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398 Safety of 62-week treatment of psoriasis with cyclosporine
ABSTRACTS | Clinical Research: Patient Outcomes Research 394
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Comparison of EASI and objective-SCORAD assessments in adult atopic dermatitis R Chopra1, P Vakharia1, R Sacotte1, N Patel1, S Immaneni1, T White1, R Kantor1, D Hsu2 and JI Silverberg1 1 Northwestern University, Chicago, IL and 2 Northwestern Feinberg School of Medciine, Chicago, IL Atopic dermatitis (AD) is associated with variable severity and extent of lesions. We sought to determine the similarities and differences of objective severity assessments in AD. We performed a prospective study of 388 adolescents and adults (ages 13-93 years) with AD to determine the relationship between the Eczema Area and Severity Index (EASI), Scoring AD (ScorAD) and body surface area (BSA). Overall, EASI and objective-SCORAD were strongly correlated (Spearman correlation, rho¼0.92; P < 0.0001). However, there was a non-linear relationship between EASI and objective-SCORAD, which was better depicted using a higher order polynomial function. In particular, EASI scores 5 were unable to distinguish between fairly broad ranges of objective-ScorAD and BSA. Patients with EASI scores 5 had significantly higher objective-ScorAD scores when moderate-severe xerosis was present (MannWhitney U test, P < 0.0001). Xerosis is scored in objective-ScorAD, but not EASI. Moreover, patients with EASI scores 5 had significantly higher objective-ScorAD scores when moderate-severe lesions were localized to the face (P < 0.0001), eyelids (P < 0.0001), neck (P < 0.0001), flexural areas (P¼0.004), hands (P < 0.0001) and feet (P¼0.02). Lesional severity is weighted to the surface area affected in EASI, but not objective-ScorAD. The present study shows a complex relationship between EASI and objective-ScorAD and limited discriminative ability of low EASI scores compared with ScorAD.
Redefining colour and redness in cutaneous healing and scarring: Quantitative evaluation of erythema and pigmentation in human skin corroborated by immunohistochemical analysis S Ud-Din1, P Foden2, M Mazhari3, S Al-Habba3, M Baguneid2 and A Bayat1 1 University of Manchester, Manchester, United Kingdom, 2 University Hospital of South Manchester, Manchester, United Kingdom and 3 Central Manchester University Hospitals, Manchester, United Kingdom Skin redness and colour are extremely valuable parameters to both patients and physicians in the assessment of cutaneous skin scarring and response to therapy. Erythema is predominantly due to inflammation and is affected by the presence of pigments including haemoglobin and melanin. Therefore, the aim here was to evaluate objective devices, which quantified blood flow, haemoglobin, melanin and erythema during acute wound healing, in 20 human volunteers on days (D) 0, 7, 10, 14, 21, 28, supported by immunohistochemical (IHC) analysis of tissue-biopsies (NSD0 and D28). Blood-flow measured by full-field laser perfusion imaging and dynamic optical coherence tomography increased from NSD0 to D28 (69%, 30% respectively) (p < 0.001). IHC analysis of CD31 blood vessel density was greatest at D28 (113.5 mm3) compared to NSD0 (98.9 mm3) (p < 0.05). Angiogenic markers, VEGF-A and PLGF demonstrated increased expression at D28 (31%, 3% respectively) compared to NSD0 (9%, 14% respectively) (p < 0.05). Melanin assessment by colormeter and spectrophotometric intracutaneous analysis (SIAscopy) significantly increased from NSD0 to D28 (24%, 6% increase respectively) (p < 0.001). Melanogenesis increased by 53% from NSD0 (3%) to D28 (6.5%) (p < 0.05). Erythema increased by 60% as quantified by colormeter from NSD0 to D28 (p < 0.001). Mast-cell tryptase and chymase cell-count were highest at D28 (121cells/ mm2, 101cells/mm2 respectively) compared to NSD0 (98cells/mm2, 86cells/mm2 respectively) (p < 0.05). These findings may contribute to the development of an objective classification for assessment of erythema and pigmentation in response to scar therapies.
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Ciclosporine therapy for psoriasis leading to fathering of a healthy child in a previously infertile male R Schopf Johannes Gutenberg Univ., Mainz, Germany A 34-year-old male patient presented with generalized psoriatic skin lesions. He was treated with 4 mg/kg cyclosporine (CyA) for 12 weeks leading to clearing of psoriasis. CyA treatment was continued at a dose of 2.5 mg/kg for another 2 months. On his follow-up visit he reported that his wife had become pregnant which was quite a surprise to him because he had been diagnosed with azoospermia before. He had been married for 8 years. A healthy boy was born. His wife had previously had artificial insemination from an anonymous sperm donor resulting in a normal pregnancy and delivery. The patient presented a spermatogram dating from 4 years previously that had been obtained during diagnosis for infertility exhibiting azoosperimia. A new spermiogram was obtained after his wife now became pregnant; indeed he now had >20 Mio viable spermatozoa/ml. Further examination revealed a history of mumps orchitis; he exhibited mumps IgG antibodies. Paternity testing involving the mother, the child and the putative father using DNA technology employing multiplex-STR systems PowerPlex 16 and DNA-SE-Filer Kit according to the gene diagnosis commission guidelines ascertained that he indeed was the father with a likelihood of >99.999%.Our findings suggest that this patient may have suffered from mumps-induced autoimmune orchitis resulting in azoospermia that has resolved during cyclosporine treatment for psoriasis. Ciclosporine treatment should be considered in cases of male infertility associated with a history of mumps autoimmune orchitis.
Safety of 62-week treatment of psoriasis with cyclosporine R Schopf Johannes Gutenberg Univ., Mainz, Germany Toxicity is a major concern of cyclosporine (CyA) treatment for psoriasis although efficacy is excellent. It is recommended to discontinue treatment after 24 months. On the other hand many patients are virtually free from psoriasis during treatment. Long term-treatment studies are lacking. We therefore examined tolerance to CyA 3 mg/kg or lower during the course of treatment up to 62 months in 47 patients with moderate to severe psoriasis. Patients were seen every 3 months. Serum creatinine, urea nitrogen, uric acid, GOT, GPT, total bilirubin, eosinophils, and blood pressure were monitored. In addition we recorded cutaneous changes. The two-sided Wilcoxon’s test served for statistical comparison. We found that patients had normal blood laboratory results at the beginning; the levels were at the beginning versus month 62 (mean +/- SD): creatinine 0.92 +/- 0.16 vs. 0.97 +/- 0.16 (mg/dl), urea-N 16.0 +/-4.6 vs. 16.6 +/-2.9 mg/dl, uric acid 5.8 +/-1.4 vs. 5.8 +/- 1.6 mg/dl, GOT 23.4 +/-10.4 vs. 26.0 +/- 10.3 U/l, GPT 27.6 +/- 16.3 vs. 36.3 +/-19.1 U/l, total bilirubin 0.74 +/- 0.5 vs. 0.48 +/-0.4; eosinophils 2.7 +/- 1.8 vs. 2.2 +/- 1.2%, systolic blood pressure (bp) 134 +/- 16 vs. 137 +/- 16, diastolic bp 83 +/- 10 vs. 82 +/-8 mmHg. All of these differences were insignificant, they all failed to show a steady trend (p>0.05). Four patients developed gingival hyperplasia, which resolved after discontinuation of CyA and paradontal treatment. Two patients developed squamous cell carcinomas (SCC) which were excised, CyA was also discontinued. Our findings show that long-term CyA treatment for psoriasis is safe in terms of clinical tolerance. Examination for gingival hyperplasia and SCC is required. Under monitoring, we conclude that low-dose CyA treatment for psoriasis is safe up 64 months.
S68 Journal of Investigative Dermatology (2017), Volume 137
Predictive modeling of drug response and mechanism of action in alopecia areata clinical trials JC Chen, A Jabbari, R Clynes, J Mackay-Wiggin and AM Christiano Columbia University, New York, NY Alopecia areata (AA) is an autoimmune disease characterized by the immune-mediated destruction of hair follicles in scalp skin, resulting in partial or total hair loss. Ongoing research has identified JAK/STAT and the T cell costimulatory signaling pathways as key druggable targets, and several clinical trials have been conducted. Although efficacy signals have been impressive, there are subsets of patients in each trial that do not respond to treatment. Understanding the molecular underpinnings of both non-responder status and drug mechanism of action (MoA) will be key to refining and maximizing drug efficacy for AA treatment. To this end, our clinical trials have included the acquisition of longitudinal scalp biopsies to complement clinical response data, allowing for RNAseq analysis of molecular response to drug treatment. Using this data together with RNAseq data of untreated AA patients and reverse-engineered regulatory networks (ARACNe networks), we modeled the molecular mechanism of action of three drugs used in AA clinical trials: tofacitinib (pan-JAK inhibitor), ruxolitinib (JAK1/2 inhibitor), and abatacept (CTLA4-Ig). Network-based modeling of MoA allows for the matching of patients’ individual molecular pathologies to treatments and predicted efficacy by using master regulators to define the molecular effects of each drug. Our analysis identified three distinct molecular MoAs, one for each drug, that are quantitatively captured in as few as 5-10 transcription factors at pa priori, comparing patients’ molecular presentation of AA in pre-treatment biopsies against the predicted molecular response networks for these drugs. Systems biology approaches provide a foundation for developing precision-medicine strategies and accurate treatment selection for AA patients based on their individual molecular pathology.
Serious infections among a large cohort of subjects with systemically-treated psoriasis A Dobry MGH/HMS, Boston, MA Importance: Biologic therapy is effective for the treatment of moderate to severe psoriasis, but may be associated with an increased risk of serious infection. Objective: To estimate the serious infection rate among psoriasis patients treated with biologic agents as compared with non-biologic systemic agents within a community-based healthcare delivery setting. Design: We conducted a large-scale, epidemiologic retrospective study comparing the rates of serious infections in psoriatic subjects on biologics versus non-biologic therapy or no systemic therapy between the period of January 1, 1998 and December 31, 2011. Setting: Subjects were adult Kaiser Permanente Northern California (KNPC) health-plan members seen in the general community. Participants: We identified 5,889 subjects with psoriasis at KNPC, of which 2,258 were ever treated with biologic therapy. Exposures: We defined exposure as current use of a systemic psoriasis agent among patients who were ever exposed to systemic medication at the time of a serious infection.Main Outcomes and Measures: We calculated incidence rates and 95% confidence intervals (CI) for serious infections [sepsis, pneumonia, skin and soft tissue infections (SSTIs), meningitis, and renal/urinary tract infections]. Adjusted hazard ratios (aHRs) were calculated using Cox regression. Results: Adjusting for age, gender, race-ethnicity, and comorbidities revealed a significantly increased risk of overall serious infection among patients treated with biologics as compared to non-biologics (aHR 1.31, 95% CI 1.02-1.68). More specifically, there was a significantly elevated risk of skin and soft tissue infection (SSTI) (aHR 1.75, 95% CI 1.19-2.56) and meningitis (aHR 9.22, 95% CI 1.7748.10) during periods of active biologic use.Conclusion and Relevance: We found an increased rate of SSTIs and meningitis among psoriasis patients treated with biologic agents, suggesting that increased awareness of these adverse events during treatment in this cohort may be warranted.
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Comparison of EASI and objective-SCORAD assessments in adult atopic dermatitis R Chopra1, P Vakharia1, R Sacotte1, N Patel1, S Immaneni1, T White1, R Kantor1, D Hsu2 and JI Silverberg1 1 Northwestern University, Chicago, IL and 2 Northwestern Feinberg School of Medciine, Chicago, IL Atopic dermatitis (AD) is associated with variable severity and extent of lesions. We sought to determine the similarities and differences of objective severity assessments in AD. We performed a prospective study of 388 adolescents and adults (ages 13-93 years) with AD to determine the relationship between the Eczema Area and Severity Index (EASI), Scoring AD (ScorAD) and body surface area (BSA). Overall, EASI and objective-SCORAD were strongly correlated (Spearman correlation, rho¼0.92; P < 0.0001). However, there was a non-linear relationship between EASI and objective-SCORAD, which was better depicted using a higher order polynomial function. In particular, EASI scores 5 were unable to distinguish between fairly broad ranges of objective-ScorAD and BSA. Patients with EASI scores 5 had significantly higher objective-ScorAD scores when moderate-severe xerosis was present (MannWhitney U test, P < 0.0001). Xerosis is scored in objective-ScorAD, but not EASI. Moreover, patients with EASI scores 5 had significantly higher objective-ScorAD scores when moderate-severe lesions were localized to the face (P < 0.0001), eyelids (P < 0.0001), neck (P < 0.0001), flexural areas (P¼0.004), hands (P < 0.0001) and feet (P¼0.02). Lesional severity is weighted to the surface area affected in EASI, but not objective-ScorAD. The present study shows a complex relationship between EASI and objective-ScorAD and limited discriminative ability of low EASI scores compared with ScorAD.
Redefining colour and redness in cutaneous healing and scarring: Quantitative evaluation of erythema and pigmentation in human skin corroborated by immunohistochemical analysis S Ud-Din1, P Foden2, M Mazhari3, S Al-Habba3, M Baguneid2 and A Bayat1 1 University of Manchester, Manchester, United Kingdom, 2 University Hospital of South Manchester, Manchester, United Kingdom and 3 Central Manchester University Hospitals, Manchester, United Kingdom Skin redness and colour are extremely valuable parameters to both patients and physicians in the assessment of cutaneous skin scarring and response to therapy. Erythema is predominantly due to inflammation and is affected by the presence of pigments including haemoglobin and melanin. Therefore, the aim here was to evaluate objective devices, which quantified blood flow, haemoglobin, melanin and erythema during acute wound healing, in 20 human volunteers on days (D) 0, 7, 10, 14, 21, 28, supported by immunohistochemical (IHC) analysis of tissue-biopsies (NSD0 and D28). Blood-flow measured by full-field laser perfusion imaging and dynamic optical coherence tomography increased from NSD0 to D28 (69%, 30% respectively) (p < 0.001). IHC analysis of CD31 blood vessel density was greatest at D28 (113.5 mm3) compared to NSD0 (98.9 mm3) (p < 0.05). Angiogenic markers, VEGF-A and PLGF demonstrated increased expression at D28 (31%, 3% respectively) compared to NSD0 (9%, 14% respectively) (p < 0.05). Melanin assessment by colormeter and spectrophotometric intracutaneous analysis (SIAscopy) significantly increased from NSD0 to D28 (24%, 6% increase respectively) (p < 0.001). Melanogenesis increased by 53% from NSD0 (3%) to D28 (6.5%) (p < 0.05). Erythema increased by 60% as quantified by colormeter from NSD0 to D28 (p < 0.001). Mast-cell tryptase and chymase cell-count were highest at D28 (121cells/ mm2, 101cells/mm2 respectively) compared to NSD0 (98cells/mm2, 86cells/mm2 respectively) (p < 0.05). These findings may contribute to the development of an objective classification for assessment of erythema and pigmentation in response to scar therapies.
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Ciclosporine therapy for psoriasis leading to fathering of a healthy child in a previously infertile male R Schopf Johannes Gutenberg Univ., Mainz, Germany A 34-year-old male patient presented with generalized psoriatic skin lesions. He was treated with 4 mg/kg cyclosporine (CyA) for 12 weeks leading to clearing of psoriasis. CyA treatment was continued at a dose of 2.5 mg/kg for another 2 months. On his follow-up visit he reported that his wife had become pregnant which was quite a surprise to him because he had been diagnosed with azoospermia before. He had been married for 8 years. A healthy boy was born. His wife had previously had artificial insemination from an anonymous sperm donor resulting in a normal pregnancy and delivery. The patient presented a spermatogram dating from 4 years previously that had been obtained during diagnosis for infertility exhibiting azoosperimia. A new spermiogram was obtained after his wife now became pregnant; indeed he now had >20 Mio viable spermatozoa/ml. Further examination revealed a history of mumps orchitis; he exhibited mumps IgG antibodies. Paternity testing involving the mother, the child and the putative father using DNA technology employing multiplex-STR systems PowerPlex 16 and DNA-SE-Filer Kit according to the gene diagnosis commission guidelines ascertained that he indeed was the father with a likelihood of >99.999%.Our findings suggest that this patient may have suffered from mumps-induced autoimmune orchitis resulting in azoospermia that has resolved during cyclosporine treatment for psoriasis. Ciclosporine treatment should be considered in cases of male infertility associated with a history of mumps autoimmune orchitis.
Safety of 62-week treatment of psoriasis with cyclosporine R Schopf Johannes Gutenberg Univ., Mainz, Germany Toxicity is a major concern of cyclosporine (CyA) treatment for psoriasis although efficacy is excellent. It is recommended to discontinue treatment after 24 months. On the other hand many patients are virtually free from psoriasis during treatment. Long term-treatment studies are lacking. We therefore examined tolerance to CyA 3 mg/kg or lower during the course of treatment up to 62 months in 47 patients with moderate to severe psoriasis. Patients were seen every 3 months. Serum creatinine, urea nitrogen, uric acid, GOT, GPT, total bilirubin, eosinophils, and blood pressure were monitored. In addition we recorded cutaneous changes. The two-sided Wilcoxon’s test served for statistical comparison. We found that patients had normal blood laboratory results at the beginning; the levels were at the beginning versus month 62 (mean +/- SD): creatinine 0.92 +/- 0.16 vs. 0.97 +/- 0.16 (mg/dl), urea-N 16.0 +/-4.6 vs. 16.6 +/-2.9 mg/dl, uric acid 5.8 +/-1.4 vs. 5.8 +/- 1.6 mg/dl, GOT 23.4 +/-10.4 vs. 26.0 +/- 10.3 U/l, GPT 27.6 +/- 16.3 vs. 36.3 +/-19.1 U/l, total bilirubin 0.74 +/- 0.5 vs. 0.48 +/-0.4; eosinophils 2.7 +/- 1.8 vs. 2.2 +/- 1.2%, systolic blood pressure (bp) 134 +/- 16 vs. 137 +/- 16, diastolic bp 83 +/- 10 vs. 82 +/-8 mmHg. All of these differences were insignificant, they all failed to show a steady trend (p>0.05). Four patients developed gingival hyperplasia, which resolved after discontinuation of CyA and paradontal treatment. Two patients developed squamous cell carcinomas (SCC) which were excised, CyA was also discontinued. Our findings show that long-term CyA treatment for psoriasis is safe in terms of clinical tolerance. Examination for gingival hyperplasia and SCC is required. Under monitoring, we conclude that low-dose CyA treatment for psoriasis is safe up 64 months.
S68 Journal of Investigative Dermatology (2017), Volume 137
Predictive modeling of drug response and mechanism of action in alopecia areata clinical trials JC Chen, A Jabbari, R Clynes, J Mackay-Wiggin and AM Christiano Columbia University, New York, NY Alopecia areata (AA) is an autoimmune disease characterized by the immune-mediated destruction of hair follicles in scalp skin, resulting in partial or total hair loss. Ongoing research has identified JAK/STAT and the T cell costimulatory signaling pathways as key druggable targets, and several clinical trials have been conducted. Although efficacy signals have been impressive, there are subsets of patients in each trial that do not respond to treatment. Understanding the molecular underpinnings of both non-responder status and drug mechanism of action (MoA) will be key to refining and maximizing drug efficacy for AA treatment. To this end, our clinical trials have included the acquisition of longitudinal scalp biopsies to complement clinical response data, allowing for RNAseq analysis of molecular response to drug treatment. Using this data together with RNAseq data of untreated AA patients and reverse-engineered regulatory networks (ARACNe networks), we modeled the molecular mechanism of action of three drugs used in AA clinical trials: tofacitinib (pan-JAK inhibitor), ruxolitinib (JAK1/2 inhibitor), and abatacept (CTLA4-Ig). Network-based modeling of MoA allows for the matching of patients’ individual molecular pathologies to treatments and predicted efficacy by using master regulators to define the molecular effects of each drug. Our analysis identified three distinct molecular MoAs, one for each drug, that are quantitatively captured in as few as 5-10 transcription factors at pa priori, comparing patients’ molecular presentation of AA in pre-treatment biopsies against the predicted molecular response networks for these drugs. Systems biology approaches provide a foundation for developing precision-medicine strategies and accurate treatment selection for AA patients based on their individual molecular pathology.
Serious infections among a large cohort of subjects with systemically-treated psoriasis A Dobry MGH/HMS, Boston, MA Importance: Biologic therapy is effective for the treatment of moderate to severe psoriasis, but may be associated with an increased risk of serious infection. Objective: To estimate the serious infection rate among psoriasis patients treated with biologic agents as compared with non-biologic systemic agents within a community-based healthcare delivery setting. Design: We conducted a large-scale, epidemiologic retrospective study comparing the rates of serious infections in psoriatic subjects on biologics versus non-biologic therapy or no systemic therapy between the period of January 1, 1998 and December 31, 2011. Setting: Subjects were adult Kaiser Permanente Northern California (KNPC) health-plan members seen in the general community. Participants: We identified 5,889 subjects with psoriasis at KNPC, of which 2,258 were ever treated with biologic therapy. Exposures: We defined exposure as current use of a systemic psoriasis agent among patients who were ever exposed to systemic medication at the time of a serious infection.Main Outcomes and Measures: We calculated incidence rates and 95% confidence intervals (CI) for serious infections [sepsis, pneumonia, skin and soft tissue infections (SSTIs), meningitis, and renal/urinary tract infections]. Adjusted hazard ratios (aHRs) were calculated using Cox regression. Results: Adjusting for age, gender, race-ethnicity, and comorbidities revealed a significantly increased risk of overall serious infection among patients treated with biologics as compared to non-biologics (aHR 1.31, 95% CI 1.02-1.68). More specifically, there was a significantly elevated risk of skin and soft tissue infection (SSTI) (aHR 1.75, 95% CI 1.19-2.56) and meningitis (aHR 9.22, 95% CI 1.7748.10) during periods of active biologic use.Conclusion and Relevance: We found an increased rate of SSTIs and meningitis among psoriasis patients treated with biologic agents, suggesting that increased awareness of these adverse events during treatment in this cohort may be warranted.