This cohort study uses data from the Epidermolysis Bullosa Clinical Characterization and Outcomes Database to analyze the timing of clinical diagnosis and major clinical events in patients with epidermolysis bullosa from North America.
Key Points
Question
What are the clinical trajectories of patients with epidermolysis bullosa, specifically regarding the timing of diagnosis and subsequent major clinical events?
Findings
In this cohort study of 644 patients with epidermolysis bullosa, patients with recessive dystrophic epidermolysis bullosa were the most likely to receive a clinical diagnosis at birth if they had signs of disease at birth, and patients with junctional epidermolysis bullosa had the highest rate of confirmatory testing.
Meaning
The findings suggest that diagnostic testing for epidermolysis bullosa is more common for patients with severe phenotypes; understanding the course of major clinical events may enable improved counseling on prognosis and management of epidermolysis bullosa.
Abstract
Importance
Children with epidermolysis bullosa (EB) comprise a rare population with high morbidity and mortality. An improved understanding of the clinical trajectory of patients with EB, including age at time of clinical diagnosis and major clinical events, is needed to refine best practices and improve quality of life and clinical outcomes for patients with EB.
Objectives
To describe demographics, clinical characteristics, milestone diagnostic and clinical events (such as initial esophageal dilation), and outcomes in patients with EB using the Epidermolysis Bullosa Clinical Characterization and Outcomes Database and to determine what characteristics may be associated with overall EB severity and/or disease progression.
Design, Setting, and Participants
This cohort study included data on patients with EB who were enrolled in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database from January 1, 2011, to June 30, 2017; 17 participating EB centers in the United States and Canada contributed data to this study.
Exposures
Type of EB, including recessive dystrophic epidermolysis bullosa (RDEB), junctional epidermolysis bullosa (JEB), dominant dystrophic epidermolysis bullosa (DDEB), and epidermolysis bullosa simplex (EBS).
Main Outcomes and Measures
Demographic information, clinical characteristics (including age at onset of signs of EB and subsequent clinical diagnosis), types of diagnostic testing performed, and milestone clinical events for patients with RDEB.
Results
Of 644 enrolled patients from 17 sites included in this study, 323 were male (50.2%), with a mean (SD) age of 14.4 (11.7) years; 283 (43.9%) had RDEB, 194 (30.1%) had EBS, 104 (16.2%) had DDEB, and 63 (9.8%) had JEB. Signs of disease were present at birth in 202 patients with RDEB (71.4%), 39 with JEB (61.9%), 60 with DDEB (57.7%), and 74 with EBS (38.1%). For those with signs of disease at birth, a clinical diagnosis was made at the time of birth in 135 patients with RDEB (67.0%), 31 with DDEB (52.6%), 35 with EBS, (47.3%) and 18 with JEB (46.2%). Patients with JEB had the highest rate of any confirmatory testing (51 of 63 [81.0%]), followed by RDEB (218 of 283 [77.0%]), DDEB (71 of 104 [68.3%]), and EBS (100 of 194 [51.5%]). For all types of EB, both electron microscopy and immunofluorescence microscopy were performed at younger ages than genetic analysis. Among 283 patients with RDEB, 157 (55.5%) had esophageal dilation, 104 (36.7%) had gastrostomy tube placement, 62 (21.9%) had hand surgery, 18 (6.4%) developed squamous cell carcinoma, and 19 (6.7%) died.
Conclusions and Relevance
The findings suggest that diagnostic testing for EB is more common for patients with severe phenotypes. Earlier diagnostic testing may enable improved characterizations of patients so that appropriate counseling and clinical care may be offered, especially pertaining to milestone events for those with RDEB.
Introduction
Epidermolysis bullosa (EB) is a group of rare genetic disorders characterized by fragility of the skin and mucosa. The disease affects approximately 1 of 50 000 births in the United States.1,2 Clinical disease severity ranges from mild to devastating, and there is no widely available, disease-modifying treatment or cure for any form of EB at this time.3,4 Although several trials of emerging therapies are under way, the timeline for such treatments is in future years in most cases.3,5,6,7,8 In parallel with such efforts, research that advances our understanding of the clinical trajectory of patients with EB, including their diagnosis, clinical care, and major clinical events and outcomes is needed.9,10,11 We have termed these outcomes milestone events to connote key events in the clinical course of an individual with EB. Events include when and how the patient’s diagnosis was made and was confirmed as well as objective interventions, such as placement of a gastrostomy tube, which may be a marker of disease severity or progression.1,12,13,14,15
Because of the rarity of EB, creating a generalizable understanding of real-world care and variation in care has been difficult, especially for milestone clinical events in the disease process. Little evidence exists to guide best practices related to these events. For example, objective guidance is lacking for the appropriate time to place a gastrostomy tube when a child shows signs of nutritional failure13,16 or when to perform hand surgery to repair contractures and pseudosyndactyly.12,15 By anticipating the timing of such interventions in patients with different types of EB, potentially modifiable targets for intervention can better be anticipated and more reliable information to counsel patients and parents about prognosis can be used.
The Epidermolysis Bullosa Clinical Research Consortium is a collaborative clinical research group that was initially formed in 2010. The consortium now includes 20 sites in the United States and Canada and functions as the EB working group of the Pediatric Dermatology Research Alliance. The principal investigator of each consortium site is a dermatologist (most commonly, a board-certified pediatric dermatologist) who treats patients with EB. The EB care at each site is provided in a general dermatology clinic or a dedicated EB clinic, which often includes multiple specialists with an interdisciplinary approach. Each Epidermolysis Bullosa Clinical Research Consortium site collaborates in the Epidermolysis Bullosa Clinical Characterization and Outcomes Database (EBCCOD) to catalog well-described patient cohorts with EB for future studies and to generate longitudinal data about the course, complications, and treatment of patients with EB.17
The primary objective of this study was to describe the patients with EB within the EBCCOD, specifically reporting patient demographic information, clinical characteristics (including patient age at initial signs of EB and at clinical diagnosis), types of diagnostic testing performed, and milestone events for patients with recessive dystrophic EB (RDEB). This study gives the types of patients with EB presenting to pediatric dermatologists and EB centers to highlight gaps in the diagnosis of EB and to provide a summary of major interventions for patients with RDEB and when they occur. In addition, this study sought to build the foundation for subsequent longitudinal analyses of the association of patient characteristics and clinical care with specific milestone events to identify key targets and timing for clinical interventions and evaluation of effectiveness.
Methods
Design and Data Source
The EBCCOD is a Research Electronic Data Capture database that is housed and managed at the University of Colorado, Denver, at the Anschutz Medical Campus in Aurora, Colorado. Each participating site has approval from its local institutional review board for participation in the database, and patients gave written informed consent and enrolled as they presented for care. Data collection is ongoing and typically occurs at major annual or biannual patient clinic visits. Data are collected contemporaneously during clinic visits and through review of medical records and are entered into the database. Clinical assessments include the use of the patient-directed symptom questionnaires and outcome instruments to document clinical signs and patient-reported symptoms and disease severity.18 For this study, deidentified data were exported from Research Electronic Data Capture and analyzed. This study was approved by the Colorado Multiple Institutional Review Board, Aurora, Colorado.
Study Population
This study included patients enrolled in the EBCCOD with completed demographic and milestone event data. Seventeen participating EB centers in the United States and Canada contribute data to the EBCCOD. All patients who provided consent and enrolled from January 1, 2011, through June 30, 2017, were eligible. Types of EB were categorized as RDEB, junctional EB (JEB), dominant dystrophic EB (DDEB), and EB simplex (EBS). We excluded 41 patients without a reported diagnosis of EB type because major diagnosis type was needed to complete the planned analyses. We also excluded 3 patients with Kindler syndrome because of the rarity of the disorder.
Milestone Clinical Events and Clinical Outcomes
Baseline demographic and clinical characteristics, stratified by EB type, included (1) age, sex, race/ethnicity, and primary site of care; (2) patient age at initial signs of EB (such as blisters, erosions or wounds, and oral mucosal changes); (3) patient age at initial clinical diagnosis; (4) age at which confirmatory testing (electron microscopy [EM], immunofluorescence microscopy [IFM], or genetic analysis) was performed; and (5) proportion of patients with confirmatory testing. Because genetic analysis has become more widely available during the past decade, we also analyzed the proportion of patients who underwent genetic analysis and were younger than 10 years during the study period.19 When possible, actual dates were obtained and ages were calculated. Categorical data were used for age at onset of first clinical signs and initial clinical diagnosis because this often relied on patient and/or parent recall and accurate dates were not always available.
Only the first occurrence of events that may occur more than once during a patient’s lifetime was reported. For all patients, we reported whether aplasia cutis (absence of skin) was present at birth and whether an enrolled patient had died during the study period. Additional events for patients with RDEB were esophageal dilation, gastrostomy tube placement, hand surgery to release contractures and pseudosyndactaly, and diagnosis of squamous cell carcinoma.1,12,13,14,15 We chose to focus on these events in patients with RDEB only because they are uncommon in patients with other forms of EB and may be associated with the course of disease progression in RDEB.
Statistical Analysis
Missing data were counted as unknown or negative responses depending on the variable. To generate descriptive statistics, we calculated percentages, proportions, and means of the outcomes of interest described above. A 2-sided P = .05 was set a priori to represent a statistically significant difference. We used t tests, tests of proportions, and χ2 tests to assess for differences in demographic and clinical characteristics by type of EB. All statistical analyses were performed using Stata, version 15.1 (StataCorp).
Results
Within the EBCCOD
Of the 644 enrolled patients from 17 sites included in this study, 323 (50.2%) were male, with a mean (SD) age of 14.4 (11.7) years. The median study time that each patient contributed to the EBCCOD was 3.7 years (interquartile range [IQR], 1.6-5.1 years). Among the enrolled patients, 194 (30.1%) had EBS, 63 (9.8%) had JEB, 104 (16.2%) had DDEB, and 283 (43.9%) had RDEB. Patient demographics varied by the type of EB (Table 1). For each type of EB, the EBCCOD contained patients of all ages, although patients older than 10 years consisted of 59 patients with DDEB (56.7%) and 189 patients with RDEB (66.8%). There were no significant differences in sex across types of EB. For all types, enrolled patients were primarily white race (430, [66.8%]) (except patients with JEB) and not of Hispanic or Latino ethnicity. In addition, 316 (49.2%) of all patients received care from 3 referral EB centers. The EBCCOD includes records of 32 patients (5.0%) who died during the study period. Of the 32 decedents, 19 (59.4%) had RDEB with a median age at death of 17.9 years (IQR, 8.2-21.5 years), 12 (37.5%) had JEB with a median age at death of 0.5 years (IQR, 0.3-0.9 years), and 1 (3.1%) had EBS.
Table 1. Patient Demographics in Epidermolysis Bullosa Clinical Characterization and Outcomes Database.
| Characteristic | Type of Epidermolysis Bullosa, Patients, No. (%) | ||||
|---|---|---|---|---|---|
| Total (N = 644) | EBS (n = 194) | JEB (n = 63) | DDEB (n = 104) | RDEB (n = 283) | |
| Age as of July 1, 2017, y | |||||
| <1 | 19 (3.0) | 6 (3.1) | 4 (6.4) | 5 (4.8) | 4 (1.4) |
| 1-9 | 263 (40.8) | 95 (49.0) | 38 (60.3) | 40 (38.5) | 90 (31.8) |
| 10-19 | 220 (34.2) | 65 (33.5) | 14 (22.2) | 30 (28.9) | 111 (39.2) |
| 20-29 | 81 (12.6) | 12 (6.2) | 2 (3.2) | 13 (12.5) | 54 (19.1) |
| 30-39 | 30 (4.7) | 9 (4.6) | 2 (3.2) | 6 (5.8) | 13 (4.6) |
| 40-49 | 21 (3.3) | 5 (2.6) | 1 (1.6) | 7 (6.7) | 8 (2.8) |
| ≥50 | 10 (1.6) | 2 (1.0) | 2 (3.2) | 3 (2.9) | 3 (1.1) |
| Sex | |||||
| Male | 323 (50.2) | 102 (52.6) | 29 (46.0) | 46 (44.2) | 146 (51.6) |
| Female | 321 (49.8) | 92 (47.4) | 34 (54.0) | 58 (55.8) | 137 (48.4) |
| Race | |||||
| American Indian/Alaska Native | 4 (0.6) | 0 | 2 (3.2) | 1 (1.0) | 1 (0.4) |
| Asian | 35 (5.4) | 5 (2.6) | 4 (6.3) | 5 (4.8) | 21 (7.4) |
| Native Hawaiian/Pacific Island | 1 (0.2) | 1 (0.5) | 0 | 0 | 0 |
| Black/African American | 38 (5.9) | 14 (7.2) | 7 (11.1) | 11 (10.6) | 6 (2.1) |
| White | 430 (66.8) | 141 (72.7) | 31 (49.2) | 67 (64.4) | 191 (67.5) |
| Middle Eastern/North African | 55 (8.5) | 7 (3.6) | 12 (19.1) | 6 (5.8) | 30 (10.6) |
| Unknown | 81 (12.6) | 26 (13.4) | 7 (11.1) | 14 (13.4) | 34 (12.0) |
| Ethnicity | |||||
| Not Hispanic or Latino | 456 (70.8) | 145 (74.8) | 52 (82.5) | 74 (71.1) | 185 (65.4) |
| Hispanic or Latino | 106 (16.5) | 22 (11.3) | 4 (6.4) | 11 (10.6) | 69 (24.4) |
| Ashkenazi Jewish | 4 (0.6) | 1 (0.5) | 0 | 1 (1.0) | 2 (0.7) |
| Unknown | 78 (12.1) | 26 (13.4) | 7 (11.1) | 18 (17.3) | 27 (9.5) |
| Primary epidermolysis bullosa center | |||||
| Cincinnati Children’s Hospital | 156 (24.2) | 42 (21.7) | 19 (30.2) | 22 (21.2) | 73 (25.8) |
| Children’s Hospital Colorado | 81 (12.6) | 28 (14.4) | 3 (4.8) | 14 (13.5) | 36 (12.7) |
| Lucile Packard Children’s Hospital Stanford | 79 (12.4) | 20 (10.3) | 4 (6.3) | 5 (4.8) | 50 (18.0) |
| Hospital for Sick Children | 59 (9.2) | 22 (11.4) | 6 (9.5) | 12 (11.5) | 19 (6.7) |
| University of Massachusetts | 55 (8.6) | 17 (8.8) | 6 (9.5) | 11 (10.6) | 21 (7.4) |
| University of Minnesota | 45 (6.8) | 5 (2.6) | 10 (15.9) | 7 (6.7) | 23 (7.8) |
| Columbia University Medical Center | 38 (5.9) | 12 (6.2) | 1 (1.6) | 9 (8.6) | 16 (5.7) |
| Lurie Children’s Hospital | 36 (5.6) | 13 (6.7) | 5 (7.9) | 7 (6.7) | 11 (3.9) |
| CHU Sainte-Justine | 22 (3.4) | 13 (6.7) | 2 (3.2) | 4 (3.8) | 3 (1.1) |
| Rady Children’s Hospital | 20 (3.1) | 5 (2.6) | 4 (6.3) | 4 (3.8) | 7 (2.5) |
| Phoenix Children’s Hospital | 9 (1.4) | 3 (1.5) | 0 | 2 (1.9) | 4 (1.4) |
| Dell Children’s Medical Center | 9 (1.4) | 3 (1.5) | 0 | 1 (1.0) | 5 (1.8) |
| University of Miami | 8 (1.2) | 3 (1.5) | 1 (1.6) | 0 | 4 (1.4) |
| Children’s Hospital of San Antonio | 8 (1.2) | 0 | 1 (1.6) | 1 (1.0) | 6 (2.1) |
| Washington University in St Louis | 6 (0.9) | 4 (2.1) | 0 | 1 (1.0) | 1 (0.3) |
| Henry Ford Hospital | 5 (0.8) | 3 (1.5) | 0 | 1 (1.0) | 1 (0.3) |
| State University of New York Downstate Medical Center | 2 (0.3) | 0 | 1 (1.6) | 1 (1.0) | 0 |
| Unknown | 6 (0.9) | 1 (0.5) | 0 | 2 (1.9) | 3 (1.1) |
| Vital status after enrollment | |||||
| Living | 590 (91.6) | 183 (94.3) | 50 (79.4) | 101 (97.1) | 256 (90.5) |
| Deceased | 32 (5.0) | 1 (0.5) | 12 (19.0) | 0 | 19 (6.7) |
| Unknown | 22 (3.4) | 10 (5.2) | 1 (1.6) | 3 (2.9) | 8 (2.8) |
Abbreviations: DDEB, dominant dystrophic epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa.
Patient Age at Onset of Clinical Symptoms and Subsequent Clinical Diagnosis
Symptoms were present at birth in most patients with RDEB (202 of 283 [71.4%]), JEB (39 of 63 [61.9%]), and DDEB (60 of 104 [57.7%]), but not for EBS (74 of 194 [38.1%]) (Table 2). The incidence of aplasia cutis at birth was significantly higher among patients with RDEB (172 [60.6%]) compared with other types of EB (DDEB, 15 of 104 [14.4%]; JEB, 7 of 63 [11.1%]; and EBS, 26 of 194 [13.4%]). By the first year of life, signs were present in most patients with RDEB (220 [77.8%]), JEB (51 [81.0%]), DDEB (83 [79.8%]), and EBS (132 [68.0%]). Some patients with EBS (18 [9.3%]) did not exhibit signs until after 1 year of life. For a proportion of patients with each EB type, the timing of onset of clinical symptoms was unknown. The lag time between the onset of clinical signs and a subsequent clinical diagnosis varied based on the type of EB. For those with signs at birth, a clinical diagnosis of EB was made at the time of birth in patients with RDEB (135 [67.0%]), JEB (18 [46.2%]), DDEB (31 [52.6%]), and EBS (35 [47.3%]). Although the majority of patients received a clinical diagnosis within the first year of life, a smaller number within each category did not receive a diagnosis until they were older than 1 year (RDEB, 18 [6.4%]; DDEB, 8 [7.7%]; JEB, 8 [12.7%]; and EBS, 39 [20.1%]). A diagnosis of EB in a parent was known for 47 patients with DDEB (45.2%) and 85 patients with EBS (43.8%); DDEB and EBS are autosomal dominant disorders, and testing the child is not necessary if the parent has a known diagnosis.
Table 2. Clinical Signs and Diagnosis of Epidermolysis Bullosa, by Age.
| Patient Age | Type of Epidermolysis Bullosa, No. (%) | |||
|---|---|---|---|---|
| EBS (n = 194) | JEB (n = 63) | DDEB (n = 104) | RDEB (n = 283) | |
| Age at onset of first clinical signs, y | ||||
| Prenatal | 0 | 0 | 1 (1.0) | 1 (0.4) |
| Birth | 74 (38.1) | 39 (61.9) | 59 (56.7) | 201 (71.0) |
| <1 y | 58 (29.9) | 12 (19.1) | 23 (22.1) | 18 (6.4) |
| >1 y | 18 (9.3) | 1 (1.6) | 2 (1.9) | 5 (1.8) |
| Unknown | 44 (22.7) | 11 (17.4) | 19 (18.3) | 58 (20.4) |
| Age at time of clinical diagnosis, y | ||||
| Prenatal | 0 | 2 (3.1) | 2 (1.9) | 3 (1.0) |
| Birth | 35 (18.1) | 19 (30.2) | 31 (29.8) | 136 (48.1) |
| <1 y | 74 (38.1) | 26 (41.3) | 45 (43.3) | 65 (23.0) |
| >1 y | 39 (20.1) | 8 (12.7) | 8 (7.7) | 18 (6.4) |
| Unknown | 46 (23.7) | 8 (12.7) | 18 (17.3) | 61 (21.5) |
Abbreviations: DDEB, dominant dystrophic epidermolysis bullosa; EBS, epidermolysis bullosa simplex; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa.
Confirmatory Laboratory Diagnostic Testing and Subtype Classification
The percentage of patients with confirmatory laboratory testing (EM, IFM, or genetic analysis) to characterize EB subtype varied by type of EB (Table 3). Patients with JEB had the highest rate of any confirmatory testing (51 of 63 [81.0%]), followed by RDEB (218 of 283 [77.0%]), DDEB (71 of 104 [68.3%]), and EBS (100 of 194 [51.5%]). A subset of children had multiple confirmatory tests performed (JEB, 43 [68.3%]; RDEB, 178 [62.9%]; DDEB, 50 [48.1%]; and EBS, 87 [44.8%]). Regarding specific types of confirmatory tests, genetic analysis was the most common test for all patients (359 of 644 [55.7%] patients), followed by IFM (237, 36.8%) and EM (188, 29.2%). With the exception of EBS, among patients younger than 10 years, there were significantly higher proportions with genetic analysis compared with those older than 10 years (JEB: 35 [83.3%] vs 10 [47.6%], P = .003; DDEB: 32 [71.1%] vs 25 [42.4%], P = .004; and RDEB: 70 [74.5%] vs 114 [60.3%], P < .018). Both EM and IFM were performed at significantly younger median ages than genetic analysis for all types of EB, even after restricting the comparison to those patients younger than 10 years. Table 4 contains the final diagnostic types and subtypes of EB represented within this EBCCOD study population.
Table 3. Types of Confirmatory Laboratory Testing for Epidermolysis Bullosa and Patient Age at Testinga.
| Type of Laboratory Test and Age at the Time of the Test | Type of Epidermolysis Bullosa (N = 644) | |||
|---|---|---|---|---|
| EBS (n = 194) | JEB (n = 63) | DDEB (n = 104) | RDEB (n = 283) | |
| Any confirmatory tests | 100 (51.5) | 51 (81.0) | 71 (68.3) | 218 (77.0) |
| Multiple confirmatory tests | 87 (44.8) | 43 (68.3) | 50 (48.1) | 178 (62.9) |
| Electron microscopy | 40 (20.6) | 21 (33.3) | 29 (27.9) | 98 (34.6) |
| Age, median (IQR), mo | 3.6 (0.2-21.2) | 0.4 (0.1-18.3) | 3.1 (0.2-145.4) | 1.4 (0.2-51.6) |
| Immunofluorescence microscopy | 52 (26.8) | 33 (52.4) | 36 (34.6) | 116 (41.0) |
| Age, median (IQR), mo | 2.8 (0.2-15.8) | 0.5 (0.1-4.4) | 3.0 (0.6-15.5) | 0.6 (0.1-12.1) |
| Genetic analysis | 72 (37.1) | 45 (71.4) | 57 (54.8) | 184 (65.0) |
| Age, median (IQR), mo | 22.3 (5.4-68.9) | 12.7 (2.2-38.6) | 17.5 (4.6-164.5) | 40.4 (4.8-137.2) |
Abbreviations: DDEB, dominant dystrophic epidermolysis bullosa; EBS, epidermolysis bullosa simplex; IQR, interquartile range; JEB, junctional epidermolysis bullosa; RDEB, recessive dystrophic epidermolysis bullosa.
Data are presented as number (percentage) of patients unless otherwise indicated.
Table 4. Diagnostic Types and Subtypes Represented Within the Epidermolysis Bullosa Clinical Characterization and Outcomes Database.
| Epidermolysis Bullosa Type and Subtype | Patients, No. (%) |
|---|---|
| Epidermolysis bullosa simplex (n = 194) | |
| Generalized severe | 51 (26.3) |
| Generalized intermediate | 24 (12.4) |
| Localized | 55 (28.4) |
| Other | 51 (26.2) |
| Unspecified or unknown | 13 (6.7) |
| Junctional epidermolysis bullosa (n = 63) | |
| Generalized severe | 12 (19.1) |
| Generalized intermediate | 19 (30.2) |
| Localized | 4 (6.4) |
| Other | 9 (14.1) |
| Unspecified or unknown | 19 (30.2) |
| Dominant dystrophic epidermolysis bullosa (n = 104) | |
| Generalized | 20 (19.2) |
| Nongeneralized | 52 (50.0) |
| Unspecified or unknown | 32 (30.8) |
| Recessive dystrophic epidermolysis bullosa (n = 283) | |
| Generalized severe | 109 (38.5) |
| Nonsevere | 111 (39.2) |
| Unspecified or unknown | 63 (22.3) |
Milestone Clinical Events Specific to RDEB
Among the 283 patients with RDEB, 157 (55.5%) had an initial esophageal dilation at a median age of 6.6 years (IQR, 3.5-10.7 years) and 104 (36.7%) had gastrostomy tube placement at a median age of 5.5 years (IQR, 2.0-10.3 years) (Figure). Patients with RDEB (62 [21.9%]) had an initial hand surgery at a median age of 8.1 years (IQR, 5.5-12.1 years). Patients with RDEB (18, 6.4%) had a history of squamous cell carcinoma, with a median age at initial diagnosis of 22.6 years (IQR, 20.0-27.7 years). Finally, among the 19 (6.7%) of patients with RDEB who died, the most common attributed causes included respiratory failure (3 [15.8%]), cardiac failure (3 [15.8%]), neoplasm (1 [5.3%]), and renal failure (1 [5.3%]).
Figure. Age at First Occurrence of Selected Milestone Events in Patients With Recessive Dystrophic Epidermolysis Bullosa.
Each panel displays the distribution of ages at which patients with recessive dystrophic epidermolysis bullosa first experienced selected milestone events in 142 of 157 patients with known age of first esophageal dilation (A), 101 of 104 patients with known age of gastrostomy tube placement (B), 56 of 62 patients with known age of first hand surgery (C), and 14 of 18 patients with known age of squamous cell cancer onset (D).
Discussion
The EBCCOD contains clinical information pertaining to a large population of patients with EB representing all types of EB diagnoses, although most of the enrolled patients had RDEB. For patients within the EBCCOD, signs of EB, such as skin or mucosal erosions or blistering, were present at the time of birth in most of the patients with RDEB, JEB, and DDEB, but less so for patients with EBS. For those with signs at birth, a clinical diagnosis of EB was made at the time of birth in 67.0% of patients with RDEB and 52.6% of those with JEB, 47.3% of those with DDEB, and 46.2% of those with EBS. Patients with JEB had the highest rate of any confirmatory testing, followed by patients with RDEB, DDEB, and EBS. A subset of children had multiple confirmatory tests performed. For all types of EB, both EM and IFM were performed at younger median ages than genetic analysis. Among the patients with RDEB, the most frequent milestone clinical event was esophageal dilation, followed by gastrostomy tube placement, hand surgery, squamous cell carcinoma, and death.
Three findings from our study warrant discussion. First, use of the EBCCOD for all types of EB depends on the availability of clinical and outcomes data for patients with all types of EB. Although EBS is the most prevalent diagnosis in the general population, the EBCCOD is enriched with patients with RDEB likely because of their frequent contact with the medical system, particularly at specialty centers, and significant clinical needs that require ongoing clinical care. The EBCCOD provides rich population-level demographic and clinical data beyond what has previously been available. Although electronic health record data are increasingly available to collect and analyze, clinical registries and databases remain relevant and important to enable the identification of affected patients or children with rarer disease processes.20,21 Although International Statistical Classification of Diseases and Related Health Problems, Tenth Edition includes a code for EB (Q81) and some subtype-specific subcodes, International Classification of Diseases, Ninth Revision did not have a specific code for EB, making analysis of large administrative and clinical databases, such as outpatient Medicaid or inpatient Pediatric Hospital Information System databases difficult. To improve our knowledge of longer-term outcomes in patients with all types of EB, enrollment of patients, including those with milder forms of EB, will be critical.17
Second, an opportunity exists to improve earlier diagnosis of EB. Our study indicated that there was a lag between the observation of clinical signs and subsequent confirmatory testing, particularly genetic analysis. Our data may reflect the traditional paradigm of using EM and/or IFM to guide genetic analysis of a single candidate gene. However, the recent advent of less costly gene panels that test for all of the known EB genes simultaneously may be changing this practice. Genetic diagnosis is considered to be the criterion standard for the diagnosis of genetic disorders, and there are potential faults with clinical or biopsy-based diagnoses of EB.10 It is well established that the clinical findings of all forms of EB can be similar in newborns, but the prognosis varies widely based on the ultimate diagnosis of subtype. Clinicians can use genetic analysis to more accurately and definitively counsel families about their child’s diagnosis of EB and its expected course. Genetic analysis can also permit accurate counseling about the likelihood of recurrence with future pregnancies and provide opportunity for prenatal or preimplantation genetic diagnosis.22 In addition, even though a diagnosis may be supported by clinical signs and initial nongenetic diagnostic testing, as new therapies emerge for EB, particularly genetic-based therapy, it will be important to have a specific genetic diagnosis made as early as possible.7,23 Overall, only 61% of the cohort younger than 10 years and even fewer older than 10 years had genetic analysis done. This study did not examine specific factors contributing to lacking a genetic diagnosis, but we suspect that limited availability at the time of testing, particularly for older patients, and financial factors play key roles.
Third, for patients with RDEB, our population-level description of the prevalence and timing of milestone clinical events may enhance clinical care. These data should allow clinicians, families, and patients to better anticipate and plan for the occurrence of milestone events in RDEB, such as esophageal dilation, gastrostomy tube placement, hand surgery, diagnosis of squamous cell carcinoma, or death. This knowledge also aids clinicians in the initiation of counseling and planning at an optimal time, rather than overwhelming families with too much information at an initial visit. It may also help families accept that certain events, such as placement of a gastrostomy tube, are to be expected in RDEB and are not a failure on their part. These data will also help guide further study of patient-specific and systematic factors that might be associated with variation among milestone events. Identification of variation in management may provide valuable information to Epidermolysis Bullosa Clinical Research Consortium sites to support efforts to standardize management or develop clinical algorithms for common interventions. The Dystrophic Epidermolysis Bullosa Research Association International has commissioned expert panels to generate clinical guidelines for common EB issues; the EBCCOD may yield opportunities to supplement these expert recommendations with current, real-world evidence using a large available sample of patients with EB.
Limitations
Our findings must be interpreted within the context of several predictable limitations. Although the EBCCOD is a large, contemporary clinical database of patients with EB in North America, it only captures patients presenting for medical care at the participating EB centers. The nature of these centers biases the EBCCOD to patients with moderate to severe EB because it is conceivable that those with less severe forms of EB may seek care elsewhere or not at all. For instance, although EBS is the most prevalent diagnosis in the general population, the EBCCOD is enriched with patients with RDEB because of their frequent contact with the medical system and significant clinical needs requiring ongoing clinical care. However, the EBCCOD may not sufficiently capture patients, particularly infants, with lethal forms of EB (namely, JEB generalized severe) because they may die before study enrollment can occur. For instance, 68% of patients with JEB in the EBCCOD were older than 5 years, which likely reflects the survival of more patients with nonlethal forms of JEB based on subtype. Some patients had missing data, which we reported as unknown or a negative result depending on the variable. This decision could have led to bias in our results, such as the presence of a lag between signs for both symptoms and clinical diagnosis in either direction in the case of onset of first clinical symptoms or age at time of clinical diagnosis. The strategy for missing data may also have led to underreporting of some testing results, mainly in EM and IFM testing in older patients for whom reports were not readily available. Also, we attempted to assess for differences in the occurrence and timing of milestone events based on RDEB subtype classifications, but the completeness of the subtype data and the low frequencies of milestone events limited our ability to make meaningful comparisons between the RDEB subtypes. These analyses will be more feasible as the EBCCOD accrues more patients with complete data.
Conclusions
Approximately 33.0% of patients with RDEB and 53.8% of patients with JEB had a delay between the presence of signs at birth and subsequent clinical diagnosis of EB. Earlier diagnostic testing may enable improved characterizations of patients so that appropriate and timely counseling and clinical care may be offered, especially regarding milestone clinical events for patients with RDEB. The EBCCOD contains comprehensive patient data, especially for patients with RDEB, which will enable longitudinal studies of patient characteristics and clinical care and assist in the identification of key targets and timing for clinical interventions and evaluations of effectiveness.
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