Mortality of Bullous Skin Disorders From 1979 Through 2002 in

the United States

Jessica Risser, MD, MPH; Kevan Lewis, MD, MS; Martin A. Weinstock, MD, PhD
Arch Dermatol. 2009;145(9):1005-1008. doi:10.1001/archdermatol.2009.205.
ABSTRACT
Objectives To identify and analyze trends in bullous disease mortality from 1979
through 2002 in the United States.
Design Retrospective population-based analysis.
Setting Mortality records from the Centers for Disease Control and Prevention
mortality database.
Participants Mortality records from 1979 through 2002 for persons who died of
bullous disease.
Main Outcome Measures Age-adjusted mortality rates and trends for 4 bullous
disease subgroups: toxic epidermal necrolysis, pemphigoid, pemphigus, and
epidermolysis bullosa.
Results The overall age-adjusted (to the 2000 US standard population) annual
mortality rate from bullous diseases of the skin was 0.103 death per 100 000. The
average mortality from bullous disorders was 0.098 per 100 000 in 1979 through
1982 and remained stable at 0.099 per 100 000 during the final 4 years of the study,
1999 through 2002. Pemphigoid had a significant increase in mortality from 1979
through 2002, while pemphigus demonstrated a significant decrease in mortality. The
mortality rate for toxic epidermal necrolysis was much higher among blacks (0.192
death per 100 000) than whites (0.025 per 100 000) (P < .001), with a mortality rate
ratio of 7.57 (95% confidence interval, 6.97-8.21).
Conclusions Overall mortality from bullous diseases remained stable from 1979
through 2002, although an increasing mortality from pemphigoid and a decreasing
mortality from pemphigus occurred during this period. A very large racial disparity in
mortality from toxic epidermal necrolysis was observed.
Not since Savin1 published data in 1976 regarding international mortality from
bullous diseases have there been any significant attempts to quantify mortality and
evaluate population trends in the broad category of bullous diseases of the skin in
the United States. His analysis of mortality associated with bullous disorders
between the years 1950 and 1972 showed a declining number of deaths from
bullous diseases including pemphigus, pemphigoid, and dermatitis herpetiformis in
England and Wales and in the United States. This decline in overall mortality
coincided with the introduction of systemic corticosteroids for the treatment of bullous
disorders, and Savin's findings of declining mortality were largely thought to reflect
the therapeutic success achieved with corticosteroid medications for this group of
disorders.
Although several studies have examined mortality rates within local or hospitalbased populations since Savin's publication, 2- 12 large national analyses in the United
States are lacking and current mortality trends of these disorders are not well
established. Bullous disorders remain a major source of noncancer deaths from
dermatologic disease and continue to be therapeutically challenging diseases for
dermatologists, hospitalists, internists, and ophthalmologists. In 1998, bullous skin
disorders were the fourth most common cause of death from skin disease, following
skin cancers, ulcers, and bacterial infections. 13 Relatively high mortality rates for the

bullous skin disorders and the complexity of care they present to multiple physicians
across several disciplines highlight the need for further examination of current overall
mortality trends in these diseases.
The purpose of this study is to describe trends in US national mortality rates for the
24-year period beginning in 1979 for the spectrum of bullous diseases including toxic
epidermal necrolysis (TEN), pemphigoid, pemphigus, and epidermolysis bullosa.
METHODS
We report a population-based analysis of bullous skin disease mortality in the United
States from 1979 through 2002 based on death certificate records from the Centers
for Disease Control and Prevention mortality database (http://wonder.cdc.gov/). This
database, Wide-Ranging Online Data for Epidemiologic Research, provides access
to public health information for public health professionals and the public at large and
was accessed in January 2008.14
Mortality was analyzed in 4 general bullous disease subgroups: TEN (including
erythema multiforme and Stevens-Johnson syndrome, which share the same codes
in the International Classification of Diseases, Ninth Revision [ICD-9] and Tenth
Revision [ICD-10]), pemphigoid disorders (hereinafter referred to aspemphigoid),
pemphigus disorders (hereinafter referred to as pemphigus), and epidermolysis
bullosa.
Codes from ICD-9 were used to identify the underlying cause of death from 1979
through 1998, and ICD-10codes were used to identify the underlying cause of death
from 1999 through 2002, reflecting the transition to the updated classification
schema that occurred between these 2 periods.
The ICD-9 codes used in our study included 695.1 for TEN, 694.5 and 694.6 for
pemphigoid, 694.4 for pemphigus, and 757.3 (other specified anomalies of skin) for
epidermolysis bullosa. The ICD-10 codes that were used in our study included L51,
L10, L12, and Q81 and their subgroups for TEN, pemphigoid, pemphigus, and
epidermolysis bullosa, respectively.
Mortality rates were analyzed by both sex and race by means of StatXact (version
3.1; Cytel Software Corp, Cambridge, Massachusetts). Linear regression was
performed to assess trends in death rates over time by means of SPSS statistical
software (version 17.0; SPSS Inc, Chicago, Illinois). P < .05 was considered to be
statistically significant. Institutional review board approval was not applicable to this
study because it used publicly available data.
RESULTS
A total of 5848 deaths were attributable to bullous diseases in the United States from
1979 through 2002. The overall age-adjusted (to the 2000 US standard population)
annual mortality rate from bullous diseases of the skin was 0.103 death per 100 000.
A total of 2378 deaths in the 24-year period that we examined were from TEN.
During this same period, pemphigoid led to 1530 deaths, pemphigus to 1226 deaths,
and epidermolysis bullosa to 714 deaths; the age-adjusted mortality rate for TEN
was 0.041 death per 100 000, whereas the age-adjusted mortality rates for
pemphigoid, pemphigus, and epidermolysis bullosa were 0.028, 0.023, and 0.011
per 100 000, respectively.
Mortality varied by age, with pemphigoid and pemphigus having the highest
concentration of deaths among the very old. Deaths were also concentrated among

the elderly for patients with TEN, although less so than for pemphigoid and
pemphigus. Death from epidermolysis bullosa occurred almost exclusively among
infants, and there was a very small proportion of TEN deaths among infants as well.
Table. Distribution of Mortality Associated With Bullous Skin Diseases, 1979 Through
2002

During the first 4 years of the period studied (1979-1982), the average mortality from
bullous disorders was 0.098 death per 100 000, and during the last 4 years of the
period (1999-2002), the average mortality from bullous diseases was similar, 0.099
per 100 000.
For some of these disorders, age-adjusted mortality rates varied over time during
this 24-year period. For pemphigoid we noted a significant increase of 0.0055 death
per 100 000 per decade (95% confidence interval [CI], 0.0025-0.0086 per
100 000; F = 14.6, P = .001), from 0.020 in 1979-1982 to 0.029 twenty years later.
By contrast, there was a significant decrease in the age-adjusted mortality rate for
pemphigus of 0.0066 death per 100 000 per decade during the study period (95%
CI, 0.0096 to 0.0041 per 100 000;F = 26.5, P < .001). This change reflects a
decrease from 0.033 in 1979-1982 to 0.021 in 1999-2002. Linear regression failed to
show any significant changes in mortality trends from 1979-2002 for TEN or for
epidermolysis bullosa.
Figure.
Age-adjusted mortality rates for bullous skin diseases, 1979 through 2002. TEN
indicates toxic epidermal necrolysis.

The mortality rate for TEN was much higher among blacks (0.192 death per
100 000) than whites (0.025 per 100 000) (P < .001), with a mortality rate ratio of
7.57 (95% CI, 6.97-8.21). The relative risk of death from TEN for black females vs
black males was 1.40 (P < .001; 95% CI, 1.21-1.60), whereas the relative risk of
death from TEN for white females vs white males was 1.16 (P = .01; 95% CI, 1.031.30).
Mortality rates were also higher among blacks than whites for pemphigoid (0.051 vs
0.026 death per 100 000; P < .001). The relative risk of death from pemphigoid in
blacks vs whites was 1.95 (P < .001; 95% CI, 1.68-2.25), and females were at
slightly increased risk of death from pemphigoid (relative risk, 1.18;P = .004; 95% CI,
1.06-1.32).
Blacks had greater mortality rates for pemphigus than whites (0.030 vs 0.022 death
per 100 000), and their relative risk of death was 1.38 (P < .001; 95% CI, 1.16-1.65).
There was no significant difference in risk of death from pemphigus by sex.
The mortality rate for blacks was similarly higher than that for whites in the
epidermolysis bullosa group (0.016 vs 0.011 death per 100 000), and blacks were
1.44 times as likely as whites to die of epidermolysis bullosa (P < .001; 95% CI, 1.201.73). Females had a slightly increased risk of death from epidermolysis bullosa
(relative risk, 1.23; P = .007; 95% CI, 1.06-1.43).
COMMENT
This study of mortality from bullous disorders during a 24-year period found that
pemphigoid mortality increased while mortality from pemphigus decreased. A very
large racial disparity in mortality from TEN was observed.
A recently published study identified that the incidences of bullous pemphigoid and
pemphigus vulgaris are increasing in the United Kingdom, 15 but changes in incidence
of pemphigoid and pemphigus in the United States are unknown, as is their effect on
mortality rates. Several prospective and retrospective studies have evaluated
prognostic factors in patients with bullous pemphigoid, and the type of therapy
patients have received has not been found to be related to overall prognosis or
mortality.2,4- 6,8- 12,16- 18 There is also no obvious relationship between the introduction of
the limited number of agents used to treat bullous pemphigoid and the shifts in
mortality during the period studied. Thus, changes in therapy may not be contributing
to the observed increase in bullous pemphigoid death rates. Indeed, a recent study
found little impact in overall mortality due to bullous pemphigoid. 9 A retrospective
study by Carson et al19 suggested that mortality from pemphigus decreased
significantly with the addition of adjuvant therapy (azathioprine, cyclophosphamide,
methotrexate, andGOLD ) to corticosteroids during the period from 1969 through
1991. Further introduction of plasmapheresis and then intravenous immunoglobulin
in the mid-1990s for treatment-refractory cases may have also contributed to
declining mortality.20- 22
Mortality for black persons was significantly higher for every bullous disease studied
and was particularly marked in the TEN group of disorders, but the cause, perhaps
including social or other factors, cannot be determined from our data.
This study provides a broad descriptive analysis of trends in bullous disease
mortality in the United States during the 24-year period from 1979-2002 through
interpretation and analysis of national mortality records. Key strengths include the

use of a large population-based data source covering billions of person-years of

observation using routine death certification, and the ability to use these data to
assess trends over a quarter-century. The size of the population and the duration of
the observation period allow examination of issues that might not otherwise be
assessable. However, there were several limitations of our investigation. First, the
accuracy of the reporting of deaths from bullous disorders was not independently
verified. Hence, we may have overestimated or underestimated the true mortality of
these disorders or the trends in rates. Second, the classification schemas used to
report the diseases may also lead to inaccurate measurements of mortality rates.
This is particularly possible in the classification of epidermolysis bullosa with
the ICD-9code of 757.3, which covers a broad range of skin diseases beyond
epidermolysis bullosa alone. Therefore, mortality attributable to this group of
disorders may be overestimated for the years 1979 through 1998. Finally, very little
information about the persons who died of these diseases was available for analysis,
and therefore interpretation of the findings is limited to rather broad speculation
about the factors driving the trends observed.
We have provided an overview of trends of bullous skin diseases that demonstrates
significant shifts in mortality for both pemphigus and pemphigoid, and important
racial discrepancies in mortality. Although this study perhaps raises more questions
than it answers, we hope it will serve as a springboard to the investigation of the
causes of these trends so that dermatologists, internists, and other specialists will be
better able to reduce bullous disease mortality in the future.
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