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Systemic Lupus Erythematosus

10 Things We Hate About Lupus

An Educational Program for Community Rheumatologists

Michelle Petri MD MPH

Johns Hopkins University School of Medicine

Learning Objectives

� Describe the pathophysiology and immunology of

systemic lupus erythematosus (SLE)

� Demonstrate the ability to use current options for

assessing outcomes and measuring disease activity in

SLE

� Assess and compare the risks and benefits of

immunosuppressive drugs, hydroxychloroquine, and

biologics used in the management of mild-to-moderate

SLE and lupus nephritis

� Identify opportunities to reduce organ damage in SLE

patients

1. Lupus is a mystery disease

2. Lupus may be difficult to

diagnose

3. Lupus disease activity is

difficult to measure

4. Patients complain of pain

and fatigue

5. Too much prednisone

6. Which immunomodulator

&/or immunosuppressant

should I use?

7. Activity of lupus nephritis is

difficult to monitor

8. My patients are more likely

to die from atherosclerosis

9. My patients forget what I

tell them!

10. Thrombosis is common

Top 10 Reasons We Hate Lupus

With these challenges, how do we treat lupus to target?

Immunology of SLE

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 XCTLA4Ig

X

XCTX

Anti-CD40L Anti-CD40LX

SLE is 2/3 Genetics!

Chung SA, et al. PLoS Genetics. 2011; 7(3): e1001323

SLE is 1/3 Environmental

� Ultraviolet light

� Drugs/supplements (echinacea, trimethoprim/sulfamethoxazole)

� Smoking

� Infections

� Silica

� Mercury

� Pesticides

Parks CG, et al. Arthritis Rheum. 2002;46:1840–1850; Chiou SH, 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.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.

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Autoantibodies Precede the Diagnosis Of

SLE By Years

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

2. LUPUS MAY BE DIFFICULT

TO DIAG�OSE

SLICC* Classification Criteria

At least 1 clinical + at least 1 immunologic

criteria (for a total of 4)

OR

Lupus nephritis by biopsy

*Systemic Lupus International Collaborating Clinics

Petri M, et al. Arthritis Rheum. 2012, in press.

SLICC Revision of the

ACR Classification Criteria

Clinical Criteria

1. Acute/subacute cutaneous lupus

2. Chronic cutaneous lupus

3. Oral/Nasal ulcers

4. Nonscarring 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

SLICC Revision of the

ACR Classification Criteria

Immunologic Criteria

1. ANA above laboratory reference range

2. Anti-dsDNA above laboratory reference range

(except ELISA: twice above 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-β2 glycoprotein 1

5. Low complement

low C3

low C4

low CH50

6. Direct Coombs test in absence of hemolytic anemia

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

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Anti-C1q Is Associated

with Renal Lupus

Variable Renal

Lupus

(%)1

No Renal

Lupus

(%)1

Association with Renal Flare* (P

value)2

Anti-C1q 45.5 19.3 0.006

Anti-dsDNA 80.2 44.4 0.61-1.0**

Anti-Sm 29.7 15.0 NA

Low

complement

78.2 50.2 C3: 0.079

C4: 0.77

1. Orbai AM, et al. Abstract 1375. Presented at: American College of Rheumatology. 2011; 2. Akhter E, et al. Lupus.

2011;20(12):1267-74.

C1q=complement 1 subcomponent Q; dsDNA=double-stranded DNA; Sm-Smith

3. DISEASE ACTIVITY IS

DIFFICULT

TO MEASURE

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 monthsGladman DD, et al. Abstract 2301. Presented at American College of Rheumatology Annual Meeting. 2011.

Disease Activity Tools: Which One?

“The lack of a gold standard to measure SLE

disease activity or a surrogate marker endorsed by

international rheumatology societies or national

health authorities has impeded the development of

SLE therapies.”

----Furie RA, et al. 2009

Furie RA et al. Arthritis & Rheumatism. 2009;61(9):1143–1151

Physician’s Global Assessment

(PGA)

0 1 2 3‘Severe’ means the worst in the universe of lupus,

not the worst for an individual patient1. 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

SELENA-SLEDAI

� Safety of Estrogens in Lupus Erythematosus National

Assessment - SLE Disease Activity Index

� A validated disease activity index that evaluates 24 lupus

manifestations

� Parameters are scored if present and attributed to active lupus

� Items are weighted with scores ranging from 1-8

– maximum score 105;

• 6–12 is moderate

• 13-20 is severe

• >20 is very severe (and rare)

� Score reduction requires complete elimination of disease

manifestation or resolution of laboratory abnormality

� ≥ 3-7 point reduction = clinically meaningful improvementPetri M at al. N Engl J Med. 2005 Dec 15;353(24):2550-8; Buyon JP et al. Ann Intern Med 2005; 142:953-962

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SELENA-SLEDAI SELENA-SLEDAI: Limitations

� Limitations

– Cannot measure partial improvement of an individual parameter

– Cannot measure worsening of an existing abnormality

– Some items “unfairly” scored (e.g. thrombocytopenia)

– A composite score has limitations

• cannot distinguish patients with multiple mild manifestations

from those with fewer more severe features

• improvement in one organ may be offset by new involvement

in another organ

SRI Used in Belimumab Phase III Trials

1. Bombardier C, et al. Arthritis Rheum. 1992;35(6):630-640; 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

BILAGNo new BILAG A or

2 new BILAG B organ

domain scores2

Measures flare activity

and severity across

8 organ domains

PGANo 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

SRI Responders vs �onresponders

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

4. PATIE�TS ALWAYS

COMPLAI� OF PAI� A�D

FATIGUE

Don’t Blame EVERYTHING on SLE!

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Health-Related Quality of Life

(HRQoL) in SLE

� HRQoL reduction in SLE = that experienced by patients

with AIDS, congestive heart failure, post-myocardial

infarction1-3

� Not well correlated with disease activity or damage

cross-sectionally4

� Age, disease duration, fatigue, and psychosocial

components correlate with HRQoL4

1.Strand V, Crawford B. Expert Rev Pharmacoeconomics Outcomes Res. 2005;317-26; 2.Strand V et al. Arthritis Rheum.

2006;54:S277; 3.McElhone K, et al. Lupus 2006;15:633-43; 4.Thumboo J, Strand V. Ann Acad Med Singapore.2007;36:115-22.

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.

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):743-754.

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.

Treating Fatigue: Belimumab

FACIT-Fatigue=Functional Assessment of Chronic Illness Therapy‐Fatigue;

SF-36=Medical Outcome Survey Short Form 36;SRI=SLE Responder Index

Strand V, et al. ACR/AHCP annual meeting. November 4-9, 2011;Chicago, IL;.

5. TOO MUCH PRED�ISO�E

“The “P” in Prednisone Stands for Poison”

--- Michelle Petri, MD MPH

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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

“High-Dose” Prednisone Should Be

Redefined as > 6 mg Daily

Average Dose Prednisone Hazard Ratio* for Organ

Damage

>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;36:560–564.

High dose (organ damage) = ≥6 mg/day

Prednisone Itself Increases the

Risk of Cardiovascular Events

Prednisone use Observed

number of CVE

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) .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 mg1 14 9.9 0.9 (0.4,1.6) .56

3650-10,950 mg2 26 13.8 1.2 (0.7, 2.2) .49

10,950-36,499 mg3 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. In press.

Mild-to-Moderate Flares Do Not Always

Require Maintenance Steroids

No statistically significant difference in “any response” or in “complete response” (except

in triamcinolone group at week 2); SF-36= SF-36=Medical Outcomes Study Short Form-

36

Danowski A, et al. J Rheumatol. 2006;33:57-80.

Flares in Lupus: Outcome Assessment Trial

(FLOAT): Oral methylprednisolone vs IM

triamcinolone

SF-36

The Placebo Group had More Increased

Steroid Use Over Time than Belimumab

Petri M, et al. Presented at ACR/AHCP annual meeting, November 7-10, 2010; Atlanta, GA; 2. van Vollenhoven RF, et al. Presented at

Presented at ACR/AHCP annual meeting, November 7-10, 2010; Atlanta, GA

The Belimumab Group Was More Likely to

Reduce Prednisone Over Time Than Placebo

Petri M, et al. Presented at ACR/AHCP annual meeting, November 7-10, 2010; Atlanta, GA; 2. van Vollenhoven RF, et al. Presented at

Presented at ACR/AHCP annual meeting, November 7-10, 2010; Atlanta, GA

Reduction in prednisone dose by > 25% to < 7.5 mg/day during Weeks 40-52 in patients receiving > 7.5 mg/day at baseline.

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6. WHICH IMMU�OMODULATOR

A�D/OR IMMU�OSUPPRESSIVE DRUG

SHOULD I PICK?

� Reduces flares1

� Reduces organ damage2

� Reduces lipids3,4,5

� Reduces thrombosis6,7

� Triples mycophenolate response in lupus membranous nephritis8

� Improves survival9,10

1.Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991;324:150-4; 2. Fessler BJ, et al. Arthritis Rheum.

2005;52(5):1473-80; 3. Petri M. Lupus.1996;5(Suppl. 1):S16-S22; 4. Wallace DJ, et al. Am J Med. 1990;89:322-6; 5. Petri M. Curr

Rheumatol Rep. 2011;13(1):77-60; 6.Pierangeli SS, Harris EN. Lupus. 1996;5(5):451-5; 7. Petri M, et al. Curr Rheumatol Rep.

2011;13:77–80; 8. Kasitanon N, et al. Lupus. 2006;15(6):366-70. 9. Alarcon GS, et al. Arthritis Rheum. 2005;52:S726; 10. Ruiz-

Irastorza G, et al. Lupus. 2005;14:220.

Hydroxychloroquine:

Background Therapy for All Patients

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 or mfERG

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

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

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 CellCept 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.

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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.

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

– 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.

2020:19(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

Mycophenolate Use Beyond Nephritis

� Joints1

– did NOT work in RA2

� Cutaneous3

� CNS-SLE4

� Reduces extra-renal flares5

1. Artifoni M, Puechal X. Joint Bone Spine. 2012; epub ahead of print; 2. Schiff M, et al. Clin Drug Investig

2010:30:613-24. 3. Gammon B, et al. J Am Acad Dermatol. 2011;65(4):717-21; 4. Fong KY, Thumboo J. Lupus.

2010;19(12):1399-403; 5. Ginzler EM, et al Arthritis Rheum 2010;62:211-21.

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. ACR/AHCP annual meeting. November 4-9, 2010;Atlanta, GA

SRI 6 Over TimeLow 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

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SELENA SLEDAI Organ

Improvement (Week 52)a

Dooley MA, et al. ACR/AHCP annual meeting. November 4-9, 2010;Atlanta, GA

Improvement = decrease in SS

score within an organ domain

Belimumab vs Placebo:

Severe Flares

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

May 25–28, 2011; London, UK

7. ACTIVITY OF LUPUS

�EPHRITIS IS DIFFICULT TO

MO�ITOR

Lupus Nephritis (LN) guidelines1

� Biopsy all untreated patients with clinical evidence of active LN

� Therapies for all patients with LN:

– Hydroxychloroquine

– Angiotensin converting enzyme inhibiters (ACEi) or angiotensin receptor blockers (ARB) for patients with proteinuria ≥0.5 g/24 hours or equivalent protein/creatinine ratio

– Maintain blood pressure ≤130/80

– Statins for LDL >100 mg/dl

– Pregnancy counseling for fertile women

� Treat to target with MMF or CYC (MMF preferred in African Americans and Hispanics)

� Track patients with protein/creatinine ratio, not urine dipstick2

1. Hahn B, et al. Presented at American College of Rheumatology annual meeting; 2011; 2. Christopher-Stine L, et al. J Rheumatol.

2004;31:1557–9.

Urine Protein/Creatinine Ratio

� Gold standard is urine protein/creatinine ratio on a 24 hour collection

� Urine protein/creatinine timed collections (there is a circadian rhythm)

� Spot urine protein/creatinine quantifies proteinuria (as opposed to

dipstick)

Christopher-Stine L, et al. J Rheumatol. 2004;31:1557–9;Fine DM, et al. Kidney Int. 2009;76(12):1284-8.

0

0.5

1

1.5

2

2.5

3

3.5

<110 110-119 120-129 130-139 140-159 160+

Blood Pressure is Associated with Progression of

CKD

Meta-analysis of 11 RCTs of ACEIs

1860 patients with non-diabetic kidney disease

RR

Systolic BP (mmHg)

Jafar et al Ann Intern Med 2003;139:244-252

Slide Courtesy of Elizabeth Lightstone

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ACE/ARB Preferred: Simultaneous Impact of

Quartile of Achieved BP and Treatment Modality on

Relative Risk of Doubling SCr or ESRD

Pohl et al. J Am Soc Nephrol 2005:16;3027-3037

Slide Courtesy of Elizabeth Lightstone

8. PATIE�TS DIE FROM

ATHEROSCLEROSIS

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 1.6 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.

� 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.

9. MY PATIE�TS FORGET

WHAT I TELL THEM!

Cognitive Impairment in SLE

� Cognitive dysfunction assessed using diagnostic

evaluation suggested by American College of

Rheumatology Ad Hoc Committee (N = 67)

Normal 14 (21%)

Mild impairment 29 (43%)

Moderate impairment 20 (30%)

Severe impairment 4 (6%)

McLaurin EY, et al. Neurology 2005;64:297-303.

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COGNITIVE IMPAIRMENT

�BAD NEWS—Frequently present at

diagnosis

�GOOD NEWS-It remains stable

ANAM* Throughput Scores for Newly

Diagnosed SLE Patients and Normal Controls

Demographic/ANAM Subtests

SLE

Patients

Normal

Controls P value

Continuous performance 78.4 84.0 0.02

Matching to sample 23.8 26.1 0.02

Simple reaction time 187.6 202.0 0.09

Simultaneous spatial processing 18.8 20.1 0.15

Sternberg 64.0 71.0 0.0002

Petri M, et al. J Rheumatol. 2008; 35(9):1776-81.

*Automated Neuropsychological Assessment Metrics (ANAM)

Anti-NR2

� An advance in the understanding of cognitive impairment in murine SLE has been the recognition of a subset of anti-DNA antibodies that cross-react with the anti-NR2 glutamic receptor.

� At low concentration, the antibodies are positive modulators of receptor function (by increasing excitory postsynaptic potentials), and at high concentration, they promote excitotoxicity through enhanced mitochondrial permeability transition.

� These antibodies mediate apoptotic cell death of neurons.

DeGiorgio LA, et al. Nat Med 2001;7(11): 1189-1193.

Anti-NR2 Murine Model

� Anti-NR2 antibodies plus a break in blood brain barrier

can cause CNS changes in a murine model

� Anti-NR2 antibodies not associated with cognitive

impairment in humans

Lapteva L, et al. Arthritis Rheum.2006; 54(8):2505-14.

10. HOW DO I PREVE�T

THROMBOSIS?

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

Time Since SLE Diagnosis (years)

Cum

ula

tive S

(t)

Venous Thrombosis in SLE

6/26/2012

12

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.

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. 2001;44:1466–1467.

Aspirin Resistance More Prevalent in

Patients With Lupus

� 15% of patients with lupus have impaired antithrombotic response to

aspirin

� Associated with features of metabolic syndrome1

– Higher body mass index (P=0.05)2

– Higher serum CRP concentrations (P=0.018)2

– More likely to be obese (P=0.018)2

– More likely to have diabetes (P=0.034)2

� Likely related to inflammation, increased oxidative risk2

1. Erkan D, et al. Arthritis Rheum. 2007;56:2382-91; 2. Avalos IB, et al. Abstract 1391. Presented at: American

College of Rheumatology Annual Meeting; 2011.

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

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) There are many things to hate

about SLE, but we love

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