© Copyright Annals of Internal Medicine, 2012 Ann Int Med. 157 (3): ITC2-1. * For Best Viewing:...

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in the clinic

Systemic Lupus Erythematosus


Which patients are at elevated risk for lupus?

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

Diagnosed 9-times more often in women than men

More common and severe in women who are African American, Hispanic, other ethnic minorities


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


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


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)


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


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


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)


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


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


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


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


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)


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


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


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)


How should clinicians choose and dose drug therapy for lupus nephritis?

Class I or II: no immunosuppressive therapy

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

Class III or IV: treat aggressively


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


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/high-power field)

or

Proteinuria ≥0.5 gm per 24h + cellular casts


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


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


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


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


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


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


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


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


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


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


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


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

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