Transcript Compiled Working Group Updates ACR_2014

Myopathy working group:
Myopathy SSc database
Lori Chung, Oliver Distler, Vivien Hsu, Veronika Jäger, Britta Maurer,
Lesley Saketkoo, Uli Walker, and all SCTC and EUSTAR members
Objective
To establish a prospective observational cohort for SSc patients with
suspected muscle involvement.
Inclusion criteria are (any one is sufficient for inclusion):
• Elevated levels CK or aldolase without obvious explanation
(e.g. extensive exercise, intramuscular injections, muscle injury)
• Proximal muscle weakness on physical examination not
explainable by other causes (e.g. neuropathogenic, genetic,
metabolic, endocrinologic, infectious disorders, drug-induced,
cachexia)
• Muscle atrophy on physical examination not explainable by
other causes (e.g. neuropathy, genetic disorders, cachexia)
• Positive myositis-associated autoantibodies (Jo-1, PM-Scl, U1RNP, Ku, Mi-2, SRP, PL-7, PL-12, OJ, EJ, p155/140, MDA5,
NXP2)
Data obtained - Domains
All EUSTAR SSc data, Myopathy Domains: History, Lab Markers, Physician
Outcome Assessment (Muscle Strength etc.), Patient Reported Outcomes,
Muscle Biopsy, EMG, Imaging (MRI)
Start: May 2014
November 2014: 72 patients enrolled from 15 centers
Basel, Zurich, Paris Cochin Hospital, Verona, Niska Banja (Serbia), Roma La
Sapienza, Bucharest Cantacuzino Hospital, Istanbul, Marseille, Madrid, New
Orleans, New Brunswick/New Jersey, Strasbourg, Stanford
Please join!
Ethic approval observational study, EUSTAR membership, annual follow
recommended
Calcinosis Working Group
• Multidisciplinary effort:
– Members from US, Europe, Canada,
Australia, Mexico
– Rheumatology, Radiology, Dermatology
• How to get involved:
– Please contact Dr. Lorinda Chung
([email protected]) or Antonia
Valenzuela ([email protected])
Calcinosis Working Group
• Current projects and status
– Validated radiographic scoring system1
– Multicenter retrospective study of 5280 patients
• Prevalence of calcinosis 24%
• Strong association of calcinosis with digital ulcers (OR=3.9)
and osteoporosis (OR=4.7)
– Next steps:
• Prospective database study - SCTC grant submission
• Collection of preliminary data on PAH-specific medications
for treatment of calcinosis to support design of prospective
clinical trial
1Chung
L, Valenzuela A, Fiorentino D, Stevens K, Li S, Harris J, Hutchinson C, Assassi S, Beretta L, Lakshminarayanan S, Rodriguez-Reyna TS, Denton
CP, Taillefer RG, Herrick AL, Baron M; on behalf of the Scleroderma Clinical Trials Consortium Calcinosis Working Group. Validation of a Novel
Radiographic Scoring System for Calcinosis Affecting the Hands of Patients with Systemic clerosis.Arthritis Care Res. 2014 Aug 22.
SCTC GI Working Group Update
Zsuzsanna McMahan, MD, MHS
Dinesh Khanna, MBBS, MSc; Tracy Frech, MD, MS
ACR 2014, Boston
Overview
•
•
•
•
Brief background
Purpose and goals
Status update
Come and join us!
Review of Previous
SCTC Meetings and Outcomes
 2012 consensus: Investigational modalities are available,
but validating outcomes are needed for SSc patients with
symptomatic:
• Reflux
• Gastroparesis
• SIBO
• Constipation
• Fecal incontinence
 Recommendations summarized in article: Khanna D,
Nagaraja V, Gladue H, et al. Measuring response in the
gastrointestinal tract in systemic sclerosis. Curr Opin
Rheumatol 2013;25:700‐6.
Purpose and Plans
• 2014 SCTC seed grant funding
– PI: Dinesh Khanna (University of Michigan)
– Develop and maintain an electronic database that can
facilitate collaboration among scleroderma experts
internationally for patients with symptomatic GI
involvement.
– Inclusion/exclusion criteria, assessment and outcome
measures have been discussed among the GI working
group via conference call and with GI experts at
several institutions, including Michigan and Hopkins
Recruitment
• Who do we want to recruit?
– Patients with scleroderma who have active GI
symptoms for which there is a plan to make a
change in management
• Inclusion and exclusion criteria
– Vary depending on the GI complication
– Discussed in more detail in the GI working group
meeting
Data Collection
• Baseline Visit
–
–
–
–
–
–
Consent
MD CRF
Inclusion criteria for each condition
Symptom specific questionnaires
UCLA SCTC GIT 2.0
NIH PROMIS
• Follow up
–
–
–
–
MD Anchor
Symptom specific questionnaires
UCLA SCTC GIT 2.0
NIH PROMIS
• REDCap (Research Electronic Data Capture)
Timing of data collection and follow-up
Baseline
4 weeks
Baseline
4 weeks
GERD
Gastroparesis
Baseline
4 weeks
SIBO
Baseline weekly diary, assessment 12 weeks
Constipation
Fecal Incontinence
Baseline
12 weeks
Symptom specific questionnaires
• Reflux
– Reflux Disease Questionnaire, GERD-Q, Quality of Life in Reflux
and Dyspepsia (QOLRAD)
• Gastroparesis
– Gastroparesis Cardinal Symptom Index
• SIBO
– Likert scale
• Constipation
– Constipation weekly assessment
– Includes the Bristol stool chart
• Fecal incontinence
– Quality of life scale for fecal incontinence
Status update
• Currently the protocol is IRB approved at 3
centers
• Recruitment began in August 2014 at the
University of Michigan
• Thus far, 7 patients enrolled as of November
3,2014
• Our goal for recruitment is 500 patients
Ultimate Goals
• Validate outcome measures for clinical trials in
scleroderma gastrointestinal disease
• Improve strategies to treat GI dysmotility in
our patients
Come and join us!
S.C. e Cattedra di Reumatologia
A.O.U. di CAGLIARI
SCTC Cardiac Sub-Committee
Updates
ALESSANDRA VACCA
Present progress
Future Research Project
• Examination of Mortality and the Need
for Electrical Device Implantation in
Systemic Sclerosis Patients with Cardiac
Conduction and Rhythm Abnormalities.
Objective
• 1) to retrospectively collect, among EUSTAR centers,
SSc patients:
A. who
required
cardioverter devices
pace-maker
or
implantable
B. who died because of arrhythmia or conduction
abnormalities
• 2) to investigate possible correlations with disease
phenotype in these subgroups
• 3) To identify markers predictive of severe
arrhythmias and conduction abnormalities in SSc
Patients and Methods
•
Patients will be selected from EUSTAR database
•
EUSTAR centers will be invited to fill out a standardized
form for patients meeting inclusion criteria, with the
additional variables.
•
A control group of SSc patients with no symptoms and
normal ECG, matched for age, sex and disease duration for
comparison will be selected.
• We will consider correlations with demographic data, disease
duration, disease phenotype looking in particular at organ
involvement, auto-antibodies, specific therapies.
• All EUSTAR participating centers would be co-author(s) in
this work.
Expected Results
• 40-50 patients to be included in this study.
• High prevalence of rhythm and conduction defects, but few
and out-dated studies which lacked focus on severe rhythm
and conduction defects requiring electrical devices.
• Eustar cohort is a unique opportunity to better define the
prevalence, the specificities, risk factors and management of
this subgroup of patients.
• This may help to differentiate between mild abnormalities
and those leading to a fatal outcome with the potential of
providing data for the development of appropriate treatment
guidelines to improve the overall prognosis of SSc patients.
Agenda
• A preliminary description of the project will be soon
available on SCTC web-site
• End of November: submission for approval to EUSTAR
board
• February 2015: submission to SCTC and EUSTAR
centers.
For suggestions/comments:
[email protected]
Systemic Sclerosis Damage Index
Working Group Update
Co-chairs: Mandy Nikpour (Melbourne) and Murray Baron (Montreal)
SCTC Annual Business Meeting, Saturday November 15th 2014
Goal
 Develop a disease damage index to
systematically quantify organ damage in SSc.
Potential applications:
◦ End-point in observational and interventional
studies
◦ Quantifying disease burden in epidemiologic
studies
◦ Describing differences between cohorts
◦ Enriching studies
SSc-DI Working Group
• 25 international members
• Steering committee comprised of 7 of these
members
– Mandy Nikpour, Murray Baron
– Marie Hudson, Susanna Proudman, Wendy
Stevens
– Research Fellows: Tien Tay and Nava Ferdowsi
(Melbourne)
• Expert panel of non-rheumatologist advisors with a special
interest in SSc
• Methodologists/biostatisticians
Patient partners
• 3 patient partners representing USA, UK and
Australia
– Conceptual definition of damage
– Items included in the SSc-DI survey
– Reduced/final list of items
Progress over 12 months
• First Working Group meeting at ACR ASM
2013
• Two-round survey to obtain consensus
regarding the conceptual definition of damage
in SSc
• Systematic review of existing measures of
disease status in SSc
• Item generation
• Online survey hosted on REDCap currently
open
Conceptual definition of damage in SSc
• Permanent and irreversible loss of anatomical structure
and physiologic function
• Directly caused by SSc or its treatment and not due to
comorbidities
• Differentiated from disease activity (potentially
reversible) and severity (no distinction between damage
and activity)
• PRO not included
• Predictive of morbidity and/or mortality
• Duration that an item must be present before being
called damage depends on the item
Systematic review of measures of disease status in SSc
– Poster 721 (Sunday 9-11 am)
Measures of Disease Status in Systemic Sclerosis: A Systematic Review
T Tay1,2, N Ferdowsi1,2, M Baron3, W Stevens1, M Hudson3, S Proudman4, D Prior2,5, M Nikpour1,2
1Department of Rheumatology, St. Vincent’s Hospital, Melbourne, Australia; 2Department of Medicine, University of Melbourne, Australia; 3Department of Rheumatology, Lady Davis Institute for Medical Research
and Jewish General Hospital, Montreal, Canada; 4Department of Rheumatology, Royal Adelaide Hospital, Adelaide, Australia; 5Department of Cardiology, St Vincent’s Hospital, Melbourne, Australia.
(on behalf of the Steering Committee for the Scleroderma Clinical Trials Consortium Damage Index Working Group)
Results
Introduction
Table 3. Summary of musculoskeletal
measures of health status for SSc
The lack of clearly defined episodes of flare and remission in SSc
We identified 2 disease activity indices, 6 disease
has made it difficult to describe and quantify disease ‘activity’.
severity indices, and 2 response indices for clinical
Hence, there is no gold standard instrument for measuring disease
trials. However, there is no damage index for SSc.
activity in SSc.
Disease ‘severity’ encapsulates the total impact of disease on organ Table 1. Features of existing composite measures of
function due to disease activity and damage. However, it does not disease status in SSc
distinguish activity (reversible) from damage (irreversible).
Disease activity
Outcome
indices
measures
Disease severity indices
Outcome measures used in clinical trials assess the response to Features
Valentini Minier
Medsger Geirrson Morita Furst
Hughes Casas
CRISS EPOSS
therapy at a particular point in time, rather than disease status.
Methodology
Objectives
Consensus-based
Y
?
Y
?
?
?
?
?
Y
Y
Number of experts
3
?
20
?
?
?
?
?
9
12
Data-driven
Y
Y
Y
?
?
?
?
?
N
Y
Variables
10
17
31
5
19
33
7
9
30
14
Organ systems
5
5
9
5
9
7
5
6
11
6
Obj
To identify and appraise existing measures of disease status in SSc.
Methods
A systematic review of Medline (1966-2014), EMBASE (19742014), and Cochrane Library (inception-2014) was undertaken.
We focussed on objective measures and excluded non-English
articles, animal-only studies and those relating to morphea,
localized scleroderma or juvenile systemic sclerosis.
We searched using the following keywords: (scleroderma, systemic
OR systemic sclerosis OR scleroderma), (disease activity),
(severity scale OR disease severity OR severity of illness index),
(outcome assessment (health care) OR outcome measure OR
response measure OR measure of response), (disease status OR
disease assessment indices) and (disease damage OR damage
index. The bibliographies of relevant articles identified using our
search strategy were also reviewed for additional studies.
Sub
Obj
Sub
Obj
Sub
Obj
Sub
Obj Sub Obj Sub
Obj
Potentially relevant studies identified from searches
of Medline, EMBASE and Cochrane Library (n=5687)
Duplicate articles (n=432)
Studies excluded by screening of title and abstracts (n=5073)
• non-English, animal-only studies, case reports
• subjective measures of health status
• morphea, localized scleroderma, juvenile systemic sclerosis
Potential studies for complete review (n=182)
Excluded after full review (n=153)
• no outcome measure
• duplicate outcome measure
Studies identified from search strategy (n=29)
Additional studies identified from bibliography of
relevant articles or from hand search (n=52)
Final review (n=81)
Y
Finger range of movement
Finger-to-palm distance (FTP)
Y
Sub
Laboratory tests
Y
N
N*
N
Y
N
Y#
Y
N
N
N
N
Y~
Y
N
N
Ambulation aids
Y
N
N*
N
Y
N
Y
N
N
N
Y
Y
Y
Y
N
N
Subjective measures
Skin
Y
Y
Y
Y
Y
N
Y
N
Y
N
Y
N
Y
N
N
N
N
N
N
N
Self-reported change
Cardiac
N
Y
N
Y
Y
N
N*
N
Y
Y
Y
Y
Y
N
Y
Y
Y
Y
Y
Y
Respiratory
N
Gastrointestinal
Sub Obj Sub Obj Sub Obj
Y
N
Y
Y
N
Y
N
Y
N
Y
Y
Y
N
Y
Y
Y
Y
Y
Y
N
N
N
N
Y
N
Y
N
Y
N
Y
Y
Y
N
Y
Y
N
Y
N
N
Renal
N
N
N
N
Y
N
Y
N
Y
N
Y
N
Y
N
Y
N
Y
N
N
N
General laboratory tests
Y
Others
N
N
N
Y
N
N
N
N
?
N
?
N
Y
N
N
Y
Y
Y
Patient-reported outcomes
Y
Y
N
N
N
Y
N
N
Y
Y
Weighted score
Y
Y
N
N
N
Y
N
N
N
N
Global assessment score
Y
Y
N
N
N
Y
N
N
N
N
Y
Table 2. Summary of composite measures of health
status for SSc according to the OMERACT filter
OMERACT filter
Disease severity indices
Disease activity
indices
Valentini
Minier
Medsger Geirrson Morita
Outcome
measures
Furst
Hughes
Casas
CRISS
EPOSS
Validity
Face validity
Y
Content validity
PV
PV
Criterion validity
PV
NT
Construct validity
Discrimination
capacity
Y
NT
Reliability
Sensitivity to change
Y
Y
Y
Y
Y
Y
Y
Y
Y
N
Y
Y
N
N
Y
Y
Y
Y
?
?
N
N
NT
NT
NT
N
?
?
N
N
NT
NT
Y
Y
Y
Y
Y
Y
Y
HAQ-DI
Y
Musculoskeletal
We found 27 instruments which assess the
various components of the musculoskeletal
system in SSc.
However, there is no validated instrument to
assess joint involvement.
Table 4. Summary of health measures for
cardiac and pulmonary manifestations in SSc
according to the OMERACT filter
Measures of health status
Validity
Discrimination capacity
Feasibility
Validation
Face
Content
Criterion
Construct
Reliability
Sensitivity to change
Internal
External
Y
Y
Y
?NT
?NT
?NT
Y
Y
?NT
Y
Y
Y
?NT
?NT
?NT
No
Y
?NT
6 minute walk test
Walk distance
Y
Y
NV
PV
NT
?PV
PV
?PV
PV
?
PV
?
Y
Y
Y
Y
Y
PV
Oxygen desaturation
Y
PV
Y
PV
Y
PV
Y
Y
PV
Echocardiography
Y
NV
PV
PV
PV
ND
PV
Y
Y
Right heart catheterization
Y
Y
Y
Y
Y
?
PV
PV
PV
Cardiac-specific outcome measures
Cardiac score
Cardiac index
Pulmonary arterial hypertension
Y
NT
NT
NT
?
?
NT
NT
NT
NT
PV
NT
NT
?
?
NT
NT
NT
NT
NT
Y
NT
Y
Y
Y
N
Y
Y
Y
Y
Internal validation
Y
NT
Y
NT
?
?
NT
NT
IPR
IPR
External validation
Y
NT
Y
NT
?
?
NT
NT
IPR
IPR
Feasibility
Y
Myositis
Y
N
Y
Y
Myopathy
Y
N
Y
Muscle weakness
Y
Y
EPOSS
Y
Y
Y
Bony erosion
Calcinosis and/or acroosteolysis
Y
N
Furst Hughes Casas CRISS
Radiographic evidence of
joint disease
Y
N
Morita
Joint contracture
Y
Y
Geirrson
Y
Large joint (wrist, elbow, knee)
Small joint
Y
Y
Medsger
Tender joint count (TJC)
Tendon friction rub (TFR)
Y
N
Y
‘Arthritis’
Musculoskeletal
Y
Minier
Y
Outcome
measures
Joint/synovial/tendon disease
activity
Vascular
N
Valentini
Disease severity indices
Proximal muscle weakness
Validation
Figure 1. Flow diagram showing the result of search strategy
Disease activity
Measures of disease status
indices
Y = Yes; PV = partially validated; NT: not tested; IPR: in progress;
CRISS = Combined Response Index in Systemic Sclerosis;
EPOSS = Expert Panel on Outcome Measures in Pulmonary Arterial Hypertension
related to Systemic Sclerosis.
The Valentini disease activity score is commonly used
to assess disease activity in research studies.
However, it lacks renal and gastrointestinal items, and
some of the items, such as digital necrosis, may reflect
disease damage rather than disease activity.
The Medsger disease severity scale is commonly used
in research. However, disease severity does not
differentiate between potentially treatable disease
activity and irreversible organ damage.
VO2 max
Y
PV
NT
PV
?NT
?NT
PV
PV
PV
NYHA/WHO functional class
Y
PV
Y
PV
Y
Y
Y
Y
Y
Warrick et al.
Goldin et al.
Y
Y
Y
Y
?NT
Y
?NT
?NT
?NT
?NT
?NT
PV
Y
?
Y
Y
?NT
?NT
Goh et al.
Y
Y
Y
?NT
?NT
Y
Y
Y
Y
Respiratory
Interstitial lung disease specific
outcome measures
Outcome measures to assess
interstitial lung disease
High resolution computed
tomography
Y
Y
Y
PV
Y
NT
Y
Y
Y
Forced vital capacity
Y
NV
Y
PV
PV
Y
Y
Y
Y
Diffusion capacity for carbon
monoxide
Y
NV
Y
PV
PV
Y
Y
Y
Y
NT: not tested, PV: partially validated; NV: not validated.
Cardiac
The EPOSS group incorporates several
objective and subjective measures, including
the 6 minute walk test, echocardiography and
right heart catheterization, to assess
cardiopulmonary hemodynamics in SSc.
Internal and external validation studies are
currently underway.
Cardiac damage in SSc remains undefined.
Respiratory
Early loss of lung function (FVC, DLCO) and the extent of
fibrosis at baseline (using HRCT) are the most important
prognostic variables in SSc-related interstitial lung disease.
However, there is no universally accepted definition of
damage due to lung disease in SSc.
Vascular
There is a spectrum of vasculopathic complications,
ranging from Raynaud’s phenomenon to digital gangrene
which may reflect disease activity and damage in SSc.
Erectile dysfunction, is common but has not been included
as an outcome measure in SSc.
Microvascular changes seen on nailfold capillaroscopy is a
potential marker of disease activity, damage and severity in
SSc but requires further validation.
Skin
mRSS is the most widely used measure of skin
involvement in SSc. However, it is unclear whether the
mRSS is more reflective of disease severity than activity or
damage.
Gastrointestinal
There is a lack of objective composite and organ-specific
indices to measure disease activity and disease damage
for SSc-related gastrointestinal complications.
Renal
eGFR is the most reliable measure of renal impairment in
SSc but it does not distinguish between disease activity,
severity or damage. There is no universally accepted
definition of renal damage in SSc.
Conclusions
We have identified a number of composite and organspecific measures of disease activity, disease severity and
response criteria in SSc using a combination of objective,
subjective parameters, or both.
Most of these indices require further validation according to
the OMERACT filter.
However, none of the indices measure disease damage per
se in SSc.
Further work developing and validating an index to describe
and quantify damage in individual organs and the impact on
morbidity and/or mortality is required.
Acknowledgments: ASIG, Actelion, Bayer, CSL, Pfizer, GSK, St Vincent’s
Research Endowment Fund, Scleroderma Australia, Arthritis Australia,
NHMRC Research Fellowship (APP1071735) and University of Melbourne
David Bickart Clinician Research Fellowship (MN), Dr T Tay was supported
by the ASIG Scleroderma Australia Fellowship.
Item generation
 Based on systematic review
 Input from expert advisors
 Input from Working Group members
◦ Total of 83 items in 7 domains
1. Musculoskeletal and skin (19 items)
2. Vascular system (8 items)
3. Cardiac system (20 items)
4. Respiratory system (6 items)
5. Gastrointestinal system (17 items)
6. Renal system (4 items)
7. Damage from treatment (9 items)
Online REDCap Survey
• Each item rated according to its
appropriateness (importance and feasibility)
for inclusion in the damage index.
• Duration that an item must be present before
constituting damage also addressed
• One round only
Survey
 69 complete responses to date
 Further 12 as yet incomplete responses
100-140 respondents required to power the planned
statistical analyses to reduce the items.
All respondents acknowledged in publications.
Profile of respondents to date
Asia n=1
Australia = 15
Europe = 34
North America = 16
South America = 3
Planned analyses (next 6 months)
• Rasch modeling to reduce the items
• Structural equation modeling (SEM) to weight
the items against mortality using Australian
(and Canadian) cohort data
Working Group Meeting 8:30-9:30 pm
 L201 – 2nd floor School of Medicine (LBuilding) at 72E
◦ Further discussion of points arising from
preliminary analysis of survey data
◦ Please address enquiries to
Mandy Nikpour
[email protected]
Murray Baron
[email protected]
Please respond to the survey if you have not
done so already.
The success of this project depends on your
response.