1. What’s New in SLE? A Ten Step Program
Michelle Petri MD MPH
Johns Hopkins University School of Medicine

2. 1. Classification Criteria Help in Everyday Practice

3. 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:

4. 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:

5. 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:

6. 2. More Good Reasons to Avoid Prednisone

7. 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:

8. 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
Incidence of and risk factors for adverse cardiovascular events among patients with systemic lupus erythamatosus
Laurence S. Magder, PhD, MPH
Michelle Petri, MD, MPH
Age refers to the age of the patient at each month of follow-up.
Cumulative past dose includes information on prednisone corticosteroid exposure prior to cohort participation.
Magder LS, Petri M. Am J Epidemol. 2012;176:

9. 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-S Petri M et al. Arthritis Rheum. 2013;65: Petri M et al. Arthritis Rheum. 2002;46: Lai Z-W et al. Arthritis Rheum. 2012;64:

10. Hydroxychloroquine as Background Therapy
Reduction in Flares
Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991;324:
Reduction in organ damage
Fessler BJ et al. Arthritis Rheum. 2005;52:
Reduction in lipids
Petri M. Lupus. 1996;5(Suppl. 1):S16-S22.
Wallace DJ et al. Am J Med. 1990;89:
Reduction in thrombosis
Pierangeli SS, Harris EN. Lupus. 1996;5:
Petri M. Scand J Rheumatol. 1996;25:
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:
Prevents seizure
Hanly JG et al. Ann Rheum Dis. 2012;71;

11. Hydroxychloroquine for Lupus Nephritis
Continuing hydroxychloroquine improves complete response rates with mycophenolate mofetil
Kasitanon N et al. Lupus 2006;15:

12. Slope over range of 0-40 ng/mL Slope over range of ≥40 ng/mL (95% CI)
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)
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:

13. 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:

14. Vitamin D May Have Cardiovascular and Hematologic Benefits
Targher G et al. Semin Thromb Hemostasis. 2012;38:

15. 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 ), 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: Brøndum-Jacobsen P et al. J Thromb Haemost ;11: Grant WB. Am J Hematol. 2010;85: Lindqvist PG et al. J Thromb Haemost ;7: Kojima G et al. Stroke. 2012;43: Shanker J et al. Coron Artery Dis. 2011;22:

16. 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: Petri M et al. Arthritis Rheum. 2004;50:

17. Prasterone Reduces SLE Flares

18. 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:

19. 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:

20. 4. Mycophenolate Mofetil: The Good, the Bad, . . . . .

21. 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
Key point: MMF in african americans and hispanics
Not FDA-indicated for SLE
1. Appel GB, et al. J Am Soc Nephrol.2009;20(5): ; Ginzler EM, et al. Arthritis Rheum. 2010;62(1): ; Tornatore KM, et al. J Clin Pharmacol 2011;51: FDA Warning label for MMF.

22. Lupus Nephritis Maintenance Therapy : MMF is Superior to Azathioprine
Time to treatment failure
Time to renal flare
Dooley MA, et al. N Engl J Med. 2011;365:
Not FDA-indicated for SLE

23. 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 6.
Efficacy and safety of belimumab in patients with active systemic lupus erythematosus: a randomised, placebo-controlled, phase 3 trial.
Navarra SV, Guzmán RM, Gallacher AE, Hall S, Levy RA, Jimenez RE, Li EK, Thomas M, Kim HY, León MG, Tanasescu C, Nasonov E, Lan JL, Pineda L, Zhong ZJ, Freimuth W, Petri MA; BLISS-52 Study Group.
Lancet Feb 26;377(9767): Epub 2011 Feb 4.
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; /j x; 7. Li X, et al. Nephrol Dial Transplant. 2011; doi: /ndt/gfr484; 8. Cortes-Hernandez J, et al; Nephrol Dial Transplant. 2010;25(12): Lanata CM, et al. Lupus. 2010:19(8): Szeto CC, et al. Rheumatology. 2008;47(11): ; 11. Rovin BH, et al. Arth Rheum. 2012; doi: /art Chen W, et al. Lupus. 2012:21(7):

24. Time to Remission and Relapse After Rituximab Treatment and MMF Maintenance
Condon MB, et al. Ann Rheum Dis. 2013;72:

25. 5. Better Understanding of Belimumab

26. 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
Factors Associated With Belimumab Treatment Benefit:
Results From Phase 3 Studies in Patients With Systemic Lupus Erythematosus
R.F. van Vollenhoven,1 M. Petri,2 R. Cervera,3 C. Kleoudis,4 Z.J. Zhong,5 D. Roth,6 W. Freimuth,5 for the BLISS-52 and BLISS-76 Study Groups
1The Karolinska Institute, Stockholm, Sweden; 2Johns Hopkins University School of Medicine, Baltimore, MD; 3Hospital Clinic, Barcelona, Spain; 4GlaxoSmithKline, Durham, NC; 5Human Genome Sciences, Inc., Rockville, MD; 6GlaxoSmithKline, King of Prussia, PA
van Vollenhoven, et al. Ann Rheum Dis, [April Epub ahead of print, doi: /annrheumdis ].

27. 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

28. SELENA SLEDAI Organ Improvement (Week 52)a
Improvement = decrease in SS score within an organ domain
Manzi S, et al. Ann Rheum Dis, [May Epub ahead of print, doi: /annrheumdis ].

29. Belimumab vs Placebo: Severe Flares
In the overall pooled population, belimumab-treated
patients had reduced risk of severe flares over 52 wk vs
routine therapy alone
– The rate of severe flares/patient-y (95% CI) from wk
24−52 was 0.24 (0.18, 0.31) with placebo, 0.15 (0.11, 0.2)
with belimumab 1 mg/kg (p = 0.023), and 0.16 (0.12,
0.21) with belimumab 10 mg/kg (p = 0.040), based on
observed data in 476, 496, and 495 patients in the
3 treatment groups, respectively
Cervera R, et al. Presented at EULAR 2011: Annual European Congress of Rheumatology;
May 25–28, 2011; London, UK

30. 6. Don’t Forget New Information on Common Drugs

31. http://www. medpagetoday
(accessed on 3/12/2014)

32. New Data on PPIs

33. Proton Pump Inhibitors and Fractures
(accessed on 3/12/2014)

34. http://www. news-medical
(accessed on 3/12/2014)

35. 7. Progress on Coronary Artery Disease

36. 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: ; 2. Ward MM. Arthritis Rheum. 1999;42(2):338-46;
3. Magder LS, Petri M. Am J Epidemiol. In press.

37. 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: Maksimowicz-McKinnon K et al. J Rheumatol. 2006;33: Kiani AN et al. J Rheumatol. 2010;37:

38. 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:

39. Prevention of CAD in SLE

40. Atorvastatin Did Not Change
Coronary calcium
Carotid intima media thickness
Carotid plaque
Petri M et al. Ann Rheum Dis 2010;70: Schanberg LE et al. Arthritis Rheum. 2012;64:

41. Can We Reduce Cardiovascular Risk?
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
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 ;71(3):408-14; 4. Gibson WT, Hayden MR. Ann N Y Acad Sci Sep;1110:209-21; 5. Magder L, et al. Am J Epidemiol. 2012; in press.

42. 8. Prevention of Thrombosis in SLE: Are We There Yet?

43. Venous Thrombosis in SLE
Cumulative S(t)
Time Since SLE Diagnosis (years)
Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.

44. 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
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

45. 9. Don’t Make Fibromyalgia WORSE (It’s Bad Enough as it is!)

46. 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)
Key point: note that this study was conducted in patients with fibromyalgia; FIQ score: measures physical function, fatigue, morning tiredness, stiffness, depression, anxiety, job difficulty, and overall well being.
At 12 weeks, the tai chi group had a significantly
greater decrease in the total FIQ score
than did the control group (−27.8 points [95%
confidence interval {CI}, −33.8 to −21.8] vs. −9.4
points [95% CI, −15.5 to −3.4]). The mean betweengroup
difference was −18.4 points (95% CI, −26.9
to −9.8).
FIQ=fibromyalgia impact questionnaire;
*”clinically meaningful” change in FIQ = 8.1 points
Wang C, et al. N Engl J Med.2010;363(8):

47. 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.

48. 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 (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
Tench CM, et al. Rheumatology. 2003;42:

49. “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.”
(accessed on 3/12/2014)

50. 10. Headaches Aren’t Usually Due to Lupus

51. http://www. hopkinslupus
(accessed on 3/12/2014)