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Biomedical subjects

Mark S Freedman

Publications and source records attributed to Mark S Freedman.

15 recordsLinked to original sources
PubMed2026

Long-term safety and efficacy of ponesimod, an oral S1P1 receptor modulator, in relapsing-remitting multiple sclerosis (RRMS): Results from randomized phase 2b core and extension studies spanning up to 13 years.

BACKGROUND: Ponesimod demonstrated efficacy and safety in relapsing-remitting multiple sclerosis (RRMS) in 24-week phase-2 core study, further confirmed by an interim combined analysis of the core and open-label long-term extension (LTE) studies (NCT01093326; up to 8 years). Current study evaluated safety and efficacy of ponesimod using combined core and LTE studies data for up to 13 years. METHODS: Of 393 participants completing the core study, 353 (90%) entered LTE, having 3 treatment periods (TP). In TP1 (∼1.85 years), participants continued core treatment (ponesimod: 10, 20, or 40 mg QD) whereas placebo-treated participants were re-randomized (1:1:1) to respective ponesimod doses. In TP2 (TP2 and TP3 combined duration: ∼10.4 years), participants on 40 mg were re-randomized (1:1) to 10/20 mg, while others continued same dose; in TP3 all participants received 20 mg. Study outcomes included safety and efficacy (ARR, time-to 24-week confirmed-disability-accumulation [24-week CDA], total T1-weighted Gadolinium-enhanced (T1 Gd+) lesions, new/enlarging T2 lesions and Combined Unique Active Lesions [CUALs]). RESULTS: For 20 mg dose, total 92.4% participants experienced ≥1 TEAEs (73.1% mild/moderate severity) and 19 (13%) participants discontinued study. Mean (95% CI) ARR=0.14 (0.10-0.20); Kaplan-Meier estimate (95% CI) of confirmed relapse and 24-week CDA=52.5% (42.3-63.5) and 31.3% (22.6-42.3). Mean [SD] T1 Gd+ lesions decreased from ponesimod baseline (2.62 [7.06]) to 12.4 years (0.26 [1.48]), mean (95% CI) CUALs per participant/year=3.97 (2.75-5.73). CONCLUSION: Ponesimod treatment for up to 13 years was not associated with new safety concerns. Participants continued to experience low levels of disease activity consistently across clinical and MRI outcomes.

Humans↗
PubMed2006

Quantifying axonal loss after optic neuritis with optical coherence tomography.

OBJECTIVE: To determine to what degree changes in retinal nerve fiber layer (RNFL) thickness after optic neuritis (ON) correlate with either visual recovery or impairment. METHODS: ON can cause visible defects within the RNFL, which can be quantified using optical coherence tomography (OCT). It may be possible to predict visual recovery by measuring RNFL loss after ON. Fifty-four patients underwent repeated evaluations with optical coherence tomography and standardized ophthalmic testing after ON. Regression analyses were used to determine the relationship between RNFL thickness and visual function. RESULTS: Thinning of the RNFL was seen in the majority of patients (74%), and it tended to occur within 3 to 6 months of ON. The average RNFL value was thinner (p<0.0001) in the affected (78 microm) compared with the unaffected eye (100 microm). Patients with incomplete visual recovery demonstrated greater RNFL loss after ON. Regression analyses demonstrated a threshold of RNFL thickness (75 microm), below which RNFL measurements predicted persistent visual dysfunction. INTERPRETATION: Determination of RNFL thickness may predict visual recovery after ON, and lower RNFL values correlate with impaired visual function. Optical coherence tomography may have a potential role as a surrogate marker for axonal integrity within the optic nerve among patients with ON.

Adolescent↗
PubMed2006

Disease-modifying drugs for multiple sclerosis: current and future aspects.

Multiple sclerosis (MS) is the most common inflammatory demyelinating disorder of the human CNS, affecting an estimated 2.5 million people in the world. Until the 1990s, treatment was mainly symptomatic, but a new era began with the introduction of disease-modifying therapy that seems to alter the natural course of MS. Current drugs include three interferons (IFNs): IFN-beta1a (Avonex intramuscular; Biogen, Cambridge, USA; Rebif subcutaneous; Serono, Geneva, Switzerland), IFN-beta1b (Betaseron subcutaneous; Schering, Berlin, Germany) and glatiramer acetate (Copaxone subcutaneous; Teva, Petach Tikva, Israel). Ongoing research targeting a variety of mechanisms and processes means there is much promise for the future treatment of MS.

Animals↗
PubMed2005

Recommended standard of cerebrospinal fluid analysis in the diagnosis of multiple sclerosis: a consensus statement.

New criteria for the diagnosis of multiple sclerosis (MS) were published as the result of an internationally formed committee. To increase the specificity of diagnosis and to minimize the number of false diagnoses, the committee recommended the use of both clinical and paraclinical criteria, the latter involving information obtained from magnetic resonance imaging, evoked potentials, and cerebrospinal fluid (CSF) analysis. Although rigorous magnetic resonance imaging requirements were provided, the "new criteria paper" fell short in terms of guidelines as to how the CSF analysis should be performed and simply equated the IgG index with isoelectric focusing, without any justification. The spectrum of parameters analyzed and methods for CSF analysis differ worldwide and often yield variable results in terms of sensitivity, specificity, accuracy, and reliability, with no decided "optimal" CSF test for the diagnosis of MS. To address this question specifically, an international panel of experts in MS and CSF diagnostic techniques was convened and the result was this article, representing a consensus of all the participants. These recommendations for establishing a standard for the evaluation of CSF in patients suspected of having MS should greatly complement the new criteria in ensuring that a correct diagnosis of MS is being made.

Consensus Statements as Topic↗
PubMed2005

Discrepancies in the interpretation of clinical symptoms and signs in the diagnosis of multiple sclerosis. A proposal for standardization.

The new McDonald diagnostic criteria for multiple sclerosis (MS) incorporate detailed criteria for the interpretation and classification of magnetic resonance imaging (MRI) findings, but, in contrast, provide no instructions for the interpretation of clinical findings. Because MS according to the McDonald criteria is one of the primary endpoints in a large trial enrolling patients after the first manifestation suggestive for a demyelinating disease (BENEFIT study), it was decided to organize a centralized eligibility assessment for this trial. During this eligibility assessment it was observed that there were marked inconsistencies in the decisions of participating neurologists with respect to the classification of clinical symptoms as being caused by one or more lesions provoking discussions in about one in every five patients. This paper describes these inconsistencies and their sources, and recommends a systematic approach that attempts to reduce the variability in interpreting clinical findings.

Adolescent↗
PubMed2005

HIV risks and testing behavior among Asians and Pacific Islanders: results of the HIV Testing Survey, 2002-2003.

INTRODUCTION: The HIV Testing Survey (HITS) was developed to examine HIV testing and risk behavior in individuals at risk for HIV infection. The first Seattle HITS was conducted in 2000 (HITS-2000); HITS was conducted in Seattle again in 2002-2003 among Asians and Pacific Islanders (HITS-API). METHODS: Both HITS projects, HITS-API and HITS-2000, included anonymously targeted participants from at-risk populations. Data from the surveys were compared to see whether there were differences in HIV testing behavior between API and a general at-risk population in the Seattle area. Data were analyzed for 165 participants in HITS-API and 270 in HITS-2000. RESULTS: More API (90%) perceived themselves at some HIV risk relative to HITS-2000 participants (71%, chi2 p<0.05). In HITS-API and HITS-2000, participants reported significant HIV risks--no or inconsistent condom use with nonprimary partners or sharing injection equipment. Only 47% of HITS-API participants tested in the past year compared with 64% of HITS-2000. There was no association between HIV testing and risks in HITS-API. CONCLUSIONS: Based on self-report from HITS-API, the overall perceived risk for HIV infection was high, many engaged in high-risk behaviors, and HIV testing was suboptimal.

AIDS Serodiagnosis↗
PubMed2004

A multicenter, open-label, phase II study of the immunogenicity and safety of a new prefilled syringe (liquid) formulation of Avonex in patients with multiple sclerosis.

BACKGROUND: A new liquid formulation of Avonex (interferon beta-1a [IFNbeta-1a]) in a prefilled syringe has been developed to make administration of the drug easier for patients with multiple sclerosis (MS). This formulation does not contain human serum albumin (HSA), often added to interferon (IFN) products for stabilization. However, formulation changes may alter the secondary, tertiary, and quaternary structures of IFNbeta products. These kinds of structural changes could lead to the formation of antibodies directed against IFNbeta. Some of these anti-IFN antibodies may neutralize the biologic activity of IFNbeta. OBJECTIVE: This study was designed to determine the immunogenicity and safety of the new prefilled syringe (liquid) HSA-free formulation of Avonex in patients with relapsing MS. METHODS: This was a multicenter, single-arm, open-label study. Patients with relapsing MS received liquid, HSA-free Avonex 30 microg by IM injection from a prefilled syringe once weekly for up to 24 months. Immunogenicity and safety were assessed every 3 months. Serum levels of neutralizing antibodies (NAbs) were measured at baseline and every 3 months using a 2-step enzyme-linked immunosorbent assay and antiviral cytopathic effect assay. RESULTS: A total of 153 patients (121 women, 32 men; mean [SD] age, 39.6 [9.9] years; age range, 19.0-59.0 years) were enrolled in the study. Sera were available for analysis from 125 and 119 patients after 18 and 24 months of treatment, respectively. By 18 months, 1 patient (1%) had > or =2 consecutive titers of > or =20, a level at which the persistent presence of NAbs has been shown in some studies to have clinical consequences. By 24 months, 1 additional patient (total 2%) had > or =2 consecutive titers of > or =20. At 18 months, 5 patients (4%) had > or =1 NAb titer of > or =5; at 24 months, 6 patients (5%) had > or =1 NAb titer of > or =5. The safety profile of liquid Avonex was comparable to the lyophilized form containing HSA. CONCLUSIONS: The prefilled syringe (liquid) HSA-free formulation of Avonex was well tolerated and showed a low level of immunogenicity. Over 24 months, 2% of patients developed persistent NAbs (> or =2 consecutive titers of > or =20).

Adjuvants, Immunologic↗
PubMed2004

Treatment optimization in multiple sclerosis.

The treatment of multiple sclerosis has finally become possible with the advent of the current disease-modifying therapies (DMTs) that have had a significant impact on those living with this disease. Though demonstrating clear efficacy on a number of short-term outcome measures, unfortunately, these agents are not "cures" and many patients with multiple sclerosis continue to experience disease activity in spite of treatment. Clinicians are becoming more comfortable initiating therapy with DMTs, but it is now important to focus attention on monitoring the results of the chosen therapy and deciding whether or not a patient is responding well to treatment. At present, however, clinicians lack criteria for defining optimal versus suboptimal responses to DMTs as well as evidence-based guidelines on how to improve treatment outcomes. Using a recently published model as a framework, The Canadian Multiple Sclerosis Working Group developed practical recommendations on how neurologists can assess the status of patients on DMTs and decide when it may be necessary to modify treatment in order to optimize outcomes. The Canadian Multiple Sclerosis Working Group's recommendations are based on monitoring relapses, neurological progression and MRI activity. Other possible causes of suboptimal treatment responses or treatment failure are also considered.

Decision Support Techniques↗
PubMed2004

Primary progressive multiple sclerosis: cerebrospinal fluid considerations.

Diagnosing the 'primary progressive' form of multiple sclerosis (PPMS) requires assurance that other conditions that might cause a chronic inflammatory neurodegenerative central nervous system (CNS) disease have been ruled out. Both imaging and pathological studies have shown that this form of MS tends to be less inflammatory compared with either the relapsing-remitting or secondary progressive types. There are therefore many conditions that cause a slowly progressive wasting of the CNS that might be confused with MS. The new MS diagnostic scheme has made the presence of 'typical' MS abnormalities in the cerebrospinal fluid (CSF) a mandatory first criterion, but there may well be individuals that still have PPMS even in the absence of a typical MS CSF. Here we explore what the CSF can tell about an individual's disease process and outline the current state of the art in terms of CSF analysis. Used properly, the CSF can be very helpful in clarifying a diagnosis of PPMS.

Cerebrospinal Fluid↗
PubMed2003

Study of Herpesvirus saimiri immortalization of gammadelta T cells derived from peripheral blood and CSF of multiple sclerosis patients.

Human gammadelta T cells are an integral part of the innate immune system and have been difficult to study owing primarily to their relatively low abundance and their fastidious culture properties associated with short in vitro lifespan. Their increased presence within multiple sclerosis (MS) white matter plaques compared to peripheral blood (PB) suggests a specific interaction with central nervous system (CNS) tissues. This fact, together with their innate ability to lyse human oligodendrocytes in culture implicate them possibly in the pathogenesis of MS. To further investigate their potential role in MS, we studied whether gammadelta T cells could be effectively immortalized using Herpesvirus saimiri (HVS), so that they could be studied in longer-term cultures. Effective culture conditions were established resulting in efficient HVS growth transformation of multiple PB and CSF gammadelta T cell lines and clones that could exist in IL-2-dependent culture for periods in excess of 2 years. Phenotypic and functional comparison studies with parental nontransformed gammadelta T cells were performed to characterize the changes that possibly induced by viral transformation. Using panels of transformed gammadelta T cell clones representing discrete gammadelta TcR subtypes, there was no apparent correlation between intracytoplasmic cytokine expression or tumor cell cytotoxicity with a specific TcR. All transformed gammadelta T cells analyzed, regardless of their compartment of origin, strongly expressed intracytoplasmic IFN-gamma and TNF-alpha, but little IL-2 or anti-inflammatory IL-4 or IL-10. These results indicate that HVS transformation of gammadelta T cells can be used to generate lines and clones from both the CSF and PB compartments for further study and elucidation of their potential role in MS pathogenesis.

Cell Culture Techniques↗
PubMed2003

Monocyte-derived IL12, CD86 (B7-2) and CD40L expression in relapsing and progressive multiple sclerosis.

Multiple sclerosis has been postulated to be an autoimmune disease in which Th1 immune responses predominate. This response is associated with an increased production of IFNgamma and IL12 produced by T cells and by cells of the monocyte (MO) lineage, respectively. An increased expression of costimulatory molecules by T cells and antigen-presenting cells is also observed. We hypothesized that in relapsing-remitting MS (RRMS) (with or without of IFNbeta treatment) and in secondary progressive patients (SPMS) IL12 and costimulatory molecules (CD80 [B7-1], CD86 [B7-2], CD28, CD40, CD40L) would be differentially produced or expressed by MO or T cells. We performed cross-sectional and longitudinal flow cytometric studies (at monthly intervals) on peripheral blood mononuclear cells (PBMC) or on MO from SPMS or untreated and IFNbeta-treated patients with RRMS. We determined that CD86 and CD40L expression was highest on MO derived from SPMS patients compared to those from RRMS or from healthy controls (HC). In vitro culture of PBMC with recombinant human IL10, a cytokine that may be increased in response to treatment with IFNbeta and that down-regulates CD86 expression, reduced the expression of CD86 on MO derived from RRMS patients to a much higher degree compared to cells derived from SPMS or HC. In vitro secreted IL12 levels from freshly isolated MO from SPMS patients were more than 10-fold higher than either the treated or the untreated RRMS or HC. RRMS patients treated with IFNbeta demonstrated slightly lower levels of MO IL12 secretion. Our data suggest that a key mechanism in the pathogenesis of MS is the increased expression of CD86 and CD40L and the increased production of IL12 during disease progression. Part of the mechanism of action of IFNbeta may be to reduce MO CD86 and CD40L expression and IL12 secretion; failure to do so might signify either a lack of response or a transition to a more progressive phase of illness.

Adjuvants, Immunologic↗
PubMed2003

Acute disseminated encephalomyelitis associated with Pasteurella multocida meningitis.

OBJECTIVE: To describe a case of Pasteurella multocida meningitis associated with acute disseminated encephalomyelitis (ADEM). CASE REPORT: A 33-year-old woman employed in a dog pound presented herself to hospital with fever and meningismus and was found to have culture positive Pasteurella multocida meningitis. Despite appropriate antibiotic treatment her clinical course was characterized by a persistent fever and worsening encephalopathy, which prompted further neurological investigation. Spinal fluid exam and serial MRI scans as well as her one-year clinical course were found to be compatible with ADEM. CONCLUSION: Persistent fever and worsening encephalopathy in meningitis may indicate a para-infectious immune process such as ADEM, and may serve as indications for further neurological investigation.

Acute Disease↗
PubMed2002

gamma/delta T cells in multiple sclerosis: chemokine and chemokine receptor expression.

gamma/delta T cells are enriched in multiple sclerosis (MS) brain lesions and have been postulated to contribute to the pathogenesis of the disease. Increased expression of the chemokine receptors CCR5 and CXCR3 on T cells and raised amounts of the chemokines RANTES and IP-10 have been noted in the CSF and brain tissue of MS patients, but the contribution of gamma delta T cells to these increases is unknown. We therefore compared intracellular RANTES and IP-10 production as well as CCR5, CXCR3, and CXCR1 expression by gamma delta T cells derived from the blood and CSF of patients with MS and healthy controls (HC). We observed higher RANTES production by MS gamma delta than by alpha beta T cell lines. Most of the MS as well as the HC gamma delta and alpha beta T cell lines expressed CXCR3, while expression of CXCR1 was low. Interestingly, MS gamma delta T cell lines, compared to lines from HC, expressed lower levels of CCR5. Furthermore, CSF-derived gamma delta T cells had even lower CCR5 expression than blood-derived ones. The higher RANTES production by MS gamma delta T cell lines, together with a lower expression of CCR5, may reflect an autoregulatory loop, caused by an increased production of its ligands (RANTES, MIP-1 alpha, and MIP-1 beta) or due to other pro-inflammatory cytokines. Alternatively, we show that lower CCR5 expression could also reflect the result of repeated in vivo stimulation of gamma delta T cells by autoantigens.

Adult↗