Download - What’s New in SLE? A Ten Step Program
What’s New in SLE?A Ten Step Program
Michelle Petri MD MPHJohns 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)
ORlupus nephritis by biopsy
Petri M et al. Arthritis Rheum. 2012;64:2677-2686.
*Systemic Lupus International Collaborating Clinics
SLICC has recommended that BOTH the revised ACR criteria AND the new SLICC classification
criteria be used
SLICC Revision of ACR Classification CriteriaClinical Criteria1. Acute/subacute cutaneous lupus2. Chronic cutaneous lupus3. Oral/Nasal ulcers4. Non-scarring alopecia 5. Inflammatory synovitis with physician-observed swelling of two or more joints OR tender joints with morning stiffness6. Serositis7. 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 anemia10. 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 CriteriaImmunologic Criteria1. ANA above laboratory reference range2. Anti-dsDNA above laboratory reference range (except ELISA: >2-fold laboratory reference range)
3. Anti-Sm4. Antiphospholipid antibody
lupus anticoagulantfalse-positive test for syphilisanticardiolipin — at least twice normal or medium-high titeranti-b2 glycoprotein 1
5. Low complementlow C3low C4low 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
Thamer M et al. J Rheumatol. 2009;36:560-564.
Adjusted for confounding by indication due to SLE disease activity
Prednisone Itself Increases the Risk of Cardiovascular Events
Prednisone use
Observed Number of
CVEs
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) 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 Mild-Moderate 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 TherapyReduction 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
Disease MeasureSlope over range
of 0-40 ng/mL (95% CI)
P-valueSlope 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
Petri M et al. Arthritis Rheum. 2013;65:1865-1871.
SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index.
Model allowing slope to differ before and after 40 ng/mL
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 3 grams Caucasians 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
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.
Not FDA-indicated for SLE
Lupus Nephritis Maintenance Therapy :MMF is Superior to Azathioprine
Time to treatment failure Time to renal flareN=227
Dooley MA, et al. N Engl J Med. 2011;365:1886-95. 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 combination6-
9,12
• Approved for treatment of LN in Japan• For severe nephritis (Class IV/V)6,10
• Rituximab• LUNAR trial was negative11
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.
Leflunomide, tacrolimus, and rituximab are not FDA-indicated for SLE
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)StudyRegionRace
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-cardiovascular-problems.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.
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.
Coronary Calcium CT
Prevention of CAD in SLE
Atorvastatin Did Not Change
1. Coronary calcium2. Carotid intima media thickness3. Carotid plaque
Petri M et al. Ann Rheum Dis 2010;70:760-765. Schanberg LE et al. Arthritis Rheum. 2012;64:285-296.
• Assess traditional cardiovascular risk factors and treat to target• Hypertension• Obesity• Hyperlipidemia• Smoking• Sedentary Lifestyle
• Statin did NOT reduce progression in mice3 nor in two clinical trials:• Adult1
• Pediatric2
• Mycophenolate: slowed progression in mice3 and transplant patients4
• Prednisone > 10 mg increases CV event risk5
Can We Reduce Cardiovascular Risk?
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?
Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.
Time Since SLE Diagnosis (years)
Cum
ulat
ive
S(t)
Venous Thrombosis in SLE
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 weeks79% of tai chi group vs 39% of control had clinically meaningful improvement* (P=0.0001)
24 weeks82% 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 (50-
80% 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)
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.
http://www.obgynnews.com/single-view/naltrexone-hyperbaric-oxygen-show-promise-for-fibromyalgia/f2d53e04496f14b0294457246f645741.html (accessed on 3/12/2014)
“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.”
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)