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Erythroderma: Searching for diagnostic clues in a series of 164 patients
PEARLS FROM THE POSTERS: NEW AND NOTEWORTHY RESEARCH FINDS P7805 Erythroderma: Searching for diagnostic clues in a series of 164 patients Denis Miyashiro, MD, Hospital das Clınicas, S~ao Paulo, Brazil; Alice Nunes, MD, Hospital das Clınicas, S~ao Paulo, Brazil; Jose Antonio Sanches, PhD, Hospital das Clınicas, S~ao Paulo, Brazil Background: Erythroderma is a severe syndrome with challenging etiologic diagnosis. Despite histologic, immunophenotypic, and molecular analysis improvement, many cases remain as idiopathic ones. Objectives: Analyze clinical, laboratory, and histologic findings of 164 erythrodermic patients to find clues to the etiologic diagnosis and propose an adequate form of investigation to facilitate the management of these patients. Survival data were analyzed according to the etiologic diagnosis. Methods: In a retrospective study performed at the Hospital das Clınicas, University of S~ao Paulo Medical School (2007-2012) including 164 cases of acquired erythroderma, clinical, laboratory, and histologic data were collected according to a protocol of investigation. For qualitative variables, we the used chi-square or Fisher exact tests, and for quantitative variables we used KruskaleWallis 1-way analysis of variance. Results: The median age was 55.7 years, with a male:female ratio of 1.98:1. The atopic dermatitis group developed erythroderma in an earlier age (median, 22.5 years; P \.0001). Acute onset was associated with drug reactions (P ¼ .017) and psoriasis (P ¼ .041). Psoriasis was the most frequent etiology (20.1%), followed by eczema (18.9%), drug eruption (17.1%), Sezary syndrome (9.8%), atopic dermatitis (8.5%), mycosis fungoides (6%), and other diagnoses (5.5%), represented by pemphigus foliaceus, adult T-cell lymphoma, lichen planus, pityriasis rubra pilaris, paraneoplastic erythroderma, and HIV-associated erythroderma. In 14% of the patients, it was not possible to elucidate the cause of erythroderma. We did not observe a significant statistical correlation between the groups for both clinical and laboratory findings, except for high levels of immunoglobulin E in the atopic dermatitis group. Pathologic examination was consistent with the final diagnosis in 73.9% of cases. Monoclonal T cell proliferation in the skin was observed essentially in the mycosis fungoides and Sezary syndrome groups. At the last assessment, 65.2% of patients were alive with evidence of disease, 26.8% were alive without disease, and 7.9% had died with disease. Conclusions: Erythroderma is a challenging syndrome with difficult diagnosis approach and reserved prognosis. Young age and high immunoglobulin E levels are associated with atopic dermatitis; acute onset is observed in drug eruptions and psoriasis. Histopathologic and molecular biology tests are important tools in the investigation of erythroderma.
P7571 Immunohistochemical detection of BRAF mutation in melanoma Michelle Vernali, University of North Carolina School of Medicine, Chapel Hill, NC, United States; Dan Zedek, MD, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, United States; David W. Ollila, MD, Department of Surgical Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, United States; Nancy E. Thomas, MD, PhD, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, United States BRAF mutational status is a major factor in the clinical management of patients with metastatic melanoma. Ninety percent of mutations within this gene are accounted for by a missense substitution at amino acid position 600 (V600E), substituting valine for glutamic acid. This results in constitutive phosphorylation of downstream targets. Vemurafenib, a targeted BRAF kinase inhibitor, has demonstrated significantly increased overall and progression-free survival as compared to dacarbazine in a phase III clinical trial. BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. Recently, a monoclonal antibody (VE1) against the BRAF V600E mutant protein has been developed. In this study, we assessed the validity of VE1 in the detection of mutant BRAF V600E protein as compared to the UNC CLIA-certified method of DNA pyrosequencing. We analyzed 96 primary and metastatic melanomas from 76 patients with known mutational status. Primary melanomas were immunostained and results matched to their associated metastases to determine if staining remained consistent between the two lesions. The staining intensity of these specimens was assessed by a dermatopathologist blinded to all clinical and genetic data and scored from 0 to 3 (0 ¼ no staining, 1 ¼ weak background staining, 2 ¼ moderately positive staining, and 3 ¼ strongly positive staining). Scores of 0 and 1 were considered to be negative staining while scores of 2 and 3 were considered to be positive staining. The VE1 antibody demonstrated a sensitivity of 81% and a specificity of 100% as compared to pyrosequencing. In addition, there was 100% concordance between primary and metastatic lesions. Other BRAF mutations, including V600K, V600Q, and V600R did not positively with the VE1 immunostain. The results of this study demonstrate the clinical utility of the VE1 immunostain in the management of melanoma patients. Commercial support: None identified.
Commercial support: None identified.
P8324
P7622 A population-based study on the association between bullous pemphigoid and neurologic disease Katherine Brick, MD, Mayo Clinic, Rochester, MN, United States; Carilyn Wieland, MD, Mayo Clinic, Rochester, MN, United States; Chad Weaver, MD, Mayo Clinic, Rochester, MN, United States; Christine Lohse, MS, Mayo Clinic, Rochester, MN, United States; Lawrence Gibson, MD, Mayo Clinic, Rochester, MN, United States; Mark Pittelkow, MD, Mayo Clinic, Rochester, MN, United States; Michael Camilleri, MD, Mayo Clinic, Rochester, Minnesota, United States The association between bullous pemphigoid (BP) and multiple neurologic diseases has been well-documented, but population-based studies from the United States are lacking. BP antigen 1 has similar isoforms in neuronal and cutaneous tissues, which is one possible link to explain this association. However, the etiology of this relationship is not well understood. A population-based study was performed to examine this phenomenon. The Rochester Epidemiology Project was used to identify 87 patients who were residents of Olmsted County, Minnesota at their first lifetime diagnosis of BP between January 1, 1950 and December 31, 2009. An additional 3 age- and sex-matched subjects who were also residents of Olmsted County were used as controls for each BP case, and all charts were reviewed for the presence of neurologic disorders (ie, dementia, Alzheimer disease, Parkinson disease or other movement disorders, epilepsy, stroke, or multiple sclerosis) before or after the diagnosis of BP. Any previous diagnosis of neurologic disease was associated with a 6.85-fold increased odds of developing BP (odds ratio, 6.85; P \ .001). A history of dementia increased the odds of developing BP 6.75-fold (odds ratio, 6.75; P ¼ .002), but in the 4 patients with Parkinson disease (n ¼ 3) or a movement disorder (n ¼ 1), the increased odds were not statistically significant. For the cohort arm of this study, those with a history of BP were significantly more likely to develop Parkinson disease (hazard ratio, 8.56; P ¼ .014) as well as any type of neurologic disease (hazard ratio, 2.02; P ¼.012) during follow-up. A limitation of our study is the diagnosis of dementia could not be further subdivided because the diagnosis was based on retrospective chart review. Our study confirms the association of neurologic disorders and bullous pemphigoid, and specifically provides population-based evidence for the association with dementia and Parkinson disease. This supports need for additional investigation into the specific mechanisms that may underlie these relationships. Commercial support: None identified.
MAY 2014
Melanoma associated with TNFa inhibitors: A research on adverse drug reactions (RADAR) report Beatrice Nardone, MD, PhD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Dennis P. West, PhD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Dennis W. Raisch, PhD, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States; Gil Abramovici, MD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Jeave Reserva, MD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Josh A. Hammel, MD, Department of Dermatology, Northwestern University, Chicago, IL, United States Introduction: Tumor necrosis factor-a inhibitors (TNFa Is), are widely used for treatment of several dermatologic, rheumatologic, and gastrointestinal inflammatory disorders. Despite their therapeutic benefit, there is evidence linking these agents with the occurrence of malignancies. For 4 out of 5 TNFa Is, the FDA label states that ‘‘melanoma has been reported in patients treated with these agents.’’ Methods: We searched the FDA Adverse Event Reporting System (FAERS) database for terms related to melanoma (M) combined with TNFa Is and we calculated empirical Bayes geometric means (EBGM) for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database ( [2.2 million individual records), for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFa Is versus nonexposed subjects. Results: Since the year of the drug approval date through December 2012, 1041 reports of melanoma-associated with a TNFa I were identified in the FAERS database. A safety signal was detected for infliximab (I), n ¼ 434 (EBGM, 7.90; 95% CI, 7.138.6); golimumab (G), n ¼ 10 (EBGM, 5.34; 95% CI 2.41-9.88); etanercept (E), n ¼ 347 (EBGM, 2.49; 95% CI, 2.24-2.76); and adalimumab (A), n ¼ 237 (EBGM, 2.49; 95% CI, 2.19-2.83). Certolizumab pegol (CP), n ¼ 13 had no detectable safety signal. For the EMR cohort, 6,045 were exposed to TNFa Is, and 35 cases of M were detected (I, n ¼ 3; G, n ¼ 1; E, n ¼ 17; A, n ¼ 14; CP, n ¼ 0). Significant RR was detected for A (RR, 1.8; 95% CI, 1.06-3.0; P ¼.02) and E (RR, 2.35; 95% CI, 1.46-3.77; P ¼.0004). For TNFa Is as a class of drugs, a safety signal was detectable in FAERS database (EBGM, 3.30; 95% CI, 3.10-3.52) and RR was significant in EMR database (RR, 1.75; 95% CI, 1.25-2.43; P \.0009). Conclusion: We identified a significant association for exposure to TNFa Is and M, for all drugs except CP in the FAERS dataset and for A and E in the academic dataset. Interestingly, the current FDA labeling for certolizumab pegol does not include melanoma as an adverse effect. Our findings add to existing evidence linking these agents with the occurrence of melanoma. Additional investigations are required to further explore this association and the risk of melanoma with TNFa Is therapy. Commercial support: None identified.
J AM ACAD DERMATOL
AB1
P7571 Immunohistochemical detection of BRAF mutation in melanoma Michelle Vernali, University of North Carolina School of Medicine, Chapel Hill, NC, United States; Dan Zedek, MD, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, United States; David W. Ollila, MD, Department of Surgical Oncology, University of North Carolina School of Medicine, Chapel Hill, NC, United States; Nancy E. Thomas, MD, PhD, Department of Dermatology, University of North Carolina School of Medicine, Chapel Hill, NC, United States BRAF mutational status is a major factor in the clinical management of patients with metastatic melanoma. Ninety percent of mutations within this gene are accounted for by a missense substitution at amino acid position 600 (V600E), substituting valine for glutamic acid. This results in constitutive phosphorylation of downstream targets. Vemurafenib, a targeted BRAF kinase inhibitor, has demonstrated significantly increased overall and progression-free survival as compared to dacarbazine in a phase III clinical trial. BRAF mutation status, and therefore eligibility for BRAF inhibitors, is currently determined by sequencing methods. Recently, a monoclonal antibody (VE1) against the BRAF V600E mutant protein has been developed. In this study, we assessed the validity of VE1 in the detection of mutant BRAF V600E protein as compared to the UNC CLIA-certified method of DNA pyrosequencing. We analyzed 96 primary and metastatic melanomas from 76 patients with known mutational status. Primary melanomas were immunostained and results matched to their associated metastases to determine if staining remained consistent between the two lesions. The staining intensity of these specimens was assessed by a dermatopathologist blinded to all clinical and genetic data and scored from 0 to 3 (0 ¼ no staining, 1 ¼ weak background staining, 2 ¼ moderately positive staining, and 3 ¼ strongly positive staining). Scores of 0 and 1 were considered to be negative staining while scores of 2 and 3 were considered to be positive staining. The VE1 antibody demonstrated a sensitivity of 81% and a specificity of 100% as compared to pyrosequencing. In addition, there was 100% concordance between primary and metastatic lesions. Other BRAF mutations, including V600K, V600Q, and V600R did not positively with the VE1 immunostain. The results of this study demonstrate the clinical utility of the VE1 immunostain in the management of melanoma patients. Commercial support: None identified.
Commercial support: None identified.
P8324
P7622 A population-based study on the association between bullous pemphigoid and neurologic disease Katherine Brick, MD, Mayo Clinic, Rochester, MN, United States; Carilyn Wieland, MD, Mayo Clinic, Rochester, MN, United States; Chad Weaver, MD, Mayo Clinic, Rochester, MN, United States; Christine Lohse, MS, Mayo Clinic, Rochester, MN, United States; Lawrence Gibson, MD, Mayo Clinic, Rochester, MN, United States; Mark Pittelkow, MD, Mayo Clinic, Rochester, MN, United States; Michael Camilleri, MD, Mayo Clinic, Rochester, Minnesota, United States The association between bullous pemphigoid (BP) and multiple neurologic diseases has been well-documented, but population-based studies from the United States are lacking. BP antigen 1 has similar isoforms in neuronal and cutaneous tissues, which is one possible link to explain this association. However, the etiology of this relationship is not well understood. A population-based study was performed to examine this phenomenon. The Rochester Epidemiology Project was used to identify 87 patients who were residents of Olmsted County, Minnesota at their first lifetime diagnosis of BP between January 1, 1950 and December 31, 2009. An additional 3 age- and sex-matched subjects who were also residents of Olmsted County were used as controls for each BP case, and all charts were reviewed for the presence of neurologic disorders (ie, dementia, Alzheimer disease, Parkinson disease or other movement disorders, epilepsy, stroke, or multiple sclerosis) before or after the diagnosis of BP. Any previous diagnosis of neurologic disease was associated with a 6.85-fold increased odds of developing BP (odds ratio, 6.85; P \ .001). A history of dementia increased the odds of developing BP 6.75-fold (odds ratio, 6.75; P ¼ .002), but in the 4 patients with Parkinson disease (n ¼ 3) or a movement disorder (n ¼ 1), the increased odds were not statistically significant. For the cohort arm of this study, those with a history of BP were significantly more likely to develop Parkinson disease (hazard ratio, 8.56; P ¼ .014) as well as any type of neurologic disease (hazard ratio, 2.02; P ¼.012) during follow-up. A limitation of our study is the diagnosis of dementia could not be further subdivided because the diagnosis was based on retrospective chart review. Our study confirms the association of neurologic disorders and bullous pemphigoid, and specifically provides population-based evidence for the association with dementia and Parkinson disease. This supports need for additional investigation into the specific mechanisms that may underlie these relationships. Commercial support: None identified.
MAY 2014
Melanoma associated with TNFa inhibitors: A research on adverse drug reactions (RADAR) report Beatrice Nardone, MD, PhD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Dennis P. West, PhD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Dennis W. Raisch, PhD, College of Pharmacy, University of New Mexico, Albuquerque, NM, United States; Gil Abramovici, MD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Jeave Reserva, MD, Department of Dermatology, Northwestern University, Chicago, IL, United States; Josh A. Hammel, MD, Department of Dermatology, Northwestern University, Chicago, IL, United States Introduction: Tumor necrosis factor-a inhibitors (TNFa Is), are widely used for treatment of several dermatologic, rheumatologic, and gastrointestinal inflammatory disorders. Despite their therapeutic benefit, there is evidence linking these agents with the occurrence of malignancies. For 4 out of 5 TNFa Is, the FDA label states that ‘‘melanoma has been reported in patients treated with these agents.’’ Methods: We searched the FDA Adverse Event Reporting System (FAERS) database for terms related to melanoma (M) combined with TNFa Is and we calculated empirical Bayes geometric means (EBGM) for detection of safety signals. We also searched a large urban academic electronic medical record (EMR) database ( [2.2 million individual records), for which we calculated the relative risk (RR) of melanoma in subjects exposed to TNFa Is versus nonexposed subjects. Results: Since the year of the drug approval date through December 2012, 1041 reports of melanoma-associated with a TNFa I were identified in the FAERS database. A safety signal was detected for infliximab (I), n ¼ 434 (EBGM, 7.90; 95% CI, 7.138.6); golimumab (G), n ¼ 10 (EBGM, 5.34; 95% CI 2.41-9.88); etanercept (E), n ¼ 347 (EBGM, 2.49; 95% CI, 2.24-2.76); and adalimumab (A), n ¼ 237 (EBGM, 2.49; 95% CI, 2.19-2.83). Certolizumab pegol (CP), n ¼ 13 had no detectable safety signal. For the EMR cohort, 6,045 were exposed to TNFa Is, and 35 cases of M were detected (I, n ¼ 3; G, n ¼ 1; E, n ¼ 17; A, n ¼ 14; CP, n ¼ 0). Significant RR was detected for A (RR, 1.8; 95% CI, 1.06-3.0; P ¼.02) and E (RR, 2.35; 95% CI, 1.46-3.77; P ¼.0004). For TNFa Is as a class of drugs, a safety signal was detectable in FAERS database (EBGM, 3.30; 95% CI, 3.10-3.52) and RR was significant in EMR database (RR, 1.75; 95% CI, 1.25-2.43; P \.0009). Conclusion: We identified a significant association for exposure to TNFa Is and M, for all drugs except CP in the FAERS dataset and for A and E in the academic dataset. Interestingly, the current FDA labeling for certolizumab pegol does not include melanoma as an adverse effect. Our findings add to existing evidence linking these agents with the occurrence of melanoma. Additional investigations are required to further explore this association and the risk of melanoma with TNFa Is therapy. Commercial support: None identified.
J AM ACAD DERMATOL
AB1