systemic lupus erythematosus: an update michelle petri md mph johns hopkins university school of...
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Systemic Lupus Erythematosus:An Update
Michelle Petri MD MPH
Johns Hopkins University School of Medicine
Baltimore, Maryland USA
Faculty Disclosures
Clinical Trials– HGS/GSK– Medimmune– Pfizer– TEVA– Anthera– UCB
Consultant– Genentech– Lilly– Merck Serono
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 vs Women
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
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
Vitamin D Deficiency in Human SLE
Study Year Number of
SLE PatientsStudy 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 60Prospective 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 pressureScragg 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 BMIHe JL, Scragg RK. Am J Hypertens 2011;24:911-7.
Vitamin D was not associated with BP in Puerto RicoCaro 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.
Cross section of the left anterior descending coronary artery. In this view, calcium (pink), vessel lumen (orange)
and noncalcified plaque (green) have been identified
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 Do We Treat Fibromyalgia?
Tai Chi Stretching
Amitriptyline at bedtime
FDA-approved medications– Lyrica– Savella– Cymbalta
Effect of Prednisone on Organ DamageAdjusting 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.
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.
FLOAT TrialComparison of Oral Methylprednisolone
and Intramuscular Triamcinolone
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.
Treatments for Kidney Lupus
Mycophenolate (Cellcept)
ACE inhibitor or ARB
Hydroxychloroquine (Plaquenil)
Vitamin D
Bad News: Mycophenolate Doesn’t Work For All
Cyclophosphamide
Tacrolimus (Prograf)
Rituximab (Rituxan)
Belimumab (Benlysta)
It blocks a growth factor (called BLyS or BAFF) that keeps autoimmune B cells alive
It is most likely to work if:– the lupus requires prednisone– the lupus is VERY active– there is anti-DNA AND low complement