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Study |

Pemphigus Variant Associated With Penicillin Use A Case-Cohort Study of 363 Patients From Israel FREE

Anthony D. Heymann, BSc MB, BS, MRCGP, MHA; Gabriel Chodick, PhD; Eyal Kramer, MD; Manfred Green, MD; Varda Shalev, MD
[+] Author Affiliations

Author Affiliations: Medical Division, Maccabi Healthcare Services (Drs Heymann, Chodick, Kramer, and Shalev), and Sackler Faculty of Medicine, Tel Aviv University (Drs Heymann, Chodick, and Green), Tel Aviv, Israel.


Arch Dermatol. 2007;143(6):704-707. doi:10.1001/archderm.143.6.704.
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Published online

Objective  To determine whether medication use is associated with the development of a pemphigus variant.

Design  Population-based case-cohort study.

Setting  Health maintenance organization in Israel.

Methods  All incident pemphigus variant cases diagnosed from January 1, 1997, through December 31, 2001, among 1.5 million members were identified. A cohort of 150 000 was randomly selected from the health maintenance organization population as the control group. Data on case patients and control subjects, including all medication purchased during the 6 months before the diagnosis, were obtained using the health maintenance organization's central database.

Results  We identified a total of 363 case patients diagnosed as having pemphigus during the 5-year study (6 961 853 person-years of follow-up). The mean age at diagnosis was 49.8 (SD, 22.7) years, and 53% of the cases were women. Results of a multivariate analysis showed that increased risk for pemphigus was associated with purchasing penicillin during the 6 months before the diagnosis (odds ratio, 2.03; 95% confidence interval, 1.56-2.64). Compared with individuals with no penicillin purchases, we calculated increased risks of 1.84 (95% CI, 1.36-2.49) and 3.02 (95% CI, 1.41-6.49) in those with 1 and 3 or more purchases, respectively. None of the other examined medications, including cephalosporins, angiotensin-converting enzyme inhibitors, dipyrone, anticonvulsants, and nonsteroidal anti-inflammatory drugs, showed similar risks.

Conclusions  To our knowledge, the present research is one of the largest published epidemiological studies on pemphigus variant. The use of computerized medical and administrative databases allowed the detection of case patients in the community, resulting in a higher calculated incidence rate than previously reported. The findings suggest a relationship between the use of penicillin and pemphigus variant. Further studies to assess the nature of this statistical association are warranted.

Figures in this Article

Pemphigus is an autoimmune bullous skin disease.1 The most common variant is pemphigus vulgaris.2 Epidemiological studies from Israel3 and the United States4 suggest that Ashkenazi Jews have an increased risk for pemphigus, with annual incidence rates of 20 per 1 million to 30 per 1 million, compared with other investigated populations such as those of Saudi Arabia5 (2 per 1 million) and Bulgaria6 (5 per 1 million).

The etiology, although considered autoimmune because of the presence of pathogenic antibodies directed against desmogleins 3 and 1, may be modified by or the result of endogenous and exogenous factors.7 The former range from stress to malignancy.8,9 The latter include certain food items10 and exposure to sunlight.11 Infections and medications may be important extrinsic factors. Viral causes, such as herpes simplex viruses, Epstein-Barr virus, and cytomegalovirus, and bacteria have all been implicated.12,13

Previous studies suggested that a number of different medications can induce pemphigus variants. These can be categorized into the following 3 main groups: (1) drugs containing a sulfhydryl radical, such as penicillamine14 or captopril (an angiotensin-converting enzyme inhibitor)15; (2) masked thiols that contain an S molecule and can be converted to a thiol, such as penicillin16,17; and (3) nonthiol or other drugs such as cephalosporins.18 It has been postulated that, in a case of an abortive form of pemphigus induced by protracted penicillin treatment, the probable trigger was actually penicillamine, which was formed by the metabolic breakdown of the penicillin molecule.16 In one study,14 it was estimated that among 168 patients with arthritis who have been given penicillamine for at least 6 months, 8 developed itchy eruptions and 2 had active pemphigus with serious complications.

Except for penicillamine, these drugs induce pemphigus very rarely considering their widespread use. Previous studies of the relationship between medications and pemphigus variant have been based on relatively small numbers of patients and therefore had a low study power. Our study uses a central database that details all medication purchased by an entire insured population. The objective of the present study was to assess the relationship between exposure to certain medications and the development of pemphigus variants.

The study was based on data from January 1, 1997, through December 31, 2001, in the Maccabi Healthcare Services (MHS) health maintenance organization (a population of 1.5 million, approximately 24% of the total Israeli population). Established in 1941, MHS has become the nation's second largest health maintenance organization. According to the National Health Act in Israel–1994, MHS may not bar applicants on any grounds, including age or state of health. Thus, all Israeli population sectors are represented in MHS. Since 1997, diagnoses of MHS members are downloaded daily to a central computer. The database is automatically updated with all hospitalizations and outpatient visits. All medications prescribed by the plan's physicians, including 140 dermatologists, are recorded.

IDENTIFICATION OF CASES AND COHORT

Incident cases of pemphigus variants were identified by computerized record linkage of the entire cohort to the MHS central computerized database; this allowed the calculation of the incidence rate of the disease among MHS members. All patients who were diagnosed as having pemphigus variants according to the International Classification of Diseases, Ninth Revision, Clinical Modification (codes 694.4 or 964.61) from 1997 through 2001 were identified. The cohort was retrospectively constructed by a random sampling of 10% of the entire MHS population, excluding those with a known pemphigus variant. For every participant, the following data were obtained: age, age at diagnosis, sex, region of residence, and year of immigration to Israel. We also examined the relationship with diabetes and ischemic heart disease using physician diagnosis supported by medication purchase and laboratory tests.

EXPOSURE DATA

We examined all purchases of medications that were previously associated with pemphigus15,16,19,20 during the 6 months before the date that the pemphigus was first diagnosed. These medications included penicillins, cephalosporins, angiotensin-converting enzyme inhibitors, dipyrone, phenobarbiturate, topical anti-inflammatory drugs, and nonsteroidal anti-inflammatory medications. For the cohort participants, data on medication use were obtained for the 6 months from January 1 through June 30, 2000.

STATISTICAL ANALYSIS

For the present analysis, we used the population-based case-cohort study design. Categorical variables (age group, sex, and chronic disease) were compared with those of the standard population. We used the Pearson χ2 test of significance, with P values of less than .05 considered significant and correction for continuity where appropriate. Odds ratios (ORs) and 95% confidence intervals (CIs) of pemphigus were derived from stepwise unconditional multiple logistic regression models, fitted by the method of maximum likelihood. In the multivariate logistic regression, the following predictors in addition to medication use were assessed: age at diagnosis, sex, region of residence (southern, northern, or central Israel), and the presence of chronic diabetes and cardiovascular disease (including congestive heart failure and ischemic heart disease) as binary variables.

GENERAL FINDINGS

During the observation period from 1997 through 2001 (6 961 853 person-years of follow-up), a total of 363 incident cases of pemphigus were identified, representing an incidence rate of 5.3 per 100 000 person-years. The mean (SD) age at diagnosis was 49.8 (22.7) years, and 52.9% were women. The age-specific rates (and Fisher 95% CI) of pemphigus in the MHS population are shown by sex in the Figure. Individuals younger than 35 years had the lowest rate (<5 per 100 000); at 45 years of age, the rate increased sharply with increasing age in both sexes, reaching 30 per 100 000 among individuals 75 years or older. Pemphigus variants do not seem to be associated with the presence of comorbid diabetes; however, there was a significant association with cardiovascular disease (Table 1).

Place holder to copy figure label and caption
Figure.

Age-specific incidence of pemphigus variant in the Maccabi Healthcare Services health maintenance organization from January 1, 1997, through December 31, 2001.

Graphic Jump Location
Table Graphic Jump LocationTable 1. Distribution of Demographic Characteristics and Chronic Diseases Among Pemphigus Cases and Cohort Controls of the MHS HMO
CASE-COHORT STUDY

A total of 149 423 members of the MHS health maintenance organization were randomly selected as cohort control subjects to the 363 identified cases. The demographic characteristics of the case patients with pemphigus differed significantly from those of the controls with respect to subject age, as shown in Table 1. More than one fifth of the case patients had made at least 1 purchase of penicillin during the 6 months before diagnosis; this is compared with 13.5% of the controls. After adjusting for age and sex, the OR associated with penicillin purchase was 1.97 (95% CI, 1.52-2.57). This was the only significant difference found in medication purchases between cases and controls after adjusting for age and sex (Table 2). In the multivariate model, age was significantly associated with increased risk (for every year of age, OR, 1.04; 95% CI, 1.03-1.05) for pemphigus. Individuals with diabetes mellitus had a significantly reduced risk (OR, 0.27; 95% CI, 0.14-0.51). Use of penicillin remained significant with an OR of 2.03 (95% CI, 1.56-2.64), as shown in Table 2.

Table Graphic Jump LocationTable 2. Purchase of Selected Medications Among Case Patients With Pemphigus During the 6 Months Before Diagnosis and Among Cohort Controls During the First 6 Months in 2000

A significant (P<.001) trend of increased risk was found between the number of penicillin packs purchased and the risk of pemphigus. The fully adjusted OR of the individuals who purchased 3 or more packs was 3.02 (95% CI, 1.41-6.49) compared with nonusers, as shown in Table 3.

Table Graphic Jump LocationTable 3. Number of Penicillin Packs Purchased During the 6 Months Before Diagnosis With Respective ORs

This study shows that, among the examined medications, only penicillin is associated with the development of pemphigus. The increased ORs seen with increasing exposure support this observation. Previous retrospective surveys on pemphigus have been limited to a single geographic region4,5 or hospital ward.21 The strengths of this study are its population-based design, the inclusion of case patients diagnosed and treated in the community, and the use of complete data capture of prescribed medications and diagnosis. This eliminates threats of recall, selection, and surveillance bias, which are important methodological limitations of previous case reports. The comprehensive data sources used to identify cases in this study may explain the relatively high annual incidence rate calculated in our study (5 per 100 000) compared with 2 per 100 000 to 3 per 100 000 in a previous study4 that used data from the 1960s and 1970s. This difference can also be explained by the development of better diagnosis methods and increased awareness of the disease.

However, this research has a number of important limitations. These limitations are related to the problems of conducting epidemiological research on databases that have been designed for administrative and medical purposes22 and those inherent to case-cohort studies. Case-cohort studies determine the relative importance of a predictor variable in relation to the presence or absence of the disease. This type of study is therefore useful for generating hypotheses that can then be tested using other types of study. It should be remembered that confounding factors are a major limitation of case-cohort studies.23 Within the group of identified case patients with pemphigus, there may be misdiagnosed cases that we were not able to identify. The scope of this study did not allow us to validate each case with the pathological findings of the biopsy, and thus all pemphigus variants are examined together in this study. It could be that the index case patients were diagnosed—or misdiagnosed—as having a sore throat and then treated with penicillins or cephalosporins, when they actually had a few intraoral erosions of pemphigus variant before it was finally diagnosed.

It cannot be determined from this study whether penicillin use is causally related to pemphigus variant or whether the indication for use, overall weakened immune function, or other factors are pertinent underlying exposures. Penicillin is administered for infection, which itself is an important pemphigus trigger.

The findings of previous research that other medications such as cephalosporins or captopril may trigger pemphigus are not supported by this study. The present study may have been underpowered to show this effect, but information about induction of pemphigus by cephalosporins or angiotensin-converting enzyme inhibitors is from case reports.

Similar to a previous report from Israel,21 women in our study constituted a little more than 50% of the entire subject population. In the Mediterranean regions, pemphigus vulgaris, which accounts for more than 80% of all pemphigus cases,21 is known to affect more women than men in a ratio of approximately 1:1.5.2427 In this aspect, Israel is similar to northern countries, where the incidence of the disease is equal between the sexes. This may be partly owing to the large population of new immigrants to Israel from the former Union of Soviet Socialist Republics.

This study suggests that that there is an association between penicillin exposure and the diagnosis of pemphigus variants. Further study is warranted to determine whether penicillin is causative in the development of the disease or is a reflection of other confounding effects.

Correspondence: Anthony D. Heymann, BSc MB, MS, MRCGP, MHA, Maccabi Healthcare Services, 27 HaMered St, Tel Aviv 68125, Israel (Heymann_t@mac.org.il).

Financial Disclosure: None reported.

Accepted for Publication: October 3, 2006.

Author Contributions:Study concept and design: Heymann and Green. Acquisition of data: Heymann, Kramer, and Shalev. Analysis and interpretation of data: Heymann, Chodick, and Shalev. Drafting of the manuscript: Heymann. Critical revision of the manuscript for important intellectual content: Heymann, Kramer, Green, and Shalev. Statistical analysis: Chodick. Administrative, technical, and material support: Kramer and Shalev. Study supervision: Heymann and Green.

 Pemphigus: current concepts. Ann Intern Med 1980;92396- 405
PubMed Link to Article
Krain  LS Pemphigus: epidemiologic and survival characteristics of 59 patients, 1955-1973. Arch Dermatol 1974;110862- 865
PubMed Link to Article
Pisanti  SSharav  YKaufman  EPosner  L Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol 1974;38382- 387
PubMed Link to Article
Simon  DGKrutchkoff  DKaslow  RZarbo  R Pemphigus in Hartford County, Connecticut, from 1972 to 1977. Arch Dermatol 1980;1161035- 1037
PubMed Link to Article
Tallab  TJoharji  HBahamdan  KKarkashan  EMourad  MIbrahim  K The incidence of pemphigus in the southern region of Saudi Arabia. Int J Dermatol 2001;40570- 572
PubMed Link to Article
Tsankov  NVassileva  SKamarashev  JKazandjieva  JKuzeva  V Epidemiology of pemphigus in Sofia, Bulgaria. Int J Dermatol 2000;39104- 108
PubMed Link to Article
Hashimoto  T Recent advances in the study of the pathophysiology of pemphigus. Arch Dermatol Res 2003;295S2- S11
PubMed
Brenner  STur  EShapiro  J  et al.  Pemphigus vulgaris: environmental factors. Int J Dermatol 2001;40562- 569published correction appears inInt J Dermatol. 2003; Sep42760
PubMed Link to Article
Ota  MSato-Matsumura  KMatsumura  TTsuji  YOhkawara  A Pemphigus foliaceus and figurate erythema in a patient with prostate cancer. Br J Dermatol 2000;142816- 818
PubMed Link to Article
Brenner  SRuocco  VWolf  Rde Angelis  ELombardi  M Pemphigus and dietary factors: in vitro acantholysis by allyl compounds of the genus Allium. Dermatology 1995;190197- 202
PubMed Link to Article
Cram  DWinkelmann  R Ultraviolet-induced acantholysis in pemphigus. Arch Dermatol 1965;927- 13
PubMed Link to Article
Kalra  ARatho  RKaur  IKumar  B Role of herpes simplex and cytomegalo viruses in recalcitrant oral lesions of pemphigus vulgaris. Int J Dermatol 2005;44259- 260
PubMed Link to Article
Martín  FJPerez-Bernal  ACamacho  F Pemphigus vulgaris and disseminated nocardiosis. J Eur Acad Dermatol Venereol 2000;14416- 418
PubMed Link to Article
Marsden  RAHill  HMowat  AWalshe  MVanhegan  RRyan  T Penicillamine-induced pemphigus. Proc R Soc Med 1977;70 ((suppl 3)) 103- 108
PubMed
Ruocco  VSatriano  RGuerrera  V “Two-step” pemphigus induction by ACE-inhibitors. Int J Dermatol 1992;3133- 36
PubMed Link to Article
Ruocco  VRossi  APisani  MAstarita  CAlviggi  L An abortive form of pemphigus vulgaris probably induced by penicillin. Dermatologica 1979;159266- 273
PubMed Link to Article
Duhra  PFoulds  I Penicillin-induced pemphigus vulgaris. Br J Dermatol 1988;118307
PubMed Link to Article
Goldberg  IIngher  ABrenner  S Pemphigus vulgaris triggered by rifampin and emotional stress. Skinmed 2004;3294
PubMed Link to Article
Goldberg  IKashman  YBrenner  S The induction of pemphigus by phenol drugs. Int J Dermatol 1999;38888- 892
PubMed Link to Article
Tur  EBrenner  S Contributing exogenous factors in pemphigus. Int J Dermatol 1997;36888- 893
PubMed Link to Article
Wohl  YBrenner  S Pemphigus in Israel. Isr Med Assoc J 2003;5410- 412
PubMed
Schlesselman  JJ Case-Control Studies: Design, Conduct, Analysis.  New York, NY Oxford University Press1982;
Rundle  AGVineis  PAhsan  H Design options for molecular epidemiology research within cohort studies. Cancer Epidemiol Biomarkers Prev 2005;141899- 1907
PubMed Link to Article
Alsaleh  QANanda  AAl-Baghli  NDvorak  R Pemphigus in Kuwait. Int J Dermatol 1999;38351- 356
PubMed Link to Article
Micali  GMusumeci  MNasca  M Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus in eastern Sicily. Int J Dermatol 1998;37197- 200
PubMed Link to Article
Salmanpour  RShahkar  HNamazi  MRahman-Shenas  M Epidemiology of pemphigus in south-western Iran. Int J Dermatol 2006;45103- 105
PubMed Link to Article
Uzun  SDurdu  MAkman  A  et al.  Pemphigus in the Mediterranean region of Turkey: a study of 148 cases. Int J Dermatol 2006;45523- 528
PubMed Link to Article

Figures

Place holder to copy figure label and caption
Figure.

Age-specific incidence of pemphigus variant in the Maccabi Healthcare Services health maintenance organization from January 1, 1997, through December 31, 2001.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Distribution of Demographic Characteristics and Chronic Diseases Among Pemphigus Cases and Cohort Controls of the MHS HMO
Table Graphic Jump LocationTable 2. Purchase of Selected Medications Among Case Patients With Pemphigus During the 6 Months Before Diagnosis and Among Cohort Controls During the First 6 Months in 2000
Table Graphic Jump LocationTable 3. Number of Penicillin Packs Purchased During the 6 Months Before Diagnosis With Respective ORs

References

 Pemphigus: current concepts. Ann Intern Med 1980;92396- 405
PubMed Link to Article
Krain  LS Pemphigus: epidemiologic and survival characteristics of 59 patients, 1955-1973. Arch Dermatol 1974;110862- 865
PubMed Link to Article
Pisanti  SSharav  YKaufman  EPosner  L Pemphigus vulgaris: incidence in Jews of different ethnic groups, according to age, sex, and initial lesion. Oral Surg Oral Med Oral Pathol 1974;38382- 387
PubMed Link to Article
Simon  DGKrutchkoff  DKaslow  RZarbo  R Pemphigus in Hartford County, Connecticut, from 1972 to 1977. Arch Dermatol 1980;1161035- 1037
PubMed Link to Article
Tallab  TJoharji  HBahamdan  KKarkashan  EMourad  MIbrahim  K The incidence of pemphigus in the southern region of Saudi Arabia. Int J Dermatol 2001;40570- 572
PubMed Link to Article
Tsankov  NVassileva  SKamarashev  JKazandjieva  JKuzeva  V Epidemiology of pemphigus in Sofia, Bulgaria. Int J Dermatol 2000;39104- 108
PubMed Link to Article
Hashimoto  T Recent advances in the study of the pathophysiology of pemphigus. Arch Dermatol Res 2003;295S2- S11
PubMed
Brenner  STur  EShapiro  J  et al.  Pemphigus vulgaris: environmental factors. Int J Dermatol 2001;40562- 569published correction appears inInt J Dermatol. 2003; Sep42760
PubMed Link to Article
Ota  MSato-Matsumura  KMatsumura  TTsuji  YOhkawara  A Pemphigus foliaceus and figurate erythema in a patient with prostate cancer. Br J Dermatol 2000;142816- 818
PubMed Link to Article
Brenner  SRuocco  VWolf  Rde Angelis  ELombardi  M Pemphigus and dietary factors: in vitro acantholysis by allyl compounds of the genus Allium. Dermatology 1995;190197- 202
PubMed Link to Article
Cram  DWinkelmann  R Ultraviolet-induced acantholysis in pemphigus. Arch Dermatol 1965;927- 13
PubMed Link to Article
Kalra  ARatho  RKaur  IKumar  B Role of herpes simplex and cytomegalo viruses in recalcitrant oral lesions of pemphigus vulgaris. Int J Dermatol 2005;44259- 260
PubMed Link to Article
Martín  FJPerez-Bernal  ACamacho  F Pemphigus vulgaris and disseminated nocardiosis. J Eur Acad Dermatol Venereol 2000;14416- 418
PubMed Link to Article
Marsden  RAHill  HMowat  AWalshe  MVanhegan  RRyan  T Penicillamine-induced pemphigus. Proc R Soc Med 1977;70 ((suppl 3)) 103- 108
PubMed
Ruocco  VSatriano  RGuerrera  V “Two-step” pemphigus induction by ACE-inhibitors. Int J Dermatol 1992;3133- 36
PubMed Link to Article
Ruocco  VRossi  APisani  MAstarita  CAlviggi  L An abortive form of pemphigus vulgaris probably induced by penicillin. Dermatologica 1979;159266- 273
PubMed Link to Article
Duhra  PFoulds  I Penicillin-induced pemphigus vulgaris. Br J Dermatol 1988;118307
PubMed Link to Article
Goldberg  IIngher  ABrenner  S Pemphigus vulgaris triggered by rifampin and emotional stress. Skinmed 2004;3294
PubMed Link to Article
Goldberg  IKashman  YBrenner  S The induction of pemphigus by phenol drugs. Int J Dermatol 1999;38888- 892
PubMed Link to Article
Tur  EBrenner  S Contributing exogenous factors in pemphigus. Int J Dermatol 1997;36888- 893
PubMed Link to Article
Wohl  YBrenner  S Pemphigus in Israel. Isr Med Assoc J 2003;5410- 412
PubMed
Schlesselman  JJ Case-Control Studies: Design, Conduct, Analysis.  New York, NY Oxford University Press1982;
Rundle  AGVineis  PAhsan  H Design options for molecular epidemiology research within cohort studies. Cancer Epidemiol Biomarkers Prev 2005;141899- 1907
PubMed Link to Article
Alsaleh  QANanda  AAl-Baghli  NDvorak  R Pemphigus in Kuwait. Int J Dermatol 1999;38351- 356
PubMed Link to Article
Micali  GMusumeci  MNasca  M Epidemiologic analysis and clinical course of 84 consecutive cases of pemphigus in eastern Sicily. Int J Dermatol 1998;37197- 200
PubMed Link to Article
Salmanpour  RShahkar  HNamazi  MRahman-Shenas  M Epidemiology of pemphigus in south-western Iran. Int J Dermatol 2006;45103- 105
PubMed Link to Article
Uzun  SDurdu  MAkman  A  et al.  Pemphigus in the Mediterranean region of Turkey: a study of 148 cases. Int J Dermatol 2006;45523- 528
PubMed Link to Article

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