Constitutional symptoms and fatigue in systemic lupus erythematosus

Introduction

Constitutional symptoms are very common in systemic lupus erythematosus (SLE) but are rather nonspecific; therefore, they are not taken into account in the classification criteria for SLE. Fatigue is the most common constitutional symptom associated with SLE, affecting up to 90% of patients. Other constitutional symptoms such as fever, anorexia, lymphadenopathy, and splenomegaly are less common.

The presence of constitutional symptoms may reflect ongoing active disease. It is one of the systems assessed in British Isles Lupus Assessment Group (BILAG) 2004 disease activity index, which includes the assessment of fever, anorexia, lymphadenopathy, and splenomegaly but not fatigue because attribution to lupus is difficult and fatigue is often multifactorial, as will be discussed later. In the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), fever is the only variable that is taken into account for disease activity scoring. Clinicians should be aware that constitutional symptoms have an exhaustive list of differential diagnoses that need to be excluded before attributing the symptoms to the underlying lupus. Other differential diagnoses that need to be considered include infection, metabolic disorders, malignancy, primary hematological disorders, and other systemic rheumatic diseases.

This chapter discusses each of the constitutional symptoms that may occur in SLE in more detail, focusing the potential differential diagnosis and the potential underlying cause of the constitutional symptoms in lupus patients.

Fatigue

Fatigue is defined as “an uncommon, abnormal or extreme whole bodily tiredness disproportionate or unrelated to activity or exertion.” It is one of the most common and often most disabling symptoms, affecting up to 80%–90% of patients. It causes significant morbidity with negative impact on quality of life (QoL). Studies have shown that fatigue correlates moderately or strongly with all components of the SF-36 and is a major component of vitality domain.

Fatigue is multifactorial and is only related in part to lupus disease activity. Even patients with quiescent lupus continue to experience marked fatigue. Physical inactivity and obesity are found to be significantly associated with fatigue among SLE patients. In addition to that, a decrease in the deformability of the red blood cells membrane due to the C4d deposition and complement activation in SLE may further reduce their ability to flow through small capillaries in the brain and muscle. Hence, the defective oxygen delivery may partly explain the chronic fatigue experienced by SLE patients. Psychosocial variables have also been found to have compelling associations with fatigue levels. It is associated with high scores on subscales for depression and hysteria on the Minnesota Multiphasic Personality Inventory-2, as well as with high scores in Beck Depression Inventory. Due to the various factors that are associated with fatigue in SLE, the underlying causes need to be investigated so that appropriate intervention can be initiated ( Fig. 39.1 ).

In view of the substantial impact of fatigue on SLE patients, the Outcomes Measures in Rheumatology (OMERACT) initiative recommended the measurement of fatigue as one of the patient-reported outcomes (PROs) in SLE clinical trials. During the period of 1970-2006, the Fatigue Severity Scale (FSS) was commonly used and therefore it was recommended by the working group and expert panels of the Ad Hoc Committee on SLE Response Criteria for Fatigue. This instrument was developed in patients with SLE, has a valid psychometric property, and is commonly used in SLE studies.

Both the US Food and Drug Administration and the European Medicines Agency have also recommended the use of PROs instruments to measure fatigue as an endpoint in SLE clinical trials. The Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale has been increasingly used as it demonstrated greater sensitivity to detect differences in fatigue levels compared with the FSS and the Medical Outcomes Study Short Form 36 (SF-36) Vitality domain. Both FACIT-Fatigue and SF-36 were used in phase III Belimumab trials and were found to be able to detect the improvements, consistent with the clinical endpoints. Recently, there is an increasing interest on the Patient-Reported Outcomes Measurement Information System (PROMIS) as a tool to measure fatigue in SLE. PROMIS offers effective PRO measurement in various QoL domains and can be used for both adult and pediatric populations.

Besides fatigue, disease activity and damage, psychosocial factors are among the important predictors of poor QoL in SLE ( Fig. 39.2 ). Important factors include psychological disorders (anxiety, depression), which may be exacerbated by active disease and damage and lead to poor QoL (greater pain, helplessness and physical disability) and poor social support ( Chapter 6 ).