Update on Indices of Disease Activity in Systemic Sclerosis

Marie Hudson, MD, MPH,* Russell Steele, PhD, Canadian Scleroderma

Research Group (CSRG), and Murray Baron, MD

Objective: An important barrier in the study of systemic sclerosis (SSc) is the difficulty in measuring disease activity. We reviewed the literature on currently available global measures of disease
activity in SSc.
Methods: The PubMed database (1950-2006) was searched for the key words scleroderma in
conjunction with disease activity and then disease severity. All relevant original and review
articles in English and French were reviewed. Textbooks in rheumatology and pertinent secondary
references were also reviewed.
Results: There are currently 3 tools that are used to measure disease activity globally in SSc.
Physician global assessments have been commonly used but have not been formally evaluated. The
Valentini Disease Activity Index is a new measure that consists of 10 variables and a resulting score
ranging from 0 to 10. It appears easy to use but lacks some face and content validity and responsiveness to change has yet to be demonstrated. The Medsger Disease Severity Scale measures
disease severity in 9 organ systems. However, it assesses mostly damage and is difficult to score.
Conclusions: There is currently no gold standard measure of disease activity in SSc. Given the need
to measure disease activity in SSc and the limitations of the currently available instruments, efforts
are ongoing to develop new ones. This represents a major challenge but one that remains particularly important to undertake.
2007 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 37:93-98
Keywords: disease activity, scleroderma, outcome measures, review

ystemic sclerosis (SSc) is a chronic, multisystem

disorder characterized by thickening and fibrosis
of the skin and internal organs (1,2). It affects
mainly women (3,4) in the prime of their life (3,4) and
is associated with significant morbidity, including
pain, disability, depression (5,6), and reduced quality
of life (7,8), increased mortality (relative survival as low
as 35% at 20 years, compared with age-, sex-, and
race-matched individuals) (9) and high costs (10). Although it is a heterogeneous disorder, 2 common clin-

*Assistant Professor, Division of Rheumatology, McGill University, Montreal, Canada; and SMBD-Jewish General Hospital, Montreal, Canada.
Assistant Professor, Department of Mathematics and Statistics, McGill University, Montreal, Canada; and SMBD-Jewish General Hospital, Montreal, Canada.
Associate Professor, Division of Rheumatology, McGill University, Montreal,
Canada; and SMBD-Jewish General Hospital, Montreal, Canada.
This study was funded in part by the Canadian Institutes of Health Research, the
Scleroderma Society of Canada, and educational grants from Actelion Pharmaceuticals and Pfizer Inc. The study sponsors had no role in the design of the study, in the
collection, analysis, and interpretation of the data, in the writing of the article, and in
the decision to submit the article for publication.
Address reprint requests to: Marie Hudson, MD, MPH, SMBD-Jewish General
Hospital, Room A-216, 3755 Cote Ste. Catherine Road, Montreal, Quebec, H3T 1E2,
Canada. E-mail: marie.hudson@mcgill.ca.

0049-0172/07/$-see front matter 2007 Elsevier Inc. All rights reserved.

doi:10.1016/j.semarthrit.2007.01.005

ical subsets are recognized in terms of skin involvement, either limited (skin involvement distal to the
elbows and knees) or diffuse (skin involvement proximal to the elbows and knees in addition to the trunk)
(11). SSc is thought to affect over 16,000 Canadians
and up to 100,000 Americans (12-16). There is currently no known cure (17).
An important barrier in the study of SSc has been and
continues to be the difficulty in measuring disease activity
(18-20). Disease activity (20-23) usually measures the aspect of disease that varies over time and is potentially
reversible spontaneously or under drug treatment. This
is in contradistinction to disease damage and severity.
Damage measures irreversible tissue injury that results
from disease (20-23). Disease severity lacks an accepted
definition (21). Some (24,25) use it as a modifier of activity and incorporate it into ratings of activity (does the
disease manifestation require treatment, does it impose
functional limitations). Some (21) equate it to a measure
of prognosis. Others (22) take it to represent the total
effect of disease on organ function at a given point in time,
including both reversible (activity) and irreversible components (damage).
93

94

Measuring disease activity in SSc has been particularly

difficult, especially compared with diseases such as systemic lupus erythematosus and rheumatoid arthritis that
are characterized by episodes of inflammation, such as
synovitis, pleuritis, dermatitis, and nephritis, that can be
easily differentiated from quiescent phases (20,23). The
difficulty arises from several facts, as follows:

First, many patients, especially those with limited skin

involvement, have an indolent course without clear
signs of inflammation (20,23).
Second, from a laboratory point of view, only a few
acute phase proteins are elevated in patients with early
SSc (26), albeit in small studies, leading some to argue
that patients with SSc may have an impaired acute
phase response (19).
Third, the clinical features of SSc are attributable to
vascular and connective tissue fibrosis that is more difficult to appreciate and quantitate than inflammation
(20) and, when it becomes measurable, has often progressed to permanent damage.
Indeed, Clements noted more than a decade ago that
we have failed to measure activity in SSc in large part due
to the fact that we have relied on measures of organ dysfunction, such as serum creatinine, forced vital capacity,
left ventricular ejection fraction, and lower esophageal
sphincter pressure, that reflect damage and severity rather
than activity (18). He suggested that true activity in SSc
should be that which is abnormal when the disease is
worsening and then normalizes as the disease quiets. He
identified several clinical (increasing skin score, inflammatory foci in skin, joint tenderness count, ground-glass
changes on high resolution computed tomography of the
chest) and laboratory (von Willebrand factor VIII antigen, various cytokines, and other soluble protein markers)
variables that follow this pattern.
As it still stands, there is no gold standard measure of
disease activity in SSc. However, in recent years, some
global measures of disease activity in SSc have been proposed and are increasingly being used. We therefore undertook a review of these instruments and identified their
relative strengths and limitations.
METHODS
The PubMed database (1950-2006) was searched for the
keywords scleroderma in conjunction with disease activity and then disease severity. All relevant original
and review articles in English and French were examined. Textbooks in rheumatology and pertinent secondary references, including meeting abstracts, were
also reviewed.
RESULTS
Physician Global Assessments
In SSc, as in most rheumatic diseases, disease activity may
be manifested in various organs and measured using or-

Disease activity in systemic sclerosis

gan-specific measures (27). However, a measure that

pools several findings of activity and creates a composite
result is a common method of handling the variability of
different findings in various body systems (21). The physician global assessment is the simplest form of a composite measure to assess disease activity. In the absence of a
gold standard, the physician global assessment is often
used as the next best thing to determine disease activity
(21).
Physician global assessments of disease activity have
often been used in SSc (20,28-30). However, these have
not been formally evaluated. In the study of the construct
validity of the Valentini Disease Activity Index that will
be discussed shortly, the level of agreement in the assessment of disease activity among 4 SSc experts was low
(lowest reported correlation coefficient r 0.428, P, not
significant) (31). Thus, although this was not the main
purpose of the study, the validity of physician global assessments of disease activity in SSc remains to be demonstrated.
An alternative way of creating a single measure of disease activity is to develop an index consisting of a number
of disease variables appropriately selected and weighted.
Such disease activity indices exist in a number of rheumatic diseases (32,33) and there are 2 such indices currently available in SSc.
Valentini Disease Activity Index
In 2001, the European Scleroderma Study Group (ESSG)
developed preliminary disease activity indices to be used
in patients with SSc (34,35). Investigators from 19 European centers in 11 countries completed an extensive, 88item, standardized chart for each of 290 consecutive patients with either diffuse or limited SSc. Three experts
blindly evaluated each chart and, by consensus, assigned a
disease activity score to each chart on a scale of 0 to 10.
This constituted the gold standard. Univariate analysis
was used to select individual items in the charts that correlated with the gold standard. Multiple linear regression
analyses were performed to evaluate the combined performance of different sets of variables in predicting the gold
standard and to define the relative weight of each variable.
Three separate weighted 10-point indices of disease activity were constructed, 1 for the group as a whole and 1 for
each of the subsets with either diffuse or limited disease.
The construct validity of the 3 preliminary indices was
assessed in a subsequent report (31). The charts from a
random subset of 30 of the original 290 patients were
selected. Four clinical experts were asked to rank the
charts from least active to most active. The disease activity
index scores of each patient were calculated and compared
with the ranks given by each expert, separately. The activity scores obtained using the whole series index correlated
well with the ranks given by the 4 experts (r ranging from
0.530 to 0.712, all P values 0.003). However, some of
the correlations between the scores obtained using the

M. Hudson, R. Steele, and M. Baron

95

Table 1 Valentini Disease Activity Index for all Patients

with SSc (23,37)
Variable

Score

Modified Rodnan skin score 14

1.0
Scleredema
0.5
Change in skin symptoms in the last month*
2.0
Digital necrosis
0.5
Change in vascular symptoms in the last month*
0.5
Arthritis
0.5
Lung diffusion capacity 80% predicted
0.5
Change in cardiopulmonary symptoms*
2.0
Erythrocyte sedimentation rate 30 mm/1st
1.5
hour
Hypocomplementemia
1.0
Total disease activity index score
10.0
*Assessed by the patient.

indices for the subsets of patients with diffuse and limited

disease only were low (lowest r 0.357, P, not significant).
Thus, based on the authors own conclusions, and accepted standards that correlation coefficients 0.5 represent strong correlations (36), only the index for the whole
cohort and not the indices for the disease subsets was
judged to be valid.
The Valentini Disease Activity Index for all patients
with SSc (Table 1) was adopted by the ESSG and the
Scleroderma Clinical Trials Consortium at a symposium
held in 2002 (23,37). It consists of 10 variables with
weights ranging from 0.5 to 2.0 and resulting in a total
score ranging from 0 to 10. This index appears simple and
easy to use and is now increasingly being used in research
settings (7,38-40). This attests to the need to have a measure of disease activity in SSc.
Despite the major advance that the Valentini Disease
Activity Index for SSc represents, there are issues that
require further study:
1. The cohort used to develop the index had longstanding disease. However, SSc often progresses rapidly
within the first 2 to 4 years of onset and slows or
stabilizes thereafter (41,42). Thus, the index needs to
be studied in patients with early onset disease, before
damage has occurred (18).
2. The development of the index was hampered by a high
number of missing values and a high degree of variability among centers in the reported frequency of various disease manifestations. Although this could be
due to true geographic differences in prevalence of
different disease manifestations, it may also reflect a
lack of consistency and reliability in the clinical assessment of patients with SSc. In the end, the investigators
appropriately excluded from the analysis items that
were either missing or reported differently in the various centers. However, in so doing, they were forced to
exclude several items that prima facie could be related
to disease activity, such as alveolitis (43). In the future,

issues of missing data and reliability need to be considered.

3. Certain items included in the index lack face validity.
For example, hypocomplementemia is retained as an
element of disease activity but this does not seem intuitively appropriate as complement fixation is not
commonly thought to be important in SSc.
4. Three items in the index relate to change, namely
change in skin, vascular and cardiopulmonary symptoms in the past month. Such change items in activity
indices are problematic because they fail to capture
persistent activity (20). Others have addressed how to
capture persistent disease activity in similar diseases,
namely systemic lupus erythematosus (44), and this
needs to be considered in SSc.
5. Responsiveness to change of the index has yet to be
assessed.
Medsger Disease Severity Scale
As previously mentioned, disease severity is defined by
some as the sum of both reversible (activity) and irreversible (damage) components of disease at any given time
(22). Using this definition, there are few scales to measure
disease severity, either in an individual organ system or
globally in SSc (22,45,46). Although it has not been
widely tested, the scale developed by Medsger and the
International SSc Study Group (Table 2) (22,47) has
emerged as the most frequently used (6,20,42). It assesses
disease involvement in 9 organ systems, namely, general
health, peripheral vascular, skin, joint/tendon, muscle,
gastrointestinal tract, lungs, heart, and kidneys. Each organ system is scored separately from 0 to 4, depending on
whether there is no, mild, moderate, severe, or end-stage
involvement.
This severity scale has limitations as a measure of disease activity. First, although the stated objective of the
severity scale was to include components of activity and
damage, in preparing the final scale, the variables felt to
represent disease activity (eg, sedimentation rate, tendon
friction rubs, creatinine kinase, diastolic blood pressure)
were excluded. Second, as it stands, the scale results in 9
separate severity scores, 1 for each organ assessed, rather
than an overall score. Thus, this scale is not easy to use.
The absence of an overall score is a limitation that the
authors of the scale specifically acknowledged (22). Finally, its responsiveness to change is unknown.
DISCUSSION
Given the need to measure disease activity in SSc and
given the limitations of the available instruments, work is
ongoing to develop new ones. The Canadian Scleroderma
Research Group (CSRG) is a unique consortium of the
major Canadian stakeholders in SSc research, including
rheumatologist, basic scientists, and patient representatives, who have established a multicentered registry to
recruit large numbers of patients for longitudinal studies

96

Disease activity in systemic sclerosis

Table 2 Medsger Disease Severity Scale (22,47)

Organ system

0 (normal)

General

Wt loss 5%; Wt loss 510%;

PCV 3337%; Hb
PCV 37%;
11.012.2 g/dl
Hb 12.3
g/dl

Peripheral
vascular

No
Raynauds;
Raynauds
not
requiring
vasoldialtors
Skin
TSS 0
Joint/tendon
FTP 00.9 cm
Muscle
Normal
proximal
muscle
strength
Gastrointestinal Normal
tract
esophagram;
normal
small bowel
series
Lung
DLCO 80%;
FVC 80%;
No fibrosis
on
radiograph;
sPAP 35
mmHg
Heart
EKG normal;
LVEF 50%
Kidney

No history of
SRC with
serum
creatinine
1.3 mg/dl

1 (mild)

2 (moderate)

3 (severe)

4 (end stage)

Wt loss 1015%; PCV

2933%; Hb
9.710.9 g/dl

Wt loss 1520%; PCV Wt loss 20%;

2529%; Hb
PCV 25%; Hb
8.39.6 g/dl
8.3 g/dl%

Raynauds requiring Digital pitting scars

vasodilators

Digital tip ulcerations

Digital gangrene

TSS 114
FTP 1.01.9 cm
Proximal weakness,
mild

TSS 3039
FTP 4.04.9 cm
Proximal weakness,
severe

TSS 40
FTP 5.0 cm
Ambulation aids
required

TSS 1529
FTP 2.03.9 cm
Proximal weakness,
moderate

Antibiotics required
Distal esophageal
for bacterial
hypoperistalsis;
overgrowth
small bowel series
abnormal

Hyperalimentation
Malabsorption
required
syndrome; episodes
of pseudoobstruction

DLCO 7079%;
FVC 7079%;
Basilar rales;
fibrosis on
radiograph; sPAP
3549 mmHg

DLCO 5069%; FVC

5069%; sPAP
5064 mmHg

DLCO 50%; FVC

50%; sPAP 65
mmHg

Oxygen required

EKG conduction
defect; LVEF
4549%
History of SRC with
serum creatinine
1.5 mg/dl

EKG arrhythmia; LVEF

4044%

EKG arrhythmia
requiring Rx; LVEF
3040%
History of SRC with
serum creatinine
2.55.0 mg/dl

CHF; LVEF 30%

History of SRC with

serum creatinine
1.52.4 mg/dl

History of SRC
with serum
creatinine 5.0
mg/dl or dialysis
required

Wt, weight; PCV, packed cell volume (hematocrit); Hb, hemoglobin; TSS, total skin score; FTP, fingertip to palm distance in flexion; DLCO,
diffusing capacity for carbon monoxide, % predicted; FVC, forced vital capacity, % predicted; sPAP, estimated pulmonary artery pressure
by Doppler echo; EKG, electrocardiogram; LVEF, left ventricular ejection fraction; Rx, treatment; CHF, congestive heart failure; SRC,
scleroderma renal crisis.

in SSc. As of January 2007, 15 centers were involved and

over 500 patients had been enrolled. The CSRG is in the
process of developing a SSc disease activity index and
proposes to evaluate its psychometric properties (in particular, reliability, validity, and responsiveness) using this
cohort.
The Scleroderma Clinical Trials Consortium has also
undertaken preliminary studies to define disease activity.
Using a Delphi method (48) and data on 96 patients from
10 centers worldwide, they have identified numerous
clinical and laboratory variables that appeared to be related to disease activity (49). However, there are very few
published details of their study to date.
Experts have commented that a self-administered measure of disease activity could make disease monitoring
more practical (13). Such self-administered instruments

to measure disease activity exist in other rheumatic diseases, namely rheumatoid arthritis and ankylosing spondylitis (50-55), and are useful complements to traditional
biomedical assessments of disease activity based on clinical and laboratory measures (56). In addition, in the absence of a gold standard to define disease activity, both
physician and patient assessments of disease activity can
be used together (57,58). For example, in a study of
Raynauds phenomenon in patients with SSc, both
physician and patient assessments of Raynauds phenomenon activity were found to be valid and reliable
and the authors recommended that both be included in
the core set of measures for use in future clinical trials
in this area (59). Nevertheless, although SSc patients
are able to self-report symptoms and function accurately (60-62), it remains to be shown whether they can

M. Hudson, R. Steele, and M. Baron

distinguish between disease activity, as opposed to severity and damage.

Measures of disease activity in SSc are needed for multiple uses (19,21). In observational studies, they could be
used to describe and compare study populations and identify potentially reversible aspects of disease. Given that
research into new treatments for SSc is rapidly advancing
(17), they could be used to determine eligibility and as a
measure of outcome in upcoming clinical trials. Finally,
there has been an increasing trend toward measuring disease activity in clinical practice in several conditions (63).
This is in part the result of attempts by governments and
insurance companies to regulate prescription of expensive
new therapies. As new and surely expensive treatments
become available for SSc (eg, bosentan), measures of disease activity also have the potential to be used in clinical
practice to guide decision-making and for regulatory documentation.
Given the limitations of the currently available instruments to measure disease activity in SSc, efforts are ongoing to develop new indices. This represents a major challenge but one that remains particularly important to
pursue both epidemiological and clinical research in this
field.
ACKNOWLEDGMENTS
The CSRG Investigators include the following: M. AbuHakima, Calgary, Alberta, Canada; P. Docherty, Moncton, New Brunswick, Canada; J. Dunne, Vancouver,
British Columbia, Canada; M. Fritzler, Advanced Diagnostics Laboratory, Calgary, Alberta, Canada; S. Johnson,
Toronto, Ontario, Canada; N. Jones, Edmonton, Alberta, Canada; N. Khalidi, Hamilton, Ontario, Canada;
S. LeClercq, Calgary, Alberta, Canada; J. Markland,
Saskatoon, Saskatchewan, Canada; J-P. Mathieu, Montreal, Quebec, Canada; J. Pope, London, Ontario, Canada; P. Rahman, St Johns, Newfoundland, Canada; D.
Robinson, Winnipeg, Manitoba, Canada; D. Smith, Ottawa, Ontario, Canada; E. Sutton, Halifax, Nova Scotia,
Canada.
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