Multiple Sclerosis: Montalban X

Polman CH, Reingold SC, Barkhof F, Calabresi PA, Clanet M, Cohen JA, Cutter GR, Freedman MS, Kappos L, Lublin FD, McFarland HF, Metz LM, Miller AE, Montalban X, O'Connor PW, Panitch H, Richert JR, Petkau J, Schwid SR, Sormani MP, Thompson AJ, Weinshenker BG, Wolinsky JS. · Department of Neurology, Free University Medical Center in Amsterdam, PO Box 4075, 1007 MB Amsterdam, The Netherlands. · Neurology. · Pubmed #18362273 No free full text.

Abstract: The increasing number of established effective therapies for relapsing multiple sclerosis (MS) and emerging consensus for early treatment raise practical concerns and ethical dilemmas for placebo-controlled clinical trials in this disease. An international group of clinicians, ethicists, statisticians, regulators, and representatives from the pharmaceutical industry convened to reconsider prior recommendations regarding the ethics of placebo-controlled trials in MS. The group concluded that placebo-controlled trials can still be done ethically, with restrictions. For patients with relapsing MS for which established effective therapies exist, placebo-controlled trials should only be offered with rigorous informed consent if the subjects refuse to use these treatments, have not responded to them, or if these treatments are not available to them for other reasons (e.g., economics). Suggestions are provided to protect subject autonomy and improve informed consent procedures. Recommendations are tighter than previously suggested for placebo-controlled trials in "resource-restricted" environments where established therapies may not be available. Guidance is also provided on the ethics of alternative trial designs and the balance between study subject burden and risk, scientific rationale and interpretability of trial outcomes.

Rovaris M, Barkhof F, Calabrese M, De Stefano N, Fazekas F, Miller DH, Montalban X, Polman C, Rocca MA, Thompson AJ, Yousry TA, Filippi M. · Multiple Sclerosis Centre, Scientific Institute Santa Maria Nascente, Fondazione Don Gnocchi, Milan, Italy. · Neurology. · Pubmed #19433744 No free full text.

Abstract: It is well known that the current classification of patients with benign multiple sclerosis (BMS), i.e., those with absent or minimal locomotor disability several years after disease onset, suffers from not having any prognostic value for the subsequent evolution of multiple sclerosis (MS). The identification of markers predictive of the longer-term course of MS will help define BMS more reliably and would allow better counseling of patients, particularly when advising on the initiation of a disease-modifying treatment. MRI-based evidence suggests that there are three potential, but not mutually exclusive, explanations for the scarce clinical impact of BMS: 1) the paucity of tissue damage within and outside MS lesions; 2) the relative sparing of clinically eloquent regions; and 3) the presence of effective compensatory mechanisms. In addition, the results of correlative MRI/neuropsychology studies underpin the need for a new definition of BMS, which should consider the maintenance of a normal cognitive profile as an additional criterion.

Villoslada P, Moreno B, Melero I, Pablos JL, Martino G, Uccelli A, Montalban X, Avila J, Rivest S, Acarin L, Appel S, Khoury SJ, McGeer P, Ferrer I, Delgado M, Obeso J, Schwartz M. · Department of Neuroscience, Center for Applied Medical Research, University of Navarra, Pamplona, Spain. · Clin Immunol. · Pubmed #18534912 No free full text.

Abstract: The burden of neurological diseases in western societies has accentuated the need to develop effective therapies to stop the progression of chronic neurological diseases. Recent discoveries regarding the role of the immune system in brain damage coupled with the development of new technologies to manipulate the immune response make immunotherapies an attractive possibility to treat neurological diseases. The wide repertoire of immune responses and the possibility to engineer such responses, as well as their capacity to promote tissue repair, indicates that immunotherapy might offer benefits in the treatment of neurological diseases, similar to the benefits that are being associated with the treatment of cancer and autoimmune diseases. However, before applying such strategies to patients it is necessary to better understand the pathologies to be targeted, as well as how individual subjects may respond to immunotherapies, either in isolation or in combination. Due to the powerful effects of the immune system, one priority is to avoid tissue damage due to the activity of the immune system, particularly considering that the nervous system does not tolerate even the smallest amount of tissue damage.

Horga A, Montalban X. · Clinical Neuroinmunology Unit, Multiple Sclerosis Center of Catalonia (CEM-Cat), Vall d'Hebron University Hospital, Barcelona, Spain. · Expert Rev Neurother. · Pubmed #18457527 No free full text.

Abstract: FTY720 (fingolimod) is a structural analogue of sphingosine, an endogenous lysophospholipid, which targets sphingosine-1-phosphate receptors after biotransformation to FTY720-phosphate. The immunomodulatory properties of this agent are mainly related to its ability to entrap lymphocytes in secondary lymphoid organs, reducing their availability for cell-mediated immune responses. Emerging evidence suggests that FTY720 also exerts direct actions on glial and precursor cells of the CNS which may be relevant for the process of tissue repair after injury. The therapeutic effects of the drug observed in animal models of human multiple sclerosis have provided the experimental basis for its clinical application. A recent Phase II study has demonstrated that oral FTY720 is effective in reducing disease activity in relapsing multiple sclerosis with a favorable adverse-effect profile. These results are awaiting confirmation in the three ongoing Phase III clinical trials evaluating FTY720 for relapsing-remitting multiple sclerosis.

Seewann A, Enzinger C, Filippi M, Barkhof F, Rovira A, Gass A, Miller D, Montalban X, Thompson A, Yousry T, Tintore M, de Stefano N, Palace J, Rovaris M, Polman C, Fazekas F, Anonymous00221. · Department of Neurology, Medical University of Graz, Auenbruggerplatz 22, 8036, Graz, Austria. · J Neurol. · Pubmed #18004634 No free full text.

Abstract: BACKGROUND : Idiopathic inflammatory demyelinating lesions (IIDL) of the brain usually present with a morphologic pattern characteristic of multiple sclerosis (MS). Atypical appearances of IIDLs also exist, however, and can pose significant diagnostic problems and uncertainty regarding prognosis and adequate therapy. We attempted to improve upon this situation by reviewing the literature. METHODS : We performed a PubMed search from January 1984 through December 2004 for articles in English reporting on IIDLs which had been considered as morphologically atypical (66 articles; 270 cases reported). From these publications 69 individual patient reports allowed the extraction of adequate information on magnetic resonance imaging (MRI) and associated disease characteristics. RESULTS : Reported atypical IIDLs most frequently manifested as large ring-like lesions (n = 27) which are now considered quite suggestive of an antibodymediated form of MS. Truly atypical IIDLs were less common and exhibited appearances which we termed megacystic (n = 8), Balolike (n = 11) and diffusely infiltrating (n = 11). Despite limitations imposed by the absence of original data the inter-rater agreement in defining these subtypes of atypical IIDLs was moderate to substantial (kappa 0.48-0.68) and we noted trends for their association with certain demographic, clinical and paraclinical variables. INTERPRETATION : We suggest that IIDLs reported as atypical in the literature can be segregated into several distinct subtypes based on their MRI appearance. The recognition of these patterns may be useful for the differential diagnosis and for a future classification. Because of the limitations inherent in our review this will have to be confirmed by a prospective registry.

Montalban X. · EUI planta 2, Unitat de Neuroimmunología Clínica, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain. · J Neurol Sci. · Pubmed #17383679 No free full text.

Abstract: Multiple sclerosis (MS) is an inflammatory chronic demyelinating disease. Nowadays, there are several registered drugs aimed to control the disease activity. Because these drugs are given parenterally for years, it is of utmost importance to attain maximum adherence to treatment through close and permanent care of patients. The efficacy of the different registered drugs has been compared against placebo. Observational and head-to-head studies have shown controverted results in the degree of efficacy between the products. Despite the efficacy reported, a high proportion of patients will have a lack of response to treatment. Early identification of these patients is therefore essential in order to attempt other therapeutic approaches.

Charil A, Yousry TA, Rovaris M, Barkhof F, De Stefano N, Fazekas F, Miller DH, Montalban X, Simon JH, Polman C, Filippi M. · Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Ospedale San Raffaele, Milan, Italy. · Lancet Neurol. · Pubmed #16987731 No free full text.

Abstract: Although the diagnosis of multiple sclerosis relies on the demonstration of disease dissemination in space and time, the exclusion of other neurological disorders is also essential. The limited specificity of abnormalities disclosed by MRI may increase the likelihood of diagnosis of multiple sclerosis in patients affected by other disorders. The available criteria for diagnosis of multiple sclerosis have not taken advantage of the potential of MRI to detect features "not suggestive" of multiple sclerosis. Recognition of such features in the work-up of patients suspected of having multiple sclerosis may reduce the likelihood of a false positive diagnosis of the disorder in some, while suggesting the correct alternative diagnosis in other patients. On the basis of this, a workshop of the European MAGNIMS (Magnetic Resonance Network in Multiple Sclerosis) was held to define a series of MRI red flags in the setting of clinically suspected multiple sclerosis that is derived from evidence-based findings and educated guesses. The presence of such red flags should alert clinicians to reconsider the differential diagnosis more extensively. In this review we will report on the conclusions of this international consensus, which should represent a first step beyond the concept of "no better explanation", and inform future diagnostic criteria for multiple sclerosis.

Porcel J, Montalban X. · 2a Planta EUI, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Ps. Vall d'Hebron 119-129, 08035, Barcelona, Spain. · J Neurol Sci. · Pubmed #16674980 No free full text.

Abstract: Neuropsychological impairment is a common manifestation in multiple sclerosis (MS) and is found in 40-60% of patients. The pattern of cognitive impairment in MS is characterized by difficulties in recent memory, sustained attention, executive functions and information processing speed. These cognitive deficits have a significant impact on the patients' daily activities. However, there is no specific treatment available at present for cognitive disorders in MS patients. Treatment with acetylcholinesterase inhibitors (AChEI) has shown a positive effect on cognitive functions of patients with Alzheimer's disease and other conditions such as Lewy Body dementia, subcortical vascular dementia and Parkinson's disease. In this paper we review the results from studies and clinical trials aiming to demonstrate that AChEI could be a potential treatment for cognitive disorders in MS patients. Finally, we discuss future issues to take into consideration for AChEI treatments in the context of MS.

Friese MA, Montalban X, Willcox N, Bell JI, Martin R, Fugger L. · MRC Human Immunology Unit and Department of Clinical Neurology, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, University of Oxford, Oxford OX3 9DS, United Kingdom. · Brain. · Pubmed #16636022 links to  free full text

Abstract: The rodent model for multiple sclerosis, experimental allergic (autoimmune) encephalomyelitis (EAE), has been used to dissect molecular mechanisms of the autoimmune inflammatory response, and hence to devise and test new therapies for multiple sclerosis. Clearly, artificial immunization against myelin may not necessarily reproduce all the pathogenetic mechanisms operating in the human disease, but most therapies tested in multiple sclerosis patients are nevertheless based on concepts derived from studies in EAE. Unfortunately, several treatments, though successful in pre-clinical EAE trials, were either less effective in patients, worsened disease or caused unexpected, severe adverse events, as we review here. These discrepancies must, at least in part, be due to genetic and environmental differences, but the precise underlying reasons are not yet clear. Our understanding of EAE pathogenesis is still incomplete and so, therefore, are any implications for drug development in these models. Here, we suggest some potential explanations based on new thinking about key pathogenic concepts and differences that may limit extrapolation from EAE to multiple sclerosis. To try to circumvent these rodent-human dissimilarities more systematically, we propose that pre-clinical trials should be started in humanized mouse models.

Montalban X, Rio J. · Unitat de Neuroimmunologia Clínica, Servei de Neurologia, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · J Neurol Sci. · Pubmed #16626757 No free full text.

Abstract: Cognitive impairment in multiple sclerosis is frequent, but the effect of immunomodulating drugs and mainly interferon beta (IFNbeta) on the neuropsychological aspects of the disease has not been fully studied. The data that we have are not conclusive. This paper reviews the effect of IFNbeta on cognition in the different clinical forms of the disease and the future directions of clinical trials.

Río J, Montalban X. · Clinical Neuroimmunology Unit, Vall d'Hebron University Hospital, 08035 Barcelona, Spain. · Expert Opin Pharmacother. · Pubmed #16318438 No free full text.

Abstract: Ever since IFN-beta1b was first approved for the treatment of relapsing-remitting multiple sclerosis (RRMS) in the US and Europe, other disease-modifying drugs have become available. Phase III clinical trials have shown the efficacy of IFN-beta1b in the treatment of RRMS and secondary progressive MS in that it can reduce the annual relapse rate as well as magnetic resonance imaging parameters of activity and progression. There is mounting evidence that the best time to initiate treatment is early in the course of the disease, and available data suggest that efficacy is sustained for at least 5 years. IFN-beta1b is safe and well tolerated, although there are adverse events such as the flu-like complex and skin reactions. In the face of a proportion of RRMS patients experiencing a poor response to the drug, other therapeutic approaches need to be considered.

Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. · MS NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London, UK. · Lancet Neurol. · Pubmed #15907738 No free full text.

Abstract: The onset of multiple sclerosis (MS) in 85% of young adults is with a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Whereas multifocal brain lesions are present on MRI in many patients with a CIS, some patients have additional abnormalities on quantitative MRI in otherwise normal-appearing white and grey matter that suggest an extensive pathological process. Functional outcome for patients with symptomatic CIS lesions is determined by the interplay of inflammation, demyelination, axonal damage, remyelination, and cortical adaptation. Recovery of function may be accelerated by high dose corticosteroids, and although interferon beta delays the development of a second relapse, its long-term effect is unknown. A better understanding of pathological and pathogenetic processes in patients with a CIS will facilitate the development of disease-modifying treatments for patients with MS before they become disabled. Continued clinical and laboratory investigation of patients with a CIS should be encouraged.

Montalban X. · Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · Curr Opin Neurol. · Pubmed #15891409 No free full text.

Abstract: PURPOSE OF REVIEW: The present article reviews the currently ongoing scientific debate on the specific characteristics of primary progressive multiple sclerosis. RECENT FINDINGS: The most important observations come from the studies using magnetic resonance imaging showing involvement of the normal-appearing brain tissue and also from the clinical and magnetic-resonance-imaging descriptions in longitudinal studies. SUMMARY: Progress in the diagnosis of primary progressive multiple sclerosis has been made. Long- and short-term natural history are now better known, which will allow the designing of clinical trials in the near future. Magnetic-resonance-imaging studies have demonstrated damage of the normal-appearing brain tissue, which may explain in part the apparent clinical and radiological paradox, common to all clinical forms of multiple sclerosis but perhaps more evident in the primary progressive form. Preliminary results from exploratory trials seem to indicate that these patients should no longer be excluded from therapeutic trials.

Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. · MS NMR Research Unit, Institute of Neurology, University College London, London, UK. <> · Lancet Neurol. · Pubmed #15847841 No free full text.

Abstract: In 85% of young adults with multiple sclerosis (MS), onset is a subacute clinically isolated syndrome (CIS) of the optic nerves, brainstem, or spinal cord. Methods of assessing the prognosis for patients who present with a CIS have been sought, because only 30-70% of patients with a CIS develop MS. When clinically silent brain lesions are seen on MRI, the likelihood of developing MS is high. MS can be diagnosed within 3 months of CIS presentation with certain MRI and CSF criteria. Disability from MS is less likely in patients with a CIS of optic neuritis or sensory symptoms only, few or no MRI lesions, a long period to the first relapse, and no disability after the first 5 years. Development of more reliable prognostic markers will enable new treatments to be targeted for those who are most likely to benefit. We encourage continued clinical and laboratory assessment of patients with a CIS.

Montalban X. · Unit of Clinical Neuroimmunology, Hospitals Vall d'Hebron EUI 2a PI, Psg Vall d'Hebron 119-129, 08035, Barcelona, Spain. · J Neurol. · Pubmed #15378305 No free full text.

Abstract: Cerebral axonal damage and brain atrophy begin at the earliest stages of multiple sclerosis (MS). Progressive neuronal degeneration contributes to irreversible neurological deficit, and ultimately disability. Axonal loss, which seems to be related to the inflammatory process, occurs much more rapidly in the early than later phases of disease, providing additional impetus for early intervention. The CHAMPS (Controlled High risk Avonex MultiPle Sclerosis) and ETOMS (Early Treatment Of MS) studies show that fewer patients with a first demyelinating event and abnormal magnetic resonance imaging (MRI) had a second clinical attack within 2 years if once-weekly treatment with interferon beta-1a was started at the time of the first episode. However, these studies provide no information on long-term outcomes. The BENEFIT study (BEtaferon/betaseron in Newly Emerging multiple sclerosis For Initial Treatment) will evaluate the efficacy and tolerability of 250 micro g (8 MIU) interferon beta-1b administered every other day to patients with a first demyelinating event suggestive of MS. This study should add some information about some of the outstanding questions relating to the long-term effects of early treatment on disease course, although it is likely that further investigation will be needed before a definite picture can be obtained.

Miller DH, Filippi M, Fazekas F, Frederiksen JL, Matthews PM, Montalban X, Polman CH. · NMR Research Unit, Department of Neuroinflammation, Institute of Neurology, University College London, London, United Kingdom. · Ann Neurol. · Pubmed #15293279 No free full text.

Abstract: The diagnosis of multiple sclerosis (MS) has been improved in recent decades with the incorporation of paraclinical investigations in diagnostic workup. In the last 15 years, magnetic resonance imaging (MRI) has become an especially valuable tool for supporting MS diagnosis, and specific imaging criteria became fundamental to the guidelines for the diagnosis of MS published in 2001 by an international panel (IP). The new IP criteria include MRI evidence of dissemination in space and time, making it possible to diagnose MS after a single clinical episode. This review considers current evidence concerning the reliability of the new IP criteria for the diagnosis of relapsing-onset MS, discusses strengths and weaknesses of the criteria, and outlines areas which may need modification or should be the focus of future research directed toward improving diagnostic accuracy. It also makes practical recommendations when using MRI and the IP criteria in MS diagnosis, especially in patients with clinically isolated syndromes or atypical presentations. The IP criteria are timely and concrete and introduce an important concept to MS diagnosis. Future modifications, based on emerging evidence, should further facilitate their implementation and improve their accuracy.

Montalban X. · University Hospital Vall d'Hebron, Unitat de Neuroimmunologia Clinica, Pg Val d'Hebron 119-129 (EUI-2a P.) E-08035, Barcelona, Spain. xmontalban@.vhebron.net · Mult Scler. · Pubmed #15218812 No free full text.

Abstract: This short monograph describes a trial of interferon beta-1b in patients with primary progressive multiple sclerosis (PPMS) or transitional MS. Designed as a randomized, placebo-controlled pilot, the trial randomly placed 73 eligible patients into two groups, placebo or interferon beta-1b 8 MIU given subcutaneously every other day for two years. Significant differences favouring interferon beta-1b in the MSFC score, T2 lesion volume and TI lesion volume at 24 months were observed. Further study of interferon beta-Ib therapy in PPMS patients in warranted.

Sastre-Garriga J, Montalban X. · Unitat de Neuroimmunology Clínica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · Lupus. · Pubmed #14714905 No free full text.

Abstract: Antiphospholipid antibody syndrome (APS) may present with neurological syndromes. Cerebrovascular disease, chorea/ballismus, epileptic seizures, headache, cognitive impairment, transverse myelopathy, Devic's syndrome and multiple sclerosis-like presentations feature among others. Cerebrovascular disease is one of the most common presenting symptoms of APS, second only to deep vein thrombosis, and accounts for half of neurological manifestations in patients with APS; accelerated atherogenesis and cardioembolism are the most likely mechanisms implicated. Though infrequent, chorea is consistently associated with APS; the pathogenetic role of antiphospholipid antibodies (APLab) in this case might be routed through cerebrovascular disease in some cases and through purely immunological pathways in others. Both ischemic and immunological mechanisms have been demonstrated in the pathogenesis of epileptic seizures, which may account for 7% of neurological manifestations in APS. Although frequent in APS, a causative link between APLab and most common types of headache (migraine and tension-type headache) is more than dubious. Cognitive impairment may derive from a well-defined clinical tableau of multi-infarct dementia. Nevertheless, (highly frequent) less severe cognitive impairment has also been associated with the presence of APLab in the absence of magnetic resonance findings. A relationship between APS and transverse myelopathy seems likely but small numbers in the studies published to date preclude definite statements; routinely testing for APLab patients with neurological manifestations suggestive of multiple sclerosis seems to be unrecommended at the present time.

Pericot I, Montalban X. · Unidad de Neuroinmunología Clínica, Escuela de Enfermería, Hospital Universitario Vall d'Hebron Barcelona, Spain. · Neurologia. · Pubmed #12838451 links to  free full text

Abstract: Mitoxantrone is an antineoplastic agent that exerts a potent immunosuppresive effect, including suppression of B cell immunity and reduction of T cell numbers. Clinical trials have shown that mitoxantrone has a statistically significant impact on reduction of relapse rate and delays disability progression in patients with relapsing remitting (RR) multiple sclerosis (MS) or secondary progressive (SP) MS. Treatment is well tolerated, but the risk of cardiotoxicity at higher cumulative doses is likely to limit the duration of treatment. The maximum cumulative dose recommended is 140 mg/m2. In 2000, the FDA (Food and Drug Administration) approved the use of mitoxantrone for the treatment of active RRMS, SPMS and progressing relapsing (PR) MS.

Montalban X, Rio J. · Clinical Neuroimmunology Unit, Vall d'Hebron University Hospital, 2a Pianta Escola d'Infermeria, Barcelona, Spain. · Neurol Sci. · Pubmed #11794476 No free full text.

This publication has no abstract.

Sellebjerg F, Barnes D, Filippini G, Midgard R, Montalban X, Rieckmann P, Selmaj K, Visser LH, Sørensen PS, Anonymous00318. · Danish MS Centre, Copenhagen University Hospital, Denmark. · Eur J Neurol. · Pubmed #16324087 No free full text.

Abstract: Relapses, exacerbations or attacks of multiple sclerosis are the dominating feature of relapsing-remitting multiple sclerosis (MS), but are also observed in patients with secondary progressive MS. High-dose methylprednisolone is the routine therapy for relapses at present, but other treatments are also in current use. The objective of the task force was to review the literature on treatment of MS relapses to provide evidence-based treatment recommendations. Review was carried out on the literature with classification of evidence according to the EFNS guidelines for scientific task forces. Short-term, high-dose methylprednisolone treatment should be considered for the treatment of relapses of MS (level A recommendation). The optimal glucocorticoid treatment regimen, in terms of clinical efficacy and adverse events, remains to be established. A more intense, interdisciplinary rehabilitation programme should be considered as this probably further improves recovery after treatment with methylprednisolone (level B recommendation). Plasma exchange is probably efficacious in a subgroup of patients with severe relapses not responding to methylprednisolone therapy, and should be considered in this patient subgroup (level B recommendation). There is a need for further randomized, controlled trials in order to establish the optimal treatment regimen for relapses of MS.

Comabella M, Fernández-Arquero M, Río J, Guinea A, Fernández M, Cenit MC, de la Concha EG, Montalban X. · Centre d'Esclerosi Múltiple de Catalunya, CEM-Cat, Unitat de Neuroimmunologia Clínica, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · J Neuroimmunol. · Pubmed #19349081 No free full text.

Abstract: In the present study, we investigated the influence of HLA class I and class II genes in the response to interferon-beta (IFNbeta) in multiple sclerosis (MS) patients. HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 DNA typing was performed by polymerase chain reaction-sequence-specific oligonucleotide (PCR-SSO) in a cohort of 149 relapsing-remitting MS patients classified into IFNbeta responders (n=74) and non-responders (n=75) based on stringent clinical criteria. Distribution of HLA class I and class II alleles individually and the HLA-DR2 haplotype was similar between responders and non-responders to treatment. These findings do not support a role of the HLA class I and class II genes as modifiers of the response to IFNbeta.

O'Connor P, Comi G, Montalban X, Antel J, Radue EW, de Vera A, Pohlmann H, Kappos L, Anonymous00034. · St. Michael's Hospital, Toronto, ON, Canada. · Neurology. · Pubmed #19122034 No free full text.

Abstract: OBJECTIVE: To report the results of a 24-month extension of a phase II trial assessing the efficacy, safety, and tolerability of the once-daily oral sphingosine-1-phosphate receptor modulator, fingolimod (FTY720), in relapsing multiple sclerosis (MS). METHODS: In the randomized, double-blind, placebo-controlled core study, 281 patients received placebo or FTY720, 1.25 or 5.0 mg/day, for 6 months. During the subsequent dose-blinded extension, patients assigned to placebo were re-randomized to either dose of FTY720; those originally assigned to FTY720 continued at the same dose. Patients receiving FTY720 5.0 mg were switched to 1.25 mg during the month 15 to month 24 study visits. RESULTS: Of 281 patients randomized in the core study, 250 (89%) entered the extension phase, and 189 (75.6%) received treatment for 24 months. During the core study, FTY720 significantly reduced gadolinium-enhanced (Gd(+)) lesions and annualized relapse rate (ARR) compared with placebo, with no differences between doses. During the extension phase, patients who switched from placebo to FTY720 showed clear reductions in ARR and lesion counts compared with the placebo phase; ARR and lesion counts remained low in patients who continued FTY720 treatment. After 24 months, 79 to 91% of patients were free from Gd(+) lesions and up to 77% of patients remained relapse free. FTY720 was well tolerated; no new safety concerns emerged during months 7 to 24 compared with the 6-month core study. CONCLUSIONS: Once-daily oral treatment with FTY720, 1.25 or 5.0 mg, for up to 2 years, was well tolerated and was associated with low relapse rates and lesion activity.

Río J, Rovira A, Tintoré M, Huerga E, Nos C, Tellez N, Tur C, Comabella M, Montalban X. · Unitat de Neuroimmunologia Clinica, Hospital Universitario Vall d'Hebron, Barcelona, Spain. · Mult Scler. · Pubmed #18562504 No free full text.

Abstract: OBJECTIVE: Our objective in this study is to evaluate whether brain magnetic resonance imaging (MRI) performed at interferon-beta (IFN-beta) onset and after 12 months allow us to identify relapsing-remitting multiple sclerosis (RRMS) patients with a disability increase in the first 2 years of therapy. METHODS: This is a prospective and longitudinal study of patients with RRMS treated with IFN-beta. All patients included underwent brain MRI before the onset of therapy with IFN-beta and 12 months after. MRI measures (T2, unenhanced T1-weighted and gadolinium-enhancing T1-weighted brain lesion load, brain parenchymal fraction) were undertaken at baseline and after 12 months. The number of active lesions (new or enlarging T2 plus gadolinium-enhancing brain lesions) was also assessed on the 12 months MRI scan. Expanded Disability Status Scale (EDSS) was scored every 3 months. We defined an increase in disability as an increase of at least 1 EDSS point confirmed and sustained during the first 2 years of therapy with IFN-beta. Regression analysis was performed in order to identify MRI variables of response. RESULTS: We included 152 patients who were followed-up for at least 2 years. After 2 years of therapy, 24 patients (16%) had an increase in disability. The logistic regression model showed that active lesions in the scan performed at 12 months were the most important factor related with the increase of disability after 2 years of therapy (odds ratio 8.3, 95% confidence interval 3.1-21.9; p < 0.0001). CONCLUSIONS: In RRMS patients treated with IFN-beta the MRI changes occurring during the first year may have a prognostic value for identifying patients with a confirmed increase of disability after 2 years of therapy.

Comabella M, Julià E, Tintoré M, Brieva L, Téllez N, Río J, López C, Rovira A, Montalban X. · Unitat de Neuroimmunologia Clínica, Edif. EUI 2a planta, Hospital Universitari Vall d'Hebron, Pg. Vall d'Hebron 119-129, 08035, Barcelona, Spain. · J Neurol. · Pubmed #18484235 No free full text.

Abstract: BACKGROUND : Cytokine inhibitors, such as soluble tumor necrosis factor receptor II (sTNFRII) and interleukin-1 receptor antagonist (IL-1ra) are possible regulators of proinflammatory cytokine activity. Although previous studies have shown induction of sTNF-RII and IL-1ra by interferon-beta (IFNbeta) in patients with relapse-onset forms of multiple sclerosis (MS), to date no studies of these cytokine inhibitors have been performed in patients with essentially progressive forms of MS. OBJECTIVE : To address the effects of IFNbeta on serum levels of sTNF-RII and IL-1ra in a cohort of progressive MS patients and to assess the relationship between levels and changes of sTNF-RII and IL-1ra and clinical and radiological variables. Methods Serial blood samples were obtained from a cohort of 73 patients with progressive MS who participated in a placebo-controlled clinical trial with IFNbeta-1b. Serum levels of sTNF-RII and IL-1ra were measured by multiplex enzyme-linked immunosorbent assay at baseline and after 3, 6, 12, and 24 months. EDSS and MSFC scores were recorded at the time of blood sampling, and MR scans were obtained at baseline and after 12 and 24 months. RESULTS : Treatment with IFNbeta was associated with significant increases of sTNF-RII and IL-1ra serum levels during the followup period. A strong correlation at 24 months was observed between levels of sTNF-RII and EDSS scores in the placebo group. Finally, a trend for negative association was found between changes in sTNFRII and percentage change in T2-weighted lesion load at 24 months in the IFNbeta treated group. CONCLUSIONS : sTNF-RII and IL-1ra levels are increased in the serum of progressive MS patients during IFNbeta therapy and may be one mechanism by which IFNbeta mediates its effects in the treatment of MS.