Diffuse
Systemic Lupus Erythematosus
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Systemic Lupus Erythematosus
, Lupus, SLE, Lupus Serositis, Lupus Nephritis, Lupus Cerebritis
See Also
Cutaneous Lupus Erythematosus
Drug-induced Lupus
Background
Named in 1851 for wolf (lupus) bite-like facial rash
First described by Moritz Kaposi
Epidemiology
Prevalence
U.S.: 40 to 50 per 100,000 persons (up to 1 in 1000)
England: 200 per 100,000 women aged 18 to 65 years
Over-diagnosed in United States
Of 2 million U.S. cases, only 25% have true disease
As of 2008, estimated true
Prevalence
in U.S.: 300,000
Age distribution
Young adult onset is most typical (but onset may be at ages 15-64 years)
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
Native American
African American (twice as prevalent than in white patients)
Hispanic
Chinese
Filipino
Etiology
Idiopathic
Drug Induced Lupus
More than 80 drugs associated, esp.
Hydralazine
,
Procainamide
,
Beta Blocker
s
Pathophysiology
Tissue damage by
Antibody
and immune complex deposition
Autoantibodies form to cell nucleus components
Findings
Presentations
Most common presenting symptoms (90% of cases)
Fatigue
Weight loss
Fever
without focal infection
Women of child-bearing age (age 15 to 50 years old)
Fever
Malar Rash
Arthralgia
s (or myalgias)
Men
Less skin and joint involvement in men than women and children
Hematologic disorder
Renal disorder
Neurologic disorder (esp. CNS)
Children
Fever
Malar Rash
Arthralgia
s
Alopecia
Hematologic disorder (
Anemia
, Leukocytopenia)
Renal involvement
Drug-induced Lupus
(occurs equally in men and women, typically closer to age 50 years old)
Fever
Rash
Arthralgia
s and myalgias
Pleuritic Chest Pain
Rare renal involvement and rare CNS involvement
Resolves in most cases after offending drug is stopped (see list of drug causes above)
Symptoms
Arthralgia
s 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 Lesion
s such as
Oral Ulcer
s or mucositis (12% at presentation)
Signs
Gene
ral
Dermatologic
Discoid Rash (LR +18)
See
Cutaneous Lupus Erythematosus
Malar "butterfly" rash (50% of cases, 31% at presentation, LR+ 14)
Photosensitivity (23% at presentation, LR+ 11)
Vasculitis
Alopecia
Oral Ulcer
s or mucositis
Sicca Syndrome
Rheumatologic or musculoskeletal symptoms (95% of cases)
Arthralgia
s or
Arthritis
with symmetric
Polyarthritis
(esp. small joints)
Myalgias or
Myositis
Raynaud Phenomenon
(16% at presentation)
Fibromyalgia
(often comorbid in SLE patients)
Abdominal
Lymphadenopathy
Splenomegaly
Nephritis
Mesenteric
Vasculitis
Neuropsychiatric
Organic brain syndrome
Seizure
s (LR+ 13)
Psychosis
(LR+ 13)
Thrombotic
Cerebrovascular Accident
Transverse Myelitis
Cognitive dysfunction (spectrum from mild cognitive deficits to
Dementia
)
Migraine Headache
s
Peripheral Neuropathy
Cardiovascular
Pericarditis
Myocarditis
Acute Coronary Syndrome
Venous thrombosis (DVT)
Suggests
Antiphospholipid Antibody Syndrome
Pulmonary
Pleuritis
Pneumonitis or
Pneumonia
Interstitial Lung Disease
Pulmonary Arterial Hypertension
Pulmonary Embolism
Ocular changes (20% of SLE cases)
Anterior eye disorders
Keratoconjunctivitis Sicca
(25% of patients)
Uveitis
Episcleritis
and
Scleritis
Keratitis
Blepharitis
-like
Discoid Lupus
eyebrow involvement
Retinal Disorder
s
Cotton wool spots
Retina
l
Hemorrhage
s
Proliferative
Retinopathy
Neurologic conditions
Optic Neuritis
Ischemic Optic Neuropathy
Amaurosis Fugax
Diagnosis
ACR requires 4 of 11 criteria
Precautions
SLICC criteria broaden some of the diagnostic criteria
SLICC Criteria are not endorsed by ACR
Increase test sensitvity to 97%, but decrease
Specificity
to 84%
Malar Rash
(present in 30-50% of cases)
Erythema (may be raised) over the cheeks and sparing the nasolabial folds
Discoid rash
Raised erythematous patches with adherent keratotic
Scaling
Follicular plugging
Atrophic scarring in older patients
Photosensitivity
Atypical sunlight skin reactions
Oral Ulcer
s
Typically painless, oral or nasopharyngeal lesions
Polyarthritis
(present in 90% of cases)
Non-erosive
Arthritis
involving 2 or more joints
Lupus Serositis (Pleuritis or
Pericarditis
)
See cardiac complications and pulmonary complications described below
Pleuritic Chest Pain
, friction rub or
Pleural Effusion
Positional
Chest Pain
worse supine
Improved sitting or leaning forward
Pericardial Effusion
or friction rub
EKG changes with diffuse
ST Elevation
,
PR Depression
and no reciprocal changes
Renal disease or Lupus Nephritis (ultimately present in 60% of cases)
Persistent
Proteinuria
> 500 mg/day (>3+
Urine Protein
) or RBC
Cellular Cast
s (or mixed casts)
Neurologic disorder or Lupus Cerebritis (present in 75% of cases)
Seizure
disorder
Psychosis
Other neurologic criteria per SLICC
Thrombotic
Cerebrovascular Accident
Transverse Myelitis
Cognitive dysfunction (spectrum from mild cognitive deficits to
Dementia
)
More subtle, less specific or dramatic changes (
Migraine Headache
,
Peripheral Neuropathy
)
Hematologic disorder
Hemolytic Anemia
Leukopenia
or lymphopenia (SLICC Criteria)
Thrombocytopenia
<100,000/mm3 (SLICC Criteria)
Antinuclear Antibody
titer positive (1:80 or higher)
Titer over 1:320 is very suggestive
Prior discriminatory value was 1:40 dilution
Other immunologic disorders
Anti-dsDNA
positive
Anti-Sm
positive
Antiphospholipid Antibody
positive
Previously also included criteria of
Syphilis False Positive
Labs
Protocol
Lab interpretation described specifically below
Indications for ANA titer
Unexplained involvement of Two or more organ systems
ANA is very prevalent in normal population
Initial Screening
ANA titer positive if 1:80 dilution (prior cut-off was 1:40)
Secondary testing if ANA titer positive
Complete Blood Count
Urinalysis
Serum Creatinine
Antiphospholipid Antibody
Anticardiolipin Antibody
Double Stranded DNA Antibody
(
Anti-dsDNA
)
Smith Antibody
(
Anti-Smith
or
Anti-Sm
)
Alternative diagnosis labs to consider
Thyroid Stimulating Hormone
(
Hypothyroidism
)
Blood Culture
s (endocarditis)
HIV Test
Rheumatoid Factor
and anticyclic citrullinated
Antibody
(
Rheumatoid Arthritis
)
Labs
Interpretation
Complete Blood Count
Anemia
Lymphopenia
Thrombocytopenia
Urinalysis
Consider
24 Hour Urine Protein
Consider 24 hour
Creatinine Clearance
Lupus Nephritis findings
Persistent
Proteinuria
> 500 mg/day (>3+
Urine Protein
) or
RBC
Cellular Cast
s (or mixed casts)
Coagulation Factor
s
Prothrombin Time
Partial Thromboplastin Time
(PTT)
Increased (prolonged) in
Antiphospholipid Antibody Syndrome
Other initial basic labs
Comprehensive metabolic panel
Direct Coombs
test
Primary Antinuclear Antibodies (and other autoantibodies)
Antinuclear Antigen
(ANA)
Positive in 94-98% of true SLE cases
Typically positive in
Drug-induced Lupus
Only 5% of ANA positive patients have SLE
Smith Antibody
(
Anti-Smith
or
Anti-Sm
)
Positive in 20-30% of SLE cases
Highly specific for SLE (nearly pathognomonic)
Does not correlate with disease activity (unlike
Anti-dsDNA
)
Double Stranded DNA Antibody
(
Anti-dsDNA
)
Positive in 50-70% of SLE cases
Specific for Systemic Lupus Erythematosus
Associated with Lupus Nephritis
Associated with Lupus CNS Involvement
Also positive in
Syphilis
and
Bacterial Endocarditis
Antiphospholipid Antibody Syndrome
related labs
Antiphospholipid Antibody
Anticardiolipin Antibody
Partial Thromboplastin Time
(PTT)
Prolonged in
Antiphospholipid Antibody Syndrome
Other Autoantibodies
Anti-ribonucleoprotein (
Anti-RNP
)
Beta-2 Glycoprotein
Antibody
Anti-ribosomal P
(Lupus sensitivity: 20-30%)
Highly specific for lupus erythematosus
Associated with Lupus
Psychosis
Anti-Ro
(
Anti-SSA
)
Positive in 40% of SLE cases
Anti-La
(
Anti-SSB
)
Positive in 10-15% of SLE cases
Histone Antibody
(
Anti-histone
)
Positive in 50-70% of SLE cases (especially
Drug Induced Lupus
)
Other labs used historically in Lupus evaluation
Complement Levels
Complement C3
,
Complement C4
,
Complement CH50
Typically unreliable in predicting acute lupus flare
Low complement levels are more consistent with SLE
Syphilis Serology
(
VDRL
or RPR)
Erythrocyte Sedimentation Rate
>100 mm (LR+ 5.3)
C-Reactive Protein
May be used to gauge lupus activity
Diagnostics
Electrocardiogram
Pericarditis
See
EKG in Pericarditis
Lumbar Puncture
Evaluate differential diagnosis of Lupus Cerebritis (e.g.
Meningitis
or encephilitis,
Multiple Sclerosis
)
Findings suggestive of increased CNS Lupus activity
CSF White Blood Cell
s increased
CSF Protein
increased
Immunoglobulin
synthesis or
Immunoglobulin G
increased
Differential Diagnosis
Children
Cancer (e.g.
Leukemia
,
Lymphoma
)
Juvenile Rheumatoid Arthritis
(Juvenile RA)
Immune Thrombocytopenic Purpura
(ITP)
Infections
Thyroid
disorders
Adults
Behcet Syndrome
Dermatomyositis
Endocarditis
HIV Infection
Hypothyroidism
Fibromyalgia
Inflammatory Bowel Disease
Lyme Disease
Malignancy
Mixed Connective Tissue Disease
Psoriatic Arthritis
Reactive Arthritis
Rheumatoid Arthritis
or adult onset
Still's Disease
Sarcoidosis
Systemic Sclerosis
Sjogren's Syndrome
Thrombotic Thrombocytopenic Purpura
(TTP)
Vasculitis
Imaging
Brain MRI
Indicated in suspected Lupus Cerebritis or other neuropsychiatric findings
Findings are typically non-specific
Echocardiogram
(or
Bedside Ultrasound
)
Indicated for suspected
Myocarditis
or
Pericarditis
Evaluate for overall
Left Ventricular Dysfunction
and
Pericardial Effusion
Complications
Immunocompromised state
Hyposplenism
Immunosuppressants used to treat systemic lupus
Lupus Nephritis
Lupus Nephritis is a
Glomerulonephritis
of several different types (worst is diffuse proliferative nephritis)
Lupus Nephritis is a predictor of increased mortality risk
Lupus Cerebritis
Various presentations (see above under diagnosis) of CNS disease are seen in 75% of Lupus patients
Consider MRI and
Lumbar Puncture
(see above under imaging and diagnostics)
Cardiovascular disease
Coronary events
Coronary atherosclerosis
Autoantibody related
Vasculitis
Lupus medication adverse effects
Coronary
Vasculitis
with secondary ST segment elevation
Myocardial Infarction
(
STEMI
)
Spontaneous Coronary Artery Dissection
Pericarditis
(most common)
Risk of
Cardiac Tamponade
(has even occurred in children)
Myocarditis
Presents with conduction abnormalities,
Arrhythmia
s
Associated with
Cardiomyopathy
or
Heart Failure
Pulmonary disease
Lung
disease affects 50% of Lupus patients and is a presenting symptom in up to 5% of cases
Pleuritis and pulmonary infections are most common presentations
Interstitial Lung Disease
, pneumonitis,
Pulmonary Arterial Hypertension
,
Pulmonary Embolism
may also occur
Venous Thromboembolism
(VTE)
Higher risk by a factor of 100 in SLE (and at a younger age)
Occurs in up to 26% of lupus patients (contrast with 0.2% in the general population)
Increased risk with
Antiphospholipid Antibody
positive status
D-Dimer
has less less utility in SLE due to a high
False Positive Rate
in this population (less specific)
However, a negative
D-Dimer
in SLE suggests a very low likelihood of VTE
Wu (2008) Clin J Am Soc Nephrol 3(6): 1628-36 [PubMed]
Antiphospholipid Antibody Syndrome
(Hughes Syndrome, Anticardiolipin Syndrome)
Affects 15% of Lupus patients
Risk of thromboembolic complications (despite prolonged PTT)
Venous Thromboembolism
Acute Coronary Syndrome
Acute thrombotic stroke
Acute Limb Ischemia
Mesenteric Ischemia
Renal artery thrombosis
Raynaud's Phenomenon
(with risk of digital ischemia)
Malignancy
Non-Hodgkin Lymphoma
(risk increases 3-4 fold over general population)
Lung Cancer
Cervical Cancer
Pregnancy-related complications
Preeclampsia
Preterm Labor
Management
Gene
ral Principles
Reevaluate every 3-6 months
Employ measures to relieve
Fatigue
Sunscreen
and other protection due to photosensitivity
Reduce risk of infection (e.g.
Immunization
s)
Birth Control
is critical during exacerbations
Management
Hospitalization indications
Acute lupus presentation
Female aged 15 to 50 years old with fever,
Arthralgia
s and
Malar Rash
and associated findings (esp. nephritis)
May benefit from admission for diagnosis and acute management
Significant febrile illness
Lower threshold for hospital admission given underlying immunocompromised state and potential
Hyposplenism
Acute lupus flare with severe pain
Consider IV cytotoxic agents and
Corticosteroid
s
Lupus Nephritis (acute onset or worsening)
See below
Heralded by abnormal
Urinalysis
(
Hematuria
, 3+
Proteinuria
, RBC
Cellular Cast
s) or increased
Serum Creatinine
Renal biopsy is typically required for diagnosis of specific
Glomerulonephritis
type, which in turn drives management
Nephritis is a predictor of increased mortality and morbidity, including progression to
Renal Failure
Acute management typically makes use of
Systemic Corticosteroid
s AND
Mycophenolate
or cyclophosphamide
Lupus Cerebritis (e.g.
Seizure
s,
Psychosis
,
Dementia
)
Initial evaluation typically with MRI Brain and
Lumbar Puncture
Hospitalization for further evaluation and acute management
Acute cardiovascular conditions
Acute Coronary Syndrome
Pericarditis
Myocarditis
(may cause life threatening,
Acute Heart Failure
)
Venous Thromboembolism
Suggests
Antiphospholipid Antibody Syndrome
(higher risk of thrombotic complications)
Acute Abdominal Pain
Hospitalization indicated where diagnosis is unclear or for associated
Lactic Acidosis
Normal
Complete Blood Count
or non-diagnostic
CT Abdomen
does not exclude serious cause in SLE
Acute Abdominal Pain
in SLE presenting to the emergency department is associated with 57% morbidity and 11% mortality
Vergara-Fernandez (2009) J Gastrointest Surg 13(7): 1351-7 [PubMed]
Management
System based
See complications and hospital indications above
Musculoskeletal symptoms (
Arthralgia
s, myalgias)
Hydroxychloroquine
Corticosteroid
s
NSAID
s
Skin Involvement (70-80% of cases)
Use sun screen (minimum SPF 15)
Avoid
Photosensitizer
medications
Topical Corticosteroid
s
Hydroxychloroquine
Hematologic effects (e.g.
Leukopenia
,
Anemia
,
Thrombocytopenia
)
Reduce infection risk
Anemia
management as needed
Consider other agents (e.g.
Azathioprine
,
Mycophenolate
,
Rituximab
)
Lupus Nephritis
Lifetime
Prevalence
50%
Screen
Urinalysis
and
Serum Creatinine
every 3-6 months (reflex to
Urine Protein to Creatinine Ratio
)
Refer to renal biopsy if 1 g
Urine Protein
/day OR 0.5 g/day and
Hematuria
or cell casts
Acute management typically makes use of
Systemic Corticosteroid
s AND
Mycophenolate
or cyclophosphamide
Cardiovascular Risk
Acute Coronary Syndrome
risk increased in women 35-44 years old by factor of 52
Reduce
Cardiovascular Risk Factor
s (
Tobacco Cessation
;
Hyperlipidemia
,
Hypertension
,
Diabetes Mellitus
management)
Neuropsychiatric symptoms
Consider MRI Brain for
Headache
or
Seizure
Management
Medications
Corticosteroid
s
Indicated as a mainstay of acute management at lowest effective dose
Low dose:
Prednisone
10 mg orally daily or less (most patients)
High dose:
Prednisone
40-60 mg orally daily (for Lupus Cerebritis, nephritis,
Thrombocytopenia
)
Systemic Corticosteroid
s in moderate to severe exacerbations
Prednisone
0.5 to 1 mg/kg/day up to 4 weeks or
Solu-medrol 15 mg/kg IV for 3 days
Skin lesions (no significant evidence to support use)
Topical Corticosteroid
s
Intralesional
Corticosteroid
s
Monitoring
Serum Glucose
every 3 months
DEXA Scan
annually
Salicylate
s and
NSAID
s
Indicated for mild to moderate pain from
Arthralgia
s,
Headache
or other lupus-related conditions
Contraindicated in renal disease
Preparations
Enteric Coated ASA 650 mg PO every 4-6 hours prn
Ibuprofen
400-800 mg PO tid-qid prn
Monitoring
Obtain
Serum Creatinine
and
Complete Blood Count
annually
Cytotoxic agents (and other immunosuppressants)
Hydroxychloroquine
(
Plaquenil
)
First-line agent in Systemic Lupus management
Indicated for Lupus Nephritis,
Arthritis
and lupus-related skin lesions
Dosing: 200-400 mg/day (limit to <5-6.5 mg/kg/day to reduce
Macula
r complication risk)
Monitoring
Annual dilated
Eye Exam
Cyclophosphamide
Indicated in Lupus Nephritis or severe SLE
Daily dosing: 1.5-2.5 mg/kg/day or
Monthly dosing: 10-15 mg/kg IV every 4 weeks
Monitoring
Complete Blood Count
, comprehensive metabolic panel,
Urinalysis
every 3 months
Azathioprine
(
Imuran
)
Indicated in Lupus Nephritis and severe SLE
Dosing 1.5 to 2.5 mg/kg/day
Therapeutic response and toxicity monitored with thiopurine metabolites (6-MMP, 6-TGN)
Monitoring
Complete Blood Count
, comprehensive metabolic panel every 3 months
Mycophenolate mofetil
(
Cellcept
)
Therapeutic response and toxicity monitored with
Mycophenolic acid
(MPA)
Indicated in Lupus Nephritis and refractory SLE
Typical doses: 2-3 grams/day
Monitoring
Complete Blood Count
and comprehensive metabolic panel every 3 months
Observe for signs infection
Monoclonal antibodies (indicated for severe SLE)
Belimumab 10 mg/kg IV daily
Rituximab
1 g IV repeated in 2 weeks
Anticoagulation
Indicated in
Antiphospholipid Antibody Syndrome
(to prevent thrombotic complications)
Warfarin
(
Coumadin
) with goal INR of 2.5 to 3.0
Additional measures
Ophthalmology
Consultation
for dilated
Eye Exam
Initial exam on starting steroids or
Plaquenil
Repeat exam yearly in high risk patients
Prevention
See
Adult Health Maintenance Screening
Clinic follow-up every 3 months
Symptom screen
Physical exam
Musculoskeletal Exam
Skin exam
Lymph node exam
Mental health and
Neurologic Exam
Labs every 3 months
Complete Blood Count
Urinalysis
Specific metabolic tests (comprehensive metabolic panel is needed if on indicated medications as above)
Serum Creatinine
Serum Glucose
(if on
Corticosteroid
s)
Lupus activity markers
Anti-dsDNA
Serum complement
Immunization
s
See
Adult Immunization
Prevnar
(and consider
Pneumovax
) if on immunosuppressants longterm
Avoid
Live Vaccine
(e.g. MMR) if on immunosuppressants
Do not give
Live Vaccine
within 1 month of immunosuppressant
Other diagnostics as indicated
Dilated
Eye Exam
yearly (if on
Hydroxychloroquine
)
DEXA Scan
yearly (if on
Corticosteroid
s)
Cardiovascular Risk Reduction
See
Cardiac Risk Management
Tobacco Cessation
Manage
Hyperlipidemia
and
Hypertension
Screen for
Diabetes Mellitus
Contraception
Intrauterine Device
Avoid
Oral Contraceptive
s (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
Seizure
disorder
Lupus Nephritis
Azotemia
Onset in childhood
Resources
Lupus Foundation of America
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]
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