Systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that particularly affects women of childbearing age. The exact cause is still unknown, but a genetic predisposition, as well as hormonal and immunological influences, 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. Any organ may be affected; however, damage to the kidneys (lupus nephritis) or the nervous system is especially associated with a 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. Hydroxychloroquine is administered in the majority of cases to maintain disease remission. For acute flares, glucocorticoids are given as induction therapy, with dose and treatment duration adapted to the severity of the flare. In severe cases, additional immunosuppressants (e.g., mycophenolate, azathioprine) may be given.

• Sex: ♀ >> ♂ (10:1); more than 90% of cases reported in women
• 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.

• Genetic predisposition: HLA-DR2 and HLA-DR3 commonly found in patients with SLE
• Hormonal factors: suspected modulatory effect of hormones on immune system
• Immunological findings: ANA and anti-dsDNA autoantibodies
• Environmental factors: e.g., stimulation of immune cells through bacteria and viruses (disease flares following infection)

References:^[1]

The severity varies from case to case, with some patients only experiencing mild symptoms, while others suffer from severe symptoms and rapid disease progression. Additionally, SLE is usually characterized by a relapsing and remitting disease course and can affect any organ.

Most common presenting symptoms

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

Other symptoms

• Musculoskeletal: Myalgia and lymphadenopathy
• Serositis: :pleuritis and pericarditis; effusions and chest pain possible
• Kidneys: : nephritis with proteinuria (see Lupus nephritis)
• Heart: involvement of the myocardium, pericardium, valves, and coronary arteries; Libman-Sacks endocarditis
• Lungs: : pneumonitis, interstitial lung disease, pulmonary hypertension
• Gastrointestinal: esophagitis, hepatitis, pancreatitis
• Vascular: Raynaud's phenomenon, vasculitis, thromboembolism (see antiphospholipid syndrome)
• Neurologic: seizures, psychosis, and/or personality changes
• Hematologic: see “Diagnosis” below

Damage to the kidneys or nervous system is associated with a poor prognosis!

References:^[2]

Cutaneous lupus erythematosus

Discoid lupus erythematosus (DLE)

• Accounts for 50–85% of cases of cutaneous lupus erythematosus
• Clinical features
  • Usually seen on face, neck, and head (triggered by sunlight exposure)
  • Begins as raised erythematous, 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 approx. a 10–15% risk of developing SLE.

Subacute cutaneous lupus erythematosus (SCLE)

• About 10% of SLE patients have SCLE.
• 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: drug intake resulting in lupus-like symptoms 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 drugs
  Epidemiology
  • ♂ = ♀
  • Occurs more often in older patients (50–70 years)
• Symptoms
  • Fever
  • Polyarthritis
  • Serositis (especially pleuritis and pericarditis)
  • Myalgia
  • Rash
• Diagnosis
  • Anti-histone antibodies
  • Elevated ANA
  • No anti-dsDNA antibodies
• Prognosis: remission after discontinuing drugs

Drug-induced lupus erythematosus can have many of the features of idiopathic SLE such as fever, arthritis, malar rash, and serositis. However, unlike idiopathic SLE, DILE typically does not affect the oral mucosa, brain, or kidneys!

References:^{[3][4][5][6][7][8]}

Diagnostic criteria (according to the American college of rheumatology (ACR))

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: patients with SLE develop a rash due to an overly sensitive reaction to light Oral or nasopharyngeal ulcers: usually painless; must be observed by a physician
Internal organs	Nonerosive arthritis: involves at least two peripheral joints with swelling, tenderness, or an effusion; rarely deforming (normal x-ray) Serositis Pleuritis according to a history of pleuritic pain or a pleuritic rub during auscultation OR Pericarditis documented by ECG, a rub during auscultation, or evidence of a 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 finding of Anti-dsDNA antibodies OR Anti-Sm antibodies OR Antiphospholipid antibodies on an abnormal serum level of IgG/igM anticardiolipin anbodies Antinuclear antibodies (ANA): By immunofluorescence or an equivalent assay AND 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

Laboratory tests

• Complete blood count and differential: leukopenia, autoimmune hemolytic anemia, thrombocytopenia
• ESR is frequently elevated, while CRP is often normal.
• Electrophoresis: elevated γ-globulin
• ↓ C3 and C4 complement levels
• Antibody diagnostics

Antibodies	Characteristics
Anti-nuclear antibody (ANA)	Highest sensitivity (95%) but low specificity If ANAs are positive, further antibodies are tested to confirm the diagnosis (e.g., anti-dsDNA antibodies, anti-Sm antibodies) ANA titer of 1:160 considered positive
Anti-dsDNA antibody	Positive in 70% of patients and highly specific Correlates with disease activity Associated with lupus nephritis
Anti-C1q antibody	Correlates with disease activity
Anti-Sm antibody	Positive in only 30% of patients, but highly specific
Anti-Ro/SSA antibody	Positive in ∼ 30% of patients Associated with Sjögren's syndrome
Anti-La/SSB antibody	Positive in ∼ 20% of patients Also associated with Sjögren's syndrome
Anti-U1 RNP	Positive in ∼ 25% of patients, low sensitivity
→ See also 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 healthy 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 complaints, ultrasound to evaluate renal complications)

References:^{[9][1][10][11]}

General management

• Avoid exposure to sun
• Stop smoking
• 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 as well as UV photochemotherapy (PUVA) are contraindicated!

References:^[12]

Lupus nephritis (LN)

• Description: most crucial prognostic factor in SLE
• Epidemiology: common (∼ 50% of SLE patients)
• Pathology: classically immune complex-mediated glomerulonephritis
• Classification: classified according to differing 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 disease severity
• Treatment: Depending on the severity, corticosteroids, cytostatic drugs (mycophenolate, cyclophosphamide), and general measures to protect the kidneys (e.g., blood pressure control) may be required.

Comorbid conditions

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

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

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