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

Systemic Lupus Erythematosus Diagnosis

Diagnose SLE when a patient has an ANA titer ≥1:160 (mandatory entry criterion) plus sufficient clinical and immunologic features to meet the 2019 EULAR/ACR classification criteria, which are 96.1% sensitive and 93.4% specific for SLE. 1

Diagnostic Approach

Initial Screening

• Order ANA testing only when patients present with unexplained involvement of two or more organ systems—testing in low-probability patients yields poor predictive value despite high sensitivity 2
• An ANA titer ≥1:160 is the mandatory entry criterion for applying the 2019 EULAR/ACR classification criteria 1
• If ANA is positive, proceed with anti-dsDNA, anti-Smith antibodies, complement levels (C3, C4), complete blood count, comprehensive metabolic panel, and urinalysis with microscopy 3

Clinical Features to Assess

• Constitutional: Fever (>38.3°C) 1
• Mucocutaneous: Malar rash, discoid rash, photosensitivity, oral ulcers, non-scarring alopecia 1, 4
• Musculoskeletal: Arthritis (typically non-erosive, involving 2+ joints) 1, 4
• Hematologic: Leukopenia (<4,000/mm³), lymphopenia (<1,000/mm³), thrombocytopenia (<100,000/mm³), autoimmune hemolysis 1, 4
• Renal: Proteinuria (>0.5 g/24 hours or urine protein:creatinine ratio >0.5), active urinary sediment with red blood cell casts 1, 4
• Neuropsychiatric: Seizures, psychosis, acute confusional state, mononeuritis multiplex 1, 4
• Serositis: Pleuritis, pericarditis 1, 4

Immunologic Testing

• Anti-dsDNA antibodies: Highly specific for SLE 1, 2
• Anti-Smith antibodies: Highly specific but less sensitive 1, 2
• Low complement levels (C3, C4): Indicate active disease and immune complex consumption 1
• Antiphospholipid antibodies: Test for anticardiolipin, anti-β2-glycoprotein IgG/IgM, and lupus anticoagulant to identify antiphospholipid syndrome, which occurs in a subset of SLE patients 3

Diagnostic Thresholds

• Patients with ANA ≥1:160 plus characteristic multiorgan involvement can be diagnosed with SLE when they meet the 2019 EULAR/ACR classification criteria 1
• The older ACR criteria (requiring 4 of 11 features) have 95% specificity and 85% sensitivity, but the 2019 criteria perform better 4, 1
• ANA-negative SLE is rare but possible—if clinical suspicion remains high despite negative ANA, consider repeat testing or referral to rheumatology 2

Critical Diagnostic Pitfalls

• Do not order ANA testing in patients without multisystem involvement—the low pretest probability in primary care yields excessive false positives 2
• Significantly elevated CRP (>50 mg/L) should prompt exclusion of infection rather than attributing symptoms to SLE, as SLE typically causes minimal CRP elevation 3
• Always perform kidney biopsy before treating suspected lupus nephritis—treatment decisions depend on histological classification (Class III, IV, V) 5, 6
• Consider subacute bacterial endocarditis in patients with fever, arthritis, glomerulonephritis, and positive ANA—blood cultures and echocardiography are essential to exclude this mimicker 3
• Distinguish neuropsychiatric SLE from multiple sclerosis using MRI patterns (periventricular lesions) and CSF oligoclonal bands, though MRI sensitivity in active neuropsychiatric SLE is only 57% 3

Differential Diagnoses to Exclude

• Antiphospholipid antibody syndrome: Can occur independently or with SLE; requires persistent moderate-to-high anticardiolipin, anti-β2-glycoprotein IgG/IgM, or lupus anticoagulant 3
• Drug-induced lupus: Associated with hydralazine, procainamide, isoniazid, minocycline—typically resolves after drug discontinuation 4
• Autoimmune lymphoproliferative syndrome (ALPS): Presents with lymphadenopathy, hepatosplenomegaly, and autoimmune cytopenias mimicking SLE 3
• Infectious mimickers: Lyme disease, HTLV-1 (in endemic areas), subacute bacterial endocarditis 3
• Hematologic malignancies: Non-Hodgkin lymphoma can present with cytopenias, lymphadenopathy, and constitutional symptoms; SLE patients have increased lymphoma risk 3

When to Refer to Rheumatology

• Immediate referral: Suspected lupus nephritis (proteinuria, active urinary sediment, rising creatinine), neuropsychiatric manifestations, severe cytopenias, or any organ-threatening disease 4
• Routine referral: ANA-positive patients meeting diagnostic criteria, patients with increased disease activity despite initial management, or those experiencing adverse effects from treatment 4
• Coordinate care closely between rheumatology and primary care to optimize chronic disease management and preventive health services 4

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Treatment of Systemic Lupus Erythematosus

All SLE patients must receive hydroxychloroquine (200-400 mg daily, not exceeding 5 mg/kg actual body weight) unless contraindicated, as it reduces disease activity, prevents flares, and improves survival. 5, 1

Foundation Therapy (All Patients)

• Hydroxychloroquine is mandatory for all SLE patients—non-adherence is associated with higher flare rates and mortality 5
• Dose: 200-400 mg daily, not exceeding 5 mg/kg actual body weight 5
• Ophthalmological screening is required at baseline, after 5 years of therapy, and yearly thereafter to monitor for retinal toxicity 5
• Photoprotection with sunscreens prevents cutaneous flares 5
• Low-dose aspirin for patients with antiphospholipid antibodies, those receiving corticosteroids, or those with cardiovascular risk factors 5
• Calcium and vitamin D supplementation for all patients on long-term glucocorticoids 5

Glucocorticoid Management

• Use the lowest possible dose for the shortest duration—prolonged use of >7.5 mg/day prednisone equivalent increases irreversible organ damage risk 7, 5
• Goal: minimize to <7.5 mg/day and withdraw when possible 5
• For acute flares: Intravenous methylprednisolone pulses (500-1000 mg) provide immediate effect and enable lower starting doses of oral glucocorticoids 5
• Low-dose glucocorticoids (prednisone ≤7.5 mg/day) can be added when clinically indicated 5

Treatment by Disease Severity

Mild Disease (Mucocutaneous, Musculoskeletal)

• Start with hydroxychloroquine plus low-dose glucocorticoids if needed 5
• Methotrexate is the preferred first choice for musculoskeletal and skin manifestations due to cost and availability 5
• NSAIDs as first-line for pain and stiffness, particularly for musculoskeletal manifestations 7
• For patients with increased gastrointestinal risk, use either non-selective NSAIDs plus a gastroprotective agent (PPI or misoprostol) or a selective COX-2 inhibitor 7

Moderate to Severe Disease (Organ-Threatening)

• Do not delay immunosuppressive therapy in organ-threatening disease—early aggressive treatment prevents irreversible damage 5
• Azathioprine, mycophenolate mofetil, or cyclophosphamide for moderate to severe disease 1
• Belimumab should be added for patients with inadequate response to standard therapy (hydroxychloroquine + glucocorticoids ± immunosuppressants) 5, 6

Lupus Nephritis

• Always perform kidney biopsy before initiating therapy to confirm diagnosis and guide treatment planning 5, 6
• Induction therapy: Mycophenolate mofetil or low-dose intravenous cyclophosphamide are first-line options 5
• Maintenance therapy: Mycophenolate mofetil or azathioprine 5
• Belimumab 10 mg/kg IV (Days 0,14,28, then every 28 days) plus standard therapy significantly improves Primary Efficacy Renal Response at Week 104 (43% vs 32% placebo, OR 1.6, p=0.031) 6
• Voclosporin is FDA-approved for lupus nephritis 5, 1

Biologic Therapies for Refractory Disease

• Belimumab (BLyS-specific inhibitor): FDA-approved for active SLE (2011) and lupus nephritis (2020) 6, 1
  • IV dosing: 10 mg/kg at 2-week intervals for first 3 doses, then every 4 weeks 6
  • SC dosing for adults with SLE: 200 mg once weekly 6
  • SC dosing for adults with lupus nephritis: 400 mg (two 200-mg injections) once weekly for 4 doses, then 200 mg once weekly 6
  • Consider prophylactic premedication for infusion reactions and hypersensitivity reactions 6
• Rituximab for organ-threatening disease refractory to or with intolerance/contraindications to standard immunosuppressive agents 5
• Anifrolumab is FDA-approved for moderate-to-severe extrarenal SLE 5, 1

Monitoring and Comorbidity Management

• Use validated activity indices (SLEDAI, BILAG) at each visit 8, 5
• Monitor at each visit: Disease activity, quality of life (patient global score 0-10 VAS), medication adherence 8
• Monitor regularly: Anti-dsDNA, C3, C4, complete blood count, creatinine, proteinuria, urine sediment 5
• Assess organ damage annually 8

Cardiovascular Risk (Assess at Baseline and Yearly)

• SLE patients have 5-fold increased mortality risk compared to the general population 5
• Assess smoking, vascular events, physical activity, oral contraceptives, hormonal therapies, family history 8
• Blood tests: cholesterol, glucose 8
• Examine: blood pressure, body mass index, waist circumference 8
• Patients on glucocorticoids may need more frequent follow-up 8

Infection Prevention

• Screen for HIV, HCV/HBV, tuberculosis, and CMV before immunosuppression 5
• Vaccinate with inactivated vaccines (influenza, pneumococcus) when SLE is inactive 5
• Live vaccines should not be given concurrently with belimumab or other immunosuppressants 6
• Serious and sometimes fatal infections have occurred—use caution in patients with severe or chronic infections, and consider interrupting therapy if new infection develops 6

Osteoporosis Management

• All patients should be assessed for adequate calcium and vitamin D intake, regular exercise, and smoking habits 8, 5
• Screen and follow according to existing guidelines for postmenopausal women and patients on steroids 8, 5

Cancer Screening

• SLE patients have increased risk for non-Hodgkin lymphoma, lung cancer, and hepatobiliary cancer 5
• Cancer screening according to guidelines for the general population, including cervical smear tests 8, 5

Special Populations: Pregnancy

• Safe medications during pregnancy: Hydroxychloroquine, azathioprine, prednisolone, low-dose aspirin 7, 5
• Avoid during pregnancy: Mycophenolate mofetil, cyclophosphamide, methotrexate 7, 5
• Patients with lupus nephritis and antiphospholipid antibodies have higher risk of preeclampsia and require closer monitoring 5

Non-Pharmacological Management

• Patient education about disease and pain management strategies 7
• Regular exercise tailored to patient capabilities 7
• Physical therapy (individual or group) 7
• Psychological support for pain coping strategies 7
• Smoking cessation interventions 5

Critical Treatment Pitfalls

• Never withhold hydroxychloroquine unless there is a clear contraindication—non-adherence is associated with higher flare rates and mortality 5
• Avoid prolonged high-dose glucocorticoids (>7.5 mg/day prednisone equivalent)—they increase irreversible organ damage risk 7, 5
• Always assess medication adherence, especially to hydroxychloroquine—non-adherence is associated with higher flare rates and increased pain 7
• Regular monitoring of disease activity is essential to distinguish between pain due to active inflammation versus damage or fibromyalgia 7
• Previous anaphylaxis to belimumab is a contraindication to its use 6
• Assess for depression and risk of suicide before and during treatment with belimumab—depression and suicidality were reported in trials 6