Advances in the Management of Systemic Lupus Erythematosus (SLE)

1
Advances in the Management of Systemic Lupus
Erythematosus (SLE)

• 10 Things We Hate About Lupus
• An Educational Program for Community
  Rheumatologists

Michelle Petri, MD Professor of Medicine Johns
Hopkins University School of Medicine Congress of
Clinical Rheumatology Sandestin Hilton, Destin,
Florida May 5, 2012
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2

• Certain transitional slides have not been printed
  for conservation purposes.

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3

• 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 Human Genome Sciences,
Inc.
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4
Accreditation

• This activity has been planned and implemented
  in accordance with the Essential Areas and
  policies of the Accreditation Council for
  Continuing Medical Education (ACCME) through the
  joint sponsorship of 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.
• VCU designates this educational activity for
  a maximum of 1.5 AMA PRA Category 1 Credits.
  Physicians should only claim credit commensurate
  with the extent of their participation in the
  activity.

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5
Disclosure of Significant Relationships with
Relevant Commercial Interests

• Neither VCU nor Miller Professional Group has any
  commercial interests relevant to the content of
  this activity. The content of this CME activity
  will not contain discussion of off-label uses.
  Please consult the product prescribing
  information for full disclosure of labeled uses.

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CME Credit Statements

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

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Please Complete and Return

• In the CME section of your meeting binders you
  will find
• a program evaluation form
• a needs assessment questionnaire
• an educational effectiveness survey
• a verification of participation request 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
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• Please be aware you will receive (via e-mail) a
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  complete for this program. It will come from the
  e-mail address rheumreply_at_optonline.net.
• Please be sure to return the completed follow up
  questionnaire. Thank you.

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8
Faculty

• Michelle Petri, MD
• Baltimore, MD
• Dr. Petris Disclosure Statement indicates that
  she is a clinical trials consultant for HGS,
  Glaxo, MedImmune, Teva, UCB, Anthera and Pfizer.
• An conflicts noted above have been resolved
  according to the ACCME Standards for Commercial
  Support and VCU continuing medical education
  policies and procedures.

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9
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

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10
Top 10 Reasons We Hate Lupus

• Lupus is a mystery disease
• Lupus may be difficult to diagnose
• Lupus disease activity is difficult to measure
• Patients complain of pain and fatigue
• 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

With these challenges, how do we treat lupus to
target?
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11
ETIOLOGY

• Multifactorial genes, environment, hormones
• Predisposing genetic factors
• Environmental factors (including drugs and
  infections)
• Development of autoantibodies linked to
  pathological manifestations
• Preclinical phase with autoantibodies present
  years before clinical disease

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12
Immunology of SLE
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TACI-Ig
BAFF-R-Ig
Anti-BLyS
CTX
X
X
X
X
CTLA4Ig
X
X
Anti-CD40L
Anti-CD40L
Adapted from Ramanujam M, Davidson A. Arthritis
Res Therapy. 20046197-202.
13
SLE is 2/3 Genetics!
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Chung SA, et al. PLoS Genetics. 2011 7(3)
e1001323
14
SLE is 1/3 Environmental

• Ultraviolet light
• Drugs/supplements (echinacea, trimethoprim/sulfame
  thoxazole)
• Smoking
• Infections
• Silica
• Mercury
• Pesticides

Parks CG, et al. Arthritis Rheum.
20024618401850 Chiou SH, et al. Lupus.
200413442449 Zarmbinski MA, et al. J
Rheumatol. 19921913801384 Cooper GS, et al. J
Rheumatol. 2004311928 Costenbader KH, et al.
Arthritis Rheum. 200450(3)849-857.Karlson EW.
Autoimmunity 200538(7)541-547 Freemer, MM, et
al. Annals Rheum Dis. 200665581-584 Majka DS,
Holers VM. Annals Rheum Dis. 200665561-563.
15
Autoantibodies Precede the Diagnosis Of SLE By
Years
Arbuckle MR, et al. N Engl J Med.
2003349(16)1526-33.
16
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.
17
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 (lt 4000/mm3 at least once) OR Lymphopenia (lt 1000/mm3 at least once)
11. Thrombocytopenia (lt100,000/mm3) at least once
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18
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-b2 glycoprotein 1
5. Low complement low C3 low C4 low CH50
6. Direct Coombs test in absence of hemolytic anemia
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Complement Split Products Bound to RBCs May Help
in Diagnosis of SLE
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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 (96.3124.5) 34.9 (26.141.6) 23.5 (21.425.6)
PC4d Net MFI (CI 95) 16.2 (12.020.5) 3.6 (3.04.2) 2.0 (1.22.8)
ECR1 Net MFI (CI 95) 13.3 (12.414.1) 16.1 (15.117.1) 20.7 (19.621.7)
ANAantinuclear antibodies BC4dcomplement C4d
levels on B cells dsdouble-stranded
EC4dcomplement C4d levels on erythrocytes
ECR1complement receptor 1 levels on
erythrocytes MFImean fluorescence intensity
MVCmutated citrullinated vimentin antibodies
PC4dcomplement C4d levels on plateletsSLEsystem
ic lupus erythematous
Kalunian KC. Abstract 597. Presented at American
College of Rheumatology, 2011.
20
Anti-C1q Is Associated with Renal Lupus
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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
C1qcomponent 1 subcomponent Q
dsDNAdouble-stranded DNA Sm-Smith
1. Orbai AM, et al. Abstract 1375. Presented at
American College of Rheumatology. 2011 2. Akhter
E, et al. Lupus. 201120(12)1267-74.
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Detection of New Clinical Activity in SLE
Frequency of New Isolated Variables of Interest
in 515 Patients, 3 Visits, 18 months Follow Up
Variable Detected Number of visits with new variable (N173) Number of patients with 1 visit with new variable (N127)
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
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.
22
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.
200961(9)11431151
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Physicians Global Assessment (PGA)

• Used to assess the patients overall condition
• A visual analogue scale (10cm) ranging from 03
  points (no activity to severe life-threatening
  activity)
• 0.3-point increase (10) clinically-relevant
  worsening1
• Correlates with other disease activity indices2

1. Furie, RA et al. Arthritis Rheum
611143-51. 2. Petri et al. J Rheumatol
19921953-9.
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SELENA-SLEDAI
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• 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
• 612 is moderate
• 13-20 is severe
• gt20 is very severe (and rare)
• Score reduction requires complete elimination of
  disease manifestation or resolution of laboratory
  abnormality
• 3-7 point reduction clinically meaningful
  improvement

Petri M at al. N Engl J Med. 2005 Dec
15353(24)2550-8 Buyon JP et al. Ann Intern Med
2005 142953-962
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SELENA-SLEDA 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

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SELENA-SLEDAI
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SELENA-SLEDAI
28
SELENA-SLEDAI
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SELENA-SLEDAI Flare index
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BILAG
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• British Isles Lupus Assessment Group
• Measures improvement/ worsening in disease
  activity by organ system
• based on physicians consideration to reduce or
  increase medication
• 86 parameters are included in the assessment
  (BILAG Classic)
• individual parameters are grouped into 10 organ
  domains
• general mucocutananeous
• nervous system musculoskeletal
• cardiovascular/ respiratory vasculitis
• renal haematological
• ophthalmologic gastrointestinal
• items scored as
• not present (0), improving (1), same (2), worse
  (3), new (4)

1. Griffiths B, et al. Best Pract Res Clin
Rheumatol 200519685708. 2. Hay EM, et al. Q J
Med. 19938644745. 3. Gordon C, et al.
Rheumatology (Oxford) 20034213729. 4. Isenberg
DA, et al. Lupus 200096514
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BILAG (Contd)

• Based upon individual scores within a domain, a
  letter (range AE) is assigned to each organ
  domain
• A very active disease (requiring
  immunosuppressive drugs and/or prednisolone dose
  of gt20 mg daily)
• B moderate disease activity (requiring a lower
  dose of corticosteroids, anti-malarials or
  NSAIDs)
• C mild disease (requiring symptomatic therapy)
• D no current disease activity but the system had
  previously been affected
• E no current or previous disease activity

For educational use only. Do not reuse without
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Hay EM, et al. Q J Med. 19938644745
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BILAG (Contd)

• Simultaneous changes (improvement/ worsening) in
  different organ systems can be seen immediately,
  without being masked by a global score
• Clinically-relevant worsening 1 new A or 2
  new B organ system scores
• a single BILAG B flare may be easily triggered
• As designed, the index is not intended to assess
  overall condition
• however, a composite score does exist

1. Griffiths B, et al. Best Pract Res Clin
Rheumatol 200519685708. 2. Hay EM, et al. Q J
Med. 19938644745. 3. Gordon C, et al.
Rheumatology (Oxford) 20034213729. 4. Isenberg
DA, et al. Lupus 200096514
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33
SRI Used in Belimumab Phase II Trials
An overall assessment of changes in patient
condition and disease severity
Assesses 24 weighted variables to indicate
overall disease severity
Measures flare activity and severity across 8
organ domains
SRI

1. Bombardier C, et al. Arthritis Rheum.
   199235(6)630-640 2. Hay EM, et al. Q J Med.
   199386(7)447-458 3. Data on file, Human Genome
   Sciences, Inc.

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34
SRI Responders vs Nonresponders
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Parameter SRI Resp (n761) SRI Nonresp (n923)
gt 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 lt7.5 mg/d 25.5 16.4
Increase in prednisone to gt7.5 mg/d 4 22
Changes in DNA/C3/C4 -34/14/40 -26/9/29
SF-36 PCS/MCS (MCID2.5) 4.9/4.4 2.6/1.7
Fatigue (FACIT/SF-36 Vitality MCID4/5) 5.2/10.4 3/6.5
Furie R et al. ACR 2011 Strand V et al. ACR 2011
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Dont Blame EVERYTHING on SLE!
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36
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. 2005317-26
2.Strand V et al. Arthritis Rheum. 200654S277
3.McElhone K, et al. Lupus 200615633-43
4.Thumboo J, Strand V. Ann Acad Med
Singapore.200736115-22.
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Fatigue
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• 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.
200039(11)124954 2. Wang B, et al. J
Rheumatol. 199825(5)892-5 3. Gladman D, et al.
J Rheum. 1997242145-9 4. Bruce IN, et al.
Arthritis Rheum. 1998 41(suppl.9)S333 5. Carr
FN, et al. ACR/AHCP annual meeting. November 4-9,
2011Chicago, IL.
38
Treating Pain and Fatigue Tai Chi
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12 weeks 79 of tai chi group vs 39 of control
had clinically meaningful improvement
(P0.0001) 24 weeks 82 of tai chi vs 53
control had clinically meaningful improvement
(P0.009)
FIQfibromyalgia impact questionnaire clinicall
y meaningful change in FIQ 8.1 points
Wang C, et al. N Engl J Med.2010363(8)743-754.
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Exercise for SLE-related Fatigue
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Clinical global impression change score No () in exercise group (n33) No () in relaxation group (n28) No () in control group (n32)
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. 2003421050-54.
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Treating Fatigue Belimumab
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FACIT-FatigueFunctional Assessment of Chronic
Illness Therapy-Fatigue SF-36Medical Outcome
Survey Short Form 36SRISLE Responder Index
Strand V, et al. ACR/AHCP annual meeting.
November 4-9, 2011Chicago, IL.
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5. Too Much Prednisone

• The P in Prednisone Stands for Poison
• --- Michelle Petri, MD MPH

42
Prednisone Is Directly or Indirectly Responsible
for 80 of Organ Damage over 15 Years
CVScardiovascular system GIgastrointestinal
MSKmusculoskeletal NPneuropsychiatric
Gladman DD, et al. J Rheum. 200330(9)1955-1959
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High-Dose Prednisone Should Be Redefined as gt 6
mg Daily
Average Dose Prednisone Hazard Ratio for Organ Damage
gt0-6 mg/day 1.16
gt6-12 mg/day 1.50
gt12-18 mg/day 1.64
gt18 mg/day 2.51
High dose (organ damage) 6 mg/day
Adjusted for confounding by indication due to
SLE disease activity
Thamer M, et al. J Rheumatol. 200936560564.
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44
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) Age-adjusted rate ratios (95 CI) P value
Never taken 22 13.3 1.0 (reference group) 1.0 (reference group)
Currently taking Currently taking Currently taking Currently taking Currently taking Currently taking
1-9 mg/d 32 12.3 1.3 (0.8, 2.0) .31 .31
10-19 mg/d 31 20.2 2.4 (1.5, 3.8) .0002 .0002
20mg/d 25 35.4 5.1 (3.1,8.4) lt.0001 lt.0001
Cumulative past dose Cumulative past dose Cumulative past dose Cumulative past dose Cumulative past dose Cumulative past dose
lt3650 mg1 14 9.9 0.9 (0.4,1.6) .56 .56
3650-10,950 mg2 26 13.8 1.2 (0.7, 2.2) .49 .49
10,950-36,499 mg3 41 12.8 1.1 (0.6, 1.8) .83 .83
36,5004 30 25.3 2.2 (1.2,3.7) .0066 .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
CVEcardiovascular events
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Magder LS, Petri M. Am J Epidem. In press.
45
Mild-to-Moderate Flares Do Not Always Require
Maintenance Steroids
Flares in Lupus Outcome Assessment Trial
(FLOAT) Oral methylprednisolone vs IM
triamcinolone
SF-36
No statistically significant difference in any
response or in complete response (except in
triamcinolone group at week 2) SF-36
SF-36Medical Outcomes Study Short Form-36
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Danowski A, et al. J Rheumatol. 20063357-80.
46
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
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47
The Belimumab Group Was More Likely to Reduce
Prednisone Over Time Than Placebo
Reduction in prednisone dose by gt 25 to lt 7.5
mg/day during Weeks 40-52 in patients receiving gt
7.5 mg/day at baseline.
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
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48
Hydroxychloroquine Background Therapy for All
Patients

• 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. 1991324150-4 2. Fessler BJ, et al.
Arthritis Rheum. 200552(5)1473-80 3. Petri M.
Lupus.19965(Suppl. 1)S16-S22 4. Wallace DJ, et
al. Am J Med. 199089322-6 5. Petri M. Curr
Rheumatol Rep. 201113(1)77-60 6.Pierangeli
SS, Harris EN. Lupus. 19965(5)451-5 7. Petri
M, et al. Curr Rheumatol Rep. 2011137780 8.
Kasitanon N, et al. Lupus. 200615(6)366-70. 9.
Alarcon GS, et al. Arthritis Rheum. 200552S726
10. Ruiz-Irastorza G, et al. Lupus. 200514220.
49
Criteria of Low and Higher Risk for Developing
Retinopathy
Low Risk Higher Risk
Dosage lt 6.5 mg/kg hydroxychloroquinelt 3 mg/kg chloroquine gt6.5 mg/kg hydroxychloroquinegt 3 mg/kg chloroquine
Duration of use lt 5 years gt 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 lt 60 years gt 60 years
Marmor MF et al. Ophthalmol 20021091377-82.
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Only SLE Patients with Visual Symptoms Need High
Tech hsUHR-OCT or mfERG
Rodriguez-Padilla JA, et al. Arch Ophthalmol
2007125775-80.
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51
High-Speed UltraHigh-Resolution
OpticalCoherence Tomography Findingsin
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. 2007125775-78J0
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52
Lupus Nephritis Induction TherapyMMF 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 considered2

1. Appel GB, et al. J Am Soc Nephrol.200920(5)11
03-1112 Ginzler EM, et al. Arthritis Rheum.
201062(1)211-221 Tornatore KM, et al. J Clin
Pharmacol 2011511213-22. 2. FDA Warning label
for MMF.
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53
Lupus Nephritis Maintenance Therapy MMF is
Superior to Azathioprine
N227
Time to treatment failure
Time to renal flare
Dooley MA, et al. N Engl J Med. 20113651886-95.
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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. 2011377(9767)721-31
2. Dooley MA, et al. ACR/AHCP annual meeting.
November 4-9, 2011Chicago, IL 3. Tam LS, et al.
Lupus. 200413601-4 4. Wang HY, et al. Lupus.
200817(638-44) 5. Tam LD, et al. Ann Rheum Dis.
200665417-8 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. 201025(12)3939-489. 9.
Lanata CM, et al. Lupus. 202019(8)935-40. 10.
Szeto CC, et al. Rheumatology. 200847(11)1678-81
11. Rovin BH, et al. Arth Rheum. 2012 doi
10.1002/art.34359
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permission
55
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 201030613-24. 3. Gammon B,
et al. J Am Acad Dermatol. 201165(4)717-21 4.
Fong KY, Thumboo J. Lupus. 201019(12)1399-403
5. Dooley MA, et al N Engl J Med 20113651886-95.
For educational use only. Do not reuse without
permission
56
Belimumab Multivariate Analysis

• Characteristics associated with greater treatment
  effect (plt0.1)
• SELENA SLEDAI score 10 (vs 9)
• Complement low C3/C4 (vs normal)
• Steroid use greater (vs no/less)
• Characteristics not associated with treatment
  effect (pgt0.1)
• Study
• Region
• Race

van Vollenhoven, et al. ACR/AHCP annual meeting.
November 4-9, 2010Atlanta, GA
For educational use only. Do not reuse without
permission
57
SRI 6 Over Time
For educational use only. Do not reuse without
permission
58
Low C/Anti-dsDNA SubgroupSRI Response Rate
over 52 Weeks
van Vollenhoven RF, et al. Presented at EULAR
2011 May 25-28, 2011 London, UK
59
SELENA SLEDAI Organ Improvement (Week 52)a
Improvement decrease in SS score within an
organ domain
Dooley MA, et al. ACR/AHCP annual meeting.
November 4-9, 2010Atlanta, GA
60
Belimumab vs Placebo Severe Flares
Cervera R, et al. Presented at EULAR 2011 Annual
European Congress of Rheumatology May 2528,
2011 London, UK
61
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 gt100 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.
20043115579.
For educational use only. Do not reuse without
permission
62
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.
20043115579Fine DM, et al. Kidney Int.
200976(12)1284-8.
For educational use only. Do not reuse without
permission
63
Blood Pressure is Associated with Progression of
CKD
1860 patients with non-diabetic kidney disease
Meta-analysis of 11 RCTs of ACEIs
RR
Systolic BP (mmHg)
Jafar et al Ann Intern Med 2003139244-252 Slide
Courtesy of Elizabeth Lightstone
64
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 2005163027-3037Sli
de Courtesy of Elizabeth Lightstone
65
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 200144
2331-7 2. Ward MM. Arthritis Rheum.
199942(2)338-46 3. Magder LS, Petri M. Am J
Epidemiol. In press.
For educational use only. Do not reuse without
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66
Can We Reduce Cardiovascular Risk?

• 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 gt 10 mg increases CV event risk5

1. Petri MA, et al. Ann Rheum Dis.
201170(5)760-5 2. Schanberg LE, et al.
Arthtiris Rheum. 201264(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
Sep1110209-21 5. Magder L, et al. Am J
Epidemiol. 2012 in press.
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67
COGNITIVE IMPAIRMENT

• BAD NEWSFrequently present at diagnosis
• GOOD NEWS-It remains stable

For educational use only. Do not reuse without
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68
ANAM Throughput Scores for Newly Diagnosed SLE
Patients and Normal Controls
Demographic/ANAM Subtests SLE Patients Normal Controls T value P value
Continuous performance 77.0 89.2 2.53 .014
Matching to sample 21.5 27.9 2.77 .008
Simple reaction time 179.6 206.36 2.30 .025
Simultaneous spatial processing 16.9 21.3 2.86 .006
Sternberg 60.2 74.5 3.12 .003
Automated Neuropsychological Assessment Metrics
(ANAM)
Petri M, et al. J Rheumatol. 2008 35(9)1776-81.
69
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 200564297-303.
70
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 20017(11)
1189-1193.
71
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, Nowak M, Yarboro CH, Takada K,
  Roebuck-Spencer T, Weickert T, et al.
  Anti-N-methyl-D-aspartate receptor antibodies,
  cognitive dysfunction, and depression in systemic
  lupus erythematosus. Arthritis Rheum.2006
  54(8)2505-14.

72
Venous Thrombosis in SLE
For educational use only. Do not reuse without
permission
Cumulative S(t)
Time Since SLE Diagnosis (years)
Somers E, Magder LS, Petri M. J Rheumatol.
20022925312536.
73
Lupus Anticoagulant Is More Highly Associated
With Thrombosis Risk

• Petri M, et al. Ann Intern Med.
  1987106(4)524531.
• Derksen RH, et al. Ann Rheum Dis.
  198847(5)364371.
• Ginsberg JS, et al. Blood. 199586(10)36853689.
• Horbach DA, et al. Thromb Haemost.
  199676(6)916924.
• Simioni P, et al. Thromb Haemost.
  199676(2)187189.
• Wahl DG, et al. Lupus. 19976(5)467-73.

For educational use only. Do not reuse without
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74
Aspirin Insufficient for APS Prophylaxis

• Aspirin has NOT been proven effective to reduce
  thrombosis from Antiphospholipid Antibodies
• Ginsburg KS, et al. Ann Intern Med.
  19921179971002.
• Erkan et al. Arthritis Rheum. 20014414661467.

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permission
75
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 (P0.05)2
• Higher serum CRP concentrations (P0.018)2
• More likely to be obese (P0.018)2
• More likely to have diabetes (P0.034)2
• Likely related to inflammation, increased
  oxidative risk2

1. Erkan D, et al. Arthritis Rheum.
2007562382-91 2. Avalos IB, et al. Abstract
1391. Presented at American College of
Rheumatology Annual Meeting 2011.
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76
Hydroxychloroquine Prevents Thrombosis in SLE
Study Study Design Outcome
Wallace et al, 1987 retrospective P lt 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 20101377-80
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77
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 dxed at age
  20 has 1/6 chance of dying by age 35

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78
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79
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80
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81
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