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Biomedical subjects

B Weinstock-Guttman

Publications and source records attributed to B Weinstock-Guttman.

29 records · Page 2Linked to original sources
PubMed2000

What is new in the treatment of multiple sclerosis?

Multiple sclerosis (MS) is considered an autoimmune disease associated with immune activity directed against central nervous system antigens. Based on this concept, immunosuppression and immunomodualtion have been the mainstays of therapeutic strategies in MS. During the last decade new therapies have been shown to significantly improve MS disease course. The effective therapies have led to a better understanding of MS pathogenesis and further development of even more efficient therapeutic interventions. Recombinant interferon (IFN)beta represents the first breakthrough in MS therapy. Three large placebo-controlled, double-blind studies and several smaller studies have demonstrated the efficacy of different forms of IFNbeta administrated by either subcutaneous or intramuscular routes and at different doses in patients with active relapsing-remitting multiple sclerosis (RR-MS). The three IFNbeta drugs are IFNbeta-1b and two IFNbeta-1a preparations (Avonex and Rebif). Although each clinical trial had unique features and differences that make direct comparisons difficult, the aggregate results demonstrate a clear benefit of IFNbeta for decreasing relapses and probability of sustained clinical disability progression in patients with RR-MS. All forms of IFNbeta therapy had beneficial effects on the disease process measured by brain magnetic resonance imaging (MRI). IFNbeta-1a (Avonex) also showed benefit in slowing or preventing the development of MS related brain atrophy measured by MRI after 2 years of therapy. Glatiramer acetate, the acetate salt of a mixture synthetic polypeptides thought to mimic the myelin basic protein showed a significant positive results in reducing the relapse rate in patients with RR-MS. Follow up of these patients for approximately 3 years continued to show a beneficial effect on disease relapse rate. Recent MRI data supported the beneficial clinical results seen with glatiramer acetate in patients with RR-MS. Recent studies using intravenous immune globulin (IVIG) suggest that IVIG could be effective to some degree in patients with RR-MS. However, there is not enough evidence that IVIG is equivalent to IFNbeta or glatiramer acetate in the treatment of patients with RR-MS. There have also been recent therapeutical advances in secondary progressive MS (SP-MS). A recent large phase II, placebo-controlled study with IFNbeta-1b in patients with SP-MS convincingly documented that IFNbeta-1b slowed progression of the disease independent of the degree of the clinical disability at the time of treatment initiation and independent of presence of superimposed relapses. Mitoxantrone, an anthracenedione synthetic agent, was also shown to be effective as treatment for active SP-MS. It is well tolerated but the duration of treatment is limited by cumulative cardiotoxicity. There is a growing consensus that disease-modifying therapies should be initiated early in the course of the disease before irreversible clinical disability has developed. Different therapies should be considered and tailored based on patient condition. Combination therapies could be considered as a therapeutic option for patients that failed therapies with IFNbeta and/or glatiramer acetate. Currently, there are new ongoing studies testing safety and/or efficacy of different combination regimens (i.e. azathioprine with IFNbeta, IFNbeta with glatiramer acetate, or pulses of intravenous cyclophosphamide with IFNbeta). Determining the effect of different therapies on the course of the disease within large clinical studies appears easier than determining individual responsiveness. Therefore, standardised methods for evaluating individual patients receiving disease-modifying therapies and development of effective therapeutic algorithms are needed.

Adjuvants, Immunologic↗
PubMed2000

Detection of cytochrome P450 and other drug-metabolizing enzyme mRNAs in peripheral blood mononuclear cells using DNA arrays.

The purpose of this study was to determine whether the expression of cytochrome P450 (CYP) enzyme mRNAs, other drug-metabolizing enzyme mRNAs, and transporter mRNAs can be detected using DNA arrays. Total RNA was isolated from peripheral blood mononuclear cells of 10 multiple sclerosis patients and 10 age- and sex-matched controls. The mRNA was reverse transcribed to radiolabeled cDNA, and the resultant cDNA was used to probe a DNA array containing several thousand known human genes. The signals corresponding to several CYPs, drug-metabolizing, and transporter mRNAs was substantially above background. The results demonstrate that the DNA array technique has the sensitivity and the selectivity for applications in the pharmaceutical sciences. The mean values for mRNAs of specific CYPs and drug-metabolizing enzymes in peripheral blood cells were compared with reported values for liver. The capabilities of DNA arrays may prove useful for characterizing CYP expression in a variety of clinical samples.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

HLA-DP: a class II restriction molecule involved in epitope spreading during the development of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. It is widely believed that complex polygenic inheritance patterns involving HLA-DR and -DQ class II genes contribute to MS susceptibility, and current evidence indicates that disease risk vs disease outcome may be associated with distinctly different HLA class II alleles. We have recently shown that the early development of MS is accompanied by an extensive plasticity of myelin self-recognition with the acquisition of neo-autoreactivity, or epitope spreading, as a prominent feature. Although we did not observe a common determinant recognized by patients sharing identical HLA-DR or -DQ class II alleles, we did observe epitope spreading to the p50-63 determinant of myelin proteolipid protein (PLP) in two study subjects showing complete disparity at HLA-DR and -DQ but identity at the HLA-DP allele DPB1*0301. In the present study we show that self-recognition during the early stages in the development of MS involves HLA-DP class II restricted responses to the PLP 50-63 spreading determinant. Our results suggest that self-presentation by HLA-DP may play an important role in epitope spreading and in the propagation of self-recognition during the clinical progression of MS.

Adult↗
PubMed1998

The epitope spreading cascade during progression of experimental autoimmune encephalomyelitis and multiple sclerosis.

We have made the following observations regarding self-recognition during the development and progression of murine experimental autoimmune encephalomyelitis (EAE) and human multiple sclerosis (MS): 1) chronic progression of EAE is accompanied by a sequential, predictable cascade of neo-autoreactivity, commonly referred to as epitope spreading, presumably caused by endogenous self-priming during autoimmune-mediated tissue damage; 2) there is an invariant relationship between the progression of EAE and the emergence of epitope spreading; 3) progression of EAE can be inhibited by the induction of antigen-specific tolerance to spreading determinants after onset of initial neurologic symptoms; 4) CD4+ Th 1 cells responding to spreading determinants are autonomously encephalitogenic; 5) epitope spreading occurs during the development of MS and in some cases involves HLA-DP class II-restricted self-recognition; and 6) progression of both EAE and MS is accompanied by the decline of primary T-cell autoreactivity associated with disease onset and by the concurrent emergence of the epitope spreading cascade. Our studies directly challenge the traditional view that EAE and MS are initiated and maintained by autoreactivity directed against a single predominant myelin protein or determinant. Our results indicate that progression of EAE and MS involves a shifting of T-cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during disease progression.

Animals↗
PubMed1998

Incidence and significance of neutralizing antibodies to interferon beta-1a in multiple sclerosis. Multiple Sclerosis Collaborative Research Group (MSCRG)

BACKGROUND: Interferon beta is an effective treatment for relapsing multiple sclerosis (MS). As with other protein drugs, neutralizing antibodies (NAB) can develop that reduce the effectiveness of treatment. OBJECTIVES: To determine the incidence and biological significance of NAB to interferon beta-la (IFN-beta-1a; Avonex; Biogen, Cambridge, MA) in MS patients. METHODS: A two-step assay for NAB to IFN-beta-1a was developed and used to assay serum samples from participants in the phase III clinical trial of IFN-beta-1a, and from patients in an ongoing open-label study of IFN-beta-1a. The biological significance of NAB to IFN-beta-1a was determined by relating the NAB assay result to in vivo induction of the IFN-inducible molecules neopterin and beta-2 microglobulin, and the clinical significance was determined by comparing clinical and MRI measures of disease activity after 2 years of IFN-beta-1a therapy in patients who were NAB+ and NAB-. The incidence of NAB was compared in MS patients who had used only IFN-beta-1a with the incidence in MS patients who had used only IFN-beta-1b. RESULTS: In patients in the open-label study, development of NAB to IFN-beta-1a resulted in a titer-dependent reduction in neopterin induction after interferon injections. In patients in the phase III study, development of NAB was associated with a reduction in beta-2 microglobulin induction. In the phase III study, a trend toward reduced benefit of IFN-beta-1a on MRI activity in NAB+ versus NAB- patients was observed. The incidence of NAB to IFN-beta-1a in the open-label study was approximately 5% over 24 months of treatment of IFN-beta-1a therapy, but was four- to sixfold higher using the same assay for patients exposed only to IFN-beta-1b for a similar duration. There were no clinical, MRI, or CSF characteristics that were predictive of which patients would develop NAB. CONCLUSIONS: NAB directed against IFN-beta have in vivo biological consequences in patients with MS. The frequency with which MS patients develop NAB against IFN-beta is significantly greater with IFN-beta-1b therapy compared with IFN-beta-1a therapy. Treatment decisions in MS patients treated with IFN-beta should take into account development of NAB.

Adolescent↗
PubMed1998

A phase II study of i.v. methylprednisolone in secondary-progressive multiple sclerosis.

OBJECTIVE: To compare the tolerability and efficacy of two doses of i.v. methylprednisolone in patients with secondary-progressive MS. METHODS: I.v. methylprednisolone administered in high or low dose every other month for up to 2 years to 108 patients with secondary-progressive MS. RESULTS: No significant difference in efficacy with the primary outcome, a comparison of the proportions of patients in each treatment group who experienced sustained progression of disability. A relative treatment effect was detected with the high-dose regimen as measured by the preplanned secondary analysis, a comparison of time to onset of sustained progression of disability. Drug-related adverse events were observed more frequently in high-dose recipients but serious drug-related adverse events were uncommon, and cessation of study drug was only required in one patient. CONCLUSION: The results of the secondary analysis of this study suggest that a phase III trial of corticosteroids for secondary-progressive MS is warranted.

Adult↗
PubMed1997

Diversity and plasticity of self recognition during the development of multiple sclerosis.

Recent studies using murine animal model systems indicate that clinical progression of autoimmune disease may be due to the sequential accumulation of neoautoreactivity characterized by extensive plasticity of self recognition. In the present study, we addressed the question of whether a similar paradigm of self recognition is implicated in the development of multiple sclerosis (MS), a demyelinating disease with a presumed autoimmune etiology. Our approach was to determine serial changes over a 12-18-mo period in response to an epitope-mapping series of 265 12-mer peptides of myelin proteolipid protein (PLP) by patients with isolated monosymptomatic demyelinating syndromes (IMDS), a group of distinct clinical disorders with variable rates of progression to MS. Our data showed that an extensive array of proteolipid protein peptides could elicit autoreactivity. Moreover, differential autoreactive patterns were evident within IMDS patient subpopulations. Monocentric monophasic IMDS patients with no evidence of prior subclinical disease typically showed fully sustained autoreactivity characterized by extensive plasticity, epitope focusing, shifting, and spreading of responses to new self determinants. In contrast, multicentric monophasic IMDS patients with putative evidence of prior asymptomatic lesion formation typically showed partially sustained autoreactivity characterized by abrupt abrogation of responses to an extensive array of self determinants. No sustained autoreactivity was observed in normal control subjects or in patients with other neurologic diseases. Our results indicate that self recognition associated with the development of MS is a developmental process characterized by autoreactive diversity, plasticity, and instability.

Adult↗
PubMed1996

Newer versus older treatments for relapsing-remitting multiple sclerosis.

Multiple sclerosis (MS) is a chronic disease with an unpredictable clinical course and several distinct clinical patterns. Recent developments in immunology, molecular biology and genetics have improved our understanding of the pathophysiology of MS. Further, advances in trial methodology, including the availability of magnetic resonance imaging (MRI) as a surrogate outcome measure, have led to the identification of several new therapeutic options for relapsing-remitting (RR) MS. These therapies include corticosteroids, recombinant interferon-beta-1b (rIFN beta-1b), recombinant interferon-beta-1a (rIFN beta-1a) and copolymer-1 (Cop-1). Corticosteroids have been shown to accelerate the recovery from acute exacerbations, but there are still conflicting data on their effect on outcome and long term course. rIFN beta-1b, rIFN beta-1a and Cop-1 all effectively alter the natural history of RR-MS. These 3 agents all decrease the relapse rate by approximately one-third, but differ in their adverse effect profiles and administration regimens. Further trials are required to define the optimal treatment of RR-MS.

Adjuvants, Immunologic↗
PubMedDate not supplied

Unusual long-standing Gd-DTPA enhancement in a chronic progressive myelopathy.

Chronic spinal syndromes without evidence of cord compression often represent a real diagnostic challenge. We report a case of chronic progressive myelopathy with an unusual long-standing gadolinium-diethylenetriamine pentaacetic acid (Magnevist, Berlex Laboratories) enhanced spinal cord lesion demonstrated on MRI, through a 14 month follow-up period. In the context of continuous neurological decline the patient underwent two biopsies at 1 year intervals. The final diagnosis was obtained only after the second biopsy, which demonstrated a demyelinating plaque with reactive astrocytosis. The clinical condition of our patient has been stable for 5 years. A repeated workup including MRI of the cervical and thoracic spine demonstrated a mildly atrophic cord in the upper thoracic region, with no evidence of pathological signal or enhancement at this time. Brain MRI and visual evoked potentials were normal. This case provides interesting clinical, pathological, and MRI correlations in a longitudinal follow-up of a spinal demyelinating lesion.

Adult↗