What are the diagnostic criteria and treatment options for systemic lupus erythematosus (SLE)?

Diagnosing Systemic Lupus Erythematosus

Begin with ANA testing at 1:160 dilution as the mandatory entry criterion—without a positive ANA, you cannot proceed with SLE classification regardless of clinical manifestations. 1

Initial Diagnostic Workup

The diagnostic approach requires systematic evaluation using the EULAR/ACR 2019 classification criteria, which demand positive ANA plus involvement of at least two organ systems. 2, 1

Essential Laboratory Tests at Presentation

Order the following tests for all patients with suspected SLE:

• Antinuclear antibodies (ANA) at 1:160 dilution cutoff, which has >95% sensitivity in SLE patients 3, 1
• Anti-double-stranded DNA (anti-dsDNA) and anti-Smith antibodies for diagnostic specificity 2, 1
• Complement levels (C3, C4) to detect hypocomplementemia indicating active disease and immune complex consumption 2, 1
• Complete blood count to identify cytopenias (thrombocytopenia <100,000/mm³, leukopenia <4,000/mm³, lymphopenia <1,000/mm³) which have prognostic implications 2, 1
• Comprehensive metabolic panel including creatinine and serum albumin for renal involvement assessment 2, 1
• Urinalysis with microscopy and urine protein/creatinine ratio to detect lupus nephritis 2, 1
• Antiphospholipid antibody panel (lupus anticoagulant, anticardiolipin, anti-β2-glycoprotein I) 2

Clinical Manifestations to Systematically Evaluate

The EULAR/ACR 2019 criteria weight manifestations within each organ domain: 1

• Mucocutaneous: Acute cutaneous lupus (malar rash, photosensitive rash), subacute cutaneous lupus, chronic cutaneous lupus, oral ulcers, alopecia 1, 4
• Musculoskeletal: Symmetric joint pain with inflammatory features (morning stiffness, swelling), myalgia 1, 4, 5
• Hematologic: Leukopenia (<4,000/mm³), lymphopenia (<1,000/mm³), thrombocytopenia, autoimmune hemolytic anemia 1
• Renal: Proteinuria (>0.5 g/24h or urine protein/creatinine ratio >0.5), cellular casts, biopsy-proven lupus nephritis 1, 6
• Neuropsychiatric: Seizures, psychosis, cognitive dysfunction, headache, mood disorders, cerebrovascular disease 2, 1
• Constitutional: Fever, fatigue (though fatigue alone has limited diagnostic value) 4, 5

Organ-Specific Diagnostic Procedures

When to Perform Kidney Biopsy

Kidney biopsy is essential before initiating immunosuppressive therapy for suspected lupus nephritis and must classify disease by ISN/RPS criteria. 2, 1 Do not delay biopsy when proteinuria exceeds 0.5 g/24h with active urinary sediment or rising creatinine. 2

Neuropsychiatric Evaluation

For headache, seizures, psychosis, or cognitive impairment, obtain MRI and EEG to exclude structural brain disease. 2 The diagnostic evaluation should mirror what would be done in non-SLE patients with identical symptoms, using clinical assessment, laboratory tests, neuropsychological testing, and imaging. 1

Dermatologic Confirmation

When cutaneous manifestations are diagnostically uncertain, perform skin biopsy with histological analysis and direct immunofluorescence. 1

Interpreting Autoantibody Results

• ANA titer 1:160 or higher is required to proceed with classification 1, 7
• Anti-dsDNA combined with low complement (C3/C4) strongly supports active SLE 1, 4
• Anti-Sm antibodies are highly specific for SLE 2, 6
• Anti-C1q antibodies have nearly 100% prevalence during active lupus nephritis with excellent negative predictive value 1
• Patients with ANA titer 1:40 and characteristic multiorgan involvement can be diagnosed with SLE, but those failing to meet full clinical criteria require additional testing for anti-dsDNA and anti-Sm 7

Common Diagnostic Pitfalls to Avoid

Do not order ANA testing in patients with isolated nonspecific symptoms like malaise and fatigue without multisystem inflammatory features—the low disease prevalence in primary care yields poor predictive value. 7, 5 Only obtain ANA when patients have unexplained involvement of two or more organ systems. 7

Do not attribute all neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic derangements, or medication side effects such as steroid-induced psychosis. 2

Do not overlook antiphospholipid antibody syndrome, which requires anticoagulation (warfarin with target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) in addition to immunosuppression. 2

Post-Diagnosis Monitoring Protocol

Establish baseline disease activity using validated indices (SLEDAI, BILAG, or SLE-DAS) at each visit. 1 Monitor the following parameters:

• Every 3 months for stable patients: Anti-dsDNA, C3, C4, complete blood count, creatinine, urinalysis with microscopy, urine protein/creatinine ratio 3, 2, 1
• More frequently for uncontrolled disease with active organ involvement 3
• Every 6-12 months: Repeat anti-dsDNA and complement levels even if initially negative/normal 1
• High-risk patients (males, juvenile onset, serologically active including anti-C1q antibodies) require monitoring every 3 months to detect early organ involvement 2

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Treatment of Systemic Lupus Erythematosus

Hydroxychloroquine at ≤5 mg/kg real body weight is mandatory for all SLE patients unless contraindicated, as it reduces disease activity, prevents flares, and improves survival. 2, 8, 6

Foundation Therapy for All Patients

Hydroxychloroquine Protocol

• Dose: ≤5 mg/kg real body weight (not ideal body weight) to minimize retinal toxicity risk, which exceeds 10% after 20 years of continuous use 2, 8
• Ophthalmological screening: Baseline examination, repeat after 5 years, then yearly using visual fields examination and/or spectral domain-optical coherence tomography 2, 8
• Hydroxychloroquine is associated with significant mortality reduction and is standard of care 6

Adjunctive Therapies for All Patients

• Photoprotection with sunscreens to prevent cutaneous flares 2, 8
• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 2, 8
• Calcium and vitamin D supplementation for all patients on long-term glucocorticoids to prevent osteoporosis 2, 8

Glucocorticoid Management Algorithm

For acute flares, administer IV methylprednisolone pulse therapy (250-1000 mg daily for 1-3 days) to provide immediate therapeutic effect and enable lower starting doses of oral glucocorticoids. 8

• Tailor oral glucocorticoid doses to disease severity and organ involvement 8
• Primary goal: Minimize chronic glucocorticoid exposure to <7.5 mg/day prednisone equivalent and withdraw when possible 2, 8
• Promptly initiate immunomodulatory agents to expedite glucocorticoid tapering/discontinuation 8

Immunosuppressive Therapy Selection by Disease Severity

Mild Disease (Skin and Joint Manifestations)

Add methotrexate if hydroxychloroquine and low-dose glucocorticoids are insufficient. 2, 8

Moderate Disease Requiring Glucocorticoid-Sparing

Choose between:

• Azathioprine: Particularly suitable for women contemplating pregnancy 2, 8
• Mycophenolate mofetil: For renal and non-renal manifestations (except neuropsychiatric disease) 2, 8

Severe Organ-Threatening Disease

For lupus nephritis, cardiopulmonary, or neuropsychiatric manifestations, initiate cyclophosphamide or mycophenolate mofetil as induction therapy. 2, 8

Lupus Nephritis-Specific Treatment Protocol

Kidney biopsy is essential before initiating therapy to guide treatment selection and determine prognosis. 2, 8

Induction Therapy

• First-line agents: Mycophenolate mofetil OR low-dose IV cyclophosphamide (Euro-Lupus regimen) have the best efficacy/toxicity ratio 2, 8
• Low-dose cyclophosphamide is preferred over high-dose cyclophosphamide due to comparable efficacy and lower gonadotoxicity 8
• Combine with high-dose glucocorticoids (including IV methylprednisolone pulses) 8

Maintenance Therapy

After achieving initial response, transition to:

• Mycophenolate mofetil (first-line) OR azathioprine 2, 8

Treatment Goals

Achieve at least partial remission (≥50% reduction in proteinuria to subnephrotic levels and serum creatinine within 10% of baseline) by 6-12 months. 2 Complete remission is defined as urine protein/creatinine ratio <0.5 g/g and eGFR ≥90 mL/min/1.73 m² or no decrease in eGFR >10% from pre-flare value. 9

Organ-Specific Treatment Algorithms

Neuropsychiatric Lupus (NPSLE)

Treatment depends on the underlying pathophysiological mechanism: 8

• For inflammatory/immune-mediated mechanisms: High-dose glucocorticoids (IV methylprednisolone) plus cyclophosphamide (response rate 95% vs 54% with methylprednisolone alone, p=0.03) 8
• For thrombotic/embolic/ischemic mechanisms: Anticoagulation with warfarin (target INR 2.0-3.0 for first venous thrombosis, 3.0-4.0 for arterial or recurrent thrombosis) 2, 8
• When both mechanisms coexist: Combination of immunosuppressive and anticoagulant therapy 8

Acute Lupus Thrombocytopenia

• First-line: High-dose glucocorticoids (including IV methylprednisolone pulses) and/or IV immunoglobulin G 8
• Combine with immunosuppressive agents (azathioprine, mycophenolate mofetil, or cyclosporine) 8
• For refractory cases: Rituximab or cyclophosphamide 8

Cutaneous Manifestations

• First-line: Topical glucocorticoids, topical calcineurin inhibitors, and hydroxychloroquine 8
• Escalate to systemic immunosuppression if inadequate response 8

Biologic Therapies for Refractory Disease

Belimumab (Anti-BAFF Antibody)

Belimumab is FDA-approved as add-on treatment for active extrarenal SLE and lupus nephritis when standard therapy is insufficient. 2, 9

• In lupus nephritis (Trial 5), belimumab plus standard therapy achieved 43% primary efficacy renal response at Week 104 vs 32% with placebo (OR 1.6,95% CI 1.0-2.3, p=0.031) 9
• Complete renal response: 30% with belimumab vs 20% with placebo (OR 1.7,95% CI 1.1-2.7, p=0.017) 9
• In active SLE (Trials 2 and 3), belimumab improved SLE Responder Index response rates 9

Rituximab

Consider rituximab for organ-threatening disease refractory to standard immunosuppressive agents, particularly for hematological manifestations. 2, 8

Anifrolumab

Anifrolumab (anti-type 1 interferon receptor) is FDA-approved for moderate-to-severe extrarenal SLE. 2, 6

Voclosporin

Voclosporin is FDA-approved for lupus nephritis. 6

Special Populations: Pregnancy

Safe medications during pregnancy: Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin 8

Contraindicated medications: Mycophenolate mofetil, cyclophosphamide, and methotrexate must not be used in women who are pregnant or contemplating pregnancy. 2, 8

Comorbidity Screening and Prevention

SLE patients have a 5-fold increased mortality risk, necessitating vigilant screening for: 8

• Infections (leading cause of death in SLE) 8
• Cardiovascular disease: Assess risk in patients with persistent proteinuria, GFR <60 mL/min, and chronic glucocorticoid use 2
• Hypertension, diabetes, dyslipidemia 8
• Osteoporosis: Screen all patients on long-term glucocorticoids 8
• Malignancies, especially non-Hodgkin lymphoma 8

Critical Treatment Pitfalls to Avoid

Do not use mycophenolate mofetil, cyclophosphamide, or methotrexate in women who are pregnant or contemplating pregnancy—azathioprine, hydroxychloroquine, and prednisolone are safe alternatives. 2

Do not delay kidney biopsy in suspected lupus nephritis, as histological classification is essential for treatment selection and prognosis. 2, 8

Do not attribute all neuropsychiatric symptoms to SLE without excluding infection (especially in immunosuppressed patients), metabolic causes, or medication side effects (steroid-induced psychosis). 2

Do not overlook antiphospholipid antibody syndrome, which requires anticoagulation in addition to immunosuppression. 2