- Email: [email protected]
Endothelium-dependent vasodilation is reduced in the cutaneous circulation of psoriatic patients
3002
2957
Endothelium-dependent vasodilation is reduced in the cutaneous circulation of psoriatic patients Billie Alba, Pennsylvania State University, University Park, PA, United States; Jody Greaney, PhD, Pennsylvania State University, University Park, PA, United States; Sara Ferguson, MD, Penn State Hershey Medical Group, State College, PA, United States; Lacy Alexander, PhD, Pennsylvania State University, University Park, PA, United States Psoriasis, a chronic systemic inflammatory disease, is an independent risk factor for cardiovascular disease. Impaired vascular function in conduit and resistance vessels is evident in adults with plaque psoriasis; however, potential deficits in microcirculatory endothelial function in psoriatic patients remain unclear. Further, examining cutaneous vascular function has particular clinical relevance for this population because the skin-related symptoms are the outward manifestation of this systemic inflammatory disease process. We hypothesized that cutaneous endothelial function would be impaired in nonlesional skin of psoriatic patients. Three intradermal microdialysis fibers were placed in the forearm skin of 8 healthy adults (NP: 3M, 5F; 49 6 3 yr) and 8 adults with moderate ([5% body surface area affected) plaque psoriasis (P: 3M, 5F; 48 6 3 yr) for localized drug delivery. Microdialysis sites were perfused with lactated Ringer’s (control), ascorbate (antioxidant), or BEC (arginase-inhibitor) while an index of skin blood flow was measured using laser Doppler flowmetry during a standardized local heating protocol (428C) to elicit endothelial nitric oxide synthase (eNOS)-mediated vasodilation. Nitric oxide (NO)dependent vasodilation was quantified following the perfusion of the nonspecific NOS inhibitor L-NAME. Data were expressed as a percentage of maximum cutaneous vascular conductance (%CVCmax; 28 mM sodium nitroprusside). The local heatinginduced plateau at the control site was attenuated in psoriatic patients (NP: 99 6 1 % CVCmax vs P: 82 6 6 %CVCmax; P ¼ .03), which is mediated by reduced NOdependent vasodilation (NP: 58 6 5 %CVCmax vs P: 45 6 8 %CVCmax; P ¼ .10). Arginase-inhibition, but not ascorbate, tended to improve the local-heating induced vasodilation in psoriasis patients (Ringer’s: 82 6 6 %CVCmax vs BEC: 93 6 2 % CVCmax; P ¼ .15). These results suggest that cutaneous endothelial function is impaired in psoriatic adults due to reduced NO bioavailability and that arginase upregulation contributes to the microvascular dysfunction in these patients.
Evaluation of efficacy and safety of ABP 501 in a phase 3 study in subjects with moderate to severe plaque psoriasis: 52-week results Bruce Strober, MD, PhD, University of Connecticut, Farmington, CT, United States; Peter Foley, MD, Skin & Cancer Foundation Inc, Carlton, Victoria, Australia; Sandra Philipp, MD, University Hospital Charite, Berlin, Germany; Nan Zhang, PhD, Amgen, Thousand Oaks, CA, United States; Primal Kaur, MD, MBA, Amgen, Thousand Oaks, CA, United States Background and objectives: ABP 501 is being developed as a biosimilar candidate to adalimumab (Humira), a fully human recombinant anti-TNF monoclonal antibody and has the same amino acid sequence as adalimumab. Evidence from analytical comparisons and phase 1 human pharmacokinetic study indicates that ABP 501 is similar to adalimumab. The objective of this study was to demonstrate clinical similarity between ABP 501 and adalimumab reference product in adults with moderate to severe plaque psoriasis. Results of clinical similarity based on efficacy and safety at week 16 have been previously reported. Here we report results of efficacy and safety at 52 weeks comparing subjects receiving ABP 501 or adalimumab for the entire duration of the study. Methods: In this double-blind, active-controlled study subjects were randomized 1:1 (ABP 501: n ¼ 175; adalimumab: n ¼ 175) to receive study treatment subcutaneously 80 mg on week 1/day 1 and 40 mg at week 2 and every 2 weeks thereafter. At week 16, subjects achieving $PASI 50 response remained on study for up to 52 weeks and were rerandomized in a blinded fashion such that all subjects initially randomized to ABP 501 continued to receive ABP 501; those on adalimumab either continued on adalimumab or switched to ABP 501 in a 1:1 fashion. Subjects continued on treatment until week 48; the final efficacy assessments were conducted at week 50 and the end of study visit was week 52.
Supported by a Penn State College of HHD Grant.
Results: Baseline characteristics were comparable in the two groups [ABP 501/ABP 501 (A/A), adalimumab/adalimumab (B/B)]. The mean PASI percent improvement from baseline at week 16, 32 and 50 (evaluated descriptively) was 86.6, 87.6 and 87.2 in group A/A and 88.0, 88.2 and 88.1 in group B/B, respectively. At the end of study incidence of subjects developing anti-drug antibodies was 68.4% in A/A group and 74.7% in B/B group. Incidence of treatment-emergent adverse events (TEAEs) was 86.2% in A/A group and 78.5% in B/B group. The most frequently reported TEAEs in $5% of subjects were nasopharyngitis, headache, upper respiratory tract infection, arthralgia, back pain, psoriasis and hypertension. Incidence of serious TEAEs was 4.6% in A/A group and 5.1% in B/B group. Conclusions: At the end of 52 weeks the overall efficacy, safety and immunogenicity were comparable among the two groups. This phase 3 study was sponsored by Amgen. Amgen provided all costs associated with the study conduct, data analysis and preparation of this abstract.
3417
3889 Erythrodermic psoriasis following terbinafine use Felipe Cerci, MD, Hospital Santa Casa de Curitiba, Curitiba, Brazil; Michelly Carvalho, MD, Hospital Santa Casa de Curitiba, Curitiba, Brazil; Franciele Nihi, MD, Hospital Santa Casa de Curitiba, Curitiba, Brazil Background: Terbinafine has been linked with the occurrence of psoriasis de novo or with its exacerbation. We report a case of erythrodermic psoriasis following terbinafine use. Case report: A 67-year-old man with a 2-year history of mild psoriasis (scalp and elbows), well controlled with topical medications, was admitted to our hospital due to erythroderma. Ten days prior to its onset, he started taking terbinafine 250 mg/d for tinea cruris. He had been on enalapril, acetylsalicylic acid, simvastatin and inhaled steroids for several years due to his comorbidities. On admission, the patient had widespread erythema with diffuse scaling. He denied fever, urinary, respiratory or gastrointestinal symptoms. The white cell count was 14,080/mm3 with mild neutrophilia. Liver and kidney function tests were within the normal range. Serologies for hepatitis B, C and HIV were negative. Since no classic triggers of erythroderma were identified, terbinafine was suspended. Therapy consisted of wet wraps with moisturizers and topical steroids, which resulted in a dramatic improvement after five days. In addition, methotrexate 7.5 mg/week and folic acid 5 mg/week were started, but soon suspended due to increased transaminases. Despite significant improvement with wet wrap therapy, PUVA was started for better disease control. After 12 sessions, he had complete resolution of the erythroderma, without recurrence after a 3-month follow-up. Discussion: Cutaneous adverse effects are reported in 2.7% of patients taking oral terbinafine. Psoriasis exacerbation has been reported after its use, especially plaque and pustular psoriasis. When considering a medication as responsible for the exacerbation of a disease it is important to evaluate if there is chronological correlation. According to previous reports, the latency period between administration of terbinafine and the exacerbation of psoriasis is less than 4 weeks, categorized as short interval. Our patient developed erythroderma 10 days after starting terbinafine, which supports the association. Dermatologists should be aware of the association between oral terbinafine and psoriasis flare-up, including erythroderma. Similarly to any medication adverse event, further investigation and observation are needed to establish a solid conclusion. Commercial support: None identified.
MAY 2016
Evaluation of inflammatory bowel disease in patients with plaque psoriasis studied in phase 3 trials of ixekizumab (UNCOVER trials): Adjudicated data from the induction period Richard Langley, MD, Dalhousie University, Halifax, Nova Scotia, Canada; Ricardo Romiti, MD, University of S~ao Paulo, S~ao Paulo, Brazil; Craig Leonardi, MD, Central Dermatology, St. Louis, MO, United States; Kristian Reich, MD, Dermatologikum Hamburg, Hamburg, Germany; Richard Warren, MD, PhD, University of Manchester, Manchester, United Kingdom; Kathleen Solotikin, MSN, Eli Lilly and Company, Indianapolis, IN, United States; Wen Xu, PhD, Eli Lilly and Company, Indianapolis, IN, United States; Harald Vangerow, MD, Eli Lilly and Company, Indianapolis, IN, United Kingdom; Dana Hardin, MD, Eli Lilly and Company, Indianapolis, IN, United States; Herve Bachelez, MD, PhD, Saint Louis Hospital, Paris, France Introduction and objectives: New onset or flares of inflammatory bowel disease (IBD) including worsening of active Crohn’s disease (CD) and ulcerative colitis (UC) have been reported during treatment with biologic agents for psoriasis. The objective of this integrated safety analysis was to report the adjudicated incidence of CD and UC in 3 phase 3 clinical trials of ixekizumab, an anti-IL-17A monoclonal antibody. Methods: In each trial during an induction period, patients were randomized to one of 3 treatment arms: (1) IXE every 2 (IXE Q2W; N ¼ 1167) or every 4 weeks (IXE Q4W; N ¼ 1161) following a 160-mg starting dose; (2) etanercept (ETN; 50 mg biweekly; N ¼ 739), or (3) placebo (PBO; N ¼ 791) for 12 weeks. After the induction period, patients continuing in the trial may receive IXE Q4W, IXE Q12W or PBO during a maintenance period depending on the study design of the individual trial. We collected information on all cases of suspected IBD reported during the induction period as a treatment-emergent adverse event or serious adverse event. This information was reviewed in a blinded fashion by external experts. These cases were adjudicated according to EPIMAD criteria into the following categories: definitive, probable, or possible. Results: Of the 3858 patients enrolled in the trials, 2 patients were reported to have suspected CD and 2 were reported as suspected UC during the induction period. Adjudicators classified 1 CD case reported during induction as ‘‘probable.’’ This event occurred at day 64 and the patient received IXE Q2W. The other suspected CD was classified as ‘‘possible.’’ This event occurred at day 88 and the patient received IXE Q4W. Both of the suspected UC cases were adjudicated as ‘‘definitive.’’ Importantly, both of these patients had a prior history of UC and both received IXE Q2W. Conclusion: Of the 3858 total patients enrolled in the UNCOVER program the incidence of CD and UC was uncommon during the first 12 weeks of treatment with IXE. Additional analysis and adjudication of longer term data is currently ongoing and are required to further understand the relationship between IBD and IXE treatment. Supported by Eli Lilly and Company.
J AM ACAD DERMATOL
AB249
2957
Endothelium-dependent vasodilation is reduced in the cutaneous circulation of psoriatic patients Billie Alba, Pennsylvania State University, University Park, PA, United States; Jody Greaney, PhD, Pennsylvania State University, University Park, PA, United States; Sara Ferguson, MD, Penn State Hershey Medical Group, State College, PA, United States; Lacy Alexander, PhD, Pennsylvania State University, University Park, PA, United States Psoriasis, a chronic systemic inflammatory disease, is an independent risk factor for cardiovascular disease. Impaired vascular function in conduit and resistance vessels is evident in adults with plaque psoriasis; however, potential deficits in microcirculatory endothelial function in psoriatic patients remain unclear. Further, examining cutaneous vascular function has particular clinical relevance for this population because the skin-related symptoms are the outward manifestation of this systemic inflammatory disease process. We hypothesized that cutaneous endothelial function would be impaired in nonlesional skin of psoriatic patients. Three intradermal microdialysis fibers were placed in the forearm skin of 8 healthy adults (NP: 3M, 5F; 49 6 3 yr) and 8 adults with moderate ([5% body surface area affected) plaque psoriasis (P: 3M, 5F; 48 6 3 yr) for localized drug delivery. Microdialysis sites were perfused with lactated Ringer’s (control), ascorbate (antioxidant), or BEC (arginase-inhibitor) while an index of skin blood flow was measured using laser Doppler flowmetry during a standardized local heating protocol (428C) to elicit endothelial nitric oxide synthase (eNOS)-mediated vasodilation. Nitric oxide (NO)dependent vasodilation was quantified following the perfusion of the nonspecific NOS inhibitor L-NAME. Data were expressed as a percentage of maximum cutaneous vascular conductance (%CVCmax; 28 mM sodium nitroprusside). The local heatinginduced plateau at the control site was attenuated in psoriatic patients (NP: 99 6 1 % CVCmax vs P: 82 6 6 %CVCmax; P ¼ .03), which is mediated by reduced NOdependent vasodilation (NP: 58 6 5 %CVCmax vs P: 45 6 8 %CVCmax; P ¼ .10). Arginase-inhibition, but not ascorbate, tended to improve the local-heating induced vasodilation in psoriasis patients (Ringer’s: 82 6 6 %CVCmax vs BEC: 93 6 2 % CVCmax; P ¼ .15). These results suggest that cutaneous endothelial function is impaired in psoriatic adults due to reduced NO bioavailability and that arginase upregulation contributes to the microvascular dysfunction in these patients.
Evaluation of efficacy and safety of ABP 501 in a phase 3 study in subjects with moderate to severe plaque psoriasis: 52-week results Bruce Strober, MD, PhD, University of Connecticut, Farmington, CT, United States; Peter Foley, MD, Skin & Cancer Foundation Inc, Carlton, Victoria, Australia; Sandra Philipp, MD, University Hospital Charite, Berlin, Germany; Nan Zhang, PhD, Amgen, Thousand Oaks, CA, United States; Primal Kaur, MD, MBA, Amgen, Thousand Oaks, CA, United States Background and objectives: ABP 501 is being developed as a biosimilar candidate to adalimumab (Humira), a fully human recombinant anti-TNF monoclonal antibody and has the same amino acid sequence as adalimumab. Evidence from analytical comparisons and phase 1 human pharmacokinetic study indicates that ABP 501 is similar to adalimumab. The objective of this study was to demonstrate clinical similarity between ABP 501 and adalimumab reference product in adults with moderate to severe plaque psoriasis. Results of clinical similarity based on efficacy and safety at week 16 have been previously reported. Here we report results of efficacy and safety at 52 weeks comparing subjects receiving ABP 501 or adalimumab for the entire duration of the study. Methods: In this double-blind, active-controlled study subjects were randomized 1:1 (ABP 501: n ¼ 175; adalimumab: n ¼ 175) to receive study treatment subcutaneously 80 mg on week 1/day 1 and 40 mg at week 2 and every 2 weeks thereafter. At week 16, subjects achieving $PASI 50 response remained on study for up to 52 weeks and were rerandomized in a blinded fashion such that all subjects initially randomized to ABP 501 continued to receive ABP 501; those on adalimumab either continued on adalimumab or switched to ABP 501 in a 1:1 fashion. Subjects continued on treatment until week 48; the final efficacy assessments were conducted at week 50 and the end of study visit was week 52.
Supported by a Penn State College of HHD Grant.
Results: Baseline characteristics were comparable in the two groups [ABP 501/ABP 501 (A/A), adalimumab/adalimumab (B/B)]. The mean PASI percent improvement from baseline at week 16, 32 and 50 (evaluated descriptively) was 86.6, 87.6 and 87.2 in group A/A and 88.0, 88.2 and 88.1 in group B/B, respectively. At the end of study incidence of subjects developing anti-drug antibodies was 68.4% in A/A group and 74.7% in B/B group. Incidence of treatment-emergent adverse events (TEAEs) was 86.2% in A/A group and 78.5% in B/B group. The most frequently reported TEAEs in $5% of subjects were nasopharyngitis, headache, upper respiratory tract infection, arthralgia, back pain, psoriasis and hypertension. Incidence of serious TEAEs was 4.6% in A/A group and 5.1% in B/B group. Conclusions: At the end of 52 weeks the overall efficacy, safety and immunogenicity were comparable among the two groups. This phase 3 study was sponsored by Amgen. Amgen provided all costs associated with the study conduct, data analysis and preparation of this abstract.
3417
3889 Erythrodermic psoriasis following terbinafine use Felipe Cerci, MD, Hospital Santa Casa de Curitiba, Curitiba, Brazil; Michelly Carvalho, MD, Hospital Santa Casa de Curitiba, Curitiba, Brazil; Franciele Nihi, MD, Hospital Santa Casa de Curitiba, Curitiba, Brazil Background: Terbinafine has been linked with the occurrence of psoriasis de novo or with its exacerbation. We report a case of erythrodermic psoriasis following terbinafine use. Case report: A 67-year-old man with a 2-year history of mild psoriasis (scalp and elbows), well controlled with topical medications, was admitted to our hospital due to erythroderma. Ten days prior to its onset, he started taking terbinafine 250 mg/d for tinea cruris. He had been on enalapril, acetylsalicylic acid, simvastatin and inhaled steroids for several years due to his comorbidities. On admission, the patient had widespread erythema with diffuse scaling. He denied fever, urinary, respiratory or gastrointestinal symptoms. The white cell count was 14,080/mm3 with mild neutrophilia. Liver and kidney function tests were within the normal range. Serologies for hepatitis B, C and HIV were negative. Since no classic triggers of erythroderma were identified, terbinafine was suspended. Therapy consisted of wet wraps with moisturizers and topical steroids, which resulted in a dramatic improvement after five days. In addition, methotrexate 7.5 mg/week and folic acid 5 mg/week were started, but soon suspended due to increased transaminases. Despite significant improvement with wet wrap therapy, PUVA was started for better disease control. After 12 sessions, he had complete resolution of the erythroderma, without recurrence after a 3-month follow-up. Discussion: Cutaneous adverse effects are reported in 2.7% of patients taking oral terbinafine. Psoriasis exacerbation has been reported after its use, especially plaque and pustular psoriasis. When considering a medication as responsible for the exacerbation of a disease it is important to evaluate if there is chronological correlation. According to previous reports, the latency period between administration of terbinafine and the exacerbation of psoriasis is less than 4 weeks, categorized as short interval. Our patient developed erythroderma 10 days after starting terbinafine, which supports the association. Dermatologists should be aware of the association between oral terbinafine and psoriasis flare-up, including erythroderma. Similarly to any medication adverse event, further investigation and observation are needed to establish a solid conclusion. Commercial support: None identified.
MAY 2016
Evaluation of inflammatory bowel disease in patients with plaque psoriasis studied in phase 3 trials of ixekizumab (UNCOVER trials): Adjudicated data from the induction period Richard Langley, MD, Dalhousie University, Halifax, Nova Scotia, Canada; Ricardo Romiti, MD, University of S~ao Paulo, S~ao Paulo, Brazil; Craig Leonardi, MD, Central Dermatology, St. Louis, MO, United States; Kristian Reich, MD, Dermatologikum Hamburg, Hamburg, Germany; Richard Warren, MD, PhD, University of Manchester, Manchester, United Kingdom; Kathleen Solotikin, MSN, Eli Lilly and Company, Indianapolis, IN, United States; Wen Xu, PhD, Eli Lilly and Company, Indianapolis, IN, United States; Harald Vangerow, MD, Eli Lilly and Company, Indianapolis, IN, United Kingdom; Dana Hardin, MD, Eli Lilly and Company, Indianapolis, IN, United States; Herve Bachelez, MD, PhD, Saint Louis Hospital, Paris, France Introduction and objectives: New onset or flares of inflammatory bowel disease (IBD) including worsening of active Crohn’s disease (CD) and ulcerative colitis (UC) have been reported during treatment with biologic agents for psoriasis. The objective of this integrated safety analysis was to report the adjudicated incidence of CD and UC in 3 phase 3 clinical trials of ixekizumab, an anti-IL-17A monoclonal antibody. Methods: In each trial during an induction period, patients were randomized to one of 3 treatment arms: (1) IXE every 2 (IXE Q2W; N ¼ 1167) or every 4 weeks (IXE Q4W; N ¼ 1161) following a 160-mg starting dose; (2) etanercept (ETN; 50 mg biweekly; N ¼ 739), or (3) placebo (PBO; N ¼ 791) for 12 weeks. After the induction period, patients continuing in the trial may receive IXE Q4W, IXE Q12W or PBO during a maintenance period depending on the study design of the individual trial. We collected information on all cases of suspected IBD reported during the induction period as a treatment-emergent adverse event or serious adverse event. This information was reviewed in a blinded fashion by external experts. These cases were adjudicated according to EPIMAD criteria into the following categories: definitive, probable, or possible. Results: Of the 3858 patients enrolled in the trials, 2 patients were reported to have suspected CD and 2 were reported as suspected UC during the induction period. Adjudicators classified 1 CD case reported during induction as ‘‘probable.’’ This event occurred at day 64 and the patient received IXE Q2W. The other suspected CD was classified as ‘‘possible.’’ This event occurred at day 88 and the patient received IXE Q4W. Both of the suspected UC cases were adjudicated as ‘‘definitive.’’ Importantly, both of these patients had a prior history of UC and both received IXE Q2W. Conclusion: Of the 3858 total patients enrolled in the UNCOVER program the incidence of CD and UC was uncommon during the first 12 weeks of treatment with IXE. Additional analysis and adjudication of longer term data is currently ongoing and are required to further understand the relationship between IBD and IXE treatment. Supported by Eli Lilly and Company.
J AM ACAD DERMATOL
AB249