• Clinical science

Systemic lupus erythematosus

Summary

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 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.

Epidemiology

  • 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.

Etiology

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]

Pathophysiology

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

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

Clinical features

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 of remission and relapse. It can affect any organ.

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

  • Skin (> 70% of cases)
  • 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

SLE can cause LSE (Libman-Sacks endocarditis).

Damage to the kidneys or nervous system is associated with a poor prognosis!References:[9][4]

Subtypes and variants

Cutaneous lupus erythematosus

Discoid lupus erythematosus (DLE)

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)

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:[10][11][12][13][14][15]

Diagnostics

Approach [16]

  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
  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) [17][1]

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

ACR criteria for SLE
Dermatological
  1. Malar rash (butterfly rash): flat or raised fixed erythema over both malar eminences; tends to spare nasolabial folds
  2. Discoid rash: erythematous raised patches with adherent keratotic scaling and follicular plugging
  3. Photosensitivity: individuals with SLE develop a rash due to an overly sensitive reaction to light
  4. Oral or nasopharyngeal ulcers: usually painless
Internal organs
  1. Nonerosive arthritis: involves at least two peripheral joints with swelling, tenderness, or effusion; rarely deforming (normal x-ray)
  2. Serositis: evidence of pleuritis and/or pericarditis
  3. Renal disorder
    • Persistent proteinuria (> 0.5 g/day) OR
    • Cellular casts (red cells, hemoglobin, granular, tubular, or mixed)
  4. Neurologic disorder: Seizures OR psychosis; both in the absence of offending drugs or known metabolic derangements
Laboratory tests
  1. Hematologic disorders
  2. Immunological findings
  3. 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

Further diagnostics


References:[18][1][19][20][21]

Treatment

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
Induction therapy

UV phototherapy and UV photochemotherapy (PUVA) are contraindicated!

References:[22]

Complications

Lupus nephritis (LN)

Comorbid conditions

References:[18][22][24][25]

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

Prognosis

Mortality

  • 10-year survival rate > 90%
  • Mortality is highest in individuals > 45 years of age (65% of deaths)
  • Causes of death

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

References:[1]

Special patient groups

SLE and pregnancy

References:[27][28][26][29]