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292 Successful treatment of pemphigus vulgaris with ofatumumab
ABSTRACTS | Clinical Research: Pathophysiology and Therapeutics 291
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Establishing and validating an ichthyosis severity index N Marukian1, Y Deng2, G Gan2, I Ren1, W Thermidor1, B Craiglow1, LM Milstone1 and K Choate1 1 Yale School of Medicine, New Haven, CT and 2 Yale School of Public Health, New Haven, CT Ichthyoses comprise a heterogeneous group of disorders, characterized by the presence of hyperkeratosis, as well as a variable degree of erythema. A reliable method of assessing the clinical severity of ichthyosis is critical to evaluating the efficacy of new treatments and grading the severity of ichthyosis due to mutations in different genes. Although prior studies have used visual scales to measure ichthyosis severity, to date no widely-accepted index exists. We developed a photographic severity index that improved on existing measures by providing 1) clear written descriptions of the features characteristic of each level of severity 2) visual standards for 4 different body sites, and 3) two different sets of hyperkeratosis standards to account for different types of scale. We utilized photographic standards representing severities from 0 (normal skin) to 4 (most severely affected) for hyperkeratosis and erythema. We designed a prospective study to evaluate the reliability of the instrument using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists and one with in-person evaluations of 85 subjects by 12 dermatologists at the F.I.R.S.T. family conference. Our rigorous validation process revealed high reliability and reproducibility for both hyperkeratosis and erythema, as well as the combined scores, with Intra-class Correlation Coefficients (ICCs) consistently near or greater than 0.7. Our analysis also indicates that to reliably capture all aspects of the index, it is essential that evaluations be performed in person, a critical finding for the study design of clinical trials. We have designed and validated a standardized method of assessing ichthyosis severity, which has the potential to advance research in this rare group of disorders.
Successful treatment of pemphigus vulgaris with ofatumumab CT Richardson1 and AP Pentland2 1 University of Rochester, Rochester, NY and 2 University of Rochester Medical Center, Rochester, NY Rituximab is an anti-CD20 chimeric monoclonal antibody that is very effective in treating patients with pemphigus vulgaris (PV). One potential complication is the development of human anti-chimeric antibodies (HACA), which occurs infrequently in patients with PV. Development of HACA leads to treatment failure and can be associated with a serum sickness-like reaction. Ofatumumab is a second-generation anti-CD20 monoclonal antibody. In contrast to rituximab, ofatumumab is fully human and targets a distinct portion of CD20. Ofatumumab is approved for use in chronic lymphocytic leukemia and is under investigation for the treatment of several other conditions, including pemphigus vulgaris. There are currently no published case reports of successful treatment of PV with ofatumumab.We report a case of a patient with pemphigus vulgaris successfully treated with ofatumumab after developing human anti-chimeric antibodies to rituximab. The patient has severe PV and has failed multiple therapeutic options, including topical steroids, topical tacrolimus, prednisone, mycophenolate mofetil, IVIG and rituximab. The patient had a partial response to initial treatment with rituximab, but developed a serum sickness-like reaction and additional treatments were discontinued. After continued failure of other treatment modalities, rituximab was again attempted. The patient had no clinical response and further investigation revealed complete lack of B cell depletion, further evidence for the development of HACA in this patient. Given the patient’s extensive disease, multiple treatment failures, and successful use of ofatumumab in reported cases of patients with HACA to rituximab, a trial of ofatumumab was started. The patient had a dramatic response after one dose, and has had continued improvement until the present (seven months). Further investigation including clinical trials may be warranted for the use of ofatumumab for the treatment of pemphigus vulgaris, especially in the context of treatment failure with rituxumab.
Rational design of combination therapy in cutaneous T-cell lymphoma using an HDAC inhibitor and alkylating agent C Patrone1, M Sanchez-Martin2, M Frattini3, A Ferrando2, T Palomero2 and LJ Geskin4 1 Columbia University College of Physicians and Surgeons, New York, NY, 2 Columbia University Institute for Cancer Genetics, New York, NY, 3 Department of Medicine, Columbia University Medical Center, New York, NY and 4 Department of Dermatology, Columbia University Medical Center, New York, NY Combination regimens are the mainstay of treatment for hematologic malignancies, but there are currently no FDA-approved combination therapies for cutaneous T-cell lymphoma (CTCL), and few combinations have been studied systematically in vitro. We hypothesize that romidepsin, an HDAC inhibitor, allows a more open chromatin structure that can provide better access to the alkylating effects of mechlorethamine in malignant T cells. We have previously reported more than additive effects of romidepsin and mechlorethamine. Here, we formally evaluated synergy of these two drugs by examining their combined effect in 4 CTCL cell lines, SeAx, HH, Hut78, and Hut102, and 6 primary samples from patients with Se´zary Syndrome. Single-agent dose response curves were generated using the cell lines to determine the approximate IC50 for each drug at 24, 48, 72, and 96 hours. The cell lines were treated at fixed ratios of the drugs using Chou and Talalay’s median effect method to calculate isobolograms and combination indices (CI) to determine if the drugs are synergistic. Flow cytometry for apoptosis and cell viability was also performed to characterize the combined effects of the drug compared to single agents and controls. Our results showed synergism of romidepsin and mechlorethamine in all 4 cell lines, and 5 of 6 patient samples showed enhanced cytotoxic effects of the combination in malignant cells compared to single agents. The synergistic effects of romidepsin and mechlorethamine in CTCL/Se´zary Syndrome make a strong argument to test this drug combination in clinical trials.
IL-33 mediates the development of the tumor-promoting immune environment in chronic inflammation S Moradi Tuchayi1, T Cunningham1, K Ngo1, T Raissi1, A Ghebreselassie1, J Eliane2, A Shaffer3, M Colonna3 and S Demehri4 1 Cutaneous Biology Research Center, Department of Dermatology, MGH Cancer Center, Massachusetts General Hospital, Boston, MA, 2 Department of Pathology, Massachusetts General Hospital, Boston, MA, 3 Washington University, St. Louis, MO and 4 Cutaneous Biology Research Center, Department of Dermatology, MGH Cancer Center, Massachusetts General Hospital, Boston, MA Chronic inflammation is a well-recognized cause of cancer; however, the exact mechanism of this severe adverse event remains unclear. Herein, we demonstrate the prominent role of an epithelial-derived cytokine, interleukin 33 (IL-33), in induction of cancer in chronic inflammatory skin diseases. We and others have previously shown that type 2 inflammation is the common tumor-promoting immune environment in chronic inflammatory diseases including chronic allergic contact dermatitis (ACD). Importantly, the acute phase of many of these tumor-promoting inflammatory diseases is dominated by type 1 inflammation. We found that IL-33, a known inducer of Type 2 immune response, was increased significantly during and prior to the development of the tumor-promoting immune environment in chronic ACD. Therefore, we investigated the effect of loss of IL-33 on transition from acute to chronic ACD. IL-33 loss led to blunted T regulatory accumulation and markedly muted epidermal hyperplasia during the transitional phase. Next, we investigated the effect of loss of IL-33 in skin tumorigenesis in chronic ACD and found IL-33 deficient mice to be significantly resistant to skin cancer development (p ¼ 0.0003). We investigated carcinogenesis in the context of lupus erythematosus, and found a similar pattern of IL-33 overexpression. Importantly, increased expression of IL-33 was noted in squamous cell carcinoma and perilesional skin of patients with chronic ACD and discoid lupus. These findings highlight the potential benefit of blocking IL-33, as a novel therapeutic approach in prevention and treatment of skin cancer and perhaps cancers of other organs that are associated with chronic inflammation.
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The economic impact of Ixekizumab versus Etanercept: A cost-effectiveness analysis J Udkoff1 and LF Eichenfield2 1 Medical School, and Pediatric and Adolescent Dermatology, University of California, San Diego and Rady Children’s Hospital, La Jolla, CA and 2 University of California, San Diego and Rady Children’s Hospital, San Diego, CA The UNCOVER comparative efficacy trials studied ixekizumab, an IL-17 inhibitor, and etanercept, a TNF antagonist, in the treatment of plaque psoriasis. Ixekizumab’s superior efficacy was demonstrated and the FDA approved its use every 2 weeks for 12 weeks followed by every 4 weeks. We created a Markov cost-effectiveness model to compare ixekizumab every 2 and 4 weeks with biweekly etanercept followed by their FDA approved maintenance doses. We calculated the costs (2016 US dollars), effectiveness in quality adjusted life years (QALY), and incremental cost effectiveness ratios (ICER) from a societal perspective over 60 weeks. Costs included biologic therapies and annual healthcare utilization. Ixekizumab every 4 weeks was more cost-effective than every 2 weeks (ICER¼ $3.42 million). Etanercept had lower efficacy and greater costs than either ixekizumab algorithm (dominated). Costs were $108604, $79922 and $101297 for etanercept and ixekizumab every 4 and 2 weeks respectively. The effectiveness (QALY) was 0.825, 0.856 and 0.862 for etanercept and ixekizumab every 4 and 2 weeks. Ixekizumab every 2 weeks’ incremental effectiveness over every 4 weeks was 0.006 QALY and 0.031 QALY over etanercept. At a typical willingness to pay (WTP) threshold of $150000, ixekizumab every 2 weeks was the most cost-effective algorithm with a cost-per-dose of $197.83 (currently $4513.69). Based on this model ixekizumab every 4 weeks was the most cost-effective algorithm at over 20-fold typical WTP thresholds. Ixekizumab would require a >95% reduction in cost for ixekizumab every 2 weeks to be more cost-effective than every 4 weeks. In addition, data suggests that ixekizumab every 4 weeks during the induction phase is only slightly less efficacious. Given the high cost of biologic therapies, cost-effectiveness analysis may be useful in therapeutic decision making.
S50 Journal of Investigative Dermatology (2017), Volume 137
Bleach baths promote early induction of inflammatory pathway genes with no effect on skin bacterial dysbiosis in AD subjects SA Knowlden1, T Yoshida1, N Perez-Nazario2, CW Kwon1, A Grier2, SR Gill1, A De Benedetto1, J Thakar1 and LA Beck1 1 University of Rochester Medical Center, Rochester, NY and 2 University of Rochester, Rochester, NY We have previously shown that bleach baths (BB) improve disease severity and skin barrier function (TEWL) in adult AD subjects colonized with S. aureus (SA). Herein, we report effects of BB on skin microbiome, SA abundance and skin transcriptome in the same cohort. AD and nonatopic controls (NA) were instructed to take two BB (0.005% NaClO, 5-10 min) per wk for 12 wks. Skin swabs and biopsies were taken from nonlesional (NL) sites before BB (T0), as well as after 1 wk (T1) and 12 wks (T12) of BB. Microbiome analysis revealed expected differences between AD (n¼13) and NA (n¼5) subjects at T0, but BB did not significantly alter microbial diversity or distribution by T12. SA abundance (nuc qPCR) also remained unchanged at T1 (n¼4 AD) and T12 (n¼15 AD, n¼5 NA). The most notable changes in the transcriptome were seen at T1. RNA-seq identified 706 differentially expressed genes (DEGs) in T0 vs T1 (n¼4 AD) [FC>1.5, q < 0.05]. The top 5 DEGs were S100A8/A9, HK3, FCGR3A & SERPINA1 (all[). Inflammatory pathways represented 18 of 21 pathways identified from upregulated DEGS in T1 vs T0 (q < 0.05). Analysis of T0 vs T12 (n¼7 AD) revealed 5 significant DEGs (HEPHL1, KRT34, KRT38, KRT40 & PADI3), of which the latter 4 are epidermal-derived. These changes were not observed in NA subjects (n¼3). Our data suggests that BB do not significantly alter the skin microbiome or SA abundance in AD subjects, but rather, they induce early activation of inflammatory pathways followed by later changes in epidermal genes, which may contribute to the barrier improvements we have observed.
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Establishing and validating an ichthyosis severity index N Marukian1, Y Deng2, G Gan2, I Ren1, W Thermidor1, B Craiglow1, LM Milstone1 and K Choate1 1 Yale School of Medicine, New Haven, CT and 2 Yale School of Public Health, New Haven, CT Ichthyoses comprise a heterogeneous group of disorders, characterized by the presence of hyperkeratosis, as well as a variable degree of erythema. A reliable method of assessing the clinical severity of ichthyosis is critical to evaluating the efficacy of new treatments and grading the severity of ichthyosis due to mutations in different genes. Although prior studies have used visual scales to measure ichthyosis severity, to date no widely-accepted index exists. We developed a photographic severity index that improved on existing measures by providing 1) clear written descriptions of the features characteristic of each level of severity 2) visual standards for 4 different body sites, and 3) two different sets of hyperkeratosis standards to account for different types of scale. We utilized photographic standards representing severities from 0 (normal skin) to 4 (most severely affected) for hyperkeratosis and erythema. We designed a prospective study to evaluate the reliability of the instrument using two different settings: one that utilized scoring of 60 test photographs by 10 dermatologists and one with in-person evaluations of 85 subjects by 12 dermatologists at the F.I.R.S.T. family conference. Our rigorous validation process revealed high reliability and reproducibility for both hyperkeratosis and erythema, as well as the combined scores, with Intra-class Correlation Coefficients (ICCs) consistently near or greater than 0.7. Our analysis also indicates that to reliably capture all aspects of the index, it is essential that evaluations be performed in person, a critical finding for the study design of clinical trials. We have designed and validated a standardized method of assessing ichthyosis severity, which has the potential to advance research in this rare group of disorders.
Successful treatment of pemphigus vulgaris with ofatumumab CT Richardson1 and AP Pentland2 1 University of Rochester, Rochester, NY and 2 University of Rochester Medical Center, Rochester, NY Rituximab is an anti-CD20 chimeric monoclonal antibody that is very effective in treating patients with pemphigus vulgaris (PV). One potential complication is the development of human anti-chimeric antibodies (HACA), which occurs infrequently in patients with PV. Development of HACA leads to treatment failure and can be associated with a serum sickness-like reaction. Ofatumumab is a second-generation anti-CD20 monoclonal antibody. In contrast to rituximab, ofatumumab is fully human and targets a distinct portion of CD20. Ofatumumab is approved for use in chronic lymphocytic leukemia and is under investigation for the treatment of several other conditions, including pemphigus vulgaris. There are currently no published case reports of successful treatment of PV with ofatumumab.We report a case of a patient with pemphigus vulgaris successfully treated with ofatumumab after developing human anti-chimeric antibodies to rituximab. The patient has severe PV and has failed multiple therapeutic options, including topical steroids, topical tacrolimus, prednisone, mycophenolate mofetil, IVIG and rituximab. The patient had a partial response to initial treatment with rituximab, but developed a serum sickness-like reaction and additional treatments were discontinued. After continued failure of other treatment modalities, rituximab was again attempted. The patient had no clinical response and further investigation revealed complete lack of B cell depletion, further evidence for the development of HACA in this patient. Given the patient’s extensive disease, multiple treatment failures, and successful use of ofatumumab in reported cases of patients with HACA to rituximab, a trial of ofatumumab was started. The patient had a dramatic response after one dose, and has had continued improvement until the present (seven months). Further investigation including clinical trials may be warranted for the use of ofatumumab for the treatment of pemphigus vulgaris, especially in the context of treatment failure with rituxumab.
Rational design of combination therapy in cutaneous T-cell lymphoma using an HDAC inhibitor and alkylating agent C Patrone1, M Sanchez-Martin2, M Frattini3, A Ferrando2, T Palomero2 and LJ Geskin4 1 Columbia University College of Physicians and Surgeons, New York, NY, 2 Columbia University Institute for Cancer Genetics, New York, NY, 3 Department of Medicine, Columbia University Medical Center, New York, NY and 4 Department of Dermatology, Columbia University Medical Center, New York, NY Combination regimens are the mainstay of treatment for hematologic malignancies, but there are currently no FDA-approved combination therapies for cutaneous T-cell lymphoma (CTCL), and few combinations have been studied systematically in vitro. We hypothesize that romidepsin, an HDAC inhibitor, allows a more open chromatin structure that can provide better access to the alkylating effects of mechlorethamine in malignant T cells. We have previously reported more than additive effects of romidepsin and mechlorethamine. Here, we formally evaluated synergy of these two drugs by examining their combined effect in 4 CTCL cell lines, SeAx, HH, Hut78, and Hut102, and 6 primary samples from patients with Se´zary Syndrome. Single-agent dose response curves were generated using the cell lines to determine the approximate IC50 for each drug at 24, 48, 72, and 96 hours. The cell lines were treated at fixed ratios of the drugs using Chou and Talalay’s median effect method to calculate isobolograms and combination indices (CI) to determine if the drugs are synergistic. Flow cytometry for apoptosis and cell viability was also performed to characterize the combined effects of the drug compared to single agents and controls. Our results showed synergism of romidepsin and mechlorethamine in all 4 cell lines, and 5 of 6 patient samples showed enhanced cytotoxic effects of the combination in malignant cells compared to single agents. The synergistic effects of romidepsin and mechlorethamine in CTCL/Se´zary Syndrome make a strong argument to test this drug combination in clinical trials.
IL-33 mediates the development of the tumor-promoting immune environment in chronic inflammation S Moradi Tuchayi1, T Cunningham1, K Ngo1, T Raissi1, A Ghebreselassie1, J Eliane2, A Shaffer3, M Colonna3 and S Demehri4 1 Cutaneous Biology Research Center, Department of Dermatology, MGH Cancer Center, Massachusetts General Hospital, Boston, MA, 2 Department of Pathology, Massachusetts General Hospital, Boston, MA, 3 Washington University, St. Louis, MO and 4 Cutaneous Biology Research Center, Department of Dermatology, MGH Cancer Center, Massachusetts General Hospital, Boston, MA Chronic inflammation is a well-recognized cause of cancer; however, the exact mechanism of this severe adverse event remains unclear. Herein, we demonstrate the prominent role of an epithelial-derived cytokine, interleukin 33 (IL-33), in induction of cancer in chronic inflammatory skin diseases. We and others have previously shown that type 2 inflammation is the common tumor-promoting immune environment in chronic inflammatory diseases including chronic allergic contact dermatitis (ACD). Importantly, the acute phase of many of these tumor-promoting inflammatory diseases is dominated by type 1 inflammation. We found that IL-33, a known inducer of Type 2 immune response, was increased significantly during and prior to the development of the tumor-promoting immune environment in chronic ACD. Therefore, we investigated the effect of loss of IL-33 on transition from acute to chronic ACD. IL-33 loss led to blunted T regulatory accumulation and markedly muted epidermal hyperplasia during the transitional phase. Next, we investigated the effect of loss of IL-33 in skin tumorigenesis in chronic ACD and found IL-33 deficient mice to be significantly resistant to skin cancer development (p ¼ 0.0003). We investigated carcinogenesis in the context of lupus erythematosus, and found a similar pattern of IL-33 overexpression. Importantly, increased expression of IL-33 was noted in squamous cell carcinoma and perilesional skin of patients with chronic ACD and discoid lupus. These findings highlight the potential benefit of blocking IL-33, as a novel therapeutic approach in prevention and treatment of skin cancer and perhaps cancers of other organs that are associated with chronic inflammation.
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The economic impact of Ixekizumab versus Etanercept: A cost-effectiveness analysis J Udkoff1 and LF Eichenfield2 1 Medical School, and Pediatric and Adolescent Dermatology, University of California, San Diego and Rady Children’s Hospital, La Jolla, CA and 2 University of California, San Diego and Rady Children’s Hospital, San Diego, CA The UNCOVER comparative efficacy trials studied ixekizumab, an IL-17 inhibitor, and etanercept, a TNF antagonist, in the treatment of plaque psoriasis. Ixekizumab’s superior efficacy was demonstrated and the FDA approved its use every 2 weeks for 12 weeks followed by every 4 weeks. We created a Markov cost-effectiveness model to compare ixekizumab every 2 and 4 weeks with biweekly etanercept followed by their FDA approved maintenance doses. We calculated the costs (2016 US dollars), effectiveness in quality adjusted life years (QALY), and incremental cost effectiveness ratios (ICER) from a societal perspective over 60 weeks. Costs included biologic therapies and annual healthcare utilization. Ixekizumab every 4 weeks was more cost-effective than every 2 weeks (ICER¼ $3.42 million). Etanercept had lower efficacy and greater costs than either ixekizumab algorithm (dominated). Costs were $108604, $79922 and $101297 for etanercept and ixekizumab every 4 and 2 weeks respectively. The effectiveness (QALY) was 0.825, 0.856 and 0.862 for etanercept and ixekizumab every 4 and 2 weeks. Ixekizumab every 2 weeks’ incremental effectiveness over every 4 weeks was 0.006 QALY and 0.031 QALY over etanercept. At a typical willingness to pay (WTP) threshold of $150000, ixekizumab every 2 weeks was the most cost-effective algorithm with a cost-per-dose of $197.83 (currently $4513.69). Based on this model ixekizumab every 4 weeks was the most cost-effective algorithm at over 20-fold typical WTP thresholds. Ixekizumab would require a >95% reduction in cost for ixekizumab every 2 weeks to be more cost-effective than every 4 weeks. In addition, data suggests that ixekizumab every 4 weeks during the induction phase is only slightly less efficacious. Given the high cost of biologic therapies, cost-effectiveness analysis may be useful in therapeutic decision making.
S50 Journal of Investigative Dermatology (2017), Volume 137
Bleach baths promote early induction of inflammatory pathway genes with no effect on skin bacterial dysbiosis in AD subjects SA Knowlden1, T Yoshida1, N Perez-Nazario2, CW Kwon1, A Grier2, SR Gill1, A De Benedetto1, J Thakar1 and LA Beck1 1 University of Rochester Medical Center, Rochester, NY and 2 University of Rochester, Rochester, NY We have previously shown that bleach baths (BB) improve disease severity and skin barrier function (TEWL) in adult AD subjects colonized with S. aureus (SA). Herein, we report effects of BB on skin microbiome, SA abundance and skin transcriptome in the same cohort. AD and nonatopic controls (NA) were instructed to take two BB (0.005% NaClO, 5-10 min) per wk for 12 wks. Skin swabs and biopsies were taken from nonlesional (NL) sites before BB (T0), as well as after 1 wk (T1) and 12 wks (T12) of BB. Microbiome analysis revealed expected differences between AD (n¼13) and NA (n¼5) subjects at T0, but BB did not significantly alter microbial diversity or distribution by T12. SA abundance (nuc qPCR) also remained unchanged at T1 (n¼4 AD) and T12 (n¼15 AD, n¼5 NA). The most notable changes in the transcriptome were seen at T1. RNA-seq identified 706 differentially expressed genes (DEGs) in T0 vs T1 (n¼4 AD) [FC>1.5, q < 0.05]. The top 5 DEGs were S100A8/A9, HK3, FCGR3A & SERPINA1 (all[). Inflammatory pathways represented 18 of 21 pathways identified from upregulated DEGS in T1 vs T0 (q < 0.05). Analysis of T0 vs T12 (n¼7 AD) revealed 5 significant DEGs (HEPHL1, KRT34, KRT38, KRT40 & PADI3), of which the latter 4 are epidermal-derived. These changes were not observed in NA subjects (n¼3). Our data suggests that BB do not significantly alter the skin microbiome or SA abundance in AD subjects, but rather, they induce early activation of inflammatory pathways followed by later changes in epidermal genes, which may contribute to the barrier improvements we have observed.