Resident Editor: Megan Lockwood, MD

Faculty Editor: Sarah Goglin, MD

Background/Epidemiology

• Estimated prevalence 15–50 per 100,000 in the US
• Female:Male predominance 9:1
  • Twice as prevalent in African Americans vs Caucasians
• Onset typically after puberty, peak 20s and 30s
• Mortality rate 3 times greater than that of general population (80% 10-year survival after diagnosis, 65% 20-year survival)
  • Early mortality due to active disease and infection from immunosuppression
  • Later mortality primarily due to atherosclerotic disease
• Key predictors of disease progression: older age at diagnosis, black race, low income

 

Evaluation

• Systemic Lupus International Collaborating Clinics (SLICC) criteria provide a helpful framework for approaching the diagnosis of SLE
  • Must have > 4 criteria (at least 1 clinical and 1 laboratory criteria) OR biopsy-proven lupus nephritis with a positive ANA or dsDNA
  • Criteria are > 90 % sensitive and 85-92% specific for the diagnosis of SLE

 

Systemic Lupus International Collaborating Clinics Criteria (SLICC)
Clinical Criteria	Immunologic Criteria
Acute or Subacute Cutaneous Lupus - Malar Rash - Photosensitivity - Non-indurated psoriaform and/or annular polycyclic rash (associated with SSA/SSB)	ANA anti-dsDNA anti-Smith Anti-phospholipid Antibodies - Positive test for lupus anticoagulant - False-positive test result for rapid plasma reagin - Medium- or high-titer anticardiolipin OR beta 2 glycoprotein antibodies (IgA, IgG, or IgM) Low Complement (C3 or C4) Direct Coomb’s (independent of hemolytic anemia)
Chronic Cutaneous Lupus - Discoid
Oral or Nasal Ulcers
Non-scarring Alopecia - Diffuse thinning or hair fragility with visible broken hairs, in the absence of other causes
Arthritis - Synovitis involving 2 or more joints
Serositis - Typical pleurisy for more than 1 day OR pleural effusions OR pleural rub - Typical pericardial pain (pain with recumbency improved by sitting forward) for more than 1 day OR pericardial effusion OR pericardial rub OR pericarditis by electrocardiography
Renal - Urine Protein-To-Creatinine Ratio > 500 mg - Red Cell Casts or Dysmorphic RBCs
Neurologic - Seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, acute confusional state
Hemolytic Anemia
Leukopenia (<4000) or lymphopenia (<1000) Thrombocytopenia (<100)

 

• When there is a high clinical suspicion of SLE & positive ANA, further lab workup includes:
  • anti-DS DNA antibodies(high titers are highly specific for SLE, but only 60% sensitive)
    • Titers are often monitored as they parallel disease activity in some patients and have prognostic significance in lupus nephritis
  • anti-Smith antibodies (nearly 99% specific for SLE, only 30% sensitive)
  • CBC (for anemia and leukopenia)
  • Direct Coombs’
  • Coagulation factors
  • anti-cardiolipin antibodies, anti-beta 2 glycoprotein 1 antibodies, and lupus anticoagulant assays (e.g. Russell viper venom time, hexagonal phase)
  • ESR, CRP and C3/C4(levels change during an active flare)
    • Patients with SLE often have an elevated ESR and normal CRP; exception to this normal CRP “rule” is in patients with serositis or severe arthritis
  • Urinalysis and spot urine protein and urine creatinine (to screen for nephritis)
  • Anti-histone antibody- if considering drug-induced lupus (DILE), although is often positive in SLE as well. Unusual for DILE patients to have negative anti-histone ab, so has good negative predictive value.
• Other clinical manifestations (not included in SLICC criteria):
  • Constitutional: Fatigue, fever (rare), weight loss
  • Neurologic: Cognitive defects, delirium, psychosis, seizures, peripheral neuropathies, myelitis, increased risk of stroke
  • Ophthalmologic: Dry eye and associated keratitis, episcleritis, scleritis
  • Mucocutaneous symptoms: Dry mouth
  • Pulmonary: diffuse alveolar hemorrhage, ILD, pulmonary hypertension, PE with antiphospholipid syndrome (APS)
  • Cardiovascular: Raynaud’s, Libman-Sacks endocarditis, myocarditis, increased risk of coronary artery disease
  • GI: Cholecystitis, pancreatitis, vasculitis causing mesenteric ischemia/GIB, peritonitis (form of serositis)
  • Immunologic: Lymphadenopathy and splenomegaly
  • Musculoskeletal: Reducible deformities (Jaccoud-like arthropathy), osteonecrosis

 

Auto-antibodies

• ANA– gold standard for measurement is by indirect immunofluorescence (IIF; provides titer and pattern); multiplex bead assays used by many contemporary labs lack the sensitivity of immunofluorescence.
  • Do not re-order once diagnosis established.
  • Positive in 2-20% of normal population depending of definition of positive titer
• ANA Sub-serologies – do NOT order ANA sub-serologies if the ANA is negative by IIF; ordering an SSA for Sjogren’s is the one exception to this rule
  • dsDNA- highly specific, often parallels disease activity, associated with renal disease
  • Smith- highly specific, associated with renal disease
  • RNP- associated with Raynaud’s and musculoskeletal disease
  • SSA/Ro- associated with neonatal lupus, Sjögren’s, SCLE and PBC. Can be positive in patients with negative ANA
  • SSB/La- Associated with neonatal lupus and Sjögren’s.

 

 

ANA Sub-serologies in Connective Tissue Diseases

Autoantibody	Associated Conditions	Sensitivity	Specificity
dsDNA	SLE	50%	97%
Smith	SLE	10-20%	>90%
RNP	Mixed Connective Tissue Disorder, SLE	100%, 30%	100%, 80%
SSA	Sjogren’s, SLE	50%, 30%	87%, 90%
SSB	Sjogren’s, SLE	50%, 15%	94%
Scl-70	Diffuse Scleroderma	20%	100%
Centromere	Limited Scleroderma	65%	97%
Histone	Drug-Induced Lupus, SLE	90%, 50%	>95%, -

 

 

Treatment

• All SLE patients should be on hydroxychloroquine (HCQ) unless there is a contraindication to this medication
• Mild Disease (limited usually to rashes, serositis, arthritis, fatigue) – treatment includes HCQ (or other antimalarials), NSAIDs, and steroids (topical or low-dose systemic)
• Moderate to Severe Disease (severe skin and joint disease or any internal organ involvement) – generally requires more aggressive immunosuppressive including high doses of systemic steroids, disease modifying anti-rheumatic drugs (DMARDs), cytotoxics, and biologics

 

Antimalarials

· Hydroxychloroquine (HCQ), chloroquine, and quinacrine

· Onset of action 1-3 months; patients may not see full benefit for several months

· Adverse effects: GI upset, skin hyperpigmentation, retinopathy (not for quinacrine), infiltrative myopathy

· Monitoring: annual eye exam for HCQ; chloroquine has a higher incidence of retinal toxicity so patients need to be seen by ophtho every 3-6 months

 

Disease Modifying Anti-Rheumatic Drugs (DMARDs)

• Mycophenolate Mofetil (MMF), azathioprine (AZA) and methotrexate (MTX)
• MTX and MMF are teratogenic and should not be used during pregnancy. AZA, HCQ, and low-dose prednisone are all safe in pregnancy.
• Adverse effects: infection (particularly zoster with MMF), nausea / GI upset, myelosuppression, hepatotoxicity
• Monitoring: serial CBC+LFTs to assess for myelosuppression with both MMF and AZA (refer to RA section regarding more specific MTX monitoring)

 

Other Agents

· Cytoxan (Cyclophosphamide)

· Rituximab

· Tacrolimus

· Belimumab (Benlysta)

 

Monitoring Labs (usually every three months)

• Basic Labs: CBC with diff, Chemistry
• Urine: spot urine protein:creatinine is most sensitive measure for renal disease, also allowc for serial assessment of proteinuria
• Acute Phase Reactants: ESR (often discordant with CRP in SLE with exception of patients with arthritis or serositis where both will be elevated); CRP (not ordered routinely, more sensitive for infection in SLE)
• Immunology Labs: dsDNA, C3/C4 (with active disease complements are low because they are consumed in the setting of circulating immune complexes)

 

Preventive Care

• Lifestyle modifications:
  • Avoidance of exposure to sunlight and other sources of ultraviolet light, sunscreen daily with a SPF of 30 or greater
  • Exercise/diet modification to prevent deconditioning, fatigue, obesity, osteoporosis
  • Smoking cessation
• Health Maintenance:
  • Bone Health - supplemental calcium + vitamin D, daily weight bearing activity. Consider DEXA in those at high risk for fracture or long-term steroid use.
  • Monitor for hyperlipidemia and initiate statin if necessary based on risk factor assessment
  • Manage HTN/proteinuria with ACEI or ARB, with goal BP < 130/80
  • Pap smear annually (for those on immunosuppression)
• Vaccinations:
  • Influenza annually
  • Pneumococcal
  • HBV if risk factors present

 

When to Refer

• All patients with a diagnosis of SLE (or in whom the diagnosis is in doubt) should be referred to rheumatology for assessment of disease activity and severity and management of disease and medication toxicities

 

Bottom Line

• SLE is highly unlikely in the setting of a negative ANA
• Do not test for ANA sub-serologies without a positive ANA AND clinical suspicion for SLE
• HCQ is the cornerstone of treatment

 

References

Berstias G, et al. EULAR recommendations for the management of systemic lupus erythematosus. Ann Rheum Dis. 2008;67:195-205.

Hahn BA, et al. American College of Rheumatology Guidelines for Screening, Treatment, and Management of Lupus Nephritis. Arthritis Care Res. 2012 Jun;64(6):797—808.

Imboden JB et al. Current Rheumatology Diagnosis and Treatment. 2nd ed. New York: McGraw-Hill, 2007.

Klippel JH et al. Primer on the Rheumatic Diseases. 13th ed. New York: Springer, 2008. 

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.