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Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept
LETTERS CASE
LETTERS
Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept To the Editor: Necrobiosis lipoidica (NL) is an atrophic plaque with raised borders, occurring most commonly on the anterior, lower legs. The lesion begins with central erythema, which often turns yellow, atrophies, and develops telangiectasias. Aggressive lesions may ulcerate. Two thirds of cases are found in diabetic patients, yet there is no correction with glycemic control. The majority of cases appear in women, with an onset from ages 30 to 41 years. The pathogenesis of NL is unclear. Histopathology of NL shows an atrophic epidermis. The dermis is either necrobiotic, granulomatous, or a combination of both. Treatment of NL remains a challenge and is often unsuccessful. Etanercept (Enbrel, Immunex Corp, Thousand Oaks, Calif) is a dimeric fusion protein that binds both soluble and membrane-bound tumor necrosis factor (TNF) and inhibits the TNF inflammatory cascade. Etanercept currently is approved by the US Food and Drug Administration to treat rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.
CASE REPORT A 35-year old white woman presented with a yellow, telangiectatic, atrophic plaque with peripheral erythema on the right, anterior shin for several years. She had a history of type 1 diabetes, well controlled with insulin. Previous treatments for NL included topical corticosteroids and pulsed dye laser for the telangiectasias. Neither treatment was successful. Clinically, the lesion was consistent with NL. The patient was started on weekly intralesional etanercept (25 mg) injections into the dermis at 1-cm intervals throughout the surface area of the lesion. The injection site was anesthetized with topical lidocaine 4% cream. Initial improvement was observed by the first month of treatment (Fig 1). The size decreased; the atrophy, erythema, and yellow color deceased; and the telangiectasias diminished. The lesion continued to resolve over the next 8 months (month 5 shown in Fig 2). The patient experienced no side effects from etanercept, and pain from the injection was minimal with the use of the topical anesthetic. S120
MARCH 2006
Fig 1. Necrobiosis lipoidica plaque in a patient 1 month after initiation of treatment with etanercept.
Fig 2. Necrobiosis lipoidica plaque in the same patient after 5 months of treatment with etanercept.
DISCUSSION Treatment of NL is challenging and often unsuccessful. First-line therapies include smoking cessation and diabetic control. In addition, topical and intralesional1 corticosteroids may be effective. Second-line treatments include systemic corticosteroids, cyclosporine, ticlopidine, nicotinamide, clofazimine, and topical psoralen with ultraviolet A light. Pulsed dye lasers can improve the appearance of telangiectasias. Etanercept is a TNF-neutralizing agent, and is safe and effective in treating diseases with elevated TNF levels such as psoriasis and psoriatic arthritis. In addition, it has been used off-label to treat many diseases, including Behc¸et’s disease, polymyositis and dermatomyositis, palmoplantar psoriasis, hydradenitis suppurativa, autoimmune bullous diseases, and aphthous stomatitis. TNF is essential for forming granulomas and propagating the body’s inflammatory response.2 However, subcutaneously administered etanercept J AM ACAD DERMATOL
Letters S121
J AM ACAD DERMATOL VOLUME 54, NUMBER 3
has not been successful in treating granulomatous conditions including Crohn’s disease3 and sarcoidosis,4 although etanercept has been effective in offlabel treatment of silicone granulomas.5 The rationale behind an intralesional injection was an attempt to induce a greater local TNF inhibition in the NL lesion than would be gained from a subcutaneous injection. The success of intralesional etanercept for NL warrants further investigation into etanercept’s role in treating this particular granulomatous disease. Joshua A. Zeichner, MD Dana W. K. Stern, MD Mark Lebwohl, MD Mount Sinai Medical Center New York, NY This case report was investigator initiated. Financial support for the manuscript was provided by Amgen Inc and by Wyeth Research. Conflicts of interest: Dr Zeichner has served as a clinical investigator for Amgen, Biogen, IDEC, and Abbott Laboratories. Dr Lebwohl received an honorarium for this manuscript, and is a consultant (or has pending consulting agreements) for Abbott, Amgen, Biogen, Centocor, Genentech, Novartis, and Warner Chilcott. In the last 12 months, Dr Lebwohl also has served as a speaker for Abbott, Amgen, Biogen, Connetics, Fujisawa, Galderma, and Genentech. In the past 12 months, members of Dr Lebwohl’s department have served as investigators for Abbott, Allergan, Amgen, Biogen, Centocor, Connetics, Fujisawa, Genentech, and Novartis. Reprints not available from the authors. Correspondence to: Mark Lebwohl, MD Department of Dermatology Mount Sinai Medical Center 5 East 98 St, 5th Flr, Box 1048 New York, NY 10029 E-mail: [email protected]
REFERENCES 1. Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975;93:85-9. 2. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168:4620-7. 3. Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DJ, Baerg RD, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121:1088-94.
4. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, Vuk-Pavlovic Z, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124:177-85. 5. Pasternack FR, Fox LP, Engler DE. Silicone granulomas treated with etanercept. Arch Dermatol 2005;141:13-5. doi:10.1016/j.jaad.2005.11.1042
Treatment of coexisting bullous pemphigoid and psoriasis with the tumor necrosis factor antagonist etanercept To the Editor: The immunobullous diseases, such as bullous pemphigoid, occasionally develop in psoriatic patients. The coexistence of these inflammatory conditions represents a difficult therapeutic challenge. We describe a patient with a long history of plaque-type psoriasis who developed acute symptoms of bullous pemphigoid. Both his psoriasis and bullous pemphigoid were controlled eventually with the tumor necrosis factor (TNF) antagonist etanercept.
CASE REPORT A 64-year-old white man with more than 12 years of psoriasis presented with an acute 5-day eruption of pruritic, tense, and flaccid vesicles and bullae on his lower left abdomen, lower back, and lower extremities. He had psoriatic plaques on his scalp, trunk, and extremities that were calculated to have a Psoriasis Area Severity Index (PASI) score of 12. There was no psoriatic arthritis present. Prior therapy for his psoriasis consisted of psoralen plus ultraviolet A light therapy 8 years earlier and topical corticosteroids. He had evidence of moderate skin atrophy on his trunk and extremities. The patient’s past medical history was significant for hepatitis C, and he was on treatment with Coumadin (Bristol-Myers Squibb Company, Princeton, NJ) for thrombophlebitis. A punch biopsy of one of his bulla showed subepidermal bullous formation with large numbers of eosinophils within the bullous space, and in the papillary and reticular dermis consistent with bullous pemphigoid. Direct immunofluorescence studies revealed linear C3 and IgG deposits along the basement membrane zone consistent with bullous pemphigoid. Initial therapy consisted of mycophenolate mofetil 1 g twice daily to suppress his bullous pemphigoid and psoriasis. However, after 2 weeks of therapy, he developed more bullae on his trunk and lower extremities. Mycophenolate mofetil was discontinued, and he was started on prednisone at 60 mg/d to control his bullous pemphigoid flare. His bullae and blisters began to resolve after the fifth day, and 90% of his lesions disappeared by the 10th day. His psoriatic plaques also improved.
LETTERS
Treatment of necrobiosis lipoidica with the tumor necrosis factor antagonist etanercept To the Editor: Necrobiosis lipoidica (NL) is an atrophic plaque with raised borders, occurring most commonly on the anterior, lower legs. The lesion begins with central erythema, which often turns yellow, atrophies, and develops telangiectasias. Aggressive lesions may ulcerate. Two thirds of cases are found in diabetic patients, yet there is no correction with glycemic control. The majority of cases appear in women, with an onset from ages 30 to 41 years. The pathogenesis of NL is unclear. Histopathology of NL shows an atrophic epidermis. The dermis is either necrobiotic, granulomatous, or a combination of both. Treatment of NL remains a challenge and is often unsuccessful. Etanercept (Enbrel, Immunex Corp, Thousand Oaks, Calif) is a dimeric fusion protein that binds both soluble and membrane-bound tumor necrosis factor (TNF) and inhibits the TNF inflammatory cascade. Etanercept currently is approved by the US Food and Drug Administration to treat rheumatoid arthritis, juvenile rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, and psoriasis.
CASE REPORT A 35-year old white woman presented with a yellow, telangiectatic, atrophic plaque with peripheral erythema on the right, anterior shin for several years. She had a history of type 1 diabetes, well controlled with insulin. Previous treatments for NL included topical corticosteroids and pulsed dye laser for the telangiectasias. Neither treatment was successful. Clinically, the lesion was consistent with NL. The patient was started on weekly intralesional etanercept (25 mg) injections into the dermis at 1-cm intervals throughout the surface area of the lesion. The injection site was anesthetized with topical lidocaine 4% cream. Initial improvement was observed by the first month of treatment (Fig 1). The size decreased; the atrophy, erythema, and yellow color deceased; and the telangiectasias diminished. The lesion continued to resolve over the next 8 months (month 5 shown in Fig 2). The patient experienced no side effects from etanercept, and pain from the injection was minimal with the use of the topical anesthetic. S120
MARCH 2006
Fig 1. Necrobiosis lipoidica plaque in a patient 1 month after initiation of treatment with etanercept.
Fig 2. Necrobiosis lipoidica plaque in the same patient after 5 months of treatment with etanercept.
DISCUSSION Treatment of NL is challenging and often unsuccessful. First-line therapies include smoking cessation and diabetic control. In addition, topical and intralesional1 corticosteroids may be effective. Second-line treatments include systemic corticosteroids, cyclosporine, ticlopidine, nicotinamide, clofazimine, and topical psoralen with ultraviolet A light. Pulsed dye lasers can improve the appearance of telangiectasias. Etanercept is a TNF-neutralizing agent, and is safe and effective in treating diseases with elevated TNF levels such as psoriasis and psoriatic arthritis. In addition, it has been used off-label to treat many diseases, including Behc¸et’s disease, polymyositis and dermatomyositis, palmoplantar psoriasis, hydradenitis suppurativa, autoimmune bullous diseases, and aphthous stomatitis. TNF is essential for forming granulomas and propagating the body’s inflammatory response.2 However, subcutaneously administered etanercept J AM ACAD DERMATOL
Letters S121
J AM ACAD DERMATOL VOLUME 54, NUMBER 3
has not been successful in treating granulomatous conditions including Crohn’s disease3 and sarcoidosis,4 although etanercept has been effective in offlabel treatment of silicone granulomas.5 The rationale behind an intralesional injection was an attempt to induce a greater local TNF inhibition in the NL lesion than would be gained from a subcutaneous injection. The success of intralesional etanercept for NL warrants further investigation into etanercept’s role in treating this particular granulomatous disease. Joshua A. Zeichner, MD Dana W. K. Stern, MD Mark Lebwohl, MD Mount Sinai Medical Center New York, NY This case report was investigator initiated. Financial support for the manuscript was provided by Amgen Inc and by Wyeth Research. Conflicts of interest: Dr Zeichner has served as a clinical investigator for Amgen, Biogen, IDEC, and Abbott Laboratories. Dr Lebwohl received an honorarium for this manuscript, and is a consultant (or has pending consulting agreements) for Abbott, Amgen, Biogen, Centocor, Genentech, Novartis, and Warner Chilcott. In the last 12 months, Dr Lebwohl also has served as a speaker for Abbott, Amgen, Biogen, Connetics, Fujisawa, Galderma, and Genentech. In the past 12 months, members of Dr Lebwohl’s department have served as investigators for Abbott, Allergan, Amgen, Biogen, Centocor, Connetics, Fujisawa, Genentech, and Novartis. Reprints not available from the authors. Correspondence to: Mark Lebwohl, MD Department of Dermatology Mount Sinai Medical Center 5 East 98 St, 5th Flr, Box 1048 New York, NY 10029 E-mail: [email protected]
REFERENCES 1. Sparrow G, Abell E. Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 1975;93:85-9. 2. Roach DR, Bean AG, Demangel C, France MP, Briscoe H, Britton WJ. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002;168:4620-7. 3. Sandborn WJ, Hanauer SB, Katz S, Safdi M, Wolf DJ, Baerg RD, et al. Etanercept for active Crohn’s disease: a randomized, double-blind, placebo-controlled trial. Gastroenterology 2001; 121:1088-94.
4. Utz JP, Limper AH, Kalra S, Specks U, Scott JP, Vuk-Pavlovic Z, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003;124:177-85. 5. Pasternack FR, Fox LP, Engler DE. Silicone granulomas treated with etanercept. Arch Dermatol 2005;141:13-5. doi:10.1016/j.jaad.2005.11.1042
Treatment of coexisting bullous pemphigoid and psoriasis with the tumor necrosis factor antagonist etanercept To the Editor: The immunobullous diseases, such as bullous pemphigoid, occasionally develop in psoriatic patients. The coexistence of these inflammatory conditions represents a difficult therapeutic challenge. We describe a patient with a long history of plaque-type psoriasis who developed acute symptoms of bullous pemphigoid. Both his psoriasis and bullous pemphigoid were controlled eventually with the tumor necrosis factor (TNF) antagonist etanercept.
CASE REPORT A 64-year-old white man with more than 12 years of psoriasis presented with an acute 5-day eruption of pruritic, tense, and flaccid vesicles and bullae on his lower left abdomen, lower back, and lower extremities. He had psoriatic plaques on his scalp, trunk, and extremities that were calculated to have a Psoriasis Area Severity Index (PASI) score of 12. There was no psoriatic arthritis present. Prior therapy for his psoriasis consisted of psoralen plus ultraviolet A light therapy 8 years earlier and topical corticosteroids. He had evidence of moderate skin atrophy on his trunk and extremities. The patient’s past medical history was significant for hepatitis C, and he was on treatment with Coumadin (Bristol-Myers Squibb Company, Princeton, NJ) for thrombophlebitis. A punch biopsy of one of his bulla showed subepidermal bullous formation with large numbers of eosinophils within the bullous space, and in the papillary and reticular dermis consistent with bullous pemphigoid. Direct immunofluorescence studies revealed linear C3 and IgG deposits along the basement membrane zone consistent with bullous pemphigoid. Initial therapy consisted of mycophenolate mofetil 1 g twice daily to suppress his bullous pemphigoid and psoriasis. However, after 2 weeks of therapy, he developed more bullae on his trunk and lower extremities. Mycophenolate mofetil was discontinued, and he was started on prednisone at 60 mg/d to control his bullous pemphigoid flare. His bullae and blisters began to resolve after the fifth day, and 90% of his lesions disappeared by the 10th day. His psoriatic plaques also improved.