This cohort study assesses the cutaneous and systemic manifestations of systemic sclerosis.
Key Points
Question
What are the clinical associations and prevalence of Degos-like lesions in patients with systemic sclerosis (SSc)?
Findings
In this cohort study of 506 patients with SSc, there was a 5.3% prevalence of Degos-like lesions. Patients with Degos-like lesions were more likely to have the diffuse cutaneous SSc subtype than patients without lesions, and Degos-like lesions were associated with cutaneous vascular complications, including acro-osteolysis, digital ulcers, and calcinosis.
Meaning
Findings of this study suggest the need for a prospective longitudinal study to examine the onset of Degos-like lesions and to elucidate whether they play a role in SSc.
Abstract
Importance
Degos-like lesions are cutaneous manifestations of a small-vessel vasculopathy that appear as atrophic, porcelain-white papules with red, telangiectatic borders. No study has adequately examined Degos-like lesions in patients with systemic sclerosis (SSc).
Objective
To characterize the serologic, cutaneous, and internal organ manifestations associated with Degos-like lesions in a large cohort of patients with SSc.
Design, Settings, and Participants
This retrospective cohort study involved adult patients with SSc who were seen at Stanford Rheumatologic Dermatology Clinic between January 1, 1998, and December 31, 2018. Participants fulfilled the 2013 classification criteria for SSc. Data analysis was conducted from February 1 to June 1, 2019.
Main Outcomes and Measures
Data on demographic characteristics; autoantibody status; clinical characteristics, including cutaneous and systemic manifestations of SSc; and presence of Degos-like lesions were collected.
Results
The cohort comprised 506 patients with SSc (447 females [88.3%]; mean [SD] age at first non–Raynaud disease symptoms, 46.1 [15.2] years). Twenty-seven patients (5.3%) had Degos-like lesions, of whom 24 (89.0%) had lesions affecting the fingers. Patients with Degos-like lesions were more likely to have diffuse cutaneous SSc compared with patients without lesions (15 [55.6%] vs 181 [37.8%]; P = .04). Degos-like lesions were also associated with acro-osteolysis (10 [37.0%] vs 62 [12.9%]; P < .01), digital ulcers (15 [55.6%] vs 173 [36.1%]; P = .04), and calcinosis (15 [55.6%] vs 115 [24.0%]; P < .01). While Degos-like lesions were not associated with internal organ manifestations, such as scleroderma renal crisis, interstitial lung disease, or pulmonary arterial hypertension, there was P < .10 for the association with gastric antral vascular ectasia.
Conclusions and Relevance
Results of this study suggest an association of Degos-like lesions with diffuse cutaneous SSc and other cutaneous manifestations of vasculopathy, including acro-osteolysis, calcinosis, and digital ulcers. A prospective longitudinal study is warranted to examine the onset of Degos-like lesions and to elucidate whether these lesions play a role in SSc.
Introduction
Degos disease is a rare small-vessel vasculopathy characterized by skin lesions that are atrophic, porcelain-white papules with red, telangiectatic borders. It can present in a cutaneous or fatal systemic form, in which death most commonly results from gastrointestinal perforation or cerebral infarction.1 The literature suggests that endothelial dysfunction and immune dysregulation play a role in the pathogenesis. Degos-like lesions have been reported in autoimmune connective tissue diseases (ACTDs), including systemic sclerosis (SSc), and some researchers speculate that Degos-like lesions may represent a manifestation of vascular injury associated with the underlying condition.2,3
Vascular injury is a prominent feature of SSc, an immune-mediated disease characterized by skin and internal organ fibrosis. Subsequent tissue damage can result in vascular complications, including critical digital ischemia, gastric antral vascular ectasia (GAVE), scleroderma renal crisis (SRC), and pulmonary arterial hypertension (PAH). In this cohort study, we sought to characterize the serologic, cutaneous, and internal organ manifestations associated with Degos-like lesions in a large cohort of patients with SSc.
Methods
Study Design and Patient Population
We performed a retrospective cohort study of patients with SSc who were seen at Stanford Rheumatologic Dermatology Clinic between January 1, 1998, and December 31, 2018. All patients were at least 18 years of age and fulfilled the 2013 classification criteria for SSc of the American College of Rheumatology and European League Against Rheumatism (now European Alliance of Associations for Rheumatology). The Stanford University Institutional Review Board approved the study protocol. Patients provided written informed consent to have their data collected for the clinical database, and deidentified patient data were collected from the electronic medical records of Stanford University Hospital. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.
Data Collection
Demographic data (including race and ethnicity, which were self-reported from a list of categories: African American or Black, Asian, Pacific Islander, White, other [Hispanic], and unknown), clinical characteristics, and autoantibody profiles were collected from the electronic medical records. Information regarding cutaneous findings (telangiectasia, digital ulcer, acro-osteolysis, pitting scar, nailfold capillary abnormality, calcinosis, and digital ischemia) and systemic manifestations, such as PAH, GAVE, interstitial lung disease (ILD), and SRC, were collected. Clinical features were recorded as present if they ever occurred up to the most recent follow-up date.
Degos-like lesions were clinically diagnosed and documented by attending dermatologists (M.A.L. and D.F.F.) and a rheumatologist (L.C.). At least 1 clinician (L.C.) examined every patient at each visit. Presence of Degos-like lesions was confirmed by medical record review of the terms Degos lesions, atrophic papulosis, or porcelain-white atrophic centers surrounded by erythematous telangiectatic rim.
Results of the antinuclear antibody titer were positive if the level was 1:80 or higher by immunofluorescence assay. Pulmonary arterial hypertension was diagnosed if the mean pulmonary artery pressure was 20 mm Hg or higher with a mean pulmonary capillary wedge pressure of 15 mm Hg or lower via right heart catheterization, or if the right ventricular systolic pressure was over 40 mm Hg on transthoracic echocardiography. Gastric antral vascular ectasia was confirmed on upper endoscopy. Scleroderma renal crisis was characterized by thrombotic microangiopathy with hypertension and acute kidney injury. Interstitial lung disease was defined by ground glass, reticular, and/or fibrotic changes detected on high-resolution computed tomography of the chest.
Statistical Analysis
Demographic characteristics, autoantibody status, and cutaneous and internal organ manifestations of patients with or without Degos-like lesions were compared using χ2 tests for categorical variables, an unpaired, 2-tailed t test for age, and Wilcoxon rank sum test for duration of follow-up. For internal organ vasculopathy manifestations, including GAVE, PAH, and SRC, we applied univariate logistic regression analyses and retained variables with P < .10 for multivariate analyses. Only GAVE showed a P < .10 for the association with GAVE; thus, univariate and multivariate logistic regression models were performed to evaluate whether Degos-like lesions were indicators of GAVE. Due to the small event number, 1 covariate was chosen for the final model.
All tests were 2-sided, and P < .05 was considered to be statistically significant. All analyses were performed with SAS, version 9.4 (SAS Institute Inc). Data analysis was conducted from February 1 to June 1, 2019.
Results
A total of 506 patients fulfilled the 2013 American College of Rheumatology and European League Against Rheumatism classification criteria for SSc. The cohort was composed of 447 females (88.3%) and 59 males (11.7%), with a mean (SD) age at first non–Raynaud disease symptoms of 46.1 (15.2) years. There was no significant difference in median duration of follow-up from onset of non–Raynaud disease symptoms between patients without vs with Degos-like lesions. Over half of the cohort (300 patients [59.3%]) had White race and ethnicity, and 23 (4.5%) had African American or Black, 69 (13.6%) had Asian, 2 (0.4%) had Pacific Islander, 85 (16.8%) had other, and 27 (5.3%) had unknown race and ethnicity (Table 1). Approximately 40% of the cohort had diffuse cutaneous SSc.
Table 1. Demographic Characteristics and Clinical Features of Patients With Systemic Sclerosis.
| Variable | Patients, No. (%) | P value | |
|---|---|---|---|
| Without Degos-like lesions (n = 479) | With Degos-like lesions (n = 27) | ||
| Demographic characteristics | |||
| Sex | |||
| Male | 56 (11.7) | 3 (11.1) | >.99 |
| Female | 423 (88.3) | 24 (88.9) | |
| Age at onset, mean (SD)a | 46.1 (15.2) | 46.0 (14.9) | .92 |
| Race and ethnicity | |||
| African American or Black | 23 (4.5) | 0 | .36 |
| Asian | 67 (14.0) | 2 (7.4) | |
| Pacific Islander | 2 (0.4) | 0 | |
| White | 278 (58.0) | 22 (81.5) | |
| Otherb | 82 (17.1) | 3 (11.1) | |
| Unknown | 27 (5.3) | 0 | |
| Follow-up duration, median (range)a | 10.3 (0.7-63.7) | 10.5 (3.3-28.6) | .66 |
| Deceased | |||
| No | 394 (82.3) | 22 (81.5) | .80 |
| Yes | 84 (17.5) | 5 (18.5) | |
| Clinical features | |||
| Skin subtype | |||
| Limitedc | 284 (59.3) | 10 (37.0) | .04 |
| Diffuse | 181 (37.8) | 15 (55.6) | |
| Ever smoker | |||
| No | 313 (65.3) | 22 (81.5) | .11 |
| Yes | 155 (32.4) | 5 (18.5) | |
| ANA | |||
| Negative result | 57 (11.9) | 2 (7.4) | .76 |
| Positive result | 393 (82.1) | 23 (85.2) | |
| Anticentromere | |||
| Negative result | 258 (53.9) | 11 (40.7) | .22 |
| Positive result | 151 (31.5) | 11 (40.7) | |
| Anti-Scl-70 | |||
| Negative result | 341 (71.2) | 15 (55.6) | .11 |
| Positive result | 90 (18.8) | 8 (29.6) | |
| Anti-RNA polymerase III | |||
| Negative result | 158 (33.0) | 10 (37.0) | >.99 |
| Positive result | 53 (11.1) | 3 (11.1) | |
| Anti-PM/Scl | |||
| Negative result | 180 (37.6) | 11 (40.7) | .29 |
| Positive result | 15 (3.1) | 2 (7.4) | |
| Anti-U1RNP | |||
| Negative result | 319 (66.6) | 18 (66.7) | .32 |
| Positive result | 42 (8.8) | 4 (14.8) | |
| Cutaneous telangiectasias | |||
| Absent | 159 (33.2) | 4 (14.8) | .06 |
| Present | 317 (66.2) | 23 (85.2) | |
| Digital ulcers | |||
| Absent | 304 (63.5) | 12 (44.4) | .04 |
| Present | 173 (36.1) | 15 (55.6) | |
| Acro-osteolysis | |||
| Absent | 417 (87.1) | 17 (63.0) | <.001 |
| Present | 62 (12.9) | 10 (37.0) | |
| Digital pitting scar | |||
| Absent | 234 (48.9) | 11 (40.7) | .25 |
| Present | 113 (23.6) | 9 (33.3) | |
| Nailfold capillary abnormalities | |||
| Absent | 112 (23.4) | 7 (25.9) | .88 |
| Present | 326 (68.1) | 19 (70.4) | |
| Calcinosis | |||
| Absent | 348 (72.7) | 12 (44.4) | <.001 |
| Present | 115 (24.0) | 15 (55.6) | |
| Digital ischemic loss | |||
| Absent | 340 (71.0) | 22 (81.5) | .39 |
| Present | 51 (10.7) | 5 (18.5) | |
| SRC | |||
| Absent | 452 (94.4) | 26 (96.3) | >.99 |
| Present | 24 (5.0) | 1 (3.7) | |
| Cancer ever | |||
| Absent | 420 (87.7) | 22 (81.5) | .54 |
| Present | 57 (11.9) | 4 (14.8) | |
| ILD | |||
| Absent | 281 (58.7) | 12 (44.4) | .20 |
| Present | 180 (37.6) | 13 (48.2) | |
| PAH | |||
| Absent | 369 (77.0) | 20 (74.1) | .80 |
| Present | 95 (19.8) | 4 (14.8) | |
| GAVE | |||
| Absent | 458 (95.6) | 24 (88.9) | .09 |
| Present | 20 (4.2) | 3 (11.1) | |
Abbreviations: ANA, antinuclear antibody; GAVE, gastric antral vascular ectasia; ILD, interstitial lung disease; PAH, pulmonary arterial hypertension; SRC, scleroderma renal crisis.
Measured in years from first non–Raynaud disease symptoms.
Other category included Hispanic.
Included patients with sine sclerosis.
Twenty-seven of 506 patients (5.3%) had Degos-like lesions, of whom 24 (89.0%) had lesions affecting the fingers (Figure). Three of 27 patients (11.1%) had Degos-like lesions involving the lower extremities. The number of lesions was specified in 21 patients, with a median (range) of 2 (1-6) lesions per patient. Thirteen of 27 patients (48.1%) had at least 3 Degos-like lesions. Of 19 patients with multiple lesions that were specifically localized, 11 (57.9%) had symmetrically distributed lesions (ie, bilateral fingers). Twenty-four of the 27 patients (89.0%) were female, and 3 (11.1%) were male. Patients with Degos-like lesions were more likely to have diffuse cutaneous SSc compared with those without lesions (15 [55.6%] vs 181 [37.8%]; P = .04) (Table 1).
Figure. Examples and Locations of Degos-Like Lesions in Patients With Systemic Sclerosis.
Degos-like lesions were associated with acro-osteolysis (10 [37.0%] vs 62 [12.9%]; P < .01), digital ulcers (15 [55.6%] vs 173 [36.1%]; P = .04), and calcinosis (15 [55.6%] vs 115 [24.0%]; P < .01). While Degos-like lesions were not associated with internal organ manifestations, such as SRC, ILD, or PAH, there was P = .09 for the association with GAVE (Table 1). Multivariate logistic regression confirmed a P < .10 for the association between Degos-like lesions and GAVE and that a positive result for RNA polymerase III antibody was an indicator of GAVE (odds ratio, 8.25; 95% CI, 2.70-25.20; P < .001), as previously reported4 (Table 2).
Table 2. Logistic Regression Models.
| Clinical feature | OR for GAVE (95% CI) | P value |
|---|---|---|
| Univariate logistic regression | ||
| ANA: positive vs negative result | 0.37 (0.14-0.98) | .045 |
| Anti-RNA polymerase III: positive vs negative result | 7.97 (2.63-24.12) | <.001 |
| SRC: positive vs negative result | 4.59 (1.43-14.70) | .01 |
| Degos-like lesions: positive vs negative result | 2.86 (0.80-10.31) | .11 |
| Multivariate logistic regression | ||
| Anti-RNA polymerase III: positive vs negative result | 8.25 (2.70-25.20) | <.001 |
| Degos-like lesions: positive vs negative result | 3.16 (0.81-12.38) | <.10 |
Abbreviations: ANA, antinuclear antibody; GAVE, gastric antral vascular ectasia; OR, odds ratio; SRC, scleroderma renal crisis.
Discussion
There have been limited case reports of Degos-like lesions in patients with ACTDs.2,3 Some studies have hypothesized that Degos-like lesions may be a manifestation of vascular injury associated with the underlying autoimmune condition.2 To further investigate this association in SSc, we examined the serologic, cutaneous, and internal organ manifestations associated with Degos-like lesions. In a cohort of 506 patients with SSc, we found that the prevalence of Degos-like lesions was 5.3%. These lesions were associated with diffuse cutaneous SSc, digital ulcers, calcinosis, and acro-osteolysis.
While Degos disease has been reported more frequently in men, Degos-like lesions in ACTD have been reported more frequently in women, as found in the present cohort, which likely reflects the female predominance of many autoimmune conditions.5 Most lesions appeared along the fingers, with a few presenting in the lower extremities, primarily the ankles or knees. In previous case reports of Degos disease, the cutaneous lesions were distributed in the trunk and limbs.1,2,3 However, Degos-like lesions may have a predilection for extremities in ACTD, as found in this cohort and in case reports of Degos-like lesions in systemic lupus erythematosus, SSc, and dermatomyositis.2,5,6 We hypothesized that this finding may be associated with the greater degree of ischemia in distal extremities.
In this cohort, Degos-like lesions were associated with calcinosis, which were more prevalent in distal extremities and areas prone to trauma.7 Degos-like lesions were also associated with acro-osteolysis and digital ulcers, which was consistent with previous associations of calcinosis with acro-osteolysis and digital ischemia in SSc.8,9 While the pathophysiological process behind calcinosis is not fully understood, there is evidence that chronic inflammation, hypoxia, recurrent trauma, and bone matrix protein abnormalities are contributing factors.10 Acro-osteolysis is also more prevalent in the digits and is associated with worse vascular disease in SSc.9 The association of Degos-like lesions with calcinosis, acro-osteolysis, and digital ulcers, therefore, suggests that vasculopathy may be the pathogenetic mechanism underlying these cutaneous manifestations. Although Degos-like lesions were not indicators of macrovascular complications of SSc, such as PAH, we found that the association with GAVE approached P < .10 in multivariate analyses (Table 2).
Additionally, there is evidence of innate immune system dysfunction in Degos disease and SSc.11,12 Tissue biopsies of patients with Degos disease have revealed increased expression of MxA, a type I interferon (IFN)–inducible protein, signifying upstream IFN-alpha dysregulation, and C5b-9 membrane attack complex vascular deposition, suggesting complement-mediated injury to endothelial cells.11 Similarly, SSc has been associated with dysregulated IFN-regulated transcripts, and increased activation of type I IFN-inducible genes has been found in the peripheral blood and skin of patients with SSc.12
Limitations
Study limitations included the lack of data on SSc disease duration at onset of Degos-like lesions and lack of skin biopsy results, since most Degos-like lesions were located on fingers where there was poor wound healing in SSc. A prospective longitudinal study is warranted to confirm the incidence of Degos-like lesions in SSc and to elucidate the role of Degos-like lesions in systemic vascular disease.
Conclusions
To our knowledge, this cohort study was the first to examine Degos-like lesions in patients with SSc and showed an association with diffuse cutaneous SSc and cutaneous features of vasculopathy.
Data Sharing Statement
References
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Supplementary Materials
Data Sharing Statement
