ARTICLE
Auteur(s) : Hana Jedlickova1,
Milos Hlubinka2, Tomas Pavlik3, Vera
Semradova1, Eva Budinska3, Zdenek
Vlasin2
1Ist Department of Dermatovenereology, Masaryk
University, St. Anna Faculty Hospital, Pekarska 53,656 91, Brno,
Czech Republic
2Department of Dermatovenereology, Masaryk
University, Faculty Hospital Bohunice, Brno, Czech Republic
3Institute for Biostatistics and Analyses
of Medical Faculty, Masaryk University, Brno, Czech
Republic
accepté le 31 Juillet 2009
Bullous pemphigoid (BP) is an autoimmune blistering disorder
with formation of auto antibodies against antigens in the
dermo-epidermal junction (BPAG1 and BPAG2 of molecular weights
230 kD and 180 kD, respectively). It typically affects
elderly people over 70 years of age and men are at a higher risk
[1]. Its incidence is estimated to 6-7 cases per million per year
[2]. The etiology of BP is unknown. Aging of immunity, association
with other autoimmune diseases and induction by drugs are among
possible causes; association with malignancies is suspected,
although the actual risk is unknown [3-5]. Recently an association
with neurological disorders has been suggested [6]. Supported by a
long clinical experience, we have tried to find statistically
significant associations among bullous pemphigoid and selected
internal diseases.
Patients and methods
The data group consisted of 178 persons, of those, 89 were patients
and 89 controls. There were 44 males (49.4%) and 45 females (50.6%)
in each group.The patients with bullous pemphigoid were diagnosed
and treated at the two departments of dermatovenereology of Masaryk
University, Brno over a period of 16 years (1991-2006). Their data
were collected in the register of the Centre of bullous diseases.
The diagnosis was made on the basis of clinical picture, histology,
direct and indirect immunofluorescence; 32 cases were confirmed by
ELISA tests. All dubious cases were excluded. Most of the patients
were in- patients. Controls were recruited from patients treated
for other skin diseases at the Ist Department of Dermatology over
the period 2000-2006 and were matched for age (same age in years)
and gender by an unbiased administrative worker. Their data were
retrieved from the computer database of the hospital (which had
started in 2000). Only controls with a complete history were
included and the ratio of in- to out-patients among BP patients and
controls was preserved. Dermatological disorders in controls were
mostly drug eruptions, leg ulcers, herpes zoster, erysipelas,
several patients suffered from psoriasis, mycosis fungoides,
scabies, nummular eczema, scleroderma and lupus erythematosus. Mean
age of males was 75 years, SD 8.4; mean age of females was 77
years, SD 9.03. The earliest onset of BP was at the age of 54, the
latest at the age of 94. The age distribution is shown in figure 1.
A complete history of the patients at the time of onset of BP
had been documented and for the analysis of any possible
association with other diseases, the following were selected:
hypertension and ischemic heart disease, diabetes mellitus,
neurological diseases, malignant tumors and benign prostate
hyperplasia. The selection was based either on the frequency of the
disease in the study group or on the reported associations with BP.
We did not consider any possible drug induction of BP in this
study.
The data collected were statistically evaluated. The main aim of
the analysis was to identify factors potentially influencing the
pemphigoid occurrence rate. For this, the unconditional logistic
regression analysis, adjusted for the age and gender of the
patients, was used. Possible multi-colinearity between considered
variables was verified using the Spearman correlation coefficient.
The maximum likelihood test for contingency tables was used for the
evaluation of the prostate hyperplasia and prostate cancer and for
further evaluation of the neurological diseases.
Results
The frequency of the selected internal diseases at the onset of BP
and in the control group is shown in the table
1. The logistic regression models were built up not
considering benign prostate hyperplasia, as this variable is
relevant only for men and would thus result in a decrease in the
power of the resulting model. In the univariate evaluation of the
selected predictors, only one variable, neurological disease was
found to be significantly associated with the occurrence of BP. All
models were further adjusted for age and gender, considering both
variables separately and in interaction. In all the models
constructed, only one significant variable interaction was found –
that between neurological disease and age. Therefore, two final
logistic models for two age categories, < 80 years and ≥ 80
years were constructed. The resulting odds ratios and corresponding
p-values for these two models are given in figure 2 and table 2. The analysis has shown that patients with
neurological disease in the age group ≥ 80 years are at a
higher risk of pemphigoid occurrence than patients without
neurological disease (odds ratio 10.55, 95% CI 2.68-41.49, p-value:
0.001). This association was not found for younger patients (age
< 80 years).
Most common in the BP group were cerebral stroke (n = 17 cases,
15.3%) and dementia (n = 18 cases, 16.0%). Cerebral stroke was more
frequent in men (13 men compared with 4 women). The difference was
statistically significant (p-value: 0.029). Other disorders
included Alzheimer’s disease, epilepsy, polyneuropathy,
neurofibromatosis and neuronal paresis, history of poliomyelitis,
depressive syndrome, and schizophrenia (table
3). Only one case of cerebral stroke was found in the
control group.
In our group of patients, the onset of BP correlated with
malignancy in 13 cases - prostate cancer (2), urinal bladder
cancer, stomach cancer, concomitant breast and endometrial cancer,
breast cancer, skin cancer (2) (squamous cell carcinoma, basal cell
carcinoma), metastatic cancer of unknown origin, mycosis fungoides;
2 cases of paraproteinemia (less than 5 g/L, IgG kappa and not
specified, respectively) and one patient who was diagnosed with
cancer of colon a year after the onset of BP were also included. 6
patients had a history of malignancy (14-4 years before the
onset of BP).
The frequency of DM in the BP patients in the age group >
80 years was higher than in controls (odds ratio 3.24, CI
95%), however this result was not statistically significant
(p-value: 0.192). We also found no statistically significant
difference between the patients and the controls in the frequency
of benign prostate hyperplasia and prostate cancer (p-value:
0.516).
From all the factors analyzed, only neurological disease in
interaction with age can be statistically significantly associated
with the occurrence of BP. Patients older than 80 years with
neurological disease have more than 10 times higher risk of bullous
pemphigoid compared with patients of the same age without
neurological disease. In the age category < 80 years the
influence of neurological disease on bullous pemphigoid was not
proved.
Table 1 Frequency of selected diseases at the onset of
BP and in the control group
|
Prostate hyperplasia
|
Hypertension
|
Neurologic disease
|
Ischemic heart disease
|
Diabetes mellitus
|
Recent malignant disease
|
Malignant disease (both recent and in history)
|
|
Patients
|
43.2%
|
50.6%
|
42.7%
|
56.2%
|
34.8%
|
14.6%
|
21.3%
|
|
Controls
|
33.3%
|
60.7%
|
19.1%
|
49.4%
|
31.5%
|
11.2%
|
15.7%
|
Table 2 The results of logistic regression on the two
models
|
Variable (risk factor)
|
Age category
|
Odds ratio
|
95% CI
|
p-value
|
|
Sex (female)
|
< 80 yrs
|
1.21
|
(0.29-5.09)
|
0.694
|
|
≥ 80 yrs
|
1.86
|
(0.45-7.80)
|
0.394
|
|
Diabetes
|
< 80 yrs
|
1.25
|
(0.22-7.20)
|
0.678
|
|
≥ 80 yrs
|
3.24
|
(0.55-18.89)
|
0.192
|
|
Ischemic heart disease
|
< 80 yrs
|
0.89
|
(0.23-3.37)
|
0.774
|
|
≥ 80 yrs
|
1.75
|
(0.45-6.75)
|
0.417
|
|
Malignancy
|
< 80 yrs
|
1.74
|
(0.43-6.96)
|
0.330
|
|
≥ 80 yrs
|
1.20
|
(0.33-4.40)
|
0.779
|
|
Neurological disease
|
< 80 yrs
|
1.52
|
(0.39-5.96)
|
0.348
|
|
≥ 80 yrs
|
10.55
|
(2.68-41.49)
|
0.001*
|
|
Interaction of gender (female) and diabetes
|
< 80 yrs
|
0.86
|
(0.08-9.08)
|
0.864
|
|
≥ 80 yrs
|
0.42
|
(0.04- 4.49)
|
0.476
|
Table 3 Neurological disorders in the BP group
|
Neurological disorder (38 patients)
|
|
Male/Female
|
|
Cerebral stroke
|
17
|
13/4
|
|
Dementia
|
18
|
6/12
|
|
Neurofibromatosis
|
1
|
M
|
|
Epilepsy
|
2
|
F
|
|
Polyneuropathy
|
1
|
M
|
|
Neuronal paresis
|
1
|
M
|
|
History of poliomyelitis
|
1
|
F
|
|
Depressive syndrome
|
1
|
F
|
|
Schizophrenia
|
1
|
F
|
|
Alzheimer disease
|
1
|
F
|
Discussion
Hypertension and ischemic heart disease are common in elderly
patients and were the most frequent diseases in our patients with
BP. No differences were found among patients with BP and controls;
these results show that the patients in the control group had a
comparable health status and support the value of the findings with
other diseases. Hypertension and ischemic heart disease play a role
in the prognosis of the BP patient, as treatment by corticosteroids
may influence blood pressure and heart disease; moreover, the drugs
used for the treatment of hypertension and heart disease can induce
BP [7].
An association of BP with diabetes mellitus has been suspected
by some authors [8-10]. Complex changes caused by glycation of
proteins of the dermo-epidermal junction zone may expose the BP
antigens to an autoimmune response. However, this study did not
show higher prevalence of DM in BP patients.
Benign prostate hyperplasia (BHP) is a frequent disease in
elderly male patients and was a frequent complaint in our patients
with BP, two patients had prostate cancer; our results did not show
any difference among the groups. Interestingly anti-basement
membrane zone antibodies were reported in patients with benign
prostate hyperplasia [11]. Normal basal cells in the prostate
express hemidesmosomal proteins including BPAG1 and BPAG2, basal
cells in prostate carcinoma lack expression of BPAG2, but some of
them express BPAG1 [12].
An association of BP with malignant tumors is controversial, it
remains unclear whether the relatively high incidence of malignant
tumors in BP patients can be explained by their high age or if
there is a common pathophysiological pathway. Case control studies
were conducted by Venning and Wojnarowska, who found a slightly
higher incidence of tumors in patients with BP than in controls
[13] and by Rzany, who found an increased risk of malignancies in
patients with BP (overall risk 1.6), especially in women (overall
risk 5.6) [14]. BP was mostly reported with carcinomas – of the
prostate, breast, stomach and colon [15-18] but other malignancies
were reported as well, e.g. lymphoma and leukemia [19, 20]. In anti
laminin 332 cicatricial pemphigoid (formerly anti epiligrin
CP-AECP) an association with tumors has also been reported, e.g.
with gastric cancer [21-23] and lung cancer [24, 25]. AECP seems to
be associated with an increased relative risk for cancer [26].
Our results did not show any important difference among BP
patients and controls. Although in some cases the course of BP
could have been regarded as a true paraneoplastic exanthema,
statistically, the association was not significant. We assume that
malignant tumors may be only one of several induction factors of BP
and the BP subset associated with malignancy remains to be defined,
and thus there may be no statistical evidence.
An association of BP with neurological diseases has been
repeatedly reported. Cases of BP have been described in patients
with multiple sclerosis [27-30], with amyotrophic lateral sclerosis
[31], neurofibromatosis [32], and in patients after cerebral
stroke, often affecting the hemiplegic side [33-35]. Neurological
manifestations have also been described in neonates of mothers with
herpes gestationis [36, 37]. A possible explanation of this
association was originally proposed by Foureur, based on clinical
observation in 46 BP patients [6]. He suspected association of BP
with neuronal degenerative proteins, i.e. dystonin, a cytoskeletal
linker protein forming a bridge between F-actin and intermediate
filaments [38]. Several isoforms of BPAG1 have been described –
epidermal BPAG1-e, neuronal BPAG1-a (detected in the brain and
spinal cord), BPAG1-b (striated muscles and cartilage in mouse
embryos) and BPAG1-n (i.e. dystonin detected in the peripheral
sensory neurons, Schwann cells). The relation of both BP antigens
to neurological disorders has been investigated further. Lafitte
detected reactivity of the cerebrospinal fluid of patients with
multiple sclerosis against BPAG1-e [39]. Li reported that serum
antibody from patients with BP and brain haemorhage recognizes
BPAG1 in the mouse brain [40]. Seppänen detected collagen XVII
(i.e. BPAG2) in neurons in the human brain and has investigated the
expression of collagen XVII in the human brain in motor neuron
disease [41, 42]. Anti BPAG2 antibodies have been found in patients
with dementia without clinical signs of BP [43].
Recently, neurological disorders in patients with BP were
studied by Cordel from the French Study Group of Bullous Diseases,
who found at least one neurological disorder in 36% of patients
with BP, particularly dementia, cerebral stroke, and Parkinson
disease [44]. Stinco and co-workers also found a significant
association of BP with Parkinson disease and multiple sclerosis in
a large retrospective epidemiological study [45].
In our study we found at least one neurological disorder in
42.7% of patients with BP. Most common were cerebral stroke and
dementia. Dementia was often found in combination with other
disorders. Patients with cerebral stroke had often severe BP and we
also observed a worse course of BP on limbs affected by paresis
(figures 3A, B);
moreover, stroke was significantly more frequent in men with
BP.
Conclusion
This case control study showed a surprisingly high prevalence of
neurological disorders, especially cerebral stroke and dementia in
the BP patients, confirming the recent observations. It did not
confirm the expected association of BP with malignant tumors,
prostate hyperplasia, and diabetes mellitus. We suspect that
several mechanisms are involved in triggering the autoimmune
response in bullous pemphigoid. Among them, neurodegenerative
processes seem to play an important role, and further studies are
needed to elucidate the pathways of autoimmune reactivity against
BP antigens in neurological disorders.
Acknowledgments
We thank Prof. M. Hertl and Dr. A. Niedermeier (Department of
Dermatology and Allergology, Philipps University, Marburg, Germany)
for performing the ELISA tests. Financial support: none. Conflict
of interest: none.
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