ARTICLE Multiple
Sclerosis (MS) is a chronic demyelinating disease of the central nervous
system that occurs in young adults. The association of bullous diseases
with MS was first mentioned in 1965 by Sanders and Nelson [1] and cited
again in 1979 by Savin [2]. The first case of bullous pemphigoid (BP) was
described in detail by Simjee et al. in 1985 [3]. Since then about
thirty cases have been reported [4-13], although up to now a precise relationship
between MS and BP has not been identified. BP is considered an autoimmune
disease, and while the pathogenesis of MS has been the object of many studies
and hypothesis, it remains imperfectly understood. For both diseases numerous
triggering factors capable of determining the many alterations of the immune
system have been suggested but, so far, no common event which could in some
way explain their association has been found. We report two additional cases
of women affected by MS who subsequently developed BP and discuss the possible
causes that correlate the two diseases on the basis of the observations
of our patients and of the cases reported in literature.
Case reports
Case 1
A 54-year-old woman who had been suffering from rapidly progressing
multiple sclerosis for 3 years came to our observation because she had
developed a bullous dermatitis. The patient was bedridden because of a
spastic paraplegia with tendinous retractions, motor deficiency with spastic
hyper-tone involvement of the right upper limb, dysarthria and global
cognitive decay. She had decubitus ulcers on the sacrum and on the left
heel and had an indwelling catheter. The cutaneous picture was characterised
by tense serous blisters about 1 cm in diameter localised on the neck,
abdomen and back. The surrounding skin appeared normal. Erythematous or
erythematous-oedematous plaques of a dark red colour were also present
on the trunk and limbs where new blisters appeared after a few days (Fig.
1). The presence of 3 out of 4 Vaillant's clinical criteria [14] allowed
us to diagnose BP, which was later confirmed by laboratory tests. The
patient suffered from modest pruritus. The cytological examination showed
only connective and haematic cells. The histology revealed a dermo-epidermal
separation full of fibrin, eosinophils and neutrophils with unaffected
epidermis, modest dermal infiltrate of eosinophilic granulocytes and mononucleate
cells. Direct immunofluorescence revealed the presence of linear IgG and
complement (C3) deposits at the dermo-epidermal junction level. Salt split-skin
technique detected anti-BMZ antibodies (IgG) localized on the artificial
blister. Such findings confirmed the clinical suspicion of BP. The patient
was taking anxiolytic and spasmolytic drugs for her neurological disorder.
No other associated disease was present. The haematological examinations
revealed no alterations worthy of note. A systemic corticosteroid therapy
was started (initial dose: methyl-prednisolone 1 mg/kg/d); it resulted
in a rapid improvement of the clinical picture. After about one year without
recurrence of bullous manifestations there was a relapse which was treated
again with corticosteroids.
Case 2
A 60-year-old woman who had been affected by MS since the age of 43
came to our observation because of the appearance of a bullous dermatitis.
She was affected by severe spastic paraplegia in the lower limbs and a
marked hypo-asthenia of the upper limbs. She had no decubitus ulcers and
she had not been using an indwelling catheter for many months. The cutaneous
picture was characterised by diffused erythematous plaques varying from
bright to dark red in colour, bordered by tense blisters 1-3 cm in diameter
full of a limpid content and by ovular shaped erosions on a bright red
coloured base bordered by an epithelial edge. Oral mucosa involvement
was also present with whitish ovular erosions surrounded by a bright red
erythematous halo. The cytology excluded the presence of acantholytic
cells and evidenced only connective and haematic cells. The histologic
examination of a small blister showed an unaffected epidermis, a dermo-epidermal
separation inside which fibrin, eosinophils and neutrophils were present,
a dermal infiltrate with a prevalence of eosinophilic granulocytes and
with neutrophilic granulocytes and mononucleate cells. Direct immunofluorescence
revealed the presence of linear IgG and complement (C3) deposits at the
level of the dermo-epidermal junction. These data and indirect IMF study
performed using salt split-skin confirmed the diagnosis of BP. For her
neurological disorder the patient had taken anxiolytic and spasmolytic
drugs, but at the time of the onset of BP she was not under treatment.
The haematological examinations revealed no alterations worthy of note
and no other associated disorder was detected. Corticosteroid therapy
(initial dose: methyl-prednisolone 0.8 mg/kg/d) brought about a rapid
disappearance of the bullous lesions. About one year later erythematous
plaques, erosions and new blisters recurred but rapidly disappeared when
corticosteroid therapy was resumed.
Discussion
The cases we observed are to be added to the already numerous reports
in which BP developed in patients with various neurological disorders
(amyothrophic lateral sclerosis, senile dementia) and more frequently
with MS [15]. The observation that in our patients BP developed at an
age which is lower than the average age of onset of this dermatitis, as
confirmed in the cases reported in the literature [13], is another factor
that leads us to think that there is a correlation between the two diseases.
Among the various causes which have been suggested to explain the onset
of BP in MS patients are drug intake, bed confinement, traumatic events
and immunity [3-13]. From the revision of the literature and the observations
of our cases we can assert that many of the above mentioned causes cannot
continue to be sustained.
Drugs have often been taken into consideration as possible etiological
agents of BP and among these a very common muscle relaxant, Baclofen,
as well as topical iodates and drugs containing sulphides [3-5, 7, 8].
The pharmacological hypothesis is disproved by the absence of a temporal
correlation between the intake of the drugs and the onset of the cutaneous
manifestations and by the appearance of bullous eruptions when no drug
intake is present [13]. Moreover, in our patients there is no relation
between the onset of BP and the intake of drugs.
The bedridden state, paresia and traumatic events consequent to MS,
although always present in this disease, do not seem to be the causes
that determine the onset of BP, since a major incidence of BP is not found
in other disorders that induce bed confinement and/or paresia with catheterization
and decubitus ulcers. In our patients BP developed after years of bed
confinement and paresia, with no temporal correlation with the appearance
of decubitus ulcers or the use of catheters. As a matter of fact, in one
of the two patients, at the time of the onset of the skin disorder, no
decubitus ulcers were present and no catheter was being used. Besides,
we did not observe an increased incidence of BP in other patients of ours
who are bedridden and have similar problems.
The immunitary pathogenesis is the most likely.
Both the cutaneous and the neurological disorders have been described
in association with other immunopathogenic diseases (SLE, rheumatoid arthritis,
myasthenia, vitiligo, RCU) [16, 17]. An immunological link between BP
and MS could be investigated in the presence of 2 isoforms of the BP antigen
(BPAG1), an epthelial one and a neuronal one (BPAG1-n), as demonstrated
in mice by Brown et al. [18]. Nervous system (NS) alterations in
humans caused by MS could expose the neuronal isoform and thus trigger
an immunitary reaction that determines damage at the cutaneous level with
a cross-reaction mechanism. Something similar could also happen in the
BP of the aged, where, instead of a neurological disease, the neuro-isomero
could be exposed following the degenerative processes linked to ageing.
Such a thesis needs of course to be confirmed by further studies capable
of demonstrating whether modifications of the NS could somehow trigger
the cutaneous lesions.
To confirm that there is an association, a population study of individuals
with MS and of a suitable control population to look for the frequency
of BP might be worth performing.
Article accepted on 27/9/01
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