Portuguese Version

Year:  2003  Vol. 69   Ed. 3 - (6º)

Artigo Original

Pages: 327 to 331

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Oral involvement in pemphigus vulgaris

Author(s): Ivan Dieb Miziara[1],
João Aragão Ximenes Filho[2],
Fernando César Ribeiro2, Ana Laura Brandão[3]

Keywords: pemphigus/epidemiology, diagnosis/methods, outcome assessment.

Abstract:
Introduction: Pemphigus vulgaris (PV) is a bullous disease characterized by the presence of autoantibodies against intra-epidermal adhesion molecules. Objective: The aim of this study was to identify the characteristics of PV in each gender, forms of clinical presentation, age, diagnosis methods and management. Study Design: historical cohort. Method: Patients with PV treated in Otolaryngology Department from HC-FMUSP between 1990 and 2001. Results: From 23 patients, 91,3% were women and 8,7% men (p <0,01), proportion of 9:1. The age of diagnosis varied between 26 and 80 years, with average of 53 ± 18,4 years. In males, PV begun 24,6 ± 5,9 years earlier than in females (p=0,026). The most frequently sign in physical examination were bullous lesions in oral mucosa. Biopsy was used in 95% of the cases, direct immunofluorescence in 17,4% and indirect 8,7%. Prednisona was the therapeutic option in 78% of the patients, while deflazacort was used in 22%. Dapsona was associated in 4 cases. We obtained control of the disease in 74% of the cases and loss of the continuation after partial improvement in more 13% of the patients. We observed larger difficulty in disease control in males (p=0,04). Conclusions: The females prevailed over males. The age of diagnosis was higher in women. The treatment of choice was prednisona. PV was more easily controlled in females.

INTRODUCTION

Pemphigus vulgaris (PV) is a chronic vesicle-bullous disease of autoimmune nature. It affects the skin and mucosa and is characterized by the presence of autoantibodies against desmossome proteins found in epithelial junctions of recovering tissues 1. The most affected age range is between the 5th and 6th decades of life, being less frequent after the age of 70 years and in children 2, 3. There is disagreement in the literature concerning the affection of women. Wanke et al.4 (1990) stated that it affects equally men and women. However, Robinson et al.5 (1997) presented a proportion of 9 women for each group of 3 men.

In general, the disease starts with oral lesions, and later it affects the skin. The diagnosis is made by histopathology analysis that shows acantholytic low intradermal blisters, right over the basal membrane zone. Direct immunofluorescence helps diagnosis and reveals the presence of immunoglobulin G (IgG) in intracellular spaces of the epidermis. Differential diagnosis with pemphigus foliaceus is clinical, since the latter does not affect the mucosa 6. PV used to have a mortality of about 90% before the advance of corticoids. As a result of new therapeutic approaches, this index is somewhat below 20% 4, 5. Among the different corticoids, prednisone and deflazacort have been used as the preferred treatment for this affection 7. The other options are dapsone 3, oral therapy with gold 8, 9, cyclophosphamide 10, 11 and others less frequent ones.

The purpose of the present study was to compare the characteristics of PV in each gender, such as prevalence, most frequent age of onset, clinical presentations, duration of symptoms before diagnosis, in addition to the methods used in diagnosis. Special attention was devoted to treatment options adopted and the results they yielded.

MATERIAL AND METHOD

Sample

We reviewed the medical charts of patients with diagnosis of pemphigus vulgaris followed up and treated at the Ambulatory of Otorhinolaryngology, Hospital das Clínicas, Medical School, University of São Paulo, between January 1990 and December 2001.

We included only the medical charts that were complete and correctly filled out and had been followed up for at least 30 days or more. Medical charts with incomplete data, absence of defined diagnosis or shorter follow-up were excluded.

Method

We used a data collection form in which we included the studied variables. We recorded data concerning patients' identification, age at diagnosis, gender, race, duration of symptoms before diagnosis, complementary tests used, adopted treatment, follow-up and results obtained.
We divided the population in groups according to gender and compared the characteristics of PV in men and women and observed whether there were differences in the studied parameters. The comparisons between continuous data (age, time) were made using t Student's test. The remaining comparisons between male and female groups were made using chi-square test or Fischer's exact test. Data were analyzed in the software Microsoft Excel 2000 and SPSS 10.0 for Windows. We considered significance level of 95% (p<0.05).

RESULTS

The present study identified 23 patients with diagnosis of pemphigus vulgaris, being 21 (91.3%) female and 2 (8.7%) male subjects. Upon comparing with the data by Wanke et al. 4, in which there was no gender predominance, we found statistically significant differences (p<0.01). Upon comparing with the ratio 9 women to 3 men 5, we observed that our sample did not statistically differ from it (p=0.12) (Graph 1).

The age at diagnosis varied from 26 to 80 years, mean age of 53 ± 18.4 years. For males, the men age was 30.5 ± 6.36, whereas for women it was 55.1 ± 17.7 years. Comparing age and gender, we observed that in males, PV manifested 24.6 ± 5.9 years earlier than in females (p=0.026) (Graph 2).
The main finding in the physical examination was presence of ulcerated lesion of the oral mucosa, with the aspect similar to aphthas, no differences between genders (p=-0.39). These lesions can persist for weeks or months. The duration of symptoms before diagnosis ranged from 1 to 72 months, mean age of 24.3 ± 12.5 months (Graph 3). We did not find differences between genders (p=0.25). The main complementary tests used in order to define the diagnosis were: incisional biopsy of the oral lesion in 22 cases (95%) conducted with punch, direct immunofluorescence in 4 cases (17.4%) and indirect immunofluorescence in 2 cases (8.7%). We did not find differences between genders (p=0.47).

The main treatment modality was oral corticoid therapy, used in all cases. Prednisone was the option in 18 patients (78%), whereas deflazacort was used in 5 cases (22%). One of the patients used initially prednisone. but we replaced it by deflazacort as a result of side effects. Another used medication was dapsone, employed in 4 patients (17.4%). We did not find differences between the genders concerning the treatment options selected (p=0.09).

The results of treatments used were analyzed separately between male and female subjects (Graph 4), showing greater difficulty in controlling the disease in males (p=0.04). The follow-up time of patients varied from 6 to 84 months, with mean follow-up of 28.5 ± 14.9 (Graph 5), with no differences between genders (p=0.13).

DISCUSSION

Pemphigus vulgaris is a disease considered by many authors as having an obscure prognosis, and it may be fatal in over 90% of the untreated cases 12. Diagnosis and treatment are multidisciplinary, because they involve dentists, otorhinolaryngologists and dermatologists. In our study, we tried to assess the epidemiological characteristics of the subjects diagnosed and treated of oral PV in our service, comparing gender and observing the diagnostic methods, therapeutic options and responses to treatment.

As to number of studied subjects, we observed that other authors presented similar samples. Jimenez-Barea and Magnin8 (1990) presented 19 patients with PV, Maceira and Marques13 (1990) detected 17 cases within 9 years, whereas Fernandez and Perez14 (2001) studied 41 subjects with PV in 20 years in a large hospital in Rio de Janeiro. In our review, we detected 23 patients with PV in a 12-year period, all of them with oral affection, which demonstrates that our sample was compatible with the data reported in the literature.

The main results we obtained were differences between male and female subjects in prevalence, age of onset and responses to treatment. There is a discrepancy in the literature concerning prevalence of PV in both genders. Our sample confirmed the data of those authors that stated that female patients were more affected than males and we presented a 9:1 ratio, similarly to other auto-immune diseases. As to age and response to treatment, we did not find studies that demonstrated differences between genders. In our study, we observed that in males, PV manifested earlier and was more difficult to be controlled than the disease in females. However, since there were only two male subjects, it is difficult to infer based on such data. Multicenter studies, with more patients enrolled, are required to confirm such differences between the manifestations of PV in men and women.

The diagnosis of PV in the oral cavity is conducted by clinical pathology analysis in which rounded exfoliated acantholytic cells were evidenced 15. Direct immunofluorescence (DI), in which there is detection of the antibodies in the biopsed material, has been used to increase the sensitivity of the biopsy. Marceira and Marques13 (1990) demonstrated that this methods have high sensitivity in the diagnosis of PV. Schneider and Schneider15 (1998), however, stated that DI has little practical use. In our study, we used DI as a routine, together with the clinical pathology analysis, in order to improve sensitivity of the method.

Indirect immunofluorescence, in which detection of antibodies takes place in the peripheral blood, has also been used in PV patients. It seems to be positive in 66.6% of the diagnosis of the disease 13, but it is very useful to monitor the disease during clinical treatment with corticoids 15. In our center, we used this method as a predictive indicator of the disease activity, guiding us to tamper the anti-pemphigus medication

Many options have been used as PV treatment. Prednisone is, however, the preferred drug by most authors 3, 4, 16, presenting good results in controlling the disease. Normally, the drug is used for long periods, during months or years, up to negative responses in indirect immunofluorescence. Thus, there may be occasional significant side effects which require other therapeutic options.

In our study, we observed good results with prednisone. However, in some situations, we had to increase the dose to levels greater than 1 mg/kg/day. In such cases, we preferred to associate it with dapsone, at a dose of 100 mg/day 3, with good results. Other authors have used gold 8, 9, also with good results. However, the high cost and the side effects prevented it from becoming popular. Cyclophosphamide has also been proposed in such cases, and it may be used in intravenous pulses administered monthly or orally 11. However, the IV administration requires hospitalization for one day and has significant side effects, only justified in severe cases. The oral presentation has a significant immunosuppressing effect, requiring caution in its prescription.

Some patients presented, however, side effects even at low doses of prednisone (below 1 mg/Kg/day). In such cases, deflazacort in doses below 60 mg/day was used. This drug, despite its high cost, is the best option in such situations.

Finally, in our study, we followed up patients for up to 84 months, mean follow-up of 2 years. It is necessary to follow up patients because the therapy controls the disease, but does not cure it 12, requiring prolonged follow up, as well as patients' understanding of the natural history of the disease.

CONCLUSIONS

The main conclusion we drew from the study were:
1. The female gender prevailed over the male gender, in a 9:1 ratio.
2. The age of diagnosis was older in women;
3. Exulcerated lesion was the most frequent oral manifestation;
4. The preferred treatment was prednisone owing to its high control percentage and low cost;
5. PV was easily controlled in female patients.

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