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Oral mucous membrane pemphigoid
oral medicine Editor: JAMES
W. LITTLE,
D.M.D.,
M.S.D.
School of Dentistry University of Minnesota 515 S.E. Delaware St. Minneapolis, Minn. 55455
Oral mucous membrane pemphigoid A study of sixty-five
patients
S. Silverman, Jr., M.A., D.D.S.,* M. Gorsky, D.M.D.,** F. Lozada-Nur, D.D.S., M.S.,*** and A. Liu, D.D.S.,**** San Francisco, Calif. SCHOOL OF DENTISTRY, UNIVERSITY
OF CALIFORNIA
SAN FRANCISCO
Sixty-five patients with oral mucous membrane pemphigoid were examined, treated, and followed for a mean of 3.5 years. Seventy-two percent were women, and the mean age was 59 years. In most patients multiple oral sites were involved and the gingiva was affected in 94% of the patients. Seven patients had ocular lesions (symblepharon), and seven others had nasal, vaginal, or pharyngeal involvement. Persons with skin lesions (bullous form) were not included in this series. Topical and systemic anti-inflammatory/immunosuppressive medications were successful in controlling signs and symptoms. There were no spontaneous remissions. Candidiasis, tobacco, other diseases, and drugs did not appear to be related to the-pemphigoid. (ORAL SURC. ORAL MED. ORAL PATHOL. 61:233-237, 1986)
M
ucous membrane pemphigoid is a chronic immunocomplex disease that affects the basement membrane zone of the mucosa.’ Etiologic factors are not known. The disease seems to occur more frequently in women, and it is related to age. While the oral mucosa is the most common site, other mucous membranes can be affected. The diseaseis manifested by erythematous changes, vesicles, and pseudomembrane-covered ulcerations. Biopsy specimens are characterized by a separation of the epithelial layer from the underlying connective tissue and a nonspecific inflammatory infiltrate. Specimens also react to immunoglobulin antibodies at the basement membrane zone when they are processedby immunofluorescent techniques. The lesions are often painful. *Professor and Chairman, Oral Medicine. **Visiting Postdoctoral Scholar, Oral Medicine; Assistant Professor, Sackler School of Dental Medicine, Tel-Aviv University, Tel Aviv, Israel. ***Assistant Professor, Oral Medicine. ****Visiting Postdoctoral Scholar, Oral Medicine.
1. This 63-year-old woman, in otherwise good health, had moderate chronic gingival pain, exacerbated by food and brushing, for 2 years. The only oral lesion was gingival erythema. Biopsy confirmed mucous membrane pemphigoid.
Fig.
The purpose of this study was to characterize patients with oral mucous membrane pemphigoid with respect to diagnostic features, management, and progression of disease. 233
234 Silverman et al.
Oral
Surg.
March, 1986
Fig. 2. Painful pemphigoid of 15 months’ duration in a 70-year-old woman. The patient had mild hypertension and a symblepharon in one eye. The oral lesions were confined to the gingiva and were manifested by erythema, pseudomembrane-coveredulcerations, edema, and occasional bleeding. Note beginning vesicle (arrows).
Table I. Profile
Fig. 3. Severely painful pemphigoid of 3 years’ duration in a 74-year-old woman. The patient had mild arthritis, controlled by aspirin, and mild hypertension, controlled by a diuretic. Tenderness precluded normal eating habits and optimal hygiene. The epithelium was constantly sloughing, which caused almost constant bleeding.
of sixty-five patients with mucous membrane pemphigoid
Age in years
Duration of disease in years
Sites of involvement * (percent)
Sex
No. (95)
Mean (range)
G
P
B
L
F
T
Eye
Mean (range)
F M
41 (72) 18 (28) 65 (100)
58 (19-82) 62 (43-80) 59 (19-82)
92 joJ 94
29 41 32
23 47 29
17 Is 17
4 6 5
4 12 5
II .!I II
3.5 (0.5-12) 3.6 (0.5-I 3) 3.5 (0.5-13)
of mouth;
T = tongue.
*G = gingiva:
P = palate:
B = buccal;
L = labial
mucosa;
F = floor
II. Findings in sixty-five patients with mucous membrane pemphigoid at time of diagnosis
Table
Treatment responsesin sixty-five patients with mucous membrane pemphigoid
Table III.
Response scale*
~ Sex 33
F M
*Most
31
49
31
3
2
41
22
33
30
47
30
frequent:
Hypertension,
betes = 13%; arthritis
MATERIALS
cardiovascular
= 23%; allergies
= 14%; dia-
= 3%.
AND METHODS
The study group comprised sixty-five patients with oral mucous membrane pemphigoid seenin the Oral Medicine Clinic of the University of California San Francisco. There were forty-seven women and eighteen men, and the mean age at onset of the disease was 59 years. Sixty-two of the patients were white, and three were Orientals. Diagnoses were confirmed
Symptoms (mean)
Remission
Signs (mean)
Partial (No.)
Complete iN0.i
F
3.2
2.9
39
M
u
2j
14
.A
3.1
2.7
53
12
*Response I = slight;
scale
for
2 = moderate;
patients
with
3 = marked;
partial
improvement:
8
0 = none:
4 = complete.
by clinical appearance, chronicity, and biopsy specimens which showed epithelial-connective tissue separation and nonspecific inflammation. In addition, direct immunofluorescence was positive in 8 1%. Complete histories were obtained and examinations were performed on all patients. Treatment was undertaken, with the desired end point being the achievement of an acceptable degree of comfort for
Volume Number
hl 3
4. Pemphigoid afflicting the palate for 1 year in a 60-year-old otherwise healthy woman. The ulcerations were moderately uncomfortable, especially during mealtime.
Fig.
Fig. 5. Pemphigoid initially mistaken as either denture trauma or allergy. The ulcer was present more than 4 years prior to the correct diagnosis and corticosteroid control.
the patient with minimal medication. Each patient was treated with systemic prednisone and/or a fluocinonide (Lidex)-Orabase paste. Some patients received azathioprine (Imuran) in combination with prednisone. The mean follow-up time was 3.5 years. FINDINGS
Table I lists the characteristics of the sixty-five patients (Figs. 1 to 8). The most commonly involved site was the gingival mucosa. Seven patients (11%) had evidence of symblepharon (Figs. 9 and 10). Four patients had nasal involvement, two had vaginal lesions, and one had pharyngeal lesions. Table II indicates that associatedrisk factors were not evident. Tobacco usage and positive candidal cultures were consistent with frequencies found in
Oral mucous membrane pemphigoid
235
Fig. 6. This 67-year-old woman had pseudomembranecovered ulcers, erythema, and pain of 4 months’ duration. She also had a symblepharon of one eye and hyperglycemia secondary to obesity. Pemphigoid was confirmed by routine staining and immunofluorescence of biopsy material.
Fig. 7. In this patient with pemphigoid, the lack of epithelial-connective tissue anchoring in the basement zone is demonstrated by the easy peeling off of fullthickness epithelium.
the normal population. Forty-seven percent manifested other diseases.Cardiovascular diseaseand/or hypertension were the most frequent, occurring in twelve patients. At the time of onset of disease,only 33% of the patients were using any medications that might have triggered an antigen-antibody type of reaction. The most frequently used medications were cardiovascular regulating agents, diuretics, and tranquilizers. Table III shows symptoms and treatment outcome. It is evident that the treatment modalities were effective in decreasing the severity of both signs and symptoms in all patients. In addition, a complete remission of signs and symptoms occurred in twelve
236 Silverman et al.
oKi1SUrg. March.
1986
Fig. 9. Symblepharon of right eye caused symptoms of constant irritation, described as “sand in my eye.”
Fig. 8. Spontaneous separation of epithelium and connective tissue is shown in this biopsy specimen.
patients while they were undergoing ment.
drug treat-
DISCUSSION
This study confirms that mucous membrane pemphigoid is a chronic disease that primarily involves oral mucosa, usually appears after middle age, and has a predilection for women. Previous articlesze6 reporting a pemphigoid series combined patients with the skin-involved bullous form and those with the mucous membrane cicatricial form of the disease.The oral findings in the two types appear to be similar. Studies by other authors have reported findings similar to ours: a female predominance, mean age at onset beyond 50 years, and the gingival mucosa as the most commonly involved site.2-6However, all the other investigators found a higher frequency of eye involvement, ranging from 22% to 62%.* Symblepharon (scarring between eyelid and conjunctiva) is irreversible, sometimes progressive, and may obscure vision. Causative factors remain unknown, with no apparent evidence to support the etiologic influence of family history, food products, any drug, or a microbial agent. Therefore, an age-related autoimmune
Fig.
10. Scar extension from this symblepharon led to
blindness.
antigen-antibody reaction aimed at certain basement-membrane-zone constituents best accounts for the cause. Progression and spontaneous remission of pemphigoid are rare. Flares are frequently associated with local irritants (food, flossing, brushing). Treatment is often required becauseof associatedpain and bleeding. Systemic and/or topical corticoids will help by altering lymphocyte (antigen-antibody) complexes. The degree of remission (partial or complete) dependsupon a balance between desired reduction in signs and symptoms and tolerance of or side effects from the medications.7*8With careful titration of drug schedules and side effects, discomfort associated with the disease can be controlled. When the minimal effective dose of prednisone cannot be tolerated, a lowered effective dosecan be attained by combining prednisone with azathioprine.9 Topical corticosteroids, alone or in combination, are also effective.‘0 The corticosteroid must be potent and applied frequently. We have been most success-
Oral mucous membrane pemphigoid
Volume 61 Number 3
ful with fluocinonide ointment (0.05% Lidex) mixed with equal parts Orabase. Occasionally candidiasis will complicate control becausechanges produced by corticoids (usually increased glucose) can enhance fungal growth. In such cases,antifungal agents will effectively control these complications. Since mucous membrane pemphigoid is a chronic illness and the gingiva is the most common site (often the only involved site), the diagnosis may be missed and effective control may be precluded. Patients often are categorized as having “desquamative gingivitis, poor hygiene, or bacterial infection.” 1. Lever WF: Pemphigus and pemphigoid: a review of the advances made since 1964. J Am Acad Dermatol 1: 2-31, 1979. 2. Shklar G, McCarthy PL: Oral lesions of mucous membrane pemphigoid; a study of 85 cases. Arch Otolaryngol 93: 354-364, 1971. 3. Dabelsteen E, Ullman S, Thomsen K, Rygaard J: Demonstration of basement membrane autoantibodies in patients with benign mucous membrane pemphigoid. Acta Dermatovener (Stockh) 54: 189-192, 1974. 4. Foster ME, Nally FF: Benign mucous membrane pemphigoid (cicatricial mucosal pemphigoid): a reconsideration. ORAL SURG ORAL MED ORAL PATHOL 44: 697-705,
5. Mitchell RD: Cicatricial pemphigoid: a review of eleven cases.Aust Dent J 24: 260-265, 1979. 6. Laskaris G, Sklavounou A, Stratigos J: Bullous pemphigoid, cicatricial pemphigoid and pemphigus vulgaris; a comparative clinical survey of 278 cases. ORAL SURG ORAL MED ORAL PATHOL 54: 656-662,
1977.
1982.
7. Lozada F, Silverman S Jr, Migliorati C: Adverse side effects associated with prednisone in the treatment of patients with oral inflammatory ulcerative diseases.J Am Dent Assoc 109: 260-270, 1984. 8. Silverman S Jr, Lozada-Nur F, Migliorati C: Clinical efficacy of prednisone in the treatment of patients with oral inflammatory ulcerative diseases: a study of fifty-five patients. ORAL SURG ORAL MED ORAL PATHOL 59: 360-363, 1985.
9. Lozada F: Prednisone and azathioprine in the treatment of oral inflammatory disease. ORAL. SURG ORAL MED ORAL PATHOL 52: 257-260,
REFERENCES
237
1981.
10. Lozada F, Silverman S Jr: Topically applied fluocinonide in an adhesive base in the treatment of oral vesiculoerosive diseases.Arch Dermatol 116: 898-901, 1980. Reprint requests to:
Dr. Sol Silverman, Jr. School of Dentistry S-647 University of California San Francisco. CA 94143
W. LITTLE,
D.M.D.,
M.S.D.
School of Dentistry University of Minnesota 515 S.E. Delaware St. Minneapolis, Minn. 55455
Oral mucous membrane pemphigoid A study of sixty-five
patients
S. Silverman, Jr., M.A., D.D.S.,* M. Gorsky, D.M.D.,** F. Lozada-Nur, D.D.S., M.S.,*** and A. Liu, D.D.S.,**** San Francisco, Calif. SCHOOL OF DENTISTRY, UNIVERSITY
OF CALIFORNIA
SAN FRANCISCO
Sixty-five patients with oral mucous membrane pemphigoid were examined, treated, and followed for a mean of 3.5 years. Seventy-two percent were women, and the mean age was 59 years. In most patients multiple oral sites were involved and the gingiva was affected in 94% of the patients. Seven patients had ocular lesions (symblepharon), and seven others had nasal, vaginal, or pharyngeal involvement. Persons with skin lesions (bullous form) were not included in this series. Topical and systemic anti-inflammatory/immunosuppressive medications were successful in controlling signs and symptoms. There were no spontaneous remissions. Candidiasis, tobacco, other diseases, and drugs did not appear to be related to the-pemphigoid. (ORAL SURC. ORAL MED. ORAL PATHOL. 61:233-237, 1986)
M
ucous membrane pemphigoid is a chronic immunocomplex disease that affects the basement membrane zone of the mucosa.’ Etiologic factors are not known. The disease seems to occur more frequently in women, and it is related to age. While the oral mucosa is the most common site, other mucous membranes can be affected. The diseaseis manifested by erythematous changes, vesicles, and pseudomembrane-covered ulcerations. Biopsy specimens are characterized by a separation of the epithelial layer from the underlying connective tissue and a nonspecific inflammatory infiltrate. Specimens also react to immunoglobulin antibodies at the basement membrane zone when they are processedby immunofluorescent techniques. The lesions are often painful. *Professor and Chairman, Oral Medicine. **Visiting Postdoctoral Scholar, Oral Medicine; Assistant Professor, Sackler School of Dental Medicine, Tel-Aviv University, Tel Aviv, Israel. ***Assistant Professor, Oral Medicine. ****Visiting Postdoctoral Scholar, Oral Medicine.
1. This 63-year-old woman, in otherwise good health, had moderate chronic gingival pain, exacerbated by food and brushing, for 2 years. The only oral lesion was gingival erythema. Biopsy confirmed mucous membrane pemphigoid.
Fig.
The purpose of this study was to characterize patients with oral mucous membrane pemphigoid with respect to diagnostic features, management, and progression of disease. 233
234 Silverman et al.
Oral
Surg.
March, 1986
Fig. 2. Painful pemphigoid of 15 months’ duration in a 70-year-old woman. The patient had mild hypertension and a symblepharon in one eye. The oral lesions were confined to the gingiva and were manifested by erythema, pseudomembrane-coveredulcerations, edema, and occasional bleeding. Note beginning vesicle (arrows).
Table I. Profile
Fig. 3. Severely painful pemphigoid of 3 years’ duration in a 74-year-old woman. The patient had mild arthritis, controlled by aspirin, and mild hypertension, controlled by a diuretic. Tenderness precluded normal eating habits and optimal hygiene. The epithelium was constantly sloughing, which caused almost constant bleeding.
of sixty-five patients with mucous membrane pemphigoid
Age in years
Duration of disease in years
Sites of involvement * (percent)
Sex
No. (95)
Mean (range)
G
P
B
L
F
T
Eye
Mean (range)
F M
41 (72) 18 (28) 65 (100)
58 (19-82) 62 (43-80) 59 (19-82)
92 joJ 94
29 41 32
23 47 29
17 Is 17
4 6 5
4 12 5
II .!I II
3.5 (0.5-12) 3.6 (0.5-I 3) 3.5 (0.5-13)
of mouth;
T = tongue.
*G = gingiva:
P = palate:
B = buccal;
L = labial
mucosa;
F = floor
II. Findings in sixty-five patients with mucous membrane pemphigoid at time of diagnosis
Table
Treatment responsesin sixty-five patients with mucous membrane pemphigoid
Table III.
Response scale*
~ Sex 33
F M
*Most
31
49
31
3
2
41
22
33
30
47
30
frequent:
Hypertension,
betes = 13%; arthritis
MATERIALS
cardiovascular
= 23%; allergies
= 14%; dia-
= 3%.
AND METHODS
The study group comprised sixty-five patients with oral mucous membrane pemphigoid seenin the Oral Medicine Clinic of the University of California San Francisco. There were forty-seven women and eighteen men, and the mean age at onset of the disease was 59 years. Sixty-two of the patients were white, and three were Orientals. Diagnoses were confirmed
Symptoms (mean)
Remission
Signs (mean)
Partial (No.)
Complete iN0.i
F
3.2
2.9
39
M
u
2j
14
.A
3.1
2.7
53
12
*Response I = slight;
scale
for
2 = moderate;
patients
with
3 = marked;
partial
improvement:
8
0 = none:
4 = complete.
by clinical appearance, chronicity, and biopsy specimens which showed epithelial-connective tissue separation and nonspecific inflammation. In addition, direct immunofluorescence was positive in 8 1%. Complete histories were obtained and examinations were performed on all patients. Treatment was undertaken, with the desired end point being the achievement of an acceptable degree of comfort for
Volume Number
hl 3
4. Pemphigoid afflicting the palate for 1 year in a 60-year-old otherwise healthy woman. The ulcerations were moderately uncomfortable, especially during mealtime.
Fig.
Fig. 5. Pemphigoid initially mistaken as either denture trauma or allergy. The ulcer was present more than 4 years prior to the correct diagnosis and corticosteroid control.
the patient with minimal medication. Each patient was treated with systemic prednisone and/or a fluocinonide (Lidex)-Orabase paste. Some patients received azathioprine (Imuran) in combination with prednisone. The mean follow-up time was 3.5 years. FINDINGS
Table I lists the characteristics of the sixty-five patients (Figs. 1 to 8). The most commonly involved site was the gingival mucosa. Seven patients (11%) had evidence of symblepharon (Figs. 9 and 10). Four patients had nasal involvement, two had vaginal lesions, and one had pharyngeal lesions. Table II indicates that associatedrisk factors were not evident. Tobacco usage and positive candidal cultures were consistent with frequencies found in
Oral mucous membrane pemphigoid
235
Fig. 6. This 67-year-old woman had pseudomembranecovered ulcers, erythema, and pain of 4 months’ duration. She also had a symblepharon of one eye and hyperglycemia secondary to obesity. Pemphigoid was confirmed by routine staining and immunofluorescence of biopsy material.
Fig. 7. In this patient with pemphigoid, the lack of epithelial-connective tissue anchoring in the basement zone is demonstrated by the easy peeling off of fullthickness epithelium.
the normal population. Forty-seven percent manifested other diseases.Cardiovascular diseaseand/or hypertension were the most frequent, occurring in twelve patients. At the time of onset of disease,only 33% of the patients were using any medications that might have triggered an antigen-antibody type of reaction. The most frequently used medications were cardiovascular regulating agents, diuretics, and tranquilizers. Table III shows symptoms and treatment outcome. It is evident that the treatment modalities were effective in decreasing the severity of both signs and symptoms in all patients. In addition, a complete remission of signs and symptoms occurred in twelve
236 Silverman et al.
oKi1SUrg. March.
1986
Fig. 9. Symblepharon of right eye caused symptoms of constant irritation, described as “sand in my eye.”
Fig. 8. Spontaneous separation of epithelium and connective tissue is shown in this biopsy specimen.
patients while they were undergoing ment.
drug treat-
DISCUSSION
This study confirms that mucous membrane pemphigoid is a chronic disease that primarily involves oral mucosa, usually appears after middle age, and has a predilection for women. Previous articlesze6 reporting a pemphigoid series combined patients with the skin-involved bullous form and those with the mucous membrane cicatricial form of the disease.The oral findings in the two types appear to be similar. Studies by other authors have reported findings similar to ours: a female predominance, mean age at onset beyond 50 years, and the gingival mucosa as the most commonly involved site.2-6However, all the other investigators found a higher frequency of eye involvement, ranging from 22% to 62%.* Symblepharon (scarring between eyelid and conjunctiva) is irreversible, sometimes progressive, and may obscure vision. Causative factors remain unknown, with no apparent evidence to support the etiologic influence of family history, food products, any drug, or a microbial agent. Therefore, an age-related autoimmune
Fig.
10. Scar extension from this symblepharon led to
blindness.
antigen-antibody reaction aimed at certain basement-membrane-zone constituents best accounts for the cause. Progression and spontaneous remission of pemphigoid are rare. Flares are frequently associated with local irritants (food, flossing, brushing). Treatment is often required becauseof associatedpain and bleeding. Systemic and/or topical corticoids will help by altering lymphocyte (antigen-antibody) complexes. The degree of remission (partial or complete) dependsupon a balance between desired reduction in signs and symptoms and tolerance of or side effects from the medications.7*8With careful titration of drug schedules and side effects, discomfort associated with the disease can be controlled. When the minimal effective dose of prednisone cannot be tolerated, a lowered effective dosecan be attained by combining prednisone with azathioprine.9 Topical corticosteroids, alone or in combination, are also effective.‘0 The corticosteroid must be potent and applied frequently. We have been most success-
Oral mucous membrane pemphigoid
Volume 61 Number 3
ful with fluocinonide ointment (0.05% Lidex) mixed with equal parts Orabase. Occasionally candidiasis will complicate control becausechanges produced by corticoids (usually increased glucose) can enhance fungal growth. In such cases,antifungal agents will effectively control these complications. Since mucous membrane pemphigoid is a chronic illness and the gingiva is the most common site (often the only involved site), the diagnosis may be missed and effective control may be precluded. Patients often are categorized as having “desquamative gingivitis, poor hygiene, or bacterial infection.” 1. Lever WF: Pemphigus and pemphigoid: a review of the advances made since 1964. J Am Acad Dermatol 1: 2-31, 1979. 2. Shklar G, McCarthy PL: Oral lesions of mucous membrane pemphigoid; a study of 85 cases. Arch Otolaryngol 93: 354-364, 1971. 3. Dabelsteen E, Ullman S, Thomsen K, Rygaard J: Demonstration of basement membrane autoantibodies in patients with benign mucous membrane pemphigoid. Acta Dermatovener (Stockh) 54: 189-192, 1974. 4. Foster ME, Nally FF: Benign mucous membrane pemphigoid (cicatricial mucosal pemphigoid): a reconsideration. ORAL SURG ORAL MED ORAL PATHOL 44: 697-705,
5. Mitchell RD: Cicatricial pemphigoid: a review of eleven cases.Aust Dent J 24: 260-265, 1979. 6. Laskaris G, Sklavounou A, Stratigos J: Bullous pemphigoid, cicatricial pemphigoid and pemphigus vulgaris; a comparative clinical survey of 278 cases. ORAL SURG ORAL MED ORAL PATHOL 54: 656-662,
1977.
1982.
7. Lozada F, Silverman S Jr, Migliorati C: Adverse side effects associated with prednisone in the treatment of patients with oral inflammatory ulcerative diseases.J Am Dent Assoc 109: 260-270, 1984. 8. Silverman S Jr, Lozada-Nur F, Migliorati C: Clinical efficacy of prednisone in the treatment of patients with oral inflammatory ulcerative diseases: a study of fifty-five patients. ORAL SURG ORAL MED ORAL PATHOL 59: 360-363, 1985.
9. Lozada F: Prednisone and azathioprine in the treatment of oral inflammatory disease. ORAL. SURG ORAL MED ORAL PATHOL 52: 257-260,
REFERENCES
237
1981.
10. Lozada F, Silverman S Jr: Topically applied fluocinonide in an adhesive base in the treatment of oral vesiculoerosive diseases.Arch Dermatol 116: 898-901, 1980. Reprint requests to:
Dr. Sol Silverman, Jr. School of Dentistry S-647 University of California San Francisco. CA 94143