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Development, reliability, and validity of a novel

Epidermolysis Bullosa Disease Activity and Scarring


Index (EBDASI)
Clement C. H. Loh, BSc Med (Hons I),a,h Jaehwan Kim, MD, PhD,a,h
John C. Su, MBBS, M Epi, FRACP, FACD, FAAD,b,c,d Benjamin S. Daniel, BA, BCom, MBBS, MMed (Clin Epi),e,h
Supriya S. Venugopal, MBBS, MMed (Clin Epi),f,h Lesley M. Rhodes, RN, RM, ACN,a
Lizbeth R. A. Intong, MD, DPDS,a,h Matthew G. Law, MA, MSc, PhD,g,h and
Dedee F. Murrell, MA (Cambridge), BMBCh (Oxford), FAAD, MD, FACDa,h
Sydney and Melbourne, Australia

Background: There is a lack of validated standardized outcome measures for epidermolysis bullosa (EB)
that can separate activity from damage.
Objective: We sought to develop and validate an instrument for inherited EB of all ages and subtypes, the
EB Disease Activity and Scarring Index (EBDASI), which scores activity responsive to therapy separately
from scarring.
Methods: The EBDASI was validated by comparing its reliability and validity against the Birmingham EB
Severity (BEBS) score (partially validated with activity mixed with scarring), using the Physician Global
Assessment (PGA) scale as a reference measurement. Sixteen patients with EB (7 EB simplex, 5 dominant
dystrophic EB [DDEB], 2 junctional EB, and 2 recessive dystrophic EB) were assessed by 5 EB experts using
the EBDASI, BEBS, and PGA, and data from 9 additional patients assessed on an ad hoc basis during
routine patient clinic were also included.
Results: For interrater reliability, the overall total score intraclass correlation coefficients (95% confidence
intervals) were: EBDASI 0.964 (0.929-0.986), BEBS 0.852 (0.730-0.937), and PGA 0.873 (0.765-0.946). For
intrarater reliability, the intraclass correlation coefficients were: EBDASI 0.994 (0.976-0.998), BEBS 0.926
(0.748-0.981), and PGA 0.932 (0.764-0.982). The EBDASI had a higher correlation with PGA (r = 0.871) than
BEBS with PGA (r = 0.852). Intraclass correlation coefficients scatterplots showed the EBDASI was better at
distinguishing milder forms of EB, with better correlations at higher severity scores than the BEBS.
Limitations: A limited number of patients were recruited for this study. An independent study will be
required to demonstrate the responsiveness of the EBDASI.
Conclusion: The EBDASI demonstrated excellent reliability and validity, as compared with 2 other
outcome measures. ( J Am Acad Dermatol 2014;70:89-97.)
Key words: epidermolysis bullosa; Epidermolysis Bullosa Disease Activity and Scarring Index; outcome
measure; reliability; severity score; validation.

From the Department of Dermatology, St George Hospital, South Wales Medicine Honors Research Program (for Mr Loh to
Sydneya; Epidermolysis Bullosa Clinic, Royal Childrens Hospital, spend a year studying with Dr Murrell).
Melbourneb; Department of Pediatrics, University of Melbour- Conflicts of interest: None declared.
nec; Department of Medicine, Monash University, Melbourned; The study findings were presented as oral papers at the Epider-
Department of Medicine, St Vincents Hospital, Sydneye; De- molysis Bullosa Expert Conference in Marbella, Spain, Novem-
partment of Dermatology, Westmead Hospital, Sydneyf; and ber 2012, and at the International Investigative Dermatology
Kirby Instituteg and Faculty of Medicine,h University of New Conference in Edinburgh, May 2013, and published in the
South Wales, Sydney. Journal of Investigative Dermatology (abstract) 2013;43:S89.
Supported by Caroline Quinn Trust (grant to Dr Murrell), Premier Supplementary figures are available at http://www.jaad.org.
Dermatology R&D, Foote Family donation to the Lord Mayors Accepted for publication September 25, 2013.
Trust Fund, Victoria, the Australasian Blistering Diseases Foun- Reprint requests: Dedee F. Murrell, MA (Cambridge), BMBCh
dation, Dystrophic Epidermolysis Bullosa Research Association (Oxford), FAAD, MD, FACD, Department of Dermatology, St
New Zealand, Dystrophic Epidermolysis Bullosa Research Asso- George Hospital, Gray Street, Kogarah, Sydney, NSW 2217,
ciation Australia, Dystrophic Epidermolysis Bullosa Research Australia. E-mail: d.murrell@unsw.edu.au.
Association New South Wales (Australia), Japanese Society for 0190-9622/$36.00
Investigative Dermatology (Mr Loh), and University of New ! 2013 by the American Academy of Dermatology, Inc.
http://dx.doi.org/10.1016/j.jaad.2013.09.041

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Epidermolysis bullosa (EB) represents a group of Patients with EB of different disease subtypes and
rare inherited mechanobullous disorders character- severities were recruited for a 1-day scoring exercise
ized by fragility of epithelial-lined tissues with minimal to formally validate the EBDASI. This is identical in
trauma. Assessing disease activity in EB remains design to the study that validated the PDAI.3
difficult because of the lack of a well-validated scoring
system. Item score and generation
Current outcome measures for EB are far from The EBDASI was divided into an activity and
satisfactory. The Japanese in- damage components for all 5
dices1 contained laboratory subsections (Supplementary
parameters that had various CAPSULE SUMMARY Fig 1). Content validity was
floor and ceiling effects established by including all
d Current severity indices for epidermolysis
for measuring change. The complications of EB from the
bullosa do not separate measures for
Birmingham EB Severity literature reviewed by a
disease activity and damage.
(BEBS) score2 is a partially worldwide panel of EB
validated overall severity d This study presents a new Epidermolysis experts.4-6 The revised ver-
index that mixes disease Bullosa Disease Activity and Scarring sions were tested weekly, on
activity with damage, and Index scoring system that scores activity clinical photographs and
assesses skin involvement separately from damage. patients with EB from routine
by measuring percentage d This scoring system has demonstrated bullous clinics.
area of skin affected, which excellent reliability and validity and Revision and refinement
is less reliable than quantify- might be a useful instrument to facilitate of EBDASI score items were
ing lesion number and size future clinical trials. guided by feedback from
thresholds.3 scorers (D. F. M., J. K., and
Therefore, our goal was to L. M. R.), and from statistical
develop an objective severity index that assesses the results derived from preliminary data, until the final
overall extent of disease for use in clinical and EBDASI was created. No medical instruments were
research settings. needed when using the EBDASI.
We present the EB Disease Activity and Scarring
Index (EBDASI), which quantifies the overall Sample size requirement
severity of involvement of the skin, scalp, mucous Calculations based on a review of similar
membranes, nails, and other epithelialized surfaces studies showed that with a sample size of at least
in terms of activity and damage. 15 patients and 5 assessors, an observed intraclass
correlation coefficient (ICC) of 0.9, 0.8, and 0.7 would
be estimated with 95% confidence intervals (CI) of
METHODS 0.82 to 0.97, 0.66 to 0.94, and 0.51 to 0.89,
Study design and ethics respectively. Thus the study would have an adequate
This study received ethical approval from sample size to discriminate a high (0.9) from
the South Eastern Sydney Local Health District moderate (0.7) ICC, which we thought was an
Human Research Ethics CommitteeeSouthern acceptable level of precision.
Sector (EC00135).
We drew upon the methodology of the develop- Subject recruitment and informed consent
ment and validation of the Pemphigus Disease Area All patients recruited had biopsy-proven EB, who
Index (PDAI).3 In assessing skin involvement, the volunteered to participate and provided informed
PDAI uses a grading methodology based on thresh- consent either when attending clinic or when
olds of the number and diameter of active lesions in contacted by telephone. The patient sample
particular body sites (eg, \3 or [3 lesions/site; included a range of different disease severities and
maximum lesion size \2, 2-6, or 6-16 cm), which subtypes (Table I).
was found to be more reliable and correlated better
with the Physician Global Assessment (PGA) scale One-day EB severity scoring exercise
than the Autoimmune Bullous Skin Disorder Sixteen patients with EB came to the clinic facility
Intensity Score,3 which is similar to BEBS by for the first time on 1 day to validate the EBDASI
quantifying the percentage area of skin involved. (Fig 1). Five experts from different institutions
Therefore, this methodology of quantifying the (D. F. M., J. K., S. S. V., B. S. D., and J. C. S.) with
number and size of lesions was incorporated in the considerable experience in treating patients with EB
development of the EBDASI. were recruited as assessors. Three of these assessors
J AM ACAD DERMATOL Loh et al 91
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scores were not influenced by knowing the final


Abbreviations used:
scores for EBDASI and BEBS.
BEBS: Birmingham Epidermolysis Bullosa At the end of the entire scoring exercise, the
Severity
CI: confidence interval assessors convened and discussed the scoring
EB: epidermolysis bullosa methods and provided feedback on using the 3
EBDASI: Epidermolysis Bullosa Disease Activity severity scales.
and Scarring Index
ICC: intraclass correlation coefficient
PDAI: Pemphigus Disease Area Index Statistical analysis
PGA: Physician Global Assessment All statistical analyses were performed using
QOL: quality of life
QOLEB: quality of life in epidermolysis bullosa software (SPSS, Version 18.0, IBM Corp, Armonk,
NY; and Excel, Microsoft, Redmond, WA).
Reliability. Both interrater and intrarater relia-
bilities were assessed by the ICC with 95% CI, using a
(S. S. V., B. S. D., and J. C. S.) were from 3 different 1-way random effect analysis of variance model. An
institutions and had never used the EBDASI or BEBS ICC value of above 0.80 is considered excellent.8
before. The EBDASI, BEBS, and PGA Spearman rho correlation coefficient (r) was also
(Supplementary Figs 1 to 3) were used to rate all calculated to assess intrarater agreement. ICC scat-
patients. Before this scoring exercise, all assessors terplots and Bland-Altman plots were constructed
were sent copies of these scoring systems and to illustrate interrater differences and intrarater
clinical photographs to familiarize themselves with variability in scores for all 3 outcome instruments.
the scoring methods. Validity. Face and content validity of the EBDASI
Before the scoring exercise, all assessors com- was established by including all possible physical
pleted a 1-hour training session on using the complications of EB, mentioned in the literature,4-6
EBDASI, BEBS, and PGA to rate visual images and based on expert opinion from the EB team at St
of skin lesions seen in various EB subtypes. George Hospital, Sydney, Australia.
Assessors discussed and clarified scoring results For convergent construct validity, both EBDASI
and methodology so as to standardize the level of and BEBS were correlated with the PGA and QOLEB
assessment. scores, and the respective Spearman rho correlation
The patients were placed in individual rooms coefficients (r) with 95% CI were determined.
either alone, or with their caretaker (a person who To demonstrate that EBDASI and BEBS scores
regularly looks after the patient) if needed, and asked increase in linear proportions over increasing PGA
to complete the quality of life (QOL) in EB (QOLEB) scores, simple linear regression analysis was per-
questionnaire,7 and then undressed to their under- formed to calculate the coefficient of determination
wear and their dressings removed. Each assessor was (R2), and the generalized linear model analysis
randomly assigned to rate these patients individually of variance F test was used to assess statistical
using all 3 instruments in different orders, and significance.
assessors rotated around the patients rooms at Feasibility. Feasibility was assessed by instruct-
15-minute intervals. Each assessor also randomly ing assessors to individually document their own
rerated 2 patients for intrarater reliability. None of the start and stop times for each outcome instrument
external assessors (S. S. V., B. S. D., and J. C. S.) were during the 1-day scoring exercise. The mean time
informed beforehand that there would be a rescoring and SEM were computed for all 3 instruments.
session to minimize recall bias. Depending on which
patient was rerated, the time interval between RESULTS
the initial and subsequent rescoring ranged from EBDASI development
15 to 90 minutes, and assessors were not assigned to The EBDASI is a 4-page document shown in Fig 1
rerate the patient who they had last assessed. and Supplementary Fig 1. Each area of the skin
To protect patient privacy, the anogenital areas of was examined in order from top to bottom at
all patients were assessed only by D. F. M., who was 12 different anatomical sites. Activity (blistering/
familiar to all patients. The anogenital scores, repre- erosions/crusting) is scored out of 10 in each area.
senting a very small proportion (\5%) of the overall The features of damage (erythema, dyspigmentation,
activity score, were accepted by all other assessors. poikiloderma, skin atrophy, hyperkeratosis/scaling,
The scores for the EBDASI and BEBS were not scarring, milia) are given a 0 for absent and 1 for
added up at the time of scoring to save time for the present in each site. The process is continued for the
patients being undressed, but were only calculated scalp, mucous (Supplementary Fig 4) membranes,
after the scoring session had completed. Hence PGA nails, and other epithelialized surfaces.
92 Loh et al J AM ACAD DERMATOL
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Table I. Demographics of patients with epidermolysis bullosa in the 1-day scoring session
Patients with EB Sample for interrater analysis (N = 16) Sample for intrarater analysis (N = 10)
Age range, y 0.416-66 2-66
Mean age 6 SD, y 27.59 6 21.79 25.90 6 22.46
Male 7 (43.75%) 4 (40%)
Female 9 (56.25%) 6 (60%)
EB subtypes Sample for interrater reliability, No. (frequency) Sample for intrarater reliability, No. (frequency)
EBS, localized 4 (25%) 3 (30%)
EBS, Dowling Meara 2 (12.5%) 1 (10%)
EBS, Ogna 1 (6.3%) 0 (0)
JEB, non-Herlitz generalized 2 (12.5%) 2 (20%)
DDEB, generalized 3 (18.8%) 2 (20%)
DDEB, acral 2 (12.5%) 2 (20%)
RDEB, severe, generalized 1 (6.3%) 0 (0)
RDEB nonsevere, generalized 1 (6.3%) 0 (0)

DDEB, Dominant dystrophic epidermolysis bullosa; EB, epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional
epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa.

Baseline characteristics Bland-Altman plots also showed that the EBDASI


In the 1-day scoring exercise, 16 patients with a had lesser intrarater variability than BEBS and
range of EB subtypes (7 male [43.8%] and 9 female PGA (Supplementary Fig 5). Analysis of EBDASI
[56.2%]) with a mean age of 27.6 years (range: 4 months- subsectional ICCs for activity and damage scores
66 years) attended (Table I). Nine additional patients were also calculated (Supplementary Table IV).
with EB were assessed with the EBDASI and BEBS
during outpatient clinics (Supplementary Table I). Convergent construct validity
The correlations of the EBDASI/BEBS overall
EBDASI score distribution total scores with PGA were: EBDASI with PGA
The mean EBDASI overall total score (6SD) from (r = 0.871 [0.786-0.924]), and BEBS with PGA
the study day was 51.68 (647.40)/506. Scores ranged (r = 0.852 [0.758-0.910]) (Table III).
from 3.6 to 189, with a median of 35.90 and The correlation of overall total scores of all 3
interquartile range of 44.10. The respective EBDASI outcome instruments with QOLEB scores were
overall total scores for different EB subtypes are (Table III): EBDASI with QOLEB (r = 0.645
shown in Supplementary Table II. The mean EBDASI [0.133-0.886]), BEBS with QOLEB (r = 0.750
total activity score was 14.04 (613.01)/276 (range: [0.313-0.925]), and PGA with QOLEB (r = 0.719
1.4-49), whereas the mean EBDASI total damage [0.326-0.913]). The EBDASI total damage score
score was 37.64 (635.79)/230 (range: 2.2-140) (r = 0.734 [0.317-0.914]) has a higher correlation
(Supplementary Table III). with QOLEB than the EBDASI total activity score
(r = 0.447 [!0.124 to 0.816]).
Reliability Linear regression analysis demonstrates that the
For interrater reliability, the overall total score EBDASI correlates better with PGA (R2 = 0.828) as
ICCs (and their 95% confidence intervals) were: compared with BEBS (R2 = 0.649) (Supplementary
EBDASI 0.964 (0.929-0.986), BEBS 0.852 (0.730- Fig 6). The linear trends between the instruments
0.937), and PGA 0.873 (0.765-0.946) (Table II). ICC with PGA were examined using the generalized
scatterplots demonstrated a more appreciable linear model analysis of variance F test. The F value
increase in EBDASI scores with different types for EBDASI was 95.51, degrees of freedom = 1, P less
of EB simplex and dominant dystrophic epider- than .0001; the F value for BEBS was 19.30, degrees
molysis bullosa (DDEB) as compared with BEBS of freedom = 1, P less than .0001. The Pearson
(Supplementary Fig 2). correlation coefficient was 0.910 (0.863-0.941) for
For intrarater reliability, the overall total EBDASI with PGA and for BEBS with PGA, r = 0.805
scores ICCs were (Table II): EBDASI 0.994 (0.712-0.871).
(0.976-0.998), BEBS 0.926 (0.748-0.981), and PGA
0.932 (0.764-0.982). The Spearman r coefficients Feasibility
(95% CI) were: EBDASI 0.939 (0.758-0.986), BEBS Whichever instrument was completed first
0.939 (0.758-0.986), and PGA 0.936 (0.686-1.000). took longer than when the same instrument was
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Fig 1. The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI ). First page for
skin assessment. (Refer to Supplementary Fig 1 for full EBDASI score sheet.)
94 Loh et al J AM ACAD DERMATOL
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Table II. Reliability for Epidermolysis Bullosa Disease Activity and Scarring Index, Birmingham Epidermolysis
Bullosa Severity, and Physician Global Assessment
Interrater reliability
Scale Item ICC (95% CI)
EBDASI Skin activity 0.941 (0.884-0.976)
Skin damage 0.853 (0.732-0.937)
Total skin score (skin activity 1 skin damage) 0.941 (0.884-0.976)
Total activity 0.903 (0.816-0.960)
Total damage 0.955 (0.912-0.982)
Overall total score 0.964 (0.929-0.986)
Overall total score, patients with RDEB only 0.973 (0.819-1.000)
Overall total score, all other patients except RDEB 0.957 (0.911-0.984)
BEBS Total skin score 0.768 (0.602-0.896)
Overall total score except nails and skin 0.790 (0.635-0.907)
Overall total score 0.852 (0.730-0.937)
PGA Overall total score 0.873 (0.765-0.946)
Intrarater reliability
Scale Item ICC (95% CI) Spearman r (95% CI)
EBDASI Total activity 0.951 (0.827-0.987) 0.969 (0.802-1.000)
Total damage 0.993 (0.976-0.998) 0.988 (0.869-1.000)
Overall total score 0.994 (0.976-0.998) 0.939 (0.758-0.986)
BEBS Overall total score 0.926 (0.748-0.981) 0.939 (0.758-0.986)
PGA Overall total score 0.932 (0.764-0.982) 0.936 (0.686-1.000)

Interrater and intrarater reliabilities for all 3 outcome instruments were assessed using the ICC at 95% confidence level. Spearman rho
correlation coefficient (Spearman r) was also calculated as a measure of intrarater reliability.
BEBS, Birmingham Epidermolysis Bullosa Severity; CI, confidence interval; ICC, intraclass correlation coefficient; EBDASI, Epidermolysis Bullosa
Disease Activity and Scarring Index; PGA, Physician Global Assessment; RDEB, recessive dystrophic epidermolysis bullosa.

Table III. Convergent validity: Correlation of Epidermolysis Bullosa Disease Activity and Scarring Index/
Birmingham Epidermolysis Bullosa Severity with Physician Global Assessment/Quality of Life in Epidermolysis
Bullosa
Convergent construct validity: correlation of EBDASI/BEBS with PGA/QOLEB
Correlation of EBDASI/BEBS with PGA
Scoring system Scoring system Spearman r (95% CI)
EBDASI overall total score PGA 0.871 (0.786-0.924)
EBDASI total activity score PGA 0.762 (0.627-0.853)
BEBS overall total score PGA 0.852 (0.758-0.910)
Correlation of EBDASI/BEBS/PGA with QOLEB
Scoring system Scoring system Spearman r (95% CI)
Average EBDASI overall total score QOLEB 0.645 (0.133-0.886)
Average EBDASI total activity score QOLEB 0.447 (e0.124 to 0.816)
Average EBDASI total damage score QOLEB 0.734 (0.317-0.914)
Average BEBS overall total score QOLEB 0.750 (0.313-0.925)
Average PGA overall total score QOLEB 0.719 (0.326-0.913)

BEBS, Birmingham Epidermolysis Bullosa Severity; CI, confidence interval; EBDASI, Epidermolysis Bullosa Disease Activity and Scarring Index;
PGA, Physician Global Assessment; QOLEB, quality of life in epidermolysis bullosa.

performed second. The mean time of completion DISCUSSION


(6SD) for each instrument was 7.89 (60.464) The advantage of the EBDASI is the ability to
minutes for the EBDASI, 4.97 (60.357) minutes for distinguish activity scores that are responsive to
BEBS, and 0.0865 (60) minutes for PGA. therapy separately from damage, thus enabling
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between the assessors were small, whereas the range


of scores between patients were wide. This implied
that the assessors scored more consistently using the
EBDASI for the severe cases as well.
High interrater and intrarater ICCs for BEBS may
be a result of differences in BEBS scores being
scaled down by divisive factors in the scale
(Supplementary Fig 2). The subtotal A scores for
the nail subsection has to be divided by 4 and 8 for
lost and dystrophic nails, respectively, to obtain the
subtotal B scores. For the skin subsection, the total
percentage of damaged skin has to be divided by 2
to get the total subsection score. Hence any
interrater or intrarater differences in scores are
minimized, conferring falsely elevated ICCs. This
probably explains why BEBS did not differentiate
well between patients at low severity levels (Fig 2),
because minor differences in severity are further
minimized.
Comparing the skin subsections, BEBS (ICC
0.768) has a lower interrater agreement than the
EBDASI (ICC 0.941). This is likely because of BEBS
quantifying the percentage of total body surface
area involved using both the Rule of Nines and
Rule of Palms methods. Extensive studies have
consistently shown that there is poor accuracy in
both the Rule of Nines and Rule of Palms, with a
tendency to overestimate the total area of skin
Fig 2. Epidermolysis bullosa (EB) intraclass correlation involved.9-16 In general, the area of the patients
coefficient scatterplots. These graphs illustrate the spread palm is equivalent to 0.76% to 0.78% of total body
of scores for all 3 outcome instruments. EB Disease Activity
surface area and this proportion remains relatively
and Scarring Index (EBDASI ) (A), Birmingham EB Severity
(BEBS ) (B), and Physician Global Assessment (PGA)
constant throughout life.17,18 Hence the area of the
(C) overall total score against mean rank order. palm is not exactly equivalent to 1% of the total
The y axis gives the raw scores and the x axis gives the body surface area.15 All assessors are experienced
mean rank order for that patient. For each patient, the EB clinicians who are familiar with both rules and
mean overall total score was calculated for each use it in Psoriasis Area and Severity Index,
instrument and ranked in ascending order of the mean Autoimmune Bullous Skin Disorder Intensity
overall total scores (mean rank order). The overall total Score, SCORAD, and SCORTEN assessment tools.
scores were plotted against the mean rank order for each The EBDASI quantifies the number and size of
instrument. These graphs demonstrate that the EBDASI is lesions, and this methodology, compared with
more capable than the BEBS in distinguishing difference estimates of percentage involvement, has been
on disease severities toward the lower end of the
shown in previous studies to be a more reliable
spectrum. For example, the EBDASI is able to discriminate
between patients 1 to 5 in terms of disease severity, but not
and reproducible method of assessing cutaneous
the BEBS or PGA scales. involvement in skin diseases.3,19,20 Furthermore,
although there was a very small overlap between
the CI of the EBDASI, BEBS, and PGA, because
physicians to follow disease activity that is poten- the EBDASI has very narrow CI compared with
tially reversible that prevents damage. the other 2 measures, there is more accuracy around
Based on the ICC scatterplots, the EBDASI was the point estimate of the EBDASI instrument.21
more capable of detecting differences in severity QOLEB scores also correlate better with EBDASI
than BEBS and PGA, particularly toward the low to total damage score than the total activity score,
moderate end of the spectrum. With increasing order suggesting that QOL is more related to the degree
of disease severity, there was a narrower range of scarring than current disease activity. Treatment is
of scores for EBDASI compared with BEBS and likely to affect activity and prevent future damage but
PGA, indicating that the differences in EBDASI scores cannot alter current damage. Hence, EBDASI activity
96 Loh et al J AM ACAD DERMATOL
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scores are less likely to correlate with QOL than The heterogeneity of clinical manifestations
composite scores that include damage: the BEBS and between different subtypes makes it difficult to
PGA. Furthermore, complex psychological factors design a comprehensive score that quantifies all
such as resilience and adaptation may influence and clinical features of EB. As such, the EBDASI is 4 pages
lower the correlation between the severity scores long and certain score items are almost always
and QOLEB scores. scored 0 in certain subtypes that are unlikely to
The anogenital region was only scored by a single exhibit these clinical features, such as skin cancer
assessor (D. F. M.) as these patients would not and poikiloderma. Nevertheless, this avoids floor
tolerate getting in a position and having the and ceiling effects in the EBDASI.
anogenital area examined by 4 other assessors Longitudinal studies will need to be conducted
whom they were unfamiliar with, especially for the to establish the clinical responsiveness of the
severe cases. As some damage score items (milia and EBDASI with more investigators on a larger cohort
hyperkeratosis) are potentially reversible, these of patients over a longer period of time, particularly
damage scores may be examined individually and on patients with EB of the rarer and severe
compared in prospective clinical trials. However, subtypes.
these features are slow to change, usually over In conclusion, the EBDASI has demonstrated
months or years rather than weeks. excellent reliability, validity, and feasibility. The
We acknowledge the limited number of patients novelty of the EBDASI is in the fact that it is to our
recruited for this study, given the rarity of EB and knowledge the first validated EB instrument that
difficulties with traveling to the clinic facility in enables measurement of disease activity separately
Australia. Patients with EB recruited for this scoring from damage, and is suitable for use in all EB
exercise had limited disease extent; it was difficult subtypes and ages. The EBDASI will enable clinical
to recruit patients with more of the severe subtypes trials of the exciting new modalities being planned
to attend our scoring exercise. To compensate for for EB to have an objective instrument for EB
that, we also scored these severe cases during severity.
routine quarterly skin checks. This sample size is
The authors would like to thank all the patients with
comparable with the number of patients (15)
epidermolysis bullosa and their families who participated
recruited for the pemphigus study,3 and most of in this study. They also thank Dr William Huang and
those patients with pemphigus also had limited medical students Anh Tran and Charles Wang for assisting
disease extent. Another limitation was that this is a with logistics on the day.
single-center study, as both validity and reliability
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16. Rossiter N, Chapman P, Haywood I. How big is a hand? Burns Hashimoto T, et al. Definitions and outcome measures
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SUPPLEMENTARY TEXT clinical settings, allowing scores to be calculated


Having a validated epidermolysis bullosa (EB) quickly.
extent measure is crucial for standardized evalua- The model of the Psoriasis Area and Severity
tion of various therapeutic regimens in clinical trials, Index was avoided as the percentage area of in-
for longitudinal disease monitoring, and for the volvement has poor interrater reliability and weights
formulation of treatment strategies. From a multi- the legs and trunk over the arms and face. In EB,
disciplinary perspective, severity scores facilitate a there are often blisters and scars present on the face
common and objective appreciation of disease se- that are not easy to cover, thus impairing quality of
verity when a case is discussed between health life. Blistering of the hands and arms significantly
professionals. affects many functions. Blistering of the feet can
Our goal was to develop an overall objective impair walking and blistering of the trunk can impair
severity index that would allow standardized assess- stretching movements and sitting. Thus, we pre-
ment of the extent of involvement of skin and other ferred to give the head/neck and the hands/arms
epithelialized surfaces in terms of activity and dam- along with the buttocks/genital areas equal weight-
age, keeping in mind that it should be: (1) applicable ing with the truncal areas and legs.
to all patients with EB regardless of age, gender, and The time taken to complete each individual sec-
disease subtype; (2) valid, with face and content tion of the EB Disease Activity and Scarring Index
validity established by EB experts; (3) reliable, giving was not recorded during the 1-day scoring session,
consistent and reproducible scores between differ- but has been done during routine skin examinations
ent assessors; and (4) feasible, easy to use under after the scoring exercise.
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Supplementary Fig 1. The 4-page colored epidermolysis bullosa (EB) Disease Activity and
Scarring Index scoring system contains 5 different sections to quantify disease severity. For
section I (skin), the severity of disease is measured at 12 different skin sites. Sections II and III
measure activity and disease on the scalp and mucous membranes, respectively, whereas
section IV quantifies nail disease. Section V quantifies the presence of disease on other
epithelized surfaces encountered in EB and aggressiveness of squamous cell carcinoma (SCC).
The total activity score is calculated by adding up the respective total activity scores from all 5
sections. Similarly, the total damage score is derived from adding up the total damage scores
from all 5 sections.
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Supplementary Fig 1. (Continued).


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Supplementary Fig 1. (Continued).


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Supplementary Fig 1. (Continued).


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Supplementary Fig 2. Correlation of epidermolysis bullosa (EB) Disease Activity and


Scarring Index (EBDASI ) overall total scores against age for different EB subtypes. The
color-coded symbols and lines represent different EB subtypes: red for recessive dystrophic EB
(RDEB), orange for junctional EB (JEB), green for dominant dystrophic epidermolysis bullosa,
and blue for EB simplex (EBS ).
97.e7 Loh et al J AM ACAD DERMATOL
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=
scores from the EB scoring exercise and ad hoc scores
from individual visits in other patients. B, Mean EBDASI
total activity scores against different EB subtypes. The
trend of EBDASI activity scores is consistent with the
clinical severity of EB subtype, in which the more severe
subtypes such as recessive dystrophic EB (RDEB) have
higher activity EBDASI scores than EB simplex (EBS ),
which are less clinically severe. C, Mean EBDASI total
damage scores against different EB subtypes. The circle
number 6 denotes an outlier score by patient 6
Supplementary Fig 3. Mean epidermolysis bullosa (EB) (Supplementary Table I). The trend of EBDASI damage
Disease Activity and Scarring Index (EBDASI ) total (A), scores is consistent with the clinical severity of EB subtype,
activity (B), and damage (C) scores against EB types. A, On in which the more severe subtypes such as RDEB have
the y-axis is the mean EBDASI overall total score, whereas higher damage EBDASI scores than EBS, which are less
displayed on the x axis are different disease subtypes. This clinically severe as these EBS have milder disease and
scatterplot shows increasing EBDASI scores for increasing experience much less of the permanent effects of disease
severity of EB subtypes. The range of scores includes raw and have a much better quality of life. JEB, Junctional EB.
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Supplementary Fig 4. Photographs demonstrated that erythema caused by previous


inflammatory lesions on the back of this patient with recessive dystrophic epidermolysis
bullosa (EB) persisted for more than 6 months, hence justifying the need to include erythema as
a damage score item in the EB Disease Activity and Scarring Index.
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Supplementary Fig 5. Bland-Altman plots demonstrat-


ing the variation in patient scores, which is a measure of
the intrarater reliability for Epidermolysis Bullosa (EB)
Disease Activity and Scarring Index (EBDASI), Birming-
ham EB Severity (BEBS), and Physician Global Assessment
(PGA), respectively. The scores given by different asses-
sors are represented by different colored-coded diamonds
on the scatterplots. The EBDASI is demonstrated in this
figure to have the least variability of scores as compared
with the other 2 instruments, as proven by the distribution
of the scores close to the x-axis. This implies that the
EBDASI has the better intrarater variability as compared
with the other 2 instruments.
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Supplementary Fig 6. Based on linear regression analysis, the Epidermolysis Bullosa (EB)
Disease Activity and Scarring Index (EBDASI ) has a higher linear correlation than the Physician
Global Assessment (PGA) (R2 = 0.828) as compared with Birmingham EB Severity (BEBS ) with
PGA (R2 = 0.649).
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Supplementary Table I. Patients with epidermolysis bullosa demographics and ranges of Epidermolysis
Bullosa Disease Activity and Scarring Index, Birmingham Epidermolysis Bullosa Severity, and Physician Global
Assessment scores
Mean EBDASI Mean EBDASI Mean EBDASI
Australasian overall total activity total damage Mean Mean
No. EB registry No. EB subtype Sex Age total score score score BEBS score PGA score
1-day EB scoring exercise
1 46 EBS-L F 54 y 8.4 1.6 6.8 1.165 0.45
2 435 EBS-L F 4y 3.6 1.4 2.2 0.408 0.52
3 528 EBS-L F 2y 16.8 9.6 7.2 1.162 0.5
4 54 EBS-L M 59 y 19.4 4.2 15.2 3.11 1.65
5 64 EBS-L F 41 y 19.8 2.8 17 2.432 1.4
6 63 EBS-L F 12 y 55.4 19.8 35.6 5.123 3.15
7 325 DDEB-L F 50 y 25.4 4.6 20.8 2.652 1.1
8 494 DDEB-L M 66 y 48.4 6.6 41.8 5.785 2.35
9 403 EBS-O M 10 y 37 22.6 14.4 1.702 1.75
10 11 JEB-NH M 18 y 102.8 21.4 81.4 18.4 6.55
11 50 DDEB-L M 19 y 61.2 12.4 48.8 8.091 3.85
12 49 DDEB-L F 22 y 34.8 6.8 28 5.829 2.9
13 248 JEB-NH M 12 y 106.4 34 72.4 13.79 6.65
14 539 DDEB-L M 46 y 64.4 13.6 50.8 11.26 2.55
15 38 RDEB-GS F 26 y 189 49 140 52.58 8.9
16 529 RDEB-GNS F 5 mo 34 14.2 19.8 3.111 2.66
Ad hoc scores
1 36 RDEB-GS F 23 y 85 33 52 10.625
2 14 JEB-NH F 39 y 78.5 12.5 66 5.75
3 12 JEB-NH M 19 y 88 51 37 16.125
4 485 RDEB-GS F 64 y 103.5 20.5 83 16.5
5 363 DDEB-L F 8y 25 8 17 2.25
6 17 DDEB - Pr M 24 y 31.7 2.7 29 1.25
7 50 DDEB-L M 18 y 51.5 11.5 40 1
8 38 RDEB-GS F 26 y 165 26.5 138.5 14.5
9 534 EBS-L M 10 y 3.75 2 1.75 0.1

BEBS, Birmingham Epidermolysis Bullosa Severity; DDEB, dominant dystrophic epidermolysis bullosa; EB, epidermolysis bullosa;
EBDASI, Epidermolysis Bullosa Disease Activity and Scarring Index; EBS, epidermolysis bullosa simplex; F, female; GNS, generalized
nonsevere; GS, generalized severe; JEB, junctional epidermolysis bullosa; NH, nonHerlitz; L, localized; M, male; O, Ogna; PGA, Physician Global
Assessment; Pr, pruriginosa; RDEB, recessive dystrophic epidermolysis bullosa.
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Supplementary Table II. Distribution of Epidermolysis Bullosa Disease Activity and Scarring Index overall
total scores with different epidermolysis bullosa subtypes for the 1-day epidermolysis bullosa scoring exercise
Mean EBDASI Median EBDASI EBDASI range
EB subtypes overall total score overall total score distribution EBDASI IQR
EBS, localized 12.05 12.6 3.6-19.4 13.95
EBS, Dowling Meara 37.6 37.6 19.8-55.4
EBS, Ogna 37 37 37-37 0
JEB, non-Herlitz generalized 104.6 104.6 102.8-106.4
DDEB, acral 36.9 36.9 25.4-48.4
DDEB, generalized 53.47 61.20 34.8-64.4
RDEB, severe, generalized 189 189 189-189 0
RDEB, nonsevere, generalized 34 34 34-34 0

DDEB, Dominant dystrophic epidermolysis bullosa; EB, epidermolysis bullosa; EBDASI, Epidermolysis Bullosa Disease Activity and Scarring
Index; EBS, epidermolysis bullosa simplex; IQR, interquartile range; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic
epidermolysis bullosa.

Supplementary Table III. Distribution of Epidermolysis Bullosa Disease Activity and Scarring Index activity
and damage scores by sites for 1-day epidermolysis bullosa scoring exercise
Measure Mean (6SD) Median Range Maximum score range IQR
EBDASI disease activity
Skin 11.16 (610.13) 8.30 0.60-36.80 0-120 15.35
Scalp 0.46 (60.91) 0.00 0.00-3.40 0-10 0.60
Mucous membranes 1.34 (61.98) 0.50 0.00-6.20 0-120 1.90
Nails 0.76 (61.10) 0.20 0.00-3.60 0-20 1.05
Others 0.33 (60.76) 0.00 2.40 0-6 0.00
Total activity 14.04 (613.01) 11.00 1.40-49.00 0-276 16.70
EBDASI disease damage
Skin 15.68 (613.42) 14.20 0.80-52.60 0-84 12.75
Scalp 0.96 (62.62) 0.00 0.00-9.80 0-20 0.20
Mucous membranes 0.48 (60.99) 0.00 0.00-3.80 0-16 0.40
Nails 18.6 (616.85) 13.60 0.60-54.40 0-60 23.00
Others 1.98 (65.20) 0.30 0.00-20.40 0-50 0.75
Total damage 37.64 (635.79) 24.40 2.20-140.00 0-230 35.70
EBDASI overall total score
Overall total score 51.68 (647.40) 35.90 3.60-189 0-506 44.10

EBDASI, Epidermolysis Bullosa Disease Activity and Scarring Index; IQR, interquartile range.
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Supplementary Table IV. Inter and intrarater reliability scores by subsections for activity and damage scores
in the Epidermolysis Bullosa Disease Activity and Scarring Index
EBDASI disease activity
Section Interrater reliability ICC (95% CI) Intrarater reliability ICC (95% CI)
I: Skin 0.941 (0.884-0.976) 0.984 (0.941-0.996)
II: Scalp 0.353 (0.141-0.626) 0.419 (!0.214 to 0.813)
III: Mucous membranes 0.461 (0.239-0.710) 0.336 (!0.305 to 0.777)
IV: Nails 0.331 (0.122-0.608) 0.817 (0.448-0.950)
V: Other epithelialized surfaces 0.680 (0.483-0.850) 0.00 (!0.581 to 0.597)
Total activity 0.903 (0.916-0.960) 0.951 (0.827-0.987)
EBDASI disease damage
Section Interrater reliability ICC (95% CI) Intrarater reliability ICC (95% CI)
I: Skin 0.853 (0.732-0.937) 0.972 (0.899-0.993)
II: Scalp 0.729 (0.548-0.876) 0.705 (0.209-0.916)
III: Mucous membranes 0.619 (0.409-0.815) 0.842 (0.511-0.958)
IV: Nails 0.903 (0.816-0.959) 0.978 (0.919-0.994)
V: Other epithelialized surfaces 0.820 (0.680-0.922) 0.990 (0.963-0.997)
Total damage 0.955 (0.912-0.982) 0.993 (0.976-0.998)

CI, Confidence interval; EBDASI, Epidermolysis Bullosa Disease Activity and Scarring Index; ICC, intraclass correlation coefficient.