Systemic Lupus Erythematosus An Update Michelle Petri MD

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

Faculty Disclosures § Clinical Trials – – – HGS/GSK Medimmune Pfizer TEVA Anthera UCB § Consultant – Genentech – Lilly – Merck Serono

Why Do I Have Lupus? 2/3 Genetics 1/3 Environmental

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

What are Gene Signatures?

Genes That Define the LDG-Enriched Neutrophil Gene Signature

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.

Why Do Men Get Lupus?

Men vs Women 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

An Ounce of Prevention is Worth a Pound of Cure

Hydroxychloroquine (Plaquenil) is a Long-Term Medicine in Lupus For Prevention

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): S 16 -S 22. 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: S 726. Ruiz-Irastorza G, et al. Lupus 2005; 14: 220 Triples mycophenolate response Kasitanon N, et al. Lupus. 2006; 15(6): 36670

Hydroxychloroquine May Prevent Thrombosis Study Design (n) Wallace et al, 1987 retrospective (92) Petri et al, 1994 prospective cohort (393) Thrombosis Out. Studies come arterial + venous P < 0. 05 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): S 297; 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

Low Vitamin D is Part of Lupus

Vitamin D Deficiency in Human SLE Number of Study Design SLE Patients Measures of Disease Activity Association with Disease Activity. Study Year 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-2 K and ECLAM Ruiz-Irastorza G et al. 2010 60 Prospective Cohort SLEDAI Bonakdar ZS et al. 2011 40 Cross-sectional BILAG P = 0. 001 Reynolds JA et al. 2011 75 Cross-sectional SLEDAI-2 K P = 0. 031 Souto M et al. 2011 159 Cross-sectional SLEDAI-2 K Yeap SS et al. 2012 38 Cross-sectional SLEDAI P = 0. 018 NS NS P = 0. 03

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.

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. 021. 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.

I Don’t Understand My Lab Tests

Blood Counts § White Blood Count § Platelets § Hematocrit (anemia)

Kidney Tests § Urine protein/cr ratio § Blood creatinine

Why Does Dr. Petri Emphasize Control of Risk Factors for Heart Disease?

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

What is an Antiphospholipid Antibody? What does it Do?

§ Lupus anticoagulant = RVVT confirm § Anticardiolipin § Anti-beta 2 Glycoprotein 1

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

I am tired all the time – isn’t it my lupus?

Prevalence of Fibromyalgia Number of Patients 29. 6% had 11 or more tender points

How Do We Treat Fibromyalgia? § Tai Chi Stretching § Amitriptyline at bedtime § FDA-approved medications – Lyrica – Savella – Cymbalta

Treatment Update

Prednisone is Poison!

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.

Prednisone Itself Increases the Risk of Cardiovascular Events Prednisone use Never taken Observed number of CVE Rate of events/1000 person years Age-adjusted rate ratios (95% CI) 22 13. 3 1. 0 (reference group) P value 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 mg 1 14 9. 9 0. 9 (0. 4, 1. 6) . 56 3650 -10, 950 mg 2 26 13. 8 1. 2 (0. 7, 2. 2) . 49 10, 950 -36, 499 mg 3 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.

FLOAT Trial Comparison of Oral Methylprednisolone and Intramuscular Triamcinolone Methylprednisolone Triamcinolone 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% Complete Improvement Danowski A, et al. J Rheumatol. 2006; 33: 57 -60.

I have kidney lupus – what next?

Treatments for Kidney Lupus § Mycophenolate (Cellcept) § ACE inhibitor or ARB § Hydroxychloroquine (Plaquenil) § Vitamin D

Bad News: Mycophenolate Doesn’t Work For All § Cyclophosphamide § Tacrolimus (Prograf) § Rituximab (Rituxan)

What are the New Therapies?

Belimumab (Benlysta) § It blocks a growth factor (called BLy. S or BAFF) that keeps autoimmune B cells alive § It is most likely to work if: – the lupus requires prednisone – the lupus is VERY active – there is anti-DNA AND low complement

What Will be Available in the Future? § Anti-IL-6 § Anti-interferon alpha § Anti-BAFF/BLy. S § Anti-CD 22

Articles on Lupus Center § At the Hopkins Arthritis Center main page (www. hopkinsarthritis. org) scroll down to the bottom of the page. § Click on the “Lupus Center” link on the bottom right hand side. § At the Lupus Center main page, click the “About the Center” link near the top left corner.