Clinical Slide Set. Systemic Lupus Erythematosus.
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© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
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© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
in the clinic
Systemic Lupus
Erythematosus
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Which patients are at elevated risk
for lupus?
Diagnosed 9-times more often in women than men
More common and severe in women who are African
American, Hispanic, other ethnic minorities
Early studies suggest genetic predisposition
HLA genes + early complement components
Single-gene risk factors account for just 1-2% of cases
>30 gene polymorphisms linked to lupus
Possible contributors in those genetically predisposed
Sex chromosome genes, sex hormones
Environmental influences
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Should clinicians screen patients for
asymptomatic lupus if they are at
increased risk?
Not recommended
Including those with a family history
Test for ANA produces too many false-positives
Detected in 3-5% of healthy individuals or patients with
other autoimmune or infectious diseases
Serologic evidence may precede clinical manifestations
By 3 to 9 years
Treating during this clinically ‘silent’ period doesn’t halt or
delay development
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Screening…
Single-gene mutations causing SLE are rare
Numerous gene variants are linked to lupus
Current evidence insufficient to support screening for them
ANA testing in asymptomatic individuals is not useful
Immune reaction to nuclear antigens is not SLE-specific
Can be detected in healthy individuals
May precede SLE manifestations by many years
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What symptoms or physical exam findings
should prompt clinicians to consider lupus?
Weight loss, fatigue, low-grade fever
Initial presentation often mimics a viral syndrome
Arthralgias or arthritis
Morning stiffness, mild-to-moderate joint swelling
Non-erosive, affecting lg / sm joints; infrequent deformities
Jaccoud’s arthropathy present in 2.8-4.3%
Cutaneous manifestations (occur in up to 70%)
Acute: indurated or flat erythematous lesions
Subacute: annular lesions coalescing into polycyclic rash
or papulosquamous lesions
Chronic: scarring indurated plaques that resolve with
depigmentation (discoid lupus)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What other clinical manifestations should
clinicians look for when evaluating people
who may have lupus?
Lupus is a multi-organ disease
May present in many ways
Can mimic infectious diseases, cancer, autoimmune
conditions
ACR classification criteria facilitates systematic approach
Focuses on the most common SLE manifestations
4 of the 11 criteria required for classification
Highly sensitive + specific for diagnosing SLE
But patients with mild disease may be missed
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Malar rash: flat or raised erythema over malar eminences
Discoid rash: erythematous raised patches or atrophic scarring
Photosensitivity: skin rash from unusual reaction to sunlight
Oral ulcers: usually painless oral / nasopharyngeal ulcerations
Arthritis: nonerosive, involving ≥2 or more peripheral joints
Serositis: pleuritis or documented pericarditis
Renal disorder: persistent proteinuria >0.5 g/d or >3 (dipstick);
cellular casts red cell, hgb, granular, tubular, or mixed
Neurologic disorder: seizures or psychosis
Hematologic disorder: hemolytic anemia with reticulocytosis;
leukopenia <4000/mm ≥2 occasions; lymphopenia <1500/mm ≥2 or
more occasions; thrombocytopenia <100 000/mm
Immunologic disorder: anti-dsDNA; anti-Smith antibodies;
antiphospholipid antibodies
ANA: in absence of drugs associated with drug-induced SLE
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What laboratory tests should clinicians
use to diagnose lupus?
ANA
Negative ANA inconsistent with diagnosis of SLE
If positive, test for antigen-specific ANAs
Those targeting dsDNA or ribonucleoprotein complexes
Ro/SSA, La/SSB Smith, RNP (extractable nuclear antigens)
Basic investigations for SLE
Complement C3 and C4
CBC, ESR, CRP, comprehensive metabolic panel
Urinalysis
Direct Coombs’ test (if hemolytic anemia + reticulocytosis)
Creatine phosphokinase (if muscle weakness)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What other diagnoses should clinicians
consider in patients with possible lupus?
Chronic fatigue syndrome
Fibromyalgia
Rheumatoid arthritis
Small or medium vessel vasculitides
Thrombotic thrombocytopenic purpura
Viral arthritis
Hematopoietic cancer
Malignant lymphoproliferative syndromes
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When should clinicians consult with a
rheumatologist or other specialist for
diagnosing patients with possible lupus?
All patients
When manifestations and serologic studies suggest SLE
Goals
Timely, accurate diagnosis
Effective treatment of acute disease
Appropriate monitoring and dose adjustment
Early introduction of a steroid-sparing regimen
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Diagnosis…
Lupus often a diagnostic challenge
Multisystem (cutaneous, renal, respiratory, CV, CNS, GI)
Manifestations may characterize numerous other conditions
Use ACR classification criteria as a guide
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What medications are used to treat lupus?
Glucocorticoids
First-line agents for most manifestations
Dosage and duration based on clinical experience
Antimalarials
Hydroxychloroquine: cornerstone of SLE treatment
To prevent disease flares
NSAIDs
Immunosuppressive treatment
In lupus nephritis: based on histopathologic classifications
Other manifestations: treatment often includes
immunosuppressives and a multidisciplinary approach
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians initiate therapy in a
stable patient who is not having a flare?
Hydroxychloroquine and other antimalarials
Used to treat inflammatory arthritides for >50 years
Prevents relapses
Reduces risk for congenital heart block in neonatal SLE
Antithrombotic effects are important in antiphospholipid
antibody-related prothrombotic diathesis
Well-tolerated with rare side effects (retinopathy; skin
hyperpigmentation; neuromuscular or cardiac toxicity)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose therapy for a
patient who is having a flare?
IV glucocorticoids + immunosuppressive medications
For severe manifestations (lupus nephritis, alveolar
hemorrhage, CNS vasculitis)
Withdraw glucocorticoids once remission achieved
Oral prednisone or methlyprednisolone
For arthritis, pleuropericarditis, cutaneous vasculitis, uveitis
Overlap: lupus manifestations, glucocorticoid complications
Osteoporosis, avascular bone necrosis, myopathy, psychosis
Glucocorticoid dosage, duration: rely on clinical experience
Prolonged medium-to-high dosing increases complications
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose drug therapy
for cutaneous manifestations?
Commonly used topical treatments
Tacrolimus, R-salbutamol, or pimecrolimus
Clobetasol
Betamethasone
Photoprotection
Other treatments
Systemic hydroxychloroquine and chloroquine
Methotrexate
Mycophenolate mofetil
Azathioprine
Rituximab
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose drug
therapy for arthritis?
First-line agents
Low-dose glucocorticoids
Antimalarials
Other treatment
Methotrexate (particularly in patients without other systemic
manifestations)
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose and dose
drug therapy for lupus nephritis?
Class I or II: no immunosuppressive therapy
Class III or IV: treat aggressively
Standard therapy: cyclophosphamide + IV glucocorticoids
Dose cyclophosphamide by total body surface area,
adjusted for decreased creatinine clearance
Dose glucocorticoids using ACR recommendations
Newer regimen: mycophenolate mofetil + glucocorticoids
GI and hematologic toxicity common
Contraindicated in pregnancy (possibly teratogenic)
Class V: prednisone 0.5 mg/kg/d + mycophenolate mofetil
Class VI: preparation for renal replacement therapy
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Maintenance therapy
Mycophenolate mofetil
Azathioprine
Both superior to cyclophosphamide
For patients who don’t respond to either
Calcineurin inhibitors (cyclosporine, tacrolimus)
Rituximab (monoclonal antibody against CD20)
Either in combination with glucocorticoids
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
Indications for kidney biopsy in SLE
Increasing serum creatinine
Without compelling alternative causes
Confirmed proteinuria ≥1.0gm per 24h
24-h urine specimens or spot protein/creatinine ratio
Combination of the following:
Proteinuria ≥0.5 gm per 24h + hematuria (≥5 RBCs/highpower field)
or
Proteinuria ≥0.5 gm per 24h + cellular casts
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose drug therapy
for membranous nephritis?
Pure membranous nephritis not associated with
endocapillary proliferation
Presents with variable degree of proteinuria
Progression of renal dysfunction slow compared to
class III or IV lupus nephritis
Treat with mycophenolate mofetil + steroids
Tacrolimus / azathioprine + steroids also effective
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose therapy for
neuropsychiatric lupus?
Treatment relatively empirical
IV glucocorticoids, immunoglobulin, cyclophosphamide
Relapse may be more common in glucocorticoid vs
cyclophosphamide treatment
Rituximab may be beneficial, but relapse rate seems high
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose therapy for
respiratory manifestations?
Pleuritis
NSAIDs, low- to moderate-dose glucocorticoids
Abrupt diffuse alveolar hemorrhage
IV glucocorticoids + immunosupressants; consider
plasmapheresis
Pulmonary hypertension
PDE-5 inhibitors, ERAs, and prostacyclin analogs may be
used; with or without immunosuppressants
In interstitial lung disease: glucocorticoids, and, if poor
response, cyclophosphamide or azathioprine
Acute lupus pneumonitis
High doses of glucocorticoids and cyclophosphamide
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians choose therapy for
ocular manifestations?
Depends on severity and disease activity
Antimalarials
NSAIDs
Oral or IV glucocorticoids
Scleral or retinal involvement
Concomitant use of pulse glucocorticoids
Then 1 mg/kg prednisone equivalent + immunosuppressants
Retinal vasculitis and arterial or venous retinal occlusion
with antiphospholipid antibodies
Immunosuppressants + antiplatelet agents / anticoagulation
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What new medications are available for
treating systemic lupus?
Belimumab (1 mg/kg and 10 mg/kg dose)
Monoclonal antibody targeting B lymphocyte stimulator
Recently approved for treatment
Improves musculoskeletal, mucocutaneous manifestations
Improves immunological parameters
Fewer patients had worsening hematological parameters
Trials excluded patients with severe lupus nephritis or
severe CNS manifestations
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians monitor patients
who are being treated for lupus?
Routinely test: CBC, basic metabolic panel, urinalysis
Allows evaluation of target-organ manifestations
Routinely test?: dsDNA antibodies + C3 & C4 levels
Controversial for clinically stable patients
Treatment with prednisone of clinically stable but serologically
active patients may avert severe flare
Monitor individual disease manifestations
Monitor for immunosuppressant toxicity
If treated with hydroxychloroquine: ophthalmological
evaluation (particularly if >40y and treated for a long time)
Monitor for osteoporosis, osteonecrosis
Consider periodic lipid testing, ECHO
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What should clinicians do about
immunizations in people with lupus?
All patients with SLE should receive
Influenza vaccine
Pneumococcal vaccine
Consider quadrivalent HPV vaccine
Well-tolerated, reasonably effective in stable SLE
No live attenuated vaccines if immunocompromised
If on >20mg/d prednisone or immunosuppressants
Including: herpes zoster, Flumist, MMR, smallpox
Tuberculin skin test recommended
If glucocorticoids or immunosuppressive use prolonged
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
How should clinicians modify treatment
for pregnant patients?
Higher flare rate in pregnancy + immediate post-partum
Initial presentation with hematologic or renal manifestations
during pregnancy not uncommon
Consider pregnancy-related abnormalities that mimic SLE
(eclampsia, HELLP syndrome)
Treat active lupus manifestations
Use hydroxychloroquine and prednisone
Discontinuation associated with increased flare risk
If severe, consider IV glucocorticoids + azathioprine
Contraindicated: mycophenolate mofetil, methotrexate,
cyclophosphamide
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When should patients with lupus be
hospitalized?
Severe thrombocytopenia
Severe or rapidly progressive renal disease
Suspected lupus pneumonitis or pulmonary hemorrhage
Chest pain or severe cardiovascular manifestations
CNS and neurological manifestations
Unexplained fever
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
When should clinicians consider
consulting a rheumatologist or other
specialist for treating patients with lupus?
Rheumatologist
Should be involved in the treatment of all lupus patients
Other specialists also may be involved
Depending on organ-specific disease manifestations
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
What non-drug therapies should clinicians
recommend for lupus?
Low cholesterol diet
Exercise
Weight control
Smoking cessation
UV protection (to reduce flares from sun exposure)
Calcium and vitamin D (to prevent osteoporosis)
Routine dental evaluation
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.
CLINICAL BOTTOM LINE: Treatment…
Hydroxychloroquine
Prevents disease flares
Cornerstone of SLE treatment
Glucocorticoids
First-line for most SLE manifestations
Dose & duration based on clinical experience, consensus
Immunosuppressive treatment in lupus nephritis
Based on histopathologic classification
Guided by ACR recommendations
Treatment of other lupus manifestations
Based on clinical experience
Often immunosuppressive Rx + multidisciplinary approach
© Copyright Annals of Internal Medicine, 2012
Ann Int Med. 157 (3): ITC2-1.