0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.204.103.179. Please contact the publisher to request reinstatement.
Study |

Mortality of Bullous Skin Disorders From 1979 Through 2002 in the United States FREE

Jessica Risser, MD, MPH; Kevan Lewis, MD, MS; Martin A. Weinstock, MD, PhD
[+] Author Affiliations

Author Affiliations: Dermatoepidemiology Unit, Veterans Affairs Medical Center (Drs Risser, Lewis, and Weinstock); Department of Dermatology, Rhode Island Hospital (Drs Risser, Lewis, and Weinstock); and Departments of Dermatology (Drs Risser, Lewis, and Weinstock) and Community Health (Dr Weinstock), Brown University; Providence, Rhode Island.


Arch Dermatol. 2009;145(9):1005-1008. doi:10.1001/archdermatol.2009.205.
Text Size: A A A
Published online

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.

Figures in this Article

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 hospital-based populations since Savin's publication,212 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.

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 as pemphigoid), 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-10 codes 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.

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).

Table Graphic Jump LocationTable. 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).

Place holder to copy figure label and caption
Figure.

Age-adjusted mortality rates for bullous skin diseases, 1979 through 2002. TEN indicates toxic epidermal necrolysis.

Graphic Jump Location

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, 1.03-1.30).

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, 1.20-1.73). Females had a slightly increased risk of death from epidermolysis bullosa (relative risk, 1.23; P = .007; 95% CI, 1.06-1.43).

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.2,46,812,1618 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, and gold) 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.2022

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-9 code 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.

Correspondence: Martin A. Weinstock, MD, PhD, Dermatoepidemiology Unit, Veterans Affairs Medical Center, Mail Stop 111D, 830 Chalkstone Ave, Providence, RI 02908 (maw@brown.edu).

Accepted for Publication: February 4, 2009.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Weinstock. Acquisition of data: Risser, Lewis, and Weinstock. Analysis and interpretation of data: Risser, Lewis, and Weinstock. Drafting of the manuscript: Risser and Weinstock. Critical revision of the manuscript for important intellectualcontent: Risser and Weinstock. Statistical analysis: Risser, Lewis, and Weinstock. Study supervision: Weinstock.

Financial Disclosure: None reported.

Funding/Support: Dr Weinstock is supported by the Department of Veterans Affairs Office of Research and Development Cooperative Studies Program and by grants R01CA106592, R01CA106807, R25CA087972, and R01AR49342 from the National Institutes of Health.

Additional Contributions: Jason Machan, PhD, made invaluable contributions to our statistical analysis.

Savin  JA International mortality from bullous diseases since 1950. Br J Dermatol 1976;94 (2) 179- 189
PubMed
Bernard  PEnginger  VVenot  JBedane  CBonnetblanc  JM Survival prognosis in pemphigoid: a cohort analysis of 78 patients [in French]. Ann Dermatol Venereol 1995;122 (11-12) 751- 757
PubMed
Bystryn  JCRudolph  JL Why is the mortality of bullous pemphigoid greater in Europe than in the US? J Invest Dermatol 2005;124 (3) xx- xxi
PubMed
Colbert  RLAllen  DMEastwood  DFairley  JA Mortality rate of bullous pemphigoid in a US medical center. J Invest Dermatol 2004;122 (5) 1091- 1095
PubMed
Gudi  VSWhite  MICruickshank  N  et al.  Annual incidence and mortality of bullous pemphigoid in the Grampian Region of North-east Scotland. Br J Dermatol 2005;153 (2) 424- 427
PubMed
Joly  PBenichou  JLok  C  et al.  Prediction of survival for patients with bullous pemphigoid: a prospective study. Arch Dermatol 2005;141 (6) 691- 698
PubMed
Joly  PBenichou  JSaiag  PBernard  PRoujeau  JC Response to: mortality rate of bullous pemphigoid in a US medical center. J Invest Dermatol 2005;124 (3) 664- 665
PubMed
Nanda  AAl-Saeid  KAl-Sabah  HDvorak  RAlsaleh  QA Clinicoepidemiological features and course of 43 cases of bullous pemphigoid in Kuwait. Clin Exp Dermatol 2006;31 (3) 339- 342
PubMed
Parker  SRDyson  SBrisman  S  et al.  Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol 2008;59 (4) 582- 588
PubMed
Roujeau  JCLok  CBastuji-Garin  SMhalla  SEnginger  VBernard  P High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol 1998;134 (4) 465- 469
PubMed
Rzany  BPartscht  KJung  M  et al.  Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol 2002;138 (7) 903- 908
PubMed
Swerlick  RAKorman  NJ Bullous pemphigoid: what is the prognosis? J Invest Dermatol 2004;122 (5) xvii- xviii
PubMed
Weinstock  MAChren  M-M The epidemiology and burden of skin disease.  In: Wolff  K, Goldsmith  LA, Katz  SI, Gilchrest  B, Paller  AS, Leffell  DJ, eds. Fitzpatrick's Dermatology in General Medicine.7th ed. New York, NY: McGraw-Hill; 2008:5
Centers for Disease Control and Prevention Compressed mortality file: underlying cause-of-death. http://wonder.cdc.gov/. Accessed January 20, 2008
Langan  SMSmeeth  LHubbard  RFleming  KMSmith  CJWest  J Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study. BMJ2008337a180
PubMeddoi:10.1136/bmj.a180
Garcia-Doval  IConde Taboada  ACruces Prado  MJ Sepsis associated with dermatologic hospitalization is not the cause of high mortality of bullous pemphigoid in Europe. J Invest Dermatol 2005;124 (3) 666- 667
PubMed
Joly  PRoujeau  JCBenichou  J  et al. Bullous Diseases French Study Group, A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;346 (5) 321- 327
PubMed
Khumalo  NKirtschig  GMiddleton  PHollis  SWojnarowska  FMurrell  D Interventions for bullous pemphigoid. Cochrane Database Syst Rev 2005; (3) CD002292
PubMed
Carson  PJHameed  AAhmed  AR Influence of treatment on the clinical course of pemphigus vulgaris. J Am Acad Dermatol 1996;34 (4) 645- 652
PubMed
Bystryn  JCRudolph  JL Pemphigus. Lancet 2005;366 (9479) 61- 73
PubMed
Cianchini  GCorona  RFrezzolini  ARuffelli  MDidona  BPuddu  P Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol 2007;143 (8) 1033- 1038
PubMed
Mourellou  OChaidemenos  GCKoussidou  TKapetis  E The treatment of pemphigus vulgaris: experience with 48 patients seen over an 11-year period. Br J Dermatol 1995;133 (1) 83- 87
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Age-adjusted mortality rates for bullous skin diseases, 1979 through 2002. TEN indicates toxic epidermal necrolysis.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Distribution of Mortality Associated With Bullous Skin Diseases, 1979 Through 2002

References

Savin  JA International mortality from bullous diseases since 1950. Br J Dermatol 1976;94 (2) 179- 189
PubMed
Bernard  PEnginger  VVenot  JBedane  CBonnetblanc  JM Survival prognosis in pemphigoid: a cohort analysis of 78 patients [in French]. Ann Dermatol Venereol 1995;122 (11-12) 751- 757
PubMed
Bystryn  JCRudolph  JL Why is the mortality of bullous pemphigoid greater in Europe than in the US? J Invest Dermatol 2005;124 (3) xx- xxi
PubMed
Colbert  RLAllen  DMEastwood  DFairley  JA Mortality rate of bullous pemphigoid in a US medical center. J Invest Dermatol 2004;122 (5) 1091- 1095
PubMed
Gudi  VSWhite  MICruickshank  N  et al.  Annual incidence and mortality of bullous pemphigoid in the Grampian Region of North-east Scotland. Br J Dermatol 2005;153 (2) 424- 427
PubMed
Joly  PBenichou  JLok  C  et al.  Prediction of survival for patients with bullous pemphigoid: a prospective study. Arch Dermatol 2005;141 (6) 691- 698
PubMed
Joly  PBenichou  JSaiag  PBernard  PRoujeau  JC Response to: mortality rate of bullous pemphigoid in a US medical center. J Invest Dermatol 2005;124 (3) 664- 665
PubMed
Nanda  AAl-Saeid  KAl-Sabah  HDvorak  RAlsaleh  QA Clinicoepidemiological features and course of 43 cases of bullous pemphigoid in Kuwait. Clin Exp Dermatol 2006;31 (3) 339- 342
PubMed
Parker  SRDyson  SBrisman  S  et al.  Mortality of bullous pemphigoid: an evaluation of 223 patients and comparison with the mortality in the general population in the United States. J Am Acad Dermatol 2008;59 (4) 582- 588
PubMed
Roujeau  JCLok  CBastuji-Garin  SMhalla  SEnginger  VBernard  P High risk of death in elderly patients with extensive bullous pemphigoid. Arch Dermatol 1998;134 (4) 465- 469
PubMed
Rzany  BPartscht  KJung  M  et al.  Risk factors for lethal outcome in patients with bullous pemphigoid: low serum albumin level, high dosage of glucocorticosteroids, and old age. Arch Dermatol 2002;138 (7) 903- 908
PubMed
Swerlick  RAKorman  NJ Bullous pemphigoid: what is the prognosis? J Invest Dermatol 2004;122 (5) xvii- xviii
PubMed
Weinstock  MAChren  M-M The epidemiology and burden of skin disease.  In: Wolff  K, Goldsmith  LA, Katz  SI, Gilchrest  B, Paller  AS, Leffell  DJ, eds. Fitzpatrick's Dermatology in General Medicine.7th ed. New York, NY: McGraw-Hill; 2008:5
Centers for Disease Control and Prevention Compressed mortality file: underlying cause-of-death. http://wonder.cdc.gov/. Accessed January 20, 2008
Langan  SMSmeeth  LHubbard  RFleming  KMSmith  CJWest  J Bullous pemphigoid and pemphigus vulgaris—incidence and mortality in the UK: population based cohort study. BMJ2008337a180
PubMeddoi:10.1136/bmj.a180
Garcia-Doval  IConde Taboada  ACruces Prado  MJ Sepsis associated with dermatologic hospitalization is not the cause of high mortality of bullous pemphigoid in Europe. J Invest Dermatol 2005;124 (3) 666- 667
PubMed
Joly  PRoujeau  JCBenichou  J  et al. Bullous Diseases French Study Group, A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. N Engl J Med 2002;346 (5) 321- 327
PubMed
Khumalo  NKirtschig  GMiddleton  PHollis  SWojnarowska  FMurrell  D Interventions for bullous pemphigoid. Cochrane Database Syst Rev 2005; (3) CD002292
PubMed
Carson  PJHameed  AAhmed  AR Influence of treatment on the clinical course of pemphigus vulgaris. J Am Acad Dermatol 1996;34 (4) 645- 652
PubMed
Bystryn  JCRudolph  JL Pemphigus. Lancet 2005;366 (9479) 61- 73
PubMed
Cianchini  GCorona  RFrezzolini  ARuffelli  MDidona  BPuddu  P Treatment of severe pemphigus with rituximab: report of 12 cases and a review of the literature. Arch Dermatol 2007;143 (8) 1033- 1038
PubMed
Mourellou  OChaidemenos  GCKoussidou  TKapetis  E The treatment of pemphigus vulgaris: experience with 48 patients seen over an 11-year period. Br J Dermatol 1995;133 (1) 83- 87
PubMed

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles