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.
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
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.
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”
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).
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
Disease Activity Freedom and Disability
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
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.
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.