Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that predominantly affects women of childbearing age. The exact cause is still unknown, but hormonal and immunological influences as well as genetic predisposition are considered likely etiological factors. The presentation of the disease is variable and may range from mild localized symptoms to life-threatening systemic disease. Typical findings include fever and fatigue, a malar rash (facial butterfly rash), myalgia, and arthritis. SLE may affect any organ, but damage to the kidneys (lupus nephritis) or the nervous system (neuropsychiatric systemic lupus erythematosus, NSLE)is associated with an especially poor prognosis. The diagnosis of SLE is based on clinical findings and is further supported by antibody tests, particularly for ANA and anti-dsDNA. Management consists of supportive measures, such as avoiding sun exposure, and medication adapted to disease severity. Long-term pharmacotherapy typically involves hydroxychloroquine, which has been shown to reduce flares and decrease mortality. For acute flares, glucocorticoids are given as induction therapy, with dose and treatment duration being adapted to the severity of the flares. In severe cases, additional immunosuppressants (e.g., mycophenolate, azathioprine) may be given.

• Sex: ♀ >> ♂ (10:1)
• Peak incidence: women aged 20–40 years; no particular age of manifestation in men
• US prevalence: highest in African-American, Hispanic, and Asian populations

References:^[1]

Epidemiological data refers to the US, unless otherwise specified.

The exact etiology is unknown, but several predisposing factors have been identified:

• Genetic predisposition:
  • HLA-DR2 and HLA-DR3 are commonly present in individuals with SLE
  • Genetic deficiency of classical pathway complement proteins (C1q, C2, C4) in approx. 10% ^[2]
• Hormonal factors: : studies suggest that hyperestrogenic states (e.g., due to oral contraceptive use, postmenopausal hormonal therapy, endometriosis) are associated with an increased risk of SLE. ^[3]
• Environmental factors: UV light; , stimulation of immune cells through infection with bacteria and viruses (in particular EBV; , which causes disease flares following infection), medications (e.g., procainamide, hydralazine) ^[4]

References:^[1][4]

Hormonal and environmental factors as well as genetic predisposition (see “Etiology” above) → loss of self-tolerance → production of antibodies against perceived nuclear and cellular antigens → damage to tissue via type III hypersensitivity reaction; and, to a lesser extent, type II hypersensitivity reaction

• Possible mechanisms for the development of autoantibodies ^[5]
  • Deficiency of classical complement proteins (C1q, C4, C2) → failure of macrophages to phagocytose immune complexes and apoptotic cell material; (i.e., plasma and nuclear antigens) → dysregulated, intolerant lymphocytes begin targeting normally protected intracellular antigens → autoantibody production (e.g., ANA, anti-ds DNA)
• Mechanism of tissue damage
  • Type III hypersensitivity → antibody-antigen complex formation in microvasculature → complement activation and inflammation → damage to skin, kidneys, joints, small vessels
  • Type II hypersensitivity → IgG and IgM antibodies directed against antigens on cells (e.g., red blood cells) → cytopenia

References: ^[4][2][6][7]

The severity of SLE varies. While some individuals only experience mild symptoms, others suffer from severe symptoms and rapid disease progression. SLE is typically characterized by phases or remission and relapse. It can affect any organ.

Most common symptoms (see also ACR criteria for SLE diagnosis below)

• Skin (> 70% of cases)
  • Malar rash (butterfly rash) with sparing of the nasolabial folds
  • Photosensitivity
  • Discoid rash
  • Oral ulcers
  • Alopecia
• Joints
  • Arthritis and arthralgia (> 90% of cases)
  • Mostly nonerosive polyarthritis (normal x-ray)
• Fever; (> 50% of cases), fatigue (> 80% of cases), weight loss

Other signs and symptoms

• Musculoskeletal: myalgia and lymphadenopathy
• Serositis: pleuritis and pericarditis; effusions and chest pain may occur
• Kidneys: nephritis with proteinuria (see lupus nephritis)
• Heart: involvement of the myocardium, pericardium, valves, and coronary arteries; Libman-Sacks endocarditis (LSE)
• Lungs: pneumonitis, interstitial lung disease, pulmonary hypertension
• Gastrointestinal: esophagitis, hepatitis, pancreatitis
• Vascular: Raynaud phenomenon, vasculitis, thromboembolism (see antiphospholipid syndrome)
• Neurologic: : e.g., seizures, psychosis, personality changes, aseptic meningitis, polyneuropathy, myasthenia gravis
• Hematologic: hemolytic anemia, thrombocytopenia, leukopenia; for other features, see “Diagnosis” below.

SLE can cause LSE (Libman-Sacks endocarditis).

Damage to the kidneys or nervous system is associated with a poor prognosis!References:^[8][4]

Cutaneous lupus erythematosus

Discoid lupus erythematosus (DLE)

• Accounts for 50–85% of cases of cutaneous lupus erythematosus
• Clinical features
  • Typically affects face, neck, and head (triggered by exposure to UV light)
  • Begins as erythematous raised scaling plaques with active inflammation
  • Heals and leaves scar tissue with central atrophy
• Rare form: chilblain lupus
  • Violaceous plaques on acral areas from exposure to cold
• Diagnosis
  • Lupus band test (immunoglobulin deposits found only in macroscopically affected skin)
  • Often ANA and anti-Ro negative
• Prognosis: Patients with DLE have a 10–15% risk of developing SLE.

Subacute cutaneous lupus erythematosus (SCLE)

• Accounts for approx. 10% of cases of SLE
• Clinical features
  • Usually affects the neck, shoulders, and forearms, but spares the face
  • Small erythematous lesions that develop into either annular or psoriasiform lesions

Drug-induced lupus erythematosus (DILE)

• Description: lupus-like symptoms triggered by medication that resolve within days to months after discontinuation of the drug
• Common triggers
  • Sulfa drugs
  • Certain non-sulfa drugs: hydralazine, methyldopa, isoniazid, procainamide, phenytoin, TNF-α inhibitors (e.g., etanercept)
  • Risk factor: decreased acetyltransferase activity causing slow acetylation of the above-mentioned drugs
  Epidemiology
  • ♂ = ♀
  • More common in older individuals (50–70 years)
• Symptoms
  • Fever
  • Polyarthritis
  • Serositis (especially pleuritis and pericarditis)
  • Myalgia
  • Rash
• Diagnosis
  • Anti-histone antibodies; : Anti-histone antibodies are characteristic for DILE and manifest in approx. 95% of cases. They may also be present in SLE but are significantly less common.
  • Elevated ANA
  • No anti-dsDNA antibodies
• Prognosis: remission after discontinuation of offending drugs

Drug-induced lupus erythematosus may manifest with a variety of the features also seen in idiopathic SLE, e.g., fever, arthritis, malar rash, and serositis. However, unlike idiopathic SLE, DILE typically does not affect the oral mucosa, CNS, or kidneys!

References:^{[9][10][11][12][13][14]}

Approach ^[15]

1. Suspect SLE; in patients with symptoms in more than two of the organ systems listed in the ACR criteria for SLE.
2. Screening test: ANA titer (SLE is unlikely if the test is negative)
3. ↑ ANA titer → confirm diagnosis with tests that are highly specific for SLE
   • Anti-dsDNA antibody testing: autoantibody against double-stranded DNA (dsDNA)
     • Positive in 70% of patients and highly specific
     • Levels correlate with disease activity
     • Associated with lupus nephritis
   • Anti-Sm antibody testing
     • Autoantibody against Smith antigens (nonhistone nuclear proteins)
     • Positive in only ∼ 30% of patients, but highly specific for SLE
4. Tests listed in “Other laboratory tests” below may support the diagnosis.

Anti-nuclear antibody (ANA) testing has the highest sensitivity (95%) but low specificity for SLE. Anti-dsDNA antibody and anti-Smith antibody testing are the most specific for SLE.

Diagnostic criteria (according to the American College of Rheumatology, ACR) ^[16][1]

Requirements: at least 4 of the 11 criteria must be met (specificity: 95%, sensitivity: 85%)

	ACR criteria for SLE
	Dermatological	Malar rash (butterfly rash): flat or raised fixed erythema over both malar eminences; tends to spare nasolabial folds Discoid rash: erythematous raised patches with adherent keratotic scaling and follicular plugging Photosensitivity: individuals with SLE develop a rash due to an overly sensitive reaction to light Oral or nasopharyngeal ulcers: usually painless
Internal organs	Nonerosive arthritis: involves at least two peripheral joints with swelling, tenderness, or effusion; rarely deforming (normal x-ray) Serositis: evidence of pleuritis and/or pericarditis Pleuritis: history of pleuritic chest pain, pleuritic rub during auscultation, or pleural effusion OR Pericarditis: evidence on ECG (e.g., diffuse ST elevations), a pericardial rub during auscultation, and/or pericardial effusion Renal disorder Persistent proteinuria (> 0.5 mg/day) OR Cellular casts (red cells, hemoglobin, granular, tubular, or mixed) Neurologic disorder: Seizures OR psychosis; both in the absence of offending drugs or known metabolic derangements
Laboratory tests	Hematologic disorders Autoimmune hemolytic anemia with reticulocytes OR Thrombocytopenia < 100,000/mm3 in the absence of offending drugs OR Leukopenia < 4,000/mm3 on ≥ 2 occasions OR Lymphopenia < 1,500/mm3 on ≥ 2 occasions Immunological findings Positive findings of Anti-dsDNA antibodies OR Anti-Sm antibodies OR Antiphospholipid antibodies on an abnormal serum level of IgG/IgM anticardiolipin antibodies Antinuclear antibodies (ANA): on immunofluorescence or an equivalent assay in the absence of medications associated with drug-induced lupus

“SOAP BRAIN MD” is the acronym for the ACR diagnostic criteria for SLE:
S = Serositis
O = Oral ulcers
A = Arthritis
P = Photosensitivity

B = Blood disorders
R = Renal involvement
A = Antinuclear antibodies
I = Immunologic phenomena
N = Neurologic disorder

M = Malar rash
D = Discoid rash

Other laboratory tests

• Complete blood count and differential: autoimmune hemolytic anemia, thrombocytopenia, leukopenia, lymphopenia
• ESR is frequently elevated, while CRP is often normal.
• Electrophoresis: elevated γ-globulin
• ↓ C3 and C4 complement levels
• Urinalysis and urine microscopy: proteinuria and/or casts
• Additional antibody tests
  • Antiphospholipid antibodies may be elevated.
  • Anti-histone antibodies are elevated in drug-induced lupus erythematosus.
  • Anti-Ro antibodies are elevated in the majority of cases of neonatal lupus erythematosus.
  • For a list of additional antibodies that may be elevated in SLE, see section on antinuclear antibodies in antibody diagnosis of autoimmune diseases.

Further diagnostics

• Lupus band test (LBT): direct immunofluorescence staining of immunoglobulin and complement component deposits (IgG, IgM, IgA und C3); found along the dermoepidermal junction in affected as well as unaffected skin
• Kidney biopsy: if lupus nephritis is suspected(proteinuria, red blood cell casts, or acanthocytes in urinary sediment)
• Imaging studies: assessment of organ or joint involvement (e.g., x-ray for joint symptoms, ultrasound to evaluate renal complications)

References:^{[17][1][18][19][20]}

General management

• Avoid exposure to UV light (sunlight)
• Smoking cessation
• Immunize patients before initiating immunosuppressants

Medical therapy

	Mild symptoms, no vital organs affected	Severe symptoms, no vital organs affected	Organ damage
Basic therapy	Hydroxychloroquine (or chloroquine)
Induction therapy	Low-dose (≤ 7.5 mg), short-term, oral glucocorticoids	Medium-dose (5–15 mg), oral glucocorticoids	High-dose, IV glucocorticoids
		Immunosuppressive agents (e.g., azathioprine, mycophenolate, cyclophosphamide)

UV phototherapy and UV photochemotherapy (PUVA) are contraindicated!

References:^[21]

Lupus nephritis (LN)

• Description:
  • Most crucial prognostic factor in SLE
  • Can be nephritic or nephrotic (see also overview of glomerular diseases)
• Epidemiology: common (∼ 50% of individuals with SLE)
• Pathology: classically, immune complex-mediated glomerulonephritis; diffuse proliferative glomerulonephritis is the most common type.
• Classification: classified according to different grades of severity (WHO classes I–VI)
  • Ranging from asymptomatic hematuria to rapidly progressive glomerulonephritis
  • Ranging from asymptomatic proteinuria to nephrotic syndrome
• Diagnosis
  • Urine tests: proteinuria, hematuria, cellular casts (red cells, hemoglobin, granular or tubular)
  • Kidney biopsy: determination of severity of disease
• Treatment: Depending on the severity of the disease, corticosteroids, cytostatic drugs (mycophenolate, cyclophosphamide), and general measures to protect the kidneys (e.g., blood pressure control) may be necessary.

Neuropsychiatric systemic lupus erythematosus (NSLE)

• Description: neurological and psychiatric syndromes found in individuals with SLE that cannot be attributed to any other disorder ^[22]
• Epidemiology: found in ∼ 50% of individuals with SLE ^[23][24]
• Classification: American College of Rheumatology (ACR) distinguishes 19 NSLE syndromes ^[22]
  • Central nervous system
    • Aseptic meningitis
    • Cerebrovascular disease
    • Demyelination
    • Headache
    • Chorea
    • Myelopathy
    • Seizures
    • Acute confusional state
    • Anxiety disorder
    • Cognitive impairment
    • Mood disorder
    • Psychosis
  • Peripheral nervous system
    • Acute inflammatory demyelinating polyradiculoneuropathy (Guillain-Barre ́syndrome)
    • Autonomic disorder
    • Single mononeuropathy or mononeuropathy multiplex
    • Myasthenia gravis
    • Cranial neuropathy
    • Plexopathy
    • Polyneuropathy
• Diagnosis
  • Specific tests depend on syndrome (see the corresponding learning cards)
  • To assess mental symptoms, a battery of neuropsychological tests proposed by ACR is used ^[22]
• Treatment ^[22]
  • Immunosuppressive treatment reduces NSLE symptoms in 60–75% of patients.
  • In NSLE patients with ischemic stroke, lifelong antithrombotic therapy or treatment with warfarin is indicated.
  • Symptomatic treatment is used depending on the syndrome (e.g., antiseizure medications in seizures).

Comorbid conditions

• Accelerated atherosclerosis and cardiovascular complications (e.g., myocardial infarction)
• Pulmonary hypertension
• Pancytopenia
• Osteopenia/osteoporosis
• Antiphospholipid syndrome
• ↑ Risk of thrombosis (particularly in individuals with antiphospholipid syndrome) → avoid treatment with estrogens

References:^{[17][21][25][26]}

We list the most important complications. The selection is not exhaustive.

Mortality

• 10-year survival rate > 90%
• Mortality is highest in individuals > 45 years of age (65% of deaths)
• Causes of death
  • In early disease
    • High disease activity with renal or neurological complications
    • Infections due to immunosuppressive therapy
  • In late disease: cardiovascular complications, end-stage renal disease , adverse effects of long-term medication

Cardiovascular disease is the most common cause of death in SLE.

References:^[1]

SLE and pregnancy

• Characteristics
  • Fertility is not affected.
  • Pregnancy may cause flares in disease activity.
  • ↑ Risk of preterm birth, hypertensive complications (preeclampsia), intrauterine growth restriction, fetal AV block, and miscarriage
• Risk assessment ^[27]
  • Cardiac, lung, and kidney screening
  • Maternal antibodies: anti-Ro/SSA and anti-La/SSB
  • Anticardiolipin antibodies and lupus anticoagulant (see antiphospholipid syndrome)
• Management
  • Pregnancy planning and counseling
  • Prednisolone , azathioprine; cyclosporin, tacrolimus , and hydroxychloroquine are considered safer drug options during preconception, pregnancy, and breastfeeding.
  • Some immunosuppressive medications used to treat SLE (e.g. mycophenolate and cyclophosphamide) have severe teratogenic and other adverse fetal effects.
  • Low-dose aspirin is recommended in all pregnant women from 12 weeks gestation
• Neonatal lupus syndrome
  • Associated with the transfer of maternal antibodies (anti-Ro/SSA and anti-La/SSB)
  • Symptoms:
    • Periorbital or diffuse rash (often presents in the first weeks after birth)
    • Cytopenia
    • Hepatitis, elevated liver enzymes
    • First- to third-degree congenital AV block

References:^{[28][29][27][30]}