Systemic Lupus Erythematosus

Bridget Wright

Swati Bharadwaj

Abby Abelson

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Definition

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that has a broad range of clinical manifestations. In SLE, tissue damage in multiple organs is caused by autoantibodies and immune complexes. Because other autoimmune diseases, infectious diseases, central nervous system diseases, and fibromyalgia can also manifest with multisystem disease involvement, these other conditions need to be considered when considering a diagnosis of SLE.

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Epidemiology

SLE is a disease that can affect persons of all ages and ethnic groups and both sexes, but more than 90% of new patients presenting with SLE are women in the childbearing years. The reported prevalence of SLE is 20-150 per 100,000. In the United States, data from states with large urban populations indicated the prevalence was 104-170 per 100,000 women.1 This gender disparity is not as prominent in early life (<20 years of age) and later in life (>40 years of age).2

The LUMINA (Lupus in Minority population, Nature versus nurture) cohort is providing a more generalizable database for the epidemiology of SLE. LUMINA is a longitudinal outcome study of patients with SLE. This study does not include patients younger than 17 years. Among the LUMINA cohort, 90% of SLE patients are female, 44% are African American, 23% are Latin American, and 32% are white.3 Based on 2004 data from the National Health and Nutrition Examination Survey (NHANES), the prevalence of SLE patients receiving treatment was 100 per 100,000 among American women.4

Although patients with SLE almost uniformly present with a positive antinuclear antibody (ANA) test, other conditions exhibit positive ANAs as well. Craig and colleagues found an ANA titer of 1 : 64 or greater in 15% of healthy women younger than 40 years and in 24% of women older than 40 years.5 The American College of Rheumatology criteria for SLE ensure uniformity of patients in research studies.

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Pathophysiology

Patients with SLE have a complex array of abnormalities involving their immune system. Twin studies and genetic linkage studies suggest that heredity plays a role in the development of lupus.6 Many biochemical studies have revealed abnormalities in T cell function, B cell function, programmed cell death (apoptosis), immune complex clearance, complement function and deficiencies, and nucleosome processing.7,8 In general, these studies support an abnormal functioning immune system. It is still not clear exactly what starts the immune dysregulation, but it does appear to require a genetically susceptible host affected by either a exogenous trigger or an endogenous metabolic disturbance that causes the loss of tolerance to self antigen.9,10

Different ethnic groups have different genetic abnormalities; for example, east Asians with SLE have more cytotoxic T lymphocyte antigen-4 (CTLA-4), and whites with lupus nephritis have more abnormalities in Fc-γ receptors.11,12 In the future, a specific genetic and immunity-based diagnosis may be given, such as T cell protein kinase type I deficiency.13

The majority of the pathology in lupus is related to deposits of immune complex. The immune complexes deposit in various organs, which triggers complement and other mediators of inflammation. Autoantibodies in SLE are directed against a wide variety of self antigens. Autoantibodies directed against nuclear self antigen (ANA) are the most characteristic of SLE.13 Commonly found target nuclear antigens in SLE include native DNA, denatured DNA, histone, Smith, U1 ribonuclear protein (RNP), SSA, SSB, and ribosomal RNP. Among these, double-stranded DNA (dsDNA) and Smith appear to be unique to SLE. Therefore, it can be helpful, in diagnosing SLE, to look for these more-specific autoantibodies to help in establishing the diagnosis.

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Clinical presentation

Constitutional

SLE can affect any of the major organ systems. As its name implies, SLE can also have systemic or constitutional symptoms. These symptoms can mimic other autoimmune diseases, infectious diseases, endocrine abnormalities, chronic fatigue, and fibromyalgia. Because the general symptoms are not specific, it is important to use them along with more organ-specific symptoms that can help differentiate lupus from other diseases. Common symptoms elicited by history include fever, fatigue, weight loss, myalgia, and arthralgia. There are many reports of these nonspecific symptoms with or without rash occurring after sun exposure.

Dermatologic

Lupus was first described as a dermatologic condition. The SLE patient often presents to a physician when the cutaneous manifestations occur. Because of the photosensitive nature of the rash, the prevalence of rash in SLE depends on the region of the world in which the patient lives. It is also important to remember that lupus can be limited to the integumentary system. Box 1 lists the common forms of lupus when it involves the skin.

Box 1: Common Forms of Cutaneous Lupus
Acute cutaneous lupus
Chronic or discoid lupus
Lupus panniculitis
Lupus pernio
Subacute cutaneous lupus
Tumid lupus

Red plaques that occur on sun-exposed areas of the body characterize acute cutaneous lupus. Acute cutaneous lupus can have associated alopecia, but the rash and hair loss do not lead to scarring. The malar or butterfly rash is the best-known manifestation of acute cutaneous lupus. The malar rash spares the nasolabial folds; the body of the butterfly is separate from its wings.

Discoid lesions can also occur in systemic lupus but are not as common as the acute cutaneous lupus rash. Discoid lesions are often scarring. The rash of subacute cutaneous lupus often appears as annular rings with crusted margins and spares the mid face. Lupus panniculitis manifests as a deeper rash that is often tender; it can look like erythema nodosum, which is another type of panniculitis. SLE can manifest with a vasculitic type of rash: palpable purpura or pernio. Pernio is an erythematous, often painful area at the tip of a digit seen after cold exposure.

The oral and nasal ulcers of systemic lupus are classically described as painless; however, these lesions may be quite painful. Oral involvement most commonly affects the posterior aspect of the hard palate. The nasal and oral ulcers usually are recurrent or chronic. Mucous membrane involvement can also involve the vagina. Young sexually active women should be evaluated with this in mind.

Musculoskeletal

The most common initial manifestation of SLE is arthralgia or arthritis,14 with a frequency of 48% in patients followed for 10 years.15 Arthralgia, expressed by the patient as pain and stiffness, is more common than objective arthritis. The arthritis in SLE can be migratory and transient; it may be present at the time the patient makes the appointment but resolved by the time of the evaluation. Arthritis in SLE tends to have fewer erosions and fixed deformities compared with rheumatoid arthritis.

There is a clinical condition described as “rhupus.” These patients have a rheumatoid arthritis-like presentation along with other characteristics of lupus; this is a rare entity, but one that should be kept in mind. Periarticular inflammation is more common in lupus. This periarticular inflammation often involves the tendon sheaths and can lead to Jaccoud's arthropathy. Jaccoud's arthropathy involves swan-neck deformities of the fingers, which are reducible.16,17

Muscle disease is fairly common in SLE. These patients often present with myalgia complaints, and the cause of these muscle pains is not always clear. Again, it is important to recognize that SLE patients often have coexisting fibromyalgia complaints related to chronic disease, poor sleep, inactivity, and depression or mood problems. Some SLE patients have myositis that can be proved by biopsy. The frequency of myositis in lupus patients is approximately 4%. The biopsy is often similar to polymyositis. If myositis is suspected by elevations in the creatine kinase without specific muscle weakness, magnetic resonance imaging (MRI) of the gluteal and upper thigh muscles can be used to look for an abnormal signal, which might lead to a potential biopsy site. It is important to distinguish nonspecific myalgia from myositis, because treatment could be affected.

Osteonecrosis is an important musculoskeletal component of SLE. It can manifest as acute joint pain in patients with advanced disease or during periods of high-dose corticosteroid use. Retrospective studies have shown that higher doses of corticosteroids in the first 6 to 18 months of treatment are associated with osteonecrosis.18,19 Duration of treatment or disease severity does not correlate with the onset of osteonecrosis.18 It is important to investigate large joint pain, particularly hip or knee pain, in a patient with SLE. Because the beginning stages of osteonecrosis do not show changes on plain film, MRI should be considered in patients with negative plain films and persistent or unexplained pain. Osteonecrosis can be debilitating, however, and early diagnosis with limited weight bearing can prevent subsequent joint replacement in some.

Pulmonary

Serositis can affect both the cardiac and pulmonary systems, and cardiac and pulmonary serositis often coexist. Most large studies on the outcomes and frequency of particular manifestations of lupus assess for serositis but not for specific types. In patients with lupus followed for 10 years, pleural effusions occur in as many as 50% of patients. These effusions are often small and bilateral but occasionally can be unilateral and quite large. Effusions are often accompanied by pleuritic chest pain. It is important to consider infection in patients with newly diagnosed or longstanding SLE presenting with pleural effusions. Box 2 reviews the results of pleural effusion evaluation in SLE.

Box 2: Findings in Patients with SLE-Related Pleural Effusion
Lupus pleuritis or pleural effusions
Exudate
Normal glucose (low in rheumatoid arthritis)
White blood cell count moderately increased
Polymorphonuclear predominance early
Lymphocyte predominance late
Antinuclear antibodies
Negative cultures

SLE, systemic lupus erythematosus.


Lupus patients can develop other forms of pulmonary disease including shrinking lung, acute pneumonitis, chronic or fibrotic pneumonitis, alveolar hemorrhage, pulmonary hypertension, and thromboembolic-related disease. Shrinking lung is believed to be related to diaphragmatic weakness and decreased chest wall compliance.20,21 Pulmonary function tests in these patients do not explain the patient's complaints of dyspnea, but chest radiographs reveal bibasilar atelectasis and upward deviation of the diaphragm.

Acute pneumonitis has an abrupt onset with fever, cough, pleuritic chest pain, hemoptysis, and dyspnea. Pulmonary function tests might reveal severe restriction, and pulmonary infiltrates are seen on chest radiography.22 The incidence of acute pneumonitis is not clear, but Matthay observed an incidence of 11.7% in his SLE population.22 Infectious causes must always be ruled out in these patients before the diagnosis of acute lupus pneumonitis is entertained. This workup usually requires bronchoscopy with cultures. Biopsies consistent with lupus pneumonitis reveal acute alveolar injury with edema, hyaline membrane formation, and perivascular inflammation.23 It has been noted that a higher-than-expected percentage of lupus patients with pneumonitis are positive for SSA.24

Chronic pneumonitis is an insidious form of lung involvement with progressive dyspnea and diffuse interstitial lung infiltrates on plain chest radiography. Pulmonary function testing shows a restrictive pattern with decreased diffusion capacity. The incidence of chronic lung involvement in lupus is less than 10%.25

Pulmonary vascular involvement in lupus is also observed. This includes diffuse alveolar hemorrhage, thromboembolic disease, and pulmonary hypertension. Diffuse alveolar hemorrhage is an emergency manifesting with sudden-onset shortness of breath, dropping hemoglobin, and diffuse infiltrates on chest radiography. Although hemoptysis generally occurs at some point in this illness, less than one half of patients presenting with lupus-related alveolar hemorrhage have this symptom. Bronchoscopy can demonstrate red blood cells and hemosiderin-laden macrophages. These patients require high-dose corticosteroids.

Thromboembolic disease associated with antiphospholipid antibodies can lead to acute pulmonary embolism with acute pulmonary hypertension. Chronic small pulmonary embolisms can be associated with this disease and lead to slowly worsening pulmonary hypertension. Pulmonary hypertension can develop as a sequela from thromboembolic lung disease, but it can also be primary (cor pulmonale). It is important to keep this in mind, especially in patients with breathlessness, normal oximetry, and normal chest radiography, because an echocardiogram can indicate the diagnosis.

Cardiac

Cardiac involvement occurs in 20% to 30% of patients with SLE. It is most common in Latin Americans, followed by African Americans, then whites.26 Pericardial effusions are seen in about 20% of patients with SLE; however, more than 50% are found to have effusions on autopsy. When symptoms do occur, they include precordial chest pain, which is worse with lying down and relieved with leaning forward. A pericardial rub can often be heard on clinical examination. Many patients with clinically silent disease are found to have pericardial effusions when enlarged cardiac silhouette is seen on chest radiography, fluid is found on computed tomography (CT) of the chest, or echocardiogram obtained for other reasons reveals effusion. It is unusual (<1%) for pericardial effusions related to lupus to progress to tamponade.27 However, when pericardiocentesis has been necessary, the fluid reveals leukocytosis with neutrophil predominance, low glucose, reduced complement levels, low complement activity, and positive ANA.27 Pericardial and pleural effusions usually respond to corticosteroid therapy.

Valvular involvement in lupus is common and often asymptomatic. The mitral valve is involved most often. Mitral valve prolapse has been observed in 25% of lupus patients as opposed to 9% of controls.28 Valvular abnormalities in lupus include vegetations, regurgitation, and valvular stenosis. Because stroke, peripheral embolism, heart failure, death, and infective endocarditis can be associated with valvular abnormalities, cardiac auscultation and palpation should be done routinely. If abnormalities or changes from previous examination are noted, further investigation with echocardiography should be pursued.

Verrucous endocarditis is also common in SLE. Verrucae consist of immune complexes, mononuclear cells, fibrin, and platelet thrombi. In a study using transesophageal echocardiography, 43% of SLE patients were found to have verrucous lesions. Scarring and valve deformation can occur subsequent to the healing of these lesions. These lesions are often asymptomatic; however, awareness of these lesions is important because they can produce emboli or become secondarily infected.

Myocarditis also can occur in SLE but is uncommon. It should be suspected if there is resting tachycardia. Myocarditis can lead to global cardiac dysfunction as well as electrophysiologic abnormalities. Myocardial biopsy may be needed in cases where acute myocarditis is suspected versus fibrosis or myocardial infarction. Treatment for acute myocarditis requires high-dose glucocorticoids plus additional immunosuppression.

Coronary artery disease (CAD) has been recognized in several studies to be increased in patients with SLE compared with the general population, even when traditional cardiac risk factors are eliminated. Important risk factors in lupus patients include use of glucocorticoids, chronic nephritis, antiphospholipid antibodies,29 and increased oxidative stress.30 It is important to be aware of the increased incidence of CAD, especially because SLE often affects young women who are traditionally not thought to be at high risk for CAD. Any traditional risk factors for CAD such as smoking, inactivity, obesity, and elevated cholesterol should be addressed in this population. Hypertension should be aggressively controlled, which can be difficult in patients with underlying renal disease. In addition, since women with SLE have a 7- to 50-fold increased risk of CAD, which can lead to significant morbidity and premature death, a high index of suspicion is warranted when SLE patients present with dyspnea, chest pain, chest pressure, decreased exercise tolerance, or atypical symptoms.

Vascular

Raynaud's phenomenon occurs in one third of patients at the onset of SLE, and more than one half develop it during the course of their disease. Unlike Raynaud's phenomenon in systemic sclerosis, patients with lupus rarely develop ischemic digits or digital ulcers. Raynaud's phenomenon can affect the fingers, toes, ears, nose, and even the tongue. It is often triggered by cold, cigarette smoke, caffeine, over-the-counter cold medications, and stress. Livedo reticularis also is commonly seen in lupus patients and is due to spasm of the dermal ascending arterioles.

Venous thromboembolism is known to be associated with antiphospholipid antibody syndrome, which can coexist with SLE. However, venous thromboembolism is also increased in lupus patients who have a history of smoking at the time of diagnosis, increased disease activity over time, increased mean dose of glucocorticoids, shorter disease duration at the time of diagnosis, and presence of lupus anticoagulant.31

Lupus patients can also develop inflammatory vascular disease in the form of vasculitis. It is difficult to estimate the incidence of vasculitis in lupus because reporting has been mainly in the form of case reports or series, and the diagnosis of vasculitis is often based on clinical acumen without biopsy-proven vasculitis. Vasculitis in SLE is due to a complex interplay between immune cells, endothelial cells, deposition of autoantibodies, and immune complex deposition. In addition to reports of small- and medium-vessel vasculitis involving all the major organs including the skin, gastrointestinal (GI), pulmonary, cardiac, and genitourinary systems, there are reports of vasculitis affecting the placenta, leading to fetal mortality. There have also been case reports of SLE and Takaysu's arteritis.

Renal

Lupus nephritis is a common and potentially devastating manifestation of lupus. Renal disease in lupus is associated with significant morbidity and mortality. In general, lupus nephritis occurs in more than half of SLE patients. However, there is a disparity between nephritis in Latin Americans and African Americans compared with whites. The incidence of nephritis is 60% for Latin Americans, 69% for African Americans, and 29% for whites.32

Although nephritis can occur during a flare of SLE with skin manifestations or other organ system involvement, it often occurs without other clinical signs of active lupus. Thus, it is of key importance that patients with lupus have routine urine analysis with microscopy looking for protein, blood, and cellular casts. Patients can present with constitutional symptoms including fatigue, weight loss, and fever, as well as hypertension and edema, but generally patients do not develop symptoms until late in the disease process of nephritis.

Lupus nephritis is primarily caused by the deposition of immune complexes. The size of the complexes determines the location of deposition and therefore leads to differences in classification (mesangial, focal, diffuse).33 Once deposited, the immune complexes can set off the complement cascade, producing cellular damage and chemoattractants (C3a and C5a), leading to further recruitment of inflammatory cells. Immune complexes also can lead to upregulation of adhesion molecules on endothelial cells, leading to recruitment of immune cells such as macrophages and T cells, which in turn produce cytokines. Damaged glomerular cells also can produce cytokines that lead to further increase in the inflammatory infiltration.33-35

The classification of lupus nephritis is based on renal biopsy. The specific class does give helpful information regarding outcomes and specific therapeutic regimens. If possible, a biopsy should be obtained on any patient in whom renal involvement in suspected. Although there are studies looking at the presence of renal abnormalities in patients with no suspected renal involvement, renal biopsy need not be done routinely on patients with normal creatinine values and normal urine analysis. The 2003 revision of the classification of glomerulonephritis in SLE divides the disease process into six classes, with subdivisions of classes III and IV (Box 3).

Box 3: International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003 Classification of Lupus Nephritis
Class I: Minimal mesangial lupus nephritis
Class II: Mesangial proliferative lupus nephritis
Class III: Focal lupus nephritis
  • III (A): active lesions
  • III (A/C): active and chronic lesions
  • III (C): chronic lesions
Class IV: Diffuse lupus nephritis (≥50% of glomeruli)
  • Diffuse segmental (IV-S) or global (IV-G) lupus nephritis
  • IV (A): active lesions
  • IV (A/C): active and chronic lesions
  • IV (C): chronic lesions
Class V: Membranous lupus nephritis
Class VI: Advanced sclerosing lupus nephritis (≥90% globally sclerosed glomeruli without residual activity)

The primary complication of lupus nephritis is permanent renal damage. This damage may be severe enough that it leads to renal failure and dependence on dialysis. All of the complications associated with renal failure apply to these patients, such as hypertension, fluid overload, premature vascular calcifications, hyperlipidemia, and premature coronary artery disease.

Gastrointestinal

GI effects from SLE are not clearly defined. SLE can involve any part of the GI tract as a result of disease activity or side effects of medications.36

Oral Cavity

About one half of patients with systemic lupus have oral ulcers that are usually painful if discoid and painless if erythematous. They tend to be located on the hard palate, on the buccal mucosa, or along the vermilion border.37 Oral ulcers are one of the nonspecific findings in lupus and are by no means diagnostic of the disease itself. They can support a diagnosis of lupus when present with other lupus symptoms and serologies. In a setting of established lupus they could represent a disease flare, side effects of medications such as methotrexate, or an opportunistic infection. Treatment of oral ulcers is directed at the cause and consists of controlling the disease activity, administering folic or folinic acid (if they are caused by methotrexate), or treating the infection. Symptomatic treatment is directed at relieving the pain with pain medications or local application of crushed 1-mg prednisone tablets.

Esophagus

Lupus patients occasionally complain of dysphagia or odynophagia. This can be multifactorial from hypomotility,38 from reflux disease, or from candidiasis from immunosuppression. If the symptoms are severe, they deserve a regular dysphagia evaluation with motility studies, x-rays, and maybe an endoscopy. Although treatment is directed at the cause, motility drugs are no longer favored due to their arrythmogenic potential. Antireflux medications or antifungals are used when appropriate.

Abdomen

Abdominal pain is a diagnostic challenge in SLE and is probably one of the most clinically threatening GI manifestation to be aware of. Min and colleagues looked at causes of acute abdominal pain in SLE patients in emergency departments (EDs). They documented that 59.1% of visits to the ED by SLE patients were from pain due to ischemic bowel disease.39 The other causes were splenic infarcts, renal venous thrombosis, pancreatitis, serositis, upper GI bleeds, pelvic inflammatory disease, and ectopic pregnancy. Peptic ulcer disease with perforation also manifested as an acute abdomen in a small number of patients with SLE and concomitant NSAID use.37 Medina and colleagues emphasized the importance of early laparotomy in SLE patients with higher SLE disease activity index (SLEDAI) scores and acute abdominal pain. They studied the relation between SLEDAI scores and sources of an acute abdomen in 51 SLE patients and found that patients with intra-abdominal vasculitis (19) or thrombosis (3) had higher SLEDAI scores than 14 patients who had active SLE with non-SLE-related acute abdomen. Fifteen patients with inactive SLE had intra-abdominal pathology unrelated to SLE.40 Treatment of acute abdominal pain is directed at the cause, with appropriate medical or surgical management of the presenting manifestation.

Intestines

In the bowel, SLE can manifest with vasculitis, malabsorption, or dysmotility.37 Mesenteric vasculitis in lupus can manifest as an acute abdomen with fever, nausea, vomiting, diarrhea, and rectal bleeding or with the characteristic mesenteric ischemic pain related to meals. The mesenteric involvement can be attributed to either a lupus flare or antiphospholipid antibodies. Suspicion based on a clinical, angiographic, or CT examination of mesenteric vasculitis without bowel perforation warrants an evaluation by a rheumatologist and a possible aggressive therapeutic approach with intravenous steroids with or without other cytotoxic agents, besides the routine treatments with nothing by mouth, IV fluids, cultures, and broad-spectrum antibiotics.41 If there is intestinal perforation from vasculitis, surgery is the first option followed by cautious start of steroids and cytotoxic agents in the postoperative period. Malabsorption in the form of a protein-losing enteropathy in lupus is uncommon and manifests with diarrhea, abdominal pain, and anasarca. The enteropathy might respond to steroids with or without cytotoxic drugs.

Pancreas

Pancreatitis in lupus is uncommon and could occur in a setting of high SLEDAI scores, antiphospholipid antibody syndrome, and probable steroid use.37 The more likely causes, as in any other setting, are gallstones, alcohol, and hypertriglyceridemia. Treatment is the same as for pancreatitis from any other cause and includes nothing by mouth, IV fluids, withholding causal drugs, and, rarely, use of steroids if the cause is established by exclusion.

Liver

Drugs, viruses, fatty infiltration, or congestion have been implicated as more common causes of liver enzyme abnormalities in SLE patients.37 Hepatitis from lupus (lupus hepatitis), although uncommon, manifests as a mild elevation in liver enzymes (aspartate transaminase [AST], alanine transaminase [ALT)], lactate dehydrogenase [LDH], alkaline phosphatase), usually in a setting of active lupus. Such biochemical liver abnormalities from an SLE flare have a tendency to reverse with steroids. Lupoid hepatitis is a separate entity and is considered a subset of chronic active autoimmune hepatitis, where the liver is the main organ of involvement. Patients with lupus hepatitis and lupoid hepatitis can have arthralgias, hypergammaglobulinemia, and positive ANAs.37 Serologic differentiation may be possible at times and in general involves the presence of anti–ribosomal P and dsDNA autoantibodies in lupus hepatitis versus anti–smooth muscle and auto–liver-kidney-mitochondrial (LKM) antibodies in lupoid hepatitis. Definite differentiation is only possible on histology, which shows a lobular involvement in lupus hepatitis versus rosetting of liver cells and dense lymphoid infiltrate in lupoid hepatitis.

Neuropsychiatric

Neuropsychiatric SLE (NPSLE) could be defined as the neurologic syndromes of the central, peripheral, and autonomic nervous systems and the psychiatric syndromes observed in patients with SLE in which other causes have been excluded.42,43 NPSLE has many diagnostic and prognostic implications. The American College of Rheumatology (ACR) committee has developed 19 NPSLE case definitions with diagnostic criteria, exclusions, associations, and ascertainment, as well as reporting standards. The complete case definitions are on the ACR website (http://www.rheumatology.org). The proposed pathologic mechanisms of NPSLE are highly complex and poorly understood. They could be vasculopathic (injury, infarcts, accelerated atherosclerosis, perivascular inflammation), occasionally vasculitic, autoantibody mediated (antiphospholipid, antineuronal, anti-RNP), steroid mediated, or biochemically mediated.

Neurologic Manifestations

Neurologic manifestations can be primary (from SLE) or secondary (due to disease complications and treatment). They can then be either organic or functional (psychosis).

Seizures occur in one third of the cases and portend a poor overall prognosis.44 They could be generalized or partial and simple or complex and can be acute or from chronic scarring. For seizures, treatment data are scarce, and appropriate antiseizure medications are used along with a short course of steroids if there is an SLE flare.

CNS vasculitis tends to manifest with fevers, headaches, cognitive deficits, and confusion in the setting of serologic and radiologic markers of a lupus flare and can rapidly progress to seizures, loss of consciousness, and psychosis. Evaluation requires a brain MRI, magnetic resonance angiogram (MRA), and a spinal tap. Treatment is intravenous pulse steroids followed by oral steroids and cyclophosphamide.

Headaches in lupus are very common, but they have been reported to have no causal relation, no association with disease severity, and no particular mechanisms and require the regular headache evaluation, unless there are sudden headaches in a person who was previously free of headache and who has neurologic and psychiatric changes.45 SLE headaches are managed as usual headaches unless there is a definite lupus flare.

Stroke can occur in 19% of patients either from a lupus flare or from secondary antiphospholipid antibody syndrome.46 Treatment for stroke is empirical and is tailored to each patient based on the presentation. General principles of aggressive primary and secondary stroke prevention also apply in a lupus patient. If a stroke is from high antiphospholipid antibody (APLA) titers, chronic anticoagulation is recommended if there is no concomitant danger of intracranial hemorrhage. If this is catastrophic APLA syndrome, plasmapheresis, pulse steroids, and cytoxan are also considered. If the stroke is from a lupus flare (i.e., is not thrombotic), steroids with or without cytoxan traditionally have been used.47

Neuropathies can be peripheral, autonomic, or cranial.48 Wrist drops and foot drops occasionally result from peripheral nerve vasculitis. Besides an electromyogram (EMG), a nerve biopsy could also be obtained. For EMG-positive peripheral neuropathy, initial treatment is typically higher doses of prednisone, especially in patients with sensorimotor loss, along with neurontin or tricyclic antidepressants. Steroid-sparing agents such as imuran may be used thereafter. If the EMG is negative, neurontin or a tricyclic antidepressant should suffice. With cranial neuropathies, the mainstay of treatment is higher doses of prednisone.

Movement disorders (chorea and ataxia) tend to be self-limited without treatment.

Transverse myelitis is coincident with a lupus flare and is a rheumatologic emergency. This manifests with a sudden onset of lower extremity weakness or sensory loss plus loss of rectal and urinary bladder sphincter control, usually with clinical symptoms of a lupus flare.49 Transverse myelitis needs to be aggressively treated with pulse steroids followed by 1 mg/kg oral prednisone, cytoxan, and, sometimes, plasmapheresis.50

Ophthalmic involvement can occur as a rash on the eyelids, keratoconjuctivitis, retinal vasculitis, retrobulbar optic neuritis, or retinal vein or artery occlusions.51 Eye involvement can result from SLE or concomitant APLA. Ophthalmic treatment options are prednisone, plaquenil, and occasionally cytoxan for optic neuritis that does not respond to prednisone. If there is retinal artery or vein involvement from APLA, anticoagulation should be considered.

Meningitis in SLE is rare and has a CSF picture of aseptic meningitis.

Psychiatric Manifestations

Psychiatric manifestations of SLE can be either primary and organic (psychosis, cognitive dysfunction, dementia) or secondary and functional (depression, anxiety, mania, personality disorders). The distinction should be based on psychological testing and on diagnostic studies such as CT, MRI, electroencephalography, evoked potential studies, cerebrospinal fluid studies, and single-photon emission CT (SPECT).52

Psychosis occurs in about 5% of SLE patients either from the lupus itself or from steroids and is a diagnosis of exclusion. Besides antipsychotic medications and a strong social support system, high doses of intravenous steroids have been used for a few weeks in divided doses. Cytoxan or azathioprine can also be tried if there has been no improvement with steroids in a couple of weeks.

Cognitive disorders are common and occur in 20% to 80% of patients. Treatment is based on the cause (drug or disease) and should also involve cognitive retraining. Dementia is severe cognitive dysfunction from multiple small ischemic strokes that may be worsened by high doses of steroids; therefore social support and antidepressants are key.53

Neonatal Lupus

Neonatal lupus occurs in 1% to 2% of babies.54 At-risk babies are those born to mothers with SLE, anti-Ro/SSA, and anti-La/SSB. These babies are at risk for neonatal heart blocks, AV nodal damage due to binding of antibodies, and, rarely, sinoatrial node damage. They can have partial or complete heart blocks, bradycardia, and a self-limited erythematous annular rash on the scalp and periorbital area. Fetal bradycardia during routine fetal auscultation, ultrasound, or echocardiogram in a high-risk mother should raise suspicion of neonatal heart block. Other uncommon manifestations are transposition of the great vessels, ostium primum atrial septal defect, ventricular septal defect, endocardial fibroelastosis, and myocarditis. Other systemic manifestations reported are hepatobiliary and hematologic.

Prenatal screening in high-risk mothers is important and guides the use of fetal echocardiograms. Fetal echocardiograms are routinely done once a week in the second trimester and then every other week until 32 weeks' gestation.

A pediatric rheumatologist should be involved early. Fetal monitoring in high-risk pregnancies and postnatal monitoring in affected babies are important. Incomplete heart block in the fetus tends to respond to fluorinated glucocorticoids if started immediately and continued until delivery. It is usually stopped if there is no response in 4 to 6 weeks. A baby with complete heart block might need a pacemaker.

Drug-Induced Lupus

Drug-induced lupus is epidemiologically, clinically, and serologically different from SLE. The male-to-female distribution is equal and the average age is 50 years. The most common drugs implicated are isoniazid, hydralazine, and procainamide. Other drugs implicated include minocycline, aldomet, diltiazem, penicillamine, infliximab, etanercept, rifampin, quinidine, captopril, beta blockers, anticonvulsants, sulfa, and amiodarone.

Most patients present with arthralgias or arthritis, and about one half of the patients have serositis. Organ involvement is uncommon in drug-induced lupus. Serologically, 95% of patients are antihistone positive, and the Sm and dsDNA are rarely positive. In comparison, in SLE, most patients are dsDNA positive and 80% are antihistone positive.55

Diagnosis should be suspected with acute lupus-like clinical signs and symptoms not involving a major organ and antihistone antibodies without dsDNA antibodies in the setting of an offending drug. Besides stopping the implicated medication, other treatment options are NSAIDs, antimalarials, and sometimes steroids and cytotoxic agents for drug-induced vasculitis or serositis. The disease tends to resolve within 6 months of discontinuing the drug.

Antiphospholipid Antibody Syndrome

APLA syndrome can be primary (idiopathic) or secondary (e.g., from SLE, infection, drugs). It causes arterial and venous thromboses leading to strokes, myocardial infarction, pulmonary embolism, deep venous thrombosis, fetal loss, anemia, thrombocytopenia, and livedo reticularis–like skin rash. In the clinical setting of lupus, an elevated partial thromboplastin time (PTT) should raise the suspicion of the presence of APLAs. Suspicion should be higher in an SLE patient who suffers a thrombotic event.

Besides a rapid plasma reagin, which gives a false-positive lupus anticoagulant test result, evaluation should involve a detailed lupus anticoagulant panel, which should ideally include prothrombin time (PT), activated PTT, dRVVT/KCT (dilute Russell's viper venom time and kaolin clotting time), mixing study, hex phase screen, hex phase confirm, platelet neutralization, and circulating anticoagulant. Lupus anticoagulant can be present in healthy subjects and can be transient in infections, and its presence should be interpreted in the right clinical and serologic settings. High-titer immunoglobulin (Ig) G/IgM cardiolipin antibodies and β2 glycoprotein have been associated with higher risk of thrombotic events and should also be tested.

For a definite diagnosis of APLA, the ACR has criteria. Briefly, frequent miscarriages and stillbirths or one or more clinical episodes of arterial or venous thrombosis confirmed by imaging or histology and the presence of lupus anticoagulant or medium to high titer IgG/IgM cardiolipin antibody or β2 glycoprotein antibody on at least two occasions 6 weeks apart is confirmatory for APLA syndrome.

Treatment is mainly anticoagulation and must be tailored to the clinical setting.56 In a patient with thrombosis and positive ALPA, heparin initially followed by long-term warfarin therapy is recommended. In a patient with positive ALPA but no thrombotic events, a trial of prophylactic aspirin 81 mg daily (clopidogrel for patients allergic to aspirin) or aspirin with plaquenil have been tried. In catastrophic APLA with organ damage, anticoagulation and high-dose intravenous steroids for 3 days followed by 1 to 2 mg/kg of prednisone daily have been used with or without plasmapheresis. Cyclophosphamide may be added and is most useful in a concomitant acute lupus flare. The traditional belief has been that primary APLA syndrome might not respond to cytotoxic therapy; however, cyclophosphamide is sometimes lifesaving in catastrophic APLA syndrome by an unknown mechanism. Intravenous immune globulin has also been tried in APLA-associated microangiopathies.

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Diagnosis

Diagnosis of SLE is made on clinical criteria supported by serologic data and appropriate imaging studies and biopsies as indicated. The ACR criteria for SLE are available on the ACR website. Four of 11 criteria are required to make a diagnosis of SLE. Although the criteria are helpful, not all patients fulfill these criteria clinically, and criteria have to be used with caution in clinical settings.

Tests

A patient referred for incidental positive ANA should have a careful history and physical examination to look for clinical findings of SLE. Not all patients with a positive ANA have SLE or a connective tissue disease. Two percent to 5% of healthy persons carry a low to moderate positive ANA. On the other hand, if there is a clinical suspicion of SLE, a detailed workup should be initiated with appropriate blood tests, urine tests, x-rays, and other studies that may be required based on the presentation.

In an outpatient setting, most rheumatologists order a white blood cell count (WBC) with differential, comprehensive metabolic panel (CMP), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), ANA panel, Smith, RNP, SSA and SSB, complements C3 and C4, dsDNA, and a urine analysis. Most rheumatologists also screen their patients for tuberculosis, hepatitis, thyroid diseases, and pregnancy, because a positive test affects the choice of immunosuppression and future follow-up. It is also worthwhile to check for APLAs (lupus anticoagulant, cardiolipin antibodies, and β2 microglobulin) because SLE and APLA commonly coexist and are often found together in patients with prior thrombotic events or frequent miscarriages.

If one suspects primary Sjögren's syndrome, rheumatoid factor (RF), cryoglobulin levels, and β2 microglobulins should be checked. Primary Sjögren's syndrome patients tend to have a positive ANA, rheumatoid factor, and SSA or SSB. Occasionally these patients have sicca symptoms and negative laboratory results, in which case a lip biopsy with a focus score is required to prove or disprove the diagnosis of primary Sjögren's syndrome. Sjögren's syndrome, however, can also be secondary to any underlying connective tissue disease, especially SLE and rheumatoid arthritis.

Other diagnostic tests are ordered as indicated and consist of joint x-rays and chest x-ray; renal ultrasound; CT scans of the chest, abdomen, and pelvis; echocardiograms; CT angiograms; electromyography and nerve conduction tests; neuropsychiatric testing; vascular studies; and biopsies of the skin, kidneys, nerves, and lungs.

Diagnosis

In the right clinical setting, leukopenia or lymphopenia, anemia, or thrombocytopenia with a positive ANA of 1 : 60 or higher suggests a diagnosis of SLE. The ANA panel might exhibit antibody patterns such as dsDNA, RNP, Smith, SSA, SSB, or histones. If it does, other multisystem diseases should be considered in addition to SLE, including Sjögren's syndrome, myositis, or drug-induced lupus, depending on the clinical features and autoantibodies isolated.

Table 1 lists some of the common tests and expected abnormalities, the possible mechanisms, clinical features, autoantibodies, and suggested specificities.57 This table is not a standardized guideline, and tests can vary in different clinical settings. The clinical assessment and tests must be combined to make an appropriate diagnosis of SLE.

Table 1: Diagnostic Tests for Systemic Lupus Erythematosus
Test Possible Abnormalities Mechanism Significance and Use
CBC plus differential Anemia, thrombocytopenia,
   leukopenia, lymphopenia,
   occasional neutropenia
Autoantibodies to
   RBCs (Coombs),
   lymphocytes,
   platelets
Disease activity markers for SLE and
   APLA
Monitor drug side effects
Basic metabolic panel Elevated BUN/Cr ratio Immune complex
   glomerulonephritis
   in SLE
Renal artery
   thrombosis from
   APLA
Diagnosis
Follow SLE nephritis
Monitor drug side effects
ESR and CRP Elevated Inflammatory markers Disease activity marker for follow-up if
   elevated at diagnosis
Complements (C3, C4) Low Immune complex
   consumption
Disease activity marker
Low C3 and C4 can also be seen in
  some primary complement deficiencies
Urine chemistry Proteinuria, hematuria,
   RBCs, red cell and mixed
   casts
Glomerulonephritis or
   glomerular damage
SLE nephritis and/or nephrotic syndrome
LFTs Elevated transaminases
   and/or alkaline
   phosphatase
Low protein or albumin
Unknown
   mechanism or
   concomitant
   NSAID use
Lupus hepatitis, nephrotic syndrome (low
   albumin), drug side effects
ANA (IFA + EIA) Useful as a screening test
  +ANA > 1 : 80 or
   ≥1 : 60 in right clinical
   setting are suggestive,
   although not diagnostic, of
   SLE
Titers > 1 : 640: look
   harder for ANA+ diseases
   if no obvious symptoms
ANA-negative lupus is rare (manifests
   with photosensitivity, Raynaud's
   syndrome, rash, serositis) ANA+ can be
   present in 2%-5% of healthy people and
   in other CTDs some of which are RA,
   JIA, scleroderma, MCTD, Sjögren's
   syndrome, dermatomyositis,
   polymyositis, Hashimoto's thyroiditis,
   lupoid hepatitis, and (occasionally) as
   an epiphenomenon in cancer, hepatitis,
   or transient infections ANA is not a
   disease activity marker and is mainly
   diagnostic
ENA panel Anti-Sm, anti-RNP,
   antihistone, anti-SSA/Ro,
   anti-SSB/La,
   antiribosomal P, SCL-70,
   and anticentromere
These are not disease
   activity markers and are
   purely diagnostic
Antibodies to specific
   nuclear proteins
Anti-Sm: Highly specific for SLE
Anti-histone: drug-induced lupus (95%)
   and SLE (80%)
Anti-SSA/SSB: primary Sjögren's
   syndrome, SCLE, neonatal lupus and
  SLE with secondary Sjögren's syndrome Anti-RNP: SLE (musculoskeletal,
   Raynaud's phenomenon), MCTD Antiribosomal P: SLE (psychiatric and
   CNS)
SCL-70: systemic sclerosis
Anticentromere: CREST syndrome
dsDNA antibody Positive
Higher titers seem to
   predict disease severity at
   times
Antibodies to the
   dsDNA
Diagnostic of SLE
May be used as a disease activity marker
Absent in drug-induced lupus
Higher titers in renal involvement
APLAs Lupus anticoagulant panel,
   cardiolipin antibody panel,
   β2 glycoprotein
Antibodies to
   membrane
   phospholipids
Moderate to high titers of IgG and IgM in
   primary or secondary APLA syndrome

APLA, antiphospholipid antibody; BUN, blood urea nitrogen; CBC, complete blood count; CNS, central nervous system; Cr, creatinine; CREST, calcinosis, Raynaud's syndrome, esophageal involvement, sclerodactyly, telangiectasia; CRP, C-reactive protein; CTD, connective tissue disease; dsDNA, double-stranded DNA; EIA, enzyme immunoassay; ENA, extractable nuclear antigens; ESR, erythrocyte sedimentation rate; IFA, immunofluorescent antibody; Ig, immunoglobulin; JIA, juvenile idiopathic arthritis; LFTs, liver function tests; MCTD, mixed connective tissue disease; NSAID, nonsteroidal anti-inflammatory drug; RA, rheumatoid arthritis; RBC, red blood cell count; RNP, ribonuclear protein; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome.

Assessing Organ Risk and Activity

If the SLE is active, the ESR and CRP are usually elevated, although sometimes they are normal. The complements C3 and C4 are usually low, especially in the setting of organ involvement such as the kidneys, but they can also be normal. A urine analysis is very important, and one must look for evidence of microscopic blood and proteinuria. If there is proteinuria, a 24-hour urine protein-to-creatinine ratio should be checked. If the dipstick is positive for blood, the urine should be manually spun in a centrifuge to look for dysmorphic red cells, granular casts, hyaline casts, and red blood cell or mixed casts to rule out renal involvement from SLE. Red cell casts and mixed casts tend to suggest inflammatory activity in the glomeruli and usually indicate the need for a kidney biopsy and referral to a nephrologist. If other organs are involved, such as the brain, lungs, or GI tract, appropriate laboratory, imaging, and biopsy studies may be required.

Follow-up Data

If immunosuppressive treatment is started with methotrexate, azathioprine, or mycophenolate mofetil, the complete blood count (CBC), basic metabolic profile, liver function tests, ESR, and CRP are usually monitored every month for the first 3 months and every 2 months for the next 6 months, and then the intervals are gradually increased if the results are acceptable. The frequency of blood tests depends on the choice of immunosuppressive medications. Cyclophosphamide requires more frequent monitoring than the other cytotoxic agents and should be done by a rheumatologist on a regular basis. Use of hydroxychloroquine requires only annual eye examinations and is usually used in mild SLE with mucocutaneous, skin, joint, or serosal symptoms without organ involvement.

The dsDNA, C3, C4, ESR, CRP, CBC, basic metabolic profile, liver function tests, and urine sediment can all be used as markers of disease activity. When there is more systemic involvement, such as the lungs and brain, appropriate imaging studies should also be followed periodically.

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Treatment

Treatment options include steroids, hydroxychloroquine, dapsone, azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide, and rituximab. Two studies of lupus treatment of randomized controlled trials (RCTs) were recently published. The EXPLORER (Efficacy and Safety of Rituximab in Patients with SLE) was a phase II/III randomized, double-blind, placebo-controlled multicenter trial evaluated treatment with rituximab in patients with active SLE but excluded patients with active nephritis, or who were being treated with high-dose prednisone or cytoxan. Preliminary results concluded that rituximab was not superior to rituximab in these patients. The LUNAR Study (Efficacy and Safety of Rituximab in patients with ISN/PRS Class II or III lupus nephritis was a phase III randomized, double-blind, placebo-controlled trial that compared the efficacy and safety of rituximab plus mycophenylate with placebo plus mycophenylate in SLE patients with proliferative nephritis. Preliminary results showed that rituximab plus mycophenylate was not superior to mycophenylate. Treatments have been discussed briefly with each section separately. Because SLE has a wide spectrum of symptoms and organ involvement, treatment strategies must be individualized for each patient, the organ system involved, and the severity of involvement. Immunosuppressive agents should be used only after infection and malignancy have been ruled out. In patients undergoing immunosuppressive treatment, physicians must continue to be vigilant for infections, both common and opportunistic, and for malignancies. Care of patients with SLE involves ongoing assessment of the patient's lupus activity and other comorbid conditions.

Osteoporosis prevention and treatment (especially in patients taking steroids), lipid and blood pressure control, antibiotic prophylaxis, and vigilant ongoing age-appropriate malignancy screenings are all treatment measures that are essential for the care of patients with SLE.

Standardized measures of disease activity such as SLICC (Systemic Lupus International Collaborating Clinics), BILAG (British Isles Lupus Assessment Group), and SLE activity scales are usually used in research settings. The SLICC/ACR damage index for SLE encompasses net damage from disease, treatment, or other events. A full history, physical examination, and serologic data such as complements, dsDNA, inflammatory markers, and a urine analysis can be used as markers of disease activity.

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Outcome and prognosis

Even with better survival rates, the mortality rate from SLE is still three times higher than the general population. Prognosis is worse in African American patients, in patients with early-onset disease, and in patients with renal, cardiopulmonary, and CNS involvement. Treatment of SLE with immunosuppressive drugs and cytotoxic agents can result in significant morbidity and mortality from concomitant infections. However, the prognosis for SLE patients in the United States has improved dramatically since the 1950s due to improved diagnostic methods, vigilant follow-up, and newer treatment options. Ongoing research and clinical progress will help improve prognosis and the future quality of life of patients with SLE.

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Summary

  • SLE is a prototypic autoimmune disease that can manifest with symptoms involving multiple organ systems in all ages and both sexes, but most initially presenting patients are women of childbearing age.
  • The diagnosis of SLE is based on clinical features and the presence of autoantibodies. High-titer IgG antibodies to dsDNA and antibodies to the Smith antigen are both specific for SLE.
  • ANAs are positive in more than 95% of patients with SLE, so repeated negative tests make the diagnosis unlikely. Positive ANAs, especially in low titers, can be seen in up to 30% of healthy persons.
  • Lupus manifestations of nephritis, cardiovascular disease, neurologic disease, pulmonary disease and hematologic syndromes can require urgent intervention with immunosuppressive therapies.
  • Patients with SLE are at higher risk for some malignancies.
  • Patients with SLE are at higher risk of cardiovascular disease and stroke, and the excess risk is not explained by traditional risk factors.
  • When patients with SLE taking immunosuppressive therapy present with additional symptoms that could result from flares of their disease, they must be evaluated to rule out infection before increasing their immunosuppression.

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Suggested Readings

  • Buyon JP, Clancy RM. Neonatal lupus syndromes. Curr Opin Rheumatol. 2003, 15: 535-541.
  • Buyon JP, Petri MA, Kim MY, et al: The effect of combined estrogen and progesterone hormone replacement therapy on disease activity in systemic lupus erythematosus: A randomized trial. Ann Intern Med. 2005, 142: (12 Pt 1): 953-962.
  • Calvo-Alen J, Toloza SM, Fernandez M, et al: Systemic lupus erythematosus in a multiethnic US cohort (LUMINA). XXV. Smoking, older age, disease activity, lupus anticoagulant, and glucocorticoid dose as risk factors for the occurrence of venous thrombosis in lupus patients. Arthritis Rheum. 2005, 52: (7): 2060-2068.
  • Cervera R, Khamashta MA, Font J, et al: Morbidity and mortality in systemic lupus erythematosus during a 10-year period: A comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore). 2003, 82: (5): 299-308.
  • D’Cruz DP, Khamashta MA, Hughes GR. Systemic lupus erythematosus. Lancet. 2007, 369: (9561): 587-596.
  • Greco TP, Conti-Kelly AM, Matsuura E, et al: Antiphospholipid antibodies in patients with coronary artery disease: New cardiac risk factors?. Ann N Y Acad Sci. 2007, 1108: 466-474.
  • Hanly JG. ACR classification criteria for systemic lupus erythematosus: Limitations and revisions to neuropsychiatric variables. Lupus. 2004, 13: (11): 861-864.
  • Jennekens FG, Kater L. The central nervous system in systemic lupus erythematosus. Part 1. Clinical syndromes: A literature investigation. Rheumatology (Oxford). 2002, 41: (6): 605-618.
  • Joseph G, Lammie GA, Scolding NJ. CNS lupus: A study of 41 patients. Neurology. 2007, 69: 644-654.
  • Lockshin MD, Erkan D. Treatment of the antiphospholipid syndrome. N Engl J Med. 2003, 349: 1177-1179.
  • Maksimowicz-McKinnon K, Magder LS, Petri M. Predictors of carotid atherosclerosis in systemic lupus erythematosus. J Rheumatol. 2006, 33: (12): 2458-2463.
  • Oelke K, Richardson B. Pathogenesis of lupus. Arthritis Rheum. 2002, 47: (3): 343-345.
  • Peponis V, Kyttaris VC, Tyradellis C, et al: Ocular manifestations of systemic lupus erythematosus: A clinical review. Lupus. 2006, 15: (1): 3-12.
  • Petri M. Monitoring systemic lupus erythematosus in standard clinical care. Best Pract Res Clin Rheumatol. 2007, 21: (4): 687-697.
  • Uribe AG, McGwin G Jr, Reveille JD, Alarcon GS. What have we learned from a 10-year experience with the LUMINA (Lupus in Minorities; Nature vs. Nurture) cohort? Where are we heading?. Autoimmun Rev. 2004, 3: (4): 321-329.
  • Zoma A. Musculoskeletal involvement in systemic lupus erythematosus. Lupus. 2004, 13: (11): 851-853.