[Progressive multifocal leukoencephalopathy as a complication of natalizumab therapy]. / Progressiivinen multifokaalinen leukoenkefalopatia natalitsumabihoidon komplikaationa.

Natalizumab medication used in the treatment of active relapsing-remitting multiple sclerosis is associated with a risk of contracting progressive multifocal leukoencephalopathy (PML). Current risk of the PML disease in connection with natalizumab therapy in multiple sclerosis patients is 2.77/1,000. By December 2012, more than 108,000 multiple sclerosis patients worldwide have received natalizumab therapy. There are 350 multiple sclerosis patients receiving natalizumab in Finland. We describe the first one of the two Finnish multiple sclerosis patients having so far been diagnosed with PML disease as a complication of natalizumab therapy.

Simvastatin as add-on therapy to interferon ß-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial.

BACKGROUND: Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective. We aimed to establish whether add-on of simvastatin, a statin with anti-inflammatory properties, improves this efficacy. METHODS: We enrolled treatment-naive patients with relapsing-remitting multiple sclerosis in a multicentre, placebo-controlled, double-blind, randomised, parallel-group trial of simvastatin (80 mg daily) as add-on treatment to intramuscular interferon beta-1a (30 µg weekly). After starting treatment with interferon beta, patients were randomly assigned (in computer-generated blocks of four patients) to simvastatin 80 mg per day or placebo for 1-3 years. Patients and treating and evaluating physicians were masked to treatment allocation. The primary outcome measure was annual rate of documented relapses; analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00492765. FINDINGS: We randomly assigned 307 patients to interferon beta plus simvastatin (n=151) or plus placebo (n=156). Annual rate of documented relapses was 0·19 (95% CI 0·13 to 0·28) in the simvastatin group and 0·14 (95% CI 0·09 to 0·23) in the placebo group (absolute difference 0·059, 95% CI -0·21 to 0·09; p=0·35). Time to first documented relapse (20th percentile) was 18·1 months in patients on simvastatin and 21·5 months in those on placebo (hazard ratio 1·21, 95% CI 0·74 to 1·99; p=0·51). Mean number of new or enlarging T2 lesions was 2·96 in the simvastatin group and 2·52 in the placebo group (ratio of new lesions, 1·17, 95% CI 8·89 to 1·55; p=0·25). Eight (6%) patients on simvastatin and 17 (13%) on placebo had no disease activity (odds ratio 0·42, 95% CI 0·17 to 1·00; p=0·05). No unexpected adverse events were seen. Generally, adverse events were mild and there were no group differences in infections or musculoskeletal disorders, including myalgia (five [3%] patients on simvastatin and nine [6%] on placebo). Rhabdomyolysis and myoglobinuria were not reported and there were no differences in serum creatine phosphokinase. INTERPRETATION: We found no beneficial effect of simvastatin as add-on therapy to interferon beta-1a. Although unlikely, we can not exclude that combination of other statins with other disease-modifying drugs still could be beneficial. FUNDING: Biogen Idec.

Temporal relationship between environmental influenza A and Epstein-Barr viral infections and high multiple sclerosis relapse occurrence.

BACKGROUND: Multiple sclerosis (MS) relapses have been associated with viral and bacterial infection epidemics in MS patients who have not used interferon. OBJECTIVES: We studied whether environmental viral infections in the general population can be associated with increased MS relapse occurrence using retrospective data from 1986 to 1995 when interferons were not yet available. METHODS: Logistic regression modelling was used to compare retrospectively the monthly relapse occurrence from 407 MS patients in Turku University hospital archives and data on ten different specifically diagnosed viral infection epidemics in the general population of Southwestern Finland from 1986 to 1995. The outcome was the odds ratio (OR) of very high relapse occurrence versus low relapse occurrence, or moderate versus low relapse occurrence. RESULTS: After a peak in diagnosed influenza A cases in the general population, the MS relapse occurrence was 6.5 times more likely to be very high (95% CI 1.8-24.0) and 7.1 times more likely to be moderately high (95% CI 1.5-33.2). An increase in MS relapse counts also followed Epstein-Barr virus (EBV) infections (OR 4.4, 95% CI 1.3-15.1), but we found no significant association with adenovirus infections and MS relapses. The MS relapse occurrence was lowest in the summer months July-August (Chi-square test, p<0.01). CONCLUSIONS: Our findings suggest that influenza A and EBV viral infections in the general population are associated with a higher occurrence of exacerbations in MS patients, and thus environmental infection data should be included in epidemiological models on MS relapses.

[Vaccinations and neurological disease]. / Rokotukset ja neurologinen sairaus: Guillain-Barrén oireyhtymä, MS-tauti ja ADEM.

Symptoms appearing after vaccination are easily interpreted as resulting from the vaccination, although the association with vaccination would be only temporal. Vaccinations are useful and safe also in context with neurological diseases. Refraining from vaccinations should be considered only in those fallen ill with the Guillain-Barré syndrome (GBS) after vaccination, or if the vaccination has exacerbated the symptoms of GBS. Influenza vaccines should be recommended as part of treatment practice in multiple sclerosis (MS), because influenza infections are associated with increased risk of exacerbations of MS. Vaccines containing viable pathogens should not be used during immunosuppressive therapy.

[Update on current care guidelines: diagnostics, treatment and rehabilitation of multiple sclerosis]. / MS-taudin diagnoosi, lääkehoito ja kuntoutus.

Treatment is initiated when the McDonald criteria for relapsing-remitting multiple sclerosis (RRMS) are fulfilled. High-risk patients with clinically isolated syndrome are followed using magnetic resonance imaging for one year after the first imaging. Interferon-beta or glatiramer acetate are the first-line immunomodulating drugs (IMD) for RRMS. MxA protein is measured 12 and 24 months after initiation of Interferon-beta to evaluate possible development of neutralizing antibodies. If MxA protein may not be detected repeatedly interferon-beta treatment is discontinued. If the disease is active in spite of treatment with first-line IMD, natalizumab may be considered as a second-line therapy. IMD is stopped when the transition to secondary progressive phase has occurred (or upon transition to secondary progressive phase).

Beta-interferon protects multiple sclerosis patients against enhanced susceptibility to infections caused by poor air quality.

BACKGROUND: The monthly multiple sclerosis relapse rate was studied from January 1995 to March 2001 from hospital records in Southwestern Finland as a retrospective open-label study. METHODS: The relapse rates of beta-interferon users and nonusers were compared to ambient air inhalable particle levels and viral infections in the population with logistic regression. RESULTS: In the non-user group, relapses were more frequent 1 month following the episodes when PM(10) was in the highest quartile [logistic regression odds ratio = 1.196 (95% CI = 1.019-1.404), p = 0.028] and following adenovirus epidemics in the general population [logistic regression odds ratio = 2.234 (95% CI = 1.013-4.926), p = 0.046]. PM(10) and virus infections had no significant effects in interferon users. CONCLUSION: In addition to being antiviral, interferon also protected multiple sclerosis patients against an enhanced susceptibility to infections caused by PM(10).

Enhancement of Th2 responses to replicative herpes simplex virus type 1 vectors by immunomodulative chemotherapy.

Replicating, neuroattenuated gamma(1)34.5-deleted herpes simplex virus (HSV)-vectors are tools for experimental therapy of gliomas and autoimmune diseases. Immunomodulative treatment with Linomide (quinoline-3-carboxamide) has earlier been shown to facilitate some virus infections and reduce autoimmunity. Now we aimed at elucidating the safety of immunomodulatory therapy during infection of mice with HSV vectors. We focused on immunological and virological changes in the nervous system. BALB/c mice were infected intranasally with the HSV-1 recombinant viruses R3616, R3659 and R8306 (with mouse IL-4 transgene) and either treated with Linomide or left untreated as control groups. Treatment with Linomide was started 7 days before infection. Virological analysis consisted of viral culture and PCR for HSV DNA. Cytokine responses were studied with quantitative RT-PCR and EIA. Immunomodulatory treatment did not change the clinical course of infections. The expression of IL-4 and IL-10 in brains increased in Linomide-treated mice, particularly in infection with R8306. The expression of IL-23p19 was decreased in brains in Linomide-treated, vector-infected mice, in comparison with nontreated but virus-infected animals. Immunomodulatory treatment did not increase the viral load in brains in any of the mouse groups infected with R3616, R3659 or R8306. Immunomodulative treatment with Linomide did not compromise the safety of replicating HSV-vectors, not even the one with IL-4 transgene, suggesting that combination of immunomodulation with virotherapy may be beneficial in the treatment of certain diseases of the central nervous system. Further investigations are needed to elucidate the effects of immunomodulatory therapy in order to improve vector survival and efficacy of gene therapy.

Downregulation of VLA-4 on T cells as a marker of long term treatment response to interferon beta-1a in MS.

We determined longitudinally the expression of a panel of adhesion molecules on T cells and soluble ICAM-1, VCAM-1 and tumor necrosis factor apoptosis inducing ligand (TRAIL) in serum during first year of the PRISMS Study with IFNbeta1a in MS. Clinical data and quantitative MRI data were available for 4 years. VLA-4 was down-regulated on T cells and VCAM-1 was up-regulated in serum during the first 3 to 6 months of therapy in patients with favorable long-term treatment response (EDSS progression

Cytokines in experimental herpes simplex virus infection.

Herpes simplex virus (HSV) causes productive and latent forms of infection in humans and experimental animals. The primary infection and reactivation of the latent infection evoke an immune response in the host organism, involving activities of macrophages, CD4+ and CD8+ lymphocytes, and B lymphocytes. Strong cytokine responses are associated with the acute and recurrent phases of HSV infection. Also, during the latent phase of HSV infection in the sensory ganglia, expression of certain cytokines can be detected. The cytokine response to HSV infection is dominated by proinflammatory and Th1 type cytokines; however, Th2 type cytokines such as interleukin-4 also are expressed in the infected tissue. The use of novel HSV-derived, cytokine-expressing gene therapy vectors necessitates studies on the possible modulation of the host responses by the virus-encoded cytokine transgenes. This review focuses on the roles of certain Th1 and Th2 type cytokines in different phases of the experimental HSV infections.

Herpes simplex virus type 1 infection induces upregulation of interleukin-23 (p19) mRNA expression in trigeminal ganglia of BALB/c mice.

We investigated the expression kinetics of several cytokines in trigeminal ganglia (TG) and in brains of BALB/c mice during the course of ocular herpes simplex virus type 1 (HSV-1) infection. All mice recovered from the infection within 2 weeks. The quantitative rapid real-time RT-PCR method was used to analyze interleukin-4 (IL-4), interferon-gamma (IFN-gamma), IL-12p35, IL-12p40, and the recently described IL-23 (p19) mRNA in TG, brain, and splenocyte samples. In TG, we found elevated expression of mRNA for IL-23 (p19) from early acute infection (day 3) to the beginning of the latent phase (day 14). The increase was not detected in brain or in the spleen. IL-4 expression occurred in both TG and brain from the beginning of the experiment to the latent phase. During the latent phase (days 14 and 31), IL-4 expression was significantly elevated in the brain when compared with the uninfected controls (p < 0.05). Considerable expression of IFN-gamma mRNA was detected in TG of mice during acute HSV-1 infection. The expression of IL-23 was detected also in the brains of the mice, even though no significant changes were found during the acute HSV-1 infection. This is, to our knowledge, the first report to show elevated expression of IL-23 (p19) mRNA (p < 0.05) during viral infection in TG of mice.