Presentation on theme: "Systemic Lupus Erythematosus Emilio B"— Presentation transcript:
1 Systemic Lupus Erythematosus Emilio B Systemic Lupus Erythematosus Emilio B. González, MD Professor and Director, Rheumatology UTMBMay 18th, 2010
2 Systemic Lupus Erythematosus A chronic inflammatory systemic autoimmune disease of unknown etiology characterized by polyclonal B-cell activation and abnormal autoantibodies
3 SLE – Epidemiology and Genetics Incidence: 1 in 1, ,000Female to male ratio: 9-1More common in African-Americans but it affects all racesMean age of onset: 28 yearsPositive family history in % of patientsMonozygotic 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
4 Immunogenetics Increased Risk for SLE in: HLA-DR2 (anti-DNA Abs) HLA-DR3 (anti-Ro Abs)Null alleles at C2 and C4 lociSLE may be transmitted in an autosomal dominant pattern (family studies)
5 SLE – Genetic Susceptibility MHC RelatedHLA-DR1, 2, 3, 4Alleles of HLA-DRB1, IRF5,and STAT4C2 - C4 deficiencyTNF- polymorphismsNot MHC RelatedC1q deficiency (rare but highest risk)Chromosome 1 region 1q41-43 (PARP), region 1q23 (FcγRIIA, FcγRIIIA)IL-10, IL-6 and MBL polymorphismsChromosome 8.p23.1: reduced expression of BLK and increased expression of C8orf13 (B cell tyrosine kinase), chromosome 16p11.22: integrin genes IGAM-ITGAXB cell gene BANK1X chromosome-linked gene IRAK1
9 SLE-Clinical and Laboratory Features Musculoskeletal %Skin %Renal %CNS %Severe thrombocytopenia %Positive ANA %Also, cardiopulmonary involvement, thrombotic tendency (APS), and “premature” or accelerated atherosclerosis!
14 Arthritis in lupus can be deforming but is typically non-erosive!
15 Autoantibodies Anti-dsDNA ENA (anti-Sm and anti-RNP) Anti-Ro and anti-LaAnti-Jo1Scl-70Anti-centromereAnti-histoneLupus (occasionally other CTDs)SLE - MCTD - UCTDSjögren’s, SLE, neonatal lupusPolymyositis-DermatomyositisSclerodermaCREST SxSLE and drug-induced lupus
16 ENA = Extractable Nuclear Antigens Almost exclusively seen in lupus but present only in about 30 percent of cases. Occasionally seen in other CTDs, e.g., MCTDHigh titers typically in MCTD but (+) also in lupus, PM-DM, scleroderma, Sjögren’s, UCTD, etcAnti-Smith or anti-Sm:Anti-RNP (ribonucleoprotein):
17 SLE – Pathogenetic Mechanisms Immune complex-mediated damage: glomerulonephritisDirect autoantibody-induced damage: thrombocytopenia and hemolytic anemiaAntiphospholipid antibody-induced thrombosisComplement-mediated inflammation: CNS lupus (C3a), hypoxemia, and also anti-phospholipid mediated fetal lossEither failure of or abnormal response to normal apoptosis
18 Anti-native DNAFairly specific for SLE but present only in 60% of cases at bestTiters correlate with disease activityHigher titers with nephritisDR2 gene associationCan be useful for:DiagnosisPrognosisTherapeutic monitoring
19 Immune-complex Injury in SLE DNA + Anti-DNA = DNA - Anti-DNA complexC C4Tissue InjurySLE: Anti-DNA, C3, C4
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 wasteDC become activated by viral infections, producing interferon. After viral infections resolve, interferon disappearsDC proliferate and become activated when blood cells from normal donors are cultured with sera from lupus patientsIFN identified as the primary substance responsible for this effectPascual V, Banchereau J, Palucka KA. The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol. 2003; 15(5):548–556.
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 IFNImmune complexes containing nucleic acid released by necrotic or late apoptotic cells and lupus IgG induce IFN production in pDCAbnormal secretion of alpha interferon in lupus: the signature cytokine for the diseaseDendritic cells activate B and T cells, leading to a chronic autoimmune state = lupusLovgren 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):
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 TNFIn SLE, it appears that alpha interferon is the main pro-inflammatory cytokinePascual V, Banchereau J, Palucka KA. The central role of dendritic cells and interferon-alpha in SLE. Curr Opin Rheumatol. 2003; 15(5):548–556.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):
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 populationThe risk of adverse cardiovascular outcomes is by a factor of 7 to 17 in patients with lupus as compared with the Framingham cohortYoung women (between ages 35 and 44) are significantly more likely (52-fold increased risk) to experience an MI if they have lupusWard MM. Arthritis Rheum 1999; 42(2):Manzi S et al. Am J Epidemiol 1997; 145:Petri M, et al. Am J Med 1992; 93: 513-9Sturfelt G, et al. Medicine (Baltimore) 1992; 71:Esdaile JM, et al. Arthritis Rheum 2001; 44:
29 Leading Causes of Death in SLE Active lupusInfectionCardiovascular disease
30 SLE - Mortality Study Site: California¹ Toronto² Denmark³ Patient #:Deaths:Active lupus: (34%) (16%) (15.5%)Infection: (22%) (32%) (20.5 %)CV disease: (16%) (15.4%) (26.2%)1. Ward MM, et al. A&R 1995; 38:2. Abu-Shakra M, et al. J Rheum 1995; 22:3. Jacobsen S, et al. Scand J Rheumatol 1999; 28: 75-80
31 Lung Disease in Lupus Pleural disease Interstitial lung disease Most common pulmonary involvementInflammatory and exudativeChylothorax rarely*Interstitial lung diseaseAcute hypoxemia with normal CXR – Improves with steroidsAlveolar 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
32 Renal Disease in Lupus Nephrotic and nephritic syndromes GlomerulonephritisMesangial (type II WHO classification)Focal proliferative (type III WHO classification)Diffuse proliferative (type IV WHO (classification)Membranous (type V WHO classification)Tubulo-interstitial diseaseBurnt-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!
33 Renal immunofluorescence in lupus - The “full house” effect: multiple (+) immune reactants: IgG, IgM, C1q, C3, C4, etc
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?What are the patient’s clinical features that suggest lupus?Photosensitivity, serositis, thrombocytopenia, proteinuria,skin rashes?An ANA should only be ordered if the clinical picture warrantsit!About 6-10% of people in the general population are ANA (+)
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 reticularisBut also: heart valve vegetations, chorea, transverse myelitis, multiple sclerosis-like syndrome, cognitive dysfunction, AVNLabs: positive antiphospholipid (APL) Abs, and/or (+) lupus anticoagulant (LAC), and/or (+) anti-2-glycoprotein 1 (anti-2GPI) antibodiesThere is no consensus yet as to what clinical and lab features should be included or excluded in the definition of APS!
44 Primary and Secondary APS APS can exist by itself = Primary APS (PAPS)orSLE and other connective tissue diseases can associate with APS = Secondary APSAre SLE and APS perhaps different clinical expressions in the same autoimmune spectrum? Are they one and the same?
46 SLE and APS – Risk of Thrombosis About 20% of lupus pts have ACL and/or anti-2-glycoprotein 1 antibodies, and yet don’t have clinical thrombosis, i.e., they are at risk. However, if any of the following factors present, alone or in combination:SmokingDrug use, e.g., cocaine, and/orEstrogens, e.g., OC or HRTPerhaps hyperhomocysteinemia and other factorsClinical Thrombosis!(DVTs, MIs, CVAs, PVDs)
47 APS – Lab Diagnostic Criteria Serologic: anticardiolipin antibodies IgG, IgM (rarely IgA), or anti- β2 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!Functional: “the lupus anticoagulant” or LAC: Prolonged PTT, Russell viper venom test (RVVT), Kaolin clotting time, platelet inhibitor assays, etc.- Can’t do LAC if patient on anti-coagulant!False-positive RPR may be a clue that APS is present although not sensitive
48 APS – Mechanisms of Thrombosis by APL Antibodies Endothelial cell activation (upregulating tissue factor and adhesion molecules)Platelet activation and aggregationComplement activationMacrophagesInhibitory effects on the fibrinolytic and other pathways in the coagulation cascade
49 Targets of Anti-Phospholipid Antibodies 2-glycoprotein 1Protein SProtein CThrombomodulinAnnexin VProthrombinAPS Abs (anti-β2GP1) also likely contribute to endothelial dysfunction and accelerated atherosclerosis in lupus – they also cross-react with oxidixed LDL
50 Causes of Cardiovascular Complications in Lupus Procoagulant State(multifactorial, APS)Strokes PVDPremature or AcceleratedAtherosclerosisMIs
51 SLE: Therapeutic Approaches NSAIDS: but be careful with ibuprofen-other NSAIDS and aseptic meningitisCorticosteroids, including IV “pulse” RxHydroxychloroquine (Plaquenil®): controls and prevents SLE, anticoagulant,cardioprotectiveCytotoxics: cyclophosphamide (Cytoxan®), MTX, mycophenolate mophetil(CellCept®), azathioprine (Imuran®)IVIG: short-lived correction of thrombocytopenia*Plasmapheresis: not well documented. Used for CAPSExperimental: LJP394 (B cell tolerogen for anti-DNA Abs), CTLA4Ig(abatacept), anti-C5 (? efficacy), anti-T and B cell targets (CD40-CD40L,rituximab (Rituxan®), anti-BLYS Rx (lymphostat-B, belimumab), MEDI-545, an anti-IFN monoclonal antibody (MedImmune, Inc.), kinase inhibitors, prolactin inhibitors, etcExperimental combination Rx: Cytoxan® + CTLA4Ig, other combos, etcBone marrow approaches: ablative therapy and stem cell transplant*Gonzalez EB, Truslow W, Miller SB. Intravenous immunoglobulin (IVIG) offers short-term limited benefit in lupusthrombocytopenia. Arthritis & Rheumatism 36: S228, 1993
52 Hydroxychloroquine (Plaquenil®) has beneficial effects in lupus and RA because: It is cardioprotective and prophylactic of cardiovascular complicationsIt is an anti-platelet agentIt prevents lupus flare-ups and progression of diseaseIt 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-bacterialEspinola R, Pierangeli S, Gharavi A, Harris N. Thromb and Haemost 2002; Petri et al. Am J Med 1994; 96: 254-9