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Development and initial validation of the vasculitis damage index for the standardized clinical assessment of damage in the systemic vasculitides.

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ARTHRITIS & RHEUMATISM
Vol. 40, No. 2, February 1997, pp 371-380
0 1997, American College of Rheumatology
371
DEVELOPMENT AND INITIAL VALIDATION OF THE
VASCULITIS DAMAGE INDEX FOR THE
STANDARDIZED CLINICAL ASSESSMENT OF DAMAGE IN
THE SYSTEMIC VASCULITIDES
A. R. EXLEY, P. A. BACON, R. A. LUQMANI, G. D. KITAS, C. GORDON, C. 0. S. SAVAGE, and D. ADU
Objective. To develop and validate the Vasculitis
Damage Index (VDI)for the standardized clinical assessment of damage in the systemic vasculitides.
Methods. Using a nominal group consensus approach, the Birmingham Vasculitis Group generated
guiding principles for assessment of damage in all
systemic vasculitides. Damage was defined as irreversible change resulting from scars. Consensus principles
were developed into the VDI, including guidelines for
use, a list of items of damage, and a glossary.
Results. For 100 surviving patients with systemic
vasculitis, the median VDI score at last observation was
3 (range 0-8). Within the Wegener’s granulomatosis
subgroup, the median VDI score for 12 non-survivors
was higher than for 47 survivors (non-survivors median
score 7, interquartile range 5-8 versus survivors median
score 4, interquartile range 2-5; P = 0.003). VDI scores
for 100 patients with systemic vasculitis increased from
initial presentation to last observation by a median
score of 3 (range 1-4; P C 0.001). The VDI assesses
more items and is more sensitive to change than other
indices of damage (P < 0.001). Using the VDI, trained
observers can produce moderately consistent damage
scores.
Conclusion. The VDI is a sensitive, reproducible,
comprehensive, and credible clinical tool for quantifying
damage. The data presented herein should enable furSupported by the Arthritis and Rheumatism Council.
A. R. Exley, MD, MRCP, P. A. Bacon, FRCP, R. A.
Luqmani, DM, MRCP, G. D. Kitas, PhD, MRCP, C. Gordon, MD,
MRCP, C. 0. S. Savage, PhD, FRCP, D. Adu, FRCP: The University
of Birmingham, Birmingham, UK.
Address reprint requests to A. R. Exley, MD, MRCP, Department of Rheumatology, The Medical School, Birmingham B15
2TT, UK.
Submitted for publication February 23, 1996; accepted in
revised form August 21, 1996.
ther validation and testing of the VDI in specific vasculitic syndromes, and should facilitate the comparison of
different therapies.
Earlier studies based on postmortem series established the systemic vasculitides as severe life-threatening
diseases (1,2). The introduction of cyclophosphamide
for the treatment of Wegener’s granulomatosis altered
the clinical course of this disease, improved survival, and
dramatically reduced overall mortality (3,4). The systemic vasculitides still have an early acute mortality, but
they have become chronic relapsing diseases. Thus,
within 5 years of remission, systemic vasculitis may
relapse in the majority of patients (5). Active disease
accounts for half the patient-years of followup, reflecting
both a poor initial treatment response in some patients
and relapses in others. Remission is not achieved without cost, since more than half the patients experience
serious morbidity due to disease or to drug toxicity (6).
When the systemic vasculitides are viewed as
chronic relapsing diseases, mortality is less appropriate
as an outcome measure. Quality of survival becomes
critical, and global assessment of disease severity and
outcome is required. However, different aspects of
disease should be assessed separately. Disease activity,
damage, and functional ability differ conceptually and
indicate very dissimilar treatment needs (7). We have
previously described the Birmingham Vasculitis Activity
Score (8), a disease activity score based on the intention
to treat active, potentially reversible disease with cytotoxic drugs. These drugs have a narrow therapeutic
range in patients with chronic relapsing diseases. Damage or scarring is unlikely to respond to immunosuppression. Therefore, we developed the Vasculitis Damage
Index (VDI) to aid in the separation of damage from
disease activity and to rationalize selection of therapy.
Herein we describe the development and initial valida-
EXLEY ET AL
372
tion of the VDI for the standardized clinical assessment
of damage in the systemic vasculitides.
MATERIALS AND METHODS
Development of the VDI. The standardized assessment
of damage in chronic diseases is a concept in evolution. In both
systemic lupus erythematosus (SLE) and systemic vasculitis,
the need to measure changes in morbidity has arisen from the
substantial reduction in mortality achieved by modern therapy.
The multidisciplinary Birmingham Vasculitis Group formed a
nominal group to discuss standardized damage assessment in
systemic vasculitis, borrowing from the principles of the Systemic Lupus International Cooperating Clinics (SLICC) and
American College of Rheumatology (ACR) Damage Index for
SLE (9). Guiding principles for damage assessment in systemic
vasculitis were generated by consensus.
The principles of damage assessment include a definition, a time frame, pro forma recording of data, attribution,
accumulation, weighting, and feasibility. In group discussions,
damage was defined as an irreversible process, the result of
scars, not acute inflammation nor grumbling disease activity.
Evidence to support a distinction between activity and damage,
based on the duration of symptoms, was sought. In our own
series of patients with active disease, remission usually occurred within 3 months of treatment (5). It was agreed that
scoring should include all possible events recorded since the
vasculitic syndrome began, with the understanding that events
not necessarily related to vasculitis would be included. All
events prior to the onset of vasculitis would be excluded. At
presentation, the specific diagnosis may be unclear and patients with systemic vasculitis may be reclassified (10). Therefore, items of damage characteristic of each type of systemic
vasculitis were included. A framework based on organ systems
was chosen to facilitate the recording of any items of damage
a patient might have.
Achieving consensus on the pro forma recording of
items of damage was difficult. Assessors from different specialties had different perspectives on damage. For example,
chronic sinusitis was regarded as either a clinical or a radiologic diagnosis. Hearing loss might be due to either impaired
conduction or nerve damage. Cranial neuropathy might include sensorineural deafness and blindness from optic nerve
damage. Group members wished to separate subglottal stenosis that did not require surgery from subglottal stenosis that
required surgery. It became clear that a final arbiter, available
to each assessor, would be required. A glossary of definitions
for each item of damage was thus compiled.
During this process, other aspects related to recording
items of damage were highlighted. For example, some acute
events, such as resection of infarcted gut, are essentially
irreversible, whereas other acute events may subsequently heal
or result in damage. The nominal group felt that reproducibility might be impaired if the assessor made additional judgments of attribution and weighting. These judgments could be
made separately. An alternative approach, in which damage
would be recorded as simply present or absent, was considered.
A global view of outcome was preferred, in which all
events since the appearance of first symptoms would contribute to the assessment of each patient’s outcome. Thus, early
events should contribute to each subsequent assessment of
damage. In addition, group members agreed that damage
assessment should be considered only part of a comprehensive
clinical assessment. Therefore, standardized assessment of
damage should be practical, easy to complete in a short period
of time, and accesd~leto rtatistical analysis.
The consensus guiding principles were used to generate a list of items of damage occurring in the systemic
vasculitides. This list was further refined by extensive discussions between members of the Birmingham Vasculitis Group
and other members of the European Community Concerted
Action Group for the Study of Therapeutic Trials in Systemic
Vasculitis (ECSYSVASTRIAL) (12). Preliminary results were
subject to peer review in presentations at international meetings on systemic vasculitis (13). The consensus principles were
developed into the VDI, including guidelines for its use
(described below), a list of items of damage (Table I), and a
glossary (Appendix 1).
Guidelines for application of the VDI. Damage was
defined as the presence of irreversible scars which have
occurred since the onset of vasculitis. Onset of vasculitis was
defined as the onset of first symptoms attributable to vasculitis
(it is useful, for later analyses, to record dates of presentation
to the hospital and date of diagnosis). Events must be present
for at least 3 months before they can be scored as damage; this
time limit was set arbitrarily to differentiate from current
active inflammation. Acute irreversible events, such as gut
resection, should be scored 3 months after the acute event to
ensure consistency in scoring. A repeat episode can be scored,
for items indicated, provided that it occurred at least 3 months
since the first event.
Damage can be scored as either present or absent. This
is irrespective of whether damage may be later attributable to
the vasculitic syndrome, complications of treatment, infection,
or concurrent diseases, provided that the damage occurred
since the onset of vasculitis. The index is cumulative; thus, the
VDI score can only remain stable or increase. All previously
scored items count at each subsequent assessment. The VDI
score is the simple sum of the items of damage.
Statistical analysis. Statistical analysis was performed
using Minitab for Windows, Release 10.2 (Minitab, State
College, PA). It was assumed that all data did not follow a
Gaussian distribution. Therefore, nonparametric tests were
used. Median values and interquartile ranges are given, unless
otherwise stated. The Wilcoxon signed rank test was used for
comparison of paired data, and the Mann-Whitney U test was
used for comparison between 2 groups. The Kruskal-Wallis
test was used as an extension of the Mann-Whitney U test for
comparisons between more than 2 groups. Correlations between paired data were examined by determining Pearson’s
correlation coefficients. All tests were 2-tailed, unless otherwise stated.
The reproducibility of the VDI was examined in an
informal assessment exercise. In May 1995, 4 members of
ECSYSVASTRIAL from 3 different countries assessed patients with systemic vasculitis in the Birmingham Vasculitis Clinic.
The VDI was scored for 8 patients who were seen in random
order, according to a latin square design. A series of 2 x 2 tables
was constructed between pairs of observers for each system
within the VDI. The kappa statistic was calculated to determine agreement greater than that expected by chance (11).
DEVELOPMENT AND VALIDATION OF THE VDI
373
Table 1. Items of damage in the Systemic Necrotizing Vasculitis (SNV) Damage Index and the Systemic Lupus International Cooperating
ClinicsiAmerican College of Rheumatology (SLICCiACR) Damage Index compared with the Vasculitis Damage Index (VDI)*
Items in common
with VDI
System, item
I. Musculoskeletal
1. Significant muscle atrophy or weakness
2. Deforming or erosive arthritis
3. Avascular necrosis
4. Osteoporosis with fractures or vertebral collapse
5. Osteomyelitis
11. Skin
1. Alopecia
2. Skin ulceration
3. Oral ulceration
111. Ear, nose, and throat
1. Hearing loss
2. Nasal blockage or chronic discharge or crusting
3. Nasal bridge collapse or septa1 perforation
4. Chronic sinusitis or radiologic evidence of bone
destruction
5. Subglottal stenosis without surgery
6. Subglottal stenosis with surgery
IV. Pulmonary
1. Pulmonary hypertension
2. Pulmonary fibrosiskavity
3. Pleural fibrosis
4. Pulmonary infarction
5. Chronic asthma
6. Significant chronic breathlessness
7. Impaired pulmonary function tests
V. Cardiovascular
1. Anginaicoronary artery bypass
2. Myocardial infarction
3. Second myocardial infarction
4. Cardiomyopathy
5. Valvular disease
6. Pericarditis
7. Hypertension
VI. Renal
1. Estimated or measured GFR <50%
2. Proteinuria of >0.5 gmi24 hours
3. End-stage renal failure
SNV SLICCiACR
+
+
+
+
+
+
+
-
+
+
+
+
-
+
+
+
+
+
+
+
-
+s
+s
+$
Items in common
with VDI
System, item
VII. Gastrointestinal
1. Gut infarction
2. Mesenteric insufficiency or pancreatitis
3. Chronic peritonitis
4. Esophageal stricture or upper GI tract surgery
VIII. Peripheral vascular
1. Absent peripheral pulse in 1 limb
2. Second episode of absent pulse in 1 limb
3. Absent peripheral pulses in 2 2 limbs
4. Major vessel stenosis
5. Claudication of the extremities
6. Complicated venous thrombosis
7. Minor tissue loss
8. Major tissue loss
9. Second episode of major tissue loss
IX. Ocular
1. Cataract
2. Retinal change
3. Optic atrophy
4. Visual impairment/diplopia
5. Blindness in 1 eye
6 . Blindness in second eye
7. Orbital wall destruction
X. Neuropsychiatric
1. Cognitive impairment
2. Major psychosis
3. Seizures
4. Cerebrovascular accident
5. Second cerebrovascular accident
6 . Cranial nerve lesion
7. Peripheral neuropathy
8. Transverse myelitis
XI. Other damage
1. Premature gonadal failure
2. Marrow failure
3. Diabetes mellitus
4. Chronic chemical cystitis
5. Malignancy
6. Other features#
SNV SLICCiACR
+
+-
+
+
+
+I
-
-
-
-
-
-
-
+t
+t
+
+
+
+
+
+
+
+
+
+
+
-
+
+$
+*
-
-
-
-
-
++
+
+
+
+TI
-
-
+
+
+$
+$
+
+
+
+$
+$
+
+
+
+
* + or - indicates presence or absence of a common item. Items of damage listed as “second” are repeat events that are scorable if >3 months have
elapsed since the first event. GFR = glomerular filtration rate; GI = gastrointestinal.
i Items of damage in the VDI that are grouped together as single items in the SNV Damage Index.
$ Adjacent items of damage in the VDI that are grouped together as single items in the SLICCiACR Damage Index.
5 An item of damage in the VDI that is listed as 2 items in the SLICCiACR Damage Index.
llAn item of damage in the VDI that is listed as 2 items in the SNV Damage Index.
# Any other items of damage the assessor wishes to record that are not listed in the VDI (these items are not included in the VDI score).
RESULTS
Content and face validity (comprehensiveness
and credibility). The VDI was applied to 100 patients
diagnosed with systemic vasculitis according to standard
criteria (10,14-16), to derive VDI Scores for the last
observation of each patient (Table 2). One assessor
(ARE) carried out all the assessments. The median
duration of disease from first symptoms to last observation was 6 years (range 3.2-10.0 years). The median VDI
was 3 (range 0-8) (Figure 1). No items of damage
were scored in 5 patients (5%). A wide variety Of items
of damage were x m e d in the 100 Patients with systemic
vasculitis, and some items of damage were scored in
every organ system. Seventeen items, including 4 repeat
items, were not used in these patients. A further 6 items
EXLEY ET AL
374
Table 2. Diagnoses of 100 patients with systemic vasculitis
No. of
patients
Diagnosis
13
12
20
21
Secondary systemic vasculitis*
Polyarteritis nodosa
Classic Wegener’s granulomatosis
Localized (non-renal) Wegener’s granulomatosis
Giant cell arteritist
Unclassified systemic vasculitis
Hennch-Schonlein purpura
Churg-Strauss syndrome
Microscopic polyangiitis
All
I
4
4
5
8
100
* Systemic rheumatoid vasculitis (n = 4), systemic lupus erytematosus
vasculitis (n = l), and BehGet’s syndrome (n = 8).
t Takayasu arteritis (n = 6) and giant cell (temporal) arteritis (n = 1).
were used in a second group made up of 20 nonsurvivors with systemic vasculitis. The remaining items
were avascular necrosis, pulmonary hypertension, pleural fibrosis, cognitive impairment, transverse myelitis,
chronic pericarditis, esophageal stricture or upper gastrointestinal tract surgery, and 4 repeat items. Nineteen
different items, including 6 cases of sicca syndrome,
were recorded once in the category “Other features.”
These items are not representative of damage in systemic vasculitis and therefore were not added to the
VDI score.
The ability of the VDI to record the accumulation of damage over time was examined by determining
the change in VDI score over time. The increase in VDI
score in 100 patients with systemic vasculitis from pre-
Number of Patients
35
-I
30
25
20
15
10
5
0
0
1
2
3
4
5
6
7
8
9
10
Damage Score
Figure 1. Damage index scores at last observation, as determined for
100 patients with systemic vasculitis. Gray bars = unweighted Systemic
Lupus International Cooperating ClinicsiAmerican College of Rheumatology Damage Index score. Open bars = unweighted Systemic
Necrotizing Vasculitis Damage Index score. Solid bars = Vasculitis
Damage Index score.
sentation to last observation was determined. The median interval was 5 years (range 2.5-8 years). There was
a significant increase in the VDI score, by a median
score of 3 (range 1-4; P < 0.001).
Criterion validity (agreement with external criteria). In the absence of a true gold standard for damage
in systemic vasculitis, death was used as a surrogate gold
standard. The VDI score for all patients with Wegener’s
granulomatosis who were non-survivors was compared
with that for survivors: 12 non-survivors versus 47 survivors at last observation. Irreversible events present at
the final admission were scored as damage in the final
VDI score. The VDI score for non-survivors was significantly higher than that for survivors (non-survivors
median score 7, interquartile range 5-8 versus survivors
median score 4, interquartile range 2-5; P = 0.003).
Construct/convergent validity (comparison with
other indices). The convergent validity of the VDI was
examined by comparison with 2 other damage indices:
the Systemic Necrotizing Vasculitis (SNV) Damage Index (17) and the SLICCiACR Damage Index (18). The
VDI was designed to apply to the systemic vasculitides.
There are 64 items of damage, including 5 items of
repeat episodes of damage, and 1 item to record any
other damage that is not scored.
The SNV Damage Index was used in a comparison of damage in patients with polyarteritis nodosa and
Churg-Strauss syndrome (17). The SNV Damage Index
has 34 items, including 4 items not found in the VDI,
namely arrhythmia, peripheral vascular repair, infarction of abdominal organ (e.g., spleen, gall bladder), and
chronic peptic ulceration. No items of damage in the ear,
nose, and throat (ENT) system are included (Table 1).
All aspects of renal damage count as 1 item, peripheral
neuropathy is separated into motor and sensory neuropathies, and 9 items are weighted 2-fold. Events are
required to persist for at least 6 months before they can
be scored as damage, apart from certain irreversible
events including cerebrovascular accident, myocardial
infarction, and gut infarction.
Although the SLICC/ACR Damage Index was
developed for SLE, vasculitis is an important component
of this disease. The SLICC/ACR Damage Index includes
40 items, with 5 repeat items (Table 1). There are 2
items unique to this index, namely shrinking lung and
ruptured tendons, and no items of damage in the ENT
system. The presence of end-stage renal failure excludes
scoring other items of renal damage and is weighted
3-fold. Cranial and peripheral neuropathies count as 1
item. Events are required to persist for at least 6 months
before they can be scored as damage.
DEVELOPMENT AND VALIDATION OF THE VDI
Table 3. Correlation between damage scores at last observation, in
100 patients with systemic vasculitis*
Damage index
~
Scores in original format
SNV
SLICC/ACR
Scores with weightings removed
SNV
SLICCiACR
VDI
SNV
0.594
0.570
0.807
0.670
0.632
0.786
~~
* All correlations (using Pearson’s correlation coefficients) were statistically significant (P< 0.001). See Table 1 for definitions.
The 3 damage indices were compared by disregarding the time limits for differentiating activity from
damage. Weighted scores for the S N V Damage Index
and for the SLICC/ACR Damage Index were calculated
(9,17,18). Unweighted scores were also derived by scoring items of renal damage separately and removing
weightings. No patients had any of the items unique to
the SLICC/ACR Damage Index, nor the first 3 items of
damage unique to the SNV Damage Index. Ascertainment of chronic peptic ulceration was incomplete and,
therefore, this item was disregarded.
The 3 damage indices were applied to 100 patients with systemic vasculitis (Table 2), and scores at
last observation were derived. There was good correlation between the indices (Table 3), although the correlation was not absolute. There was a lower correlation
between the VDI and weighted SNV Damage Index and
between the VDI and the weighted SLICC/ACR Damage Index. The VDI scored significantly more items of
damage than either the unweighted SNV Damage Index
or the unweighted SLICC/ACR Damage Index (VDI
median score 3, range 2-5 versus SNV median score 2,
range 1-3 versus SLICC/ACR median score 1, range
1-2; P < 0.001) (Figure 1). The VDI also scored
significantly more items of damage than either the
weighted SNV Damage Index or the weighted SLICCi
ACR Damage Index (VDI median score 3, range 2-5
versus SNV median score 3, range 1-4 versus SLICC/
ACR median score 1, range 1-2; P < 0.001).
The VDI has a wider range of scores than either
the unweighted SNV Damage Index or the unweighted
SLICC/ACR Damage Index. The number of additional
items scored by the VDI accounts for a sizable proportion of the VDI score at last observation. In 61% of
patients, additional items scored accounted for at least
half the total VDI score. In 22% of patients, additional
items scored accounted for at least three-quarters of the
total VDI score. Sensitivity is increased by maximizing
the number of items of damage scored.
375
The ability of the 3 different damage indices to
record the accumulation of damage over time was
examined. Each damage index was applied to 100 patients with systemic vasculitis (as previously described),
and the number of additional items scored between
presentation and last observation was compared. The
additional items of damage scored showed a good
correlation among the different indices (Table 4), although the correlation was not absolute. There was a
lower correlation between each pair of damage indices
after weighting the SNV Damage Index and SLICC/
ACR Damage Index.
The VDI scored significantly more additional
items of damage between presentation and last observation than did the SNV Damage Index or the SLICC/
ACR Damage Index (VDI median number of additional
items scored 3, range 2-5 versus SNV median number 2,
range 1-3 versus SLICC/ACR median number 1, range
1-2; P < 0.001) (Figure 2). The increase in VDI score
(median increase 3, range 2-5) between presentation
and last observation was significantly greater than the
increase in the weighted SNV Damage Index (median
increase 2, range 0.25-3; P = 0.002) or in the weighted
SLICC/ACR Damage Index (median increase 1, range
0-2; P < 0.001).
Construct/discriminant validity (comparison of
disease groups). The power of the damage indices to
detect damage in each of the systemic vasculitides was
examined in 100 patients with a range of vasculitic
syndromes (Table 2). In particular, the ability of the
VDI to detect more items of damage than the SNV
Damage Index and the SLICC/ACR Damage Index was
compared for each vasculitic syndrome. The additional
sensitivity of the VDI was clearly seen in vasculitic
syndromes poorly recognized by the other indices. VDI
scores at last observation were higher, particularly in
Wegener’s granulomatosis, Churg-Strauss syndrome, gi-
Table 4. Correlation between damage scores for sensitivity to
change, in 100 patients with systemic vasculitis*
~~~
~
Damage index
Scores in original format
SNV
SLICCiACR
Scores with weightings removed
SNV
SLICCiACR
VDI
SNV
0.651
0.699
0.695
0.721
0.704
0.819
* Sensitivity to change determined by subtracting damage scores at
presentation from damage scores at last observation. All correlations
(using Pearson’s correlation coefficients) were statisitcally significant
( P < 0.001). See Table 1 for definitions.
EXLEY ET AL
376
Number of Patients
35 1
30
25
20
15
10
5
0
0
1
2
3
4
5
6
7
a
-
Increase in Damage Score (Last observation Presentation)
Figure 2. Sensitivity to change among the 3 damage indices. The
incremental change in damage scores from presentation to last observation was determined for 100 patients with systemic vasculitis. Gray
bars = change in unweighted Systemic Lupus International Cooperating ClinicsiAmerican College of Rheumatology Damage Index score.
Open bars = change in unweighted Systemic Necrotizing Vasculitis
Damage Index score. Solid bars = change in Vasculitis Damage Index
score.
ant cell arteritis, and the secondary vasculitides (P <
0.001) (Figure 3). A similar pattern was seen for the
additional items of damage scored between presentation
and last observation (P = 0.002) (Figure 4). The additional sensitivity of the VDI over the other damage
indices was unaffected by weighting the SNV Damage
Index and the SLICC/ACR Damage Index.
Reliability. Reliability or reproducibility was examined by comparing the VDI scores as determined by
independent assessors. A novice assessor was given a
brief introduction to the principles and practice of
scoring the VDI. Paired VDI scores were then determined in 50 patients with systemic vasculitis by 1 expert
assessor and 1 novice assessor. The paired VDI assessments were carried out in random order, and scores for
6 months after presentation were determined. Paired
VDI scores were identical in 64% of patients, and within
1 point in 78%. Reliability was dependent on strict
adherence to the definition and guidelines for the
application of the VDI. The differences in scoring
were attributable to a few consistent errors, and a
learning effect was apparent. In particular, the novice
assessor did not consistently score all damage since the
onset of first symptoms, and did not consistently score
damage only if events were present for at least 3 months.
These errors were seen for patients with secondary
systemic vasculitis and for those with polyarteritis nodosa
versus all other diagnoses; for these groups, the median
difference in scoring was 3.5 for systemic vasculitis versus 1
for polyarteritis nodosa versus 0 for all other diagnoses
(P < 0.001).
In the assessment exercise, there was complete
agreement between all assessors for two-thirds of the
VDI, although these were items of damage scored as
absent in all 8 patients. In order to highlight areas of
disagreement, the analysis was confined to the 21 items
in which any assessor scored damage. The mean value of
the kappa statistic for each assessor was 0.41, 0.38, 0.36,
and 0.34. Analysis of agreement for each of the systems
in the VDI revealed important differences between
assessors. There was good agreement between all assessors for renal/neurologic systems (mean kappa statistic
0.61) and the ENT system (mean kappa statistic 0.41). In
the other systems, there was good agreement between 2
assessors versus poor agreement between the other
assessors. Thus, the mean kappa values were 0.65 versus
0.1 for musculoskeletaVskin systems, 0.53 versus 0.15 for
the pulmonary system, and 0.53 versus 0.24 for
cardiovascular/peripheral vascular systems.
Feasibility. The score sheet for the VDI is a
tabulated list of items of damage grouped into 10
Additional Items of Damage
4-
321 -
A I+
T
f
T
A
01
SSV
PAN
WG
LWG
GCA
USV
HSP
CSS
I
MPA
Specific Diagnosis
Figure 3. Power of the Vasculitis Damage Index (VDI) to detect
more damage than the Systemic Necrotizing Vasculitis Damage Index
(SNV) or the Systemic Lupus International Cooperating Clinics/
American College of Rheumatology Damage Index (SLICC/ACR), in
each of the systemic vasculitides. Damage scores in 100 patients with
systemic vasculitis were measured at last observation using the VDI,
the SNV, and the SLICCIACR. All weightings were removed. The
number of additional items scored by the VDI was dependent on the
specific diagnosis (n = 2 X 100 scores; P < 0.001). Results are expressed as the median and interquartile range for each diagnosis. SSV
= secondary systemic vasculitis; PAN = polyarteritis nodosa; WG =
classic Wegener’s granulomatosis; LWG = localized (non-renal) Wegener’s granulomatosis; GCA = giant cell arteritis; USV = unclassified systemic vasculitis; HSP = Henoch-Schonlein purpura; CSS =
Churg-Strauss syndrome; MPA = microscopic polyangiitis.
DEVELOPMENT AND VALIDATION OF THE VDI
Additional Items of Damage
*w
3
T T
41
01 -
SSV
PAN
WG
LWG
f€
GCA
USV
HSP
*
T
CSS
MPA
Specific Diagnosis
Figure 4. Power of the VDI to detect a greater increment in damage
than the SNV or the SLICC/ACR, in each of the systemic vasculitides.
The increment in damage scores (sensitivity to change) between
presentation and last observation in 100 patients with systemic vasculitis was measured using the VDI, the SNV, and the SLICC/ACR. All
weightings were removed. The VDI detected a greater increment in
damage scores (was more sensitive to change) than the other indices,
and the additional items scored vary depending on the specific
diagnosis (n = 2 X 100 scores; P = 0.002). Results are expressed as the
median and interquartile range for each diagnosis. See Figure 3 for
definitions.
organ-based systems, 1 general category, and a space for
other comments (Table 1). The tabulated score sheet
and glossary enable the clinician to rapidly (within 5
minutes) record items of damage present at the
assessment visit. At subsequent assessments, additional items of damage are added to new columns on
the score sheet. A simple computer program, written
in dBase IV (Borland International, Scott Valley,
CA), enables scores to be transferred from the score
sheets or directly entered. An integrated package, the
Vasculitis Integrated Total Assessment Log, has been
developed for the standardized assessment of disease
activity, damage (using the VDI), and function in
patients with systemic vasculitis (12).
DISCUSSION
The quality of survival is critical in chronic relapsing diseases with a high morbidity, such as the
systemic vasculitides. We have developed a vasculitis
damage index to enable a detailed assessment of damage
in the systemic vasculitides. The VDI is an integrated
package that includes guidelines for its application, a list
of items of damage, and a glossary. The tabulated layout
of the VDI, based on organ systems, enhances its clinical
377
utility. Some of the principles underlying the VDI are
shared by the SLICC/ACR Damage Index and the SNV
Damage Index. There is good correlation between damage indices, but the more comprehensive VDI has
increased sensitivity, both at single assessments and over
time. The power of the VDI to record the accumulation
of items of damage over time supports its validity as a
clinical index of outcome. This initial validation suggests
that the VDI is a sensitive, reproducible, comprehensive,
and credible clinical instrument for recording the accumulation of damage. Thus, the VDI should prove to be
a useful clinical tool for the investigation of different
therapies.
The distinction between disease activity and damage is fundamental (7). The Birmingham Vasculitis
Activity Score was based on an intention to treat disease
with immunosuppressive therapy. Implicit in the development of the Birmingham Vasculitis Activity Score was
the concept that disease activity is potentially reversible.
Disease activity was defined as the development of
disease features that were new or worse within the last 4
weeks (8). Remission induction in patients with systemic
vasculitis is, in our experience, generally achieved within
3 months of treatment (5). In contrast, the fundamental
attribute of damage is its irreversibility. Although the
time limit of 3 months used to distinguish disease activity
from damage is arbitrary, it does have a clinical validity.
Moreover, a definite time limit is essential for reproducible assessment of damage. The measurement of damage
rather than activity is particularly important in assessment of long-term outcome in chronic diseases (19).
Indeed, an assessment of damage revealed an unexpectedly poor outcome in patients with Wegener’s granulomatosis, despite treatment with cytotoxic drugs (6).
Studies can now be undertaken to look for a lack of
correlation between current activity and damage score,
which would confirm that these 2 elements are different
measures of disease.
The VDI is a purpose-built package that incorporates items of damage applicable to each of the
systemic vasculitides. There are more items of damage in
the VDI than in either of the other damage indices. The
VDI includes the additional items of musculoskeletal
and peripheral vascular damage. Items of damage in the
ENT system are also incorporated, to reflect their
significant impact in patients with Wegener’s granulomatosis. These items include early-onset deafness,
chronic sinusitis, nasal deformity, and subglottal stenosis. The absolute number of additional items scored for
each patient is low. Nevertheless, this increment does
contribute a significant proportion to the total score.
378
Moreover, there is a wider range of damage scores in the
VDI than in the other damage indices. The VDI detects
more additional items of damage between presentation
to hospital and last observation.
In this initial validation study, the power of the
VDI was highlighted by its ability to detect more damage, compared with the other indices, in common vasculitic syndromes, e.g., Wegener’s granulomatosis, giant
cell arteritis, and secondary systemic vasculitis. The
increased power of the VDI was unaffected by weighting
other damage indices, and reflects more than the larger
number of items of damage listed in the VDI. Our data
indicate that these additional items of damage do occur
in the systemic vasculitides, both early and later in the
course of the disease, depending on the vasculitic syndrome. It seems likely that the design of the VDI will
result in greater power to discriminate between different
interventions.
An index that provides a large number of items
maximizes information and sensitivity. However, too
large a number of items will restrict the feasibility of the
index in a clinical setting. Using the VDI, items from
each organ system were scored in our patients with
systemic vasculitis. Few items of damage from the VDI
were not represented in 100 patients with systemic
vasculitis. Nevertheless, the optional open category
“Other features” failed to reveal significant items of
damage not already included. Although 19 other features were noted, each occurred in only 1 patient and
was therefore not included in the VDI score. Identification of a few items among many is aided by the format of
the VDI. The tabulated layout enables early items of
damage to be readily carried forward to each subsequent
assessment. Data collection is not dependent on computer support, although a computer program will assist
in data collection and analysis.
Reproducibility of the VDI is enhanced by training. Errors made by inexperienced assessors highlighted
a need to establish clear guidelines for application of the
VDI. An informal assessment exercise revealed good
agreement between some assessors, while others had
particular problems scoring items of damage in the
musculoskeletal/skin and pulmonary systems. Therefore,
a more explicit glossary was devised. It is likely that
reproducibility will be enhanced by the results and
written text presented herein. New assessors are advised
to carefully study the guidelines for application of the
VDI (as previously described) and the glossary (Appendix 1). We are currently establishing a training program
for the VDI, with the help of other members of the
ECSYSVASTRIAL group.
EXLEY ET AL
The VDI records the presence or absence of
items of damage, to indicate the cumulative toll of
systemic vasculitis, its treatment, and comorbidity. We
believe this approach minimizes interobserver variation.
The distinction between damage due to the vasculitic
syndrome, drug toxicity, infection, or concurrent disease
may not be clear when the VDI assessment is undertaken. Damage may be multifactorial, and thus, attribution of damage is controversial. Reproducibility is preserved by retaining a basic database which can be
transformed as desired. The itemized design of the VDI
readily allows analysis in terms of the total score or the
number of organs involved. Items can be selected and
grouped according to a variety of criteria. A nominal
group consensus approach can highlight items that may
be significant in a variety of outcomes. This process of
selection can be tested against gold standards of damage. In the absence of a true gold standard, the VDI
score for non-survivors was chosen as a surrogate. As
expected, non-survivors had high damage scores. This
analysis could be extended to other surrogate standards,
e.g., the development of end-stage renal failure. Damage
can also be judged against the important outcome
functional class, since preliminary studies have revealed
significant functional impairment, even in patients with
inactive disease (20). Serial studies of the VDI could be
used to investigate early indicators of poor prognosis.
Selection rather than weighting may be a more flexible,
powerful, and reproducible approach to analysis of
outcome.
The development and initial validation of the
VDI, as described herein, suggests that this index should
be applicable to each of the systemic vasculitides. However, further validation is required; e.g., to test discriminant validity, studies could compare the VDI scores for
different vasculitic syndromes such as microscopic polyangiitis versus polyarteritis nodosa or localized (nonrenal) versus classic Wegener’s granulomatosis, as well
as the VDI scores for patients who experience a single
relapse versus those who have multiple relapses. We
propose that the VDI should be used as a clinical tool to
compare different therapeutic regimens and to investigate the contribution of damage to morbidity and mortality in the systemic vasculitides. Clearly, we need to
improve outcome without exchanging damage due to
disease for additional damage due to treatment. The
present VDI scoring system has been adopted by the
ECSYSVASTRIAL group as an integral part of its
record books for 3 core protocols in systemic vasculitis.
Data from these therapeutic trials will allow further
prospective validation of the VDI.
DEVELOPMENT AND VALIDATION OF THE VDI
ACKNOWLEDGMENTS
W e ar e grateful for the support of o u r clinical colleagues who referred their patients for assessment. W e thank
the members of t h e Birmingham Vasculitis G r o u p , Dr. Kirsten
d e Groot, and the ECSYSVASTRIAL group, as well as Dr.
Pradeep Bambury and Dr. Deborah Symmons, for their help
and advice.
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APPENDIX 1: THE VASCULITIS DAMAGE INDEX GLOSSARY
System, item
1. Musculoskeletal
1 .l. Significanr muscle arrophy or weakness: Demonstrated on clinical examination (not attributable to cerebrovascular accident).
1.2. Deforming or erosive arthritis: Deformities on clinical examination confirmed by radiographs (excluding avascular necrosis); demonstrated on clinical
examination and radiographs.
1.3. 0,slropormic with fractures or veilebral collapse: By history, confirmed on
radiographs (excluding avascular necrosis); ever, since the onset of vasculitis.
1.4.Avusculur necrosis: Demonstrated by appropriate radiologic techniques; ever,
since the onset of vasculitis.
I .5. 0.steomyelilU: Documented clinically, confirmed by radiographs and/or culture.
2. Skin
2.1. Alopecia: Major (c.g., requiring wig) chronic hair loss with or without
scars, documented clinically.
2.2. Skin ulceration: Open Sore on skin surface, excluding that causcd by
venous thrombosis.
2.3. Oral ulceration: Recurrent crops or persistent mouth ulcers requiring
therapy.
3. Ear, nose, and throat (ENT)
3.1. Hearing loss: Any hearing loss due to middle ear involvement or to
auditory nerveicochlear damage, preferably confirmed by audiometry.
3.2. Nasal blockagelchronic dischargelcnisting: Difficulties with breathing
through the nose and/or with purulent discharge and/or with crust formation
usually requiring nasal lavage.
3.3. Nasal bridge cullapseiseptal perfuratiun: Saddle nose deformity andlor
perforation of nasal septum.
3.4. Chronic sinusitis/radiologic evidence uf bone destruction: Chronic purulent
nasal discharge with sinus pain and/or radiologic evidence of sinusitis with or
without bone destruction.
3.5. Subglottal stenosis without ,sup?ry: Persistent hoarseness and/or stridor,
preferably confirmed by endoscopy and/or radiographs.
3.6. Subglottal stenosis with surgery: Confirmed by otolaryngnlogy surgeon.
EXLEY ET AL
4. Pulmonary
4.1. Pulmonary hypertension: Right ventricular prominence or loud P2 (confirmed by cardiologic investigation if appropriate).
4.2. Pulmonary fibrosisicavity: According to physical signs and radiographs
(confirmed by relevant tests if necessary); this may include patients who
require pulmonary resection.
4.3. Pleural fibrosis: According to chest radiographs.
4.4. Pulmonary infarction: According to chest radiographs or ventilation/
perfusion scan.
4.5. Chronic asthma: Significant reversible airways obstruction.
4.6. Significant chronic breathlessness: Significant sympotomatic breathing
difficulties and/or shortness of breath without bard signs on radiographs or
lung function tests.
4.7. Impaired pulmonary function tests: Forced expiratory volume in 1
second or forced vital capacity 570%, or transfer coefficient for carbon
monoxide (KCO) 570%.
5. Cardiovascular
5.1. Anginalcoronury artery bypass: On history, confirmed at least by electrocardiographic changes.
5.2. Myocardial infarction: On history, confirmed at least by electrocardiographic changes or cardiac enzyme elevation; ever, since the onset of vasculitis.
5.3. Second myocardial infarction: At least 3 months after first event.
5.4. Cardiomyuputhy: Chronic ventricular dysfunction, documented clinically
or on appropriate investigation,
5.5. Valvular diseuse: Significant diastolic or systolic murmur, confirmed by
cardio~ogictests if appropriate.
5.6. Pencarditis: Symptomatic pericardial inflammation or constriction for at
least 3 months or pericardiectomy.
5.7. Hypertension: With a diastolic blood pressure >95 mm Hg or requiring
antihypertensive drugs.
6. Renal
6.1. Estimated or measured glomerularfiltration rate <SO%: By any locally used
method.
6.2. Proteinuria of >0.5 gm/24 hours: According to locally determined method.
6.3. End-stage renalfailure: Failure of native kidneys for >3 months regardless
of subsequent dialysis or transplantation.
7. Gastrointestinal
7.1. Gut infarction: Infarction or resection of bowel below duodenum or of gall
bladder, spleen, or liver: ever, since the onset of vasculitis.
7.2. Mesenteric insufficiencyipancreatitis: Typical abdominal pain confirmed on
angiography or enzyme changes.
7.3. Chronic peritonitis: Typical abdominal pain and peritoneal irritation on
clinical examination.
7.4. Esophageal stricture or upper gastrointestinal (GI) tract surgery: Documented endoscopically or radiologically: GI surgery ever, since the onset of
vasculitis.
8. Peripheral vascular
8.1. Absent peripheralpulse: In 1 limb, detected clinically.
8.2. Second episode absent peripheral pulse: In 1 limb, detected clinically, at
least 3 months after first event.
8.3. Ab.sent peripheral pulses: In at least 2 limbs, detected clinically.
8.4. Major vessel stenosis: Such as carotid or renal stenosis, documented on
Doppler echocardiography or angiography.
8.5. Claudication: Exercise-related ischemic pain in peripheral large vessel
present for at least 3 months.
8.6. Complicated venous thrombosis: With persistent swelling, ulceration, or
clinical evidence of venous stasis.
8.7. Minor tissue loss: Such as loss of fingertip pulp space; ever, since the onset
of vasculitis.
8.8. Major tissue loss: Such as the loss of digit(s) or limb(s), including by
surgical resection; ever, since the onset of vasculitis.
8.9. Second episode of major tissue loss: At least 3 months after first event.
9. Ocular
9.1. Cataract: A lens opacity (cataract) in either eye, documented by ophthalmoscopy.
9.2. Retinal change: Any significant change, documented by ophthalmoscopic
examination: may result in field defect, legal blindness.
9.3. Optic atrophy: Documented by ophthalmoscopic examination.
9.4. Visual impairment/diplopia: Restricted eye movements (not due to nerve
palsies), reduced visual acuity, double vision, or tunnel vision.
9.5. Blindness: Complete loss of vision in 1 eye.
9.6. Blindness in second eye: At least 3 months after first event.
9.7. Orbital wall destruction: Determined by plain radiographs or computed
tomography scan.
10. Neuropsychiatric
10.1. Cognitive impairment: Memory deficit, difficulty with calculation, poor
concentration, difficulty in spoken or written language, impaired performance
level, as documented on clinical examination (e.g., short mental test score) or
by formal neurocognitive testing.
10.2. Major psychosis: Altered ability to function in normal activity due to
psychiatric reasons. Severe disturbance of the perception of reality characterized by the following features: delusions, hallucinations (auditory, visual),
incoherence, marked loose associations, impoverished thought content,
marked illogical thinking, bizarre, disorganized, or catatonic behavior.
10.3. Seizures: Paroxysmal electrical discharge occurring in the brain and
producing characteristic physical changes including tonic and clonic movements, and certain behavioral disorders. Only seizures requiring therapy for
more than 3 months are counted as damage.
10.4. Cerebrovascular accident: Resulting in focal findings such as paresis,
weakness, etc., or surgical resection for causes other than malignancy; ever,
since the onset of vasculitis.
10.5. Second cerebrovascular accident: At least 3 months after first event.
10.6. Cranial nerve lesion: Cranial neuropathy, excluding optic newe or
sensorineural deafness.
10.7. Peripheral neuropathy: Resulting in either motor or sensory dysfunction.
10.8. Transverse mye1iti.s: Lower extremity weakness or sensory loss with loss of
sphincter control (rectal and urinary bladder).
11. Other damage
11.1. Premature gonadal failure: Onset of menopause before the age of 40
years.
11.2. Marrow failure: Leukopenia (white blood cells <4,000 per microliter) or
thrombocytopenia (platelets <140) or anemia (hemoglobin <lo), preferably
confirmed by marrow aspiration.
11.3. Diabetes mellitus: Requiring any type of therapy.
11.4. Chronic chemical cystitis: Persistent hematuria or shrunken bladder. This
does not include acute hemorrhagic cystitis, which should be scored in the
adverse drug reactions.
11.5. Malignancy: Documented by pathology, excluding dysplasias.
11.6. Other features: Any feature considered by patient or doctor to be an
important scar or consequence which has arisen since onset of disease.
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