What’s New in SLE?
A Ten Step Program
Michelle Petri MD MPH
Johns Hopkins University School of Medicine
1. Classification Criteria Help in
Everyday Practice
SLICC* Classification Criteria
At least 1 clinical + at least 1 immunologic
criterion (for a total of 4)
OR
lupus nephritis by biopsy
SLICC has recommended that BOTH the revised
ACR criteria AND the new SLICC classification
criteria be used
*Systemic Lupus International Collaborating Clinics
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
SLICC Revision of ACR Classification Criteria
Clinical Criteria
1. Acute/subacute cutaneous lupus
2. Chronic cutaneous lupus
3. Oral/Nasal ulcers
4. Non-scarring alopecia
5. Inflammatory synovitis with physician-observed swelling of two or more joints
OR tender joints with morning stiffness
6. Serositis
7. Renal: Urine protein/creatinine (or 24-hr urine protein) representing at least
500 mg of protein/24 hr or red blood cell casts
8. Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or
cranial neuropathy, cerebritis (acute confusional state)
9. Hemolytic anemia
10. Leukopenia (<4000/mm3 at least once)
OR
Lymphopenia (<1000/mm3 at least once)
11. Thrombocytopenia (<100,000/mm3) at least once
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
SLICC Revision of ACR Classification Criteria
Immunologic Criteria
1. ANA above laboratory reference range
2. Anti-dsDNA above laboratory reference range
(except ELISA: >2-fold laboratory reference range)
3. Anti-Sm
4. Antiphospholipid antibody
lupus anticoagulant
false-positive test for syphilis
anticardiolipin — at least twice normal or medium-high titer
anti-b2 glycoprotein 1
5. Low complement
low C3
low C4
low CH50
6. Direct Coombs’ test in absence of hemolytic anemia
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
2. More Good Reasons to Avoid
Prednisone
A Prednisone Dose of 6 mg or More
Increases Organ Damage by 50%
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
Adjusted for confounding by indication due to SLE disease activity
Thamer M et al. J Rheumatol. 2009;36:560-564.
Prednisone Itself Increases the Risk of
Cardiovascular Events
Prednisone
use
Never taken
Observed
Number of
CVEs
Rate of
Events/1000
PersonYears
22
13.3
Age-Adjusted
Rate Ratios
(95% CI)
P Value
1.0 (reference
group)
Currently taking
1-9 mg/d
32
12.3
1.3 (0.8, 2.0)
0.31
10-19 mg/d
31
20.2
2.4 (1.5, 3.8)
0.0002
20+mg/d
25
35.4
5.1 (3.1,8.4)
<0.0001
Magder LS, Petri M. Am J Epidemol. 2012;176:708-719.
3. Non-immunosuppressive
Immunomodulators Can Control MildModerate SLE, Helping to Avoid Steroids
• Hydroxychloroquine1
• Vitamin D2
• Prasterone (synthetic dihydroepiandrosterone,
or DHEA)3
• N-acetylcysteine4
1. Petri M. Lupus. 1996;5(Suppl 1):S16-S22. 2. Petri M et al. Arthritis Rheum. 2013;65:1865-1871 . 3 Petri M et al.
Arthritis Rheum. 2002;46:1820-1829. 4. Lai Z-W et al. Arthritis Rheum. 2012;64:2937-2946.
Hydroxychloroquine as Background
Therapy
Reduction in Flares
Canadian Hydroxychloroquine Study Group. N Engl J
Med. 1991;324:150-154.
Reduction in organ damage
Fessler BJ et al. Arthritis Rheum. 2005;52:1473-1480.
Reduction in lipids
Petri M. Lupus. 1996;5(Suppl. 1):S16-S22.
Wallace DJ et al. Am J Med. 1990;89:322-326.
Reduction in thrombosis
Pierangeli SS, Harris EN. Lupus. 1996;5:451-455.
Petri M. Scand J Rheumatol. 1996;25:191-193.
Improvement in survival
Alarcon GS et al. Arthritis Rheum. 2005;52:S726.
Ruiz-Irastorza G et al. Lupus. 2005;14:220.
Triples mycophenolate
mofetil response
Kasitanon N et al. Lupus. 2006;15:366-370.
Prevents seizure
Hanly JG et al. Ann Rheum Dis. 2012;71;1502-1509.
Hydroxychloroquine for Lupus Nephritis
Continuing hydroxychloroquine improves
complete response rates with
mycophenolate mofetil
Kasitanon N et al. Lupus 2006;15:366-370.
Increasing 25-Hydroxy Vitamin D Modestly
Helps Disease Activity and Urine Protein/CR
Model allowing slope to differ before and after 40 ng/mL
Disease Measure
Slope over range
of 0-40 ng/mL
(95% CI)
P-value
Slope over range
of ≥40 ng/mL
(95% CI)
P-value
Physician’s Global
Assessment
–0.04
(–0.08, –0.01)
0.026
0.01
(–0.02, 0.04)
0.50
SELENA-SLEDAI
–0.22
(–0.41, –0.02)
0.032
0.12
(–0.01, 0.24)
0.065
Log Urinary
Protein/Creatinine
–0.03
(–0.05, –0.02)
0.0004
–0.01
(–0.01, 0.00)
0.24
SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic
Lupus Erythematosus Disease Activity Index.
Petri M et al. Arthritis Rheum. 2013;65:1865-1871.
20-Unit Increase in 25-Hydroxy Vitamin D
• 13% decrease in odds of having a PGA score of
1 or more
• 21% decrease in odds of having a SLEDAI score
of 5 or more
• 15% decrease in odds of having a
urine pr/cr > 0.5
Petri, et al. Arthritis Rheum 2013;65:1865-71
Vitamin D May Have Cardiovascular and
Hematologic Benefits
Targher G et al. Semin Thromb Hemostasis. 2012;38:114-124.
Vitamin D Reduced Thrombosis in Some
Clinical Studies
• Cancer RCT: calcitriol+docetaxel vs. docetaxel (P=0.01)1
• General population lowest tertile of vitamin D:
• 37% (CI 15-64%) increased rate of VTE2
• Higher rates of VTE in African-Americans3
• VTE are seasonal: highest risk in winter; sunbathing reduces rise of VTE by
30%4
• Honolulu Heart Program: Low vitamin D predicted 34-year incident
stroke in Japanese-American men. HR 1.22 (CI 1.02-1.47), P=0.0385
• Asian Indian cohort: mean vitamin D lower in CAD P=0.0366
1. Beer TM et al. Br J Haematol. 2006;135:392-394. 2. Brøndum-Jacobsen P et al. J Thromb Haemost . 2013;11:423-431.
3. Grant WB. Am J Hematol. 2010;85:908. 4. Lindqvist PG et al. J Thromb Haemost . 2009;7:605-610. 5. Kojima G et al.
Stroke. 2012;43:2163-2167. 6. Shanker J et al. Coron Artery Dis. 2011;22:324-332.
DHEA (Prasterone) 200 mg Daily
• NOT FDA-approved
• In women with disease activity, reduction in
prednisone to ≤7.5 mg/day achieved in 51% vs.
29% on placebo (P=0.03).1
• In women with disease activity, improvement or
stabilization achieved in 58.5% vs. 44.5% on
placebo (P=0.017)2
1. Petri M et al. Arthritis Rheum. 2002;46:1820-1829. 2. Petri M et al. Arthritis Rheum. 2004;50:2858-2868.
Prasterone Reduces SLE Flares
DHEA and Bone Density
• Prasterone provides mild protection against
bone loss
• At month 18 with 200 mg vs. 100 mg:
Dose-dependent increase in spine BMD (P=0.02)
Sanchez-Guerrero J et al. J Rheumatol. 2008;35:1567-1575.
N-acetylcysteine
• Blocks mTOR in T cells
• At 2.4 and 4.8 g, it reduced SLEDAI at 1, 2, 3 and 4
months
• But 4.8 g caused reversible nausea in 33%
Lai Z-W et al. Arthritis Rheum. 2012;64:2937-2946.
4. Mycophenolate Mofetil:
The Good, the Bad, . . . . .
Lupus Nephritis Induction Therapy:
MMF = IV Cyclophosphamide Therapy
• In non-Caucasians, MMF is superior
• In renal transplant literature:
 African-Americans
 Caucasians
3 grams
2 grams
• New issue: MMF interferes with oral
contraceptive dosing
“It is recommended that oral contraceptives are coadministered
with MMF with caution and additional birth control methods be
considered”2
Not FDA-indicated for SLE
1. Appel GB, et al. J Am Soc Nephrol.2009;20(5):1103-1112; Ginzler EM, et al. Arthritis Rheum. 2010;62(1):211-221; Tornatore KM,
et al. J Clin Pharmacol 2011;51:1213-22. 2. FDA Warning label for MMF.
Lupus Nephritis Maintenance Therapy :
MMF is Superior to Azathioprine
N=227
Time to treatment failure
Dooley MA, et al. N Engl J Med. 2011;365:1886-95.
Time to renal flare
Not FDA-indicated for SLE
Lupus Nephritis: Other Options
• Belimumab
• Not studied specifically in SLE patients with active nephritis1,2
• Leflunomide
• For mild-to-moderate SLE disease3
• Induction therapy for renal flare4,5
• Tacrolimus
• Consider in MMF-resistant or partial response patients, alone or in combination69,12
• Approved for treatment of LN in Japan
• For severe nephritis (Class IV/V)6,10
• Rituximab
• LUNAR trial was negative11
Leflunomide, tacrolimus, and rituximab
are not FDA-indicated for SLE
1. Navarra S, et al. Lancet. 2011;377(9767):721-31; 2. Dooley MA, et al. ACR/AHCP annual meeting. November 4-9, 2011;Chicago, IL;
3. Tam LS, et al. Lupus. 2004;13:601-4; 4. Wang HY, et al. Lupus. 2008;17(638-44); 5. Tam LD, et al. Ann Rheum Dis. 2006;65:417-8;
6. Yap DY et al. Nephrology. 2012; 10.1111/j.1440-1797.2012.01574.x; 7. Li X, et al. Nephrol Dial Transplant. 2011; doi:
10.1093/ndt/gfr484; 8. Cortes-Hernandez J, et al; Nephrol Dial Transplant. 2010;25(12):3939-489. 9. Lanata CM, et al. Lupus.
2010:19(8):935-40. 10. Szeto CC, et al. Rheumatology. 2008;47(11):1678-81; 11. Rovin BH, et al. Arth Rheum. 2012; doi:
10.1002/art.34359. 12. Chen W, et al. Lupus. 2012:21(7):944-952.
Time to Remission and Relapse After Rituximab
Treatment and MMF Maintenance
Condon MB, et al. Ann Rheum Dis. 2013;72:1280-6.
5. Better Understanding of
Belimumab
Belimumab Multivariate Analysis
Characteristics associated with greater treatment effect (p<0.1)
SELENA
SLEDAI score: ≥10 (vs ≤9)
Complement: low C3/C4 (vs normal)
Steroid use: greater (vs no/less)
Characteristics not associated with treatment effect (p>0.1)
Study
Region
Race
van Vollenhoven, et al. Ann Rheum Dis, 2012. [April Epub ahead of print, doi: 10.1136/annrheumdis-2011-200937].
Low C/Anti-dsDNA + Subgroup:
SRI Response Rate over 52 Weeks
van Vollenhoven RF, et al. Presented at EULAR 2011; May 25-28, 2011; London, UK
SELENA SLEDAI Organ
Improvement (Week 52)a
Improvement = decrease in SS
score within an organ domain
Manzi S, et al. Ann Rheum Dis, 2012. [May Epub ahead of print, doi: 10.1136/annrheumdis-2011-200831].
Belimumab vs Placebo:
Severe Flares
Cervera R, et al. Presented at EULAR 2011: Annual European Congress of Rheumatology;
May 25–28, 2011; London, UK
6. Don’t Forget New Information on
Common Drugs
http://www.medpagetoday.com/PainManagement/PainManagement/44253 (accessed on 3/12/2014)
New Data on PPIs
Proton Pump Inhibitors and Fractures
http://www.fda.gov/drugs/resourcesforyou/healthprofessionals/ucm221672.htm (accessed on 3/12/2014)
http://www.news-medical.net/news/20130711/Research-shows-proton-pump-inhibitors-may-cause-cardiovascularproblems.aspx (accessed on 3/12/2014)
7. Progress on Coronary Artery
Disease
Coronary Artery Disease in SLE
• Substantial increased risk that cannot be completely
explained by traditional Framingham risk factors1
• Hospitalization for acute myocardial infarction (AMI) 2.3
times higher in SLE2
• Risk of cardiovascular events is 2.66 times higher in SLE
vs Framingham cohort3
1. Esdaile JM, et al. Arthritis Rheum 2001;44: 2331-7; 2. Ward MM. Arthritis Rheum. 1999;42(2):338-46;
3. Magder LS, Petri M. Am J Epidemiol. In press.
How Can We Detect Cardiovascular
Disease Early in SLE?
• Coronary calcium CT1
• Carotid duplex2
• In the FUTURE, techniques such as coronary CTA can
detect early noncalcified coronary plaques3
1. Kiani AN et al. J Rheumatol. 2008;35:1300-1306. 2. Maksimowicz-McKinnon K et al. J Rheumatol.
2006;33:2458-2463. 3. Kiani AN et al. J Rheumatol. 2010;37:579-584.
Coronary Calcium CT
Cross section of the left anterior descending coronary
artery. In this view, calcium (pink), vessel lumen (orange)
and noncalcified plaque (green) have been identified.
Kiani AN et al. J Rheumatol. 2010;37:579-584.
Prevention of CAD in SLE
Atorvastatin Did Not Change
1. Coronary calcium
2. Carotid intima media thickness
3. Carotid plaque
Petri M et al. Ann Rheum Dis 2010;70:760-765. Schanberg LE et al. Arthritis Rheum. 2012;64:285-296.
Can We Reduce Cardiovascular Risk?
• Assess traditional cardiovascular
risk factors and treat to target
•
•
•
•
•
Hypertension
Obesity
Hyperlipidemia
Smoking
Sedentary Lifestyle
• Mycophenolate: slowed
progression in mice3 and
transplant patients4
• Prednisone > 10 mg
increases CV event risk5
• Statin did NOT reduce progression
in mice3 nor in two clinical trials:
• Adult1
• Pediatric2
1. Petri MA, et al. Ann Rheum Dis. 2011;70(5):760-5; 2. Schanberg LE, et al. Arthtiris Rheum. 2012;64(1):285-96;
3. van Leuven SI, et al. Ann Rheum Dis. 2012 ;71(3):408-14; 4. Gibson WT, Hayden MR. Ann N Y Acad Sci. 2007
Sep;1110:209-21; 5. Magder L, et al. Am J Epidemiol. 2012; in press.
8. Prevention of Thrombosis in SLE:
Are We There Yet?
Cumulative S(t)
Venous Thrombosis in SLE
Time Since SLE Diagnosis (years)
Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.
Hydroxychloroquine Prevents
Thrombosis in SLE
Study
Study Design
Outcome
Wallace et al, 1987
retrospective
P < 0.05
Petri et al, 1994
prospective cohort
OR 0.3
Ruiz-Irastorza et al, 2006
prospective cohort
HR 0.28
Tektonidou et al, 2009
case-control
HR 0.99
Jung et al, 2010
nested case-control
OR 0.31
Petri M. Curr Rheumatol Reports 2010:13:77-80
9. Don’t Make Fibromyalgia WORSE
(It’s Bad Enough as it is!)
Treating Pain and Fatigue: Tai Chi
12 weeks
79% of tai chi group vs 39% of control had clinically
meaningful improvement* (P=0.0001)
24 weeks
82% of tai chi vs 53% control had clinically
meaningful improvement (P=0.009)
FIQ=fibromyalgia impact questionnaire;
*”clinically meaningful” change in FIQ = 8.1 points
Wang C, et al. N Engl J Med.2010;363(8):743-754.
Fatigue
• Among most common complaints in lupus patients (5080% of patients)1
• Chronic fatigue does not correlate with disease activity2
• Highly correlated with fibromyalgia, pain, depression,
sleep abnormalities, poor quality of life2-5
• Associated with reduced physical fitness6
1. Tench CM et al. Rheumatology. 2000;39(11):1249–54; 2. Wang B, et al. J Rheumatol. 1998;25(5):892-5; 3. Gladman D, et al. J
Rheum. 1997;24:2145-9; 4. Bruce IN, et al. Arthritis Rheum. 1998; 41(suppl.9):S333; 5. Carr FN, et al. ACR/AHCP annual meeting.
November 4-9, 2011;Chicago, IL.
Exercise for SLE-related Fatigue
Clinical global
impression
change score
No (%) in
exercise group
(n=33)
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)
0
0
0
Very much worse
Tench CM, et al. Rheumatology. 2003;42:1050-54.
No (%) in
relaxation
group (n=28)
No (%) in
control group
(n=32)
“Overall, 11 of 22 patients completing a 90-day
treatment with naltrexone had a robust response
with 41% improvement on the Revised Fibromyalgia
Impact Questionnaire.”
http://www.obgynnews.com/single-view/naltrexone-hyperbaric-oxygen-show-promise-forfibromyalgia/f2d53e04496f14b0294457246f645741.html (accessed on 3/12/2014)
10. Headaches Aren’t Usually
Due to Lupus
http://www.hopkinslupus.org/lupus-info/lupus-affects-body/lupus-nervous-system/migraine-prevention-diet/
(accessed on 3/12/2014)