PMC:3605436 / 15002-22596 JSON TXT

Annnotations TAB JSON ListView MergeView

NEUROSES

2_test

{"project":"2_test","denotations":[{"id":"23555589-19995840-90220103","span":{"begin":337,"end":339},"obj":"19995840"},{"id":"23555589-18775064-90220104","span":{"begin":1100,"end":1102},"obj":"18775064"},{"id":"23555589-20942577-90220105","span":{"begin":2039,"end":2041},"obj":"20942577"},{"id":"23555589-22558238-90220106","span":{"begin":2310,"end":2312},"obj":"22558238"},{"id":"23555589-19560168-90220107","span":{"begin":2316,"end":2318},"obj":"19560168"},{"id":"23555589-22558238-90220108","span":{"begin":2735,"end":2737},"obj":"22558238"},{"id":"23555589-21454981-90220109","span":{"begin":3162,"end":3164},"obj":"21454981"},{"id":"23555589-12665396-90220110","span":{"begin":5485,"end":5487},"obj":"12665396"},{"id":"23555589-19389584-90220111","span":{"begin":5645,"end":5647},"obj":"19389584"},{"id":"23555589-9042108-90220112","span":{"begin":5817,"end":5819},"obj":"9042108"},{"id":"23555589-19150053-90220113","span":{"begin":6029,"end":6031},"obj":"19150053"},{"id":"23555589-15124762-90220114","span":{"begin":6155,"end":6157},"obj":"15124762"},{"id":"23555589-17452584-90220115","span":{"begin":6545,"end":6547},"obj":"17452584"},{"id":"23555589-16510744-90220116","span":{"begin":6551,"end":6553},"obj":"16510744"}],"text":"Discussion\nThis one-armed, clinical trial showed that there was an improvement of fatigue after 12 months of natalizumab treatment. Both the physical and the mental component of fatigue improved in a time-dependent manner. The average improvement corresponded to a reduction from severe to moderate fatigue, according to the FSMC scale [14], which is presently recommended as the best scale for multidimensional analysis of MS fatigue [20]. Likewise, several of the secondary outcome variables measuring depression, cognitive function, sleepiness, and general quality of life, displayed statistically significant improvements over the 12-month study period.\nNo controlled studies have been reported that have primarily addressed impact of DMTs on fatigue, and currently there is no consensus regarding how therapies directed against the neuroinflammatory component affect MS-related fatigue. Some uncontrolled studies indicate, however, that the use of DMTs may positively influence fatigue.\nIn two studies of glatiramer acetate (GA), the fatigue impact scale (FIS) [16] and the modified FIS (MFIS) [18] were utilised. While the results of these studies were positive, the improvements observed were modest. In the study by Metz et al., the proportion of patients improving by more than one SD was 25% in the GA-treated group, which was significantly different than the IFNβ-treated group (14%. In a study by Ziemsen et al. 291 treatment-naïve patients were evaluated with MFIS at baseline and after one year of GA treatment. The MFIS decreased from 34.6 to 27.0. However, since the cut-off value for fatigue with the MFIS scale is 38, the clinical meaningfulness of this reduction is hard to interpret. There is no evidence to indicate whether treatment with IFNs have an effect on fatigue. In one study assessing fatigue while initiating IFN treatment in MS patients, there was an initial tendency for improvement of fatigue measured by MFIS in the first 6 months, but reverted to baseline levels in two of the three IFN groups studied [15]. There are no studies where fatigue has been specifically investigated during fingolimod treatment.\nTwo published studies have longitudinally studied the effect of natalizumab on MS fatigue as the primary outcome variable, and they both reported a favorable outcome [19], [21]. In the study by Putzki et al. 42 patients were followed over 6 months, MFIS and fatigue severity scale (FSS) improved significantly. In the recently published study by Iaffaldano et al., 100 patients were followed for one year and 53 patients were followed for two years, the mean FSS score at baseline was 4.01 and 45% of the patients scored \u003e4.6, the cut-off level for fatigue interfering with daily activities [19]. After 12 months of natalizumab treatment, these scores were significantly reduced to 3.61 and 29%, respectively. Finally, a cross-sectional study comparing the level of fatigue between 49 patients receiving natalizumab with 53 patients treated with IFN/GA matched for age, gender and disability indicated a lower level of fatigue in the natalizumab-treated group base on all MFIS subscales except the psychosocial domain [22]. Prevalence of severe fatigue was 34.7% in the natalizumab group compared with 51% for IFN/GA group.\nThe TYNERGY trial is the most comprehensive and systematic study to evaluate the effects of highly-active immunomodulatory treatment on fatigue, as well as a large set of related symptoms crucial for the well-being of MS patients. The study was performed in a clinical trial setting with all statistical analyses predefined and thus eliminating spurious post-hoc observations of questionable importance. A broad repertoire of these predefined scales measuring HRQoL, sleepiness, cognitive functions, walking speed and depression displayed robust and significant improvement during 12 months treatment with natalizumab.\nIt was not considered ethical to include a control arm, as these patients had high disease activity, in addition to no other second-line treatment available at the start of the study. It is therefore a risk that our data, at least partly, can be explained by the strong placebo effect from starting a new and more efficient treatment and hence, one must be cautious with the final interpretation of the results.\nAnother confounder could be that the patients experienced a temporary increased level of fatigue due to relapse at the time of natalizumab treatment start. We therefore analysed this factor and could determine that the time from last relapse to treatment start did not influence the positive response on fatigue observed after the start of natalizumab treatment. Another possible source of error could be that the improvement of fatigue simply was a relief of side effects from IFN treatment, the AE of which may result in increased fatigue. Also in this aspect, correction for type of previous DMT treatment, including no treatment at all, did not diminish the positive effect of natalizumab treatment on fatigue. It is therefore reasonable to conclude that the main reason to the suspected improvement in MS-related fatigue observed in this study was possibly a direct result of the improved inflammatory control imposed by the initiation of natalizumab treatment.\nIt has been suggested that MS fatigue is closely related to immunological factors. During relapse patients often report increased fatigue symptoms and some immunomodulators are known to produce fatigue as a side effect [23]. In MS, peripheral cytokines are able to enter the brain since the blood-brain barrier in certain regions of the brain is either less restricted or absent [24]. In addition, cytokines themselves have the potential to contribute to the destruction of the blood brain barrier and hereby facilitate entrance of inflammatory cells [25]. Certain cytokines are discussed to be related to fatigue. Interleukin (IL) -1α, IL-1β, IL-6, tumour necrosis factor (TNF) α as well as IFNγ have been shown to be related to fatigue-like symptoms in animals [26]. In MS patients, TNFα and IFNγ have been shown to be the variables most likely to be associated with fatigue [27], [28], [29]. The fact that natalizumab seemed to reduce fatigue symptoms in our cohort of patients might be related to the interference with inflammatory cells relevant for the genesis of fatigue in MS.\nNatalizumab has a well-documented effect on direct disease-related parameters such as relapse rate, disease progression and inflammatory activity as measured by magnetic resonance imaging (MRI) [30], [31]. It is a common experience among clinicians working with MS patients that the consequences of the disease affecting quality of life are of great importance and should therefore be taken into account in the evaluation of different DMTs. We therefore believe that the results of the TYNERGY trial add important information to the pivotal studies regarding these modalities of treatment efficacy.\nIn conclusion, this study indicates that initiation of natalizumab in MS improves relevant factors related to quality of life and well-being. The one-armed study design was a prerequisite for conducting a study in second line MS, as no alternative treatment has been available for highly active MS or patients with breakthrough disease activity, until recently. The results of the TYNERGY study, together with the results from the other cohort studies previously discussed, suggests that natalizumab may improve fatigue in MS patients. These results should be regarded as preliminary, and a comparative trial to verify the findings is warranted."}

PMC:3605436 / 15002-22596 JSONTXT

Annnotations TAB JSON ListView MergeView

NEUROSES

2_test

PMC:3605436 / 15002-22596 JSON TXT