduce BV decline over the second and third years of treatment. High dose, high frequency IFNbeta demonstrated no clear effect on BV loss during this time period. Current evidence suggests that changes in BV after immunoablation may not be due entirely to the resolution of edema but may be related to potential chemotoxicity of high dose cyclophosphamide. Natalizumab reduces the development of BV decline in the second and third years of treatment. IV immunoglobulin showed a positive effect on decelerating BV reduction in relapsing and advanced stages of MS. These differences between DMAs may be explained by the extent of their therapeutic effects on inflammation and on the balance between inhibition or promotion of remyelination and neuronal repair in the CNS. We described the mechanisms of action by which DMAs induce accelerated, non-tissue-related BV loss (pseudoatrophy) in the short term but, in the long run, may still potentially lead to permanent BV decline. The effects of corticosteroid therapy on changes in BV in patients with MS help clarify the mechanisms through which potent anti-inflammatory treatments may prevent, stabilize, or induce BV loss.

Pharmacokinetics and pharmacodynamics of the interferon-betas, glatiramer acetate, and mitoxantrone in multiple sclerosis

Five disease-modifying agents are currently approved for long-term treatment of multiple sclerosis (MS), namely three interferon-beta preparations, glatiramer acetate, and mitoxantrone 1 1 A sixth disease-modifying agent, natalizumab, has been approved for treatment of multiple sclerosis after acceptance of this manuscript. Its pharmacokinetics and pharmacodynamics are not subject of this review. . Pharmacokinetics describes the fate of drugs in the human body by studying their absorption, distribution, metabolism and excretion. Pharmacodynamics is dedicated to the mechanisms of action of drugs. The understanding of the pharmacokinetics and pharmacodynamics of the approved disease-modifying agents against MS is of importance as it might contribute to the development of future derivatives with a potentially higher efficacy and a more favourable safety profile. This article reviews data thus far present both on the pharmacokinetics as well as on the putative mechanisms of action of the interferon-betas, glatiramer acetate, and mitoxantrone in the immunopathogenesis of MS.

Long-term treatment of multiple sclerosis with interferon-beta may be cost effective.

Multiple sclerosis (MS) is a devastating disease that can occur in early life, progressing to rapid disability and loss of physical, psychosocial and economic functioning, significantly affecting quality of life. The traditional treatment for MS has been symptomatic, treating acute relapses without affecting the underlying disease. The introduction of interferon-beta (IFN beta) has offered significant clinical benefits by reducing the frequency of relapses and slowing disease progression. Although the costs of this treatment are high, the costs to society of caring for a patient disabled by MS are greater, and if IFN beta can delay disease progression in the longer term, the economic impact would be substantial. Previous pharmacoeconomic studies of IFN beta have suggested that benefits can only be achieved at extremely high cost, with reported cost-effectiveness measures of up to 1 million pounds sterling (Pound) per quality-adjusted life year (QALY) [1995 values]. However, these studies have considered only the short term benefits of IFN beta treatment: over 2 to 3 years, the impact of treatment on patients' quality of life is relatively small, and cost-utility analyses that do not consider longer term benefits nor include societal costs may be misleading. The model reported here is based on the hypothesis that the delay in disease progression seen in short term clinical trials is likely to continue if treatment is continued. The model also assumes that the delay in disease progression, which represents a reduction in brain atrophy, will result in lasting clinical benefits even if treatment is stopped. These assumptions are strongly supported by clinical trial data and the treatment hypothesis itself. A delay in disease progression will result in a significant improvement in functioning and quality of life, and if the costs associated with increased disability can be postponed, even long term treatment of MS with IFN beta can be shown to be cost effective. Using resource utilisation costs derived from an economic evaluation of MS in the UK, it was possible to calculate the impact of delaying disease progression in terms of both health service and societal costs. An estimate of mean disease progression in patients with MS treated with IFN beta-1a compared with patients who did not receive disease-modifying agents suggested that significant cost savings would be realised after about 12 years' treatment with IFN beta-1a. The application of utility scores to the disease progression curves also facilitated estimates of cost effectiveness, with cost per QALY values ranging from 27,036 Pounds after 2 years' treatment with IFN beta-1a to 37,845 Pounds after 20 years' treatment (1995 values).

Long-term treatment of multiple sclerosis with azathioprine.

Nineteen patients with multiple sclerosis were treated with azathioprine for two years. There was no evidence that treatment prevented deterioration or reduced the number or severity of the relapses when compared with 24 control patients observed over the same period.