Systemic Lupus Erythematosus: A Review and Update 4th Annual Advanced Pharmacology Conference Innovation and Advancement for the Future April 15, 2011 INTEGRIS Baptist Medical Center Joe Rawdon, MS RN ACNS-BC Objectives • At the conclusion of this activity, participants should be able to: – Identify key concepts in the pathogenesis, diagnosis, and symptoms of Systemic Lupus Erythematosus. – Discuss matters related to sub-optimal responses or failures of agents used in the treatment of Systemic Lupus Erythematosus. – Describe the basis for standard-of-care therapies including dosing, efficacy, safety and tolerability profiles. – Outline effective strategies for disease management using current therapies. Types of Lupus • • • • Drug-Induced Lupus (DILE) Cutaneous Lupus Erythematosus Systemic Lupus Erythematosus (SLE) Overlap Syndromes – UCTD, Rheumatoid Arthritis, Sjogren’s Syndrome, APLS, Polymyositis, Dermatomyositis, Scleroderma, ITP Drug-Induced Lupus • A side effect of certain medications: Hydralazine, Isoniazid, Methyldopa, Minocycline, Procainamide, Quinidine, Chlorpromizine • Symptoms include rash, joint and muscle pain, arthritis, flu-like symptoms, inflammation of heart/lungs. • Symptoms resolve when medication is stopped D T M WHAT CAUSES LUPUS? B complement Systemic LUPUS Brain Eyes Parotid glands Thyroid Heart, Lungs Serous linings of Heart, Lungs, GI tract Kidneys Liver Spleen Special Complications of Pregnancy Joints Blood Vessels and Blood Proteins Inflammation vs. Coagulation Inflammatory multisystem disease Skin Highly variable from patient to patient Waxing and Waning Significant constitutional symptoms Associated with characteristic autoantibodies Serious Sequelae * early: disease activity late: therapy complications and disease damage Antibiotics: 20th Century Miracle Drugs Lupus • Not an Infection • There is no cure for SLE • But there is one small population with lupus we can cure! Congenic Dissection of Lupus Pathogenesis 1 3 2 NZM2410 Lupus-prone B6 Lupus-resistant 1 B6.Sle1 2 B6.Sle2 3 B6.Sle3 Loss in immune B cell hyperactivity T cell activation and tolerance to chromatin decreased apoptosis Mohan et al., J. Immunology, 1998 Mohan C, et al. J Clin Invest. 1998;101:1362-1372. Re-assembly of Lupus Pathogenesis by various combinations of congenic intervals 1 2 3 >90% Fatal lupus B6.Sle1,2,3 1 B6.Sle1 2 1 2 ~15% Fatal lupus Re-assembly of congenic intervals B6.Sle2 3 B6.Sle3 Morel et al. PNAS 97:6670-6675, 2000 B6.Sle1,2 1 3 ~50% Fatal lupus B6.Sle1,3 2 3 B6.Sle2,3 0% Fatal lupus HUMANS ARE NOT MICE 20 12 IL10 15 IL8 10 8 6 10 4 Bioplex Units 5 2 0 0 P1 P2 P3 P4 P5 300 250 IFN ALPHA 200 150 100 50 0 P1 P2 P3 P4 P5 P1 P2 P3 P4 P5 P6 P6 P6 160 140 120 100 80 60 40 20 0 TNF ALPHA P1 P2 P3 P4 P5 P6 Six Lupus Patients with “Arthritis” D INF alpha B1 Make antibodies IFN- Activate other cells Make inflammatory Proteins B T Adapted from: Ramanujam M, Davidson A. Arthritis Research and Therapy 2004; 197 IMPROVED SURVIVAL IN SLE: 1955-1990 % The Major Difference has been due to Steroids YEARS Wallace in Arthr and Allied Cond, 13th Ed V2, p1319 Koopman, ed Epidemiologic Data Based on SLE Cause of Death TLR inhibitors D INF alpha inhibitors Riquent, Edritide IFN- B Anti IL6 Cellcept RITUXIMAB Ocrelizumab Epratuzumab IDEC 131 Biogen product ABATACEPT Anti-ICOS BENLYSTA, Other BLys and BLys/April inhibitors TNF inhibitors T Treatment: Medications • Non‐steroidal anti‐inflammatory drugs (NSAIDs) • Topical steroids • Systemic steroids • Antimalarial drugs •Plaquenil (hydroxychloroquine) • Aralen (chloroquine) •Atabrine (quinicrine) Plaquenil (hydroxychloroquine) • Used to treat malaria, lupus, and inflammatory arthritis • Decreases autoimmune activity • Helpful for rash, arthritis, and fatigue • Typical dose is 200mg twice a day • Baseline eye exam and exam every 6‐12 months • GI upset is common • May take months for full effect Treatment: Medications Disease Modifying/Cytotoxic Agents •Imuran (azathioprine) •Cellcept (mycophenolate mofetil) •Rheumatrex or Trexall (methotrexate) •Arava (leflunomide) •Cytoxan (cyclophosphamide) •Sandimmune and Neoral (cyclosprine) BENLYSTA (belimumab) • recognize and inhibit the biological activity of B-lymphocyte stimulator (BLyS) • 10 mg/kg at 2-week intervals for the first 3 doses and at 4-week intervals thereafter • IV over 1 hour, no premedication necessary SLE Classification: ACR Criteria 8 CLINICAL Malar rash (rash on cheeks that spares the naso-labial folds) Discoid rash (anywhere on body) Photosensitivity Oral or nasal ulcers Arthritis (nonerosive arthritis of two or more peripheral joints, with tenderness, swelling, or effusion) Serositis (Pleurisy or pericarditis) Renal Disorder (0.5 g protein in urine or cellular casts) Neurologic Disorder (seizures or psychosis) Definite diagnosis of SLE: 4 of 11 criteria present SLE Classification: ACR Criteria 3 LABORATORY Low blood cell counts Leukopenia (<4000/ µl) Lymphopenia (<1500/µl) Hemolytic anemia Thrombocytopenia (<100,000/µl) Antinuclear antibodies Specific autoantibodies anti-DNA, anti-Sm, or antiphospholipid family Definite diagnosis of SLE: 4 of 11 criteria present Autoantibodies in SLE • ANA • • • • • Seen in 95% of SLE Not specific for SLE Seen in many inflammatory, infectious, and neoplastic diseases Seen in 5% to 30% of normal persons Common is people over 60, liver disease, changes frequently from lab to lab. ANA Titers in Normal Individuals with no clinical consequence 1:40 20-30% 1:80 10-12% 1:160 5% 1:320 3% Autoantibodies in SLE • Anti-ds DNA • • • • Seen as high as 60% of populations with SLE Highly specific for SLE Low titer rarely seen in other inflammatory conditions Strongest clinical association is with nephritis • Anti-Sm (Smith) • • Seen in 10% to 30% of SLE patients Highly specific for SLE WHAT TESTS HELP? • CBC – Leukopenia, lymphopenia, neutropenia, – Thrombocytopenia – Coombs + LHD (hemolytic anemia) • CHEM SCREEN – Renal (BUN, creatinine, albumin) – Hepatitis (SGOT/SGPT) • URINALYSIS – Renal, urine prot/creat ratio WHAT TESTS HELP? • ANA – Ro and La – Sm and RNP – Anti-dsDNA (anti-ssDNA, anti-histone) • ANTIBODIES TO TARGET ORGANS – Anti-phospholipid family – white blood cells, brain, kidneys, placenta THE COMPLEMENT STORY Low C3 Low C4 Low CH50 Low C2 Y YY Systemic Lupus Erythematosus • Clinical symptoms related to the degree of inflammation in various organs • • • • • • • Skin and mucous membranes Arthritis or arthralgia Hematologic involvement Kidneys Fevers 30 - 60% 55 - 90% 50% 5% 5% ACR recommends early referral after 1st signs suggesting SLE. Minimum recommended follow-up is every 3 months. Disease Tracking Disease Tracking Lupus and pregnancy • Fertility of lupus patients is similar to the general population • Patients with lupus are considered high-risk • Preferred - Lupus should be under control (ideally for 6 months) before getting pregnant • Pregnancy does not increase the risk of lupus flares • Neonatal lupus occurs in 1-2% of pregnancies mild malar rash to heart block •Ro and La Antibodies •ACL antibodies – •Hypertension, edema, pre-eclampsia, miscarriage, early delivery, low birth weight • Some medications taken for lupus are probably safe to take during pregnancy OC-SELENA trial http://www.nejm.org/doi/full/10.1056/NEJMoa051135 When to Consider a Diagnosis of SLE •Women of childbearing age who present with: • • • • • Constitutional symptoms of fever, weight loss, malaise, and severe fatigue Skin rash and/or stomatitis Arthritis – most common presenting feature Renal disease Cytopenias When to Consider a Diagnosis of SLE • Genetic predisposition – Most cases are sporadic but may cluster in families – 5-12% have family member with SLE – Lupus is polygenic (more that one gene responsible) • Although 90% of patients are female, SLE can be seen at any age in either sex • 1,000,000 to 2,000,000 Americans have lupus (.012-.05% of the population) • More common in African American and Asian populations The End….or other slides if there’s time. Pericardial Involvement in SLE 25% incidence of evident pericarditis 50% incidence of pericardial effusion 80% incidence of pericardial abn at autopsy Libman Sacks Endocarditis in up to 43% of patients by TEE (nonbacterial thrombotic endocarditis) Prevalence of Lupus vs Other Diseases ( in USA x 1000) JDRF Society Nat Inst Neur Dis and Stroke Lupus Foundation of America Susan Komen Foundation Disease-Specific Funding per Year (normalized to patient numbers) Millions/year/pt www.nih.gov.news Lupus in People From Different Genetic Backgrounds: Risk is not Destiny 35 30 25 Caucasian n=185 Native Amer n=40 African Amer n=67 20 15 10 5 0 anti- discoid dsDNA renal SLE Genes: Ethnic Differences GENE CAUC AFR references TNF alpha X Hum Immunol 65:622 16q12-13 X X X E J Hum Gen 12:668 12q24 FcgRIIIa FcgRIIa 11p13 (discoid) NO synth prom FasL 1q23 Am J Hum Gen 74:73 Rheum (Ox) 42:446 X X X X J Clin Invest 95:1348 J Inv Derm Sym 9:64 J Rheum 30:60 J Immun 170:132