SLE: Neuropsychiatric Lupus. Disclosures. Learning Objective 4/16/2018

Transcription

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 1

2 I Hate the Word Cerebritis Neuropsychiatric Lupus Syndromes Central Nervous System Acute Confusional State Cognitive Dysfunction Myasthenia Gravis Anxiety Disorder Headache Aseptic Meningitis Neuropathy, Cranial Movement Disorder (Chorea) Psychosis Cerebrovascular Disease Mood Disorders Seizures and Seizure Disorders Demyelinating Syndrome Peripheral Nervous System Acute Inflammatory Demyelinating Polyradiculoneuropathy (Guillain- Barré Syndrome) Myelopathy Mononeuropathy (single/multiplex) Plexopathy Autonomic Disorder Polyneuropathy 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: Mechanisms of Injury in SLE Ab Direct Binding Immune Complex ADCC CDCC FcR Ab Ab IC Fc C CNS dysfunction Apoptosis C ATP AHA (warm) AHA (cold) Kidney 6 2

3 Mechanisms of Injury in SLE Cells Neutrophils Plasmacytoid dendritic cells Myeloid dentritic cells B cells Plasma cells T cells NK cells (cytotoxic) Macrophages Endothelial cells 7 Mechanisms of Injury in SLE Vasculature Thrombosis Thrombotic microangiopathy Leukoagglutination 8 Neuropsychiatric Lupus Pathophysiologic Classification Vascular Atherosclerotic Vasculitis Small vessel Large vessel Vasculopathy Embolic Thrombotic Single vessel occlusion Multiple vessel occlusion» Thrombotic microangiopathy» Leukoagglutination 3

4 Neuropsychiatric Lupus Pathophysiologic Classification Extra-vascular Ab-mediated dysfunction Cell-mediated injury Cytokine-mediated NP Lupus Treatment Pathophysiology 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 4

5 Case: 45 y/o F with 8- year history of SLE admitted for chest pain. PE: possible rub ECHO: Intracardiac Thrombus Stroke Valvular Disease Libman-Sacks Endocarditis Libman-Sacks verruca: Fibrin, nuclear debris, inflammatory cells, granulation tissue 5

6 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? 6

7 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 7

8 APS: Secondary Prevention Retrospective Comparison of Antithrombotic Treatments Antithrombotic Treatment No. Patients Annualized Event Rate None P Value ASA Warfarin INR < 3 / with ASA Warfarin INR > 3 / with ASA 67 / / / / / 0 <0.001 / <0.001 Khamashta M et al. N Engl J Med. 1995; 332: APS: Secondary Prevention Prospective Comparison of High- and Moderate-Intensity Warfarin Groups Outcome INR (n=56) INR (n=58) P Value Recurrent Thrombosis Bleeding Any / Major 14 / 3 11 / / 0.96 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 8

9 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 Plt PT/PTT DIC screen LAC Creatinine 6.8 g/dl 12 K/uL 12/66seconds normal positive 1.9 mg/dl Thrombotic Microangiopathy LDH Haptoglobin Reticulocyte count Direct Coombs test Blood smear 1200 not detectable 15.5 % negative Treatment: Plasmapheresis: complete response within 1 week 9

10 Thrombotic Microangiopathy Thrombotic Microangiopathy 1 1. Thrombocytopenia 2. Microangiopathic hemolytic anemia (schistocytes) 3. Organ dysfunction (kidney; brain; heart; GB) Issues: 1. Relationship to ahus, to CAPS 2. Role of eculizumab in treating TMA 3. Need for chronic anticoagulation 1 Symmers W. Br Med J, 2 (1952), pp SLE/APS Vasculopathy Venous thrombosis (large vessel) Occlusive Arteriopathy Thrombotic Microangiopathy 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 10

11 Differential Diagnosis 1. Stroke 2. Venous sinus thrombosis 3. Intracranial hemorrhage 4. Meningitis 5. 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 (EMBLEM TM ) and Lupus Headache 227 patients in dose-ranging study At baseline: 15 headache (8 points) Petri et al. ACR

12 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-responsive thrombocytopenia was referred for evaluation of possible SLE. She had no other inflammatory manifestations. During the interview, she had spontaneous flailing movements of the right wrist as well as choreic movements of the fingers of the right hand. Livedo Reticularis 12

13 Movement Disorders PET Scan Furie R et al. Neurology , Chorea Associated with SLE and with PAPS Striatal hypermetabolism Pathogenesis unknown Microvascular occlusion apl binding to striatal tissue Peripheral Neuropathies (contrasting cases) Medical Histories 1. 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. 13

14 Peripheral Neuropathies in 4924 Chinese SLE Patients Overall frequency: 1.5% Wang X et al. Medicine (Baltimore) 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: Nerve Fiber Classification Medium-sized fibers A-gamma fibers Myelinated Innervate muscle spindles 14

15 Nerve Fiber Classification 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 Epidermal Nerve Fiber Density Normal NFD Abnormal NFD Courtesy of Bruce Blake; copyright Therapath Small Fiber Neuropathy Symptoms and signs Paresthesias, dysesthesias, autonomic dysfunction Distal, symmetric ( stocking-glove ) Allodynia, hyperalgesia, hypoalgesia Strength, reflexes, proprioception preserved Normal EMG/NCS 15

16 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 16

17 Reversible Posterior Leukoencephalopathy Syndrome Diagnosis MRI: extensive white matter abnormalities (edema) in posterior lobes Treatment Correct the cause MRI Scans of Patient 11 Hinchey J et al. N Engl J Med 1996;334: 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 17

18 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 Diseases 1 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 1 Molloy E and Calabrese L; Arthritis Rheum 2012 Progressive Multifocal Leukoencephalopathy Prevalence in SLE 1 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) 1 Molloy E and Calabrese L; Arthritis Rheum

19 Progressive Multifocal Leukoencephalopathy Risk factors for PML (natalizumab-treatment) 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? 1 Bloomgren 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 negative Received TPA MRI/MRA normal, TEE normal apl 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 19

20 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 infarcts Angio: severe left carotid stenosis (Moya-Moya like) Treatment: 1. Left superficial temporal artery to MCA microanastomosis 2. Warfarin 3.? Immunosuppressives I Need Help With 4. Transverse myelitis 5. Fatigue 6. Cognitive dysfunction 7. Psychosis 8. Peripheral sensory neuropathies NP Lupus Treatment Pathophysiology 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 20

21 Thank You Questions? Answers? more questions than answers 21