clinical assessment of patients with multiple sclerosis ( ms ) typically focuses on observer - based measures of physical disability . however , there is an acknowledged need to also monitor patient - reported health - related quality of life ( hrqol ) over time when evaluating disease progression and making treatment and management decisions . patient - reported hrqol provides a broad measure of disease impact ( including health dimensions that can not be evaluated using observer - based measures of physical disability ) , may predict future disability progression [ 3 , 4 ] , and is associated with lesion burden and brain atrophy measured using magnetic resonance imaging . the compare study was primarily designed to assess and compare the usefulness and psychometric properties of two hrqol instruments in a large cohort of patients with relapsing ms treated with subcutaneous interferon -1a ; primary and secondary endpoint results from this study have been reported previously . the compare study also offered the opportunity for analyses of associations of changes over time in different dimensions of hrqol with changes in traditional clinician - assessed parameters of disease severity and activity . here , we report the results of these analyses . briefly , compare was a 24-month , phase iv , observational , open - label , single - arm study conducted across 34 ms clinics in canada ( clinicaltrials.gov identifier : nct01141751 ) . the study enrolled patients who had a confirmed diagnosis of relapsing ms according to the mcdonald ( 2001 ) diagnostic criteria   and were eligible for , and willing to start , treatment with interferon -1a subcutaneously three times weekly as prescribed by their treating physician . patients were excluded if they had taken a disease - modifying drug ( dmd ) within the last month ( or 30 days ) before study entry . all patients received treatment with interferon -1a 44  g or 22  g subcutaneously three times weekly . clinic visits were scheduled at baseline and at 6 , 12 , 18 , and 24 months . patients who withdrew from the study were invited to return for an early termination visit . at each visit , patients completed the multiple sclerosis quality of life-54 ( msqol-54 ) questionnaire , an hrqol measure that yields summary scores for physical health ( physical health composite score [ pcs ] ) and mental health ( mental health composite score [ mcs ] ) . both pcs and mcs are expressed on a scale of 0 ( poorest quality of life ) to 100 ( best possible quality of life ) . site investigators also rated patients ' expanded disability status scale ( edss ) scores at each visit . the study was conducted in accordance with the declaration of helsinki ( 2004 ) , international conference on harmonization harmonized tripartite guideline for good clinical practice , and local regulations . an institutional review board or independent ethics committee approved the protocol at each center before study initiation . the baseline characteristics of patients with and without month 24 or early termination visits were compared using the two - sided mann - whitney u test ( quantitative variables ) or two - sided fisher 's exact test ( qualitative variables ) . paired changes from baseline to 6 , 12 , 18 , and 24 months in msqol-54 pcs and mcs and edss scores were analyzed using two - sided wilcoxon matched pairs signed - rank test . used to explore unique associations of edss progression with hrqol , msqol-54 pcs or mcs at 6 , 12 , 18 , or 24 months was included as a dependent variable , and 1- or 1.5-point increase in edss score from baseline to the respective follow - up visit was included as an independent variable . in the models used to explore unique associations of relapse occurrence with hrqol , msqol-54 pcs or mcs at 12 or 24 months was included as a dependent variable , and occurrence of one or more relapses from baseline to 12 months or after month 12 to 24 months , respectively , was included as an independent variable . all models included age , sex , highest level of education ( categorized as either not greater than or greater than secondary ) , whether dmd - nave at study onset , whether terminated the study early , and baseline hrqol measure score as independent variables , except for the analysis with relapses after month 12 to 24 months , in which the hrqol measure score at 12 months was an independent variable . of 334 patients enrolled in the study , 196 ( 59% ) completed the end - of - study visit at 24 months . of the 138 patients who withdrew from the study before 24 months , 81 ( 59% ) attended an early termination visit . the mean ( standard deviation [ sd ] ) time on study was 19.5 ( 7.2 ) months ( median [ range ] 23.5 [ 0.030.8 ] months ) . baseline demographic and disease characteristics of the overall study cohort , together with characteristics for subgroups of patients with and without data from month 24 or early termination visits , are presented in table 1 . the majority of patients ( 80% ) were dmd - nave and 75% had a baseline edss score 2.5 ( table 1 ) . significant mean paired improvements were observed both in msqol-54 pcs and in msqol-54 mcs from baseline to 12 months and from baseline to 24 months ( p < 0.03 for pcs ; p  0.0003 for mcs ; table 2 ) . a small but significant improvement in edss score was seen from baseline to 12 months ( p < 0.05 ) , while mean paired changes in edss score from baseline to 24 months and from baseline to the early termination visit were not significant ( table 2 ) . at least one relapse was reported in 86 ( 26% ) of 334 patients between baseline and 12 months and in 50 ( 21% ) of 241 patients after month 12 to 24 months . an increase in edss score of 1 point ( table 3 ) or 1.5 points ( data not shown ) was significantly associated with lower ( worse ) msqol-54 pcs at all time points ( p < 0.04 for all ) , except at 12 months for an increase in edss score of 1.5 points . there was a significant association between lower mcs and an increase in edss score of 1.5 points at 24 months ( p < 0.01 ) ; there were no significant associations between mcs and an increase in edss score of 1.5 points at other time points or for an increase in edss score of 1 point ( table 3 ) . the occurrence of one or more relapses between baseline and 12 months was significantly associated with both lower ( worse ) follow - up pcs ( p = 0.005 ) and mcs ( p < 0.05 ; table 4 ) . there were no significant associations between the occurrence of one or more relapses after month 12 to 24 months and follow - up pcs or mcs ( table 4 ) . in this observational study of patients with relapsing ms treated with interferon -1a 44  g or 22  g subcutaneously three times weekly , patient - reported hrqol appeared to improve over 2 years for those completing the study . this observation is consistent with previous studies suggesting that subcutaneous interferon -1a therapy may have a positive effect on the hrqol of patients with relapsing - remitting ms [ 9 , 10 ] , although attribution is not possible in the absence of a concurrent nontreatment comparator group . results from our prespecified analyses showed that changes in edss score were associated with changes in the physical but not the mental health dimension of hrqol ; therefore , the physical components of the hrqol score over time appear to correspond with the clinical situation of the patient in terms of physical disability as evaluated by an external rater . in contrast , the occurrence of one or more relapses during the first 12 months was associated with poorer outcomes not only in physical health but also in mental health dimensions of hrqol . the lack of association between edss change and mental health aspects of hrqol at most time points is likely a reflection of ms - related impairments , such as fatigue and depression , which are not or are only minimally evaluated by edss . regarding limitations , we note that we did not capture data on whether study participants had a clinical diagnosis of depression , which is an important contributor to hrqol in ms . however , the msqol-54 mental health composite score does include items on depressive symptomatology and thus taps into the construct of depression . to minimize missing data , we invited study participants who left the study early to attend an early termination visit . fifty - nine percent of those patients who withdrew from the study before 24 months attended the early termination visit ; therefore , we were able to include early termination visit data in our analyses , covarying for early termination status in multivariable models . neither month 24 nor early termination visit data were available for 17% ( 57/334 ) of patients ; however , the baseline characteristics of patients with and without month 24 or early termination visits were not significantly different ( table 1 ) . another limitation of the present study was entry criteria , which specified that while patients should be willing to start medication , they should not be receiving dmd treatment ; our patient cohort did not include more severely disabled patients , and half of the patients had been diagnosed with ms within the previous 4 months . consequently , the findings of the exploratory analyses may not be applicable to patients with relapsing ms who have a greater level of disability or patients at a later stage of disease . finally , we acknowledge that the interpretation of changes in hrqol over time can also be complicated by  response shift ,  whereby hrqol self - reported by the patient might be influenced by psychological phenomena such as adaptation to the disease . prespecified multivariable analyses from a 24-month observational study in patients with relapsing ms receiving subcutaneous interferon -1a suggest that , over the initial 12 months following enrollment , edss changes are solely associated with the physical health domain of hrqol , but relapse occurrence is broadly associated with both physical and mental health aspects of hrqol .
objective . to compare patterns of associations of changes in mental and physical health dimensions of health - related quality of life ( hrqol ) over time with relapse occurrence and changes in expanded disability status scale ( edss ) scores in patients with relapsing multiple sclerosis ( rms ) 
 . methods . this 24-month , phase iv , observational study enrolled 334 patients with rms who received interferon -1a 44  g or 22  g subcutaneously three times weekly . at each 6-month visit 
 , patients completed the multiple sclerosis quality of life-54 ( msqol-54 ) and site investigators assessed edss and recorded relapse occurrence . 
 a generalized linear model procedure was used for multivariable analyses ( per protocol ) that explored unique associations of edss score change and relapse occurrence with msqol-54 physical health composite score ( pcs ) and mental health composite score ( mcs ) . 
 results . 
 hrqol improved over 2 years among those who completed the study . 
 occurrence of 1 relapse was significantly associated with lower msqol-54 pcs and mcs . 
 changes in edss score were significantly associated with msqol-54 pcs , but not mcs . conclusions . 
 hrqol assessments , particularly those that examine mental health , may provide information on the general health status of patients with rms that would not be recognized using traditional clinician - assessed measures of disease severity and activity . 
 this trial is registered with clinicaltrials.gov ; identifier : nct01141751 .