Systemic Lupus Erythematosus
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1 Systemic Lupus Erythematosus Marc C. Hochberg, MD, MPH Professor of Medicine and Head, Division of Rheumatology University of Maryland School of Medicine
2 CASE: HISTORY A 26-year-old woman is seen for migratory polyarthritis of 6 months duration. She also reports some fatigue and a photosensitive skin rash. ROS is positive for: Patchy hair loss 4 months ago that regrew Aphthous-like mouth ulcers every 4 to 6 weeks A diagnosis of walking pneumonia made last month based on symptoms of pleuritic chest pain Raynaud s phenomenon
3 CASE: PHYSICAL EXAMINATION Mild synovitis over the MCP and PIP joints of both hands Rash over her face, legs, and trunk Mouth ulcers Cool pale fingertips without digital ulcers or pitting scars
4 CASE: LABORATORY DATA Hgb 11.1 gm/dl; WBC 3,600/mm 3 ; Platelet count 110,000/mm 3 ; ESR 33 mm/hr UA 3+ protein; 0 RBCs; no casts CMP normal x serum albumen = 2.5 gm/dl
5 APPROACH TO MULTISYSTEM INFLAMMATORY DISEASE How should you approach a patient who presents with multisystem inflammatory disease?
6 QUESTIONS TO BE ADDRESSED When do you think of the diagnosis of lupus? How do you evaluate a patient for lupus? How do you initially manage a patient with lupus? When do you refer a patient with lupus to a rheumatologist?
7 SYSTEMIC LUPUS ERYTHEMATOSUS Inflammatory multisystem disease primarily seen in young women Highly variable course and prognosis Often accompanied by significant constitutional symptoms Associated with characteristic autoantibodies
8 WHEN TO CONSIDER A DIAGNOSIS OF SLE Usually seen in women of childbearing age with: Constitutional symptoms of fever, weight loss, malaise, and severe fatigue Photosensitive skin rash Stomatitis Nondeforming polyarthritis Renal disease Cytopenias NB: SLE can be seen at any age in either sex
9 DESCRIPTIVE EPIDEMIOLOGY One of the most common autoimmune diseases Prevalence ~ 1 : 1000 in women of child-bearing age Mean age at diagnosis ~ 30 years Vast majority of cases diagnosed between ages 15 and 45 years Female : male ratio 9 : 1. African-American and Hispanic women have a 3-5 fold greater incidence compared to whites Associated with excess mortality Early mortality due to active disease and infection Late mortality due to cardiovascular and end-stage renal disease
10 SLE: PROTOTYPICAL SYSTEMIC AUTOIMMUNE DISEASE Multiorgan involvement Variable presentation Course characterized by flare and remissions Characterized by autoabs against nuclear, cytoplasmic and cell surface components
11 SYSTEMIC LUPUS ERYTHEMATOSUS CLINICAL SYMPTOMS RELATED TO THE DEGREE OF IMMUNE- MEDIATED INFLAMMATION IN VARIOUS ORGANS Skin and mucous membranes Synovium (joints) Serosal membranes Kidneys Central nervous system Lungs Heart Hematopoietic system
12 ACR CLASSIFICATION CRITERIA OF SLE 1. Malar Rash 2. Discoid rash 3. Photosensitivity 4. Oral ulcers 5. Arthritis 6. Serositis 7. Renal disorder 8. Neurologic disorder o Seizures o Organic psychosis 9. Hematologic disorder o Hemolytic anemia o Leukopenia (<4000/mm3) x 2 o Lymphopenia (<1500/mm3) x 2 o Thrombocytopenia (< 100,000) 10. Immunologic disorder o Anti-ds DNA OR o Anti-Sm OR o Antiphospholipid antibody 11. Abnormal titer of ANA Sensitivity/Specificity: 86%/93%
13 1. MALAR RASH Erythema on the malar, nose and chin areas Worsened by sun
14 2. DISCOID LUPUS Coin and round-shaped erythematous plaques with adherent scale Hyperpigmentation at the periphery and depressed central scarring, atrophy and depigmentation
15 WIDESPREAD DISCOID LESIONS
16 3. PHOTOSENSITIVITY SUBACUTE CUTANEOUS LUPUS The most photosensitive lupus rash, associated with anti-ro (SSA) antibodies
17 4. ORAL ULCERS: BULLOUS LESIONS, PALATE
18 5. SLE -ARTHRITIS Nonerosive, transitory arthritis usually involving small joints of hands; periarticular laxity induces reversible swan neck deformities (Jaccoud s arthopathy)
19 6. SEROSITIS Pleuritis (pleural effusion) and/or pericarditis
20 7. RENAL INVOLVEMENT Proteinuria and/or cellular casts
21 WHO CLASSIFICATION OF LUPUS NEPHRITIS CLASS I Minimal mesangial LN (Mesangial immune deposits seen by IF) CLASS II Mesangial proliferative LN CLASS III Focal proliferative LN (<50% of glomeruli with focal subendothelial immune deposits) CLASS IV Diffuse proliferative LN (> 50% of glomeruli with subendothelial immune deposits) CLASS V Membranous LN (Global or segmental subepithelial deposits) CLASS VI Advanced sclerosing LN (> 90% of glomeruli globally sclerosed)
22 8. NEUROPSYCHIATRIC SLE CENTRAL NERVOUS SYSTEM Aseptic meningitis Cerebrovascular disease Demyelinating syndrome/ transverse myelopathy Headache Movement disorder (chorea) Organic psychosis Seizure disorder Anxiety or mood disorder Cognitive dysfunction PERIPHERAL NERVOUS SYSTEM Guillain - Barre syndrome Autonomic disorder Mononeuropathy, single/multiplex Myasthenia Gravis Neuropathy, cranial Plexopathy Polyneuropathy
23 9. HEMATOLOGIC Hemolytic anemia Leukopenia (<4000/mm 3 ) Lymphopenia (<1500/mm 3 ) Thrombocytopenia (< 100,000/mm 3 )
24 AUTOANTIBODIES
25 AUTOANTIBODIES Heterogenous antibodies develop over time Directed against: Nuclear antigens Nucleic acids/proteins: anti-dsdna anti-histone Extractable nuclear antigens: anti-sm, anti-nrnp anti-ss-a(ro), anti-ssb (La) Cell surface antigens Red blood cells, lymphocytes, thrombocytes Extracellular components Phosphoprotein complexes
26 AUTOANTIBODIES IN SLE ANA Seen in >95% of patients Not specific for SLE Seen in many inflammatory, infectious, and neoplastic diseases Seen in 5% to 15% of normal persons
27 AUTOANTIBODIES IN SLE Anti-ds DNA Seen in 50-60% of patients with SLE Highly specific for SLE Strongest clinical association is with nephritis Anti-Sm (Smith) Seen in 10-30% of SLE patients Highly specific for SLE Controversial association with CNS disease
28 ANTI-PHOSPHOLIPID (APL) ANTIBODIES Autoantibodies against phospholipids and/or phospholipid-binding proteins (β-2 glicoprotein I) Detection: ELISA (anticardiolipin abs) Biologic false positive test for syphilis (anticardiolipin ab cross-react on VDRL substrate) In vitro prolongation of PTT (lupus anticoagulant) In vivo effect: thrombosis (arterial or venous) pregnancy loss
29 SLICC REVISION OF THE ACR CLASSIFICATION CRITERIA: BACK TO THE FUTURE
30 CLINICAL CRITERIA 1. Acute/subacute cutaneous lupus 2. Chronic cutaneous lupus 3. Oral ulcers 4. Nonscarring alopecia (diffuse thinning or hair fragility with visible broken hairs) 5. Synovitis ( 2 joints) OR joint tenderness and AM stiffness > 30 minutes 6. Serositis 7. Renal: >500 mg protein/24 hours OR red blood cell casts 8. Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, acute confusional state 9. Hemolytic anemia 10. Leukopenia (<4,000/mm 3 ) OR lymphopenia (<1,000/mm 3 ) 11. Thrombocytopenia (<100,000/mm 3 ) Petri M et al. Arthritis Rheum 2012;64(8):2677
31 IMMUNOLOGIC CRITERIA 1. ANA 2. Anti-dsDNA antibody 3. Anti-Sm antibody 4. Antiphospholipid antibody lupus anticoagulant false-positive test result for syphilis anticardiolipin antibody (IgA, IgG, or IgM) at least 2x over normal anti β2-glycoprotein I 5. Low complement level Either low C3, low C4 or low CH50 6. Direct Coombs' test in the absence of hemolytic anemia Petri M et al. Arthritis Rheum 2012;64(8):2677
32 FOR DIAGNOSIS Biopsy-proven lupus nephritis with ANA or anti-dsdna OR Four criteria (at least one clinical and one immunologic) Performance of SLICC vs ACR Criteria: Better sensitivity (97% vs. 83%) No difference in specificity (96% vs. 86%) No difference in misclassifications (74 vs 62) Clinically more relevant: important in clinical trials and longitudinal observational studies Petri M et al. Arthritis & rheumatism, 2012, 64, 8, 2677
33 DISEASE COURSE AND TREATMENT
34 COURSE AND PROGNOSIS Characterized by flares and remissions Biomarkers associated with flares: Increased dsdna titer Low C3, C4 levels due to complement activation by immune complexes Mortality: 3-5 times greater than general population Causes of death: Active disease: nephritis, vasculitis, organ failure Complications of immunosuppressive therapy: infections Late sequelae of glucocorticoid therapy: accelerated atherosclerosis (MI, stroke)
35 REASONS TO REFER A PATIENT TO A RHEUMATOLOGY Confirm the diagnosis Recommend a treatment plan for patients with mild disease Provide ongoing subspecialty care for patients with moderate and severe disease as a partnership in the holistic management of the patient 58
36 TREATMENT MILD DISEASE
37 HYDROXYCHLOROQUINE: OLD REMEDY AND NEW FAVORITE
38 HYDROXYCHLOROQUINE BENEFITS Reduction in flares Reduction in organ damage Reduction in lipids Reduction in thrombosis Improvement in survival Lower odds of persistent LAC and/or apl Improves rates of MMF response in LN Reduces risk of recurrent cardiac manifestations of neonatal lupus Ruiz-Irastorza G et al. Ann Rheum Dis Jan; 69(1):20; Tsakomas E et al. The Canadian Hydroxychloroquine Study Group. NEJM 1991;324: Kasitanon N Lupus.2006:15(6):366
39 TREATMENT MODERATE - SEVERE DISEASE Manifestations of SLE Agents Constitutional Musculoskeletal Serositis Cutaneous Major Organ High Dose Corticosteroids Prednisone 1 mg/kg/day (1 g IV methylprednisolone) Immunosuppressives Azathioprine Cyclophophamide Methotrexate Mycophenylate mofetil Cyclosporine
40 SIMPLE TASKS Simple Tasks is a public awareness campaign by the American College of Rheumatology that strives to increase awareness of rheumatic diseases and the work of rheumatologists. Stop by the Simple Tasks booth #211: Get your own copy of Clinical Cases: Lupus, featuring another example case study Learn more about the simple tasks that can become impossible for patients because of rheumatic disease
41 THANK YOU
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