E P ID EMIOL O GY AN D HE AL TH S ER VI CE S R ESEA RCH BJD British Journal of Dermatology

Comparison of patients with and without digital ulcers

in systemic sclerosis: detection of possible risk factors
C. Sunderkötter, I. Herrgott, C. Brückner,* P. Moinzadeh, C. Pfeiffer, J. Gerß,§ N. Hunzelmann, M. Böhm,
T. Krieg, U. Müller-Ladner,– E. Genth,** E. Schulze-Lohoff, M. Meurer, I. Melchers, the DNSS Centers
and G. Riemekasten*
Department of Dermatology, University of Münster, Von-Esmarch-Str. 58, 48149 Münster, Germany
*Rheumatology and Clinical Immunology, Charité, Berlin, Germany
Department of Dermatology and Venereology, University of Cologne, Cologne, Germany
Department of Dermatology, Dresden University Hospital, Dresden, Germany
§Department of Medical Informatics and Biomathematics, Coordinating Centre for Clinical Trials, University of Münster, Münster, Germany
–Department of Rheumatology and Clinical Immunology, Kerckhoff Clinic, Justus-Liebig University Giessen, Bad Nauheim, Germany
**Rheumatology, University of Aachen, Aachen, Germany
Medical Clinic I, Hospital Cologne-Merheim, Cologne, Germany
Clinical Research Unit for Rheumatology, University Medical Center Freiburg, Freiburg, Germany

Summary

Correspondence Background Digital ulcers (DU) are a major complication in the course of systemic
Cord Sunderkötter. sclerosis (SSc). In recent years, efficacious, but expensive therapies (e.g. iloprost,
E-mail: cord.sunderkoetter@ukmuenster.de sildenafil, bosentan) have been shown to improve healing or to reduce the recur-
rence of DU. For optimal management it would be useful to identify the risk fac-
Accepted for publication
20 October 2008 tors for DU. Such statistical analyses have been rare because they require a high
number of patients.
Key words Objectives To identify potential risk factors for DU in patients with SSc.
digital ulcers, German Network, Raynaud’s Methods We used the registry of the German Network for Systemic Scleroderma
phenomenon, risk factors, systemic sclerosis and evaluated the data of 1881 patients included by August 2007. We assessed
potential risk factors for DU by comparing patients with (24.1%) and without
Conflicts of interest
None declared. active DU at time of entry (75.9%).
Results Multivariate analysis revealed that male sex, presence of pulmonary arterial
The first two authors contributed equally to this hypertension (PAH), involvement of the oesophagus, diffuse skin sclerosis (only
study. when PAH was present), anti-Scl70 antibodies, young age at onset of Raynaud’s
phenomenon (RP), and elevated erythrocyte sedimentation rate (ESR) signifi-
Current address: C. Pfeiffer, Department of
Dermatology and Allergology, University of Ulm, cantly impacted on the appearance of DU. Certain combinations increased the
Ulm, Germany. patients’ probability of presenting with DU, with the highest probability (88%)
for male patients with early onset of RP, ESR > 30 mm h)1, anti-Scl70 anti-
Co-authors of the study are listed at the end of bodies and PAH. Patients with DU developed RP, skin sclerosis and organ
the article. involvement approximately 2–3 years earlier than patients without DU.
Conclusions The results reveal possible risk factors for the occurrence of DU in SSc.
DOI 10.1111/j.1365-2133.2008.09004.x
As DU are prone to local complications, prophylactic vasoactive treatment for
patients presenting with these factors may be justified.

Digital ulcers (DU) are a major complication in the course of
systemic sclerosis (SSc), which significantly influences the per-
sonal and professional life of the patient. Various studies have
revealed that among patients with SSc, 15–25% have active DU1
and 35% have active DU or have had DU in the past.2 These
numbers vary in different studies, possibly due to different geo-
graphical areas or different study methods and designs.3,4
DU in the course of SSc are painful, heal slowly
(3–15 months) and are difficult to treat. Complications
include secondary infections (superficial infection in 50% of
patients, osteomyelitis in 1% of patients), leading to surgery5
or amputation in 7–20%.6,7 Recurrent ulcers also result in the
chronic use of pain relievers or antibiotics and eventually hos-
pitalization either for (intravenous) treatment of active DU or
for surgery.
There is evidence that, in patients with SSc and Raynaud’s
phenomenon (RP), a timely use of adequate therapeutic mea-
sures facilitates healing, reduces the formation of DU or

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Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843 835
836 Digital ulcers in systemic sclerosis, C. Sunderkötter et al.
prevents amputations.8–11 It was demonstrated in clinical stud-
ies that the prostaglandin E2 analogue iloprost, for example,
accelerates healing and prevents new ulcers10 and the phos-
phodiesterase inhibitor sildenafil was shown to increase heal-
ing according to some case reports.12 The oral dual endothelin
receptor antagonist bosentan did not accelerate healing, but
significantly reduced the number of new DU and improved
hand function.13 Because of these results, the label for bosen-
tan has recently been extended to cover the prevention of new
digital ulceration in patients suffering from SSc with DU, pro-
vided the circumstances of its use are documented for each
patient by the prescribing physicians. In contrast, the use of
iloprost or sildenafil for prevention or treatment of RP or DU
is completely off-label.
These three substances are very expensive especially for
long-term therapy and they usually require hospital admission
for a 6-h intravenous injection.11 Therefore, uncertainties
about appropriate indications and about coverage by health
insurance may explain why at least in Germany management
of RP and of DU does not always exploit the full range of
therapeutic options.14 Because it is important for patients as
well as for the healthcare system to define and adjust thera-
peutic options according to individual needs, it would be use-
ful to know if there are distinct risk factors or constellations
of factors which favour the formation of DU.
To date, only a few studies have revealed associations of
antibody profile, sex or disease subset, by univariate analysis,
with the development of DU.3,5,15–17 A major limitation of
such analyses is the high number of patients needed in
order to calculate valid statistical statements. As SSc is a rare
disease high numbers of patients are difficult to achieve.
Only one study so far has been published in which multi-
variate analysis was performed6 in order to detect indepen-
dent variables or risk factors for DU, but the patient
number (103) was relatively low. None of these studies has
analysed associations between DU and involvement of other
organs.
In order to detect possible risk factors for DU in SSc we
performed a large-scale statistical work-up on data obtained
from more than 1880 patients who were registered in the
German Network for Systemic Scleroderma.14
Patients and methods
A total of 1881 patients were analysed. On average less than
10% of data were lacking or had to be ignored due to faulty
documentation. Because mouth involvement was included into
the data sheet after initiation of the registry, 19Æ6% of the
charts did not contain data about this variable. For multivariate
analysis the data of 1164 patients (62%) were available.
The German Network for Systemic Scleroderma
(Deutsches Netzwerk für Systemische Sklerodermie)
The German Network for Systemic Scleroderma (Deutsches
Netzwerk für Systemische Sklerodermie – DNSS) was founded
Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843
in October 2003 supported by a grant from the German
Ministry of Education and Research. The Network com-
prises different subspecialties, i.e. rheumatology, dermatology,
pulmonology and nephrology. At present it includes 32 clini-
cal centres of which 14 are rheumatological centres (Aachen,
Bad Bramstedt, Baden-Baden, Bad-Nauheim, Bad Säckingen,
Berlin, Cologne, Erlangen, Freiburg, Hamburg, Heidelberg,
Inzell, Regensburg, Treuenbrietzen) and 13 are dermatological
centres (Berlin, Dresden, Göttingen, Cologne, Leipzig, Mainz,
Minden, Munich, Münster, Regensburg, Ulm, Wuppertal,
Würzburg); two centres jointly register patients from their
dermatology and rheumatology departments (Düsseldorf and
Tübingen). In addition, a pulmonary centre in Giessen, a pul-
monary–dermatology centre in Graz (Austria) and a nephrol-
ogy centre in Cologne-Merheim participated; these centres are
nationally known for their expertise in treating specific com-
plications of pulmonary or renal involvement of SSc.
Data recording of network patients
Patients were enrolled into the network from 2003 to 2007.
This data analysis is based on all patients who were recruited
until August 2007 (1881 patients) and used data at the time
of enrolment.
With the consent of all the network members, a four-page
registration form was created to collect information on sex,
date of birth, height, weight, family history of rheumatic dis-
ease, signs and symptoms of organ involvement concerning
skin, heart, lung, gastrointestinal tract, kidney, musculoskeletal
system and nervous system, as well as the extent of skin scle-
rosis as assessed by the modified Rodnan skin score (mRSS)
and characteristic laboratory data such as antinuclear anti-
bodies (ANA) and erythrocyte sedimentation rate (ESR). To
ensure consistency of registered patients’ data in the network
centres, a 13-page reference document was prepared. This
document includes definitions and recommendations for diag-
nostic procedures as previously described.18
Active DU were defined as a loss of both epidermis and
dermis in an area of at least 2 mm in diameter on the distal
phalanx of the fingers. They were also differentiated from pits
(atrophic skin with punctuate retractions).
Organ involvement was evaluated and defined according to
diagnostic procedures suggested for patients recruited into the
network (described in detail by Hunzelmann et al.19)
The DNSS maintains a centralized online patient registry
using MACRO software for clinical trials (Tethys Solutions, San
Jose, CA, U.S.A.) in which all patient data from the registration
form are entered. A Central Office for Coordination, set up at
the Department of Dermatology at the University of Cologne,
acts as data manager which also validates the registration forms
before they are finally entered into the online registry.
The ethics committee of the coordinating centre, i.e. the
Cologne University Hospital, approved the registry. On the
basis of this approval and according to German law, all partic-
ipating centres received the approval of their local ethics com-
mittees prior to registering patients.14
 2009 The Authors

Data analysis
For statistical analysis of risk factors we assigned patients to
two groups: one containing all the patients within the DNSS
who had not experienced DU and a second group which
included those patients who had DU at entry into the registry.
Statistical analysis and tabular representation were conducted
using SPSS 15.0 (SPSS Inc., Chicago, IL, U.S.A.), SAS 9.1.3. (SAS
Institute Inc., Cary, NC, U.S.A.) and Excel (Microsoft, Red-
mond, WA, U.S.A.). The alternative hypothesis was accepted at
a statistical significance level of P < 0Æ05 on all applied statistical
tests. Descriptive statistics were performed to obtain frequencies
and distribution of the variables among all DNSS patients. The
v2 test was used in bivariate analysis to compare proportions of
the group presenting DU with the group having no ulcers.
To assess which factors might be associated with the devel-
opment of DU, crude odds ratios (ORs) and the correspond-
ing 95% confidence intervals (CIs) were calculated as
preliminary estimates of relative risks. Continuous variables
were analysed using the independent sample t-test.
Multivariate logistic regression analysis was then performed
in order to control for potentially confounding variables,
resulting in adjusted ORs. Only variables that were clinically
interesting and statistically significant in the foregoing v2 test
were entered into the logistic regression models. Variable
selection was performed by means of a likelihood-based
approach using forward and backward procedures. For contin-
uous variables we chose arbitrary cut-off points at 10, 20, 30
and 40 mm per first hour for ESR and at 10, 20, 30 and
40 years of age at onset of RP.
If a factor is declared a significant risk factor in multivariate
regression analysis, it reflects that the probability of a patient
presenting an ulcer is significantly enhanced when this specific
factor is present compared with being absent, assuming all
other factors remain unchanged.
The probability for the appearance of DU for combinations
of certain risk factors was assessed based on the final multivar-
iate logistic regression model; this is of more clinical signifi-
cance, because patients with SSc usually do not present with
only one symptom of the disease or one risk factor.
Results
Of the 1881 patients recruited, data from 1690 patients were
evaluable for DU. Out of these, 408 (24Æ1%) had active DU at
the time of entering the patient registry of the DNSS.
Odds ratio according to univariate analysis (binary
parameters)
Patients with SSc suffer from involvement of different organs
and they develop multiple symptoms during the course of
their disease. As expected, RP was the most prevalent symp-
tom in patients with SSc and its prevalence was slightly higher
in patients with DU (98%) compared with patients without
DU (94%; P = 0Æ001).
 2009 The Authors
Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843
Digital ulcers in systemic sclerosis, C. Sunderkötter et al. 837
Involvement of organs other than the skin or digital arteries
(RP) was diagnosed in 88% of all registered SSc patients.
Compared with patients without DU, patients with DU
showed a significantly higher frequency of pulmonary fibrosis
(45% in the group with DU vs. 33% in the group without
DU; P < 0Æ0001), of pulmonary arterial hypertension (PAH;
24% vs. 13%; P < 0Æ0001), as well as a higher degree of heart
(18% vs. 13%; P = 0Æ01), upper gastrointestinal (18% vs.
13%; P = 0Æ014) and oesophageal involvement (71% vs. 57%;
P < 0Æ0001). Furthermore, sclerosis of the skin (95%) and
mouth involvement (36%) were also significantly more often
associated with ulcerations compared with patients without
DU (P < 0Æ0001) (Table 1).
Among patients with DU, 43% presented with limited and
43% with diffuse skin sclerosis. However, patients without
DU more often had a limited form (49%) than a diffuse form
of SSc (only 27%).
The prevalence of ANA in serum was significantly higher
(95%; P < 0Æ0001) in the group of patients with DU com-
pared with patients without DU (88%). In particular, anti-
Scl70 antibodies could be detected in 42% of patients with
active DU, while only 31% had anticentromere antibodies
(ACA). There was no difference in the presence of anti-U1
ribonucleoprotein (anti-U1RNP) antibodies in patients with or
without DU (4Æ4% vs. 4Æ6%) (Table 1).
In contrast, comparing different antibody profiles in patients
with SSc, the prevalence of DU was highest in patients with
anti-Scl70 antibodies (36%) compared with patients who were
ACA positive (21%) or anti-U1RNP-antibody positive (24%).
The presence of ACA seemed to confer a lower risk of devel-
oping ulcers (Fig. 1).
Although women are at higher risk of suffering from SSc,20
and even though they present the largest proportion of all
patients with DU (76%), the percentage of women who
developed ulcers (22%) was significantly lower than the per-
centage of afflicted men (34%) (P < 0Æ0001) (Fig. 1). The
female to male ratio in the group of patients without DU was
5Æ7 : 1, compared with a ratio of only 3 : 1 in the group with
DU. Therefore, male sex can be considered a potential risk
factor for the development of DU according to the univariate
analysis.
Consistent with the higher prevalence of DU among male
patients and among patients with diffuse SSc, the estimated
relative risk of DU was increased when patients were male
(OR = 1Æ85), anti-Scl70-antibody positive (OR = 2Æ23) or
suffering from diffuse SSc (OR = 2Æ08). Conversely, the risk
of having DU was lower for female patients, or patients with
the limited form of SSc or with ACA (OR = 0Æ54, 0Æ79, 0Æ73,
respectively). Corresponding to the higher rate of organ
involvement among patients with ulceration the risk for
ulceration was also increased in the presence of specific organ
involvement. Here the OR was highest when PAH was present
(OR = 2Æ08), followed by involvement of the oesophagus
(OR = 1Æ91), pulmonary fibrosis (OR = 1Æ66), involvement
of the mouth (OR = 1Æ69), of the heart (OR = 1Æ48), and of
the upper gastrointestinal tract (OR = 1Æ46) (Table 1).
838 Digital ulcers in systemic sclerosis, C. Sunderkötter et al.

Table 1 Sex, systemic sclerosis (SSc) subtype, antibodies and disease presentation among patients with or without digital ulcers. The numbers in
parentheses are the total number of datasets evaluable for digital ulcers and the relevant feature

No digital ulcers Digital ulcers

n % n % OR 95% CI P-Value
Total number of patients (n = 1690) 1282 75Æ9 408 24Æ1
Sex
Female 1090 (1281) 85Æ1 308 (408) 75Æ5 0Æ54 0Æ41–0Æ71 < 0Æ0001
Male 191 (1281) 14Æ9 100 (408) 24Æ5 1Æ85 1Æ41–2Æ43 < 0Æ001
SSc subtype
Limited 625 (1278) 48Æ9 175 (408) 42Æ9 0Æ79 0Æ63–0Æ98 0Æ034
Diffuse 342 (1278) 26Æ8 176 (408) 43Æ1 2Æ08 1Æ65–2Æ62 < 0Æ0001
MCTD 144 (1278) 11Æ3 36 (408) 8Æ8 0Æ76 0Æ52–1Æ12 NS
UCTD 133 (1278) 10Æ4 18 (408) 4Æ4 0Æ4 0Æ24–0Æ66 < 0Æ0001
SSc sine scleroderma 9 (1278) 0Æ7 3 (408) 0Æ7 1Æ04 0Æ28–3Æ88 NS
Autoantibodies
ANA positive 1123 (1273) 88Æ2 387 (408) 94Æ9 2Æ46 1Æ54–3Æ94 < 0Æ001
ACA positive 477 (1243) 38Æ4 127 (406) 31Æ3 0Æ73 0Æ58–0Æ93 0Æ01
Anti-Scl70 antibody positive 309 (1274) 24Æ3 170 (408) 41Æ7 2Æ23 1Æ76–2Æ82 < 0Æ001
Anti-U1RNP positive 58 (1269) 4Æ6 18 (407) 4Æ4 0Æ97 0Æ56–1Æ66 NS
Organ manifestations
Raynaud’s phenomenon 1200 (1276) 94 400 (407) 98Æ3 3Æ62 1Æ66–7Æ91 0Æ001
Skin sclerosis 1112 (1277) 87Æ1 387 (406) 95Æ3 3Æ02 1Æ85–4Æ93 < 0Æ0001
Lung fibrosis 421 (1282) 32Æ8 183 (408) 44Æ9 1Æ66 1Æ33–2Æ09 < 0Æ0001
PAH 165 (1282) 12Æ9 96 (408) 23Æ5 2Æ08 1Æ57–2Æ76 < 0Æ0001
Heart involvement 164 (1280) 12Æ8 73 (408) 17Æ9 1Æ48 1Æ1–2Æ01 0Æ01
Kidney involvement 146 (1280) 11Æ4 60 (408) 14Æ7 1Æ34 0Æ97–1Æ85 NS
Oesophagus involvement 725 (1281) 56Æ6 291 (408) 71Æ3 1Æ91 1Æ5–2Æ43 < 0Æ0001
Involvement of upper GI tract 164 (1280) 12Æ8 72 (408) 17Æ6 1Æ46 1Æ08–1Æ97 0Æ014
(from stomach to ileum)
Colon involvement 68 (1280) 5Æ3 26 (408) 6Æ4 1Æ21 0Æ76–1Æ93 NS
Musculoskeletal involvement 564 (1153) 48Æ9 192 (386) 49Æ7 1Æ03 0Æ82–1Æ30 NS
Involvement of nervous system 84 (1242) 6Æ8 21 (392) 5Æ4 0Æ78 0Æ48–1Æ28 NS
Sicca syndrome 522 (1241) 42Æ1 160 (392) 40Æ8 0Æ95 0Æ75–1Æ2
Mouth involvement 275 (1108) 24Æ8 133 (372) 35Æ8 1Æ69 1Æ31–2Æ17 < 0Æ0001

OR, odds ratio; CI, confidence interval; MCTD, mixed connective tissue disease; UCTD, undifferentiated connective tissue disease; ANA, anti-
nuclear antibodies; ACA, anticentromere antibodies; anti-U1RNP, antiribonucleoprotein antibodies; PAH, pulmonary arterial hypertension;
GI, gastrointestinal.

onset of organ involvement (48Æ11 ± 14Æ48 years) were all

Descriptive statistics of continuous clinical parameters
in patients with systemic sclerosis with and without
ulcerations
The mRSS is a good parameter for measuring skin sclerosis.
In patients with DU, the mRSS was significantly higher
(13Æ56 ± 10Æ05) than in patients without ulcers (8Æ84 ±
8Æ58) (P < 0Æ0001) (Table 2). This was also the case when
only the added scores of hands and fingers were assessed: it
was 6Æ89 ± 3Æ66 for patients with and 4Æ65 ± 4Æ62 for
patients without ulcers (P < 0Æ0001).
The ESR was significantly higher in patients with DU. The
mean rate for patients with ulcers was 23Æ49 ± 20Æ05 mm per
first hour, while it was 19Æ74 ± 16Æ98 mm per first hour for
patients without ulcers (P = 0Æ002). For further evaluation by
multivariate analysis we chose arbitrary cut-off points at 10,
20, 30 and 40 mm.
In addition, the mean ages at onset of RP (42Æ62 ± 15Æ27
years), at onset of skin sclerosis (45Æ22 ± 14Æ04 years) and at
significantly lower in patients with DU compared with
patients without ulcers (44Æ62 ± 15Æ6; 48Æ68 ± 14Æ22; 50Æ71 ±
14Æ0 years, respectively).
In summary, patients with ulcers developed other manifes-
tations such as RP, skin sclerosis and organ involvement
approximately 2–3 years earlier than patients without ulcers.
Interestingly, the time from skin sclerosis to the involve-
ment of other organs was shorter in patients without DU
(1Æ77 ± 5Æ94 years) than in the patients with DU (on average
2Æ75 ± 6Æ41 years; P = 0Æ02).
Multivariate analysis
Datasets from 1164 patients were complete and available for
multivariate analysis. The multivariate analysis confirmed the
results of most univariate comparisons. Male sex was the
most powerful independent predictor for the presence of DU
(OR = 2Æ24). PAH (OR = 1Æ84), anti-Scl70 antibodies (OR =

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Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843
 Digital ulcers in systemic sclerosis, C. Sunderkötter et al. 839

DU (%) No DU (%)

0% 20% 40% 60% 80% 100%

n = 308 OR = 0·54; P < 0·001 n = 1090 Female (n = 1398)

n = 100 OR = 1·85; P < 0·001 n = 191 Male (n = 291)

n = 175 OR = 0·79; P = 0·034 n = 625 Limited form (n = 800)

n = 176 OR = 2·08; P < 0·001 n = 342 Diffuse form (n = 518)

n = 36 OR = 0·76; NS n = 144 MCTD (n = 180)

n = 18 OR = 0·40; P < 0·001 n = 133 UCTD (n = 151)

n=3 OR = 1·04; NS n=9 Sine scleroderma (n = 12)

Fig 1. Relationship between digital ulcers
(DU) in systemic sclerosis (SSc) and n = 387 OR = 2·46; P < 0·001 n = 1123 ANA+ (n = 1510)
clinicoepidemiological features. MCTD,
n = 127 OR = 0·73; P = 0·01 n = 477 ACA+ (n = 604)
mixed connective tissue disease; UCTD,
undifferentiated connective tissue disease; OR = 2·23; P < 0·001
n = 170 n = 309 Anti-Scl70+ (n = 479)
ANA, antinuclear antibodies; ACA,
anticentromere antibodies; anti-U1 RNP, n = 18 OR = 0·97; NS n = 58 Anti-U1RNP+ (n = 76)
anti-U1 ribonucleoprotein antibodies.

Table 2 Descriptive statistics of continuous

clinical parameters in patients with systemic No digital
sclerosis with or without digital ulcers ulcers Digital ulcers

Mean SD Mean SD P-value

Age (years)
At onset of RP 44Æ62 15Æ6 42Æ62 15Æ27 0Æ03
At onset of skin sclerosis 48Æ68 14Æ22 45Æ22 14Æ04 < 0Æ0001
At onset of organ involvement 50Æ71 14Æ0 48Æ11 14Æ48 0Æ004
Duration (years)
From first RP to skin sclerosis 3Æ68 8Æ49 3Æ15 7Æ75 NS
From first RP to first other organ 5Æ49 10Æ56 5Æ77 9Æ55 NS
manifestation
From skin sclerosis to first other 1Æ77 5Æ94 2Æ75 6Æ41 0Æ02
organ manifestation
mRSS
Total 8Æ84 8Æ58 13Æ56 10Æ05 < 0Æ0001
mRSS of hands 4Æ65 4Æ62 6Æ89 3Æ66 < 0Æ0001
ESR (mm ⁄ first hour) 19Æ74 16Æ98 23Æ49 20Æ05 0Æ002

RP, Raynaud’s phenomenon; mRSS, modified Rodnan skin score; ESR, erythrocyte sedi-
mentation rate; NS, not significant.

1Æ80) (but not ACA), involvement of the mouth (OR = 1Æ62)
or oesophagus (OR = 1Æ51), elevated ESR (OR = 1Æ01 per
1 mm; 1Æ10 per 10 mm), or onset of RP at a young age
(OR = 0Æ98 per year) were all highly significant in represent-
ing risk factors for the presence of DU (P < 0Æ05) (Table 3).
An OR of 0Æ98 per year for the variable ‘onset of RP’ means
that the chance of developing an ulcer is reduced by a factor
of 0Æ98 per year, i.e. each year that a patient develops RP later
than other patients decreases his risk by 2%. Correspondingly,
the OR decreases by a factor of 0Æ82 (0Æ9810) or 18% in a
patient aged 60 years at the onset of RP compared with a
patient who is 10 years younger (i.e. 50 years of age).
Despite anti-Scl70 being an independent risk factor, the
diffuse form of SSc was not an independent risk factor, i.e.
the form of SSc did not independently increase the risk for
DU. Only when PAH was present did the presence of diffuse
skin sclerosis increase the risk of developing ulcers—OR
up to 2Æ49 (compared with a patient with PAH and no
diffuse sclerosis). On the other hand, when diffuse skin
sclerosis was present, PAH increased the OR up to 4Æ1
(Table 3).
The mRSS was not included in the multivariate analysis
because the number of datasets that were complete or consist-
ent enough was not sufficiently high.

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840 Digital ulcers in systemic sclerosis, C. Sunderkötter et al.

Table 3 Multivariate predictors for digital ulcers

Standard
Factor OR error 95% CI P-value
Male sex 2Æ24 0Æ4054 1Æ57–3Æ20 < 0Æ0001
Age at onset of RP (per year) 0Æ98 0Æ0047 0Æ97–0Æ99 0Æ0003
Age at onset of RP (per 10 year) 0Æ84 0Æ0401 0Æ77–0Æ92 0Æ0003
Oesophageal dysfunction 1Æ51 0Æ2371 1Æ11–2Æ06 0Æ0082
Anti-Scl70+ 1Æ80 0Æ2969 1Æ30–2Æ49 0Æ0004
ESR (per mm) 1Æ01 0Æ0039 1Æ00–1Æ02 0Æ0127
ESR (per 10 mm) 1Æ10 0Æ0428 1Æ02–1Æ19 0Æ0127
(Diffuse SSc vs. no diffuse SSc) given PAH+ 2Æ49 0Æ8624 1Æ26–4Æ91 0Æ0085
(Mouth involvement vs. no mouth involvement) given PAH) 1Æ62 0Æ2802 1Æ16–2Æ28 0Æ0052
(PAH+ vs. PAH)) given (no diffuse SSc, no mouth involvement) 1Æ84 0Æ5183 1Æ06–3Æ19 0Æ0309
(PAH+ vs. PAH)) given (diffuse SSc, no mouth involvement) 4Æ10 1Æ4109 2Æ08–8Æ05 < 0Æ0001
(Diffuse SSc and PAH+) vs. (no diffuse SSc and PAH)) given no 4Æ57 1Æ5111 2Æ39–8Æ74 < 0Æ0001
mouth involvement
(Diffuse SSc and PAH+ and mouth involvement) vs. (PAH) and 3Æ60 1Æ2044 1Æ87–6Æ94 0Æ0001
no diffuse SSc and no mouth involvement)

OR, odds ratio; CI, confidence interval; RP, Raynaud’s phenomenon; ESR, erythrocyte sedimentation rate; SSc, systemic sclerosis; PAH,
pulmonary arterial hypertension.

As patients with SSc do not present with just a single symp-
tom or one risk factor, it is clinically relevant to evaluate the
probability for DU when distinct combinations of more than
two of the above-mentioned risk factors are encountered in
one patient. We calculated that the risk for DU in the course
of the disease is highest (probability 88%) with the combin-
ation of male sex, an early onset of RP, an elevated ESR
> 30 mm h)1, anti-Scl70 antibodies and organ involve-
ment, i.e. the pulmonary artery system and the oesophagus.
A slight decrease of risk occurs with a higher age at onset
of RP (40 < 30 < 20 years of age) or a lower ESR
(10 < 20 < 30 < 40 mm h)1). A patient with the same com-
bination of risk factors except for the presence of ACA instead
of anti-Scl70 antibodies has a probability of only 63% for
developing ulcers. A female patient with anti-Scl70 antibodies
and the same combination of risk factors has a reduced proba-
bility of 78%. There was no difference between patients with
diffuse or limited skin sclerosis if they had the same antibody
or risk factor profile. PAH has a stronger effect than the
involvement of the oesophagus. Further organ involvement
(such as of the kidneys, heart or musculoskeletal system) does
not enhance the maximum risk.
Medication
According to the data retrieved from the DNSS registry about
46% of patients without ulcers and only 67% of the patients
with DU received a vasoactive medication (e.g. calcium chan-
nel blocker or iloprost) when they first presented to the DNSS
centres (P < 0Æ0001).
Among the treatments for ulcerations, calcium channel
blockers were the only therapy in 28% of patients (three
times as often as prostacyclins), and in only 12% were they
combined with other vasoactive medications (such as prosta-
cyclins, bosentan, sildenafil or an angiotensin receptor blocker).
Only 21% of patients already suffering from DU received
prostacyclins compared with 9% without DU. This is remark-
able because iloprost has been proven in several studies to
support the healing of ulcers.10 Sildenafil, another drug pro-
moting healing of DU, was given to 4%, while bosentan was
given to 6% of patients with DU (vs. 2Æ4% and 1Æ9% of
patients without DU, respectively). Altogether, only 24% of
patients with DU received prostacyclins or sildenafil.
Discussion
Multivariate analysis of datasets from 1881 patients with SSc
revealed that male sex, presence of PAH, involvement of the
oesophagus, the extent of skin sclerosis as assessed by the
mRSS, anti-Scl70 antibodies (but not ACA), young age at
onset of RP, and an elevated ESR represent significant risk fac-
tors for the occurrence of DU in SSc.
In the univariate analysis these factors and the presence of
the diffuse form of SSc, lung fibrosis and involvement of the
heart or upper gastrointestinal tract were significantly more
frequent among patients with DU and resulted in an elevated
relative risk for DU with an OR of 1Æ46 (involvement of upper
gastrointestinal tract) or 1Æ85 (male sex) and 2Æ23 (presence
of anti-Scl70 antibodies). A high total mRSS and mRSS of the
hands, and young age at the onset of RP, skin sclerosis or
organ involvement were also associated with DU.
The highest probability for DU in the course of the disease
(probability of 88%) is given by the combination of male sex,
an early onset of RP, an elevated ESR > 30 mm h)1, anti-
Scl70 antibodies and involvement of the pulmonary artery
system or the oesophagus.

 2009 The Authors

Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843

In the DNSS registry 408 patients (24Æ1%) had active DU
when first recruited. Former studies revealed a prevalence of
SSc in the population of about 40–200 per 100 000 (0Æ04–
0Æ2%). Extrapolation of our results indicates a prevalence of
SSc-related DU in the total population of 0Æ01–0Æ048%. Data
on frequencies, however, vary considerably in different stud-
ies,1–3 probably due to differences in climate and study
design.
This study did not assess the percentage of patients who
had either active DU or DU in the past which can amount to
35%.2 In a retrospective study of SSc, 65% of the patients
developed DU within 4 years of diagnosis.21
Our finding that patients with a limited form of disease suf-
fer less frequently from ulcers (22%) than patients with dif-
fuse sclerosis (34%) is in contrast to most previous studies
which reported a higher prevalence of DU in patients with the
limited form of the disease.7,22,23 One recent study, however,
also showed by univariate analysis (n = 3656) a higher fre-
quency of severe digital vasculopathy among patients with dif-
fuse SSc than among patients with limited SSc.24 We suggest
that the higher occurrence of DU in diffuse SSc compared
with limited SSc indicates that ulceration results not only from
local impairment of blood flow (reflected by RP), but also
from other pathological processes which in diffuse SSc, but
not in limited SSc, contribute to more organ complications.25
As the extent of skin sclerosis was consistently higher for
patients with the diffuse form of SSc, the higher mRSS in
patients with DU could be anticipated. This, however, does
not necessarily mean that the extent of sclerosis of the fingers
and hands must also be higher in patients with DU. Our anal-
ysis now shows that these patients do indeed have higher val-
ues for fibrosis on their hands according to the mRSS, thus
allowing the hypothesis that a higher grade of sclerosis of the
fingers and hands may favour the formation of DU. Although
this selective use of the mRSS for hands and fingers has not
been approved as a measurement of disease activity, it may
suggest a pathophysiological relationship because a higher
grade of sclerosis of the fingers and hands impedes blood flow
and wound healing and may favour the formation of DU.26
One factor that could have an influence on the outcome of
our analysis is the concomitant use of drugs. It is known that
iloprost and bosentan, for example, reduce the chance for
relapse of ulcers10–13 and that patients without vasodilatative
therapy could be at increased risk of developing DU.6 How-
ever, we found that therapy of severe RP often does not fully
exploit the available medications14 and that less than 25% of
patients with DU had received prostacyclins or sildenafil when
entered into the network registry. Therefore, a significant pro-
portion of patients in both groups had never been treated
with iloprost or other vasoactive drugs, in spite of severe RP
or DU.
Out of the factors that were significantly more frequent in
patients with DU according to univariate analysis, only
involvement of the heart and gastrointestinal tract and lung
fibrosis did not turn out to be possible risk factors in the
multivariate analysis. Notably, the involvement of muscles,
 2009 The Authors
Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843
Digital ulcers in systemic sclerosis, C. Sunderkötter et al. 841
kidneys or of the nervous system altogether was not associated
with a higher risk among patients with DU.
It may be surprising that the kidneys are not part of this
combination of risk factors despite their high vascularization
and propensity for severe involvement in SSc. However, so far
the pathophysiological or causal relationship between all the
listed factors and the development of DU is unclear. The same
is true for the pathophysiological relevance of male sex.
Previous studies on the risk factors for DU, performing
multivariate analysis of 103 patients with SSc, reported that
young age at onset of RP, high mRSS, lack of vasoactive ther-
apy and anti-Scl70 antibodies were the strongest independent
predictors for DU.6,24
A univariate analysis on 333 patients showed a higher prev-
alence of DU in patients with SSc who were male, and had
diffuse skin sclerosis and anti-Scl70 antibodies. A multivariate
analysis was not performed.5 Thus, these studies confirmed
some of the risk factors we identified by univariate analysis.
They did not, however, analyse associations of DU with other
organ manifestations of SSc. In addition, our analysis on 1881
patients detected a significantly higher frequency of DU in
patients with a high total mRSS and mRSS of the hands, with
young age at onset of RP, skin sclerosis or organ involvement,
lung fibrosis, and involvement of the heart or upper gastro-
intestinal tract.
A large study by the EULAR Scleroderma Trials and
Research (EUSTAR) network analysed demographic, clinical
and laboratory characteristics of disease presentation in subsets
of SSc using uni- and multivariate analysis on 3656 patients.
They found that late onset of RP was negatively associated
with DU.24
The high number of recruited patients with complete data-
sets allowed a large-scale statistical work-up and performance
of multivariate analysis in our study which is important for
assessing the degree by which individual factors or their com-
bination increase the probability for DU. This is relevant as
patients usually present with a number of disease symptoms
and thus with a combination of the described risk factors which
considerably increases the probability of developing or present-
ing with DU. The degree by which given factors would
increase this probability is also important for the decision on
how vigorously patients with secondary RP should be treated
(and at what costs one wants to treat) to prevent development
of DU. We revealed that diffuse skin sclerosis in combination
with PAH is the most powerful predictor for the occurrence or
development of DU, followed by male sex, anti-Scl70 anti-
bodies, PAH and involvement of mouth and oesophagus. Cor-
respondingly, we calculated that the highest probability for DU
(> 80%) is found in patients who are male, have an early onset
of RP (20 years of age), an elevated ESR > 30 mm h)1, pres-
ence of anti-Scl70 antibodies and involvement of the pulmo-
nary artery system and the oesophagus. It should be noted that
in women with the same combination of risk factors the proba-
bility is only slightly lower (77%) than in men, which is rele-
vant, because women present a much larger group of patients
with SSc (83% vs. 17% in the DNSS registry). In this context
842 Digital ulcers in systemic sclerosis, C. Sunderkötter et al.
the elevation of ESR could be secondary to the inflammatory
process associated with DU, or it could be a reflection of a gen-
erally higher inflammatory activity in these patients with SSc.
In conclusion, our results indicate that there is a distinct
constellation of organ involvement associated with a higher
risk of DU. Male sex, young age at onset of RP and anti-Scl70
antibodies are early and helpful factors associated with the
presence of DU, at a later stage complemented by PAH or
oesophagus dysfunction, and extensive skin sclerosis. These
results are of clinical relevance for counselling patients and for
considering prophylactic strategies for patients with secondary
RP who have not yet developed DU.
Taking into account that DU in the course of SSc are pain-
ful, slow to heal, difficult to treat, and prone to a severe indi-
vidual and high socioeconomic burden, discussion of the
possibilities and conditions for prophylactic treatment such as
an early vasoactive therapy is justified.
Acknowledgments
This study was supported by the German Federal Ministry of
Education and Research (BMBF) (01 GM 0310).
Co-authors of the study
M. Worm, P. Klaus (University Hospital Charité, Department
of Dermatology, Venereology and Allergology, Berlin, Ger-
many); A. Rubbert (University of Cologne, Department of
Rheumatology, Cologne, Germany); K. Steinbrink, Boris
Grundt (University of Mainz, Department of Dermatology,
Mainz, Germany); Rudolf Mierau (Rheumatology, University
of Aachen, Aachen, Germany); R. Hein (University of Munich,
Department of Dermatology and Allergology, Munich, Ger-
many); R. Hinrichs (University of Ulm, Department of Der-
matology and Allergology, Ulm, Germany); R.-M. Szeimies,
S. Karrer (University of Regensburg, Department of Dermatol-
ogy, Regensburg, Germany); A.M. Müller, R. Meyering (Uni-
versity of Regensburg, Department of Internal Medicine,
Regensburg, Germany); C. Seitz, E. Schmidt (University of
Würzburg, Department of Dermatology, Venereology and
Allergology, Würzburg, Germany); P. Lehmann (Private Uni-
versity Witten-Herdecke, HELIOS Klinikum Wuppertal, Depart-
ment of Dermatology, Allergology and Environmental
Medicine, Wuppertal, Germany); I. Foeldvári (Hospital Eilbek,
Hamburg, Germany); F. Reichenberger (Medical Clinic and
Outpatient Department II, University Hospital Gießen and
Marburg GmbH, Germany); L. Gross (Clinic for Rheumatol-
ogy, Bad Bramstedt, Germany); A. Kuhn, M. Haust (University
of Düsseldorf, Department of Dermatology, Düsseldorf, Ger-
many); K. Reich (Georg-August-University of Göttingen,
Department of Dermatology and Venerology, Göttingen, Ger-
many); M. Becker (Rheumatology and Clinical Immunology,
Charité, Berlin, Germany); P. Saar, T. Schmeiser (Department
of Rheumatology and Clinical Immunology, Justus-Liebig Uni-
versity Giessen, Kerckhoff Clinic, Bad Nauheim, Germany);
G. Fierlbeck, I. Kötter (University of Tübingen, Department of
Journal Compilation  2009 British Association of Dermatologists • British Journal of Dermatology 2009 160, pp835–843
Dermatology, Tübingen, Germany); H.-M. Lorenz, N. Blank
(University of Heidelberg, Department of Internal Medicine,
Heidelberg, Germany); K. Gräfenstein, A. Juche (Johanniter
Hospital in Fläming GmbH, Center of Rheumatology of Bran-
denburg, Germany); E. Aberer, G. Bali (University of Graz,
Department of Dermatology, Graz, Austria); C. Fiehn (Center
of Rheumatology, Department of Internal Medicine, Baden-
Baden, Germany); R. Stadler, V. Bartels (Clinic of Minden,
Department of Dermatology, Minden, Germany); M. Buslau
(Rheumaklinik Bad Säckingen ⁄Sanitas Alpenklinik Inzell, Ger-
many); J. Distler (Department of Internal Medicine III and
Institute for Clinical Immunology, University Hospital Erlan-
gen, Germany); M. Sticherling (Department of Dermatology,
University Hospital Leipzig, Germany).
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