A great deal is happening in lupus-related research. This presentation will update participants on recent research developments and their impact on those affected by lupus. Dr. Petri will provide an overview of current lupus research and the prospects for the future of lupus treatments. Learn how to better manage your lupus and make knowledgeable decisions regarding your treatment plan.

1. Systemic Lupus Erythematosus:
An Update
Michelle Petri MD MPH
Johns Hopkins University School of Medicine
Baltimore, Maryland USA

2. Lupus is 2/3 Genetic
(but only 2% of your children
will get it)

3. Manhattan Plot of GWAS
Criswell LA. The Rheumatologist. 2011;February:26-32.

4. What are Gene Signatures?

5. Neutrophil Gene Signature
Predicts MI and DVT

6. 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.

7. 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

8. Kidney Lupus
 Activity – urine protein/cr ratio
 Damage – blood creatinine

9. Treatment
 Beginning
– Steroids and mycophenolate
 Maintenance
– Mycophenolate

10. Game Changers
 May NOT need steroids
– Rituxilup
 Mycophenolate and tacrolimus may be better
at beginning.
– Multi-target

11. An Ounce of Prevention is
Worth a Pound of Cure

12. Hydroxychloroquine
(Plaquenil)

13. 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

14. 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

15. 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.

16. Vitamin D

17. 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

18. 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.

19. 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.

20. Coronary Artery Disease

21. The risk of CAD
is increased 2.66-fold

22. 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.

23. Cross section of the left anterior descending coronary
artery. In this view, calcium (pink), vessel lumen (orange)
and noncalcified plaque (green) have been identified

24. Target Traditional Risk Factors
 NO smoking
 BP 120 mm systolic (SPRINT study)
 LDL cholesterol < 100
 Ideal body weight (BMI 24.9)

25. What is Homocysteine
 Amino acid
 Increases stroke and heart attacks

26. Lupus Factors That Contribute to CAD
 SLEDAI
 Low C3
 Lupus anticoagulant

27. Antiphospholipid Antibodies:
Lupus Anticoagulant

28. Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.
Time Since SLE Diagnosis (y)
CumulativeS(t)Kaplan-Meier Estimate of Remaining Free of Deep Venous
Thrombosis Adjusted for Lupus Anticoagulant

29. How to Prevent Blood Clots
 Aspirin (maybe)
 Hydroxychloroquine

30. Fatigue

31. Prevalence of Fibromyalgia
29.6% had 11 or more tender points
NumberofPatients

32. 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.

33. Treatment Update

34. Prednisone is Poison!

35. 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.

36. How to Avoid Prednisone
 Hydroxychloroquine
 Vitamin D
 DHEA

37. 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.

38. 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

39. New Data on PPIs

40. 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

41. 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]

42. El Greco – St. Sebastian (Prado)