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)