Systemic lupus erythematosus

Although survival rates improved markedly during the past 5 decades, patients with systemic lupus erythematosus (SLE) still die at a rate 3 to 4 times that of the general population. (1-4) The Centers for Disease Control and Prevention (5) recently reported that between 1979 and 1998 the number of deaths due to SLE increased by 60%. In addition to experience in caring for patients with SLE, knowledge of the epidemiology, pathophysiology, and morbidity and mortality factors may contribute to improvements in the management of these patients. In 2 separate studies Ward, (6,7) found that hospitals that treated large numbers of patients with SLE had 68% less mortality than did hospitals with less experience with such patients. The risk of in-hospital mortality was even lower, 95% less, for patients cared for at facilities that treated 100 or more critically ill patients with SLE a year. Adjusting for the size of the hospital, urban or rural location, and teaching status did not alter the results. (7)

Despite the serious nature of SLE, however, studies on causes of admission to the intensive care unit (ICU), short- and long-term outcomes of ICU admissions, and specific ICU nursing needs of patients with SLE are lacking. In this article, we briefly review the epidemiology and pathophysiology of SLE and describe common pathological changes that bring these patients to the ICU. Some of the data presented are extrapolated from studies on morbidity and mortality in patients with SLE and in patients with rheumatoid arthritis that included patients with SLE in the sample.

Background

SLE is a chronic, multisystem autoimmune disorder that provokes inflammation in various organs of the body. The inflammation is due to the production of antibodies that attack cells of host organs, including the skin, muscles, joints, blood, kidneys, and the brain. The disease persists for life and is characterized by sudden flare-ups, repeated life-threatening infections, mild-to-severe kidney impairments, repeated miscarriages, strokes, and, sometimes, permanent disability and death. With the use of glucocorticosteroids, chemotherapeutic agents, antibiotics, and skilled nursing care in ICUs, SLE has evolved into a chronic illness, and patients have long-term survival. However, frequent hospitalizations remain a common feature.

Epidemiology

Estimations of the exact incidence of SLE in the United States vary. In 1995, Hochberg et al (8) reported that it was 124 cases per 100 000. In 2002, Bongu et al (1) reported that the incidence in the continental United States and Europe ranged from 14.6 to 68 per 100 000. Some reports indicate that because of improved diagnostic measures, the incidence of SLE is increasing. For example, in a study covering a span greater than 40 years, Uramoto et al (9) found that the pooled incidence of SLE had more than tripled from 1.51 per 100 000 during 1950 to 1979 to 5.56 per 100 000 during 1980 to 1992. In a recent review of 19 studies published from 1995 to 2000, Ruiz-Irastorza et al (10) reported an even higher incidence rate: 7.3 per 100 000. The frequency of SLE is much higher among first-degree relatives of patients who have either SLE or other autoimmune disorders than among the general population.

The incidence of SLE also varies according to age, sex, and race. Globally, SLE primarily affects younger women; 9 of 10 patients with SLE are females between the ages of 15 and 45 years. (1,11) The disease often begins at menarche, and many women with SLE experience sudden flare-ups during specific phases of the menstrual cycle or shortly after delivering a baby. In addition, the incidence of SLE is about 3 times higher in African American women than in white women. (1,11,12) Data on the incidence of SLE among Hispanics and Asian Americans are lacking. (1) However, in the United States, morbidity and mortality appear to be greater among Hispanics than among whites. (1)

The mean age at diagnosis also differs according to race. At the time of diagnosis, African American women are younger than are white women (mean age, 35.2 years vs 39.8 years). (11,12) More significantly, morbidity and mortality associated with SLE are higher among African Americans than among whites. (13) Although SLE is not prevalent in men, among patients who have the disease, renal, neurological, hematologic, and vascular outcomes are more severe in men than in women. (14) The pathogenesis of SLE is insidious, and a definitive diagnosis may take up to 10 years, so organ damage is often severe by the time the diagnosis is confirmed.

Immunopathophysiolgy

SLE is considered a prototype of an autoimmune disorder in which self-tolerance fails. Hence, the main immunopathologic manifestation of SLE is autoimmunity, the production of antibodies against self-tissues. These antibodies are directed against molecules on the surfaces of targeted host organ cells as well as against intracellular organelles as deep in the center of the cell as the nucleus. For example, antinuclear antibodies develop in more than 95% of patients with SLE. Moreover, once developed, these antibodies bind to the DNA, the RNA, the ribosomes, and nuclear proteins. In addition, antibodies against host immunoglobulins, such as antibodies to immunoglobulin (Ig) G, and against coagulation factors, such as antibodies to phospholipids that induce clotting, are also found in the serum of patients with SLE. Because of the fundamental role the organelles and the immunoglobulins play in maintaining cellular health, the overall detrimental effects of these autoantibodies is self-evident.

Overview of the Immune System

The immune system is composed of the well-orchestrated innate and adaptive responses. The innate immune response involves such barriers as the skin, mucosa, sebaceous glands, sweat, and tears. (15) In contrast, the adaptive response has specialized immune cells, the lymphocytes, that are programmed to recognize and attack foreign antigens and immunogens and then store the memory of the antigens or immunogens. The adaptive system functions along with immune organs that include the bones, thymus gland, lymph nodes, and spleen.

Lymphocytes are subdivided into B and T lymphocytes. This terminology reflects their final residence after they are manufactured in the bone marrow; B lymphocytes remain in the bone marrow, whereas T cells travel to the thymus gland. Both B and T cells are immature and incompetent in their early genesis. Each encounter with an immunogen gives them an everlasting memory of the identity of that immunogen. After each encounter, lymphocytes return to their residence organs to encode their experience with the immunogen into their DNA. Hence in the maturation of constantly renewed and improved lymphocytes, the health of the bone marrow, the thymus gland, and the lymph nodes plays a fundamental role. When these organs are compromised, adaptive immunity is also compromised. (15-17)

At the cellular level, the adaptive immune response is categorized as humoral and cellular. The humoral response is mediated by B lymphocytes and immunoglobulins. Immunoglobulins are glycoproteins produced by plasma cells, the progeny of B cells. Five types of immunoglobulins occur: IgA, IgM, IgG, IgD, and IgE. Cellular immunity, on the other hand, is mediated by T lymphocytes, which are classified according to their cell-surface markers or clusters of differentiation. More than 150 markers have been identified. Most T cells that carry the CD4 marker are known as helper cells, whereas those that carry the CD8 marker are known as suppressor cells. CD4 cells initiate the immune response by stimulating B-cell reactivity; CD8 cells bring the immune response to closure once the pathogens or foreign antigens are eliminated. B and T lymphocytes work together in astonishing cooperation, communicating with each other through elaborate pathways with the help of messenger proteins called cytokines. (15-17)

Both the innate and the adaptive immune responses are also armed by natural killer cells. In addition to killing pathogens on first encounter, natural killer cells also produce some of the cytokines so essential for immune reactivity. Any consideration of the management of immunologic diseases must take into account the collaborative responses of the immune organs, the immune cells, and the cytokines. (16)

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How do these immune cells recognize pathogens or immunogens as being different from normal body molecules or cells? This recognition comes from the presence of host cell markers known as the major histocompatibility complex (MHC) antigens or the human leukocyte antigens. MHC antigens are proteins present on the surface of nearly all nucleated body cells. Genes located on the short arm of chromosome 6 determine the structure of these antigens. Three major classes of MHC antigens exist, and each class has surprising variability. No two individuals (except maybe identical twins) have the same MHC antigens. In a complex process known as antigen presentation, macrophages or B cells place the cell markers of a foreign antigen (eg, a pathogen) next to their own MHC antigens and then present the MHC--foreign antigen complex to T cells. (17) Cytokines recruit T helper cells to the site where antigen is being presented. At this point, the immune response begins with T cells calling B cells into action. The Figure summarizes the mounting of an immune response.

Immunopathology of SLE

Immune reactivity as described occurs in SLE against self-tissues. That is, stimulation of T helper cells and B cells and subsequent production of immunoglobulins occur in the absence of a pathogen. However, the etiology of this misguided response is not known. A genetic predisposition is suspected, and as many as 40 genes are thought to play a role in the pathogenesis of SLE. These genes include those that encode MHC antigens, those that affect clearance of antibody-antigen complexes, those that encode complement proteins, those that are involved in cytokine production or attenuation, and also those that regulate apoptosis (programmed cell death). Alleles (genetic variations on the same chromosomal location) for MHC antigens and complement are among the most accepted genetic factors. (19) In addition, an inability to terminate a legitimate immune response may occur after an encounter with a pathogen (most likely a virus), perhaps because of alterations in the ratio of T helper cells to T suppressor cells. Also, because SLE predominantly affects women, female hormones such as estrogens may play a role. (20,21) Environmental triggers, including ultraviolet light, infectious agents such as bacteria or viruses, and drugs such as sulfa antibiotics, have all been implicated in triggering the onset of the disease and/or its flare-ups.

SLE is also classified as a type III hypersensitivity reaction. The major pathophysiological phenomenon in this type of hypersensitivity reaction is the formation of antigen-antibody complexes, called immune complexes. Immune complexes in SLE contain IgM, IgG, and IgA. Deposition of immune complexes is accompanied by the activation of the complement system, the very potent nonspecific defense mechanism involved in inflammation and infection. Complement proteins have a chemotactic affect on neutrophils, drawing these cells to the site of inflammation. In an attempt to eliminate the immune complexes, neutrophils release lysosomal enzymes, which damage local tissues. In SLE the deposition of the immune complexes and subsequent complement activity initiate the pathological changes. Immune complexes have a high affinity for vessel walls and the glomerular basement membrane of the kidneys, and the changes caused by their deposition in these areas can progress to cause organ damage in such vital organs as the kidneys, lungs, and heart.

Patterns of ICU Admission for Patients With SLE

Exacerbations in SLE requiring ICU admission may result from acute or persistent disease activity, the side effects of treatment, or both. The disease activity is directly associated with specific organ damage such as cardiovascular and cerebrovascular diseases, pulmonary hypertension, renal failure, skin lesions, and Jaccoud arthropathy, a deforming, nonerosive joint disease. (22) Although end-stage renal failure is often associated with morbidity and mortality in SLE, it may develop in only about 15% of patients with SLE. For example, in the 539 patients in the Hopkins Lupus Cohort Study, (23) the most frequent areas of organ damage were in the musculoskeletal (22%), neuropsychiatric (20%), renal (15%), ocular (13%), cardiovascular (9%), and pulmonary (7%) systems.

Factors that bring patients with SLE to the ICU, however, differ from the factors that contribute to the general morbidity associated with the disease. Research during the past 10 years indicated that the usual cause for admission to the ICU is infection. Thong et al (24) examined the reasons for ICU admission of 28 patients with rheumatic diseases from August 1999 to August 2000. Of the 28 patients in the sample, 20 (71.4%) had SLE. The chart audit of these patients revealed that within a 12-month period, the 28 patients had a total of 29 admissions to the medical ICU, and 18 (62%) of the admissions were due to infection and/or sepsis. In the study by Noel et al, (25) infections developed in 57 (66%) of the 87 patients who had SLE, and 8 (14%) of the 57 had to be admitted to the ICU for immediate treatment. In an earlier study, Ansell et al (26) also reported that of 30 SLE patients admitted to the ICU, 11 (37%) were admitted because of infection; 8 (73%) of the 11 had pneumonia, 2 had urinary tract infections, and 1 had meningitis. These findings corroborate the earlier findings of the Hopkins Lupus Cohort Study (27) that the main cause of hospitalization for patients with SLE was the disease activity with infection.

In a 5-year multicenter study (2) of 1000 patients with SLE in several European clinics, 270 patients (27%) had infection. The most frequent site of infection was the urinary system (113 patients or 11.3%). Other frequent sites were the respiratory, abdominal, and central nervous systems and the bloodstream (sepsis). In this study, (2) infection was the leading cause of morbidity; next, in order, were hypertension, osteoporosis, cytopenia, and gastrointestinal bleeding. In a study (28) in Mexico, among 180 patients with SLE who came to emergency units, fever was the main cause of admission and infection was the main discharge diagnosis. The second most common discharge diagnosis in this sample was disease activity.

Because infection is among the leading causes of morbidity associated with SLE, we reviewed research on the variables associated with infection. In a retrospective chart study of 87 patients with SLE, Noel et al (25) found that 57 infections occurred; 48% were community acquired and 19% were nosocomial. Bacteria were responsible for the 82% of the infections that primarily affected the lower respiratory tract. Nine infections were caused by varicella zoster virus.

Among the patients studied by Noel et al, (25) none of the clinical or biological variables, such as white blood cell counts including lymphocytes or the levels of inflammatory and immunologic markers, were predictive of the occurrence of infectious episodes for the patients admitted to the hospital. However, prolonged use of corticosteroids (P < .005), pulse treatment (monthly bolus administration) with cyclophosphamide (P < .003), and plasmapheresis (P < .01) were significant risk factors for infection. Both corticosteroids and cyclophosphamide are powerful immunosuppressants that block proliferation of T and B cells. Plasmapheresis, used to remove autoantibodies (eg, the antibodies to DNA and to phospholipids), also removes immunoglobulins, further compromising the immunocompetence of patients. (29)

The second most frequent reason for ICU admission differed in the studies we reviewed. Ansell et al (26) found that acute renal failure was the second most common diagnosis; 8 (27%) of the 30 patients admitted were in renal failure. In the study by Thong et al, (24) hypotension due to sepsis (16 of 29 admissions; 55%) and acute respiratory failure (14 of 29 admissions; 48%) were the second and third most common reasons for admission to the ICU. Table 1 ranks the reasons reported by researchers during the past decade for admission to the ICU for patients with SLE.

The relationship between ICU admissions, age, and sex of patients with SLE has not been widely studied. However, the few studies in which demographic variables were examined in relation to ICU admission indicated that patients with SLE who were admitted to the ICU were relatively young. The median and mean ages, respectively, for these patients were 29 years in the study by Ansell et al (26) and 38.9 (SD 16.3) years in the study by Thong et al. (24) In the sample of Noel et al, (25) the mean age was 33.7 (range 16-80 years).

In the research studies cited in this review, more than 70% of the patients were women. In studies of general populations of patients with SLE, female sex, age, and ethnicity influenced morbidity. For example, Ward (6) found that women with SLE aged 18 to 44 years were 8 times more likely to be hospitalized with cardiovascular events than were women in the same age group who did not have SLE. Petri (31) found a specific relationship between age and clinical patterns of SLE: patients who were younger at the time of onset of SLE had significantly more cutaneous and renal manifestations of the disease and significantly more hypocomplementemia, whereas patients who were more than 40 years old at the time of onset had a greater prevalence of cardiovascular risk factors and stroke. In an earlier article on the same group of subjects, Petri (19) reported that African Americans had more renal and cardiac manifestations of SLE than did whites. In addition, African Americans had more organ damage. Petri (19) also found that African Americans experienced significantly more musculoskeletal damage in the form of avascular necrosis of the bone than did whites.

Common Interventions for Patients With SLE

The specific ICU nursing care needs of patients with SLE remain largely unexplored, particularly the psychosocial needs of these patients and their families. However, ICU nurses are familiar with the stressors sustained in the ICU by all critically ill patients, including fear, anxiety, isolation, and loss of autonomy. Thus, nurses should provide holistic care along with thoughtful explanations of the interventions and expected outcomes, steps that may help relieve the stress and anxiety related to serious illness.

We found just 2 studies in which the investigators examined specific nursing care needs of patients with SLE. Ansell et al (26) reported that of the 30 patients admitted to the ICU, 4 (13%) required mechanical ventilation for a median duration of 8 days (range 2-64 days). In the study by Thong et al, (24) the number of patients with SLE who required mechanical ventilation was 87%, a significantly higher percentage than the percentage in the study by Ansell et al. In terms of pharmacological treatments, of the 30 SLE patients in the study by Ansell et al, (26) 16 required dobutamine, 28 required corticosteroids, 13 required cyclophosphamide, and 7 required azathioprine. In addition, 4 patients received plasmapheresis, and another 4 required dialysis to treat renal failure. In the study by Thong et al, (24) in 20 (70%) of the 29 admissions of patients with SLE to the medical ICU, the patients required inotropic support for 46.1 (SD 62.1) hours; in 2, the patients required dialysis; and in 1, the patient required plasmapheresis for pulmonary hemorrhage.

The reported Acute Physiology and Chronic Health Evaluation II (APACHE II) scores of patients with SLE admitted to the ICU provide some insight into the nursing care needs of these patients. In general, more severely ill patients usually have APACHE scores higher than 20. In the study by Ansell et al, (26) the median APACHE II score of the SLE patients was 18 (range 8-42). However, the APACHE II scores were of little value in predicting outcomes and were an underestimation of the patients' severity of illness. In the study by Thong et al, (24) the mean APACHE II score of the patients with SLE was 24.0 (SD 9.5). This finding means that 68% of the patients in the study had a mean APACHE II score between 14.5 and 33.5, reflecting a wide variability in the general severity of illness at the time of the ICU stay.

Reported length of ICU stay for patients with SLE was difficult to extrapolate. In the study by Thong et al, (24) the mean length of ICU stay for patients with SLE was 5.5 (SD 3.7 days). However, in the study by Ansell et al, (26) the median stay was much longer, 13 days (range 2-72 days).

General and ICU Mortality Patterns in SLE

Bongu et al (1) reported that although mortality has significantly improved, death rates for patients with SLE, in general, remain 3 to 5 times greater than those for the general population. A series of studies (32,33) of patients with SLE in general indicated distinct mortality patterns in SLE. Deaths that occurred within 5 years of diagnosis were due to active SLE and infection, whereas those that occurred more than 5 years after onset were due to atherosclerotic complications such as coronary heart disease and its sequelae. Urowitz and Gladman (33) also reported that infection was the major manifestation associated with mortality in SLE. Similarly, in their review of the mortality studies, Bongu et al (1) found that deaths that occurred later in the course of the disease were due to cardiovascular events, congestive heart failure, end-organ damage (renal, pulmonary), and treatment side effects. Hence, the data indicate that whereas younger patients have greater susceptibility to infections, late-stage mortality in SLE is due to cardiovascular changes and other SLE-related causes. In a review of 91 SLE studies published between 1995 and 2000, Ruiz-Irastorza et al (10) found that infection was the major cause of mortality in all stages of SLE; the next major cause was thrombosis associated with the formation of antibodies to phospholipids.

Worldwide, infection is also the major cause of death in patients with SLE. Cervera et al (2) reported that in a 5-year multicenter study of 1000 SLE patients in Europe, 28.9% of the patients died of infections, 28.9% died of active SLE, and 26.7% died of thromboses. The most frequent infections were bacterial sepsis of the pulmonary (8.9%), abdominal (8.9%), and urinary (6.7%) systems. Cervera et al reported that among patients with SLE who died of active disease, most deaths were due to multisystem involvement or renal causes. By comparison, in Brazil nearly twice as many patients with SLE, 58%, died of infection. (34) In an earlier study (35) with Caribbean patients, the cause of death was infection in 50% of patients, cardiovascular events in 18%, and other SLE-related causes in 32%.

Race and ethnicity, for example, consistently affect mortality in SLE. In a recent cohort study, (36) the reason for death differed among the 3 racial/ethnic groups: of the 34 patients with SLE, 80% of the Hispanic patients died of active disease, whereas 50% of the African American patients died of infection. However, 50% of the deaths among the white patients were related to other SLE-related causes. Most recently, the Centers for Disease Control and Prevention (5) reported that from 1979 to 1998, death rates for patients with SLE were more than 3 times higher for African Americans than for whites. Although research, in general, indicated that the most common cause of death was active disease or infection for most patients, Walsh et al (13) suggested that renal disease might account for excess death among African Americans. The Centers for Disease Control and Prevention (5) also reported that death rates were more than 5 times higher for women than for men. These studies collectively suggest marked age-, sex-, and race-specific differences in SLE mortality. Table 2 gives the causes of death for patients with SLE in ICUs.

The survival rate of the patients with SLE admitted to the ICU ranged from 33% to 47%. In the study by Ansell et al, (26) for example, of the 30 patients with SLE who were admitted to the ICU between 1982 and 1993, 47% died while being treated, and 2 died after discharge. The median age of the patients in the study was 29 years (range 16-58). In an earlier European study (30) with 69 patients with systemic rheumatic diseases, 16 of whom had SLE, the death rate among those admitted to the ICU was 33%. The causes of death of patients with SLE admitted to the ICU were multiple organ failure, infective complications with septic shock, intractable renal failure, pulmonary embolism, and cardiomyopathy. Godeau et al (30) reported that the death rate was high (63%) among patients in their sample who received mechanical ventilation.

In summary, although survival in SLE has significantly improved during the past 50 years, patients with SLE still have a 3- to 5-fold increased mortality rate compared with the general population, and in the fight against early mortality in SLE, African Americans are the highest casualties.

Summary

The prototype autoimmune disorder SLE is a highly variable disease characterized by episodic exacerbations, some of which are severe enough to require admission to the ICU. Infection, disease activity, and cardiovascular complications are among the major reasons for admission. Drugs, particularly the immunosuppressants used to treat SLE, often cause as much injury to the immune system as the disease itself, and intensive treatments are often required to combat the side effects of these drugs. Studies indicate that sex, age, and race affect both morbidity and mortality in SLE. Despite well-documented patterns of morbidity and mortality and episodic exacerbations requiring admission to the ICU, the specific nursing care needs of patients with SLE admitted to the ICU have not been investigated.

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Ayhan Aytekin Lash, RN, PhD

Brigid Lusk, RN, PhD

Authors

Ayhan Aytekin Lash is a professor at Northern Illinois University, School of Nursing DeKalb, Ill.

Brigid Lusk is an associate professor at Northern Illinois University, School of Nursing, DeKalb, Ill.

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