Conceived and designed the experiments: MT PI RGV. Performed the experiments: PI RGV DP GL EP BG VD MD MPA MT SZ. Analyzed the data: PI MT. Wrote the paper: PI RGV MT.
The authors have read the journal's policy and have the following conflicts: Maria Trojano received honoraria for consultancy or speaking from Biogen, Sanofi-Aventis, Merck Serono and Bayer-Schering and research grants from Merck Serono, Biogen and Novartis; Maria Pia Amato serves on scientific advisory boards for Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis and receives research support and honoraria for speaking from Biogen-Idec, Merck Serono, Bayer Schering and Sanofi Aventis; Rosa Gemma Viterbo serves on scientific advisory boards for Biogen-Idec and received honoraria for speaking from Novartis and Biogen; Damiano Paolicelli received honoraria for consultancy and/or speaking from Biogen Idec, Novartis and Bayer-Schering and research grant from Serono Foundation; Emilio Portaccio serves on a scientific advisory board for Biogen Idec and receives research support and honoraria from Merck Serono, Biogen Idec, Bayer Schering, Sanofi Aventis and Novartis; Benedetta Goretti serves on scientific advisory boards for Biogen Idec and honoraria from Merck Serono, Biogen Idec and Novartis; all other authors declare that there is no conflict of interest. Natalizumab is marketed by Biogen Idec. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.
Natalizumab reduces the relapse rate and magnetic resonance imaging activity in patients with Relapsing-Remitting Multiple Sclerosis (RRMS). So far the influence of natalizumab on cognitive functions and fatigue in MS remains uncertain. The aim of this prospective, open-label, observational study was to evaluate the possible effects of natalizumab on cognition and fatigue measures in RRMS patients treated for up to two years.
Cognitive performances were examined by the Rao's Brief Repeatable Battery (BRB), the Stroop test (ST) and the Cognitive Impairment Index (CII), every 12 months. Patients who failed in at least 3 tests of the BRB and the ST were classified as cognitively impaired (CI). Fatigue Severity Scale (FSS) was administered every 12 months to assess patient's self-reported fatigue. One hundred and 53 patients completed 1 and 2 year-natalizumab treatment, respectively.
After 1 year of treatment the percentage of CI patients decreased from 29% (29/100) at baseline to 19% (19/100) (
These results demonstrate that a short-term NTZ treatment may significantly improve cognitive performances and fatigue in RRMS patients.
Cognitive Impairment (CI) and fatigue are common features of Multiple Sclerosis (MS), with an estimated prevalence ranging approximately from 40 to 65% of patients
Improvement in measures of information processing speed, verbal memory and verbal learning has been reported in relapsing-remitting (RR) MS patients treated with intramuscular Interferon beta (IFNβ)-1a
Glatiramer Acetate (GA) treatment failed to demonstrate significant effects on cognition, even in a long-term follow-up
A post hoc analysis of the two pivotal trials of natalizumab (NTZ), AFFIRM
Here we report the results of an open label, prospective, observational study aimed to further assess the effect of NTZ on cognition and fatigue in a large population of RRMS patients who were followed for up to two years.
All the MS patients who started the standard NTZ regimen (300 mg ev monthly) treatment in two Italian academic (Bari and Florence) MS centers from 2007 were followed through scheduled clinical and neuropsychological assessments. The relapses occurred in the last year prior to the treatment and every new relapse occurring during the treatment were recorded. Annualized relapse rate (ARR) in the last year pre-treatment (baseline) and at the end of the first and second year of treatment was calculated for each patient. A complete neurological examination including the EDSS score assessment was performed at baseline and every 3 months throughout treatment. Cognitive functioning, using the Rao's Brief Repeatable Battery (BRB)
Cognitive impairment was defined as the failure in at least 3 tests on BRB and ST using a 5th percentile cut-off for each test, which corresponded to a z-score 2 standard deviation (SD) below the mean Italian normative values
Fatigue and depression were respectively, assessed, by the Fatigue Severity Scale (FSS)
The local Ethics Committees of the University of Bari and of the University of Florence approved the study, and written informed consent was obtained from all patients prior to entering the study.
Descriptive analyses were performed at the baseline. No imputation of missing data was considered. To test differences across different time points in related samples non parametric tests were used. The Wilcoxon signed – rank test for paired samples and the Friedman two-way test for repeated measures with post-hoc correction were used to compare mean values in paired examinations or when three or more evaluations were available for continuous variables. Cochran Q test for repeated measures and McNemar test for pairwise comparisons were used to assess changes over time in categorical variables. A value of
At the end of September 2011, 100 and 53 RRMS patients completed 1 and 2 years of treatment, respectively. Patients' demographic and clinical characteristics at baseline are shown in
Variable | 100 patients | 53 patients | |
with 1 year | with 2 years | ||
NTZ | NTZ | ||
Treatment | Treatment | ||
Sex (F/M) | 72/28 | 37/16 | |
Age at baseline (Mean ±SD) |
34.55±9.25 | 33.41±8.85 | |
Disease duration in years (Mean ±SD) |
11.09±7.52 | 9.67±6.14 | |
Educational level years (Mean ±SD) |
12.51±3.27 | 12.56±3.63 | |
ARR (Mean ±SD) | 1.91±0.82 | 1.98±0.87 | |
EDSS (Mean ±SD) | 3.66±1.14 | 3.58±1.12 | |
Number of previous DMDs treatment (Median (Range)) | 2 (0–4) | 2 (0–4) | |
Last DMD (n and %) | Interferon-beta | 79 (79%) | 42 (79.2%) |
Glatiramer Acetate | 14 (14%) | 7 (13.2%) | |
Mitoxantrone | 1 (1%) | 0 | |
Azathioprine | 2 (2%) | 1 (1.9%) | |
Treatment naïve | 4 (4%) | 3 (5.7%) | |
Previous treatment duration (Mean ±SD)† | 53.99±41.53 | 55.99±41.67 | |
BDI score (median; Range) | 9 (0–32) | 9 (0–28) | |
Absence/Presence of | No Depression (0–9) | 56 | 28 |
Depression by the | Mild Depression (10–18) | 26 | 13 |
BDI score | Moderate Depression (19–29) | 17 | 12 |
Severe Depression (30–63) | 1 | 0 |
Data expressed in years; †Data expressed in months
Abbreviations: NTZ = Natalizumab; ARR = Annualized Relapse Rate; EDSS = Expanded Disability Status Scale; DMD = Disease Modifying Drug; BDI = Beck Depression Inventory.
In the subgroup of patients receiving NTZ for two years, the mean ARR and the mean EDSS score significantly decreased during the treatment (Friedman test:
At baseline 29/100 (29%) of RRMS patients failed in at least three tests of the BRB and the ST and were classified as cognitively impaired. In patients completing 1 year-NTZ treatment, the number of patients cognitively impaired decreased to 19/100 (19%) (
Timepoint | Patients with CI | Patients without CI | Proportion of |
patients with CI | |||
Baseline (n = 100) | 29 | 71 | 29% |
Year 1 | 19 | 81 | 19% |
Baseline (n = 53) | 12 | 41 | 22.6% |
Year 1 | 10 | 43 | 18.9% |
Year 2 | 9 | 44 | 17% |
Parameter | Timepoint | Mean [SD] | |
CII (n = 100) | Baseline | 13.52 [6.85] | <.0001 |
Year 1 | 10.48 [7.12] | ||
CII (n = 53) | Baseline | 12.94 [7.09] | <.0001 |
Year 1 | 9.64 [6.89] | <.0001 |
|
Year 2 | 8.26 [6.75] | .008 |
|
FSS (n = 100) | Baseline | 4.01 [1.63] | .008 |
Year 1 | 3.61 [1.56] | ||
FSS (n = 53) | Baseline | 4.30 [1.58] | .004 |
Year 1 | 3.70 [1.41] | N.S.θ | |
Year 2 | 3.49[1.75] | .001 |
Wilcoxon signed-rank test;
Wilcoxon signed-rank test pair-wise comparison: Year 1 vs Baseline;
Wilcoxon signed-rank test pair-wise comparison: Year 2 vs Baseline;
Wilcoxon signed-rank test pair-wise comparison: Year 1 vs Year 2.
In the subgroup of patients receiving NTZ for two years, the percentage of cognitively impaired patients decreased from 22.6% (12/53) to 18.9% (10/53) at 1 year and to 17% (9/53) at 2 years, although this decrease did not achieve the statistical significance (Cochran Q test,
In patients treated for up to 2 years the CII significantly decreased (Friedman test:
The results of the multivariate logistic regression (
Parameter | Baseline | OR | 95%Confidence | |
Variable | Interval | |||
Improvement of CII | Constant | 2.492 | 0.719 | |
at year 1 (n = 100) | Sex | 1.367 | (0.399–4.688) | 0.619 |
Age | 0.957 | (0.894–1.025) | 0.210 | |
Disease Duration | 0.991 | (0.913–1.077) | 0.834 | |
|
|
|
|
|
EDSS | 0.984 | (0.559–1.733) | 0.956 | |
FSS score | 0.844 | (0.571–1.248) | 0.396 | |
BDI score | 1.021 | (0.940–1.110) | 0.621 | |
Time from the last steroid | ||||
Pulse | 0.974 | (0.760–1.250) | 0.840 | |
ARR | 0.736 | (0.385–1.405) | 0.352 | |
Improvement of FSS | Constant | 4.140 | 0.518 | |
at year 1 (n = 100) | Sex | 1.029 | (0.317–2.865) | 0.956 |
Age | 0.973 | (0.917–1.032) | 0.359 | |
Disease Duration | 1.012 | (0.940–1.090) | 0.748 | |
Educational School level | 0.966 | (0.821–1.135) | 0.672 | |
EDSS | 0.848 | (0.524–1.374) | 0.504 | |
BDI score | 1.028 | (0.956–1.105) | 0.460 | |
CII | 0.974 | (0.904–1.049) | 0.487 | |
Time from the last steroid | ||||
Pulse | 1.000 | (0.820–1.220) | 0.998 | |
ARR | 0.948 | (0.502–1.790) | 0.869 |
Abbreviations: ARR = Annualized Relapse Rate; EDSS = Expanded Disability Status Scale; BDI = Beck Depression Inventory.
1 year Treatment (n = 100) | 2 years Treatment (n = 53) | ||||
Baseline | Year 1 | Baseline | Year 1 | Year 2 | |
|
|||||
|
|||||
SRT-LTS | 35.20 (13.90) | 36.68 (13.58) | 35.49 (14.10) | 37.94 (13.94) | 36.64 (15.09) |
SRT-CTLR | 26.83 (14.60) | 26.67 (14.87) | 28.15 (14.63) | 28.32 (15.58) | 28.24 (16.65) |
SRT-D | 7.11 (2.65) | 7.54 (3.62) | 7.13 (2.55) | 7.98 (4.41) | 7.34 (3.93) |
|
|||||
|
|||||
SPART | 17.65 (6.14) | 18.90 (6.04) |
18.58 (6.36) | 18.40 (6.47) | 19.68 (5.99) |
SPART-D | 6.30 (3.48) | 6.51 (2.55) | 6.85 (4.10) | 6.66 (2.56) | 6.60 (2.17) |
|
|||||
SDMT | 42.87 (12.33) | 46.29 (12.44) |
43.32 (12.99) | 48.06 (12.09) | 49.57 (12.92) |
PASAT-3 | 34.01 (14.02) | 34.24 (14.94) | 35.75 (14.53) | 36.34 (14.80) | 38.88 (14.46) |
PASAT-2 | 25.61 (12.81) | 28.09 (12.85) |
26.94 (14.25) | 31.03 (13.12) | 32.45 (13.59) |
|
|||||
|
|||||
WLG | 19.98 (6.02) | 20.48 (5.79) | 20.81 (5.66) | 20.41 (5.42) | 22.15 (5.48) |
ST | 70.90 (15.18) | 69.98 (18.45) | 69.35 (13.70) | 69.40 (13.27) | 65.42 (14.30) |
p<0.05 (Wilcoxon signed-rank test);
p<0.0001 (Wilcoxon signed-rank test);
p<0.01 (Friedman two-way test);
Abbreviations: SRT-LTS = Selective Reminding Test – Long-Term Storage; SRT-CTLR = Selective Reminding Test – Consistent Long-Term Retrieval; SRT-D = Selective Reminding Test –Delayed; SPART = 10/36 Spatial Recall Test; SPART-D = 10/36 Spatial Recall Test-Delayed; SDMT = Symbol Digit Modalities Test; PASAT 3 = Paced Auditory Serial Addition Test three second rate; PASAT 2 = Paced Auditory Serial Addition Test two second rate; WLG = Word List Generation; ST = Stroop Test.
Values are expressed as Mean (SD).
At baseline the mean FSS score was 4.01 (±1.63), and 45/100 patients (45%) reported levels of fatigue which interfered with daily activities (FSS score ≥4.5). After 1 year of NTZ treatment, the mean FSS score significantly decreased to 3.61 (±1.56) (
The results of the multivariate logistic regression (
The results of this observational study confirm the efficacy of NTZ treatment in reducing disease activity and disability progression in RRMS patients already demonstrated in NTZ pivotal trials
It is noteworthy that in the current study we used, also, a measure of the global change of cognitive performances that is the CII. We found a significant improvement in the mean CII value after 1 year NTZ treatment and this value was furtherly improved in the second year of treatment. The CII
The significant improvement of fatigue measures after 1 and 2 years of NTZ treatment that we have found, is also in line with a previous German study
The effect of potential clinical and demographic confounders which could affect the changes of neuropsychological performances and fatigue scores at the end of the 1st year of treatment was ruled out by a logistic regression analysis that demonstrated that both cognitive impairment and fatigue were independent from other clinical variables, in this cohort. The only covariate with a positive predictive effect on the neuropsychological performances was the educational level, as measured by the time spent in formal school education, in accordance with recent reports
The degree and the time-trend of the improvement induced by NTZ on cognitive functions and fatigue in the current and previous studies
We recognize that the main limit of this observational study is the lack of a concurrent control group. However it must be considered that many barriers may prevent the execution of a controlled observational study aimed to evaluate the effects of a second line drug (i.e. NTZ) on a population of MS patients with high disease activity. The inclusion of a placebo group, that remains untreated for up to 2 years, is not feasible and ethical. Moreover a comparison between patients treated with a second line treatment (NTZ) and patients treated with a first line treatment (IFN β or GA) is also difficult to carry out, because the unbalanced baseline measures of disease activity (i.e. ARR, EDSS, MRI) between the two groups (indication bias) may influence the measured association between exposure and outcome. Within-subject methods, including self-controlled case-series method
Nevertheless an analysis is ongoing aimed to identify a suitable active drug control group among the DMD treated MS patients collected, in the same period of time, in the MS databases (Imed-web) in Bari and Florence Centers. We are using a propensity score matching technique
Although no direct comparison could be made, our findings allow to speculate that the effects of NTZ on both cognition and fatigue measures might be greater than first line DMDs.
A longer follow-up in a larger population, including a propensity score matched control group, is needed to confirm whether the early beneficial effects of NTZ in improving cognitive performances and fatigue, we found in this study, hold-up in the long-term.