Definition: The prototypical systemic autoimmune disorder characterized by autoantibody formation, immune complexes deposition, and multiorgan involvement with a wide range of clinical manifestations across affected patients.

Etiology / Risk Factors

• Female: Male ratio 9:1. The estimated prevalence in the United States is 20-150/100,000. The prevalence is ~2.5x greater among African American women relative to white women.
• Age of onset typically after puberty with a peak in the 20s-30s
• Mortality 2-5x higher than general population. Early mortality predominately due to active disease and infection in the setting of immunosuppression. Later mortality primarily due to atherosclerotic disease.
• Poor prognostic factors: older age at diagnosis, low socioeconomic status, Black race, renal disease, male sex, high disease activity, presence of antiphospholipid antibodies and/or concomitant antiphospholipid syndrome.

Evaluation

Differential Diagnosis

• Drug-induced lupus (DIL)
  • Many drugs can induce an autoimmune response and ANA production without overt clinical signs/symptoms, whereas a subset of drugs cause pathologic ANA formation and clinical manifestations that mimic idiopathic SLE
  • In general, drug-induced lupus is less severe than idiopathic SLE. Most commonly causes fever, myalgias, rash, arthritis, serositis; renal and CNS involvement is rare
  • Anti-histone antibodies are present in the majority of patients with drug-induced lupus associated with the following culprit medications: procainamide (1/3^rd treated with this drug may develop sx of drug-induced SLE), hydralazine, chlorpromazine, quinidine. Anti-histone antibodies do not distinguish from idiopathic SLE (many patients with idiopathic SLE also make anti-histone antibodies) but those with idiopathic SLE are more likely to have other positive sub-serologies
  • Other culprit medications: antithyroid drugs (+/- ANCA Ab, vasculitis rash, rare pulmonary and kidney disease), minocycline, penicillamine, INH, TNF-alpha inhibitors (greater prevalence of +dsDNA and renal involvement relative to other forms of DIL), interferon-alpha, methyldopa, practolol
• Autoimmune multisystem disease (RA, adult-onset Still disease, Sjogren syndrome, ANCA-associated vasculitis, mixed connective tissue disease), infections (viruses can present with fever, myalgias, rash, cytopenias), malignancy

2019 Diagnostic Criteria

The European League Against Rheumatism (EULAR) and American College of Rheumatology (ACR) 2019 criteria have validated a new weighted criterion and entry criterion (positive ANA) that is more sensitive and specific than ACR 1997 and SLICC 2012 criteria. These criteria were developed for research purposes but can be helpful as a reference for clinicians.

Entry criterion: ANA at a titer of >1:80 on HE-p2 cells with indirect immunofluorescence or an equivalent positive test (ever) then consider the additive criteria below.

Rules for additive criteria include:

1. Do not count criterion if there is a more likely explanation than SLE

2. Ok to count criteria if it has occurred at least once

3. Criteria do not need to all be present at once

4. Within each clinical domain, only count the highest weighted criteria towards the total score

Clinical domains and criteria (weight)		Score
Constitutional: fever (2)
Hematologic: leukopenia (3), thrombocytopenia (4), autoimmune hemolysis (4)
Neuropsychiatric: delirium (2), psychosis (3), seizure (5)
Mucocutaneous: non-scarring alopecia (2), oral ulcers (2), subacute cutaneous OR discoid lupus (4), acute cutaneous lupus (6)
Serosal: pleural or pericardial effusion (5), acute pericarditis (6)
Musculoskeletal: joint involvement (6)
Renal: proteinuria >0.5g/24h (4), renal biopsy class II or V lupus nephritis (8), class III or IV lupus nephritis (10)
Antiphospholipid antibodies: anti-cardiolipin antibodies OR anti-beta-2 glycoprotein 1 antibodies OR lupus anticoagulant (2)
Complement proteins: low C3 OR low C4 (3), low C3 AND low C4 (4)
SLE-specific antibodies: anti-dsDNA antibody OR anti-Smith antibody (6)
Total: if ≥10, likely SLE

For definitions of criteria see Aringer (2019) below.

Other clinical manifestations (not included in criteria)

• Constitutional: Fatigue, weight loss
• Neurologic: Cognitive impairment, headache, peripheral neuropathies, transverse myelitis, stroke, meningoencephalitis
• Ophthalmologic: Dry eye and associated keratitis, episcleritis, scleritis
• Mucocutaneous symptoms: Dry mouth, nasal ulcers
• Pulmonary: ILD (rare), pulmonary arterial hypertension, diffuse alveolar hemorrhage, PE among patients with secondary antiphospholipid syndrome (APS)
• Cardiovascular: Raynaud’s, Libman-Sacks endocarditis, myocarditis, increased risk of coronary artery disease
• GI: Hepatitis, protein-losing enteropathy, acute pancreatitis, mesenteric vasculitis or ischemia, peritonitis (form of serositis)
• Immunologic: Lymphadenopathy, splenomegaly
• Musculoskeletal: Reducible deformities (Jaccoud-like arthropathy), hypermobility, osteonecrosis

Autoantibodies

• 2-20% of general population have positive ANA
• ANA titers are not helpful to monitor in patients with established SLE and therefore it is not helpful to repeat testing after the initial positive test and diagnosis
• Do not order ANA sub-serologies if ANA is negative (exception- SSA for Sjogren’s Syndrome)
• ANA sub-serologies associated with lupus:
  • dsDNA: highly specific, often parallels disease activity, associated with renal disease
  • Smith: highly specific, associated with renal disease
  • RNP: associated with Raynaud’s, musculoskeletal disease, and mixed-connective tissue disease (MCTD)
  • SSA/Ro: associated with neonatal lupus, Sjögren’s, SCLE and PBC
  • SSB/La: associated with neonatal lupus and Sjögren’s

Special Considerations

• Lupus nephritis: occurs in 70%. Anti-dsDNA is a marker for risk. Kidney biopsy is diagnostic and essential for definition of histological subtype and appropriate therapy
  • Indications for kidney biopsy: increase in serum Cr without explanation, proteinuria >1g/24hrs, proteinuria >500 mg/24 hrs + hematuria and/or cellular casts
  • Presentations vary but can include lower extremity edema, active urine sediment (cellular casts, hematuria, proteinuria), elevated blood pressure, and elevated serum creatinine
  • Higher risk patients (e.g. males, +anti-C1q Ab, juvenile lupus onset) and those with active disease warrant regular monitoring (q3 months) for kidney disease
  • Treatment includes an induction phase (cyclophosphamide or mycophenolate + high dose glucocorticoids) and maintenance or remission phase (mycophenolate or azathioprine)
• Antiphospholipid antibodies: should be checked at least once in every lupus patient given associated increased risk of thrombotic and obstetric complications
  • Include lupus anticoagulant, anticardiolipin antibody (IgG/IgM), and beta2-glycoprotein I Ab (IgG/IgM). Found in approximately 40% of patients with SLE
  • Women with SLE and positive aPL warrant prophylactic low dose aspirin during pregnancy
  • APS (antiphospholipid antibody syndrome): see Hematology. Treat underlying lupus. Management is not different for APS primary vs. SLE-APS (warfarin goal INR 2-3, LMWH during pregnancy)
• Pregnancy: associated with increased risk of active disease and pregnancy complications. Consult rheumatology within 24 hours in all patients with positive urine pregnancy tests and systemic multi-organ disease. Should be co-managed with high-risk maternal fetal medicine as outpatient
  • 2-5x higher miscarriage, stillbirth, premature delivery, and 8x higher IUGR. Highest risk of mortality and morbidity in patients with active disease, especially nephritis, and patients with anti-Ro/SSA and/or APL antibodies
  • Defer pregnancy until disease quiescent for at least 6 months on stable non-teratogenic therapy prior to conception for best outcome
  • Pregnant lupus patients should have evaluation for SSA status, APL status, iron deficiency, and pulmonary hypertension
  • Pearl: differentiate preeclampsia/eclampsia (increased serum urate) vs. disease flare (increased dsDNA, hypocomplementemia, active urine sediment)
  • Anti-Ro/SSA, anti-La/SSB antibodies in mom confer risk for fetus developing neonatal lupus, 2% develop congenital heart block (treatment includes pacing)
  • Treatment: HCQ should be continued during pregnancy. Azathioprine is also safe and should be continued in women with active SLE during pregnancy. Most other DMARDs are teratogenic and should be discontinued 8 weeks prior to conception
  • Monitor post-partum for flares
• Birth control: as pregnancy is high-risk due to medication and disease activity, patients should be routinely counseled about birth control options, especially at time of hospital discharge (even if for non-lupus events) as this can have life-altering impact on maternal and fetal mortality/morbidity
  • If tolerated, long-acting reversible contraception (e.g. IUD) is ideal in women with moderate/high disease activity, current organ-threatening flares or on teratogenic medications (MMF, CYC, MTX)
  • Avoid estrogen-containing OCPs for women with APS or +APLs given increased risk of clot

Management

Workup of presumed lupus flare:

• CBC with differential, Cr, albumin, LFTs, ESR/CRP (to evaluate for infection), UA with urine protein/creatinine spot ratio, pregnancy test in females. C3/ C4 (will be low in active disease due to consumption via circulating immune complexes), dsDNA to assess SLE activity. Surveillance labs are similar and are completed every 3 months (active patients) to annually (inactive disease).
• Important to differentiate SLE flare from infection. SLE flare is usually associated with low WBC and normal CRP (exception is in patients with serositis or vasculitis). Infection associated with high WBC and CRP. High fever is an unusual manifestation of SLE.

Treatment

• Adjunct treatment for all patients: sun protection (avoidance, no UV light sources, SPF ³30, sun protective clothing), vaccinations (influenza annually, pneumococcal for immunosuppressed patients), daily exercise (including weight bearing activities), smoking cessation, aggressive CV risk reduction (weight, BP, lipids, serum glucose)
  • ACE/ARB in patients with HTN/proteinuria, goal BP <130/80
• All patients should be on hydroxychloroquine (HCQ), unless contraindicated
• Mild disease: constitutional symptoms, mild arthritis/rash
  • HCQ, low dose steroid prn flares
• Moderate disease: RA-like arthritis, rash, serositis, serologic activity (cytopenias, elevated dsDNA, hypocomplementemia)
  • HCQ and additional DMARD selected based on clinical manifestations: methotrexate (e.g. for active arthritis), azathioprine, mycophenolate (e.g. skin-predominant disease), belimumab
• Severe disease: major organ threatening disease (nephritis, neuropsychiatric lupus, pneumonitis, mesenteric vasculitis, severe thrombocytopenia, secondary HLH)
  • Rheumatologic emergency: consult rheumatology asap, treatment includes cyclophosphamide versus MMF as well as high-dose steroids
• Considerations of DMARDs treatment
  • Avoid MMF, CYC, MTX in women who are pregnant
  • Increases infection risk, particularly zoster with MMF
  • Common side effects include nausea/GI upset, myelosuppression, hepatotoxicity; laboratory monitoring includes serial CBC+LFTs

Prognosis

• Worse prognosis associated with: pediatric-onset disease; Black, Asian and LatinX race/ethnicity; renal involvement; increased number of diagnostic criteria; and evidence of end organ damage.
• High association of cardiovascular disease and SLE. Chest pain or other symptoms suggestive of angina should be taken seriously in SLE patients regardless of age, gender, or suspicion of serositis. Aggressive long-term control of blood pressure and cholesterol is advised.

Key points

• Highly varied clinical manifestations with potential to affect nearly every organ system.
• Most commonly presents in women in 20s and 30s.
• Gold standard is ANA by indirect immunofluorescence (will provide titer and pattern), which is required for diagnosis. Do not repeat ANA testing among patients with prior confirmed test.
• Treatment focuses on decreasing active inflammation, prevention of organ damage, and symptom management.
• HCQ is cornerstone of treatment.
• Rule out infection before attributing new symptoms to SLE flare as most patients with SLE are treated with immunosuppressive medications and therefore are at higher risk for infectious diseases. Additionally, infections can trigger SLE disease flares.
• Ensure all patients have rheumatologist at time of discharge.

References

Aringer M, Costenbader K, Daikh D, et al. 2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus. Ann Rheum Dis. 2019;78(9):1151-1159.

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):736-745.

Gatto M, Zen M, Iaccarino L, Doria A. New therapeutic strategies in systemic lupus erythematosus management. Nat Rev Rheumatol. 2019;15(1):30-48.

Petri M et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012 Aug;64(8):2677–86.

Marchetti T, Ribi C, Perneger T, et al. Prevalence, persistence and clinical correlations of classic and novel antiphospholipid antibodies in systemic lupus erythematosus. Rheumatology (Oxford). 2018;57(8):1350-1357. doi:10.1093/rheumatology/key095

L Andreoli et al, EULAR recommendations for women’s health and the management of family planning, assisted reproduction pregnancy, and menopause in patients with systemic lupus erythematosus and/or antiphospholipid syndrome. Ann Rheum Dis 2017;76:476–485. doi:10.1136/annrheumdis-2016-209770

With adaptations from 2018 UCSF Outpatient Handbook, Agile MD (Resident Editor: Megan Lockwood, Faculty Editor: Sarah Goglin Updated 6/2020 (MJ