Many questions about systemic lupus erythematosus (SLE, lupus) remain unanswered. Why is this disease so difficult to diagnose even for rheumatologists? Why does lupus tend to develop in previously healthy young women? Why does the disease manifest in so many ways? Why are our current treatments suboptimal?
This article addresses these questions in a brief overview and update of SLE, with an emphasis on clinical pearls regarding prevention and treatment that are relevant to any physician who sees patients with this disease.
WOMEN AND MINORITIES ARE OVERREPRESENTED
Women have a much higher prevalence of almost all autoimmune diseases. SLE has a 12:1 female-to-male ratio during the ages of 15 to 45 years, but when disease develops in either children or the elderly, the female-to-male ratio is only 2:1.
African Americans, Asian Americans, and Hispanics have about a three to four times higher frequency of lupus than white non-Hispanics and often have more severe disease.
WHY IS SLE SO DIFFICULT TO DIAGNOSE?
SLE is frequently overlooked; patients spend an average of 4 years and see three physicians before the disease is correctly diagnosed. Part of the problem is that presentations of the disease vary so widely between patients and that signs and symptoms evolve over time. Often, physicians do not consider SLE in the differential diagnosis.
On the other hand, SLE is also often over-diagnosed. Narain et al1 evaluated 263 patients who had a presumptive diagnosis of SLE. Only about half of the patients had a confirmed diagnosis; about 5% had a different autoimmune disease, such as scleroderma, systemic sclerosis, Sjögren syndrome, or polymyositis; 5% had fibromyalgia; 29% tested positive for ANA but did not have an autoimmune disease; and 10% had a nonrheumatic disease, such as a hematologic malignancy with rheumatic disease manifestations. For patients referred by a community rheumatologist, the diagnostic accuracy was better, about 80%.
The traditional classification criteria for SLE2,3 are problematic. Some criteria are very specific for SLE but are not very sensitive—eg, anti-double-stranded DNA is present in about half of patients with SLE. Others tests, like ANA, are sensitive but not specific—although ANA is present in 95% of patients with SLE, the positive predictive value of the test for SLE for any given patient is only 11%.
Other criteria are highly subjective, including oral ulcers and photosensitivity. These signs may be present in normal individuals who get an occasional aphthous ulcer or who are fair-skinned and burn easily with prolonged sun exposure. It takes a trained clinician to distinguish these from the photosensitivity and oral ulcers associated with lupus.
Many diseases can mimic SLE
Fibromyalgia frequently presents in women and may include joint and muscle aches, fatigue, and occasionally a positive ANA. ANA may be seen in about 15% of healthy women.
Sjögren syndrome can also present with arthritis, fatigue, and a positive ANA; it is commonly overlooked because physicians do not often think to ask about the classic symptoms of dry eyes and dry mouth.
Dermatomyositis causes rashes that have many features in common with SLE. Even the skin biopsy is often indistinguishable from SLE.
Hematologic problems, such as idiopathic or thrombotic thrombocytopenic purpura, primary antiphospholipid syndrome, and hematologic neoplasms, can cause serologic changes, a positive ANA, and other manifestations seen in SLE.
Drug-induced lupus should always be considered in older patients presenting with SLE-like disease. Now with the use of minocycline (Minocin) and other related agents for the treatment of acne, we are seeing younger women with drug-induced lupus.
PATIENTS ASK ‘WHY ME?’
Lupus typically develops in a young woman who was previously healthy. Such patients inevitably wonder, why me?
Lupus is like a puzzle, with genetics, gender, and the environment being important pieces of the puzzle. If all the pieces come together, people develop defective immune regulation and a break in self-tolerance. Everyone generates antibodies to self, but these low-affinity, nonpathologic antibodies are inconsequential. In SLE, autoantibodies lead to the formation of immune complexes, complement activation, and tissue damage.
Genetics plays an important role
Genetics plays an important role but is clearly not the only determining factor. Clustering in families has been shown, although a patient with lupus is more likely to have a relative with another autoimmune disease, especially autoimmune thyroid disease, than with SLE. The likelihood of an identical twin of a patient with SLE having the disease is only 25% to 30%, and is only about 5% for a fraternal twin.
In the first few months of 2008, four major studies were published that shed light on the genetics of SLE.4–7 Together, the studies evaluated more than 5,000 patients with SLE using genome-wide association scans and identified areas of the genome that are frequently different in patients with lupus than in healthy controls. Three of the four studies identified the same genetic area as important and supported the concept that B cells and complement activation play important roles in the disease pathogenesis.
Although over 95% of cases of SLE cannot be attributed to a single gene, there are rare cases of lupus that may provide important clues to mechanisms of disease. For example a homozygous deficiency of C1q (an early component of complement) is extremely rare in lupus but is associated with the highest risk (nearly 90%) of developing the disease. Deficiencies in other components of the complement cascade also carry a high risk of disease development.
Investigators discovered that C1q plays an important role in clearing away apoptotic cellular debris. If a person is deficient in C1q, clearance of this debris is impaired. In a person genetically predisposed to getting lupus, the immune system now has an opportunity to react to self-antigens exposed during apoptosis that are not being cleared away.
Even though lupus cases cannot be explained by an absence of C1q, a defect in the clearance of apoptotic cells is a common, unifying feature of the disease.
Immune response is enhanced by environmental factors
Environmental factors, especially sun exposure, are also important. Following sunburn, skin cells undergo massive cell death, and patients with lupus have a huge release of self-antigens that can be recognized by the immune system. Sunburn is like having a booster vaccine of self-antigen to stimulate autoantibody production. Not only does the skin flare, but internal organs can also flare after intense sun exposure.