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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 renal, 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. 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. Serological findings are important in suggesting the possibility of SLE, with some antibodies (eg, anti-double-stranded DNA [dsDNA] and anti-Smith [Sm]) highly associated with this condition.
The approach to the diagnosis and differential diagnosis of SLE will be reviewed here. An overview of the symptoms and signs that can occur in SLE, discussions of particular sites of involvement (eg, skin, kidneys, central nervous system), and the treatment and prognosis of SLE are presented separately. (See "Overview of the clinical manifestations of systemic lupus erythematosus in adults" and "Overview of the management and prognosis of systemic lupus erythematosus in adults".)
EVALUATION FOR SUSPECTED 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 make 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 women of childbearing age. In addition, SLE occurs more commonly in certain racial and ethnic groups, particularly African Americans, Asians, African Caribbeans, and Hispanic Americans, compared with Caucasians. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Epidemiology'.)
As an example, the diagnosis of SLE is more likely in a young woman who presents with complaints of fatigue, arthralgia, and pleuritic chest pain and who 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 leukopenia or single-organ involvement (eg, nephritis or pericarditis). Such patients may subsequently develop the characteristic multisystem features of SLE over a period of months or years. (See "Overview of the clinical manifestations of systemic lupus erythematosus in adults".)
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 observed differ according to stage of disease [1-5].
Clinical manifestations — Given the broad range of clinical manifestations of SLE, it is helpful to consider the various features according to frequency at disease onset (table 1). Our general approach to the history and physical examination for patients with suspected SLE is described below.
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
●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
●Recurrent miscarriages (see "Pregnancy in women with systemic lupus erythematosus")
We also ask about exposure to medications associated with drug-induced lupus (eg, hydralazine and others) (see "Drug-induced lupus"). 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
●Polyarticular arthritis which is often symmetric
●Subluxation at the metacarpal phalangeal (MCP) joints and rheumatoid-like swan neck deformities in the hands may be observed, which are usually not reducible
●Decreased or abnormal breath sounds may indicate a pleural effusion, pneumonitis, or interstitial lung disease
●Lower extremity edema and hypertension may be due to renal involvement
Detailed discussions of the various physical findings associated with SLE are discussed in detail separately. (See "Overview of cutaneous lupus erythematosus" and "Musculoskeletal manifestations of systemic lupus erythematosus" and "Pulmonary manifestations of systemic lupus erythematosus in adults" and "Diagnosis and classification of renal disease in systemic lupus erythematosus" and "Neurologic manifestations of systemic lupus erythematosus" and "Neuropsychiatric manifestations of systemic lupus erythematosus" and "Non-coronary cardiac manifestations of systemic lupus erythematosus in adults" and "Coronary heart disease in systemic lupus erythematosus".)
Laboratory testing — We obtain the following routine laboratory tests, which may provide diagnostically useful information:
●Complete blood count and differential may reveal leukopenia, mild anemia, and/or thrombocytopenia
●Elevated serum creatinine may be suggestive of renal dysfunction
●Urinalysis with urine sediment may reveal hematuria, pyuria, proteinuria, and/or cellular casts
In addition to the routine laboratories described above, we perform the following laboratory tests which support the diagnosis of SLE if abnormal:
●Antiphospholipid antibodies (lupus anticoagulant [LA], IgG and IgM anticardiolipin [aCL] antibodies; and IgG and IgM anti-beta2-glycoprotein [GP] I)
●C3 and C4 or CH50 complement levels
●Erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) levels
●Urine protein-to-creatinine ratio
The ANA test is positive in virtually all patients with SLE at some time in the course of their disease (see "Measurement and clinical significance of antinuclear antibodies"). If the ANA is positive, one should test for other specific antibodies such as dsDNA, anti-Sm, Ro/SSA, La/SSB, and U1 ribonucleoprotein (RNP). In some labs, a positive ANA test by indirect immunofluorescence will automatically result in testing for such additional antinuclear antibodies that are often present in patients SLE.
●Anti-dsDNA and anti-Sm antibodies are highly specific for SLE, but anti-Sm antibodies lack sensitivity [6,7]. Anti-dsDNA and anti-Sm antibodies are seen in approximately 70 and 30 percent of patients with SLE, respectively. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)
●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 syndrome . (See "The anti-Ro/SSA and anti-La/SSB antigen-antibody systems".)
●Anti-U1 RNP antibodies are observed in approximately 25 percent of patients with SLE, but they also occur in patients with other conditions and high levels are almost always present in patients with mixed connective tissue disease (MCTD) [6,7]. (See "Antibodies to double-stranded (ds)DNA, Sm, and U1 RNP".)
●Antiribosomal P protein antibodies have a high specificity for SLE, but have low sensitivity for SLE. They also lack specificity for involvement of a particular organ system or disease manifestation. (See "Antiribosomal P protein antibodies", section on 'Clinical utility of antiribosomal P antibodies'.)
If the initial ANA test is negative, but the clinical suspicion of SLE is high, then additional antibody testing may still be appropriate. This is partly related to the differences in the sensitivity and specificity among the methods used to detect ANA. A more detailed discussion on the techniques used to detect ANA is presented separately. (See "Measurement and clinical significance of antinuclear antibodies", section on 'Advantages and disadvantages of methods to detect ANA' and 'ANA-negative lupus' below.)
We perform the following laboratory tests in selected patients:
●Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP) antibodies – In patients with predominant arthralgias or arthritis, RF and anti-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 diagnosis and assessment of rheumatoid arthritis", section on 'Rheumatoid factors' and "Biologic markers in the diagnosis and assessment of rheumatoid arthritis", section on 'Anti-citrullinated peptide antibodies'.)
●Serological studies for infection – In patients with a brief history (for example, 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 (HBV) and hepatitis C virus (HCV) in patients with multisystemic clinical findings. In areas endemic for Lyme disease, we may consider serologic studies for Borrelia as well. Testing for Epstein-Barr virus (EBV) infection may also be indicated in the appropriate clinical setting. (See "Diagnosis and differential diagnosis of rheumatoid arthritis", section on 'Viral polyarthritis' and "Specific viruses that cause arthritis" and "Diagnosis of Lyme disease", section on 'Indications for serologic testing'.)
●Creatine kinase (CK) – An elevated CK may reflect myositis, which is relatively uncommon in patients with SLE. Myositis may also suggest an alternative diagnosis such as MCTD, polymyositis (PM), or dermatomyositis (DM).
Imaging — 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 of swollen joints. Unlike affected joints in RA, erosions are observed infrequently in SLE . Depending on the stage of disease, deformities may be present on radiograph. Deformities should also be present on physical exam.
●Ultrasonography of painful joints. Ultrasound can be used to detect synovitis and tenosynovitis in the hands and wrists in patients with SLE [9,10].
●Renal ultrasonography to assess kidney size and to rule out urinary tract obstruction when there is evidence of renal 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).
Biopsy — Biopsy of an involved organ (eg, skin or kidney) is 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 "Diagnosis and classification of renal disease in systemic lupus erythematosus" and "Overview of cutaneous lupus erythematosus".)
Additional studies in selected patients — Other tests that may be necessary are typically dictated by the clinical presentation and associated differential diagnostic possibilities. Examples include:
●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 (DLCO) to assess for suspected pulmonary hemorrhage and to estimate the severity of interstitial lung disease
CLASSIFICATION CRITERIA — Classification criteria have been developed for systemic lupus erythematosus (SLE) as a means of categorizing patients for study purposes. These criteria can be useful for clinicians in systematically documenting key disease features, but their imperfect sensitivity and specificity limits their use for diagnostic purposes.
In 2012, the Systemic Lupus International Collaborating Clinics (SLICC) proposed revised classification criteria that were developed to address inherent weaknesses of the 1997 American College of Rheumatology (ACR) classification criteria . 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.
2012 SLICC criteria — A consensus group of experts on SLE, the SLICC, has proposed revised criteria for SLE (table 2) . 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 antinuclear antibodies (ANA) or anti-double-stranded DNA (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).
However, 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 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. Out of 622 patients, 319 (50 percent) were classified at the same time using either criteria set, 78 (12 percent) earlier and 225 (35 percent) later (mean 4.4 years) with the SLICC criteria than with the ACR criteria . Among the patients diagnosed later with the SLICC criteria, in the majority of cases, the delay was due to the combination of malar rash and photosensitivity into the acute cutaneous SLE criterion.
1997 ACR criteria — Previously, most clinicians relied for the diagnosis of lupus upon the classification criteria that were developed by the American Rheumatism Association (ARA, now the ACR) (table 3) [13-15]. The criteria were established by cluster analyses, primarily in academic centers and primarily in Caucasian patients.
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 [13,14]. A positive LE cell test, used in older criteria, was replaced by the presence of antiphospholipid antibodies . 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 and severity 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.)
In the absence of existing "diagnostic criteria," we describe our general approach to the diagnosis that takes into consideration the strengths of both classification systems described above. However, our general guidelines do not adequately address the myriad manifestations or subtleties of some clinical features, nor do they substitute for clinical judgment. Thus, it is often appropriate to refer patient in whom the diagnosis of SLE is suspected to a rheumatologist with experience in this disease .
Our diagnostic criteria
Definite SLE — After excluding alternative diagnoses, we diagnose SLE in the patient who fulfills the 1997 American College of Rheumatology (ACR) criteria or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria (table 2). 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 (dsDNA) antibodies.
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 :
•Optic neuritis, aseptic meningitis
•Pneumonitis, pulmonary hemorrhage, or pulmonary hypertension, interstitial lung disease
•Myocarditis, verrucous endocarditis (Libman-Sacks endocarditis)
•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.
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 SLE or a related connective tissue disorder, or even resolve.
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 do not meet the ACR criteria for SLE or another defined connective tissues disease . (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
Case series have been published that summarize the outcome of patients who have UCTD at presentation [19-23]. 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 (RA), scleroderma, or an inflammatory myopathy (myositis) [19-23] (see "Undifferentiated systemic rheumatic (connective tissue) diseases 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.
ANA-negative lupus — ANA-negative SLE has been recognized since the 1970s, but was later shown to be influenced by the testing methods used to detect ANA. At that time it was estimated that about 5 percent of patients with SLE were ANA-negative by indirect immunofluorescence . However, this negative finding occurred because sera were tested using rodent and not human tissues as the substrate for the indirect immunofluorescence test for ANA . By comparison, anti-Ro antibodies were found in many of these patients when a human cell line extract was used as substrate for anti-Ro antibody testing.
The subsequent substitution of HEp2 cells (a human cell line) for rodent tissue sections in the indirect immunofluorescence ANA assay has resulted in even fewer SLE patients with negative ANA by indirect immunofluorescence. Nevertheless, on rare occasions, the presence of anti-Ro antibodies may suggest a systemic autoimmune disease, despite the presence of a negative ANA indirect immunofluorescence. As an example, in one study in Sweden, among 4025 sera tested for ANA, 64 patients with negative ANA by indirect immunofluorescence had anti-Ro antibodies . Of these 64 patients, 12 had SLE and five had cutaneous LE.
The clinician should understand the technique used to detect the ANA since this can influence the result. As an example, a negative ANA by indirect immunofluorescence is clinically useful as it dramatically decreases the likelihood of SLE. On the other hand, in a patient with a strong clinical suspicion for SLE and a negative ANA result by a solid phase assay, the test should be repeated using indirect immunofluorescence method with Hep-2 cells given the increased risk of a false negative result for the initial ANA test by solid phase assay. A detailed discussion of the methods used to detect ANA is presented separately. (See "Measurement and clinical significance of antinuclear antibodies".)
Other factors that may also influence ANA negativity in SLE patients include disease duration and treatment exposure . 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.
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 (RA) – Early 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, important distinguishing features are 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. (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) diseases and overlap syndromes", section on 'Early undifferentiated systemic rheumatic disease'.)
●Mixed connective tissue disease (MCTD) – 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 . (See "Definition and diagnosis of mixed connective tissue disease".)
●Undifferentiated connective tissue disease (UCTD) – As mentioned above, patients with 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 serological 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 . (See "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)
●Systemic sclerosis (SSc) – 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, telangiectasias, calcinosis, and malignant hypertension with acute renal 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 (dsDNA) and anti-Smith (Sm) antibodies which 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 where there is overlap of these diseases, such as in MCTD. (See "Diagnosis and differential diagnosis of systemic sclerosis (scleroderma) in adults".)
●Sjögren's syndrome – Patients with Sjögren's syndrome may have extraglandular manifestations that can be observed in SLE, such as neurologic and pulmonary abnormalities. However, patients with Sjögren's syndrome should have objective signs of keratoconjunctivitis sicca and xerostomia, and characteristic findings on salivary gland biopsy which are not typical of SLE. Also, patients with Sjögren's syndrome commonly express antibodies to Ro and La antigens. (See "Diagnosis and classification of Sjögren's syndrome".)
●Vasculitis – Patients with medium and small vessel vasculitides such as polyarteritis nodosa (PAN), granulomatosis with polyangiitis (GPA) (Wegener's), or microscopic polyangiitis (MPA) may present with overlapping features of SLE including constitutional symptoms, skin lesions, neuropathy and renal dysfunction. However, patients with these types of vasculitides are usually ANA-negative. Rather, these patients frequently display antibodies to neutrophil cytoplasmic antigens (ANCA). (See "Clinical manifestations and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)
●Behçet's syndrome – Oral aphthae are present in almost all patients with Behçet's syndrome, and may be observed in patients with SLE. Other overlapping features include inflammatory eye disease, neurologic disease, vascular disease, and arthritis. However, patients with Behçet's are more commonly male and ANA-negative. Also, vascular involvement of any size (small, medium, large) is more commonly a feature of Behçet's syndrome rather than SLE. (See "Clinical manifestations and diagnosis of Behçet's syndrome".)
●Dermatomyositis (DM) and polymyositis (PM) – Patients with SLE can present with a low-grade myositis, whereas patients with 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 Still's disease (ASD) – Some of the clinical manifestations observed in ASD such as fever, arthritis or arthralgias, and lymphadenopathy, are not unusual for patients with SLE. However, patients with ASD often present with a leukocytosis rather than the leukopenia observed in SLE, and they typically are negative for ANA. (See "Clinical manifestations and diagnosis of adult Still's disease".)
●Kikuchi's disease – Kikuchi's disease is a benign and usually self-limited form of histiocytic-necrotizing lymphadenitis. Clinical features at presentation include lymphadenopathy as well as 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's 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, ANAs 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. However, other characteristic features of SLE such as a photosensitive rash, arthritis, and multisystem organ involvement are absent. However, fibromyalgia occurs more commonly in patients with systemic rheumatic diseases than in the general population; thus, patients with SLE may have concomitant fibromyalgia. (See "Clinical manifestations and diagnosis of fibromyalgia in adults".)
●Infections – Several viral infections can produce signs and symptoms present in SLE, including cytomegalovirus (CMV) and Epstein-Barr virus (EBV). In addition, EBV infection may lead to a positive ANA [30,31]. 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 (HBV), hepatitis C virus (HCV). 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 (MS) – Although rare, patients with SLE can present with cranial neuropathies that must be distinguished from MS. Unilateral optic neuritis and pyramidal syndrome, with lesions detected by magnetic resonance imaging (MRI) suggesting dissemination in space and time are characteristic of MS. (See "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 (LDH) levels. Patients with angioimmunoblastic T cell lymphoma (AITL) may be distinguished by findings on an excisional tissue biopsy, most commonly a lymph node.
●Thrombotic thrombocytopenic purpura (TTP) – Although patients with SLE may have fever and thrombocytopenia, patients with TTP also have microangiopathic hemolytic anemia, acute renal insufficiency, fluctuating neurological manifestations, and/or low levels of ADAMSTS13. (See "Acquired TTP: Clinical manifestations and diagnosis".)
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 5th to 6th 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 10th to 12th 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 (SLE) (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●The initial evaluation for systemic lupus erythematosus (SLE) 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. As part of the medical history and physical examination, we pay particular attention to the following symptoms and signs (see 'Evaluation for suspected SLE' 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
•Joint pain or swelling which can be migratory or symmetrical
•Symptoms of serositis/pericarditis
●We obtain a complete blood count and differential as well as serum creatinine level and urinalysis in all patients suspected of having SLE (see 'Laboratory testing' above). In addition to these routine laboratory studies, we perform selected laboratory tests which support the diagnosis of SLE if abnormal. These include antinuclear antibodies (ANA) (and if positive, other specific autoantibodies such as anti-double-stranded DNA [dsDNA], anti-Smith [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.
●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 'Imaging' above and 'Biopsy' above and 'Additional studies in selected patients' above.)
●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.)
●The diagnosis of 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. Given the great variability in the expression and severity of SLE, the diagnosis of SLE is sometimes challenging and referral to a rheumatologist with experience in this disease is often appropriate. (See 'Our diagnostic criteria' above.)
●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 or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) classification criteria (table 2). (See 'Definite SLE' 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 the following:
-Optic neuritis, aseptic meningitis
-Pneumonitis, pulmonary hemorrhage, or pulmonary hypertension, interstitial lung disease
-Myocarditis, verrucous endocarditis (Libman-Sacks endocarditis)
-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 (UCTD) – Other patients who have even fewer features suggestive of SLE may be classified as UCTD. This term is used to describe patients with signs and symptoms suggestive of a systemic autoimmune disease but do not meet the ACR criteria for SLE or another defined connective tissues disease. (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. The frequency of ANA-negative SLE is even 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.
●The differential diagnosis of SLE is broad. It includes many systemic connective diseases as well as other autoimmune disorders. (See 'Differential diagnosis' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Peter Schur, MD, who contributed to an earlier version of this topic review.
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