Multiple Sclerosis: Arnason BG

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.

Arnason BG. · University of Chicago Hospital, Department of Neurology, Chicago, Illinois 60637, USA. · J Neurol. · Pubmed #16170497 No free full text.

Abstract: The interferon beta-1b (IFNbeta-1b, Betaferon/Betaseron) molecule was cloned some 20 years ago. In a pilot dose-finding trial involving 30 multiple sclerosis (MS) patients, the 10 MS patients receiving 250 microg (8 MIU) IFNbeta-1b every other day at 6 months showed a reduced attack frequency relative to 6 patients receiving placebo. Based on these extremely preliminary results a Phase III placebo-controlled trial was undertaken. Treatment with IFNbeta-1b was shown to reduce attack frequency and severity and to markedly reduce magnetic resonance imaging-(MRI) measured activity and disease burden. IFNbeta-1b therapy was subsequently shown to reduce MRI activity within 2 weeks of starting treatment. The benefits of treatment with IFNbeta-1b observed in the original pivotal study are maintained in the longer term, with consistent treatment effects seen after 5 years. IFNbeta-1b has subsequently been shown to reduce accumulation of disability in MS patients with early active secondary progressive disease, to increase cerebral metabolism, and to improve cognitive performance.IFNbeta-1b therapy is generally well tolerated. Classical systemic side effects related to all beta interferons can effectively be managed by dose escalation, and the use of an autoinjector minimises injection site reactions.About one-third of MS patients receiving IFNbeta-1b develop anti-interferon antibodies, typically within the first year of therapy. These antibodies have variable titres that fall with time and ultimately disappear in most patients. The clinical consequences of the presence of antibodies are presently unclear and inconsistent-some patients without antibodies respond poorly to treatment, whereas others with high-titre antibodies respond well to treatment. It is possible that immune complexes formed when anti-interferon antibodies encounter IFNbeta may enhance some of the immunomodulatory actions of the drug by improving CD8 cell-mediated suppressor function. Until the clinical relevance of antibodies is better understood, treatment decisions should be based on clinical grounds only.

Burks JS, Arnason BG, Coyle PK, Ford CC, Noronha A, Rammohan KW. · Washoe Institute of Neurosciences, University of Nevada School of Medicine, Reno 89509, USA. · Neurorehabil Neural Repair. · Pubmed #12462762 No free full text.

Abstract: The objective of this roundtable discussion of experts in the field of multiple sclerosis (MS) was to summarize the current understanding of MS and its therapeutic options. The experts discussed subjects ranging from the etiology of MS to the current standards for patient care. Specific topics included the subtypes of MS, with a focus on the benign subtype, brain atrophy, the role of magnetic resonance imaging or "neuroimaging studies," disease-modifying therapies, biological markers as indicators of drug efficacy, and combination therapies. In addition, the experts speculated as to what will be available in the near future for the improved diagnosis and management of MS. This review summarizes the main points of this discussion and is intended to serve as a reference for neurologists involved in the care of patients with MS.

Arnason BG. · Department of Neurology, University of Chicago, IL 60637, USA. · Biomed Pharmacother. · Pubmed #10554668 No free full text.

Abstract: Interferon beta is a cytokine that modulates immune responsiveness. Treatment with recombinant interferon b, either subcutaneously or intramuscularly, favorably affects the natural history of multiple sclerosis. Attack frequency and attack severity are both reduced and the progression of accumulating disability is slowed. Magnetic resonance image scanning of treated patients reveals a lessening of accumulating permanent disease burden and an up to 80% reduction in newly active lesions, the majority subclinical, within the white matter of the brain. Many newly active lesions resolve spontaneously. The drug is well tolerated and safe. Systemic flu-like symptoms, transient in nature, commonly follow drug injection when treatment begins, but these usually lessen in frequency and severity over the first few weeks on drug. Red skin reactions are usual at sites of subcutaneous injection. Interferon b treatment is only partially effective. There is an unmet need to do better in the therapy of multiple sclerosis.

Arnason BG. · Department of Neurology, Pritzker School of Medicine, Chicago, Illinois, USA. · Annu Rev Med. · Pubmed #10073279 No free full text.

Abstract: Three interferon beta preparations (Betaseron, Avonex, and Rebif) have shown efficacy in the treatment of relapsing-remitting multiple sclerosis (MS). Attack frequency is reduced by 30% and major attacks to an even greater extent. Accumulating disease burden as measured by annual T2-weighted magnetic resonance imaging is markedly lessened, and disease activity as measured by serial gadolinium-enhanced MRI scanning is reduced by over 80%. A fourth preparation, Copaxone, a basic copolymer of four amino acids, lessens MS attack frequency by 30% and also lessens disease activity as measured by gadolinium-enhanced MRI. Betaseron lessens accumulation of disability in MS patients with secondary progressive disease regardless of the severity of disability at the time treatment is commenced. MS is now a treatable disease.

Qu ZX, Pliskin N, Jensen MW, White D, Arnason BG. · University of Chicago, Department of Neurology, 5841 S Maryland Ave, MC 2030, Chicago, IL 60637, USA. · Arch Neurol. · Pubmed #11176940 links to  free full text

Abstract: BACKGROUND: Interferon beta treatment is only partially effective in multiple sclerosis (MS) suggesting a potential role for adjunctive therapies. Retinoids can augment the clinical efficacy of type 1 interferons in patients with cancer. We reasoned that the same might hold in MS. Interferon beta-1b added to peripheral blood mononuclear cells in vitro partially reverses the CD8 suppressor cell defect of patients with MS. All-trans retinoic acid added to peripheral blood mononuclear cells from untreated patients with MS or from controls potentiates this ability of interferon beta-1b to augment CD8 suppressor cell function in vitro. OBJECTIVE: To determine whether retinoid administration to patients with MS who are being treated with interferon beta-1b augments their CD8 suppressor cell function. SETTING: A university hospital MS clinic. PARTICIPANTS: Patients with MS who were being treated with interferon beta-1b, 14 patients with secondary progressive MS and 3 patients with relapsing remitting MS. RESULTS: Seventeen patients with MS received etretinate treatment for up to 6 months. Planned dosing was 10 mg 3 times daily for the first month, 25 mg twice daily for the second and third months, and 10 mg twice daily thereafter. The 25-mg twice daily dose was not well tolerated and of the 14 patients who remained in the phase 1 clinical trial through month 3 dose reduction to 10 mg thrice daily was required in 1 patient and to 10 mg twice daily in 4 patients. Eleven patients completed the trial. Etretinate treatment significantly augmented suppressor function over baseline values at 1, 3, and 6 months. No meaningful change was noted in disability or quality of life over the course of the phase 1 clinical trial. Neuropsychological testing of completers suggested improvement on selected aspects of verbal memory at 6 months compared with baseline values. CONCLUSIONS: Etretinate treatment at a dose of 10 mg twice or three times daily augments suppressor cell function in patients with MS receiving interferon beta-1b. Higher dose etretinate treatment (25 mg twice daily) is poorly tolerated by patients with MS. Even at 10 mg twice daily adverse experiences involving the mucous membranes and the skin become troublesome for some, but not all, patients. Whether pulse therapy or administration of retinoid restricted to the day of interferon beta dosing will also augment suppressor function, while being better tolerated, remains to be determined.

Javed A, Balabanov R, Arnason BG, Kelly TJ, Sweiss NJ, Pytel P, Walsh R, Blair EA, Stemer A, Lazzaro M, Reder AT. · Department of Neurology, University of Chicago, Chicago, IL 60637, USA. · Mult Scler. · Pubmed #18573828 No free full text.

Abstract: Devic's disease is often considered as a variant of multiple sclerosis (MS). However, evidence suggests that Devic's disease may be distinct from MS. Devic's disease can coexist with connective tissue diseases, particularly Sjögren's disease, but this association is rare with MS. Diagnosis of Sjögren's disease in patients with neurological symptoms is often difficult. During early stages of Sjögren's disease, patients may not fulfill all criteria for Sjögren's disease. A high percentage of patients with Sjögren's disease have inflammatory infiltrates in minor salivary glands, and this may be a reliable indicator of early or subclinical disease. We show high prevalence (80%) of salivary gland inflammation in Devic's disease and longitudinally extensive transverse myelitis (LETM). We diagnosed 16 patients with Devic's disease, and 2 of these satisfied criteria for Sjögren's disease as did 2 of 9 patients with LETM. Anti-SSA/B titers were infrequently elevated. Although most did not satisfy criteria for Sjögren's disease. 9 of 12 Devic's disease patients and 7 of 8 LETM patients had severe salivary gland inflammation. Thus: (1) patients with Devic's disease or with LETM who have positive labial biopsies but do not satisfy criteria for Sjögren's disease could have subclinical Sjögren's diseases. Alternatively, (2) as patients with Devic's disease have elevated titers of several autoantibodies, so there may exist a set of antibodies that react with antigens in minor salivary glands and cause inflammation. Minor salivary gland biopsy is more sensitive than anti-SSA/B serology in providing histological evidence for possible Sjögren's disease with CNS lesions.

Boullerne AI, Rodriguez JJ, Touil T, Brochet B, Schmidt S, Abrous ND, Le Moal M, Pua JR, Jensen MA, Mayo W, Arnason BG, Petry KG. · Department of Neurology, University of Chicago, Chicago, Illinois 60637, USA. · J Neurosci. · Pubmed #11756495 links to  free full text

Abstract: Multiple sclerosis (MS) is characterized by inflammation within the CNS. This inflammatory response is associated with production of nitric oxide (NO) and NO-related species that nitrosylate thiols. We postulated that MS patients would exhibit an antibody (Ab) response directed against proteins containing S-nitrosocysteine (SNO-cysteine) and showed that anti-NO-cysteine Abs of the IgM isotype are in fact present in the sera of some MS patients (Boullerne et al., 1995). We report here the presence of a seemingly identical Ab response directed against SNO-cysteine in an acute model of MS, experimental autoimmune encephalomyelitis (EAE) induced in Lewis rats with the 68-84 peptide of guinea pig myelin basic protein (MBP(68-84)). Serum levels of anti-SNO-cysteine Abs peaked 1 week before the onset of clinical signs and well before the appearance of anti-MBP(68-84) Abs. The anti-SNO-cysteine Ab peak titer correlated with the extent of subsequent CNS demyelination, suggesting a link between Ab level and CNS lesion formation. In relapsing-remitting MS patients, we found elevated anti-SNO-cysteine Ab at times of relapse and normal values in most patients judged to be in remission. Two-thirds of patients with secondary progressive MS had elevated anti-SNO-cysteine Ab levels, including those receiving interferon beta-1b. The data show that a rise in circulating anti-SNO-cysteine Ab levels precedes onset of EAE. Anti-SNO-cysteine Abs are also elevated at times of MS attacks and in progressive disease, suggesting a possible role for these Abs, measurable in blood, as a biological marker for clinical activity.