What are the clinical manifestations and treatment options for Systemic Lupus Erythematosus (SLE)?

Clinical Manifestations and Treatment of Systemic Lupus Erythematosus (SLE)

Systemic Lupus Erythematosus (SLE) is a multisystemic autoimmune disease characterized by autoantibodies, immune complex deposition, and chronic inflammation affecting multiple organs, with the most common manifestations being mucocutaneous, musculoskeletal, and hematological abnormalities, requiring a treatment approach based on hydroxychloroquine as the foundation with additional therapies tailored to organ involvement and disease severity. 1, 2

Clinical Manifestations

Constitutional Symptoms

• Fatigue, fever, and weight loss are common early manifestations of SLE 2
• Constitutional symptoms often precede organ-specific manifestations 3

Mucocutaneous Manifestations

• Skin involvement occurs in up to 82% of SLE patients 4
• Common cutaneous manifestations include:
  • Malar (butterfly) rash - fixed erythema over the cheeks and nasal bridge 5
  • Discoid lesions - indurated scaly plaques with scarring and pigmentary changes, typically on face, scalp, and ears 5
  • Subacute cutaneous lupus erythematosus (SCLE) - photosensitive rash on upper back, shoulders, neck, and chest 5
  • Oral/nasal ulcers - often painless 1
  • Alopecia - patchy or diffuse hair loss 5
• Photosensitivity is present in many patients with cutaneous manifestations 1, 5

Musculoskeletal Manifestations

• Arthritis and arthralgia affect 73-85% of patients 4
• Typically non-erosive, symmetric polyarthritis involving small joints of hands, wrists, and knees 6
• Myalgia and myositis can occur 2

Renal Manifestations

• Lupus nephritis develops in approximately 40% of SLE patients 3
• Clinical presentations include proteinuria, hematuria, cellular casts, and declining renal function 6
• Renal biopsy is crucial for classification and treatment decisions 1
• About 10% of patients with lupus nephritis progress to end-stage kidney disease within 10 years 3

Neuropsychiatric Manifestations

• Neuropsychiatric lupus includes seizures, psychosis, acute confusional states, cognitive dysfunction, headaches, and peripheral neuropathies 6
• Diagnostic workup should be similar to that in the general population presenting with the same manifestations 6

Hematological Manifestations

• Common abnormalities include anemia, leukopenia, lymphopenia, and thrombocytopenia 7
• Autoimmune hemolytic anemia and immune thrombocytopenia may require specific treatment 7

Cardiovascular and Pulmonary Manifestations

• Serositis (pleuritis, pericarditis) is common 4
• Accelerated atherosclerosis leads to increased cardiovascular risk 8
• Pulmonary manifestations include pleuritis, pneumonitis, pulmonary hypertension, and shrinking lung syndrome 6

Other Manifestations

• Gastrointestinal involvement can include peritonitis, pancreatitis, and hepatitis 6
• Ocular manifestations such as keratoconjunctivitis sicca and retinal vasculitis 6
• Secondary antiphospholipid syndrome with thrombotic events and pregnancy complications 6

Treatment Approaches

General Principles

• The goal of treatment is to achieve remission or low disease activity, prevent organ damage, and minimize medication side effects 1
• Treatment should be tailored to disease severity and organ involvement 1

Pharmacological Treatment

First-Line Therapy

• Antimalarials (hydroxychloroquine) should be used in all SLE patients unless contraindicated 1, 3
• Hydroxychloroquine reduces disease activity, flares, damage accrual, and mortality 3
• Recommended dose not exceeding 5 mg/kg real body weight to minimize retinal toxicity 1
• Regular ophthalmological screening at baseline, after 5 years, and yearly thereafter 1

Glucocorticoids

• Used for acute flares and active disease 6
• Should be tapered to ≤7.5 mg/day (prednisone equivalent) for maintenance and withdrawn when possible 1
• Pulse intravenous methylprednisolone (1-3 days) may be used for severe manifestations 7

Immunosuppressive Agents

• For non-responsive patients or those unable to reduce steroids to acceptable levels 6:
  • Azathioprine - useful for maintenance therapy 6, 7
  • Mycophenolate mofetil - particularly effective for lupus nephritis and refractory cutaneous disease 6, 1
  • Methotrexate - effective for cutaneous and joint manifestations 1
  • Cyclophosphamide - reserved for severe manifestations, especially nephritis 6, 7
  • Calcineurin inhibitors (cyclosporine, tacrolimus) - alternative options for specific manifestations 7

Biologic Therapies

• Belimumab - FDA-approved for active SLE and lupus nephritis 4, 3
  • Shown to reduce disease activity, severe flares, and steroid use 4
  • In lupus nephritis, significantly improved renal responses compared to standard therapy alone 4
• Rituximab - considered for refractory cases, especially hematological manifestations 7
• Anifrolumab - recently approved for active SLE 3
• Voclosporin - approved for lupus nephritis 3

Organ-Specific Treatment Approaches

Cutaneous Lupus

• Topical therapies (glucocorticoids, calcineurin inhibitors) for localized disease 1
• Systemic therapies for widespread or refractory disease:
  • Hydroxychloroquine as foundation 1
  • Methotrexate, retinoids, or dapsone for specific subtypes 1
  • Mycophenolate mofetil for refractory cases 1

Lupus Nephritis

• Treatment based on histological classification 6
• Induction therapy with high-dose glucocorticoids plus either:
  • Mycophenolate mofetil or
  • Cyclophosphamide 6, 4
• Maintenance therapy with lower-dose glucocorticoids plus:
  • Mycophenolate mofetil or
  • Azathioprine 6
• Consider belimumab or voclosporin as add-on therapy 4, 3

Neuropsychiatric Lupus

• Immunosuppressive therapy for manifestations considered to be of inflammatory origin (optic neuritis, acute confusional state, neuropathy, psychosis, myelitis) 6
• Symptomatic treatment for non-inflammatory manifestations 6

Hematological Manifestations

• Moderate to high doses of glucocorticoids combined with immunosuppressive agents for significant cytopenias 7
• Consider intravenous immunoglobulin for inadequate response 7
• Rituximab for refractory cases 7
• Splenectomy only as last resort for severe, refractory thrombocytopenia 7

Adjunctive Therapies and Preventive Strategies

• Photoprotection for patients with cutaneous manifestations 6, 1
• Lifestyle modifications:
  • Smoking cessation 6, 9
  • Weight control 6, 9
  • Regular exercise 9
• Cardiovascular risk management:
  • Low-dose aspirin for patients with antiphospholipid antibodies 6
  • Statins for dyslipidemia 6
  • Antihypertensives, including ACE inhibitors for proteinuria 6
• Bone health:
  • Calcium and vitamin D supplementation 6
  • Bisphosphonates for patients on chronic glucocorticoids 6
• Infection prevention:
  • Vaccination (avoid live vaccines during immunosuppression) 6
  • Prophylactic antibiotics during high-intensity immunosuppression 6

Special Considerations

Pregnancy

• SLE may flare during pregnancy, though flares are usually mild 6
• Higher risk of preeclampsia in patients with lupus nephritis and antiphospholipid antibodies 6
• Increased risk of miscarriage, stillbirth, premature delivery, and intrauterine growth restriction 6
• Safe medications during pregnancy include:
  • Prednisolone
  • Azathioprine
  • Hydroxychloroquine
  • Low-dose aspirin 6
• Mycophenolate mofetil, cyclophosphamide, and methotrexate must be avoided 6

Antiphospholipid Syndrome

• Consider low-dose aspirin for primary prevention of thrombosis and pregnancy loss 6
• Long-term anticoagulation for secondary prevention of thrombosis 6
• Combined unfractionated or low-molecular-weight heparin and aspirin during pregnancy 6

Monitoring and Follow-up

• Regular assessment of disease activity using validated indices 1
• Monitoring for drug toxicity:
  • Regular ophthalmological screening for hydroxychloroquine 1
  • Complete blood count, liver and renal function for immunosuppressants 6
• Vigilance for comorbidities:
  • Infections
  • Atherosclerosis
  • Hypertension
  • Dyslipidemia
  • Diabetes
  • Osteoporosis
  • Avascular necrosis
  • Malignancies (especially non-Hodgkin lymphoma) 6