Multiple Sclerosis: Goodin DS

Goodin DS, Arnason BG, Coyle PK, Frohman EM, Paty DW, Anonymous00113. · Therapeutics and Technology Assessment Subcommittee, American Academy of Neurology, St. Paul, MN 55116, USA. · Neurology. · Pubmed #14638950 No free full text.

Abstract: Mitoxantrone is the first drug approved for the treatment of secondary progressive multiple sclerosis (SPMS) in the United States. This assessment considers use of mitoxantrone in the treatment of MS. Mitoxantrone probably reduces the clinical attack rate and reduces attack-related MRI outcomes in patients with relapsing MS (Type B recommendation). Also, mitoxantrone may have a beneficial effect on disease progression in patients with MS whose clinical condition is worsening (Type B recommendation). The potential for serious toxicity of mitoxantrone, however, must be taken into account when considering this therapy in individual patients. Moreover, because the potential clinical benefits on disease progression appear to be only modest, the results of the single phase III trial should be replicated in another (and hopefully much larger) clinical study before this agent is widely recommended for the treatment of patients with MS.

Frohman EM, Goodin DS, Calabresi PA, Corboy JR, Coyle PK, Filippi M, Frank JA, Galetta SL, Grossman RI, Hawker K, Kachuck NJ, Levin MC, Phillips JT, Racke MK, Rivera VM, Stuart WH, Anonymous00118. · University of Texas Southwestern Medical Center at Dallas, USA. · Neurology. · Pubmed #12963748 No free full text.

Abstract: Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Goodin DS, Frohman EM, Garmany GP, Halper J, Likosky WH, Lublin FD, Silberberg DH, Stuart WH, van den Noort S, Anonymous00242. · No affiliation provided · Neurology. · Pubmed #11805241 No free full text.

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Arnold DL, Goodin DS. · No affiliation provided · Ann Neurol. · Pubmed #19334057 No free full text.

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Goodin DS. · No affiliation provided · Ann Neurol. · Pubmed #18626947 No free full text.

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Goodin DS, Cohen BA, O'Connor P, Kappos L, Stevens JC, Anonymous00358. · University of California at San Francisco, USA. · Neurology. · Pubmed #18765653 No free full text.

Abstract: The clinical and radiologic impact of natalizumab (Tysabri) as therapy for multiple sclerosis (MS) is assessed. On the basis of Class I evidence, natalizumab has been demonstrated to reduce measures of disease activity and to improve measures of disease severity in patients with relapsing-remitting (RR) MS (Level A). The relative efficacy of natalizumab compared to current disease-modifying therapies cannot be defined accurately (Level U). Similarly, the value of natalizumab in the treatment of secondary progressive (SP) MS is unknown (Level U). The value of combination therapy using natalizumab and interferon in the treatment of RRMS is also unknown (Level U). There is an increased risk of developing progressive multifocal leukoencephalopathy (PML) in natalizumab-treated patients (Level A for combination therapy, Level C for monotherapy) and possibly an increased risk of other opportunistic infections (Level C). The PML risk in a pooled clinical trial cohort has been estimated to be 1 person for every 1,000 patients treated for an average of 17.9 months, although this figure could change in either direction with more experience with the drug.

Goodin DS, Biermann LD, Bohlega S, Boiko A, Chofflon M, Gebeily S, Gouider R, Havrdova E, Jakab G, Karabudak R, Karussis D, Miller A, Pakdaman H, Selmaj K, Sharief M, Anonymous00295. · Department of Neurology, University of California, San Francisco, CA 94121, USA. email: · Curr Med Res Opin. · Pubmed #17908370 No free full text.

Abstract: BACKGROUND: As results from an increasing number of clinical trials with disease-modifying drugs (DMDs) in multiple sclerosis (MS) become available, the challenge for the treating neurologist is how to decide on the appropriate therapy for an individual patient. OBJECTIVE: An International Working Group for Treatment Optimization in MS met to consider how the principles of evidence-based medicine (EBM) should be used to assess the current best evidence regarding the treatment of MS. This report summarizes the outcome from the workshop at which this topic was addressed. RESULTS: Class I evidence from head-to-head studies provides the best tool for direct comparisons of DMDs. However, other EBM approaches to data analysis from placebo-controlled trials can be used to help determine the benefits and risks of a particular DMD relative to placebo by calculating the number needed to treat to achieve a positive outcome, such as avoiding a relapse, and the number needed to harm to produce an additional adverse event, such as having a therapy-related dropout. This provides a structured basis for comparisons between DMDs. CONCLUSION: While such comparisons have their limitations, particularly when drugs with substantially different side-effect profiles are to be compared, they can provide useful information to guide treatment decisions.

Goodin DS. · Department of Neurology, University of California, San Francisco, San Francisco, CA 94143-0114, USA. · Ann Neurol. · Pubmed #16566022 No free full text.

Abstract: OBJECTIVE: The validity of magnetic resonance imaging (MRI) as a surrogate outcome measure in multiple sclerosis (MS) clinical trials has been greeted skeptically both by the US Food and Drug Administration and by clinical researchers because the correlation between current MRI measures and clinical disability, although significant, has generally been low. Thus, the reported correlations have varied between rho = 0.09 and rho = 0.60, and have often been at the lower end of this range. Nevertheless, it still appears possible that this apparently poor correlation is due not to any deficiency either with our current MRI measures or with our disability scale, but rather to the intrinsic variability in the clinical expression of MS plaques in different anatomical locations. METHODS: This article explores this possibility through the development of a general mathematical model for the relation between MRI changes and clinical disability in patients with MS. RESULTS: Under the conditions of this general model, the maximum expected correlation between clinical disability and MRI will typically be quite low (eg, rho = 0.2-0.3), even when it is assumed that the MRI changes are the sole determinant of disability and, furthermore, that the scale used to measure disability is ideal. INTERPRETATION: These observations, together with the significant relations already reported between MRI and disability (with observed correlations in the range of 0.2-0.6), actually suggest that our available clinical and MRI measures are considerably better than is currently believed and, in fact, that the MRI may be a valid surrogate marker in the assessment of treatment efficacy in MS.

Goodin DS. · Department of Neurology, University of California, San Francisco, USA. · Int MS J. · Pubmed #16422017 links to  free full text

Abstract: Evidence-based medicine (EBM) describes a structured (non-consensus-based) process, in which medical literature is assessed critically to define the value of different therapeutic interventions. Ultimately, the goal is to improve both physician decision making and patient outcome. These assessments begin by defining the specific clinical questions to be answered. Following a structured literature search, evidence that bears on these questions is assembled and classified with respect to the quality of the evidence provided by each study. Lastly, using a set of pre-specified rules, this evidence is translated into specific conclusions and recommendations. Its relative objectivity means that evidence-based medicine can be a powerful tool for practising physicians. As a result, it is important for them to become familiar with this analytical method.

Goodin DS. · Department of Neurology, University of California at San Francisco, Fort Miley Veterans Administration Hospital, 94121, USA. · Int MS J. · Pubmed #16417818 links to  free full text

Abstract: The present manuscript uses an evidence-based approach to review and analyse evidence for the use of human beta interferon in the treatment of MS. Human beta interferon modulates many of the biological processes believed to be involved in MS development. Beta interferon is a member of a large family of secreted proteins that are involved in an organisms defence against viral infections, cell growth regulation and in modulation of immune response. The therapeutic efficacy of beta interferon in relapsing-remitting and secondary progressive MS has been established in several clinical trials, and evidence indicates that the total weekly dosage of beta interferon and/or the frequency of beta interferon administration are important factors in its clinical use. Future therapeutic developments in MS will be fuelled by our increasing understanding of the physical and biological roles of the interferons, in health and in MS pathogenesis.

Goodin DS. · Department of Neurology Room M794, University of California San Francisco, 505 Parnassus Avenue, San Francisco, CA 94143-0114, USA. · J Neurol. · Pubmed #15549356 No free full text.

Abstract: The use of so-called evidence-based medicine represents a structured way in which to critically assess the medical literature with the goal of defining the value of different therapeutic interventions and, ultimately, improving both physician decision-making and patient outcome. This is not a consensus-based process of the type that has often been employed previously in the development of treatment guidelines. Rather, these assessments involve a series of structured steps. Initially, the specific clinical questions to be answered are defined and the evidence is assembled following a structured literature search. Then, the individual studies are classified as to the quality of the evidence provided, and, finally, using a set of pre-specified rules, this evidence is translated into specific recommendations and conclusions. In this manner, evidence-based medicine can be a very powerful tool for practicing physicians and, consequently, it is important that they become familiar with the fundamentals of this analytical approach. It is the purpose of this manuscript, therefore, to provide an overview of this process using examples from two recently completed assessments on disease-modifying therapies in multiple sclerosis.

Goodin DS. · Department of Neurology, Room M794, University of California San Francisco, 505 Parnassus Avenue, San Francisco, California 94143-0114, USA. · J Neurol. · Pubmed #15549352 No free full text.

Abstract: Several types of errors are commonly made during the conduct, analysis, and interpretation of clinical trials in multiple sclerosis (MS). These include statistical errors of overestimating the significance of trial results, particularly when multiple endpoints are evaluated. They also include errors arising from the use of inappropriate covariate analyses, meta-analyses, and post hoc subgroup analyses. Interpretation of trial results can also be confounded by regression to the mean, by post hoc data re-analysis, and by the use of a non-concurrent control population. As these kinds of errors continue to plague the medical literature, it has become important for physicians to be able to assess critically the reports of clinical trial results. In turn, this has made it necessary for physicians to become familiar with the rudiments of the fields of statistics, epidemiology, and trial design. It is the purpose of this manuscript, therefore, to provide an overview of these principles through a detailed analysis of these kinds of clinical trial errors, together with examples that have actually occurred in the recently published MS literature.

Cree BA, Goodin DS, Hauser SL. · Department of Neurology, University of California San Francisco, USA. · Semin Neurol. · Pubmed #12524556 No free full text.

Abstract: Whether neuromyelitis optica (NMO), the co-occurrence of myelitis and optic neuritis, is a variant of multiple sclerosis (MS) or a unique disease is controversial. Distinct neuropathological features and a fulminant clinical course argue in favor of NMO as a distinct disease. However, the combination of neurological impairments of myelitis and optic neuritis occurs in patients with several inflammatory disorders, including multiple sclerosis and collagen vascular diseases. NMO is also associated with certain infectious diseases. The fact that the NMO phenotype occurs in a variety of disease states suggests that NMO does not represent a specific clinical entity. To better understand NMO and its associations with recognized diseases, a systematic review of the literature using MEDLINE was conducted. The history of NMO, its nosology, associations with other diseases, and current concepts of its pathogenesis and treatment is reviewed in this article.

Goodin DS. · Department of Neurology, University of California, San Francisco 94143-0114, USA. · Drugs. · Pubmed #11693459 No free full text.

Abstract: There have been considerable advances made recently in the treatment of multiple sclerosis (MS). In particular, interferon (IFN)beta has been demonstrated in several independent, multicentre clinical trials to lower unequivocally the biological activity of this illness. The results of these trials have been remarkably consistent, demonstrating a reduction in both disease activity and cumulative disability, using a combination of clinical and magnetic resonance imaging outcome measures. Nevertheless, the importance of the total weekly IFNbeta dose in the clinical management of individual patients has been controversial. However, there is considerable information available regarding the effect of IFNbeta dose on the various biochemical and clinical markers that are affected by IFNbeta, which is derived both from pre-clinical studies and multicentre clinical trials. On balance, convincing evidence is provided to support the notion that there is a clinically relevant dose-response in the use of IFNbeta to treat patients with relapsing/remitting MS. However, many of the clinical trials of IFNbeta in MS have confounded the potential effects of dose with the possible effects of frequency of IFNbeta administration. As a result, it is possible that the apparent dose-response observed in these clinical trials may be due, in part, to the more frequent dose administration schedule rather than the total weekly dose.

Goodin DS. · Department of Neurology, M-794, University of California, San Francisco, CA 94143-0114, USA. · Expert Opin Investig Drugs. · Pubmed #11060700 No free full text.

Abstract: Recently there have been considerable advances made in the treatment of multiple sclerosis. For the first time since its initial clinical description in the 1800s, there are now available several medications which unequivocally exert favourable clinical effects through the lowering of the biological activity of the human illness. The therapeutic efficacy of IFN-beta preparations seems particularly well established in this regard on the basis of five large, independent, trials of this agent. These trials have demonstrated remarkably consistent reductions in both attack rates and disability levels using a combination of clinical and magnetic resonance imaging outcome measures. The therapeutic benefit of glatiramer acetate also has been well established, although there is less available data on this agent than there is for interferon. It is important to recognise, however, that, although these agents represent an important first step in the management of patients with multiple sclerosis, they are only partial therapies. In order to actually cure the illness or even to substantially improve patient outcome we need considerably better agents than we have currently. Nevertheless, it is likely that, with improved knowledge of the role that interferon beta plays in the pathogenesis of multiple sclerosis and with better understanding of the mechanism by which glatiramer acetate exerts its therapeutic effect, greatly improved therapeutic agents will be available in the future. In addition, it seems likely that, in the future (by analogy to the experience in oncology), we will begin utilising combinations of therapies in order to better control the biological activity of this debilitating disease. Such combination therapy will almost certainly include combinations of partially effective agents as well as combinations of these agents with other medications (e.g., the immunosuppressive drugs) which, by themselves, have only been demonstrated to exert marginal clinical benefits on the course of illness. Moreover, it also seems likely that, increasingly, therapeutic strategies that enhance or promote myelin repair will become a major focus of clinical research in this area.

Goodin DS. · Department of Neurology, University of California, San Francisco, Calif. 94143-0114, USA. · Neuroepidemiology. · Pubmed #10023128 No free full text.

Abstract: Therapeutic trials in multiple sclerosis, in part because of the marked intra- and inter-individual variability of its clinical course, are prone to serious flaws in both design and interpretation. As a consequence, it has been a common historical pattern that treatment regimens, which are enthusiastically recommended at one point in time, are later proven to be ineffective by more definitive studies. This review considers several recently published therapeutic trials in order to exemplify some of the difficulties that commonly arise in this area of clinical research.

Panitch H, Goodin DS, Francis G, Chang P, Coyle PK, O'Connor P, Monaghan E, Li D, Weinshenker B, Anonymous00008, Anonymous00009. · University of Vermont College of Medicine, Burlington, VT 05401, USA. · Neurology. · Pubmed #12451188 No free full text.

Abstract: BACKGROUND: Interferon beta (IFNbeta) reduces relapses and MRI activity in relapsing-remitting MS (RRMS), with variable effects on disability. The most effective dose regimen remains controversial. METHODS: This randomized, controlled, multicenter trial compared the efficacy and safety of IFNbeta-1a (Rebif) 44 micro g subcutaneously three times weekly (tiw), and IFNbeta-1a (Avonex) 30 micro g IM once weekly (qw) in 677 patients with RRMS. Assessors blinded to treatment performed neurologic and MRI evaluations. The primary endpoint was the proportion of patients who were relapse free at 24 weeks; the principal MRI endpoint was the number of active lesions per patient per scan at 24 weeks. RESULTS: After 24 weeks, 74.9% (254/339) of patients receiving IFNbeta-1a 44 micro g tiw remained relapse free compared with 63.3% (214/338) of those given 30 micro g qw. The odds ratio for remaining relapse free was 1.9 (95% CI, 1.3 to 2.6; p = 0.0005) at 24 weeks and 1.5 (95% CI, 1.1 to 2.1; p = 0.009) at 48 weeks, favoring 44 micro g tiw. Patients receiving 44 micro g tiw had fewer active MRI lesions (p < 0.001 at 24 and 48 weeks) compared with those receiving 30 micro g qw. Injection-site reactions were more frequent with 44 micro g tiw (83% vs 28%, p < 0.001), as were asymptomatic abnormalities of liver enzymes (18% vs 9%, p = 0.002) and altered leukocyte counts (11% vs 5%, p = 0.003) compared with the 30 micro g qw dosage. Neutralizing antibodies developed in 25% of 44 micro g tiw patients and in 2% of patients receiving 30 micro g qw. CONCLUSIONS: IFNbeta-1a 44 micro g subcutaneously tiw was more effective than IFNbeta-1a 30 micro g IM qw on all primary and secondary outcomes investigated after 24 and 48 weeks of treatment.

Mowry EM, Beheshtian A, Waubant E, Goodin DS, Cree BA, Qualley P, Lincoln R, George MF, Gomez R, Hauser SL, Okuda DT, Pelletier D. · Department of Neurology, University of California, San Francisco, 94117, USA. · Neurology. · Pubmed #19451531 No free full text.

Abstract: BACKGROUND: Health-related quality of life (HRQOL) is reduced in multiple sclerosis (MS). It is unclear whether HRQOL is associated with white matter lesion burden or measures of brain atrophy. METHODS: A cross-sectional baseline analysis of 507 patients with MS in a prospective cohort study at the University of California, San Francisco was performed. Multivariate linear regression models were used to determine whether MRI measures were associated with the Emotional Well-Being and Thinking/Fatigue subscale scores of the Functional Assessment in Multiple Sclerosis, a validated HRQOL measure in MS. The difference in each MRI metric associated with a minimal clinically important difference in each HRQOL subscale was calculated. RESULTS: Higher T1 lesion load (15 mL; p = 0.024), normalized T1 lesion volume (20 mL; p = 0.016), or T2 lesion load (25 mL; p = 0.028) was associated with worse scores for Emotional Well-Being. Meaningfully lower scores on this subscale were correlated with lower normalized gray matter volume (118 mL; p = 0.037). Reduced Thinking/Fatigue scores were associated with higher normalized T1 lesion volume (21 mL; p = 0.024), or T2 lesion load (22 mL; p = 0.010) and with lower normalized gray matter (87 mL; p = 0.004), white matter (85 mL; p = 0.025), or brain parenchymal (98 mL; p = 0.001) volume. CONCLUSIONS: Aspects of health-related quality of life (HRQOL) in multiple sclerosis are associated with MRI evidence of white matter lesions and brain atrophy. These findings strengthen the argument for the use of HRQOL outcome measures in trials and suggest that lesion burden on conventional MRI is important for HRQOL.

Goodin DS. · Department of Neurology, University of California San Francisco, San Francisco, California, USA. · PLoS One. · Pubmed #19242548 links to  free full text

Abstract: BACKGROUND: MS pathogenesis seems to involve both genetic susceptibility and environmental risk factors. Three sequential factors are implicated in the environmental risk. The first acts near birth, the second acts during childhood, and the third acts long thereafter. Two candidate factors (vitamin D deficiency and Epstein-Barr viral infection) seem well suited to the first two environmental events. METHODOLOGY/PRINCIPAL FINDINGS: A mathematical Model for MS pathogenesis is developed, incorporating these environmental and genetic factors into a causal scheme that can explain some of the recent changes in MS-epidemiology (e.g., increasing disease prevalence, a changing sex-ratio, and regional variations in monozygotic twin concordance rates). CONCLUSIONS/SIGNIFICANCE: This Model suggests that genetic susceptibility is overwhelmingly the most important determinant of MS pathogenesis. Indeed, over 99% of individuals seem genetically incapable of developing MS, regardless of what environmental exposures they experience. Nevertheless, the contribution of specific genes to MS-susceptibility seems only modest. Thus, despite HLA DRB1*1501 being the most consistently identified genetic marker of MS-susceptibility (being present in over 50% of northern MS patient populations), only about 1% of individuals with this allele are even genetically susceptible to getting MS. Moreover, because genetic susceptibility seems so similar throughout North America and Europe, environmental differences principally determine the regional variations in disease characteristics. Additionally, despite 75% of MS-patients being women, men are 60% more likely to be genetically-susceptible than women. Also, men develop MS at lower levels of environmental exposure than women. Nevertheless, women are more responsive to the recent changes in environmental-exposure (whatever these have been). This explains both the changing sex-ratio and the increasing disease prevalence (which has increased by a minimum of 32% in Canada over the past 35 years). As noted, environmental risk seems to result from three sequential components of environmental exposure. The potential importance of this Model for MS pathogenesis is that, if correct, a therapeutic strategy, designed to interrupt one or more of these sequential factors, has the potential to markedly reduce or eliminate disease prevalence in the future.

Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, Hauser SL, Pelletier D. · Department of Neurology, University of California San Francisco, UCSF Multiple Sclerosis Center, San Francisco, CA 94117, USA. · Neurology. · Pubmed #19073949 No free full text.

Abstract: BACKGROUND: The discovery and broad application of MRI in medicine has led to an increased awareness in the number of patients with incidental white matter pathology in the CNS. Routinely encountered in clinical practice, the natural history or evolution of such individuals with respect to their risk of developing multiple sclerosis (MS) is unclear. OBJECTIVE: To investigate the natural history of patients who exhibit incidental imaging findings highly suggestive of MS pathology. METHODS: Detailed clinical and radiologic data were obtained from asymptomatic patients with MRI anomalies suggestive of MS. RESULTS: The cohort consisted of 41 female and 3 male subjects (median age = 38.5, range: 16.2-67.1). Clinical evaluations were performed in 44 patients at the time of initial imaging; longitudinal clinical follow-up occurred for 30 patients, and longitudinal MRI data were acquired for 41 patients. Neurologic examination at the time of the initial MRI scans was normal in nearly all cases. While radiologic progression was identified in 59% of cases, only 10 patients converted to either clinically isolated syndrome or definite MS. The presence of contrast-enhancing lesions on the initial MRI was predictive of dissemination in time on repeat imaging of the brain (hazard ratio [HR] = 3.4, 95% confidence interval [1.3, 8.7], p = 0.01). CONCLUSION: Individuals with MRI anomalies highly suggestive of demyelinating pathology, not better accounted for by another disease process, are very likely to experience subsequent radiologic or clinical events related to multiple sclerosis. Additional studies will be necessary to fully define this risk.

Goodin DS. · Department of Neurology, University of California, San Francisco, CA, USA. · Neurology. · Pubmed #19064873 No free full text.

Abstract: As new therapies become available for the treatment of multiple sclerosis, the relative value of established and newer disease-modifying therapies must be considered. However, comparing the apparent efficacy of different agents across clinical trials is not easy and can be misleading when different therapies have been studied during different time periods. There has been a shift in current clinical trials toward enrolling patients with less advanced or less active disease compared with trials undertaken when no effective therapies were available. If early treatment is more effective than late treatment, this practice will produce a bias in favor of newer agents. Head-to-head trials offer the most reliable means of comparing therapies, but these trials are expensive and time consuming. Consequently, cross-trial comparisons are necessary, but a reliable means to make such comparisons is needed. One useful (but imperfect) approach is to compute the relative risk of therapy and the number-needed-to-treat, applying both measures to any cross-trial comparison. These measures capture different aspects of the trials (relative and absolute differences) and, if they agree, this suggests that the cross-trial comparison may be valid. If the two methods disagree, no reliable conclusion about relative efficacy can be made. There are only two valid conclusions from the available head-to-head and cross-trial data. First, high-dose interferon-beta (IFN beta)-1a or IFN beta-1b subcutaneous has a greater impact than weekly IFN beta-1a IM on several clinical and MRI outcomes. Second, high-dose IFN beta-1a or IFN beta-1b subcutaneous has a similar clinical impact to glatiramer acetate, although IFN beta subcutaneous is superior on some MRI outcome measures.

Okuda DT, Srinivasan R, Oksenberg JR, Goodin DS, Baranzini SE, Beheshtian A, Waubant E, Zamvil SS, Leppert D, Qualley P, Lincoln R, Gomez R, Caillier S, George M, Wang J, Nelson SJ, Cree BA, Hauser SL, Pelletier D. · UCSF Multiple Sclerosis Center, University of California, San Francisco, San Francisco, California 94117, USA. · Brain. · Pubmed #19022862 No free full text.

Abstract: Genetic susceptibility to multiple sclerosis (MS) is associated with the human leukocyte antigen (HLA) DRB1*1501 allele. Here we show a clear association between DRB1*1501 carrier status and four domains of disease severity in an investigation of genotype-phenotype associations in 505 robust, clinically well characterized MS patients evaluated cross-sectionally: (i) a reduction in the N-acetyl-aspartate (NAA) concentration within normal appearing white matter (NAWM) via (1)HMR spectroscopy (P = 0.025), (ii) an increase in the volume of white matter (WM) lesions utilizing conventional anatomical MRI techniques (1,127 mm(3); P = 0.031), (iii) a reduction in normalized brain parenchymal volume (nBPV) (P = 0.023), and (iv) impairments in cognitive function as measured by the Paced Auditory Serial Addition Test (PASAT-3) performance (Mean Z Score: DRB1*1501+: 0.110 versus DRB1*1501-: 0.048; P = 0.004). In addition, DRB1*1501+ patients had significantly more women (74% versus 63%; P = 0.009) and a younger mean age at disease onset (32.4 years versus 34.3 years; P = 0.025). Our findings suggest that DRB1*1501 increases disease severity in MS by facilitating the development of more T2-foci, thereby increasing the potential for irreversible axonal compromise and subsequent neuronal degeneration, as suggested by the reduction of NAA concentrations in NAWM, ultimately leading to a decline in brain volume. These structural aberrations may explain the significant differences in cognitive performance observed between DRB1*1501 groups. The overall goal of a deep phenotypic approach to MS is to develop an array of meaningful biomarkers to monitor the course of the disease, predict future disease behaviour, determine when treatment is necessary, and perhaps to more effectively recommend an available therapeutic intervention.

Baranzini SE, Wang J, Gibson RA, Galwey N, Naegelin Y, Barkhof F, Radue EW, Lindberg RL, Uitdehaag BM, Johnson MR, Angelakopoulou A, Hall L, Richardson JC, Prinjha RK, Gass A, Geurts JJ, Kragt J, Sombekke M, Vrenken H, Qualley P, Lincoln RR, Gomez R, Caillier SJ, George MF, Mousavi H, Guerrero R, Okuda DT, Cree BA, Green AJ, Waubant E, Goodin DS, Pelletier D, Matthews PM, Hauser SL, Kappos L, Polman CH, Oksenberg JR. · Department of Neurology, University of California, San Francisco, CA 94143-0435, USA. · Hum Mol Genet. · Pubmed #19010793 No free full text.

Abstract: Multiple sclerosis (MS), a chronic disorder of the central nervous system and common cause of neurological disability in young adults, is characterized by moderate but complex risk heritability. Here we report the results of a genome-wide association study performed in a 1000 prospective case series of well-characterized individuals with MS and group-matched controls using the Sentrix HumanHap550 BeadChip platform from Illumina. After stringent quality control data filtering, we compared allele frequencies for 551 642 SNPs in 978 cases and 883 controls and assessed genotypic influences on susceptibility, age of onset, disease severity, as well as brain lesion load and normalized brain volume from magnetic resonance imaging exams. A multi-analytical strategy identified 242 susceptibility SNPs exceeding established thresholds of significance, including 65 within the MHC locus in chromosome 6p21.3. Independent replication confirms a role for GPC5, a heparan sulfate proteoglycan, in disease risk. Gene ontology-based analysis shows a functional dichotomy between genes involved in the susceptibility pathway and those affecting the clinical phenotype.

Goodin DS, Hurwitz B, Noronha A. · Department of Neurology, University of California, San Francisco 94143-0114, USA. · J Int Med Res. · Pubmed #17542405 No free full text.

Abstract: The clinical impact of neutralizing antibodies (NAbs) on interferon beta (IFNbeta) efficacy was studied in three large patient cohorts comprising 6698 multiple sclerosis (MS) patients receiving IFNbeta-1b across North America, Europe, and Australia. In North America and Europe, NAb testing was generally undertaken because of a poor clinical response; in Australia, it was mandatory for every patient. Of the 6697 patients tested, 28.9% had at least one NAb titre > or = 20 neutralizing units (NU)/ml, 14.4% had NAb titres > or = 100 NU/ml and 7.7% had NAb titres > or = 400 NU/ml. The NAb-positive rate of 37.0% in Australia was significantly greater than those in North America (21.3%) and Europe (27.6%), and this was observed at every NAb titre level. Our results suggest that NAbs are not responsible for poor clinical responses and that NAb status is of little clinical value. These findings will need to be confirmed in a large independent study.

Goodin DS. · No affiliation provided · Neurology. · Pubmed #17030783 No free full text.

This publication has no abstract.