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.