Given the potentially serious complications associated with SLE, these authors provide expert tips on diagnosing the disease and offer pertinent insights on various treatment options.

Systemic lupus erythematosus (SLE), which is commonly referred to as lupus, is a chronic, multi-system autoimmune disease that affects between 150,000 and 500,000 Americans. Women, especially those during the childbearing years of 15 to 40, are nine times more likely to have the disease than men. African-Americans have the highest prevalence of SLE (a 4:1 ratio) yet all ethnicities can be affected.

Patients with SLE present with varied clinical manifestations, including arthritis, skin changes and gastrointestinal disturbances. In addition, they may have hematologic manifestations, serologic changes and major organ damage such as renal disease. The diagnosis of SLE is often preceded by years of autoantibody production and most patients remain asymptomatic during this time.1,2 The disease is characterized by flares and remissions.



Systemic lupus erythematosus is a complex disease that has multiple etiologic factors and likely involves a complex interplay between genetics, hormones and the environment. Interactions between environmental agents and susceptibility genes (either multiple or single genes) may activate key immune pathways that lead to autoimmunity, immune complex formation and ultimate organ damage.

A genetic predisposition appears to contribute to the development of SLE. For example, researchers have shown that genetic markers such as human leukocyte antigen (HLA) alleles and select members of the complement cascade, as well as susceptibility genes in specific chromosomal regions, contribute to SLE predisposition.3

Since lupus is predominantly a female disease, hormones may also be a factor in SLE etiology. In regard to a direct relationship between sex steroid hormones and SLE, there is no conclusive evidence such as estradiol, testosterone, prolactin, progesterone and dehydroepiandrosterone (DHEA) as the levels of these hormones usually differ between SLE patients and unaffected individuals.4 Environmental agents (including ultraviolet light and cigarette smoke) and infectious agents, such as Epstein Barr Virus (EBV), may also contribute to lupus development.5

Essential Keys To Diagnosing SLE
Frontline clinicians are often called upon to evaluate and identify patients with SLE, and prescribe initial therapy for these patients. Since SLE is a multisystem disease, clinicians must consider a variety of conditions and other syndromes in the differential diagnosis. These conditions include other inflammatory conditions such as rheumatoid arthritis and sarcoidosis, chronic infections, post-viral syndromes, malignancies, drug-induced lupus and fibromyalgia (see “A Guide To The Differential Diagnosis Of SLE”).

The American College of Rheumatology developed criteria for the classification of patients with SLE to be included in research studies. These criteria were subsequently revised in 1982 and 1997. One may diagnose a patient with SLE if he or she demonstrates four of the following 11 criteria: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematological disorder, immunologic disorder, and antinuclear antibody.6,7 (See “Key Criteria For Diagnosing SLE”.)



These criteria have become a useful tool in evaluating patients who might have SLE.8 Diagnosing SLE involves developing a complete clinical picture including a patient history, a physical exam, serologic and other laboratory studies. Arthritis and constitutional symptoms are some of the most common SLE manifestations and clinicians can easily identify these symptoms via a complete history and physical exam.9 A family history may also be helpful as some patients may have relatives with SLE or other autoimmune diseases.

When it comes to diagnosing SLE, select baseline labs are useful and may include a complete blood count (CBC), chemistry panel, sedimentation rate, urinalysis and anti-nuclear antibody test (ANA).

Thrombocytopenia, lymphopenia and leukopenia are all processes that one may find in patients with SLE and clinicians can identify these processes via a CBC. For example, up to 85 percent of untreated SLE patients may experience lymphopenia and up to 60 percent of SLE patients may experience leucopenia.

An elevated sedimentation rate (ESR) is also a very common laboratory finding in untreated, active lupus and can also serve as an important surrogate marker. The ESR does increase with age and is higher in women than men. Therefore, a rule of thumb is the upper level of a normal ESR in women is the patient’s age plus 10 divided by two (e.g. age+10/2 or 46+10/2=28, the upper normal ESR for a 46-year old female). The upper level of a normal ESR for men is just their age divided by two.

Of course, an elevated ESR is just a marker of increased inflammation and can be elevated with other inflammatory, infectious and neoplastic states. A urinalysis test provides early evidence of renal disease, demonstrating an active urinary sediment and/or proteinuria. A chemistry panel also gives insight into end organ damage as it may show an elevated creatinine and renal disease, and elevated liver enzymes with autoimmune hepatitis. The total protein to albumin ratio is often elevated in SLE, indicating the presence of high levels of autoantibodies, which are uniformly common among patients with SLE.

Although a positive ANA can be helpful, this test does not always indicate a diagnosis of SLE. This test is highly sensitive but it is not specific. A titer of 1:120 is most helpful as false positives are very common at the lower levels detected with 1:40 or 1:80 titers. Also keep in mind that you may see a positive ANA in those with chronic infectious states, those with other systemic rheumatic diseases, family members of rheumatic disease patients and in healthy adults. However, a negative ANA is important in order to rule out SLE and shift the focus of diagnosis elsewhere.

Furthermore, anti-dsDNA and complement levels are very useful following the initial patient screen. Complement levels, including CH50, C3 and C4, are often low and are likely secondary to consumption one may note with active SLE. While anti-dsDNA is specific for SLE, it is reportedly only positive in approximately 40 percent of SLE patients. Titers have also been shown to fluctuate in flares. Anyone with a clinically significant positive anti-dsDNA should also have a positive ANA. Anti-Sm and anti-ribosomal P proteins are additional autoantibodies specific for SLE and one usually identifies these in later screens.

Pertinent Insights
On Preventive Measures
Once one has made the SLE diagnosis, the clinician must institute preventative measures. Since SLE manifests in a multitude of ways, one may initiate medical therapy on an individual basis. Quarterly evaluations to assess disease activity require careful clinical evaluations and monitoring with CBC, chemistry and urinalysis.

Sunscreen is highly encouraged when sun exposure is necessary. Otherwise, one should urge patients to avoid sun exposure since photosensitivity may induce flares. Clinicians should encourage immunizations, including the pneumococcal vaccine and the influenza vaccine. When treating patients with SLE, one should also encourage gentle exercise programs and maintaining near ideal body weights.

What You Should Know
About SLE Treatment Modalities
For initial medical therapy, clinicians should direct treatment toward the specific, existing clinical features and the severity of the disease process. For mild cutaneous manifestations, sun avoidance, sunscreen and short courses of topical steroid creams may be sufficient. Clinicians commonly use nonsteroidal antiinflammatory drugs (NSAIDs) in SLE for the treatment of arthralgias, mild arthritis, mild pleuritis and constitutional symptoms such as malaise, myalgias and mild fevers. It is also common to use NSAIDs in conjunction with other immunomodulatory drugs.

Corticosteroids are potent antiinflammatory drugs and clinicians use them for a variety of SLE manifestations. Although they are quite effective in the treatment of arthritis, serositis, rashes and constitutional manifestations, one should strive to use the lowest dose for the shortest duration based upon potentially serious complications. That said, steroid dose packs used for other acute conditions are usually counterproductive for SLE as rapid discontinuation will often lead to disease flares. Modest doses of steroids (equivalent to 20 mg of prednisone per day in a single dose) are usually sufficient to treat all but major life- or organ-threatening disease.



Antimalarial drugs, usually hydroxychloroquine (Plaquenil, Sanofi-Aventis), have become the mainstay of SLE therapy with nearly all SLE patients being afforded a therapeutic trial with these medications. Hydroxychloroquine has been effective at reducing skin, musculoskeletal, serositis and constitutional manifestations. It has also demonstrated efficacy when it comes to decreasing the frequency/severity of flares and slowing the progression of disease damage in SLE.10

When there is major organ involvement, such as renal disease, low- or high-dose systemic corticosteroids may be indicated. Knowing when to refer to a specialist, such as a nephrologist or rheumatologist, is also crucial to proper management of these patients.

For SLE patients with major organ involvement, such as hematologic, renal, central nervous system (CNS) or serositis findings, traditional immunosuppressives are often necessary at least intermittently (see “A Review Of Common Medications For SLE”). These medications are purine synthesis inhibitors such as azathioprine and mycophenylate mofetil (MMF).11,12 A steroid-sparing agent, azathioprine is indicated in treating cutaneous manifestations of SLE and serositis as well as major organ involvement, including lupus nephritis and nephropathy.11,12 Mycophenylate mofetil is a reversible inhibitor of purine synthesis and is usually indicated in severe lupus nephritis (class III, IV, and V) as well as serositis (pericarditis and pleuritis).12,13

Cyclophosphamide has been the standard of treatment for lupus nephritis and vasculitis as well as central nervous system complications of SLE.14 In patients with cutaneous symptoms as well as active arthritis and pleuritis, methotrexate reduces disease activity and the need for higher-dose corticosteroids.15 Cyclosporine A and tacrolimus are additional immunosuppressive agents that block T-lymphocyte activation by blocking transcription of interleukin 2. Although Cyclosporine A has severe side effects, it reportedly improves membranous nephritis without altering antibody formation and reduces the occurrence of rashes and skin disease associated with SLE when patients use it as a topical agent.12 Thalidomide is an additional agent that some clinicians use to treat severe discoid lesions. However, its use is limited due to severe teratogenic side effects.16 Dapsone remains an important medication to treat forms of cutaneous manifestations of systemic lupus and discoid lupus.

New medications currently being evaluated include hormones such as DHEA. Researchers have shown that DHEA helps with constitutional manifestations of lupus and may be indicated in a subset of lupus patients.13 LJP 394 (Riquent, La Jolla Pharmaceutical Company) is a new biologic that targets antibodies to dsDNA with the potential of controlling certain renal flares.13 Anti-CD 20 or rituximab (Rituxan, Genentech), which is currently approved for use in select malignancies and rheumatoid arthritis, is under investigation for use in treating hematologic manifestations, CNS disease and renal disease with SLE.12,13 (Editor’s note: As this issue went to press, the FDA issued a warning about the off-label use of rituximab for SLE. See page 8 for more details.) Additional agents currently being studied for SLE treatment include anti-TNF-alpha, anti-interleukin-6 and -18, anti-BLyS, and CTLA4-Ig, just to name a few.12, 13

How To Identify Serious Complications Among
Patients With SLE
When it comes to patients with SLE, select complications are more common based upon the underlying disease process and medications. Accelerated atherosclerosis, hypertension, infections, malignancies and osteoporosis are all unusually common and significantly increase morbidity and mortality in lupus patients. Early identification and treatment of concurrent illnesses and risk factors can potentially and dramatically improve outcomes among these patients.

Recently, researchers have shown that atherosclerosis is higher in patients with SLE.17,18 Indeed, women with SLE between 35 and 44 years of age may have as much as a 40-fold increase of accelerated atherosclerosis compared to non-SLE matched individuals. Rates of myocardial infarction are also higher in SLE patients and cardiovascular events are the leading cause of mortality among patients with lupus.

Hypertension is quite common in SLE patients and poorly controlled blood pressure is associated with progression to end stage renal disease in patients with SLE. Therefore, one should facilitate careful monitoring and control of blood pressure with these patients as the clinician would do with other high-risk groups such as patients with diabetes. Osteoporosis and osteopenia are also much more prevalent in SLE. Recognition of those at risk through bone mineral density screening allows one to institute calcium/vitamin D supplementation and bisphosphonate therapy before fractures occur.19



Patients with SLE also have increased risks of infection, likely resulting from immunosuppressive medications and intrinsic lupus immune defects.20 Early recognition and treatment are warranted. These patients also have an increased risk of malignancies and age/gender appropriate evaluation for cancers is needed.
While pregnancy is not contraindicated in patients with SLE per se, clinicians must discuss the risks with the patient. Ideally, patients will either be in remission or have suppressed the disease before becoming pregnant as patients with active SLE often have increased disease activity or flares during pregnancy and often poor pregnancy outcomes.21 Of course, these patients must cease taking medications such as methotrexate before considering pregnancy and clinicians may need to implement alternative medication.

Clinicians should also consider pregnant patients with SLE as high-risk pregnancies and ensure appropriate monitoring of these patients. Patients with anti-Ro antibodies have an increased risk of having children with complete congenital heart block or neonatal lupus. Anti-phospholipid antibodies are associated with pregnancy loss. Again, one should emphasize close monitoring of these patients and consider the need for alternative treatments.

Although the survival rate for SLE patients has improved dramatically since the near 50 percent mortality levels in the 1950s, this disease is still serious. In a 2002 study from the Centers for Disease Control and Prevention (CDC), the crude death rate from SLE had increased from 39 to 52 people per 10 million. In addition, the death rate was five times higher in females and three times higher among African-Americans. Crude death rates increased the most between the ages of 45 and 64 among African-American women.22 Identification of SLE in this patient population, implementing appropriate therapy and ensuring regular monitoring and treatment of co-morbidities are of paramount importance.

In Conclusion
Diagnosis and treatment of SLE is complicated. No single therapeutic plan is correct for all patients. Since various complications associated with SLE may be severe, providers on the frontlines need to be familiar with the key signs, symptoms and differential diagnosis in order to monitor patients for such changes and to know when to refer patients to specialists.