Chapter 29 Constitutional Features of Systemic Lupus Erythematosus

INTRODUCTION

Constitutional features are a common but rather nonspecific aspect of SLE. This chapter will review the assessment, differential diagnosis, and treatment of these features of SLE. Initially, fatigue will be reviewed. This is a somewhat controversial area as many people do not believe that fatigue can be attributed to SLE; however, it is the most common symptom described by patients. The term “fatigue” should reflect a subjective feeling of extraordinary tiredness, often associated with weariness, exhaustion, or lassitude, and frequently but not necessarily associated with irritability, inefficiency, and decreased capacity for work, as defined in the glossary for the European Consensus Lupus Assessment Method (ECLAM).¹ The chapter then covers fever, weight loss, lymphadenopathy, and anorexia. Splenomegaly, although sometimes considered part of the constitutional features of lupus, as in the British Isles Lupus Assessment Group (BILAG) index of disease activity for lupus,¹ is usually considered part of the hematologic manifestations of lupus because it is often associated with thrombocytopenia (see Chapter 36). Hepatomegaly is discussed in the chapter on gastrointestinal features of SLE (see Chapter 36). Nausea and vomiting, which are sometimes considered with anorexia under general features (as in the BILAG index¹), are discussed in Chapter 36. Finally, this chapter briefly reviews sicca symptoms due to secondary Sjögren’s syndrome in SLE patients, with some overlap with Chapters 34 and 39.

FATIGUE

Association with Disease Activity

If you ask SLE patients what disturbed their quality of life most, the answer is fatigue, and it is one of the most common complaints by lupus patients, occurring in about 50 to 86% of patients.³^–⁵ There has been much debate about whether fatigue is due to lupus. There is no doubt that fatigue (or malaise or lethargy) is often present during flares of active lupus disease. Patients will say, “I feel as tired in the morning as when I go to bed,” or “I sleep at least 10 hours at night and get up in the morning for 1 or 2 hours and am ready to go back to bed and do actually sleep for another 2 or 3 hours.” The fatigue associated with active lupus disease is an overwhelming feeling of fatigue that is associated with an ability to sleep, and is quite distinct from the fatigue that comes from patients with sleep deprivation due to various sleep disorders. It tends to be more variable than the fatigue that occurs in patients with fibromyalgia or depression. These patients tend to complain that fatigue is present most of the time, irrespective of the amount of sleep that the patient has had. Patients with active lupus disease may describe a reduced capacity to undertake physical activities, but this is often associated with other manifestations of active lupus, such as arthralgia or arthritis with early morning stiffness, or myalgia with or without weakness due to a myositic component. The fatigue in these patients will often show variation over time in parallel with improvement or deterioration in the other manifestations of lupus. In patients prone to fever (discussed below), for example, the fatigue will often be most evident during the periods of fever and be relatively less troublesome when the fever abates. In these patients, hydroxychloroquine may be helpful in relieving fatigue and the tendency to fever flares (see Chapter 44). There is some evidence that stopping hydroxychloroquine results in increased fatigue, but no controlled trials show that it reduces fatigue. Therapy with hydroxychloroquine was associated with more fatigue in one study,¹ but this probably reflects confounding by indication for therapy with hydroxychloroquine.

Patients with inflammatory disease affecting their joints and muscles may well describe difficulty carrying out activities as a result of their inflammatory process. Patients who have been on long-term corticosteroids may develop a myopathy with proximal weakness in the upper and lower limbs. Similarly, patients with cardiorespiratory activity or damage, and those with neurologic problems may also feel that many activities are “rather an effort.” These difficulties related to activity or damage associated with specific system involvement need to be distinguished from the symptom fatigue. Although some studies have shown an association between disease activity and lupus,^4,⁵ others have not shown a close association between fatigue and disease activity or damage with in SLE patients.^6,⁷ The problem is that patients without active disease also complain about fatigue. This is likely to reflect the multifactoral nature of fatigue in lupus, and it is therefore important to consider other possible underlying causes (Table 29.1).

TABLE 29.1 CAUSES AND ASSOCIATIONS OF FATIGUE IN SYSTEMIC LUPUS ERYTHEMATOSUS

Causes of Fatigue	Underlying Conditions
Active lupus disease
Anemia	Anemia of chronic disease Hemolytic anemia Iron-deficiency anemia Folate deficiency Pernicious anemia Celiac disease Renal failure
Hypothyroidism
Fibromyalgia
Depression
Sleep disorders
Impaired aerobic capacity	Low anaerobic threshold Physical deconditioning

BOX 29.1 CONSTITUTIONAL FEATURES IN SYSTEMIC LUPUS ERYTHEMATOSUS

Association with Anemia or Thyroid Disease

Anemia is the most common condition associated with and contributing to fatigue in lupus patients, but is rarely severe enough to account for the degree of fatigue experienced by the patients.¹ A mild anemia of chronic disease due to lupus is often present. In addition, many women with SLE, particularly those on warfarin, develop iron-deficiency anemia as a result of menstrual blood loss. This may be compounded by deficient intake of iron in the diet or gastrointestinal blood loss, usually due to drugs rather than disease. Hemolytic anemia (see Chapter 36) is less common but can be severe. Occasionally anemia related to folic acid deficiency is seen, usually in association with high red-cell turnover in hemolytic anemia. Otherwise, folate deficiency is rare and patients with this problem should be investigated for celiac disease, particularly if they have coincidental iron and calcium deficiency. Celiac disease is one of the autoimmune conditions that can coexist with SLE, because they are both associated with the human leukocyte HLA-B8 and HLA-DR3 histocompatibility antigens.¹ Another autoimmune condition that can contribute to anemia is vitamin B12 deficiency. Pernicious anemia with antibodies to intrinsic factor resulting to impaired absorption of B12 may be present in patients before the diagnosis of SLE or appear after the diagnosis of SLE.¹ There is also an increased frequency of pernicious anemia in the relatives of patients with SLE. Similarly, autoimmune hypothyroidism can either precede or follow a diagnosis of SLE, be present in the relatives of patients with SLE and can undoubtedly contribute to fatigue in SLE patients.¹ In patients with chronic renal disease, fatigue may be associated with anemia that can be helped by treatment with erythropoietin, although they may also have an unresponsive degree of fatigue associated with uremia. Otherwise, treatment is dependent on the cause of the anemia or appropriate to the degree of hypothyroidism present (Table 29.2).

TABLE 29.2 POSSIBLE TREATMENTS FOR FATIGUE IN SYSTEMIC LUPUS ERYTHEMATOSUS (DEPENDING ON UNDERLYING CAUSE)

Treatment for Fatigue	Comments and Examples
Treatment of active disease	Hydroxychloroquine Immunosuppression as appropriate to systems involved and severity
Correction of anemia	Immunosuppression Iron Folic acid B12 injections Erythropoietin
Treament of hypothyroidism
Antidepressants
Self-management program	To improve self-efficacy and problem solving
Psychoeducational intervention	With or without partner
Exercise program	Graded aerobic activity Cardiovascular training

Association with Fibromyalgia, Impaired Health Status, and Sleep Disturbance

Patients with lupus may develop fibromyalgia.¹ It is important to establish whether patients have had chronic fatigue for at least 3 months, with chronic widespread pain above and below the diaphragm and on both sides of the body associated with the tender points characteristic of fibromyalgia,¹ as this will influence the management of fatigue. Previous studies have shown an association between fatigue and the number of tender points in lupus patients.^7,¹¹ In a cross-sectional study of 260 patients attending two lupus clinics in Birmingham and London, only 10% of the lupus patients fulfilled criteria for fibromyalgia syndrome, whereas 50% complained of fatigue.¹ In North America, studies have shown a frequency of fibromyalgia closer to 20 to 25% in SLE patients.^12,¹³ This gap may reflect differences in the ethnic population in various lupus cohorts, and a difference in psychosocial influences on the development of fatigue, fibromyalgia, and impaired quality of life in general in lupus patients (see Chapter 4).

We and others have shown that fatigue which is part of the assessment of vitality in the SF36 health survey is determined, like other domains of the SF36 health survey, predominantly by psychosocial factors and only to a small extent by any aspects of disease activity or chronic damage.^7,^12,¹⁴^–¹⁷ Patients that are depressed often have fatigue.^5,⁶ The possibility that fatigue in lupus patients may be associated with neuropsychiatric disease and disturbances in cerebral blood flow has been assessed using SPECT scanning.¹ However, no such association was found. Fatigue may be associated with sleep disorders,^5,¹⁹ with or without associated fibromyalgia. The study by Costa and colleagues¹ suggested that depressed mood, prednisone use, and lack of exercise contribute to decreased overall sleep quality.