A. G. Beiske

Pain and sensory complaints in multiple sclerosis

Pain is a frequent and disabling symptom among multiple sclerosis (MS) patients. The importance of this problem was investigated in a hospital based MS population.

NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial

BACKGROUND Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis. METHODS NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527. FINDINGS 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks. INTERPRETATION Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts.

Vitamin D and disease activity in multiple sclerosis before and during interferon-β treatment

Objective: Studies based on deseasonalized vitamin D levels suggest that vitamin D may influence the disease activity in multiple sclerosis (MS), and high doses are suggested as add-on treatment to interferon-β (IFN-β). Seasonal fluctuation of vitamin D varies between individuals, thus the relationship to disease activity should preferentially be studied by repeated and simultaneous vitamin D and MRI measurements from each patient. Methods: This was a cohort study comprising 88 patients with relapsing-remitting MS who were followed for 6 months with 7 MRI and 4 25-hydroxyvitamin D measurements before initiation of IFN-β, and for 18 months with 5 MRI and 5 25-hydroxyvitamin D measurements during IFN-β treatment. Results: Prior to IFN-β treatment, each 10 nmol/L increase in 25-hydroxyvitamin D was associated with 12.7% (p = 0.037) reduced odds for new T1 gadolinium-enhancing lesions, 11.7% (p = 0.044) for new T2 lesions, and 14.1% (p = 0.024) for combined unique activity. Patients with the most pronounced fluctuation in 25-hydroxyvitamin D displayed larger proportion of MRI scans with new T1 gadolinium-enhancing lesions (51% vs 23%, p = 0.004), combined unique activity (60% vs 32%, p = 0.003), and a trend for new T2 lesions (49% vs 28%, p = 0.052) at the lowest compared to the highest 25-hydroxyvitamin D level. No association between 25-hydroxyvitamin D and disease activity was detected after initiation of IFN-β. HLA-DRB1*15 status did not affect the results. Conclusion: In untreated patients with MS, increasing levels of 25-hydroxyvitamin D are inversely associated with radiologic disease activity irrespective of their HLA-DRB1*15 status.

ω-3 Fatty Acid Treatment in Multiple Sclerosis (OFAMS Study): A Randomized, Double-Blind, Placebo-Controlled Trial

OBJECTIVE To investigate whether ω-3 fatty acids reduce magnetic resonance imaging (MRI) and clinical disease activity in patients with multiple sclerosis, both as monotherapy and in combination with interferon beta-1a treatment. DESIGN Multicenter, randomized, double-blind, placebo-controlled clinical trial conducted from 2004 to 2008. SETTING Thirteen public neurology departments in Norway. PARTICIPANTS Patients aged 18 to 55 years with active relapsing-remitting multiple sclerosis, with a disability score equivalent to 5.0 or less on the Kurtzke Expanded Disability Status Scale. Ninety-two patients were randomized to ω-3 fatty acids (n = 46) or placebo capsules (n = 46). INTERVENTIONS Administration of 1350 mg of eicosapentaenoic acid and 850 mg of docosahexaenoic acid daily or placebo. After 6 months, all patients in addition received subcutaneously 44 μg of interferon beta-1a 3 times per week for another 18 months. MAIN OUTCOME MEASURE The primary outcome measure was MRI disease activity as measured by the number of new T1-weighted gadolinium-enhancing lesions during the first 6 months. Secondary outcome measures included MRI disease activity after 9 months and 24 months, relapse rate, disability progression, fatigue, quality of life, and safety. RESULTS The cumulative number of gadolinium-enhancing MRI lesions during the first 6 months were similar in the ω-3 fatty acids and placebo groups (median difference, 1; 95% CI, 0 to 3; P = .09). No difference in relapse rate was detected after 6 (median difference, 0; 95% CI, 0 to 0; P = .54) or 24 (median difference, 0; 95% CI, 0 to 0; P = .72) months. The proportion of patients without disability progression was 70% in both groups (P > .99). No differences were detected in fatigue or quality-of-life scores, and no safety concerns appeared. Serum analyses of fatty acids showed an increase in ω-3 fatty acids (mean difference, 7.60; 95% CI, 5.57 to 7.91; P < .001) in the patients treated with ω-3 fatty acids compared with the placebo group. CONCLUSION No beneficial effects on disease activity were detected from ω-3 fatty acids when compared with placebo as monotherapy or in combination with interferon beta-1a. Magnetic resonance imaging disease activity was reduced as expected by interferon beta-1a. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00360906.

Health-related quality of life in secondary progressive multiple sclerosis.

Common disability scales in multiple sclerosis (MS) are often weighted towards physical disability. Non-motor symptoms such as depression, fatigue and pain substantially influence wellbeing in MS. Health-related quality of life (HRQoL) measures the broader impact of MS and might indicate less obvious disease burdens. We analysed HRQoL, using the Nottingham Health Profile Part I (NHP-I), among 345 secondary progressive MS (SPMS) patients participating in a randomized trial of interferon-β1a (IFN-β1a), 22 μg subcutaneously weekly, or matching placebo. The results did not reveal any beneficial effect of IFN-β1a in any outcome measure. NHP-I sub- and sum scores were compared for 217 population controls and correlated with demographic and clinical disease variables. SPMS patients had lower NHP-I sum and all subscores than the controls. Patients experiencing disease progression reported worse NHP-I sum scores. Increased fatigue, Expanded Disability Status Scale (EDSS) and Arm Index scores were independently associated with reduction in several NHP-I subscores. SPMS patients had significantly lower HRQoL than controls and physical disability (EDSS and Arm Index), disease progression and fatigue strongly influenced this. MS

IL-10 promoter haplotype influence on interferon treatment response in multiple sclerosis.

The level of interleukin‐10 (IL‐10) expression is related to polymorphisms ‐1082 (G/A), ‐819 (T/C) and ‐592 (A/C) in the promoter region of the IL‐10 gene, which constitute three haplotypes, GCC, ATA, and ACC. The ATA (a non‐GCC) haplotype, which is associated with low IL‐10 expression, has been shown to improve interferon (IFN) treatment response in hepatitis C. We analysed the distribution of IL‐10 promoter haplotype combinations to determine whether they could influence initial IFN treatment response in 63 patients with relapsing‐remitting multiple sclerosis (MS). The patients were grouped into non‐GCC or GCC haplotypes, and the clinical and magnetic resonance imaging (MRI) disease activity was compared in the two groups. During the first 6 months of treatment, MS patients with non‐GCC haplotypes experienced fewer new MRI T1‐contrast enhancing lesions [0.77 ± 0.36 (SEM)] than patients with the GCC haplotype (2.45 ± 0.57) (P = 0.05, Mann‐Whitney U test). No differences were detected on clinical disease activity. The results suggest an influence of IL‐10 promoter polymorphisms on IFN treatment response in MS.

Retinol levels are associated with magnetic resonance imaging outcomes in multiple sclerosis.

Background: Vitamin A has immunomodulatory properties and may regulate the transcription of genes involved in remyelination. Objective: To investigate the association between retinol and disease activity in multiple sclerosis (MS). Methods: Cohort study of 88 relapsing–remitting MS patients, originally included in a randomised placebo-controlled trial of omega-3 fatty acids in MS (the OFAMS study), followed prospectively for 24 months with repeated assessments of serum-retinol and magnetic resonance imaging (MRI). All patients were initiated on interferon β-1a after month 6. Results: Each 1 µmol/L increase in serum-retinol reduced the odds (95% confidence interval) for new T1 gadolinium enhanced (Gd+) lesions by 49 (8–70)%, new T2 lesions by 42 (2–66)%, and combined unique activity (CUA) by 46 (3–68)% in simultaneous MRI scans, and 63 (25–82)% for new T1Gd+ lesions, 49 (3–73)% for new T2 lesions and 43 (12–71)% for CUA the subsequent month. Serum-retinol also predicted new T1Gd+ and T2 lesions six months ahead. The associations were not affected by HLA-DRB1*15, or serum levels of 25-hydroxyvitamin D, eicosapentaenoic acid or docosahexaenoic acid. Conclusion: Serum retinol is inversely associated with simultaneous and subsequent MRI outcomes in RRMS.

Antibodies to Epstein-Barr virus and MRI disease activity in multiple sclerosis:

Background: Previous reports indicate an association between Epstein-Barr virus (EBV) antibody levels and multiple sclerosis (MS) disease activity, but the results have been conflicting. Objectives: The objective of this paper is to study if EBV antibody levels reflect MRI disease activity in MS and examine the potential for EBV antibody levels as biomarkers for treatment response. Methods: A total of 87 MS patients were followed for two years prior to and during interferon beta (IFNB) treatment, with MRI examinations and serum measurement of IgM and IgG antibodies to viral capsid antigen (VCA), EBV nuclear antigen 1 (EBNA-1) and early antigen (EA). Associations between EBV antibody levels and MRI activity were assessed by a logistic regression model. Results: Higher anti-EBNA-1 IgG levels were associated with increased MRI activity, OR = 2.95 (95% CI 1.07–8.10; p = 0.036) for combined unique activity (CUA; the sum of T1Gd+ lesions and new or enlarging T2 lesions). Although most patients were anti-VCA IgM negative, there was an inverse association, OR = 0.32 (95% CI 0.12–0.84; p = 0.021) with CUA during IFNB treatment. Conclusions: This study supports an association between anti-EBNA-1 IgG levels and MS disease activity. We also found an inverse association with anti-VCA IgM levels during IFNB treatment not previously described, indicating anti-VCA IgM as a possible biomarker for IFNB treatment response.

Increasing serum levels of vitamin A, D and E are associated with alterations of different inflammation markers in patients with multiple sclerosis

To explore the relationships between vitamin A, D and E and inflammation in relapsing remitting multiple sclerosis, we assessed their associations with 11 inflammation markers in 9 serial serum samples from 85 patients, before and during interferon-β1a treatment. A negative association was found between vitamin A and pentraxin 3 independent of interferon-β1a use, whereas positive associations between vitamin D and interleukin-1 receptor antagonist and secreted frizzled-related protein 3 were seen before, and between vitamin E and chemokine (C-X-C motif) ligand 16 during interferon-β1a treatment. These findings suggest associations with diverse inflammatory pathways, which may be differentially influenced by interferon-β1a treatment.

Quality of life among young patients with ischaemic stroke compared with patients with multiple sclerosis.

Objectives –  We aimed to evaluate the quality of life among young ischaemic stroke (IS) patients at long‐term follow‐up by comparing them with multiple sclerosis (MS) patients with secondary progressive course. The mean age at stroke onset was 41.6 years.