Fatigue and health-related quality of life in relapsing-remitting multiple sclerosis after 2 years glatiramer acetate treatment are predicted by changes at 6 months: an observational multi-center study

In this study we observed, first, that persons with RRMS who were treated for 2 years with GA had preserved at the end of the 2-year period the improvements in fatigue and HRQoL experienced in the first year; second, that the improvements in the first 6 or 12 months correlated significantly with the 2-year level of fatigue and HRQoL; and, third, that throughout 2 years GA treatment significant changes in disability or mood were absent.

In a previous paper, we reported that in treatment-naïve RRMS, but not in pre-treated RRMS, fatigue and HRQoL significantly improved within 6 months after start of GA treatment and that the improvements were sustained at 12 months (FOCUS study) [5]. In contrast, in the present FOCUS-Extension study population improvements at 6 and 12 months were also seen in the pre-treated group, and also in the second year the levels of fatigue and HRQoL did not differ between the two groups (Figs. 1, 2, 3). As an explanation for these discrepancies we thought it likely that the pre-treated FOCUS-Extension group might not represent the original pre-treated FOCUS group. Indeed, the pre-treated persons participating in the extension study seemed to constitute a positive selection, as they had an almost fourfold (3.85) stronger decrease in the 12-month FIS score than the pre-treated FOCUS group (mean −11.79 vs. −3.06), and a fourfold greater improvement in the 12-month HRQoL score (mean +1.59 vs. +0.40). The non-representative character of the pre-treated extension group is confirmed by differences in disease duration (8.1 vs. 6.3 years) and female-to-male ratio (1.64 vs. 3.33). The fact that pre-treated extension patients had more decrease in fatigue and increase in HRQoL in the first year of GA treatment, compared to the total pre-treated group, suggests that these beneficial changes have positively influenced the decision to continue treatment. Thus, data suggest that mainly the responders—in terms of fatigue and HRQoL—in the pre-treated group continued treatment, and that the non-responders have discontinued GA treatment during or at the end of the 1-year FOCUS study.

To further compare the changes over time between the pre-treated and treatment-naive extension groups, we classified the HRQoL status as ‘improved’ (LMSQoL increase at least 3 points), ‘worsened’ (LMSQoL decrease at least -3 points) or ‘unchanged’, similar to the categories applied in the main study. It appeared that, overall, in both groups the HRQol status that had been observed at month 6 was maintained or had positively changed at month 24. E.g., in the pre-treated group five of 13 persons with ‘no change’ status at month 6 reached improvement at month 24, and in the treatment-naive group nine of 17 persons with ‘no change’ at month 6 reached ‘improved’ status at month 24. Similar trends were seen for fatigue and for the comparisons between other time points (month 12 vs. month 24, month 6 vs. month 18, month 12 vs. month 18). These observations underline the similarities between the two extension groups, and contrast with the differences found between the pre-treated and treatment-naive groups in the main study.

We choose to express the relative changes as SD of baseline values. In the whole group the mean changes after 24 months treatment were 0.52 SD for fatigue and 0.68 SD for HRQoL. In a systematic review of the literature on the interpretation of changes in HRQoL Norman et al. found that in all studies (n = 6) the estimated minimally important differences were close to one half SD (mean = 0.495, SD = 0.155) [15]. The frequent use of half a SD as a threshold for clinical relevance suggests that in our patient group the observed changes were indeed beneficial and deserve to be qualified as improvements.

It is not known whether the improvements in fatigue during GA treatment relate to the immunomodulation as such or to specific properties of GA. Circumstantial evidence suggests that in RRMS immunomodulation per se is capable of reducing or stabilizing fatigue. A single-center study in 50 persons with RRMS showed a decreased mean MFIS score after 12 months treatment with subcutaneously administered (sc.) interferon-beta-1a (INF-beta-1a) [16]. Moreover, in a group of 331 persons with RRMS treated for 3 years with sc. INF-beta-1a the pre-existent low mean MFIS score remained stable throughout the study period [17].

In RRMS an increase in disability results from relapses or transition to secondary progression (SP). The absence of an increase in disability during 2 years GA treatment indicates a substantial decline in the frequency and severity of relapses. In the 1-year FOCUS study, the mean (SD) annualized relapse rate decreased moderately by 27 % from 1.15 (0.62) to 0.84 (1.09); in the extension study relapses were not documented. Importantly, a report on a retrospective, observational study in MS patients who were treated with GA in clinical practice showed that during the first year of treatment the relapse rate decreased by 60 % [18]. Recently, Ford et al. published a 15-year follow-up to the pivotal phase III GA trial and concluded that MS patients who received GA for up to 15 years had reduced relapse rates, decreased disability progression, and fewer transitions to SPMS [19, 20]. Our findings of unchanged disability in RRMS patients treated for 2 years are in line with both the extension phase III and observational naturalistic data.

We found rather strong and highly significant correlations between the fatigue and HRQoL improvements in the first 6 months and the levels at 24 months. Of course, correlations between short- and long-term changes within the same parameter are to be expected. Yet, the course of fatigue and HRQoL over 24 months (Figs. 1, 2, 3) suggests that the high correlations can be explained by two phenomena: the improvements in the first 6 months and their stabilization thereafter up to month 24. Therefore, we think that beneficial changes in fatigue and HRQoL in the first 6 months of GA treatment are to a certain extent predictive of sustained long-term improvements. This is to say for treatment-naive patients, and less so for pre-treated ones, as pre-treated FOCUS-Extension patients were not representative of the pre-treated FOCUS group.

Our study was practice based and motivated by questions that may be asked in real life by PwMS who have been treated for 12 months with GA, like ‘Does my improved fatigue lasts when I continue treatment for another 12 months?’, ‘What are my chances of being still on treatment in another 12 months?’, and ‘What will be my condition at the end the second year of treatment?’. For them it may be helpful to know that three out of four persons (77.6 %) who continue treatment are still on treatment at the end of the second year, and that the levels of neurological (dis)abilities, fatigue and HRQoL that they experienced at 6 or 12 months after start of treatment, are likely to be sustained in the second year.

Finally, the documentation of HRQoL changes during DMD treatment may have practical implications. It has been demonstrated that low mental HRQoL and low self-rated health are correlated with increased disability scores 1 year later [21]. As to our study, it may be expected that patients with sustained HRQoL improvement in the second year of GA treatment have increased odds of an unchanged disability in the following year.

In conclusion, in persons with RRMS who completed 2 years GA treatment, we observed that the improvements in fatigue and HRQoL seen after 1 year treatment were sustained, and that the 2-year levels of fatigue and HRQoL correlated strongly with the improvements at 6 and 12 months. Perhaps equally important, disability and mood remained unchanged compared to baseline. Thus, our findings may help to answer real-life questions asked by PwMS in daily practice.