Understanding Fatigue in Lupus:
Data from the LUMINA Study

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Graciela S. Alarcón, M.D., M.P.H.
From Lupus News

Introduction
The LUMINA Study
Measuring fatigue
Analyses of data
Factors relating to fatigue
About the author
References

Introduction

Fatigue is a poorly understood symptom that lacks an objective correlate. The most extreme situation is that of persistent and unexplained fatigue, the so-called "chronic fatigue syndrome" (CFS), which is only diagnosed after all other possible causes of fatigue have been ruled out.

Fatigue is present in a variety of disorders. It is commonly reported by lupus patients, and may occur even in the absence of other clinical manifestations indicative of active disease. This suggests that factors other than disease activity may be involved.

Physicians often become frustrated when confronting such patients-the assumption is that the complaint of fatigue lacks a relationship with lupus per se and thus may be due to a concomitant but unrelated problem, specifically secondary fibromyalgia.

Their frustration is compounded by the fact that there are no known interventions that have been clearly shown to modify this manifestation, which is the case in lupus as well as in fibromyalgia and CFS.

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The LUMINA Study

We are currently following a cohort of patients with lupus (as per the American College of Rheumatology criteria). This group is made up of individuals from three well-defined ethnic groups-Hispanic, African American and Caucasian-who have disease of relatively recent onset (5 years or less).

This study group has been named The LUMINA Cohort (for Lupus in Minority populations: Nature Vs Nurture). Study visits have been conducted yearly to determine socioeconomic-demographic, clinical, immunologic, immunogenetic, behavioral and cultural variables.

We felt that we could use this rich database to explore the factors predisposing to fatigue in lupus, and subsequently, to explain how and why fatigue occurs in certain individuals. Only by understanding these factors can we hope to design interventions aimed at modifying this pervasive and oftentimes incapacitating clinical manifestation.

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Measuring fatigue

Fatigue was measured using the original instrument developed by Krupp et al, the Fatigue Severity Scale (FSS), that had previously been used in patients with lupus. According with this 9-item questionnaire, fatigue is considered present if the score is 3 or more. We were first struck by how common fatigue was, regardless of the patients' gender or ethnic group (86 percent, overall). However, the scores were numerically higher in the Caucasian patients than in the non-Caucasians. The distribution of the fatigue scores in the three ethnic groups is shown in Figure 1.

Table 1A
Variables From Different Domains and Their Relationship
With Fatigue in LUMINA Patients (n=223)

Variable	Correlation*
Physical functioning	0.59
Mental functioning	0.40
Maladaptive behaviors	0.37
Helplessness	0.35
Pain (from lupus)	0.35
Disease activity+	0.27
Age	0.11
Poor social support	0.27

*The higher the value, the stronger the relationship (0=no relationship; 1=perfect relationship). Only those variables that were significantly associated with fatigue are shown.
†Measure with the Systemic Lupus Activity Measure or SLAM (excluding fatigue).

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Table 1B

Fatigue Severity Scores as a Function of Selected Features in LUMINA Patients (n=223)

Variable*	Yes		No
	(n)	Median Score	(n)	Median Score
Neurological manifestations	(148)		(81)	4.8
Exercise	(81)		(142)	5.6
Smoking	(37)		(186)	5.8
Difficulties in accessing care	(101)		(122)	5.0
Health insurance	(157)		65)	5.6
Full-time employment	(79)		(142)	5.6

*Only those variables in which the fatigue scores were significantly different in those with and without the feature are shown.

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Analyses of data

Next, we examined the relationship between the fatigue scores, as per the FSS, and specific socioeconomic-demographic, clinical, laboratory, therapeutic, behavioral, and psychological features (these data are summarized in Table 1). These exploratory analyses allowed us to build a model that sorted out which independent contribution of variables appeared to be related to fatigue in the first set of analyses. (Certain variables were purposely left out of the model because they were thought to be the result, rather than the cause, of fatigue, including exercise, physical and mental functioning, and employment.) The results of these analyses are shown in Table 2.

Table 2

Multivariable Analysis of Fatigue in LUMINA Patients

Feature*	Association
Maladaptive health-related behaviors	Positive
Age	Positive
Pain	Positive
Helplessness	Positive
Neurological manifestations	Presence
Ethnicity	Caucasian
Health Insurance	Absence

*Only features retained in the model are shown

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Factors relating to fatigue

The magnitude of the fatigue experienced by our LUMINA patients relates to a variety of factors, which contribute independently to the degree of fatigue observed:
- older age
- non-Caucasian ethnicity
- lack of health insurance
- maladaptive health-related behaviors
- degree of disease activity
- helplessness
- pain (attributable to lupus) and
- neurological manifestations.

Based on the analyses described, and our understanding of lupus in general, we went on to graph the relationship between fatigue and these different variables (Figure 2).

It should be noted that in some cases, the relationship between variables is clearly bi-directional. Fatigue may occur as a result of seemingly unrelated events-for example, worsening disease activity may lead to fatigue, but so may the lack of exercise, or the use of destructive health-related behaviors.

We should add that at the time these analyses were performed, we had not yet started to systematically assess the presence of fibromyalgia (generalized pain and tender points in at least 11 of 18 defined anatomical sites). Subsequent analyses performed in our cohort have revealed that fibromyalgia and fatigue are related, but by no means is fibromyalgia as frequently seen as fatigue.

The relative paucity of fibromyalgia in our patients suggest that fibromyalgia cannot be the main explanatory factor for the occurrence of fatigue or for the severity of the fatigue our patients experience. That has also been the experience of other investigators. We suspect, however, that in the presence of other features (such as disease activity, maladaptive health-related behaviors, lack of exercise), fibromyalgia contributes to this symptom.

What can be done to help lupus patients with this symptom? First, of course, is to determine the obvious, that is whether patients have any lupus or non-lupus related cause for their fatigue (e.g. anemia, renal insufficiency, hypothyroidism, ongoing disease activity, depression, deconditioning, poor sleeping habits) and intervene accordingly. A negative work up may suggest that other factors are more important and the physician may at least attempt to address them (behavioral interventions). We have however, to admit that there are no systematically gathered data (being that randomized clinical trials or longitudinal observational studies) that can support such interventions. We hope to be able to produce such data in due time.

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About the Author

Graciela S. Alarcón, MD, M.P.H. has the Jane Knight Lowe Chair of Medicine in Rheumatology at the University of Alabama at Birmingham in Alabama. She filed this report on behalf of the LUMINA group.

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References

1. Zonana-Nacach A, Roseman JM, McGwin G, Jr., Friedman AW, Baethge BA, Reveille JD et al:Systemic lupus erythematosus in three ethnic groups, VI: Factors associated with fatigue within 5 years of criteria diagnosis. Lupus. 2000;9:101-9.

2. Alarcón GS, Roseman J, Bartolucci AA, Friedman AW, Moulds JM, Goel N et al:Systemic lupus erythematosus in three ethnic groups: II. Features predictive of disease activity early in its course. Arthritis Rheum. 1998;41:1173-80.

3. Alarcón GS, Friedman AW, Straaton KV, Moulds JM, Lisse J, Bastian HM et al:Systemic lupus erythematosus in three ethnic groups: III. A comparison of characteristics early in the natural history of the LUMINA cohort. Lupus. 1999;8:197-209.

4. Reveille JD, Moulds JM, Ahn C, Friedman AW, Baethge B, Roseman J et al:Systemic lupus erythematosus in three ethnic groups: I. The effect of HLA class II, C4, and CR1 alleles, socioeconomic factors, and ethnicity at disease onset. Arthritis Rheum. 1998;41:1161-72.

5. Demitrack MA. Chronic fatigue syndrome and fibromyalgia. Dilemmas in diagnosis and clinical management. Psychiatric Clin N Am. 1999;21:671-92.

6. Gregory R, Brooks KT, Fessler BJ, McGwin G, Jr., Bastian HM, Chapman V et al:Unexpected lack of occurrence of fibromyalgia among a cohort of SLE patients from three ethnic groups. Arthritis Rheum . 1999;42:S285

7. Omdal R, Mellgren SI, Koldingsnes W, Jacobsen EA, Husby G. Fatigue in patients with systemic lupus erythematosus: lack of associations to serum cytokines, antiphospholipid antibodies, or other disease characteristics. J Rheumatol. 2002;29:482-6.

8. Tench C, Bentley D, Vleck V, McCurdie I, White P, D'Cruz D. Aerobic fitness, fatigue, and physical disability in systemic lupus erythematosus. J Rheumatol. 2002;29:474-8.

9. Tayer WG, Nicassio PM, Weisman MH, Schuman C, Daly J. Disease status predicts fatigue in systemic lupus erythematosus. J Rheumatol. 2001;28:1999-2007.

10. Tench CM, McCurdie I, White PD, D'Cruz DP. The prevalence and associations of fatigue in systemic lupus erythematosus. Rheumatol. 2000;39:1249-54.

11. Taylor J, Skan J, Erb N, Carruthers D, Bowman S, Gordon C et al:Lupus patients with fatigue-is there a link with fibromyalgia syndrome? Rheumatol. 2000;39:620-3.

12. Bruce IN, Mak VC, Hallett DC, Gladman DD, Urowitz MB. Factors associated with fatigue in patients with systemic lupus erythematosus. Ann Rheum Dis. 1999;58:379-81.

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July 31, 2003