EM@3AM: Systemic Lupus Erythematosus

Answer: Systemic lupus erythematosus (SLE)

Background:¹

• SLE is an autoimmune disorder that primarily affects women (increased prevalence in African American women)
• In those with SLE, there is an exaggerated B cell and T cell response to antigens, as well as a loss of immune tolerance against self-antigens
• This leads to complement activation, cytokine cascades, immune complex tissue deposition, and production and defective elimination of antibodies
• All of the above contributes to a wide range of clinical manifestations with an extensive amount of organ systems affected

Etiology:²

• The mechanism that triggers the autoimmune response is largely still unknown
• There is a genetic component, shown by a high rate of concordance in monozygotic twins compared to dizygotic twins
• There are also specific genes that are associated with SLE
  • Most of these genes are within the major histocompatibility complex – HLA Class I and Class II
  • For example, HLA-DR3 seems to be related to anti-Ro/SSA and anti-La/SSB production
  • Approximately 60% of those diagnosed with SLE were found to have an overexpression of IFN-alpha-induced genes
• Some of the autoantibodies that are implicated, but not required for the diagnosis of SLE:
  • anti-nuclear (ANA)
  • anti-ssDNA, anti-dsDNA
    • Anti-dsDNA is associated with disease activity and specific organ damage
  • anti-histone
  • anti-Ro/SSA, anti-La/SSB
  • anti-RNP
  • anti-cardiolipin
  • anti-B2-glycoprotein 1
• Hormonal factors
  • Sexual hormones (compared to controls)
    • Women with SLE may have low levels of DHEA, testosterone, and progesterone
    • Men with SLE may have low DHEA, normal testosterone and estradiol, and high prolactin
  • Thyroid hormones: in patients with SLE, elevated levels of antithyroid antibodies and serum TSH levels can be seen
    • The prevalence of hypothyroidism in those diagnosed with SLE ranges from 3-21.4% (compared to the general US population, which has a prevalence of around 5%)^3,4
  • Hypothalamic axes: patients diagnosed with SLE have an altered autonomic nervous system response (increased prevalence of sympathetic activity and decreased parasympathetic tone),⁵which can be more pronounced with the corticotropin-releasing hormone CRH stress test
    • This is associated with increased rates of inflammation and also with the development of cardiovascular disease⁵
•  Environmental factors
  • Epstein Barr Virus (EBV) is found in high titer in kids with SLE
  • UV light can lead to autoantibody formation
  • Silica dust and smoking cigarettes both increase the risk of developing SLE
  • Several medications have been reported as causative agents of SLE (Drug-Induced Lupus, DIL)
    • The two medications that have the highest incidence with DIL are procainamide (risk has been reported to be as high as 30%) and hydralazine (risk reported between 5-10%)⁶
    • Other drugs associated with DIL: anti-TNF agents (eg, etanercept and infliximab), carbamazepine, chlorpromazine, ethosuximide, penicillamine, phenytoin, PTU, rifampin, sulfasalazine⁶
    • The exact pathophysiology of DIL is unknown, but there have been different mechanisms identified⁶
      • Procainamide and hydralazine-induced SLE have been linked to slow acetylators with genetic deficiency of N-acetyltransferase, as well as inhibition of DNA methylation⁶
    • A moderate consumption of alcohol can be a protective factor⁷
      • While the exact mechanism is unknown, there is evidence that suggests that a low to moderate consumption of alcohol can lead to increased production of anti-inflammatory mediators that help decrease disease severity in multiple autoimmune disorders⁷

Epidemiology:

• Based on a nationwide ED sample, those diagnosed with SLE are more likely to be between the ages of 31-50 years of age and female⁸
  • Female:male ratio is 9:1⁹
• African American women are most likely to be affected^10–12
  • Disease severity is also higher in this population^1,11,12

Clinical Presentation:

• Common presentations for patients with SLE coming to the ED:¹³
  • Fever
  • Non-specific chest pain
  • Abdominal pain
  • Musculoskeletal pain
  • Sepsis due to:
    • UTI,
    • Pneumonia,
    • Skin and soft tissue infection
  • Other possible manifestations of SLE by organ system can be found in Table 1

• Patients with known SLE receiving chronic maintenance therapy may present with side effects and complications of their medications (Table 3)²

Diagnosis:²

• ACR (American College of Rheumatology) Criteria (Table 4)
  • 4 or more of the 11 criteria are present, either serially or simultaneously, during any interval of observation 
• SLICC (Systemic Lupus International Collaborating Clinics) Criteria (Table 5)
  • 4 or more criteria (at least 1 has to be clinical, at least 1 has to be immunologic)

ED Evaluation:

• If suspecting a new diagnosis of SLE:^2,16
  • ANA, anti-DNA
  • Bedside ECHO – if there is clinical concern for pericardial effusion, valvular dysfunction, myocardial infarction, or pulmonary embolism (PE)
  • Complement factors C3/C4
  • Complete blood count (CBC) – for anemia, leukopenia, thrombocytopenia
  • Comprehensive metabolic panel (CMP) – for liver/renal dysfunction
  • C-reactive protein (CRP)/erythrocyte sedimentation rate (ESR)
  • Urinalysis (UA) – for casts, hematuria, proteinuria
  • Urine pregnancy testing – as this may impact management choices
• If suspecting SLE flare:
  • Same as above (with the exception of ANA, as it is controversial whether this test is not helpful for tracking disease activity)¹⁷
  • Normal or elevated CRP, leukopenia, low C3/4, and elevated anti-DNA are suggestive of flares¹⁶
  • Further testing directed toward specific organ involvement (Table 6)

Treatment:²

• For patients with a suspected new diagnosis of SLE with severe symptoms/organ damage, rheumatology should be consulted early
• Rheumatology should also be consulted in the ED for patients with known SLE and suspected flare
  • If rheumatology consultation is unavailable and the emergency clinician has a high suspicion for SLE flare without suspicion for infection, it is reasonable to consider administration of corticosteroids
    • Methylprednisolone 125–500 mg/day X 3 days are recommended¹⁸
  • Medications commonly used for SLE flares and chronic management that may be recommended by rheumatology include:
    • Non-steroidal anti-inflammatory drugs (NSAIDs)
    • Antimalarials (i.e. hydroxychloroquine)
    • Corticosteroids
    • Immunosuppressants
    • Biologics
  • SLE flare patients with high disease activity [as measured by the SLEDAI (https://www.mdcalc.com/calc/10099/systemic-lupus-erythematosus-disease-activity-index-2000-sledai-2k) or SLE-DAS [http://sle-das.eu/)], concomitant infection, or organ damage typically require admission.^19–23
  • Discharge recommendations should include: sun protection, good diet and nutrition, exercise, smoking cessation, appropriate immunizations
    • SLE patients are at higher risk for infection than the general population due to the disease itself as well as immunosuppressing medications used to treat it²⁴
    • Routine vaccination should include: COVID-19, hepatitis B, herpes zoster, human papillomavirus (HPV), influenza, pneumonia, and tetanus/diphtheria/pertussis^24,25
    • Live vaccines should be avoided in patients with high disease activity or who are on immunosuppressants²⁵

Prognosis:

• In the United States – survival rate ranges from 95% at 5 years to 78% at 20 years²
• Mortality is related to vital organ damage, not high rates of disease activity²⁶
  • Renal insufficiency contributed to mortality in 40.9% of SLE ED events in one study
  • Pulmonary hypertension is another factor that leads to high mortality

Pearls:

• SLE is an autoimmune condition that can affect any organ system
• While it is unlikely we will diagnose SLE in the ED, this needs to be on the differential so that patients can receive appropriate follow-up
• Patients with established SLE may present with medication side effects or flares
• Immunosuppressant therapy should only be ordered in conjunction with rheumatology recommendations

Further Reading: