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Systemic Lupus Erythematosus Emilio B. Gonzlez, MD Professor and Director, Rheumatology UTMB May 18 th, 2010 Slide 2 Systemic Lupus Erythematosus A chronic inflammatory systemic autoimmune disease of unknown etiology characterized by polyclonal B- cell activation and abnormal autoantibodies Slide 3 SLE Epidemiology and Genetics Incidence: 1 in 1,000 -10,000 Female to male ratio: 9-1 More common in African-Americans but it affects all races Mean age of onset: 28 years Positive family history in 10 -15% of patients Monozygotic twins exhibit a greater rate of concordance (24%) than dizygotic twins (1-3%) Several complement deficiencies associated with SLE: C1q, C1r, C1s, C4, C2, C1 inhibitor deficiency, CR1 receptor deficiency Slide 4 Immunogenetics Increased Risk for SLE in: HLA-DR2 (anti-DNA Abs) HLA-DR3 (anti-Ro Abs) Null alleles at C2 and C4 loci SLE may be transmitted in an autosomal dominant pattern (family studies) Slide 5 SLE Genetic Susceptibility MHC Related HLA-DR1, 2, 3, 4 Alleles of HLA-DRB1, IRF5, and STAT4 C2 - C4 deficiency TNF- polymorphisms Not MHC Related C1q deficiency (rare but highest risk) Chromosome 1 region 1q41-43 (PARP), region 1q23 (FcRIIA, FcRIIIA) IL-10, IL-6 and MBL polymorphisms Chromosome 8.p23.1: reduced expression of BLK and increased expression of C8orf13 (B cell tyrosine kinase), chromosome 16p11.22: integrin genes IGAM-ITGAX B cell gene BANK1 X chromosome-linked gene IRAK1 Slide 6 Slide 7 1982 ACR (Revised 1997) SLE Classification Criteria 1. Malar (butterfly) rash 2. Discoid lesions 3. Photosensitivity 4. Oral ulcers 5. Non-deforming arthritis (non-erosive for the most part) 6. Serositis: pleuropericarditis, aseptic peritonitis 7. Renal: persistent proteinuria 0.5 g/d or 3+ or cellular casts 8. Neurologic disorders: seizures, psychosis 9. Heme: hemolytic anemia; leukopenia, thrombocytopenia 10. Immune: anti-DNA, or anti-Sm, or APS (ACA IgG, IgM), or lupus anticoagulant (standard) or false + RPR 11. Positive FANA (fluorescent antinuclear antibody) Definite SLE = 4 or more positive criteria Definite SLE = 4 or more positive criteria Slide 8 Slide 9 SLE-Clinical and Laboratory Features Musculoskeletal 90% Skin80% Renal50% CNS15% Severe thrombocytopenia 5-10% Positive ANA 95+% Also, cardiopulmonary involvement, thrombotic tendency (APS), and premature or accelerated atherosclerosis! Slide 10 Slide 11 Slide 12 Joint involvement in lupus mimics rheumatoid arthritis (RA) but milder Slide 13 Jaccouds arthropathy Slide 14 Arthritis in lupus can be deforming but is typically non-erosive! Slide 15 Autoantibodies Anti-dsDNA ENA (anti-Sm and anti-RNP) Anti-Ro and anti-La Anti-Jo1 Scl-70 Anti-centromere Anti-histone Lupus (occasionally other CTDs) Lupus (occasionally other CTDs) SLE - MCTD - UCTD SLE - MCTD - UCTD Sjgrens, SLE, neonatal lupus Sjgrens, SLE, neonatal lupus Polymyositis-Dermatomyositis Polymyositis-Dermatomyositis Scleroderma Scleroderma CREST Sx CREST Sx SLE and drug-induced lupus SLE and drug-induced lupus Slide 16 ENA = Extractable Nuclear Antigens Anti-Smith or anti-Sm: Anti-RNP (ribonucleoprotein): Almost exclusively seen in lupus but present only in about 30 percent of cases. Occasionally seen in other CTDs, e.g., MCTD Almost exclusively seen in lupus but present only in about 30 percent of cases. Occasionally seen in other CTDs, e.g., MCTD High titers typically in MCTD but (+) also in lupus, PM-DM, scleroderma, Sjgrens, UCTD, etc High titers typically in MCTD but (+) also in lupus, PM-DM, scleroderma, Sjgrens, UCTD, etc Slide 17 SLE Pathogenetic Mechanisms Immune complex-mediated damage: glomerulonephritis Direct autoantibody-induced damage: thrombocytopenia and hemolytic anemia Antiphospholipid antibody-induced thrombosis Complement-mediated inflammation: CNS lupus (C3a), hypoxemia, and also anti-phospholipid mediated fetal loss Either failure of or abnormal response to normal apoptosis Slide 18 Anti-native DNA Fairly specific for SLE but present only in 60% of cases at best Titers correlate with disease activity Higher titers with nephritis DR2 gene association Can be useful for: Diagnosis Prognosis Therapeutic monitoring Slide 19 Immune-complex Injury in SLE DNA + Anti-DNA = DNA - Anti-DNA complex C3 C4 C3 C4 Tissue Injury Tissue Injury SLE: Anti-DNA, C3, C4 Slide 20 Slide 21 Lupus Complement Levels Patients who are always hypocomplementemic regardless of clinical disease activity may have an underlying complement deficiency! Slide 22 SLE Pathogenesis The Dendritic cell Alpha Interferon Hypothesis Slide 23 SLE The Role of Dendritic Cells (DC) and Alpha Interferon (IFN ) Normally, resting DC mediate tolerance, i.e., no immune response to own tissues: they capture dead cells debris, and the immune system never encounters this waste DC become activated by viral infections, producing interferon. After viral infections resolve, interferon disappears DC proliferate and become activated when blood cells from normal donors are cultured with sera from lupus patients IFN identified as the primary substance responsible for this effect Pascual V, Banchereau J, Palucka KA. The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol. 2003; 15(5):548556. Slide 24 SLE The Role of Dendritic Cells (DC) and Alpha Interferon In lupus, the normal immune response appears altered as plasmacytoid dendritic cells (pDC) become hyperactivated by IFN Immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG induce IFN production in pDC Abnormal secretion of alpha interferon in lupus: the signature cytokine for the disease Dendritic cells activate B and T cells, leading to a chronic autoimmune state = lupus Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 2004; 50 (6):1861-72 Slide 25 Cytokines in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA) Many pro-inflammatory mediators, chemokines, and cytokines are involved in both diseases, however: In RA, mainly TNF In SLE, it appears that alpha interferon is the main pro-inflammatory cytokine Pascual V, Banchereau J, Palucka KA. The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol. 2003; 15(5):548556. Lovgren T, Eloranta ML, Bave U, Alm GV, Ronnblom L. Induction of interferon-alpha production in plasmacytoid dendritic cells by immune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG. Arthritis Rheum 2004; 50 (6):1861-72 Slide 26 SLE Cardiac Disease Pericarditis Inflammatory fluid Rarely tamponade Myocarditis Coronary vasculitis Rare Libmann-Sachs endocarditis Premature or accelerated atherosclerotic disease Slide 27 Slide 28 Coronary Heart Disease in Lupus The prevalence ranges from 6 to 15% The incidence of myocardial infarction is five times higher in lupus than in the general population The risk of adverse cardiovascular outcomes is by a factor of 7 to 17 in patients with lupus as compared with the Framingham cohort Young women (between ages 35 and 44) are significantly more likely (52-fold increased risk) to experience an MI if they have lupus Ward MM. Arthritis Rheum 1999; 42(2): 338-46 Ward MM. Arthritis Rheum 1999; 42(2): 338-46 Manzi S et al. Am J Epidemiol 1997; 145: 408-15 Manzi S et al. Am J Epidemiol 1997; 145: 408-15 Petri M, et al. Am J Med 1992; 93: 513-9 Petri M, et al. Am J Med 1992; 93: 513-9 Sturfelt G, et al. Medicine (Baltimore) 1992; 71: 216-23 Sturfelt G, et al. Medicine (Baltimore) 1992; 71: 216-23 Esdaile JM, et al. Arthritis Rheum 2001; 44: 2331-7 Esdaile JM, et al. Arthritis Rheum 2001; 44: 2331-7 Slide 29 Leading Causes of Death in SLE Active lupus Infection Cardiovascular disease Slide 30 SLE - Mortality Study Site: California Toronto Denmark Patient #: 408 665 513 Deaths: 144 124 122 Active lupus: 49 (34%) 20 (16%) 19 (15.5%) Infection: 32 (22%) 40 (32%) 25 (20.5 %) CV disease: 23 (16%) 19 (15.4%) 32 (26.2%) 1. Ward MM, et al. A&R 1995; 38: 1492-9 2. Abu-Shakra M, et al. J Rheum 1995; 22: 1259-64 3. Jacobsen S, et al. Scand J Rheumatol 1999; 28: 75-80 Slide 31 Lung Disease in Lupus Pleural disease Most common pulmonary involvement Inflammatory and exudative Chylothorax rarely* Interstitial lung disease Acute hypoxemia with normal CXR Improves with steroids Alveolar hemorrhage Typically in the setting of APS *Morgan C, Gonzalez E. Chylothorax as a rare complication in systemic lupus erythematosus. Poster presentation at the ACP-ASIM Georgia Chapter meeting, May 3-5, 2002 Slide 32 Renal Disease in Lupus Nephrotic and nephritic syndromes Glomerulonephritis Mesangial (type II WHO classification) Focal proliferative (type III WHO classification) Diffuse proliferative (type IV WHO (classification) Membranous (type V WHO classification) Tubulo-interstitial disease Burnt-out or sclerosed kidneys In a patient with newly diagnoses lupus, even if mild clinically, e.g., skin and joints, always check a UA so as to not miss an active urine sediment! In a patient with newly diagnoses lupus, even if mild clinically, e.g., skin and joints, always check a UA so as to not miss an active urine sediment! Slide 33 Renal immunofluorescence in lupus - The full house effect: multiple (+) immune reactants: IgG, IgM, C1q, C3, C4, etc Slide 34 Slide 35 SLE Heme Manifestations Autoimmune hemolytic anemia (AHA) Autoimmune thrombocytopenia, ITP-like Leukopenia Pancytopenia Lymphopenia Anti-phospholipid antibodies False positive RPRs (neg FTA) RPRs (neg FTA) Lymphadenopathy Rarely, aplastic anemia (from anti-stem cell antibodies) Slide 36 CNS Lupus Seizures - Epilepsy Strokes with hemiparesis Coma (lupus cerebritis) Cranial nerve and peripheral neuropathies Brain stem/cord lesions Aseptic meningitis Transverse myelitis Psychiatric: memory loss, cognitive changes Myasthenia gravis, multiple-sclerosis like Slide 37 Slide 38 Ro (SSA) and La (SSB) Primary Sjgren's Syndrome Neonatal lupus with congenital heart block ANA negative lupus Subacute cutaneous lupus erythematosus (SCLE) C2 deficiency and lupus-like syndrome DR3 gene association Slide 39 Slide 40 Subacute cutaneous lupus (SCLE) Anti-Ro antibody-mediated Slide 41 SLE The Use of Positive ANAs A positive ANA alone is not enough to diagnose SLE! Are there other autoantibodies present, e.g., anti-DNA, anti- Sm, anti-Ro? Sm, anti-Ro? What are the patients clinical features that suggest lupus? Photosensitivity, serositis, thrombocytopenia, proteinuria, Photosensitivity, serositis, thrombocytopenia, proteinuria, skin rashes? skin rashes? An ANA should only be ordered if the clinical picture warrants it! it! About 6-10% of people in the general population are ANA (+) About 6-10% of people in the general population are ANA (+) Slide 42 Slide 43 Anti-Phospholipid Antibody Syndrome (APS) Clinical and Laboratory Features Recurrent arterial and/or venous thrombosis (thrombophilia) Recurrent fetal loss (usually late miscarriages) Thrombocytopenia, autoimmune hemolytic anemia (AHA) Livedo reticularis But also: heart valve vegetations, chorea, transverse myelitis, multiple sclerosis-like syndrome, cognitive dysfunction, AVN Labs: positive antiphospholipid (APL) Abs, and/or (+) lupus anticoagulant (LAC), and/or (+) anti- 2 -glycoprotein 1 (anti- 2 GPI) antibodies There is no consensus yet as to what clinical and lab features should be included or excluded in the definition of APS! There is no consensus yet as to what clinical and lab features should be included or excluded in the definition of APS! Slide 44 Primary and Secondary APS APS can exist by itself = Primary APS (PAPS) or or SLE and other connective tissue diseases can associate with APS = Secondary APS Are SLE and APS perhaps different clinical expressions in the same autoimmune spectrum? Are they one and the same? Are SLE and APS perhaps different clinical expressions in the same autoimmune spectrum? Are they one and the same? Slide 45 Slide 46 SLE and APS Risk of Thrombosis About 20% of lupus pts have ACL and/or anti- 2 -glycoprotein 1 antibodies, and yet dont have clinical thrombosis, i.e., they are at risk. However, if any of the following factors present, alone or in combination: About 20% of lupus pts have ACL and/or anti- 2 -glycoprotein 1 antibodies, and yet dont have clinical thrombosis, i.e., they are at risk. However, if any of the following factors present, alone or in combination: Smoking Drug use, e.g., cocaine, and/or Estrogens, e.g., OC or HRT Perhaps hyperhomocysteinemia and other factors Clinical Thrombosis! Clinical Thrombosis! (DVTs, MIs, CVAs, PVDs) (DVTs, MIs, CVAs, PVDs) Slide 47 APS Lab Diagnostic Criteria Serologic: anticardiolipin antibodies IgG, IgM (rarely IgA), or anti- 2 glycoprotein 1 IgG or IgM antibody, by ELISA, on 2 or more occasions, at least 12 weeks apart -Test doable even if patient on anticoagulant! -Test doable even if patient on anticoagulant! Functional: the lupus anticoagulant or LAC: Prolonged PTT, Russell viper venom test (RVVT), Kaolin clotting time, platelet inhibitor assays, etc. - Cant do LAC if patient on anti-coagulant! - Cant do LAC if patient on anti-coagulant! False-positive RPR may be a clue that APS is present although not sensitive Slide 48 APS Mechanisms of Thrombosis by APL Antibodies Endothelial cell activation (upregulating tissue factor and adhesion molecules) Platelet activation and aggregation Complement activation Macrophages Inhibitory effects on the fibrinolytic and other pathways in the coagulation cascade Slide 49 Targets of Anti-Phospholipid Antibodies 2 -glycoprotein 1 Protein S Protein C Thrombomodulin Annexin V Prothrombin APS Abs (anti-2GP1) also likely contribute to endothelial dysfunction and accelerated atherosclerosis in lupus they also cross-react with oxidixed LDL Slide 50 Causes of Cardiovascular Complications in Lupus Procoagulant State (multifactorial, APS) Strokes PVD Premature or Accelerated Atherosclerosis MIs Slide 51 SLE: Therapeutic Approaches NSAIDS: but be careful with ibuprofen-other NSAIDS and aseptic meningitis Corticosteroids, including IV pulse Rx Hydroxychloroquine (Plaquenil): controls and prevents SLE, anticoagulant, cardioprotective cardioprotective Cytotoxics: cyclophosphamide (Cytoxan), MTX, mycophenolate mophetil (CellCept), azathioprine (Imuran) (CellCept), azathioprine (Imuran) IVIG: short-lived correction of thrombocytopenia* Plasmapheresis: not well documented. Used for CAPS Experimental: LJP394 (B cell tolerogen for anti-DNA Abs), CTLA4Ig (abatacept), anti-C5 (? efficacy), anti-T and B cell targets (CD40-CD40L, (abatacept), anti-C5 (? efficacy), anti-T and B cell targets (CD40-CD40L, rituximab (Rituxan), anti-BLYS Rx (lymphostat-B, belimumab), MEDI- rituximab (Rituxan), anti-BLYS Rx (lymphostat-B, belimumab), MEDI- 545, an anti-IFN monoclonal antibody (MedImmune, Inc.), kinase inhibitors, prolactin inhibitors, etc 545, an anti-IFN monoclonal antibody (MedImmune, Inc.), kinase inhibitors, prolactin inhibitors, etc Experimental combination Rx: Cytoxan + CTLA4Ig, other combos, etc Bone marrow approaches: ablative therapy and stem cell transplant *Gonzalez EB, Truslow W, Miller SB. Intravenous immunoglobulin (IVIG) offers short-term limited benefit in lupus thrombocytopenia. Arthritis & Rheumatism 36: S228, 1993 thrombocytopenia. Arthritis & Rheumatism 36: S228, 1993 Slide 52 Hydroxychloroquine (Plaquenil) has beneficial effects in lupus and RA because: It is cardioprotective and prophylactic of cardiovascular complications It is an anti-platelet agent It prevents lupus flare-ups and progression of disease It lowers glycemia and lipids (although modestly) It downregulates the inflammatory state at different levels (DNA Abs, prostaglandins, T cell activation, etc) It is anti-malarial and anti-bacterial Espinola R, Pierangeli S, Gharavi A, Harris N. Thromb and Haemost 2002; Petri et al. Am J Med 1994; 96: 254-9 Espinola R, Pierangeli S, Gharavi A, Harris N. Thromb and Haemost 2002; Petri et al. Am J Med 1994; 96: 254-9 Slide 53 FIN Questions?