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Multiple sclerosis associated fatigue during disease modifying treatment with natalizumab, interferon-beta and glatirameracetate: 1 year follow-up

Murat Yildiz, Stefanie Müller, Jochen Vehoff & Barbara Tettenborn

abstract

Background
Fatigue is regarded as one of the most common symptoms encountered in multiple sclerosis (MS), leading to a severe impairment of quality of life. Our insight about the underlying causes is limited. Evidence regarding the effectiveness of pharmacological management of fatigue in MS patients is restricted.
 
Methods
Study Design
This was a cross-sectional case control study. A retrospective chart review was undertaken in a cohort of MS patients aged between 18 and 65 years. We measured fatigue severity in 65 consecutive patients treated with natalizumab (ntz, all patients treated at our center at time of study). We excluded from our analysis 16 patients treated less than one year with ntz, and one patient because she stopped ntz due to pregnancy planning. For the remaining 48 patients fatigue severity data from the previous year were available. We compared the long term ntz treated cohort to 520 MS patients in our database. Forty-four patients from our database met the inclusion criteria (remitting, relapsing MS patients treated with interferon beta (IFN) or glatiramer acetate (GA) and radiological examination in the past two years) and were matched for age, gender and disability (n=34 (77%) treated with IFN, n=10 (23%) treated with GA). The study was conducted in accordance with requirements of the local ethical committee.

Aim
The objective of this study was the observation of the prevalence and severity of MS associated fatigue in long-term ntz treated patients over 12 months and in comparison to IFN and GA.

Outcome
Fatigue was measured with the Modified Fatigue Impact Scale (MFIS). The MFIS is a 21-item questionnaire ranging from 0 to 48, (higher scores indicating more fatigue). A cut-off score of 38 discriminates “severely fatigued” from “non-fatigued” patients.

Statistical Analysis
Means and standard deviations were used to describe patients’ characteristics. Categorical data were compared with Chi-square test or Fisher’s exact test. The primary analysis of differences in MFIS was performed using non-parametric Wilcoxon test for dependent variables and Mann-Whitney U-Test for independent variables. For correlation analysis between age, sex, disease duration, EDSS, previous disease modifying therapies, annualized relapse rate (ARR) and MFIS we used Spearman's rho test for ordinal scaled parameter and Pearson's correlation for interval scaled parameter. The analysis of efficacy was carried out on an intent-to-treat basis. All tests have been performed two-sided. P-values <0.05 have been considered statistically significant. Analysis was performed with SPSS 19.0 (Chicago, IL).

Results
Patients and Treatment
Mean treatment duration was 30.4 ± 8.8 months for ntz treated patients and 29.8 ± 14.7 months for the control group (treated with IFN or GA). The mean ARR did not significantly change from 0.2 ± 0.2 after one year of ntz treatment to 0.1 ± 0.1. However the ARR in the ntz group was significantly lower compared to the control group 0.7 ± 0.7 (p<0.001). Gd enhancement was more common in the control group than in the ntz group (p<0.01). Additionally, patients treated with ntz had significantly more spinal lesions on T2 weighted MRI than the control group (p<0.001). See table 1 for detailed patient characteristics.

Disease Activity Freedom and Disability Progression
Over the period of 12 months 83% of patients (n = 40) in the ntz group and 43% (n=19) in the control group were clinically disease activity free (no relapse, no EDSS progression, p<0.001). The mean EDSS scores at baseline did not significantly change neither in the ntz group from 2.9 ± 1.2 in the observation period to 2.8 ± 1.5 (p=0.67) nor from 2.5 ± 1.4 to 2.6 ± 1.5 in the control group (p=0.36). In addition, the percentage of progression-free patients (defined as <1.0-point increase in EDSS) was 92% (44/48) in the ntz group and 84% (37/44) in the control group.

MFIS Observation over 12 months
Mean total MFIS Score increased significantly in the ntz group from 32.6 ± 20.9 over the observation period of 12 months to 49.1 ± 20.0 (p<0.001). The total MFIS Score 49.1 ± 20.0 of the ntz treated group was not significantly lower compared to the control group 54.0 ± 20.4 (p=0.24). Fatigue increased in ntz treated patients over the observation period of one year on all subscales of the MFIS (all p<0.001), in comparison to the control group there were no significant differences. See figure 1 for detailed information on the subscales of MFIS.

Limitations of the Study
The main indication for natalizumab in Switzerland is as a second line treatment for patients with relapsing remitting MS who show signs of breakthrough disease in spite of treatment with first line drugs such as interferon beta. Therefore disease activity in the ntz group is higher than in the IFN/GA group. This is limiting the comparability of both groups.

Conclusion
Our results indicate that even after mean natalizumab treatment duration of 30 months the annualized relapse rate stays consistently low at 0.1. But, this study provides evidence that fatigue symptoms in MS patients treated with natalizumab increase over time.
   
keywords multiple sclerosis, natalizumab, interferon-beta, glatirameracetate, fatigue, disease modifying treatment
   
citation yildiz m, Müller S, Vehoff J, & Tettenborn B (2011). Multiple sclerosis associated fatigue during disease modifying treatment with natalizumab, interferon-beta and glatirameracetate: 1 year follow-up. In P03.225 (pp. 1): keiner.
   
type conference paper/poster (English)
name of conference AAN (Honolulu, Hawaii, USA)
date of conference 9-4-2011
title of proceedings P03.225
pages 1
publisher keiner
contact Jochen Vehoff