ARTICLE
In 1990, Anhalt et al. delineated a new autoimmune syndrome characterized
by 5 criteria: (I) mucocutaneous lesions with blisters and/or erosions,
(II) epidermal acantholysis and interface changes in histology, (III)
epidermal and basement membrane-zone deposition of IgG and complement
detected by direct immunofluorescence, (IV) detection of serum antibodies
to various epithelia, and (V) immunoprecipitation of a characteristic
complex of proteins from keratinocytes with serum antibodies [1]. In all
cases reported so far, this syndrome has been associated with underlying,
usually malignant neoplasms (e.g. non-Hodgkin lymphoma, chronic
lymphocytic leukemia, Castleman's disease, thymoma, spindle cell neoplasms
and Waldenström's macroglobulinemia) [1, 2]. Therefore, the term
paraneoplastic pemphigus (PNP) was introduced.
PNP is a severe, life-threatening disease and most patients described
so far have succumbed shortly after diagnosis despite extensive immunosuppressive
therapy. We report the clinical course of a patient with PNP and Waldenström's
macroglobulinemia who was treated twice with an i.v. dexamethasone/cyclophosphamide
pulse therapy followed by oral cyclophosphamide.
Case report
A 84-year-old man with Waldenström's macroglobulinemia presented
with a 5-week history of a symmetrical rash. On the trunk and extremities
multiple confluent erythematous macules and plaques were present some
of which had a targetoid appearence. There were focal desquamation and
erosions, whereas flaccid bullae were scarce (Fig.
1a). The Nikolski sign was positive. Oral and genital mucosa were
severely affected with multiple painful erosions, the eyes showed bilateral
conjunctivitis (Fig. 2a).
Laboratory findings
Routine histological examination of skin lesions showed parakeratosis,
focal suprabasal acantholysis, degenerated keratinocytes, vacuolization
of the basal cell layer and exocytosis of inflammatory cells into the
epidermis (Fig. 3). Direct
immunofluorescence revealed intercellular binding of IgG and C3 within
the epidermis. Circulating antibodies bound intercellularly to monkey
esophagus (IgG 1:320; IgA 1:2) and to rat bladder transitional epithelium
(IgG 1:80; IgM, IgA and C3 positive).
Clinical course
Treatment with i.v. dexamethasone/cyclophosphamide pulse therapy (day
1: cyclophosphamide 500 mg i.v.; day 1-3: dexamethasone 100 mg i.v.) was
initiated and repeated after 3 weeks. After the second cycle, therapy
was continued with oral cyclophosphamide 50 mg/d. The skin lesions vanished
after 4 weeks leaving widespread post-inflammatory hyperpigmentation,
and the oral and genital mucous membranes improved significantly (Figs.
1b, 2b). Despite the positive response to treatment the patient
attempted to commit suicide and suffered a rib fracture with subsequent
pneumonia.
Under treatment, the titer of circulating autoantibodies (monkey oesophagus:
IgG 1:80; rat bladder: negative) as well as serologically detectable IgM
lambda decreased significantly. Leukocytopenia, which occurred as a side
effect of oral cyclophosphamide therapy, was successfully treated with
granulocyte colony stimulating factor (GCSF).
The patient was discharged from hospital after 2 months with mild erosions
of the oral mucosa and moderate conjunctival inflammation. Local antiseptic
treatment was continued. Three months later, severe stomatitis and conjunctivitis
recurred but the patient rejected any further systemic treatment.
Discussion
We report a patient with Waldenström's macroglobulinemia who developed
clinical, histological and immunopathological features characteristic
of PNP. Waldenströms's macroglobulinemia, a B-cell malignancy, is
typically associated with PNP [1-4].
The etiology of the syndrome is a matter of speculation, but there is
reason to believe that the tumor may initiate a cell-mediated and/or humoral
immune response. The disease is characterized by autoantibody production
to desmoplakin I, desmoplakin II, bullous pemphigoid antigen, and other
antigens in the desmosomal complex. The tumor may possibly express these
epithelial proteins which are targeted by the antitumor immune response.
Cross reactivity with normal epithelial proteins may occur and cell-mediated
cytotoxicity against epithelium may cause the polymorphous mucosal and
skin lesions [1-4]. Because of these assumed pathogenetic mechanisms it
seems rational to treat the disorder with immunosuppressive drugs if surgical
eradication of the underlying tumor is not possible.
Various immunosuppressive agents have been tried and although there
are recent reports of long-time survivors most patients died because of
complications due to medical treatment or from the disease or neoplasm.
Improvement of PNP has been observed in some cases, with cyclosporine
[5-7], azathioprine in combination with corticosteroids [7-10], and plasmapheresis
[11].
The dexamethasone/cyclophosphamide pulse regimen
applied in our patient has been used with great success in the treatment
of pemphigus vulgaris, foliaceus and erythematosus. Pasricha et al.
achieved 60 remissions in 79 cases treated with this regimen [12]. Kaur
and Kanwar as well as Appelhans et al. presented similar encouraging
results [13, 14]. Pandya et al. reported a case of cicatrical pemphigoid
successfully treated with high-dose cyclophosphamide pulse therapy in
combination with oral prednisone [15]. Pulse intravenous cyclophosphamide
treatment of autoimmune blistering diseases seems to have advantages as
compared to oral therapy. The total cumulative dose of cyclophosphamide
is lower in patients treated with pulses rather than oral cyclophosphamide,
which may reduce long term side effects. However, multicenter studies
are needed to verify this assumption [16]. For these reasons and because
cyclophosphamide has cytotoxic effects on
B-cells, dexamethasone/cyclophosphamide pulse therapy was chosen in our
PNP-patient with Waldenström's macroglobulinemia. Specific treatments
for Waldenström's hypergammaglobulinemia were not needed.
The skin lesions responded rapidly and completely whereas the mucous
membranes healed slowly and only partially which is in agreement with
previous observations. Optimal therapy for mucosal involvement of PNP
still remains uncertain [4, 5, 7].
In spite of responding to our therapy and tolerating the medication
well the patient attempted to commit suicide. Personality changes ranging
from nervousness, insomnia, euphoria or mood swings to psychotic changes
are well-known but rare side effects of systemically administered corticosteroids.
Psychiatric examination could not exclude the possibility of a corticosteroid-associated
side effect in our patient but a link between therapy and suicide attempt
seemed questionable because the patient had tolerated previous corticosteroid
treatments in the past. Suicide as a side effect of dexamethasone/cyclophosphamid
pulse therapy has never been reported in earlier studies.
After the second pulse therapy, the patient was treated with oral low
dose cyclophosphamide for a short time and afterwards solely with local
antiseptics. Two months after discharge from hospital the severe oral
lesions reappeared simultaneously with recurrent bacterial conjunctivitis.
However, the patient refused any further immunosuppressive treatment of
the exacerbation and died only a few weeks later.
Treatment of PNP has to be a combination of mostly palliative therapy
of the underlying neoplasm and immunosuppression of the autoimmune process.
With regard to the latter, dexamethasone/cyclophosphamide pulse therapy
seems to be a promising therapeutic approach although long-term experience
is missing.
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