ARTICLE
Auteur(s) : L
Peramiquel, MA Barnadas, CL Pimentel, MP García Muret, LL Puig,
C Gelpí, M Agustí, A Alomar
Hospital de la Santa Creu i Sant Pau, Dermatology department,
St. Antoni Ma Claret, 167, 08025-Barcelona, Spain
accepté le 8 Juillet 2006
Multiple sclerosis (MS) is a chronic demyelinating disease of the
central nervous system that predominantly affects young individuals
in temperate climates. It is a T cell-mediated autoimmune disease
triggered by as yet unknown exogenous agents in subjects with a
specific genetic background. An infectious etiology is indicated by
epidemiological studies because of similarities to infectious
demyelinating diseases [1].Bullous pemphigoid (BP) is a chronic
blistering disease most frequently seen in elderly patients. The
highest incidence is found in the seventh decade of life and there
is no known sex predilection. Patients with BP usually have
circulating antibodies against two hemidesmosomal glycoproteins, BP
230 (BPAG1) and BP 180 (BPAG2).Many autoimmune disorders have been
associated with BP: systemic lupus erythematosus [2, 3], rheumatoid
arthritis, pernicious anemia [3, 4], myasthenia gravis [3, 5],
primary biliary cirrhosis, vitiligo [3, 6], Hashimoto’s thyroiditis
[3, 7], insulin-dependent diabetes mellitus (type I) [8],
ulcerative colitis [9], polymyositis [10], polymyalgia rheumatica
[11], alopecia areata [12] and multiple sclerosis [3].The
association of BP with demyelinating or degenerative central
nervous system diseases was first mentioned by Sanders and Nelson
in 1965 [13] and was again described by Savin in 1979. [14]
According to a Medline search, 25 cases [15-29] (table 1) of BP
associated with MS have been described in detail since 1985. We
report an 2 additional cases of this association.
Case reports
Case 1
( Table 1 )A 20-year-old woman visited
our department in November 2001. She had a 1-month history of
distal blisters on her upper limbs involving her palms. The lesions
had progressively spread to the abdomen, lower limbs and soles. At
the moment of consultation she presented urticariform plaques and
blisters located over healthy and non-healthy skin.
Her past medical history revealed that she had been diagnosed
with MS 5 years earlier. Since that time, she had been on treatment
with baclofen and tizanidine, subcutaneous beta interferon 1b every
48 hours was added in 1998. She had occasionally been treated with
systemic corticosteroids, most recently in November 2000.
A skin biopsy showed a subepidermal vesicle with an inflammatory
infiltrate composed of neutrophils and occasional eosinophils (
(figure 1)
).
The direct immunofluorescence test (DIF) demonstrated linear
deposits of IgG and C3 at the dermal-epidermal junction. The DIF
study using the patient’s skin previously treated with 1M NaCl
localized the IgG at the epidermal side. BP was diagnosed.
Repeated indirect immunofluorescence tests (IIF) using guinea
pig and monkey esophagus, as substrates did not detect
anti-basement membrane antibodies in 3 tests performed over 3
years.
Therapy with prednisone 60 mg/day, topical corticosteroids and
dapsone 50mg/day was initiated and the disease was well controlled.
She completed 15 months of corticosteroid therapy and 23 months of
dapsone without any recurrence. In January 2004 she presented with
a new flare of vesicles on the left sole and right palm. Dapsone
and topical corticosteroids were reintroduced and the disease was
controlled. The other drugs were continued throughout this period
and propanolol, gabapentin and glatiramer acetate were added.
Table 1 Characteristics of patients reported in the
literature and the present study
|
Authors (year)
|
Age/Sex
|
Interval: MS-first blisters (years)
|
Direct IF
|
Indirect IF
|
Western blot
|
Treatment duration (months)
|
Follow-up (months)
|
Recurrences
|
Other diseases
|
|
CLNa
|
|
|
|
|
|
|
Simjee et al. (1985) [15]
|
49/F
|
13
|
+
|
NR
|
NR
|
NR
|
Syst Cort (6 m)
|
48 m
|
No
|
RF >1/320
|
|
Simjee et al. (1985) [15]
|
62/F
|
23
|
NR
|
+ 1:640
|
NR
|
NR
|
Syst Cort (8 m)
|
42 m
|
No
|
|
|
Simjee et al. (1985) [15]
|
35/M
|
18
|
+
|
+ 1:640
|
NR
|
NR
|
Top Cort (NR)
|
3y
|
No
|
|
|
Pedragosa et al. (1986) [16]
|
53/M
|
16
|
+
|
–
|
NR
|
NR
|
Syst Cort (NR)
|
NR
|
No
|
|
|
Masouyé et al. (1988) [17]
|
83/M
|
48
|
+
|
–
|
–
|
220 kDa
|
Syst S Top Cort (8 m)
|
48 m-died
|
No
|
Evans’ syndrome pulmonary malignancy ANA 1/50
|
|
Masouyé et al. (1988) [17]
|
53/M
|
13
|
+
|
+ 1:50
|
+
|
220 to 240 kDa
|
Syst Cort Ch (6 m)
|
60 m
|
No
|
|
|
Masouyé et al. (1988) [17]
|
63/F
|
29
|
+
|
–
|
–
|
240 kDa
|
Top Cort (4 m)
|
5 m
|
No
|
Rheumatoid arthritis (RF -), AH
|
|
Saada et al. (1990) [18]
|
52/M
|
8
|
+
|
+ 1:100
|
NR
|
NR
|
Syst Cort AZA (>6 m)
|
6 m
|
No
|
Psoriasis
|
|
Gebauer et al. (1990) [19]
|
78/F
|
20
|
+
|
+
|
NR
|
NR
|
Syst Cort AZA (NR)
|
NR
|
No
|
|
|
Gebauer et al. (1990) [19]
|
62/M
|
30
|
+
|
+
|
NR
|
NR
|
Syst Cort AZA (NR)
|
NR
|
No
|
|
|
Trozak DJ. (1990) [20]
|
43/M
|
19
|
+
|
NR
|
NR
|
NR
|
Syst Cort (15 m) Tripelennamine (21 m)
|
31 m
|
No
|
|
|
Machet et al. (1991) [21]
|
73/F
|
40
|
+
|
+ 1:100
|
NR
|
NR
|
Syst Cort (>18 m)
|
18 m
|
No
|
|
|
Doutre et al. (1991) [22]
|
48/M
|
11
|
+
|
+ 1:100
|
NR
|
NR
|
Syst Cort AZA (24 m)
|
30 m
|
No
|
|
|
Tomasini et Bonfacini (1991) [23]
|
50/M
|
21
|
+
|
+ 1:80
|
NR
|
NR
|
Syst Cort (NR)
|
NR
|
No
|
|
|
Martín-Ortega et al. (1991) [24]
|
56/M
|
20
|
+
|
+
|
NR
|
NR
|
Erythromycin Top Cort (NR)
|
NR
|
No
|
|
|
Tohme et al. (1993) [25]
|
40/F
|
15
|
+
|
NR
|
NR
|
NR
|
Syst Cort (5 m)
|
6 m
|
No
|
|
|
Nuñez et al. (1995) [26]
|
63/M
|
26
|
+
|
+ 1:640
|
NR
|
NR
|
Syst Cort (11 m)
|
60 m
|
No
|
|
|
Kirtschig et al. (1995) [27]
|
45/M
|
16
|
+
|
NR
|
+
|
230 and faintly 180 kDa
|
Syst Cort AZA (24 m)
|
96 m
|
No
|
|
|
Kirtschig et al. (1995) [27]
|
75/F
|
13
|
+
|
NR
|
+
|
230 kDa
|
Syst Cort (18 m)
|
24 m–died
|
No
|
AH, trigeminal neuralgia, asthma
|
|
Kirtschig et al. (1995) [27]
|
47/F
|
29
|
–
|
NR
|
+
|
180 kDa
|
Syst Cort (12 m)
|
12 m
|
No
|
AH
|
|
Stinco et al. (2002) [28]
|
54/F
|
3
|
+
|
NR
|
+
|
NR
|
Syst Cort (NR)
|
NR
|
1year
|
|
|
Stinco et al. (2002) [28]
|
60/F
|
17
|
+
|
NR
|
+
|
NR
|
Syst Cort (NR)
|
NR
|
1year
|
|
|
Stinco et al. (2005)
|
57/F
|
14
|
+
|
NR
|
NR
|
NR
|
Syst Cort
|
NR
|
No
|
|
|
Stinco et al. (2005)
|
49/F
|
6
|
+
|
NR
|
NR
|
NR
|
Syst Cort
|
NR
|
No
|
|
|
Stinco et al. (2005)
|
53/F
|
3
|
+
|
NR
|
NR
|
NR
|
Syst Cort Plasma–pheresis AZA
|
NR
|
No
|
|
|
Peramiquel et al. Case 1
|
20/F
|
5
|
+
|
–
|
NR
|
NR
|
Syst Cort (15 m) Dapsone (23 m)
|
23 m
|
25 m
|
|
|
Peramiquel et al. Case 2
|
59/F
|
10
|
+
|
–
|
NR
|
NR
|
Syst Cort (14 m)
|
15 m
|
No
|
|
Case 2
A 59-year-old woman attended our department in July 2002 presenting
with a 2-week history of urticarial plaques on her arms. The
lesions had spread to the abdomen and lower limbs and were
associated with tense blisters, mainly located over the
urticariform plaques. She did not present any lesions on her palms
or soles. She had been diagnosed with MS 10 years earlier. She was
under treatment with baclofen and had not required systemic
corticosteroids in the previous 3 years ( (figure 2) ).
Histopathologic examination of an urticarial plaque revealed
chronic superficial perivascular dermatitis with focal epidermal
spongiosis. There was no vesiculation or acantholysis.
DIF demonstrated a linear deposit of IgG and C3 at the
dermal-epidermal junction ( (figure 3). ) The DIF study
using the patient’s skin previously treated with 1M NaCl, localized
the IgG on the epidermal side. BP was diagnosed.
Repeated IIF using guinea pig and monkey esophagus as substrates
did not detect anti-basement membrane antibodies in either of the
two determinations performed over one year.
Therapy with prednisone 60 mg/day was initiated and the disease
was controlled. The patient completed a 14-month course of
corticosteroids and continued to take baclofen. She has had no
recurrence and is presently in remission without treatment.
ELISA studies
In both cases we performed the ELISA test using the commercial kit
MBL that identifies antibodies directed against epitopes located in
the domain NC16A of the extracellular fragment of the BP180 (BP
antigen 2).
In the first patient, the ELISA test performed 2 months after
starting corticotherapy was positive, 32 U/mL (Normal < 9 U/mL).
A second ELISA test performed 20 months after diagnosis, when BP
was controlled only with dapsone, continued to be positive, 63
U/mL. The third test, which was performed during the new flare-up 2
months after dapsone was stopped, was also positive, 88 U/mL.
In the second patient, the ELISA test was performed at the onset
of the BP episode and was strongly positive, 106 U/mL
(Normal < 9 U/mL). It decreased to 7 U/mL eleven months later
but increased to 42 U/mL four months after therapy was stopped,
while she was asymptomatic.
Discussion
We report two patients who had been diagnosed with MS 5 and 10
years prior to the development of BP. BP was extensive in both
patients and was easily controlled with systemic corticosteroids
and dapsone.
A review of the literature showed an association between BP and
MS in 35 cases, the first being published by Sanders and Nelson in
1965. [13] However, only 25 cases were reported in detail, the
first of these by Simjee et al. in 1985 [15].
Twelve of the 25 patients were males and 13 were females. The
age of onset of BP ranged between 35 and 83 years with a mean of 56
years. We would like to emphasize the younger age of this group of
patients compared with usual BP patients. All patients presented
with BP after having been diagnosed with MS for years, with a mean
interval of 19 years.
BP diagnosis was confirmed by histopathologic examination and
direct immunofluorescence in most patients. Indirect ID was
performed in 19 cases and was positive in 16, 8 were tested on
1mol/L sodium chloride-separated skin. Western blotting was
performed in only 6 cases, two of whom had antibodies against 180
KDa antigen as in our two cases, and five had antibodies against
either 230 KDa antigen or very close antigens (220-240 KDa) that
most likely represents BP230 [17, 27]. According to our findings we
can not rule out the presence of antibodies against the BPAG1.
We did not find any cases of BP associated with MS, which were
studied by the ELISA technique. The results obtained with this
technique in the two present patients allowed us to establish a BP
diagnosis.
It should be emphasized that while IIF studies were repeatedly
negative, the ELISA test was positive. Some authors consider the
ELISA technique is more sensitive than other standard techniques
for detecting circulating BP autoantibodies such as IIF, IIF on
salt split skin and even other enzyme-linked immunoabsorbent assays
and immunoblotting studies. [30] The ELISA test may be therefore
more useful for diagnosis of BP than IIF [30].
Most patients in the reported studies required systemic
treatment: thirteen received oral corticosteroids alone, in six
corticosteroids were combined with azathioprine, and other
therapeutic modalities were used in the remaining cases. Two
patients were treated only with topical corticosteroids. Treatment
with systemic corticosteroids lasted between 5 and 24 months with a
mean of 13 months. Only two cases presented a documented flare-up
after one year of follow-up [28]. None of the patients died due to
BP.
Foureur [31] reported a higher prevalence of neurological
diseases in BP patients in comparison to a group of patients with
other skin diseases of similar age. Stinco et al. [29] recently
reported an epidemiological study that showed a highly significant
association of BP with MS or Parkinson’s disease. These studies
suggest that there may be a pathogenic link between BP and
neurological disorders.
It has been suggested that drugs, decubital lesions, traumatic
events and immunity are triggering factors for BP during the course
of neurological pathologies [17-29, 31].
The possibility that MS patients present drug-induced BP has
been discussed in the literature [20, 27, 29]. Baclofen is the most
frequently administered drug in this group of patients. The fact
that our second patient is in remission in spite of continuing
baclofen appears to contradict this hypothesis. However, recurrence
in the first patient raises the question about the possible
triggering role of baclofen or tizanidine. Furthermore, Trozak [20]
did not observe a chronological relationship between therapy with
baclofen and the flares of BP in one patient. The possibility of
drug-induced BP in these patients is therefore unlikely as in most
reported cases medication did not influence the course of BP.
The influence of physical traumas, decubital lesions or
paralysis can be ruled out because of a lack of any temporal
relation of these events with the BP course [29].
In isolated cases, BP has been associated with several
autoimmune diseases, although a large case control study performed
by Taylor et al. [32] in 1993 did not confirm this hypothesis.
Furthermore, these authors were unable to detect any particular
haplotype associated to BP.
The homology between the dystonin gene(dt), which is found in
mice neurons, and the BPAG1 gene raises the question about the
possible connection between these disorders [33].
Laffite et al. detected antibodies against the recombinant
protein [GST)-BPAG1-e 1880-2649 in the cerebrospinal
fluid (CSF) of 2 out of 18 (11%) MS patients. This observation
raises the possibility that a subset of patients with MS can
develop antibodies against the neuronal variants of BPAG-1, most
probably in the context of an intermolecular epitope-spreading
phenomenon. These findings suggest that neuronal BPAG-1 variants
may be potential novel targets of central nervous system diseases
[34].
Acknowledgements
Financial support: None. Conflict of interest: None.
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