Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder with heterogeneous presentation and severity.

Epidemiology: Twenty percent of patients present by the age of 20. SLE is more common in females than males and is more common and severe in nonwhite populations.

Pathophysiology: SLE is associated with dysfunction of both the innate and adaptive immune systems. Autoreactive B and T cells are responsible for the generation of autoantibodies. These antibodies can cause disease directly or through immune complex activation and deposition in various tissues, triggering an inflammatory response. Activation of dendritic cells, interferon type I signaling, and defective clearance of apoptotic cellular debris are also implicated in potentiating the proinflammatory disease state.

Clinical Manifestations

Constitutional features:

• fatigue

• fever (usually low-grade temperature [100-101°F/38°C] rather than high-spiking fever)

• weight loss (unintentional)

Mucocutaneous involvement:

• rashes (photosensitive, malar, discoid, vasculitic)

• oral ulcers (typically nonpainful ulceration on hard palate, but can be painful buccal ulcers)

• alopecia (short, friable hairs, easily pulled with gentle traction)

(Source: Malar Rash. N Engl J Med 2021.)

(Source: Cutaneous Lupus — “The Pimple That Never Went Away.” N Engl J Med 2016.)

Musculoskeletal involvement:

• nonerosive polyarthritis (typically of the small joints of the hands)

• arthralgias and myalgias

Hematologic involvement:

• autoimmune hemolytic anemia (+Coombs/DAT)

• thrombotic microangiopathic anemia

• immune-mediated thrombocytopenia

• leukopenia (usually lymphopenia)

• macrophage activation syndrome

• antiphospholipid antibody syndrome leading to thrombosis

Renal involvement:

• glomerulonephritis: due to immune complex deposition, can present with nephritic or nephrotic syndrome

• “full house” immunofluorescence pattern on biopsy: diffuse immune complex deposits containing C3, C1q, IgG, IgA, IgM (see image below)

• renal artery or vein thrombosis: in patients with a hypercoagulable state; may be associated with antiphospholipid antibodies

Neuropsychiatric involvement:

• seizures

• psychosis

• cognitive impairment (“brain fog”)

• transient ischemic attack/stroke

• transverse myelitis

• chorea

• cranial nerve palsy

• lupus headache (unremitting and unresponsive to medications; controversial as a neuropsychiatric manifestation of SLE)

Cardiac involvement:

• pericarditis

• valvular abnormalities (e.g., Libman-Sacks endocarditis, valvular regurgitation)

• myocarditis

• increased risk of coronary artery disease (myocardial infarctions reported in young women with SLE)

Pulmonary involvement:

• pleural effusions

• interstitial lung disease

• acute lupus pneumonitis

• diffuse alveolar hemorrhage

• shrinking lung syndrome (pleuritic chest pain, shortness of breath, and progressive decrease in lung volumes)

Gastrointestinal involvement:

• autoimmune hepatitis

• mesenteric vasculitis

• pancreatitis

• protein-losing enteropathy

• esophageal dysmotility and reflux

Diagnosis

History and Physical Exam

• Pay attention to potential clinical features of SLE (as noted above)

Laboratory Evaluation

• antinuclear antibody (ANA) test: very sensitive for diagnosis of SLE (positive in >98% of patients) but not specific (positive in 10%-20% of healthy children)

  • interpretation of ANA profile:

    • anti-double-stranded DNA (dsDNA): specific for SLE, associated with renal disease, and can be tracked as a marker of disease activity

    • anti-Smith: 100% specific for SLE

    • anti-ribonucleoprotein (RNP): seen in patients with SLE and in mixed connective tissue disease (high titer)

    • anti-Scl-70: seen in patients with scleroderma and overlap syndromes

    • anti-SSA and -SSB: seen in either primary Sjögren syndrome or SLE

• complement levels: monitor for low C3 and C4

  • low levels trend as markers of disease activity

  • very low CH50 can suggest genetic complement deficiency

• antiphospholipid antibodies: positive antiphospholipid antibodies are associated with a higher prevalence of thrombosis, pregnancy-associated morbidity, neuropsychiatric SLE, and SLE-associated cardiovascular disease

  • prolonged partial thromboplastin time (PTT)

  • dilute Russell’s viper-venom time (DRVVT, aka lupus anticoagulant)

  • anti-cardiolipin IgM/IgG

  • anti-beta-2-glycoprotein IgM/IgG

  • false-positive rapid plasma reagin (RPR)

• CBC with differential: monitor for

  • leukopenia (absolute leukocyte count <4000/mm³)

  • lymphopenia (<1500/mm³)

  • thrombocytopenia (<100,000/mm³)

  • autoimmune hemolytic anemia

• direct antiglobulin test (DAT or Coombs test): especially if anemia is present

• peripheral smear: obtain if hemolytic anemia present to evaluate for schistocytes suggestive of thrombotic microangiopathy (thrombotic thrombocytopenic purpura [TTP]/hemolytic uremic syndrome [HUS]) instead of antibody-mediated hemolysis

• inflammatory markers: often low-normal C-reactive protein (CRP) with very elevated erythrocyte sedimentation rate (ESR)

• CMP: elevated creatinine and hypoalbuminemia suggests renal disease with proteinuria

• urinalysis/protein-to-creatinine ratio: if proteinuria is present, obtain first morning urine protein-to-creatinine ratio (normal value, <0.2)

• total IgG: often elevated in new-onset SLE

Additional Evaluation

• renal biopsy: consider if concern for renal involvement; biopsy and histologic classification guide management (see International Society of Nephrology/Renal Pathology Society [ISN/RPS] classification of lesions in lupus nephritis)

• echocardiogram and electrocardiogram: for baseline screening and monitoring as needed

• chest x-ray: if signs or symptoms of pleural or pericardial effusions

Classification Criteria

Classification criteria for identifying SLE disease in clinical studies are often used to guide the diagnosis of SLE, but it is important to note that they were developed for classification in clinical research studies and not as diagnostic criteria. Although the classification criteria do not always perform well in clinical practice and should not be strictly followed for diagnosis, they can be useful as a guide or starting point when SLE is under consideration.

For decades, researchers used the American College of Rheumatology (ACR) Criteria for the Classification of SLE, which included 11 possible criteria (listed below). A patient was considered to have SLE if 4 criteria were positive. In 2012, an expert panel developed the Systemic Lupus International Collaborating Clinics Classification (SLICC) Criteria that required 4 of 17 items be present, with at least 1 clinical and 1 immunologic criterion or biopsy-proven lupus nephritis with positive ANA or anti-DNA test. The SLICC criteria and a 2019 European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) update represent improved classification schemes. The three classification criteria are frameworks to guide the work up for patients with concern for SLE. No one classification schema is considered a gold standard.

The criteria are cumulative, occurring either serially or simultaneously (e.g., even if malar rash has faded at the time of development of a palatal ulcer, both of these criteria are counted).

• the American College of Rheumatology (ACR) criteria

• the Systemic Lupus International Collaborating Clinics (SLICC) criteria

• the 2019 European League Against Rheumatism and American College of Rheumatology (EULAR/ACR) criteria

Treatment

• hydroxychloroquine

  • for all patients except those with toxicity or intolerance

• glucocorticoids

  • oral for mild-to-moderate disease

  • intravenous (IV) pulse methylprednisolone for lupus nephritis or other severe manifestations (autoimmune cytopenias, neuropsychiatric lupus, severe cutaneous involvement)

  • for induction with the goal of gradual taper over months; some patients require low-dose prednisone long term

• glucocorticoid-sparing agents

  • mycophenolate mofetil: for lupus nephritis, mild-to-moderate hematologic manifestations

  • IV cyclophosphamide: for proliferative lupus nephritis, neuropsychiatric lupus, organ-threatening disease

  • methotrexate: for arthritis or mucocutaneous predominant disease

  • azathioprine: an alternative to mycophenolate mofetil for maintenance medication and can be used during pregnancy

  • voclosporin: approved for patients aged ≥18 to treat SLE nephritis

  • biologics:

    • rituximab: for severe hematologic manifestations, antiphospholipid antibody syndrome, neuropsychiatric lupus

    • belimumab: as adjunctive therapy to standard of care for refractory SLE manifestations

    • anifrolumab: approved for 18 and older for active SLE despite standard therapy, more effective in cutaneous disease

  • plasmapheresis: adjunctive/salvage therapy for neuropsychiatric lupus, severe autoimmune cytopenias, or thrombotic microangiopathic anemia

• sunscreen

  • minimum SPF of 30 with UVA and UVB protection to prevent ultraviolet light from triggering disease flares

  • Encourage reduction in sun exposure, long sleeves, hats

• vitamin D and calcium supplementation

  • to optimize bone health, especially with chronic use of glucocorticoids

• immunizations

  • avoid live vaccines (varicella, measles-mumps-rubella [MMR], intranasal influenza) for individuals on immunosuppressive medications

  • administer inactivated influenza vaccine annually

  • additional pneumococcal vaccines are recommended for SLE patients on immunosuppressive medications

    • as of 2023, a combination of PCV13 and PSV23 (to be repeated after 5 years) or PCV20 alone (given one time) are accepted regimens

  • encourage COVID-19 vaccination (including current CDC guidance on third dose and booster dose depending on age and immunocompromised status)