Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a systemic autoimmune disorder with varied manifestations and severity. It most commonly occurs in women during their childbearing years and in Black, Hispanic, and Asian people more frequently and severely than in white people.

The pathogenesis of SLE involves direct effects of autoantibodies (e.g., Coombs-positive hemolytic anemia) and through immune complex deposition in various tissues, which triggers an inflammatory response (e.g., glomerulonephritis).

Clinical Manifestations

SLE is notable for its heterogeneity — patients can have SLE with different manifestations, including:

• mucocutaneous involvement

  • Raynaud phenomenon

  • aphthous ulcers

  • nonscarring alopecia

  • numerous rashes, most of which are photosensitive; not all patients with cutaneous lupus develop systemic lupus

    • acute cutaneous lupus: characteristic malar or butterfly rash, but can also be generalized (nearly all patients with acute cutaneous lupus will have SLE)

    • subacute cutaneous lupus: psoriasiform plaques or annular/polycyclic plaques with central clearing (all usually nonscarring; about 50% will have SLE)

    • chronic cutaneous lupus: most commonly discoid plaques (discoid lupus), which heal with scarring, and localized alopecia (about 5-25% will have SLE)

  

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

• musculoskeletal involvement

  • nonerosive inflammatory polyarthralgia or polyarthritis is common

  • myalgia

  • myositis

  • Jaccoud arthropathy, characterized by rheumatoid arthritis (RA)-like joint-alignment abnormalities that are reducible (unlike in RA) and not associated with bony erosions

• kidney involvement

  • lupus nephritis (see the 2018 Revision of the International Society of Nephrology/Renal Pathology Society classification of lupus nephritis)

  • renal artery or vein thrombosis in patients with a hypercoagulable state (may be associated with antiphospholipid antibodies or nephrotic syndrome)

• neuropsychiatric involvement

  • headache

  • cognitive dysfunction

  • mood disorder

  • transverse myelitis

  • cerebral vasculitis

  • peripheral neuropathy

  • seizure

• cardiovascular involvement

  • pericarditis (often asymptomatic)

  • myocarditis

  • valvular abnormalities (e.g., Libman-Sacks [nonbacterial] endocarditis)

  • increased risk of ischemic heart disease

• pulmonary

  • pleurisy/pleural effusions

  • interstitial lung disease

  • acute lupus pneumonitis

  • diffuse alveolar hemorrhage (rare)

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

• hematologic involvement

  • anemia, leukopenia, thrombocytopenia

  • hypercoagulability and antiphospholipid antibody syndrome (APLS)

• gastrointestinal involvement

  • esophageal dysmotility

  • sterile peritonitis

  • mesenteric vasculitis

  • mesenteric thrombosis (in patients with APLS)

  • autoimmune hepatitis

Diagnosis

Diagnosis of SLE is dependent on both the characteristics listed above and the following investigations:

• laboratory studies, including complement components (C3, C4), coagulation studies with lupus anticoagulant, direct antigen test, and urine albumin or protein analysis

• tests for autoantibodies

  • antinuclear antibody (ANA) — highly sensitive (99%) for SLE

  • antibodies to Smith antigen and double-stranded DNA (dsDNA) — specific for SLE, but not sensitive

  • antibodies to Ro, La, and ribonucleoprotein (RNP) — not specific for SLE but if present markedly increase the chances of SLE or other ANA-associated autoimmune rheumatic disease, such as Sjögren syndrome or mixed connective tissue disease

  • antiphospholipid antibodies (anticardiolipin, anti-beta 2-glycoprotein 1, lupus anticoagulant)

Of the antibodies listed above, the only antibody that is known to correlate with disease activity is the anti-dsDNA level, which correlates strongly with lupus nephritis. All other autoantibodies, while important diagnostically, cannot be used to determine disease activity.

Some patients will have serologic evidence of antibody formation and activity (such as hypocomplementemia and polyclonal hypergammaglobulinemia) that may mirror clinically active disease; in such patients, these biomarkers may be useful for monitoring disease activity. In others, these biomarkers are permanently abnormal or normal, and their monitoring utility is less useful. In other patients, there might be no evidence of complement activation or polyclonal antibody formation despite supportive serology for diagnosis. In this last group of patients, it is critical that the symptom description be weighed heavily in determining the degree of disease activity.

Additional investigations are dependent on the manifestations of disease (e.g., transthoracic echocardiography; electrocardiography; imaging of the chest, abdomen, or central nervous system; pulmonary function tests; nerve conduction studies; renal biopsy).

Classification: For decades, researchers used the American College of Rheumatology Criteria for the classification of SLE, which included 11 possible criteria. A patient was considered to have SLE if 4 criteria were positive. In 2012, an expert panel developed revised criteria that required 4 of 17 items be present, but this time at least 1 clinical and 1 immunologic criterion had to be met or the patient had to have lupus nephritis proven by biopsy with a positive ANA or anti-dsDNA test. This Systemic Lupus International Collaborating Clinics Classification (SLICC/ACR) Criteria and a 2019 update represent improved classification schemes. Although classification criteria do not always perform well in clinical practice and should not be strictly followed for diagnosis, they can be quite useful as a guide or starting point when SLE is under consideration.

§Additional criteria items within the same domain will not be counted. *Note: In an assay with at least 90% specificity against relevant disease controls (Source: 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Ann Rheum Dis 2019.)

Treatment

Hydroxychloroquine: In general, patients with SLE should be started on hydroxychloroquine (unless allergic, not tolerated, or the patient declines for other reasons). Hydroxychloroquine has been shown to prevent lupus flares, decrease the risk of organ damage, and improve mortality in patients with SLE. It may also provide an antithrombotic effect in patients with antiphospholipid syndrome and may prevent development of neonatal lupus and congenital heart block in infants of mothers with anti-Ro antibodies. Otherwise, treatment is aimed at the active manifestations of the disease.

Additional treatment options include the following and are given based on disease manifestations:

• nonsteroidal anti-inflammatory drugs

• glucocorticoids

• methotrexate (for inflammatory arthritis)

• azathioprine

• mycophenolate mofetil (MMF) or mycophenolate sodium

• calcineurin inhibitors: tacrolimus, voclosporin

• cyclophosphamide

• B-cell-targeted therapies: rituximab (anti-CD20), belimumab (anti-BlyS)

• anifrolumab (a type I interferon blocker and newer agent that may be useful in patients with skin and joint disease)

The following figure summarizes commonly used medications for treatment of SLE:

(Source: 2019 Update of the EULAR Recommendations for the Management of Systemic Lupus Erythematosus. Ann Rheum Dis 2019.)

Note: Belimumab is approved for intravenous or subcutaneous injection.