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Dapsone in the treatment of erosive lichen planus
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Dapsone in the treatment of erosive lichen planus David K. Falk, M.D.,* Dana L. Latour, M.D., and Lloyd E, King, Jr,, M.D., Ph.D, Nashville, TN A patient with erosive lichen planus responded to therapy with dapsone after multiple therapeutic modalities had failed, The potential usefulness of dapsone therapy for lymphocyte-mediated inflammatory diseases such as erosive lichen planus is suggested, (J AM ACAt) D~RMATOL12:567-570, 1985.)
Dapsone (diaminodiphenylsulfone) has been used to treat several infectious and noninfectious diseases that affect the skin, 1 In many of the noninfectious diseases responsive to dapsone, polymorphonuelear leukocytes (PMLs) are the predominant cell type in the inflammatory infiltrates in the skin, The rationale for using dapsone in these PML-related dermatoses is its purported ability to inhibit the myeloperoxidase (MPO)hydrogen peroxide (HzO2)-halide system in PMLs. 2 We present a patient with erosive lichen planus (LP), a predominantly lymphocyte-mediated process, whose ulcerative lesions resolved during dapsone treatment. The response of this patient with LP and other patients with buUous lupus erythematosus (LE) 3 to dapsone emphasizes the broad spectrum of dermatoses not ordinarily associated with PMLs that respond to dapsone. CASE REPORT
A 57-year-old black man developed a pruritic, violaceous papular eruption over the dorsum of his right hand beginning in March, 1973. The skin lesions spread to involve his buccal mucosa as whitish lesions, From the Division of Dermatology, Department of Medicine, Veterans Administration Medical Center and Vanderbilt University School of Medicine. Supported by the Veterans Administration, Reprint requests to: Lloyd E. King, Jr., M,D,, PLD., Division of Dermatology, VA Medical Center, 1310 24th Ave., South, Nashville, TN 37203. *Present address: Section of Dermatology, lackson Clinic, 345 W. Washington Ave., Madison, WI 53703.
his dorsal forearms, and both the dorsal and ventral aspects of his feet and hands. The lesions were occasionally bullous but usually became erosions as the result of friction and/or trauma. As the lesions resolved; the involved sites became atrophic, hypopigmented, denuded patches that healed poorly (Fig. 1). The erosive and bullous lesions that developed on the patient's hands and feet were associated with such severe pain on ambulation that he became confined to a wheelchair, The patient's lesions were resistant to treatment with both topical and systemic agents for more than 9 years. During this period he was presented at several local and regional dermatologic meetings to seek alternative therapeutic and/or diagnostic assistance. Buccal mucosal lesions characteristic of LP, negative antinuclear antibody determinations, and negative direct immunofluorescent staining for immunoglobulins in several samples showing characteristic histologic findings of LP led to the diagnosis of erosive lichen planus and excluded both Systemicand discoid LE (SLE and DLE) and the LE-LP overlap syndrome. Results of the following laboratory studies were repeatedly normal or negative: complete blood count with differential counts, serum chemistry panel, serum protein electrophoresis, antinuclear antibody, anti-double-stranded DNA antibody, LE preparations, reactive protein reagin, total hemolytic complement, cryoglobulins, 24-hour urine porphyrin studies. The erythrocyte sedimentationrate was elevated to as high as 45 mm/hr (38-45, n = 3), and the rheumatoid factor was detected at low titer in a dilution of 1:20, 1:40 (n = 5). Skin biopsies repeatedly demonstrated histologic changes of lichen planus (Fig. 2), Indirect immunofluorescence studies were negative on several occasions, Direct ira567
568 Falk et al
Journal of the American Academy of Dermatology
Fig. 1. A, Buccal mucosa ulcerations arising within white reticulated striae. B, Erosive plantar lesions. C, Erosive palmar lesions.
Fig. 2. Skin biopsy specimen from right thenar eminence shows orthokeratotic hyperkerat0sis, hypergranulosis, irregular acanthosis with sawtooth pattern, vacuolization with dense lichenoid lymphocytic reaction at dermoepidermal junction. (Hematoxylineosin stain; original magnification, x 200.)
Volume 12 Number 3 March, 1985
Dapsone in erosive lichen planus
569
Fig. 3. Healed lesions 15 months after dapsone therapy was started. Disease activity is minimal and repigmentation has begun. A, Buccal mucosa. B, Soles. C, Palms.
munofluorescence studies of involved and uninvolved skin were negative for IgG and IgM at the dermoepidermal junction. Cytoid bodies stained with IgM, but little or no staining was seen with IgG or IgA. Fibrinogen and C3 staining was only variably present at the dermoepidermal junction in involved skin only. The patient was treated with several different topical fluorinated corticosteroid preparations with and without occlusion, various emollients, nonfluorinated corticosteroid creams, dextranomer (Debrisan) beads, antibiotic powders, 10% benzoyl peroxide, and zinc oxide. Despite therapeutic trials with numerous topical medications, the patient's erosive skin lesions continued to worsen. Systemic prednisone therapy was started in 1977 with doses ranging from 40 mg/day to 15 mg every other day. Azathioprine, 100 mg/day, was added
in 1977 but stopped by the patient because of nausea and vomiting. The patient required pentazocine hydrochloride in doses up to 50 mg every 4 hours to control the pain when the lesions were very active. In 1979 hydroxychloroquine was started at 200 mg twice a day. After 10 months of this therapy and no obvious effects of the hydroxyehloroquine on the bullous and erosive lesions, the drug was discontinued. When corticosteroid complications began to increase, prednisone was slowly tapered and then stopped in January, 1982, despite continued disease activity. While the patient was receiving topical therapy alone, the skin lesions flared and the patient was confined to a wheelchair. Before beginning a skin-glafting procedure previously used successfully in patients with erosive lichen planus, 4 we started dapsone, 50 rag/day, after testing
570 Falk et al
for the presence of glucose-6-phosphate-dehydrogenase. After 3 months of dapsone the patient's lesions were much improved, with all new ulcerative lesions beginning to resolve. After 9 months of dapsone therapy the patient could walk and wear regular shoes. Fifteen months after treatment was begun, the patient no longer had active skin lesions (Fig. 3). DISCUSSION Dapsone therapy eliminated the formation of new bullous and erosive lichen planus lesions in our patient. Dapsone was previously shown to stop the formation of new bullae in SLE. a In these patients with bullous S L E w h o were successfully treated with dapsone, Hall et al a described P M L infiltration into the dermal papillae. Our patient was therefore different in that the erosive lesions always arose in lymphocyte-rich, PML-poor lesions, suggesting that dapsone was not primarily affecting PML. Although any explanation for the effectiveness of dapsone in our patient is conjectural, the drug may be working through a mechanism similar to that proposed for PML-mediated cytotoxicity3 Clark and Klebanoff 5 have shown that the MPO-H202-hali~de cofactor system is present in PMLs. The release of the MPO-H2Ozhalide system's eytotoxic factors m a y modulate the extent of the inflammatory response. However, the eytotoxicity of the MPO-HzO2-halide system was shown to be very similar for both PML and mononuclear cells. 5 Since mononuclear cells also contain MPO, 6 dapsone may change the inflammatory response in o u r patient's lichenoid infiltrates b y its inhibition o f mononuclear cellmediated MPO cytotoxicity. Several other disease processes have been reported in which dapsone controlled a predominantly lymphocyte-mediated process. 1'7 In addi-
J'oumal of the American Academy of Dermatology
tion to potential effects on the MPO-H202-halide system, dapsone may help control these diseases by modulating the release of inflammatory and/or PML chemotactic factors from mast cells, s The usefulness of dapsone in these cases and in the present case emphasizes that dapsone therapy is also effective in treating diseases usually not characterized by PML infiltrates or cytotoxicity, Whether other variants of lichen planus, lichen planus pemphigoides, 9 or the LE-LP overlap syndrome 1° would respond to dapsone is unknown but of interest, REFERENCES 1. Lang PG: Sulfones and sulfonamides in dermatology today. J AM ACAODERMATOL1:479-492, 1979. 2. Stendahl O, Molin L, Dahlgren C: Tile inhibition of polymorphonuclear leukocytecytotoxicity by dapsone. J Clin Invest 62:214-220, 1978, 3. Hall RP, Lawley TJ, Smith HR, Katz SI: Bullous eruption of systemic lupus erythematosus: Dramatic response to dapsone. Ann Intern Med 97:165-170, 1982, 4. Lendrum J: Surgical treatment of lichen planus of the soles. Br J Plast Surg 27:171-175, 1974, 5, Clark RA, Klebanoff SJ: Myeloperoxidase-H~O,-halide system: Cytotoxie effect on human blood leukocytes. Blood 50:65-70, 1977, 6. Territo M, Cline MJ: Macrophages and their disorders in man, in Nelson DS, editor: Immunobiology of the macrophage, New York, 1976, Academic Press Inc., pp. 593-616. 7. Rogers RS, Seehafer JR, Perry HO: Treatment of cicatrieial (benign mucous membrane) pemphigoid with dapsone. J AM ACADDERMATOL6:215-223, 1982. 8. Ruzicka T, Wasserman si, Soter NA, Printz MP: Inhibition of rat mast cell arachidonic acid cyclooxygenase by dapsone. J AllergyClin Immunol 72:365-370, 1983. 9. Lang PG Jr, Maize JC: Coexisting lichen planus and bullous pemphigoid or lichen planus pemphigoides? J AM ACADDERMATOL9:133-140, 1983. 10. Romem RW, Nesbitt LT Jr, Reed RJ: Unusual variant of lupus erythematosus or lichen planus: Clinical, histopathologic and immunofluorescent studies. Arch Dermatol 113:741-748, 1977.
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Dapsone in the treatment of erosive lichen planus David K. Falk, M.D.,* Dana L. Latour, M.D., and Lloyd E, King, Jr,, M.D., Ph.D, Nashville, TN A patient with erosive lichen planus responded to therapy with dapsone after multiple therapeutic modalities had failed, The potential usefulness of dapsone therapy for lymphocyte-mediated inflammatory diseases such as erosive lichen planus is suggested, (J AM ACAt) D~RMATOL12:567-570, 1985.)
Dapsone (diaminodiphenylsulfone) has been used to treat several infectious and noninfectious diseases that affect the skin, 1 In many of the noninfectious diseases responsive to dapsone, polymorphonuelear leukocytes (PMLs) are the predominant cell type in the inflammatory infiltrates in the skin, The rationale for using dapsone in these PML-related dermatoses is its purported ability to inhibit the myeloperoxidase (MPO)hydrogen peroxide (HzO2)-halide system in PMLs. 2 We present a patient with erosive lichen planus (LP), a predominantly lymphocyte-mediated process, whose ulcerative lesions resolved during dapsone treatment. The response of this patient with LP and other patients with buUous lupus erythematosus (LE) 3 to dapsone emphasizes the broad spectrum of dermatoses not ordinarily associated with PMLs that respond to dapsone. CASE REPORT
A 57-year-old black man developed a pruritic, violaceous papular eruption over the dorsum of his right hand beginning in March, 1973. The skin lesions spread to involve his buccal mucosa as whitish lesions, From the Division of Dermatology, Department of Medicine, Veterans Administration Medical Center and Vanderbilt University School of Medicine. Supported by the Veterans Administration, Reprint requests to: Lloyd E. King, Jr., M,D,, PLD., Division of Dermatology, VA Medical Center, 1310 24th Ave., South, Nashville, TN 37203. *Present address: Section of Dermatology, lackson Clinic, 345 W. Washington Ave., Madison, WI 53703.
his dorsal forearms, and both the dorsal and ventral aspects of his feet and hands. The lesions were occasionally bullous but usually became erosions as the result of friction and/or trauma. As the lesions resolved; the involved sites became atrophic, hypopigmented, denuded patches that healed poorly (Fig. 1). The erosive and bullous lesions that developed on the patient's hands and feet were associated with such severe pain on ambulation that he became confined to a wheelchair, The patient's lesions were resistant to treatment with both topical and systemic agents for more than 9 years. During this period he was presented at several local and regional dermatologic meetings to seek alternative therapeutic and/or diagnostic assistance. Buccal mucosal lesions characteristic of LP, negative antinuclear antibody determinations, and negative direct immunofluorescent staining for immunoglobulins in several samples showing characteristic histologic findings of LP led to the diagnosis of erosive lichen planus and excluded both Systemicand discoid LE (SLE and DLE) and the LE-LP overlap syndrome. Results of the following laboratory studies were repeatedly normal or negative: complete blood count with differential counts, serum chemistry panel, serum protein electrophoresis, antinuclear antibody, anti-double-stranded DNA antibody, LE preparations, reactive protein reagin, total hemolytic complement, cryoglobulins, 24-hour urine porphyrin studies. The erythrocyte sedimentationrate was elevated to as high as 45 mm/hr (38-45, n = 3), and the rheumatoid factor was detected at low titer in a dilution of 1:20, 1:40 (n = 5). Skin biopsies repeatedly demonstrated histologic changes of lichen planus (Fig. 2), Indirect immunofluorescence studies were negative on several occasions, Direct ira567
568 Falk et al
Journal of the American Academy of Dermatology
Fig. 1. A, Buccal mucosa ulcerations arising within white reticulated striae. B, Erosive plantar lesions. C, Erosive palmar lesions.
Fig. 2. Skin biopsy specimen from right thenar eminence shows orthokeratotic hyperkerat0sis, hypergranulosis, irregular acanthosis with sawtooth pattern, vacuolization with dense lichenoid lymphocytic reaction at dermoepidermal junction. (Hematoxylineosin stain; original magnification, x 200.)
Volume 12 Number 3 March, 1985
Dapsone in erosive lichen planus
569
Fig. 3. Healed lesions 15 months after dapsone therapy was started. Disease activity is minimal and repigmentation has begun. A, Buccal mucosa. B, Soles. C, Palms.
munofluorescence studies of involved and uninvolved skin were negative for IgG and IgM at the dermoepidermal junction. Cytoid bodies stained with IgM, but little or no staining was seen with IgG or IgA. Fibrinogen and C3 staining was only variably present at the dermoepidermal junction in involved skin only. The patient was treated with several different topical fluorinated corticosteroid preparations with and without occlusion, various emollients, nonfluorinated corticosteroid creams, dextranomer (Debrisan) beads, antibiotic powders, 10% benzoyl peroxide, and zinc oxide. Despite therapeutic trials with numerous topical medications, the patient's erosive skin lesions continued to worsen. Systemic prednisone therapy was started in 1977 with doses ranging from 40 mg/day to 15 mg every other day. Azathioprine, 100 mg/day, was added
in 1977 but stopped by the patient because of nausea and vomiting. The patient required pentazocine hydrochloride in doses up to 50 mg every 4 hours to control the pain when the lesions were very active. In 1979 hydroxychloroquine was started at 200 mg twice a day. After 10 months of this therapy and no obvious effects of the hydroxyehloroquine on the bullous and erosive lesions, the drug was discontinued. When corticosteroid complications began to increase, prednisone was slowly tapered and then stopped in January, 1982, despite continued disease activity. While the patient was receiving topical therapy alone, the skin lesions flared and the patient was confined to a wheelchair. Before beginning a skin-glafting procedure previously used successfully in patients with erosive lichen planus, 4 we started dapsone, 50 rag/day, after testing
570 Falk et al
for the presence of glucose-6-phosphate-dehydrogenase. After 3 months of dapsone the patient's lesions were much improved, with all new ulcerative lesions beginning to resolve. After 9 months of dapsone therapy the patient could walk and wear regular shoes. Fifteen months after treatment was begun, the patient no longer had active skin lesions (Fig. 3). DISCUSSION Dapsone therapy eliminated the formation of new bullous and erosive lichen planus lesions in our patient. Dapsone was previously shown to stop the formation of new bullae in SLE. a In these patients with bullous S L E w h o were successfully treated with dapsone, Hall et al a described P M L infiltration into the dermal papillae. Our patient was therefore different in that the erosive lesions always arose in lymphocyte-rich, PML-poor lesions, suggesting that dapsone was not primarily affecting PML. Although any explanation for the effectiveness of dapsone in our patient is conjectural, the drug may be working through a mechanism similar to that proposed for PML-mediated cytotoxicity3 Clark and Klebanoff 5 have shown that the MPO-H202-hali~de cofactor system is present in PMLs. The release of the MPO-H2Ozhalide system's eytotoxic factors m a y modulate the extent of the inflammatory response. However, the eytotoxicity of the MPO-HzO2-halide system was shown to be very similar for both PML and mononuclear cells. 5 Since mononuclear cells also contain MPO, 6 dapsone may change the inflammatory response in o u r patient's lichenoid infiltrates b y its inhibition o f mononuclear cellmediated MPO cytotoxicity. Several other disease processes have been reported in which dapsone controlled a predominantly lymphocyte-mediated process. 1'7 In addi-
J'oumal of the American Academy of Dermatology
tion to potential effects on the MPO-H202-halide system, dapsone may help control these diseases by modulating the release of inflammatory and/or PML chemotactic factors from mast cells, s The usefulness of dapsone in these cases and in the present case emphasizes that dapsone therapy is also effective in treating diseases usually not characterized by PML infiltrates or cytotoxicity, Whether other variants of lichen planus, lichen planus pemphigoides, 9 or the LE-LP overlap syndrome 1° would respond to dapsone is unknown but of interest, REFERENCES 1. Lang PG: Sulfones and sulfonamides in dermatology today. J AM ACAODERMATOL1:479-492, 1979. 2. Stendahl O, Molin L, Dahlgren C: Tile inhibition of polymorphonuclear leukocytecytotoxicity by dapsone. J Clin Invest 62:214-220, 1978, 3. Hall RP, Lawley TJ, Smith HR, Katz SI: Bullous eruption of systemic lupus erythematosus: Dramatic response to dapsone. Ann Intern Med 97:165-170, 1982, 4. Lendrum J: Surgical treatment of lichen planus of the soles. Br J Plast Surg 27:171-175, 1974, 5, Clark RA, Klebanoff SJ: Myeloperoxidase-H~O,-halide system: Cytotoxie effect on human blood leukocytes. Blood 50:65-70, 1977, 6. Territo M, Cline MJ: Macrophages and their disorders in man, in Nelson DS, editor: Immunobiology of the macrophage, New York, 1976, Academic Press Inc., pp. 593-616. 7. Rogers RS, Seehafer JR, Perry HO: Treatment of cicatrieial (benign mucous membrane) pemphigoid with dapsone. J AM ACADDERMATOL6:215-223, 1982. 8. Ruzicka T, Wasserman si, Soter NA, Printz MP: Inhibition of rat mast cell arachidonic acid cyclooxygenase by dapsone. J AllergyClin Immunol 72:365-370, 1983. 9. Lang PG Jr, Maize JC: Coexisting lichen planus and bullous pemphigoid or lichen planus pemphigoides? J AM ACADDERMATOL9:133-140, 1983. 10. Romem RW, Nesbitt LT Jr, Reed RJ: Unusual variant of lupus erythematosus or lichen planus: Clinical, histopathologic and immunofluorescent studies. Arch Dermatol 113:741-748, 1977.