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Systemic Lupus Erythematosus:
An Update
Michelle Petri MD MPH
Johns Hopkins University School of Medicine
Baltimore, Maryland USA
Lupus is 2/3 Genetic
(but only 2% of your children
will get it)
Manhattan Plot of GWAS
Criswell LA. The Rheumatologist. 2011;February:26-32.
What are Gene Signatures?
Neutrophil Gene Signature
Predicts MI and DVT
Environmental Triggers of SLE
Ultraviolet light
Drugs
Smoking‡
Infections
– Pet dogs*
– Lab workers†
Silica††
Mercury**
Pesticides
††Parks CG, et al. Arthritis Rheum. 2002;46:1840–1850.
*Chiou S-H, et al. Lupus. 2004;13:442–449. †Zarmbinski MA, et al. J Rheumatol. 1992;19:1380–1384.
**Cooper GS, et al. J Rheumatol 2004;31:1928.
‡Costenbader KH, et al. Arthritis Rheum 2004;50(3):849-857.
Costenbader KH, Karlson EW. Autoimmunity 2005;38(7):541-547.
Freemer, MM, et al. Annals Rheum Dis 2006;65:581-584.
Majka DS, Holers VM. Annals Rheum Dis 2006;65:561-563.
Men Have Worse Lupus
Male Female OR P-value
Photosensitivity 42% 65% 0.4 <0.0001
Oral Ulcers 35% 61% 0.4 <0.0001
Raynauds 35% 58% 0.4 <0.0001
Nephrotic Syndrome 24% 10% 2.7 <0.0001
Renal Failure 13% 5% 2.8 0.0010
Myocardial infarction 11% 3% 3.1 0.0009
Kidney Lupus
Activity – urine protein/cr ratio
Damage – blood creatinine
Treatment
Beginning
– Steroids and mycophenolate
Maintenance
– Mycophenolate
Game Changers
May NOT need steroids
– Rituxilup
Mycophenolate and tacrolimus may be better
at beginning.
– Multi-target
An Ounce of Prevention is
Worth a Pound of Cure
Hydroxychloroquine
(Plaquenil)
Hydroxychloroquine as Background Therapy
Reduction in Flares Canadian Hydroxychloroquine Study
Group. N Engl J Med. 1991;324:150-4
Reduction in organ damage Fessler BJ, et al. Arthritis Rheum. 2005
May;52(5):1473-80
Reduction in lipids Petri M. Lupus. 1996;5(Suppl. 1):S16-S22.
Wallace DJ, et al. Am J Med. 1990;89:322-6
Reduction in thrombosis Pierangeli SS, Harris EN. Lupus. 1996
Oct;5(5):451-5.
Petri M. Scand J Rheumatol. 1996;25:191-3
Improvement in survival Alarcon GS, et al. Arthritis Rheum
2005;52:S726.
Ruiz-Irastorza G, et al. Lupus 2005;14:220
Triples mycophenolate
response
Kasitanon N, et al. Lupus. 2006;15(6):366-
70
Hydroxychloroquine May
Prevent Thrombosis
Study Study Design (n) Thrombosis
Studies
Out-
come
Wallace et al, 1987 retrospective (92) arterial +
venous
P < 0.05
Petri et al, 1994 prospective cohort (393) arterial OR 0.36
Ruiz-Irastorza et al, 2006 prospective cohort (232) arterial +
venous
HR 0.28
Tektonidou et al, 2009 case-control cases (144)
controls (144)
arterial +
venous
HR 0.99
Jung et al, 2010 nested case-control cases (54)
controls (108)
arterial +
venous
OR 0.32
Wallace, et al. Arthritis Rheum. 1987;30:1435-6; Petri et al, Arthritis Rheum.
1994;37 (Suppl. 9):S297; Ruiz-Irastorza et al, Lupus. 2006;15:577-83; Tektonidou
et al, Arthritis Rheum. 2009;61:29-36; Jung et al, Arthritis Rheum. 2010;62:863-8
Top: Normal Spectralis spectral domain optical coherence tomography (SD OCT) image with intact photoreceptor
inner segment/outer segment junction (IS/OS). Bottom: Spectralis SD OCT from the left eye of patient 10 showing
the “flying saucer” sign of hydroxychloroquine retinopathy, an ovoid appearance of the central fovea created by
preservation of central foveal outer retinal structures (seen between the black arrows) surrounded by perifoveal loss
of the photoreceptor IS/OS junction, and perifoveal outer retinal thinning.
Abbreviations: ILM, internal limiting membrane; IPL, inner plexiform layer; OPL, outer plexiform layer; ELM,
external limiting membrane; RPE, retinal pigment epithelium.
From: Chen E1, Brown DM, Benz MS, Fish RH, Wong TP, Kim RY, Major JC. Spectral domain optical coherence tomography as an
effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign). Clin Ophthalmol. 2010 Oct 21;4:1151-8. doi:
10.2147/OPTH.S14257.
Vitamin D
Vitamin D Deficiency in Human SLE
Study Year Number of
SLE Patients Study Design
Measures of
Disease Activity
Association with
Disease Activity.
Becker A et al. 2001 57 Cross-sectional SLAM P = 0.02
Borba VZ et al. 2009 36 Cross-sectional SLEDAI P = 0.0005
Amital H et al. 2010 378 Cross-sectional SLEDAI-2K and
ECLAM P = 0.018
Ruiz-Irastorza G et al. 2010 60 Prospective
Cohort SLEDAI NS
Bonakdar ZS et al. 2011 40 Cross-sectional BILAG P = 0.001
Reynolds JA et al. 2011 75 Cross-sectional SLEDAI-2K P = 0.031
Souto M et al. 2011 159 Cross-sectional SLEDAI-2K NS
Yeap SS et al. 2012 38 Cross-sectional SLEDAI P = 0.03
25-OH Vitamin D May (or May Not) Be
Inversely Associated with Blood Pressure
Inverse association of 25-OH vitamin D and
systolic blood pressure Scragg R, et al. Am J Hypertens 2007;20:713-9.
PTH may mediate most of the association
between 25-OH vitamin D and BP, which is
not significant when adjusted for BMI He JL, Scragg RK. Am J Hypertens 2011;24:911-7.
Vitamin D was not associated with BP in
Puerto Rico Caro et al. P R Health Sci J 2012;31:123-9.
Vitamin Reduced Thrombosis in
Some Clinical Studies Cancer RCT: calcitriol+docetaxel vs. docetaxel p=0.01
Beer et al. Br J Haematol 2006;135:392-4.
General population
– lowest tertile of vitamin D: 37% (15-64%) rate of VTE Brøndum-Jacobsen et al. J Thromb Haemost 2013;11:423-31.
– Higher rates of VTE in African-Americans Grant et al. Am J Hematol 2010;85:908.
– TE are seasonal: highest risk in winter; sunbathing reduces rise of
VTE by 30% Lindqvist et al. J Thromb Haemost 2009;7:605-10.
Cardiovascular Honolulu Heart Program: Low vitamin D predicted
34 yr incident stroke in Japanese-American men HR 1.22 (1.02-
1.47), p=0.038 Kojima et al. Stroke 2012;43:2163-7.
Asian Indian cohort: mean vitamin D lower in CAD p = 0.036 Shanker et al. Coron Artery Dis 2011;22:324-32.
Coronary Artery Disease
The risk of CAD
is increased 2.66-fold
Prednisone Itself Increases the
Risk of Cardiovascular Events Prednisone use Observed
number of CVE
Rate of
events/1000
person years
Age-adjusted rate
ratios (95% CI)
P value
Never taken 22 13.3 1.0 (reference group)
Currently taking
1-9 mg/d 32 12.3 1.3 (0.8, 2.0) .31
10-19 mg/d 31 20.2 2.4 (1.5, 3.8) .0002
20+mg/d 25 35.4 5.1 (3.1,8.4) <.0001
Cumulative past dose
<3650 mg1 14 9.9 0.9 (0.4,1.6) .56
3650-10,950 mg2 26 13.8 1.2 (0.7, 2.2) .49
10,950-36,499 mg3 41 12.8 1.1 (0.6, 1.8) .83
36,500+4 30 25.3 2.2 (1.2,3.7) .0066
1. 3650 mg equals 10 mg/day for 1 year, or an equivalent cumulative exposure; 2. 1-3 years with 10
mg/day or an equivalent cumulative exposure; 3. 3-10 years with 10 mg/day or an equivalent cumulative
exposure; 4.10+ years with 10 mg/day or an equivalent cumulative exposure; CVE=cardiovascular events
Magder LS, Petri M. Am J Epidem 176:708-19, 2012.
Cross section of the left anterior descending coronary
artery. In this view, calcium (pink), vessel lumen (orange)
and noncalcified plaque (green) have been identified
Target Traditional Risk Factors
NO smoking
BP 120 mm systolic (SPRINT study)
LDL cholesterol < 100
Ideal body weight (BMI 24.9)
What is Homocysteine
Amino acid
Increases stroke and heart attacks
Lupus Factors That Contribute to CAD
SLEDAI
Low C3
Lupus anticoagulant
Antiphospholipid Antibodies:
Lupus Anticoagulant
Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.
Time Since SLE Diagnosis (y)
Cu
mu
lati
ve
S(t
) Kaplan-Meier Estimate of Remaining Free of Deep Venous
Thrombosis Adjusted for Lupus Anticoagulant
How to Prevent Blood Clots
Aspirin (maybe)
Hydroxychloroquine
Fatigue
Prevalence of Fibromyalgia
29.6% had 11 or more tender points N
um
ber
of P
atients
Exercise for SLE-related Fatigue
Clinical global
impression
change score
No (%) in
exercise
group (n=33)
No (%) in
relaxation
group (n=28)
No (%) in
control group
(n=32)
Very much better 3 (9) 4 (14) 1 (3)
Much better 13 (40) 4 (14) 4 (13)
A little better 5(15) 4(14) 3(9)
No change 6(18) 10(36) 14(41)
A little worse 4(12) 4(15) 10(31)
Much worse 2(6) 2(7) 1(3)
Very much worse 0 0 0
Tench CM, et al. Rheumatology. 2003;42:1050-54.
Treatment Update
Prednisone is Poison!
Effect of Prednisone on Organ Damage Adjusting for Confounding by Indication
Due to SLE Disease Activity
Prednisone Average Dose Hazard Ratio
> 0-6 mg/day 1.16
> 6-12 mg/day 1.50
>12-18 mg/day 1.64
> 18 mg/day 2.51
Thamer M, et al. J Rheumatol. 2009;36:560–564.
How to Avoid Prednisone
Hydroxychloroquine
Vitamin D
DHEA
What Can Be Done For a Flare
Methyl-
prednisolone Triamcinolone
Complete Improvement 1 week 8.3% 8.6%
2 weeks 20.8% 12.5%
3 weeks 20.8% 30.4%
4 weeks 25% 34.7%
Partial Improvement Day one 41.6% 69.5%
Health Status 4 weeks 66.6% 73.9%
Danowski A, et al. J Rheumatol. 2006;33:57-60.
What is Benlysta (Belimumab) for?
Who should get it? – Very active lupus
– low complement/anti-dsDNA
– prednisone helps but is too high
Phase 3 studies – BLISS 52
Navarro, Lancet 2011;377:721-31
– BLISS 76 Furie R, et al. Arthritis Rheum 2011;63(12): 3918-30
5 year open label followup – ↓ severe flares
– ↓ pathogenic autoantibodies Chatham, EULAR 2010
New Data on PPIs
Proton Pump Inhibitors Increase
Osteoporotic Fractures
Yu EW, et al. Proton pump inhibitors and risk of fractures: a meta-
analysis of 11 international studies. Am J Med. 2011;124:519-26.
Maggio M, et al. Use of proton pump inhibitors is associated with
lower trabecular bone density in older individuals. Bone.
2013;57:437-42.
Ding J, et al. The relationship between proton pump inhibitor
adherence and fracture risk in the elderly. Calcif Tissue Int.
2014;94:597-607.
Moberg LM, et al. Use of proton pump inhibitors (PPI) and history
of earlier fracture are independent risk factors for fracture in
postmenopausal women. The WHILA study. Maturitas.
2014;78:310-5
Proton-Pump Inhibitors Increase
Risk of Cardiovascular Events
Ghebremariam YT, et al. Unexpected effect of proton pump
inhibitors: elevation of the cardiovascular risk factor
asymmetric dimethylarginine. Circulation. 2013;128:845-53
Zou JJ, et al. Increased risk for developing major adverse
cardiovascular events in stented Chinese patients treated with
dual antiplatelet therapy after concomitant use of the proton
pump inhibitor. PLoS One. 2014;9(1):e84985.
Shih CJ, et al. Proton pump inhibitor use represents an
independent risk factor for myocardial infarction. Int J Cardiol.
2014;177:292-7.
Leonard CE, Comparative Risk of Ischemic Stroke Among
Users of Clopidogrel Together With Individual Proton Pump
Inhibitors. Stroke. 2015 Feb 5. pii: STROKEAHA.114.006866.
[Epub ahead of print]
El Greco – St. Sebastian (Prado)