Latest Multiple Sclerosis therapy articles

December 2007 archive:-

Delayed allergic reaction to natalizumab associated with early formation of neutralizing antibodies. Related Articles Latest multiple sclerosis therapy articles

Delayed allergic reaction to natalizumab associated with early formation of neutralizing antibodies.

Arch Neurol. 2007 Sep;64(9):1331-3

Authors: Latest multiple sclerosis therapy articles Krumbholz M, Pellkofer H, Gold R, Hoffmann LA, Hohlfeld R, Kümpfel T

BACKGROUND: Natalizumab is a new therapeutic option for relapsing-remitting multiple sclerosis. As with other antibody therapies, hypersensitivity reactions have been observed. In the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) trial, infusion-related hypersensitivity reactions developed in 4% of patients, usually within 2 hours after starting the infusion. OBJECTIVE: To report a significant, delayed, serum sickness-like, type III systemic allergic reaction to natalizumab. DESIGN: Case report describing clinical follow-up and the serial measurement of antinatalizumab antibodies. Patient: A 23-year-old man with relapsing-remitting multiple sclerosis developed a fever, arthralgias, urticarial exanthema, and a swollen lower lip during several days after his second infusion of natalizumab. RESULTS: The patient developed a delayed, serum sickness-like, type III systemic allergic reaction to natalizumab. Five weeks after initiation of this therapy, he tested positive for antinatalizumab antibodies and exhibited persistent antibody titers 8 and 12 weeks later. His symptoms completely resolved with a short course of oral glucocorticosteroids. CONCLUSION: Clinicians and patients should be alert not only to immediate but also to significantly delayed substantial allergic reactions to natalizumab.

PMID: 17846274 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results. Related Articles

Daclizumab phase II trial in relapsing and remitting multiple sclerosis: MRI and clinical results.

Neurology. 2007 Aug 21;69(8):785-9

Authors: Latest multiple sclerosis therapy articles Rose JW, Burns JB, Bjorklund J, Klein J, Watt HE, Carlson NG

OBJECTIVE: Daclizumab is an interleukin 2 receptor alpha chain specific humanized monoclonal antibody that has shown promising therapeutic effects in multiple sclerosis (MS). Daclizumab treatment in patients with relapsing and remitting MS was administered to determine effects on MRI and clinical outcomes. METHODS: Patients with MS on interferon (IFN) therapy but with continuing relapses and contrast enhancing lesions (CEL) were selected. Patients were evaluated with monthly MRI scans and clinical rating scales starting 3 months prior to treatment and then at 0.5 to 27.5 months during treatment. Daclizumab (1 mg/kg IV) was administered twice in the first month (initiated and administered again in 2 weeks), followed by treatments every 4 weeks. IFN was continued until 5.5 months after daclizumab was initiated. Patients were then placed on daclizumab monotherapy. Patients with recurrent CEL were restarted on IFN with daclizumab therapy at (1.5 mg/kg IV) every 28 days. RESULTS: Nine patients qualified for inclusion and completed the trial. Efficacy measured by both total CEL and new CEL (p < 0.001), relapses, timed ambulation, Expanded Disability Status Scale, and Neurologic Rating Scale (p < 0.05 to p < 0.01) was observed. CONCLUSION: Daclizumab was effective in reducing contrast enhancing lesions and improving clinical scores in patients with relapsing and remitting multiple sclerosis with active disease not controlled by interferon therapy. These results provide evidence for long-term efficacy and support further clinical development of daclizumab.

PMID: 17709711 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Combination immunosuppressive therapies: the promise and the peril. Related Articles

Combination immunosuppressive therapies: the promise and the peril.

Arch Dermatol. 2007 Aug;143(8):1053-7

Authors: Latest multiple sclerosis therapy articles Robinson MR, Korman BD, Korman NJ

BACKGROUND: Targeted immunotherapeutic agents (TIs), also known as biological agents, are efficacious treatments for many immunologically mediated disorders, including psoriasis. In several of these diseases, including rheumatoid arthritis, Crohn's disease, and multiple sclerosis, certain TIs have been studied in combination with nonspecific immunosuppressive agents and with other TIs. OBSERVATIONS: Recently, the rheumatology, neurology, and gastroenterology literature has reported several examples of possible associated toxic effects when certain TIs are used in combination with other immunosuppressive agents. These toxic effects have included an increased risk of infection and malignancy. CONCLUSIONS: Combination therapies are often used by dermatologists. Several TIs have been approved for psoriasis; however, clinical trials using these drugs in combination with other immunosuppressive agents have not yet been performed. The implications for dermatologists of the toxic effects associated with TI combination therapy are unclear. However, combination therapy with certain TIs should be used with caution until more data are available.

PMID: 17709665 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Clinically isolated syndromes: predicting and delaying multiple sclerosis. Related Articles

Clinically isolated syndromes: predicting and delaying multiple sclerosis.

Neurology. 2007 Jun 12;68(24 Suppl 4):S12-5

Authors: Latest multiple sclerosis therapy articles Thrower BW

Multiple sclerosis (MS) represents a spectrum of demyelination that depends on disease duration and clinical categorization. Most patients present with the relapsing-remitting form of the disease. The earliest clinical presentation of relapsing-remitting MS (RRMS) is the clinically isolated syndrome (CIS). Predicting which CIS patients are at high risk for MS is complicated by the disparity between clinical attacks and the extent of axon pathology. However, recent interferon-beta (IFN-beta) trials have demonstrated a delay in time to the second demyelinating event with early treatment, and early treatment could also slow the progression from RRMS to secondary-progressive MS (SPMS). Clinical findings in combination with brain MRI and CSF analysis can be used in CIS patients to evaluate their risk for clinically definite MS (CDMS). Application of the McDonald criteria also allows an earlier MS diagnosis by using new MRI lesions to define dissemination in time. Early immunomodulatory therapy for selected CIS patients may eventually prevent future axon pathology and progression of disability in this lifelong disease.

PMID: 17562845 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Aggressive therapy for neurosarcoidosis: long-term follow-up of 48 treated patients. Related Articles

Aggressive therapy for neurosarcoidosis: long-term follow-up of 48 treated patients.

Arch Neurol. 2007 May;64(5):691-6

Authors: Latest multiple sclerosis therapy articles Scott TF, Yandora K, Valeri A, Chieffe C, Schramke C

BACKGROUND: Neurosarcoidosis (NS) is a relatively rare neurologic disorder for which no accepted treatment guidelines are available. Treatment with corticosteroids has been described as the primary means of controlling progressive symptoms. However, some physicians have recently advocated early intervention with alternative immunosuppressive therapies in patients who present with disabling symptoms. OBJECTIVE: To investigate our experience during the last decade regarding alternative immunosuppressive treatments, including corticosteroids and alternative therapies, in patients with NS. DESIGN: Observational, retrospective, consecutive case series with longitudinal follow-up. SETTING: Allegheny Neurological Clinic. Patients Seventy-eight patients with sarcoidosis were evaluated and classified as having possible, probable, or definite NS according to accepted criteria. Five cases of isolated NS were also included. MAIN OUTCOME MEASURES: Patients with probable, definite, or isolated NS were scored before treatments and at final follow-up using estimated modified Rankin scores and the Disease Steps in Multiple Sclerosis scales. RESULTS: Forty-three patients were categorized as having either definite or probable NS according to accepted criteria and an additional 5 as having isolated NS. Thirty patients were categorized as having possible NS and were not included in the analysis of treatment response. Patients had a mean +/- SD number of visits of 7.2 +/- 6.4 and were followed up for a mean +/- SD of 44.1 +/- 43.6 months. Twenty patients were treated with pulse and/or maintenance corticosteroids alone. Twenty-six patients were treated with alternative immunosuppressive medications, with 23 of them receiving these medications at the time of diagnosis or within 6 months of the diagnosis of NS. Of the patients treated with alternative immunosuppressive therapies, 18 (69%) improved, 4 (15%) remained stable, and 4 (15%) worsened (including 1 death). Of the patients treated with corticosteroids alone, 7 (35%) improved, 11 (55%) remained stable, and 2 (10%) worsened. Two patients received no treatment. CONCLUSIONS: Approximately half of all patients with NS seen at our clinic were believed to have disabling disease and to be at high risk for disease progression. These high-risk patients were treated with corticosteroids plus alternative immunosuppressive therapy, and favorable outcomes were obtained in almost all patients. Toxic effects related to treatments were minimal.

PMID: 17502468 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]CD24 on the resident cells of the central nervous system enhances experimental autoimmune encephalomyelitis. Related Articles

CD24 on the resident cells of the central nervous system enhances experimental autoimmune encephalomyelitis.

J Immunol. 2007 May 15;178(10):6227-35

Authors: Latest multiple sclerosis therapy articles Liu JQ, Carl JW, Joshi PS, RayChaudhury A, Pu XA, Shi FD, Bai XF

CD24 is a cell surface glycoprotein that is expressed on both immune cells and cells of the CNS. We have previously shown that CD24 is required for the induction of experimental autoimmune encephalomyelitis (EAE), an experimental model for the human disease multiple sclerosis (MS). The development of EAE requires CD24 expression on both T cells and non-T host cells in the CNS. To understand the role of CD24 on the resident cells in the CNS during EAE development, we created CD24 bone marrow chimeras and transgenic mice in which CD24 expression was under the control of a glial fibrillary acidic protein promotor (AstroCD24TG mice). We showed that mice lacking CD24 expression on the CNS resident cells developed a mild form of EAE; in contrast, mice with overexpression of CD24 in the CNS developed severe EAE. Compared with nontransgenic mice, the CNS of AstroCD24TG mice had higher expression of cytokine genes such as IL-17 and demyelination-associated marker P8; the CNS of AstroCD24TG mice accumulated higher numbers of Th17 and total CD4+ T cells, whereas CD4+ T cells underwent more proliferation during EAE development. Expression of CD24 in CD24-deficient astrocytes also enhanced their costimulatory activity to myelin oligodendrocyte glycoprotein-specific, TCR-transgenic 2D2 T cells. Thus, CD24 on the resident cells in the CNS enhances EAE development via costimulation of encephalitogenic T cells. Because CD24 is increased drastically on resident cells in the CNS during EAE, our data have important implications for CD24-targeted therapy of MS.

PMID: 17475850 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis. Related Articles

Quantifying the risks and benefits of natalizumab in relapsing multiple sclerosis.

Neurology. 2007 May 1;68(18):1524-8

Authors: Latest multiple sclerosis therapy articles Dorsey ER, Thompson JP, Noyes K, Dick AW, Holloway RG, Schwid SR

Using published data, we quantified the risk and benefits of natalizumab in relapsing multiple sclerosis using quality-adjusted life years (QALYs) as a metric. Over the first 2 years of therapy, the negative health effects from progressive multifocal leukoencephalopathy were small (loss of 0.001 QALYs) relative to the positive effects on relapses and disability resulting in 0.033 QALYs (12 quality-adjusted days) gained. For context, we performed an analogous calculation for interferon beta-1a, which also had a net health benefit of 0.033 QALYs (12 quality-adjusted days).

PMID: 17470756 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor. Related Articles

Kinematic analysis of thalamic versus subthalamic neurostimulation in postural and intention tremor.

Brain. 2007 Jun;130(Pt 6):1608-25

Authors: Latest multiple sclerosis therapy articles Herzog J, Hamel W, Wenzelburger R, Pötter M, Pinsker MO, Bartussek J, Morsnowski A, Steigerwald F, Deuschl G, Volkmann J

Deep brain stimulation of the thalamus (thalamic DBS) is an established therapy for medically intractable essential tremor and tremor caused by multiple sclerosis. In both disorders, motor disability results from complex interaction between kinetic tremor and accompanying ataxia with voluntary movements. In clinical studies, the efficacy of thalamic DBS has been thoroughly assessed. However, the optimal anatomical target structure for neurostimulation is still debated and has never been analysed in conjunction with objective measurements of the different aspects of motor impairment. In 10 essential tremor and 11 multiple sclerosis patients, we analysed the effect of thalamic DBS through each contact of the quadripolar electrode on the contralateral tremor rating scale, accelerometry and kinematic measures of reach-to-grasp-movements. These measures were correlated with the anatomical position of the stimulating electrode in stereotactic space and in relation to nuclear boundaries derived from intraoperative microrecording. We found a significant impact of the stereotactic z-coordinate of stimulation contacts on the TRS, accelerometry total power and spatial deviation in the deceleration and target period of reach-to-grasp-movements. Most effective contacts clustered within the subthalamic area (STA) covering the posterior Zona incerta and prelemniscal radiation. Stimulation within this region led to a mean reduction of the lateralized tremor rating scale by 15.8 points which was significantly superior to stimulation within the thalamus (P < 0.05, student's t-test). STA stimulation resulted in reduction of the accelerometry total power by 99%, whereas stimulation at the ventral thalamic border (68%) or within the thalamus proper (2.5%) was significantly less effective (P < 0.01). Concomitantly, STA stimulation led to a significantly higher increase of tremor frequency and decrease in EMG synchronization compared to stimulation within the thalamus proper (P < 0.001). In reach-to-grasp movements, STA stimulation reduced the spatial variability of the movement path in the deceleration period by 28.9% and in the target period by 58.4%, whereas stimulation within the thalamus was again significantly less effective (P < 0.05), with a reduction in the deceleration period between 6.5 and 21.8% and in the target period between 1.2 and 11.3%. An analysis of the nuclear boundaries from intraoperative microrecording confirmed the anatomical impression that most effective electrodes were located within the STA. Our data demonstrate a profound effect of deep brain stimulation of the thalamic region on tremor and ataxia in essential tremor and tremor caused by multiple sclerosis. The better efficacy of stimulation within the STA compared to thalamus proper favours the concept of a modulation of cerebello-thalamic projections underlying the improvement of these symptoms.

PMID: 17439979 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Treatment of pediatric multiple sclerosis and variants. Related Articles

Treatment of pediatric multiple sclerosis and variants.

Neurology. 2007 Apr 17;68(16 Suppl 2):S54-65

Authors: Latest multiple sclerosis therapy articles Pohl D, Waubant E, Banwell B, Chabas D, Chitnis T, Weinstock-Guttman B, Tenembaum S,

Studies in adult patients with multiple sclerosis (MS) suggest significant benefit of early treatment initiation. However, there are no approved therapies for children and adolescents with MS. For adult MS, tolerability and efficacy of several immunomodulatory and immunosuppressive drugs have been demonstrated. Guidelines for the use of these MS therapies in children do not exist. Several small cohort studies of the safety and tolerability of disease-modifying therapies (DMT) in children and adolescents with MS have been recently reported. The side effects of interferon beta (IFNB) and glatiramer acetate (GA) appear to be similar to those reported by adults. The long-term tolerability and safety have yet to be established and efficacy data have yet to be studied. In view of the potential for significant long-term physical and cognitive disability in children with MS, and recent evidence that initiation of immunomodulatory therapy early in the course of MS improves long-term prognosis, an increasing number of children and adolescents with MS are being offered the DMT approved for adults. This review summarizes current knowledge of DMT in pediatric MS and experience in several centers treating pediatric MS and MS variants such as neuromyelitis optica or Devic disease, Balo concentric sclerosis, Marburg acute MS, and Schilder disease (myelinoclastic diffuse sclerosis). Finally, an overview of symptomatic MS therapies and experiences with these treatments in pediatric patients is provided.

PMID: 17438239 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Genome-wide network analysis reveals the global properties of IFN-beta immediate transcriptional effects in humans. Related Articles

Genome-wide network analysis reveals the global properties of IFN-beta immediate transcriptional effects in humans.

J Immunol. 2007 Apr 15;178(8):5076-85

Authors: Latest multiple sclerosis therapy articles Fernald GH, Knott S, Pachner A, Caillier SJ, Narayan K, Oksenberg JR, Mousavi P, Baranzini SE

IFN-beta effectively controls clinical exacerbations and magnetic resonance imaging activity in most multiple sclerosis patients. However, its mechanism of action has not been yet fully elucidated. In this study we used DNA microarrays to analyze the longitudinal transcriptional profile of blood cells within a week of IFN-beta administration. Using differential expression and gene ontology analyses we found evidence of a general decrease in the cellular activity of T lymphocytes resembling the endogenous antiviral response of IFNs. In contrast, most of the differentially expressed genes (DEGs) from untreated individuals were involved in cellular physiological processes. We then used mutual information (MI) to build networks of coregulated genes in both treated and untreated individuals. Interestingly, the connectivity distribution (k) of networks generated with high MI values displayed scale-free properties. Conversely, the observed k for networks generated with suboptimal MI values approximated a Poisson distribution, suggesting that MI captures biologically relevant interactions. Gene networks from individuals treated with IFN-beta revealed a tight core of immune- and apoptosis-related genes associated with higher values of MI. In contrast, networks obtained from untreated individuals primarily reflected cellular housekeeping functions. Finally, we trained a neural network to reverse engineer the directionality of the main interactions observed at the biological process level. This is the first study that incorporates network analysis to investigate gene regulation in response to a therapeutic drug in humans. Implications of this method in the creation of personalized models of response to therapy are discussed.

PMID: 17404290 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Reactivation of JC virus and development of PML in patients with multiple sclerosis. Related Articles

Reactivation of JC virus and development of PML in patients with multiple sclerosis.

Neurology. 2007 Mar 27;68(13):985-90

Authors: Latest multiple sclerosis therapy articles Khalili K, White MK, Lublin F, Ferrante P, Berger JR

The attention of researchers and clinicians specializing in both multiple sclerosis (MS) and JC virus (JCV), the etiologic agent of progressive multifocal leukoencephalopathy (PML), was rekindled by the development of PML in two patients with MS enrolled in a clinical trial of combination therapy with natalizumab (Tysabri) and interferon beta-1A (Avonex) in recent years. PML had not been previously reported with either MS or treatment with interferon beta alone. This occurrence of PML with alpha4beta1-integrin inhibition in MS raised a number of issues in terms both of the scientific understanding of these diseases and for the future of immunomodulatory treatment for MS. In this review, we examine the current status of knowledge of the virus, its molecular biology, life cycle, and pathogenetic mechanisms, and how this relates to the basic science and clinical perspectives of MS. A better understanding of the specific steps from JCV infection to the development of PML is key to this issue. Other critical issues for further investigation include the role of alpha4beta1-integrin inhibition by natalizumab in the re-expression of JCV from latent sites and in the inhibition of entry into the brain and peripheral sites.

PMID: 17389301 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Related Articles

Neutralizing antibodies to interferon beta: assessment of their clinical and radiographic impact: an evidence report: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Neurology. 2007 Mar 27;68(13):977-84

Authors: Latest multiple sclerosis therapy articles Goodin DS, Frohman EM, Hurwitz B, O'Connor PW, Oger JJ, Reder AT, Stevens JC

The clinical and radiologic impact of developing neutralizing antibodies (NAbs) to interferon beta (IFNbeta) while on this therapy for multiple sclerosis (MS) is assessed. On the basis of Class II and III evidence, it is concluded that treatment of patients with MS with IFNbeta (Avonex, Betaseron, or Rebif) is associated with the production of NAbs (Level A). NAbs in the serum are probably associated with a reduction in the radiographic and clinical effectiveness of IFNbeta treatment (Level B). In addition, the rate of NAb production is probably less with IFNbeta-1a treatment than with IFNbeta-1b treatment, although the magnitude and persistence of this difference is difficult to determine (Level B). Finally, it is probable that there is a difference in seroprevalence due to variability in the dose of IFNbeta injected or in the frequency or route of its administration (Level B). Regardless of the explanation, it seems clear that IFNbeta-1a (as it is currently formulated for IM injection) is less immunogenic than the current IFNbeta preparations (either IFNbeta-1a or IFNbeta-1b) given multiple times per week subcutaneously (Level A). However, because NAbs disappear in some patients even with continued IFNbeta treatment (especially in patients with low titers), the persistence of this difference is difficult to determine (Level B). Although the finding of sustained high-titer NAbs (>100 to 200 NU/mL) is associated with a reduction in the therapeutic effects of IFNbeta on radiographic and clinical measures of MS disease activity, there is insufficient information on the utilization of NAb testing to provide specific recommendations regarding when to test, which test to use, how many tests are necessary, or which cutoff titer to apply (Level U).

PMID: 17389300 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions. Related Articles

Potential risk of progressive multifocal leukoencephalopathy with natalizumab therapy: possible interventions.

Arch Neurol. 2007 Feb;64(2):169-76

Authors: Latest multiple sclerosis therapy articles Stüve O, Marra CM, Cravens PD, Singh MP, Hu W, Lovett-Racke A, Monson NL, Phillips JT, Cohen Tervaert JW, Nash RA, Hartung HP, Kieseier BC, Racke MM, Frohman EM, Hemmer B

Natalizumab (Tysabri) is an effective therapy for multiple sclerosis. Recently, 3 patients who were treated with natalizumab developed progressive multifocal leukoencephalopathy (PML), an opportunistic infection of the brain with the polyomavirus JC. The pathogenesis of natalizumab-associated PML may be different from that of PML not associated with the drug. We reviewed biologically feasible interventions for patients diagnosed as having PML or other infections while receiving natalizumab therapy. Existing interventions include antiviral treatment, immunomodulatory therapies, hematopoietic growth factors, plasma exchange, intravenous immunoglobulins, and leukapheresis and autotransfusion of leukocytes. In addition, we examined the feasibility of experimental therapies, including small interfering RNA, the in vivo use of antiserum, and recombinant natalizumab-blocking molecules. There is only circumstantial evidence that any of the proposed treatments will benefit patients with multiple sclerosis treated with natalizumab who may develop PML. In addition, the expected incidence of PML in this patient population will likely be too low to test any of the proposed interventions in a controlled manner. Because it is currently impossible to identify patients at risk, and thus to prevent PML as a consequence of natalizumab therapy, it is important that neurologists be aware of possible therapeutic interventions.

PMID: 17296831 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Intravesical atropine compared to oral oxybutynin for neurogenic detrusor overactivity: a double-blind, randomized crossover trial. Related Articles

Intravesical atropine compared to oral oxybutynin for neurogenic detrusor overactivity: a double-blind, randomized crossover trial.

J Urol. 2007 Jan;177(1):208-13; discussion 213

Authors: Latest multiple sclerosis therapy articles Fader M, Glickman S, Haggar V, Barton R, Brooks R, Malone-Lee J

PURPOSE: We tested the efficacy and side effect profiles of intravesical atropine compared to oxybutynin immediate release when used by individuals with multiple sclerosis. MATERIALS AND METHODS: We performed a study to determine the most effective dose of atropine. Eight participants used increasing doses of intravesical atropine during a 12-day period. Bladder diary data showed that the instillation of 6 mg atropine 4 times daily was most effective for increasing bladder capacity (voided/catheter volumes). We then did a randomized, double-blind crossover trial. Participants received 14 days of treatment with oral oxybutynin or with intravesical atropine, followed by 14 days of alternative treatment. Participants recorded a bladder diary and rated side effects and quality of life. The primary outcome variable was bladder capacity. RESULTS: A total of 57 participants with multiple sclerosis completed the study. Average change in bladder capacity was higher in the atropine arm. The mean +/- SD oxybutynin change was 55.5 +/- 67.2 ml, the mean atropine change was 79.6 +/- 89.6 ml and the mean difference between arms was 24.1 ml (95% CI -0.4, 49.7; p = 0.053). Changes in incontinence events and voiding frequency were not statistically different between the arms. Changes in total side effect and dry mouth scores were significantly better in the atropine treatment arm. CONCLUSIONS: Intravesical atropine was as effective as oxybutynin immediate release for increasing bladder capacity and it was probably better with less antimuscarinic side effects. We recommend that intravesical atropine should be made available to patients with neurogenic detrusor overactivity and voiding problems requiring intermittent catheterization as an alternative to oral therapy, which often has troublesome side effects.

PMID: 17162046 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Coadministration of plasmid DNA constructs encoding an encephalitogenic determinant and IL-10 elicits regulatory T cell-mediated protective immunity in the central nervous system. Related Articles

Coadministration of plasmid DNA constructs encoding an encephalitogenic determinant and IL-10 elicits regulatory T cell-mediated protective immunity in the central nervous system.

J Immunol. 2006 Dec 1;177(11):8241-7

Authors: Latest multiple sclerosis therapy articles Schif-Zuck S, Wildbaum G, Karin N

We have previously shown that Ag-specific IL-10-producing regulatory T cells (Tr1) participate in the regulation of experimental autoimmune encephalomyelitis and that their specificity undergoes determinant spread in a reciprocal manner to effector T cell specificity. The current study shows that coadministration of plasmid DNA vaccines encoding IL-10 together with a plasmid encoding a myelin basic protein (MBP) encephalitogenic determinant during an ongoing disease rapidly amplifies this Tr1-mediated response, in a disease-specific manner. Thus, coadministration of both plasmids, but not the plasmid DNA encoding MBP alone, rapidly suppresses an ongoing disease. Tolerance included elevation in Ag-specific T cells producing IL-10 and an increase in apoptosis of cells around high endothelial venules in the CNS after successful therapy. Tolerance could be transferred by MBP-specific primary T cells isolated from protected donors and reversed by neutralizing Abs to IL-10 but not to IL-4. Due to the nature of determinant spread in this model, we could bring about evidence implying that rapid and effective induction of Tr1-induced active tolerance is dependent on redirecting the Tr1 response to the epitope to which the effector function dominates the response at a given time. The consequences of these findings to multiple sclerosis, and possibly other inflammatory autoimmune diseases are discussed.

PMID: 17114502 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Interferon inhibitory activity in patients with multiple sclerosis. Related Articles

Interferon inhibitory activity in patients with multiple sclerosis.

Arch Neurol. 2006 Nov;63(11):1579-84

Authors: Latest multiple sclerosis therapy articles Chadha K, Weinstock-Guttman B, Zivadinov R, Bhasi K, Muhitch J, Feichter J, Tamaño-Blanco M, Abdelrahman N, Ambrus J, Munschauer F, Ramanathan M

BACKGROUND: Interferon inhibitory activity (IIA) is a logical candidate for explaining neutralizing antibody-negative partial responsiveness to interferon beta in multiple sclerosis (MS), but its role has not been evaluated. OBJECTIVE: To investigate the role of IIA and soluble interferon-alpha/beta receptor (sIFNR) in determining response of patients with MS to interferon beta therapy. DESIGN: Parallel-group, open-label study. SETTING: Baird Multiple Sclerosis Center, Buffalo, NY. Patients Blood was obtained before and 24 hours after injection of interferon beta-1a from 38 anti-interferon beta neutralizing antibody-negative patients with relapsing-remitting MS and 16 untreated healthy controls. On the basis of clinical parameters of response to interferon beta therapy, the patients were divided into stable or good-responder (n = 20) and active or partial-responder (n = 18) groups. MAIN OUTCOME MEASURES: Quantitative analyses of magnetic resonance imaging were obtained; the IIA and sIFNR levels were measured using bioassay and enzyme-linked immunosorbent assay, respectively. RESULTS: The IIA and sIFNR levels were elevated in MS patients compared with controls (P<.001). The IIA levels were higher in active or partial responders compared with stable or good responders (P<.001); the sIFNR levels were not different between groups. The Extended Disability Status Score and T2 lesion volumes were higher in the active or partial-responder group compared with the stable or good-responder group. Interferon beta-1a did not have short-term effects on the IIA and sIFNR levels. In univariate general linear model and stepwise regression analyses, IIA levels were associated with T2 lesion volume. CONCLUSION: The levels of IIA are associated with increased MS disease activity and with responsiveness to interferon beta therapy in anti-interferon beta neutralizing antibody-negative MS patients.

PMID: 17101826 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Related Articles

Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.

Arch Neurol. 2006 Oct;63(10):1383-7

Authors: Latest multiple sclerosis therapy articles Stüve O, Marra CM, Bar-Or A, Niino M, Cravens PD, Cepok S, Frohman EM, Phillips JT, Arendt G, Jerome KR, Cook L, Grand'Maison F, Hemmer B, Monson NL, Racke MK

BACKGROUND: Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an alpha4beta(1) integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection. OBJECTIVE: To test the effect of natalizumab treatment on the CD4(+)/CD8(+) T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood. DESIGN: Prospective longitudinal study. SETTING: Academic and private multiple sclerosis centers. PATIENTS: Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients. MAIN OUTCOME MEASURES: CD4(+) and CD8(+) T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound alpha4 integrin on peripheral blood CD4(+) and CD8(+) T cells was analyzed before and after natalizumab therapy. RESULTS: Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4(+)/CD8(+) ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4(+)/CD8(+) ratios normalized. The expression of unbound alpha4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4(+) vs CD8(+) T cells. CONCLUSIONS: Natalizumab treatment alters the CSF CD4(+)/CD8(+) ratio. Lower expression of unbound alpha4 integrin on CD4(+) T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

PMID: 17030653 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: a comparative study. Related Articles

Effects of glatiramer acetate and interferon-beta on neurodegeneration in a model of multiple sclerosis: a comparative study.

Am J Pathol. 2006 Oct;169(4):1353-64

Authors: Latest multiple sclerosis therapy articles Maier K, Kuhnert AV, Taheri N, Sättler MB, Storch MK, Williams SK, Bähr M, Diem R

Axonal destruction and neuronal loss occur early during multiple sclerosis (MS), an autoimmune inflammatory central nervous system disease that frequently manifests with acute optic neuritis. Glatiramer acetate (GA) and interferon-beta-1b (IFN-beta-1b) are two immunomodulatory agents that have been shown to decrease the frequency of MS relapses. However, the question of whether these substances can slow neurodegeneration in MS patients is the subject of controversy. In a rat model of experimental autoimmune encephalomyelitis, we investigated the effects of GA and IFN-beta-1b on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve. For each substance, therapy was started 14 days before immunization, on the day of immunization, or on the day of clinical disease onset. After myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis became clinically manifest, optic neuritis was monitored by recording visual evoked potentials. The function of RGCs was measured by electroretinograms. Although early GA or IFN-beta-1b treatment showed benefit on disease activity, only treatment with GA exerted protective effects on RGCs, as revealed by measuring neurodegeneration and neuronal function. Furthermore, we demonstrate that this GA-induced neuroprotection does not exclusively depend on the reduction of inflammatory infiltrates within the optic nerve.

PMID: 17003491 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Related Articles

Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS.

Neurology. 2006 Sep 26;67(6):944-53

Authors: Latest multiple sclerosis therapy articles Kappos L, Traboulsee A, Constantinescu C, Erälinna JP, Forrestal F, Jongen P, Pollard J, Sandberg-Wollheim M, Sindic C, Stubinski B, Uitdehaag B, Li D

OBJECTIVE: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. RESULTS: LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. CONCLUSIONS: Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

PMID: 17000959 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]What is meant by a "flare" in atopic dermatitis? A systematic review and proposal. Related Articles

What is meant by a "flare" in atopic dermatitis? A systematic review and proposal.

Arch Dermatol. 2006 Sep;142(9):1190-6

Authors: Latest multiple sclerosis therapy articles Langan SM, Thomas KS, Williams HC

OBJECTIVE: To make preliminary recommendations for defining a flare of atopic dermatitis (AD) in clinical research based on a systematic review of the literature and experience in running clinical trials. DATA SOURCES: A sensitive electronic search of MEDLINE :- Latest multiple sclerosis therapy articles biographic database was conducted on April 19, 2005, using the following search terms: flare$, exacerbation$, relaps$, remission$, worse$, and *recurrence. The search was restricted to all prospective studies of AD in humans, using the Cochrane search terms for AD and prospective studies. In addition, we searched the literature on 3 chronic intermittent diseases (asthma, rheumatoid arthritis, and multiple sclerosis) to gain insight as to how other disciplines had tackled the definition of flares. DATA SYNTHESIS: A total of 401 citations were reviewed, of which 16 articles (15 studies) were relevant. All were clinical trials. The definitions of disease flare or relapse in retrieved articles could be categorized into 3 broad themes: (1) composite definitions that include at least 2 different factors (eg, symptoms, severity duration, or treatment) (4 studies); (2) score thresholds or changes in severity scores (8 studies); and (3) behavioral definitions, such as the use of rescue therapy (3 studies). Only 1 investigative group (3 studies) used the same definition. None of the included studies were primarily designed to develop a definition of "flare." Evidence from other disciplines suggested at least 2 measures-totally controlled weeks and well-controlled weeks from asthma research-that could be used successfully in AD research. CONCLUSIONS: Defining an AD flare is a complex process, and this review has highlighted the need for standardization in defining measures of long-term disease control. We propose that a flare of AD be simply defined as an episode requiring escalation of treatment or seeking additional medical advice. Consideration should also be given to totally controlled weeks and well-controlled weeks to assess overall disease activity in patients with AD. Together, these definitions are intuitive, simple to use, and easy to understand. Future work is required to test the applicability of these recommendations in a variety of research settings.

PMID: 16983006 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction. Related Articles

Glutamic acid decarboxylase autoimmunity with brainstem, extrapyramidal, and spinal cord dysfunction.

Mayo Clin Proc. 2006 Sep;81(9):1207-14

Authors: Latest multiple sclerosis therapy articles Pittock SJ, Yoshikawa H, Ahlskog JE, Tisch SH, Benarroch EE, Kryzer TJ, Lennon VA

OBJECTIVE: To describe novel neurological manifestations associated with glutamic acid decarboxylase (GAD65) autoimmunity. PATIENTS AND METHODS: This retrospective study (1987-2003) describes 62 patients Incidentally found to have a serum autoantibody that bound selectively to synapse-rich central nervous system tissues. The immunostaining pattern was determined to be GAD65-specific by radiolmmunoprecipitation assay. These cases were identified among samples submitted for paraneoplastic autoantibody evaluation using indirect immunofluorescence. In no case had GAD65 or any other islet cell antibody testing been requested. RESULTS: In most cases, the patients' presentations were initially considered neurodegenerative or inflammatory (multiple sclerosis or paraneoplastic). Median age at onset was 50 years, and 77% were women. Of the 44 patients seen at the Mayo Clinic, 23% were African American; in contrast, less than 10% of Mayo Clinic's neurology patients are African American. Median follow-up was 24 months. The radioimmunoprecipitation assay values for GAD65 antibody were extremely high (median, 1429 nmol/L; Interquartile range, 643-3078 nmol/L) and correlated significantly with immunofluorescence titers (median, 3840; interquartile range, 1920-15,360; r = 0.81; P < .001). Neurological manifestations were multifocal in 41 patients and included cerebellar ataxia (63%), brainstem involvement (29%), seizures (27%), stiff-man phenomena (26%), extrapyramidal signs (16%), and myelopathy (8%). One third of the patients had type 1 diabetes mellitus, 53% had thyroid autoantibodies, and 16% had vitiligo. Eleven of 20 patients identified as African American had brainstem involvement. Some patients appeared to benefit from short-term immunosuppression (none received long-term therapy). CONCLUSIONS: The neurological spectrum of GAD65 autoimmunity includes brainstem, extrapyramidal, and spinal cord syndromes. In our experience, African American patients were disproportionately affected. A patient with a presumed neurodegenerative disorder of new onset, with high levels of GAD65 antibody (>20 nmol/L), merits consideration of immunotherapy.

PMID: 16970217 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Potential for interferon beta-induced serum antibodies in multiple sclerosis to inhibit endogenous interferon-regulated chemokine/cytokine responses within the central nervous system. Related Articles

Potential for interferon beta-induced serum antibodies in multiple sclerosis to inhibit endogenous interferon-regulated chemokine/cytokine responses within the central nervous system.

Arch Neurol. 2006 Sep;63(9):1296-9

Authors: Latest multiple sclerosis therapy articles Shapiro AM, Jack CS, Lapierre Y, Arbour N, Bar-Or A, Antel JP

BACKGROUND: A proportion of patients with multiple sclerosis (MS) receiving systemic interferon beta therapy will develop serum neutralizing antibodies (NAbs) that can reduce the activity of the drug. Interferon-beta (IFN-beta) is produced by glial cells within the central nervous system. Although systemic interferon beta does not access the central nervous system, titers of serum NAbs may be sufficient that some will access the central nervous system. OBJECTIVE: To address whether serum samples that contain high titers of NAbs could inhibit glial cell production of chemokines and cytokines that are regulated by endogenous IFN-beta. DESIGN: We used an in vitro assay involving toll-like receptor 3 ligand (polyinosinic-polycytidylic acid) signaling to assess the effect of serum samples containing high titers of NAbs (1800-20 000 U) on production of the chemokine CXCL10 and the cytokine interleukin 6 by human astrocytes. RESULTS: Serum samples positive for NAbs significantly inhibited polyinosinic-polycytidylic acid-induced CXCL10 and IL-6 production by astrocytes. CONCLUSION: High-titer NAbs to interferon beta may block endogenous IFN-beta function and alter the chemokine/cytokine microenvironment within the central nervous system, thereby modulating the profile and course of the local inflammatory response.

PMID: 16966508 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis. Related Articles

Immunomodulatory effect of combination therapy with lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside alleviates neurodegeneration in experimental autoimmune encephalomyelitis.

Am J Pathol. 2006 Sep;169(3):1012-25

Authors: Latest multiple sclerosis therapy articles Paintlia AS, Paintlia MK, Singh I, Singh AK

Combination therapy with multiple sclerosis (MS) therapeutics is gaining momentum over monotherapy for improving MS. Lovastatin, an HMG-CoA reductase inhibitor (statin), was immunomodulatory in an experimental autoimmune encephalomyelitis (EAE) model of MS. Lovastatin biases the immune response from Th1 to a protective Th2 response in EAE by a different mechanism than 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, an immunomodulating agent that activates AMP-activated protein kinase. Here we tested these agents in combination in an EAE model of MS. Suboptimal doses of these drugs in combination were additive in efficacy against the induction of EAE; clinical symptoms were delayed and severity and duration of disease was reduced. In the central nervous system, the cellular infiltration and proinflammatory immune response was decreased while the anti-inflammatory immune response was increased. Combination treatment biased the class of elicited myelin basic protein antibodies from IgG2a to IgG1 and IgG2b, suggesting a shift from Th1 to Th2 response. In addition, combination therapy lessened inflammation-associated neurodegeneration in the central nervous system of EAE animals. These effects were absent in EAE animals treated with either drug alone at the same dose. Thus, our data suggest that agents with different mechanisms of action such as lovastatin and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside, when used in combination, could improve therapy for central nervous system demyelinating diseases and provide a rationale for testing them in MS patients.

PMID: 16936274 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Successful treatment of posttraumatic hemiballismus with intrathecal baclofen therapy. Related Articles

Successful treatment of posttraumatic hemiballismus with intrathecal baclofen therapy.

Am J Phys Med Rehabil. 2006 Sep;85(9):779-82

Authors: Latest multiple sclerosis therapy articles Francisco GE

Intrathecal baclofen (ITB) therapy is widely used in the management of spastic hypertonia and dystonia resulting from a multitude of conditions that present with upper motor neuron syndrome signs, such as cerebral palsy, stroke, brain and spinal injuries, and multiple sclerosis. We report successful management of posttraumatic hemiballismus and dystonia with ITB in a 43-yr-old man who sustained a traumatic brain injury secondary to an assault in 1978. He subsequently developed hemiballismus in the right lower limb and dystonia of the distal right upper limb spreading proximally to involve the shoulder. The ballistic movement of the lower limb was severe enough to cause the patient to fall out of his chair and limit his ability to perform activities of daily living safely. He had been on various oral medications and received botulinum toxin and phenol injections, but none alleviated the symptoms. The patient elected to receive the ITB pump. Before ITB, he had an average of 10-12 ballism episodes of the right lower limb per hour. During observed episodes, the right hip would flex up to about 90 degrees, with a fully extended knee. After ITB pump implantation and upward dose titration, the frequency of ballistic right leg movements decreased to about three per day, and the right hip flexed to only 30 degrees. In addition, there was increased ability to isolate individual distal joint movements in the right lower limb. The patient currently receives 202.4 microg/day ITB and continues to benefit almost 6 yrs after ITB pump implantation. This report highlights the emerging role of ITB in managing movement disorders other than dystonia spastic hypertonia and dystonia.

PMID: 16924190 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis. Related Articles

High-dose cyclophosphamide for moderate to severe refractory multiple sclerosis.

Arch Neurol. 2006 Oct;63(10):1388-93

Authors: Latest multiple sclerosis therapy articles Gladstone DE, Zamkoff KW, Krupp L, Peyster R, Sibony P, Christodoulou C, Locher E, Coyle PK

BACKGROUND: High-dose cyclophosphamide is active in immune-mediated illnesses. OBJECTIVE: To describe the effects of high-dose cyclophosphamide on severe refractory multiple sclerosis. DESIGN, SETTING, AND PATIENTS: Patients with multiple sclerosis with an Expanded Disability Status Scale (EDSS) score of 3.5 or higher after 2 or more Food and Drug Administration-approved disease-modifying therapy regimens were evaluated. INTERVENTIONS: Patients received 200 mg/kg of cyclophosphamide over 4 days. MAIN OUTCOME MEASURES: Patients had brain magnetic resonance imaging and neuro-ophthalmologic evaluations every 6 months and quarterly EDSS and quality-of-life evaluations for 2 years. RESULTS: Twelve patients were evaluated for clinical response (median follow-up, 15.0 months; follow-up range, 6-24 months). During follow-up, no patients increased their baseline EDSS scores by more than 1.0. Five patients decreased their EDSS scores by 1.0 or more (EDSS score decrease range, 1.0-5.0). Two of 11 patients had a single enhancing lesion at baseline; these lesions resolved after high-dose cyclophosphamide treatment. At 12 months, 1 patient showed 1 new enhancing lesion without a corresponding high-intensity T2-weighted or fluid-attenuated inversion recovery signal. Patients reported improvement in all of the quality-of-life parameters measured. Neurologic improvement involved changes in gait, bladder control, and visual function. Treatment response was seen regardless of the baseline presence or absence of contrast lesion activity. Patient quality-of-life improvement occurred independently of EDSS score changes. In this small group of patients with treatment-refractory multiple sclerosis, high-dose cyclophosphamide was associated with minimal morbidity and improved clinical outcomes. CONCLUSIONS: High-dose cyclophosphamide treatment in patients with severe refractory multiple sclerosis can result in disease stabilization, improved functionality, and improved quality of life. Further studies are necessary to determine the most appropriate patients for this treatment.

PMID: 16908728 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis. Related Articles

Brain damage as detected by magnetization transfer imaging is less pronounced in benign than in early relapsing multiple sclerosis.

Brain. 2006 Aug;129(Pt 8):2008-16

Authors: Latest multiple sclerosis therapy articles De Stefano N, Battaglini M, Stromillo ML, Zipoli V, Bartolozzi ML, Guidi L, Siracusa G, Portaccio E, Giorgio A, Sorbi S, Federico A, Amato MP

The trend to start disease-modifying therapy early in the course of multiple sclerosis makes it important to establish whether the benign form is a real entity. In previous studies, measures of magnetization transfer (MT) ratio (MTr) have been shown to provide good estimates of the amount of tissue damage occurring in multiple sclerosis brains. Thus, with the hypothesis that if benign multiple sclerosis patients were really benign, sensitive measures of subtle tissue damage would be less pronounced in these patients than in very early relapsing-remitting (RR) multiple sclerosis patients. We carried out conventional MRI and MT imaging in 50 patients with benign multiple sclerosis [defined as having Kurtzke Expanded Disability Status Score (EDSS) <3 and disease duration >15 years] and in 50 early RR patients selected to have similar disability (EDSS <3) and short disease duration (<3 years). Data were compared with those of 32 demographically-matched normal controls. We used a fully automated procedure to measure lesional-MTr, perilesional-MTr, normal-appearing white matter (NAWM) MTr and cortical-MTr. We found that, after correction for common effects of age, lesional-MTr and perilesional-MTr of benign patients were significantly (P < 0.0001) lower than WM of normal controls, but significantly (P < 0.0001) higher than corresponding tissues of RR patients. In NAWM and cortex, MTr values of benign patients were similar to those of normal controls (P > 0.5) and significantly higher than those of the RR patients (P < 0.0001 and P < 0.01, respectively). Similar differences in MTr measures between benign and RR patients were found when patient groups were selected to have no disability (EDSS < or = 2) and, for benign multiple sclerosis, very long disease duration (>20 years) or when both groups were matched for high lesion load (T2-weighted lesion volume >10 cm3). We conclude that lesional and non-lesional MTr values can be significantly less pronounced in benign multiple sclerosis than in a cohort of RR patients at their earliest disease stages, suggesting that brain tissue damage is milder in benign multiple sclerosis than in early RR disease. This can be due to an extraordinary beneficial response to demyelination of benign patients and may represent the evidence that benign multiple sclerosis truly exists and might be differentiated from other forms of this illness.

PMID: 16815879 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Brain atrophy after immunoablation and stem cell transplantation in multiple sclerosis. Related Articles

Brain atrophy after immunoablation and stem cell transplantation in multiple sclerosis.

Neurology. 2006 Jun 27;66(12):1935-7

Authors: Latest multiple sclerosis therapy articles Chen JT, Collins DL, Atkins HL, Freedman MS, Galal A, Arnold DL,

The authors measured brain atrophy in nine patients undergoing immunoablation and autologous hematopoietic stem cell transplantation for multiple sclerosis. From baseline to 1 month after treatment, atrophy was 10 times faster than before treatment. A patient with non-CNS lymphoma showed comparable acute brain atrophy after analogous therapy. These observations suggest that brain atrophy after immunoablation may not be due entirely to the resolution of edema but may be related to chemotoxicity.

PMID: 16801665 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis. Related Articles

Therapeutic induction of regulatory, cytotoxic CD8+ T cells in multiple sclerosis.

J Immunol. 2006 Jun 1;176(11):7119-29

Authors: Latest multiple sclerosis therapy articles Tennakoon DK, Mehta RS, Ortega SB, Bhoj V, Racke MK, Karandikar NJ

In the setting of autoimmunity, one of the goals of successful therapeutic immune modulation is the induction of peripheral tolerance, a large part of which is mediated by regulatory/suppressor T cells. In this report, we demonstrate a novel immunomodulatory mechanism by an FDA-approved, exogenous peptide-based therapy that incites an HLA class I-restricted, cytotoxic suppressor CD8+ T cell response. We have shown previously that treatment of multiple sclerosis (MS) with glatiramer acetate (GA; Copaxone) induces differential up-regulation of GA-reactive CD8+ T cell responses. We now show that these GA-induced CD8+ T cells are regulatory/suppressor in nature. Untreated patients show overall deficit in CD8+ T cell-mediated suppression, compared with healthy subjects. GA therapy significantly enhances this suppressive ability, which is mediated by cell contact-dependent mechanisms. CD8+ T cells from GA-treated patients and healthy subjects, but not those from untreated patients with MS, exhibit potent, HLA class I-restricted, GA-specific cytotoxicity. We further show that these GA-induced cytotoxic CD8+ T cells can directly kill CD4+ T cells in a GA-specific manner. Killing is enhanced by preactivation of target CD4+ T cells and may depend on presentation of GA through HLA-E. Thus, we demonstrate that GA therapy induces a suppressor/cytotoxic CD8+ T cell response, which is capable of modulating in vivo immune responses during ongoing therapy. These studies not only explain several prior observations relating to the mechanism of this drug but also provide important insights into the natural immune interplay underlying this human immune-mediated disease.

PMID: 16709875 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis. Related Articles

Anti-IL-23 therapy inhibits multiple inflammatory pathways and ameliorates autoimmune encephalomyelitis.

J Clin Invest. 2006 May;116(5):1317-26

Authors: Latest multiple sclerosis therapy articles Chen Y, Langrish CL, McKenzie B, Joyce-Shaikh B, Stumhofer JS, McClanahan T, Blumenschein W, Churakovsa T, Low J, Presta L, Hunter CA, Kastelein RA, Cua DJ

IL-23 is a member of the IL-12 cytokine family that drives a highly pathogenic T cell population involved in the initiation of autoimmune diseases. We have shown that IL-23-dependent, pathogenic T cells produced IL-17 A, IL-17 F, IL-6, and TNF but not IFN-gamma or IL-4. We now show that T-bet and STAT1 transcription factors are not required for the initial production of IL-17. However, optimal IL-17 production in response to IL-23 stimulation appears to require the presence of T-bet. To explore the clinical efficacy of targeting the IL-23 immune pathway, we generated anti-IL-23p19-specific antibodies and tested to determine whether blocking IL-23 function can inhibit EAE, a preclinical animal model of human multiple sclerosis. Anti-IL-23p19 treatment reduced the serum level of IL-17 as well as CNS expression of IFN-gamma, IP-10, IL-17, IL-6, and TNF mRNA. In addition, therapeutic treatment with anti-IL-23p19 during active disease inhibited proteolipid protein (PLP) epitope spreading and prevented subsequent disease relapse. Thus, therapeutic targeting of IL-23 effectively inhibited multiple inflammatory pathways that are critical for driving CNS autoimmune inflammation.

PMID: 16670771 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Reevaluation of P-selectin and alpha 4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis. Related Articles

Reevaluation of P-selectin and alpha 4 integrin as targets for the treatment of experimental autoimmune encephalomyelitis.

J Immunol. 2006 May 15;176(10):6225-34

Authors: Latest multiple sclerosis therapy articles Kerfoot SM, Norman MU, Lapointe BM, Bonder CS, Zbytnuik L, Kubes P

There has been a great deal of interest in adhesion molecules as targets for the treatment of multiple sclerosis and other inflammatory diseases. In this study, we systematically evaluate alpha(4) integrin and P-selectin as targets for therapy in murine models of multiple sclerosis-for the first time directly measuring the ability of their blockade to inhibit recruitment and relate this to clinical efficacy. Experimental autoimmune encephalomyelitis was induced in C57BL/6 or SJL/J mice and intravital microscopy was used to quantify leukocyte interactions within the CNS microvasculature. In both strains, pretreatment with blocking Abs to either alpha(4) integrin or P-selectin reduced firm adhesion to a similar extent, but did not block it completely. The combination of the Abs was more effective than either Ab alone, although the degree of improvement was more evident in SJL/J mice. Similarly, dual blockade was much more effective at preventing the subsequent accumulation of fluorescently labeled leukocytes in the tissue in both strains. Despite evidence of blockade of leukocyte recruitment mechanisms, no clinical benefit was observed with anti-adhesion molecule treatments or genetic deletion of P-selectin in the C57BL/6 model, or in a pertussis toxin-modified model in SJL/J mice. In contrast, Abs to alpha(4) integrin resulted in a significant delay in the onset of clinical signs of disease in the standard SJL/J model. Despite evidence of a similar ability to block firm adhesion, Abs to P-selectin had no effect. Importantly, combined blockade of both adhesion molecules resulted in significantly better clinical outcome than anti-alpha(4) integrin alone.

PMID: 16670333 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research. Related Articles

Understanding pathogenesis and therapy of multiple sclerosis via animal models: 70 years of merits and culprits in experimental autoimmune encephalomyelitis research.

Brain. 2006 Aug;129(Pt 8):1953-71

Authors: Latest multiple sclerosis therapy articles Gold R, Linington C, Lassmann H

In view of disease heterogeneity of multiple sclerosis and limited access to ex vivo specimens, different approaches must be undertaken to better understand disease pathogenesis and new therapeutic challenges. Here, we critically discuss models of experimental autoimmune encephalomyelitis (EAE) that reproduce specific features of the histopathology and neurobiology of multiple sclerosis and their shortcomings as tools to investigate emerging therapeutic approaches. By using EAE models we have understood mechanisms of T-cell mediated immune damage of the CNS, and the associated effector cascade of innate immunity. Also, the importance of humoral components of the immune system for demyelination has been delineated in EAE, before it was applied therapeutically to subtypes of multiple sclerosis. Yet, similar to multiple sclerosis, EAE is also heterogeneous and influenced by the selected autoantigen, species and the genetic background. In particular, the relevance of cytotoxic CD8 T cells for human multiple sclerosis has been underestimated in most EAE models, and no EAE model exists that mimics primary progressive disease courses of multiple sclerosis. Seventy years after the first description of EAE and the publication of >7000 articles, we are aware of the obvious limitations of EAE as a model of multiple sclerosis, but feel strongly that when used appropriately it will continue to provide a crucial tool for improving our understanding and treatment of this devastating disease.

PMID: 16632554 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells. Related Articles

Atorvastatin fails to prevent the development of autoimmune diabetes despite inhibition of pathogenic beta-cell-specific CD8 T-cells.

Diabetes. 2006 Apr;55(4):1004-10

Authors: Latest multiple sclerosis therapy articles Lozanoska-Ochser B, Barone F, Pitzalis C, Peakman M

Statins, the widely used inhibitors of cholesterol biosynthesis, also have immunomodulatory properties. Statins have recently been shown to have beneficial prophylactic and therapeutic effects in actively induced, short-term animal models of the autoimmune diseases multiple sclerosis and rheumatoid arthritis, leading to clinical trials. We therefore investigated whether statins' protective effects could be reproduced in the nonobese diabetic (NOD) mouse, a spontaneous, chronic model of autoimmune diabetes. Mice were treated with 0, 1, 10, or 50 mg x kg(-1) x day(-1) oral atorvastatin from 6 or 12 weeks of age, without effect on the rate or prevalence of diabetes development, islet infiltration, or islet major histocompatibility complex class II expression. However, there was clear evidence of a disease-relevant immunological effect of statins in vivo, since short-term (12-day) treatment significantly reduced the number of proinflammatory (gamma-interferon-producing) CD8 cells recognizing a dominant pathogenic epitope. This effect was absent in mice treated for longer periods, suggesting that atorvastatin loses efficiency in inhibiting autoantigen-specific T-cells over time. This observation may explain the discrepancy between the reported success of statins in acutely induced models and the lack of it in a chronic, spontaneous model of autoimmune disease and has implications for the adoption of such therapy in humans.

PMID: 16567522 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Natalizumab plus interferon beta-1a for relapsing multiple sclerosis. Related Articles

Natalizumab plus interferon beta-1a for relapsing multiple sclerosis.

N Engl J Med. 2006 Mar 2;354(9):911-23

Authors: Latest multiple sclerosis therapy articles Rudick RA, Stuart WH, Calabresi PA, Confavreux C, Galetta SL, Radue EW, Lublin FD, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA, Sandrock AW,

BACKGROUND: Interferon beta is used to modify the course of relapsing multiple sclerosis. Despite interferon beta therapy, many patients have relapses. Natalizumab, an alpha4 integrin antagonist, appeared to be safe and effective alone and when added to interferon beta-1a in preliminary studies. METHODS: We randomly assigned 1171 patients who, despite interferon beta-1a therapy, had had at least one relapse during the 12-month period before randomization to receive continued interferon beta-1a in combination with 300 mg of natalizumab (589 patients) or placebo (582 patients) intravenously every 4 weeks for up to 116 weeks. The primary end points were the rate of clinical relapse at 1 year and the cumulative probability of disability progression sustained for 12 weeks, as measured by the Expanded Disability Status Scale, at 2 years. RESULTS: Combination therapy resulted in a 24 percent reduction in the relative risk of sustained disability progression (hazard ratio, 0.76; 95 percent confidence interval, 0.61 to 0.96; P=0.02). Kaplan-Meier estimates of the cumulative probability of progression at two years were 23 percent with combination therapy and 29 percent with interferon beta-1a alone. Combination therapy was associated with a lower annualized rate of relapse over a two-year period than was interferon beta-1a alone (0.34 vs. 0.75, P<0.001) and with fewer new or enlarging lesions on T(2)-weighted magnetic resonance imaging (0.9 vs. 5.4, P<0.001). Adverse events associated with combination therapy were anxiety, pharyngitis, sinus congestion, and peripheral edema. Two cases of progressive multifocal leukoencephalopathy, one of which was fatal, were diagnosed in natalizumab-treated patients. CONCLUSIONS: Natalizumab added to interferon beta-1a was significantly more effective than interferon beta-1a alone in patients with relapsing multiple sclerosis. Additional research is needed to elucidate the benefits and risks of this combination treatment. (ClinicalTrials.gov number, NCT00030966.).

PMID: 16510745 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Relationship between inflammatory lesions and cerebral atrophy in multiple sclerosis. Related Articles

Relationship between inflammatory lesions and cerebral atrophy in multiple sclerosis.

Neurology. 2006 Feb 28;66(4):551-6

Authors: Latest multiple sclerosis therapy articles Richert ND, Howard T, Frank JA, Stone R, Ostuni J, Ohayon J, Bash C, McFarland HF

OBJECTIVE: To investigate the temporal relationship between inflammation and cerebral atrophy in a longitudinal study of 19 patients with relapsing-remitting multiple sclerosis (RRMS) using serial monthly contrast enhanced MRI examinations and monthly measurements of brain fractional volume (BFV) for an average of 4 (range 2.4 to 10) years. METHODS: In this retrospective study, all patients had an active MRI scan at entry with a minimum of two new contrast enhancing lesions (CEL) on baseline MRI examinations. Patients were followed for a minimum of 3 months during a baseline (pretreatment) phase and subsequently followed during treatment with recombinant interferon beta (IFN) and various other immunomodulatory agents. Pre- and post contrast axial images were obtained using 3-mm slice thickness and a gadolinium contrast dose of 0.1 mmol/kg. Monthly CEL were sequentially numbered on hardcopy films and monthly BFV was determined on precontrast T1W images using a semiautomated program. For BFV measurements, all T1W scans were registered to the entry examination, which served as a mask image. Cerebral atrophy was measured as percent brain fractional volume change (PBVC) compared to the entry baseline scan. RESULTS: The results demonstrate that cerebral atrophy paralleled that of contrast enhancing lesion accumulation. The correlation between cumulative CEL and PBVC ranged from R2 = 0.47 to 0.81. Immunomodulatory agents that effectively reduced CEL accumulation also slowed the rate of atrophy. CONCLUSIONS: The correlation between contrast enhancing lesions (CEL) and atrophy suggests that patients who are not responding to therapy with a decrease in CEL may also be at risk for developing increased atrophy.

PMID: 16505310 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event. Related Articles

IM interferon beta-1a delays definite multiple sclerosis 5 years after a first demyelinating event.

Neurology. 2006 Mar 14;66(5):678-84

Authors: Latest multiple sclerosis therapy articles Kinkel RP, Kollman C, O'Connor P, Murray TJ, Simon J, Arnold D, Bakshi R, Weinstock-Gutman B, Brod S, Cooper J, Duquette P, Eggenberger E, Felton W, Fox R, Freedman M, Galetta S, Goodman A, Guarnaccia J, Hashimoto S, Horowitz S, Javerbaum J, Kasper L, Kaufman M, Kerson L, Mass M, Rammohan K, Reiss M, Rolak L, Rose J, Scott T, Selhorst J, Shin R, Smith C, Stuart W, Thurston S, Wall M,

BACKGROUND: The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM interferon beta-1a (IFNbeta-1a) significantly slows the rate of development of clinically definite multiple sclerosis (CDMS) over 2 years in high-risk patients who experience a first clinical demyelinating event. This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]). OBJECTIVE: To determine if the benefits of IFNbeta-1a observed in CHAMPS are sustained for up to 5 years. METHODS: CHAMPS patients at participating CHAMPIONS sites were enrolled in the study. All patients were offered, but not required to take, IFNbeta-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization). Patients who received placebo in CHAMPS were considered the delayed treatment (DT) group, and patients who received IFNbeta-1a in CHAMPS were considered the immediate treatment (IT) group. The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years. RESULTS: Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS. The median time to initiation of IFNbeta-1a therapy in the DT group was 29 months. The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03). Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of neurologic symptoms. Few patients in either group developed major disability within 5 years. CONCLUSIONS: These results support the use of IM interferon beta-1a after a first clinical demyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

PMID: 16436649 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]The effect of glatiramer acetate treatment on pre-existing headaches in patients with MS. Related Articles

The effect of glatiramer acetate treatment on pre-existing headaches in patients with MS.

Neurology. 2006 Jan 24;66(2):275-7

Authors: Latest multiple sclerosis therapy articles Pöllmann W, Erasmus LP, Feneberg W, Straube A

During the first 6 months of glatiramer acetate therapy in 82 consecutive patients with multiple sclerosis, in only 6% frequency of pre-existing headaches increased by more than 50%. This is less than the headache aggravation reported in an earlier study in up to 35% of patients during the first 6 months on interferon beta.

PMID: 16434675 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging. Related Articles

Efficacy of azathioprine on multiple sclerosis new brain lesions evaluated using magnetic resonance imaging.

Arch Neurol. 2005 Dec;62(12):1843-7

Authors: Latest multiple sclerosis therapy articles Massacesi L, Parigi A, Barilaro A, Repice AM, Pellicanò G, Konze A, Siracusa G, Taiuti R, Amaducci L

BACKGROUND: Azathioprine is an immunosuppressive agent that reduces relapse rates in patients with multiple sclerosis (MS), but its efficacy in suppressing new brain lesions has never been evaluated. OBJECTIVE: To evaluate the efficacy of azathioprine therapy on new brain lesion suppression in MS. DESIGN: Open-label treatment vs baseline study. SETTING: Outpatient MS clinical center at a university hospital. PATIENTS: Fourteen patients with relapsing-remitting MS of short duration and at least 3 gadolinium-enhancing (Gd+) brain lesions observed within 6 months before treatment. INTERVENTION: Azathioprine, up to 3 mg/kg daily, individually adjusted according to blood lymphocyte number and the occurrence of adverse events. MAIN OUTCOME MEASURES: Brain Gd+ lesions evaluated by monthly magnetic resonance imaging for 6 months before and 6 months during treatment and new T2 lesions evaluated during the same periods and after an additional 6 months. RESULTS: The treatment reduced to 0 the median Gd+ lesion number and volume per magnetic resonance image (P<.001 for both), resulting in a Gd+ lesion number reduction of 50% or more in 12 of 14 patients (P<.01). An equivalent reduction in the new T2 lesion number was observed (P<.02); this activity also persisted during the additional treatment period evaluated using this outcome measure (P<.01). The median azathioprine dose administered (2.6-2.8 mg/kg daily) reduced the mean blood lymphocyte count to 57% of the baseline value. Adverse events were transient or reversible with dose adjustment. CONCLUSIONS: This study indicates for the first time that azathioprine, administered at lymphocyte-suppressing doses, is effective in reducing MS new brain inflammatory lesions and is well tolerated.

PMID: 16344342 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Pharmacogenomics of responsiveness to interferon IFN-beta treatment in multiple sclerosis: a genetic screen of 100 type I interferon-inducible genes. Related Articles

Pharmacogenomics of responsiveness to interferon IFN-beta treatment in multiple sclerosis: a genetic screen of 100 type I interferon-inducible genes.

Clin Pharmacol Ther. 2005 Dec;78(6):635-46

Authors: Latest multiple sclerosis therapy articles Cunningham S, Graham C, Hutchinson M, Droogan A, O'Rourke K, Patterson C, McDonnell G, Hawkins S, Vandenbroeck K

OBJECTIVES: Interferon IFN-beta is indicated for the treatment of multiple sclerosis. A significant proportion of patients show a poor clinical response to therapy. Type I interferon exerts its effect at least partially through interaction of specific transcription factors with interferon-stimulated response elements (ISREs), mostly located in promoter regions of its target genes. We hypothesized that polymorphisms may occur within or close to ISRE elements, altering type I interferon inducibility and ultimately leading to a modified clinical response in carriers. METHODS: We selected 100 ISRE-containing genes and sequenced their promoter regions in small genomic deoxyribonucleic acid pools of responding and nonresponding patients, as well as healthy control subjects. A selection of polymorphisms discovered by this approach was scrutinized subsequently in a collection of individual deoxyribonucleic acid samples. RESULTS: We identified 4 genes containing polymorphisms associated with response to recombinant IFN-beta: IFNAR1 (P = .036), LMP7 (P = .002; odds ratio [OR], 6.37 [95% confidence interval (CI), 1.84-24.1]), CTSS (P = .02; OR, 0.38 [95% CI, 0.18-0.84]), and MxA (P = .015; OR, 3.37 [95% CI, 1.11-11.4]). Logistic regression analysis with treatment outcome used as the dependent variable and genotype as the independent variable revealed 2 genes, LMP7 (OR, 0.55 [95% CI, 0.34-0.89]) and MxA (OR, 0.41 [95% CI, 0.19-0.88]), that were independently associated with treatment response. CONCLUSIONS: Our work confirms and extends previous indications for a polygenic mechanism involved in bringing about responsiveness to recombinant IFN-beta. The identification of 2 genes active in the antigen processing and presentation cascade; that is, LMP7, coding for the proteasome subunit beta, and CTSS, coding for cathepsin S; as potential response modifiers may identify this pathway as being of particular relevance to phenotypic expression of response heterogeneity.

PMID: 16338279 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Response to interferon beta-1a treatment in African American multiple sclerosis patients. Related Articles

Response to interferon beta-1a treatment in African American multiple sclerosis patients.

Arch Neurol. 2005 Nov;62(11):1681-3

Authors: Latest multiple sclerosis therapy articles Cree BA, Al-Sabbagh A, Bennett R, Goodin D

BACKGROUND: African Americans (AAs) with multiple sclerosis (MS) seem to have a more severe disease course than white Americans (WAs). To our knowledge, it is not known to what extent treatment with interferon beta-1a will effect the MS disease course within the AA population. OBJECTIVE: To compare the response to treatment with interferon beta-1a between AA and WA MS patients. DESIGN: This is an exploratory post hoc analysis of the Evidence of Interferon Dose-Response: European North American Comparative Efficacy (EVIDENCE) study. SETTING: The EVIDENCE study is a randomized controlled trial that compared the efficacy of once weekly, intramuscular, 30-microg interferon beta-1a treatment with thrice weekly, subcutaneous, 44-microg interferon beta-1a therapy in treatment-naïve MS subjects. PARTICIPANTS: Thirty-six AA subjects were compared with 616 WA subjects. MAIN OUTCOME MEASURES: The number of MS exacerbations, the proportion of exacerbation-free subjects, and the number of new MS lesions present on brain magnetic resonance imaging were compared between AA and WA subjects at 24 and 48 weeks after initiating treatment with interferon beta-1a. RESULTS: The AA subjects experienced more exacerbations and were less likely to remain exacerbation free (statistical trends). The AA subjects developed more new MS lesions on T2-weighted brain magnetic resonance imaging at 48 weeks (P = .04). CONCLUSIONS: Despite the small sample size, AA subjects appeared less responsive to treatment than WA subjects on outcome measures, reaching significance only for T2-weighted lesion count at 48 weeks. However, it is difficult to base these differences solely on response to treatment given the potential differing in MS disease course in AA patients.

PMID: 16286540 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. Related Articles

The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes.

J Am Coll Cardiol. 2005 Oct 18;46(8):1425-33

Authors: Latest multiple sclerosis therapy articles Ray KK, Cannon CP

Emerging data suggest that acute presentations of coronary artery disease may involve a complex interplay between the vessel wall, inflammatory cells, and the coagulation cascade. Although a culprit thrombotic lesion may be treated effectively by antithrombotic therapy and revascularization, this will have little effect on the global processes that determine recurrent events at non-culprit sites. Thus, additional systemic treatment is required to modulate the adverse biological features that are the hallmark of acute coronary syndromes (ACS). Statins possess multiple beneficial effects that are independent of low-density-lipoprotein cholesterol (LDL-C) lowering and that have favorable effects on inflammation, the endothelium, and the coagulation cascade. In the Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis In Myocardial Infarction 22 (PROVE IT-TIMI 22) trial, differences were seen based on achieved LDL-C that could be further discriminated by the achieved C-reactive protein level. Studies of non-vascular disease such as multiple sclerosis have shown that statins reduce inflammation, supporting the presence of lipid-independent effects of statins. This review focuses on the potential importance of these effects in the management of ACS.

PMID: 16226165 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]A randomized crossover study of bee sting therapy for multiple sclerosis. Related Articles

A randomized crossover study of bee sting therapy for multiple sclerosis.

Neurology. 2005 Dec 13;65(11):1764-8

Authors: Latest multiple sclerosis therapy articles Wesselius T, Heersema DJ, Mostert JP, Heerings M, Admiraal-Behloul F, Talebian A, van Buchem MA, De Keyser J

BACKGROUND: Bee sting therapy is increasingly used to treat patients with multiple sclerosis (MS) in the belief that it can stabilize or ameliorate the disease. However, there are no clinical studies to justify its use. METHODS: In a randomized, crossover study, we assigned 26 patients with relapsing-remitting or relapsing secondary progressive MS to 24 weeks of medically supervised bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20) were used to administer bee venom three times per week. The primary outcome was the cumulative number of new gadolinium-enhancing lesions on T1-weighted MRI of the brain. Secondary outcomes were lesion load on T2*-weighted MRI, relapse rate, disability (Expanded Disability Status Scale, Multiple Sclerosis Functional Composite, Guy's Neurologic Disability Scale), fatigue (Abbreviated Fatigue Questionnaire, Fatigue Impact Scale), and health-related quality of life (Medical Outcomes Study 36-Item Short Form General Health Survey). RESULTS: During bee sting therapy, there was no significant reduction in the cumulative number of new gadolinium-enhancing lesions. The T2*-weighted lesion load further progressed, and there was no significant reduction in relapse rate. There was no improvement of disability, fatigue, and quality of life. Bee sting therapy was well tolerated, and there were no serious adverse events. CONCLUSIONS: In this trial, treatment with bee venom in patients with relapsing multiple sclerosis did not reduce disease activity, disability, or fatigue and did not improve quality of life.

PMID: 16221950 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]MRI as a marker for disease heterogeneity in multiple sclerosis. Related Articles

MRI as a marker for disease heterogeneity in multiple sclerosis.

Neurology. 2005 Oct 11;65(7):1071-6

Authors: Latest multiple sclerosis therapy articles Bielekova B, Kadom N, Fisher E, Jeffries N, Ohayon J, Richert N, Howard T, Bash CN, Frank JA, Stone L, Martin R, Cutter G, McFarland HF

BACKGROUND: Whereas recent data from imaging studies challenge the prevailing notion that multiple sclerosis (MS) is purely an inflammatory disease, pathologic studies suggest differences in the disease processes between individual patients with MS. The ability to dissect the pathophysiologic disease heterogeneity, if it indeed exists, by methodologies that can be applied in vivo is important both for the development of new therapeutics and for the ability to identify the optimal therapy for an individual patient. OBJECTIVE: To design a stratification algorithm for patients with MS based on accepted MRI measurements reflective of inflammation and axonal damage/tissue loss and to assess if such MS subgroups retain their intergroup differences long term. METHODS: Mathematical modeling was used to select three discriminatory MRI measures for clinical outcome based on the cross-sectional analysis of 71 patients with untreated MS and tested general applicability of the stratification scheme on the independent longitudinal cohort of 71 MS patients. RESULTS: By consecutive employment of MRI measures reflective of inflammation and tissue loss, the authors were able to separate MS patients into four clinically meaningful subgroups. The analysis of the longitudinal confirmatory cohort demonstrated persistence of the intergroup differences in selected MRI measures for 8 years. CONCLUSIONS: The inflammatory activity and destructiveness of the multiple sclerosis process are to some degree independent of each other, and the successive evaluation of both of these variables can strengthen prediction of clinical outcome in individual patients.

PMID: 16217061 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis. Related Articles

Clinical stabilization and effective B-lymphocyte depletion in the cerebrospinal fluid and peripheral blood of a patient with fulminant relapsing-remitting multiple sclerosis.

Arch Neurol. 2005 Oct;62(10):1620-3

Authors: Latest multiple sclerosis therapy articles Stüve O, Cepok S, Elias B, Saleh A, Hartung HP, Hemmer B, Kieseier BC

BACKGROUND: The anti-CD20 monoclonal antibody rituximab effectively depletes B lymphocytes and has been successfully used in the therapy of immune-mediated disorders of the peripheral nervous system. A limited effect of rituximab on B lymphocytes in the cerebrospinal fluid compartment of patients with primary progressive multiple sclerosis (MS) was recently reported. OBJECTIVE: To determine the effect of rituximab on clinical, magnetic resonance imaging, and immunological variables in a patient with relapsing-remitting MS. DESIGN: A patient with relapsing-remitting MS was treated with rituximab. The patient was repeatedly examined clinically and by magnetic resonance imaging. The frequency of peripheral blood and cerebrospinal fluid B lymphocytes was assessed by flow cytometry before, during, and after rituximab therapy. RESULTS: Rituximab monotherapy resulted in significant clinical improvement. Inflammatory surrogate markers on magnetic resonance imaging were also reduced. B lymphocytes were depleted in the cerebrospinal fluid and peripheral blood. CONCLUSIONS: Our data demonstrate beneficial clinical effects of rituximab in relapsing-remitting MS, mediated through modulation of humoral systemic and central nervous system intrinsic immune responses. Clinical trials should determine optimal therapeutic strategies for patients with relapsing-remitting MS.

PMID: 16216948 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations. Related Articles

Therapeutic considerations for disease progression in multiple sclerosis: evidence, experience, and future expectations.

Arch Neurol. 2005 Oct;62(10):1519-30

Authors: Latest multiple sclerosis therapy articles Frohman EM, Stüve O, Havrdova E, Corboy J, Achiron A, Zivadinov R, Sorensen PS, Phillips JT, Weinshenker B, Hawker K, Hartung HP, Steinman L, Zamvil S, Cree BA, Hauser S, Weiner H, Racke MK, Filippi M

In the management of patients with multiple sclerosis (MS), providers are all faced with the highly formidable challenge of ascertaining whether, and to what degree, disease-modifying therapy is effective in the individual patient. While much has been learned in randomized, controlled clinical trials, we cannot simply extrapolate the outcomes of these initiatives and apply them to the care of a single patient. In the future, the application of pharmacogenetic techniques, proteomics, and microarray analysis will yield novel profiling information on individual patients that will substantially refine the specific therapeutic questions of relevance: (1) What is the best treatment for an individual patient? (2) Which patients require intensive therapeutic combination regimens to optimize control of the disease process? (3) What are the appropriate drug dosing targets for an individual patient? and (4) Which patients will be predisposed to the development of drug-related adverse events? Such data may provide a novel variable of drug responsiveness that will mandate its inclusion into the process of covariate analyses for clinical trials.

PMID: 16216934 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort. Related Articles

The reproductive effects of beta interferon therapy in pregnancy: a longitudinal cohort.

Neurology. 2005 Sep 27;65(6):807-11

Authors: Latest multiple sclerosis therapy articles Boskovic R, Wide R, Wolpin J, Bauer DJ, Koren G

OBJECTIVE: To determine whether interferon therapy during human pregnancy increases reproductive risks in women. METHODS: This longitudinal, controlled cohort study consisted of three groups of women: an exposed group, a disease matched unexposed group, and a healthy comparative group. Subjects were selected from women contacting the Motherisk Program regarding maternal beta interferon exposure, mostly for multiple sclerosis during pregnancy, from 1997 to 2004. After delivery all of the women were re-contacted for a follow-up interview regarding maternal health, pregnancy outcome, and neonatal health. RESULTS: The study group (n = 16 women, 23 pregnancies) were exposed to interferon beta-1a (Avonex, Rebif) and interferon-1b (Betaseron). There was a decrease in mean birth weight in the exposed group (3,189 +/- 416 g) as compared to healthy controls (3,783 +/- 412 g, p = 0.002). Women exposed to beta interferon had a higher rate of miscarriages and stillbirths (39.1%) vs healthy controls (5%) (p = 0.03), even after correction for potential confounders. There were two major malformations (abnormality in the X chromosome, Down's syndrome) among exposed fetuses. CONCLUSIONS: Beta interferon therapy in the first trimester of pregnancy appears to be associated with an increased risk for fetal loss and low birth weight.

PMID: 16186517 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody. Related Articles

Suppression of ongoing disease in a nonhuman primate model of multiple sclerosis by a human-anti-human IL-12p40 antibody.

J Immunol. 2005 Oct 1;175(7):4761-8

Authors: Latest multiple sclerosis therapy articles 't Hart BA, Brok HP, Remarque E, Benson J, Treacy G, Amor S, Hintzen RQ, Laman JD, Bauer J, Blezer EL

IL-12p40 is a shared subunit of two cytokines with overlapping activities in the induction of autoreactive Th1 cells and therefore a potential target of therapy in Th1-mediated diseases. We have examined whether ongoing disease in a nonhuman primate model of multiple sclerosis (MS) can be suppressed with a new human IgG1kappa Ab against human IL-12p40. Lesions developing in the brain white matter were visualized and characterized with standard magnetic resonance imaging techniques. To reflect the treatment of MS patients, treatment with the Ab was initiated after active brain white matter lesions were detected in T2-weighted images. In placebo-treated control monkeys we observed the expected progressive increase in the total T2 lesion volume and markedly increased T2 relaxation times, a magnetic resonance imaging marker of inflammation. In contrast, in monkeys treated with anti-IL-12p40 Ab, changes in the total T2 lesion volume and T2 relaxation times were significantly suppressed. Moreover, the time interval to serious neurological deficit was delayed from 31 +/- 10 to 64 +/- 20 days (odds ratio, 0.312). These results, in a disease model with high similarity to MS, are important for ongoing and planned trials of therapies that target IL-12 and/or IL-23.

PMID: 16177124 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Effects of interferon beta-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations. Related Articles

Effects of interferon beta-1b on black holes in multiple sclerosis over a 6-year period with monthly evaluations.

Arch Neurol. 2005 Nov;62(11):1684-8

Authors: Latest multiple sclerosis therapy articles Bagnato F, Gupta S, Richert ND, Stone RD, Ohayon JM, Frank JA, McFarland HF

BACKGROUND: Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. OBJECTIVE: To analyze the effects of interferon beta-1b in reducing the duration of T1 BHs in patients with multiple sclerosis. DESIGN: Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen. SETTING: Outpatient service of the Neuroimmunology Branch at the National Institutes of Health, Bethesda, Md. PATIENTS: Six patients with relapsing-remitting multiple sclerosis were included. One patient did not form any BHs during the therapy phase. Analyses were performed on the remaining 5 individuals. INTERVENTIONS: Interferon beta-1b at the dosage of 8 million international units every other day. MAIN OUTCOME MEASURES: Number and duration (in months) of newly formed BHs. RESULTS: Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (chi2(1) = 2.47, P = .12). CONCLUSIONS: Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.

PMID: 16157739 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury. Related Articles

Treatment of passive experimental autoimmune encephalomyelitis in SJL mice with a recombinant TCR ligand induces IL-13 and prevents axonal injury.

J Immunol. 2005 Sep 15;175(6):4103-11

Authors: Latest multiple sclerosis therapy articles Offner H, Subramanian S, Wang C, Afentoulis M, Vandenbark AA, Huan J, Burrows GG

The major goal of this study was to evaluate the efficacy and mechanism of a rTCR ligand (RTL) construct (I-A(s)/proteolipid protein (PLP)-139-151 peptide = RTL401) for treatment of SJL/J mice developing passive experimental autoimmune encephalomyelitis (EAE) that did not involve coimmunization with the highly inflammatory CFA. Our results demonstrated clearly that RTL401 was highly effective in treating passive EAE, with kinetics of recovery from disease very similar to treatment of actively induced EAE. The potent RTL401 treatment effect was reflected by a partial reduction of infiltrating mononuclear cells into CNS, minimal inflammatory lesions in spinal cord, and preservation of axons injured in vehicle-treated mice during the progression of EAE. Interestingly, in the absence of CFA, RTL401 treatment strongly enhanced production of the Th2 cytokine, IL-13, in spleen, blood, and spinal cord tissue, with variable effects on other Th1 and Th2 cytokines, and no significant effect on the Th3 cytokine, TGF-beta1, or on FoxP3 that is expressed by regulatory T cells. Moreover, pretreatment of PLP-139-151-specific T cells with RTL401 in vitro induced high levels of secreted IL-13, with lesser induction of other pro- and anti-inflammatory cytokines. Given the importance of IL-13 for protection against EAE, these data strongly implicate IL-13 as a dominant regulatory cytokine induced by RTL therapy. Pronounced IL-13 levels coupled with marked reduction in IL-6 levels secreted by PLP-specific T cells from blood after treatment of mice with RTL401 indicate that IL-13 and IL-6 may be useful markers for following effects of RTL therapy in future clinical trials in multiple sclerosis.

PMID: 16148160 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Telephone-administered psychotherapy for depression. Related Articles

Telephone-administered psychotherapy for depression.

Arch Gen Psychiatry. 2005 Sep;62(9):1007-14

Authors: Latest multiple sclerosis therapy articles Mohr DC, Hart SL, Julian L, Catledge C, Honos-Webb L, Vella L, Tasch ET

BACKGROUND: Several studies have shown that telephone-administered cognitive-behavioral therapy (T-CBT) is superior to forms of no treatment controls. No study has examined if the skills-training component to T-CBT provides any benefit beyond that provided by nonspecific factors. OBJECTIVE: To test the efficacy of a 16-week T-CBT against a strong control for attention and nonspecific therapy effects. DESIGN: Randomized controlled trial including 12-month follow-up. SETTING: Telephone administration of psychotherapy with patients in their homes. PARTICIPANTS: Participants had depression and functional impairments due to multiple sclerosis. INTERVENTIONS: A 16-week T-CBT program was compared with 16 weeks of telephone-administered supportive emotion-focused therapy. MAIN OUTCOME MEASURES: Hamilton Depression Rating Scale score, Structured Clinical Interview for DSM-IV diagnosis of major depressive disorder, Beck Depression Inventory score, and Positive Affect scale score of the Positive and Negative Affect Scale. RESULTS: Of the 127 participants randomized, 7 (5.5%) dropped out of treatment. There were significant improvement during treatment on all outcome measures (P<.01 for all) and an increase in Positive Affect Scale score. Improvements over 16 weeks of treatment were significantly greater for T-CBT, compared with telephone-administered supportive emotion-focused therapy, for major depressive disorder frequency (P = .02), Hamilton Depression Rating Scale score (P = .02), and Positive Affect Scale score (P = .008), but not for the Beck Depression Inventory score (P = .29). Treatment gains were maintained during 12-month follow-up; however, differences across treatments were no longer evident (P > .16 for all). CONCLUSIONS: Patients showed significant improvements in depression and positive affect during the 16 weeks of telephone-administered treatment. The specific cognitive-behavioral components of T-CBT produced improvements above and beyond the nonspecific effects of telephone-administered supportive emotion-focused therapy on evaluator-rated measures of depression and self-reported positive affect. Attrition was low.

PMID: 16143732 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]Increased risk for demyelinating diseases in patients with inflammatory bowel disease. Related Articles

Increased risk for demyelinating diseases in patients with inflammatory bowel disease.

Gastroenterology. 2005 Sep;129(3):819-26

Authors: Latest multiple sclerosis therapy articles Gupta G, Gelfand JM, Lewis JD

BACKGROUND & AIMS: Reports of multiple sclerosis (MS), demyelination, and optic neuritis (ON) associated with anti-tumor necrosis factor alpha therapy resulted in warnings on prescribing instructions for infliximab, etanercept, and adalimumab. However, the underlying relationship between IBD and these neurologic conditions has not been established. METHODS: We performed a retrospective cohort study and a retrospective cross-sectional study using 1988 to 1997 data from the General Practice Research Database. A total of 7988 Crohn's disease and 12,185 ulcerative colitis patients were matched for age, sex, and primary care practice to 80,666 randomly selected controls. In the cohort study, incident cases of MS, demyelination, and/or ON (MS/D/ON) had to occur at least 1 year after registration with the physician and after the diagnosis of IBD. In the cross-sectional study, the diagnosis of MS/D/ON could either precede or follow the IBD diagnosis. RESULTS: In the cohort study, the incidence of MS/D/ON was higher in patients with Crohn's disease and ulcerative colitis compared with their matched controls, reaching statistical significance for ulcerative colitis (ulcerative colitis incidence rate ratio [IRR], 2.63; 95% confidence interval, 1.29-5.15; Crohn's disease IRR, 2.12; 95% confidence interval, .94-4.50). In the cross-sectional study, MS/D/ON was more prevalent in patients with Crohn's disease and ulcerative colitis compared with their matched controls (Crohn's disease odds ratio, 1.54; 95% confidence interval, 1.03-2.32; ulcerative colitis odds ratio, 1.75; 95% confidence interval, 1.28-2.39). CONCLUSIONS: Demyelinating diseases occur more commonly among patients with IBD than among non-IBD patients. Future studies should clarify whether treatment with tumor necrosis factor alpha blockers results in further increased incidence of MS/D/ON among IBD patients.

PMID: 16143121 [PubMed - indexed for MEDLINE :- Latest multiple sclerosis therapy articles]

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