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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.