Download Proposed preliminary core set measures for

Rheumatology 2001;40:1262–1273
Report
Proposed preliminary core set measures for
disease outcome assessment in adult and juvenile
idiopathic inflammatory myopathies
F. W. Miller*, L. G. Rider*, Y.-L. Chung1, R. Cooper2,
K. Danko3, V. Farewell4, I. Lundberg5, C. Morrison6, L. Oakley7,
I. Oakley7, C. Pilkington8, J. Vencovsky9, K. Vincent10,
D. L. Scott11 and D. A. Isenberg12 for the International Myositis
Outcome Assessment Collaborative Study Groupy
Center for Biologics Evaluation and Research, US Food and Drug
Administration, Bethesda, Maryland, USA, 1MRI Unit, Hammersmith Hospital,
Du Cane Road, London W12 OHS, 2Rheumatic Disease Centre, Hope Hospital,
Salford M6 8HD, UK, 3Department of Internal Medicine, Medical University of
Debrecen, Moricz Zs KRT 22, Hungary, 4University College London, Gower
Street, London WC1E 6BT, UK, 5Rheumatology Unit, Department of Medicine,
Karolinska Institute, S-171 76 Stockholm, Sweden, 6Department of
Rheumatology, Kings College Hospital (Dulwich), East Dulwich Grove, London
SE22 8PT, 7Dermatomyositis and Polymyositis Support Group, 146 Newtown
Road, Woolston, Southampton SO19 9HR, 8Centre for Rheumatology,
Middlesex Hospital, London W1P 9PL, UK, 9Institute of Rheumatology, 12850
Praha 2, Czech Republic, 10Department of Academic Rheumatology GKT,
Weston Education Centre, Cutcombe Road, London SE5 9PJ,
11
King’s College Hospital (Dulwich), East Dulwich Grove, London W1P 9PG
and 12The Centre for Rheumatology, University College London Hospital,
Arthur Stanley House, 40–50 Tottenham Street, London WIP 9PC, UK
Abstract
In order to develop a preliminary core set of disease outcome measures for use in clinical trials
of idiopathic inflammatory myopathies (IIM), we evaluated those measures used in previous
trials, assessed the validation of published instruments and discussed these at an international
consensus conference. The initial proposals were further refined by a multidisciplinary group
of adult and paediatric specialists experienced in IIM using the Delphi method. The proposed
preliminary core set of disease activity measures consists of five domains: physician and
patientuparent global assessments of disease activity; muscle strength; physical function; serum
activity of muscle enzymes; and an assessment tool to capture extra-skeletal muscle disease
activity. The group recommended further development of a core set of disease damage measures
for assessment of persistent changes in anatomy, pathology and function of at least 6 months’
Submitted 29 March 2001; accepted 12 April 2001.
Correspondence to: F. W. Miller, Environmental Autoimmunity
Group, Office of Clinical Research, National Institute of Environmental Health Sciences, National Institutes of Health, 9 Memorial
Drive, Room 1W101, MSC 0958, Bethesda, MD 20892, USA.
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*These authors contributed equally to this work.
y
A complete list of members can be found in Appendix A.
Core set outcome measures for myositis
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duration. The group recommended that patient-reported outcomes should include generic
health-related quality of life assessments using the Medical Outcomes Study 36-item Short Form
(SF-36) health survey in adult IIM patients and a validated quality of life instrument for
paediatric patients. We propose the core set of outcome measures as a minimum group of
assessments to include in all IIM therapeutic studies. The use of this core set should assist in
standardizing outcome measurement and in optimizing therapeutic trials in myositis.
KEY WORDS: Idiopathic inflammatory myopathies, Outcome measures.
The idiopathic inflammatory myopathies (IIM) are
a heterogeneous group of systemic connective tissue
diseases defined by the clinical and pathological consequences of chronic muscle inflammation. The primary
forms of the myositis syndromes, dermatomyositis
(DM), polymyositis (PM) and inclusion body myositis
(IBM), affect both adults and children and, although
relatively rare, may be increasing in incidence w1x.
Although the primary focus of myositis research has
been on skeletal muscle disease, the frequent involvement of other organs, particularly the cutaneous, gastrointestinal, pulmonary, and cardiac systems, contributes
greatly to the morbidity and mortality of the IIM w2x.
While corticosteroids and other immunosuppressive
agents are the primary treatments for patients with IIM
w3x, few therapies have been shown to be efficacious
in randomized controlled trials w4–6x, and only oral
corticosteroids are currently approved by the US Food
and Drug Administration for the treatment of myositis.
The lack of proven therapies is due in part to the rarity
and heterogeneity of these diseases and in part to the
lack of standardized and validated approaches for
assessing disease activity and damage in patients with
IIM. This deficiency of standardized methods for assessing IIM not only inhibits the capacity of clinicians to
evaluate therapeutic responses in individual patients,
but also limits interpretation of the few trials that have
been conducted.
As part of an ongoing international effort to develop
validated disease activity and damage indices in the
major clinicopathological groups of adult and juvenile
IIM, a group of adult and paediatric specialists and
patient support group leaders with expertise in IIM
met in Oxford, UK in March 2000 to develop core set
measures for assessing myositis outcomes for clinical
trials. The task of the committee was to develop
common disease outcome measures that would be
applicable to all myositis patients, including DM, PM
and IBM in both children and adults. The group
decided that in order to facilitate the development of
a disease activity index, it would be useful to define
core set measures that would be obtained in all patients,
and extended assessments that would be optional,
because the tools were not validated, less widely used,
or relied on measures not available at all centres. It is
anticipated that these preliminary core assessments
will undergo periodic revision as new tools with
improved responsiveness are developed and validated.
This report summarizes the proposals that have resulted
from this effort.
General principles in assessing myositis
disease activity and damage
Although DM, PM and IBM each have their own
unique characteristics, and probably differ in disease
pathogenesis, presentation, responses to therapy and
prognoses, they share chronic skeletal muscle inflammation that results in muscle weakness. Muscle weakness
is primarily proximal in DM and PM, but in as many as
80% of patients, axial and distal muscles can be involved
in both adults and children w7, 8x. The IIM are systemic
diseases, with clinically important articular, cardiac,
pulmonary, gastrointestinal tract, and cutaneous manifestations (extra-skeletal muscle disease) present in
10–50% of patients, often resulting in high morbidity
and mortality w2, 9, 10x. Therefore, it is important for
IIM assessment tools to capture fully and attempt to
quantitate the involvement of all target organs.
In order to understand the totality of the effects of
a disease or its therapies upon patients, it is useful to
develop measures that assess disease activity, damage
and patient self-assessment. Studies in patients with systemic lupus erythematosus (SLE) have shown that
activity and damage can be distinguished w11x. For
other systemic connective tissue diseases, disease activity
has been defined as reversible manifestations resulting
directly from inflammatory processes, whereas disease
damage is reflected in persistent changes in anatomy,
physiology, pathology or function which result from
prior active disease (causing scarring, fibrosis and
atrophy), as well as from complications of therapy or
other events w12x. Changes associated with damage are
often post-inflammatory, irreversible and cumulative.
The use of standardized, comprehensive activity and
damage assessment tools not only allows for the comparison among therapeutic trials of different agents,
but also helps to ensure that therapies which improve
disease activity do not result in an inappropriate
increase in disease damage.
Criteria for selecting assessment techniques for
musculoskeletal clinical trials have been extensively
reviewed. In brief, these methods should be practical,
comprehensive, reliable and valid. In the development
of assessment measures for musculoskeletal clinical
trials, several validation approaches are often examined,
including face validity (measures that appear to capture
the attribute of interest), content validity (comprehensiveness), convergent construct validity (correlation
of new measures with established measure), and discriminant validity (responsiveness) w13x. A review of
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which outcome measures have been used in previous
myositis trials, as well as the status of validation of
different measures, guided the committee’s discussions
and choice of outcome measures for the IIM.
The consensus approach utilized
A search of PubMed (http://www.ncbi.nlm.nih.gov/
PubMed/ ), using the terms myositis and treatment,
was performed for English-language peer-reviewed
publications between January 1966 and March 2000,
and all prospective therapeutic trials were reviewed.
Case reports, retrospective series and studies without
pre-defined disease assessments were excluded from
the analysis. To ensure that a comprehensive listing of
all IIM therapeutic trials in adults and children was
achieved, additional references in the retrieved papers,
as well as those in published review articles on myositis
therapy, were also obtained. Similar approaches were
used to retrieve published literature on validation
studies of myositis disease activity assessment, damage
assessment, and patient-reported outcomes.
Summaries of these reports were presented to the
committee at the Oxford meeting, followed by open
discussion of the issues and structured consensusbuilding sessions. Further discussions were held following the meeting among key participants, and finally,
written comments on the proposals generated at the
Oxford meeting were solicited from over 60 additional
rheumatologists, neurologists, dermatologists, statisticians and other researchers around the world with
interest and expertise in adult and juvenile myositis who
were not in attendance at Oxford (see Appendix A for
additional members of the International Myositis
Outcome Assessment Collaborative Study Group).
Assessment of myositis disease activity in
published therapeutic trials
Seventeen therapeutic trials were identified that met the
pre-specified search criteria: 15 studies were of adult
disease (seven PMuDM, three PM, two IBM, one DM
and two PMuDMuIBM) and two studies were of juvenile
DM. No common standards have been used in the
conduct of these IIM therapeutic investigations, which
utilized different myositis classification criteria; separate inclusionuexclusion criteria; varying concomitant
therapy, trial designs and durations; and different
outcome measures (Table 1), some of which do not discriminate well between disease activity and damage w12x.
In the published therapeutic trials, 16 of 17 used
muscle strength as the primary outcome assessment or
a component of the primary assessment, and this was
most often measured by manual muscle testing (MMT).
The number of muscle groups tested and the methods
to perform MMT, however, varied among studies. The
Medical Research Council 0–5 point MMT scale was
commonly used in the early reports w5, 6, 15–18, 20, 23x,
but the more sensitive, expanded 0–10 point MMT
scale was used frequently in more recently published
investigations w22, 24–26x. Two studies also measured
muscle strength of a limited number of muscles by
either sphygmomanometry w18x or myometry w24x and
one assessed strength by electromyometry alone w15x.
Potential problems with muscle strength as a primary
outcome measure in clinical trials include: that muscle
strength does not discriminate between active myositis
and disease damage; that in patients with longstanding
disease, muscle strength may not improve significantly
because of fixed deficits due to muscle atrophy; that
assessment of muscle strength by itself omits the assessment of other important elements of myositis activity,
particularly activity in extra-skeletal muscles; and that
a variety of methods are used to assess muscle strength.
Evaluation of physical function using the modified
Convery questionnaire to assess activities of daily living
(ADL) was a component of primary endpoints in five
therapeutic trials in which improvement was defined
by a composite index requiring increases in both MMT
and physical function scores w5, 16, 20, 23, 25x. Another
study used a composite index consisting of both MMT
and a neuromuscular symptom score w6x and in one
study a functional disability score was the sole primary
outcome assessment w14x. One recent trial used a composite measurement of muscle strength, endurance and
function as a primary outcome assessment w27x.
Again, lack of uniformity in functional measures and
the use of non-validated instruments are evident from
the published trials. Serum activity of creatine kinase
(CK) was used less commonly as a primary outcome
measure w4, 19, 26x.
In three randomized controlled trials of steroidsparing agents, the primary measure of clinical response
was shown to be statistically different from either
placebo (using azathioprine w14x or intravenous gammaglobulin w6x) or a comparison therapy (combination
oral methotrexate plus azathioprine vs intravenous
methotrexate w23x), while in one controlled trial of
plasmapheresis or leukapheresis compared with sham
apheresis, no differences among treatment arms were
seen w5x.
Secondary outcome measures in these 17 published
trials were more variable. The most common measures
were serum activity levels of muscle-associated enzymes:
CK was used in 12 studies w5, 14–18, 20, 21, 23–25x,
aldolase in four w19–21, 25, 27x, aspartate aminotransferase (AST) in three w18, 20, 25x, alanine aminotransferase (ALT) in two w20, 25x and lactate dehydrogenase
(LD) in one w20x. Other assessments included pulmonary
function testing (forced vital capacity anduor carbon
monoxide diffusing capacity) in six trials w5, 16, 20,
23, 25, 26x, corticosteroid dose in six studies w14–16, 18,
25, 26x and physician subjective assessment of rash
w6, 15, 18x and muscle biopsy features w4, 6, 20x in three
studies each. Short tau inversion recovery (STIR)
magnetic resonance imaging (MRI) of proximal thighs
was used as a secondary measure of clinical response
in six trials w5, 16, 20, 23, 25, 27x. Objective (videofluoroscopy and ultrasound) and subjective (swallowing symptom questionnaire) measures of swallowing
TABLE 1. Outcomes assessed in prospective therapeutic studies for the IIM
Primary outcome assessment
Secondary outcome assessment
IIM group
Reference
Strength (MMT of 18 muscles, 0 to 24), CK
Muscle biopsy score
PM
Functional disability score
CK, steroid dose
PM
w14x
Strength (electromyometry of four muscles, 0–5 scale)
Strength (MMT of 16 muscles, 0–5 scale) + function (modified Convery)
Steroid dose, rash, well-being, (CK)a
CK, steroid dose (MRI, PFTs)a
JDM
PMuDMuIBM
w15x
w16x
w4x
Strength (MMT, specific muscles tested not given, 0–5 scale)
CK
PMuDM
w17x
Strength (MMT of four muscles, 0–5 scale), sphygmomanometry
Rash, CK, AST, steroid dose
JDM
w18x
w19x
Aldolase
PMuDM
CK (MRI, PFTs)a
PMuDM
w5x
Strength (MMT of 16 muscles, 0–5 scale) + function (modified Convery)
CK, aldolase, LD, ALT, AST,
muscle biopsy (MRI, PFTs)a
IBM
w20x
Strength (MMT of 18 muscles, 0–5 scale) + symptom score
Strength (MMT of eight muscles, 0–10 scale)
Rash, function (Barthel Index), muscle biopsy
CK, aldolase
DM
PMuDM
w6x
w21x
Strength (MMT of 26 muscles, 0–10 scale)
TQNE, megascore, patient globals,
swallowing: symptoms, video-fluoroscopy, ultrasound
IBM
w22x
Strength (MMT of 16 muscles, 0–5 scale) + function (modified Convery)
CK (MRI, PFTs)a
PMuDM
w23x
Strength (MMT and myometry of eight muscles, 0–10 scale), function
CK
PMuDMuIBM
w24x
Strength (MMT of 20 muscles, 0–10 scale) + function (modified Convery)
Composite global, MDA, PBMC flow cytometry
PMuDM
w25x
Strength (MMT of 11 muscles, 0–10 scale), CK
Function (HAQ), steroid dose, PFTs
PM
w26x
Strength + endurance + function (MEFT)
CA, global patient’s assessment, MRI, CK, myoglobin, IL-1Ra
PMuDM
w27x
MMT, manual muscle testing; CK, serum activity of creatine kinase; LD, serum activity of lactate dehydrogenase; ALT, serum activity of alanine aminotransferase; AST, serum activity of
aspartate aminotransferase; ADL, activities of daily living.
Modified Convery, modified Convery with 13 functional areas each graded on a 0–4 scale; JDM, juvenile DM; PFTs, pulmonary function testing wforced vital capacity (FVC) and carbon
monoxide diffusing capacity (DLCO)x; TQNE CM megascore, Tuft’s Quantitative Neuromuscular Examination Combination Megascore = the maximum voluntary isometric contraction
(MVIC) + pulmonary function scores; composite globals = MMT (0–5 points) + swallowing (0–3) + sittinguwalking (0–2) + shirt over head (0–2) + arthritis (0–2) + rash (0–2) + DLCO
(0–3) + speechuswallowing (0–3) + sense of well-being (0–2) + CK and aldolase (0–3) + MRI (0–3), total range = 0–30; MDA, muscle disease activity score = change in MMT from previous 1–2
month visit (0–3 points) + CK, ALTuAST (0–3) + MRI score (0–3), total range = 0–10; PBMC = peripheral blood mononuclear cells; MEFT, muscle endurance and functional test = repetitive
tests for elbow flexion + shoulder flexion + shoulder abduction + hip flexion and abduction + step test + toe lifting + heel lifting + head lifting + moving side to side and from lying to sitting,
total range = 0–56; CA, composite clinical assessment = fever (0–1) + weight loss (0–1) + Raynaud’s (0–1) + arthralgia (0–1) + arthritis (0–2) + contractures (0–1) + falling episodes
(0–1) + muscle atrophy (0–1) + dysphonia (0–2) + dyspnoea on exertion (0–1) + dyspnoea at rest (0–2) + interstitial disease on CXR (0–2) + dysphagia (0–2) + trismus (0–1) + ability to
rise from squat (0–4) + functional grades for arms (0–5) + functional grades for legs (0–5), total score = 0–33; IL-1Ra, serum levels of interleukin-1 receptor antagonist.
a
Obtained as secondary outcomes but not published.
Core set outcome measures for myositis
Strength (MMT of eight muscles, 0–10 scale), CK
Strength (MMT of 16 muscles, 0–5 scale) + function (modified Convery)
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were assessed in two studies w22, 25x. Physical function,
assessed by the Barthel Index w22x or the Health Assessment Questionnaire (HAQ) w26x, was measured in two
studies. Other secondary outcome assessments were
used less frequently (Table 1).
Validated measures
of myositis disease activity
While validation has varying definitions, and no consistent criteria are applied to quantitate claims of validity,
here a broad view is taken in evaluating the few measures
of disease activity that have been partially validated
in the IIM (Table 2). Large, multicentre studies and
systematic approaches to validating disease activity
instruments have enabled the Juvenile DM Disease
Activity Collaborative Study Group to develop and
validate a number of tools preliminarily. To date,
this group has validated physician and patientuparent
global assessments of disease activity and damage,
demonstrating that these assessments have excellent
inter-reliability (Cronbach’s alpha 0.98, weighted kappa
0.88), moderate responsiveness wstandardized response
mean (SRM) =20.48 to 20.58x, and satisfactory content validity w28x. They have also undertaken validation
of manual muscle strength testing in juvenile DM w29x,
demonstrating that scores of a total of 26 muscles, as
well as scores of eight muscles tested unilaterally, both
exhibit very good to excellent reliability wKendall’s
coefficient of concordance 0.39–0.76 for inter-rater
reliability, Spearman correlation among raters (rs) 0.77
for intra-rater reliabilityx, moderate responsiveness
(SRM = 0.41–0.69) and good construct validity
(rs = 0.30–0.73 with global disease activity, measures
of physical function). The Childhood Health Assessment Questionnaire (CHAQ), a parentupatient selfreport of physical function, has been shown to have
good construct validity (rs = 20.40–0.71 with muscle
strength and disease severity) and to be reliable (intraclass correlation coefficient = 0.87 in subjects without
change in muscle strength) and responsive (responsiveness coefficient = 0.90 in subjects with treatmentinduced clinical change) in a small study of juvenile
DM w30x, and to have good content validity (item to
total correlations= 0.47–0.81), moderate convergent
construct validity (rs = 0.40–0.74 with global disease
activity, muscle strength and function and skin activity)
and excellent responsiveness wSRM = 0.87 in patients
improving >1 cm on visual analogue scale (VAS) global
activityx in a larger, multicentre study w31x.
The Childhood Myositis Assessment Scale (CMAS),
a novel observational tool of muscle function, strength,
and endurance, has demonstrated excellent interand intra-rater reliability (Kendall’s coefficient of concordance = 0.84–1.0 for individual items, 0.95 for overall
score; correlation coefficient between assessments =
0.97–0.99) and good construct validity (R2 = 0.36–0.88
with global disease activity, muscle strength, patientassessed physical function and CK) in a preliminary
validation study w33x. The Cutaneous Assessment Tool,
a measure that evaluates a variety of skin rashes present
in DM and assesses aspects of their activity and damage,
demonstrates good inter-rater reliability (intra-class
correlation coefficients 0.44–0.94) w40x. Of interest,
whereas periungual nailfold density relates best to skin
and physician global activity (R2 = 27–49% with global
disease activity, skin activity, and physical function)
w41x, swallowing symptoms and clinical examination
findings correlate best with measures of physical function and muscle strength w42x (LG Rider, unpublished
observations).
Among the measures of physical function, the
Myositis Functional Index, an observational tool which
assesses muscle function, strength and endurance, and
includes pulmonary function testing, has demonstrated
excellent inter-rater reliability w34x, and timed functional tests, such as repetitive rising from a chair, demonstrate reproducibility and responsiveness w43x. Other
muscle activity assessments that have been partially
validated in small studies include additional measures
of muscle strength and physical function, as well
as electromyography and muscle biopsy pathology
w12, 44x.
The activity of serum enzymes derived from muscle in
myositis patients has long been used as an indicator of
myositis disease activity in clinical practice. Serum
enzyme activities, however, have not been fully validated
for this purpose in the clinical trial setting and do not
correlate with clinical improvement as measured by a
combination of muscle strength and physical function
w5, 23, 27x. Furthermore, different enzyme assessments
may be optimal in different groups of patients. Current
data suggest that serum LD activity correlates best with
global disease activity in juvenile DM w35x and either
LD or AST is best in detecting increases in juvenile
DM disease activity w45x, whereas CK may be better
for assessing adult IIM, particularly PM w36x. In juvenile
IIM patients, LD in combination with one other serum
muscle enzyme (CK, aldolase, AST, or ALT) predict
global disease activity as well as four serum muscle
enzymes measured in combination w35x. Circulating
levels of troponin and other myocyte components or
metabolites have not been validated, but in small series
have been reported to be useful in assessing myositis
disease activity w12x.
MRI, although expensive and not readily available to
all physicians, is increasingly utilized to assess disease
activity and damage in IIM. STIR and T2-weighted fatsuppressed images are useful in assessing the degree of
water content in muscle, skin and subcutaneous tissue,
which appears to represent active inflammation in these
tissues w37, 38, 46x. MRI has good face and content validity, high discriminant construct validity, and STIR or
T2-weighted images appear to be responsive to change
w37, 39x. A number of investigations have suggested
that quantitative P-31 magnetic resonance spectroscopy
(MRS) studies may be useful for assessing disease activity in DM patients w47x. MRS has been shown to be
sensitive to change and have some discriminant validity.
TABLE 2. Partially validated IIM disease activity assessments
Measure
IIM group studied
Comments wReferencex
JIIM
Face and content validity; high inter-rater reliability (Cronbach’s alpha 0.98, weighted kappa 0.88),
moderately responsive (SRM = 20.58) w28x
Patientuparent global activity (Likert, VAS)
JIIM
Moderately responsive for parents (SRM = 20.54), but unresponsive for patients >10 yr
of age (SRM = 20.21). Correlates significantly with physician ratings, but not
redundant (rs = 0.41) w28x
MMT (0–5, 0–10 point scales)
JDM
Well-accepted definitions; very good to excellent reliability for scores but not for individual muscles wKendall’s
coefficient of concordance 0.39–0.76 for inter-rater reliability, Spearman correlation among raters (rs) 0.77
for intra-rater reliabilityx; moderate responsiveness (SRM 0.41–0.69); and good construct validity (rs = 0.30–0.73
with global disease activity, measures of physical function). Applicable for children >4 yr of age w29x
CHAQ
JIIM
Good content validity (item to total correlations = 0.47–0.81), moderate convergent construct validity
(rs = 0.40–0.74 with global disease activity, muscle strength and function and skin activity), excellent reliability
(intra-class correlation coefficient = 0.87 in subjects without change in muscle strength) and excellent
responsiveness (SRM = 0.87 in patients improving >1 cm on VAS global activity) w30–32x. Measures ADL physical
function, as assessed by parentupatient questionnaire. Applicable to children of all ages
CMAS
JIIM
Face validity, excellent inter- and intra-rater reliability (Kendall’s coefficient of concordance = 0.84 –1.0 for
individual items, 0.95 for overall score; correlation coefficient between assessments = 0.97– 0.99) and good
construct validity (R2 = 0.36–0.88 with global disease activity, muscle strength, patient-assessed physical
function and CK) w33x. Observational tool of muscle function, strength and endurance. Applicable for children
>2 yr of age
Myositis Functional Index (MFI)
PM
Observational tool of muscle function, endurance and strength, including PFTs. High inter-rater reliability.
Correlates with MMT w34x
Serum muscle enzyme activity
JDM, IIM
Construct validity. Responsiveness pending. LD or transaminases may be best for assessing JDM w35x.
CK better for assessing adult PM w36x
MRI (STIR, fat-suppressed T2-weighted)
PMuDM, JDM
Face and content validity, high discriminant construct validity, high inter-rater reliability, and responsiveness;
quantitated by Likert scale using a reference atlas or digital computer-assisted assessment w37–39x
Cutaneous Assessment Tool
JDM
Face validity; good inter-rater reliability (intra-class correlation coefficients 0.44–0.94). Construct validation
and responsiveness pending w40x
Nailfold capillaroscopy
JDM
Good construct validity (R2 = 27–49% with global disease activity, skin activity and physical function) w41x
Core set outcome measures for myositis
Physician global activity (Likert, VAS)
MMT, manual muscle testing; ADL, activities of daily living; HAQ, Health Assessment Questionnaire; CHAQ, Childhood Health Assessment Questionnaire; VAS, visual analogue scale;
CMAS, Childhood Myositis Assessment Scale; IIM, idiopathic inflammatory myopathy; JIIM, juvenile IIM; JDM, juvenile dermatomyositis; PM, polymyositis; MRI, magnetic resonance
imaging; STIR, short tau inversion recovery.
Disease activity refers to those changes that are due to the underlying disease process and are potentially reversible (inflammation and associated reversible disease manifestations).
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However, the general lack of availability of these
methods limits their current applicability to clinical
studies.
The evaluation of extra-skeletal muscle disease, particularly articular, cardiac, and pulmonary manifestations, has been examined in small studies using a variety
of methods, none of which has been formally validated
w12x. Additionally, measurements of immunological parameters have been explored in preliminary ways for their
capacity to reflect disease activity and, in small studies,
have often been shown to have construct validity or
to be responsive to change (reviewed in w12x). Because
of their limited availability, cost, and incomplete
validation, however, further studies are needed before
any of these surrogate markers of disease activity can
be recommended for routine use in IIM therapeutic
trials.
Committee consensus on domains
and measures of myositis disease activity
After extensive discussion and consideration of the
published outcome measures of disease activity in IIM
trials, including their validity, availability, ease of use,
and applicability to all forms of myositis, the committee
which met in Oxford proposed preliminary core and
extended measures to assess five domains that were
agreed to capture myositis disease activity in a comprehensive manner (Table 3). The five core set activity
domains that were proposed for inclusion in all myositis
clinical trials are global disease activity, muscle strength,
physical function, laboratory evaluation and assessment
of extra-skeletal muscle involvement. The committee
also recommended specific measures to assess the proposed core set domains, including: physician and patientu
parent global disease activity assessments using VAS or
Likert scale; MMT of proximal, distal and axial muscles
tested by a validated method; functional assessment
using an instrument validated in IIM patients; laboratory assessment of serum activity of at least two muscle
enzymes (selected from CK, aldolase, LD, ALT, and
AST); and an assessment of extra-skeletal muscle disease
using a comprehensive validated tool that captures cutaneous, gastrointestinal, pulmonary, cardiac, and articular disease activity. Because children less than 4 yr
of age cannot reliably perform MMT, two functional
assessment tools could be used in such patients as an
alternative to MMT, including both an observational
tool, such as the CMAS, as well as a parentupatient
questionnaire of ADL function, such as the CHAQ.
Because measures to assess extra-skeletal muscle
involvement have not been fully validated at present,
the committee has recommended that such assessment
tools be developed and incorporated into the core set
due to the high frequency and impact of these manifestations in IIM patients. Candidates for such assessment instruments include: a modification of the British
Isles Lupus Activity Group (BILAG) tool for SLE w48x;
a series of Likert scales modified from the Vasculitis
Disease Activity Index w49x; or other tools currently
undergoing validation w40, 42x. The committee proposed
extended evaluations to assess each of the five myositis
activity domains, which could be included as optional
measures, but are currently less well studied, not validated, not widely available anduor too costly for routine
use in therapeutic studies (Table 3). These extended
measures, however, may have particular value in trials
focused on certain groups of IIM patients or in assessing
the outcome of a particular organ system.
Assessment of myositis disease damage
Assessment of disease damage is an important part of
understanding the natural history of a disease or differences between disease subgroups, as well as in following
the long-term outcome of therapeutic interventions.
Furthermore, in the clinical trial setting it may be important to assess damage as an outcome measure, with a
goal of preventing increased damage over the relatively
short interval of most trials.
Little information is available regarding appropriate
measures to assess disease damage in IIM, and few tools
have been validated. Physician assessment of global
disease damage, using either Likert or VAS scales, has
been shown in juvenile myositis to have face and content
validity, to be comprehensive, and to have excellent
inter-rater reliability w28x. Although it remains unclear
how accurately the disability index of the HAQ assesses
damage, the disability index increased with disease
duration and in the presence of avascular necrosis in a
longitudinal study of a national cohort of adult DM and
PM patients w50x. Because the rate of increase in HAQ
scores appeared to be slow, follow-up of longer than
5 yr may be needed to capture damage accumulation in
some IIM groups. In contrast, most juvenile patients
have little physical dysfunction within 14 yr of diagnosis when assessed by the CHAQ, but a number
of patients have developed calcinosis or growth
impairment w10x.
MRI is perhaps one of the few tools that can readily
discriminate between disease activity and damage in the
IIM. T1-weighted MRI of the thighs assesses muscle
and subcutaneous atrophy, as well as fatty infiltration
and fibrosis, and thus appears to be a good indicator of
damage w39, 46, 51x. Serum creatinine decreases with
longstanding disease as muscle mass decreases, although
this is a relatively insensitive measure of muscle atrophy
w36x. Reduced ratios of choline and creatine to lipid
levels, measured by proton spectroscopy, are also present in PM and DM patients with longstanding disease
w51, 52x. Assessments of other aspects of damage which
have been observed in natural history studies, including the development of joint contractures, calcinosis,
pulmonary fibrosis, gastrointestinal dysmotility and
persistent dysphagia, as well as lipodystrophy, have not
been formally validated.
1269
Committee consensus on measures of
myositis disease damage
For abbreviations see Tables 1 and 2.
a
Not recommended for children less than 4 yr of age.
b
One validated tool is recommended for adults and children more than 4 yr of age and two tools for children less than 4 yr of age.
A validated approach that is comprehensive and assesses cutaneous,
gastrointestinal, joint, cardiac and pulmonary activity needs to be developed
Extra-skeletal muscle disease
At least two serum muscle enzyme activities from the following: CK, aldolase,
LD, AST, or ALT
Laboratory assessment
Physical functionb
Muscle strength
Validated patientuparent questionnaire of ADL (HAQuCHAQ)
Validated observational tool of function, strength and endurance (CMAS)
None at present
None at present
Sphygmomanometry; dynamometry; pull gauge, myometry,
electromyometry, TQNE CM megascore, maximum voluntary
isometric contraction or other quantitative strength assessment
Myositis Functional Index, Barthel Index,
other assessments of endurance and fatigability
Timed tests
MRI (STIR or T2-weighted images), muscle biopsy,
soluble immune markers (such as sCD4, sIL-2R, neopterin),
cell surface markers (such as CD19)
Cutaneous Assessment Tool, nailfold capillaroscopy,
high resolution computed tomography, echocardiography,
PFTs, swallowing studies (modified barium swallow,
ultrasound swallow) and questionnaires, biopsies
Physician global disease activity assessment by Likert or VAS
Parentupatient global disease activity assessment by Likert or VAS
MMT by a 0–10 point or expanded 0–5 point scale to include proximal,
distal and axial musclesa
Global activity
Core set measures
Domain
TABLE 3. Proposed preliminary core and extended set measures for disease activity assessment for therapeutic trials in adult and juvenile IIM
Extended set measures
Core set outcome measures for myositis
The committee agreed that changes related to disease
damage should be present for at least 6 months (or the
pathology that led to the feature must have been present
for at least 6 months) despite prior immunosuppressive,
rehabilitation, or other therapy. Damage is defined as
persistent pathological changes, including such postinflammatory changes as fibrosis, scarring or atrophy,
or as persistent changes in anatomy, physiology or function, and it should be ascertained by clinical assessment
or widely available laboratory investigations. Damage
may be the result, in part, of other causes of pathology,
such as drug toxicities and sequelae of unrelated disease
processes that can sometimes be distinguished from
damage related to underlying myositis, and for some
studies it may be desirable to attempt to distinguish the
underlying aetiology resulting in damage.
The committee agreed that it is premature to define
core and extended set measures to assess disease
damage because of the currently limited information
available regarding appropriate assessments, and
recommended further development and validation of
measures to assess damage in myositis. Nonetheless,
possible candidates for a core set of measures to assess
damage in myositis include: physician global damage
assessments; the HAQuCHAQ as measures of physical
function, which appear to measure cumulative functional abnormalities in natural history studies of adult
w50x and juvenile w31x myositis; an assessment of the
severity of damage of different organ systems using
VAS; and a modification of the Systemic Lupus
International Collaborative Clinics (SLICC)uAmerican
College of Rheumatology (ACR) Damage Index which
assesses the extent of damage in different organ systems
w53x. Approaches that combine these variables may
be most useful, as they may capture complementary
information and assess varying aspects of damage.
Candidate measures for an extended damage set include:
T1-weighted MRI w39, 51x, assessment of fibrosis, scarring, and atrophy in muscle or other tissue biopsies,
serum creatinine levels, proton spectroscopy to measure
muscle metabolites which accumulate in atrophied
muscle w51x, and a cutaneous assessment tool which
captures skin damage w36x.
Committee consensus on patient assessments
of health-related quality of life (HR-QOL)
HR-QOL is an important domain to assess in clinical
trials and observational studies in many diseases w54x.
The committee proposed that the Medical Outcomes
Study 36-item Short Form (SF-36) be used as a generic
quality of life measure for adults in myositis clinical
trials given its extensive validation in other rheumatic
diseases and widespread use, although its inclusion in
trials may not necessarily satisfy specific requirements
of regulatory agencies for marketing claims. Other
1270
F. W. Miller et al.
HR-QOL measures, such as the Nottingham Health
Profile, have been piloted in myositis w55x, but they are
not widely translated and have not been applied to many
other chronic disorders. The committee recommended
further development of a validated, disease-specific
HR-QOL measure, which will focus on capturing all
domains that are important to the patient. Such a tool
for IIM is in development and should be available for
use in trials once validation studies have been completed
(K. Vincent, personal communication). Measures to
assess patient fatigue also need to be developed and
validated, with attention to measures applicable for
age for paediatric patients. Validated generic HR-QOL
measures that are appropriate for paediatric patients
and which assess a number of domains, including physical, social, and psychological function, are emerging. Of
two recently validated generic instruments, the Childhood Health Questionnaire is modelled more closely
to the SF-36 than is the PedsQL Pediatric Quality of
Life Inventory w56, 57x.
Discussion
The goals of this international committee of specialists were to review and evaluate the current practices
and validation regarding myositis measures and to
develop a proposal for the most appropriate core measures to assess disease activity, damage and patient selfassessment in order to promote uniformity in assessing
outcomes in IIM therapeutic trials. The consensus
process leading to the domains and outcome measures
chosen was driven by the validity and feasibility of use
of the measures as well as by their general applicability
to all forms of myositis in children and adults.
The proposed preliminary disease activity core set
measures (Table 3) should capture the broad range of
IIM activity and, based upon validation studies conducted to date (Table 2), are likely to be at least moderately sensitive to change. Other disease activity measures
used in IIM clinical trials (Table 1) were not chosen as
core set measures for any of several reasons, including
incomplete validation in patients with myositis,
expense, difficulty in use, insensitivity to change, or
redundancy (that they were likely to be collinear with
or to duplicate information provided by one of the core
measures). In addition to the core set measures suggested for use in all trials, ancillary and novel assessments (extended set measures) may also be included in
attempts to develop tools with greater accuracy, responsiveness and efficiency. These extended measures may
be particularly useful in trials involving a specific group
of IIM patients, and if further study demonstrates their
superiority, they could eventually replace one or more
of the current core measures in later versions of the
recommended core set.
An attempt has been made by this group to choose
core outcome assessments that would be applicable to
all forms of the IIM. We realize, however, that outcome
measures, and the disease activity indices which will be
developed from such measures, may have different
response characteristics in different IIM groups (DM
vs PM vs IBM, or adults vs children) and may need to be
modified accordingly as experience is gained with these
and other tools. We appreciate that these recommendations are based upon a limited database and that most
of the tools proposed are only partially validated. It
is expected that as additional data become available
in these areas, they will be incorporated into updated
versions of revised core and extended disease activity
and damage sets in an evolving process.
Although therapies are often tested for the treatment
of the muscle disease component of myositis patients, it
is possible that future therapeutics may target another
particular manifestation of IIM, such as cutaneous
or interstitial lung disease. In such cases, it would be
appropriate to develop validated outcome measures
for a specific target organ, which could be employed as
the primary outcome assessed in a focused therapeutic
study. Nonetheless, even in these cases, we propose that
the core set be measured and utilized as secondary outcome assessments so that effects on the overall IIM
disease activity can be monitored.
In conclusion, we propose a preliminary core set of
outcome measures to be included in all IIM trials as
a first step towards standardizing trial methodology in
these orphan diseases. The proposed measures are the
result of extensive discussion and consultation among
adult and paediatric rheumatologists, neurologists,
dermatologists and other myositis researchers from
around the world. Both prospective and retrospective
studies are now being planned to determine how these
measures perform in practice.
Acknowledgements
We are grateful to the following members of the JDM
Disease Activity Collaborative Study Group for sharing
unpublished data for the Oxford meeting: Drs Susan
Ballinger, Suzanne Bowyer, Elizabeth Dugan, Brian
Feldman, Jeanne Hicks, Adam Huber, Ildy Katona,
Peter Lachenbruch, Carol Lindsley, Lauren Pachman,
Murray Passo, Maria Perez, Ann Reed, Robert
Rennebohm, Barbara Sonies, Carol Wallace, Patience
White, and Lawrence Zemel. We thank Drs Kent
Johnson, James Witter, Sahar Dawisha and other
members of the FDA Rheumatology Working Group
for valuable input, and Drs Jeffrey Siegel and Dorothy
Scott for insightful comments on the manuscript. This
work was supported in part by the Dermatomyositis
and Polymyositis Support Group. Dr Vencovsky’s
work is supported in part by the Internal Grant
Agency of the Ministry of Health in the Czech
Republic, grant no. NIu5369-3.
The statements in this article reflect the opinions of
the authors and not necessarily those of the institutions they represent. This article is not endorsed as
the regulatory policy of the US Food and Drug
Administration or other regulatory agencies.
Core set outcome measures for myositis
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Appendix A
Additional members of the International Myositis Outcome
Assessment Collaborative Study Group
Elizabeth Adams, Bethesda, MD, USA
Helene Alexanderson, Stockholm, Sweden
Nancy Armentrout, Harrisonburg, VA, USA
Zohar Argov, Jerusalem, Israel
Richard Barohn, Dallas, TX, USA
Suzanne Bowyer, Indianapolis, IN, USA
Hermine Brunner, Cincinnati, OH, USA
Ruben Burgos-Vargas, Mexico City, Mexico
Jeffrey Callen, Louisville, KY, USA
Gail Cawkwell, Las Vegas, NV, USA
Patrick Cherin, Paris, France
Mary Cronin, Milwaukee, WI, USA
Joyce Davidson, Liverpool, UK
Brian Feldman, Toronto, Canada
Richard Finkel, Philadelphia, PA, USA
Ignacio Garcia de la Torre, Guadalajara, Mexico
Ekkehard Genth, Aachen, Germany
Edward Giannini, Cincinnati, OH, USA
Gerald Hengstman, Nijmegen, The Netherlands
Jeanne Hicks, Bethesda, MD, USA
Adam Huber, Halifax, Canada
Hans-Iko Huppertz, Bremen, Germany
Lisa Imundo, New York, NY, USA
Joseph Jorizzo, Winston-Salem, NC, USA
Lawrence Kagen, New York, NY, USA
John Kissel, Columbus, OH, USA
Marisa Klein-Gitelman, Chicago, IL, USA
Abraham Garcia Kutzbach, Guatemala City, Guatemala
Bianca Lang, Halifax, Canada
Carol Lindsley, Kansas City, KS, USA
Daniel Lovell, Cincinnati, OH, USA
Peter Malleson, Vancouver, Canada
Alberto Martini, Pavia, Italy
Thomas Medsger, Pittsburgh, PA, USA
Kevin Murray, London, UK
Chester Oddis, Pittsburgh, PA, USA
Lauren Pachman, Chicago, IL, USA
Maria Perez, Houston, TX, USA
Paul Plotz, Bethesda, MD, USA
Core set outcome measures for myositis
Dieter Pongratz, Munchen, Germany
Ann Reed, Rochester, MN, USA
Robert Rennebohm, Columbus, OH, USA
Nicolino Ruperto, Pavia, Italy
Seward Rutkove, Boston, MA, USA
Jean-Luc Senecal, Montreal, Canada
Georges Serratrice, Marseille, France
Jacques Serratrice, Marseille, France
David Sherry, Seattle, WA, USA
Kumaraswamy Sivakumar, Phoenix, AZ, USA
Yeong Song, Seoul, Korea
Richard Sontheimer, Iowa City, IA, USA
Ira Targoff, Oklahoma City, OK, USA
Maria Turner, Bethesda, MD, USA
Basiel van Engelen, Nijmegen, The Netherlands
Maria Villalba, Rockville, MD, USA
Victoria Werth, Philadelphia, PA, USA
Patience White, Washington, DC, USA
Robert Wortmann, Tulsa, OK, USA
Steven Ytterberg, Rochester, MN, USA
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