Development of Evidence
Based
“Best Standard Treatments” in
Pediatric Rheumatology
Carol A. Wallace MD
Professor of Pediatrics
University of Washington School of Medicine
Seattle Children’s Hospital and Research Institute
Immediate Past Chair of CARRA
Why do we want “Best
Standard Treatments”?
• Standardized care results in decreased
variation in patient care, which has been shown
to result in improved quality and outcomes
• Enable comparative effectiveness research to
identify the safest, most effective and most
cost effective treatments
• Prevent complications by use of safest
possible treatments
• Disseminated widely to improve overall
standards of patient care nationwide
The National Childhood Cancer Mortality Rate and the
Pediatric Cooperative Groups
8
Mortality
per
100,000,
AgeAdjusted
Annual USA Cancer Mortality Rate
Children <15 Years
6
4
IRSG
( )
NWTSG
2
SWOG Pediatric Division
POG
CALGB Pediatric Division
C
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G
CCG
1950
1960
1970
1980
1990
2000 2005
How do we develop evidence
based
Best Standard Treatments?
• Analyze data from clinical trials
• Analyze data from large prospective
cohorts followed from initial
presentation with detailed information
on treatment and outcomes
We have neither available data sources…
In the absence of data, one approach is to
start with development of
“Consensus Treatment Plans”
• Consensus formed; with broad input
• Reasonable, common and practical
• Once developed, these can facilitate
the development of evidence based
Best Standard Care by:
– Decreasing treatment variation
– Enabling analysis of prospectively collected data
of presenting features, treatments and outcomes
In response to NIAMS RFA 05-AR-102
Comparative Effectiveness Research in
Pediatric Rheumatic Diseases: Leveraging
CARRA for Improved Child Health
“CARRA-
”
Childhood
Arthritis and
Rheumatology
Research
Alliance
CARRA is:
A research net work of North American
Pediatric Rheumatologists and Health
Care Professionals dedicated to
improving the treatment and health
related outcomes of children with
rheumatic diseases through clinical
research.
CARRA Site Map
CARRA ORGANIZATIONAL
STRUCTURE
Elected Steering Committee
JIA Research Committee
Chairs of the Disease Committees
Small and Large Center Reps,
Finance Chair, Past Chair
Chair, Vice Chair,
SLE Research Committee
JDM Research Committee
Pain Research Committee
Small Center Rep
Large Center Rep
304 members
(71 trainees)
Vasculitis/Scleroderma
Research Committee
Translational Research and
Technology Committee
Finance
Committee
92 SITES
www.carragroup.org
What makes CARRA a Network?
Member Participation
 Disease Specific Committee work
 Conduct of Research
 Education, training and mentoring
 Annual Meeting
 Collaborations with other organizations
A Research Network Can…
 Improve the standard of care through
clinical studies
 Promote a “culture” of research at
Pediatric Rheumatology sites
 Develop Best Standard Treatments for
better patient outcomes
Specific Aims CARRA• To develop multiple standardized treatment
plans for use in new onset patients with: JIA,
SLE, JDM and localized scleroderma
– Use of consensus methodology
– Specify of outcome measures, data collection
details and time points
• Develop mechanisms to enable rapid
dissemination and use of the consensus
developed treatment plans
• Develop analysis plans for the data collected
to determine the clinical efficacy and safety
of patients treated with these plans
Overall Concept of CARRA• When a new patient presents, a physician
would choose to use one of the standardized
treatment plans that most fits what they
would normally do.
• Data would be collected on the patients
treated with these standardized treatments
• Data would be analyzed to determine the
most efficacious treatment with the least side
effects
• Thru this process, we would create evidence
based “Best Standard Treatment”
CARRACarol Wallace (contact PI)
Norm Ilowite (PI)
JDM Module
Linear Scl Module
Ann Reed - Leader
Adam Huber
Co-leader
Rob Fuhlbrigge-Leader
JIA Module
SLE Module
Yuki Kimura- Leader
Emily Von Scheven
Leader
Esi Morgan DeWitt
Co-leader
Hermine Brunner
Co-leader
Suzanne Li
Co-Leader
CARRA-
Advisory Board
Overall Grant Consultant
Chair- Edward Giannini
Dan Solomon, Brian Feldman, Pamela
Weiss, Peter Boehm, Vincent Del Gaizo
Carol Wallace (contact PI)
Norm Ilowite (PI)
Dan Solomon
JDM Module
Linear Scl Module
Ann Reed -Leader
Adam Huber
Co-leader
Rob Fuhlbrigge-Leader
JIA Module
SLE Module
Yuki Kimura-Leader
Emily Von Scheven
Leader
Esi Morgan DeWitt
Co-leader
Hermine Brunner
Co-leader
Suzanne Li
Co-Leader
CARRA-
Advisory Board
Overall Grant Consultant
Chair- Edward Giannini
Dan Solomon, Brian Feldman, Pamela
Weiss, Peter Boehm, Vincent Del Gaizo
Carol Wallace (contact PI)
Norm Ilowite (PI)
Dan Solomon
JDM Module
Linear Scl Module
Ann Reed - Leader
Adam Huber
Co-leader
Lay Members
Rob Fuhlbrigge -Leader
JIA Module
Yuki Kimura-Leader
Esi Morgan DeWitt
Co-leader
Lay Members
SLE Module
Emily Von Scheven
Leader
Hermine Brunner
Co-leader
Lay Members
Suzanne Li
Co-Leader
Lay Members
Consensus Methodology Choices
• Convene a panel of experts
• NIH model:
– Public discussion of questions and evidence
before an expert panel, followed by private
unstructured deliberations of the panel
• Delphi Questionnaire Technique
• Nominal Group Technique
• Combination of the Delphi Questionnaires
and Nominal Group Technique
Development process for
Consensus Treatment Plans
***** Workgroup*****
Development process for
Consensus Treatment Plans
Initial CARRA wide surveys
JIA: new onset systemic JIA
SLE: new onset nephritis
JDM: new onset moderate to severe disease
Localized scleroderma: new onset
***** Workgroup*****
Development process for
Consensus Treatment Plans
CARRA wide
survey
Refinement,
finalization
of plans
Consensus
Meeting
CARRA wide, case-based treatment survey
Review of literature
***** Workgroup*****
Treatment of Linear Scleroderma:
Survey of Current Practice
Case 1: 4yo F with 2 mo history of
linear scleroderma of lower leg.
Lesion crosses ankle and initially had
erythematous- violaceous border.
Now warm with SQ tissue loss.
Labs show ESR
Treatment of Linear Scleroderma:
Survey of Current Practice
Case 1: 4yo F with 2 mo history of
linear scleroderma of lower leg.
Lesion crosses ankle and nitially had
erythematous- violaceous border.
4% use
MTX only
MTX only
CS + MTX
Now warm with SQ tissue loss.
Labs show ESR
96% use methotrexate (MTX)
+ corticosteroid (CS)
This looks pretty good. But what
about treatment specifics?
Li et al. J Rheum 2010;37: 175-81
What type of CS were chosen?
Case 1: 4 yo F with linear scleroderma of leg
4% do not
use CS
no CS
Oral CS only
IV CS only
IV + Oral CS
27% use IV + Oral
CS
30% use oral CS
39% use IV CS
How about specific CS doses
and dosing regimens?
CS use in LS: Dosing regimens
and duration
3 main oral CS regimens:
-1 mg/kg/d (28)
-2 mg/kg/d (18)
-0.5 mg/kg/d (11)
4 IV CS regimens:
-3d/mo (33)
-1/wk (19)
-3d/wk (19)
-1/mo (5)
Pred 1mg/kg/d x 1
mo: 9 PR
IV 3d/mo x 3 mo:
27 PR
Pred 0.75x6
Pred 0.5 x1
Pred 0.5 x2
Pred 0.5 x6
Pred 0.5 xNS
Pred 1 x1
Pred 1 x2
Pred 1 x 2.5
Pred 1 x3
Pred 1 x6
Pred 2 x0.5
Pred 2 x1
Pred 2 x2
Pred 2 x3
Pred 2 x6
Pred 2 xNS
IV 1/wk x1
IV 1/wk x2
IV 1/wk xNS
IV 1/mo x1
IV 1/mo x6
IV 1/mo x7
IV 1/mo x18
IV 3/mo x1
IV 3/mo x3
IV 3/mo x24
IV 3/mo+add IVMP
IV 3/mo xNS
IV 3/wk x0.25
IV 3/wk x0.5 +add IVMP
IV 3/wk x3
IV 3/wk x NS
IV 1/mx6 + pred2/kg x 12
IV 1/m x1 + pred1/kg x1
IV 1/wk x1 +pred 0.5 x1
IV 1/wk x3 +pred0.5x3
IV 1/wkx1 +pred 1/kgx1
IV 1/wk xNS +pred 1/kg x3
IV 1/wkx1 +pred 2/kg x1
IV 1/wkx1 +pred 0.5x1
IV 1/wkx2 +Pred 2/kgQOD x1
IV 1/wk x2 +pred 2/kg x1
IV 3/mo x1 then pred
IV 3/mox1 +pred2/kg QOD x1
IV 3/mox3 then pred
IV 3/mox1+pred 1/kgx1
IV 3/mo x3 +pred 1/kgx1
IV 3/mox6 +pred 1/kgx1
IV 3/wkX0.25 then pred
IV 3/wkX0.25 +pred0.5/kg x2
IV 3/wk x0.25 +pred 0.5x1
IV 3/wk X0.25 +pred2/kg x2
IV 3/wk X0.25 +pred 1/kg x3
IV 3/wk xNS =Pred 1/kg x1
IV 3/wk x0.5 +pred 1/kg x3
IV 3/wk x0.25 +pred 2/kg x1
IV 3/wk x0.5 +pred 2/kg x1
IV 3/wk x0.5 +pred 2/kg x3
IV 3/wk x1 +pred 2/kg x1
IV 3/wk x0.25 +pred 1/kgx 1
MTX Treatment Regimens in LS
13 different initial doses
27 different initial doses and routes
0.3 pox15
0.3, 0.6 sq/po x 25
0.5 sq x7
0.5 sq x12
0.5 sq x 13
0.5,1 sq x14
0.5, 0.3 sq x21
0.5 sq x24
0.5 sq/po x36
0.5 NS xNS
0.6sq x15
0.6 sq/po, po x NS
0.75, 1 sq, 0.5po x 24
0.75 sq x 24
0.75 po x NS
0.875 sq/po, 0.75 sq, 1 po x 14
1 sq x 3
1 sq, 20 sq x13
1 sq x 15
1 sq/po, 15 sq/10po x 18
1 po x 24
1 sq, 0.3po x 24
1 sq x 27
1 sq/po x 30
1 sq x 36
1 sq x 48
1 po, 1 taper x 18
1 sq/po, taper x>12
1 sq x>12
1 sq x 36+
1 sq, 15 po x 24_
10 po x 15
10 sq/po, 15 sq/po x30
12 sq/po x 24
12.5 sq/po,1sq,, 10 po x12
15 sq x12
15 sq x15
15 sq x 24
15 sq/po x30
15 sq/po x 42
15 sq/po x 48
15 x sq x NS
20 sq x 15
0.3 po x24
0.5 sq x6
0.5 sq x 9
0.5, 1 po x 13
0.5, 0.75 sq x 13
0.5 sq x18
0.5 po x24
0.5, 1 sq x26
0.5 sq x12+
0.6 po x12
0.6 sq xNS
0.75 po x12
0.75 po x24
0.75 sq x30
0.8 sq x NS
0.875 sq/po x 24
1 sq x12
1 sq/po, 1 sq x15
1 sq, 0.5 sq x 18
1 sq x 18
1 sq x 24
1 po x 27
1 sq, 0.75sq x30
1 sq x30
1 sq x 42
1 sq/po x 48
1 sq/10 sq x24+
1 sq, taper x>10
1 sq, 0.5 sq x 12+
1 sq x NS
10 sq x13
10 sq/po, 15 po x 26
10 po x NS
12 po x NS
15 po x 12
15 sq/po x 12
15 po x 24
15 po, 10 po x 26
15 sq x 36
15 sq x 48
15 po x NS
17.5 sq x 24
20 po x 21
Development process for
Consensus Treatment Plans
CARRA wide
survey
Refinement,
finalization
of plans
Consensus Meetings at CARRA
Annual meeting 2010
Case-based survey CARRA wide survey
Review of literature
***** Workgroup*****
 Consensus
methodologies
facilitated and
promoted the
highest quality
team work
 However, this is
REALLY hard and
time consuming!
CARRA-
CARRAGuiding Principles
• Evidence-based when possible
– Considered the best available literature
• Compatible with the current practice
– Assessed by the surveys
• Consensus agreement
– Delphi Questionnaires
– Nominal group technique
Development of Consensus
Standardized Treatments
• Distill what we do- using
collective judgment and
consensus processes
• Forced us to:
– Think critically about what we do
– Use facts when present, not beliefs
or “this is how I always do this”
– Emphasis on decreased variation
Development of Consensus
Standardized Treatments
• Not rigorous protocols- but rather menus
of standardized treatments
• Not perfect or exactly what each
physician might do, but what he/she can
live with
• The goal is to reduce variation so we
can treat in a standardized fashion, collect
data and compare patient outcomes
Common Module Work
• Define the patient characteristics
and exclusions for use of the
treatment plans
• What to do if better, worse or
adverse event
• Essential data to be collected
• Essential labs to be collected
• Key data collection time points
Challenges
• Steroids
– How to standardize dosages and routes
– Standardization of steroid taper rate
• JIA:
– Patient characteristics: how early to allow treatment may need to treat before fulfilling ILAR criteria for JIA
– Include a new medication not yet approved?
• SLE: Induction and maintenance, or just induction?
• Linear scleroderma:
– Lack of outcome measures
– Lack of definitions for improvement, worsening
SLE Breakout sessions
Topic
Group Coordination
M= moderator
N= note taker
1
Outcome
measures/response
variables
M: Hermine Brunner
N: Joyce Hsu
2
Cyclophosphamide plan
M: Emily von Scheven
N: Eyal Muscal
3
Mycophenolate plan
M: Anne Eberhard
N: Marisa Klein-Gitelman
4
Steroid regimens – doses
and tapering
M: Lynn Punaro
N: Linda Wagner-Weiner
5
QOL/patient perspectives/
AEs
M: Stacey Ardoin
N: Nandini Moorthy, Jenny Palter
Localized Scleroderma Consensus Treatment Plans
Regimen A
B
MTX alone MTX + Intravenous
steroid
C
MTX + Oral prednisone
MTX weekly 1mg/kg SQ
dose
(max 25 mg)
1mg/kg SQ (max 25 mg)
1mg/kg SQ (max 25 mg)
Steroid
dose,
Duration
None
30 mg/kg/dose (max 1gm) 2 mg/kg/d (max 60 mg) divided
EITHER: 3 consecutive
bid
daily doses/mo, Duration: at least 2 weeks
OR: 1 dose/week
Duration: 3 months
Steroid
taper
targets
None
None
Dose reduced to:
1 mg/kg/d (max 30 mg) by end of
wk 8
0.5 mg/kg/d (max 15 mg) by end
of wk 16
0.25 mg/kg/d (max 7.5 mg) by
end of wk 24
Off CS by end of week 48
JIA Module
• Developed 4 treatment plans:
– Steroid only
– Methotrexate
– Anakinra
– Tocilizumab
• Possible steroid plans :
– IV 30/kg/day X 3 days
– Oral
• 1 mg/kg/day – taper over 1, 3 or 6 months
• 2 mg/kg/day – taper over 1, 3 or 6 months
Plan B: Methotrexate
Methotrexate (MTX) 0.5mg/kg PO or SQ weekly
Optional corticosteroids : PDN 1mg/kg (60mg max); IV MP pulse 30mg/kg X 3 d
ASSESS AT 1-2 WEEKS
Improved
Taper PDN (if on)
(choose rapid, fast, slow)
Unchanged
Worsened
Continue same dose PDN
If not on oral PDN, add at 1mg/kg;
Optional: Add or repeat IV MP
(can be weekly)
If on PDN, increase to 2mg/kg;
Add/Repeat IV MP (can be weekly)
ASSESS AT 1 MONTH
If Worse
If Improved
If Unchanged
Continue same dose MTX
Increase MTX to 1mg/kg (30mg
max) SQ weekly ; Continue same
dose PDN , reassess monthly
Start/Continue PDN taper,
reassess monthly
Increase MTX to 1mg/kg SQ
weekly; Increase (or continue)
PDN to 2mg/kg (max 100mg);
repeat IV MP, reassess monthly
ASSESS AT 3 MONTHS
If Improved
*If on PO PDN, taper PDN
Continue same dose MTX, reassess monthly
If Unchanged , Worse, or on >50% steroid dose
Continue same dose PDN and MTX , Plus
Add additional therapy, choose and follow either:
anakinra plan or tocilizumab plan
Systemic JIA data collection
Category
Items
History
demographics, date symptom onset,
comorbidities, medications, recent
rash or serositis, suspected MAS
Patient and Physician
assessments
pain
HRQOL
physical function
parent/patient global assessment
provider global assessment
Physical Exam
Ht, Wt, BMI, active joint count,
hepatomegaly, lymphadenopathy,
rash, serositis, splenomegaly
Labs
CBC
c-reactive protein, ESR, ferritin
albumin, LDH
Treatment-related
factors
Medications
SAE or IME
if discontinuation then provide reason
Development process for
Consensus Treatment Plans
CARRA
wide
survey
Consensus
Meeting
Case-based CARRA wide survey
Review of
literature
***** Workgroup*****
Refinement,
finalization of
plans; CARRA
2011 meeting
Consensus Treatment Plans
developed for new onset:
• Systemic JIA
–
–
–
–
Steroids
MTX +/- steroids
Anakinra +/steroids
Tocilizumab +/steroids
• Juvenile
Dermatomyositis
– Pred + MTX
– Pred + MTX + IV methylpred
– Pred + MTX + IV methylpred
+ IVIG
• Renal disease in SLE
– Cell cept induction
– IV cytoxan induction
• Linear Scleroderma
– MTX
– MTX +Oral steroid
– MTX + IV methyl pred
•All Modules have submitted the Treatment Plans and their
development for publication
Next Steps
• Parallel to this effort has been the development of
a large foundational pediatric rheumatology
registry:
CARRAnet
– 60 participating pediatric rheumatology sites
– 6,000 patients enrolled
• Plan is that new onset patients treated with one
of the Consensus Treatment Plans will have
specific data collected using the CARRAnet
platform
Consensus Treatment Plans
 CARRA website




Publication progress:
JDM – AC&R
SLE – AC&R
Systemic JIA – revision AC&R
Localized scleroderma – revision AC&R
Implementation of
Consensus Treatment Plans
 Protocol for the CARRA Registry and Consent
form allows for data collection that will cover
the basic registry and additional sub-studies.
 Actual additional data collection will occur at
sites participating in the pilot studies.
 All CARRA members are encouraged to use
the CTP on new patients, regardless of
participation in the pilot studies
Consensus Treatment Plans:
Pilot Studies
 JDM: Friends of CARRA and CUREJM
 10 sites/ 40 patients
 Systemic JIA: Arthritis Foundation
 15 sites/ 30 patients
 SLE: Lupus Foundation of America
 15 sites/ 40 patients
 Localized Scleroderma: Arthritis Foundation
 11 sites/ 50 patients
Future Steps
• Analysis of the data collected through the
CARRAnet platform will allow for comparisons
between treatments for determination of
effectiveness, outcomes and side effects
• Evidence based Best Standard Treatments can
then be identified and widely disseminated
• Over time these can be improved upon in an
iterative fashion to improve the outcomes of
children with rheumatic diseases
• Development of standardized treatment plans for
additional phases/categories of disease are
underway
Plan A: Steroid
Prednisone (PDN) 1mg/kg (max 60mg) daily
Optional IV MP pulse 30mg/kg (max 1g) daily for 3 days
ASSESS AT 1-2 WEEKS
Improved
Unchanged
Worsened
Taper PDN
Continue same dose PDN
(choose rapid, fast, slow)
Add or repeat IV MP
Increase PDN to 2mg/kg (max
100mg); Repeat IV MP
ASSESS AT 1 MONTH
If Unchanged or Worse
If Improved
Continue (or initiate) PDN taper
Increase (or continue) PDN to 2mg/kg (max 100mg);
repeat IV MP (can be weekly), reassess monthly
ASSESS AT 3 MONTHS
Patient on <50% starting steroid dose
Patient on >50% starting steroid dose
Continue to taper PDN, reassess monthly
Continue same dose PDN , Plus
If improved, continue PDN taper
Add additional therapy, choose and follow either :
If unchanged or worsened, add additional therapy (plan B, C, D)
methotrexate, anakinra, tocilizumab plan
Plan C: Anakinra
Anakinra (ANK) 2mg/kg (max 100mg) SQ daily
Optional corticosteroids : PDN 1mg/kg (60mg max) with IV MP pulse 30mg/kg/d X 3
ASSESS AT 1 -2 WEEKS
Improved
Unchanged
Continue same dose ANK
If on PDN, taper (choose rapid,
fast, slow)
Continue same dose ANK
If on PDN, continue same dose
Optional: Add or repeat IV MP
Worsened
Increase ANK to 4mg/kg
(200mgmax) SQ daily;
If on PDN, continue same dose
Optional: Add or repeat IV MP
ASSESS AT 1 MONTH
If Unchanged
If Improved
Continue same dose ANK
Start/Continue PDN taper,
reassess monthly
If Improved
If Worse
Increase ANK to 4mg/kg (200mg
max) SQ daily;
Continue same dose PDN
reassess monthly
Continue same dose ANK
If not on oral PDN, add or increase
PDN to 2mg/kg; Add/Repeat
IVMP; reassess monthly
ASSESS AT 3 MONTHS
*If on PO PDN, taper PDN
If Unchanged , Worse, or on >50% steroid dose
Continue same dose PDN
Continue same dose ANK
Plus either
reassess monthly
add MTX, or switch to tocilizumab plan
Plan D: Tocilizumab
Tocilizumab (TOC) 8mg/kg (if >30 kg) or 12 mg/kg (if <30 kg) IV every two weeks
Optional corticosteroids: PDN 1mg/kg (60mg max) with IV MP pulse 30mg/kg/d X 3
ASSESS AT 2 WEEKS
Improved
Unchanged
Worsened
If on PDN, taper
If on PDN, continue same dose
(choose rapid, fast, slow)
Optional: Add/Repeat IV MP
If not on oral PDN, add at 1mg/kg
If on PDN, increase to 2mg/kg;
Optional: Add/Repeat IV MP
ASSESS AT 1 MONTH
If Improved
If Unchanged or Worse
Continue same dose TOC
Continue same dose TOC; If not on oral PDN, add; If
on PDN increase (or continue) to 2mg/kg (max
100mg); repeat IV MP , reassess monthly
Start/Continue PDN taper, reassess monthly
If Improved
ASSESS AT 3 MONTHS
*If on PO PDN, taper PDN
If Unchanged , Worse, or on >50% steroid dose
Continue same dose PDN /IV MP pulses
Continue same dose TOC
Plus either
reassess monthly
add MTX or switch to anakinra plan