Neuropsychiatric Lupus

Robin L. Brey, M.D. Supported by NIH/NINDS R01-NS35477 and NCRR No other disclosures to report.

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 more frequently than Non-Hispanic Whites.

SLE Diagnosis
Malar Rash Discoid Rash Photosensitivity Oral or Nasopharyngeal Ulcerations Arthritis without deformity Serositis Renal Disorder Neurologic Disorder (seizures or psychosis) Hematologic Disorder Immunologic Disorder ANA Positive

SLE: Prognosis
51% 5-year survival in the 1950s 90% 5-year survival in 1990s Early deaths due to SLE flares (kidney and CNS most frequent) or infection Late deaths due to vascular causes

Neuropsychiatric SLE
Over 80% of SLE patients experience some type of nervous system manifestation at some time during the disease course Seizures and psychosis are the only manifestations that are part of the diagnostic criteria for the diagnosis of SLE

Diagnosis of Neuropsychiatric SLE

Primary SLE-mediated nervous system disease Secondary manifestations related to vascular disease, infection, kidney failure, medication side effects

Prevalence of Neuropsychiatric SLE

NPSLE manifestations occur as single or multiple events even during periods of no non-nervous system disease activity 40% of NPSLE manifestations develop before diagnosis of SLE 63% occur within first year of diagnosis

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

Scope of Problem
1976 Landmark study of Urowitz and colleagues showed 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 SLE patients

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

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

Increased risk for Heart Disease and Stroke in Women with SLE
(Ward, Arthritis Rheum 1999;42:338)
Reason for Hospitalization:

Age 18-44 years d Risk

8.5 11.1 8.7 8.5 13.2 10.1

Age 45-64 d Risk

2.8 3.3 2.5 2.9 3.7 2.7

Age 65 years d Risk

0.7 1.2 0.7 0.8 1.3 0.7

Heart Attack Heart Failure Stroke Heart Attack Heart Failure Stroke

Traditional Cardiovascular Risk Factors Fail to Fully Account for Accelerated Atherosclerosis in SLE
(Esdaile. Arthritis Rheum 2001;44:2331)

263 SLE patients without prior vascular events studied over 8.6 years
34 had Cardiac events
17 nonfatal MI 12 Cardiac deaths

16 had Strokes

Cardiovascular Risk Factors in Women with SLE vs. Controls

(Bruce. Arthritis Rheum 2003;48:3159) Risk Factor
HTN Cholesterol Low HDL Current smoker

SLE (N=250)
83 (33%) 84 (34%) 33 (13%) 42 (17%)

Controls (N=250)
32 (13%) 91 (36%) 26 (10%) 49 (20%)

Risk
2.6X No No No

DM
Fam Hx CAD

12 (5%)
49 (20%)

2 (1%)
42 (17%)

6X
No

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

Antiphospholipid Antibodies (aPL) and Stroke in SLE

European Working Party on SLE
Most common cause of death in last 5 years was thrombosis
Always associated with aPL

Most common thrombotic events

Stroke (11.8%) MI (7.4%) PE (5.9%)

Suggests an important role of aPL in recurrent thrombosis in SLE

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

Take Home Message

In addition to treating SLE, people with SLE need to be sure to do all they can to lower their traditional cardiovascular risks:
Control blood pressure Normalize cholesterol Control diabetes Stop smoking Exercise

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

ACR Case Definitions (1999) Peripheral Nervous System

Autonomic Neuropathy Myasthenia Gravis Peripheral neuropathy Sensorineural Hearing Loss Cranial neuropathy

Overall NPSLE Prevalence Estimates in Adults

Studies using the ACR Case Definitions found a prevalence of 14% to over 80%:
Manifestation Headache Seizures Cardiovascular disease
Psychosis Cranial neuropathy Movement disorder

Percent 39%-61% 8%-18% 2%-8%

3%-5% 1.5%-2.1% 1%

NP-SLE Syndromes: Cognitive

Attention Concentration Memory Word-finding Importance of corticosteroid use controversial Cognitive impairment not always progressive

Spectrum of NPSLE
60 50 40
Percent

SALUD Literature

30 20 10 0
Seizure PN Chorea Headache Psychiatric Disease

Spectrum of NPSLE - Cognitive Dysfunction

60 50 40

Percent

30 20 10 0
None Mild Moderate Severe

SALUD Finland

Cognitive Dysfunction

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

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.)

NPSLE Treatment Issues

Is therapy directed at treating the immune system indicated for a specific NPSLE manifestation? Should this therapy for a short time or continued over a long time period? Are treatments needed to treat symptoms that are not effective at also treating the underlying disease? Are other non-drug therapies needed?

NPSLE Treatment
Approach to therapy begins with making the most precise diagnosis possible
Everything is NOT SLE!

Therapy for NPSLE

There are no specific drugs for NPSLE manifestations. Drugs used are the same ones we use to treat other serious SLE manifestations
Steroids Immuran Cytoxan Cellcept Others

Symptomatic Treatments
Medications
Drugs used to treat headache, seizures, stroke and other NPSLE manifestations work as well in SLE 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

Summary
1. NPSLE manifestations are an important source of morbidity for many patients with Lupus and are still underrecognized 2. Predictors of specific NPSLE syndromes must be identified 3. Lowering non-SLE risk factors for cardiovascular disease is crucial