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Neuropsychiatric Lupus

Robin L. Brey, M.D.

Supported by NIH/NINDS

R01-NS35477 and NCRR

No other disclosures to report.

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Systemic Lupus

Erythematosus (SLE)

SLE is an inflammatory disease affecting

many organ systems

Prevalence = 130/100,000 in the U.S. Female to Male ratio = 5:1

African Americans affected 5-10 times and

Mexican Americans 2-3 times morefrequently than Non-Hispanic Whites.

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SLE Diagnosis

Malar Rash

Discoid Rash

Photosensitivity

Oral or Nasopharyngeal Ulcerations

Arthritis without deformity Serositis

Renal Disorder

Neurologic Disorder (seizures orpsychosis)

Hematologic Disorder

Immunologic Disorder

ANA Positive

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Neuropsychiatric SLE

Over 80% of SLE patients experiencesome type of nervous system manifestation

at some time during the disease course

Seizures and psychosis are the onlymanifestations that are part of the

diagnostic criteria for the diagnosis of SLE

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Diagnosis of Neuropsychiatric SLE

Primary SLE-mediated nervous systemdisease

Secondary manifestations related to

vascular disease, infection, kidney failure,medication side effects

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Prevalence of Neuropsychiatric

SLE NPSLE manifestations occur as single or

multiple events even dur ing per iods o f no

non-nervous sys tem disease act iv i ty

40% of NPSLE manifestations develop

before diagnosis of SLE

63% occur within first year of diagnosis

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Neuropsychiatric SLE: Risk

Factors

Antiphospholipid antibodies:thrombosis, thrombocytopenia,

recurrent fetal loss, cognitive problems Anti-ribosomal P antibodies: psychosis

Anti-glutamate receptor antibodies:

cognitive problems, depression Secondary effects of renal disease,

vascular disease infection and

medication side effects

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Scope of Problem

1976 Landmark study of Urowitz and colleaguesshowed bimodal mortality over time in SLE Early deaths due to SLE activity or infection

Late deaths due to cardiovascular disease

Risks for Cardiovascular disease higher in SLEpatients 6 to10X increase for Stroke in SLE

Stroke cause of death in 15% of SLE deaths

5 to 50X increase for MI in SLE MI cause of death in 20% of SLE deaths

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Major Issues to Consider

Premature atherosclerosis Role of traditional risk factors

Role of autoimmune disease process

Secondary effects of organ damage Role of inflammation

Role of corticosteroid therapy

Clotting Disorders

Antiphospholipid antibodies

Cardiac lesions

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Increased risk for Heart Disease and Stroke in

Women with SLE(Ward, Arthritis Rheum 1999;42:338)

Reason forHospitalization:

Age

18-44 years

d Risk

Age

45-64

d Risk

Age

65 years

d Risk

Heart AttackHeart Failure

Stroke

8.511.1

8.7

2.83.3

2.5

0.71.2

0.7

Heart Attack

Heart Failure

Stroke

8.5

13.2

10.1

2.9

3.7

2.7

0.8

1.3

0.7

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Cardiovascular Risk Factors in Women

with SLE vs. Controls(Bruce. Arthritis Rheum 2003;48:3159)

Risk Factor SLE

(N=250)

Controls

(N=250)

Risk

HTN 83 (33%) 32 (13%) 2.6X

Cholesterol 84 (34%) 91 (36%) No

Low HDL 33 (13%) 26 (10%) No

Current smoker 42 (17%) 49 (20%) No

DM 12 (5%) 2 (1%) 6X

Fam Hx CAD 49 (20%) 42 (17%) No

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Cardiovascular Risk Factors Fail to Fully

Account for Accelerated Atherosclerosis in

SLE(Esdaile. Arthritis Rheum 2001;44:2331)

After controlling for traditional vascular risk

factors 10-fold increased risk for nonfatal MI

17-fold increased risk for cardiac death

7.9-fold increased risk for stroke

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Hahn, B. H. N Engl J Med 2003;349:2379-2380

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Take Home Message

In addition to treating SLE, people with SLEneed to be sure to do all they can to lower

their traditional cardiovascular risks:

Control blood pressure Normalize cholesterol

Control diabetes

Stop smoking Exercise

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American College of Rheumatology

(ACR) Case Definitions (1999) Central

Nervous System Aseptic Meningitis

Cerebrovascular disease

Cognitive Disorders

Delirium (Acute confusional state) Dementia

Demyelinating syndrome

Headaches

Movement disorders (Chorea) Myasthenia Gravis

Psychiatric Disorders

Seizure Disorders

Transverse Myelopathy

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ACR Case Definitions (1999)

Peripheral Nervous System

Autonomic Neuropathy

Myasthenia Gravis

Peripheral neuropathy

Sensorineural Hearing Loss

Cranial neuropathy

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Overall NPSLE Prevalence Estimates

in Adults

Studies using the ACR Case Definitions

found a prevalence of 14% to over 80%:

Manifestation PercentHeadache 39%-61%

Seizures 8%-18%

Cardiovascular disease 2%-8%Psychosis 3%-5%

Cranial neuropathy 1.5%-2.1%

Movement disorder 1%

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NP-SLE Syndromes: Cognitive

Attention Concentration

Memory

Word-finding Importance of corticosteroid use

controversial

Cognitive impairment not alwaysprogressive

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Spectrum of NPSLE - Cognitive

Dysfunction

0

10

20

30

40

50

60

None Mild Moderate Severe

Cognitive Dysfunction

Percent

SALUDFinland

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Risk Factors for Cognitive

Dysfunction in SALUD

Hispanic ethnicity

Higher depression scores

Higher SLE-related damage score Higher SLE-related acute disease activity

scores

Consistent prednisone use Persistently positive antibodies

Antiphospholipid antibodies

Anti-Ribosomal P antibodies

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Morbidity and Mortality Associated with

NPSLE Manifestations

Decreased quality of life and increased

SLE-related organ damage is associated

with NPSLE manifestations in adults (Hanly.Arthritis Rheum 2007;56:265)

Mortality rate over a 20-year period was

45% in children with NPSLE and 17.4% in

those without them (Sibbitt. J Rheumatol 2002;29:1536.)

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NPSLE Treatment Issues

Is therapy directed at treating theimmune system indicated for a specificNPSLE manifestation?

Should this therapy for a short time orcontinued over a long time period?

Are treatments needed to treat

symptoms that are not effective at alsotreating the underlying disease?

Are other non-drug therapies needed?

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NPSLE Treatment

Approach to therapy begins with

making the most precise diagnosis

possible Everything is NOT SLE!

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Therapy for NPSLE

There are no specific drugs for NPSLEmanifestations.

Drugs used are the same ones we use to

treat other serious SLE manifestations Steroids

Immuran

Cytoxan Cellcept

Others

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Symptomatic Treatments Medications

Drugs used to treat headache, seizures, strokeand other NPSLE manifestations work as well inSLE patients as in people without SLE

Many SLE patients (up to 66%!) use alternative

medicines Non-Pharmacologic

Stress management

Life-style changes

Psychotherapy Cognitive rehabilitation

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Summary

1. NPSLE manifestations are an importantsource of morbidity for many patients

with Lupus and are still under-recognized

2. Predictors of specific NPSLEsyndromes must be identified

3. Lowering non-SLE risk factors forcardiovascular disease is crucial