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Systemic Lupus Erythematosus
Emilio B. González, MD
Professor and Director, Rheumatology
UTMB
May 16, 2012
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
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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
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MHC = Major Histocompatibility Complex

(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
The Genetics of SLE – A Complex
Disease
Immune complex
processing: C1q, C2-4, CRP,
ITGAM, FcGR2A, etc
TLR/type I, IFN pathway:
STAT 1, IRAK1,
TREX1, etc
Immune signal
transduction: HLA-DR, IRF5,
STAT4, BANK1, PTPN22, BLK,
TNFSF4, etc
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
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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 in Lupus
 Anti-dsDNA
 ENA (anti-Sm and anti-
RNP)
 Anti-Ro (SSA) and anti-
La (SSB)
 Anti-histone
Lupus, occasionally other
CTDs
SLE - MCTD - UCTD
Sjögren’s, SLE, neonatal
lupus
SLE and drug-induced
lupus
SLE – Pathogenetic Mechanisms
 Immune complex-mediated damage: glomerulonephritis
 Direct autoantibody-induced damage: thrombocytopenia and hemolytic
anemia
 Antiphospholipid antibody-induced thrombosis
 BLYS (BAFF) over-expression: B lymphocyte stimulator
 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
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
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
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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
Anti-Ro (SSA) and Anti-La (SSB) Abs
 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
Anti-Phospholipid Antibody Syndrome (APS) –
Clinical and Laboratory Features
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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, IgG, IgM, or IgA
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: the
“2nd hit” hypothesis
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:
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Smoking, long flights, surgery, immobilization
Drug use, e.g., cocaine
Estrogens, e.g., OC or HRT
Perhaps hyperhomocysteinemia, infection, lupus flares,
other factors
Clinical Thrombosis!
(DVTs, PE, 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 interpret 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 – C5 studies
 Macrophages and monocytes
 Inhibitory effects on the fibrinolytic and other pathways
in the coagulation cascade
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®)
Biologic: belimumab, anti-BLYS Rx (Benlysta®): corticosteroid-sparing
IVIG: short-lived correction of thrombocytopenia*
Plasmapheresis: not well documented. Used for CAPS
Experimental: rituximab, CTLA4Ig (abatacept), anti-C5 (? efficacy),
MEDI-545, an anti-IFN monoclonal antibody, kinase and 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 (HCQ)
 It prevents thrombotic events in lupus patients. Randomized multi-center trial
in APS to start soon, APS ACTION, including UTMB (PI: Dr. S. Pierangeli)
 It is an anti-platelet agent, inhibiting aPL-induced GPIIb/IIIa expression; it
does not prolong bleeding time
 It prevents lupus flare-ups and progression of disease, including lupus
nephritis (LUMINA). It prevents diabetes in patients with RA receiving it
 It lowers glycemia and lipids (although modestly)
 It downregulates inflammation at different levels: prostaglandins, DNA Abs,
T cell activation, inhibits intracellular TLR activation (7 & 9), inhibits IL-1 and
IL-6 production, protects the annexin-5 anticoagulant shield from aCL, etc
Willis R, Jajoria P, Harper BE, González EB, Petri M, Akhter E, Fang H, Pierangeli SS. Lupus (in press), Abstract 613, ACR
annual scientific meeting, Chicago, Nov 2011
Jung H, et al. Arthritis & Rheumatism 2010; 62: 863-868
Rand JH, et al. Blood, Nov 30, 2009 (online)
Experimental Newer Therapies for SLE
 Epratuzumab: anti-CD22 inhibition on B lymphocytes – It showed
clinically meaningful BILAG improvements in moderate-to-severe SLE in
all affected body systems. Efficacy was particularly prominent in cardiorespiratory and neuropsychiatric systems - Phase III
 Laquinimod: Unknown immunomodulation - Recruitment for Phase IIa
clinical trials for lupus nephritis began 2Q 2010 and is currently being
investigated for fast track approval by the FDA for MS; commercial
availability could be as early as 2012 – Phase IIa
 LY2127399: BAFF (cell-bound and soluble) monoclonal Ab - It may be
more effective than belimumab (Benlysta®) since it neutralizes cell-bound
and soluble BAFF. Trials initiated 3Q 2010 - Phase III
Newer Therapies for Lupus (Conted)
 Lupuzor: Phase IIb - B and T lymphocyte inhibition - Prior
phase IIb study had high placebo response with marginally
statistically significant efficacy at lower doses
 Rontalizumab: Phase II - Alpha interferon inhibition -
Phase II trial in moderate-to-severe active lupus; study
initiated in August 2009 with data expected 4Q 2012
 Sifalimumab: Phase II - Alpha interferon inhibition - Phase
II trial in moderate to severe active lupus; study initiated
October 2009 with data expected 2013
FIN
Questions?