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Effect of colchicine in the subcorneal pustular dermatosis type of IgA pemphigus
Effect of colchicine in the subcorneal pustular dermatosis type of IgA pemphigus Emmilia Hodak, MD, Moshe Lapidoth, MD, and Michael David, MD Tel Aviv, Israel Background: IgA pemphigus of the subcorneal pustular dermatosis (SPD) type is characterized by subcorneal acantholysis and by an abundance of neutrophils, making colchicine a reasonable pharmacologic option for treatment. Objective: We attempted to determine the efficacy of colchicine in the treatment of SPDtype IgA pemphigus. Methods: Two patients with SPD-type IgA pemphigus were treated with colchicine 1.5 mg/day as monotherapy. Results: A sustained clinical response was achieved within 2 to 3 weeks of therapy. Relapses were noted each time colchicine was stopped. Conclusion: Colchicine should be considered in the treatment of SPD-type IgA pemphigus. (J Am Acad Dermatol 1999;40:91-4.)
IgA pemphigus is characterized by in vivo bound IgA antibodies, with or without circulating IgA anti-intercellular antibodies. It is divided into two clinicopathologic subtypes with distinct antigen profiles1: Intraepidermal neutrophilic IgA dermatosis (IEN), manifested by pustule formation through the entire epidermis, and subcorneal pustular dermatosis (SPD), manifested by subcorneal pustules. Colchicine has a therapeutic effect on skin disorders characterized by accumulation of polymorphonuclear leukocytes, including Behcet’s syndrome,2 leukocytoclastic vasculitis,3 urticarial vasculitis,4 Sweet’s syndrome,5 pustulosis palmoplantaris,6 dermatitis herpetiformis,7 adult linear IgA disease,8 and chronic bullous dermatosis of childhood.9 Because there is an abundance of polymorphonuclear leukocytes in the epidermal blisters in IgA pemphigus, colchicine is a logical option. Successful treatment with colchicine has been reported in a single case of IgA pemphigus, IEN type.10
From the Department of Dermatology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University. Reprint requests: E. Hodak, MD, Department of Dermatology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/93687
We describe two patients with IgA pemphigus, SPD type, treated with colchicine. CASE REPORTS
Patient 1 A 59-year-old woman had a 6-year history of IgApemphigus and a recent exacerbation. She had been treated with prednisone 10 to 30 mg/day. For several weeks, the prednisone had been stopped in view of a long-lasting remission. Examination revealed a symmetric eruption on the trunk, with prominent involvement of the axillae, submammary areas, and groin (Fig 1). It was composed of grouped vesicopustular lesions mostly on erythematous skin, as well as a few similar discrete isolated lesions. There was an accumulation of pus in the lower half of some of the pustules. No mucosal involvement was detected. A biopsy specimen revealed a subcorneal vesicle containing acantholytic cells and numerous neutrophils. Direct immunofluorescence (IF) showed only intercellular IgA deposits in the spinous layer. Indirect IF was negative. Colchicine, 0.5 mg 3 times daily, was begun. Within 2 weeks there was clearing of all skin lesions (Fig 2). During the next 2 months of colchicine therapy there were only mild relapses of short duration. On her own initiative the patient discontinued colchicine. Two weeks later a severe exacerbation was observed. Resumption of colchicine, 1.5 mg/day, resulted in the disappearance of all lesions within 10 days. During the next 3 months, the patient remained lesion-free. She then discontinued therapy again, after which several new lesions appeared; nevertheless, she refused further
91
92 Hodak, Lapidoth, and David
Journal of the American Academy of Dermatology January 1999
Fig 1. A and B. Patient 1. Numerous superficial pustules on erythematous bases before colchicine treatment.
Fig 2. A and B. Patient 1. After 2 weeks of colchicine treatment.
therapy. Several months later there was a severe flareup. Colchicine was begun for the third time and again resulted in complete clearance in 2 weeks.
Patient 2 A 48-year-old woman had a chronic relapsing pustu-
lar eruption for 7 years treated with topical corticosteroids without benefit. Examination revealed a symmetrical eruption located mainly in flexural areas—the axillae, submammary areas, and inguinal folds—and on the mons pubis. The eruption was composed of grouped vesiculopustules on both erythematous and normal
Journal of the American Academy of Dermatology Volume 40, Number 1
Hodak, Lapidoth, and David 93
Fig 3. Patient 2. Erosions and blistering of the axillary fold before colchicine treatment.
Fig 4. Patient 2. After 3 weeks of colchicine treatment.
skin, as well as isolated lesions, with occasional accumulation of pus in the lower half of the pustules. There were wide areas of erosion, especially in the axillary (Fig 3) and submammary folds. No mucosal involvement was noted. A biopsy specimen revealed a subcorneal vesicle containing numerous neutrophils and acantholytic cells. Direct IF showed only intercellular IgA deposits in the spinous layer. Indirect IF was negative. IgA-pemphigus was diagnosed. The patient was treated with colchicine, 0.5 mg 3 times a day. During the next 12 months there were only mild relapses manifested by a few transitory vesiculopustules. After 1 year, colchicine was discontinued. Two weeks later there was a severe exacerbation. Colchicine therapy was resumed with significant regression of most of the lesions within 3 weeks (Fig 4).
lowering of neutrophil endothelial adhesiveness,13-15 and inhibition of lysosomal enzyme release by neutrophils resulting from an increase in cyclic adenosine monophosphate level.16 The drug has also been found to inhibit immunoglobulin secretion from plasma cells.17 Thus, in IgA pemphigus, colchicine may interfere with neutrophil function and may also inhibit secretion of IgA from plasma cells. IgA is associated with leukocyte chemotaxis, and neutrophils possess receptors for IgA.18 There is direct experimental evidence that cutaneous IgA deposits in linear IgA bullous dermatitis and dermatitis herpetiformis can function as ligands for neutrophil adherence and be involved in the localization of inflammation in these disorders.19 Likewise, neutrophils, which are attracted by epidermal intercellular IgA, may accumulate in the epidermis, producing the typical histologic picture of IgA pemphigus.20 Administered in low doses, colchicine has few side effects.11 The most common are mild transient diarrhea and abdominal discomfort. Neuromyopathy has been reported infrequently,
DISCUSSION
Our results demonstrate the beneficial effect of colchicine in 2 patients with SPD-type IgA pemphigus. Colchicine exerts its anti-inflammatory effects in neutrophil-rich diseases by numerous mechanisms11: inhibition of neutrophil chemotaxis,12
94 Hodak, Lapidoth, and David particularly in elderly patients with mild chronic renal insufficiency. Other side effects of colchicine, such as bone marrow depression, are extremely rare with low-dose therapy.21 In view of our experience and the previous report on the successful use of colchicine in a patient with IENtype IgA pemphigus, we recommend a trial with colchicine in patients with IgA pemphigus before using corticosteroids or dapsone. REFERENCES 1. Hashimoto P, Kigokawa C, Mori O, Miyasato M, Chidgey MAJ, Garrod DR, et al. Human desmocollin 1 (Dsc 1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997; 102:127-31. 2. Jorizzo JL, Hudson D, Schmulstieg FC, Daniels JC, Apisarnthanarax P, Henry JC, et al. Behcet’s syndrome: immune regulation, circulating immune complexes, neutrophil eruption, and colchicine therapy. J Am Acad Dermatol 1984;10:205-14. 3. Sais G, Vidaller A, Jucgla A, Gallnardo F, Peyri J. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Arch Dermatol 1995;131:1399-402. 4. Wiles JC, Hansen RC, Lynch PJ. Urticarial vasculitis treated with colchicine. Arch Dermatol 1985;121:802-5. 5. Suehisa S, Tagami H. Treatment of acute febrile neutrophilic dermatosis (Sweet’s syndrome) with colchicine [letter]. Br J Dermatol 1981;105:483. 6. Takigawa M, Migachi Y, Uehana M, Tagami H. Treatment of pustulosis palmaris et plantaris with oral doses of colchicine. Arch Dermatol 1982;118:458-60. 7. Silvers DN, Juhlin GA, Berczella PH, McSorley J. Treatment of dermatitis herpetiformis with colchicine. Arch Dermatol 1980;116:1373-4. 8. Homayoun A. Linear IgA bullous dermatosis. Successful treatment with colchicine. Arch Dermatol 1984;120:960-1. 9. Zeharia A, Hodak E, Mukamel M, Danziger Y, Mimouni M. Successful treatment of chronic bullous dermatosis of childhood with colchicine. J Am Acad Dermatol 1994; 30:660-1.
Journal of the American Academy of Dermatology January 1999
10. Grangoux P, Tennsted D, Lachapelle JN. Intra-epidermal neutrophilic IgA dermatosis: pemphigus-like IgA deposits. Dermatology 1992;185:311-3. 11. Malkinson FD. Colchicine: new uses for an old, old drug. Arch Dermatol 1982;118:453-7. 12. Ehrenfeld M, Levy M, Bar Eli M, Gallily R, Eliakim M. Effect of colchicine on PMN leucocyte chemotaxis in human volunteers. J Clin Pharmacol 1980;10:297-300. 13. Asako H, Kubes P. Balthye BA, Wolf RE, Glanger DN. Colchicine and methotrexate reduce leucocyte adherence and emigration in rat mesenteric venules. Inflammation 1992;16:45-6. 14. Molad Y, Reibman J, Levin RI, Cronstein BN. A new mode of action for an old drug: colchicine decreases surface expression of adhesion molecules on both neutrophils (PMN) and endothelium. Arthritis Rheum 1992; 35(Suppl 9):535 (Abstract). 15. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RL, Weismann G. Colchicine alters the quantitative and quality display of selectins on endothelial cells and neutrophils. J Clin Invest 1995;96:914-1002. 16. Rudolph SA, Greengard P, Malawista SE. Effect of colchicine on cyclic AMP levels in human leucocytes. Proc Natl Acad Sci U S A 1977;74:3404-8. 17. Antoine JC, Maurice M, Feldman G, Avrameas S. In vivo and in vitro effects of colchicine and vinblastine on the secretory process of antibody-producing cells. J Immunol 1980;125:1939-49. 18. Schroder JM, Szperalski B, Koh CJ, Christophers E. IgA-associated inhibition of polymorphonuclear leukocyte chemotaxis in neutrophilic dermatoses. J Invest Dermatol 1981;77:464-8. 19. Hendrix JD, Mangum KL, Zone JJ, Gammon WR. Cutaneous IgA deposits in bullous diseases function as legands to mediate adherence of activated neutrophils. J Invest Dermatol 1990;94:667-72. 20. Hodak E, David M, Ingber A, Rotem A, Hazaz B, Sandbank M. The clinical and histopathologic spectrum of IgA-pemphigus: report of two cases. Clin Exp Dermatol 1990;15:433-7. 21. Levy M, Spino M, Read SE. Colchicine: a state of the art review. Pharmacotherapy 1991;11:196-211.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the Journal of the American Academy of Dermatology for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted at a cost of $17.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Periodical Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.
IgA pemphigus is characterized by in vivo bound IgA antibodies, with or without circulating IgA anti-intercellular antibodies. It is divided into two clinicopathologic subtypes with distinct antigen profiles1: Intraepidermal neutrophilic IgA dermatosis (IEN), manifested by pustule formation through the entire epidermis, and subcorneal pustular dermatosis (SPD), manifested by subcorneal pustules. Colchicine has a therapeutic effect on skin disorders characterized by accumulation of polymorphonuclear leukocytes, including Behcet’s syndrome,2 leukocytoclastic vasculitis,3 urticarial vasculitis,4 Sweet’s syndrome,5 pustulosis palmoplantaris,6 dermatitis herpetiformis,7 adult linear IgA disease,8 and chronic bullous dermatosis of childhood.9 Because there is an abundance of polymorphonuclear leukocytes in the epidermal blisters in IgA pemphigus, colchicine is a logical option. Successful treatment with colchicine has been reported in a single case of IgA pemphigus, IEN type.10
From the Department of Dermatology, Rabin Medical Center, Beilinson Campus, Petah Tiqva, and Sackler Faculty of Medicine, Tel Aviv University. Reprint requests: E. Hodak, MD, Department of Dermatology, Rabin Medical Center, Beilinson Campus, Petah Tiqva 49100, Israel. Copyright © 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16/1/93687
We describe two patients with IgA pemphigus, SPD type, treated with colchicine. CASE REPORTS
Patient 1 A 59-year-old woman had a 6-year history of IgApemphigus and a recent exacerbation. She had been treated with prednisone 10 to 30 mg/day. For several weeks, the prednisone had been stopped in view of a long-lasting remission. Examination revealed a symmetric eruption on the trunk, with prominent involvement of the axillae, submammary areas, and groin (Fig 1). It was composed of grouped vesicopustular lesions mostly on erythematous skin, as well as a few similar discrete isolated lesions. There was an accumulation of pus in the lower half of some of the pustules. No mucosal involvement was detected. A biopsy specimen revealed a subcorneal vesicle containing acantholytic cells and numerous neutrophils. Direct immunofluorescence (IF) showed only intercellular IgA deposits in the spinous layer. Indirect IF was negative. Colchicine, 0.5 mg 3 times daily, was begun. Within 2 weeks there was clearing of all skin lesions (Fig 2). During the next 2 months of colchicine therapy there were only mild relapses of short duration. On her own initiative the patient discontinued colchicine. Two weeks later a severe exacerbation was observed. Resumption of colchicine, 1.5 mg/day, resulted in the disappearance of all lesions within 10 days. During the next 3 months, the patient remained lesion-free. She then discontinued therapy again, after which several new lesions appeared; nevertheless, she refused further
91
92 Hodak, Lapidoth, and David
Journal of the American Academy of Dermatology January 1999
Fig 1. A and B. Patient 1. Numerous superficial pustules on erythematous bases before colchicine treatment.
Fig 2. A and B. Patient 1. After 2 weeks of colchicine treatment.
therapy. Several months later there was a severe flareup. Colchicine was begun for the third time and again resulted in complete clearance in 2 weeks.
Patient 2 A 48-year-old woman had a chronic relapsing pustu-
lar eruption for 7 years treated with topical corticosteroids without benefit. Examination revealed a symmetrical eruption located mainly in flexural areas—the axillae, submammary areas, and inguinal folds—and on the mons pubis. The eruption was composed of grouped vesiculopustules on both erythematous and normal
Journal of the American Academy of Dermatology Volume 40, Number 1
Hodak, Lapidoth, and David 93
Fig 3. Patient 2. Erosions and blistering of the axillary fold before colchicine treatment.
Fig 4. Patient 2. After 3 weeks of colchicine treatment.
skin, as well as isolated lesions, with occasional accumulation of pus in the lower half of the pustules. There were wide areas of erosion, especially in the axillary (Fig 3) and submammary folds. No mucosal involvement was noted. A biopsy specimen revealed a subcorneal vesicle containing numerous neutrophils and acantholytic cells. Direct IF showed only intercellular IgA deposits in the spinous layer. Indirect IF was negative. IgA-pemphigus was diagnosed. The patient was treated with colchicine, 0.5 mg 3 times a day. During the next 12 months there were only mild relapses manifested by a few transitory vesiculopustules. After 1 year, colchicine was discontinued. Two weeks later there was a severe exacerbation. Colchicine therapy was resumed with significant regression of most of the lesions within 3 weeks (Fig 4).
lowering of neutrophil endothelial adhesiveness,13-15 and inhibition of lysosomal enzyme release by neutrophils resulting from an increase in cyclic adenosine monophosphate level.16 The drug has also been found to inhibit immunoglobulin secretion from plasma cells.17 Thus, in IgA pemphigus, colchicine may interfere with neutrophil function and may also inhibit secretion of IgA from plasma cells. IgA is associated with leukocyte chemotaxis, and neutrophils possess receptors for IgA.18 There is direct experimental evidence that cutaneous IgA deposits in linear IgA bullous dermatitis and dermatitis herpetiformis can function as ligands for neutrophil adherence and be involved in the localization of inflammation in these disorders.19 Likewise, neutrophils, which are attracted by epidermal intercellular IgA, may accumulate in the epidermis, producing the typical histologic picture of IgA pemphigus.20 Administered in low doses, colchicine has few side effects.11 The most common are mild transient diarrhea and abdominal discomfort. Neuromyopathy has been reported infrequently,
DISCUSSION
Our results demonstrate the beneficial effect of colchicine in 2 patients with SPD-type IgA pemphigus. Colchicine exerts its anti-inflammatory effects in neutrophil-rich diseases by numerous mechanisms11: inhibition of neutrophil chemotaxis,12
94 Hodak, Lapidoth, and David particularly in elderly patients with mild chronic renal insufficiency. Other side effects of colchicine, such as bone marrow depression, are extremely rare with low-dose therapy.21 In view of our experience and the previous report on the successful use of colchicine in a patient with IENtype IgA pemphigus, we recommend a trial with colchicine in patients with IgA pemphigus before using corticosteroids or dapsone. REFERENCES 1. Hashimoto P, Kigokawa C, Mori O, Miyasato M, Chidgey MAJ, Garrod DR, et al. Human desmocollin 1 (Dsc 1) is an autoantigen for the subcorneal pustular dermatosis type of IgA pemphigus. J Invest Dermatol 1997; 102:127-31. 2. Jorizzo JL, Hudson D, Schmulstieg FC, Daniels JC, Apisarnthanarax P, Henry JC, et al. Behcet’s syndrome: immune regulation, circulating immune complexes, neutrophil eruption, and colchicine therapy. J Am Acad Dermatol 1984;10:205-14. 3. Sais G, Vidaller A, Jucgla A, Gallnardo F, Peyri J. Colchicine in the treatment of cutaneous leukocytoclastic vasculitis. Arch Dermatol 1995;131:1399-402. 4. Wiles JC, Hansen RC, Lynch PJ. Urticarial vasculitis treated with colchicine. Arch Dermatol 1985;121:802-5. 5. Suehisa S, Tagami H. Treatment of acute febrile neutrophilic dermatosis (Sweet’s syndrome) with colchicine [letter]. Br J Dermatol 1981;105:483. 6. Takigawa M, Migachi Y, Uehana M, Tagami H. Treatment of pustulosis palmaris et plantaris with oral doses of colchicine. Arch Dermatol 1982;118:458-60. 7. Silvers DN, Juhlin GA, Berczella PH, McSorley J. Treatment of dermatitis herpetiformis with colchicine. Arch Dermatol 1980;116:1373-4. 8. Homayoun A. Linear IgA bullous dermatosis. Successful treatment with colchicine. Arch Dermatol 1984;120:960-1. 9. Zeharia A, Hodak E, Mukamel M, Danziger Y, Mimouni M. Successful treatment of chronic bullous dermatosis of childhood with colchicine. J Am Acad Dermatol 1994; 30:660-1.
Journal of the American Academy of Dermatology January 1999
10. Grangoux P, Tennsted D, Lachapelle JN. Intra-epidermal neutrophilic IgA dermatosis: pemphigus-like IgA deposits. Dermatology 1992;185:311-3. 11. Malkinson FD. Colchicine: new uses for an old, old drug. Arch Dermatol 1982;118:453-7. 12. Ehrenfeld M, Levy M, Bar Eli M, Gallily R, Eliakim M. Effect of colchicine on PMN leucocyte chemotaxis in human volunteers. J Clin Pharmacol 1980;10:297-300. 13. Asako H, Kubes P. Balthye BA, Wolf RE, Glanger DN. Colchicine and methotrexate reduce leucocyte adherence and emigration in rat mesenteric venules. Inflammation 1992;16:45-6. 14. Molad Y, Reibman J, Levin RI, Cronstein BN. A new mode of action for an old drug: colchicine decreases surface expression of adhesion molecules on both neutrophils (PMN) and endothelium. Arthritis Rheum 1992; 35(Suppl 9):535 (Abstract). 15. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RL, Weismann G. Colchicine alters the quantitative and quality display of selectins on endothelial cells and neutrophils. J Clin Invest 1995;96:914-1002. 16. Rudolph SA, Greengard P, Malawista SE. Effect of colchicine on cyclic AMP levels in human leucocytes. Proc Natl Acad Sci U S A 1977;74:3404-8. 17. Antoine JC, Maurice M, Feldman G, Avrameas S. In vivo and in vitro effects of colchicine and vinblastine on the secretory process of antibody-producing cells. J Immunol 1980;125:1939-49. 18. Schroder JM, Szperalski B, Koh CJ, Christophers E. IgA-associated inhibition of polymorphonuclear leukocyte chemotaxis in neutrophilic dermatoses. J Invest Dermatol 1981;77:464-8. 19. Hendrix JD, Mangum KL, Zone JJ, Gammon WR. Cutaneous IgA deposits in bullous diseases function as legands to mediate adherence of activated neutrophils. J Invest Dermatol 1990;94:667-72. 20. Hodak E, David M, Ingber A, Rotem A, Hazaz B, Sandbank M. The clinical and histopathologic spectrum of IgA-pemphigus: report of two cases. Clin Exp Dermatol 1990;15:433-7. 21. Levy M, Spino M, Read SE. Colchicine: a state of the art review. Pharmacotherapy 1991;11:196-211.
AVAILABILITY OF JOURNAL BACK ISSUES As a service to our subscribers, copies of back issues of the Journal of the American Academy of Dermatology for the preceding 5 years are maintained and are available for purchase from Mosby until inventory is depleted at a cost of $17.00 per issue. The following quantity discounts are available: 25% off on quantities of 12 to 23, and one third off on quantities of 24 or more. Please write to Mosby, Inc., Periodical Subscription Services, 11830 Westline Industrial Dr., St. Louis, MO 63146-3318, or call (800)453-4351 or (314)453-4351 for information on availability of particular issues. If unavailable from the publisher, photocopies of complete issues may be purchased from UMI, 300 N. Zeeb Rd., Ann Arbor, MI 48106, (313)761-4700.