Systemic Lupus Erythematosus

See Also

Background

Named in 1851 for wolf (lupus) bite-like facial rash
First described by Moritz Kaposi

Epidemiology

Prevalence
1. U.S.: 40 to 50 per 100,000 persons (up to 1 in 1000)
2. England: 200 per 100,000 women aged 18 to 65 years
Over-diagnosed in United States
1. Of 2 million U.S. cases, only 25% have true disease
2. As of 2008, estimated true Prevalence in U.S.: 300,000
Age distribution
1. Young adult onset is most typical (but onset may be at ages 15-64 years)
2. Children comprise 10-15% of cases
More common in women (especially child-bearing age) by ratio of 9:1 (women 90%, men 10%)
Ethnic and racial predisposition
1. Native American
2. African American (twice as prevalent than in white patients)
3. Hispanic
4. Chinese
5. Filipino

Etiology

Idiopathic
Drug Induced lupus
1. More than 80 drugs associated, esp. Hydralazine, Procainamide, Beta Blockers

Pathophysiology

Tissue damage by Antibody and immune complex deposition
Autoantibodies form to cell nucleus components

Findings
Presentations

Most common presenting symptoms (90% of cases)
1. Fatigue
2. Weight loss
3. Fever without focal infection
Women of child-bearing age (age 15 to 50 years old)
1. Fever
2. Malar Rash
3. Arthralgias (or myalgias)
Men
1. Less skin and joint involvement in men than women and children
2. Hematologic disorder
3. Renal disorder
4. Neurologic disorder (esp. CNS)
Children
1. Fever
2. Malar Rash
3. Arthralgias
4. Alopecia
5. Hematologic disorder (Anemia, Leukocytopenia)
6. Renal involvement
Drug-induced Lupus (occurs equally in men and women, typically closer to age 50 years old)
1. Fever
2. Rash
3. Arthralgias and myalgias
4. Pleuritic Chest Pain
5. Rare renal involvement and rare CNS involvement
6. Resolves in most cases after offending drug is stopped (see list of drug causes above)

Symptoms

Arthralgias and myalgias (95% at presentation)
Fatigue (Prevalence overall: 90%)
Fever
Malaise
Weight loss
Malar Rash (31% at presentation)
Photosensitivity (23% at presentation)
Pleuritic Chest Pain (16% at presentation)
Raynaud Phenomenon (16% at presentation)
Oral Lesions such as Oral Ulcers or mucositis (12% at presentation)

Signs
General

Dermatologic
1. Discoid Rash (LR +18)
  1. See Cutaneous Lupus Erythematosus
2. Malar "butterfly" rash (50% of cases, 31% at presentation, LR+ 14)
3. Photosensitivity (23% at presentation, LR+ 11)
4. Vasculitis
5. Alopecia
6. Oral Ulcers or mucositis
7. Sicca Syndrome
Rheumatologic or musculoskeletal symptoms (95% of cases)
1. Arthralgias or Arthritis with symmetric Polyarthritis (esp. small joints)
2. Myalgias or Myositis
3. Raynaud Phenomenon (16% at presentation)
4. Fibromyalgia (often comorbid in SLE patients)
Abdominal
1. Lymphadenopathy
2. Splenomegaly
3. Nephritis
4. Mesenteric Vasculitis
Neuropsychiatric
1. Organic brain syndrome
2. Seizures (LR+ 13)
3. Psychosis (LR+ 13)
4. Thrombotic Cerebrovascular Accident
5. Transverse Myelitis
6. Cognitive dysfunction (spectrum from mild cognitive deficits to Dementia)
7. Migraine Headaches
8. Peripheral Neuropathy
Cardiovascular
1. Pericarditis
2. Myocarditis
3. Acute Coronary Syndrome
4. Venous thrombosis (DVT)
  1. Suggests Antiphospholipid Antibody Syndrome
Pulmonary
1. Pleuritis
2. Pneumonitis or Pneumonia
3. Interstitial Lung Disease
4. Pulmonary Arterial Hypertension
5. Pulmonary Embolism
Ocular changes (20% of SLE cases)
1. Anterior eye disorders
  1. Keratoconjunctivitis Sicca (25% of patients)
  2. Uveitis
  3. Episcleritis and Scleritis
  4. Keratitis
  5. Blepharitis-like Discoid Lupus eyebrow involvement
2. Retinal Disorders
  1. Cotton wool spots
  2. Retinal Hemorrhages
  3. Proliferative Retinopathy
3. Neurologic conditions

Diagnosis
EULAR/ACR Criteria 2019

Antinuclear Antibody (ANA) positive is required for all SLE Diagnoses
1. Titer >1:80 on HEp-2 Cells or equivalent positive at any time in patient's past history
2. Titer over 1:320 is very suggestive
3. Prior discriminatory value was 1:40 dilution
Adjunctive Criteria Background
1. SLE diagnosis requires at least one clinical criterion and at least 10 total points
2. Criteria may have occurred previously and need not occur simultaneously with other criteria
3. Only count criteria that can be attributed to SLE, and not to another more likely diagnosis
4. Only count the highest weighted criterion from each domain, when a domain has more than one positive feature
5. New 2019 EULAR/ACR guidelines included many of the SLICC Criteria
Adjunctive Clinical: Constitutional
1. Weight 2: Fever (>38.3 C or 101 F)
Adjunctive Clinical: Hematologic
1. Weight 3: Leukopenia (<4000/uL)
2. Weight 4: Thrombocytopenia (<100,000/mm3)
3. Weight 4: Autoimmune Hemolysis or Hemolytic Anemia
  1. Findings include Reticulocytosis, low Haptoglobin, increased Indirect Bilirubin, increased LDH, positive Direct Coombs test
Adjunctive Clinical: Neuropsychiatric
1. Weight 2: Delirium
  1. Altered consciousness for <2 days, fluctuating throughout the day, affecting cognition or behavior, mood or affect
2. Weight 3: Psychosis
  1. Findings include Delusions and/or Hallucinations without insight, and without comorbid Delirium
3. Weight 5: Seizure Disorder (generalized or partial/focal)
4. Findings
  1. Neurologic changes or Lupus Cerebritis is ultimately present in 75% of SLE cases
  2. Other neurologic criteria per SLICC (not part of EULAR/ACR Criteria)
    1. Thrombotic Cerebrovascular Accident
    2. Transverse Myelitis
    3. Cognitive dysfunction (spectrum from mild cognitive deficits to Dementia)
    4. More subtle, less specific or dramatic changes (Migraine Headache, Peripheral Neuropathy)
Adjunctive Clinical: Mucocutaneous (findings must be observed by clinician)
1. Weight 2: Non-scarring Alopecia
2. Weight 2: Oral Ulcers
  1. Typically painless, oral or nasopharyngeal lesions
3. Weight 4: Subacute cutaneous or Discoid Lupus
  1. Annular or papulosquamous (psoriaform) skin eruption typically in sun exposed regions (and phoosensitivity)
  2. Raised erythematous patches with adherent keratotic Scaling
  3. Follicular plugging
  4. Atrophic scarring in older patients
4. Weight 6: Acute Cutaneous Lupus
  1. Generalized maculopapular rash
  2. Malar Rash (present in 30-50% of SLE cases)
    1. Erythema (may be raised) over the cheeks and sparing the nasolabial folds
  3. Photosensitivity
    1. Atypical sunlight skin reactions
  4. Biopsy findings
    1. Perivascular lymphohistiocytic infiltrate
Adjunctive Clinical: Serosal (Lupus Serositis)
1. See cardiac complications and pulmonary complications described below
2. Weight 5: Pleural or Pericardial Effusion
3. Weight 6: Acute Pericarditis
4. Findings
  1. Pleuritic Chest Pain, friction rub or Pleural Effusion
  2. Positional Chest Pain worse supine
    1. Improved sitting or leaning forward
    2. Pericardial Effusion or friction rub
  3. EKG changes with diffuse ST Elevation, PR Depression and no reciprocal changes
Adjunctive Clinical: Musculoskeletal
1. Weight 6: Joint involvement (SLE Polyarthritis)
  1. Synovitis (swelling or effusion) involving 2 or more joints OR
  2. Joint tenderness and >=30 minutes morning stiffness affecting 2 or more joints
2. Findings
  1. Polyarthritis is present in 90% of SLE cases
  2. SLE Polyarthritis is non-erosive and involves 2 or more joints
Adjunctive Clinical: Renal
1. Weight 4: Proteinuria >0.5g/24 hours (or equivalent Urine Protein to Creatinine Ratio)
2. Weight 8: Renal biopsy class 2 or 5 Lupus Nephritis
3. Weight 10: Renal biopsy class 3 or 4 Lupus Nephritis
4. Findings
  1. Renal disease or Lupus Nephritis is ultimately present in 60% of SLE cases
  2. Persistent Proteinuria >500 mg/day (>3+ Urine Protein)
  3. RBC Cellular Casts (or mixed casts) may also be present
Adjunctive Immunologic: Antiphospholipid Antibodies
1. Weight 2: Anti-cardiolipin antibodies (medium or high titer) OR anti-B2GP1 Antibodies OR Lupus Anticoagulant
Adjunctive Immunologic: Complement Proteins
1. Weight 3: Low C3 OR low C4
2. Weight 4: Low C3 AND Low C4
Adjunctive Immunologic: SLE Specific Antibodies
1. Weight 6: Anti-dsDNA Antibody OR Anti-Smith Antibody
References
1. Aringer (2019) Arthritis Rheumatol 71(9):1400-12 +PMID: 31385462 [PubMed]

Labs
Protocol

Lab interpretation described specifically below
Indications for ANA titer
1. Unexplained involvement of Two or more organ systems
2. ANA is very prevalent in normal population
Initial Screening
1. ANA titer positive if 1:80 dilution (prior cut-off was 1:40)
Secondary testing if ANA titer positive
Alternative diagnosis labs to consider
1. Thyroid Stimulating Hormone (Hypothyroidism)
2. Blood Cultures (endocarditis)
3. HIV Test
4. Rheumatoid Factor and anticyclic citrullinated Antibody (Rheumatoid Arthritis)

Labs
Interpretation

Complete Blood Count
1. Anemia
2. Lymphopenia
3. Thrombocytopenia
Urinalysis
1. Consider 24 Hour Urine Protein
2. Consider 24 hour Creatinine Clearance
3. Lupus Nephritis findings
  1. Persistent Proteinuria > 500 mg/day (>3+ Urine Protein) or
  2. RBC Cellular Casts (or mixed casts)
Coagulation Factors
1. Prothrombin Time
2. Partial Thromboplastin Time (PTT)
  1. Increased (prolonged) in Antiphospholipid Antibody Syndrome
Other initial basic labs
1. Comprehensive metabolic panel
2. Direct Coombs test
Primary Antinuclear Antibodies (and other autoantibodies)
1. Antinuclear Antigen (ANA)
  1. Positive in 94-98% of true SLE cases
  2. Typically positive in Drug-induced Lupus
  3. Only 5% of ANA positive patients have SLE
2. Smith Antibody (Anti-Smith or Anti-Sm)
  1. Positive in 20-30% of SLE cases
  2. Highly specific for SLE (nearly pathognomonic)
  3. Does not correlate with disease activity (unlike Anti-dsDNA)
3. Double Stranded DNA Antibody (Anti-dsDNA)
  1. Positive in 50-70% of SLE cases
  2. Specific for Systemic Lupus Erythematosus
  3. Associated with Lupus Nephritis
  4. Associated with Lupus CNS Involvement
  5. Also positive in Syphilis and Bacterial Endocarditis
Antiphospholipid Antibody Syndrome related labs
1. Antiphospholipid Antibody
2. Anticardiolipin Antibody
3. Partial Thromboplastin Time (PTT)
  1. Prolonged in Antiphospholipid Antibody Syndrome
Other Autoantibodies
1. Anti-ribonucleoprotein (Anti-RNP)
2. Beta-2 Glycoprotein Antibody
3. Anti-ribosomal P (Lupus sensitivity: 20-30%)
  1. Highly specific for lupus erythematosus
  2. Associated with Lupus Psychosis
4. Anti-Ro (Anti-SSA)
  1. Positive in 40% of SLE cases
5. Anti-La (Anti-SSB)
  1. Positive in 10-15% of SLE cases
6. Histone Antibody (Anti-histone)
  1. Positive in 50-70% of SLE cases (especially drug induced lupus)
Other labs used historically in Lupus evaluation
1. Complement Levels
  1. Complement C3, Complement C4, Complement CH50
  2. Typically unreliable in predicting acute lupus flare
  3. Low complement levels are more consistent with SLE
2. Syphilis Serology (VDRL or RPR)
3. Erythrocyte Sedimentation Rate >100 mm (LR+ 5.3)
4. C-Reactive Protein
  1. May be used to gauge lupus activity

Diagnostics

Electrocardiogram
1. Pericarditis
  1. See EKG in Pericarditis
Lumbar Puncture
1. Evaluate differential diagnosis of Lupus Cerebritis (e.g. Meningitis or encephilitis, Multiple Sclerosis)
2. Findings suggestive of increased CNS Lupus activity
  1. CSF White Blood Cells increased
  2. CSF Protein increased
  3. Immunoglobulin synthesis or Immunoglobulin G increased

Differential Diagnosis

Children
1. Cancer (e.g. Leukemia, Lymphoma)
2. Juvenile Rheumatoid Arthritis (Juvenile RA)
3. Immune Thrombocytopenic Purpura (ITP)
4. Infections
5. Thyroid disorders
Adults
1. Behcet Syndrome
2. Dermatomyositis
3. Endocarditis
4. HIV Infection
5. Hypothyroidism
6. Fibromyalgia
7. Inflammatory Bowel Disease
8. Lyme Disease
9. Malignancy
10. Mixed Connective Tissue Disease
11. Psoriatic Arthritis
12. Reactive Arthritis
13. Rheumatoid Arthritis or adult onset Still's Disease
14. Sarcoidosis
15. Systemic Sclerosis
16. Sjogren's Syndrome
17. Thrombotic Thrombocytopenic Purpura (TTP)
18. Vasculitis

Imaging

Brain MRI
1. Indicated in suspected Lupus Cerebritis or other neuropsychiatric findings
2. Findings are typically non-specific
Echocardiogram (or Bedside Ultrasound)
1. Indicated for suspected Myocarditis or Pericarditis
2. Evaluate for overall Left Ventricular Dysfunction and Pericardial Effusion

Complications

Immunocompromised state
1. Hyposplenism
2. Immunosuppressants used to treat systemic lupus
Lupus Nephritis
1. Lupus Nephritis is a Glomerulonephritis of several different types (worst is diffuse proliferative nephritis)
2. Lupus Nephritis is a predictor of increased mortality risk
Lupus Cerebritis
1. Various presentations (see above under diagnosis) of CNS disease are seen in 75% of Lupus patients
2. Consider MRI and Lumbar Puncture (see above under imaging and diagnostics)
Cardiovascular disease
1. Coronary events
  1. Coronary atherosclerosis
    1. Autoantibody related Vasculitis
    2. Lupus medication adverse effects
  2. Coronary Vasculitis with secondary ST Segment elevation Myocardial Infarction (STEMI)
  3. Spontaneous Coronary Artery Dissection
2. Pericarditis (most common)
  1. Risk of Cardiac Tamponade (has even occurred in children)
3. Myocarditis
  1. Presents with conduction abnormalities, Arrhythmias
  2. Associated with Cardiomyopathy or Heart Failure
Pulmonary disease
1. Lung disease affects 50% of Lupus patients and is a presenting symptom in up to 5% of cases
2. Pleuritis and pulmonary infections are most common presentations
3. Interstitial Lung Disease, pneumonitis, Pulmonary Arterial Hypertension, Pulmonary Embolism may also occur
Venous Thromboembolism (VTE)
1. Higher risk by a factor of 100 in SLE (and at a younger age)
  1. Occurs in up to 26% of lupus patients (contrast with 0.2% in the general population)
2. Increased risk with Antiphospholipid Antibody positive status
3. D-Dimer has less less utility in SLE due to a high False Positive Rate in this population (less specific)
  1. However, a negative D-Dimer in SLE suggests a very low likelihood of VTE
  2. Wu (2008) Clin J Am Soc Nephrol 3(6): 1628-36 [PubMed]
Antiphospholipid Antibody Syndrome (Hughes Syndrome, Anticardiolipin Syndrome)
1. Affects 15% of Lupus patients
2. Risk of thromboembolic complications (despite prolonged PTT)
  1. Venous Thromboembolism
  2. Acute Coronary Syndrome
  3. Acute thrombotic stroke
  4. Acute Limb Ischemia
  5. Mesenteric Ischemia
  6. Renal artery thrombosis
  7. Raynaud's Phenomenon (with risk of digital ischemia)
Malignancy
1. Non-Hodgkin Lymphoma (risk increases 3-4 fold over general population)
2. Lung Cancer
3. Cervical Cancer
Pregnancy-related complications
1. Preeclampsia
2. Preterm Labor

Management
General Principles

Reevaluate every 3-6 months
Employ measures to relieve Fatigue
Sunscreen and other protection due to photosensitivity
Reduce risk of infection (e.g. Immunizations)
Birth Control is critical during exacerbations

Management
Hospitalization indications

Acute lupus presentation
1. Female aged 15 to 50 years old with fever, Arthralgias and Malar Rash and associated findings (esp. nephritis)
2. May benefit from admission for diagnosis and acute management
Significant febrile illness
1. Lower threshold for hospital admission given underlying Immunocompromised state and potential Hyposplenism
Acute lupus flare with severe pain
1. Consider IV cytotoxic agents and Corticosteroids
Lupus Nephritis (acute onset or worsening)
1. See below
2. Heralded by abnormal Urinalysis (Hematuria, 3+ Proteinuria, RBC Cellular Casts) or increased Serum Creatinine
3. Renal biopsy is typically required for diagnosis of specific Glomerulonephritis type, which in turn drives management
4. Nephritis is a predictor of increased mortality and morbidity, including progression to Renal Failure
5. Acute management typically makes use of Systemic Corticosteroids AND Mycophenolate or cyclophosphamide
Lupus Cerebritis (e.g. Seizures, Psychosis, Dementia)
1. Initial evaluation typically with MRI Brain and Lumbar Puncture
2. Hospitalization for further evaluation and acute management
Acute cardiovascular conditions
1. Acute Coronary Syndrome
2. Pericarditis
3. Myocarditis (may cause life threatening, Acute Heart Failure)
Venous Thromboembolism
1. Suggests Antiphospholipid Antibody Syndrome (higher risk of thrombotic complications)
Acute Abdominal Pain
1. Hospitalization indicated where diagnosis is unclear or for associated Lactic Acidosis
2. Normal Complete Blood Count or non-diagnostic CT Abdomen does not exclude serious cause in SLE
3. Acute Abdominal Pain in SLE presenting to the emergency department is associated with 57% morbidity and 11% mortality
  1. Vergara-Fernandez (2009) J Gastrointest Surg 13(7): 1351-7 [PubMed]

Management
System based

See complications and hospital indications above
Musculoskeletal symptoms (Arthralgias, myalgias)
Skin Involvement (70-80% of cases)
1. Use sun screen (minimum SPF 15)
2. Avoid Photosensitizer medications
3. Topical Corticosteroids
4. Hydroxychloroquine
Hematologic effects (e.g. Leukopenia, Anemia, Thrombocytopenia)
1. Reduce infection risk
2. Anemia management as needed
3. Consider other agents (e.g. Azathioprine, Mycophenolate, Rituximab)
Lupus Nephritis
1. Lifetime Prevalence 50%
2. Screen Urinalysis and Serum Creatinine every 3-6 months (reflex to Urine Protein to Creatinine Ratio)
3. Refer to renal biopsy if 1 g Urine Protein/day OR 0.5 g/day and Hematuria or cell casts
4. Acute management typically makes use of Systemic Corticosteroids AND Mycophenolate or cyclophosphamide
Cardiovascular Risk
1. Acute Coronary Syndrome risk increased in women 35-44 years old by factor of 52
2. Reduce Cardiovascular Risk Factors (Tobacco Cessation; Hyperlipidemia, Hypertension, Diabetes Mellitus management)
Neuropsychiatric symptoms
1. Consider MRI Brain for Headache or Seizure

Management
Medications

Corticosteroids
1. Indicated as a mainstay of acute management at lowest effective dose
  1. Low dose: Prednisone 10 mg orally daily or less (most patients)
  2. High dose: Prednisone 40-60 mg orally daily (for Lupus Cerebritis, nephritis, Thrombocytopenia)
2. Systemic Corticosteroids in moderate to severe exacerbations
  1. Prednisone 0.5 to 1 mg/kg/day up to 4 weeks or
  2. Solu-medrol 15 mg/kg IV for 3 days
3. Skin lesions (no significant evidence to support use)
  1. Topical Corticosteroids
  2. Intralesional Corticosteroids
4. Monitoring
  1. Serum Glucose every 3 months
  2. DEXA Scan annually
Salicylates and NSAIDs
1. Indicated for mild to moderate pain from Arthralgias, Headache or other lupus-related conditions
2. Contraindicated in renal disease
3. Preparations
  1. Enteric Coated ASA 650 mg PO every 4-6 hours prn
  2. Ibuprofen 400-800 mg PO tid-qid prn
4. Monitoring
  1. Obtain Serum Creatinine and Complete Blood Count annually
Cytotoxic agents (and other immunosuppressants)
1. Hydroxychloroquine (Plaquenil)
  1. First-line agent in Systemic Lupus management
  2. Indicated for Lupus Nephritis, Arthritis and lupus-related skin lesions
  3. Dosing: 200-400 mg/day (limit to <5-6.5 mg/kg/day to reduce Macular complication risk)
  4. Monitoring
    1. Annual dilated Eye Exam
2. Cyclophosphamide
  1. Indicated in Lupus Nephritis or severe SLE
  2. Daily dosing: 1.5-2.5 mg/kg/day or
  3. Monthly dosing: 10-15 mg/kg IV every 4 weeks
  4. Monitoring
    1. Complete Blood Count, comprehensive metabolic panel, Urinalysis every 3 months
3. Azathioprine (Imuran)
  1. Indicated in Lupus Nephritis and severe SLE
  2. Dosing 1.5 to 2.5 mg/kg/day
  3. Therapeutic response and toxicity monitored with thiopurine metabolites (6-MMP, 6-TGN)
  4. Monitoring
    1. Complete Blood Count, comprehensive metabolic panel every 3 months
4. Mycophenolate mofetil (Cellcept)
  1. Therapeutic response and toxicity monitored with Mycophenolic acid (MPA)
  2. Indicated in Lupus Nephritis and refractory SLE
  3. Typical doses: 2-3 grams/day
  4. Monitoring
    1. Complete Blood Count and comprehensive metabolic panel every 3 months
    2. Observe for signs infection
Monoclonal antibodies (indicated for severe SLE)
1. Belimumab 10 mg/kg IV daily
2. Rituximab 1 g IV repeated in 2 weeks
Anticoagulation
1. Indicated in Antiphospholipid Antibody Syndrome (to prevent thrombotic complications)
2. Warfarin (Coumadin) with goal INR of 2.5 to 3.0
Additional measures
1. Ophthalmology Consultation for dilated Eye Exam
  1. Initial exam on starting steroids or Plaquenil
  2. Repeat exam yearly in high risk patients

Prevention

See Adult Health Maintenance Screening
Clinic follow-up every 3 months
1. Symptom screen
2. Physical exam
  1. Musculoskeletal Exam
  2. Skin exam
  3. Lymph Node exam
  4. Mental health and Neurologic Exam
Labs every 3 months
1. Complete Blood Count
2. Urinalysis
3. Specific metabolic tests (comprehensive metabolic panel is needed if on indicated medications as above)
  1. Serum Creatinine
  2. Serum Glucose (if on Corticosteroids)
4. Lupus activity markers
  1. Anti-dsDNA
  2. Serum complement
Immunizations
1. See Adult Immunization
2. Prevnar (and consider Pneumovax) if on immunosuppressants longterm
3. Avoid Live Vaccine (e.g. MMR) if on immunosuppressants
  1. Do not give Live Vaccine within 1 month of immunosuppressant
Other diagnostics as indicated
1. Dilated Eye Exam yearly (if on Hydroxychloroquine)
2. DEXA Scan yearly (if on Corticosteroids)
Cardiovascular Risk Reduction
1. See Cardiac Risk Management
2. Tobacco Cessation
3. Manage Hyperlipidemia and Hypertension
4. Screen for Diabetes Mellitus
Contraception
1. Intrauterine Device
2. Avoid Oral Contraceptives (due to Hypercoagulable state)

Prognosis

Drug-induced Lupus typically resolves spontaneously after stopping the offending agent
Overall five year survival: 91-97%
Worse prognostic factors
1. Seizure Disorder
2. Lupus Nephritis
3. Azotemia
4. Onset in childhood

Resources

Lupus Foundation of America
1. http://www.lupus.org

References

Edworthy in Ruddy (2001) Kelly's Rheumatology, 1105-19
Green (2014) Crit Dec Emerg Med 28(10): 2-9
Sercombe in Marx (2002) Rosen's Emergency, p. 1607-13
Ali (2018) Am Fam Physician 98(3): 164-70 [PubMed]
Gill (2003) Am Fam Physician 68:2179-86 [PubMed]
Lam (2016) Am Fam Physician 94(4): 284-94 [PubMed]