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Systemic Lupus Erythematosus Emilio B. González, MD Professor and Director, Rheumatology UTMB May 18th, 2010

Systemic Lupus Erythematosus A chronic inflammatory systemic autoimmune disease of unknown etiology characterized by polyclonal Bcell activation and abnormal autoantibodies

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

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)

SLE – Genetic Susceptibility MHC Related

Not MHC Related

 HLA-DR1, 2, 3, 4

 C1q deficiency (rare but highest risk)

 Alleles of HLA-DRB1, IRF5,

 Chromosome 1 region 1q41-43

and STAT4  C2 - C4 deficiency  TNF- polymorphisms

 

 

(PARP), region 1q23 (FcγRIIA, FcγRIIIA) 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

1982 ACR (Revised 1997) SLE Classification Criteria 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11.

Malar (butterfly) rash Discoid lesions Photosensitivity Oral ulcers Non-deforming arthritis (non-erosive for the most part) Serositis: pleuropericarditis, aseptic peritonitis Renal: persistent proteinuria › 0.5 g/d or ›3+ or cellular casts Neurologic disorders: seizures, psychosis Heme: hemolytic anemia; leukopenia, thrombocytopenia Immune: anti-DNA, or anti-Sm, or APS (ACA IgG, IgM), or lupus anticoagulant (standard) or false + RPR Positive FANA (fluorescent antinuclear antibody)

Definite SLE = 4 or more positive criteria

SLE-Clinical and Laboratory Features      

Musculoskeletal Skin Renal CNS Severe thrombocytopenia Positive ANA

90% 80% 50% 15% 5-10% 95+%

Also, cardiopulmonary involvement, thrombotic tendency (APS), and “premature” or accelerated atherosclerosis!

Joint involvement in lupus mimics rheumatoid arthritis (RA) but milder

Jaccoud’s arthropathy

Arthritis in lupus can be deforming but is typically non-erosive!

Autoantibodies  Anti-dsDNA

Lupus (occasionally other CTDs)

 ENA (anti-Sm and anti-RNP)

SLE - MCTD - UCTD

 Anti-Ro and anti-La

Sjögren’s, SLE, neonatal lupus

 Anti-Jo1

Polymyositis-Dermatomyositis

 Scl-70

Scleroderma

 Anti-centromere

CREST Sx

 Anti-histone

SLE and drug-induced lupus

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

High titers typically in MCTD but (+) also in lupus, PM-DM, scleroderma, Sjögren’s, UCTD, etc

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

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

Immune-complex Injury in SLE  DNA + Anti-DNA = DNA - Anti-DNA

complex C3

C4

Tissue Injury SLE:

Anti-DNA,

C3, C4

Lupus – Complement Levels Patients who are always hypocomplementemic regardless of clinical disease activity may have an underlying complement deficiency!

SLE – Pathogenesis The Dendritic cell – Alpha Interferon Hypothesis

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):548–556.

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

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):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):1861-72

SLE – Cardiac Disease  Pericarditis  Inflammatory fluid  Rarely tamponade  Myocarditis  Coronary vasculitis – Rare  Libmann-Sachs endocarditis  Premature or accelerated atherosclerotic disease

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 Manzi S et al. Am J Epidemiol 1997; 145: 408-15 Petri M, et al. Am J Med 1992; 93: 513-9 Sturfelt G, et al. Medicine (Baltimore) 1992; 71: 216-23 Esdaile JM, et al. Arthritis Rheum 2001; 44: 2331-7

Leading Causes of Death in SLE  Active lupus

 Infection  Cardiovascular disease

SLE - Mortality Study Site: Patient #: Deaths:

California¹ 408 144

Toronto² 665 124

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

Denmark³ 513 122

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

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!

Renal immunofluorescence in lupus - The “full house” effect: multiple (+) immune reactants: IgG, IgM, C1q, C3, C4, etc

SLE – Heme Manifestations      

Autoimmune hemolytic anemia (AHA) Autoimmune thrombocytopenia, ITP-like Leukopenia Pancytopenia Lymphopenia Anti-phospholipid antibodies – False positive RPRs (neg FTA)  Lymphadenopathy  Rarely, aplastic anemia (from anti-stem cell antibodies)

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

Ro (SSA) and La (SSB)  Primary Sjögren'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

Subacute cutaneous lupus (SCLE) – Anti-Ro antibody-mediated

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, antiSm, 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 warrants

it! About 6-10% of people in the general population are ANA (+)

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2GPI) antibodies There is no consensus yet as to what clinical and lab features should be included or excluded in the definition of APS!

Primary and Secondary APS  APS can exist by itself = Primary APS (PAPS)

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?

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:    

Smoking Drug use, e.g., cocaine, and/or Estrogens, e.g., OC or HRT Perhaps hyperhomocysteinemia and other factors Clinical Thrombosis! (DVTs, MIs, CVAs, PVDs)

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

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

Targets of Anti-Phospholipid Antibodies  2-glycoprotein 1  Protein S

 Protein C  Thrombomodulin  Annexin V  Prothrombin APS Abs (anti-β2GP1) also likely contribute to endothelial dysfunction and accelerated atherosclerosis in lupus – they also cross-react with oxidixed LDL

Causes of Cardiovascular Complications in Lupus

Procoagulant State

Premature or Accelerated Atherosclerosis

(multifactorial, APS)

Strokes

PVD

MIs

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, 

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 

cardioprotective Cytotoxics: cyclophosphamide (Cytoxan®), MTX, mycophenolate mophetil (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, rituximab (Rituxan®), anti-BLYS Rx (lymphostat-B, belimumab), MEDI545, 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

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

FIN Questions?