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Histologic changes associated with the topical use of isotretinoin on oral lichen planus
Histologic changes associated with the topical use of isotretinoin on oral lichen planus Joseph A. Regezi, D.D.S., MS.,* Charles N. Ellis, M.D.,** Jeffrey C. B. Stewart, D.D.S., M.S.. * and Thomas A. Giustina, Ann Arbor, Mich. UNIVERSITY
OF MICHIGAN
SCHOOLS
OF DENTISTRY
AND
M.D., **
MEDICINE
B
0th systemic and topical synthetic retinoids (vitamin A derivatives) have been used extensively in the treatment of keratotic skin diseases that feature abnormal epithelial cell proliferation and differentiation. Dramatic results have been reported following the treatment of psoriasis and acne with etretinate and isotretinoin (13~cis retinoic acid).‘-4 Because of the antikeratinizing and immunomodulating effects of retinoids,‘.4*s the use of these compounds has been extended to the treatment of patients with cutaneous and oral lichen planus. Systemic retinoids-etretinate, isotretinoin, and tretinoin (all-trans retinoic acid)-have produced clinically significant results in patients with oral lichen planus.‘-l3 In one study, however, only marginal improvement was noted in patients with erosive lichen planus. I4 Because of side effects, the investigators thought that treatment with systemic etretinate did not justify the results. Topical tretinoin has produced generally good results in patients with oral lichen planus, without the complications of cheilitis, dry skin, eievation of serum liver enzymes, and elevation of serum triglycerides and cholesterol that are commonly associated with systemic therapy. ‘. ‘w’ Until recently, studies using topical agents have been limited to the use of tretinoin. A related retinoid-isotretinoin-had been made available to us in a 0.1% gel for clinical testing and showed considerable efficacy in the treatment of oral lichen planus. I8 Atrophic and erosive lesions responded less dramatically than reticular lesions. This double-blind clinical trial spanned 8 weeks of twice-daily application of isotretinoin gel (Figs. 1 *Department of Oral Pathology. **Department of Dermatology.
Fig. 1. Typical reticular form of lichen planus before treatment. A, Right buccal mucosa. B, Left buccal mucoSC3.
and 2). The patients were instructed to first dry the lesions with a gauze square and then to apply a small amount of gel with the finger. The purpose of this article is to describe the histopathologic and immunohistochemical changes associated with the use of topical isotretinoin on oral lichen planus over an 8-week period. 479
480
Regezi et al.
Oral May,
Surf.. 1986
anti S-100, were counted in five consecutive highpower (x400) fields parallel to the surface. Only cells in which nuclei were present were included. Macrophages were counted in five consecutive highpower (x400) fields of antimuramidase stained sections. RESULTS
Fig. 2. Same patient as shownin Fig. 1 after 8-week treatment with topical isotretinoin gel. A, Right buccal mucosa.B, Left buccalmucosa.
MATERIALS
AND METHODS
Of the twenty patients studied, six (randomly selected) underwent buccal mucosal biopsies before and after isotretinoin treatment. Tissues obtained were fixed in formalin and embedded in paraffin. Sections stained with hematoxylin and eosin were prepared in the usual manner. Sections for immunohistochemistry were prepared from the paraffinembedded tissue and processed as previously described.*O Briefly, sections were pretreated with trypsin (1:250, Difco, Detroit, Michigan) and incubated with one of three antibodies: anti S-100 (Dako, Santa Barbara, California), anti HLA-DR (gift from Dr. B. Wilson, University of Michigan), and antimuramidase (Calbiochem, LaJolla, California). Sections were then treated with biotinylated secondary antibody, followed by incubation with avidinbiotin complex (Vector, Burlingame, California). Sections were developed with diaminobenzidine and counterstained with hematoxylin. Negative controls consisted of replacement of primary antibody with appropriate normal serum. Langerhans cells, stained with anti HLA-DR and
Compliance with the regimen in this study was thought to be very good in five patients. One patient apparently used the gel haphazardly, consuming less than half the recommended dosage. This was judged by interview and by measure of the amount of drug surrendered at the end of the study. It was believed that this patient’s poor compliance was responsible for the relatively insignificant changes noted between his two biopsy specimens. This is reflected in the results. Initial biopsy specimens from all patients exhibited the microscopic changes typical of oral lichen planus: hyperkeratosis, lymphophagocytic infiltrate located at the epithelial connective tissue interface, and basal cell liquefaction (Fig. 3). Varying numbers of necrotic keratinocytes were also seen in the basilar zone of the diseased tissues. Biopsy specimens of treated tissues generally showed less keratinization than pretreatment biopsy material (Fig. 4). In two cases there was no measurable difference in keratin thickness in pretreatment and posttreatment specimens. In five of the six patients, interface changes were less severe following treatment. Basal cells were better preserved, the basement membrane zone was better defined, and necrotic keratinocytes were fewer in number. In five cases, the lymphophagocytic infiltrate was less intense and more dispersed in the submucosa. Capillaries were often prominent in posttreatment biopsy specimens (Fig. 5). In only one case did the posttreatment biopsy tissue appear normal. Immunostaining for S- 100 protein generally showed fewer Langerhans cells in the treated tissue than in the untreated tissue (Figs. 6 and 7). Specifically, the mean number of Langerhans cells was reduced from 18.2 to 12.3 (Table I). The change was not statistically significant for the number of patients studied. Patient 4 was the participant who showed poor compliance. Indeterminate cells (Langerhans cell precursors), which stain positive for S-100 protein in the submucosa, persisted after isotretinoin treatment. Their numbers appeared to be unchanged or slightly increased after treatment. Staining for HLA-DR antigen also demonstrated fewer Langerhans cells in treated mucosa than in
Volume Number
6I 5
Histologic
changes with topical use of isotretinoin
481
Fig. 3. Biopsy specimenfrom buccal mucosaof patient with lichen planus showing hyperkeratosis, lymphophagocyticinfiltrate, and interface changes.(Hematoxylin and eosinstain. Original magnification, X250.)
Fig. 4. Tissueappearanceafter 8 weeksof isotretinoin treatment. Note relative reductionof keratin and dispersionof lymphocytes.(Hematoxylin and eosinstain. Original magnification,X250.)
untreated mucosa (Table I). The mean decrease went from 14.2 to 10.3 Langerhans cells per highpower field (not statistically significant for the numbers studied). Keratinocyte membrane staining was noted in four cases initially, with three of these becoming negative after treatment. Indeterminate cells were stained with anti-HLA-DR but were admixed with other positive-staining macrophages and lymphocytes. The number of phagocytes, as stained for muramidase, remained approximately the same in treated and untreated tissues. The reduced number
of round cells in the infiltrate of treated cases was thought to be due primarily to a reduction in the number of lymphocytes. DISCUSSION
The results are consistent with the two effectsantikeratinization and immunomodulation-generally attributed to retinoids. As judged from the sections, stained with hematoxylin and eosin, keratinization was generally reduced after 8 weeks of topical isotretinoin therapy. From the immunostained sections, alterations in the population of
402
Regezi et al.
Oral Surg. May, 1986
5. Isotretinoin-treated tissue showing prominenceof capillaries. (Hematoxylin and eosin stain. Original magnification,X250.)
Fig.
6. Lichen planus before treatment immunostainedfor S-100 protein. Note positive intraepithelial dendritic cells and positive indeterminatecells (arrows) in the upper submucosa.(DAB chromagenwith hematoxylin counterstain.Original magnification, X250.) Fig.
immunocompetent cells was also apparent. Although the significance level of the Langerhans cell counts was not in the range usually regarded as significant, a clear trend in the reduction of cells was apparent. It was thought that higher numbers of patients would have produced significant results in this aspect of the study. Additional studies to confirm the results appear warranted. Langerhans cells, known to have the function of antigen processing, are increased in immune challenge conditions, such as graft-versus-host disease:’ contact dermatitis,22 and lichen planus.2o Their
apparent decrease in number after isotretinoin treatment may have been due to reduced antigen expression rather than an absolute reduction in the number of cells. Evaluation of T6 antigen on frozen sections would be necessary to confirm an actual “dropping out” of Langerhans cells in treated tissue.23 Epithelial cells, which may also develop an antigen-processing role, may express HLA-DR antigens when challenged by foreign materials.‘** I9 Reversion to a state in which no HLA-DR antigen can be detected, as seen in three of four cases in this study, also suggests reduced immunologic challenge. Dis-
Volume Number
61 5
Histologic
changes with topical use of isotretinoin
483
7. Immunostainfor S-100 protein on biopsyspecimenfrom buccal mucosaof lichen planuspatient after 8 weeksof topical isotretinointherapy. Note relative reductionof Langerhansand indeterminatecells (arrows). (DAB chromagenwith hematoxylin counterstain.original magnification,x250.)
Fig.
pcrsion of the infiltrate away from the epithelialconnective tissue interface also suggests an immunomodulatory effect of isotretinoin. Reduced expression of S-100 and HLA-DR antigens on Langerhans cells and dispersion of the lymphophagocytic infiltrate suggest a local immunomodulating effect. It could not be determined from this study whether the isotretinoin had a direct or an indirect effect on the lymphocytes. It is possible that, because of reduced antigen processing by the Langerhans cells, there is no incentive or need for lymphocytes (Tq and TB) to appear or remain in the area. The topical gel used in this study likely produced a relatively high local concentration of retinoid, causing an apparent focal alteration in the immune response. Other studies have also demonstrated microscopic evidence of the modulating effects of retinoids on cutaneous diseases. Systemic etretinate, used to treat psoriasis, caused a decrease in HLA-DR-positive Langerhans cells. 20*2’ In one of these studies T6positive Langerhans cells declined initially but increased in later stages of treatment.26 In another study, systemic etretinate caused an increase in HLA-DR and T6-positive Langerhans cells in cutaneous lichen planus. *’ Systemic isotretinoin produced a mild immunostimulation in patients with acne as shown by an elevation in circulating T and B lymphocytes.** The variations in immune response noted in this and other retinoid studies may be due to a number of factors. Retinoid dosage, treatment duration, type of
Table
I s-100
HLA-DR
Patient
Before
After
Before
After
1 2 3 4 5 6 Mean
26* 21 27 18 10 I iii7
5 7 23 23 2 14 123
19 10 13 21 9 13 14.2
8 5 12 24 4
*Average number of Langerhans cells svained for S-100 protein and HLA-DR
per high-power
antigens
9 10.3
field in lichen before and after
planus
isotreti-
noin treatment.
retinoid used, route of administration, and type of disease treated could significantly influence or determine the fluctuations in immune cell numbers, as well as intensity of antigen expression. Isotretinoin gel suppliedcourtesy of Stiefel Laboratories, Coral Cables,Florida. REFERENCES 1. Elias P, Williams M: Retinoids, Dermatol 117: 160-180, 1981. 2. Ellis CN, Grekin RC, Kragballe
cancer,
and the skin. Arch
K, Voorhees
JJ: Retinoids.
In StoneJ (editor):Dermatologic immunology andallergy, St. Louis,1985,TheC. V. MosbyCompany,pp. 851-875. 3. Peck G: Retinoids-therapeutic 24: 341-351, 1982. 4. VoorheesJ, OrfanosC:
use in dermatology.
Drugs
Oral retinoids-broadspectrum dermatologic therapyfor the 1980s.Arch Dermatol117: 418-421,1981.
5. Pawson
B, Ehmann
C, Itri L, Sherman
M: Retinoids
at the
484
6. 7.
8.
9. 10.
II.
12.
13. 14.
15. 16.
17. 18.
19.
Regezi et al. threshold: their biological significance and theraputic potential. J Med Chem 25: 1269-1277, 1982. Thomas J, Doyle J: The therapeutic uses of topical vitamin A acid. J Am Acad Dermatol 4: 505-513, 1981. Camisa C, Olsen R, Bowen R, Allen C: Indirect immunofluorescence and lectin binding studies of oral lichen planus and responses to oral isotretin therapy. Clin Res 33: 629A, 1985. Gunther S: The therapeutic value of retinoic acid (vitamin A acid) in lichen planus of the oral mucous membrane. Dermatologica 147: 130-l 36, 1973. Handler HL: Isotretinoin for oral lichen planus (letter to the editor). J Am Acad Dermatol 10: 674, 1984. Hersle K, Mobacken H, Sloberg K, Thilander H: Severe oral lichen planus: treatment with an aromatic retinoid (etretinate). Br J Dermatol 106: 77-80, 1982. Sloberg K, Hersle K, Mobacken H, Thilander H: Severe oral lichen planus: remission and maintenance with vitamin A analogues. J Oral Pathol IZ: 473-477, 1983. Stern RS: Treatment of oral lichen planus with low-dose isotretinoin (letter to the editor). J Am Acad Dermatol 11: 527-528, 1984. Woo TY: Systemic isotretinoin treatment of oral and cutaneous lichen planus. Cutis 35: 385-393, 1985. Ferguson M, Simpson N, Hammersley N: The treatment of erosive lichen planus with a retinoid-etretinate. ORAL SURG ORAL MED ORAL PATHOL 58: 283-287, 1984. Gunther S: Vitamin A acid in treatment of oral lichen planus. Arch Dermatol 107: 277, 1973. Slobere K. Hersle K. Mobacken H. Thilander H: Tonical tretinoyn therapy and oral lichen planus. Arch Dermatol’l15: 716-718, 1979. Zegarelli D: Treatment of oral lichen planus with topical vitamin A acid. J Oral Med 39: 186-191, 1984. Giustina TA, Stewart JCB, Ellis CN, Regezi JA, Annesley TM, Woo TY, Voorhees JJ: Topical application of isotretinoin improves lichen planus: a double blind clinical trial. Arch Dermatol (in press). Sloberg K, Jonsson R, Jontell M: Assessment of Langerhans
Oral Surg. May, 1986
20.
21.
22. 23.
24.
25.
26.
27.
28.
cells in oral lichen planus using monoclonal antibodies. .I Oral Pathol 13: 516-524, 1984. Regezi J, Stewart J, Headington .I, Lloyd R: Immunohistochemical staining of Langerhans cells and macrophages in oral lichen planus. ORAL SURG ORAL MED ORAL PATHOL 60: 396-402. 1985. Kaye V, Neumann P, Kersey J, Goltz R, Baldridge B. Michael A, Platt J: Identity of immune cells in graftversus-host disease of the skin. Am J Pathol 116: 436-440. 1984. Wolff K, Stingle G: The Langerhans cell. J invest Dermatol 80 (Suppl. 6): 17s-21s 1983. Daynes R, Emam M, Krueger G, Roberts L: Expression of la antigen on epidermal keratinocytes after the grafting of normal skin to nude mice. J Immunol 130: 1536, 1983. Lampert I, Suitters A, Chisholm P: Expression of la antigen on epidermal keratinocytes in graft-versus-host disease. Nature 293: 149-150, 1981. Haftek M, Faure M, Schmitt J, Thivolet J: Effects of aromatic retinoid treatment on epidermal Langerhans cells in psoriasis. J Invest Dermatoi 78: 327, 1982. Ranki A, Lauharanta J, Kanerva L: Effect of etretinate on the distribution of Langerhans cells and T lymphocytes in psoriatic skin. Arch Dermatol Res 276: 102-104, 1984. Bussy R, Schmitt D, Mauduit G, Thivolet J: Effects of aromatic retinoid (Ro109359) on Langerhans cell in lichen planus. Arch Dermatol Res 275: 105-108. 1983. ‘Holland D, Gowland G, Cunliffe W: Inflammatory responses in acne patients treated with l3-cis-retinoic acid (isotretinoin). Br J Dermatol 110: 343-345, 1984.
Reprint requests to. Dr. Joseph A. Regezi Department of Oral Pathology University of Michigan School Ann Arbor, Ml 48109
of Dentistry
OF MICHIGAN
SCHOOLS
OF DENTISTRY
AND
M.D., **
MEDICINE
B
0th systemic and topical synthetic retinoids (vitamin A derivatives) have been used extensively in the treatment of keratotic skin diseases that feature abnormal epithelial cell proliferation and differentiation. Dramatic results have been reported following the treatment of psoriasis and acne with etretinate and isotretinoin (13~cis retinoic acid).‘-4 Because of the antikeratinizing and immunomodulating effects of retinoids,‘.4*s the use of these compounds has been extended to the treatment of patients with cutaneous and oral lichen planus. Systemic retinoids-etretinate, isotretinoin, and tretinoin (all-trans retinoic acid)-have produced clinically significant results in patients with oral lichen planus.‘-l3 In one study, however, only marginal improvement was noted in patients with erosive lichen planus. I4 Because of side effects, the investigators thought that treatment with systemic etretinate did not justify the results. Topical tretinoin has produced generally good results in patients with oral lichen planus, without the complications of cheilitis, dry skin, eievation of serum liver enzymes, and elevation of serum triglycerides and cholesterol that are commonly associated with systemic therapy. ‘. ‘w’ Until recently, studies using topical agents have been limited to the use of tretinoin. A related retinoid-isotretinoin-had been made available to us in a 0.1% gel for clinical testing and showed considerable efficacy in the treatment of oral lichen planus. I8 Atrophic and erosive lesions responded less dramatically than reticular lesions. This double-blind clinical trial spanned 8 weeks of twice-daily application of isotretinoin gel (Figs. 1 *Department of Oral Pathology. **Department of Dermatology.
Fig. 1. Typical reticular form of lichen planus before treatment. A, Right buccal mucosa. B, Left buccal mucoSC3.
and 2). The patients were instructed to first dry the lesions with a gauze square and then to apply a small amount of gel with the finger. The purpose of this article is to describe the histopathologic and immunohistochemical changes associated with the use of topical isotretinoin on oral lichen planus over an 8-week period. 479
480
Regezi et al.
Oral May,
Surf.. 1986
anti S-100, were counted in five consecutive highpower (x400) fields parallel to the surface. Only cells in which nuclei were present were included. Macrophages were counted in five consecutive highpower (x400) fields of antimuramidase stained sections. RESULTS
Fig. 2. Same patient as shownin Fig. 1 after 8-week treatment with topical isotretinoin gel. A, Right buccal mucosa.B, Left buccalmucosa.
MATERIALS
AND METHODS
Of the twenty patients studied, six (randomly selected) underwent buccal mucosal biopsies before and after isotretinoin treatment. Tissues obtained were fixed in formalin and embedded in paraffin. Sections stained with hematoxylin and eosin were prepared in the usual manner. Sections for immunohistochemistry were prepared from the paraffinembedded tissue and processed as previously described.*O Briefly, sections were pretreated with trypsin (1:250, Difco, Detroit, Michigan) and incubated with one of three antibodies: anti S-100 (Dako, Santa Barbara, California), anti HLA-DR (gift from Dr. B. Wilson, University of Michigan), and antimuramidase (Calbiochem, LaJolla, California). Sections were then treated with biotinylated secondary antibody, followed by incubation with avidinbiotin complex (Vector, Burlingame, California). Sections were developed with diaminobenzidine and counterstained with hematoxylin. Negative controls consisted of replacement of primary antibody with appropriate normal serum. Langerhans cells, stained with anti HLA-DR and
Compliance with the regimen in this study was thought to be very good in five patients. One patient apparently used the gel haphazardly, consuming less than half the recommended dosage. This was judged by interview and by measure of the amount of drug surrendered at the end of the study. It was believed that this patient’s poor compliance was responsible for the relatively insignificant changes noted between his two biopsy specimens. This is reflected in the results. Initial biopsy specimens from all patients exhibited the microscopic changes typical of oral lichen planus: hyperkeratosis, lymphophagocytic infiltrate located at the epithelial connective tissue interface, and basal cell liquefaction (Fig. 3). Varying numbers of necrotic keratinocytes were also seen in the basilar zone of the diseased tissues. Biopsy specimens of treated tissues generally showed less keratinization than pretreatment biopsy material (Fig. 4). In two cases there was no measurable difference in keratin thickness in pretreatment and posttreatment specimens. In five of the six patients, interface changes were less severe following treatment. Basal cells were better preserved, the basement membrane zone was better defined, and necrotic keratinocytes were fewer in number. In five cases, the lymphophagocytic infiltrate was less intense and more dispersed in the submucosa. Capillaries were often prominent in posttreatment biopsy specimens (Fig. 5). In only one case did the posttreatment biopsy tissue appear normal. Immunostaining for S- 100 protein generally showed fewer Langerhans cells in the treated tissue than in the untreated tissue (Figs. 6 and 7). Specifically, the mean number of Langerhans cells was reduced from 18.2 to 12.3 (Table I). The change was not statistically significant for the number of patients studied. Patient 4 was the participant who showed poor compliance. Indeterminate cells (Langerhans cell precursors), which stain positive for S-100 protein in the submucosa, persisted after isotretinoin treatment. Their numbers appeared to be unchanged or slightly increased after treatment. Staining for HLA-DR antigen also demonstrated fewer Langerhans cells in treated mucosa than in
Volume Number
6I 5
Histologic
changes with topical use of isotretinoin
481
Fig. 3. Biopsy specimenfrom buccal mucosaof patient with lichen planus showing hyperkeratosis, lymphophagocyticinfiltrate, and interface changes.(Hematoxylin and eosinstain. Original magnification, X250.)
Fig. 4. Tissueappearanceafter 8 weeksof isotretinoin treatment. Note relative reductionof keratin and dispersionof lymphocytes.(Hematoxylin and eosinstain. Original magnification,X250.)
untreated mucosa (Table I). The mean decrease went from 14.2 to 10.3 Langerhans cells per highpower field (not statistically significant for the numbers studied). Keratinocyte membrane staining was noted in four cases initially, with three of these becoming negative after treatment. Indeterminate cells were stained with anti-HLA-DR but were admixed with other positive-staining macrophages and lymphocytes. The number of phagocytes, as stained for muramidase, remained approximately the same in treated and untreated tissues. The reduced number
of round cells in the infiltrate of treated cases was thought to be due primarily to a reduction in the number of lymphocytes. DISCUSSION
The results are consistent with the two effectsantikeratinization and immunomodulation-generally attributed to retinoids. As judged from the sections, stained with hematoxylin and eosin, keratinization was generally reduced after 8 weeks of topical isotretinoin therapy. From the immunostained sections, alterations in the population of
402
Regezi et al.
Oral Surg. May, 1986
5. Isotretinoin-treated tissue showing prominenceof capillaries. (Hematoxylin and eosin stain. Original magnification,X250.)
Fig.
6. Lichen planus before treatment immunostainedfor S-100 protein. Note positive intraepithelial dendritic cells and positive indeterminatecells (arrows) in the upper submucosa.(DAB chromagenwith hematoxylin counterstain.Original magnification, X250.) Fig.
immunocompetent cells was also apparent. Although the significance level of the Langerhans cell counts was not in the range usually regarded as significant, a clear trend in the reduction of cells was apparent. It was thought that higher numbers of patients would have produced significant results in this aspect of the study. Additional studies to confirm the results appear warranted. Langerhans cells, known to have the function of antigen processing, are increased in immune challenge conditions, such as graft-versus-host disease:’ contact dermatitis,22 and lichen planus.2o Their
apparent decrease in number after isotretinoin treatment may have been due to reduced antigen expression rather than an absolute reduction in the number of cells. Evaluation of T6 antigen on frozen sections would be necessary to confirm an actual “dropping out” of Langerhans cells in treated tissue.23 Epithelial cells, which may also develop an antigen-processing role, may express HLA-DR antigens when challenged by foreign materials.‘** I9 Reversion to a state in which no HLA-DR antigen can be detected, as seen in three of four cases in this study, also suggests reduced immunologic challenge. Dis-
Volume Number
61 5
Histologic
changes with topical use of isotretinoin
483
7. Immunostainfor S-100 protein on biopsyspecimenfrom buccal mucosaof lichen planuspatient after 8 weeksof topical isotretinointherapy. Note relative reductionof Langerhansand indeterminatecells (arrows). (DAB chromagenwith hematoxylin counterstain.original magnification,x250.)
Fig.
pcrsion of the infiltrate away from the epithelialconnective tissue interface also suggests an immunomodulatory effect of isotretinoin. Reduced expression of S-100 and HLA-DR antigens on Langerhans cells and dispersion of the lymphophagocytic infiltrate suggest a local immunomodulating effect. It could not be determined from this study whether the isotretinoin had a direct or an indirect effect on the lymphocytes. It is possible that, because of reduced antigen processing by the Langerhans cells, there is no incentive or need for lymphocytes (Tq and TB) to appear or remain in the area. The topical gel used in this study likely produced a relatively high local concentration of retinoid, causing an apparent focal alteration in the immune response. Other studies have also demonstrated microscopic evidence of the modulating effects of retinoids on cutaneous diseases. Systemic etretinate, used to treat psoriasis, caused a decrease in HLA-DR-positive Langerhans cells. 20*2’ In one of these studies T6positive Langerhans cells declined initially but increased in later stages of treatment.26 In another study, systemic etretinate caused an increase in HLA-DR and T6-positive Langerhans cells in cutaneous lichen planus. *’ Systemic isotretinoin produced a mild immunostimulation in patients with acne as shown by an elevation in circulating T and B lymphocytes.** The variations in immune response noted in this and other retinoid studies may be due to a number of factors. Retinoid dosage, treatment duration, type of
Table
I s-100
HLA-DR
Patient
Before
After
Before
After
1 2 3 4 5 6 Mean
26* 21 27 18 10 I iii7
5 7 23 23 2 14 123
19 10 13 21 9 13 14.2
8 5 12 24 4
*Average number of Langerhans cells svained for S-100 protein and HLA-DR
per high-power
antigens
9 10.3
field in lichen before and after
planus
isotreti-
noin treatment.
retinoid used, route of administration, and type of disease treated could significantly influence or determine the fluctuations in immune cell numbers, as well as intensity of antigen expression. Isotretinoin gel suppliedcourtesy of Stiefel Laboratories, Coral Cables,Florida. REFERENCES 1. Elias P, Williams M: Retinoids, Dermatol 117: 160-180, 1981. 2. Ellis CN, Grekin RC, Kragballe
cancer,
and the skin. Arch
K, Voorhees
JJ: Retinoids.
In StoneJ (editor):Dermatologic immunology andallergy, St. Louis,1985,TheC. V. MosbyCompany,pp. 851-875. 3. Peck G: Retinoids-therapeutic 24: 341-351, 1982. 4. VoorheesJ, OrfanosC:
use in dermatology.
Drugs
Oral retinoids-broadspectrum dermatologic therapyfor the 1980s.Arch Dermatol117: 418-421,1981.
5. Pawson
B, Ehmann
C, Itri L, Sherman
M: Retinoids
at the
484
6. 7.
8.
9. 10.
II.
12.
13. 14.
15. 16.
17. 18.
19.
Regezi et al. threshold: their biological significance and theraputic potential. J Med Chem 25: 1269-1277, 1982. Thomas J, Doyle J: The therapeutic uses of topical vitamin A acid. J Am Acad Dermatol 4: 505-513, 1981. Camisa C, Olsen R, Bowen R, Allen C: Indirect immunofluorescence and lectin binding studies of oral lichen planus and responses to oral isotretin therapy. Clin Res 33: 629A, 1985. Gunther S: The therapeutic value of retinoic acid (vitamin A acid) in lichen planus of the oral mucous membrane. Dermatologica 147: 130-l 36, 1973. Handler HL: Isotretinoin for oral lichen planus (letter to the editor). J Am Acad Dermatol 10: 674, 1984. Hersle K, Mobacken H, Sloberg K, Thilander H: Severe oral lichen planus: treatment with an aromatic retinoid (etretinate). Br J Dermatol 106: 77-80, 1982. Sloberg K, Hersle K, Mobacken H, Thilander H: Severe oral lichen planus: remission and maintenance with vitamin A analogues. J Oral Pathol IZ: 473-477, 1983. Stern RS: Treatment of oral lichen planus with low-dose isotretinoin (letter to the editor). J Am Acad Dermatol 11: 527-528, 1984. Woo TY: Systemic isotretinoin treatment of oral and cutaneous lichen planus. Cutis 35: 385-393, 1985. Ferguson M, Simpson N, Hammersley N: The treatment of erosive lichen planus with a retinoid-etretinate. ORAL SURG ORAL MED ORAL PATHOL 58: 283-287, 1984. Gunther S: Vitamin A acid in treatment of oral lichen planus. Arch Dermatol 107: 277, 1973. Slobere K. Hersle K. Mobacken H. Thilander H: Tonical tretinoyn therapy and oral lichen planus. Arch Dermatol’l15: 716-718, 1979. Zegarelli D: Treatment of oral lichen planus with topical vitamin A acid. J Oral Med 39: 186-191, 1984. Giustina TA, Stewart JCB, Ellis CN, Regezi JA, Annesley TM, Woo TY, Voorhees JJ: Topical application of isotretinoin improves lichen planus: a double blind clinical trial. Arch Dermatol (in press). Sloberg K, Jonsson R, Jontell M: Assessment of Langerhans
Oral Surg. May, 1986
20.
21.
22. 23.
24.
25.
26.
27.
28.
cells in oral lichen planus using monoclonal antibodies. .I Oral Pathol 13: 516-524, 1984. Regezi J, Stewart J, Headington .I, Lloyd R: Immunohistochemical staining of Langerhans cells and macrophages in oral lichen planus. ORAL SURG ORAL MED ORAL PATHOL 60: 396-402. 1985. Kaye V, Neumann P, Kersey J, Goltz R, Baldridge B. Michael A, Platt J: Identity of immune cells in graftversus-host disease of the skin. Am J Pathol 116: 436-440. 1984. Wolff K, Stingle G: The Langerhans cell. J invest Dermatol 80 (Suppl. 6): 17s-21s 1983. Daynes R, Emam M, Krueger G, Roberts L: Expression of la antigen on epidermal keratinocytes after the grafting of normal skin to nude mice. J Immunol 130: 1536, 1983. Lampert I, Suitters A, Chisholm P: Expression of la antigen on epidermal keratinocytes in graft-versus-host disease. Nature 293: 149-150, 1981. Haftek M, Faure M, Schmitt J, Thivolet J: Effects of aromatic retinoid treatment on epidermal Langerhans cells in psoriasis. J Invest Dermatoi 78: 327, 1982. Ranki A, Lauharanta J, Kanerva L: Effect of etretinate on the distribution of Langerhans cells and T lymphocytes in psoriatic skin. Arch Dermatol Res 276: 102-104, 1984. Bussy R, Schmitt D, Mauduit G, Thivolet J: Effects of aromatic retinoid (Ro109359) on Langerhans cell in lichen planus. Arch Dermatol Res 275: 105-108. 1983. ‘Holland D, Gowland G, Cunliffe W: Inflammatory responses in acne patients treated with l3-cis-retinoic acid (isotretinoin). Br J Dermatol 110: 343-345, 1984.
Reprint requests to. Dr. Joseph A. Regezi Department of Oral Pathology University of Michigan School Ann Arbor, Ml 48109
of Dentistry