A novel assay to detect low-titred antibodies to interferon beta in multiple sclerosis patients

Neutralizing antibodies (NAbs) may compromise interferon (IFN) clinical efficacy in patients with multiple sclerosis (MS) receiving IFN-beta treatment. When bioassays are used for anti-IFN-beta antibody detection, they are unable to discriminate between NAbs or other interfering substances with anti-IFN activity. Here we report the development of an anti-IFN-beta Western blot method that facilitates the detection of IFN low-titred antibodies and characterizes such low neutralizing activity as specifically due to the presence of particular IFN antibodies. The assay was characterized using serum samples from patients with MS treated with IFN-beta. It was developed by adding anti-IFN-positive antibody sera to Dynabeads M-280 tosylactivated followed by Western blot analysis. All sera samples from MS patients with IFN-betala NAbs (< or = 50 t1/10) proved to be antibody-positive using this new method and, more importantly, four of 27 binding antibody-negative sera samples were scored as IFN antibody-positive. The method was found to be rapid, specific and sensitive and consistent with respect to well-established antiviral neutralization or commercial enzyme-linked immunosorbent assays.     

Modelling the cost effectiveness of interferon beta and glatiramer acetate in the management of multiple sclerosis

ObjectiveTo evaluate the cost effectiveness of four disease modifying treatments (interferon betas and glatiramer acetate) for relapsing remitting and secondary progressive multiple sclerosis in the United Kingdom.DesignModelling cost effectiveness.SettingUK NHS.ParticipantsPatients with relapsing remitting multiple sclerosis and secondary progressive multiple sclerosis.ResultsThe base case cost per quality adjusted life year gained by using any of the four treatments ranged from £42 000 ($66 469; €61 630) to £98 000 based on efficacy information in the public domain. Uncertainty analysis suggests that the probability of any of these treatments having a cost effectiveness better than £20 000 at 20 years is below 20%. The key determinants of cost effectiveness were the time horizon, the progression of patients after stopping treatment, differential discount rates, and the price of the treatments.ConclusionsCost effectiveness varied markedly between the interventions. Uncertainty around point estimates was substantial. This uncertainty could be reduced by conducting research on the true magnitude of the effect of these drugs, the progression of patients after stopping treatment, the costs of care, and the quality of life of the patients. Price was the key modifiable determinant of the cost effectiveness of these treatments.

What is already known on this topic

Interferon beta and glatiramer acetate are the only disease modifying therapies used to treat multiple sclerosisEconomic evaluations of these drugs have had flaws in the specification of the course of the disease, efficacy, duration of treatment, mortality, and the analysis of uncertaintyNone of the existing estimates of cost effectiveness can be viewed as robust

What this study adds

The cost per quality adjusted life year gained is unlikely to be less than £40 000 for interferon beta or glatiramer acetateExperience after stopping treatment is a key determinant of the cost effectiveness of these therapiesKey factors affecting point estimates of cost effectiveness are the cost of interferon beta and glatiramer acetate, the effect of these therapies on disease progression, and the time horizon evaluated     

A role for the interferon system in the pathogenesis of multiple sclerosis?

MS may be caused by an as yet unidentified virus whose life-long persistence in the body may deregulate the immune system so as to make it react against central nervous system tissue. Interferon are endogenous, hormone-like proteins with antiviral and immunomodulatory properties. This paper analyses current knowledge on the production and action of these proteins in the perspective of their possible involvement in the pathogenesis of MS. It also reviews observations made sofar on interferon production and action in MS patients.     

Human T-cell receptor V beta gene polymorphism and multiple sclerosis.

Population-based genetic associations have been reported between RFLPs detected with probes corresponding to the genes encoding the beta chain of the T-cell receptor for antigen (TCRB) and a variety of autoimmune disorders. In the case of multiple sclerosis (MS), these studies have localized a putative disease-associated gene to a region of approximately 110 kb in length, located within the TCRB locus. In the current study, all 14 known TCRBV (variable region) genes within the region of localization were mapped and identified. The nucleotide sequences of these genes were determined in a panel of six MS patients and six healthy controls, who were human-leukocyte antigen and TCRB-RFLP haplotype matched. Nine of the 14 TCRBV genes studied showed evidence of polymorphism. PCR-based assays for each of these polymorphic genes were developed, and allele and genotype frequencies were determined in a panel of DNA samples from 48 MS patients and 60 control individuals. No significant differences in allele, genotype, or phenotype frequencies were observed between the MS patients and controls for any of the 14 TCRBV-gene polymorphisms studied. In light of the extensive linkage disequilibrium across the region studied, the saturating numbers of polymorphisms examined, and the direct sequence analysis of all BV genes in the region, these results suggest that it is unlikely that germ-line polymorphism in the TCRBV locus makes a major contribution to MS susceptibility.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cytotoxic activity and interferon production by lymphocytes from patients with multiple sclerosis

Peripheral blood lymphocytes from MS patients and from healthy control donors were compared for their ability to mediate spontaneous and antibody-dependent cell-mediated cytotoxicity. They were also compared for their ability to respond to infection with various strains of measles and sSPE viruses with interferon production and enhanced NK activity. Neither SLMC nor ADCC against several different target cells was found to be impaired in the MS population. Furthermore, no defect was detected in the response of patients' lymphocytes to virus challenge in vitro in terms of both activation of NK cells and interferon production. Enhanced NK activity was also induced by an exogenous interferon preparation and by Poly I:C to the same extent in patients and controls.     

Glatiramer in the treatment of multiple sclerosis

Multiple sclerosis (MS) is a disease of the central nervous system with both an inflammatory and degenerative component. The disease primarily affects young adults and results in significant physical and cognitive disability. Several disease-modifying agents are currently used in the management of multiple sclerosis. Glatiramer acetate (GA, Copaxone, co-polymer 1) is a disease-modifying agent approved for the treatment of relapsing remitting multiple sclerosis. Apart from its unique mode of action, there is evidence pointing toward a possible neuroprotective role. This review will critically discuss GA's potential mechanisms of action, the results of clinical trials, safety profile, and future directions of treatment.     

Role of steroids and immunosuppression and effects of interferon beta-1b in multiple sclerosis.

Corticosteroids, corticotropin, azathioprine, cyclophosphamide, and IFN-beta 1b have each had a substantial effect on the care of patients with multiple sclerosis and the design of subsequent clinical trials of experimental therapeutics for MS. The use of MRI scanning and more sensitive clinical outcome measures will possibly enable us to complete clinical trials in a fraction of the time required for earlier trials. The release of Betaseron, which favorably alters the attack rate in ambulatory patients with relapsing-remitting MS has brought a sense of renewed optimism to patients with MS, their families, and their care providers. New promising therapies for chronic progressive MS and biologic products possibly capable of enhancing the effects of IFN-beta 1b in patients with relapsing MS are setting the stage for additional important therapeutic advances in this disease.     

Polyunsaturated fatty acids in treatment of acute remitting multiple sclerosis.

One hundred and sixteen patients with acute remitting multiple sclerosis (MS) took part in a double-blind controlled trial of treatment with polyunsaturated fatty acids and were randomly allocated to one of four groups. Two groups received linoleic acid, one alone as a spread and one with gamma-linolenic acid in capsules (Naudicelle); and two control groups received oleic acid, one as a spread and one in capsules. Rates of clinical deterioration and frequencies of attacks were not significantly different between treated and control groups. Exacerbations were shorter and less severe in patients receiving a high dose of linoleic acid than in controls, but those receiving a lower dose--that is, Naudicelle--showed no such difference. Thus supplementing the diet with 20 g linoleic acid marginally affected the duration and severity of relapses of MS but had no effect on overall disability. The dose of Naudicelle used provided insufficient supplementation.