Systemic lupus erythematosus

Last updated: August 23, 2022

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Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that predominantly affects women of childbearing age and is the most common form of lupus. The exact cause is still unknown, but hormonal and immunological features and genetic predisposition are considered likely etiological factors. Disease presentation is variable but is usually characterized by phases of remission and relapse. Symptoms can range from mild and localized to life-threatening systemic disease. SLE can affect any organ, but typical findings include arthritis, a malar rash (facial butterfly rash), and constitutional symptoms such as fever and fatigue. Involvement of the kidneys is common and can lead to lupus nephritis. Potential manifestations of SLE include cutaneous lupus erythematosus (CLE) and neuropsychiatric systemic lupus erythematosus (NPSLE); however, they can also occur independently from SLE. Other forms of lupus in addition to SLE include drug-induced lupus erythematosus (DILE) and neonatal lupus. The diagnosis of lupus is based on clinical findings and is further supported by laboratory studies, including the presence of antinuclear antibodies (ANAs) and antigen-specific ANAs (i.e., anti-dsDNA, anti-Sm). The 2019 EULAR/ACR classification criteria for SLE do not need to be fulfilled to make a diagnosis but may further support it. Management consists of general measures, such as avoiding sun exposure, and ASCVD prevention. Long-term immunosuppressive therapy depends on disease severity and organ involvement; hydroxychloroquine is typically used, as it has been shown to reduce flares and decrease mortality. In severe cases, additional immunosuppressants (e.g., mycophenolate, azathioprine) or biological agents may be given. Cardiovascular, neurological, and renal disease (lupus nephritis), together with infections, are the main causes of death in patients with SLE.

  • Sex: : > (10:1) [1]
  • Peak incidence and prevalence [1][2]
    • Age of onset
      • Women: 15–44 years
      • Men: no particular age
    • Race: highest in populations of African descent

Epidemiological data refers to the US, unless otherwise specified.

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

The exact pathomechanism of SLE is not fully understood, but the following two processes are the most widely accepted hypotheses: [5]

SLE is a systemic disease characterized by phases of remission and relapse. Some individuals only experience mild symptoms, while others experience severe symptoms and rapid disease progression. SLE can affect any organ.

Common [6]

Both rheumatoid arthritis and SLE arthritis affect the MCP and PIP joints, but SLE does not usually lead to deformities.

Less common [3]

SLE can cause LSE (Libman-Sacks Endocarditis).

General principles [9][10]

  • SLE is a clinical diagnosis.
    • Consider a diagnosis of SLE in patients with constitutional symptoms and features involving ≥ 2 organs or systems.
    • Rule out alternative diagnoses to avoid unnecessary and potentially harmful interventions (e.g., immunosuppressants).
  • Diagnostic studies support the diagnosis and serve as markers of disease activity and/or organ damage.
  • Rheumatology consultation is advised for all patients with suspected SLE.

The 2019 EULAR/ACR classification criteria for SLE may be considered to further support the diagnosis, but do not need to be fulfilled to establish a diagnosis of SLE. [6][9][10]

SOAP BRAIN, MD:” Serositis, Oral and/or nasal ulcers, Arthritis, Photosensitivity, Blood disorders, Renal involvement, ANAs, Immunological phenomena (anti-dsDNA, anti-Sm, antiphospholipid antibodies), Neurological disorders, and Malar or Discoid rash are the features of SLE.

Laboratory studies [9][10]

The following studies are commonly part of a minimum diagnostic workup if SLE is clinically suspected. [9]

ANAs have the highest sensitivity but low specificity for SLE. Anti-dsDNA and anti-Sm antibodies are the most specific antibodies for SLE.

RPR and VDRL are usually used to test for syphilis but may also be positive in SLE.

Classification criteria for SLE [6][12]

The classification criteria for SLE were originally developed for research purposes (not as diagnostic criteria). Nevertheless, these criteria are often used in clinical practice to support the diagnosis of SLE.

  • Indication: Use in patients who have an ANA titer of ≥ 1:80; (i.e., entry criterion; for the classification criteria). [6]
  • Further considerations
    • Consider other, more likely diagnoses before attributing a criterion to SLE.
    • Criteria do not need to occur simultaneously.
    • The occurrence of any criterion at least once is sufficient.
2019 EULAR/ACR classification criteria for SLE [6][12]
Domain

Criteria

Weight
Clinical
  • Constitutional
  • Fever > 38.3°C (100.9°F)
  • 2
  • Hematologic
  • 3
  • 4
  • 4
  • Neuropsychiatric
  • 2
  • 3
  • 5
  • Mucocutaneous
  • 2
  • 2
  • 4
  • 6
  • 5
  • 6
  • Musculoskeletal
  • Joint involvement (one of the following):
  • 6
  • Renal
  • 4
  • 8
  • 10
Immunological
  • 2
  • ↓ C3 or ↓ C4
  • 3
  • ↓ C3 and ↓ C4
  • 4
  • 6

SLE classification requires all of the following to be met:

  • Entry criterion
  • At least one clinical criterion
  • Total additive score ≥ 10 points (calculated by adding the highest-weighted criteria within each domain together)

Additional diagnostics [9]

Request additional tests based on suspected organ involvement (see also “Specific clinical manifestations” and “Clinical features”).

Imaging studies

Imaging studies can help in the assessment of organ or joint involvement.

Histopathology [13]

Biopsy of an affected organ (e.g., skin, kidney) can be performed to support the diagnosis but is not required for all patients.

ASCVD risk assessment [9]

Patients with SLE have double the cardiovascular risk compared to patients without SLE. Cardiovascular disease is among the most common causes of death in patients with SLE. [10]

General principles [10][13][15]

Specialist consultation is advised, i.e., rheumatology and other departments based on the patient's clinical presentation.

  • Patients with SLE usually require life-long immunosuppressants.
    • Management is guided by disease severity and the systems or organs affected (see also “Specific clinical manifestations”).
    • Patients should be frequently monitored for medication-induced adverse effects.
  • NSAIDs can provide symptomatic relief. [9]
  • Nonpharmacological measures include:
    • Lifestyle changes (e.g., smoking cessation, aerobic exercise)
    • Avoidance of UV light
  • Optimize primary and secondary prevention of ASCVD and offer preconception counseling (see also “SLE and pregnancy”). [10]

Admit patients with SLE and unexplained fever, severe disease (e.g., lupus nephritis, alveolar hemorrhage, NPSLE), or complications (e.g., sepsis, thrombosis), as these features are associated with increased mortality.

Disease severity

Disease severity can be classified based on the presence of clinical features and laboratory markers of disease activity and/or organ damage in SLE.

Management should be guided by disease severity, the patient's safety (e.g., childbearing potential, adverse effects), and medication cost. Therapy may be modified further based on the main organs affected.

Pharmacotherapy [9][12][13]

Depending on the systems or organs affected (e.g., skin, kidneys), a specialist may decide on a different pharmacological approach.

Overview of the recommended pharmacological treatment for patients with non-renal SLE [9][13]
Disease severity
Mild to moderate Severe
Standard therapy (for all patients)
Additional therapy Glucocorticoids
Other immunosuppressive agents

Prevention and monitoring for medication-induced adverse effects [9][10][13]

Administer glucocorticoids at the lowest effective dose and only for short periods of time to reduce the risk of adverse effects (e.g., hyperglycemia, atherosclerosis, myopathy).

Offer vaccinations before initiating pharmacological therapy based on the patient's individual risk and potential adverse effects of the prospective agent, and perform laboratory studies.

The specific manifestations of SLE are classified based on the systems affected.

Cutaneous lupus erythematosus (CLE)

Some patients with lupus present with predominantly cutaneous manifestations. Cutaneous manifestations are classified based on their chronicity (acute, subacute, or chronic).

Acute cutaneous lupus erythematosus (ACLE) [6][17][18]

ACLE is frequently associated with systemic disease.

Subacute cutaneous lupus erythematosus (SCLE) [3][17]

Discoid lupus erythematosus (DLE) [7][17]

DLE is the most common form of chronic CLE.

DLE is the most common form of chronic CLE; it is rarely associated with systemic disease.

Management of CLE [9][13]

Lupus nephritis

Description [19]

Pathophysiology [19]

Clinical features

Diagnostics [9]

Abbreviated histopathologic classification of lupus nephritis [20]
Class I
  • Minimal mesangial disease
Class II
  • Mesangial proliferative disease
Class III
Class IV
Class V
Class VI

Perform regular urinalysis follow-up in patients with SLE, as early detection and treatment of renal disease can prevent progression to severe disease.

Management of lupus nephritis [13]

Patients with class I, II, or V lupus nephritis do not usually require specific immunosuppressive therapy. [9][13]

Neuropsychiatric systemic lupus erythematosus (NPSLE) [21]

  • Description: the presence of neurological and psychiatric symptoms in patients with SLE that cannot be attributed to another condition [22]
  • Epidemiology: found in ∼ 40% of patients with SLE [21]
  • Classification: The American College of Rheumatology has identified 19 NPSLE syndromes. [22]

Drug-induced lupus erythematosus (DILE) [9][23]

  • Description: : lupus-like symptoms triggered by medication
  • Epidemiology
    • =
    • DILE accounts for ∼ 10% of all SLE cases.
    • Most common in white populations
    • Most common in individuals 50–70 years of age
  • Etiology
  • Clinical features (usually manifest ≥ 1 month after medication initiation)
  • Diagnostics [9][23]
    • ANAs are positive in nearly all patients.
    • Antihistone antibodies
      • Antihistone antibodies are seen in 90–95% of patients.
      • Nonspecific: They may also be present in ∼ 75% of patients with SLE.
    • Anti-dsDNA antibodies: uncommon in patients with DILE
  • Treatment
    • Stop the triggering drug.
    • If necessary, start temporary pharmacotherapy (see the “Treatment” section).
  • Prognosis: Most cases resolve within a few weeks after the causative medication has been discontinued.

My Two HIPS”: Methyldopa/Minocycline, TNF-α inhibitors, Hydralazine, Isoniazid, Procainamide/Phenytoin, and Sulfa drugs are triggers for DILE.

DILE can manifest with various features that are also seen in idiopathic SLE (e.g., fever, arthritis, malar rash, serositis) but typically does not affect the CNS or kidneys, unlike SLE.

Undifferentiated connective tissue disease (UCTD)

  • Definition: a term used to describe a clinical entity that manifests with features of autoimmunity without fulfilling the criteria for any specific connective tissue disease
  • Classification criteria [24]
    • Clinical features that suggest a systemic autoimmune disease
    • Positive ANAs on two separate occasions
    • Disease duration of ≥ 3 years
  • Approach to management [24]
    • Provide the patient with clear information on the diagnosis.
    • Refer to a rheumatologist for periodical follow-up.
    • No specific therapy is required; consider symptomatic management.
  • Prognosis: Up to 25% of patients with UCTD progress to an identifiable systemic autoimmune disease within 1–3 years. [24]

In patients with UCTD, the presence of serositis, fever, and/or anti-Sm or anti-dsDNA antibodies has been associated with progression to SLE. [25]

SLE and pregnancy

Avoid estrogen-containing hormonal contraceptives in patients with antiphospholipid syndrome because of the increased risk of thrombosis.

Educate patients of reproductive age about contraceptive methods, planned pregnancy, and the potential teratogenic effects of pharmacological treatment.

Neonatal lupus syndrome [26][27]

Infections [13][28]

Patients with SLE are at increased risk of developing infections because of disease-related factors (e.g., pancytopenia) and/or immunosuppressive treatment.

Cardiovascular disease [15]

Other comorbidities [3][29]

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

Redness In Cheeks” (malar rash): Renal disease, Infections, and Cardiovascular complications are the three most common causes of death in SLE.

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

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