The Effect of Etanercept on Fatigue in

Patients with either Recent or Established

Rheumatoid Arthritis

19/12/06: Larry W Moreland MD, Mark C Genovese MD, Reiko Sato PhD and Amitabh Singh PhD 

Introduction

Fatigue – often described as a general feeling of weariness, daily lack of energy and tiredness – is a characteristic symptom of rheumatoid arthritis (RA). People with RA usually report higher fatigue levels than the general population¹. In one study, 87% of RA patients reported feeling fatigue; in about half of them the fatigue was considered clinically important². In another study, 69% of patients felt severely or very severely fatigued³. Although the precise cause for fatigue among RA patients is not well understood, rheumatologists believe that there may be several causes including active inflammation, lack of sleep and depression. Fatigue may have a stronger impact on quality of life for RA patients than pain, joint tenderness or active inflammation⁴. Most surprisingly, many RA patients consider relief of their fatigue as one of the most important treatment goals^3.5.

Current RA treatment involves the use of disease-modifying anti-rheumatic drugs (DMARDs) such as methotrexate and sulfasalazine. These drugs can reduce symptoms but merely slow down disease progression for most patients. Typically, patients discontinue therapy with DMARDs after several years because they no longer work or produce unacceptable side effects^6.7. Newer agents, the biologic response modifiers, including etanercept, directly target those factors in the body that are involved in inflammation^8.9. The safety and efficacy of etanercept for the treatment of RA is established^10-12. It is used to reduce signs and symptoms of moderate to severe RA, inhibit progressive joint damage, and improve physical function.

When patients are very fatigued, they tend to have more pain, depression, anxiety and stress^1,13-17. They do not necessarily experience more of the traditional symptoms of RA, such as swollen joints or a higher erythrocyte sedimentation rate¹³, measures usually used in clinical trials to determine the effectiveness of anti-rheumatic therapies. Thus, given the importance of fatigue in patient quality of life, it is critical to assess the impact on fatigue when studying RA treatments. Therefore, researchers from the University of Alabama at Birmingham, Stanford University, and Wyeth looked at the long-term effect of etanercept on fatigue using data from two clinical trials¹⁸: one enrolled patients with recently diagnosed RA¹⁰, the other patients with established RA¹¹. The researchers also assessed how fatigue correlated with other key treatment outcome measures.

METHODOLOGY

In the trial of recently diagnosed RA, 304 patients who had RA for an average of 11 monthjs and no prior treatment with methotrexate, were randomly assigned to etanercept (25 mg) injections twice weekly or to oral methotrexate (20 mg) once weekly for 24 months (see figure below)¹⁰. During the first 12 months, neither the patient nor the investigators knew which treatment the patient was receiving (double-blind hase). After 24 months, etanercpt was given to all patients for an additional 20 months; 33% of the patients originally assigned to methotrexate continued taking methotrexate during this time.

Recently diagnosed RA

In the trial of established RA, 1312 patients, who had RA for an average of 12 years and had been previously treated with up to 4 DMARDs, were randomly assigned to etanercapt (25 mg) injections twice weekly or placebo (an inactive substance that was administrered as if it was a therapy)¹¹. During the first 6 months, neither the patient nor the investigators knew which treatment the patient was receiveing (double-blind phase). After 6 months, etanercapt was given to all patients for additional 40 months (see figure below).

Established RA

Fatigue was measured by asking patients about their energy level during the previous 4 weeks¹⁹. The questions were as follows:

• Did you feel full of pep?
• Did you feel worn out?
• Did you have a lot of energy?
• Did you feel tired?

Patients responded on a 5-point scale, ranging from 1 (all of the time) to 5 (none of the time).

• Patient responses were transformed to a score that ranged from 0 to 100, with a higher value indicating greater fatigue.
• The researchers found that a 20-point drop on this scale can be considered a clinically meaningful improvement in fatigue.

FINDINGS

Study with Patients who were Recently Diagnosed with RA

• Patients who started on etanercept felt more rapid relief from fatigue than patients who started on methotrexate.
• Relief of fatigue was significantly greater in etanercept patients than in methotrexate patients 2, 4 and 8 weeks after treatment initiation.
• Relief of fatigue remained greater for patients who started on etanercept (23% to 29% drop relative to pre-treatment levels) than for those who started on methotrexate (17% to 24% drop) for the remainder of the study; however, these differences were not statistically significant.
• A clinical meaningful improvement – defined as a 20-point drop on a scale from 0 to 100 – was achieved by 32% to 46% of etanercept patients and 25% to 40% of patients originally assigned to methotrexate from month 2 until the end of the study.
• Fatigue relief was sustained throughout the entire 44 months of the study for both groups.

Study with Patients who had established RA

• During the initial 6 months of the study, patients treated with etanercept experienced a significant reduction in fatigue, while fatigue levels remained unchanged in patients receiving placebo.
• Upon initiation of etanercept therapy at month 6, the placebo group felt an immediate drop in fatigue.
• After at least 4 weeks of etanercept treatment, fatigue was reduced by 25% to 36% in patients who initially were treated with etanercept and by 20% to 27% in patients who initially were receiving placebo.
• After being on etanercept therapy for at least 6 months, 34% to 44% of patients initially receiving placebo achieved a clinically meaningful improvement of fatigue throughout the remainder of the study.
• Among patients who started on etanercept, 44% to 56% achieved a clinically meaningful improvement in fatigue at all time points from month 2 until the end of the study.

In both trials, reductions in fatigue score followed the same pattern as decreases in pain and disability and improvements in RA symptoms as defined by the American College of Rheumatology. This confirms the relevance of fatigue as a measure of treatment success in RA clinical trials.

WHAT DOES IT MEAN?

Many RA patients suffer from chronic fatigue, which has tremendous impact on their quality of life. This study has shown that etanercept treatment leads to rapid, sustained and substantial relief from fatigue in patients with recently diagnosed or established RA. For most patients, reduction of fatigue went hand in hand with other improvements such as less pain and reduced disability. Thus, etanercept provides long-term relief from fatigue together with reduced pain and physical recovery and may significantly improve the quality of life of those who suffer from RA.

REFERENCES

1 Belza BL. Comparison of self-reported fatigue in rheumatoid arthritis and controls. J Rheumatol. 1995;22(4):639-43.

2 Wolfe F, Hawley DJ, Wilson K. The prevalence and meaning of fatigue in rheumatic disease. J Rheumatol. 1996;23(8):1407-17.

3 Katz PP. The stresses of rheumatoid arthritis: appraisals of perceived impact and coping efficacy. Arthrititis Care Res. 1998;11(1):9-22.

4 Suurmeijer TP, Waltz M, Moum T, Guillemin F, van Sonderen FL, Briancon S, et al. Quality of life profiles in the first years of rheumatoid arthritis: results from the EURIDISS longitudinal study. Arthritis Rheum. 2001;45(2):111-21.

5 Carr A, Hewlett S, Hughes R, Mitchell H, Ryan S, Carr M, et al. Rheumatology outcomes: the patient’s perspective. J Rheumatol. 2003;30(4):880-3.

6 Wolfe F, Hawley DJ, Cathey MA. Termination of slow acting antirheumatic therapy in rheumatoid arthritis: a 14-year prospective evaluation of 1017 consecutive starts. J Rheumatol. 1990;17(8):994-1002.

7 Aletaha D, Smolen JS. Effectiveness profiles and dose dependent retention of traditional disease modifying antirheumatic drugs for reheumatoid arthritis. An observational study. J Rheumatol. 2002;29(8):1631-8.

8 Smolen JS, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 2003;2(6):473-88.

9 Goldbach-Mansky R, Lipsky PE. New concepts in the treatment of rheumatoid arthritis. Annu Rev Med. 2003;54:197-216.

10 Bathon JM, Martin RW, Fleischmann RM, Tesser JR, Schiff MH, Keystone EC, et al. A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis. N Engl J Med. 2000;343(22):1586-93.

11 Moreland LW, Schiff MH, Baumgartner SW, Tindall EA, Fleischmann RM, Bulpitt KJ, et al. Etanercept therapy in rheumatoid arthrtis. A randomized, controlled trial. Ann Intern Med. 1999;130(6):478-86.

12 Weinblatt ME, Krmer JM, Bankhurst AD, Bulpitt KJ, Fleischmann RM, Fox RI, et al. A trial of etanercept, a recombinant tumor necrosis factor receptor:Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate. N Engl J Med. 1999;340(4):253-9.

13 Huyser BA, Parker JC, Thoreson R, Smarr KL, Johnson JC, Hoffman R. Predictors of subjective fatigue among individuals with rheumatoid arthritis. Arthritis Rheum. 1998;41(12):2230-7.

14 Riemsma RP, Rasker JJ, Taal E, Griep EN, Wouters JM, Wiegman O. Fatigue in rheumatoid arthritish: the role of self-efficacy and problematic social support. Br J Rheumatol. 1998;37(10):1042-6.

15 Fifield J, McQuillan J, Tennen H, Sheehan TJ, Reisine S, Hesselbrock V, et al. History of affective disorder and the temporal trajectory of fatigue in rheumatoid arthritis. Ann Behav Med. 2002;23(1):34-41.

16 Belza BL, Henke CJ, Yelin EH, Epstein WV, Gilliss CL. Correlates of fatigue in older adults with rheumatoid arthritis. Nurs Res. 1993;42(2):93-9.

17 Wolfe F. Fatigue assessments in rheumatoid arthritis: comparative performance of visual analog scales and longer fatigue questionnaires in 7760 patients. J Rheumatol. 2004;31(10):1896-902.

18 Moreland LW, Genovese MC, Sato R, Singh A. Effect of etanercept on fatigue in patients with recent or established rheumatoid arthritis. Arthritis Rheum. 2006;55(2):287-93.

19 Fries JF, Singh G, Ramey DR. Stanford RA, January 1996, Phase 30. Palo Alto, CA:Stanford Univ: 1996.