Systemic Lupus Erythematosus (SLE) 

Updated: Dec 12, 2018
Author: Christie M Bartels, MD, MS; Chief Editor: Herbert S Diamond, MD 

Overview

Practice Essentials

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease that is characterized by an autoantibody response to nuclear and cytoplasmic antigens. SLE has protean manifestations and follows a relapsing and remitting course. More than 90% of cases of SLE occur in women, frequently starting at childbearing age. See the image below.

Photosensitive systemic lupus erythematosus (SLE) Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Although the interphalangeal spaces are affected, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints are spared. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.

 

See Cutaneous Clues to Accurately Diagnosing Rheumatologic Disease, a Critical Images slideshow, to help recognize cutaneous manifestations of rheumatologic diseases. Also, see the Autoimmune Disorders: Making Sense of Nonspecific Symptoms slideshow to help identify several diseases that can cause a variety of nonspecific symptoms.

Signs and symptoms

SLE is a chronic inflammatory disease that can affect almost any organ system, although it mainly involves the skin, joints, kidneys, blood cells, and nervous system. Its presentation and course are highly variable, ranging from indolent to fulminant.

In childhood-onset SLE, several clinical symptoms are more commonly found than in adults, including malar rash, ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, seizures, thrombocytopenia, hemolytic anemia, fever, and lymphadenopathy.[1]

In adults, Raynaud pleuritis and sicca are twice as common as in children and adolescents.[1]

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE.[2, 3]

Patients may present with any of the following manifestations[4] :

  • Constitutional (eg, fatigue, fever, arthralgia, weight changes)

  • Musculoskeletal (eg, arthralgia, arthropathy, myalgia, frank arthritis, avascular necrosis)

  • Dermatologic (eg, malar rash, photosensitivity, discoid lupus)

  • Renal (eg, acute or chronic renal failure, acute nephritic disease)

  • Neuropsychiatric (eg, seizure, psychosis)

  • Pulmonary (eg, pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, interstitial lung disease)

  • Gastrointestinal (eg, nausea, dyspepsia, abdominal pain)

  • Cardiac (eg, pericarditis, myocarditis)

  • Hematologic (eg, cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia)

In patients with suggestive clinical findings, a family history of autoimmune disease should raise further suspicion of SLE.

See Presentation for more detail.

Diagnosis

The diagnosis of SLE is based on a combination of clinical findings and laboratory evidence. Familiarity with the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex disease based on the pattern of target-organ manifestations.

The American College of Rheumatology (ACR) criteria, proposed in 1982 and revised in 1997, summarize features that may aid in the diagnosis. The presence of 4 of the 11 ACR criteria yields a sensitivity of 85% and a specificity of 95% for SLE.[5, 6]

When the Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE classification criteria in 2012, they classified a person as having SLE in the presence of biopsy-proven lupus nephritis with ANA or anti–double-stranded DNA (anti-dsDNA) antibodies or if 4 of the diagnostic criteria, including at least 1 clinical and 1 immunologic criterion, have been satisfied.[7]

ACR mnemonic of SLE diagnostic criteria

The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:

  • Serositis

  • Oral ulcers

  • Arthritis

  • Photosensitivity

  • Blood disorders

  • Renal involvement

  • Antinuclear antibodies

  • Immunologic phenomena (eg, dsDNA; anti-Smith [Sm] antibodies)

  • Neurologic disorder

  • Malar rash

  • Discoid rash

Testing

The following are useful standard laboratory studies when SLE is suspected:

  • CBC with differential

  • Serum creatinine

  • Urinalysis with microscopy

Other laboratory tests that may be used in the diagnosis of SLE are as follows:

  • ESR or CRP level

  • Complement levels

  • Liver function tests

  • Creatine kinase assay

  • Spot protein/spot creatinine ratio

  • Autoantibody tests

Imaging studies

The following imaging studies may be used to evaluate patients with suspected SLE:

  • Joint radiography

  • Chest radiography and chest CT scanning

  • Echocardiography

  • Brain MRI/MRA

  • Cardiac MRI

Procedures

Procedures that may be performed in patients with suspected SLE include the following:

  • Arthrocentesis

  • Lumbar puncture

  • Renal biopsy

See Workup for more detail.

Management

Management of SLE often depends on the individual patient’s disease severity and disease manifestations,[8] although hydroxychloroquine has a central role for long-term treatment in all SLE patients.

Pharmacotherapy

Medications used to treat SLE manifestations include the following:

  • Antimalarials (eg, hydroxychloroquine)

  • Corticosteroids (eg, methylprednisolone, prednisone), short-term use recommended

  • Nonbiologic DMARDS: Cyclophosphamide, methotrexate, azathioprine, mycophenolate, cyclosporine 

  • Nonsteroidal anti-inflammatory drugs (NSAIDS; eg, ibuprofen, naproxen, diclofenac)

  • Biologic DMARDs (disease-modifying antirheumatic drugs): Belimumab, rituximab, and/or IV immune globulin

See Treatment and Medication for more detail.

See also the following Medscape articles:

Pathophysiology

SLE is an autoimmune disorder characterized by multisystem inflammation with the generation of autoantibodies. Although the specific cause of SLE is unknown, multiple factors are associated with the development of the disease, including genetic, epigenetic, ethnic, immunoregulatory, hormonal, and environmental factors.[9, 10, 11, 12]  Many immune disturbances, both innate and acquired, occur in SLE (see the image below).

In systemic lupus erythematosus (SLE), many geneti In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab) responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity. HLA = human leukocyte antigen; UV = ultraviolet light.

Potential mechanisms

It is important to note that antibodies may be present for many years before the onset of the first symptoms of SLE.[13] One longstanding proposed mechanism for the development of autoantibodies involves a defect in apoptosis that causes increased cell death and a disturbance in immune tolerance.[14, 15, 10, 16] The redistribution of cellular antigens during necrosis/apoptosis leads to a cell-surface display of plasma and nuclear antigens in the form of nucleosomes. Subsequently, dysregulated (intolerant) lymphocytes begin targeting normally protected intracellular antigens. The defective clearance of the apoptotic cell debris allows for the persistence of antigen and immune complex production.[17]

T cells have long been thought to play a central role in SLE pathogenesis, and T cells from patients with lupus show defects in both signaling and effector function.[18, 19] These T cells secrete less interleukin (IL)-2, and one defect in signaling seems to be linked to an increase in calcium influx, possibly due to changes in the CD3 signaling subunits. The following seem to be adversely affected in T cells from patients with SLE: effector activity such as CD8 cytotoxicity; T-regulatory, B-cell help; migration; and adhesion.

However, the method by which each of these deficits contributes to the exact clinical syndrome seen in an individual patient is still unknown. These T-cell abnormalities are currently being explored as targets for therapy, as seen with the recent approval of belimumab, which targets the B-lymphocyte stimulator (BLys) signaling pathway.[18, 19]

Many clinical manifestations of SLE are mediated by circulating immune complexes that form with antigens in various tissues or the direct effects of antibodies to cell surface components. Immune complexes form in the microvasculature, leading to complement activation and inflammation. Moreover, antibody-antigen complexes deposit on the basement membranes of skin and kidneys. In active SLE, this process has been confirmed by demonstration of complexes of nuclear antigens such as DNA, immunoglobulins, and complement proteins at these sites.

Autoantibodies have been found to be biomarkers for future neuropsychiatric events in SLE. A prospective study (=10 years) of 1047 SLE patients demonstrated that individuals who had evidence of lupus anticoagulant (LA) had an increased future risk of intracranial thrombosis and that those with anti-ribosomal P antibodies had an increased future risk of lupus psychosis.[20]

Serum antinuclear antibodies (ANAs) are found in nearly all individuals with active SLE. Antibodies to native double-stranded DNA (dsDNA) are relatively specific for the diagnosis of SLE. Whether polyclonal B-cell activation or a response to specific antigens exists is unclear, but much of the pathology involves B cells, T cells, and dendritic cells. Cytotoxic T cells and suppressor T cells (which would normally down-regulate immune responses) are decreased. The generation of polyclonal T-cell cytolytic activity is impaired. Helper (CD4+) T cells are increased. A lack of immune tolerance is observed in animal lupus models. Reports pointing to important roles of interferon-alpha, transcription factors, and signaling variations also point to a central role for neutrophils.[21]

Genetics

There is a clear genetic component in SLE, with a sibling risk ratio 8-fold to 29-fold higher than that in the general population and a 10-fold increase in disease concordance in identical twins. In addition, there is a 24-56% concordance rate in monozygotic twins, compared with a 2-5% risk in dizygotic twins.[22]

Although some single genes have been implicated to play a causative role in SLE, current knowledge points toward a large number of genes being involved in a multifactorial-type inheritance pattern in most patients.[23, 24] Genome-wide association studies have identified more than 60 risk loci for SLE susceptibility across populations, with most of the genetic risk shared across borders and ethnicities.[25]

Many of the loci with a strong association with SLE are involved in the immune and related biologic systems.[22] Genes previously associated with other autoimmune diseases have been associated with SLE (eg, PTPN22 and diabetes; STAT4 and rheumatoid arthritis).

Genetic studies point to disruptions in lymphocyte signaling, interferon response, clearance of complement and immune complexes, apoptosis, and DNA methylation.[26] Several genes associated with T-cell function and signaling have been associated with SLE, including PTPN22, TNFSF4, PDCD1, IL10, BCL6, IL16, TYK2, PRL, STAT4, and RASGRP3, as have immune-complex processing and innate immunity genes, including several complement genes (eg, C2, C4A, and C4B).[27]

A meta-analysis of the association of interferon regulatory factor 5 (IRF5) with SLE found that a specific T allele, IRF5 rs2004640, is significantly associated with SLE in populations of European, Asian, and Latin American origins, whereas the A allele IRF5 rs10954213 is associated with SLE in patients of European origin but not in those of Asian origin.[28] Overall, the IRF5 gene polymorphism was found to be associated with SLE in multiple ethnic populations. The results also offer insights into the epigenetics of SLE:

Hypomethylation (a form of epigenetic modification) of genes involved in osmotic lysis, apoptosis, inflammation, and cytokine pathways, among other immunologic functions, have been associated with SLE.[28, 29]

The higher risk of developing SLE in women and in men with Klinefelter syndrome (ie, genotype XXY) may relate to enhanced expression of toll-like receptor 7 (TLR7), a key pathogenic factor in SLE that is encoded on an X chromosome locus. Souyris et al reported that in both women and males with Klinefelter syndrome, substantial fractions of primary B lymphocytes, monocytes, and plasmacytoid dendritic cells express TLR7 on both X chromosomes, leading to greater immunoglobulin secretion.[30]

For further discussion, see Genetics of Systemic Lupus Erythematosus

Etiology

Although the specific cause of SLE is unknown, multiple genetic predispositions and gene-environment interactions have been identified (see the chart in the image below). This complex situation perhaps explains the variable clinical manifestations in persons with SLE.

In systemic lupus erythematosus (SLE), many geneti In systemic lupus erythematosus (SLE), many genetic-susceptibility factors, environmental triggers, antigen-antibody (Ab) responses, B-cell and T-cell interactions, and immune clearance processes interact to generate and perpetuate autoimmunity. HLA = human leukocyte antigen; UV = ultraviolet light.

SLE has a modest recurrence rate in families: 8% of affected patients have at least one first-degree family member (parents, siblings, and children) with SLE; this is in contrast to 0.08% of the general population.[31] In addition, SLE occurs in both twins in 25% of identical twins and 5-10% of nonidentical twins, which may be due to a combination of genetic and environmental factors.[12]

Some studies have synthesized what is known about the mechanisms of SLE disease and genetic associations.[10, 26, 32] At least 35 genes are known to increase the risk of SLE.[26] A genetic predisposition is supported by 40% concordance in monozygotic twins; if a mother has SLE, her daughter's risk of developing the disease has been estimated to be 1:40, and her son's risk, 1:250.[26, 32]

A genome-wide study in a northern European population replicated the association of SLE with susceptibility genes related to B-cell receptor pathway signaling, as well as confirmed the association of SLE with genes at the interferon regulatory factor 5 (IRF5)-TNPO3 locus.[33] The investigators also confirmed other loci associations with SLE (TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542); however, those loci had a lower significance level and a lower contribution to individual risk for SLE.[33]

Studies of human leukocyte antigens (HLAs) reveal that HLA-A1, HLA-B8, and HLA-DR3 are more common in persons with SLE than in the general population. The presence of the null complement alleles and congenital deficiencies of complement (especially C4, C2, and other early components) are also associated with an increased risk of SLE.

Numerous studies have investigated the role of infectious etiologies that may also perpetuate autoimmunity.[34] Patients with SLE have higher titers of antibodies to Epstein-Barr virus (EBV), have increased circulating EBV viral loads, and make antibodies to retroviruses, including antibodies to protein regions homologous to nuclear antigens. In patients with SLE and EBV infection, the B cells are not primarily defective; rather, the SLE/EBV phenomenon is due to a T-cell abnormality, which causes failure in normal immunoregulation of the B-cell response.[35] Viruses may stimulate specific cells in the immune network. Chronic infections may induce anti-DNA antibodies or even lupuslike symptoms, and acute lupus flares often follow bacterial infections.

A study by Manfredo Vieira et al found that in a mouse strain that is predisposed to autoimmunity, translocation of a gut pathobiont, Enterococcus gallinarum, to the liver and other systemic tissues (as might occur with loss of integrity of the gut barrier) triggers autoimmune responses. in a genetic background predisposing to autoimmunity. In this model, antibiotic treatment prevented mortality in this model, suppressed growth of E gallinarum in tissues, and eliminated pathogenic autoantibodies and T cells.[36]

Furthermore, these researchers recovered E gallinarum–specific DNA from liver biopsies of autoimmune patients, and found that cocultures of human hepatocytes with E gallinarum induced autoimmune-promoting factors, replicating the murine findings. Those results suggest that similar processes occur in susceptible humans.[36]

Environmental and exposure-related causes of SLE are less clear. Possible early-life risk factors include the following[37] :

  • Low birthweight (< 2,500 g)
  • Preterm birth (≥1 month early)
  • Childhood exposure to agricultural pesticides

Other potential factors include the following:

  • Silica dust and cigarette smoking may increase the risk of developing SLE

  • Estrogen use in postmenopausal women appears to increase the risk of developing SLE.

  • Photosensitivity is clearly a precipitant of skin disease

  • Ultraviolet light stimulates keratinocytes, which leads not only to overexpression of nuclear ribonucleoproteins (snRNPs) on their cell surfaces but also to the secretion of cytokines that simulate increased autoantibody production.[38]

  • Breastfeeding is associated with a decreased risk of developing SLE

Pregnancy can be a time when lupus initially presents or flares, although more recent data suggests that pregnancy outcomes are favorable and flares are infrequent among patients with inactive or stable mild-moderated SLE.[39]

Vitamin D is involved in both in both innate and acquired immunity, and vitamin D deficiency has been implicated in autoimmunity and the development of rheumatic diseases, including SLE.[40, 41] Young et al studied 436 individuals who reported having a relative with SLE but who did not have SLE themselves, and found that the combination of vitamin D deficiency and carriage of specific single-nucleotide polymorphisms was associated with significantly increased risk of transitioning to SLE.[42] Hu et al reported that in an Asian population, carriage of certain polymorphisms in the vitamin D receptor gene BsmI (Bb + BB genotype and B allele) can significantly increase risk for developing SLE.[43]

Epidemiology

United States statistics

Estimates of the annual incidence of SLE from the 1970s to 2000s have ranged from approximately 1 to 10 per 100,000 population, while the prevalence of SLE has been estimated to range from approximately 5.8 to 130 per 100,000 population.[44]

The Lupus Foundation of America estimates prevalence to be at least 1.5 million cases,[45] which likely reflects inclusion of milder forms of the disease. A 2008 report from the National Arthritis Data Working Group estimated a prevalence of 161,000 cases of definite SLE and 322,000 cases of definite or probable SLE.[46]

The frequency of SLE varies by race and ethnicity, with higher rates reported in blacks and Hispanics. A study in the predominantly white population of Olmsted County, Minnesota found an age-adjusted prevalence of 30.5 per 100,000 population.[44] In a study of a racially diverse population in Michigan, the prevalence of SLE was 2.3-fold higher in blacks than in whites; in that study, the age-adjusted prevalence of lupus in blacks was 105.8 or 103 per 100,000 population, depending on whether the ACR or a rheumatologiist's definition of SLE was used.[47]

Registries have been established in San Francisco and New York City to provide annual prevalence estimates for Hispanics and Asians,[48] but a  2001 study found a prevalence of 100 per 100,000 Hispanics in Nogales, Arizona.[49]

In the Michigan study, the prevalence of SLE was 10-fold higher in females than in males and was over twice as high in black females as in white females, reaching 1 in 537 among black females.[47] SLE is also more frequent in Asian women than in white women.[50]

International statistics

Worldwide, the prevalence of SLE varies. The highest rates of prevalence have been reported in Italy, Spain, Martinique, and the United Kingdom Afro-Caribbean population.[51] Although the prevalence of SLE is high in black persons in the United Kingdom, the disease is rarely reported in blacks in Africa, suggesting that there may be an environmental trigger, as well as a genetic basis, for disease in the UK population.[52]

Race-, sex-, and age-related demographics

Worldwide, the prevalence of SLE appears to vary by race. However, there are different prevalence rates for people of the same race in different areas of the world. The contrast between low reported rates of SLE in black women in Africa and high rates in black women in the United Kingdom suggests that there are environmental influences.[52] In general, black women have a higher rate of SLE than women of any other race, followed by Asian women and then white women.[51]

In the United States, black women are  two to four times more likely to have SLE than white women.[47, 51] A review of SLE across Asia-Pacific countries revealed considerable variation in prevalence and survival rates.[53] For example, overall prevalence rates ranged from 4.3 to 45.3 per 100,000, and the overall incidence ranged from 0.9 to 3.1 per 100,000 per year. Moreover, Asians with SLE had higher rates of renal involvement than whites did, and cardiovascular involvement was a leading cause of death in Asians.[53]

Female-to-male ratio

More than 90% of cases of SLE occur in women, frequently starting at childbearing age.[34, 54] The use of exogenous hormones has been associated with lupus onset and flares, suggesting a role for hormonal factors in the pathogenesis of the disease.[55] The risk of SLE development in men is similar to that in prepubertal or postmenopausal women. Interestingly, in men, SLE is more common in those with Klinefelter syndrome (ie, genotype XXY). In fact, a study by Dillon et al found that men with Klinefelter syndrome had a more severe course of SLE than women but a less severe course than other men.[56]

The female-to-male ratio peaks at 11:1 during the childbearing years.[57] A correlation between age and incidence of SLE mirrors peak years of female sex hormone production. Onset of SLE is usually after puberty, typically in the 20s and 30s, with 20% of all cases diagnosed during the first 2 decades of life.[58]

A review of the worldwide literature (predominantly North America, Europe, and Asia) found that the incidence of pediatric-onset SLE ranged from 0.36 to 2.5 per 100,000 per year and the prevalence ranged from 1.89 to 25.7 per 100,000.[59]

The prevalence of SLE is highest in women aged 14 to 64 years. SLE does not have an age predilection in males, although it should be noted that in older adults, the female-to-male ratio falls.[60] This effect is likely due to loss of the estrogen effect in older women.

Prognosis

Systemic lupus erythematosus (SLE) carries a highly variable prognosis for individual patients. The natural history of SLE ranges from relatively benign disease to rapidly progressive and even fatal disease. SLE often waxes and wanes in affected individuals throughout life, and features of the disease vary greatly between individuals.

The disease course is milder and survival rate higher in persons with isolated skin and musculoskeletal involvement than in those with renal disease[61] and CNS disease.[62] A consortium report of 298 SLE patients followed for 5.5 years noted falls in SLE Disease Activity Index 2000 (SLEDAI-2K) scores after the first year of clinical follow-up and gradual increases in cumulative mean Systemic Lupus International Collaborating Clinics (SLICC) damage index scores.[63]

It is important to distinguish between the disease activity and the damage index (irreversible organ dysfunction). Although the most effective instrument to measure SLE disease activity is still open to debate, there are several validated measures, including the Systemic Lupus Activity Measure (SLAM), SLEDAI, Lupus Activity Index (LAI), European Consensus Lupus Activity Measurement (ECLAM), and British Isles Lupus Activity Group (BILAG) Index.

Prognostic factors from the 2008 European League Against Rheumatism (EULAR) recommendations included the following[64] :

  • Clinical findings: Skin lesions, arthritis, serositis, neurologic manifestations such as seizures and psychosis, and renal involvement

  • Diagnostic study results: Anemia, thrombocytopenia, leukopenia, increased serum creatinine levels

  • Immunologic test results: Serum C3 and C4 concentration (which may be low), as well as the presence of anti–double-stranded DNA (anti-dsDNA), anti-Ro/ Sjögren syndrome A (SSA), anti-La/Sjögren syndrome B (SSB), and antiphospholipid (aPL), and anti-ribonucleoprotein (anti-RNP)

Mortality

Mortality in patients with SLE has decreased over the past few decades.[65] Prior to 1955, the 5-year survival rate in SLE was less than 50%; currently, the average 10-year survival rate exceeds 90%,[66, 62] and the 15-year survival rate is approximately 80%.[67] Previously, mortality was due to the disease itself; currently, mortality is often a result of medication side effects (eg, fatal infections in individuals receiving potent immunosuppressive medications) or cardiovascular events.

Ten-year survival rates in Asia and Africa are significantly lower than those in the United States, ranging from 60-70%,[68, 69] but this may reflect detection bias of severe cases only.

Decreased mortality rates associated with SLE can be attributed to earlier diagnosis (including milder cases), improvement in disease-specific treatments, and advances in general medical care. According to the Centers for Disease Control and Prevention (CDC), however, 35% of SLE-related deaths in the United States occur in patients younger than 45 years, making this a serious issue despite declining overall mortality rates.[48]

The EULAR task force also identified the following comorbidities as increasing the risk of morbidity and mortality in patients with SLE[64] :

  • Infections

  • Hypertension

  • Lipid disorders (dyslipidemia), atherosclerosis, and coronary heart disease

  • Diabetes mellitus

  • Bone-related conditions: Osteoporosis; avascular bone necrosis

  • Malignancies such as non-Hodgkin lymphoma, lung cancer, and hepatobiliary cancer

In 1976, Urowitz first reported bimodal mortality in early versus late SLE, noting that SLE-related deaths usually occurred within the first 5-10 years of symptom onset.[70] Mortality in the first few years of illness is typically from severe SLE disease (eg, CNS, renal, or cardiovascular involvement) or infection related to immunosuppressive treatment. Infections account for 29% of all deaths in these patients.[71]

Late deaths (after age 35 years) are generally from myocardial infarction or stroke secondary to accelerated atherosclerosis[65, 72, 66, 73] ; inflammation is central to SLE pathogenesis and plays a major role in the development and accelerated progression of atherosclerosis. Manzi et al reported that women aged 35-44 years with SLE were 50 times more likely to develop myocardial ischemia than healthy Framingham study control women.[72] The presence of lupus nephritis may increase these risks.[74] The presence of traditional and nontraditional risk factors increases the risk of cardiovascular (CVD) disease in patients with SLE.

In a study by Petri et al that evaluated a large sample of SLE patients, the investigators reported that more than 50% of these patients had at least 3 classic cardiac risk factors, with the most common ones being a sedentary lifestyle, obesity, and hypercholesterolemia.[75] In another study, Salmon et al found that nontraditional CVD risk factors in SLE patients included having higher homocysteine levels, renal impairment, enhanced LDL oxidation, and chronic inflammation.[76]

Causes of accelerated coronary artery disease in persons with SLE are likely multifactorial. They include endothelial dysfunction, inflammatory mediators, corticosteroid-induced atherogenesis, and dyslipidemia.

The influence of race on prognosis has been widely debated. The LUMINA study group examined SLE in black, white, and Hispanic patients in the United States (including Puerto Rico) and reported that both disease activity and poverty predicted higher mortality in racial and ethnic minorities.[77] In the Michigan Lupus Epidemiology and Surveillance program, the proportion of patients with renal disease was 2.2-fold higher, and that of progression to end-stage renal disease was 3.4-fold higher, in blacks than in whites.[47]  

Patient Education

Stress the importance of adherence to medications and follow-up appointments for detection and control of SLE disease. Instruct patients with SLE to seek medical care for evaluation of new symptoms, including fever. Advise them regarding their heightened risks for infection and cardiovascular disease. Educate patients with SLE regarding aggressive lipid and blood pressure goals to minimize the risk of coronary artery disease.

Instruct patients with SLE to avoid exposure to sunlight and ultraviolet light. Also, encourage them to receive nonlive vaccines during stable periods of disease, to quit smoking, and to carefully plan pregnancies.

For patient education information, see the Arthritis Center, as well as Lupus (Systemic Lupus Erythematosus.

See also the American College of Rheumatology’s patient fact sheets for SLE, Systemic Lupus Erythematosus in Children and Teens, and Antiphospholipid Syndrome.

 

Presentation

History

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that can affect almost any organ system. Its presentation and course are highly variable, ranging from indolent to fulminant.

In a meta-analysis that reviewed the clinical manifestations of childhood-onset and adult-onset SLE, there were several statistically significant clinical symptoms more commonly found in childhood-onset SLE, including malar rash, ulcers/mucocutaneous involvement, renal involvement, proteinuria, urinary cellular casts, seizures, thrombocytopenia, hemolytic anemia, fever, and lymphadenopathy. Raynaud pleuritis and sicca were twice as common in adults as in children and adolescents.[1]

The classic presentation of a triad of fever, joint pain, and rash in a woman of childbearing age should prompt investigation into the diagnosis of SLE.[2, 3] However, patients may present with any of the following types of manifestations[4] :

  • Constitutional

  • Musculoskeletal

  • Dermatologic

  • Renal

  • Neuropsychiatric

  • Pulmonary

  • Gastrointestinal

  • Cardiac

  • Hematologic

In patients with suggestive clinical findings, a family history of autoimmune disease should raise further suspicion of SLE.

Constitutional

Fatigue, fever, arthralgia, and weight changes are the most common symptoms in new cases or recurrent active SLE flares. Fatigue, the most common constitutional symptom associated with SLE, can be due to active SLE, medications, lifestyle habits, or concomitant fibromyalgia or affective disorders.

SLE-specific fatigue or fever generally occurs in concert with other clinical markers. Fever may reflect active SLE, infection, and reactions to medications (ie, drug fever). Always exclude an infectious etiology; patients with SLE are considered immunocompromised and are therefore at higher risk for developing infections and complications. Most infections are bacterial in origin, but clinicians should always consider the possibility of atypical and opportunistic infections, particularly when these individuals are receiving immunomodulating or immunosuppressive therapy. Careful history taking may help differentiate between the potential causes of fatigue or fever. Note that an acute infectious process may also trigger SLE and that the two can occur concomitantly.

Weight loss may occur in patients with active SLE. Weight gain may also be due to corticosteroid treatment or active disease, such as nephrotic syndrome (with anasarca) or myocarditis.

Musculoskeletal

Joint pain is one of the most common reasons for the initial clinical presentation of patients with SLE. Arthralgia, myalgia, and frank arthritis may involve the small joints of the hands, wrists, and knees (usually symmetrical, polyarticular). In contrast to rheumatoid arthritis, SLE arthritis or arthralgia may be asymmetrical, with pain that is disproportionate to swelling.

SLE arthropathy is rarely erosive or deforming. Characteristic hand deformities are swan neck deformities that result from recurrent synovitis and inflammation of the joint capsule, tendons, and ligaments. These deformities are usually reducible and nonerosive (resembling Jaccoud arthropathy, which is a nonerosive arthritis following acute rheumatic fever).

Another important consideration is the increased prevalence of avascular necrosis (AVN) in the SLE population relative to healthy individuals. It may be due to SLE pathogenesis and/or concomitant heavy steroid use.[78] Asymptomatic AVN is seen in up to 44% of SLE patients in the first year of therapy with high-dose corticosteroids. The most commonly affected site is the femoral head.[78] Independent risk factors for AVN in patients with SLE include the use of glucocorticosteroid or cytotoxic agents and the presence of arthritis.[79]

Dermatologic

Cutaneous manifestations of SLE include 3 American College of Rheumatology (ACR) lupus diagnostic criteria: malar rash, photosensitivity, and discoid lupus.

The first criterion is a malar rash[80] characterized by an erythema over the cheeks and nasal bridge (but sparing the nasolabial folds, which is in contrast to the rash of dermatomyositis) (see the image below). It lasts from days to weeks and is occasionally painful or pruritic.

The classic malar rash, also known as a butterfly The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.

The second diagnostic feature is photosensitivity, which may be either acute or chronic.[80] The history of photosensitivity may be elicited from patients by asking if they have had any unusual rash or symptom exacerbation after sun exposure, with expected duration of approximately 2 days in classic cases.

The third feature is discoid lupus, a chronic lupus rash.[80] Discoid lesions often also develop in sun-exposed areas but are plaquelike in character, with follicular plugging and scarring. They may be part of systemic lupus or may represent discoid lupus without organ involvement, which is a separate diagnostic entity. Discoid lesions can develop in up to 25% of patients with SLE; a small case series suggested that the presence of such lesions may indicate milder disease or less renal involvement.[81] In another review, it was reported that patients with discoid lesions rarely progressed to systemic SLE disease; there is a 5% risk of discoid lupus disease developing into the systemic condition.[82]

Subacute cutaneous lupus is a rash seen in up to 10% of SLE cases, but importantly, 50% of patients with this condition will have it in isolation without systemic lupus.[80] The characteristic lesion appearance is an annular or psoriaform patch with crusted margins. Lesions often occur on the limbs or torso in sun-exposed areas. Alopecia is an often less specific cutaneous feature of SLE. It often affects the temporal regions or creates a patchy pattern of hair loss.

Other cutaneous manifestations related to, but not specific to, SLE include the following:

  • Raynaud phenomenon

  • Livedo reticularis

  • Panniculitis (lupus profundus)

  • Bullous lesions

  • Vasculitic purpura

  • Telangiectasias

  • Urticaria

Renal

The kidney is the most commonly involved visceral organ in SLE. Although only approximately 50% of patients with SLE develop clinically evident renal disease, biopsy studies demonstrate some degree of renal involvement in most patients.[83] Therefore, it is important to correctly classify the extent of renal involvement in SLE to improve the correlation between histologic findings and the prognosis of the renal disease (see Biopsies and Histologic Features under Workup).Glomerular disease usually develops within the first few years of SLE onset and is often asymptomatic.

Acute or chronic renal failure may cause symptoms related to uremia and fluid overload. Acute nephritic disease may manifest as hypertension and hematuria. Nephrotic syndrome may cause edema, weight gain, or hyperlipidemia.

For additional information, see the Medscape Reference article Lupus Nephritis.

Neuropsychiatric

The CNS lupus nomenclature has been revised to catalog many manifestations.[84, 85, 86] Because of the difficulty distinguishing causal SLE associations with some neurologic symptoms, only seizure and psychosis were typically included in the diagnostic criteria. Seizures related to SLE may be generalized or partial and may precipitate status epilepticus. Psychosis may manifest as paranoia or hallucinations.

However, the American College of Rheumatology (ACR) created standardized case definitions and diagnostic testing recommendations for 19 neuropsychiatric syndromes in SLE, including seizures/seizure disorders and psychosis.[87] The remainder of the neuropsychiatric syndromes are as follows[87] :

  • Acute confusional state

  • Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre syndrome)

  • Anxiety disorder

  • Aseptic meningitis

  • Autonomic disorder

  • Cerebrovascular disease

  • Cognitive dysfunction

  • Cranial neuropathy

  • Demyelinating syndrome

  • Headache

  • Mononeuropathy (single/multiplex)

  • Mood disorders

  • Movement disorder (chorea)

  • Myasthenia gravis

  • Myelopathy

  • Plexopathy

  • Polyneuropathy

Delirium represents a spectrum of fluctuating altered consciousness characteristic of SLE. Delirium may be caused by CNS vasculitis, encephalopathy, cerebritis, or the manifestations previously called organic brain syndrome. Aseptic meningitis, myelopathy, optic neuropathy, or other demyelinating disorders may also require urgent evaluation.

Transverse myelitis with spastic paraparesis and sensory loss at a given level is a rare but severe complication of SLE or antiphospholipid antibody syndrome. Stroke and transient ischemic attack (TIA) may be related to antiphospholipid antibody syndrome or SLE vasculitis. Posterior reversible encephalopathy syndrome (PRES) is, as the name implies, a reversible encephalopathy linked to hypertension that even may be a presenting feature for young SLE patients.[88]

Cognitive disorders may be variably apparent in many patients with SLE. Formal neuropsychiatric testing reveals deficits in 21-67% of patients with SLE. Whether this represents true encephalopathy, neurologic damage, medication effects, depression, or some other process is unclear. A 2010 multicenter study found that depression was associated with significantly poorer cognitive function in 111 patients newly diagnosed with SLE.[89]

Migraine headaches may be linked to antiphospholipid syndrome. Headache and mood disorders may be the most commonly reported neurologic manifestation of SLE, but cause and effect may be difficult to distinguish.

Acute psychiatric manifestations in CNS lupus should be considered as a diagnosis of exclusion in an SLE patient.

For additional information, see the Medscape Reference article Neurologic Manifestations of Systemic Lupus Erythematosus.

Pulmonary

Pulmonary features of SLE may manifest acutely or indolently, representing a spectrum of SLE complications. SLE may lead to multiple pulmonary complications, including pleurisy, pleural effusion, pneumonitis, pulmonary hypertension, and interstitial lung disease. The chronic steroids prescribed to patients also place them at increased risk for atypical infections.

Pleuritis is one of the formal diagnostic criteria for SLE, and it can induce chest pain and a pleural effusion. The pleural effusion in lupus is exudative, with an elevated lactate dehydrogenase level. Pleurisy with pleuritic chest pain with or without pleural effusions is the most common feature of acute pulmonary involvement in SLE. Shortness of breath or dyspnea may be due to many causes. Pulmonary embolism, lupus pneumonitis, chronic lupus interstitial lung disease, pulmonary hypertension, complement-mediated pulmonary leukoaggregation, alveolar hemorrhage, or infection may be related to lupus disease.

Most seriously, hemoptysis may herald diffuse alveolar hemorrhage, a rare, acute, life-threatening pulmonary complication of SLE.

Gastrointestinal

In general, gastrointestinal symptoms secondary to SLE are less common than adverse effects of medication or nonspecific complaints. Special consideration should be given to infectious causes (bacterial, viral [eg, CMV]), because of immunosuppression. Nausea and dyspepsia are common symptoms in patients with active SLE and are sometimes difficult to correlate with objective evidence of gastrointestinal involvement. Peptic ulcer disease is a common complication, especially in SLE patients treated with nonsteroidal anti-inflammatory agents (NSAIDs) and glucocorticoids.[90]

Occasional abdominal pain in active SLE may be directly related to active lupus, including peritonitis, pancreatitis, mesenteric vasculitis, and bowel infarction. Jaundice due to autoimmune hepatobiliary disease may also occur.

Cardiac

Heart failure or chest pain must be carefully assessed in patients with SLE. Pericarditis is the most common cardiac feature of SLE, manifesting as positional chest pain that is often relieved when the patient leans forward. Myocarditis may occur in SLE with heart failure symptoms. Pulmonary hypertension may present with indolent chest pain or dyspnea.

Coronary vasculitis manifesting as angina or infarction is rarely reported. Libman-Sacks endocarditis is noninfectious but may manifest as symptoms similar to those of infective endocarditis in patients with SLE or antiphospholipid syndrome. More commonly, accelerated ischemic coronary artery disease (CAD) is associated with SLE and may present indolently as atypical anginal equivalents.

Hematologic

A history of multiple cytopenias such as leukopenia, lymphopenia, anemia, or thrombocytopenia may suggest SLE, among other etiologies, such as medication-related cytopenias. Leukopenia and, more specifically, lymphopenia are common in SLE; this, coupled with immunosuppression, may predispose persons with SLE to frequent infections.

Anemia is occasionally overlooked in young menstruating women, and a history of lymphopenia may be overlooked. Thrombocytopenia may be mild or part of a full thrombotic thrombocytopenic purpura (TTP)–like syndrome or antiphospholipid antibody syndrome. A history of recurrent early miscarriages or a single late pregnancy loss may be clues to lupus or isolated antiphospholipid antibody syndrome.[91]

Physical Examination

Almost any organ system can be involved in active SLE. The constellation of several physical findings may suggest a diagnosis of SLE. The American College of Rheumatology (ACR) diagnostic criteria are discussed in Workup. Examination findings are discussed by system.[4]

Fever is a challenging problem in SLE. It can be a manifestation of active lupus, infection, malignancy, or a drug reaction. Low-grade fever is observed in patients on immunosuppressive agents, and lymphadenopathy or splenomegaly may be found.

In patients with fever, infectious causes—both viral and bacterial—need to be ruled out. Lupus patients may be functionally asplenic and may be at risk for encapsulated bacterial infections such as meningococcemia. Patients with SLE who are on immunosuppressive therapy are at a higher risk of death due to viral infection (eg, herpes simplex virus [HSV], cytomegalovirus [CMV], varicella-zoster virus [VZV]) and should be treated accordingly if an infection is suspected.[92] An infection can mimic a lupus flare, and delays in diagnosis and treatment can increase the risk of mortality.[93]

A postdiagnostic 5-year follow-up study showed that males had a higher prevalence of thromboses, nephropathy, strokes, gastrointestinal symptoms, and antiphospholipid syndrome and that females were more likely to present with arthralgia, hair loss, Raynaud syndrome, and photosensitivity.[94] In addition, male patients were more likely to present with tendonitis, myositis, nephropathy, and respiratory tract infections.

Skin and mucous membrane findings

Malar rash is a fixed erythema that typically spares the nasolabial folds. It is a butterfly-shaped rash that can be flat or raised over the cheeks and bridge of the nose (see the images below).

The classic malar rash, also known as a butterfly The classic malar rash, also known as a butterfly rash, with distribution over the cheeks and nasal bridge. Note that the fixed erythema, sometimes with mild induration as seen here, characteristically spares the nasolabial folds.
Dermatomyositis. Acute onset of confluent macular Dermatomyositis. Acute onset of confluent macular erythema in a periorbital and malar distribution (involving the cheeks and extending over the nasal bridge), with extension to the chin in a female with juvenile dermatomyositis. Note the perioral sparing. In some patients, there may be more extensive involvement of the face, including the perioral region, forehead, lateral face, and ears. In contrast to SLE , in dermatomyositis with malar erythema, the nasolabial folds are often not spared.

Photosensitive rash is often macular or diffusely erythematous in sun-exposed areas of the face, arms, or hands and generally persists for more than 1 day (see the image below).

Photosensitive systemic lupus erythematosus (SLE) Photosensitive systemic lupus erythematosus (SLE) rashes typically occur on the face or extremities, which are sun-exposed regions. Although the interphalangeal spaces are affected, the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints are spared. Photo courtesy of Dr. Erik Stratman, Marshfield Clinic.

Discoid rash occurs in 20% of patients with SLE and can result in disfiguring scars. The discoid rash can present as erythematous patches with keratotic scaling over sun-exposed areas of the skin. Follicular plugging may create scarring that may be well demonstrated in the ears. Systemic manifestations of SLE may be absent (ie, limited discoid lupus).

Lupus should be considered in all patients who experience oral, or less frequently, vaginal ulcers; ulcers classically occur more than 3 times per year and are painless. Palatal ulcers are most specific for SLE.

Many other cutaneous findings are not explicitly diagnostic features but support impressions of SLE. Alopecia in SLE often causes hair loss at the temporal regions or creates a patchy pattern. Vascular lesions such as livedo reticularis (characterized by a lacy, mottled, erythematous skin pattern), periungual erythema (as seen in nailfold capillaroscopy, which can be performed with an ophthalmoscope to search for dilated capillary nailfold loops), telangiectasias, and Raynaud phenomenon (blue, white, and red color changes at the distal digital tips) may develop in some patients with SLE or antiphospholipid antibody syndrome. However, these are nonspecific findings, as they can occur in other connective tissue disorders with prominent vascular involvement, such as scleroderma and dermatomyositis. Panniculitis, bullous lesions, vasculitic purpura, and urticaria are other skin lesions that are sometimes seen in SLE.

Musculoskeletal

Arthritis of the proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints of the hands, as well as the wrists, is the most common musculoskeletal finding in SLE. Tenderness, edema, and effusions accompany a polyarthritis that is symmetric, nonerosive, and usually nondeforming. Jaccoud arthropathy is the term used to describe the nonerosive hand deformities due to chronic arthritis and tendonitis that develop in 10% of patients with SLE.

Myositis may manifest as weakness in SLE but is more commonly related to overlap syndromes or corticosteroid-induced myopathy. Fibromyalgia, distinguished as myofascial tenderness without weakness, is commonly concomitant with SLE, causing generalized widespread pain, arthralgia, and myalgia.

With focal pain in areas such as the hips, knees, and shoulders, consider avascular necrosis in patients who are taking glucocorticoids. Consider septic arthritis when one joint is inflamed out of proportion to all other joints or if fever is present.

Renal

Hypertension or hematuria may signal nephritic SLE. Edema of periorbital or peripheral regions, anasarca, and morning presacral edema upon arising from bed are common physical findings related to nephrotic syndrome or volume overload with renal failure. Specific signs and symptoms of renal disease may not be apparent until advanced nephrotic syndrome or renal failure is present; therefore, it is important to obtain a urine analysis, protein estimate, serum BUN, and creatinine level on a regular basis.

Neuropsychiatric

About 28-40% of neuropsychiatric SLE findings arise before or around the time of diagnosis.[95] Headache is the most commonly seen CNS finding in SLE, occurring in 39-61% of adults and 72% of children,[95] but it is nonspecific. Altered mental status in SLE may be secondary to aseptic meningitis, seizures, psychosis, or organic brain syndrome. All types of seizures have been reported, with the most frequent being grand mal seizure. Sensory or sensorimotor neuropathies occur.

Mononeuritis may manifest as the functional loss of one or a few isolated peripheral nerves and is observed in some patients with SLE vasculitis or antiphospholipid disease. Deficits below a dermatomal level or spastic paraparesis should raise consideration of transverse myelitis. Focal neurologic deficits may represent stroke, transient ischemic attack (TIA), or mononeuritis. The incidence of stroke is high in SLE, and those with antiphospholipid antibodies are at higher risk for such events.

Cardiopulmonary

Pleuropericardial friction rubs and signs of effusions may be found. Tachypnea, cough, and fever are common manifestations of lupus pneumonitis. Hemoptysis may signify pulmonary hemorrhage secondary to the disease. However, infection is the most common cause of infiltrates seen on radiographs. Hemodynamic instability and hypoxia may suggest pulmonary embolism. Heart failure signs or arrhythmias may point to ischemia or inflammatory myocarditis.

Systolic murmurs are reported in up to 70% of cases. Murmurs may represent Libman-Sacks endocarditis, superimposed infective endocarditis, thromboembolic disease, or demand-related phenomena in fever, hypoxia, or anemia. Digital infarcts and splinter hemorrhages may be observed with Libman-Sacks endocarditis. Pulmonary hypertension may be evidenced by a loud P2 heart sound.

Pulmonary hypertension, vasculitis with digital infarcts, and splinter hemorrhages may be observed.

Pericarditis has an incidence of 20-30% and is the most common presentation of heart involvement clinically, although examination rubs are less common. It is usually associated with small effusions, but it may involve larger effusions when uremia is concomitant. Myocarditis can cause heart failure symptoms and arrhythmias.

Gastrointestinal

Occasionally, abdominal tenderness and pain may be linked to peritonitis, pancreatitis, mesenteric vasculitis, or non–lupus-related processes. Lupus peritonitis is a less-common serositis that may be present, even in the absence of ascites.

Ophthalmologic

Funduscopic examination is important in patients with visual complaints. Slit-lamp examinations are recommended every 6 months for SLE patients who are on hydroxychloroquine to screen for the rare side effect of maculopathy. Retinal vasculitis can lead to blindness and is demonstrated by sheathed narrow retinal arterioles with white exudates adjacent to the vessels. SLE-associated optic neuritis is uncommon, but it should be considered in patients with vision loss.[96]

Diagnostic Criteria for SLE

Table 1, below, lists the 1997 update of the American College of Rheumatology (ACR) criteria for the diagnosis of systemic lupus erythematosus (SLE).[97, 5, 6]

Table 1. Updated American College of Rheumatology Diagnostic Criteria for SLE (Open Table in a new window)

Criterion

Definition

SLE can be diagnosed if any 4 or more of the following 11 criteria are present, serially or simultaneously, during any interval of observation.

1. Malar rash

Fixed, flat or raised erythema over the malar eminences, tending to spare the nasolabial folds

2. Discoid rash

Erythematous raised patches with adherent keratotic scaling and follicular plugging (older lesions may demonstrate atrophic scarring)

3. Photosensitivity

Skin rash as a result of unusual reaction to sunlight, by patient history or physician observation

4. Oral ulcers

Oral or nasopharyngeal ulceration, usually painless, observed by a physician

5. Arthritis

Nonerosive arthritis involving =2 peripheral joints, characterized by tenderness, swelling, or effusion

6. Serositis

(A) Pleuritis: Convincing history of pleuritic pain or rub heard by a physician or evidence of pleural effusion

or

(B) Pericarditis: Documented by ECG or rub or evidence of pericardial effusion

7. Renal disorder

(A) Persistent proteinuria >0.5 g/day or >3+ if quantitation not performed

or

(B) Cellular casts: May be red blood cell, hemoglobin, granular, tubular, or mixed

8. Neurologic disorder

(A) Seizures: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)

or

(B) Psychosis: In the absence of offending drugs or known metabolic derangements (eg, uremia, ketoacidosis, electrolyte imbalance)

9. Hematologic disorder

(A) Hemolytic anemia: With reticulocytosis

or

(B) Leukopenia: < 4000/mm3 total on =2 occasions

or

(C) Lymphopenia: < 1500/mm3 on =2 occasions

or

(D) Thrombocytopenia: < 100,000/mm3 in the absence of offending drugs

10. Immunologic disorder

(A) Anti-DNA: Antibody to native DNA in abnormal titer

or

(B) Anti-Sm: Presence of antibody to Smith (Sm) nuclear antigen

or

(C) Positive finding of antiphospholipid antibodies based on (1) an abnormal serum level of IgG or IgM anticardiolipin antibodies, (2) a positive test result for lupus anticoagulant using a standard method, or (3) a false-positive serologic test for syphilis known to be positive for =6 months and confirmed by Treponema pallidum immobilization or fluorescent treponemal antibody absorption tests

11. Antinuclear antibody (ANA)

An abnormal titer of antinuclear antibody by immunofluorescence or an equivalent assay at any point in time and in the absence of drugs known to be associated with drug-induced lupus syndrome

Sources: (1.) American College of Rheumatology. 1997 Update of the 1982 American College of Rheumatology revised criteria for classification of systemic lupus erythematosus. Available at: http://tinyurl.com/zrfsuhs Accessed: September 19, 2016[97] ; (2.) Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. Sep 1997;40(9):1725.[5]

ECG = electrocardiogram; Ig = immunoglobulin; SLE = systemic lupus erythematosus.

 

 

In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE classification criteria. The SLICC classification criteria expand the number of criteria from 11 to 17, adding numerous acute and chronic rashes, as well as alopecia, additional neurologic manifestations, hypocomplementemia, and direct Coomb test positivity. The SLICC classify a person as having SLE in the presence of biopsy-proven lupus nephritis with ANA or anti–double-stranded DNA (anti-dsDNA) antibodies or if 4 of their 17 diagnostic criteria, including at least 1 clinical and 1 immunologic criterion.[7]

 

DDx

Diagnostic Considerations

Before making a diagnosis of systemic lupus erythematosus (SLE), ruling out drugs as the cause of the condition is important. Many pharmacologic agents have been associated with a lupuslike syndrome (see see Drug-Induced Lupus Erythematosus), but procainamide, hydralazine, and isoniazid have been studied the most extensively. Many patients who take these medications have positive antinuclear antibody test results and other serologic findings. Only a few have the clinical manifestations. Drug-induced lupus differs from SLE by the following features:

  • Sex ratios are nearly equal

  • Antibodies to histones are usually found in 80-90%

  • Nephritis and central nervous system features are not commonly present

  • There are no antibodies to native DNA or hypocomplementemia

  • Discontinuation of the drug leads to resolution of clinical manifestations and reversion of abnormal laboratory values to normal

A syndrome of drug-induced SLE has been observed with minocycline and propylthiouracil. Both drugs have a decreased frequency of antihistone antibodies and anti–double-stranded DNA antibodies, and results for antineutrophil cytoplasmic antibodies are sometimes positive. Anti-TNF drugs are reported to cause severe drug-induced lupus, including production of many SLE autoantibodies and, rarely, even nephritis.[98]

Other problems to be considered in the differential diagnosis of SLE include the following:

  • Discoid skin lesions

  • Erythematous macules

  • Interstitial lung disease

  • Leukemia

  • Leukopenia

  • Parvovirus or other viral infections

  • Photodistributed rash

  • Pleuritic chest pain

  • Pneumonitis

  • Polyarthritis/polyarthralgia

  • Renal vasculitis

  • Seizures

  • Stroke

  • Thrombocytopenia

  • Vasculitis

Differential Diagnoses

 

Workup

Approach Considerations

The diagnosis of systemic lupus erythematosus (SLE) must be based on the proper constellation of clinical findings and laboratory evidence. Familiarity with the diagnostic criteria helps clinicians to recognize SLE and to subclassify this complex disease based on the pattern of target-organ manifestations.

The 1982 American College of Rheumatology (ACR) criteria summarized features necessary to diagnose SLE.[97, 5] These criteria were last updated in 1997.[5, 6] The presence of 4 of the 11 criteria yields a sensitivity of 85% and a specificity of 95% for SLE (see Table 1). Keep in mind that individual features are variably sensitive and specific. Patients with SLE may present with any combination of clinical features and serologic evidence of lupus.

The Systemic Lupus International Collaborating Clinics (SLICC) group revised and validated the ACR SLE classification criteria in 2012.[7] According to the revision, a patient is classified as having SLE if the patient has biopsy-proven lupus nephritis with ANA or anti-dsDNA antibodies or if the patient satisfies 4 of the diagnostic criteria (see below), including at least 1 clinical and 1 immunologic criterion.[7]

Also in 2012, the ACR published “ Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in Adults,” as well as an evidence report for lupus nephritis.[99]

ACR mnemonic of SLE diagnostic criteria

The following are the ACR diagnostic criteria in SLE, presented in the "SOAP BRAIN MD" mnemonic:

  • Serositis - Pleurisy, pericarditis on examination or diagnostic electrocardiogram (ECG) or imaging

  • Oral ulcers - Oral or nasopharyngeal, usually painless; palate is most specific

  • Arthritis - Nonerosive, 2 or more peripheral joints with tenderness or swelling

  • Photosensitivity - Unusual skin reaction to light exposure

  • Blood disorders - Leukopenia (< 4 × 103 cells/µL on >1 occasion), lymphopenia (< 1500 cells/µL on >1 occasion), thrombocytopenia (< 100 × 103 cells/µL in the absence of offending medications), hemolytic anemia

  • Renal involvement – Based on presence of proteinuria (>0.5 g/day or 3+ positive on dipstick testing) or cellular casts (including red blood cells [RBCs], hemoglobin, granular, tubular, or mixed)[99] or based on the opinion of a rheumatologist or nephrologist[99]

  • Antinuclear antibodies (ANAs) - Higher titers generally more specific (>1:160); must be in the absence of medications associated with drug-induced lupus

  • Immunologic phenomena - dsDNA; anti-Smith (Sm) antibodies; antiphospholipid antibodies (anticardiolipin immunoglobulin G [IgG] or immunoglobulin M [IgM] or lupus anticoagulant); biologic false-positive serologic test results for syphilis, lupus erythematosus (LE) cells (omitted in 1997 revised criteria)

  • Neurologic disorder - Seizures or psychosis in the absence of other causes

  • Malar rash - Fixed erythema over the cheeks and nasal bridge, flat or raised

  • Discoid rash - Erythematous raised-rimmed lesions with keratotic scaling and follicular plugging, often scarring

In patients with high clinical suspicion and/or high ANA titers, additional testing is indicated. This commonly includes evaluation of antibodies to dsDNA, complement, and ANA subtypes such as Sm, SSA, SSB, and ribonucleoprotein (RNP) (often called the ENA panel), as well as screening anticardiolipin antibodies, lupus anticoagulant, and +/- beta-2 glycoprotein antibodies.

Diagnostic Studies

Standard laboratory studies that are diagnostically useful when systemic lupus erythematosus (SLE) is suspected should include the following:

  • Complete blood count (CBC) with differential

  • Serum creatinine

  • Urinalysis with microscopy

The CBC count may help screen for leukopenia, lymphopenia, anemia, and thrombocytopenia. Urinalysis and creatinine studies may be useful to screen for kidney disease.

Other laboratory tests that may be used in the diagnosis of SLE are as follows:

  • Erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP)

  • Complement levels

  • Liver function tests

  • Creatine kinase assay

  • Spot protein/spot creatinine ratio

Levels of inflammatory markers, including the ESR and CRP, may be elevated in any inflammatory condition, including SLE. However, the level of ESR elevation may show a discrepancy relative to a normal CRP level in SLE flares; if both markers are markedly elevated, suspect the presence of an infectious process. CRP levels change more acutely, and the ESR lags behind disease changes.

Measurement of complement may be useful, because C3 and C4 levels are often depressed in patients with active SLE as a result of consumption by immune complex–induced inflammation. In addition, some patients have congenital complement deficiency that predisposes them to SLE.

Liver test results may be mildly elevated in acute SLE or in response to therapies such as azathioprine or nonsteroidal anti-inflammatory drugs (NSAIDS). Creatine kinase levels may be elevated in myositis or overlap syndromes.

The spot protein/spot creatinine ratio may be used to quantify proteinuria. The 2012 ACR guidelines for lupus nephritis indicate that a spot protein/spot creatinine ratio greater than 0.5 g/day can substitute for the 24-hour protein measurement and that an active urinary sediment (defined as >5 red blood cells [RBCs] per high-power field [hpf]; >5 white blood cells [WBCs]/hpf in the absence of infection; or cellular casts limited to RBC or WBC casts) can substitute for cellular casts.[99]

Autoantibody tests

Table 3, below, summarizes the autoantibody tests that are used in the diagnosis of SLE.[100]

Table 3. Autoantibody Tests for SLE (Open Table in a new window)

Test

Description

ANA

Screening test; sensitivity 95%; not diagnostic without clinical features

Anti-dsDNA

High specificity; sensitivity only 70%; level is variable based on disease activity

Anti-Sm

Most specific antibody for SLE; only 30-40% sensitivity

Anti-SSA (Ro) or Anti-SSB (La)

Present in 15% of patients with SLE and other connective-tissue diseases such as Sjögren syndrome; associated with neonatal lupus

Anti-ribosomal P

Uncommon antibodies that may correlate with risk for CNS disease, including increased hazards of psychosis in a large inception cohort, although the exact role in clinical diagnosis is debated[101]

Anti-RNP

Included with anti-Sm, SSA, and SSB in the ENA profile; may indicate mixed connective-tissue disease with overlap SLE, scleroderma, and myositis

Anticardiolipin

IgG/IgM variants measured with ELISA are among the antiphospholipid antibodies used to screen for antiphospholipid antibody syndrome and pertinent in SLE diagnosis

Lupus anticoagulant

Multiple tests (eg, direct Russell viper venom test) to screen for inhibitors in the clotting cascade in antiphospholipid antibody syndrome

Direct Coombs test

Coombs test–positive anemia to denote antibodies on RBCs

Anti-histone

Drug-induced lupus ANA antibodies are often of this type (eg, with procainamide or hydralazine; p-ANCA–positive in minocycline-induced drug-induced lupus)

ANA = antinuclear antibody; CNS = central nervous system; ds-DNA = double-stranded DNA; ELISA = enzyme-linked immunoassay; ENA = extractable nuclear antigen; Ig = immunoglobulin; p-ANCA = perinuclear antineutrophil cytoplasmic antibody; RBCs = red blood cells; RNP = ribonucleic protein; SLE = systemic lupus erythematosus; Sm = Smith; SSA = Sjögren syndrome A; SSB = Sjögren syndrome B.

Radiologic Studies

Joint radiography often provides little evidence of systemic lupus erythematosus (SLE), even in the presence of Jaccoud arthropathy with deformity or subluxations. The most common radiographs in SLE show periarticular osteopenia and soft-tissue swelling without erosions.

Chest imaging studies include radiography (see the first image below) and computed tomography (CT) scanning (see the second image below). These modalities can be used to monitor interstitial lung disease and to assess for pneumonitis, pulmonary emboli, and alveolar hemorrhage.

The chest x-ray from a patient with lupus demonstr The chest x-ray from a patient with lupus demonstrates a right-sided pleural effusion (yellow arrow) and atelectasis with scarring in the left lung base (blue arrow). In severe complications, a fibrothorax may develop.
Vasculitis, antiphospholipid antibodies, and renal Vasculitis, antiphospholipid antibodies, and renal failure are commonly found in patients with lupus; these conditions greatly increase the risk of developing pulmonary emboli. The diagnosis in a patient with shortness of breath, hemoptysis, and pleuritic chest pain is commonly made with ventilation-perfusion scans or computed tomography (CT) angiography. The CT angiogram demonstrates a filling defect in the left anterior segmental artery (arrow).

Echocardiography is used to assess for pericardial effusion, pulmonary hypertension, or verrucous Libman-Sacks endocarditis (see the image below).

Libman-Sacks endocarditis is the most characterist Libman-Sacks endocarditis is the most characteristic cardiac manifestation of lupus. It is characterized by clusters of verrucae on the ventricular surface of the mitral valve. These lesions consist of accumulation of immune complexes, platelets, and mononuclear cells. This can lead to heart failure, valvular dysfunction, emboli, and secondary infective endocarditis. Diagnosis is best made via echocardiography, which may reveal the characteristic valvular masses (arrows). IVS = interventricular septum; LA = left atrium; LV = left ventricle.

Brain magnetic resonance imaging (MRI)/magnetic resonance angiography (MRA) is used to evaluate for central nervous system (CNS) lupus white-matter changes (see the following image), vasculitis, or stroke, although findings are often nonspecific and may be absent in as many as 42% of cases with neuropsychiatric symptoms.[102]

This axial, T2-weighted brain magnetic resonance i This axial, T2-weighted brain magnetic resonance image (MRI) demonstrates an area of ischemia in the right periventricular white matter of a 41-year-old woman with long-standing systemic lupus erythematosus (SLE). She presented with headache and subtle cognitive impairments but no motor deficits. Faintly increased signal intensity was also seen on T1-weighted images, with a trace of enhancement following gadolinium that is too subtle to show on reproduced images. Distribution of the abnormality is consistent with occlusion of deep penetrating branches, such as may result from local vasculopathy, with no clinical or laboratory evidence of lupus anticoagulant or anticardiolipin antibody. Cardiac embolus from covert Libman-Sacks endocarditis remains less likely due to distribution.

Investigators have suggested that cardiac MRI (CMR) provides an excellent alternative to clinical assessment, electrocardiography, and echocardiography for diagnosing SLE myocarditis.[103] They reported that patients who were positive for infectious myocarditis on CMR were more symptomatic than those with active SLE disease and that more than 50% of patients with CMR-positive myocarditis had a concurrent positive endomyocardial biopsy.[103]

Joint Effusion and CSF Studies

Arthrocentesis

Arthrocentesis may be performed in patients with joint effusions, which can be inflammatory or noninflammatory. The cell count may range from less than 25% polymorphonuclear neutrophils (PMNs) in noninflammatory effusions to more than 50% in inflammatory effusions. Viscosity will be high in noninflammatory effusions and low in inflammatory effusions. The gross appearance of these fluids will be straw-colored or clear in noninflammatory cases and either cloudy or yellow in inflammatory ones.

Lumbar puncture

Lumbar puncture may be performed to exclude infection with fever or neurologic symptoms. Nonspecific elevations in cell count and protein level and decrease in glucose level may be found in the cerebrospinal fluid of patients with central nervous system lupus.

Biopsies and Histologic Features

Renal biopsies

The 2012 American College of Rheumatology (ACR) guidelines for lupus nephritis recommend renal biopsy for all cases of active, previously untreated lupus nephritis, unless contraindicated.[99] Renal biopsy is used to confirm the presence of lupus nephritis; to aid in classification of systemic lupus erythematosus (SLE) nephritis based on the International Society of Nephrology/Renal Pathology Society (ISN/RPS) classification (see Table 4, below); and to guide therapeutic decisions.[99] Another benefit of renal biopsy is in distinguishing renal lupus from renal vein thrombosis, which may be a complication of antiphospholipid antibody syndrome and require anticoagulation rather than immunomodulatory therapy.

Renal biopsy is indicated in the presence of the following features[99] :

  • Increasing serum creatinine in the absence of strong evidence for another etiology (eg, sepsis, hypovolemia, medication)

  • Proteinuria of more than 1.0 g per 24 hours, as confirmed by 24-hour urine specimens or spot protein/spot creatinine ratios

  • Proteinuria of 0.5 g or more per 24 hours, along with either (1) hematuria (≥5 RBCs/hpf) or (2) cellular casts, as confirmed by a minimum of 2 tests within a short period and in the absence of alternative causes

The ISN/RPS published revisions to the World Health Organization (WHO) classification for lupus nephritis in 2003. The classification is based on light microscopy, electron microscopy, and immunofluorescence findings from renal biopsy results, as summarized in the table below.[104]

Table 4. International Society of Nephrology 2003 Revised Classification of SLE Nephritis (Open Table in a new window)

Class

Classification

Features

Class I

Minimal mesangial

Normal light microscopy findings; abnormal electron microscopy findings

Class II

Mesangial proliferative

Hypercellular on light microscopy

Class III

Focal proliferative

< 50% of glomeruli involved

Class III lupus nephritis is further subclassified as follows:

  • Class III (A), focal proliferative: Active lesions

  • Class III (A/C), focal proliferative and sclerosing: Active and chronic lesions

  • Class III (C ) (focal sclerosing): Chronic lesions

Class IV

Diffuse proliferative

=50% of glomeruli involved; classified segmental or global; treated aggressively

Class IV lupus nephritis is also further subclassified, as follows:

  • Class IV-S: Diffuse segmental proliferative

  • Class IV-G: Diffuse global proliferative

  • Class IV-S or IV-G, active (A) or chronic (C)

Note: It remains to be determined whether further subcategories have a prognostic difference.[105] There are conflicting data from studies; some investigators report that class IV-G (A) has a better prognosis relative to class IV-S (A/C), which is less responsive to treatment.

Class V

Membranous

Predominantly nephrotic disease

Note: Class V may occur with class III or IV (then, both cases would be diagnosed)[99]

Class VI

Advanced sclerosing

=90% of glomeruli involved without residual activity[99]

Chronic lesions and sclerosis

Source (except as noted otherwise) : Weening JJ, D'Agati VD, Schwartz MM, et al. The classification of glomerulonephritis in systemic lupus erythematosus revisited. J Am Soc Nephrol. Feb 2004;15(2):241-50.[106]

SLE = systemic lupus erythematosus.

Histologic images of a normal renal cortex and of various stages of SLE are shown below.

Histologic image of a normal renal cortex, includi Histologic image of a normal renal cortex, including the glomerulus (1) and proximal (2) and distal (3) convoluted tubule. [Image from Wikipedia: http://en.wikipedia.org/wiki/File:Histology-kidney.jpg]
Mesangial proliferative lupus nephritis with moder Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
Focal lupus nephritis. International Society of Ne Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
Membranous lupus nephritis showing thickened glome Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).

Skin biopsies

Skin biopsy can help in diagnosing SLE or unusual rashes in patients with this condition. Many different rashes may herald SLE, making review by a dermatopathologist important.

Lupus skin rash often demonstrates inflammatory infiltrates at the dermoepidermal junction and vacuolar change in the basal columnar cells. Discoid lesions demonstrate more-significant skin inflammation, with hyperkeratosis, follicular plugging, edema, and mononuclear cell infiltration at the dermoepidermal junction. In many SLE rashes, immunofluorescent stains demonstrate immunoglobulin and complement deposits at the dermoepidermal basement (see the images below).

Lupus band test. Microphotograph of a histologic s Lupus band test. Microphotograph of a histologic section of human skin prepared for direct immunofluorescence using an anti-IgG antibody. The skin is from a patient with systemic lupus erythematosus and shows IgG deposit at 2 different places: the first is a band-like deposit along the epidermal basement membrane ("lupus band test" is positive); the second is within the nuclei of the epidermal cells (anti-nuclear antibodies).
Microphotograph of a fixed Hep-2 line cell prepare Microphotograph of a fixed Hep-2 line cell prepared for indirect immunofluorescence. The preparation was exposed to a serum of a patient with systemic lupus erythematosus and labeled using a murine anti-human immunoglobulin G (IgG) antibody. It shows IgG deposit in the nucleus and nonspecific deposit in the cytoplasm.
 

Treatment

Approach Considerations

Management of systemic lupus erythematosus (SLE) often depends on disease severity and disease manifestations,[8] although hydroxychloroquine has a central role for long-term treatment in all SLE patients. The LUMINA (Lupus in Minorities: Nature versus Nurture) study and other trials have offered evidence of a decrease in flares and prolonged life in patients given hydroxychloroquine, making it the cornerstone of SLE management.[107]

In general, cutaneous manifestations, musculoskeletal manifestations, and serositis represent milder disease, which may wax and wane with disease activity. These are often controlled with nonsteroidal anti-inflammatory drugs (NSAIDS) or low-potency immunosuppression medications beyond hydroxychloroquine and/or short courses of corticosteroids. More prolonged steroid use is generally reserved for patients with involvement of vital organs. For example, central nervous system involvement and diffuse proliferative renal disease must be recognized as more severe disease manifestations, and these are often treated with more aggressive immunosuppression. Evidence suggests a relative undertreatment of SLE patients with end-stage renal disease (ESRD), because the extent of lupus activity may be underestimated.[108]

EULAR recommendations

In 2007, the European League Against Rheumatism (EULAR) released recommendations for the treatment of SLE.[64] In patients with SLE without major organ manifestations, glucocorticoids and antimalarial agents may be beneficial.[64] NSAIDs may be used for short periods in patients at low risk for complications from these drugs. Consider immunosuppressive agents (eg, azathioprine, mycophenolate mofetil, methotrexate) in refractory cases or when steroid doses cannot be reduced to levels for long-term use.[109]

EULAR recommendations for the management of SLE with neuropsychiatric manifestations support the evaluation and treatment of these symptoms in the same way as they are evaluated and treated in patients without SLE; if symptoms persist, management of these symptoms as an extension of SLE should be considered.[86, 64] For example, in patients with neuropsychiatric manifestations that may have an inflammatory etiology, immunosuppressive agents may be considered.[64]

Other guidelines

In 2009, an American College of Rheumatology (ACR) Task Force generated a quality indicator set.[110] In 2012, the ACR published “ Guidelines for the Screening, Diagnosis, Treatment and Monitoring of Lupus Nephritis in Adults,” as well as an evidence report for lupus nephritis. These and other guidelines are available at the ACR's Clinical Practice Guidelines Web site.

Adjunctive therapies

Vitamin D insufficiency and deficiency are more common in patients with SLE than in the general population.[111] Vitamin D supplementation may decrease disease activity and improve fatigue.[112, 113] In addition,supplementation may improve endothelial function, which may reduce cardiovascular disease.[114, 115, 116]

No diet-based treatment of SLE has been proven effective. Patients with SLE should be reminded that activity may need to be modified as tolerated. Specifically, stress and physical illness may precipitate SLE flares. Additionally, persons with SLE should wear sunscreen and protective clothing or avoid sun exposure to limit photosensitive rash or disease flares.

Consultations

The multisystemic nature of SLE often requires involvement of consultants, depending on the organ system involved. Consultation with any of the following specialists may be necessary:

  • Rheumatologist
  • Infectious disease specialist
  • Neurologist
  • Pulmonologist
  • Cardiologist
  • Gastroenterologist
  • Nephrologist
  • Dermatologist
  • Hematologist
  • High-risk obstetrician

Biologic DMARD Therapy

Belimumab

The monoclonal antibody belimumab (Benlysta), a B-lymphocyte stimulator–specific inhibitor, has been found to reduce disease activity and possibly decrease the number of severe flares and steroid use in patients with SLE when used in combination with standard therapy.[117] In March, 2011, the US Food and Drug Administration (FDA) approved the use of belimumab in combination with standard therapies (including steroids, nonbiologic DMARDS [eg, hydroxychloroquine, azathioprine, methotrexate]) to treat active autoantibody-positive SLE.[118]  In July 2017, a subcutaneous (SC) formulation was approved that allows patients to self-administer a once-weekly dose.[119]

Patients of African-American or African descent did not show significant responses to belimumab in phase III post-hoc analysis, but those studies were not powered to assess for this effect; in a phase II trial, blacks had a greater treatment response. These results indicate that the benefits of belimumab in SLE patients remain inconclusive and that further investigation is needed. Patients with severe active lupus nephritis or CNS lupus or patients previously treated with other biologics or cyclophosphamide have been excluded from participation in early trials.

The SLE Responder Index (SRI) is a tool that was developed following phase II trials and is composed of the following scores[120] :

  • SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus: National Assessment– Systemic Lupus Erythematosus Disease Activity Index)

  • BILAG (British Isles Lupus Assessment Group)

  • PGA (physician global assessment)

SRI response is defined by the following[120] :

  • A 4-point or greater reduction in the SELENA-SLEDAI score

  • No new BILAG A or no more than 1 new BILAG B domain score

  • No deterioration from baseline in the PGA by 0.3 or more points.

A multinational phase III study (BLISS-52) that evaluated the efficacy and safety of IV belimumab, in 867 patients with a minimum SELENA-SLEDAI score of 6, reported that patients given belimumab had significantly higher SRI scores at 52 weeks than did those given placebo.[121] All groups had similar rates of adverse events.

Similarly, a phase III trial of 819 SLE patients who were positive for either antinuclear antibody or anti–double-stranded DNA at baseline screening found that IV belimumab at 10 mg/kg plus standard therapy resulted in a significantly greater SRI score (43.2%) than placebo (33.5%) at 1 year (those who received belimumab 1 mg/kg plus standard therapy had a 40.6% response rate).[122] Overall, the addition of belimumab to standard therapy reduced SLE disease activity and severe flares, and the medication was well tolerated.[122]

Approval for SC belimumab was based on the BLISS-SC phase III study (n=839), which documented reduction in disease activity at week 52 in patients receiving belimumab plus standard of care, compared with those receiving placebo plus standard of care. SRI response with belimumab versus placebo was 61.4% vs 48.4%, respectively (P = 0.0006). In the belimumab group, both time to and risk of severe flare were improved (median 171 days vs 118 days; P = 0.0004), and more patients were able to reduce their corticosteroid dosage by ≥25% (to ≤7.5 mg/day) during weeks 40-52 (18.2% vs 11.9%; P = 0.0732), compared with placebo.[123]

Rituximab

B-cell depletion with rituximab (Rituxan) has been used successfully for rheumatoid arthritis, but studies have shown mixed results for the treatment of SLE. An open study using rituximab showed positive results as rescue therapy for patients with active SLE who were unresponsive to standard immunosuppressant therapy.[124]

There have also been case reports of patients with severe refractory SLE in which off-label use of rituximab showed benefits with tolerable safety profiles.[125, 126, 127] For example, in a retrospective study of 115 patients with severe or refractory SLE, 40% of patients had a complete response and 27% had a partial response, as measured by BILAG scores recorded 6 months after the first rituximab treatment.[128]

However, three placebo-controlled studies, including the Exploratory Phase II/III SLE Evaluation of Rituximab [EXPLORER] trial and the Lupus Nephritis Assessment with Rituximab [LUNAR] trial,[129, 130] failed to show an overall significant response. Despite the negative results in these trials, rituximab continues to be used to treat patients with severe SLE disease that is refractory to standard therapy.

Pharmacologic agents targeting specific pathways such as cytokines and complement, as well as combinations of rituximab with costimulatory inhibition with anti-CD40L or CTLA-4Ig, may prove to be more effective in treating SLE.[131]

Emergency Department Management

Acute emergencies in patients with systemic lupus erythematosus (SLE) include the following:

  • Severe neurologic involvement

  • Systemic vasculitis

  • Profound thrombocytopenia with a thrombotic thrombocytopenia (TTP)–like syndrome

  • Rapidly progressive glomerulonephritis

  • Diffuse alveolar hemorrhage[132]

These conditions may be treated with high-dose intravenous steroids and cytotoxic therapy such as cyclophosphamide. Strokes, acute myocardial infarctions, and pulmonary emboli occurring as complications of SLE are managed in the same way as they are in patients without SLE. In patients who present with fever, it may be necessary to limit immunosuppression to steroids and to empirically treat for an infection until culture results have been received.

In rare cases, diffuse alveolar hemorrhage may require plasma exchange, or profound steroid-refractory thrombocytopenia may require therapy with intravenous immunoglobulin (IVIG). Catastrophic antiphospholipid antibody syndrome also requires aggressive acute management.

For more information, see the Medscape article Antiphospholipid Syndrome.

Hospitalization

Fever in patients with systemic lupus erythematosus (SLE) is grounds for hospital admission because of the difficulty of distinguishing a disease flare from infection in these immunocompromised hosts. Patients with SLE are often complement deficient and functionally asplenic; therefore, they are at particular risk for infections with encapsulated organisms. For example, meningococcemia in young females with lupus may be catastrophic.

Although it is known that chronically low complement levels and functional asplenia may result in a low level of susceptibility to infection, it is not known to what degree.[133, 134] Overall, it is likely that the primary reason patients with SLE die of infections is immunosuppressive medications.Stress-dose steroid protocols should be used in patients who are receiving maintenance corticosteroids when they are admitted with infectious or perioperative stress.

Central nervous system lupus with depressed consciousness or alveolar hemorrhage may prompt transfer to an intensive care unit and consideration of protective intubation. Thrombotic thrombocytopenic purpura and catastrophic antiphospholipid antibody syndrome should prompt transfer to a center capable of offering plasma exchange therapy.

For more information, see the Medscape articles Neurologic Manifestations of Systemic Lupus Erythematosus and Thrombotic Thrombocytopenic Purpura.

Lupus Nephritis

The 2012 American College of Rheumatology (ACR) guidelines for lupus nephritis recommend that treatment of this condition be largely based on classification by the International Society of Nephrology/Renal Pathology Society (ISN/RPS) histologic criteria (see Biopsies and Histologic Features).[99]

Lupus nephritis is managed with a combination of glucocorticoids[135] and immunosuppressive agents to slow the progression to end-stage renal disease (ESRD), along with maintaining normal blood pressure levels (ie, target of ≤130/80 mm Hg).[64, 99] In general, individuals with class I or II lupus nephritis do not need management with immunosuppression.[99]

Patients with class III or IV disease, as well as those with a combination of class V and class III or IV disease, generally undergo aggressive therapy with glucocorticoid drugs and immunosuppressants.[99] Immunosuppressive therapy consists of induction and maintenance therapy. Induction therapy involves potent immunosuppressive drugs (eg, mycophenolate mofetil, cyclophosphamide) to achieve remission; these drugs are generally used for 3 months to 1 year, with an average of 6 months’ treatment having been shown to be more efficacious and safer than long-term therapy.[136]

A large randomized trial that compared induction therapy consisting of oral mycophenolate mofetil with cyclophosphamide therapy in patients with lupus nephritis showed that mycophenolate mofetil was not inferior to cyclophosphamide.[137] The investigators suggested that mycophenolate mofetil was associated with both a trend toward greater complete remissions and a greater safety profile.[137] This study’s findings were confirmed with the large, international Aspreva Lupus Management Study (ALMS) trial.[138]

Once remission is achieved, start maintenance therapy with azathioprine or mycophenolate mofetil (ie, use less potent agents relative to long-term cyclophosphamide). The ALMS maintenance trial also found that mycophenolate mofetil was superior to azathioprine in the maintenance of the renal response to treatment and in the prevention of relapse in patients with lupus nephritis.[139] In the MAINTAIN trial, there was a trend toward fewer renal flares in patients receiving mycophenolate mofetil than in those receiving azathioprine[140] ; however, these results did not reach statistical significance.

When Griffiths et al compared the corticosteroid-sparing effect of cyclosporine with azathioprine in patients with severe SLE, they concluded that azathioprine may be considered first-line therapy, whereas cyclosporine requires close monitoring of blood pressure and serum creatinine. However, the investigators noted that in patients who are unable to tolerate azathioprine, cyclosporine may be considered.[141]

Unfortunately, significant side effects are associated with cyclophosphamide-based regimens, which are the only ones with proven long-term efficacy. An alternative consideration is mycophenolate mofetil, which may be as effective as pulse cyclophosphamide but with less severe adverse effects. In refractory cases (lack of treatment response by 6 months), consider intensifying therapy with mycophenolate mofetil.[64]

In patients with SLE and nephritis who progress to end-stage renal disease, dialysis and transplantation may be required; these treatments have rates of long-term patient and graft survival that are similar to those observed in patients without diabetes and SLE.[64] However, transplantation is considered the treatment of choice because of improved survival rates.[64]

For more information, see Lupus Nephritis.

Adjunctive therapy

Unless contraindicated, hydroxychloroquine should be used as adjunctive therapy in lupus nephritis because of the potential for reduction in rates of disease flare; damage accrual, ,including renal damage; and risk of thrombotic events.[99]

Administer angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) to all patients with lupus nephritis (except pregnant women) who have proteinuria of 0.5 g or more per 24 hours (or equivalent by protein/creatinine ratios on spot urine tests).[99] This treatment has been reported to not only reduce proteinuria by about 30% but also significantly delay the doubling of serum creatinine and the progression to ESRD (in patients with nondiabetic chronic renal disease).[142]

Statin therapy is recommended in patients with low-density lipoprotein cholesterol (LDL-C) levels greater than 100 mg/dL because both renal dysfunction alone and SLE alone are independent risk factors for accelerated atherosclerosis.[99]

Antiphospholipid Syndrome

In patients with systemic lupus erythematosus (SLE), the presence of antiphospholipid antibodies is common; depending on the assay, these antibodies have been reported in up to 30-50% of SLE patients.[143] Therefore, it is important to evaluate these patients for risk factors for thrombosis, such as use of estrogen-containing drugs, being a smoker, immobility, previous surgery, and the presence of severe infection or sepsis.[64] The European League Against Rheumatism (EULAR) has noted that low-dose aspirin in individuals with SLE and antiphospholipid antibodies is potentially useful for primary prevention of thrombosis and pregnancy loss.[64]

Secondary prevention of thrombosis in nonpregnant patients with SLE and thrombosis associated with antiphospholipid syndrome can be managed with long-term use of oral anticoagulants.[64] In pregnant patients with SLE and antiphospholipid syndrome, unfractionated or low-molecular-weight heparin and aspirin may reduce the risk of pregnancy loss.

For additional information, see Antiphospholipid Syndrome and Systemic Lupus Erythematosus and Pregnancy.

SLE in Pregnancy

Fertility rates in women with systemic lupus erythematosus (SLE) may be similar to those in the general population. However, the incidence of spontaneous abortion, premature labor, early preeclampsia/eclampsia, fetal growth restriction, and intrauterine death are somewhat higher in women with SLE,[64, 144] especially in those with SSA(Ro)/SSB(La) antibodies, antiphospholipid antibodies,[91] or lupus nephritis.[142] One study suggested that women with SLE have fewer live births than the general population.[145] In this study, decreased live births were associated with exposure to cyclophosphamide and high SLE disease activity.

SLE can also flare during or after pregnancy. Whether flares of SLE are more frequent during pregnancy is controversial. The flares do not seem to be exceedingly more serious than those in nonpregnant patients, although pregnancy outcomes are generally more likely to be complicated. Increased rates of hypertension during pregnancy, premature delivery, unplanned cesarean delivery, postpartum hemorrhage, and maternal venous thromboembolism are all more frequent in women with SLE.

To minimize complications in pregnancy, SLE ideally should be well controlled for at least 4-6 months before conception. Obstetricians who handle high-risk pregnancies should optimally offer pregnancy planning consultation and monitor all pregnancies in patients with SLE. Suggestions for treatment of SLE during pregnancy are also included in the European League Against Rheumatism (EULAR) recommendations. High-dose aspirin and NSAIDs should be avoided in later pregnancy.

The EULAR recommendations indicate that in pregnant women with SLE, prednisolone, azathioprine, hydroxychloroquine (unnecessary discontinuation of hydroxychloroquine during pregnancy may result in lupus flares), and low-dose aspirin may be used.[64] Prednisone, prednisolone, and methylprednisolone are the corticosteroids of choice during pregnancy because of their minimal placental transfer. However, mycophenolate mofetil, cyclophosphamide, and methotrexate are strictly contraindicated.[64]

Neonatal lupus erythematosus (NLE) can develop in the babies of mothers with antibodies to SSA/Ro. Neonates with NLE can present with rash around 4-6 weeks of life, elevated liver function test results, thrombocytopenia around 1-2 weeks of life, neutropenia, and hydrocephalus.[146] NLE can also manifest as a congenital atrioventricular conduction block,[147] with as many as 1-5% of pregnancies in mothers with anti- SSA/SSB antibodies leading to heart block, rising to a 6-25% risk for subsequent pregnancies after one affected child is born.[148]

For additional information, see Systemic Lupus Erythematosus and Pregnancy and Neonatal and Pediatric Lupus Erythematosus.

Prevention

Patients with SLE should be educated to avoid triggers for flare. Persons with SLE should avoid ultraviolet light and sun exposure to minimize worsening of symptoms from photosensitivity. Diet modification should be based on the disease activity. A balanced diet is important, but patients with SLE and hyperlipidemia, for example, should be placed on a low-fat diet. Many patients with SLE have low levels of vitamin D because of less sun exposure; therefore, these patients should take vitamin D supplements. Exercise is important in SLE patients to avoid rapid muscle loss, bone demineralization, and fatigue. Smoking should also be avoided.

Antimalarial therapy (hydroxychloroquine) has been shown to prevent disease flares and to decrease mortality.[107] In contrast, high rates of sulfa allergy and anecdotal reports of disease flares have led to avoidance of sulfa-based medications in patients with SLE.

Contraception and family planning are important considerations given the risks of disease flare with exogenous estrogens and pregnancy and with the teratogenic risks of some SLE drugs. Estrogen therapies have typically been avoided to prevent disease flares; progesterone-only contraception is more often considered.[149] However, studies have suggested that oral estrogen-containing contraceptives may not be associated with disease flares or thrombosis risk in patients with mild lupus without antiphospholipid antibodies.[55, 150]

Preventive measures are necessary to minimize the risks of steroid-induced osteoporosis and accelerated atherosclerotic disease.[151] The American College of Rheumatology (ACR) Guidelines for the prevention of glucocorticoid-induced osteoporosis suggest the use of traditional measures (eg, calcium, vitamin D) and the consideration of prophylactic bisphosphonate therapy.

The ACR Quality of Care statement[152] recommends annual cardiovascular disease risk assessment; some researchers suggest that the cardiovascular risk for SLE is similar to that for diabetes mellitus. The 10-year coronary event rate is 13-15% in patients with active SLE, which is comparable to the 10-year event rate of 18.8% in patients with known coronary artery disease.[153] African American patients with SLE may be particularly vulnerable to premature cardiovascular disease and related death.[154]

Angiotensin-converting enzyme (ACE) inhibitors and/or angiotensin receptor blockers may be useful in patients with renal disease. Aggressive blood pressure and lipid goals may help prevent CAD or renal disease progression.[153]

The European League Against Rheumatism (EULAR) vaccination recommendations for rheumatic diseases, including lupus, advocate baseline assessment and delivery of nonlive vaccines during stable disease.[155] Particularly important is immunization against encapsulated organisms, such as meningococcal vaccine, pneumococcal vaccine, and routine Haemophilus influenzae childhood vaccination. Annual influenza vaccine is also encouraged.

Long-Term Monitoring

Periodic follow-up and laboratory testing, including complete blood counts with differential, creatinine, and urinalyses, are imperative for detecting signs and symptoms of new organ-system involvement and for monitoring response and adverse reactions to therapies. At least quarterly visits are recommended in most cases.[156] Periodic complement levels and dsDNA titers may be used as adjuncts to clinical evaluation for detecting lupus flares.

Opportunistic infections can develop, most often in patients receiving chronic immunosuppressive therapy. Another less-common complication is osteonecrosis, especially of the hips and knees after prolonged high-dose corticosteroid usage. More commonly, premature atherosclerotic disease and myocardial infarction are indolent complications of chronic inflammation and steroids.

Vitamin D

Studies from around the world have documented a higher prevalence of vitamin D insufficiency and deficiency in patients with SLE, compared with the general population, especially in conjunction with obesity.[111, 157, 158, 159, 160, 113] Studies from Australia,[157] France,[160] the Mediterranean region,[112] and Taiwan[159] —but not from Mexico[158] —have shown an association between serum vitamin D levels and SLE disease activity.

Limited evidence suggests that supplementation may be clinically beneficial in SLE patients with low levels of vitamin D. In Mediterranean patients,  female patients who were not receiving supplemental vitamin D showed more fatigue and received more oral corticosteroids than those with normal levels of vitamin D.[112] In Australian patients, an increase in serum vitamin D levels was associated with reduced disease activity over time.[157]

A randomized, double-blind, placebo-controlled trial in 40 patients with juvenile-onset SLE suggests that cholecalciferol supplementation for 24 weeks is effective in decreasing disease activity and improving fatigue in these patients. Compared with the placebo group, patients receiving oral cholecalciferol 50,000 IU/week demonstrated significant improvement in Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores (P = 0.010) and European Consensus Lupus Activity Measurement (ECLAM) scores (P = 0.006), along with a reduction of fatigue related to social life, as measured by the Kids Fatigue Severity Scale (K-FSS) score (P = 0.008).[113]

Endothelial dysfunction and increased risk of cardiovascular disease occur in SLE.[114] In vitro and clinical studies have demonstrated a beneficial effect of vitamin D supplementation on endothelial function in SLE.[115, 116]

 

 

 

Medication

Medication Summary

Treatment of systemic lupus erythematosus (SLE) is guided by the individual patient's manifestations. Fever, rash, musculoskeletal manifestations, and serositis generally respond to treatment with hydroxychloroquine, nonsteroidal anti-inflammatory drugs (NSAIDS), and steroids in low to moderate doses, as necessary, for acute flares. Medications such as methotrexate may be useful in chronic lupus arthritis, and azathioprine and mycophenolate have been widely used in lupus of moderate severity.[161]

Central nervous system involvement and renal disease constitute more serious disease and often require high-dose steroids and other immunosuppressive agents, such as cyclophosphamide, azathioprine, or mycophenolate. Class IV diffuse proliferative lupus nephritis has also been treated with aggressive cyclophosphamide induction therapy.[162, 163] In the past several years, trials of mycophenolate have demonstrated efficacy for induction, particularly in black patients.[164, 165, 166] Rituximab trials, however, have not documented a benefit with this agent.[129, 130] The MAINTAIN trial offered data showing no statistically significant difference between mycophenolate and azathioprine for lupus nephritis maintenance.[140]

Antimalarials

Class Summary

Antimalarial agents may work through numerous proposed mechanisms in SLE, mediating subtle immunomodulation without causing overt immunosuppression. These drugs are useful in preventing and treating lupus skin rashes, constitutional symptoms, arthralgias, and arthritis; antimalarials also help to prevent lupus flares and have been associated with reduced morbidity and mortality in SLE patients followed in observational trials.[107]

Hydroxychloroquine sulfate (Plaquenil)

Hydroxychloroquine inhibits chemotaxis of eosinophils and locomotion of neutrophils and impairs complement-dependent antigen-antibody reactions. Hydroxychloroquine sulfate 200 mg is equivalent to 155 mg hydroxychloroquine base and 250 mg chloroquine phosphate. Weight-based dose adjustment and monitoring help to mitigate the risk of retinal toxicity. This agent is also commonly used for suppression and treatment of malaria.

NSAIDs

Class Summary

Nonsteroidal anti-inflammatory agents (NSAIDS) provide symptomatic relief for arthralgias, fever, headache, and mild serositis. NSAIDs may cause elevated creatinine or liver function test results in patients with active systemic lupus erythematosus. Additionally, concomitant administration with prednisone may increase the risk of gastrointestinal ulceration.

Ibuprofen (Advil, Motrin)

Ibuprofen is the drug of choice for patients with mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis.

Naproxen (Aleve, Anaprox, Naprosyn)

Naproxen is used for relief of mild to moderate pain. It inhibits inflammatory reactions and pain by decreasing activity of the enzyme cyclooxygenase, resulting in prostaglandin synthesis.

Diclofenac (Voltaren XR, Cataflam)

Diclofenac inhibits prostaglandin synthesis by decreasing activity of enzyme cyclo-oxygenase, which in turn decreases formation of prostaglandin precursors.

DMARDS, Immunomodulators

Class Summary

Disease-modifying antirheumatic drugs (DMARDS) are immunomodulatory agents that act as immunosuppressives and cytotoxic and anti-inflammatory medications. The specific agent selection is generally indicated by the patient’s organ involvement and disease severity. Due to toxicity, cyclophosphamide is reserved for severe organ-threatening disease. At the other end of the spectrum, methotrexate or azathioprine may be helpful for milder arthritis or skin disease. DMARDS can be used in patients whose condition has had an inadequate response to glucocorticoids. Azathioprine, mycophenolate, and cyclosporine have all been studied for lupus manifestations such as nephritis.

Cyclophosphamide

Cyclophosphamide is used for immunosuppression in cases of serious SLE organ involvement, especially severe CNS involvement, vasculitis, and lupus nephritis. This agent is chemically related to nitrogen mustards. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.

Methotrexate (Otrexup, Rasuvo)

Methotrexate is used for managing arthritis, serositis, cutaneous, and constitutional symptoms. It blocks purine synthesis and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), thus increasing anti-inflammatory adenosine concentration at sites of inflammation. Methotrexate ameliorates symptoms of inflammation and is particularly useful in arthritis treatment.

Azathioprine (Imuran, Azasan)

Azathioprine is an immunosuppressant and a less toxic alternative to cyclophosphamide. It is used as a steroid-sparing agent in nonrenal disease. Azathioprine antagonizes purine metabolism and inhibits synthesis of DNA, RNA, and proteins. It may decrease proliferation of immune cells, which results in lower autoimmune activity.

Mycophenolate (CellCept, Myfortic)

Mycophenolate is useful for maintenance in lupus nephritis and other serious lupus cases. This agent inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Mycophenolate also inhibits antibody production.

Immune globulin IV (IGIV) (Bivigam, Carimune, Gammagard S/D, Flebogamma, Gamunex-C)

Intravenous immune globulin is used for immunosuppression in serious SLE flares. It neutralizes circulating myelin antibodies through anti-idiotypic antibodies. This agent downregulates proinflammatory cytokines, including interferon-gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells; and augments suppressor T cells. Immune globulin also blocks complement cascade, promotes remyelination, and may increase cerebrospinal fluid IgG (10%).

Rheumatologics, Other

Class Summary

Rheumatologic agents such belimumab reduce immune response and B-cell mediated immunity.

Belimumab (Benlysta)

Belimumab inhibits the biologic activity of B-lymphocyte stimulator (BLyS); BLyS is a naturally occurring protein required for survival and for development of B-lymphocyte cells into mature plasma B cells that produce antibodies. In autoimmune diseases, elevated BLyS levels are thought to contribute to production of autoantibodies.

This agent is indicated for active, autoantibody-positive SLE that is refractory to standard therapy including hydroxychloroquine (see Treatment for more details).

Corticosteroids

Class Summary

Corticosteroid agents are used predominantly for anti-inflammatory activity and as immunosuppressants. Preparations include oral, intravenous, topical, and intra-articular injections.

Methylprednisolone (A-Methapred, Medrol, Solu-Medrol, Depo-Medrol)

Methylprednisolone is used for acute organ-threatening exacerbations. It decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Prednisone

Prednisone is an immunosuppressant for treatment of autoimmune disorders. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocytes and antibody production. Low-dose oral prednisone can be used for milder SLE, but more severe involvement necessitates high doses of oral or intravenous therapy.

DMARDs, Other

Class Summary

Rituximab is a monoclonal antibody and an immunosuppressant that eliminates mature circulating B-cells.

Rituximab (Rituxan)

B-cell depletion with rituximab has been used successfully for rheumatoid arthritis, but it has shown mixed results for the treatment of SLE. One open study using rituximab reported excellent results as rescue therapy for patients with active SLE who were unresponsive to standard immunosuppressant therapy. However, 2 large placebo-controlled studies failed to show an overall significant response. Note that rituximab has an off-label indication for SLE.