Systemic Lupus Erythematosus

SLE is prevalent among young women, with a peak age of onset between late teens is more common within certain ethnic groups, such as people with African or Asian origins. The clinical course of SLE is variable and may be characterised by periods of remissions and chronic or acute relapses. The inflammatory and immunologic assault seen in SLE can be life-threatening when major organs are affected, but more commonly results in chronic debilitating ill health. Consequently, patients require extensive health education in terms of managing their condition and in lifestyle decisions to reduce or prevent associated problems, such as osteoporosis and athersclerotic heart disease. An ongoing relationship between the primary care physician and the rheumatologist is essential for the optimal management of SLE patients.

Clinical presentation

SLE is a multisystemic disease. As a result, the classical presentation of a young woman with inflammatory arthritis and characteristic butterfly facial rash is uncommon. The onset of the disease may be acute, resembling an infectious process, or it may be a progression of vague symptoms over several years. SLE is typically signaled by one or several of the following features: unexplained nonspecific symptoms such as fever, fatigue, weight loss, or anaemia; photosensitive skin rashes, arthralgia or arthritis, Raynaud’s phenomenon, serositis (pleuritis, pericarditis, peritonitis), nephritis or nephrotic syndrome, neurologic symptoms such as seizures or psychosis, alopecia or phlebitis.

Laboratory testing may reveal leucopenia, anaemia, an elevated serum creatinine level, hypoalbuminemia, proteinuria, an active cellular urinary sediment, hypocomplementemia and a positive Coombs test. Positive screens for antinuclear antibodies, including those to double stranded DNA and the Smith antigen, are diagnostically specific to SLE.

Noting the range of symptoms, it is not surprising that there is often considerable delay before SLE is diagnosed in patients with low-grade disease. However, early diagnosis and treatment are central to improving prognosis.

Diagnosis

Primary care physicians are often called upon to diagnose, and provide initial therapy for, lupus. The diagnosis of SLE is predominantly clinical in patients who present with several compatible clinical features and with supportive laboratory studies. A good example is a young woman who presents with complaints of fatigue, arthralgia, and pleuritic chest pain, who is found to have hypertension, a malar rash, a pleural friction rub, several tender and swollen joints, and mild peripheral edema.

In more complex cases, however, diagnosis can be elusive. Many of the symptoms characteristic of SLE overlap with those of patients who have infections or cancer, which must be ruled out before the diagnosis can progress. A full clinical evaluation should be undertaken, inclusive of a complete systems review and examination and further investigations guided by the extent of organ involvement. Helpful diagnostic criteria have been developed by the American College of Rheumatology (ACR) to aid in identifying SLE patients (see ‘At a glance’). The diagnosis of SLE is made if four or more of the manifestations are present, either serially or simultaneously, during any interval of observations. Patients can then be further classified as follows:

• Classical SLE; many criteria

• Definite SLE; four or more criteria

• Probable SLE; three criteria

• Possible SLE; two criteria

Additional considerations

Laboratory tests can provide diagnostically useful information when SLE is suspected. Initial screening includes a complete blood count and differential, full chemistry panel and urinalysis, followed by laboratory tests for specific autoantibodies (e.g. serologic test for syphilis, antinuclear antibodies (ANA), antiphospholipid antibodies, antibodies to double stranded DNA and antiSmith (Sm) antibodies).

Abnormalities in these test results should guide further investigations. Additional immunologic studies that may aid in diagnosis, and in assessing the activity of SLE, include complement levels (total hemolytic complement [CH50], C3, and C4).

It should be noted that antinuclear antibodies are also present, usually in lower titer, in a variety of other disorders. Diseases that often are associated with a positive ANA test include Sjögren’s syndrome (in 68% of affected patients), scleroderma (40% to 75%, especially with a speckled-pattern of ANAs), juvenile rheumatoid arthritis (16%) and rheumatoid arthritis (25% to 50%, especially with a diffuse pattern of ANAs). Two autoantibodies, however, are highly specific for SLE: anti-double-stranded DNA (dsDNA) antibodies and anti-Sm antibodies. The percentage of SLE patients who have anti-dsDNA antibodies (i.e. the sensitivity of the test) does vary in published studies from 25% to 75% respectively. In summary, the finding of anti-dsDNA antibodies supports the diagnosis of SLE, while the absence of anti-dsDNA antibodies does not rule out SLE.

Diagnostic imaging may be valuable but is not routinely obtained unless indicated by the presence of symptoms, clinical findings, or laboratory abnormalities. Examples include:

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Plain radiographs of involved joints.

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Renal ultrasonography to assess kidney size and rule out a obstructive postrenal etiology when there is evidence of renal failure.

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Chest radiography.

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Echocardiography (e.g., for suspected pericardial involvement or to assess for a source of emboli).

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Computer aided tomography (CT) (for abdominal pain, suspected pancreatitis).

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Magnetic resonance imaging (for focal neurologic deficits or cognitive dysfunction).

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Contrast angiography may be valuable if vasculitis affecting medium sized arteries is suspected (e.g., mesenteric or limb threatening ischemia).

For patients who present with organ dysfunction, a biopsy may be required. Typical histologic findings in various organs in SLE are not discussed here, but may be found in topic reviews devoted to particular organ systems.

Additional tests are typically dictated by clinical presentation and associated differential diagnostic possibilities. Examples include electrocardiography in the assessment of chest pain that may be due to pericarditis, assessment for pulmonary embolism in a patient with pleuritic chest pain and dyspnea, and diffusing capacity for carbon monoxide (DLCO) to assess for suspected pulmonary haemorrhage and estimate the severity of interstitial pneumonitis.

Treatment

The major challenge for physicians overseeing patients with SLE is to treat the active flare without allowing the treatment itself to cause long-term damage. This balance is best achieved in partnership with a rheumatologist, who can design a regime that is both effective and safe.

Nonsteroidal anti-inflammatory medicines (NSAIDs), such as naproxen, ibuprofen and celecoxib, retain an important role in treating milder manifestations of lupus. These are generally effective in controlling musculoskeletal complaints, mild serositis and low-grade fever. These are not disease-modifying drugs, however, and side effects include potential cardiovascular, renal and gastrointestinal risks.

Antimalarials, such as hydroxychloroquine or quinacrine, have become the mainstay of SLE therapy in recent years and should be considered in all patients. They are generally well tolerated and are most useful for skin manifestations and for musculoskeletal complaints that do not adequately respond to NSAIDs. In long-term studies, the use of antimalarials, such as hydroxychloroquine, prevented major damage to the kidneys and central nervous system. Their use may also reduce the risk of disease flares; though this is less clear for renal and central nervous system manifestations. Antimalarials are not the drugs of choice for disease in these organ systems. Eye exams within the first year of treatment, and 6-12 monthly thereafter, and not exceeding a hydroxychloroquine dose of 6.5 mg per kg of body weight, minimises the risk of retinal toxicity.

Systemic glucocorticoids used alone or in combination with immunosuppressive agents are reserved for patients with significant organ involvement, particularly renal and central nervous system disease. As an example, mycophenolate or cyclophosphamide are given with glucocorticoids to patients with more than mild lupus nephritis, and cyclophosphamide to those with alveolar hemorrhage, systemic vasculitis, and to most patients with significant central nervous system involvement. In the author’s experience, “pulse” (high dose intravenous) methylprednisolone in doses of 500 mg daily is as effective as 1000 mg daily and has a lower incidence of infectious complications.

Experimental therapies

Patients with severe organ involvement who are resistant to cyclophosphamide therapy generally do poorly. The optimal approach to such patients is uncertain, but novel treatments include:

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Haematopoietic stem cell transplantation

The proposed mechanism of action of haematopoietic stem cell transplantation is that it provides a period free from memory T cell influence, during which maturation of new lymphocyte progenitors can occur without recruitment to anti-self activity.

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Immunoablation

Immunoablation without bone marrow or stem cell support has been effective in some patients with moderate to severe SLE refractory to corticosteroids and immunosuppressive therapy.

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Anti-B cell antibodies

Monoclonal anti-B lymphocyte antibodies may be beneficial for patients with disease that is resistant to other immunosuppressive therapy (rituximab, cyclophosphamide, and glucocorticoids). The combination of the B cell depleting chimeric monoclonal antibody, rituximab, cyclophosphamide, and high-dose glucocorticoids, as used in the treatment of lymphoma, has shown some promise in uncontrolled, observational studies.

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Epratuzumab

Epratuzumab, a humanised monoclonal antibody that binds to CD22 on B cell surfaces, is a promising treatment for SLE. CD22 is a member of the Ig superfamily, which binds to sialic acid-bearing molecules on other haematopoietic and non-haematopoietic cells. In a 12-week uncontrolled study in 14 patients with active SLE, all the patients tolerated the treatment and all improved. Additional studies of this anti-B cell immunomodulatory agent are anticipated.

A number of other therapeutic approaches have been tried or are under investigation in SLE.

These include intravenous immune globulin, thalidomide, bromocriptine, zileuton, cyclosporine, anti-CD40, LJP 394, anti-C5 complement monoclonal antibody, anti-IL-10, antagonists to B lymphocyte stimulator (BLyS), infliximab, mizoribine, immunoadsorption (via perfusion of patients’ blood through a column of immobilised C1q or polyclonal sheep anti-human immunoglobulin), and use of recombinant human interleukin-1 receptor antagonists.

Prognosis

SLE can run a varied clinical course, ranging from a relatively benign illness to a rapidly progressive disease with fulminant organ failure and death. Most patients have a relapsing and remitting course, which may be associated with the use of high dose steroids during the treatment of severe flares.

The five-year survival rate in SLE has dramatically increased over the last several decades from approximately 40% in the 1950s to more than 90% in studies beginning after 1980. The major cause of death in the first few years of illness is active disease (e.g., CNS, renal, or cardiovascular disease) or infection due to immunosuppression, while late deaths are either caused by the illness itself (for example, end-stage renal disease), treatment complications (including infection and coronary disease), non-Hodgkin’s lymphoma, and lung cancer.

Despite a reduction in the risk of premature death, patients with SLE are still at risk for significant morbidity due to both active disease and the side effects of drugs such as corticosteroids and cytotoxic agents.

Steroid-induced avascular necrosis of the hips and knees, osteoporosis, fatigue, and cognitive dysfunction have become particularly important problems as patients live longer with their illness with a concomitant increase in steroid use. Athersclerotic heart disease is also now a major contributor to SLE morbidity and mortality, and intensive modification of risk factors is essential.

Conclusion

While our understanding of SLE has evolved in recent decades, the etiology of the disease remains elusive.

As a result, delays in diagnosis, particularly in patients with low-grade SLE,remain a challenge and no single therapeutic plan is correct for all patients. Since various complications associated with SLE may be severe, primary care physicians should be familiar with the key signs and symptoms of the disease in order to know when to refer patients to specialists.