Systemic lupus erythematosus in adults: Clinical manifestations and diagnosis

INTRODUCTION — 

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown cause that can affect virtually any organ of the body. Immunologic abnormalities, especially the production of a number of antinuclear antibodies (ANA), are a prominent feature of the disease.

Patients present with variable clinical features ranging from mild joint and skin involvement to life-threatening kidney, hematologic, or central nervous system involvement. The clinical heterogeneity of SLE and the lack of pathognomonic features or tests pose a diagnostic challenge for the clinician. To complicate matters, patients may present with only a few clinical features of SLE, which can resemble other autoimmune, infectious, or hematologic diseases.

The diagnosis of SLE is generally based on clinical and laboratory findings after excluding alternative diagnoses. Serologic findings are important in suggesting the possibility of SLE, with some antibodies (eg, anti-double-stranded deoxyribonucleic acid [anti-dsDNA] and anti-Smith [anti-Sm]) highly associated with this condition. In the absence of SLE diagnostic criteria, SLE classification criteria are often used by clinicians as guidance to help identify some of the salient clinical features when making the diagnosis.

The clinical manifestations and an approach to the diagnosis of SLE will be reviewed here. Separate topic reviews related to SLE in adults include the following:

●(See "Systemic lupus erythematosus in adults: Overview of the management and prognosis".)

●(See "Systemic lupus erythematosus: Epidemiology and pathogenesis".)

●(See "Drug-induced lupus".)

The diagnosis and treatment of specific clinical manifestations of SLE are discussed separately:

●(See "Overview of cutaneous lupus erythematosus".)

●(See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus".)

●(See "Lupus nephritis: Diagnosis and classification".)

●(See "Lupus nephritis: Therapy of lupus membranous nephropathy".)

●(See "Lupus nephritis: Initial and subsequent therapy for focal or diffuse lupus nephritis".)

●(See "Systemic lupus erythematosus: Hematologic manifestations".)

●(See "Gastrointestinal manifestations of systemic lupus erythematosus".)

●(See "Systemic lupus erythematosus in adults: Coronary artery disease".)

●(See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults".)

●(See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus".)

●(See "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system".)

The approach to contraception and pregnancy in females with SLE is covered separately:

●(See "Approach to contraception in women with systemic lupus erythematosus".)

●(See "Pregnancy in women with systemic lupus erythematosus".)

CLINICAL MANIFESTATIONS

Range of symptoms — Patients with systemic lupus erythematosus (SLE) can experience a broad range of symptoms. The type and intensity of symptoms may fluctuate over time, and symptoms respond variably to systemic immunosuppression. Certain manifestations are more common at disease onset (eg, arthralgia or arthritis, rash), while others become increasingly prevalent throughout the disease course (eg, lupus nephritis [LN], Raynaud phenomenon) (table 1).

There are ongoing efforts to identify clinically meaningful subsets of patients with SLE based on the disease phenotype and/or underlying pathophysiology. One such model describes two overlapping types of SLE: type 1 SLE refers to a subset of disease manifestations that are thought to be driven by inflammation, autoimmunity, and/or organ damage (eg, LN, inflammatory arthritis, and rash), while type 2 SLE includes symptoms that are not necessarily thought to reflect inflammation and are relatively less responsive to immunosuppression (eg, fatigue, widespread pain, and mood disturbances) [1,2].

Major clinical features and organ involvement

Constitutional symptoms — Constitutional symptoms such as fatigue, fever, and weight loss are present in most patients with SLE at some point during the course of the disease.

●Fatigue – Fatigue is the most common complaint, occurring in 80 to 100 percent of patients, and can sometimes be disabling. Its presence is not clearly correlated with other measures of disease activity and is more frequently associated with depression, sleep disturbances, and concomitant fibromyalgia [3-7]. Fatigue has been described as a feature of type 2 lupus [1].

●Fever – Fever can be a manifestation of active disease and is seen in over 50 percent of patients with SLE [8]. However, in clinical practice, distinguishing fever associated with a lupus flare from other causes of fever, such as infection, a drug reaction, or malignancy, can be difficult. Clinically, there are no specific features that definitively distinguish fever due to SLE from fever due to other causes. The history may be helpful in determining the cause of the fever. As an example, fever in the setting of moderate or high doses of glucocorticoids should lead one to strongly suspect new infection, particularly if other signs of active disease are not present. Fever that does not respond to nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, and/or low to moderate doses of glucocorticoids should raise the suspicion of an infectious or drug-related etiology since most fevers due to active SLE will remit with use of these agents [9]. In addition, a low white blood cell (WBC) count in the setting of fever would be more consistent with lupus activity rather than infection. Infection should clearly be ruled out in a patient with SLE presenting with fever.

Serious infections are a major cause of morbidity among patients and should be considered in all immunocompromised SLE patients with fever. (See 'Clinical manifestations' above.)

●Myalgia – Myalgia is also common among patients with SLE, whereas severe muscle weakness or myositis is relatively uncommon. Myalgia is also a feature of type 2 SLE [1,2]. Myalgia and muscle weakness are discussed in more detail separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Muscle involvement'.)

●Weight change – Weight changes are frequent in patients with SLE and may be related to the disease or to its treatment. Weight loss often occurs prior to the diagnosis of SLE. Unintentional weight loss may be due to decreased appetite, side effects of medications (particularly diuretics and occasionally hydroxychloroquine), and gastrointestinal disease (eg, gastroesophageal reflux, abdominal pain, peptic ulcer disease, or pancreatitis) (see "Gastrointestinal manifestations of systemic lupus erythematosus"). Weight gain in SLE may be due to salt and water retention associated with hypoalbuminemia (eg, due to nephrotic syndrome or protein-losing enteropathy) or, alternatively, due to increased appetite associated with the use of glucocorticoids. (See "Overview of heavy proteinuria and the nephrotic syndrome" and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Protein-losing enteropathy'.)

Arthritis and arthralgias — Arthritis and arthralgias occur in over 90 percent of patients with SLE and are often one of the earliest manifestations [10]. Arthritis, with demonstrable inflammation, occurs in 65 to 70 percent of patients and tends to be migratory, polyarticular, and symmetrical. The arthritis is moderately painful, usually does not cause erosion, and is rarely deforming (picture 1A-B). When deformities are present, they are often reducible, in contrast to fixed deformities in conditions such as rheumatoid arthritis (RA). However, occasionally patients with SLE also develop a deforming erosive arthritis, which is similar to that of RA [11]; this condition is sometimes referred to as "rhupus" and may be associated with antibodies to citrullinated proteins (ACPAs). The clinical characteristics and management of arthritis and arthralgias in SLE are discussed in detail elsewhere. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Joint involvement'.)

Mucocutaneous involvement — Most patients develop skin and mucous membrane lesions at some point during the course of their disease. There is marked variability in the type of skin involvement in SLE. The most common lesion is a facial eruption that characterizes acute cutaneous lupus erythema (also known as "the butterfly rash") that presents as erythema in a malar distribution over the cheeks and nose (but sparing the nasolabial folds) that appears after sun exposure (picture 2A-B). Some patients may develop discoid lesions, which are more inflammatory and have a tendency to scar (picture 3A-B); in addition, discoid lesions lead to loss of pigmentation. Photosensitivity is also a common theme for skin lesions associated with SLE. The various cutaneous manifestations of SLE are presented in detail separately. (See "Overview of cutaneous lupus erythematosus".)

Many patients develop oral and/or nasal ulcers, which are usually painless in contrast to herpetic chancre blisters. Nasal ulcers may lead to nasal septal perforation. Nonscarring alopecia is also observed in many SLE patients at some point during the course of their disease. Scarring alopecia can occur in patients with discoid lupus erythematosus. (See "Overview of cutaneous lupus erythematosus", section on 'Discoid lupus erythematosus'.)

Cardiac involvement and vascular manifestations — A variety of cardiac and vascular abnormalities can occur in patients with SLE.

●Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. Pericarditis, with or without an effusion, is the most common cardiac manifestation of SLE, occurring in approximately 25 percent of patients at some point during their disease course [12]. Verrucous (Libman-Sacks) endocarditis is usually clinically silent, but it can produce valvular insufficiency and can serve as a source of emboli (picture 4). Myocarditis is uncommon but may be severe. Patients with SLE also have an increased risk of coronary artery disease. (See "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Systemic lupus erythematosus in adults: Coronary artery disease".)

Neonatal lupus, which can occur in babies of mothers with SLE expressing anti-Ro/SSA and anti-La/SSB, can cause heart block of varying degrees that may be noted in utero and/or that may present as congenital heart block and is discussed separately. (See "Neonatal lupus: Epidemiology, pathogenesis, clinical manifestations, and diagnosis".)

●Raynaud phenomenon – Raynaud phenomenon in SLE is a vasospastic process induced by cold and other factors that occurs in up to 50 percent of patients with SLE (picture 5) [8]. Raynaud phenomenon is characterized by intermittent acral pallor followed by cyanosis and erythroderma [13]. Raynaud phenomenon is discussed in detail separately. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

●Vasculitis – Estimates of the prevalence of vasculitis among SLE patients from large cohorts range from 11 to 36 percent [14]. The clinical spectrum of vasculitis in the setting of SLE is broad due to the potential for inflammatory involvement of vessels of all sizes. Small vessel involvement is the most common, often manifesting as cutaneous lesions; however, medium- and large-vessel involvement have also been observed. Cutaneous small-vessel vasculitis can manifest as palpable purpura, petechiae, papulonodular lesions, livedo reticularis, panniculitis, splinter hemorrhages, and superficial ulcerations (see "Evaluation of adults with cutaneous lesions of vasculitis"). As an example, a large series of 670 SLE patients identified vasculitis among 11 percent of patients [15]. Cutaneous lesions were the main clinical presentation of vasculitis, present in 89 percent of patients. The remaining 11 percent of patients with vasculitis had visceral involvement (eg, peripheral nerves, lung, pancreas, and kidney).

Other areas that may be affected by vasculitis in SLE include mesenteric arteries, liver, pancreas, coronary arteries, lungs, retina, and peripheral or central nervous system. A few cases of aortitis, similar to that seen in Takayasu arteritis, have been reported [16]. (See "Overview of cutaneous lupus erythematosus" and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Autoimmune hepatitis' and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Acute pancreatitis' and "Gastrointestinal manifestations of systemic lupus erythematosus", section on 'Mesenteric vasculitis/ischemia' and "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system" and "Retinal vasculitis associated with systemic disorders and infections", section on 'Systemic immune-mediated causes'.)

●Thromboembolic disease – Thromboembolic disease is a feature of SLE, particularly in the context of antiphospholipid antibodies (aPL). Although the precise mechanism is unknown, thromboembolic disease can affect both venous and arterial circulation [17,18]. As an example, in a large observational cohort of 554 newly diagnosed SLE patients followed for a median of 6.3 years, an arterial thrombotic event (ATE) occurred in 11 percent, a venous thrombotic event (VTE) occurred in 5 percent, and the estimated 10-year risks were 10 percent for VTE, 26 percent for ATE, and 33 percent for any thrombotic event [18]. Antimalarials may be protective for the development of thromboembolic disease in SLE [19].

Kidney involvement — Kidney involvement is clinically apparent in approximately 50 percent of SLE patients and is a significant cause of morbidity and mortality [20]. Thus, periodic screening for the presence of LN with urinalyses, quantitation of proteinuria, and estimation of the glomerular filtration rate is an important component of the ongoing management of SLE patients. Several forms of glomerulonephritis can occur, and kidney biopsy is useful to define the type and extent of kidney involvement. The clinical presentation of LN is highly variable, ranging from asymptomatic hematuria and/or proteinuria to nephrotic syndrome to rapidly progressive glomerulonephritis with loss of kidney function. Some patients with LN also have hypertension. (See "Lupus nephritis: Diagnosis and classification".)

Gastrointestinal involvement — Gastrointestinal symptoms are common in SLE, occurring in up to 40 percent of patients. The majority of gastrointestinal symptoms are caused by adverse medication reactions and viral or bacterial infections [21]. SLE-related gastrointestinal abnormalities can involve almost any organ along the gastrointestinal tract and include esophagitis, intestinal pseudo-obstruction, protein-losing enteropathy, lupus hepatitis, acute pancreatitis, mesenteric vasculitis or ischemia, and peritonitis. The gastrointestinal manifestations of SLE are discussed in detail elsewhere. (See "Gastrointestinal manifestations of systemic lupus erythematosus".)

Pulmonary involvement — During the course of their disease, many patients develop symptoms secondary to pulmonary involvement of SLE. Pulmonary manifestations of SLE include pleuritis (with or without effusion), pneumonitis, interstitial lung disease, pulmonary hypertension, shrinking lung syndrome, and alveolar hemorrhage. Respiratory symptoms must also be distinguished from infection, particularly in patients on immunosuppressive therapy. The risk of thromboembolic involvement is increased in those with aPL or with lupus anticoagulant (LA). (See "Pulmonary manifestations of systemic lupus erythematosus in adults".)

Neurologic and neuropsychiatric involvement — Neuropsychiatric involvement of SLE consists of a broad range of neurologic and psychiatric manifestations, including stroke, seizures, cognitive dysfunction, delirium, psychosis, and/or peripheral neuropathies. Other less common problems are movement disorders, cranial neuropathies, myelitis, and meningitis. (See "Neurologic and neuropsychiatric manifestations of systemic lupus erythematosus" and "Manifestations of systemic lupus erythematosus affecting the peripheral nervous system".)

Thromboembolic events, often in association with aPL or with LA, may occur in a substantial minority (20 percent) of patients with SLE [22]. Arterial thromboemboli may cause focal neurologic problems, such as stroke or seizures and/or more diffuse cognitive defects [22]. (See "Clinical manifestations of antiphospholipid syndrome".)

Hematologic abnormalities — Hematologic abnormalities are common in SLE, and all three blood cell lines can be affected. Anemia of chronic disease (also called anemia of inflammation and anemia of chronic inflammation) is the most common type of anemia among patients with SLE. Leukopenia, typically driven by lymphopenia, is common and generally correlates with clinically active disease. Neutropenia may also occur due to disease activity or toxicity from immunosuppressive medications. Thrombocytopenia is another common hematologic abnormality and is typically mild but rarely may be severe and require treatment. Autoimmune hemolytic anemia is also relatively rare but can be severe, requiring immediate therapy. A more detailed discussion of the hematologic manifestations of SLE is presented separately. (See "Systemic lupus erythematosus: Hematologic manifestations".)

Lymph node enlargement commonly occurs in association with active SLE and usually involves the cervical, axillary, and inguinal regions. Splenomegaly can also be observed among SLE patients, particularly with active disease. (See "Systemic lupus erythematosus: Hematologic manifestations", section on 'Lymphadenopathy' and "Systemic lupus erythematosus: Hematologic manifestations", section on 'Splenomegaly'.)

Ophthalmologic involvement — Any structure of the eye can be involved in SLE, including the lacrimal gland (typically resulting in sicca), extraocular muscles, and other orbital tissues, leading to pain, proptosis, lid swelling, and diplopia [23]. Keratoconjunctivitis sicca is the most common manifestation as a result of secondary Sjögren's disease [24], followed by retinal vasculopathy in the form of cotton wool spots. (See "Clinical manifestations of Sjögren's disease: Exocrine gland disease" and "Retinal vasculitis associated with systemic disorders and infections", section on 'Systemic immune-mediated causes'.)

Other less common ophthalmologic manifestations of SLE include optic neuropathy, choroidopathy, episcleritis, scleritis, and anterior uveitis (iritis, iridocyclitis). (See "Optic neuropathies", section on 'Systemic autoimmune disease' and "Episcleritis" and "Clinical manifestations and diagnosis of scleritis" and "Uveitis: Etiology, clinical manifestations, and diagnosis", section on 'Systemic inflammatory diseases'.)

In addition, there are specific ocular toxicities secondary to medications seen in patients with SLE, including glucocorticoid-induced glaucoma and retinal toxicity due to antimalarial therapy. (See "Major adverse effects of systemic glucocorticoids", section on 'Ophthalmologic effects' and "Antimalarial drugs in the treatment of rheumatic disease", section on 'Ocular effects'.)

Other associated conditions and complications — A number of comorbid medical conditions related to either the underlying disease or therapy can occur in patients with SLE.

●Immunodeficiencies – Hereditary angioedema is a rare genetic disorder primarily caused by a defect in the C1 inhibitor. It can be associated with some inflammatory and autoimmune disorders, including SLE [25]. (See "Hereditary angioedema (due to C1 inhibitor deficiency): Pathogenesis and diagnosis".)

Patients with other forms of complement deficiency like C2 also have forms of SLE. Often the manifestations depend on whether such deficiencies are homozygous. Patients with complete C4 deficiency and C1q deficiency often present with SLE [26]. Inherited C4 deficiency is discussed in detail separately (see "Inherited disorders of the complement system", section on 'C4 deficiency'). Acquired low immunoglobulin levels can also be observed in patients with SLE [27].

●Antiphospholipid syndrome (APS) – aPL are detected in 40 percent of patients with SLE [28]. However, the development of APS is much less common. (See "Antiphospholipid syndrome: Diagnosis" and "Clinical manifestations of antiphospholipid syndrome".)

●Fibromyalgia – Patients with SLE, as well as several other systemic rheumatic diseases, have a higher prevalence of fibromyalgia than the general population [29]. Fibromyalgia is characterized by widespread pain in association with fatigue, mood disturbance, and cognitive dysfunction and is categorized as a feature of type 2 SLE [1,2]. (See "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Systemic lupus erythematosus and Sjögren's disease'.)

●Osteonecrosis – The estimated risk of osteonecrosis, which can present with severe joint pain among patients with SLE, varies widely, ranging from 3 to 40 percent [30]. The increased risk is thought to be related to the underlying disease as well as the concomitant use of glucocorticoids. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Osteonecrosis'.)

●Osteoporosis – Osteoporosis is a common complication of SLE and is discussed in detail separately. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Osteoporosis'.)

●Infection – Serious infectious complications, especially of the skin, respiratory, and urinary systems, develop in up to 50 percent of SLE patients [8,31-34]. A large cohort from a Medicaid database of 33,565 SLE patients, 7113 of whom had lupus nephritis (LN), found that the incidence rate (per 100 person-years) of serious infections requiring hospitalization was 10.8 in the SLE cohort and 23.9 in the LN subcohort [35]. A large majority of infections (approximately 80 percent) are due to bacteria [34]. Opportunistic infections, including those due to fungi, can be related to the use of immunosuppressive therapy and are a common cause of death [36-39]. Consequently, ascribing fever to SLE in an immunocompromised patient should be done only after reasonable efforts have been made to exclude infection.

Risk factors for infection include active SLE disease [40], long-term disease damage, neutropenia, lymphopenia, hypocomplementemia, hypogammaglobulinemia, kidney involvement, neuropsychiatric manifestations, and the use of glucocorticoids and other immunosuppressive drugs [34,41]. In nationwide cohort study, risk for infection was increased in Black Americans and for male sex; antimalarials have been found to be protective [35]. Viral infections are also common, including parvovirus B19 (which can cause a lupus-like syndrome), Epstein-Barr virus, cytomegalovirus, varicella-zoster virus, and human papillomavirus. Mycobacterial infections, including non-tuberculosis, have been noted to be more frequent in patients with SLE [31,34].

●Other autoimmune diseases – There is an increased prevalence of thyroid disease among patients with SLE, usually in the form of Hashimoto's thyroiditis. Myasthenia gravis has also been reported to co-occur in patients with SLE. There is a high prevalence of autoimmune diseases among relatives of patients with SLE [42-44]. (See "Clinical manifestations of myasthenia gravis", section on 'Epidemiology'.)

LABORATORY FINDINGS — 

As is the case with clinical manifestations, patients with systemic lupus erythematosus (SLE) can develop a wide range of laboratory abnormalities. Some findings may suggest active disease or development of certain complications, including the following:

●Complete blood count (CBC) and differential may reveal leukopenia (especially lymphopenia), mild anemia, and/or mild thrombocytopenia.

●Elevated serum creatinine and/or abnormal urinalysis with urine sediment (eg, hematuria, pyuria, proteinuria, and/or cellular casts) may be suggestive of kidney dysfunction.

●Immunoglobulin G (IgG) levels may be elevated and serum protein electrophoresis (SPEP) may demonstrate a hypergammaglobulinemia that is suggestive of a systemic inflammatory process.

●Elevated inflammatory markers may be elevated, typically with a more robust increase in erythrocyte sedimentation rate (ESR) compared with C-reactive protein (CRP).

●Complement levels (as measured by C3, C4, and/or CH50) may be decreased.

●Elevated creatinine kinase may reflect myositis, which is relatively uncommon in patients with SLE. Myositis may also suggest an alternative diagnosis, such as hyperthyroidism (especially caused by to Hashimoto's thyroiditis), mixed connective tissue disease (MCTD), polymyositis, or dermatomyositis.

Additional information regarding the interpretation of abnormalities of the ESR and CRP in patients with SLE can be found elsewhere. (See "Systemic lupus erythematosus in adults: Overview of the management and prognosis", section on 'Laboratory evaluation'.)

In addition, certain autoantibodies can be found in patients with SLE, including the following:

●Antinuclear antibody (ANA) – ANA testing is positive in virtually all patients with SLE at some time in the course of their disease. However, in early disease, up to 6 percent of patients may have a negative ANA by immunofluorescence [45]. (See 'ANA-negative SLE' below and "Measurement and clinical significance of antinuclear antibodies".)

●Anti-Smith (Sm) and anti-double-stranded DNA (dsDNA) – Anti-Sm antibodies and moderate to high levels of anti-dsDNA antibodies are highly specific for SLE, but anti-Sm antibodies lack sensitivity [46,47]. Anti-Sm and anti-dsDNA antibodies are seen in approximately 30 and 70 percent of patients with SLE, respectively. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)

●Anti-Ro/SSA and anti-La/SSB – Anti-Ro/SSA and anti-La/SSB antibodies are present in approximately 30 and 20 percent of patients with SLE, respectively; however, both antibodies are more commonly associated with Sjögren's disease [46]. (See 'ANA-negative SLE' below and "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Systemic lupus erythematosus'.)

●Anti-U1 ribonucleoprotein (RNP) – While anti-U1 RNP antibodies are observed in approximately 25 percent of patients with SLE, they also occur in patients with other conditions, and high levels are almost always present in patients with MCTD [46,47]. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)

●Anti-ribosomal P – Antiribosomal P protein antibodies have high specificity but low sensitivity for SLE. Data are mixed on whether they have some degree of specificity for certain types of organ involvement, including central nervous system and liver disease. (See "Antiribosomal P protein antibodies", section on 'Associations with specific manifestations of SLE'.)

EVALUATION

When to suspect SLE — The initial diagnosis of systemic lupus erythematosus (SLE) depends on the manner of presentation and the exclusion of alternative diagnoses. Given the heterogeneity of clinical presentations, there are some patients for whom the constellation of presenting clinical features and supportive laboratory studies makes the diagnosis of SLE relatively straightforward. By contrast, there are others who present with isolated complaints or infrequent disease characteristics and represent more of a diagnostic challenge. Demographics should also be taken into account when evaluating a patient for SLE, since it occurs primarily in young female patients of childbearing age. In addition, SLE occurs more commonly in certain racial and ethnic groups, particularly Black, Asian, and Hispanic populations compared with White populations [48]. (See "Systemic lupus erythematosus: Epidemiology and pathogenesis", section on 'Geography and race/ethnicity'.)

As an example, the diagnosis of SLE is more likely to be present in a young female who develops fatigue, arthralgia, and pleuritic chest pain and is found to have hypertension, a malar rash, a pleural friction rub, several tender and swollen joints, and mild peripheral edema. Laboratory testing may reveal leukopenia, anemia, an elevated serum creatinine, hypoalbuminemia, proteinuria, an active urinary sediment, hypocomplementemia, and positive tests for antinuclear antibodies (ANA), including those to double-stranded DNA (dsDNA) and the Smith (Sm) antigen. By contrast, another patient may present with fatigue and arthralgias without evidence of organ involvement in the setting of a positive ANA test. Such patients may or may not subsequently develop characteristic multisystem features of SLE in the following months or years. (See 'Clinical manifestations' above.)

Thus, the initial evaluation requires a careful history and physical exam, along with selected laboratory testing to identify features that are characteristic of SLE or that suggest an alternative diagnosis. Patients presenting with symptoms for a shorter duration of time will need close follow-up, as the frequency with which various features of SLE are observed differs according to stage of disease [49-53].

History and physical examination — We perform a thorough medical history, with particular attention to the following symptoms and signs:

●Constitutional symptoms, such as fever, fatigue, lymphadenopathy, or weight loss

●Photosensitive skin lesions, such as a malar rash

●Painless oral or nasal ulcers

●Hair loss that is patchy or frontal/peripheral

●Raynaud phenomenon

●Joint pain or swelling, which can be migratory or symmetrical

●Dyspnea or pleuritic chest pain suggestive of serositis

●Chest pain suggestive of pericarditis

●Lower-extremity edema

●Neurologic symptoms, such as seizures or psychosis

●In females, recurrent miscarriages (see "Pregnancy in women with systemic lupus erythematosus")

●Exposure to medications associated with drug-induced lupus (see "Drug-induced lupus")

Some clinical features are relatively more common at disease onset, as illustrated in the table (table 1).

A complete physical examination is indicated since any organ system can be involved in SLE. Pertinent physical examination findings include the following:

●Skin lesions consistent with a malar rash or discoid lesions

●Scarring or nonscarring patchy alopecia

●Oral or nasopharyngeal ulcers, nasal septal perforation

●Polyarticular arthritis, which is often symmetric

●Subluxation at the metacarpophalangeal joints and rheumatoid-like swan neck deformities in the hands

●Decreased or abnormal breath sounds that may indicate a pleural effusion, pneumonitis, or interstitial lung disease

●Lower-extremity edema and hypertension

Laboratory testing — When evaluating a patient for possible SLE, we obtain the following laboratory tests:

●Complete blood count (CBC) and differential

●Basic metabolic panel (BMP) and liver function tests (LFTs)

●Creatinine kinase

●Urinalysis with urine sediment and urine protein-to-creatinine ratio

●Serum protein electrophoresis (SPEP)

●ANA (ideally by indirect immunofluorescence testing)

●Extractable nuclear antigen (ENA) panel (ie, anti-Sm, anti-U1 ribonucleoprotein [RNP], anti-Ro/SSA, anti-La/SSB)

●Anti-dsDNA

●Antiphospholipid antibodies (lupus anticoagulant [LA], immunoglobulin G [IgG] and IgM anticardiolipin [aCL] antibodies, and IgG and IgM anti-beta2 glycoprotein I [anti-beta2GPI])

●C3 and C4 or CH50 complement levels

●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels

●Thyroid stimulating hormone (TSH) and anti-thyroglobulin and anti-thyroid peroxidase (TPO) antibodies

Laboratory findings that are suggestive of SLE are described above. (See 'Laboratory findings' above.)

In some cases when there is relatively low suspicion for SLE, we initially obtain a more limited set of tests (eg, check an ANA but not other specific autoantibodies) and expand as needed based on the initial laboratory results. Some laboratories may reflexively perform ENA antibody testing based on a positive ANA, especially if the ANA is performed using a solid-phase assay. It is important to note that a positive ANA must be interpreted in the setting of other clinical and laboratory findings due to a relatively high rate of positive tests in patients without SLE, including healthy patients. (See "Measurement and clinical significance of antinuclear antibodies", section on 'Clinical utility and limitations of ANA testing'.)

It is also important to note that if a patient has a negative ANA test, they may still require additional testing for SLE depending on the assay used to detect the ANA and the degree of clinical suspicion for SLE. This is because, on rare occasions, patients with SLE may have a negative ANA test (see 'ANA-negative SLE' below). A negative ANA by indirect immunofluorescence (IIF) is clinically useful as it is more sensitive and significantly decreases the likelihood of SLE; however, if there is still a strong suspicion of SLE despite a negative IIF ANA test, then we send additional autoantibody testing (ie, ENA panel and anti-dsDNA). On the other hand, if we suspect SLE in the setting of a negative ANA result by a solid-phase assay, then we repeat an ANA test using IIF.

In addition, we perform the following additional laboratory tests in selected patients:

●Rheumatoid factor and anti-cyclic citrullinated peptide antibodies – In patients with predominant arthralgias or arthritis, rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies may help exclude a diagnosis of rheumatoid arthritis (RA). RF has less diagnostic utility, since 20 to 30 percent of people with SLE have a positive RF. Anti-CCP antibodies, however, have a much higher specificity for RA and may be more useful for distinguishing the arthritis associated with RA. (See "Biologic markers in the assessment of rheumatoid arthritis", section on 'Rheumatoid factors' and "Biologic markers in the assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)

●Serologic studies for infection – In patients with a brief history (eg, less than six weeks) of predominant arthralgias or arthritis, we perform serologic testing for human parvovirus B19. We also perform serologic testing for hepatitis B virus and hepatitis C virus in patients with multisystemic clinical findings. In areas endemic for Lyme disease, we may send serologic studies for Borrelia as well. Testing for Epstein-Barr virus infection may also be indicated in the appropriate clinical setting. (See "Diagnosis of Lyme disease" and "Viral arthritis: Causes and approach to evaluation and management".)

●24-hour urine collection – If the spot urine protein-to-creatinine ratio is above 0.05 g/mmol, then a 24-hour urine collection should be performed, as the spot urine collection may not reflect the true amount of proteinuria [54]. (See "Evaluation of proteinuria in adults", section on '24-hour urine collection'.)

Finally, testing for cell-bound complement split products (CB-CAPS, including erythrocyte-bound C4d [EC4d]) may be useful in some patients with SLE, especially in complex cases. This is performed through a proprietary system called AVISE which includes a number of autoantibodies in addition to the CB-CAPS. Providers should check with their local institution for availability and insurance coverage of this assay.

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

●Plain radiographs (eg, of swollen joints; unlike affected joints in RA, erosions are observed infrequently in SLE [55]). The absence of erosions may help distinguish arthritis related to SLE from other forms of inflammatory arthritis, although these are not always present in early stages. (See "Arthritis and other musculoskeletal manifestations of systemic lupus erythematosus", section on 'Clinical characteristics'.)

●Musculoskeletal ultrasonography (eg, of painful joints to detect synovitis and tenosynovitis in the hands and wrists [56,57]).

●Kidney ultrasonography (eg, to assess kidney size and to rule out urinary tract obstruction when there is evidence of kidney impairment).

●Chest radiography (eg, for suspected pleural effusion, interstitial lung disease, cardiomegaly).

●Echocardiography (eg, for suspected pericardial involvement, to assess for a source of emboli, or noninvasive estimation of pulmonary artery pressure; and for evaluation of suspected valvular lesions, such as verrucae).

●Computed tomography (CT; eg, for abdominal pain, suspected pancreatitis, interstitial lung disease).

●Magnetic resonance imaging (MRI; eg, for focal neurologic deficits or cognitive dysfunction).

Additional testing may be required in patients with certain signs or symptoms to assess for potential complications of SLE or alternative diagnoses. Examples include:

●Biopsy of an involved organ (eg, skin or kidney), which may be necessary in some cases. Typical histologic findings in various organs in SLE are discussed in topic reviews devoted to the particular sites of involvement. (See "Lupus nephritis: Diagnosis and classification" and "Overview of cutaneous lupus erythematosus".)

●Electrocardiography in the assessment of chest pain that may be due to pericarditis or to myocardial ischemia.

●Tests to assess for pulmonary embolism in a patient with pleuritic chest pain and dyspnea.

●Diffusing capacity for carbon monoxide to assess for suspected pulmonary hemorrhage or shrinking lung syndrome and to estimate the severity of interstitial lung disease.

CLASSIFICATION CRITERIA — 

Several classification criteria have been developed for systemic lupus erythematosus (SLE) as a means of categorizing patients for inclusion in research studies. These criteria can be useful for clinicians in systematically documenting key disease features, but their imperfect sensitivity and specificity limit their use for diagnostic purposes.

●2019 EULAR/ACR criteria – The European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism)/American College of Rheumatology (ACR) classification criteria for SLE were developed to improve detection of early- or new-onset SLE as well as improve the sensitivity and specificity compared with previous criteria (table 2A-B) [58,59]. The classification for SLE requires the presence of a positive antinuclear antibody (ANA) test as an entry criterion; more information on available types of ANA testing is presented separately (see "Measurement and clinical significance of antinuclear antibodies", section on 'Techniques to detect ANA and nomenclature'). Additive criteria consist of seven clinical (ie, constitutional, hematologic, neuropsychiatric, mucocutaneous, serosal, musculoskeletal, renal) and three immunologic (ie, antiphospholipid antibodies [aPL], complement proteins, SLE-specific antibodies) categories, each of which are weighted from 2 to 10. Patients are classified as having SLE with a score of 10 or more points. In the validation cohort, which included patients with early disease, the EULAR/ACR criteria had a sensitivity of 96.1 percent and a specificity of 93.4 percent, compared with the 96.7 percent sensitivity and 83.7 percent specificity of the Systemic Lupus International Collaborating Clinics (SLICC) criteria and the 82.8 percent sensitivity and 93.4 percent specificity of the ACR criteria.

The performance of the EULAR/ACR classification criteria was evaluated using the combined derivation and validation cohorts consisting of 1197 patients with SLE and 1074 patients without SLE, but with a variety of conditions mimicking SLE, and reported a sensitivity and specificity of a positive ANA of 99.5 and 19.5 percent, respectively [60]. The sensitivities of the specific criteria items were highly variable, but the specificities were more consistently high (eg, at least 80 percent). In addition, the EULAR/ACR criteria have prognostic value, with a score of 20 or above signifying a poor prognosis in terms of persistent disease activity and accumulation of damage [61,62].

●2012 SLICC criteria – In 2012, the SLICC proposed classification criteria that were developed to address inherent weaknesses of the 1997 ACR classification criteria (table 3) [63]. As an example, one of the major limitations of the 1997 ACR criteria is that patients with biopsy-confirmed lupus nephritis could still fail to fulfill criteria. Other concerns regarding the ACR criteria included the possible duplication of highly correlated cutaneous features (such as malar rash and photosensitivity), the lack of inclusion of other cutaneous manifestations (such as maculopapular or polycyclic rash), and the omission of many neurologic manifestations of SLE (such as myelitis). The ACR criteria also did not include relevant immunologic information such as low serum levels of complement components.

Classification as having SLE by the SLICC criteria requires either that a patient satisfy at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria, or that the patient has biopsy-proven nephritis compatible with SLE in the presence of ANA or anti-double-stranded DNA (anti-dsDNA) antibodies.

The SLICC criteria were validated by analysis of 690 patients with SLE or other rheumatic diseases. In this initial validation testing, the SLICC revised criteria had greater sensitivity but lower specificity than the 1997 ACR classification criteria (sensitivity of 97 versus 83 percent and specificity of 84 versus 96 percent, respectively).

Despite the improved sensitivity compared with the ACR criteria, the SLICC criteria might delay the diagnosis of SLE in a significant number of patients, and some patients might not be classified at all. These situations were demonstrated in a study in which patients with SLE from two large cohorts were grouped according to whether the SLICC criteria were met before, at the same time as, or after the ACR criteria, and the groups were then compared [64]. Among the patients diagnosed later with the SLICC criteria, in the majority of cases, the delay was due to the fact that the combination of malar rash and photosensitivity both fall within the acute cutaneous SLE category and thus only count as one criterion.

●1997 ACR criteria – The classification criteria that were developed by the American Rheumatism Association (ARA, now the ACR) for the classification of SLE were established by cluster analyses, primarily in academic centers and in White American patients [65-67].

The patient is classified with SLE using the ACR criteria if four or more of the manifestations are present, either serially or simultaneously, during any interval of observations (table 3) [65,66]. A positive lupus erythematosus cell test, used in older criteria, was replaced by the presence of aPL [65]. When tested against other rheumatic diseases, these criteria have a sensitivity and specificity of approximately 96 percent.

DIAGNOSIS — 

The diagnosis of systemic lupus erythematosus (SLE) is based upon the judgment of an experienced clinician who recognizes characteristic constellations of symptoms and signs in the setting of supportive serologic studies after excluding alternative diagnoses. This is often challenging due to the great variability in the expression of SLE. Although the classification criteria were designed for research purposes, many clinicians refer to aspects of these criteria when making the diagnosis of SLE. (See 'Classification criteria' above.)

Our diagnostic criteria — In the absence of existing "diagnostic criteria," we describe our general approach to the diagnosis that takes into consideration the strengths of the 1997 American College of Rheumatology (ACR) criteria, the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria (table 3), or the 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR classification criteria (table 2A). (See 'Classification criteria' above.)

Note that our general diagnostic approach does not adequately address the myriad manifestations or subtleties of some clinical features, nor does it substitute for clinical judgment. Thus, it is often appropriate to refer the patient in whom the diagnosis of SLE is suspected to a rheumatologist with experience in this disease [68].

Definite SLE — After excluding alternative diagnoses, we diagnose SLE in the patient who fulfills the 1997 ACR criteria, the 2012 SLICC criteria (table 3), or the 2019 EULAR/ACR criteria (table 2A). As previously mentioned, the ACR criteria require that a patient satisfy at least 4 of 11 criteria. The SLICC criteria require either that a patient satisfy at least 4 of 17 criteria, including at least 1 of the 11 clinical criteria and one of the six immunologic criteria, or that the patient has biopsy-proven nephritis compatible with SLE in the presence of antinuclear antibodies (ANA) or anti-double-stranded DNA (anti-dsDNA) antibodies. According to the EULAR/ACR criteria, a patient can be classified as having SLE if they have a positive ANA ≥1:80 and score 10 or more points. This number has been shown to be valid in a number of cohorts. (See 'Classification criteria' above.)

Probable SLE — There are patients who do not fulfill the classification criteria for SLE but in whom we still diagnose the disorder. These patients include those presenting with an inadequate number of ACR or SLICC criteria or those who have other SLE manifestations not included in either classification criteria.

As a loose guide, we diagnose SLE in patients who have two or three of the ACR or SLICC criteria, along with at least one other feature that may be associated with but is not specific for SLE. Some of these features include the following [69]:

●Optic neuritis, aseptic meningitis

●Glomerular hematuria

●Pneumonitis, pulmonary hemorrhage, pulmonary hypertension, interstitial lung disease

●Myocarditis, verrucous endocarditis (Libman-Sacks endocarditis)

●Abdominal vasculitis

●Raynaud phenomenon

●Elevated acute phase reactants (eg, erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP])

Possible SLE — We consider SLE a possible diagnosis in individuals who have only one of the ACR/SLICC criteria, in addition to at least one or two of the other features listed above. Other terms that have been used to describe patients with probable or possible SLE include incipient or latent lupus, which has been defined as patients who have three or fewer of the ACR or SLICC criteria [70].

In general, patients with either probable or possible SLE are managed similarly to patients with SLE and treated according to their predominant symptoms and manifestations. Over time, the symptoms in these patients may persist, evolve into definite SLE or a related connective tissue disorder, or even resolve. In addition, these patients may develop positive serology over time and become more clearly diagnosable as SLE. However, patients treated with high doses of prednisone may "lose" their antibodies, and it may be more difficult to diagnose the underlying disease.

Undifferentiated connective tissue disease — Other patients who have even fewer features suggestive of SLE may be classified as having undifferentiated connective tissue disease (UCTD). This term is used to describe patients with signs and symptoms suggestive of a systemic autoimmune disease but who do not meet the ACR criteria for SLE or another defined connective tissue disease [71]. (See "Undifferentiated systemic rheumatic (connective tissue) disease and overlap syndromes".)

Case series have been published that summarize the outcome of patients who have UCTD at presentation [72-76]. Up to one-third of patients have all symptoms and signs disappear over a 10-year follow-up period. Anywhere from 40 to 60 percent of patients continue to exhibit their initial clinical features, while 5 to 30 percent evolve and meet classification criteria for a definite disease, such as SLE, rheumatoid arthritis, scleroderma, or an inflammatory myopathy (myositis) [72-76] (see "Undifferentiated systemic rheumatic (connective tissue) disease and overlap syndromes"). Thus, patients with UCTD should be followed carefully, encouraged to report new symptoms, and have periodic laboratory testing to assess for the emergence of new clinical features or laboratory findings. Appropriate testing should include the laboratory testing described above. (See 'Laboratory testing' above.)

ANA-negative SLE — Uncommonly, the diagnosis of SLE can still be made in the setting of a negative ANA based on a combination of consistent clinical signs and symptoms, laboratory testing, and/or biopsy results. As examples, patients may be diagnosed with ANA-negative SLE if they have evidence of lupus nephritis (LN) on kidney biopsy; a combination of other classic findings such as nonerosive inflammatory arthritis, rash, pleurisy, and/or pericarditis; and/or consistent signs and symptoms in the presence of other autoantibodies that may not be captured by ANA testing (eg, anti-Ro/SSA, anti-dsDNA).

Patients with SLE may have a negative ANA test because of limitations of the laboratory assays. Solid-phase assays for ANA assess a narrower set of autoantigens and may also be less sensitive for detecting ANA compared with indirect immunofluorescence (IIF). In addition, false-negative testing for ANA using the IIF method can be due to the substrate used (eg, using rodent instead of human tissue, also known as human epithelial type 2 [HEp-2] cells) [77] or other difficulties in detecting anti-Ro/SSA antibodies. Patients with isolated positive anti-Ro/SSA or dsDNA antibodies may have a negative ANA. More information on the limitations of various methods to detect ANA and anti-Ro/SSA antibodies is provided separately. (See "Measurement and clinical significance of antinuclear antibodies", section on 'Methodologies' and "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems", section on 'Detection of anti-Ro and anti-La antibodies'.)

Other factors can also influence ANA negativity in SLE patients, including disease duration and treatment exposure [78]. In our experience, the frequency of ANA-negative SLE is lower in patients presenting at an early stage of their disease. In addition, SLE patients who have longstanding disease and/or have undergone treatment may lose ANA reactivity and become serologically negative over time.

As a result of these various factors, several studies have described the incidence of "ANA-negative SLE" based on IIF testing. In the 1970s, it was estimated that about 5 percent of patients with SLE were ANA-negative by IIF [79]. Despite the subsequent substitution of Hep-2 cells for rodent tissue sections, patients with SLE and isolated anti-Ro/SSA antibodies may still have negative ANA on rare occasions. As an example, one study in Sweden that tested 4025 sera samples for ANA using IIF identified 64 patients with negative ANA and positive anti-Ro/SSA antibodies [80]; of those patients, 12 had SLE and 5 had cutaneous lupus erythematosus. Another study reported that up to 6 percent of patients with recent-onset SLE may have a negative ANA by IIF [45].

DIFFERENTIAL DIAGNOSIS — 

Given the protean manifestations of systemic lupus erythematosus (SLE), the differential diagnosis is correspondingly broad. While it is beyond the scope of this review to provide a comprehensive list of all possible alternative diagnoses, we present several here.

●Rheumatoid arthritis – Early rheumatoid arthritis (RA) may be difficult to distinguish from the arthritis of SLE, since both conditions cause joint tenderness and swelling (table 4). Features such as swan neck deformities, ulnar deviation, and soft tissue laxity, which are observed in later stages of RA in patients with more destructive disease, can also be seen in some patients with SLE. However, an important distinguishing feature is that the joint deformities in SLE are often reducible and infrequently erosive on plain radiographs.

Some extraarticular RA manifestations, including serositis, sicca symptoms, subcutaneous nodules, anemia, and fatigue, are other features that may also be observed in SLE. These features are more common in RA patients with more severe or advanced disease. Serologic abnormalities, such as the presence of anti-cyclic citrullinated peptides (CCP), are more supportive of the diagnosis of RA and can help distinguish the diseases. It should be recognized that the antinuclear antibodies (ANA) may be positive in up to one-half of patients with RA. Conversely, rheumatoid factor (RF) may be present in approximately one-third of SLE patients. Also, anti-CCP can be present in 5 to 10 percent of patients with SLE [81]. (See "Diagnosis and differential diagnosis of rheumatoid arthritis".)

●Rhupus – The term rhupus has been used to describe patients with overlapping features of both SLE and RA. Whether rhupus is clinically and immunologically a distinct entity, a true overlap of SLE and RA, or a subset of patients with SLE remains a matter of debate. In addition to having serologies consistent with both SLE and RA, some patients classified as rhupus may have an erosive arthropathy that is atypical for SLE. (See "Undifferentiated systemic rheumatic (connective tissue) disease and overlap syndromes", section on 'Diagnostic challenges'.)

●Mixed connective tissue disease – Mixed connective tissue disease (MCTD) is characterized by overlapping features of SLE, systemic sclerosis (SSc), and polymyositis (PM), and by the presence of high titers of antibodies against U1 ribonucleoprotein (RNP). However, the diagnosis of MCTD is often complicated, since many of its characteristic features occur sequentially, often over a period of years. In addition, some patients with MCTD may evolve into another connective tissue disease, including SLE, during the clinical course [82]. (See "Mixed connective tissue disease".)

●Undifferentiated connective tissue disease – As mentioned above, patients with undifferentiated connective tissue disease (UCTD) have signs and symptoms suggestive of a systemic autoimmune disease but do not satisfy the classification criteria for a defined connective tissue disease such as SLE or MCTD. These patients may have symptoms such as arthritis and arthralgias, Raynaud phenomenon, and serologic findings that are difficult to distinguish from early phases of SLE. The majority of patients with UCTD maintain an undefined profile and have a mild disease course [83]. (See "Undifferentiated systemic rheumatic (connective tissue) disease and overlap syndromes".)

●Systemic sclerosis – The coexistence of Raynaud phenomenon and gastroesophageal reflux is typically observed in SSc; however, these findings are nonspecific and may be seen in patients with SLE or healthy individuals. By contrast, sclerodactyly, telangiectasia, calcinosis, and malignant hypertension with acute kidney failure are more consistent with SSc rather than SLE. Further, a positive ANA is present in most patients with SSc, while other serologies, such as anti-double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies that are more specific for SLE, are not commonly observed in SSc. Correspondingly, patients with SSc commonly express antibodies to an antigen called Scl-70 (topoisomerase I) or antibodies to centromere proteins. Distinguishing SSc from SLE can be particularly difficult in cases in which there is overlap of these diseases, such as in MCTD. (See "Clinical manifestations and diagnosis of systemic sclerosis (scleroderma) in adults".)

●Sjögren's disease – Patients with Sjögren's disease may have extraglandular manifestations that can be observed in SLE, such as neurologic and pulmonary abnormalities. However, patients with Sjögren's disease should have objective signs of keratoconjunctivitis sicca and xerostomia and characteristic findings on salivary gland biopsy that are not typical of SLE. Patients with Sjögren's disease commonly express antibodies to Ro and La antigens. Also, some patients may have SLE with associated Sjögren's disease. (See "Diagnosis and classification of Sjögren's disease".)

●Vasculitis – Patients with medium- and small-vessel vasculitides, such as polyarteritis nodosa, granulomatosis with polyangiitis, or microscopic polyangiitis, may present with overlapping features of SLE, including constitutional symptoms, skin lesions, neuropathy, and kidney dysfunction. However, patients with these types of vasculitides are usually ANA-negative. Rather, these patients frequently display antibodies to neutrophil cytoplasmic antigens. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

●Behçet syndrome – Oral aphthae are present in almost all patients with Behçet syndrome and may be observed in patients with SLE. Other overlapping features include inflammatory eye disease, neurologic disease, vascular disease, and arthritis. However, the oral aphthae in Behçet syndrome are typically painful, and patients with Behçet syndrome are more commonly male and ANA-negative. Also, vascular involvement of any size (small, medium, large) is more commonly a feature of Behçet syndrome than SLE. (See "Clinical manifestations and diagnosis of Behçet syndrome".)

●Dermatomyositis and polymyositis – Patients with SLE can present with a low-grade myositis, whereas patients with dermatomyositis (DM) and PM generally demonstrate more overt proximal muscle weakness. A positive ANA is observed in approximately 30 percent of patients with DM and PM, compared with almost all patients in SLE. Patients with DM may have characteristic skin findings, including Gottron's papules, a heliotrope eruption, and photodistributed poikiloderma (including the shawl and V signs). Clinical findings characteristic of SLE, such as oral ulcers, arthritis, nephritis, and hematologic abnormalities, are absent in DM and PM. Patients with DM or PM may also express myositis-specific antibodies, such as anti-Jo-1. (See "Clinical manifestations of dermatomyositis and polymyositis in adults".)

●Adult-onset Still's disease – Some of the clinical manifestations observed in adult-onset Still's disease (AOSD), such as fever, arthritis or arthralgias, and lymphadenopathy, are not unusual for patients with SLE. However, patients with AOSD often present with a leukocytosis rather than the leukopenia observed in SLE, and they are typically negative for ANA. Markedly elevated serum ferritin concentrations are also more frequently observed in AOSD. (See "Adult-onset Still's disease: Clinical manifestations and diagnosis".)

●Kikuchi disease – Kikuchi disease is a benign and usually self-limited form of histiocytic-necrotizing lymphadenitis. Clinical features at presentation include lymphadenopathy, fever, myalgias, arthralgias, and, less commonly, hepatosplenomegaly. Associations with SLE have been reported, but the clinical course is usually favorable, with spontaneous remission often occurring within four months. The diagnosis of Kikuchi disease is based on a lymph node biopsy, which reveals a histiocytic cellular infiltrate. (See "Kikuchi disease".)

●Serum sickness – Many of the clinical features observed in serum sickness, such as fever, lymphadenopathy, cutaneous eruptions, and arthralgias, are often observed in SLE. Furthermore, during severe episodes, complement measurements including C3 and C4 can be depressed, as in SLE. Unlike SLE, however, ANA are typically negative, and the course tends to be self-limited. (See "Serum sickness and serum sickness-like reactions".)

●Fibromyalgia – Patients with SLE may present with generalized arthralgias, myalgias, and fatigue, much like patients with fibromyalgia, or develop comorbid fibromyalgia. Patients with fibromyalgia in isolation should not have other characteristic features of SLE, such as a photosensitive rash, arthritis, and multisystem organ involvement, or laboratory abnormalities consistent with SLE. (See "Fibromyalgia: Clinical manifestations and diagnosis in adults" and "Overview of chronic widespread (centralized) pain in the rheumatic diseases", section on 'Systemic lupus erythematosus and Sjögren's disease'.)

●Infections – Several viral infections can produce signs and symptoms present in SLE, including cytomegalovirus and Epstein-Barr virus. In addition, Epstein-Barr virus infection may lead to a positive ANA [84,85]. Human parvovirus B19 can cause flu-like symptoms and hematologic abnormalities such as leukopenia and thrombocytopenia, which can be observed in SLE, and patients may present with arthralgias or arthritis.

Other viral infections that may present with multisystem involvement include human immunodeficiency virus (HIV), hepatitis B virus, and hepatitis C virus. However, serologic assays can be diagnostic for many of these viruses. Some bacterial infections such as Salmonella or tuberculosis should also be considered, if appropriate.

●Multiple sclerosis – Although rare, patients with SLE can present with cranial neuropathies that must be distinguished from multiple sclerosis (MS). Unilateral optic neuritis and pyramidal syndrome, with lesions detected by MRI suggesting dissemination in space and time, are characteristic of MS. (See "Evaluation and diagnosis of multiple sclerosis in adults".)

●Malignancies – Leukemia or myelodysplastic syndromes may present with hematologic and constitutional symptoms similar to those observed in SLE. However, monoclonal expansion of B and T cells (as assessed by immunophenotyping), monocytosis, or macrocytosis can distinguish these malignancies from SLE. Patients with lymphoma also typically have additional findings such as splenomegaly, lymphadenopathy, or increased lactate dehydrogenase levels. Patients with angioimmunoblastic T cell lymphoma may be distinguished by findings on an excisional tissue biopsy, most commonly a lymph node.

●Thrombotic thrombocytopenic purpura – Although both patients with thrombotic thrombocytopenic purpura (TTP) and SLE may have fever and thrombocytopenia, patients with TTP also have microangiopathic hemolytic anemia, acute kidney insufficiency, fluctuating neurologic manifestations, and/or low levels of ADAMSTS13. (See "Diagnosis of immune TTP".)

●Other – Some patients with psychiatric disorders (eg, bipolar disorder, substance use disorders) are thought to have SLE on the basis of a positive ANA and leukopenia that may actually be drug- or medication-induced. Thus, these patients should be evaluated for other clinical features consistent with SLE. (See "Drug-induced lupus" and "Drug-induced neutropenia and agranulocytosis".)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Systemic lupus erythematosus".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Lupus (The Basics)")

●Beyond the Basics topics (see "Patient education: Antinuclear antibodies (ANA) (Beyond the Basics)" and "Patient education: Systemic lupus erythematosus (Beyond the Basics)")

PATIENT PERSPECTIVE TOPIC — 

Patient perspectives are provided for selected disorders to help clinicians better understand the patient experience and patient concerns. These narratives may offer insights into patient values and preferences not included in other UpToDate topics. (See "Patient perspective: Systemic lupus erythematosus".)

SUMMARY AND RECOMMENDATIONS

●Clinical manifestations – Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serologic manifestations that can affect virtually any organ. The disease course is often marked by remissions and relapses and may vary from mild to severe. (See 'Introduction' above.)

Major clinical manifestations of SLE include the following (table 1):

•Constitutional symptoms – Constitutional symptoms, such as fatigue, fever, and weight loss, are present in most patients with SLE at some point during the course of the disease. (See 'Constitutional symptoms' above.)

•Arthritis and arthralgias – Arthritis and arthralgias occur in over 90 percent of patients with SLE and are often one of the earliest manifestations. (See 'Arthritis and arthralgias' above.)

•Mucocutaneous involvement – Many patients also have skin and/or mucous membrane lesions. (See 'Mucocutaneous involvement' above.)

•Cardiovascular involvement – Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. Several vascular abnormalities, including Raynaud phenomenon, vasculitis, microvascular angina, and thromboembolic disease, can also be observed. (See 'Cardiac involvement and vascular manifestations' above.)

•Kidney involvement – Kidney involvement is clinically apparent in approximately 40 percent of patients and is a significant cause of morbidity and mortality. (See 'Kidney involvement' above.)

•Gastrointestinal involvement – Gastrointestinal abnormalities can involve almost any organ along the gastrointestinal tract. However, the majority of symptoms are related to adverse medication reactions or infection. (See 'Gastrointestinal involvement' above.)

•Pulmonary involvement – Pulmonary manifestations of SLE include pleuritis (with or without effusion), pneumonitis, interstitial lung disease, pulmonary hypertension, shrinking lung syndrome, and alveolar hemorrhage. (See 'Pulmonary involvement' above.)

•Neuropsychiatric involvement – Neuropsychiatric involvement of SLE consists of a broad range of neurologic and psychiatric manifestations, including cognitive dysfunction, organic brain syndromes, delirium, psychosis, seizures, headache, and/or peripheral neuropathies. (See 'Neurologic and neuropsychiatric involvement' above.)

•Hematologic abnormalities – Hematologic abnormalities can include anemia, leukopenia, and thrombocytopenia. Lymphadenopathy and splenomegaly can also be observed. (See 'Hematologic abnormalities' above.)

●Evaluation – As part of the medical history and physical examination, we pay particular attention to the following symptoms and signs (see 'Evaluation' above):

•Photosensitive skin lesions, such as a malar rash or discoid lesions

•Painless oral or nasal ulcers

•Hair loss that is patchy or frontal/peripheral

•Raynaud phenomenon

•Joint pain or swelling, which can be migratory or symmetrical

•Symptoms of serositis/pericarditis

•Fever, fatigue, and aching, including widespread pain

We also ask about exposure to medications associated with drug-induced lupus (eg, hydralazine). (See "Drug-induced lupus".)

●Laboratory testing – We obtain a complete blood count and differential as well as serum creatinine level and urinalysis. We also test for antinuclear antibodies (ANA; and if positive, other specific autoantibodies, such as anti-double-stranded DNA [anti-dsDNA] and anti-Smith [anti-Sm]), antiphospholipid antibodies, C3 and C4 or CH50 complement levels, erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels, and the urine protein-to-creatinine ratio. (See 'Laboratory testing' above.)

●Additional testing in selected patients – Additional studies, such as diagnostic imaging or biopsy of an involved organ, may be necessary; such testing is dictated by the clinical presentation and associated differential diagnostic possibilities. (See 'Additional testing in selected patients' above.)

●Classification criteria – Classification criteria have been developed for SLE as a means of categorizing patients for study purposes. These criteria can be useful for clinicians in systematically documenting key disease features. (See 'Classification criteria' above.)

●Diagnosis – In the absence of existing "diagnostic criteria," our general approach to the diagnosis of SLE is as follows (see 'Our diagnostic criteria' above):

•Definite SLE – After excluding alternative diagnoses, we diagnose SLE in the patient who fulfills the 1997 American College of Rheumatology (ACR) criteria, the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria (table 3), or the 2019 European Alliance of Associations for Rheumatology (EULAR)/ACR criteria (table 2A). (See 'Definite SLE' above and 'Classification criteria' above.)

•Probable SLE – There are patients who do not fulfill the classification criteria for SLE but in whom we still diagnose the disorder. These patients include those presenting with an inadequate number of ACR or SLICC criteria or those who have other SLE manifestations not included in either classification criteria. (See 'Probable SLE' above.)

As a loose guide, we diagnose SLE in patients who have two or three of the ACR or SLICC criteria, along with at least one other feature that may be associated with but is not specific for SLE. Some of these features include:

-Optic neuritis, aseptic meningitis

-Glomerular hematuria

-Pneumonitis, pulmonary hemorrhage, or pulmonary hypertension, interstitial lung disease

-Myocarditis, verrucous endocarditis (Libman-Sacks endocarditis)

-Abdominal vasculitis

-Raynaud phenomenon

-Elevated acute phase reactants (eg, ESR and CRP)

•Possible SLE – We consider SLE a possible diagnosis in individuals who have only one of the ACR/SLICC criteria, in addition to at least one or two of the uncommon features listed above. (See 'Possible SLE' above.)

•Undifferentiated connective tissue disease – Other patients who have even fewer features suggestive of SLE may be classified as undifferentiated connective tissue disease (UCTD). (See 'Undifferentiated connective tissue disease' above.)

•ANA-negative SLE – Less than 5 percent of patients with SLE are negative for ANA as detected by indirect immunofluorescence. (See 'ANA-negative SLE' above.)

ACKNOWLEDGMENT — 

The UpToDate editorial staff acknowledges Peter Schur, MD, who contributed to an earlier version of this topic review.