Systemic Lupus Erythematosus

See Also

Background

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

Epidemiology

Prevalence
1. England: 200 per 100,000 women aged 18 to 65 years
2. U.S
  1. Adults: 40 to 50 per 100,000 persons (up to 1 in 1000)
  2. Children 3.3 to 8.8 per 100,000 persons
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 to 20% of cases (median onset 11 to 12 years, uncommon before age 8)
Gender
1. More common in women (especially child-bearing age) by ratio of 9:1 (women 90%, men 10%)
2. Ratio 4-5:1 male to female in children
Ethnic and racial predisposition
1. Native American
2. African American (twice as prevalent than in white patients)
3. Hispanic
4. Chinese
5. Filipino
References
1. Duarte-García (2022) Ann Rheum Dis +PMID: 35577385 [PubMed]
2. Kamphuis (2010) Nat Rev Rheumatol 6(9):538-46 +PMID: 20683438 [PubMed]

Causes

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

Consider SLE when multiple organ systems are involved
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 (often painless Oral Ulcers on Palate)
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

Background
1. New 2019 EULAR/ACR guidelines included many of the SLICC Criteria (2012), which replaced original ACR Criteria (1997)
2. Test Sensitivity: 96%
3. Test Specificity: 93%
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
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 positivity at low titers <1:320 is very prevalent in normal population (esp. children)
Initial Screening
1. ANA titer positive if 1:80 dilution (prior cut-off was 1:40)
Secondary testing if ANA titer positive
1. Complete Blood Count
2. Comprehensive metabolic panel including Serum Creatinine
3. Urinalysis
4. Antiphospholipid Antibody
5. Anticardiolipin Antibody
6. Double Stranded DNA Antibody (Anti-dsDNA)
7. Smith Antibody (Anti-Smith or Anti-Sm)
8. Anti-ribonucleoprotein (Anti-RNP)
9. Anti-Beta2-Glycoprotein1
10. C-Reactive Protein
11. Direct Coombs
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. Chronic Fatigue Syndrome
3. Dermatomyositis
4. Endocarditis
5. Fibromyalgia
6. HIV Infection
7. Hypothyroidism
8. Fibromyalgia
9. Inflammatory Bowel Disease
10. Lyme Disease
11. Malignancy
12. Mixed Connective Tissue Disease
13. Psoriatic Arthritis
14. Reactive Arthritis
15. Rheumatoid Arthritis or adult onset Still's Disease
16. Sarcoidosis
17. Systemic Sclerosis
18. Sjogren's Syndrome
19. Thrombotic Thrombocytopenic Purpura (TTP)
20. 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 (50% lifetime Prevalence)
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
3. Renal biopsy is typically required for diagnosis of specific Glomerulonephritis type, which in turn drives management
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 (28 to 40% lifetime Prevalence)
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)
Hematologic (most SLE patients)
1. Thrombocytopenia
2. Autoimmune Hemolytic Anemia
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
3. Miscarriage or Stillbirth
4. Pregnancy may trigger increased SLE acitivity and flares
5. Risk Factors for increased pregnancy complications
  1. Active disease 6 months before pregnancy
  2. Lupus Nephritis
  3. Discontinuation of Hydroxychloroquine

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
Monitor Disease Activity: Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
1. https://www.mdcalc.com/calc/10099/systemic-lupus-erythematosus-disease-activity-index-2000-sledai-2k
2. Mild Disease: Score <=6 on SLEDAI-2K
3. Moderate Disease: Score 7 to 12 on SLEDAI-2K
4. Severe Disease: Score >12 on SLEDAI-2K

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 Induction Management
  1. Systemic Corticosteroids AND
  2. 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 (Arthralgias, myalgias in 95% of cases)
1. First-Line Medications
2. Medications in Refractory cases
  1. Methotrexate
  2. Mycophenylate
Skin Involvement (70-80% of cases)
1. Use sun screen (minimum SPF 15)
2. Avoid Photosensitizer medications
3. First-Line Medications
  1. Topical Corticosteroids (and consider Systemic Corticosteroids)
  2. Topical Calcineurin Inhibitors
  3. Hydroxychloroquine
4. Medications in Refractory cases
  1. Methotrexate
  2. Retinoids
  3. Dapsone
  4. Mycophenylate
Hematologic effects (e.g. Leukopenia, Anemia, Thrombocytopenia)
1. Thrombocytopenia
  1. Monitor Platelet Count weekly if Platelets <50,000 cells/mm3
  2. Glucocorticoids AND Immunosuppressants (e.g. Azathioprine, mycophenylate, Cyclosporine)
  3. Consider Rituximab in refractory cases
2. Automimmune Hemolytic Anemia
  1. Monitor Hematocrit, Hemoglobin And Reticulocyte Count weekly in severe Hemolytic Anemia
  2. Glucocorticoids AND Immunosuppressants
3. Leukopenia
  1. Reduce infection risk
Lupus Nephritis
1. Lifetime Prevalence 50%
2. Screen Urinalysis and Serum Creatinine every 3-6 months (reflex to Urine Protein to Creatinine Ratio)
3. Renal biopsy indications
  1. Proteinuria >=1 g per 24 hours OR
  2. Hematuria > 0.5 g per 24 hours OR
  3. Cellular Casts
4. Acute Induction Management
  1. Systemic Corticosteroids AND
  2. Mycophenolate or Cyclophosphamide
5. Chronic Maintenance Management
  1. Mycophenolate or Azathioprine
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
2. Risk of Cerebrovascular Accident

Management
Pregnancy

General measures
1. Aspirin 81 mg orally daily started after 12 weeks (due to risk of Preeclampsia)
2. Consider Anticoagulant (e.g. LMWH) during pregnancy and Postpartum Period in Antiphospholipid Antibody Syndrome
3. Consult Maternal-Fetal Medicine and Rheumatology for co-management during pregnancy
SLE Control Medications
1. Continue Hydroxychloroquine during pregnancy
  1. Decreases pregnancy complications and controls SLE
2. Other medications that may be used in pregnancy
3. Contraindicated Medications in Pregnancy (transition to safe medications at least 3 months before conception)
Monitor for Fetal Cardiac Complications (cardiac neonatal lupus)
1. Risk of congenital Heart Block in 1 to 3% of seropositive SLE
2. Hydroxychloroquine during pregnancy reduces risk of cardiac neonatal lupus
3. Risk Factors: Cardiotoxic Antibodies
  1. Antiphospholipid Antibodies positive
  2. Anti-Ro or SS-A Antibody Positive
  3. Anti-La or SS-B Antibody Positive
4. Obtain serial fetal echo between 12 and 26 weeks gestation if Anti-Ro or Anti-La Antibody Positive
  1. Incomplete Heart Block (treated with Dexamethasone)
  2. Complete Heart Block (no known treatment as of 2023)

Management
Severity Based for Non-Renal SLE

Background
1. Severity based on Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K)
  1. https://www.mdcalc.com/calc/10099/systemic-lupus-erythematosus-disease-activity-index-2000-sledai-2k
2. Goals of therapy
  1. Remission (SLEDAI-2K of 0, on Hydroxychloroquine and no Corticosteroids) OR
  2. Low disease activity (SLEDAI-2K of <=4, on Hydroxychloroquine and Prednisone <=7.5 mg/day)
Mild Disease: Score <=6 on SLEDAI-2K
1. First-Line
  1. Hydroxychloroquine AND
  2. Systemic Corticosteroids (as needed)
2. Refractory
  1. Add Methotrexate
Moderate Disease: Score 7 to 12 on SLEDAI-2K
1. First-Line
  1. Hydroxychloroquine AND
  2. Systemic Corticosteroids (as needed) AND
  3. Other agents (choose one to add)
2. Refractory
  1. Add Belimumab (Benlysta)
Severe Disease: Score >12 on SLEDAI-2K
1. First-Line
  1. Hydroxychloroquine AND
  2. Systemic Corticosteroids (as needed) AND
  3. Other agents (choose one to add)
    1. Mycophenolate
    2. Cyclophosphamide
2. Refractory
  1. Add Rituximab (Rituxan)
References
1. Fanouriakis (2019) Ann Rheum Dis 78(6):736-45 +PMID: 30926722 [PubMed]

Management
Medications

Corticosteroids
1. Longterm goal (once controlled) is to minimize the use of Glucocorticoids
2. Indicated as a mainstay of acute flare management at lowest effective dose (then taper off or to dose <=7.5 mg/day)
  1. Low dose: Indicated for most patients
    1. Prednisone 7.5 to 10 mg orally daily or less
  2. High dose: Indicated in Lupus Cerebritis, nephritis, Thrombocytopenia
    1. Prednisone 40-60 mg orally daily
    2. Acute organ-threatening disease may require IV doses 250 to 1000 mg/day for up to 3 days
3. 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
4. Skin lesions (no significant evidence to support use)
  1. Topical Corticosteroids
  2. Intralesional Corticosteroids
5. Monitoring
  1. Serum Glucose every 3 months
  2. DEXA Scan every 1 to 2 years
  3. Monitor for symptoms of avascular necrosis (e.g. Hip Pain)
  4. Use every visit to attempt to taper Corticosteroids, and employ steroid-sparing agents instead
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): First-Line
1. Hydroxychloroquine (Plaquenil)
  1. First-line agent in Systemic Lupus management (prevents flares, organ injury, thrombosis and decreases mortality)
  2. Also indicated for Lupus Nephritis, Arthritis and lupus-related skin lesions
  3. Dosing: 200-400 mg/day (limit to <5 mg/kg/day to reduce Macular complication risk)
  4. Effects are delayed for 2 to 8 weeks
  5. Monitoring
    1. Annual dilated Eye Exam and Visual Field testing (including baseline exam)
    2. Low risk patient dilated Eye Exams may be spaced to every 5 years
Cytotoxic agents (and other Immunosuppressants): Second-Line
1. 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
    2. Observe for hepatotoxicity, lymphoproliferative disorders, myelosuppression
2. Methotrexate
  1. Indicated in Arthritis, Cutaneous Lupus, serositis and severe SLE
  2. Dosing: 7.5 to 15 mg per week
  3. Monitoring
    1. Complete Blood Count, comprehensive metabolic panel every 3 months
    2. Observe for hepatotoxicity, myelosuppression
Cytotoxic agents (and other Immunosuppressants): Third-Line
1. 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 OR 500 to 1000 mg/m2 IV every 4 weeks
  4. Monitoring
    1. Complete Blood Count, comprehensive metabolic panel, Urinalysis every 3 months
    2. Risk of hemorrhagic cystitis, myelo and Immunosuppression, malignancy
2. 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, myelosuppression
3. Voclosporin (Lupkynis)
  1. Oral Calcineurin Inhibitor
  2. Indicated in Lupus Nephritis (in combination with Mycophenolate and steroids)
  3. Dose 23.7 mg orally every 12 hours
  4. Monitor GFR at baseline, then every 2 weeks for first month, then every 4 weeks
  5. Monitor Blood Pressure every 2 weeks
Monoclonal antibodies (indicated as third-line agent for severe SLE)
1. Anifrolumab (Saphnelo)
  1. IgG 1 Kappa Monoclonal Antibody against Interferon (type 1)
  2. Dose: 300 mg every 4 weeks via IV infusion
  3. Risk of respiratory infection, Hypersensitivity
2. Belimumab (Benlysta)
  1. B Lymphocyte Stimulating Factor
  2. Dose: 10 mg/kg IV OR 200 mg SQ once weekly
  3. Risk of serious infections, malignancy
3. Rituximab (Rituxan)
  1. Dose: 1 g IV repeated in 2 weeks (one time delivery of 2 doses)
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
Co-management with rheumatology
Clinic follow-up every 3 to 6 months in stable disease (more often in moderate to severe disease)
1. Symptom screen
2. Physical exam
  1. Cardiopulmonary exam
  2. Musculoskeletal Exam
  3. Skin exam
  4. Lymph Node exam
  5. Mental health and Neurologic Exam
3. Screen for signs and symptoms of malignancy
4. Medication monitoring
  1. Each medication has specific monitoring recommendations (see above)
Labs every 3 months (or at each clinic visit)
1. Complete Blood Count
2. Urinalysis
  1. Obtain Urine Protein to Creatinine Ratio (or 24 Hour Urine Protein) if Lupus Nephritis suspected
  2. See Lupus Nephritis management above
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 levels
Immunizations
1. See Adult Immunization
2. Prevnar 20 (PCV20) if Lupus Nephritis or on Immunosuppressants longterm
  1. Pneumovax (PPSV23) is also needed if PCV15 is used
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 and optimize control of Diabetes Mellitus
5. Encourage Exercise and Healthy Diet
6. Obesity Management
Contraception
1. Intrauterine Device
2. Avoid Oral Contraceptives (due to Hypercoagulable state, esp. in Antiphospholipid Antibody Syndrome)

Prognosis

Drug-induced Lupus typically resolves spontaneously after stopping the offending agent
Overall five year survival: 91-97%
Worse prognosis for childhood onset
1. Lupus Nephritis occurs in 40% of children with SLE (half of these will have CKD 4)
2. Neuropsychiatric manifestations in one third of children
3. Increased risk of infection, cardiovascular disease
4. Much higher mortality in children (10 fold higher than adults)
  1. Untreated mortality approaches 90% at 5 years
Other worse prognostic factors
References
1. Ambrose (2016) Lupus 25(14):1542-50 +PMID: 27147622 [PubMed]
2. Cimaz (2016) Nat Rev Rheumatol 12(7):382-3 +PMID: 27305850 [PubMed]

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
Orandi (2024) Mayo Clinic Pediatric Days, lecture attended 1/18/2024
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]
Lam (2023) Am Fam Physician 107(4): 383-95 [PubMed]