Multiple Sclerosis Resource Centre

Welcome to the Multiple Sclerosis Resource Centre. This website is intended for international healthcare professionals with an interest in Multiple Sclerosis. By clicking the link below you are declaring and confirming that you are a healthcare professional

You are here

Multiple sclerosis relapses are associated with increased fatigue and reduced health-related quality of life – A post hoc analysis of the TEMSO and TOWER studies

Multiple Sclerosis and Related Disorders, Volume 7, May 2016, Pages 33–40

Abstract

Background

Two pivotal phase 3 teriflunomide studies provided data on relapses, fatigue, and health-related quality of life (HRQoL) in patients with relapsing forms of multiple sclerosis (MS).

Objectives

Using pooled data from the TEMSO (NCT00134563) and TOWER (NCT00751881) studies, we investigated the association between relapse severity, and changes from baseline to Week 108 in fatigue and HRQoL outcomes.

Methods

Four definitions of relapse severity were applied in this analysis: sequelae post-relapse; relapse leading to hospitalization; relapse requiring intravenous corticosteroids; and intense relapse. We assessed the association between relapse severity and changes in Fatigue Impact Scale score (n=959), physical and mental health component summary scores from the Short Form (SF)-36 questionnaire (n=904), and SF-6D utility index scores (n=820).

Results

Irrespective of the definition of relapse severity applied, in patients experiencing severe relapse(s), fatigue was increased and HRQoL was decreased; these changes were statistically significant (p<0.0001), and were also clinically significant in many cases. The greatest worsening in fatigue and HRQoL was observed in patients with relapses leading to hospitalization.

Conclusions

Given that severe relapses adversely affect patient-reported fatigue and HRQoL, prevention of severe relapses should be an important therapeutic aim in the treatment of patients with MS.

Highlights

  • We used data from >900 MS patients from the TEMSO and TOWER teriflunomide trials.
  • Patient-reported health-related quality of life (HRQoL) and fatigue were assessed.
  • We used four definitions to identify severe MS relapses.
  • Some 420 patients had relapse(s); most met at least one definition of severe relapse.
  • Patients experiencing severe relapse(s) had worsening in fatigue and HRQoL

Abbreviations: ARR - annualized relapse rate, EDSS - Expanded Disability Status Scale, FIS - fatigue impact scale, FS - functional system, HRQoL - health-related quality of life, MCS - (short form 36) mental health component summary, MID - minimally important difference, PCS - (short form 36) physical health component summary, QoL - quality of life, SF-6D - short form 6-dimension, SF-36 - short form 36.

Keywords: Multiple sclerosis, Quality of life, SF-36, FIS, Relapse, Sequelae, Teriflunomide, Fatigue.

1. Introduction

Multiple sclerosis (MS) is a chronic, progressive, demyelinating disease of the central nervous system and represents a major cause of disability in young adults (Trapp and Nave, 2008). In the majority of cases, MS initially presents in a relapsing-remitting form, characterized by episodes of clinically significant neurological worsening (Trapp and Nave, 2008 and Vollmer, 2007). Patients experiencing a relapse often require increased care and may require hospitalization (Morrow, 2007 and Oleen-Burkey et al, 2012). Relapse symptoms may appear at different times: by convention, any symptoms appearing within 30 days of a first symptom are considered part of the same relapse (Coles, 2009). While periods of remission usually follow a relapse, symptoms do not always resolve completely, and will impact the daily life of patients (Hirst et al., 2008). Recovery from relapses varies greatly among individuals, with residual neurological deficits persisting in over half of patients (Leone et al, 2008 and Vercellino et al, 2009). Given variability both in the care required at the time of relapse and in the persistence of residual deficits, relapses can be considered to have different levels of severity (Leone et al, 2008, Vercellino et al, 2009, and Morrow, 2007). In addition to experiencing the direct health consequences of MS relapses, patients with MS often report a reduction in health-related quality of life (HRQoL) (Aronson, 1997 and Ford et al, 2001), and increased fatigue (Crayton and Rossman, 2006 and Ford et al, 2001). It is therefore important to understand the relationship between relapses and HRQoL and fatigue. Patient perceptions of HRQoL may differ from the opinions of a treating physician (Kremenchutzky and Walt, 2013). Accordingly, patient-reported measures have been developed to evaluate fatigue and HRQoL, including the Fatigue Impact Scale (FIS) patient questionnaire (Fisk et al, 1994a and Fisk et al, 1994b), and the Short Form-36 (SF-36) health survey, which assesses mental and physical health and also provides a measure of utility (Rudick and Miller, 2008 and Ware and Sherbourne, 1992).

Teriflunomide (Aubagio®, Sanofi Genzyme, Cambridge, MA, USA) is a once-daily oral disease-modifying therapy approved for treatment of relapsing–remitting MS (RRMS) (Sanofi-Aventis, 2014). In the pivotal phase 3 TEMSO (NCT00134563) and TOWER (NCT00751881) studies, each including more than 1000 patients with relapsing MS, teriflunomide 14 mg reduced annualized relapse rate (ARR) compared with placebo (relative risk reduction: 31.5%, TEMSO; 36.3%, TOWER; both p<0.001). Teriflunomide 7 mg also significantly reduced ARR in both studies (O’Connor et al, 2011 and Confavreux et al, 2014). TEMSO and TOWER further demonstrated that teriflunomide 14 mg significantly reduced the risk of sustained disability progression (confirmed for 12 weeks) in patients with relapsing MS. The manageable safety profile of teriflunomide has been demonstrated in long-term safety studies of at least 8.5 years (O’Connor et al, 2011, Confavreux et al, 2014, and Confavreux et al, 2012).

Post hoc analysis of TEMSO showed that, versus placebo, teriflunomide 14 mg significantly reduced annualized rates of relapses with sequelae defined by an increase of Expanded Disability Status Scale/Functional System (EDSS/FS) score ≥30 days post-relapse (sequelae-EDSS/FS), relapses with sequelae according to the investigator (sequelae-investigator), relapses leading to hospitalization, and relapses requiring intravenous (IV) corticosteroids (O’Connor et al., 2013). In TOWER, teriflunomide 14 mg reduced annualized rates of all these types of relapses and also the annualized rate of intense relapses (Miller et al., 2014). In both studies, teriflunomide 7 mg significantly reduced annualized rates of relapse with sequelae-EDSS/FS and relapses requiring IV corticosteroids, and in TEMSO, teriflunomide 7 mg significantly reduced rates of relapses leading to hospitalization (O’Connor et al, 2013 and Miller et al, 2014).

In TEMSO and TOWER, teriflunomide reduced fatigue (FIS score) compared with placebo, with a significant difference noted for the 14 mg group in TOWER (p<0.05, change from baseline to last visit) (O’Connor et al, 2011 and Confavreux et al, 2014). Results from TOWER also showed a significant effect of teriflunomide 14 mg in ameliorating the decline in SF-36 mental health component summary (MCS) score observed in the placebo group (p=0.02, change from baseline to last visit). Taken together, these observations suggest that teriflunomide treatment may reduce fatigue and positively affect aspects of HRQoL (Confavreux et al., 2014).

In a previous post hoc analysis of the TEMSO cohort, the occurrence of severe relapses was associated with worsening fatigue and HRQoL (Miller, 2012). Our current analysis extends this approach to assess the association between relapse severity and fatigue and HRQoL in the pooled TEMSO and TOWER cohorts.

2. Patients and methods

2.1. Study designs

TEMSO and TOWER were phase 3, multinational, randomized, double-blind, placebo-controlled studies designed to assess the efficacy and safety of teriflunomide in patients with relapsing MS. Detailed methodology for both studies has been published previously (Confavreux et al, 2014 and O’Connor et al, 2011). Both studies enrolled patients with relapsing MS, aged 18–55 years, with EDSS scores ≤5.5 and ≥1 relapse in the previous 12 months or ≥2 relapses in the prior 24 months. Patients were excluded if they experienced a relapse within 60 (TEMSO) or 30 (TOWER) days prior to randomization. Patients were randomized to receive teriflunomide 14 mg, teriflunomide 7 mg, or placebo.

TEMSO was a 2-year trial; treatment duration in TOWER was variable and ended 48 weeks after the last patient was randomized. The primary endpoint of both studies was ARR. Similarities in TEMSO and TOWER study designs, the nature and timing of evaluations, and patient populations, allowed for pooling of data to assess relapse outcomes in a larger cohort.

Both studies were conducted in accordance with the International Conference on Harmonisation Guidelines for Good Clinical Practice and the Declaration of Helsinki. Protocols were approved by central and local ethics committees and each site’s institutional review board, and patients gave written consent prior to participation.

2.3. Study evaluations

Relapses were defined as the appearance of a new clinical sign/symptom or clinical worsening of a previous sign/symptom that persisted for ≥24 h in the absence of fever. Upon occurrence of suspected relapse, patients were required to contact the investigator for examination within 7 days. Relapses were confirmed by the treating neurologist and required a 1-point increase in at least two FS functions, or a 2-point increase in at least one FS function (excluding bowel/bladder and cerebral), or an increase of ≥0.5 points in EDSS score (or ≥1 point when EDSS=0), from the previous clinically stable assessment. Relapses could be treated with IV corticosteroids according to the judgment of the investigator.

In the absence of a standard definition of severe relapse, four definitions were applied: one definition of relapse with a persisting neurological deficit (sequela) post-relapse and three definitions based on the initial relapse assessment. Sequelae were defined by a confirmed increase in EDSS/FS score, as described above, persisting for ≥30 days after relapse onset (O’Connor et al, 2013 and Miller et al, 2014). A time period of ≥30 days was used in TEMSO and TOWER to allow a relapse-associated persisting EDSS/FS increase to be considered as a sequela. The three definitions of relapse based on initial assessment were relapses leading to hospitalization, relapses requiring treatment with IV corticosteroids, and ‘intense relapses’; relapses meeting the definition of a ‘severe relapse’ from the EVIDENCE study (an increase in EDSS score of >2 points, a change in one or two FS functions of ≥3 points, or a change in four or more functions of ≥2 points) (Panitch et al., 2002).

2.4. Outcome measures

Fatigue and HRQoL were assessed using the FIS (Fisk et al., 1994b) and SF-36 health survey, respectively (Ware and Sherbourne, 1992). The measures were chosen as being well-validated scales that were evaluated in both TEMSO and TOWER. FIS scores range from 0 to 160, with higher scores reflecting increased fatigue, and a minimally important difference (MID) ranging from 10 to 20 points (Rendas-Baum et al., 2010). Physical health component summary (PCS) and MCS scores were derived from the SF-36 survey with scores (1–100) standardized to 50 for the general population (lower scores reflecting poorer HRQoL), and with a MID in patients with MS of 2.5–5.0 (Ware and Sherbourne, 1992 and Rudick et al, 2007). Responses to the SF-36 can be used to calculate a preference-based health utility index. An algorithm is used to convert the SF-36 responses into a six-dimensional health state classification (the SF-6D) and a weighting process is used to derive the health utility index (a missing answer for one item leads to a missing derived utility) (Brazier et al., 2002). The SF-6D estimates a preference-based measure for health with a set of parametric preference weights obtained from a sample of the general population using the recognized valuation technique of standard gamble. The SF-6D is scored from 0 (worst health state) to 1 (best health state) (Brazier et al., 2002). In patients with a range of chronic conditions, the MID for the SF-6D has been estimated as 0.041 (Walters and Brazier, 2005).

2.5. Statistical analyses

The modified intent-to-treat population for TEMSO and TOWER was defined as all patients randomized and exposed to study treatment for ≥1 day (n=2251). From this population, patients with data available at baseline and Week 108 (‘completers’) for the FIS or SF-36 questionnaires or the SF-6D utility index were included; analysis populations were n=959 for FIS, n=904 for SF-36 MCS and PCS, and n=820 for SF-6D utility index.

Analyses assessed the impact of protocol-defined relapses (using the four definitions of relapse severity described previously) on fatigue and HRQoL. For each definition of relapse, three subgroups were analyzed: Group 1, patients without relapse; Group 2, patients with relapse(s) not considered severe; Group 3, patients with ≥1 severe relapse. Mean change from baseline at Week 108 for each outcome in each subgroup was analyzed, and results were evaluated using analysis of covariance (covariates: study, treatment, region, patient status relative to relapse severity definition, EDSS strata at baseline, and baseline value of parameter of interest [e.g. FIS baseline score when assessing FIS score change]). As subgroups were defined based on post-randomization outcomes, there could be confounding between subgroups and study treatment; protection provided by study randomization is not maintained.

3. Results

3.1. Baseline characteristics

Patient demographics and baseline disease characteristics of the TEMSO and TOWER cohorts have been described previously and were comparable, except for a higher percentage of Asians and patients with RRMS in TOWER, making the studies sufficiently similar to allow pooling of data (Confavreux et al, 2014 and O’Connor et al, 2011). Patient demographics and baseline disease characteristics are presented according to each definition of relapse severity for FIS completers in Table 1. Baseline disease characteristics were similar in SF-36 completers and in SF-6D utility index completers (Supplementary Tables 1 and 2). Baseline disease characteristics for individual groups were generally similar, with only small differences among groups; notably, patients without relapse (Group 1) had fewer relapses in the 2 years before study entry than patients in other groups.

Table 1 Patient demographics and baseline disease characteristics of groups according to each relapse definition (pooled TEMSO and TOWER studies, patients with complete information for FIS at baseline and Week 108), n=959.

Relapse definition No relapse Patients with relapse(s), n=420
Sequelae-EDSS/FS Leading to hospitalization Requiring IV corticosteroids Intense relapse (Panitch et al., 2002)
Groupa 1 2 3 2 3 2 3 2 3
(No relapse) (Non-severe) (Severe) (Non-severe) (Severe) (Non-severe) (Severe) (Non-severe) (Severe)
n 539 146 274 279 141 60 360 313 107
Age, mean (SD), years 39.1 (8.8) 37.2 (9.0) 37.1 (8.6) 37.5 (8.6) 36.4 (8.9) 38.7 (8.2) 37.0 (8.7) 37.6 (8.6) 35.6 (8.7)
Female, n (%) 388 (72.0) 116 (79.5) 196 (71.5) 212 (76.0) 100 (70.9) 47 (78.3) 265 (73.6) 226 (72.2) 86 (80.4)
Time since first MS symptom, mean (SD), years 8.5 (6.9) 8.6 (7.1) 8.8 (6.9) 8.9 (6.9) 8.4 (7.0) 8.4 (7.5) 8.8 (6.9) 8.9 (7.0) 8.4 (6.8)
Number of relapses within past 2 years, mean (SD) 2.0 (0.9) 2.3 (1.0) 2.3 (1.1) 2.4 (1.1) 2.3 (1.0) 2.2 (0.7) 2.4 (1.1) 2.3 (1.0) 2.5 (1.2)
EDSS score, mean (SD) 2.5 (1.3) 2.8 (1.3) 2.7 (1.3) 2.6 (1.3) 3.1 (1.2) 2.4 (1.1) 2.8 (1.3) 2.9 (1.3) 2.4 (1.1)
FIS total score, mean (SD) 48.2 (36.6) 52.6 (36.9) 53.0 (36.1) 47.7 (35.5) 63.1 (35.9) 51.8 (40.5) 53.0 (35.7) 54.0 (36.5) 49.5 (35.9)
SF-6D utility index, mean (SD) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1) 0.6 (0.1) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1) 0.7 (0.1)
SF-36 PCS score, mean (SD) 45.2 (9.6) 43.6 (9.9) 44.0 (9.3) 44.7 (9.6) 42.2 (9.1) 44.8 (10.4) 43.7 (9.4) 43.4 (9.7) 45.4 (8.7)
SF-36 MCS score, mean (SD) 43.8 (11.5) 44.4 (11.5) 43.0 (12.0) 44.7 (12.1) 41.1 (11.0) 44.5 (11.2) 43.3 (12.0) 43.3 (11.8) 44.0 (12.0)

a Group 1, patients without relapse; Group 2, patients with relapse(s) not considered severe according to the definition applied; Group 3, patients with at least one severe relapse according to the definition applied.

EDSS, Expanded Disability Status Scale; FIS, Fatigue Impact Scale; FS, Functional System; IV, intravenous; MCS, mental health component summary; PCS, physical health component summary; SD, standard deviation; SF-36, Short Form-36 (health survey); SF-6D, Short Form 6-dimension.

3.2. Incidence of severe relapse(s)

A total of 420 patients (43.8%) experienced relapse(s) (Table 1).

The definition of intense relapse applied to only 107 patients; by contrast, the majority (n=360) of patients with a relapse were treated with IV corticosteroids and were considered to have had a severe relapse under this definition. Severe relapse(s), defined by a need for hospitalization or occurrence of sequelae, occurred in 141 and 274 patients, respectively.

There was overlap between the definitions used (Supplementary Fig. 1). For example, 38.9% of patients defined as having a severe relapse requiring IV corticosteroids were also hospitalized and thus included under both definitions.

3.3. Fatigue and HRQoL outcomes in patients with severe relapse(s)

Regardless of the definition of severe relapse applied in our analysis, patients who experienced severe relapse(s) (Group 3) also experienced significant (p<0.0001) worsening in fatigue and HRQoL compared with patients without relapse (Group 1; Fig 1, Fig 2, Fig 3, and Fig 4).

Fig. 1.

Fig. 1 Impact of relapses with sequelaea on fatigue and HRQoL outcomes (pooled TEMSO and TOWER studies, change from baseline to Week 108). (aRelapse with sequelae defined by an increase in EDSS/FS score at least 30 days post-relapse.) *p<0.05; **p<0.001; ***p<0.0001; compared with Group 1. p<0.05; ††p<0.01; compared with Group 2. Patients with data available at baseline and 108 weeks; analysis populations were n=959 for FIS, n=904 for SF-36 MCS and PCS, and n=820 for SF-6D utility index. EDSS, Expanded Disability Status Scale; FIS, Fatigue Impact Scale; FS, Functional System; HRQoL, health-related quality of life; MCS, mental health component summary; ns, not significant; PCS, physical health component summary; SF-36, Short Form-36 (health survey); SF-6D, Short Form 6-dimension.

Fig. 2.

Fig. 2 Impact of relapses leading to hospitalization on fatigue and HRQoL outcomes (pooled TEMSO and TOWER studies, change from baseline to Week 108). *p<0.05; **p<0.001; ***p<0.0001; compared with Group 1. p<0.05; ††p<0.01; compared with Group 2. Patients with data available at baseline and 108 weeks; analysis populations were n=959 for FIS, n=904 for SF-36 MCS and PCS, and n=820 for SF-6D utility index. FIS, Fatigue Impact Scale; HRQoL, health-related quality of life; MCS, mental health component summary; ns, not significant; PCS, physical health component summary; SF-36, Short Form-36 (health survey); SF-6D, Short Form 6-dimension.

Fig. 3.

Fig. 3 Impact of relapses requiring treatment with IV corticosteroids on fatigue and HRQoL outcomes (pooled TEMSO and TOWER studies, change from baseline to Week 108). *p<0.05; ***p<0.0001; compared with Group 1. Patients with data available at baseline and 108 weeks; analysis populations were n=959 for FIS, n=904 for SF-36 MCS and PCS, and n=820 for SF-6D utility index. FIS, Fatigue Impact Scale; HRQoL, health-related quality of life; IV, intravenous; MCS, mental health component summary; ns, not significant; PCS, physical health component summary; SF-36, Short Form-36 (health survey); SF-6D, Short Form 6-dimension.

Fig. 4.

Fig. 4 Impact of intense relapses (Panitch et al., 2002)a on fatigue and HRQoL outcomes (pooled TEMSO and TOWER studies, change from baseline to Week 108). (aSee Section 2.) *p<0.05; ***p<0.0001; compared with Group 1. p<0.05; ††p<0.01; compared with Group 2. Patients with data available at baseline and 108 weeks; analysis populations were n=959 for FIS, n=904 for SF-36 MCS and PCS, and n=820 for SF-6D utility index. FIS, Fatigue Impact Scale; HRQoL, health-related quality of life; MCS, mental health component summary; ns, not significant; PCS, physical health component summary; SF-36, Short Form-36 (health survey); SF-6D, Short Form 6-dimension.

Differences in FIS score changes from baseline to Week 108 between Group 3 and Group 1 for each definition of severe relapse ranged from 9.993 (relapse requiring IV corticosteroids; Fig. 3) to 14.785 (relapse leading to hospitalization; Fig. 2). Since the MID for the FIS in patients with MS has been estimated at 10–20 points (Rendas-Baum et al., 2010), the increase in fatigue in patients experiencing severe relapses is likely to be clinically meaningful.

Similar observations were made when comparing changes from baseline to Week 108 in SF-36 PCS or MCS scores between Groups 3 and 1. Differences ranged from −3.264 to −4.639 for PCS scores and −2.986 to −4.364 for MCS scores, depending on the definition of severe relapse applied. The MID for SF-36 component scores in patients with MS is generally held to be 2.5–5.0 (Ware and Sherbourne, 1992 and Rudick et al, 2007), therefore, as noted for fatigue, these decreases in HRQoL are likely to be clinically relevant.

For groups of patients with relapses leading to hospitalization, or intense relapses, differences between Groups 3 and 1 in changes from baseline to Week 108 in SF-6D utility index exceeded the estimated MID of 0.041 (Walters and Brazier, 2005); this was not the case for groups of patients with relapses with sequelae or relapses requiring IV corticosteroids.

When comparing patients in Group 3 with patients who experienced relapses not considered severe (Group 2), impact on fatigue was consistently more pronounced in Group 3, with between-group differences reaching statistical significance with regard to relapses with sequelae, relapses leading to hospitalization, and intense relapses. Worsening in HRQoL measures was generally also more pronounced in Group 3 versus Group 2, though not always significantly so.

3.4. Fatigue and HRQoL outcomes in patients with non-severe relapse(s)

Differences in the changes from baseline to Week 108 between patients who experienced relapses that did not qualify as severe (Group 2) and patients without relapse (Group 1) were significant (p<0.05) for all definitions of severe relapse and all outcome measures, except for FIS in Group 2 defined by relapses not requiring IV corticosteroids (Fig 1, Fig 2, Fig 3, and Fig 4). Differences in changes from baseline to Week 108 between Group 1 and Group 2 were generally smaller than the MID for each outcome measure.

3.5. Fatigue and HRQoL outcomes in patients free from relapse

The group of patients without relapse (Group 1) did not experience any clinically meaningful change in any of the outcome measures examined in this analysis (all mean changes from baseline were smaller than the MID for each outcome measure; Fig 1, Fig 2, Fig 3, and Fig 4).

4. Discussion

4.1. Key findings

We were able to analyze the pooled cohort from the TEMSO and TOWER studies given similarities in study designs and patient populations. Notably, HRQoL at baseline was similar for all patients. In both studies, teriflunomide 14 mg significantly decreased ARR (O’Connor et al, 2011 and Confavreux et al, 2014) and the occurrence of severe relapses (O’Connor et al, 2013 and Miller et al, 2014). Therefore, the pooled TEMSO/TOWER study population contained patients with differing rates of relapse occurrence and different relapse severities and could be used to analyze the impact of relapses on fatigue and HRQoL. Over the course of the TEMSO and TOWER studies, we found that change in fatigue and HRQoL showed a clear correlation with the severity of relapses.

4.2. Interpretation

Our results confirm and extend those of others who have investigated the association between MS relapses and aspects of patients’ physical and psychological QoL (Halper, 2007, Kalb, 2007, Oleen-Burkey et al, 2012, and Healy et al, 2012). We found that patients experiencing severe relapses had statistically and clinically significant worsening in fatigue and HRQoL, as evidenced by differences versus those not experiencing a relapse that were within the MID range calculated for patients with MS. Non-severe relapses were also associated with a statistically significant worsening in fatigue and HRQoL; however, considering the MID for fatigue and HRQoL measures, it is likely that non-severe relapses would not have a clinically significant impact on these outcomes.

Since there is no universally accepted definition for a severe relapse, we applied four different overlapping classifications in this study. It is worth noting that corticosteroid use and hospitalization may reflect local practices, in addition to being an indicator of relapse severity. We also acknowledge that while relapses leading to persisting symptoms post-relapse that are not associated with an EDSS/FS score increase could be considered severe, they may not have been captured in the relapse with sequelae group in this analysis. Overall, we conclude it is important to evaluate a range of definitions of relapse severity.

While there is debate regarding how relapses influence the disease course of MS (Confavreux et al., 2000; Bosca et al., 2008) long-term (20-year) follow-up of patients with MS showed that relapses have the greatest effect on disease progression in the first few years of disease (Tremlett et al., 2009). It is, therefore, clearly very valuable to prevent relapses, and especially severe relapses in MS, and to evaluate their effects fully. The present analysis addresses this by adding effects on patient-reported outcomes to our understanding of the overall effects of relapses and severe relapses on patients.

4.3. Limitations

This study, like any post hoc analysis, has inherent limitations; analysis groups are defined using post-randomization information and not protected by randomization. As relapses were included under multiple definitions for analysis, the analyses presented for each relapse definition are not independent. The study was not powered a priori to evaluate the outcomes analyzed herein; further prospective confirmation is required to support our observations. In future, it would be of interest to extend this analysis to assess the cumulative impact of multiple severe or non-severe relapses on fatigue and HRQoL. The interrelation of relapses and disability progression means that the changes in patient-reported outcomes we consider in this analysis may be a consequence not only of relapses but also of changes in disability progression.

5. Conclusion

In summary, this analysis of a large cohort of patients with relapsing MS demonstrates that severe relapses are associated with worsening of key patient-reported outcomes. This finding highlights the importance of using disease-modifying treatments that reduce relapse severity, in addition to mitigating disease progression. Our observations suggest that the focus on ARR as a key indicator of patient response to therapy should be expanded to include relapse severity as an additional dimension of efficacy.

Authors’ contributions

Acquisition and analysis of data was performed by M. Mäurer, G. Comi, M.S. Freedman, L. Kappos, T.P. Olsson, J.S. Wolinsky, A.E. Miller, and P.W. O’Connor. Statistical analyses were conducted by C. Dive-Pouletty and S. Bozzi. All authors contributed towards the preparation of the manuscript, had full access to the data, had final responsibility for the decision to submit for publication, and approved the final submitted version.

Conflict of interest statement

M. Mäurer has received honoraria for lectures from Bayer HealthCare, Biogen Idec, Boehringer Ingelheim, Genzyme, Merck Serono, Novartis, sanofi-aventis, Talecris, and Teva.

G. Comi has received consulting fees from Almirall, Bayer, Biogen, Chugai, Excemed, Genzyme, Merck Serono, Novartis, Receptos, Roche, Sanofi, Serono Symposia International Foundation, and Teva; compensation for speaking activities from Almirall, Bayer, Biogen, Excemed, Genzyme, Merck Serono, Novartis, Sanofi, Serono Symposia International Foundation, and Teva.

M.S. Freedman has received research/educational grant support from Bayer HealthCare and Genzyme; and honoraria/consultation fees from Actelion, Bayer HealthCare, Biogen Idec, Chugai, EMD Canada, Novartis, sanofi-aventis, and Teva Canada Innovation. He was or is a member of Company Advisory Boards/Board of Directors/or other similar group(s) for Actelion, Bayer HealthCare, Biogen Idec, Merck Serono, Novartis, Opexa and sanofi-aventis.

L. Kappos’ institution (University Hospital Basel) has received in the last 3 years and used exclusively for research support: steering committee, advisory board, and consultancy fees (Actelion, Addex, Bayer HealthCare, Biogen Idec, Biotica, Genzyme, Lilly, Merck, Mitsubishi, Novartis, Ono Pharma, Pfizer, Receptos, sanofi-aventis, Santhera, Siemens, Teva, UCB, and XenoPort); speaker fees (Bayer HealthCare, Biogen Idec, Merck, Novartis, sanofi-aventis, and Teva); support of educational activities (Bayer HealthCare, Biogen Idec, CSL Behring, Genzyme, Merck, Novartis, Sanofi, and Teva); royalties (Neurostatus Systems GmbH); grants (Bayer HealthCare, Biogen, Merck, Novartis, Roche, Swiss MS Society, the Swiss National Research Foundation, the European Union, and Roche Research Foundations).

T.P. Olsson has received consulting fees and/or research support from Biogen Idec, Merck Serono, and sanofi-aventis, and has participated in scientific advisory boards and/or speaking activities for Biogen Idec, Merck Serono, and sanofi-aventis.

J.S. Wolinsky has consulting/speakers agreements with AbbVie, Alkermes, Athersys, Inc., Bayer HealthCare, Celgene, EMD Serono, Forward Pharma, Genentech, Genzyme, Jansen R&D, Novartis, Roche, Sanofi, Teva, Teva Neurosciences, to-BBB, and XenoPort; royalties from Chemicon International; research/contractual support from Genzyme, Sanofi, the National Institutes of Health, and National MS Society.

A.E. Miller has received research support from Acorda Therapeutics, Biogen Idec, Genentech, Genzyme, Novartis, Roche, Sanofi-Aventis, and Teva; consulting fees from Acorda Therapeutics, Avanir, Biogen Idec, BioMarin, Chelsea Therapeutics, Daiichi-Sankyo, EMD Serono, GlaxoSmithKline, La-Ser, Merck Serono, Novartis, Nuron Biotech, ONO, and sanofi-aventis.

C. Dive-Pouletty was an employee of Sanofi Genzyme during the study and during the development of this manuscript.

S. Bozzi is an employee of Sanofi Genzyme.

P.W. O’Connor has received consulting fees and/or research support from Actelion, Bayer, Biogen Idec, BioMS, Cognosci, Daiichi Sankyo, EMD Serono, Genentech, Genmab, Novartis, Roche, sanofi-aventis, Teva, and Warburg Pincus.

Role of the funding source

This study was supported by Sanofi Genzyme. The sponsor was jointly responsible for the study design, along with the other authors. It was also responsible for the execution, data collection, and analysis of TEMSO and TOWER. Preparation of the manuscript was supported by Sanofi Genzyme; Sanofi Genzyme was jointly responsible for the decision to publish the manuscript, along with the other authors.

Acknowledgments

Professor Christian Confavreux (University Claude Bernard Lyon 1, Lyon, France), who passed away in September 2013, was a member of the Steering Committee and contributed to the design and conduct of the TEMSO and TOWER studies, as well as to the analysis and interpretation of the data. This manuscript was reviewed by Deborah Dukovic, Steven Hass, Stephanie Jurgensen, and Larisa Miller of Sanofi Genzyme. Editorial assistance was provided by Victoria Lawson of Fishawack Communications Ltd., also funded by Sanofi Genzyme.

Appendix A. Supplementary material

Fig. S1

Fig. S1 Overlap between definitions of severe relapse (pooled TEMSO and TOWER studies, patients with complete information for FIS at baseline and Week 108, and severe relapse by ≥1 definition), n=400. EDSS, Expanded Disability Status Scale; FIS, Fatigue Impact Scale; FS, Functional System.

Download file

Supplementary material

References

  • Aronson, 1997 K.J. Aronson. Quality of life among persons with multiple sclerosis and their caregivers. Neurology. 1997;48:74-80
  • Bosca et al., 2008 I. Bosca, F. Coret, C. Valero, A.M. Pascual, M.J. Magraner, L. Landete, B. Casanova. Effect of relapses over early progression of disability in multiple sclerosis patients treated with beta-interferon. Mult. Scler.. 2008;14:636-639
  • Brazier et al., 2002 J. Brazier, J. Roberts, M. Deverill. The estimation of a preference-based measure of health from the SF−36. J. Health Econ.. 2002;21:271-292
  • Coles, 2009 A. Coles. Multiple sclerosis. Pract. Neurol.. 2009;9:118-126
  • Confavreux et al., 2012 C. Confavreux, D.K. Li, M.S. Freedman, P. Truffinet, H. Benzerdjeb, D. Wang, A. Bar-Or, A.L. Traboulsee, L.E. Reiman, P.W. O’connor, G. Teriflunomide Multiple Sclerosis Trial. Long-term follow-up of a phase 2 study of oral teriflunomide in relapsing multiple sclerosis: safety and efficacy results up to 8.5 years. Mult. Scler.. 2012;18:1278-1289
  • Confavreux et al., 2014 C. Confavreux, P. O’connor, G. Comi, M.S. Freedman, A.E. Miller, T.P. Olsson, J.S. Wolinsky, T. Bagulho, J.-L. Delhay, D. Dukovic, P. Truffinet, L. Kappos, O.B.O.T.T.T. Group. Oral teriflunomide for patients with relapsing multiple sclerosis (TOWER): a randomised, double-blind, placebo controlled, phase 3 trial. Lancet Neurol.. 2014;13:247-256
  • Confavreux et al., 2000 C. Confavreux, S. Vukusic, T. Moreau, P. Adeleine. Relapses and progression of disability in multiple sclerosis. N. Engl. J. Med.. 2000;343:1430-1438
  • Crayton and Rossman, 2006 H.J. Crayton, H.S. Rossman. Managing the symptoms of multiple sclerosis: a multimodal approach. Clin. Ther.. 2006;28:445-460
  • Fisk et al., 1994a J.D. Fisk, A. Pontefract, P.G. Ritvo, C.J. Archibald, T.J. Murray. The impact of fatigue on patients with multiple sclerosis. Can. J. Neurol. Sci.. 1994;21:9-14
  • Fisk et al., 1994b J.D. Fisk, P.G. Ritvo, L. Ross, D.A. Haase, T.J. Marrie, W.F. Schlech. Measuring the functional impact of fatigue: Initial validation of the fatigue impact scale. Clin. Infect. Dis.. 1994;18(Suppl. 1):S79-S83
  • Ford et al., 2001 H.L. Ford, E. Gerry, M.H. Johnson, A. Tennant. Health status and quality of life of people with multiple sclerosis. Disabil. Rehabil.. 2001;23:516-521
  • Halper, 2007 J. Halper. The psychosocial effect of multiple sclerosis: the impact of relapses. J. Neurol. Sci.. 2007;256(Suppl. 1):S34-S38
  • Healy et al., 2012 B.C. Healy, I.R. Degano, A. Schreck, D. Rintell, H. Weiner, T. Chitnis, B.I. Glanz. The impact of a recent relapse on patient-reported outcomes in subjects with multiple sclerosis. Qual. Life Res.. 2012;21:1677-1684
  • Hirst et al., 2008 C. Hirst, G. Ingram, O. Pearson, T. Pickersgill, N. Scolding, N. Robertson. Contribution of relapses to disability in multiple sclerosis. J. Neurol.. 2008;255:280-287
  • Kalb, 2007 R. Kalb. The emotional and psychological impact of multiple sclerosis relapses. J. Neurol. Sci.. 2007;256(Suppl. 1):S29-S33
  • Kremenchutzky and Walt, 2013 M. Kremenchutzky, L. Walt. Perceptions of health status in multiple sclerosis patients and their doctors. Can. J. Neurol. Sci.. 2013;40:210-218
  • Leone et al., 2008 M.A. Leone, S. Bonissoni, L. Collimedaglia, F. Tesser, S. Calzoni, A. Stecco, P. Naldi, F. Monaco. Factors predicting incomplete recovery from relapses in multiple sclerosis: a prospective study. Mult. Scler.. 2008;14:485-493
  • Miller, 2012 A. Miller. Impact of relapses with sequelae on disability, health-related quality of life, and fatigue in a population with relapsing forms of multiple sclerosis (RMS) using data from TEMSO, a pivotal Phase III teriflunomide trial. Neurology. 2012;P07:082
  • Miller et al., 2014 A. Miller, R. Macdonell, G. Comi, M. Freedman, L. Kappos, M. Maurer, T. Olsson, J. Wolinsky, S. Bozzi, C. Dive-Pouletty, P. O’connor. Teriflunomide reduces relapses with sequelae and relapses leading to hospitalizations: Results from the TOWER study. J. Neurol.. 2014;261:1781-1788
  • Morrow, 2007 T.J. Morrow. The costs and consequences of multiple sclerosis relapses: a managed care perspective. J. Neurol. Sci.. 2007;256(Suppl. 1):S39-S44
  • O’Connor et al., 2013 P. O’Connor, F. Lublin, J. Wolinsky, C. Confavreux, G. Comi, M. Freedman, T. Olsson, A. Miller, C. Dive-Pouletty, G. Bégo-Le-Bagousse, L. Kappos. Teriflunomide reduces relapse-related neurological sequelae, hospitalizations and steroid use. J. Neurol.. 2013;260:2472-2480
  • O’Connor et al., 2011 P. O’Connor, J.S. Wolinsky, C. Confavreux, G. Comi, L. Kappos, T.P. Olsson, H. Benzerdjeb, P. Truffinet, L. Wang, A. Miller, M.S. Freedman. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N. Engl. J. Med.. 2011;365:1293-1303
  • Oleen-Burkey et al., 2012 M. Oleen-Burkey, J. Castelli-Haley, M.J. Lage, K.P. Johnson. Burden of a multiple sclerosis relapse: the patient’s perspective. Patient. 2012;5:57-69
  • Panitch et al., 2002 H. Panitch, D.S. Goodin, G. Francis, P. Chang, P.K. Coyle, P. O’connor, E. Monaghan, D. Li, B. Weinshenker. Randomized, comparative study of interferon beta-1a treatment regimens in MS: the EVIDENCE Trial. Neurology. 2002;59:1496-1506
  • Rendas-Baum et al., 2010 R. Rendas-Baum, M. Yang, F. Cattelin, G.V. Wallenstein, J.D. Fisk. A novel approach to estimate the minimally important difference for the Fatigue Impact Scale in multiple sclerosis patients. Qual. Life Res.. 2010;19:1349-1358
  • Rudick et al., 2007 R.A. Rudick, D. Miller, S. Hass, M. Hutchinson, P.A. Calabresi, C. Confavreux, S.L. Galetta, G. Giovannoni, E. Havrdova, L. Kappos, F.D. Lublin, D.H. Miller, P.W. O’connor, J.T. Phillips, C.H. Polman, E.W. Radue, W.H. Stuart, A. Wajgt, B. Weinstock-Guttman, D.R. Wynn, F. Lynn, M.A. Panzara. Health-related quality of life in multiple sclerosis: effects of natalizumab. Ann. Neurol.. 2007;62:335-346
  • Rudick and Miller, 2008 R.A. Rudick, D.M. Miller. Health-related quality of life in multiple sclerosis: current evidence, measurement and effects of disease severity and treatment. CNS Drugs. 2008;22:827-839
  • Sanofi-Aventis, 2014 Sanofi-Aventis, 2014. Aubagio tablets: US Prescribing Information.
  • Trapp and Nave, 2008 B.D. Trapp, K.A. Nave. Multiple sclerosis: an immune or neurodegenerative disorder?. Ann. Rev. Neurosci.. 2008;31:247-269
  • Tremlett et al., 2009 H. Tremlett, M. Yousefi, V. Devonshire, P. Rieckmann, Y. Zhao. Impact of multiple sclerosis relapses on progression diminishes with time. Neurology. 2009;73:1616-1623
  • Vercellino et al., 2009 M. Vercellino, A. Romagnolo, A. Mattioda, S. Masera, C. Piacentino, A. Merola, A. Chio, R. Mutani, P. Cavalla. Multiple sclerosis relapses: a multivariable analysis of residual disability determinants. Acta Neurol. Scand.. 2009;119:126-130
  • Vollmer, 2007 T. Vollmer. The natural history of relapses in multiple sclerosis. J. Neurol. Sci.. 2007;256(Suppl. 1):S5-13
  • Walters and Brazier, 2005 S.J. Walters, J.E. Brazier. Comparison of the minimally important difference for two health state utility measures: EQ-5D and SF-6D. Qual. Life Res.. 2005;14:1523-1532
  • Ware and Sherbourne, 1992 J.E. Ware Jr., C.D. Sherbourne. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care. 1992;30:473-483

Footnotes

a Klinik für Neurologie, Caritas Krankenhaus Bad Mergentheim, Uhlandstraße 7, 97980 Bad Mergentheim, Germany

b Department of Neurology and Institute of Experimental Neurology, University Vita-Salute San Raffaele, Via Olgettina 60, 20132 Milan, Italy

c University of Ottawa and the Ottawa Hospital Research Institute, The Ottawa Hospital – General Campus, 501 Smyth Road, Ottawa, ON, Canada K1H 8L6

d Neurology, Departments of Medicine, Clinical Research and Biomedicine, University Hospital Basel, Petersgraben 4, CH-4031 Basel, Switzerland

e Neuroimmunology Unit, Department of Clinical Neurosciences, Karolinska Hospital, CMM L8:04, 17176 Stockholm, Sweden

f Department of Diagnostic and Interventional Imaging, University of Texas Health Science Center at Houston, 6431 Fannin Street, Houston, TX 77030, USA

g Corinne Goldsmith Dickinson Center for MS, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY 10029, USA

h Health Economics/Outcomes Research, Sanofi Genzyme, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France

i St Michael’s Hospital, Division of Neurology, 30 Bond Street, Toronto, ON, Canada M5B 1W8

Corresponding author.


Search this site

Stay up-to-date with our monthly e-alert

If you want to regularly receive information on what is happening in MS research sign up to our e-alert.

Subscribe »

About the Editors

  • Prof Timothy Vartanian

    dsc_0787_400x400.jpg Timothy Vartanian, Professor at the Brain and Mind Research Institute and the Department of Neurology, Weill Cornell Medical College,...
  • Dr Claire S. Riley

    headshotcsr1_185x250.jpg Claire S. Riley, MD is an assistant attending neurologist and assistant professor of neurology in the Neurological Institute, Columbia...
  • Dr Rebecca Farber

    picforelsevier.jpg Rebecca Farber, MD is an attending neurologist and assistant professor of neurology at the Neurological Institute, Columbia University, in...

This online Resource Centre has been made possible by a donation from EMD Serono, Inc., a business of Merck KGaA, Darmstadt, Germany.

Note that EMD Serono, Inc., has no editorial control or influence over the content of this Resource Centre. The Resource Centre and all content therein are subject to an independent editorial review.

The Grant for Multiple Sclerosis Innovation
supports promising translational research projects by academic researchers to improve understanding of multiple sclerosis (MS) for the ultimate benefit of patients.  For full information and application details, please click here

Journal Editor's choice

Recommended by Prof. Brenda Banwell

Causes of death among persons with multiple sclerosis

Gary R. Cutter, Jeffrey Zimmerman, Amber R. Salter, et al.

Multiple Sclerosis and Related Disorders, September 2015, Vol 4 Issue 5