Post on 27-May-2020
transcript
6/26/2012
1
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.
6/26/2012
2
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
6/26/2012
3
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
6/26/2012
4
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!
6/26/2012
5
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
6/26/2012
6
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.
6/26/2012
7
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.
6/26/2012
8
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
6/26/2012
9
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
6/26/2012
10
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.
6/26/2012
11
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