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

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Presentation on theme: "What’s New in SLE? A Ten Step Program Michelle Petri MD MPH Johns Hopkins University School of Medicine."— Presentation transcript:

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 Petri M et al. Arthritis Rheum. 2012;64: *Systemic Lupus International Collaborating Clinics SLICC has recommended that BOTH the revised ACR criteria AND the new SLICC classification criteria be used

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/mm 3 at least once) OR Lymphopenia (<1000/mm 3 at least once) 11. Thrombocytopenia (<100,000/mm 3 ) 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-  2 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/day1.16 >6-12 mg/day1.50 >12-18 mg/day1.64 >18 mg/day2.51 Thamer M et al. J Rheumatol. 2009;36: Adjusted for confounding by indication due to SLE disease activity

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 (reference group) Currently taking 1-9 mg/d (0.8, 2.0) mg/d (1.5, 3.8) mg/d (3.1,8.4)< Magder LS, Petri M. Am J Epidemol. 2012;176:

9 3. Non-immunosuppressive Immunomodulators Can Control Mild- Moderate SLE, Helping to Avoid Steroids Hydroxychloroquine 1 Vitamin D 2 Prasterone (synthetic dihydroepiandrosterone, or DHEA) 3 N-acetylcysteine 4 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 Increasing 25-Hydroxy Vitamin D Modestly Helps Disease Activity and Urine Protein/CR 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) (–0.02, 0.04) 0.50 SELENA-SLEDAI –0.22 (–0.41, –0.02) (–0.01, 0.24) Log Urinary Protein/Creatinine –0.03 (–0.05, –0.02) –0.01 (–0.01, 0.00) 0.24 Petri M et al. Arthritis Rheum. 2013;65: 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

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 VTE 2 Higher rates of VTE in African-Americans 3 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= Asian Indian cohort: mean vitamin D lower in CAD P= Beer TM et al. Br J Haematol. 2006;135: Brøndum-Jacobsen P et al. J Thromb Haemost. 2013;11: Grant WB. Am J Hematol. 2010;85: Lindqvist PG et al. J Thromb Haemost. 2009;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-Americans3 grams  Caucasians2 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): ; Ginzler EM, et al. Arthritis Rheum. 2010;62(1): ; Tornatore KM, et al. J Clin Pharmacol 2011;51: FDA Warning label for MMF. Not FDA-indicated for SLE

22 Lupus Nephritis Maintenance Therapy : MMF is Superior to Azathioprine Time to treatment failureTime to renal flare N=227 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 nephritis 1,2 Leflunomide For mild-to-moderate SLE disease 3 Induction therapy for renal flare 4,5 Tacrolimus Consider in MMF-resistant or partial response patients, alone or in combination 6- 9,12 Approved for treatment of LN in Japan For severe nephritis (Class IV/V) 6,10 Rituximab LUNAR trial was negative 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): Leflunomide, tacrolimus, and rituximab are not FDA-indicated for SLE

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 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 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 (accessed on 3/12/2014)

32 New Data on PPIs

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

34 problems.aspx /Research-shows-proton-pump-inhibitors-may-cause-cardiovascular- problems.aspx (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 factors 1 Hospitalization for acute myocardial infarction (AMI) 2.3 times higher in SLE 2 Risk of cardiovascular events is 2.66 times higher in SLE vs Framingham cohort 3 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 CT 1 Carotid duplex 2 In the FUTURE, techniques such as coronary CTA can detect early noncalcified coronary plaques 3 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 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: Coronary Calcium CT

39 Prevention of CAD in SLE

40 Atorvastatin Did Not Change 1.Coronary calcium 2.Carotid intima media thickness 3.Carotid plaque Petri M et al. Ann Rheum Dis 2010;70: Schanberg LE et al. Arthritis Rheum. 2012;64:

41 Assess traditional cardiovascular risk factors and treat to target Hypertension Obesity Hyperlipidemia Smoking Sedentary Lifestyle Statin did NOT reduce progression in mice 3 nor in two clinical trials: Adult 1 Pediatric 2 Mycophenolate: slowed progression in mice 3 and transplant patients 4 Prednisone > 10 mg increases CV event risk 5 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 ;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 Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536. Time Since SLE Diagnosis (years) Cumulative S(t) Venous Thrombosis in SLE

44 Hydroxychloroquine Prevents Thrombosis in SLE StudyStudy DesignOutcome Wallace et al, 1987retrospectiveP < 0.05 Petri et al, 1994prospective cohortOR 0.3 Ruiz-Irastorza et al, 2006prospective cohortHR 0.28 Tektonidou et al, 2009case-controlHR 0.99 Jung et al, 2010nested case-controlOR 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) 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 activity 2 Highly correlated with fibromyalgia, pain, depression, sleep abnormalities, poor quality of life 2-5 Associated with reduced physical fitness 6 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 better3 (9)4 (14)1 (3) Much better13 (40)4 (14)4 (13) A little better5(15)4(14)3(9) No change6(18)10(36)14(41) A little worse4(12)4(15)10(31) Much worse2(6)2(7)1(3) Very much worse000 Tench CM, et al. Rheumatology. 2003;42:

49 fibromyalgia/f2d53e04496f14b f html fibromyalgia/f2d53e04496f14b f 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.”

50 10. Headaches Aren’t Usually Due to Lupus

51 (accessed on 3/12/2014)

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