Systemic Lupus Erythematosus: Diagnosis and Treatment

Nguyet-Cam V. Lam; Judy Abu Brown; Richa Sharma

NGUYET-CAM V. LAM, MD, JUDY ABU BROWN, MD, AND RICHA SHARMA, MD

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

Clinical recommendation	Evidence rating	Comments
Treatment of systemic lupus erythematosus should aim for complete remission or low disease activity and prevention of flare-ups in all organs using the lowest possible dose of glucocorticoids.^19,22,23	C	Expert opinion and consensus guideline
Hydroxychloroquine is recommended for all patients with systemic lupus erythematosus.^19,29	C	Consensus guideline based on inconsistent or limited-quality patient-oriented evidence
Hydroxychloroquine should be continued during pregnancy because it has been shown to control disease activity. It may reduce pregnancy complications, including preeclampsia and cardiac neonatal lupus.^47–50	B	Inconsistent or limited-quality patient-oriented evidence and expert opinion
Patients with active disease should be evaluated at least every one to three months, and measurements of blood pressure, anti–double-stranded DNA antibodies, and complement and C-reactive protein levels; urinalysis; complete blood count; and kidney and liver function tests should be performed.⁴⁶	C	Expert opinion and consensus guideline

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

System	ACR criteria (1997)*	SLICC criteria (2012)†	EULAR/ACR (2019)‡
Cardiovascular/pulmonary	Pleuritis (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)
Constitutional	—	—	Fever > 100.9°F (38.3°C) (2)
Hematologic	Hemolytic 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)
Immunologic	Positive test result for antinuclear antibodies; elevated anti-dsDNA, anti-Smith, or antiphospholipid antibodies; discoid rash; photosensitivity; oral or nasal ulcers	Positive 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 ulcers	Anticardiolipin 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/mucosal	Malar rash	Acute cutaneous lupus or subacute cutaneous lupus	Nonscarring alopecia (2); oral ulcers (2); subacute cutaneous or discoid lupus (4); acute cutaneous lupus (6)
Musculoskeletal	Nonerosive arthritis involving two or more joints	Synovitis involving two or more joints or tenderness at two or more joints and at least 30 minutes of stiffness in the morning	Joint involvement (6)
Neuropsychiatric	Seizure or psychosis	Seizure, psychosis, mononeuritis complex, myelitis, or peripheral or cranial neuropathy	Delirium (2); psychosis (3); seizure (5)
Renal	Persistent proteinuria (> 0.5 g in 24 hours or > 3+ on urine dipstick testing) or cellular casts	Urinary creatinine (or 24-hour urinary protein) > 500 mg or red blood cell casts	Proteinuria > 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

Diagnosis

CLINICAL PRESENTATION

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 diagnosis	Distinguishing features	Diagnostic approach
Adult-onset Still disease	Arthralgia, fever, lymphadenopathy, splenomegaly	Elevated erythrocyte sedimentation rate, elevated ferritin level, leukocytosis, and anemia
Behçet syndrome	Aphthous ulcers, arthralgia, uveitis	Recurrent oral ulcers plus two of the following: eye lesions, genital ulcers, skin lesions
Chronic fatigue syndrome	Persistent and unexplained fatigue that significantly impairs daily activities	Perform 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
Endocarditis	Arterial emboli, arthralgia, fever, heart murmur, myalgia	Positive echocardiography findings with vegetation on heart valve; positive blood culture
Fibromyalgia	Poorly localized musculoskeletal pain with hyperalgesia and allodynia	Digital palpation of soft tissue tender points: gluteal, greater trochanter, knee, lateral epicondyle, low cervical, occiput, second rib, supraspinatus, trapezius
HIV infection	Arthralgia, fever, lymphadenopathy, malaise, myalgia, peripheral neuropathy, rash	Western blot assay for detection of HIV antibodies
Inflammatory bowel disease	Diarrhea, peripheral arthritis, rectal bleeding, tenesmus	Perform colonoscopy to assess disease activity; measure C-reactive protein level, platelets, and erythrocyte sedimentation rate; test for anemia
Lyme disease	Arthritis, carditis, erythema migrans, neuritis	Perform serologic testing for Lyme disease
Mixed connective tissue disease	Arthralgia, myalgia, puffy fingers, Raynaud phenomenon, sclerodactyly	Elevated erythrocyte sedimentation rate and hypergammaglobulinemia; positive anti-U1RNP antibodies
Psoriatic arthritis	Psoriasis before or after joint disease, nail changes in fingers and toes	Inflammatory 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 arthritis	Acute nonpurulent arthritis from infection elsewhere in the body; evaluate for infectious urethritis or colitis	Clinical diagnosis to identify triggers; serologic findings of recent infections may be present
Rheumatoid arthritis	Morning joint stiffness lasting more than one hour; affected joints are usually symmetrical, tender, and swollen	Positive test results for rheumatoid factor and anti-cyclic citrullinated antibodies; synovial fluid reflects inflammatory state
Sarcoidosis	Cough, dyspnea, fatigue, fever, night sweats, rash, uveitis	Perform chest radiography; bilateral adenopathy with biopsy revealing noncaseating granuloma; elevated angiotensin-converting enzyme level
Systemic sclerosis	Arthralgia, decreased joint mobility, myalgia, Raynaud phenomenon, skin induration	Perform tests for specific autoantibodies
Thyroid disease	Dry skin, fatigue, feeling cold, weakness	Measure thyroid-stimulating hormone

INITIAL EVALUATION

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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Classification Criteria

Diagnosis

CLINICAL PRESENTATION

INITIAL EVALUATION

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Diagnosis

CLINICAL PRESENTATION

INITIAL EVALUATION

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