ARTICLE
Auteur(s) : Paolo
Amerio1, Daniela Di Rollo1,2, Angelo
Carbone1, Matteo Auriemma1, Maria Elena
Marra1, Pierluigi De Remigis3, Claudio
Feliciani2, Marco Tracanna1, Antonio
Tulli1
1Dept of Dermatology, University
of Chieti-Pescara, Chieti, Italy
2Dept of Dermatology, Catholic University
of the Sacred Heart, Rome, Italy
3Service of Endocrinology, SS. Annunziata Hospital,
ASL Chieti, Italy
accepté le 12 Janvier 2010
Vitiligo is an acquired hypomelanotic disorder, characterized by
depigmented macules resulting from the loss of functional
melanocytes. It has been classified into two major groups:
segmental and non segmental vitiligo (table
1). Many different etiologic hypotheses have been presented
for vitiligo. The most recent of these hypotheses supports the
combination of environmental and genetic factors interacting to
contribute to autoimmune melanocyte destruction [1, 2].
Among the most powerful features in support of an autoimmune
origin of vitiligo there is the epidemiological association with
autoimmune diseases. Recently, several candidate genes have been
identified that appear to mediate susceptibility both to
generalized vitiligo and to a specific group of vitiligo-associated
autoimmune diseases [3-6]. The most frequent type of autoimmune
condition described is thyroid autoimmune disease (present,
according to the literature, in 14-34% of vitiligo patients).
Thyroid autoimmune disease is sometimes part of a condition
termed “autoimmune polyglandular syndrome” (APS). APS has been
defined as an heterogeneous group of diseases associating
autoimmune disorders with multiple endocrine-gland insufficiencies.
In 1980, Neufeld and Blizzard set out the first APS classification,
dividing this syndrome into three subtypes [7]. Recently this
classification it has been modified describing four subtypes:
APS-1 is characterized by presence of chronic candidiasis,
chronic hypoparathyroidism and Addison's disease (at least two
conditions must be present); APS-2 describes the presentation
of Addison's disease with autoimmune thyroid disease and/or type
1 diabetes mellitus. Autoimmune thyroid disease associated to
other autoimmune diseases (excluding Addison's disease and/or
hypoparathyroidism) is the main characteristic of APS-3, which is
subdivided into: APS-3A which includes all endocrine diseases;
APS-3B where there is the association of thyroid disease with
gastrointestinal autoimmune diseases; APS-3C is the association of
thyroid autoimmune conditions with skin, haemopoietic and nervous
system autoimmune pathologies and, finally, APS-3D is associated
with all collagen diseases and vasculitis. APS-4, futhermore,
groups all clinical associations not included in the previous APS
subtypes [8] (table 2).
Vitiligo has been described in APS-1 and APS-2 with
various frequencies; however, the most frequent association appears
to be that present in APS-3 [9]. Here we report 31 cases of
APS diagnosed in 113 patients with vitiligo according to the
newest classification, stressing the need to thoroughly investigate
all patients with vitiligo for other autoimmune diseases.
Subjects and methods
One hundred and thirteen consecutive vitiligo patients from the
Dermatology Autoimmune Disease Clinic of the Department of
Dermatology of the University of Chieti from September 2003 to
July 2007 were included in the study.
This clinic provides consultation for patients who present with
autoimmune diseases or a family history of autoimmune disease,
referred by general practitioners and dermatologists. For each
patient we tested serum levels of: thyroid stimulating hormone
(TSH) (Roche Diagnostics, Milan, Italy), thyroid autoantibodies,
anti-thyroglobulin antibodies (HTG-Ab) and anti-thyroid peroxidase
antibodies (TPO-Ab), (Medical Systems spa, Genova, Italy),
anti-nuclear antibodies (ANA), extractable nuclear antibodies (ENA)
(Diametra, Milan, Italy), anti-gastric parietal cell antibodies
(APCA), anti-liver-kidney-muscle antibodies (LKM), anti-adrenal
gland antibodies (Menarini Diagnostics Firenze, Italy),
anti-gliadin antibodies, anti-endomysium antibodies and
anti-transglutaminase antibodies (TG-Ab) (Chematil Srl, Salerno,
Italy). All tests were performed according to the manufacturer's
suggestions.
If the serological tests on autoimmunity were positive, patients
underwent specific instrumental examinations such as ultrasound
examination of the thyroid gland (7.5 MHz transducer),
gastroscopy, etc. to confirm the diagnosis. Each patient was also
asked to complete a self administered questionnaire containing
questions about their vitiligo characteristics, time of disease
onset and familiar autoimmune disease associations. Only
50 patients completed and returned the questionnaire.
Table 1 Classification of vitiligo
|
Segmental Vitiligo
|
Clinical features
|
|
Zoosteriformis
|
Macules distributed along a dermatome
|
|
Non segmental Vitiligo
|
Clinical features
|
|
Localized or partial or focal
|
1-2 macules
|
|
Acrofacialis
|
Macules localized on the face and on the tips of the hands and
feet
|
|
Generalized
|
Macules involving the hands, face, axillae, and limbs
|
|
Mucosal
|
Macules of mucous membranes
|
Table 2 Classification of APS (modified from [8])
|
APS 1
|
APS 2
|
APS 3
|
APS 4
|
|
Chronic candidiasis
|
Addison's disease always present
|
Autoimmune thyroid disease (Hashimoto's thyroiditis, primary
myxoedema, symptomless autoimmune thyroiditis, Graves’ disease,
pretibial myxoedema, endocrine ophatlmophaty) always present
plus
|
Combinations not included in the previous groups for example
vitiligo and alopecia, Type 1 DM and coeliac disease, Type 1 DM and
vitiligo and others
|
|
and/or Chronic hypoparathyroidism
|
Autoimmune thyroid disease
|
APS 3A
|
APS 3B
|
APS 3C
|
APS 3D
|
|
and/or Addison's disease
|
and/or Type 1 diabetes mellitus
|
Endocrine Disease
|
Gastrointestinal or Hepatic Autoimmune Disease
|
Skin, Neural or Neuromuscolar Autoimmune Disease
|
Collagen, Vascular or Haematologic Autoimmune Disease
|
|
At least 2 of above must be present
|
AD always present plus one or two of the others
|
Type 1 DM, adeno- and neurohypophysitis, premature ovarian failure,
Hirata's disease
|
Autoimmune gastritis, pernicious anaemia, coeliac disease, chronic
inflammatory bowel diseases, autoimmune hepatitis, primary biliary
cirrhosis
|
Vitiligo, alopecia, myasthenia gravis, multiple sclerosis,
stiff-man syndrome, chronic urticaria
|
Systemic and discoid lupus erythematosus, rheumatoid arthritis,
seronegative arthritis, systemic sclerosis, Sjogren's syndrome,
Werlhof's syndrome, antiphospholipid syndrome, vasculitis
|
Results
The clinical characteristics of the 113 patients are
summarized in table 3.
Thyroid disease
We found that 23.8% of study group presented with autoimmune
thyroid dysfunction characterized by elevated values of TSH,
positivity to anti-thyroid auto-antibodies and non-homogeneous
structure of the gland in the thyroid ultrasonography. Within those
affected by autoimmune thyroiditis about 30% presented anti-TPO,
25% anti-HTG and the remaining 45% presented both.
Table 3 Clinical characteristics of patients included
in the study
|
Males
|
Females
|
|
38 (33.6%)
|
75 (66.3%)
|
|
Subtypes of vitiligo
|
|
Acrofacial
|
50 (44.2%)
|
|
Generalized
|
59 (52.2%)
|
|
Segmental
|
4 (3.5%)
|
|
Mean age at onset
|
|
Male
|
25 years
|
|
Female
|
32 years
|
|
Age (range)
|
|
Males
|
Females
|
|
20-71 years
|
19-70 years
|
Autoimmunity screening test
Positivity to PCA was present in 3.53% of vitiligo patients and
gastric biopsy always confirmed autoimmune gastritis. Three percent
of patients were positive for ANA at a titer of > 1:320 and
0.8% were positive for anti-adrenal gland auto-antibodies (figure 1).
Cases of autoimmune polyglandular syndromes
Within this study population we identified 22 cases of APS
type 3C: 21 of them were affected by autoimmune thyroiditis
and vitiligo and 1 case had autoimmune thyroiditis, vitiligo
and alopecia areata. Three cases of APS type 3B+C were affected by
vitiligo, autoimmune thyroiditis and autoimmune gastritis. One case
of APS 3C+A was affected by autoimmune thyroiditis, vitiligo,
alopecia areata and anti-adrenal gland autoantibody positivity and
this patient also presented ANA positivity. Five cases were of APS
type 4: one patient affected by vitiligo, myastenia gravis, and
bullous pemphigoid with PCA positivity, one patient affected by
vitiligo and autoimmune gastritis with APCA positivity, two
patients affected by vitiligo and alopecia, and one patient
affected by vitiligo and undifferentiated arthritis with ANA
positivity (table 4).
Most APS patients (58%) presented generalized vitiligo while 38%
of these patients had an acrofacial type of vitiligo; the
percentage of patients with segmental vitiligo was minimal (3%)
(table 4). Female sex (n = 20) was
preponderant among APS cases (mean age 55 years; range
40-70 years). The 11 males had a mean age of
41 years (range 20-59 years). The mean duration of
vitiligo in these patients was 14.6 years (range
6-37 years).
Table 4 Types of APS identified in the study
population: sub-classification by vitiligo type
|
APS 3C
|
APS 3B+C
|
APS 4
|
APS 3C+A
|
Patients
|
|
Generalized vitiligo
|
11
|
3
|
3
|
1
|
18
|
|
Acrofacial vitiligo
|
10
|
0
|
2
|
0
|
12
|
|
Segmental vitiligo
|
1
|
0
|
0
|
0
|
1
|
Questionnaire
Among the vitiligo patients who returned the questionnaire, 46%
presented a familiar history for autoimmune disease. Of these: 55%
reported family cases of vitiligo, 39% cases of autoimmune
thyroiditis and in 6% of patients there was a familiar history of
diabetes mellitus type I (figure 2).
Discussion
Vitiligo is a chronic disease which is mostly acquired early in
life. In our study, the mean age at onset was 25 years in
males and 32 years in females. In a recent paper, the
frequency of vitiligo was reported to be approximately equal in
males and females. We observed a female preponderance (66.3%). This
observation could be due to a referral bias to our clinic or to
female interest in cosmetic care [10, 11].
The pathogenesis of this disease is still not clear but is
considered to be multifactorial, since multiple triggering factors
may intervene on a genetic background, in order to induce
biochemical changes in melanin formation, or autoimmune changes
that ultimately lead to the hypopigmented macules of vitiligo [12,
13]. The autoimmune hypothesis has been the most studied in
vitiligo [1, 2]. Among the features in support of this mechanism
there is the association of vitiligo with other autoimmune diseases
[14]. Genetic association studies have shown that HLA-DRB4, HLA-A2,
CTLA4, PTPN22 alleles predispose to generalized vitiligo.
These genetic associations tend to be more frequent among patients
and families affected by generalized vitiligo associated with
autoimmune disease [6, 15].
The most frequent vitiligo-associated autoimmune disease is
autoimmune thyroiditis. However other diseases, such as rheumatoid
arthritis, diabetes mellitus, pernicious anemia and many others,
have been described in variable percentages depending upon the
genetics of the population studied [16-18].
Sometimes this association is thought to be part of a syndrome
characterized by the failure of several endocrine glands as well as
other organs, caused by an immune-mediated destruction of tissues
known as Autoimmune Polyglandular Syndromes [7, 8]. Vitiligo can be
present in all types of APS, however, the most frequent association
is with type 3 APS (autoimmune thyroiditis and vitiligo and/or
another skin related autoimmune disease) [9].
Our series of patients suggests that vitiligo-associated
autoimmune disease presentation is more complex than thought.
We think, as we have already suggested [19], that there is a
need for periodical screening for anti-thyroid autoantibodies in
vitiligo patients at least every 3 years. In the case of
positivity for anti-thyroid autoantibodies, it is necessary to test
for other autoantibodies, like anti-gastric parietal cell,
anti-pancreatic islet-cell and anti-adrenal gland autoantibodies.
Only with this extensive research will we be able to better
follow-up the complexity of autoimmune diseases associated with
vitiligo.
Most of our patients with associated autoimmune diseases
presented generalized vitiligo, while a small percentage presented
a segmental type of vitiligo. These latter patients, thus, may be
excluded from this extensive search. We were not able to find any
differences in the natural histories of the disease in
APS-associated vitiligo and vitiligo-only patients. Our study
confirms a higher incidence of autoimmune diseases in female
patients, as previously described in literature, reporting
20 female cases of APS and only 11 male cases of APS.
We found a well defined correlation between vitiligo and serum
anti-thyroid auto-antibody presence. Many other authors have
demonstrated how thyroid auto-antibodies are more frequent in
vitiligo patients compared to control groups, with frequencies
varying from 18 to 50%, so our data reflect those from the
literature [14, 20].
In our series we did not find any vitiligo patient with
anti-gliadin or anti-transglutaminase autoantibody positivity, this
is in accordance with other authors and suggests that there is only
a coincidental correlation between vitiligo and celiac disease
[21].
Our study shows a well documented association between vitiligo
and autoimmune gastritis, with presence of anti-parietal cell
auto-antibodies (APCA) and a further association of vitiligo and
alopecia areata [22, 23]. Vitiligo occurs with increased frequency
in the rare recessive autoimmune
polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome
(APECED), caused by a mutation of the autoimmune regulator gene
(AIRE) on chromosome 21q22.3. Recently, in the literature, an
association between alopecia areata and single nucleotide
polymorphisms in the AIRE gene has been reported [24]. Although
none of our patients had APECED, we found the association of
vitiligo and alopecia areata in three subjects.
In our patient series, the association between vitiligo and
Addison's disease was very rare. We found one case of Addison's
disease in 113 patients, which is far higher than reported
frequencies in the healthy population.
In our series of patients, ANA positivity was 3% at a titer of
1: 320. This finding is not very different from that reported in a
normal population. This finding reflects the data from other
authors that have demonstrated how, in series of patients with
vitiligo, ANA positivity is not statistically different from that
found in the control population. Moreover it seems that ANA do not
necessarily play a role in the pathogenesis of vitiligo [25] and
have not been associated with multiple autoimmune diseases in these
patients. We think that this is also the case in our series of
patients and that, thus, this kind of investigation could be
avoided in the vitiligo work-up. In another series of patients, ANA
positivity was only related to a smaller thyroid volume when
thyroid disease was present, however, in the same study there was
no difference in ANA frequency from control population [26].
We were surprised by the high rate of patients who presented
with three or more autoimmune conditions. To our knowledge, this is
the first time that so many associations have been described in a
series of patients.
We acknowledge that our data analysis could be incomplete for
the lack of a control population and that a referral bias to our
autoimmune clinic is probably present. Nevertheless the frequency
of different APS was impressive. Our figures are in accordance with
the literature data which shows that more than 50% of vitiligo
patients may present with organ specific auto-antibodies. This
strong association is specific for vitiligo, since it is not
present in other autoimmune diseases such as alopecia areata
[27].
Moreover, studies conducted in the Italian population have shown
that systemic and organ-specific autoimmune disease may occur in
5-8% of people [28], thus, with a far lower frequency than that
reported in the present study.
In conclusion, these results add to our previously published
study [19] concerning the usefulness of regular screening to
evaluate the coexistence of different auto-antibodies in patients
affected by vitiligo and/or autoimmune thyroiditis. This screening
should be performed for a long period of time, since the interval
between vitiligo and the occurrence of thyroid disease can be over
20 years [29]. This is the most effective way to find vitiligo
patients who are incubating another autoimmune disease, which would
otherwise remain unknown and untreated.
Acknowledgements
Financial support: none. Conflict of interest: none.
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