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4/16/2018 1 SLE: Neuropsychiatric Lupus Richard Furie, MD Chief, Division of Rheumatology Northwell Health Professor of Medicine Zucker School of Medicine at Hofstra Northwell Disclosures Nothing to disclose in relationship to this topic Learning Objective 1. Review the classification of neuropsychiatric lupus 2. Describe mechanisms of injury in lupus 3. Discuss specific neuropsychiatric complications of lupus and the approach to treatment

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4/16/2018

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SLE: Neuropsychiatric Lupus

Richard Furie, MDChief, Division of Rheumatology

Northwell HealthProfessor of Medicine

Zucker School of Medicine at Hofstra Northwell

Disclosures

Nothing to disclose in relationship to this topic

Learning Objective

1. Review the classification of neuropsychiatric lupus2. Describe mechanisms of injury in lupus3. Discuss specific neuropsychiatric complications of

lupus and the approach to treatment

4/16/2018

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I Hate the Word Cerebritis

Neuropsychiatric Lupus Syndromes

Central Nervous SystemAcute Confusional State Cognitive DysfunctionMyasthenia Gravis Anxiety DisorderHeadache Aseptic MeningitisNeuropathy, Cranial Movement Disorder (Chorea)Psychosis Cerebrovascular DiseaseMood Disorders Seizures and Seizure DisordersDemyelinating Syndrome

Peripheral Nervous SystemAcute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain-

Barré Syndrome)Myelopathy Mononeuropathy (single/multiplex)Plexopathy Autonomic DisorderPolyneuropathy

ACR Ad Hoc Committee of Neuropsychiatric Lupus Nomenclature. The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes. Arthritis Rheum. 1999;42:599–608

Ab

C’

Mechanisms of Injury in SLE

CNS dysfunction

Apoptosis

Ab

Direct Binding

IC

Kidney

Immune Complex

Ab

CDCC

AHA (cold)

C’

Fc

ADCC

ATP

AHA (warm)

FcR

6

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Mechanisms of Injury in SLE

• Neutrophils• Plasmacytoid dendritic cells• Myeloid dentritic cells• B cells• Plasma cells• T cells • NK cells (cytotoxic)• Macrophages• Endothelial cells

Cells

7

Mechanisms of Injury in SLE

• Thrombosis • Thrombotic microangiopathy• Leukoagglutination

Vasculature

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Neuropsychiatric LupusPathophysiologic Classification

• Vascular

– Atherosclerotic

– Vasculitis

• Small vessel

• Large vessel

– Vasculopathy

• Embolic

• Thrombotic

– Single vessel occlusion

– Multiple vessel occlusion

» Thrombotic microangiopathy

» Leukoagglutination

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Neuropsychiatric LupusPathophysiologic Classification

• Extra-vascular

– Ab-mediated dysfunction

– Cell-mediated injury

– Cytokine-mediated

NP Lupus TreatmentPathophysiology Treatment

• Vascular (occlusion vs hemorrhage)

– Vasculitis steroids, IS

– Vasculopathy

• Thrombotic

– Thrombotic microangiopathy plasmapheresis

eculizumab

– Leukoagglutination steroids

– Single vessel occlusion anticoagulation

• Embolic anticoagulation

• Extra-vascular

– Ab-mediated dysfunction steroids, IS

– Cell-mediated injury steroids, IS

– Cytokine-mediated steroids, IS

Embolic Complications

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Intracardiac Thrombus

Stroke

• Case: 45 y/o F with 8-year history of SLE admitted for chest pain.

PE: possible rub

ECHO:

Valvular Disease

Libman-Sacks Endocarditis

Libman-Sacks verruca: Fibrin, nuclear debris, inflammatory cells, granulation tissue

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Thrombotic Complications

Thrombotic Complications

• Case: 58 y/o F– 30 year history of SLE complicated by AHA

controlled with MMF and rituximab

– Initial visit labs notable for:• Beta-2 glycoprotein I IgG Ab: >150 (<15)

• Anticardiolipin IgG Ab: 120 (<15)

– No history of miscarriage or thrombosis

• Would you advise therapy for primary prevention?

• If so, which medicine?– ASA

– Clopidogrel

– Warfarin

– Prednisone

– Something else?

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• Case continued– Placed on ASA 81 mg per day

• Stroke – Treated with heparin and then warfarin

• What are the data for secondary prevention?

• What is the appropriate INR target?

Preventing the First Clot

• Risk of thrombosis < 5% per year

• Confounded by other factors

• APLASA (Erkan 2007): ASA 81 mg vs placebo

– N=98; f/u 2.3 years

– ASA (3 events); placebo (0)

– ASA did not protect against thrombosis

• ?? ASA for primary prevention ??

• ?? HCQ for primary prevention ??

Preventing the Second Clot

• Retrospective Studies– Warfarin better than ASA– Warfarin HD better than LD

• Prospective Studies– Warfarin Mod Intensity = High Intensity

Targeting a specific INR is easier said than done

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Antithrombotic Treatment

No. Patients

Annualized Event Rate

P Value

None 84 0.29

ASA 70 0.18 0.013

Warfarin INR < 3/ with ASA

67 / 14 0.23 / 0.22 0.27 / 0.53

Warfarin INR > 3/ with ASA

64 / 17 0.015 / 0 <0.001 / <0.001

APS: Secondary PreventionRetrospective Comparison of Antithrombotic Treatments

Khamashta M et al. N Engl J Med. 1995; 332:993-997

OutcomeINR 3.1 - 4.0

(n=56)INR 2.0 - 3.0

(n=58)P Value

RecurrentThrombosis

6 2 0.15

BleedingAny / Major

14 / 3 11 / 4 0.13 / 0.96

APS: Secondary PreventionProspective Comparison of High- and Moderate-Intensity

Warfarin Groups

Crowther MA et al. N Engl J Med. 2003; 349:113-8

Treatment of Warfarin-Refractory Disease

• Anti-platelet agents– ASA, clopidigrel

• Anticoagulants– Heparins– Direct thrombin inhibitors

• Hydroxychloroquine• Steroids• Cyclophosphamide• Rituximab• Eculizumab• Plasmapheresis• IVIG

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Thrombotic Microangiopathy

Medical History

27 year old female with a 5 year history of SLE was admitted to the hospital because of confusion and fever.

Stupor turned to coma

Thrombotic Microangiopathy

Laboratory Results

Hb 6.8 g/dLPlt 12 K/uL

PT / PTT 12 / 66 secondsDIC screen normalLAC positive

Creatinine 1.9 mg/dL

LDHHaptoglobinReticulocyte countDirect Coombs testBlood smear

1200not detectable15.5 %negative

Thrombotic Microangiopathy

Treatment: Plasmapheresis: complete response within 1 week

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Thrombotic Microangiopathy1

1. Thrombocytopenia2. Microangiopathic hemolytic anemia (schistocytes)3. Organ dysfunction (kidney; brain; heart; GB)

Issues:1. Relationship to aHUS, to CAPS2. Role of eculizumab in treating TMA3. Need for chronic anticoagulation

Thrombotic Microangiopathy

1Symmers W. Br Med J, 2 (1952), pp. 897-903

SLE/APS Vasculopathy

Venous thrombosis (large vessel)

Thrombotic Microangiopathy

Occlusive Arteriopathy

Venous Thrombosis small ; large vessel

Headache

• Case: 28 y/o F with a 4-year history of SLE complicated by rash and Raynauds. She was admitted because of acute headache

PE: unremarkable

Labs: unremarkable except for RNP Ab

Imaging studies: normal

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Differential Diagnosis

1.Stroke2.Venous sinus thrombosis3. Intracranial hemorrhage4.Meningitis5.Aseptic meningtis (NSAIDs)6.Central nervous system lupus

Headache in SLE

SLEDAI definition:

"severe, persistent headache; may be migrainous, but must be nonresponsive to narcotic analgesia”

Epratuzumab (EMBLEMTM) and Lupus Headache

• 227 patients in dose-ranging study

• At baseline:– 15 headache (8 points)

Petri et al. ACR 2011.

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Headache in SLE

Prevalence:

All headache: 33-78%Migraine: 32%Tension: 24%

Davey R et al. Cephalagia 2008; Davey R et al. Arthritis Rheum 2007

Movement Disorders

Case: A 24 y/o F with steroid-responsivethrombocytopenia was referred for evaluationof possible SLE. She had no otherinflammatory manifestations. During theinterview, she had spontaneous flailingmovements of the right wrist as well as choreicmovements of the fingers of the right hand.

Livedo Reticularis

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Movement DisordersPET Scan

Furie R et al. Neurology 1994. 44, 2197–2199.

Chorea

• Associated with SLE and with PAPS• Striatal hypermetabolism• Pathogenesis unknown

• Microvascular occlusion• aPL binding to striatal tissue

Peripheral Neuropathies(contrasting cases)

Medical Histories1. A 27 y/o F with an 8-year history of SLE (arthritis, DNA Ab) on HCQ developed a right foot drop. She had a long recovery on steroids and MMF.

2. A 29 y/o F with a 4-year history of SLE (rash, SSA Ab) has been plagued by progressive bilateral LE dysesthesias despite gabapentin.

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Peripheral Neuropathies in 4924 Chinese SLE Patients

Overall frequency: 1.5%

Wang X et al. Medicine (Baltimore). 2015 Mar; 94(11): e625.

Nerve Fiber Classification

• Large nerve fibers– A-alpha fibers

• Myelinated

• Mediate motor strength

– A-beta fibers• Mediate vibratory and touch sensation

Tavee J, Zhou L. Clev Clin J Med 2009; 76: 297-305

• Medium-sized fibers– A-gamma fibers

• Myelinated

• Innervate muscle spindles

Nerve Fiber Classification

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• Small fibers– Myelinated A-delta fibers

– Unmyelinated C fibers• Innervate skin (somatic fibers)

• Innervate involuntary muscles, including cardiac and smooth muscles (autonomic fibers)

• Mediate pain, thermal sensation, and autonomic function

Nerve Fiber Classification

Epidermal Nerve Fiber Density

Courtesy of Bruce Blake; copyright Therapath

Normal NFD Abnormal NFD

Small Fiber Neuropathy

• Symptoms and signs– Paresthesias, dysesthesias, autonomic

dysfunction

– Distal, symmetric (“stocking-glove”)

– Allodynia, hyperalgesia, hypoalgesia

– Strength, reflexes, proprioception preserved

• Normal EMG/NCS

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Small Fiber Neuropathy

• Skin biopsy: measure intra-epidermal nerve fiber density (few labs perform)

• Nerve biopsy not justified

• Therapy– Gabapentin, pregabalin

– Amitriptyline, nortriptyline

– Lidocaine patch

– Analgesics

– ? Role of steroids, IS

Complications of Treatment

• Reversible Posterior Leukoencephalopathy Syndrome• Progressive Multifocal Leukoencephalopathy• Peripheral neuropathy

• Thalidomide

Reversible Posterior Leukoencephalopathy Syndrome

• Background– 1996: 15 cases reported (Hinchey J et al. NEJM 1996)

• Clinical Presentation– Headache, altered mental status– Hypertension– Seizures, cortical blindness

• Causes– Malignant hypertension (4), eclampsia (3)– Tacrolimus or cyclosporin (7), interferon (1)– Hypercalcemia

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Reversible Posterior Leukoencephalopathy Syndrome

• Diagnosis– MRI: extensive white matter abnormalities (edema) in

posterior lobes• Treatment

– Correct the cause

Hinchey J et al. N Engl J Med 1996;334:494-500

MRI Scans of Patient 11

Progressive Multifocal Leukoencephalopathy

• JC virus

– Polyoma virus: DNA virus

– 40 - 60% of population have Ab to JCV

– Demyelination destroys subcortical white matter (parietal/occipital lobes)

• Clinical presentation

– Weakness, paralysis, vision loss, impaired speech, and cognitive deterioration

– Rapidly progressive

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Progressive Multifocal Leukoencephalopathy

• Diagnosis– MRI:

• Multifocal hyperintense lesions on T2W images

• Non-enhancing with IV contrast

• Cortical white matter, but brainstem and cerebellum may be involved

– Test for JC virus DNA in CSF or brain bx

Progressive Multifocal Leukoencephalopathy

• Prevalence in Autoimmune Rheumatic Diseases1

– 34 cases in FDA AE Reporting System DB

– SLE (17); RA (10); Vasculitis (4); DM (3)

– 15 treated with > 1 biologic• Rituximab (14); 10 on concomitant IS

• TNF inhibitor (6)

– 19 treated with non-biologic IS• 14 had received an alkylating agent

1Molloy E and Calabrese L; Arthritis Rheum 2012

Progressive Multifocal Leukoencephalopathy

• Prevalence in SLE1

– 17 cases in FDA AE Reporting System DB• Rituximab (5);

– 5 on IS; 3 had received alkylating agents

• Non-biologic agents (12)– 10 had received an alkylating agent

– 2 on IS alone (MTX; AZA)

1Molloy E and Calabrese L; Arthritis Rheum 2012

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Progressive Multifocal Leukoencephalopathy

• Risk factors for PML (natalizumab-treatment) 1

– 212 cases in nearly 100,000 treated patients

– Risk:• Natalizumab: 2.1 cases/1000)

– Seronegative patients: 0.09 cases/1000

– Seropositive and IS use and natalizumab for 2-4 years: 11 cases/1000

– Should we be evaluating JC serologies?

1Bloomgren G et al. N Engl J Med 2012

I Need Help With…

1. TIA: 47 y/o F chronically serologically active (low C’, high DNA Ab) and leukopenia on HCQ with acute RUE weakness. History of migraine.

CT negativeReceived TPAMRI/MRA normal, TEE normalaPL Ab negative

Treatment: ASA, clopidogrel? Immunosuppressives

I Need Help With…

2. Psychosis: 42 y/o F with 6-year history of SLE consisting of arthritis treated with MTX. Labs notable for mild elevation of DNA Ab. She became acutely psychotic but responded to haloperidol. She has continued to have intermittent psychotic episodes.

? Immunosuppressives

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I Need Help With…

3. Carotid stenosis/stroke: 37 y/o F with SLE (DLE, arthritis, Raynauds) and APS (DVT) chronically treated with steroids, HCQ, MMF, and rivaroxaban. She has been serologically active (Sm Ab) and aPL Ab positive.

She had an acute cerebral infarct resulting in right hemiplegia

MRI: left MCA and PCA territory infarctsAngio: severe left carotid stenosis (Moya-Moya like)

Treatment:1. Left superficial temporal artery to MCA microanastomosis2. Warfarin3. ? Immunosuppressives

I Need Help With…

4. Transverse myelitis5. Fatigue6. Cognitive dysfunction7. Psychosis8. Peripheral sensory neuropathies

NP Lupus TreatmentPathophysiology Treatment

• Vascular (occlusion vs hemorrhage)

– Vasculitis steroids, IS

– Vasculopathy

• Thrombotic

– Thrombotic microangiopathy plasmapheresis

eculizumab

– Leukoagglutination steroids

– Single vessel occlusion anticoagulation

• Embolic anticoagulation

• Extra-vascular

– Ab-mediated dysfunction steroids, IS

– Cell-mediated injury steroids, IS

– Cytokine-mediated steroids, IS

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Thank You

Questions?

Answers?

more questions than answers