Fatigue is a common symptom of multiple sclerosis 12345, reported by around three-quarters of affected patients 3, and considered one of the most distressing symptoms of disease by over half 2. Many patients experience debilitating fatigue every day 2. In multiple sclerosis, fatigue has a major detrimental impact on quality of life 678, is frequently associated with depression 910 and is a leading cause of absence from work or impaired work performance 61112. The pathophysiology of fatigue in multiple sclerosis is poorly understood, but is likely to be multifactorial 13141516

Treatment of fatigue in multiple sclerosis is thus a major challenge, which cannot be adequately achieved at the present time. Both non-pharmacological and pharmacological interventions have been proposed for the management of fatigue in multiple sclerosis patients 1517, although the benefits of drugs such as modafenil and amantadine have not been demonstrated unequivocally 181920.

Immunomodulatory treatments for relapsing-remitting multiple sclerosis, namely glatiramer acetate and the β-interferons, provide a marked reduction in relapse rates and in MRI markers of disease activity 21. It is therefore of interest to explore whether such treatments might influence fatigue symptoms as well. A retrospective chart review of 218 Canadian patients receiving an immunomodulatory treatment during the late 1990s revealed that fatigue improved over the six months following treatment initiation 22. Of particular interest was the observation that a significantly higher proportion of glatiramer acetate treated patients than β-interferon-treated patients improved by at least one standard deviation of the Fatigue Impact Scale (FIS).

In order to investigate further the potential impact of immunomodulatory treatment on fatigue in multiple sclerosis, we initiated a prospective, observational, non-interventional study to monitor fatigue in treatment-naive RRMS patients initiating therapy with glatiramer acetate under conditions of daily practice. The primary objective of study was to determine the impact of initiating treatment with glatiramer acetate on fatigue and absenteeism. Secondary objectives were to evaluate the effect of treatment on clinical and MRI outcomes and to determine the tolerability of treatment.

This study was a prospective, observational, non-interventional study of patients with relapsing remitting multiple sclerosis treated with glatiramer acetate conducted in Germany. 130 ambulatory and hospital neurologists participated in the study. The study was performed between November 2002 and October 2004.

In this study, immunomodulatory treatment of relapsing-remitting multiple sclerosis with glatiramer acetate was associated with a reduction in subjective perceptions of fatigue and with the numbers of days taken off work due to illness. We observed a reduction of approximately one-quarter in both MFIS scores and in a VAS measure of fatigue. These findings are consistent with an earlier retrospective study, which also reported an improvement in fatigue measured with the FIS following initiation of glatiramer acetate treatment in 24.8% of patients 22. The two studies cannot, however, be directly compared due differences in methodology.

The amelioration observed following treatment with glatiramer acetate may be a non-specific consequence of improved overall disease status in treated patients or alternatively result from a specific action of the medication on the pathophysiology of multiple sclerosis fatigue. For example, it has been suggested that fatigue may be aggravated by the production of high levels of pro-inflammatory cytokines 2627. The ability of glatiramer acetate to attenuate the secretion and activity of these cytokines within the central nervous system 2829 may provide such a specific mechanism. Others have proposed, on the basis of magnetic resonance spectroscopy (MRS) findings, that fatigue may be associated with axonal injury in the cortex rather than inflammatory white matter lesions per se 30. In a recent trial, Tedeschi et al. could demonstrate that among MS patients with low disability those with high-fatigue show higher white and gray matter atrophy and higher lesion load. They suggest that in MS, independent of disability, white and gray matter atrophy is a risk factor to have fatigue 31. In additon, a recent trial of Rocca et al. using functional imaging in MS patients with fatigue and interferon beta-1a treatment pointed out that an abnormal recruitment of the fronto-thalamic circuitry is associated with interferon-induced fatigue in MS patients 32. In contrast to the interferon's, the specific action of glatiramer acetate to improve MRS markers of axonal injury in multiple sclerosis might contribute to a reduction in fatigue 3334.

We also observed a dramatic reduction of over fifty percent in the number of patients who needed to take time off work due to their multiple sclerosis. This is consistent with findings from an American study, which also reported a marked decrease in days off work in patients treated with glatiramer acetate 35, but less so with beta-interferons. This is an important functional effect of treatment since the ability to hold down a job satisfactorily is critical for self-esteem and because, in certain countries such as the USA, remaining in full-time employment is an important determinant of obtaining insurance for reimbursement of treatment costs.

Again, the impact of glatiramer acetate on time off work may be an indirect consequence of reduced relapse frequency, although the data from the US study showing a differential effect on time off work between glatiramer acetate and β-interferons would argue against this. Alternatively, the observed effect may be secondary to a reduction in fatigue, which has been identified in other studies to be a major reason why patients with multiple sclerosis need to take time off work 1112. Finally, it should be noted that the low incidence of debilitating side-effects reported with glatiramer acetate 36 means that patients are unlikely to need to take time off work due to treatment side-effects.

The strength of this study include the naturalistic design, which means that the findings can probably be generalised to standard care, at least in Europe, with confidence, the prospective nature of the data collection and the relatively large numbers of patients evaluated. Limitations include the absence of a comparator group against which the magnitude of the observed treatment effects could be assessed, and data collection during physician consultations rather than with patients' diaries, which may have introduced some degree of anamnestic error into the findings. The absence of a control group might overestimate the improvement in fatigue symptoms. As a placebo group is probably not ethical it will be further of interest to compare prospectively the benefit on fatigue in a group of naive MS patients treated with GA vs. a group treated with IFN-beta in a next study.

In conclusion, this non-interventional prospective study demonstrated that treatment with glatiramer acetate was associated with a reduction in patient-reported fatigue ratings and in days missing from work, concomitant with an improvement in clinical manifestations of disease activity. These functional outcomes are of critical importance for overall patient well-being.

JH and RA are employed by TEVA Germany. TZ has received honoraria and financial compensation by Bayer Healthcare, Biogen Idec, Merck Serono, Pfizer, Sanofi-Aventis and Teva. SK has received honoraria and financial compensation by Bayer Healthcare, Biogen Idec, Sanofi-Aventis and Teva. Research Projects of TZ and SK were funded by the Roland-Ernst-Foundation, Robert-Pfleger-Foundation, Sanofi-Aventis/TEVA and Bayer Healthcare. In the MS center Dresden, clinical studies are performed for Bayer Healthcare, Biogen Idec, BioMS, Genzyme, Glaxo Smith Kline, Sanofi-Aventis and Teva.

RA, JH and TZ were responsible for the conception of the study. TZ drafted the article. All authors contributed to the interpretation of the results and revising the article for important intellectual content. All authors read and approved the final manuscript.