Evaluation and Management of Systemic Lupus Erythematosus, 2015

Michelle Petri, MD, MPH Professor of Medicine,

Johns Hopkins University School of Medicine Director, Hopkins Lupus Center

Baltimore, MD

February 20, 2016 CSRO

JW Marriott San Francisco, CA

• This CME activity is intended for practicing physicians, and other health care providers who may treat patients who have Systemic Lupus Erythematosus.

• There is no fee for participation in this CME activity.

This program is made possible through an

educational grant from UCB, Inc.

Accreditation

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of University Health Services Professional Education Programs (UHS-PEP) of Virginia Commonwealth University Health System and Miller Professional Group. UHS-PEP is accredited by the ACCME to provide continuing medical education for physicians.

UHS-PEP designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

CME Credit Statements

To receive continuing education credit, please complete the evaluation and Verification of Participation form and submit following the meeting. Credit Statements will be mailed within four weeks of activity completion.

IT IS ALSO A REQUIREMENT UPON EACH SPEAKER TO NOTIFY HIS/HER AUDIENCE

WHENEVER OFF-LABEL USE IS DISCUSSED.

Please Complete and Return

In the CME section of your meeting folders you will find the

• Program evaluation form

• Verification of participation form

These documents are used to evaluate the effectiveness of our programming, and to justify future educational programs of this quality.

Please be sure to return these completed forms to the speaker at the end of the program.

Please be aware you will receive (via e-mail) a follow-up questionnaire similar to the educational effectiveness survey you will complete for this program. It will come from the e-mail address rheumreply@optonline.net

Please be sure to return the completed follow up questionnaire.

Conflict of Interest Disclosures

Presenters

Michelle Petri, MD has reported participated in clinical trials for GSK, Medimmune, Pfizer and UCB; and is a Consultant for GSK, Pfizer, UCB and BMS.

The Planners of this activity report the following disclosure information:

John Boothby, Director, Continuing Medical Education, UHS-PEP has nothing to disclose.

Alan Epstein, MD is a member of the Speaker’s Bureau for Abbvie, Janssen, BMS, Celgene, Pfizer, Genentech and GSK.

Max Hamburger, MD is a member of the Speaker’s Bureau for UCB, BMS, Abbvie, Crescendo Bio and GSK; and is a Grant Recipient for UCB, BMS and Abbvie.

Objectives

Upon completion of this program, attendees will be able to:

• Evaluate the importance of the disease burden in SLE, consequences of inadequate disease control, and consequences of inflammatory burden on patients, their families, their communities and the healthcare system;

• Describe and discuss the impact of disease activity on patient outcomes, and the challenges of implementing treat to target concepts as applicable in the management of this highly pleomorphic disease;

• Apply current concepts of management including approaches to measurement of organ inflammation and/or involvement and disease activity;

• Collaborate with patients in the implementation of treatment goals; and

• Apply the principles of evidence based medicine to optimize SLE patient care by

1) Effectively using currently available tools for assessing disease activity in patients with lupus; evaluating the EULAR monitoring guidelines and applying them into the care of their lupus patients; and

2) Applying the treatment strategies from the EULAR and ACR guidelines and SLICC in their clinical practices and thereby optimizing patient care and functioning.

Treat to Target(s)

The Lupus 12 Step Program

Michelle Petri MD MPH

Johns Hopkins University School of Medicine

1. Classification Criteria Help in Everyday Practice (i.e. Diagnosis)

SLICC* Classification Criteria

At least 1 clinical + at least 1 immunologic criterion (for a total of 4)

OR

lupus nephritis by biopsy (in the presence of ANA or anti-DNA antibodies)

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 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.

DERMATOLGIC

4 OTHER SYSTEMS

HEMATOLOGIC

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. Understand Lupus Activity Indices Used in Clinical Trials

(Measure Activity That is Really Lupus)

Physician’s Global Assessment (PGA)

0 1 2 3

‘Severe’ means the worst in the universe of lupus,

not the worst for an individual patient

1. Furie, RA et al. Arthritis Rheum 61:1143-51.

2. Petri et al. J Rheumatol 1992;19:53-9.

• Used to assess the patient’s overall condition

• A visual analogue scale (10cm) ranging from 0–3 points

(no activity to severe life-threatening activity)

• ≥0.3-point increase (10%) = clinically-relevant worsening1

• Correlates with other disease activity indices2

Petri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8;

SELENA-SLEDAI

SELENA-SLEDAI Flare index

Petri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8;

9 Organ Systems are individually scored:

Constitutional, Mucocutaneous, Neuropsychiatric,

Musculoskeletal, Cardiorespiratory, Gastrointestinal,

Ophthalmic, Renal, Haematological

Each organ is scored for severity over the past month:

based on the net impact of individual symptoms

A=severe B=moderate C=mild D=inactive organ E=never active organ

Symptom Last Month Progress This Month Score Organ System

Severe Arthritis Same or Worse A Musculoskeletal

Severe Arthritis Significantly Improving B Musculoskeletal

No Rash New Severe Rash A Mucocutaneous

Severe Rash Significantly Improving B Mucocutaneous

Moderate Rash Significantly Improving C Mucocutaneous

BILAG 2004

SLE Responder Index (SRI) Used in Belimumab Phase III Trials

1. Petri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8; 2. Hay EM, et al. Q J Med.

1993;86(7):447-458; 3.Navarra SV, et al. Lancet 2011;377:721-31.

SRI

SELENA-SLEDAI ≥4-point reduction in

SELENA-SLEDAI

score1

Assesses 24 weighted variables to indicate

overall disease severity

BILAG No new BILAG A or

2 new BILAG B organ

domain scores2

Measures flare activity and severity across

8 organ domains

PGA No worsening in PGA

(<0.3-point increase)3

An overall assessment of changes in patient condition

and disease severity

SRI Responders Had to Meet All 3 Criteria

Landmark assessment All organs with moderate or severe activity at baseline (BILAG A) have improved: BILAG A (severe) improves to B (moderate) C (mild) or D (no activity) BILAG B (moderate) improves to C (mild) or D (no activity) and There is no worsening by BILAG, SLEDAI or Physician’s Global Assessment (PGA may not increase by more than 10% of the scale)

BILAG-based Composite Lupus Assessment: BICLA Used in Epratuzumab Phase II and III Trials

SLE Responder Index: Responders vs Nonresponders

Furie R et al. ACR 2011; Strand V et al. ACR 2011

Parameter SRI Resp (n=761)

SRI Nonresp (n=923)

> 7 point reduction 40.3% 1.3%

# organ domains improved (BILAG/SS) 1.45/2.00 0.40/0.39

% Change in PGA -58.3% -34.9%

Severe flare rate (SLE Flare Index) at wk 52 6.2% 29.1%

Reduction in prednisone to <7.5 mg/d 25.5% 16.4%

Increase in prednisone to >7.5 mg/d 4% 22%

Changes in DNA/C3/C4 -34%/14%/40% -26%/9%/29%

SF-36: PCS/MCS (MCID=2.5) 4.9/4.4 2.6/1.7

Fatigue (FACIT/SF-36 Vitality; MCID=4/5) 5.2/10.4 3/6.5

Furie et al. Lupus Sci Med. 2014 Jun 26;1:e000031. doi: 10.1136/lupus-2014

3. Avoid Maintenance Prednisone > 6 mg

Prednisone Is Directly or Indirectly Responsible for 80% of Organ Damage over 15 Years

Gladman DD, et al. J Rheum. 2003;30(9):1955-1959

CVS=cardiovascular system; GI=gastrointestinal; MSK=musculoskeletal

NP=neuropsychiatric

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.

4. Non-immunosuppressive Immunomodulators Can Control Mild-Moderate SLE, Helping to

Avoid Steroids

Immunomodulators

• Hydroxychloroquine1

• Vitamin D2

• Prasterone (synthetic dihydroepiandrosterone,

or DHEA)3

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.

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.

Criteria of Low and Higher Risk for Developing Retinopathy

Low Risk Higher Risk

Dosage < 6.5 mg/kg hydroxychloroquine < 3 mg/kg chloroquine

>6.5 mg/kg hydroxychloroquine > 3 mg/kg chloroquine

Duration of use < 5 years > 5 years

Habitus Lean or average fat High fat level (unless dosage is appropriately low)

Renal/liver disease None Present

Concomitant retinal disease

None Present

Age < 60 years > 60 years

Marmor MF et al. Ophthalmol 2002;109:1377-82.

Only SLE Patients with Visual Symptoms Need High Tech hsUHR-OCT (Optical Coherence Tomography) or mfERG (multifocal electroretinogram)

Rodriguez-Padilla JA, et al. Arch Ophthalmol 2007;125:775-80.

• Optical Coherence Tomography

• Serous retinopathy

• Multifocal Electroretinogram

• Cataracts

Common Causes of Abnormalities

Top: Normal Spectralis spectral domain optical coherence tomography (SD OCT) image with intact photoreceptor inner segment/outer segment junction (IS/OS). Bottom: Spectralis SD OCT from the left eye of patient 10 showing the “flying saucer” sign of hydroxychloroquine retinopathy, an ovoid appearance of the central fovea created by preservation of central foveal outer retinal structures (seen between the black arrows) surrounded by perifoveal loss of the photoreceptor IS/OS junction, and perifoveal outer retinal thinning. Abbreviations: ILM, internal limiting membrane; IPL, inner plexiform layer; OPL, outer plexiform layer; ELM, external limiting membrane; RPE, retinal pigment epithelium.

From: Chen E1, Brown DM, Benz MS, Fish RH, Wong TP, Kim RY, Major JC. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the “flying saucer” sign). Clin Ophthalmol. 2010 Oct 21;4:1151-8. doi: 10.2147/OPTH.S14257.

High-Speed Ultra–High-Resolution Optical Coherence Tomography Findings in Hydroxychloroquine Retinopathy¹

Question: are early toxic effects from hydroxychloroquine (HCQ) detectable by hsUHR-OCT before clinical signs or symptoms

Fifteen patients referred for evaluation of HCQ maculopathy were studied.

Six age-matched patients with normal visual function were studied with hsUHR-OCT

hsUHR-OCT abnormality severity of maculopathy seemed to correlate with severity of mfERG and visual field testing

Unable to find an asymptomatic patient with evidence of definite damage on hsUHR-OCT

¹Julio A. Rodriguez-Padilla, et al, Arch Ophthalmol. 2007;125:775-78J0

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)

0.026 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.

5. Treatment of Lupus Nephritis is NOT Just Immunosuppression!

ACR Guidelines for Kidney Biopsy

Indications for Kidney Biopsy*

Increasing serum creatinine without compelling alternative causes (eg, sepsis, hypovolemia, or medication)

Confirmed proteinuria of 1.0 gm/24 hours (either 24-hour urine specimens or spot protein-creatinine ratios)

Combinations of the following, assuming the findings are confirmed in at least 2 tests done within a short period of time and in the absence of alternative causes:

• Proteinuria 0.5 gm per 24 hours plus hematuria, defined as 5 RBCs per HPF

• Proteinuria 0.5 gm per 24 hours plus cellular casts

*All recommendations are level of evidence C. Hahn BH, et al. Arthritis Care Res. 2012;64:797-808.

EULAR Guidelines for Kidney Biopsy

Indications for Kidney Biopsy Level of

Evidence Statement Strength

Any sign of renal involvement; in particular, urinary findings including reproducible proteinuria ≥0.5 g/24 hours especially with glomerular haematuria and/or cellular casts

2 C

Clinical, serological or laboratory tests correlate modestly with renal biopsy findings. Proteinuria of ≥0.5 g/24 hours.

2 B

Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.

Adjunctive Therapy for Proteinuria

ACE-inhibitor

Angiotensin receptor blocker Duran-Barragan S, et al. Rheumatology 2008 47:1093-1096.

Spironolactone 25 mg or eplerenone 50 mg Epstein. Am J Med 2006;119:912-919.

ACR Guidelines: Adjunctive Therapies All SLE patients with nephritis should be treated with a background of

hydroxychloroquine unless there is a contraindication (level C evidence)

For patients with proteinuria 0.5 gm/24 hours (or equivalent by protein/creatinine ratios on spot urine samples), a blockade of the renin–angiotensin system, which drives intraglomerular pressure, is recommended (level A evidence for nondiabetic chronic renal disease)

Target blood pressure of 130/80 mm Hg (level A evidence for nondiabetic chronic renal disease)

Statin therapy should be introduced in patients with low-density lipoprotein cholesterol 100 mg/dL (level C evidence)

Women of child-bearing potential with active or prior lupus nephritis receive should counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence)

Hahn BH, et al. Arthritis Care Res. 2012;64:797-808.

EULAR Guidelines: Adjunctive Therapies Angiotensin-converting enzyme (ACE) inhibitors or angiotensin

receptor blockers (ARBs) for proteinuria or hypertension (level of evidence: 2; strength of statement: B)

Cholesterol lowering with statins for persistent dyslipidaemia (strength of statement: C)

Hydroxychloroquine (level of evidence: 3; strength of statement: C)

Acetyl-salicylic acid in patients with anti-phospholipid antibodies (strength of statement: C)

Calcium and vitamin D supplementation (strength of statement: C)

Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.

Initial Therapy: Class IV

ACR

– Mycophenolate mofetil (2-3 gm total daily orally) or IV cyclophosphamide along with glucocorticoids is recommended (level A evidence)

• Evidence suggestions that mycophenolate mofetil may be more likely to induce improvement in patients who are African American or Hispanic

EULAR

– Mycophenolic acid (mycophenolate mofetil target dose: 3 g.day for 6 months or mycophenolic acid sodium at equivalent dose) (level of evidence: 1; statement strength: A) or low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) in combination with glucocorticoids (level of evidence: 1; statement strength: B) are recommended as initial treatment as they have the best efficacy/toxicity ratio

Hahn BH, et al. Arthritis Care Res. 2012;64:797-808. Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.

Non-Caucasians Do Better with Mycophenolate

0

10

20

30

40

50

60

70

Asian Caucasion Combined Other* African American

Mycophenolate Mofetil IV Cyclophosphamide

P = 0.24

P = 0.83

P = .03

P = 0.39

Post Hoc Analysis

Re

spo

nd

ers

(%)

*Includes African Americans. Isenberg D, et al. Rheumatology (Oxford). 2010;49:128-140.

Initial Therapy: Class IV How Much Steroid? ACR

– Pulse IV glucocorticoids (500-1000 mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended, followed by daily oral glucocorticoids (0.5-1 mg/kg/ day), followed by a taper to the minimal amount necessary to control disease (level C evidence)

EULAR

– To increase efficacy and reduce cumulative glucocorticoid doses, treatment regimens should be combined initially with 3 consecutive pulses of IV methylprednisolone 500-750 mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to ≤10 mg/day by 4-6 months

Hahn BH, et al. Arthritis Care Res. 2012;64:797-808. Bertsias GK, et al. Ann Rheum Dis. 2012;71:1771-1782.

There May Still Be a Role for Rituximab: Can We Avoid Steroids?

Condon MB, et al. Ann Rheum Dis. 2013;72:1280-6; Fischer-Betz et al. J Rheumatol. 2012;39:2111-7.

Multitarget Therapy for Induction Treatment of Lupus Nephritis

Multi-Target (Tacrolimus + MMF) IV Cytoxan

Complete Remission 45.9% 25.6%

Overall Response 83.5% 63.0%

Liu Z, et al. Ann Intern Med 2015;162:18-26.

Lupus Nephritis Maintenance Therapy : MMF is Superior to Azathioprine

Time to treatment failure Time to renal flare

N=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

6. Biologics in SLE

There are Many Potential Targets for

SLE Biologics

M. Ramanujam and A. Davidson. Arthritis Research and Therapy. 2004. 6:197-202.

Adapted from Ramanujam M, Davidson A. Arthritis Res Therapy. 2004;6:197-202.

X

TACI-Ig

BAFF-R-Ig

Anti-BLyS

X X CTLA4Ig

X

X

E-mab

CTX

Anti-CD40L Anti-CD40L X

X Sifalimumab

X Anti-IL-6

A Post-hoc Analysis Identifies SLE Patients

Likely to Respond to Belimumab

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].

The Subgroup with BOTH High Anti-dsDNA and Low Complement is About 20% More Likely to

Respond to Belimumab

van Vollenhoven RF, et al. Presented at EULAR 2011; May 25-28, 2011; London, UK

A Post-hoc Analysis Shows the Organ

Systems that Respond to Belimumab

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 Reduced Severe Flares

Cervera R, et al. Presented at EULAR 2011: Annual European Congress of Rheumatology;

May 25–28, 2011; London, UK

Open label 296 patients

SLE Responder Index

Year 2 – 57%

Year 7 65%

Anti-dsDNA 40-60%↓

Prednisone 50-55%↓

Seven Year Followup on Belimumab

Ginzler EM, et al. J Rheumatol. 2014;41:300-7

1Tedder T F & Engel P. Immunol Today. 1994;15:450-454. 2Mok M Y. Int J Rheum Dis. 2010;13(1):3-11.

3Dörner T et al. Int Rev Immunol. 2012;31:363-378. 4Sieger N et al. Arth Rheum. 2013;65:770-779.

Epratuzumab (Anti-CD22) Mechanism of Action

2. CD22 negatively

regulates the BCR on B

cells3

Effector molecule recruitment3

CD22

1. Antigen binds to the

BCR and induces B cell

activation1,2

Cascade of downstream signalling

leading to calcium influx1

Gene transcription1

B cell activation2

BCR

CD79α/β

5Carnahan J et al. Clin Cancer Res. 2003;9:3982S-90S. 6Qu Z et al. Blood. 2008;111:2211-2219. 7Rossi E A et al. Blood. 2013;122:3020-3029. 8Jacobi A M et al. Ann Rheum Dis 2008;67:450–457.

3. Emab binds CD22 and acts

as a regulator of BCR-driven

activation of B cells3

Internalisation5 and

removal of BCR

proteins from the B cell

surface7

Reduced calcium flux4

Reduced BCR signalling4

B cell modulation8

Localisation4

CD22

phosphorylation5,6

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en

t of S

LE

Glossary

Epratuzumab Mechanism of Action

Epratuzumab induces the loss of BCR-related proteins from the B cell

surface in vitro

Adapted from Rossi, E. et al. Blood. 2013; 122(17):3020-29

% o

f untr

eate

d

Epratuzumab

Labetuzumab (isotype control)

CD22 internalised into B cells

CD19 trogocytosis on to monocytes

Experiments with Daudi B cell line and

primary human monocytes

Experiments with primary human B

cells

7. SLE Pregnancy is High Risk

•4,500/year U.S. SLE pregnancies

•20-fold increase mortality

•OR 1.7 C-section

•OR 2.4 Preterm labor

•OR 3.0 Pre-eclampsia

Ginzler EM, et al. Am J Obstet Gynecol. 2008;199:127.e1-6

Adverse Pregnancy Outcome

APO No APO

LAC 39% 3% (p < 0.0001)

Lockshin MD et al. Arthritis Rheum. 64:2311-8, 2012.

Comparison of Heparin/Aspirin vs Aspirin for Pregnancy-APS

Author Year Size Comparison

Arm 1

Comparison

Arm 2

Study Outcome

Kutteh 1996 50 Heparin initiated at

10,000 units

daily in 2

divided doses

Aspirin 81 mg/day

Aspirin 81 mg Heparin/aspirin

Rai 1997 90 UF Heparin 5000

units twice daily

Aspirin 75 mg

Aspirin 75 mg Heparin/aspirin

Farquharson 2002 98 LMW Heparin 5000

units

Aspirin 75 mg

Aspirin 75 mg No difference

8. 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.

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.

• Assess traditional cardiovascular risk factors and treat to target • Hypertension

• Obesity

• Hyperlipidemia (hydroxychloroquine)

• Smoking

• Sedentary Lifestyle

• Diabetes (hydroxychloroquine)

• 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.

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

Lupus Anticoagulant Is More Highly Associated With Thrombosis Risk

Petri M, et al. Ann Intern Med. 1987;106(4):524–531.

Derksen RH, et al. Ann Rheum Dis. 1988;47(5):364–371.

Ginsberg JS, et al. Blood. 1995;86(10):3685–3689.

Horbach DA, et al. Thromb Haemost. 1996;76(6):916–924.

Simioni P, et al. Thromb Haemost. 1996;76(2):187–189.

Wahl DG, et al. Lupus. 1997;6(5):467-73.

Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:2531–2536.

Time Since SLE Diagnosis (years)

Cum

ula

tive S

(t)

If Lupus Anticoagulant is Present, There is a 50% Chance of Thrombosis

Aspirin Insufficient for APS Prophylaxis

Aspirin has NOT been proven effective to reduce thrombosis from antiphospholipid antibodies

Ginsburg KS, et al. Ann Intern Med. 1992;117:997–1002; Erkan et al. Arthritis Rheum 2007;56:2382-2391.

Erkan et al. Arthritis Rheum. 2001;44:1466–1467.

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

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

Treating Pain: 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 (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.

11. Don’t Forget New Information on Common Drugs

Cardiovascular Risk of NSAIDS

Salvo F, et al. Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies. Expert Opin Drug Saf. 2014;13:573-85.

Chinthapalli K. High dose NSAIDs may double the risk of heart attacks and heart failure, says new study. BMJ. 2013;346:f3533.

Trelle S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.

New Data on PPIs

Proton Pump Inhibitors Increase Osteoporotic Fractures Yu EW, et al. Proton pump inhibitors and risk of fractures: a

meta-analysis of 11 international studies. Am J Med. 2011;124:519-26.

Maggio M, et al. Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. Bone. 2013;57:437-42.

Ding J, et al. The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int. 2014;94:597-607.

Moberg LM, et al. Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas. 2014;78:310-5

Proton-Pump Inhibitors Increase Risk of Cardiovascular Events Ghebremariam YT, et al. Unexpected effect of proton pump

inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013;128:845-53

Zou JJ, et al. Increased risk for developing major adverse cardiovascular events in stented Chinese patients treated with dual antiplatelet therapy after concomitant use of the proton pump inhibitor. PLoS One. 2014;9(1):e84985.

Shih CJ, et al. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. Int J Cardiol. 2014;177:292-7.

Leonard CE, Comparative Risk of Ischemic Stroke Among Users of Clopidogrel Together With Individual Proton Pump Inhibitors. Stroke. 2015 Feb 5. pii: STROKEAHA.114.006866. [Epub ahead of print]

12. Don’t Confuse Permanent Organ Damage with Active SLE or Co-

Morbidity

Percentage of Patients With Permanent Organ Damage

Chambers SA, et al. Rheumatology (Oxford). 2009;48:673-675.

One-Third of SLE Patients Accrue Permanent Organ Damage Within 5 Years of Diagnosis

Pe

rce

nt

of

Pat

ien

ts W

ith

SD

I ≥1

5 Years (N=232)

1 Year (N=232)

10 Years (N=232)

15 Years (N=143)

20 Years (N=75)

25 Years (N=6)

0.11 0.42 0.77 1.01 1.26 2.17 Mean

Damage Score

Retrospective analysis of records for patients with ≥10 years of consistent follow-up presenting at the University College London Hospital SLE clinic. Year 0 represents time of diagnosis. Mean age at diagnosis was 31.2 years, 95% of patients were female, 72% were white, 14% were black, 10% were Asian (Indian), and 4% were "other."

Percentage of Patients With Organ Damage Over 5 Years of Follow-up (N=298)

Disease Activity Over 5 Years of Follow-up (N=298)

Patients Still Accrue Organ Damage Even With Low Disease Activity

Urowitz MB, et al. Arthritis Care Res. 2012;64:132-137.

Me

an T

ota

l SLE

DA

I-2

K

Years in Registry

Pe

rce

nt

of

Pat

ien

ts W

ith

SD

I >0

Years in Registry

Prospective analysis of patients in the SLICC cohort recruited within 15 months of diagnosis and followed annually for ≥5 years. Mean age at enrolment: 35.3 years; 87% female; 55% white, 12% black, 14% Asian, 16% Hispanic, 2% “other.” At enrollment, mean disease duration=5.5 months; mean SLEDAI-2K score=5.9.

Myasthenia Gravis

0.2%

Headache

44.9%

Mood Disorders

15.4%

Myelopathy

1.1%

Pyschosis

2.0%

Polyneuropathy

3.3%

Mononeuropathy

2.2%

Acute Confusional State

3.6%

Cerebrovascular Disease

4.9%

Cognitive Dysfunction

5.3%

Anxiety Disorder

5.8%

Autonomic Disorder

0.2%

Demyelinating Syndrome

0.3%

Movement Disorder

0.9%Aseptic Meningitis

0.8%Neuropathy, Cranial

1.4%

Seizures and Seizure

Disorders

7.7%

NP Events at Enrollment (n=1404) (637 Events in 413 Patients)

Hanly JG, Urowitz MB, et al. Arthritis Rheum 56:265-73, 2007.

Headache Differential

SLE headache

Migraine headache: worsened by SSRIs Katsiari CG, et al. Headache 2011. Tjensvoll AB, etal. Cephalalgia 2010;31:401-408.

Cerebral venous sinus thrombosis (if LAC+)

Drug headache: NSAIDs, IVIG

Infection

Tumor

Heal Your Headache. D Buchholz and SG Reich. Workman Publishing Co., 1st ed., 2002

Headache in SLE

Headache is NOT increased in SLE compared to controls Mitsikostas DD, et al. Brain 127:1200-1209, 2004. Whitelaw DA, Spangenberg JJ. Lupus 18:613-617, 2009.

Mood Disorders

Depression very common: 20% Utset TO et al. J Rheumatol 21:2039-2045, 1994.

Depression correlates with cognitive impairment Petri M, et al. J Rheumatol 37:2032-2038, 2010..

Depression may be related to SLE Utset TO et al. J Rheumatol 21:2039-2045, 1994.

– Neuropsychiatric lupus OR 3.43 p=0.0005

– Secondary Sjogren’s OR 2.97 p=0.0006

Cognitive Impairment is Frequent at Baseline in an Inception Cohort

Scale Mean±SD (range)

SELENA SLEDAI 3.9±4.6 (0-28)

SLICC Damage Index 0.7±1.1 (0-4)

Krupp Fatigue Inventory 4.7±1.7 (1-7)

Calgary Depression Scale 5.0±4.6 (0-18)

Automated Neuronetics Assessments Matrix (ANAM):

1 SD below controls: 60%

2 SD or more below controls: 19%

Petri M, et al. J Rheumatol 37:2032-2038, 2010

Cognitive Impairment at Diagnosis of SLE Improves or is Stable Over Time

Cognitive impairment is common at baseline

It improves over time

Depression is the MOST important associate

Additional Slides

ETIOLOGY

Multifactorial

Predisposing genetic factors---2/3risk

Environmental factors---1/3 risk

Development of autoantibodies linked to pathologic manifestations

Preclinical phase with autoantibodies present years before clinical disease

Autoantibodies Precede the Diagnosis Of SLE By Years

Arbuckle MR, et al. N Engl J Med. 2003;349(16):1526-33.

Clinical SLE Preceded by Complicated Autoimmune Changes

ANA, Anti-Ro, Anti-La, Antiphospholipid antibodies appear first

Anti-dsDNA antibodies appear next

Anti-Sm and Anti-RNP antibodies appear just before disease onset

The number of autoantibody types continues to increase until the time of diagnosis

Immunopathogenesis

Induction of Surface Blebs during Apoptosis

Rahman A, Isenberg DA. N Engl J Med 2008;358:929-939.

Mechanism Summary-I In SLE patients there is defective clearance of apoptotic cells

Leads to exposure of intracellular immunogenic components

Taken up by DC and presented to autoreactive B cells

In the right genetic environment, these

B cells may become activated to produce

autoantibodies

Mechanism Summary-II

Once autoantibodies (particularly anti-DS DNA) are present, they can complex with DNA exposed on dying cells

Results in high levels of IFN-a production

IFN-a encourages a feed-forward mechanism of continued plasma cell activation to produce increased amounts of autoantibodies and encourage further disease progression and tissue destruction

The interferon signature and its regulation in SLE More than half of patients with SLE show a dysregulation in the expression of genes in the IFN pathway The type I IFNs are potent cytokines (IFNα and IFNβ) and also mediate the Th1 response, sustain activated T cells, sustain B cell survival, and lower the B cell activation threshold These responses propagate proinflammatory cytokines, contributing to chronic inflammation and tissue damage IFN also acts as a bridging mechanism between the innate and adaptive immune systems

One of the mechanisms of action of Plaquenil is to inhibit interferon alpha production by pDC’s (also inhibits TLR signaling)

Complement Split Products Bound to RBCs May Help in Diagnosis of SLE

SLE Other

Diseases

Normal

Healthy

EC4d Net MFI (CI 95%) 17.6 (15.2-20.0) 6.3 (5.7-6.8) 5.3 (4.6-6.1)

BC4d Net MFI (CI 95%) 110.4 (96.3–124.5) 34.9 (26.1–41.6) 23.5 (21.4–25.6)

PC4d Net MFI (CI 95%) 16.2 (12.0–20.5) 3.6 (3.0–4.2) 2.0 (1.2–2.8)

ECR1 Net MFI (CI 95%) 13.3 (12.4–14.1) 16.1 (15.1–17.1) 20.7 (19.6–21.7)

Kalunian KC. Abstract 597. Presented at: American College of Rheumatology, 2011.

ANA=antinuclear antibodies; BC4d=complement C4d levels on B cells; ds=double-stranded;

EC4d=complement C4d levels on erythrocytes; ECR1=complement receptor 1 levels on erythrocytes;

MFI=mean fluorescence intensity; MVC=mutated citrullinated vimentin antibodies; PC4d=complement C4d

levels on platelets;SLE=systemic lupus erythematous

Detection of New Clinical Activity in SLE

Variable Detected Number of visits with

new variable (N=173)

Number of patients with

≥1 visit with new

variable (N=127)

Cast 16 16

Hematuria 10 9

Proteinuria 15 15

Pyuria 42 35

Low complement 55 45

DNA antibodies 36 32

Thrombocytopenia 8 7

Leukopenia 7 7

Serum creatinine 9 8

Hemoglobin 6 6

Frequency of New Isolated Variables of Interest in 515

Patients, ≥3 Visits, ≥18 months Follow Up

Key point: Patients should be followed with

clinical and laboratory measures every 3 months Gladman DD, et al. Abstract 2301. Presented at American College of Rheumatology Annual Meeting. 2011.

Hormone Replacemant Therapy

The largest study of 351 postmenopausal women with SLE suggested only a small increase in the risk of flares

Buyon et al, Ann Int Med 2005;142:953

Oral Contraceptive Therapy Double blind, randomized, noninferiority trial.

183 women with inactive(76%) or stable active(24%).

Severe flares occurred in 7.7%receiving OC’s and 7.6%receiving placebo.

Rates of mild-moderate flares were 1.40 flares per person-year in patients on OC’s and 1.44 flares per patient-year for subjects receiving placebo.

Conclusion: oral contraceptives do not increase the risk of flare in women with SLE whose disease is stable.

Petri et al. NEJM 353;24:2550, 2005.

Rate of SLE Mortality Remains High Relative to the General Population Age 16-24---19.2X

Age 25-39---8X

Age 40-59---3.7X

Age >60------1.4X

Bernatsky S, et al. Arthritis Rheum. 2006;54:2550-2557.

Work Loss Is a Common Consequence of SLE • At baseline, 26% were aged 18-34 years and 60% were

35-55 years

– Individuals who reached age 65 without work loss were censored

• Overall, 33% (160/484) of patients stopped working during the 4-year follow-up period

• Work loss associated with incident SLE manifestations by Year 4:

– Musculoskeletal: 34% (58/170)

– Neuropsychiatric: 38% (68/179)

– Thrombotic: 58% (34/59)

Yelin E, et al. Arthritis Care Res (Hoboken). 2012;64:169-175.

ORGAN DAMAGE

Despite Improvements in Survival Rates, SLE Remains a Chronic Disease With Higher Than Expected Mortality Rate

• Survival rates significantly improved in patients diagnosed 1980-1992 vs patients diagnosed 1950-1979

• However, survival is significantly worse than in the general population

Uramoto KM, et al. Arthritis Rheum. 1999;42:46-50.

CONCLUSIONS 1) SLE is a complex disease with predisposing genetic and environmental factors.

2) SLE is difficult to diagnose.

3) SLE is not a pain disease.

4) Limit the use of Prednisone.

5) Selecting treatment can be difficult, but data are emerging that can help.

6) Follow renal disease with urine protein/creatinine ratio.

7) Risk of coronary heart disease greatly increased in patients with SLE.

8) Hydroxychloroquine

9) We have a lot of work to do: pt dx’ed at age 20 has 1/6 chance of dying by age 35