Multiple Sclerosis: Lublin FD

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.

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.

This publication has no abstract.

Cutter GR, Lublin FD. · No affiliation provided · Neurology. · Pubmed #18362265 No free full text.

This publication has no abstract.

Tullman MJ, Lublin FD. · No affiliation provided · J Neurol Sci. · Pubmed #14759625 No free full text.

This publication has no abstract.

Lublin FD. · Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, 5 East 98th Street, Box 1138, New York, New York 10029, USA. · J Neurol Sci. · Pubmed #17337274 No free full text.

Abstract: Relapsing-remitting multiple sclerosis (RRMS) is often associated with accrual of disability, even though it precedes the progressive phase of the disease, in which clinical disability is most apparent. Changes in T1 and T2 magnetic resonance imaging (MRI) findings, as well as clinical trials of drugs that target RRMS, have established correlations between relapse episodes and disability progression. Briefly reviewed herein are relevant data that link relapses with disability accrual, including a recent direct analysis of well-defined clinical trial databases that shows MS relapses to have a measurable and sustained effect on disability. These studies pinpoint the measurable residual deficits of relapses that had, up to this point, only been implied by prior research, confirming the existence of relapse-associated step-wise worsening in patients with RRMS and lending credence to the continued development of long-term treatment targeted at the early phases of the disorder.

Derwenskus J, Lublin FD. · Department of Neurology, Northwestern University, Chicago, Illinois, USA. · Adv Neurol. · Pubmed #16400838 No free full text.

This publication has no abstract.

Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O'Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS. · VU Medical Center Amsterdam, Free University, PO Box 7057, 1007 MB Amsterdam, the Netherlands. · Ann Neurol. · Pubmed #16283615 No free full text.

Abstract: New diagnostic criteria for multiple sclerosis integrating magnetic resonance image assessment with clinical and other paraclinical methods were introduced in 2001. The "McDonald Criteria" have been extensively assessed and used since 2001. New evidence and consensus now strengthen the role of these criteria in the multiple sclerosis diagnostic workup to demonstrate dissemination of lesions in time, to clarify the use of spinal cord lesions, and to simplify diagnosis of primary progressive disease. The 2005 Revisions to the McDonald Diagnostic Criteria for MS should simplify and speed diagnosis, whereas maintaining adequate sensitivity and specificity.

Tullman MJ, Lublin FD. · The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, NY 10029, USA. · Curr Neurol Neurosci Rep. · Pubmed #15865891 No free full text.

Abstract: Over the past decade, multiple sclerosis (MS) has become a treatable neurologic illness. However, given the rather modest benefit of the currently available disease-modifying agents, as well as the challenges associated with performing placebo-controlled, equivalence, and superiority trials, the logic of combining therapies in MS has considerable appeal. Selecting agents for combination requires careful consideration, as the immunomodulating activity of one drug could potentially interfere with the therapeutic effect of another, and certain combinations may be associated with unforeseen adverse effects. Rigorously controlled studies are needed to determine the safest and most effective use of new and existing MS therapies.

Lublin FD. · Mount Sinai Medical Center, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, 5 East 98th Street, Box 1138, New York, NY 10029-6574, USA. · Neurol Clin. · Pubmed #15661085 No free full text.

This publication has no abstract.

Tullman MJ, Lublin FD, Miller AE. · The Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, New York, NY 10029, USA. · J Rehabil Res Dev. · Pubmed #12051470 No free full text.

Abstract: Over the past decade, multiple sclerosis (MS) has become a treatable neurological disease. This paper reviews the therapies that have been studied to treat MS and discusses various treatment approaches on the horizon. Immunosuppressive and immunomodulatory therapies have been shown to alter the long-term course of MS. Therapies are currently available for relapsing-remitting, secondary progressive, and progressive relapsing disease. Although effective, these therapies have a modest impact on reduction in relapse rate and slowing of disease progression. Much work is needed to improve upon this modest effect and hopefully obtain a cure.

Lublin FD. · Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai Medical Center, New York, NY, USA. · Curr Opin Neurol. · Pubmed #12045721 No free full text.

Abstract: Multiple sclerosis is a clinical diagnosis and as such requires the integration of historical information with neurological examination and relevant laboratory and paraclinical tools, such as magnetic resonance imaging. A recent revision of the diagnostic guidelines for multiple sclerosis has been published that formalizes the use of magnetic resonance imaging information along with the clinical picture. These new guidelines should provide for the earlier and easier diagnosis of multiple sclerosis, useful for both clinical trials and neurological practice.

Lublin FD. · Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Mount Sinai School of Medicine, New York, NY 10029, USA. · Mult Scler. · Pubmed #11936495 No free full text.

This publication has no abstract.

Kalman B, Lublin FD. · Department of Neurology, Mount Sinai School of Medicine, 1 Gustave L. Levy Place, Box 1137, New York, NY 10029-6574, USA. · Curr Neurol Neurosci Rep. · Pubmed #11898526 No free full text.

Abstract: The aim of this review is to highlight recent observations concerning the pathogenesis of acute and chronic inflammatory demyelinating diseases in the central nervous system. Without attempting to provide a didactic classification or a complete survey, we emphasize the discriminative nature of new clinical, imaging, and immunopathologic data, which, even in the absence of specific molecular markers, modify our views about the nosologic relations among these overlapping clinicopathologic entities. In the light of new findings, multiple sclerosis may represent a spectrum of demyelinating diseases rather than a single entity.

Ben-Zacharia AB, Lublin FD. · Nurse Practitioner, Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Department of Neurology, The Mount Sinai Medical Center, New York, New York 10029, USA. · Neurol Clin. · Pubmed #11854101 No free full text.

Abstract: Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) and can be characterized by acute exacerbations or gradual worsening of neurological function and disability. The course of the disease is highly variable and unpredictable, however, there are short and long-term favorable and unfavorable predictive factors, which may provide some information about the future pattern of the disease. Palliative care in MS is directed at symptom management, psychosocial support, and rehabilitation. The goal in palliative care is to achieve a high quality of life. The disease modifying agents, interferon beta, Glatiramer acetate and Mitoxantrone are the mainstay of treatment in MS. Symptomatic relief and counseling of patients with MS have a strong impact on quality of life.

Kalman B, Lublin FD. · Department of Neurology, MCP-Hahnemann University, Philadelphia, PA 19102, USA. · Biomed Pharmacother. · Pubmed #10554670 No free full text.

Abstract: Multiple sclerosis (MS) is characterized by chronic inflammation and demyelination in the central nervous system (CNS). Although the etiology of MS is unknown, both genetic and environmental contributions to the pathogenesis are inferred from epidemiologic studies. Geographic distributions and epidemics of MS and data from migration studies provide evidence for some, thus far unidentified, environmental effects. The co-occurrence of MS with high and low frequencies in ethnic groups often sharing an environment, the increased recurrence rate in families, and the high concordance rate among identical twins point to inheritable determinants of susceptibility. Based on the autoimmune hypothesis of demyelination, genetic studies sought associations between MS and polymorphic alleles of candidate genes which regulate either the immune response or myelin production. The most consistent finding in case-control studies was the association with the major histocompatibility complex (MHC) (also called human leukocyte antigen--HLA) class II, DR15, DQ6, Dw2 haplotype. Studies on other gene products encoded within or close to the MHC complex on chromosome 6p21.3 (e.g., HLA DP, complement components, transporter proteins, tumor necrosis factor, and myelin-oligodendrocyte glycoprotein) resulted in conflicting observations in different patient populations. The potential contribution of polymorphic alleles within the genes of the T-cell receptor alpha beta chains, immunoglobulins, cytokines, and oligodendrocyte growth factors or their receptors to MS susceptibility either remains equivocal or is rejected. Studies on families with multiple affected members have revealed that MS is a complex trait, that the contribution of individual genes to susceptibility is probably small, and that differences are possible between familial and sporadic forms. The development of molecular and computer technologies have facilitated the performance of comprehensive genomic scans in multiplex families, which have confirmed the possible linkage of multiple loci to susceptibility, each with a minor contribution. Several provisional sites were reported, but only 6p21 (MHC complex), 5p14, and 17q22 were positive in more than one study. The British update demonstrated segregation among regions of interest depending on DR15 sharing, and excluded a gene of major effect from 95%, and one with a moderate effect from 65% of the genome. The extended study by the US collaboration group revealed that the MHC linkage was limited to families segregating HLA DR2 alleles, which suggested that linkage to the MHC is related to the HLA DR2 association, and that sporadic and familial MS share at least one common susceptibility marker. Further identification of MS susceptibility loci may involve additional family sets, more polymorphic markers, and the exploration of telomeric chromosomal regions. Data from these studies may further elucidate pathogenic mechanisms of MS.

McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS. · Royal College of Physicians, London, United Kingdom. · Ann Neurol. · Pubmed #11456302 No free full text.

Abstract: The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."

Havrdova E, Galetta S, Hutchinson M, Stefoski D, Bates D, Polman CH, O'Connor PW, Giovannoni G, Phillips JT, Lublin FD, Pace A, Kim R, Hyde R. · Charles University in Prague, Department of Neurology, First Faculty of Medicine, Prague, Czech Republic. · Lancet Neurol. · Pubmed #19201654 No free full text.

Abstract: BACKGROUND: The efficacy of natalizumab on clinical and radiological measures in the phase III Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study has prompted the investigation of whether natalizumab can increase the proportion of patients with relapsing-remitting multiple sclerosis who do not have disease activity. METHODS: Post-hoc analyses of data from the AFFIRM study were done to determine the effects of natalizumab compared with placebo on the proportion of patients who were free of disease activity over 2 years. Absence of disease activity was defined as no activity on clinical measures (no relapses and no sustained disability progression), radiological measures (no gadolinium-enhancing lesions and no new or enlarging T2-hyperintense lesions on cranial MRI), or a composite of the two. FINDINGS: 383 (64%) of 596 patients taking natalizumab and 117 (39%) of 301 taking placebo were free of clinical disease activity (absolute difference 25.4%, 95% CI 18.7-32.1%, p<0.0001); 342 (58%) of 593 and 42 (14%) of 296 were free of radiological disease activity (43.5%, 37.9-49.1%, p<0.0001); and 220 (37%) of 600 and 22 (7%) of 304 were free of combined activity (29.5%, 24.7-34.3%, p<0.0001) over 2 years. The effect of natalizumab versus placebo was consistent across subgroups of patients with highly active or non-highly active disease at baseline. INTERPRETATION: Disease remission might become an increasingly attainable goal in multiple sclerosis treatment with the use of newer, more effective therapies.

Miller DH, Soon D, Fernando KT, MacManus DG, Barker GJ, Yousry TA, Fisher E, O'Connor PW, Phillips JT, Polman CH, Kappos L, Hutchinson M, Havrdova E, Lublin FD, Giovannoni G, Wajgt A, Rudick R, Lynn F, Panzara MA, Sandrock AW, Anonymous00097. · Institute of Neurology, University College London, London, UK. · Neurology. · Pubmed #17452584 No free full text.

Abstract: BACKGROUND: In a 2-year, placebo-controlled trial (the Natalizumab Safety and Efficacy in Relapsing Remitting Multiple Sclerosis [AFFIRM] study), involving 942 patients with relapsing multiple sclerosis (MS), natalizumab significantly reduced the relapse rate by 68% and progression of sustained disability by 42% vs placebo. We report the effect of natalizumab on MRI measures from the AFFIRM study. METHODS: The number and volume of gadolinium (Gd)-enhancing, new or enlarging T2-hyperintense, and new T1-hypointense lesions and brain parenchymal fraction were measured from annual scans obtained at baseline, 1 year, and 2 years. RESULTS: Compared with placebo, natalizumab produced a 92% decrease in Gd-enhancing lesions (means 2.4 vs 0.2; p < 0.001), an 83% decrease in new or enlarging T2-hyperintense lesions (means 11.0 vs 1.9; p < 0.001), and a 76% decrease in new T1-hypointense lesions (means 4.6 vs 1.1; p < 0.001) over 2 years. Median T2-hyperintense lesion volume increased by 8.8% in the placebo group and decreased by 9.4% in the natalizumab group (p < 0.001); median T1-hypointense lesion volume decreased by 1.5% in the placebo group and decreased by 23.5% in the natalizumab group (p < 0.001). Brain atrophy was greater in year 1 and less in year 2 in natalizumab-treated patients. CONCLUSION: Natalizumab has a sustained effect in preventing the formation of new lesions in patients with relapsing multiple sclerosis.

Balcer LJ, Galetta SL, Calabresi PA, Confavreux C, Giovannoni G, Havrdova E, Hutchinson M, Kappos L, Lublin FD, Miller DH, O'Connor PW, Phillips JT, Polman CH, Radue EW, Rudick RA, Stuart WH, Wajgt A, Weinstock-Guttman B, Wynn DR, Lynn F, Panzara MA. · Department of Neurology, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA. · Neurology. · Pubmed #17438220 No free full text.

Abstract: OBJECTIVE: To examine the effects of natalizumab on low-contrast letter acuity as a prespecified tertiary endpoint in two randomized clinical trials and to evaluate the usefulness of low-contrast letter acuity testing as a candidate test of visual function in multiple sclerosis (MS). METHODS: AFFIRM and SENTINEL were randomized, double-blind, placebo-controlled, multicenter, phase 3 clinical trials of natalizumab in relapsing MS. Natalizumab was evaluated as monotherapy in AFFIRM and as add-on to interferon beta-1a in SENTINEL. Vision testing was performed at 100% contrast (visual acuity) and low-contrast (2.5% and 1.25%). RESULTS: The risk of clinically significant visual loss (predefined as a two-line worsening of acuity sustained over 12 weeks) at the lowest contrast level (1.25%) was reduced in the natalizumab treatment arms by 35% in AFFIRM (hazard ratio = 0.65; 95% CI: 0.47 to 0.90; p = 0.008) and by 28% in SENTINEL (hazard ratio = 0.72; 95% CI: 0.54 to 0.98; p = 0.038, Cox proportional hazards models). Mean changes in vision scores from baseline were also significantly different, reflecting worsening in non-natalizumab groups. CONCLUSIONS: Natalizumab reduces visual loss in patients with relapsing multiple sclerosis. Low-contrast acuity testing has the capacity to demonstrate treatment effects and is a strong candidate for assessment of visual outcomes in future multiple sclerosis trials.

Phillips JT, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Polman CH, Lublin FD, Giovannoni G, Wajgt A, Lynn F, Panzara MA, Sandrock AW, Anonymous00379. · Multiple Sclerosis Center at Texas Neurology, Dallas, TX 75214, USA. · Neurology. · Pubmed #17101921 No free full text.

This publication has no abstract.

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, Anonymous00011. · Mellen Center for Multiple Sclerosis Treatment and Research, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. · N Engl J Med. · Pubmed #16510745 links to  free full text

Abstract: 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.).

Polman CH, O'Connor PW, Havrdova E, Hutchinson M, Kappos L, Miller DH, Phillips JT, Lublin FD, Giovannoni G, Wajgt A, Toal M, Lynn F, Panzara MA, Sandrock AW, Anonymous00010. · Vrije Universiteit Medical Center, Amsterdam, The Netherlands. · N Engl J Med. · Pubmed #16510744 links to  free full text

Abstract: BACKGROUND: Natalizumab is the first alpha4 integrin antagonist in a new class of selective adhesion-molecule inhibitors. We report the results of a two-year phase 3 trial of natalizumab in patients with relapsing multiple sclerosis. METHODS: Of a total of 942 patients, 627 were randomly assigned to receive natalizumab (at a dose of 300 mg) and 315 to receive placebo by intravenous infusion every four weeks for more than two years. The primary end points were the rate of clinical relapse at one year and the rate of sustained progression of disability, as measured by the Expanded Disability Status Scale, at two years. RESULTS: Natalizumab reduced the risk of sustained progression of disability by 42 percent over two years (hazard ratio, 0.58; 95 percent confidence interval, 0.43 to 0.77; P<0.001). The cumulative probability of progression (on the basis of Kaplan-Meier analysis) was 17 percent in the natalizumab group and 29 percent in the placebo group. Natalizumab reduced the rate of clinical relapse at one year by 68 percent (P<0.001) and led to an 83 percent reduction in the accumulation of new or enlarging hyperintense lesions, as detected by T2-weighted magnetic resonance imaging (MRI), over two years (mean numbers of lesions, 1.9 with natalizumab and 11.0 with placebo; P<0.001). There were 92 percent fewer lesions (as detected by gadolinium-enhanced MRI) in the natalizumab group than in the placebo group at both one and two years (P<0.001). The adverse events that were significantly more frequent in the natalizumab group than in the placebo group were fatigue (27 percent vs. 21 percent, P=0.048) and allergic reaction (9 percent vs. 4 percent, P=0.012). Hypersensitivity reactions of any kind occurred in 25 patients receiving natalizumab (4 percent), and serious hypersensitivity reactions occurred in 8 patients (1 percent). CONCLUSIONS: Natalizumab reduced the risk of the sustained progression of disability and the rate of clinical relapse in patients with relapsing multiple sclerosis. Adhesion-molecule inhibitors hold promise as an effective treatment for relapsing multiple sclerosis. (ClinicalTrials.gov number, NCT00027300.).

Wolinsky JS, Narayana PA, Noseworthy JH, Lublin FD, Whitaker JN, Linde A, Gjörstrup P, Sullivan HC. · Department of Neurology, The University of Texas-Houston Health Science Center 77030, USA. · Neurology. · Pubmed #10802777 No free full text.

Abstract: OBJECTIVE: To determine the safety and efficacy of roquinimex (linomide) in the management of relapsing-remitting and secondary progressive MS as monitored by MRI. BACKGROUND: Preclinical studies and several short term randomized trials of linomide suggested clinical and MRI-measured benefits with acceptable risk for closely followed MS patients. METHODS: The North American Linomide Trial formally screened 853 individuals for relapsing or secondary progressive, clinically definite MS; recent disease activity or progression; and an Expanded Disability Status Scale score at entry of 3.0 to 6.5 inclusive. MRI was obtained on 811 subjects at pre-enrollment, 718 cases at enrollment, and then at three monthly intervals until the trial was prematurely terminated for unacceptable toxicity. RESULTS: Enhancement was found on 40.2% of 718 entry scans. Statistically robust correlations were found between clinical demographic data and several entry MRI measures including CSF volume, a reflection of brain atrophy. Assessment of the effect of treatment on MRI-measured disease was limited by early trial termination. However, active treatment for 3 months reduced the proportion of patients with one or more enhancements. An exploratory analysis suggested that 2.5 mg was the most active of three doses tested in limiting the total volume of enhanced tissue, the proportion of MRI-defined lesions designated as "black holes," and by a novel MRI composite disease measure. CONCLUSIONS: The short term signature of the effect of linomide on MRI-measured aspects of the disease suggests that safer drugs of this class might be useful in the management of MS. The use of a composite index of the heterogeneous nature of the pathology of MS as captured by MRI may have merit as an outcome measure in clinical trials.

Noseworthy JH, Wolinsky JS, Lublin FD, Whitaker JN, Linde A, Gjorstrup P, Sullivan HC. · Department of Neurology, Mayo Clinic/Mayo Foundation, Rochester, MN 55905, USA. · Neurology. · Pubmed #10802775 No free full text.

Abstract: OBJECTIVE: To determine whether linomide (roquinimex) is better than placebo in slowing the time to confirmed clinical worsening in patients with relapsing-remitting (RR) and secondary progressive (SP) MS. METHODS: In this 27-center, randomized, double-blind, placebo-controlled, multiple-dose, phase III trial, 715 patients with active RRMS (n = 90) or SPMS (n = 625) were randomized to receive either linomide (1.0, 2.5, or 7.5 mg orally daily) or placebo. Patients were evaluated at 3-month intervals clinically and with MRI. The planned primary outcome was the time to the development of "confirmed" clinical worsening (increase of >/= 1.0 Expanded Disability Status Scale [EDSS] score for an enrollment EDSS score </= 5.0, or >/= 0.5 point for an enrollment EDSS score of >/= 5.5) not associated with an acute relapse. RESULTS: The trial was terminated 1 month after it became fully enrolled due to unanticipated serious cardiopulmonary toxicities (pericarditis, pleural effusion, myocardial infarction, and possible pulmonary embolism), pancreatitis, and death. Notable arthralgia, myalgia, bursitis, and facial and peripheral edema were common adverse events. The high dose of linomide (7.5 mg) was not well tolerated. The trial was too brief to determine unequivocal clinical benefits. Trends suggested an unconfirmed early effect on change in EDSS score at 6 months for the medium dose (2.5 mg daily). CONCLUSION: MS patients may be more prone to develop important linomide treatment-related adverse events than other previously studied patients. However, linomide may be a potentially more toxic drug than was suspected from observations made in smaller studies for other indications. Phase III trials may identify infrequent and important toxicities that may not be anticipated by phase I and II trials.

Rice GP, Ebers GC, Lublin FD, Knobler RL. · London Health Sciences Centre, Ontario, Canada. · Neurology. · Pubmed #10371541 No free full text.

Abstract: Flu-like symptoms and injection site reactions are adverse effects of treatment with interferon beta-1b in patients with MS. We compared gradual dose escalation, ibuprofen treatment, or their combination in an open-label study. The combination reduced the incidence of flu-like symptoms to rates comparable with the placebo group in the pivotal trial but increased the frequency of injection site reactions, albeit modestly and transiently.