Systemic Lupus Erythematosus (SLE) - 25-Mark Notes

Definition

Epidemiology

• Predominantly affects women of child-bearing age, usually 15-45 years.
• Female:male ratio is about 9:1 during reproductive years.
• More frequent and often more severe in people of African, Asian, Hispanic, and Indigenous ancestry.
• Familial clustering occurs.
• Survival has greatly improved, but mortality may result from active renal/CNS disease, infection, thrombosis, and premature cardiovascular disease.

Etiopathogenesis

1. Genetic factors

• Association with HLA-DR2 and HLA-DR3.
• Deficiency of early complement components, especially C1q, C2, and C4, predisposes strongly to SLE.
• Multiple genes influence interferon signalling, B-cell activation, and clearance of apoptotic cells.

2. Environmental triggers

• Ultraviolet light exposure
• Infections, particularly viral triggers
• Smoking
• Physical or emotional stress
• Some drugs

3. Hormonal factors

• Female predominance suggests a role for estrogen.
• Disease may flare during pregnancy or the puerperium.

4. Immunological mechanisms

1. Defective clearance of apoptotic nuclear material exposes self-antigens.
2. Loss of B-cell and T-cell tolerance causes autoantibody production.
3. Plasmacytoid dendritic cells produce excess type I interferon, a central pathway in SLE.
4. B cells produce ANA, anti-dsDNA, anti-Sm, and antiphospholipid antibodies.
5. Antigen-antibody immune complexes deposit in tissues.
6. Complement activation, inflammation, vasculitis, and thrombosis cause organ injury.

• Type III hypersensitivity: immune-complex deposition
• Type II hypersensitivity: antibody-mediated cytopenias
• Antiphospholipid antibody-mediated thrombosis

Clinical Features

A. Constitutional

• Fever
• Fatigue
• Weight loss
• Malaise
• Lymphadenopathy

B. Musculoskeletal manifestations

• Arthralgia and symmetrical inflammatory polyarthritis
• Usually affects small joints of hands, wrists, and knees
• Characteristically non-erosive arthritis
• Jaccoud arthropathy: reducible deformities due to ligament/tendon laxity
• Myalgia and inflammatory myositis may occur

C. Mucocutaneous manifestations

Acute cutaneous lupus

• Malar or butterfly rash over cheeks and bridge of nose
• Typically spares nasolabial folds
• Photosensitive rash

Subacute cutaneous lupus

• Annular or papulosquamous lesions, usually on sun-exposed areas
• Often associated with anti-Ro/SSA antibodies

Chronic cutaneous lupus

• Discoid lupus erythematosus: well-defined erythematous scaly plaques, scarring, pigmentary changes, and alopecia

• Photosensitivity
• Oral or nasal ulcers, usually painless
• Non-scarring diffuse alopecia
• Raynaud phenomenon
• Livedo reticularis
• Cutaneous vasculitis and digital ischemia

D. Renal involvement: lupus nephritis

• Proteinuria
• Hematuria
• Red-cell casts
• Hypertension
• Raised serum creatinine
• Nephrotic syndrome or nephritic syndrome

ISN/RPS classes of lupus nephritis

E. Neuropsychiatric SLE

• Seizures
• Psychosis
• Cognitive dysfunction
• Acute confusional state
• Headache
• Stroke or transient ischemic attack
• Peripheral neuropathy
• Myelopathy

F. Hematological manifestations

• Autoimmune hemolytic anemia
• Leukopenia, especially lymphopenia
• Thrombocytopenia
• Pancytopenia, rarely
• Antiphospholipid antibody syndrome causing arterial, venous, or placental thrombosis

G. Cardiovascular manifestations

• Pericarditis: commonest cardiac manifestation
• Myocarditis
• Libman-Sacks endocarditis: sterile valvular vegetations
• Accelerated atherosclerosis and premature coronary artery disease
• Hypertension

H. Respiratory manifestations

• Pleuritis with pleural effusion
• Acute lupus pneumonitis
• Interstitial lung disease
• Pulmonary hemorrhage
• Pulmonary arterial hypertension
• Pulmonary embolism, especially with antiphospholipid antibodies

I. Gastrointestinal and other manifestations

• Mesenteric vasculitis
• Pancreatitis
• Hepatosplenomegaly
• Autoimmune hepatitis, rarely
• Retinal vasculitis

Investigations

1. Basic tests

• Complete blood count: anemia, leukopenia, lymphopenia, thrombocytopenia
• ESR: often raised
• CRP: may remain normal or mildly elevated in uncomplicated lupus activity. A disproportionately high CRP suggests infection, serositis, or another inflammatory condition.
• Urinalysis: proteinuria, hematuria, casts
• Urine protein-creatinine ratio or 24-hour urine protein
• Renal function tests: serum creatinine, urea, eGFR
• Liver function tests

2. Immunological tests

3. Renal biopsy

Classification Criteria

2019 EULAR/ACR Classification Criteria

• Entry criterion: ANA positive at a titre of at least 1:80 on HEp-2 cells, at least once.
• After the entry criterion, weighted clinical and immunological features are scored.
• A score of 10 or more, with at least one clinical criterion, classifies SLE.

• Constitutional: fever
• Hematological: leukopenia, thrombocytopenia, autoimmune hemolysis
• Neuropsychiatric: delirium, psychosis, seizures
• Mucocutaneous: oral ulcers, non-scarring alopecia, acute/subacute cutaneous lupus
• Serosal: pleural/pericardial effusion, acute pericarditis
• Musculoskeletal: joint involvement
• Renal: proteinuria and biopsy-proven lupus nephritis
• Immunological: antiphospholipid antibodies, low complement, anti-dsDNA or anti-Sm

Older ACR criteria

Differential Diagnosis

• Rheumatoid arthritis
• Sjögren syndrome
• Systemic sclerosis
• Mixed connective tissue disease
• Dermatomyositis
• Viral infections, including HIV and hepatitis
• Tuberculosis or infective endocarditis
• Hematological malignancy
• Fibromyalgia
• Drug-induced lupus
• Antiphospholipid syndrome without SLE

Drug-induced lupus

• Arthralgia, myalgia, fever, and serositis
• Anti-histone antibodies frequently positive
• Renal and CNS disease are uncommon
• Improves after withdrawal of the offending drug

Management

General measures

• Patient education and regular follow-up
• Avoid ultraviolet exposure: protective clothing and broad-spectrum sunscreen
• Smoking cessation
• Regular exercise, weight control, and cardiovascular risk reduction
• Vaccination where appropriate, preferably before intensive immunosuppression
• Screen for osteoporosis in those receiving glucocorticoids
• Monitor blood pressure, renal function, urine protein, CBC, anti-dsDNA, C3/C4, and drug toxicity
• Assess infection before increasing immunosuppression

Hydroxychloroquine

• Reduces flares
• Helps mucocutaneous and joint disease
• Reduces thrombosis and long-term damage
• Improves survival

• Dose should be weight-based to reduce retinal toxicity.
• Baseline and periodic ophthalmological screening are necessary.

Treatment according to severity

Management of lupus nephritis

• Renal biopsy guides treatment.
• Proliferative lupus nephritis, class III or IV with or without V, needs induction therapy followed by maintenance therapy.
• Induction usually includes glucocorticoids combined with mycophenolate mofetil or intravenous cyclophosphamide.
• Maintenance commonly uses mycophenolate mofetil or azathioprine.
• Selected patients may receive add-on belimumab or a calcineurin inhibitor such as voclosporin/tacrolimus.

• Control blood pressure
• ACE inhibitor or ARB for proteinuria where indicated
• Control lipids
• Avoid nephrotoxic drugs
• Monitor proteinuria and renal function closely

Antiphospholipid syndrome

• Test for lupus anticoagulant, anticardiolipin, and anti-beta-2-glycoprotein I antibodies.
• Definite thrombotic antiphospholipid syndrome generally requires long-term anticoagulation.
• Low-dose aspirin may be considered in selected high-risk antibody-positive patients without thrombosis.

SLE and Pregnancy

Pre-pregnancy evaluation

• Disease activity
• Renal function and proteinuria
• Anti-Ro/SSA and anti-La/SSB antibodies
• Antiphospholipid antibodies
• Medication review

Drugs generally compatible with pregnancy

• Hydroxychloroquine
• Azathioprine
• Low-dose corticosteroids where required
• Calcineurin inhibitors in selected settings

Drugs to avoid in pregnancy

• Mycophenolate mofetil
• Methotrexate
• Cyclophosphamide, except exceptional life-threatening circumstances
• ACE inhibitors and ARBs

Complications

• Lupus nephritis progressing to chronic kidney disease or end-stage kidney disease
• Severe infection due to disease or immunosuppressive treatment
• Thromboembolism and recurrent pregnancy loss due to antiphospholipid syndrome
• Accelerated atherosclerosis and myocardial infarction
• Pulmonary hypertension
• Osteoporosis and avascular necrosis from corticosteroids
• Infertility or premature ovarian failure, particularly after cyclophosphamide
• Malignancy risk with long-term immunosuppression

Prognosis

• Lupus nephritis, especially proliferative disease
• CNS involvement
• Persistent high disease activity
• Severe thrombocytopenia
• Antiphospholipid syndrome
• Delayed diagnosis or poor adherence
• Recurrent infection
• Low socioeconomic access to specialist care

Key takeaway