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At a glance

  • Serologic presence of antinuclear antibody (ANA) is widely considered the first and most appropriate confirmatory test for systemic lupus erythematosus (SLE) and other
    connective-tissue autoimmune diseases.
  • The high prevalence of positive ANA titers in the normal population makes this a poor screening test.

  • Lupus autoantibodies are known to be present in the serum of lupus patients as long as five years prior to the development of clinical disease.

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  • Although there is a strong familial aggregation, most cases of SLE are sporadic.

  • Hydroxychloroquine modifies cell signaling and, as a result, reduces the activation of dendritic cells that mitigate the inflammatory process. It is used for maintenance therapy as well as treatment.

  • Patients can help themselves by using sun protection and not smoking.

Care for the patient with lupus and other autoimmune diseases has changed dramatically over the past few decades. Advancements in our understanding of the molecular mechanisms of autoimmunity and cell injury have led to useful prevention strategies and safer treatments.

In the early 1960s, the five-year mortality for systemic lupus erythematosus (SLE) was 50%, and treatment-related morbidity was high. The picture is very different today. Survival for people with SLE in the United States, Canada and Europe has risen to approximately 95% at five years, 90% at 10 years and 78% at 20 years, and now approaches that of matched controls without lupus.

Background immunology

The response of certain cells (typically lymphocytes) of the immune system to components of the organism that produced them is called “autoimmunity.” Inborn mechanisms of self-tolerance normally protect an individual from potentially self-reactive lymphocytes. Early on, as the field of immunology was emerging, scientists thought that all self-reactive lymphocytes were eliminated during the maturation process.

By the late 1970s, however, it became known that not all self-reactive lymphocytes are deleted. Some survive with the potential to cause disease. Interestingly, the presence of self-reactive lymphocytes does not inevitably result in disease. Immunologists now know that the activity of these cells is highly regulated in normal individuals by some sort of effective suppression. A failure of this suppression leads to persistent self-reactive clones of T- and B-cells that can target self-antigens.

In certain environments, this deregulation amplifies and persists, resulting in significant damage to target cells or organs and creating autoimmune diseases, some of which can be fatal. Most immunologists divide autoimmune diseases in humans into organ-specific and systemic autoimmune processes.

Organ-specific autoimmune diseases. In some autoimmune diseases, antibodies act as agonists, binding to receptors and taking the place of normal ligands. This results in the stimulation of inappropriate activity. For example, Graves disease, with its attendant thyroid storm, develops when the thyroid-stimulating hormone receptor is the target. 

In other autoimmune conditions, antibodies act as antagonists and block receptor function. Myasthenia gravis results when muscle activation is inhibited by antibodies that have targeted the receptor on the motor end plates. 

In some autoimmune processes, direct cellular damage is inflicted when lymphocytes or antibodies bind to cell membrane antigens and cause cell lysis and/or inflammation. Hashimoto’s thyroiditis and autoimmune hemolytic anemia are classic examples of this process. 

Systemic autoimmune diseases. In systemic autoimmune diseases, the response is directed toward a broad range of target antigens and involves a number of organs and tissues. Tissue damage may be widespread. Damage is inflicted by several mechanisms. Cell-mediated responses and direct cellular damage from autoantibodies or immune complex deposition are seen. 

Connective tissue diseases. Autoimmune diseases that target the connective tissues are the most common type of systemic autoimmune disease. The older, long out-of-date term for this group of systemic rheumatic diseases is “collagen vascular diseases.” 

Connective tissue is one of the four traditional classes of tissue (the others being epithelial, muscle and nervous tissues). Connective tissue is widespread, and it has three main components: cells, fibers and extracellular matrix. Connective tissue makes up a wide variety of physical structures including, tendons, blood, cartilage, bone, adipose tissue and lymphatic tissue. 

All of the connective-tissue autoimmune diseases (CTDs) share similar clinical and pathologic features. Widespread inflammation and autoantibody production are the hallmarks, but then the diseases diverge and clinical distinctions become apparent. Although there are overlaps in target organs (Table 1), each of the CTDs has primary organs most typically affected and produces unique autoantibodies.

Systemic lupus erythematosus 

The prototypical autoimmune CTD, SLE is a chronic disease of complex etiology. In both humans and mouse models, SLE is characterized by widespread immunologic abnormalities with the potential for multiorgan damage. Affected individuals may produce autoantibodies to a vast array of tissue antigens, from DNA to clotting factors.

When immune complexes form from union of autoantibody with antigen, a dramatic cascade of complement and its membrane-attack complexes is generated. These products damage blood vessel walls, which can lead to vasculitis and nephritis. This potentially wide array of damage can make the clinical picture of SLE seem baffling. The disease can begin subtly or dramatically and have great impact on patients, particularly women in the reproductive years. 

Why one group of lupus patients has low-grade, limited disease and another group develops life-threatening organ failure is a function of the interplay among susceptibility genes and environmental triggers. Lupus autoantibodies are now known to be present in the serum of lupus patients as long as five years prior to the development of clinical disease. Thus, when the genetic load is sufficient and immune triggers present themselves, it seems that chance and timing trigger immune system activation and the disease process turns on.

Persons with high titers of antinuclear antibodies (ANAs) but no lupus-specific symptoms need no therapy. Instead, they should be followed with watchful waiting. The percentage of these patients who will develop clinical disease is unknown. The most relevant behavioral changes that patients can make to help themselves are stopping smoking and using sun protection. 

A new era in genetic studies. SLE is a complex genetic disease. Multiple interactive susceptibility genes appear to have a role. The manifestations of the disease that emerge depend on which of the various genes are expressed. In the past few years, enormous progress has been made in our understanding of the genetics of SLE. 

The large numbers of DNA samples collected from lupus patients through the support of government agencies, foundations, industry and academic centers have made studies of genetic variants more affordable. Genome-wide association studies (GWAS) in humans as well as the identification of susceptibility genes in mouse models of lupus has led to far better understanding of the mechanism of this disease. 

Data from these studies have confirmed several candidate genes previously associated with lupus, identified some new lupus-associated genes and gene loci, and identified variants in a novel gene (ITGAM) whose protein product had been studied in SLE but was not previously known to have a genetic association with lupus.

The mouse model. Several strains of inbred mice spontaneously develop a lupus-like syndrome. These strains allow researchers to tease out a simplified version of human lupus from which to work.

In order to put the mouse strains in clinical perspective, it has been said that one lupus mouse strain represents one patient. However, it is one patient that can be bred in 100 copies, thus providing a base for detailed, sensitive and finely-tuned studies. Toward this end, about a half-dozen inbred strains have been studied by linkage analysis to produce significant statistical associations for more than 100 genomic regions with lupus-related characteristics (ANA subsets, skin, nephritis, and so forth).

Magnitude of SLE in clinical practice 
and investigational settings

SLE is uncommon. One of the challenges for both clinical practice and laboratory investigation is the small size of the patient population. 

Estimates of SLE prevalence vary widely, from a high of 1.5 million1 to approximately 250,000.2 That same group estimated a 2005 prevalence of 161,000 persons with definite SLE and 322,000 persons with definite or probable SLE.2 Currently, the prevalence rate in the United States is probably 40 to 50 persons per 100,000.3