Comparative effectiveness of teriflunomide and dimethyl fumarate: A nationwide cohort study.

OBJECTIVE: To compare on-treatment efficacy and discontinuation outcomes in teriflunomide (TFL) and dimethyl fumarate (DMF) in the treatment of relapsing-remitting multiple sclerosis (RRMS) in a real-world setting. METHODS: We identified all patients starting TFL or DMF from the Danish Multiple Sclerosis Registry and compared on-treatment efficacy outcomes between DMF using TFL, adjusted for clinical baseline variables and propensity score-based methods. RESULTS: We included 2,236 patients in the study: 1,469 patients on TFL and 767 on DMF. Annualized relapse rates (ARRs) in TFL and DMF were 0.16 (95% confidence interval [CI] 0.13-0.20) and 0.09 (95% CI 0.07-0.12), respectively. Relapse rate ratio for DMF/TFL was 0.58 (95% CI 0.46-0.73, p < 0.001). DMF had a higher relapse-free survival proportion at 48 months of follow-up (p < 0.05). We observed no difference in Expanded Disability Status Scale score worsening. Discontinuations due to disease breakthrough were 10.2% (95% CI 7.6%-12.8%) and 22.1% (95% CI 19.2%-25.0%) for DMF and TFL, respectively. A subgroup analysis of ARRs in 708 patients with available baseline MRI T2 lesion amount reported similar results after adjustment. CONCLUSION: We found lower ARR, higher relapse-free survival, and lower incidence of discontinuation due to disease breakthrough on treatment with DMF compared with TFL. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, DMF is more effective in preventing relapses and has lower discontinuation due to disease breakthrough compared with TFL.

Rhabdomyolysis following interferon-beta treatment in a patient with multiple sclerosis - A case report.

BACKGROUND: Multiple sclerosis is an inflammatory disease of the central nervous system for which there is currently no cure. Interferon-beta-1-alpha is worldwide one of the most widely used treatments in multiple sclerosis. To our knowledge there is one previous reported case of rhabdomyolysis associated with Interferon-beta treatment. CASE PRESENTATION: We describe a 30 year old man with relapsing remitting multiple sclerosis who developed rhabdomyolysis and increased creatine kinase following Interferon-beta-1-alpha therapy. After the medication was discontinued, the patient rapidly improved. CONCLUSION: Clinicians should be aware of the possibility of rhabdomyolysis occurring during Interferon-beta-1-alpha therapy. In cases where patients complain of severe myalgia, and in particular if weakness is reported, creatine kinase activity should be measured to prevent irreversible rhabdomyolysis during Interferon-beta-1-alpha therapy in patients with multiple sclerosis.

Statin treatment in multiple sclerosis: a systematic review and meta-analysis.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease that leads to progressive disability. Statins [hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors] are widely prescribed drugs in hypercholesterolemia. They exert immunomodulatory and neurotrophic effects and are attractive candidates for MS treatment due to reliable safety profiles and favorable costs. Studies of statins in a murine MS model and in open-label trials in MS have shown decreased disease severity. OBJECTIVE: Our objective was to assess current evidence to support statin treatment in MS and clinically isolated syndrome (CIS). METHODS: We conducted a systematic literature review of EMBASE, PubMed, and CINAHL databases, clinical trials registries, and unpublished conference meeting abstracts as well as reference lists between 1 and 8 June 2014 and repeated it on 1 December 2014. Randomized controlled trials (RCTs) of statins, in any form or dosage, as monotherapy or add-on to established therapy in relapsing-remitting MS (RRMS), progressive MS, and CIS were included. Data were extracted using pre-defined fields to measure study quality. Meta-analysis was performed with regards to pre-defined outcome measures of relapse activity, magnetic resonance imaging (MRI) activity, Expanded Disability Status Scale (EDSS) progression, and adverse events using a fixed-effects model due to low heterogeneity between studies. RESULTS: Eight trials were included in the review [five of statin add-on to interferon (IFN)-ß treatment in RRMS, one of statin monotherapy in CIS, one of statin monotherapy in optic neuritis (ON)/CIS, and one of statin monotherapy in secondary progressive MS (SPMS)]. Three trials with eligible characteristics had not been published in peer-reviewed journals and were therefore not included. Due to the low number of trials in CIS and SPMS, meta-analysis of primary outcomes was only performed for RRMS studies. Meta-analysis showed no significant effect of statin add-on to IFNß therapy. Indeed, a trend towards an increase in disease activity was shown in the statin group with regards to new T2 lesions, proportion of patients with relapse, and whole brain atrophy but not for EDSS progression. In SPMS, statin monotherapy showed significant reduction in brain atrophy and disability progression but no effect on relapse rate. In CIS, a phase II trial showed no difference in relapse activity, MRI activity or risk of MS between statin monotherapy and placebo. In acute ON, statin monotherapy produced better visual outcome but no difference in relapse activity, MRI activity, or risk of MS. CONCLUSIONS: The pleiotropic effects and effects in the murine model of MS could not be converted to a proven effect in relapsing MS and hence statin therapy either as a monotherapy or in combination with IFNß treatment for RRMS, and statin monotherapy for CIS cannot at present be recommended. However, indications are that statins may be beneficial in SPMS. The benefit thereof and whether this is due to a direct immunomodulatory and neuroprotective effect warrant further studies.

Differential diagnoses to MS: experiences from an optic neuritis clinic.

Optic neuritis (ON) is closely linked to multiple sclerosis (MS). It may, however, also be associated to a range of autoimmune or infectious diseases. The purpose of this study was to assess the differential diagnoses in patients with suspected ON. In this retrospective study, we reviewed the files of all patients referred to the Clinic of Optic Neuritis, Glostrup Hospital, University of Copenhagen, Denmark, between January 2000 and November 2011. All patients were referred by ophthalmologists with possible ON. Patients diagnosed with MS prior to referral were excluded from the study. A total of 643 patients were included in the study. Apart from ON, the most frequent diagnoses were tumors (n = 15), ischemic or hypertensive neuropathies (n = 13), and retinal or choroid disorders (n = 9). Six patients were diagnosed with neuromyelitis optica. Rarer causes of visual loss were infections (n = 5), giant cell arteritis (n = 4), sarcoidosis (n = 3), thyrotoxicosis (n = 2), and hereditary or toxic neuropathies (n = 2). Nine percent of patients referred to the Clinic of Optic Neuritis had symptoms caused by medical, neurosurgical or ophthalmic disorders, and 0.9 % of our patients had NMO. Though most of these conditions are rare, it is of importance to keep them in mind upon encountering patients with symptoms of ON.

Effector and regulatory T cells in patients with acute optic neuritis.

OBJECTIVE: Optic neuritis (ON) is an autoimmune acute demyelinating disease of the optic nerve and may occur in patients with confirmed multiple sclerosis (MS) or as a clinically isolated syndrome. T lymphocytes play a central role in the pathogenesis of MS. The phenotype of different T cell subsets is usually characterized by the expression of distinct cell surface receptors such as CD45RA, CD45RO, CCR7, CD27 and CD28. The aim of this study was to characterize the phenotype of distinct subsets of CD4 and CD8 T cells in patients with isolated ON. METHODS: CD4 and CD8 T cell subsets were characterized by flow cytometry in fresh peripheral blood and cerebrospinal fluid (CSF) samples using the surface markers CD27, CD25, CD45RA, CD45RO and intracellular FOXP3. The T cell subsets expressed in patients with acute ON (n = 64; symptom onset of ON within the preceding 28 days) were compared to those of a gender- and age-matched healthy control (HC) group (n = 32). RESULTS: Both CD4+ and CD8+ naïve T cells in the ON group were significantly reduced in the CSF. In contrast, most of the intermediate-stage and late effector CD4+ and CD8+ T cell subsets as well as the CD4+ T regulatory cells were expressed in ON patients, though not at all in the CSF of the HC group. CONCLUSION: These results add important evidence for inflammatory and regulatory activity in ON and early MS.

Simvastatin improves final visual outcome in acute optic neuritis: a randomized study.

BACKGROUND: In recent years, small-scale clinical trials have indicated that statins or 3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitors exert pleiotropic immunomodulatory effects, with potential therapeutic implications in multiple sclerosis (MS). OBJECTIVE: To investigate whether simvastatin treatment (80 mg daily for 6 months) in patients with optic neuritis (ON) had a beneficial effect on visual outcome and on brain MRI. METHODS: Sixty-four patients with acute ON were randomized to simvastatin treatment (n = 32) or placebo (n = 32) for 6 months. None of the patients had been on immunosuppressive therapy for 6 months prior to inclusion or treated with steroids from symptom onset. Contrast sensitivity (Arden plates), visual acuity, colour perception, visual evoked potentials (VEP)--latency and amplitude, Visual Analogue Scale (VAS) score, and gadolinium enhancing and T2 lesions on brain MRI were evaluated at screening visit, day 14 (except brain MRI), day 90 and day 180. RESULTS: Simvastatin had a beneficial effect on VEP in both latency (p = 0.01) and amplitude (p = 0.01), a borderline effect on the Arden score (p = 0.06) and VAS (p = 0.04), and no effect on brain MRI or on relapse rate between the groups. CONCLUSION: This study provides Class I evidence that simvastatin 80 mg daily is well tolerated and possibly effective in patients with acute ON.

Neither retinal nor brain atrophy can be shown in patients with isolated unilateral optic neuritis at the time of presentation.

BACKGROUND: Acute monosymptomatic optic neuritis (ON) may be the earliest manifestation of multiple sclerosis (MS). Atrophy has been shown to be a prominent feature of MS with great impact on disability. OBJECTIVES: The objectives of this study were to evaluate retinal and brain atrophy and possible associations at the earliest possible stages of MS. METHODS: In a prospective observational cohort study we included 60 untreated patients with monosymptomatic ON and 19 healthy volunteers. Unaffected fellow eyes were examined with optical coherence tomography (OCT) and normalized brain volumes were calculated based on MRI. Additionally, visual evoked potentials (VEPs) were recorded. RESULTS: Neither OCT measurements nor brain volume measures revealed signs of localized or generalized atrophy in patients compared with healthy volunteers. Stratification of patients into high risk based on the presence of white matter lesions did not reveal differences. The association between OCT measures and brain volumes previously found could not be confirmed at the time of the first clinical event. VEP latency was significantly prolonged in patients with white matter lesions compared to those without lesions. A trend towards a relationship between VEP amplitude of fellow eyes and brain volumes was noted. CONCLUSIONS: In this cohort we were not able to show atrophic features in the retina or the brain, and the association between structural measures of the retina and the brain as indicated in the later stages of MS could not be reproduced. These findings suggest that atrophy does require time to evolve and indicate the complexity of the relationship between local and general structural measures.

Increased immunopotency of monocyte derived dendritic cells from patients with optic neuritis is inhibited in vitro by simvastatin.

Multiple sclerosis (MS) is an autoimmune disease where myelin-reactive lymphocytes and their activation depend on interactions with antigen presenting cells (APCs). Dendritic cells (DC) are professional APCs dependent on maturation to attain full T-cell priming capacity. The immunomodulatory properties of simvastatin influence the function of both T cells and APCs and could thus be a potential therapy for MS. The phenotype of myeloid DC in untreated patients with monosymptomatic optic neuritis (ON) was determined by flow cytometry and the impact of simvastatin on the function of myeloid DC derived from peripheral blood mononuclear cells (PBMC) was analysed in vitro. DC from ON patients had more mature phenotype compared with healthy controls (HC). Particularly the fraction of DC expressing CD1a and CD80 was significantly higher in ON than in HC (P<0.05). Addition of 10 muMu simvastatin significantly inhibited the maturation of DC in the ON group. Furthermore, ON derived DC induced stronger T-cell proliferation in the mixed leukocyte reaction (MLR), and simvastatin solely inhibited this proliferation of T-cells in the ON group and not in HC. In conclusion DC from ON patients have a more mature phenotype and an increased stimulatory capacity. Simvastatin has an inhibitory effect on the differentiation and maturation of DC, and selectively reduce the T-cell proliferation induced by DC from patients with ON. The results from these in vitro assays suggest potential beneficial inhibitory effects of Simvastatin in the inflammation in ON and early MS, but we need more clinical trials to confirm it.

Eosinophilic cystitis induced by penicillin.

A 30-year-old woman developed classic symptoms of painful bladder disease and eosinophilic cystitis as an adverse effect of penicillin for abdominal actinomycosis. The symptoms were reversible after stopping penicillin.