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

Why Do I Have Lupus?

2/3 Genetics

1/3 Environmental

Manhattan Plot of GWAS

Criswell LA. The Rheumatologist. 2011;February:26-32.

What are Gene Signatures?

Genes That Define the LDG-Enriched Neutrophil Gene Signature

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.

Why Do Men Get Lupus?

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

An Ounce of Prevention is Worth a Pound of Cure

Hydroxychloroquine(Plaquenil)

is a Long-Term Medicine in Lupus For Prevention

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

Low Vitamin D is Part of Lupus

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.

I Don’t Understand My Lab Tests

Blood Counts

White Blood Count

Platelets

Hematocrit (anemia)

Kidney Tests

Urine protein/cr ratio

Blood creatinine

Why Does Dr. Petri Emphasize Control of Risk Factors for

Heart Disease?

Cross section of the left anterior descending coronary artery. In this view, calcium (pink), vessel lumen (orange)

and noncalcified plaque (green) have been identified

What is an Antiphospholipid Antibody?

What does it Do?

Lupus anticoagulant = RVVT confirm

Anticardiolipin

Anti-beta2 Glycoprotein 1

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

I am tired all the time – isn’t it my lupus?

Prevalence of Fibromyalgia

29.6% had 11 or more tender pointsN

umbe

r of

Pat

ient

s

How Do We Treat Fibromyalgia?

Tai Chi Stretching

Amitriptyline at bedtime

FDA-approved medications– Lyrica– Savella– Cymbalta

Treatment Update

Prednisone is Poison!

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.

I have kidney lupus – what next?

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)

What are the New Therapies?

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

What Will be Available in the Future?

Anti-IL-6

Anti-interferon alpha

Anti-BAFF/BLyS

Anti-CD22

Articles on Lupus Center

At the Hopkins Arthritis Center main page (www.hopkinsarthritis.org) scroll down to the bottom of the page.

Click on the “Lupus Center” link on the bottom right hand side.

At the Lupus Center main page, click the “About the Center” link near the top left corner.