Systemic lupus erythematosus

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 features as well as genetic predisposition are considered likely etiological factors. The presentation of the disease is variable but usually characterized by phases of remission and relapse. Symptoms can range from mild localized symptoms 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. The diagnosis of SLE is based on clinical findings and is further supported by antibody tests, particularly for ANA, anti-dsDNA, and anti-Sm. Management consists of supportive measures, such as avoiding sun exposure, and medication adapted to disease severity. Long-term pharmacotherapy typically consists of 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 adapted to the severity of the flares. In severe cases, additional immunosuppressants (e.g., mycophenolate, azathioprine) 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 black populations

Epidemiological data refers to the US, unless otherwise specified.

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

• Genetic predisposition ^[3]
  • 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% of affected individuals
• Hormonal factors: Hyperestrogenic states (e.g., due to oral contraceptive use, postmenopausal hormonal therapy, endometriosis) are associated with an increased risk of SLE. ^[4]
• Environmental factors ^[3][4]
  • Cigarette smoking and silica exposure increase the risk of developing SLE.
  • UV light and EBV infection may trigger disease flares, but there is insufficient evidence on whether they cause SLE.
  • Drugs such as procainamide or hydralazine (see “Drug-induced lupus erythematosus”)

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

• Autoantibody development: deficiency of classical complement proteins (C1q, C4, C2) → failure of macrophages to phagocytose immune complexes and apoptotic cell material (i.e., plasma and nuclear antigens) → dysregulated, intolerant lymphocytes targeting normally hidden intracellular antigens → autoantibody production (e.g., ANA, anti-dsDNA)
• Autoimmune reactions
  • Type III hypersensitivity (most common in SLE) → antibody-antigen complex formation in microvasculature → complement activation and inflammation → damage to skin, kidneys, joints, small vessels
  • Type II hypersensitivity → IgG and IgM antibodies directed against antigens on cells (e.g., red blood cells) → cytopenia

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]

• Constitutional: fatigue, fever, weight loss
• Joints (> 90% of cases) ^[3]
  • Arthritis and arthralgia
  • Distal symmetrical polyarthritis
• Skin (85% of cases) ^[3][7]
  • Malar rash (butterfly rash): flat or raised fixed erythema over both malar eminences; (nasolabial folds tend to be spared)
  • Raynaud phenomenon
  • Photosensitivity → maculopapular rash
  • Discoid rash
  • Oral ulcers (usually painless)
  • Nonscarring alopecia (except with discoid rashes)
  • Periungual telangiectasia

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

Less common ^[3]

• Hematological: petechiae, pallor, or recurrent infections due to cytopenias
• Musculoskeletal: myalgia
• Serositis: pleuritis and pericarditis → effusions
• Kidneys: nephritis with proteinuria (see “Lupus nephritis”)
• Heart
  • Pericarditis, myocarditis, endocarditis (Libman-Sacks endocarditis)
  • Aortic valve lesions
  • Coronary artery disease
• Lungs
  • Pneumonitis
  • Interstitial lung disease
  • Pulmonary hypertension
• Vascular
  • Vasculitis
  • Thromboembolism (see “Antiphospholipid syndrome”)
• Neurological
  • Seizures
  • Psychosis
  • Personality changes
  • Lupus cerebritis
  • Aseptic meningitis
  • Polyneuropathy
• Eyes: keratoconjunctivitis sicca ^[8]

SLE can cause LSE (Libman-Sacks Endocarditis).

Cutaneous lupus erythematosus (CLE)

Discoid lupus erythematosus (DLE) ^[7][9]

• Epidemiology
  • ♀ > ♂ (3:1)
  • Most common in women aged 30–50 years
• Clinical features
  • Erythematous, inflammatory scaly plaques that are painful to remove
  • Heals, but leads to scarring alopecia, atrophy, peripheral hyperpigmentation, and central depigmentation
  • Typically affects the face, neck, and head (triggered by exposure to UV light)
• Diagnostics
  • Based on a combination of history, clinical examination, and histology
  • Lupus band test
  • Antibodies are mostly negative.
• Prognosis
  • The prognosis for DLE is better than the prognosis for SLE.
  • The risk of developing SLE is < 10%.

Subacute cutaneous lupus erythematosus (SCLE) ^[3][9]

• General information: an uncommon variant
• Clinical features
  • Extreme photosensitivity
  • Begins as a papular eruption or small scaly plaques that develop into either annular or psoriasiform lesions
  • Lesions heal without scarring but may lead to hypopigmentation.
  • Usually affects the neck, shoulders, and upper limbs, but spares the face
• Diagnostics
  • Based on a combination of history, clinical examination, and histology
  • Patients are often anti-Ro/SSA and ANA positive.

Acute cutaneous lupus erythematosus (ACLE) ^[6][9][10]

• General information: frequently associated with active SLE
• Epidemiology: most common in individuals aged 20–30 years
• Clinical features
  • Malar rash
  • Maculopapular rash (also called “maculopapular rash of lupus” or “photosensitive lupus dermatitis”)
    • When ACLE affects the hands, it must be differentiated from dermatomyositis.
    • ACLE only involves the dorsum of the hands and spares the DIP, PIP, and MCP joints, whereas dermatomyositis also affects the joints. ^[9]
• Diagnostics
  • Histology
  • Positive ANA in 95% of patients ^[9]
  • Anti-dsDNA and anti-Sm antibodies are often increased.

Drug-induced lupus erythematosus (DILE) ^[11]

• Description: lupus-like symptoms triggered by medication
• Epidemiology
  • ♂ = ♀
  • DILE accounts for ∼ 10% of all SLE cases.
  • More common in white populations
  • Most common in individuals aged 50–70 years
• Etiology
  • Genetic susceptibility
    • Decreased acetyltransferase activity resulting in slow acetylation of drugs
    • Presence of HLA-DR2, HLA-DR3, HLA-DR4, or an unexpressed C4 complement allele
  • Common drug triggers
    • Sulfa drugs
    • Certain nonsulfa drugs, e.g., procainamide, hydralazine, isoniazid, methyldopa, minocycline, phenytoin, TNF-α inhibitors
• Clinical features
  • Musculoskeletal: myalgia and polysymmetrical arthralgia
  • Constitutional: fatigue, fever, weight loss
  • Malar rash
  • Serositis
  • Skin lesions
• Diagnostics ^[11]
  • Antihistone antibodies
    • Antihistone antibodies are seen in 90–95% of cases.
    • Nonspecific: may also be present in ∼ 75% of SLE cases
  • Elevated ANA
  • No anti-dsDNA antibodies
• Treatment: stopping the triggering agent and, if necessary, initiating temporary treatment (see “Treatment”)
• Prognosis: Most cases resolve within a few weeks after the drug in question has been discontinued.

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

DILE may manifest with a variety of the features also seen in idiopathic SLE, e.g., fever, arthritis, malar rash, and serositis, but typically does not affect the CNS or kidneys in the way that SLE does.

Approach ^[6][10]

1. If symptoms suggest SLE, request an ANA test.
2. ANA test: If titer is ≥ 1:80, evaluate the patient according to the EULAR/ACR classification criteria.
3. Diagnosis involves consideration of the EULAR/ACR criteria, the clinical presentation, and any additional special investigation results.

EULAR/ACR 2019 classification criteria for SLE ^[6][10]

The EULAR/ACR classification criteria were designed for research studies. While they can raise suspicion for SLE, the diagnosis of SLE cannot be confirmed or ruled out based solely on the criteria. The entire clinical picture and special investigation findings need to be considered.

Antinuclear antibody (ANA) testing has the highest sensitivity but low specificity for SLE. Anti-dsDNA and anti-Smith antibody testing are the most specific for SLE.

Laboratory tests ^[12]

• Antibody tests: See “Antinuclear antibodies.”
• Inflammatory markers
  • ESR: elevated according to disease activity
  • CRP: often normal (may be elevated if the patient has serositis, arthritis, or an infection)
  • Complement levels: ↓ C3 and/or ↓ C4
• Markers of organ damage
  • CBC: may show leukopenia, thrombocytopenia, autoimmune hemolytic anemia, anemia of chronic disease
  • Renal dysfunction
    • Urinalysis and urine microscopy showing proteinuria and/or casts
    • Abnormal urine protein quantification
    • Elevated urea and/or creatinine
  • Abnormal liver function tests
• RPR and VDRL: usually used to test for syphilis but may be positive in SLE

Further diagnostics ^[12]

• Histopathology
  • Lupus band test (LBT): direct immunofluorescence staining of immunoglobulin and complement component deposits found along the dermoepidermal junction in affected as well as unaffected skin in patients with SLE ^[13]
  • Kidney biopsy: indicated in suspected lupus nephritis
• Imaging studies: assessment of organ or joint involvement

Goals of treatment ^[14]

• Remission of symptoms
• Prevention of disease flares and organ damage
• Minimizing drug side effects

General management ^[12][14]

• Avoid smoking and UV light
• Counsel patients on lifestyle factors that affect SLE: diet, exercise, stress relaxation techniques
• Immunize patients before initiating immunosuppressants.
• Cutaneous manifestations: topical steroids, topical calcineurin inhibitors ^[15]
• Symptom relief: NSAIDs
• Pregnancy should be planned: Contraceptive options include barrier methods, nonhormonal IUD, and progestin-only contraceptives.

Systemic therapy ^[14]

UV phototherapy and UV photochemotherapy (PUVA) are contraindicated!

Lupus nephritis

• Description ^[16]
  • Most dangerous organ complication and a common cause of death in SLE
  • Can manifest as nephritic syndrome and/or nephrotic syndrome (see “Overview of glomerular diseases”)
• Epidemiology: common (> 30% of individuals with SLE) ^[3]
• Pathophysiology: mesangial and/or subendothelial deposition of immune complexes (e.g., anti-dsDNA antibodies, anti-Sm antibodies) → expansion and thickening of mesangium, capillary walls, and/or glomerular basement membrane ^[16]
• Classification: See “Terminology of glomerular diseases.” ^[6]
• Clinical features ^[12]
  • Hypertension
  • Edema
  • Hematuria
• Diagnostics ^[12]
  • Serum studies: ↑ creatinine
  • Urine analysis: proteinuria, hematuria, cellular casts (red cells, hemoglobin, granular, tubular, or mixed)
  • Kidney biopsy: immune complex-mediated glomerulonephritis (see “Diffuse proliferative glomerulonephritis)
• Treatment: depends on the severity of the disease ^[12][14]
  • Corticosteroids, immunosuppressants (mycophenolate, cyclophosphamide)
  • ACE inhibitors

It is important to regularly screen the urine of patients with SLE, as early treatment can prevent progression to severe renal disease.

Neuropsychiatric systemic lupus erythematosus (NPSLE)

• Description: Neurological and psychiatric symptoms found in individuals with SLE that cannot be attributed to any other disorder ^[17]
• Epidemiology: found in ∼ 50% of individuals with SLE ^[18]
• Classification: The American College of Rheumatology (ACR) distinguishes 19 NPSLE syndromes. ^[17]
• Central nervous system
  • Aseptic meningitis
  • Cerebrovascular disease
  • Demyelination
  • Headache
  • Chorea
  • Myelopathy
  • Seizures
  • Acute confusional state
  • Anxiety disorder
  • Cognitive impairment
  • Mood disorder
  • Psychosis
• Peripheral nervous system
  • Acute inflammatory demyelinating polyradiculoneuropathy (Guillain Barré syndrome)
  • Autonomic disorder
  • Single mononeuropathy or mononeuropathy multiplex
  • Myasthenia gravis
  • Cranial neuropathy
  • Plexopathy
  • Polyneuropathy
• Diagnostics ^[19]
  • Specific tests depend on the clinical picture and serve to rule out other etiologies, e.g.:
    • CSF fluid PCR to rule out herpes simplex virus and JC virus
    • EEG to rule out seizure disorders
  • MRI or other neuroimaging: may detect NPSLE and also rule out other neurosurgical lesions or infections
  • Antibody tests: antiphospholipid antibodies, antinuclear antibodies
  • See also “Diagnostics” above for diagnosis of generalized SLE.
• Treatment ^[19]
  • Immunosuppressive treatment
  • In NSLE patients with ischemic stroke or antiphospholipid antibodies: antithrombotic and/or antiplatelet therapy
  • Symptomatic treatment is used depending on the syndrome (e.g., antiseizure medications in seizures).

Other comorbidities ^[3][12]

• Increased risk of thrombosis
  • Especially in individuals with secondary antiphospholipid syndrome (may lead to recurrent abortions)
  • Together with further increased risk due to accelerated atherosclerosis
    • Myocardial infarctions
    • Stroke
• Libman-Sacks endocarditis
• Pancytopenia
• Infections ^[20]
  • Responsible for 25–50% of SLE deaths ^[20]
  • Most common infections
    • Bacterial: skin, lungs, or urinary tract
    • Viral: VZV, CMV, and HPV
• Interstitial lung disease, pulmonary hypertension
• Medication-induced adverse effects
• Pregnancy-related adverse effects (see “SLE and pregnancy” in “Special patient groups” below)

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

• Mortality: 10-year survival rate is ∼ 90% ^[3][12]
• Causes of death ^[3]
  • In early disease
    • High disease activity with renal or neurological complications
    • Infections due to disease-related factors and immunosuppressive therapy
  • In late disease
    • Cardiovascular disease ^[12]
      • Complications due to atherosclerosis
      • Coronary artery disease
      • Most common cause of death in SLE ^[21]
    • End-stage renal disease ^[16]
    • Adverse effects of long-term medication

“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.

SLE and pregnancy

• General ^[22][23]
  • While fertility is not affected by SLE, it may be affected by immunosuppressive drugs.
  • Pregnancy may trigger flares in disease activity.
  • Increased severity of maternal disease correlates with increased risk of maternal and fetal complications during pregnancy (see “Complications” below).
• Risk assessment ^[22][23]
  • Cardiac, lung, and kidney screening ^[23]
  • Serological profile
    • Anti-Ro/SSA and anti-La/SSB are associated with an increased risk of neonatal lupus.
    • Anticardiolipin antibodies and lupus anticoagulant: ↑ risk of miscarriage and thrombosis-related complications (see “Antiphospholipid syndrome”)
• Management ^[23]
  • Pregnancy planning and counseling ^[22]
  • Medical treatment should not be discontinued but the drug regimen may be changed.
    • Preconception, pregnancy, and breastfeeding: hydroxychloroquine and/or azathioprine
    • Disease flares: hydroxychloroquine and/or prednisolone
    • Low-dose aspirin from 12 weeks' gestation reduces the risk of preeclampsia. ^[23]
    • Teratogenic immunosuppressive drugs (e.g., methotrexate, mycophenolate, cyclophosphamide) should be avoided.
• Complications ^[23]
  • Maternal
    • SLE flares
    • Hypertension, preeclampsia
    • Venous thromboembolism
  • Fetal-neonatal
    • Neonatal lupus syndrome
    • Miscarriage
    • Intrauterine growth restriction
    • Fetal AV block ^[22]
    • Preterm delivery

Neonatal lupus syndrome ^[22][23]

• General: rare (has a high mortality rate)
• Etiology: associated with the transfer of maternal antibodies (anti-Ro/SSA and anti-La/SSB)
• Clinical features
  • First- to third-degree congenital AV block
  • Periorbital or diffuse rash (often presents in the first weeks after birth)
  • Cytopenia
  • Hepatitis, elevated liver enzyme
• Diagnostics
  • The following two criteria must be present at birth:
    • Antibodies (anti-Ro/SSA or anti-La/SSB) in either the mother or child
    • Heart block, characteristic rash, and/or hematologic/hepatic involvement with no identifiable cause in the newborn/fetus
• Treatment: directed at specific organ involvement
• Prognosis: Symptoms usually resolve within a few months.

1. Stojan G, Petri M. Epidemiology of systemic lupus erythematosus: an update.. Curr Opin Rheumatol. 2018; 30 (2): p.144-150. doi: 10.1097/BOR.0000000000000480 . | Open in Read by QxMD
2. Systemic Lupus Erythematosus (SLE). https://www.cdc.gov/lupus/facts/detailed.html. Updated: October 17, 2018. Accessed: July 27, 2020.
3. Feather A, Randall D, Waterhouse M. Kumar and Clark's Clinical Medicine. Elsevier ; 2020
4. Barbhaiya, Costenbader. Environmental Exposures and the Development of Systemic Lupus Erythematosus. Current Opinion in Rheumatology. 2016; 28 (5). doi: 10.1097/BOR.0000000000000318 . | Open in Read by QxMD
5. Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology Classification Criteria for Systemic Lupus Erythematosus. Arthritis & Rheumatology. 2019; 71 (9): p.1400-1412. doi: 10.1002/art.40930 . | Open in Read by QxMD
6. Uva L, Miguel D, Pinheiro C, Freitas JP, Marques Gomes M, Filipe P. Cutaneous manifestations of systemic lupus erythematosus. Autoimmune Dis.. 2012; 2012 : p.834291. doi: 10.1155/2012/834291 . | Open in Read by QxMD
7. Shoughy SS, Tabbara KF. Ocular findings in systemic lupus erythematosus. Saudi Journal of Ophthalmology. 2016; 30 (2): p.117-121. doi: 10.1016/j.sjopt.2016.02.001 . | Open in Read by QxMD
8. Okon LG, Werth VP. Cutaneous Lupus Erythematosus: Diagnosis and Treatment. Best Pract Res Clin Rheumatol. 2013; 27 (3): p.391-404. doi: 10.1016/j.berh.2013.07.008 . | Open in Read by QxMD
9. Aringer M, Leuchten N, Johnson SR. New Criteria for Lupus. Curr Rheumatol Rep. 2020; 22 (6): p.18. doi: 10.1007/s11926-020-00896-6 . | Open in Read by QxMD
10. Pretel M, Marquès L, España A. Drug-Induced Lupus Erythematosus. Actas Dermo-Sifiliogr. (English Edition). 2014; 105 (1): p.18-30. doi: 10.1016/j.adengl.2012.09.025 . | Open in Read by QxMD
11. Justiz Vaillant AA, Goyal A, Bansal P, et al. Systemic Lupus Erythematosus (SLE). StatPearls. 2020 .
12. Reich A, Marcinow K, Bialynicki-Birula R. The lupus band test in systemic lupus erythematosus patients. Ther Clin Risk Manag. 2011; 24 (7): p.27-32. doi: 10.2147/tcrm.s10145 . | Open in Read by QxMD
13. Fanouriakis A, Kostopoulou M, Alunno A, et al. 2019 update of the EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2019; 78 (6): p.736-745. doi: 10.1136/annrheumdis-2019-215089 . | Open in Read by QxMD
14. Panjwani S. Early Diagnosis and Treatment of Discoid Lupus Erythematosus. The Journal of the American Board of Family Medicine. 2009; 22 (2): p.206-213. doi: 10.3122/jabfm.2009.02.080075 . | Open in Read by QxMD
15. Rosalie M. Sterner, Stella P. Hartono, and Joseph P. Grande. The Pathogenesis of Lupus Nephritis. Journal of Clinical and Cellular Immunology. 2014 .
16. The American College of Rheumatology. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis & Rheumatism. 1999; 42 (4): p.599-608. doi: 10.1002/1529-0131(199904)42:4<599::aid-anr2>3.0.co;2-f . | Open in Read by QxMD
17. Kivity et al. Neuropsychiatric lupus: a mosaic of clinical presentations. BMC Med. 2015; 13 (1). doi: 10.1186/s12916-015-0269-8 . | Open in Read by QxMD
18. Bertsias GK, Ioannidis JPA, Aringer M, et al. EULAR recommendations for the management of systemic lupus erythematosus with neuropsychiatric manifestations: report of a task force of the EULAR standing committee for clinical affairs. Ann Rheum Dis. 2010; 69 (12): p.2074-2082. doi: 10.1136/ard.2010.130476 . | Open in Read by QxMD
19. Jung JY, Suh CH. Infection in systemic lupus erythematosus, similarities, and differences with lupus flare. Korean J Intern Med. 2017; 32 (3): p.429-438. doi: 10.3904/kjim.2016.234 . | Open in Read by QxMD
20. Iozza I, Cianci S, Di Natale A, et al. Update on systemic lupus erythematosus pregnancy. J Prenat Med. 2010; 4 (4): p.67-73.
21. Knight C, Nelson-Piercy C. Management of systemic lupus erythematosus during pregnancy: challenges and solutions. Open Access Rheumatol. 2017; 9 : p.37-53. doi: 10.2147/oarrr.s87828 . | Open in Read by QxMD
22. Thomas G, Mancini J, Jourde-Chiche N, et al. Mortality Associated With Systemic Lupus Erythematosus in France Assessed by Multiple-Cause-of-Death Analysis. Arthritis Rheumatol. 2014; 66 (9): p.2503-2511. doi: 10.1002/art.38731 . | Open in Read by QxMD
23. Mok CC, Lau CS. Pathogenesis of systemic lupus erythematosus. J Clin Pathol. 2003; 56 (7): p.481-490. doi: 10.1136/jcp.56.7.481 . | Open in Read by QxMD
24. Herold G. Internal Medicine. Herold G ; 2014
25. Dillon MJ, Goonasekera CD. Reflux nephropathy. J Am Soc Nephrol. 1998; 9 (12): p.2377-2383.
26. Le T, Bhushan V, Chen V, King M. First Aid for the USMLE Step 2 CK. McGraw-Hill Education ; 2015
27. Kasitanon N, Fine DM, Haas M, Magder LS, Petri M. Hydroxychloroquine use predicts complete renal remission within 12 months among patients treated with mycophenolate mofetil therapy for membranous lupus nephritis. Lupus. 2006; 15 (6): p.366-370. doi: 10.1191/0961203306lu2313oa . | Open in Read by QxMD
28. McDaniel B, Sukumaran S, Tanner LS. Discoid Lupus Erythematosus. StatPearls. 2020 .