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Methotrexate induced skin ulceration: two patterns of clinical presentation
1547
677
Methotrexate induced skin ulceration: two patterns of clinical presentation Pallavi Gupta, MBBS, Monklands Hospital, Lanarkshire Center for Dermatology, Airdrie, United Kingdom; Helen Dilworth, MBChB, Monklands Hospital, Lanarkshire Center for Dermatology, Airdrie, United Kingdom; Goutam Dawn, MBBS, Monklands Hospital, Lanarkshire Center for Dermatology, Airdrie, United Kingdom Skin ulceration is a rare side effect of methotrexate (MTX) therapy, usually seen within few weeks of commencing the drug. In addition to a very rare toxic epidermal necrolysiselike presentation, Lawrence and Dahl reported two patterns of MTX induced skin ulceration in 1984. In type I, psoriatic plaques became painful and eroded shortly after starting MTX. In type II, ulcerations occurred in skin affected by other pathology (eg, stasis dermatitis or anal fistula) and not within the psoriatic plaques. In this type relationship to the duration of treatment was variable. We describe two patients with psoriasis on long-term low dose MTX presenting with two patterns of MTX-induced skin ulceration. A 54-year-old female on MTX 12.5 mg/week for psoriasis and psoriatic arthritis for 13 years presented with a 2-week history of painful ulcerations within psoriatic plaques. Prior to the onset of skin ulceration she had been taking aspirin 600 mg daily for 3 days for joint pains. She was admitted to hospital and MTX was stopped. Investigations showed low hemoglobin, platelet and folate level. Serum MTX level was undetectable. Herpes virus PCR was negative. Skin biopsy was consistent with chemotherapy induced skin necrosis. She was given oral folinic acid, 15 mg TID for 5 days and ulcerations healed completely within 10 days. The second case, a 59-year-old female was admitted to high dependency unit with high fever, widespread purpuric rash and ulcerations on buttocks, groins, toes and mouth. She was neutropenic with a low platelet count. She was on 10 mg/week of MTX for psoriasis for 10 years. Three months prior to admission she reported a painful 3 3 3cm ulcer on her right buttock, which was thought to be a pressure sore, as the patient was wheelchair bound. MTX was discontinued on admission and folinic acid 20 mg IV BD was started. She developed staphylococcal septicemia and required intravenous antibiotics, platelet transfusions and G-CSF. Mouth ulcers and most of the skin ulcerations healed within 14 days but buttock ulceration took 30 days to resolve. In conclusion, our first patient fits with type I ulceration although she was on long term MTX. Our second patient had an atypical presentation with bone marrow suppression on a long-term low dose MTX. We recommend considering the possibility of MTX-induced skin necrosis in any patient complaining of pain in psoriatic lesions even with normal blood parameters.
Morbilliform eruption in a patient receiving intravesical Bacillus CalmetteGu erin Holly Reid, University of Texas Medical School at Houston, Houston, TX, United States; Savina Aneja, MD, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Susan Chon, MD, University of Texas MD Anderson Cancer Center, Houston, TX, United States Background: While it is more widely known as a vaccine against tuberculosis, Bacillus Calmette-Guerin (BCG) is known to have antimalignant properties as well. Intravesical BCG immunotherapy is used in the treatment for superficial bladder cancer. Major side effects occur in less than five percent of those treated. Systemic absorption of BCG into the bloodstream and reactivation of the attenuated bacilli is known as BCG-osis, which can lead to multiorgan failure. Clinical recognition of BCG-osis is challenging and there are very few reports specifying cutaneous manifestations of this disease, which can present as purpuric patches, a pityriasis rosea-like eruption, or a morbilliform eruption. Observations: A 63-year-old Caucasian man with urothelial carcinoma of the bladder undergoing intravesical BCG treatment developed a pruritic cutaneous eruption and a fever after his third instillation of intravesical BCG. On physical examination he was noted to have multiple pink macules coalescing into patches involving his trunk and extremities. A punch biopsy showed sparse superficial perivascular dermatitis with focal minimal spongiosis, consistent with a dermal hypersensitivity reaction. Clinical suspicion of systemic hypersensitivity reaction to BCG dissemination prompted the initiation of antituberculous therapy, which led to symptomatic resolution. Conclusions and Relevance: The purpose of this manuscript is to alert dermatologists working in cancer centers to the possibility of this diagnosis in a patient with a recent exposure to intravesical BCG and an unexplained skin eruption. Since BCG reactivation can be fatal, providers must have a low threshold to begin antituberculous therapy. Commercial support: None identified.
Commercial support: None identified.
1598 Microbiopsy skin sampling in volunteers reveals no oxidative stress detected after topically applying sunscreen with zinc oxide nanoparticles Lydia Y. T. Hang, MBBS, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Lynlee L. Lin, ScD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Miko Yamada, PhD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; H. Peter Soyer, MD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Anthony P. Raphael, PhD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Tarl W. Prow, PhD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia Background: The development of nano-sized zinc oxide particles (ZnO-NP) saw the revolution of sunscreen that applied clear on skin, a step up from its less aesthetically pleasing predecessor, microparticles. Zinc oxide nanoparticles have been shown to induce oxidative stress in vitro; giving cause to the claims that topically applied sunscreens containing ZnO-NP can be cytotoxic. We recently developed a novel microneedle based skin sampling technology, microbiopsy. This approach enables rapid volunteer skin sampling without the need for local anaesthetic or sutures. We observed relative oxidative stress levels in intact and tape-stripped volunteer epidermal tissue after exposure to ZnO-NP in vivo using microbiopsied skin samples. Methods and Materials: Human volunteer skin was tape-stripped and then treated with ZnO-NP for 2 hours. Microbiopsies extracted epidermal tissues which were treated with two different oxidative stress probes. Confocal microscopy was used to assess the levels of oxidative stress reported by fluorescent probes. Images were analyzed using Image J (National Institutes of Health, Bethesda, MD). Fluorescence signal raw integrated density was acquired from the specimen. Results: Skin exposed to ZnO-NP did not show any significant increase in oxidative stress, but rather there was a trend towards lower levels of oxidative stress than untreated skin. Intact and tape-stripped skin treated with ZnO-NP sunscreen did not yield a significantly higher fluorescence signal compared to untreated skin. Fold change of ZnO-NP treated skin relative to untreated skin was 0.9 in intact and 1.1 in tape-stripped skin for the reactive oxygen and nitrogen species. A similar result was observed for the mitochondrial superoxide, 1.0- and 1.2-fold change for intact and tape-stripped skin, respectively. Conclusions: The debate regarding ZnO-NP in sunscreens is far from over given the gaps in the knowledge about nanoparticle interactions on and within the human body. In vitro studies show the potential of ZnO-NP to induce cytotoxicity, but interpretation should be limited to only that context. In vivo studies show that the skin is an effective barrier against topically applied ZnO-NP even when it is mechanically compromised. We conclude that topically applied ZnO-NP containing sunscreen does not result in significantly increased oxidative stress in the skin. Commercial support: None identified.
AB210
J AM ACAD DERMATOL
1169 Omalizumab in dermatology: A review of the literature Justin Chia, MD, Division of Dermatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; P. Regine Mydlarski, MD, PhD, Division of Dermatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada Introduction Omalizumab (Xolair; Roche/Genetech and Novartis Pharmaceuticals Inc) is a recombinant humanized monoclonal antibody that inhibits the binding of IgE to the high-affinity IgE receptor (FceRI) on the surface of mast cells and basophils. By reducing surface-bound IgE on FceRI-bearing cells, omalizumab impairs the release of inflammatory mediators. Treatment with omalizumab also reduces the number of FceRI on basophils and may also decrease other autoreactive IgE antibodies. Omalizumab has been approved for use in asthma, and new reports show promise in a variety of dermatologic diseases. Herein, we review the literature on omalizumab in dermatology and discuss the safety, efficacy and mechanisms of action for this emerging therapy. Methods: A search of the PubMed, Embase, and MEDLINE databases was performed (1990-2013) using the key words ‘‘omalizumab’’ and ‘‘Xolair’’ in combination with the following: ‘‘alopecia,’’ ‘‘angioedema,’’ ‘‘atopic dermatitis,’’ ‘‘bullous skin disease,’’ ‘‘collagen vascular disease,’’ ‘‘cryoglobulinemia,’’ ‘‘cutaneous,’’ ‘‘dermatitis,’’ ‘‘dermatologic,’’ ‘‘dermatology,’’ ‘‘dermatomyositis,’’ ‘‘eczema,’’ ‘‘epidermolysis bullosa,’’ ‘‘graft versus host disease,’’ ‘‘granulomatous disease,’’ ‘‘hyper-IgE syndrome,’’ ‘‘lupus,’’ ‘‘mastocytosis,’’ ‘‘papulosquamous,’’ ‘‘pemphigoid,’’ ‘‘pemphigus,’’ ‘‘psoriasis,’’ ‘‘scleroderma,’’ ‘‘skin,’’ ‘‘urticaria,’’ ‘‘vasculitis,’’ ‘‘vesiculobullous,’’ ‘‘vitiligo.’’ The data were extracted and the levels of evidence were graded in accordance with recommendations from the Oxford Center for Evidence-Based Medicine. Results: A total of 2272 articles were sourced and 59 full-text dermatology-related publications were identified. They included reports on the use of omalizumab in chronic urticaria (34), atopic dermatitis (20), bullous pemphigoid (3), and hyper-IgE syndrome (2). The safety and efficacy of omalizumab were also evaluated. Conclusions: Omalizumab has demonstrated therapeutic efficacy in a variety of recalcitrant immune-mediated and autoimmune skin disorders. It is a safe and effective treatment for use in chronic idiopathic urticaria (grade of recommendation: 1A). Randomized clinical trials with long-term follow-ups are warranted to firmly establish the role of omalizumab in the treatment of dermatologic disease. Commercial support: None identified.
MAY 2015
677
Methotrexate induced skin ulceration: two patterns of clinical presentation Pallavi Gupta, MBBS, Monklands Hospital, Lanarkshire Center for Dermatology, Airdrie, United Kingdom; Helen Dilworth, MBChB, Monklands Hospital, Lanarkshire Center for Dermatology, Airdrie, United Kingdom; Goutam Dawn, MBBS, Monklands Hospital, Lanarkshire Center for Dermatology, Airdrie, United Kingdom Skin ulceration is a rare side effect of methotrexate (MTX) therapy, usually seen within few weeks of commencing the drug. In addition to a very rare toxic epidermal necrolysiselike presentation, Lawrence and Dahl reported two patterns of MTX induced skin ulceration in 1984. In type I, psoriatic plaques became painful and eroded shortly after starting MTX. In type II, ulcerations occurred in skin affected by other pathology (eg, stasis dermatitis or anal fistula) and not within the psoriatic plaques. In this type relationship to the duration of treatment was variable. We describe two patients with psoriasis on long-term low dose MTX presenting with two patterns of MTX-induced skin ulceration. A 54-year-old female on MTX 12.5 mg/week for psoriasis and psoriatic arthritis for 13 years presented with a 2-week history of painful ulcerations within psoriatic plaques. Prior to the onset of skin ulceration she had been taking aspirin 600 mg daily for 3 days for joint pains. She was admitted to hospital and MTX was stopped. Investigations showed low hemoglobin, platelet and folate level. Serum MTX level was undetectable. Herpes virus PCR was negative. Skin biopsy was consistent with chemotherapy induced skin necrosis. She was given oral folinic acid, 15 mg TID for 5 days and ulcerations healed completely within 10 days. The second case, a 59-year-old female was admitted to high dependency unit with high fever, widespread purpuric rash and ulcerations on buttocks, groins, toes and mouth. She was neutropenic with a low platelet count. She was on 10 mg/week of MTX for psoriasis for 10 years. Three months prior to admission she reported a painful 3 3 3cm ulcer on her right buttock, which was thought to be a pressure sore, as the patient was wheelchair bound. MTX was discontinued on admission and folinic acid 20 mg IV BD was started. She developed staphylococcal septicemia and required intravenous antibiotics, platelet transfusions and G-CSF. Mouth ulcers and most of the skin ulcerations healed within 14 days but buttock ulceration took 30 days to resolve. In conclusion, our first patient fits with type I ulceration although she was on long term MTX. Our second patient had an atypical presentation with bone marrow suppression on a long-term low dose MTX. We recommend considering the possibility of MTX-induced skin necrosis in any patient complaining of pain in psoriatic lesions even with normal blood parameters.
Morbilliform eruption in a patient receiving intravesical Bacillus CalmetteGu erin Holly Reid, University of Texas Medical School at Houston, Houston, TX, United States; Savina Aneja, MD, University of Texas MD Anderson Cancer Center, Houston, TX, United States; Susan Chon, MD, University of Texas MD Anderson Cancer Center, Houston, TX, United States Background: While it is more widely known as a vaccine against tuberculosis, Bacillus Calmette-Guerin (BCG) is known to have antimalignant properties as well. Intravesical BCG immunotherapy is used in the treatment for superficial bladder cancer. Major side effects occur in less than five percent of those treated. Systemic absorption of BCG into the bloodstream and reactivation of the attenuated bacilli is known as BCG-osis, which can lead to multiorgan failure. Clinical recognition of BCG-osis is challenging and there are very few reports specifying cutaneous manifestations of this disease, which can present as purpuric patches, a pityriasis rosea-like eruption, or a morbilliform eruption. Observations: A 63-year-old Caucasian man with urothelial carcinoma of the bladder undergoing intravesical BCG treatment developed a pruritic cutaneous eruption and a fever after his third instillation of intravesical BCG. On physical examination he was noted to have multiple pink macules coalescing into patches involving his trunk and extremities. A punch biopsy showed sparse superficial perivascular dermatitis with focal minimal spongiosis, consistent with a dermal hypersensitivity reaction. Clinical suspicion of systemic hypersensitivity reaction to BCG dissemination prompted the initiation of antituberculous therapy, which led to symptomatic resolution. Conclusions and Relevance: The purpose of this manuscript is to alert dermatologists working in cancer centers to the possibility of this diagnosis in a patient with a recent exposure to intravesical BCG and an unexplained skin eruption. Since BCG reactivation can be fatal, providers must have a low threshold to begin antituberculous therapy. Commercial support: None identified.
Commercial support: None identified.
1598 Microbiopsy skin sampling in volunteers reveals no oxidative stress detected after topically applying sunscreen with zinc oxide nanoparticles Lydia Y. T. Hang, MBBS, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Lynlee L. Lin, ScD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Miko Yamada, PhD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; H. Peter Soyer, MD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Anthony P. Raphael, PhD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia; Tarl W. Prow, PhD, Dermatology Research Center, The University of Queensland, School of Medicine, Brisbane, Queensland, Australia Background: The development of nano-sized zinc oxide particles (ZnO-NP) saw the revolution of sunscreen that applied clear on skin, a step up from its less aesthetically pleasing predecessor, microparticles. Zinc oxide nanoparticles have been shown to induce oxidative stress in vitro; giving cause to the claims that topically applied sunscreens containing ZnO-NP can be cytotoxic. We recently developed a novel microneedle based skin sampling technology, microbiopsy. This approach enables rapid volunteer skin sampling without the need for local anaesthetic or sutures. We observed relative oxidative stress levels in intact and tape-stripped volunteer epidermal tissue after exposure to ZnO-NP in vivo using microbiopsied skin samples. Methods and Materials: Human volunteer skin was tape-stripped and then treated with ZnO-NP for 2 hours. Microbiopsies extracted epidermal tissues which were treated with two different oxidative stress probes. Confocal microscopy was used to assess the levels of oxidative stress reported by fluorescent probes. Images were analyzed using Image J (National Institutes of Health, Bethesda, MD). Fluorescence signal raw integrated density was acquired from the specimen. Results: Skin exposed to ZnO-NP did not show any significant increase in oxidative stress, but rather there was a trend towards lower levels of oxidative stress than untreated skin. Intact and tape-stripped skin treated with ZnO-NP sunscreen did not yield a significantly higher fluorescence signal compared to untreated skin. Fold change of ZnO-NP treated skin relative to untreated skin was 0.9 in intact and 1.1 in tape-stripped skin for the reactive oxygen and nitrogen species. A similar result was observed for the mitochondrial superoxide, 1.0- and 1.2-fold change for intact and tape-stripped skin, respectively. Conclusions: The debate regarding ZnO-NP in sunscreens is far from over given the gaps in the knowledge about nanoparticle interactions on and within the human body. In vitro studies show the potential of ZnO-NP to induce cytotoxicity, but interpretation should be limited to only that context. In vivo studies show that the skin is an effective barrier against topically applied ZnO-NP even when it is mechanically compromised. We conclude that topically applied ZnO-NP containing sunscreen does not result in significantly increased oxidative stress in the skin. Commercial support: None identified.
AB210
J AM ACAD DERMATOL
1169 Omalizumab in dermatology: A review of the literature Justin Chia, MD, Division of Dermatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada; P. Regine Mydlarski, MD, PhD, Division of Dermatology, Department of Medicine, University of Calgary, Calgary, Alberta, Canada Introduction Omalizumab (Xolair; Roche/Genetech and Novartis Pharmaceuticals Inc) is a recombinant humanized monoclonal antibody that inhibits the binding of IgE to the high-affinity IgE receptor (FceRI) on the surface of mast cells and basophils. By reducing surface-bound IgE on FceRI-bearing cells, omalizumab impairs the release of inflammatory mediators. Treatment with omalizumab also reduces the number of FceRI on basophils and may also decrease other autoreactive IgE antibodies. Omalizumab has been approved for use in asthma, and new reports show promise in a variety of dermatologic diseases. Herein, we review the literature on omalizumab in dermatology and discuss the safety, efficacy and mechanisms of action for this emerging therapy. Methods: A search of the PubMed, Embase, and MEDLINE databases was performed (1990-2013) using the key words ‘‘omalizumab’’ and ‘‘Xolair’’ in combination with the following: ‘‘alopecia,’’ ‘‘angioedema,’’ ‘‘atopic dermatitis,’’ ‘‘bullous skin disease,’’ ‘‘collagen vascular disease,’’ ‘‘cryoglobulinemia,’’ ‘‘cutaneous,’’ ‘‘dermatitis,’’ ‘‘dermatologic,’’ ‘‘dermatology,’’ ‘‘dermatomyositis,’’ ‘‘eczema,’’ ‘‘epidermolysis bullosa,’’ ‘‘graft versus host disease,’’ ‘‘granulomatous disease,’’ ‘‘hyper-IgE syndrome,’’ ‘‘lupus,’’ ‘‘mastocytosis,’’ ‘‘papulosquamous,’’ ‘‘pemphigoid,’’ ‘‘pemphigus,’’ ‘‘psoriasis,’’ ‘‘scleroderma,’’ ‘‘skin,’’ ‘‘urticaria,’’ ‘‘vasculitis,’’ ‘‘vesiculobullous,’’ ‘‘vitiligo.’’ The data were extracted and the levels of evidence were graded in accordance with recommendations from the Oxford Center for Evidence-Based Medicine. Results: A total of 2272 articles were sourced and 59 full-text dermatology-related publications were identified. They included reports on the use of omalizumab in chronic urticaria (34), atopic dermatitis (20), bullous pemphigoid (3), and hyper-IgE syndrome (2). The safety and efficacy of omalizumab were also evaluated. Conclusions: Omalizumab has demonstrated therapeutic efficacy in a variety of recalcitrant immune-mediated and autoimmune skin disorders. It is a safe and effective treatment for use in chronic idiopathic urticaria (grade of recommendation: 1A). Randomized clinical trials with long-term follow-ups are warranted to firmly establish the role of omalizumab in the treatment of dermatologic disease. Commercial support: None identified.
MAY 2015