What is the approach to diagnose and manage a patient with suspected systemic lupus erythematosus (SLE), particularly in women of childbearing age?

Diagnostic Workup for Systemic Lupus Erythematosus

Initial Screening: ANA Testing is Mandatory

Begin with ANA testing at a titer of ≥1:160 by indirect immunofluorescence on HEp-2 cells—this is the absolute entry criterion and without a positive ANA, you cannot proceed with SLE classification regardless of clinical manifestations. 1, 2, 3

• ANA has >95% sensitivity in SLE patients, making it the essential first step 2
• Use the 1:160 dilution cutoff in unselected populations to minimize false positives 2, 3
• If ANA is negative, SLE is effectively ruled out and alternative diagnoses should be pursued 2

Comprehensive Autoantibody Panel

Once ANA is positive, order the following immunological tests to establish prognosis and organ involvement:

• Anti-dsDNA antibodies: Use a double-screening strategy—start with last-generation solid phase assay, then confirm with Crithidia luciliae immunofluorescence test 3
• Complement levels (C3 and C4): Low complement combined with positive anti-dsDNA strongly supports active SLE 1, 2, 3
• Anti-Ro/SSA and anti-La/SSB: Essential for assessing risk of fetal congenital heart block in women of childbearing age 1
• Antiphospholipid antibodies: Critical for thrombosis risk stratification and pregnancy management 1
• Anti-RNP, anti-C1q: Anti-C1q has nearly 100% prevalence during active lupus nephritis with excellent negative predictive value 1, 2

Essential Laboratory Workup

Order these baseline tests at initial presentation:

• Complete blood count: Look for cytopenias (anemia, thrombocytopenia, leukopenia <4,000/mm³, lymphopenia <1,000/mm³) which have prognostic implications 1, 2
• Serum creatinine and albumin: Provides information on renal involvement and prognosis 1, 2
• Urinalysis with microscopy and urine protein/creatinine ratio: Essential for detecting lupus nephritis 1, 2
• Erythrocyte sedimentation rate and C-reactive protein: For monitoring disease activity 3

Systematic Clinical Evaluation

Evaluate for specific manifestations across organ systems, as the EULAR/ACR 2019 criteria require involvement of at least two organ systems:

Mucocutaneous

• Acute cutaneous lupus (malar rash, photosensitive rash) 2
• Subacute or chronic cutaneous lupus (discoid lesions) 1, 2
• Oral ulcers 1

Musculoskeletal

• Symmetric arthritis involving small joints 1, 2
• Serositis (pleuritis, pericarditis) 1, 2

Renal

• Proteinuria >0.5 g/24 hours 1
• Active urinary sediment (red blood cell casts, white blood cell casts) 1

Neuropsychiatric

• Seizures, psychosis, acute confusional state 1, 2
• Headache, mood disorders, cognitive impairment, cerebrovascular disease 2, 4

Hematologic

• Hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia 1, 2

Organ-Specific Diagnostic Procedures

For Suspected Lupus Nephritis

Perform kidney biopsy before initiating immunosuppressive therapy to confirm diagnosis, assess disease activity versus chronicity, classify by ISN/RPS criteria, and determine prognosis. 1, 2, 3

• Renal biopsy is essential when proteinuria >0.5 g/24 hours or active urinary sediment is present 1
• Biopsy findings guide appropriate immunosuppressive therapy selection 1

For Cutaneous Manifestations

• Skin biopsy with histological analysis and direct immunofluorescence is mandatory when diagnosis is uncertain 2, 3

For Neuropsychiatric Symptoms

• Diagnostic workup (clinical, laboratory, neuropsychological, and imaging tests) should mirror evaluation in the general population presenting with the same symptoms 1
• Brain MRI adds prognostic information and should be considered in selected patients 1
• Critical pitfall: Always exclude infection before attributing symptoms to NPSLE, as distinguishing infection from lupus activity can be challenging 5, 4

Apply EULAR/ACR 2019 Classification Criteria

Use the EULAR/ACR 2019 criteria as the standard for classification, which requires positive ANA as entry criterion plus weighted scoring across multiple domains to reach the threshold of 10 points. 1, 2, 3

Special Considerations for Women of Childbearing Age

Baseline Assessment

• Test for anti-Ro/SSA and anti-La/SSB antibodies (risk of fetal congenital heart block 2-4.5%) 1
• Test for antiphospholipid antibodies (increased risk of miscarriage, stillbirth, premature delivery, pre-eclampsia) 1
• Counsel about fertility preservation before starting alkylating agents like cyclophosphamide 1

Contraception Counseling

• In patients with stable/inactive SLE and negative antiphospholipid antibodies, combined hormonal contraceptives can be considered 1
• In women with positive antiphospholipid antibodies, progesterone-only contraception must be carefully weighed against thrombosis risk 1
• Intrauterine devices can be offered to all patients with SLE free of gynecological contraindications 1

Pregnancy Planning

• Pregnancy should be planned during periods of disease quiescence for at least 6 months 1
• Hydroxychloroquine is recommended preconceptionally and throughout pregnancy 1
• Low-dose aspirin should be given to women at risk of pre-eclampsia (especially those with lupus nephritis or positive antiphospholipid antibodies) 1

Post-Diagnosis Monitoring Protocol

Establish baseline monitoring using validated activity indices at each visit:

• Use SLEDAI, BILAG, or SLE-DAS to monitor lupus activity and detect flares 1, 2, 3
• Monitor every 3 months in patients doing well, more frequently for uncontrolled disease 1
• Repeat testing every 6-12 months: CBC, ESR, CRP, serum albumin, creatinine, urinalysis, anti-dsDNA, C3, and C4 levels 2, 3
• Monitor anti-dsDNA and complement levels even if initially negative/normal, as they can become positive during disease course 2, 3

Common Pitfalls to Avoid

• Do not order ANA testing in patients with only nonspecific symptoms (malaise, fatigue) as it has limited value and high false-positive rates 6
• Do not escalate immunosuppression in febrile patients without excluding infection first—this is potentially fatal 5
• Do not rely solely on imaging to distinguish infection from lupus activity in pulmonary or neurological manifestations 5
• Do not use mycophenolate mofetil, cyclophosphamide, methotrexate, or leflunomide during pregnancy—these must be avoided 1
• Do not delay diagnosis in elderly patients (onset >50-65 years) who may present with atypical features: more arthritis, serositis, sicca symptoms, lung disease; less malar rash, discoid lupus, glomerulonephritis 7

Screen for High-Risk Comorbidities

SLE patients are at increased risk for specific comorbidities requiring proactive screening:

• Infections: Urinary tract infections and opportunistic infections, especially in patients on chronic glucocorticoids >7.5 mg/day and immunosuppressants 1, 5
• Cardiovascular disease: Atherosclerosis, hypertension, dyslipidemia 1
• Metabolic complications: Diabetes, osteoporosis, avascular necrosis 1
• Malignancies: Especially non-Hodgkin's lymphoma and cervical cancer in those exposed to immunosuppressive drugs 1, 8