- Email: [email protected]
Grover disease may result from the impairment of keratinocytic cholinergic receptors
J AM ACAD DERMATOL
332 Letters
FEBRUARY 2012
remission, then maintained by methotrexate, as seen in patients 4 and 7. Dose escalation of infliximab (up to 10 mg/kg every 4 weeks) may sometimes be necessary.5 Thus the lack of efficacy seen in patients 2 and 8 could have been corrected by an increased dose of infliximab. Infliximab appears to be a good candidate as a third-line therapy for refractory cutaneous sarcoidosis. An increase in infliximab dosage in case of insufficient response and the use of concomitant low-dose methotrexate to increase infliximab efficacy may be necessary. Thomas Sene , MD,a Caroline Juillard, MD, MSc,a Michel Rybojad, MD,a Florence Cordoliani, MD,a Ce leste Lebbe , MD, PhD,a Patrice Morel, MD,a Abdellatif Tazi, MD, PhD,b and Fabien Guibal, MD, MSca Departments of Dermatologya and Pneumology,b H^ opital Saint-Louis Funding sources: None.
Correspondence to: Fabien Guibal, MD, MSc, Department of Dermatology, H^opital SaintLouis, 1 Avenue Claude-Vellefaux, 75475, Paris Cedex 10, France E-mail: [email protected]
REFERENCES 1. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153-65. 2. Badgwell C, Rosen T. Cutaneous sarcoidosis therapy updated. J Am Acad Dermatol 2007;56:69-83. 3. Baughman RP, Lower EE, Drent M. Inhibitors of tumor necrosis factor (TNF) in sarcoidosis: who, what, and how to use them. Sarcoidosis Vasc Diffuse Lung Dis 2008;25:76-89. 4. Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:149-73. 5. Thielen AM, Barde C, Saurat JH, Laffitte E. Refractory chronic cutaneous sarcoidosis responsive to dose escalation of TNFalpha antagonists. Dermatology 2009;219:59-62.
Conflicts of interest: None declared.
doi:10.1016/j.jaad.2011.05.040
CASE
LETTERS
Grover disease may result from the impairment of keratinocytic cholinergic receptors To the Editor: Grover disease is an eruption of intraepidermal acantholysis presenting as crusted reddened papules; it is usually found on the trunk of middle aged patients, with a male to female ratio of 2:1. The disease may be transient or persistent. Although the onset of Grover disease often appears to be spontaneous, the expression of Grover disease has been associated with a multitude of factors, including sun exposure, winter time, interleukin-4 administration, heat or sweat, ionizing radiation, psoralen plus ultraviolet A light phototherapy, chemotherapy, and chronic renal failure. Causation has not been established. A 50-year-old man initially developed pruritic red crusted papules on the trunk 6 days after he began taking varenicline to stop smoking. While taking varenicline, he reduced smoking from 40 to 10 cigarettes daily. A biopsy specimen revealed suprabasalar and intraspinous cell layer acantholysis, dyskeratoses, and a superficial lymphocytic infiltrate, identifying Grover disease (Fig 1). He discontinued varenicline on the eighteenth treatment day because
Fig 1. Acantholysis and dyskeratotic keratinocytes of Grover disease involving basal, suprabasal, and intraspinous cell layers. (Hematoxylineeosin stain; original magnification: 3200.)
of insomnia, poor concentration, and nausea. Within 7 days after stopping varenicline, he had resumed smoking about 30 cigarettes daily, with a concurrent reduction to about 10% of the previous number of Grover papules. After 11 weeks, the patient resumed varenicline and reduced his smoking to five cigarettes daily. The Grover disease flared. However, he again
J AM ACAD DERMATOL VOLUME 66, NUMBER 2
abandoned varenicline and increased smoking to at least 15 cigarettes daily. The Grover disease almost completely disappeared. The variables of varenicline use plus reduction in cigarette smoking were associated with the appearance of Grover disease, and the converse was followed by greatly reduced expression of disease. It seems likely, but unproven, that either factor independently might induce Grover disease. Nicotine is an agonist of nicotinic acetylcholine receptors (nAChR) and is known to induce keratinocytic adhesion.1 In normal human keratinocytes in culture, incubation with nicotine resulted in a 1.5- to 2.9-fold increase of mRNA and protein levels of a3, a5, a7, b2, and b4 subunits of the nAChR.2 Varenicline is a partial agonist of the a4b2 nAChR with 45% of nicotine’s maximal efficacy using HEK cells expressing the a4b2 subtype nAChR, attenuating the effect of nicotine on dopamine release when nicotine and varenicline are combined.3 Varenicline also acts as a nicotine antagonist because of its higher affinity for the a4b2 receptor than nicotine.4 The effect of varenicline is not limited to a4b2 receptors, but rather displays an efficacy ( functional potency) ranging from a low of \15% for a4b2-, a3b2-, and a6-containing subunits to a high of 93% and 75% for a7 and a3b4 subunits, respectively. Large differences in affinity do not necessarily correlate with functional potencies.5 In this case, the acantholysis occurred throughout the basal, suprabasal, and spinous cell layers of the trunk. The functional potency of varenicline is high with respect to a7, a3, and b4 subunits, and each of these subunits may be found in the basal, suprabasal, and granular cell zones. The acantholysis of Grover disease, at least in some cases, may depend upon impaired expression of the cholinergic receptor subunits whose type is known to vary with epidermal maturation and body site. David Paslin, MD Department of Dermatology, University of California at San Francisco School of Medicine, San Francisco, California Funding sources: None. Conflicts of interest: None declared. Correspondence to: David Paslin, MD, 460 34th St, Oakland, CA 94609 E-mail: [email protected] REFERENCES 1. Mehta JN, Martin AG. A case of pemphigus vulgaris improved by cigarette smoking. Arch Dermatol 2000;136:15-7.
Letters 333
2. Arredondo J, Nguyen V, Chernyavsky A, Shfii M, Pinkerton K, Grando S. Reciprocal changes in the expressions of nicotinic acetylcholine receptors and the cell cycle and differentiation genes can mediate pathobiologic effects of tobacco products on keratinocytes. J Invest Dermatol 2001;117:478, (abstr). 3. Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, et al. Pharmacological profile of the a4b2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacol 2007;52:985-94. 4. Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, et al. Varenicline: an a4b2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005;48:3474-7. 5. Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at a4b2 and a full agonist at a7 neuronal nicotinic receptors. Mol Pharmacol 2006;70:801-5. doi:10.1016/j.jaad.2009.08.015
Phaeohyphomycosis caused by Phaeoacremonium species in a patient taking infliximab To the Editor: We report a 74-year-old man with a history of severe rheumatoid arthritis treated with infliximab who presented with a slowly enlarging nodule on his posterior left leg. The lesion began as a small red bump approximately 1 month after being stuck with a thorn of a pyracantha bush. The bump grew in size over 4 months and was unresponsive to multiple oral antibiotics. Bacterial cultures were negative. The patient did not complain of any systemic symptoms. Physical examination showed a 1.5- 3 4-cm violaceous scaling and crusted nodule on the posterior aspect of his left leg (Fig 1). No lymphadenopathy was present. Bacterial culture and acid-fast bacillus were negative. Deep fungal culture was positive for Phaeoacremonium species. Histologic examination revealed pseudoepitheliomatous hyperplasia of the epidermis. Within the superficial and deep dermis, there was diffuse suppurative and granulomatous inflammation with areas of necrosis surrounded by histiocytes, neutrophils, and lymphocytes (Fig 2, A). Periodic acideSchiff highlighted fungal forms in the areas of necrosis (Fig 2, B). Following the positive culture for Phaeoacremonium species, infliximab was discontinued because of its potential effect on decreasing granuloma formation and increasing the risk of spread of the infection. Itraconazole, 200 mg per day, was started at that time. The lesion decreased in size over 5 months, but because of unbearable symptoms of his severe rheumatoid arthritis, infliximab was re-started. Surgical excision, with primary closure, was performed and he remains on itraconazole with no evidence of recurrence 18 months after excision. Phaeohyphomycosis is a disease caused by a group of dematiaceous fungi that rarely infect
332 Letters
FEBRUARY 2012
remission, then maintained by methotrexate, as seen in patients 4 and 7. Dose escalation of infliximab (up to 10 mg/kg every 4 weeks) may sometimes be necessary.5 Thus the lack of efficacy seen in patients 2 and 8 could have been corrected by an increased dose of infliximab. Infliximab appears to be a good candidate as a third-line therapy for refractory cutaneous sarcoidosis. An increase in infliximab dosage in case of insufficient response and the use of concomitant low-dose methotrexate to increase infliximab efficacy may be necessary. Thomas Sene , MD,a Caroline Juillard, MD, MSc,a Michel Rybojad, MD,a Florence Cordoliani, MD,a Ce leste Lebbe , MD, PhD,a Patrice Morel, MD,a Abdellatif Tazi, MD, PhD,b and Fabien Guibal, MD, MSca Departments of Dermatologya and Pneumology,b H^ opital Saint-Louis Funding sources: None.
Correspondence to: Fabien Guibal, MD, MSc, Department of Dermatology, H^opital SaintLouis, 1 Avenue Claude-Vellefaux, 75475, Paris Cedex 10, France E-mail: [email protected]
REFERENCES 1. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357:2153-65. 2. Badgwell C, Rosen T. Cutaneous sarcoidosis therapy updated. J Am Acad Dermatol 2007;56:69-83. 3. Baughman RP, Lower EE, Drent M. Inhibitors of tumor necrosis factor (TNF) in sarcoidosis: who, what, and how to use them. Sarcoidosis Vasc Diffuse Lung Dis 2008;25:76-89. 4. Hunninghake GW, Costabel U, Ando M, Baughman R, Cordier JF, du Bois R, et al. ATS/ERS/WASOG statement on sarcoidosis. American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders. Sarcoidosis Vasc Diffuse Lung Dis 1999;16:149-73. 5. Thielen AM, Barde C, Saurat JH, Laffitte E. Refractory chronic cutaneous sarcoidosis responsive to dose escalation of TNFalpha antagonists. Dermatology 2009;219:59-62.
Conflicts of interest: None declared.
doi:10.1016/j.jaad.2011.05.040
CASE
LETTERS
Grover disease may result from the impairment of keratinocytic cholinergic receptors To the Editor: Grover disease is an eruption of intraepidermal acantholysis presenting as crusted reddened papules; it is usually found on the trunk of middle aged patients, with a male to female ratio of 2:1. The disease may be transient or persistent. Although the onset of Grover disease often appears to be spontaneous, the expression of Grover disease has been associated with a multitude of factors, including sun exposure, winter time, interleukin-4 administration, heat or sweat, ionizing radiation, psoralen plus ultraviolet A light phototherapy, chemotherapy, and chronic renal failure. Causation has not been established. A 50-year-old man initially developed pruritic red crusted papules on the trunk 6 days after he began taking varenicline to stop smoking. While taking varenicline, he reduced smoking from 40 to 10 cigarettes daily. A biopsy specimen revealed suprabasalar and intraspinous cell layer acantholysis, dyskeratoses, and a superficial lymphocytic infiltrate, identifying Grover disease (Fig 1). He discontinued varenicline on the eighteenth treatment day because
Fig 1. Acantholysis and dyskeratotic keratinocytes of Grover disease involving basal, suprabasal, and intraspinous cell layers. (Hematoxylineeosin stain; original magnification: 3200.)
of insomnia, poor concentration, and nausea. Within 7 days after stopping varenicline, he had resumed smoking about 30 cigarettes daily, with a concurrent reduction to about 10% of the previous number of Grover papules. After 11 weeks, the patient resumed varenicline and reduced his smoking to five cigarettes daily. The Grover disease flared. However, he again
J AM ACAD DERMATOL VOLUME 66, NUMBER 2
abandoned varenicline and increased smoking to at least 15 cigarettes daily. The Grover disease almost completely disappeared. The variables of varenicline use plus reduction in cigarette smoking were associated with the appearance of Grover disease, and the converse was followed by greatly reduced expression of disease. It seems likely, but unproven, that either factor independently might induce Grover disease. Nicotine is an agonist of nicotinic acetylcholine receptors (nAChR) and is known to induce keratinocytic adhesion.1 In normal human keratinocytes in culture, incubation with nicotine resulted in a 1.5- to 2.9-fold increase of mRNA and protein levels of a3, a5, a7, b2, and b4 subunits of the nAChR.2 Varenicline is a partial agonist of the a4b2 nAChR with 45% of nicotine’s maximal efficacy using HEK cells expressing the a4b2 subtype nAChR, attenuating the effect of nicotine on dopamine release when nicotine and varenicline are combined.3 Varenicline also acts as a nicotine antagonist because of its higher affinity for the a4b2 receptor than nicotine.4 The effect of varenicline is not limited to a4b2 receptors, but rather displays an efficacy ( functional potency) ranging from a low of \15% for a4b2-, a3b2-, and a6-containing subunits to a high of 93% and 75% for a7 and a3b4 subunits, respectively. Large differences in affinity do not necessarily correlate with functional potencies.5 In this case, the acantholysis occurred throughout the basal, suprabasal, and spinous cell layers of the trunk. The functional potency of varenicline is high with respect to a7, a3, and b4 subunits, and each of these subunits may be found in the basal, suprabasal, and granular cell zones. The acantholysis of Grover disease, at least in some cases, may depend upon impaired expression of the cholinergic receptor subunits whose type is known to vary with epidermal maturation and body site. David Paslin, MD Department of Dermatology, University of California at San Francisco School of Medicine, San Francisco, California Funding sources: None. Conflicts of interest: None declared. Correspondence to: David Paslin, MD, 460 34th St, Oakland, CA 94609 E-mail: [email protected] REFERENCES 1. Mehta JN, Martin AG. A case of pemphigus vulgaris improved by cigarette smoking. Arch Dermatol 2000;136:15-7.
Letters 333
2. Arredondo J, Nguyen V, Chernyavsky A, Shfii M, Pinkerton K, Grando S. Reciprocal changes in the expressions of nicotinic acetylcholine receptors and the cell cycle and differentiation genes can mediate pathobiologic effects of tobacco products on keratinocytes. J Invest Dermatol 2001;117:478, (abstr). 3. Rollema H, Chambers LK, Coe JW, Glowa J, Hurst RS, Lebel LA, et al. Pharmacological profile of the a4b2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid. Neuropharmacol 2007;52:985-94. 4. Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, et al. Varenicline: an a4b2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005;48:3474-7. 5. Mihalak KB, Carroll FI, Luetje CW. Varenicline is a partial agonist at a4b2 and a full agonist at a7 neuronal nicotinic receptors. Mol Pharmacol 2006;70:801-5. doi:10.1016/j.jaad.2009.08.015
Phaeohyphomycosis caused by Phaeoacremonium species in a patient taking infliximab To the Editor: We report a 74-year-old man with a history of severe rheumatoid arthritis treated with infliximab who presented with a slowly enlarging nodule on his posterior left leg. The lesion began as a small red bump approximately 1 month after being stuck with a thorn of a pyracantha bush. The bump grew in size over 4 months and was unresponsive to multiple oral antibiotics. Bacterial cultures were negative. The patient did not complain of any systemic symptoms. Physical examination showed a 1.5- 3 4-cm violaceous scaling and crusted nodule on the posterior aspect of his left leg (Fig 1). No lymphadenopathy was present. Bacterial culture and acid-fast bacillus were negative. Deep fungal culture was positive for Phaeoacremonium species. Histologic examination revealed pseudoepitheliomatous hyperplasia of the epidermis. Within the superficial and deep dermis, there was diffuse suppurative and granulomatous inflammation with areas of necrosis surrounded by histiocytes, neutrophils, and lymphocytes (Fig 2, A). Periodic acideSchiff highlighted fungal forms in the areas of necrosis (Fig 2, B). Following the positive culture for Phaeoacremonium species, infliximab was discontinued because of its potential effect on decreasing granuloma formation and increasing the risk of spread of the infection. Itraconazole, 200 mg per day, was started at that time. The lesion decreased in size over 5 months, but because of unbearable symptoms of his severe rheumatoid arthritis, infliximab was re-started. Surgical excision, with primary closure, was performed and he remains on itraconazole with no evidence of recurrence 18 months after excision. Phaeohyphomycosis is a disease caused by a group of dematiaceous fungi that rarely infect