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Am Fam Physician. 2023;107(4):383-395

Patient information: See related handout on lupus.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial relationships.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects the cardiovascular, gastrointestinal, hematologic, integumentary, musculoskeletal, neuropsychiatric, pulmonary, renal, and reproductive systems. It is a chronic disease and may cause recurrent flare-ups without adequate treatment. The newest clinical criteria proposed by the European League Against Rheumatism/American College of Rheumatology in 2019 include an obligatory entry criterion of a positive antinuclear antibody titer of 1: 80 or greater. Management of SLE is directed at complete remission or low disease activity, minimizing the use of glucocorticoids, preventing flare-ups, and improving quality of life. Hydroxychloroquine is recommended for all patients with SLE to prevent flare-ups, organ damage, and thrombosis and increase long-term survival. Pregnant patients with SLE have an increased risk of spontaneous abortions, stillbirths, preeclampsia, and fetal growth restriction. Preconception counseling regarding risks, planning the timing of pregnancy, and a multidisciplinary approach play a major role in the management of SLE in patients contemplating pregnancy. All patients with SLE should receive ongoing education, counseling, and support. Those with mild SLE can be monitored by a primary care physician in conjunction with rheumatology. Patients with increased disease activity, complications, or adverse effects from treatment should be managed by a rheumatologist.

Systemic lupus erythematosus (SLE) is an autoimmune disease that affects multiple organ systems. Its course is typically recurrent, with periods of relative remission followed by flare-ups. SLE can affect anyone, but it is more common in women between 15 and 44 years of age. The incidence and prevalence of SLE in North America are 23.2 per 100,000 person-years and 241 per 100,000 people, respectively.1

The newest clinical criteria proposed by the European League Against Rheumatism/American College of Rheumatology in 2019 include an obligatory entry criterion: a positive antinuclear antibody titer of 1: 80 or greater.
Patients with chronic kidney disease should receive one dose of pneumococcal conjugate vaccine (PCV20 or PCV15). When PCV15 is used, it should be followed by a dose of pneumococcal polysaccharide vaccine (PPSV23).
Anifrolumab (Saphnelo) and voclosporin (Lupkynis) are new medications approved by the U.S. Food and Drug Administration in 2021 for the management of systemic lupus erythematosus.

Classification Criteria

Clinicians should have high suspicion for SLE in patients with symptoms involving multiple organ systems. Three classification approaches have evolved and provide some perspective on features of the disease, but these are not diagnostic criteria. These classification criteria are designed to standardize patients for entry into clinical trials. However, these criteria are often used clinically to evaluate patients.

Based on the 1997 update of the 1982 American College of Rheumatology (ACR) criteria, patients meet criteria for SLE if they have four or more of the 11 symptoms.2,3 However, it was noted that not all patients meeting the criteria will have lupus and not all patients with clinically diagnosed lupus will meet the threshold criteria of four or more of the 11 symptoms.4,5 Because of this, the Systemic Lupus International Collaborating Clinics (SLICC) proposed new criteria in 2012.6 According to the SLICC criteria, patients must meet at least four criteria, including at least one clinical and one immunologic criterion, or the patient should have a biopsy confirming lupus nephritis and elevated antinuclear antibody (ANA) or anti–double-stranded DNA (anti-dsDNA) levels without any other criteria.6 The SLICC criteria have increased sensitivity (97%) and decreased specificity (84%) compared with the ACR criteria.6

The newest clinical criteria proposed by the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) in 2019 include an obligatory entry criterion of a positive ANA titer of 1: 80 or greater. The EULAR/ACR criteria have a sensitivity of 96% and an increased specificity of 93%. In these criteria, points are given for each clinical and immunologic criterion met. If the ANA titer is positive, the criteria are additively weighted from 2 to 10, with a score of 10 required for classification. These weighted criteria are clinical (e.g., constitutional, hematologic, neuropsychiatric, muco-cutaneous, serosal, musculoskeletal, renal) and immunologic (i.e., antiphospholipid antibodies, complement proteins, and SLE-specific antibodies).7 A diagnosis of SLE is made in consultation with a rheumatologist. Table 1 summarizes the classification criteria of SLE.3,7,8

SystemACR criteria (1997)*SLICC criteria (2012)EULAR/ACR (2019)
Cardiovascular/pulmonaryPleuritis (pleuritic pain or rub or pleural effusion) or pericarditis (documented by electrocardiography, rub, or pericardial effusion)Serositis (pleurisy for more than one day, pleural effusion, or pleural rub; pericardial pain for more than one day, pericardial effusion, pericardial rub, or pericarditis)Pleural or pericardial effusion (5); acute pericarditis (6)
ConstitutionalFever > 100.9°F (38.3°C) (2)
HematologicHemolytic anemia, leukopenia (< 4,000 cells per mm3), lymphopenia (< 1,500 cells per mm3), or thrombocytopenia (< 100,000 cells per mm3)Hemolytic anemia; leukopenia (< 4,000 cells per mm3) more than once or lymphopenia (< 1,000 cells per mm3) more than once; thrombocytopenia (< 100,000 cells per mm3)Leukopenia (3); thrombocytopenia (4); autoimmune hemolysis (4)
ImmunologicPositive test result for antinuclear antibodies; elevated anti-dsDNA, anti-Smith, or antiphospholipid antibodies; discoid rash; photosensitivity; oral or nasal ulcersPositive test result for antinuclear antibodies; elevated anti-dsDNA, anti-Smith, or antiphospholipid antibodies; low complement (C3, C4, or CH 50) or direct Coombs test (in the absence of hemolytic anemia); chronic cutaneous lupus, nonscarring alopecia, or oral or nasal ulcersAnticardiolipin immunoglobulin G or anti-beta2-glycoprotein 1 antibodies or lupus anticoagulant (2); low C3 or C4 (3); low C3 and low C4 (4); anti-dsDNA or anti-Smith antibodies (6)
Integumentary/mucosalMalar rashAcute cutaneous lupus or subacute cutaneous lupusNonscarring alopecia (2); oral ulcers (2); subacute cutaneous or discoid lupus (4); acute cutaneous lupus (6)
MusculoskeletalNonerosive arthritis involving two or more jointsSynovitis involving two or more joints or tenderness at two or more joints and at least 30 minutes of stiffness in the morningJoint involvement (6)
NeuropsychiatricSeizure or psychosisSeizure, psychosis, mononeuritis complex, myelitis, or peripheral or cranial neuropathyDelirium (2); psychosis (3); seizure (5)
RenalPersistent proteinuria (> 0.5 g in 24 hours or > 3+ on urine dipstick testing) or cellular castsUrinary creatinine (or 24-hour urinary protein) > 500 mg or red blood cell castsProteinuria > 0.5 g in 24 hours (4); renal biopsy class II or V lupus nephritis (8); renal biopsy class III or IV lupus nephritis (10)

Figure 1 presents an algorithm for the diagnosis of SLE in the primary care setting.7,9



Patients with SLE commonly present to their family physicians with multiple nonspecific symptoms, making it difficult to diagnose. Laboratory testing may be negative early in the onset of SLE. Fatigue is the most prevalent symptom and is nonspecific but may be associated with weight loss, fever without a source of infection, and joint pain.10 Malar rash (31%; Figure 2), photosensitivity with associated acute and subacute cutaneous lupus rash (23%; Figure 39), pleuritic chest pain (16%), Raynaud phenomenon (16%), and mouth sores (12.5%) are less common.11 The differential diagnosis for SLE is summarized in Table 2.12

Differential diagnosisDistinguishing featuresDiagnostic approach
Adult-onset Still diseaseArthralgia, fever, lymphadenopathy, splenomegalyElevated erythrocyte sedimentation rate, elevated ferritin level, leukocytosis, and anemia
Behçet syndromeAphthous ulcers, arthralgia, uveitisRecurrent oral ulcers plus two of the following: eye lesions, genital ulcers, skin lesions
Chronic fatigue syndromePersistent and unexplained fatigue that significantly impairs daily activitiesPerform the following tests to rule out other diseases: complete blood count, erythrocyte sedimentation rate, C-reactive protein level, complete metabolic panel, thyroid-stimulating hormone, urinalysis
EndocarditisArterial emboli, arthralgia, fever, heart murmur, myalgiaPositive echocardiography findings with vegetation on heart valve; positive blood culture
FibromyalgiaPoorly localized musculoskeletal pain with hyperalgesia and allodyniaDigital palpation of soft tissue tender points: gluteal, greater trochanter, knee, lateral epicondyle, low cervical, occiput, second rib, supraspinatus, trapezius
HIV infectionArthralgia, fever, lymphadenopathy, malaise, myalgia, peripheral neuropathy, rashWestern blot assay for detection of HIV antibodies
Inflammatory bowel diseaseDiarrhea, peripheral arthritis, rectal bleeding, tenesmusPerform colonoscopy to assess disease activity; measure C-reactive protein level, platelets, and erythrocyte sedimentation rate; test for anemia
Lyme diseaseArthritis, carditis, erythema migrans, neuritisPerform serologic testing for Lyme disease
Mixed connective tissue diseaseArthralgia, myalgia, puffy fingers, Raynaud phenomenon, sclerodactylyElevated erythrocyte sedimentation rate and hypergammaglobulinemia; positive anti-U1RNP antibodies
Psoriatic arthritisPsoriasis before or after joint disease, nail changes in fingers and toesInflammatory articular disease and more than three of the following: dactylitis, nail changes, negative rheumatoid factor, psoriasis, radiographic evidence of new bone formation in hand or foot
Reactive arthritisAcute nonpurulent arthritis from infection elsewhere in the body; evaluate for infectious urethritis or colitisClinical diagnosis to identify triggers; serologic findings of recent infections may be present
Rheumatoid arthritisMorning joint stiffness lasting more than one hour; affected joints are usually symmetrical, tender, and swollenPositive test results for rheumatoid factor and anti-cyclic citrullinated antibodies; synovial fluid reflects inflammatory state
SarcoidosisCough, dyspnea, fatigue, fever, night sweats, rash, uveitisPerform chest radiography; bilateral adenopathy with biopsy revealing noncaseating granuloma; elevated angiotensin-converting enzyme level
Systemic sclerosisArthralgia, decreased joint mobility, myalgia, Raynaud phenomenon, skin indurationPerform tests for specific autoantibodies
Thyroid diseaseDry skin, fatigue, feeling cold, weaknessMeasure thyroid-stimulating hormone


SLE should be considered in patients who present with symptoms involving multiple organ systems after ruling out infectious causes. In addition to constitutional symptoms, the cardiovascular, gastrointestinal, hematologic, integumentary, musculoskeletal, neuropsychiatric, pulmonary, renal, and reproductive systems are most often affected.8 The reticuloendothelial system involving the phagocytic function of macrophages and monocytes also may be affected.

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