P6526Antietumor necrosis factor-alfa and psoriasis: New insights on keratino-cyte differentiation markers

Francesca Prignano, MD, PhD, Division of Clinical, Preventive and OncologyDermatology, Department of Critical Care Medicine and Surgery, University ofFlorence, Florence, Italy; Alice Gualerzi, PhD, Dipartimento di Morfologia Umanae Scienze Biomediche e Citt�a Studi, Universit�a degli Studi di Milano, Milan, Italy;Elena Donetti, PhD, Dipartimento di Morfologia Umana e Scienze Biomediche eCitt�a Studi, Universit�a degli Studi di Milano, Milan, Italy; Federica Ricceri, MD,Division of Clinical, Preventive and Oncology Dermatology, Department ofCritical Care Medicine and Surgery, University of Florence, Florence, Italy; LaraTripo, MD, Division of Clinical, Preventive and Oncology Dermatology,Department of Critical Care Medicine and Surgery, University of Florence,Florence, Italy; Leonardo Pescitelli, MD, Division of Clinical, Preventive andOncology Dermatology, Department of Critical Care Medicine and Surgery,University of Florence, Florence, Italy; Marzia Bedoni, PhD, Polo Tecnologico,Fondazione Don Carlo Gnocchi, Milan, Italy

Tumor necrosis factor-alfa (TNF-a) is a cytokine that plays a central role in thepathogenesis of psoriasis; the treatment with antieTNF-a agents, as etanercept, hasproved to be highly effective although its mechanism on the overall epidermalcytoarchitecture has still to be elucidated. The aim of the present study was toinvestigate if etanercept treatment of psoriatic patients could affect the expressionof the main biomarkers of keratinocyte terminal differentiation (TD) along withepithelial cell proliferation. Ultrastructural analysis was also performed. We inves-tigated by immunofluorescence the expression of differentiation biomarkers(keratin-10, K10; keratin-14, K14; keratin-16, K16; involucrin) and epithelialproliferation in normal (n¼ 5) and psoriatic skin before/after 4 months of treatmentwith etanercept (n ¼ 5). In psoriatic epidermis the expressions of K14, K16, andinvolucrin were altered compared with healthy subjects, while K10 localization wascomparable. The distribution pattern of the affected TD biomarkers was reverted tothe physiological condition upon treatment with etanercept. These observationswere also confirmed by transmission electron microscopy analysis. Keratinocyteproliferation was inhibited in etanercept-treated patients, reaching values similar tocontrols. The results of this preliminary study highlights a new cellular mechanismconcerning etanercept treatment; it is effective in restoring a more differentiatedkeratinocyte phenotype and the typical proliferation rate in the epidermis ofpsoriatic patients.

APRIL 20

cial support: None identified.

Commer

P6708Antietumor necrosis factor-alfaeinduced drug eruptions: One patient,more than a pattern

Joana Cabete, Dermatology Department, Hospital de Santo Ant�onio dosCapuchos - Centro Hospitalar de Lisboa Central, Lisbon, Portugal; AlexandreJo~ao, Dermatology Department, Hospital de Santo Ant�onio dos Capuchos -Centro Hospitalar de Lisboa Central, Lisbon, Portugal; Ana Ferreira, DermatologyDepartment, Hospital de Santo Ant�onio dos Capuchos - Centro Hospitalar deLisboa Central, Lisbon, Portugal; Sara Lestre, Dermatology Department, Hospitalde Santo Ant�onio dos Capuchos - Centro Hospitalar de Lisboa Central, Lisbon,Portugal; Vasco Serr~ao, Dermatology Department, Hospital de Santo Ant�onio dosCapuchos - Centro Hospitalar de Lisboa Central, Lisbon, Portugal

Background: Tumor necrosis factorealfa (TNFa) antagonists are effective in treatingseveral immune-inflammatory diseases, including psoriasis and inflammatory boweldisease. The paradoxical and unpredictable induction of psoriasis and psoriasiformskin lesions is a recognized adverse event, although of unclear aetiology. However,histologic analysis of these eruptions remains insufficient, yet suggesting that somemight constitute a new pattern of adverse drug reaction, rather than true psoriasis.

Case report: The authors report the case of a 43-year-old woman with severerecalcitrant Crohn’s disease who started treatment with infliximab. There was also apersonal history of mild plaque psoriasis without clinical expression for the past 8years. She developed a heterogeneous cutaneous eruption of psoriasiform mor-phology with pustules and crusts after the third infliximab infusion. The histopath-ologic diagnosis was of a Sweet-like dermatosis. The patient was successfully treatedwith cyclosporine in association with both topical corticosteroid and vitamin D3analogue. Three weeks after switching to adalimumab a new psoriasiform eruptionwas observed, histologically compatible with a psoriasiform drug eruption. Despitethis, and considering the beneficial effect on the inflammatory bowel disease, it wasdecided to maintain treatment with adalimumab and to treat through with topicals,with progressive control of skin disease.

Discussion: Not much is known about the pathogenesis of psoriasiform eruptionsinduced by biologic therapies, but genetic predisposition and Koebner phenome-non may contribute to it. Histopathology can add new facets to the comprehensionof psoriasiform reactions. In fact, histopathologic patterns of such skin lesionsappear to be varied, in a clear asymmetry with clinical findings.

Conclusion: The sequential identification in the same patient of 2 clinical andhistopathologic patterns of drug reaction to TNFa antagonists is rare. Additionally, tothe authors’ knowledge, there is only one other description in literature of a TNFaantagonist-induced Sweet-like dermatosis, emphasizing the singularity of this casereport.

cial support: None identified.

Commer

13

P6591Apremilast improves pruritus in subjects with moderate to severe plaquepsoriasis: Results from a phase IIB randomized, controlled study

Kim Papp, MD, PhD, Probity Medical Research, Waterloo, Ontario, Canada;ChiaChi Hu, MS, Celgene Corporation, Summit, NJ, United States; Robert Day,PhD, Celgene Corporation, Summit, NJ, United States

Background: Apremilast (APR), a small molecule specific inhibitor of phosphodies-terase-4, works intracellularly to modulate pro- and antiinflammatory mediatorproduction. APR’s clinical efficacy and effects on pruritus were evaluated in subjectswith moderate to severe plaque psoriasis.

Methods: This phase IIB, multicenter, double-blind, placebo (PBO)-controlled, dose-ranging study equally randomized subjects with moderate to severe plaque psoriasis(Psoriasis Area and Severity Index [PASI] $ 12; body surface area [BSA] $ 10%) to1 of 3 doses of oral APR (BID: 10 mg [APR10], 20 mg [APR20], or 30 mg [APR30]) orPBO for 16 weeks followed by 8 weeks of active treatment in which PBO subjectswere re-randomized to APR20 (P/20) or APR30 (P/30). APR’s effects on prurituswere measured using a visual analog scale (VAS; 0-100 mm). Mean percent changeand proportion of subjects achieving a minimal clinically important difference(MCID; $ 10 mm) over 24 weeks were assessed.

Results: The study enrolled 352 subjects (63% male; mean age 44 years; mean BMI31 kg/m2; mean PASI 18.5; mean affected BSA 22%) randomized to PBO (n ¼ 88),APR10 (n ¼ 89), APR20 (n ¼ 87), and APR30 (n ¼ 88). At week 16, mean percentreductions in pruritus VAS were significantly greater in subjects treated with APR20(-35.5%; P ¼ .005) and APR30 (-43.7%; P \ .001) vs PBO (-6.1%). A significantlygreater proportion of subjects treated with APR20 (60.9%; P ¼ .034 vs PBO) andAPR30 (63.6%; P ¼ .015) achieved MCID vs PBO (44.3%). Differences in meanreduction (-10.2%) and MCID achievement (56.2%) were not significantly differentwith APR10. At week 24, mean percent reductions in pruritus VAS were -14.5%(APR10), -36.7% (APR20), -41.5% (APR30), -41.0% (P/20), and -47.9% (P/30). Theproportions of subjects achievingMCIDwere 56.2% (APR10), 56.3% (APR20), 64.8%(APR30), 45.5% (P/20), and 61.1% (P/30). Improvements in pruritus occurredrapidly during the first 2 weeks, suggesting an initial improvement in pruritus earlyon, followed closely by improvements in PASI scores. Comparison of PASI-75 andpruritus VAS MCID achievement over time supports this observation. In subjectsreceiving APR30, pruritus VAS MCID approached significance vs PBO at week 2(P¼.0671) and was significantly greater at week 4 (P¼.0015); PASI-75 achievementwas significantly greater starting at week 6 (P\.0001).

Conclusion: APR showed efficacy in reducing pruritus in subjects with moderate tosevere plaque psoriasis.

ponsored by Celgene Corporation.

100% is s

P6765Assessor-blinded study of the metabolic syndrome and surrogate markersof increased cardiovascular risk in children with moderate to severepsoriasis compared with an age- and sex-matched population of childrenwith benign nevi, warts, or acne not treated with oral medications

Ari Goldminz, Tufts University School of Medicine, Boston, MA, United States; AliceGottlieb, MD, PhD, Tufts Medical Center, Boston, MA, United States; CatherineBuzney, Tufts University School of Medicine, Boston, MA, United States; Daniel Loo,MD, Tufts Medical Center, Boston, MA, United States; Eva Volf, Tufts Medical Center,Boston, MA, United States; Noori Kim, MD, Tufts Medical Center, Boston, MA, UnitedStates; Shiu-Chung Au, MD, Tufts Medical Center, Boston, MA, United States

Background: Adult patients with psoriasis have an increased risk of developing themetabolic syndrome (MetS) and cardiovascular disease (CVD), which can lead tosignificant morbidity and mortality. However, few studies have investigated theprevalence of MetS and other risk factors for CVD among children with psoriasis.

Methods: The purpose of this study was to determine if children with psoriasis havean increased prevalence of MetS and other CVD risk factors. In an assessor-blindedstudy, 20 children, ages 9 to 17withmoderate to severe psoriasis (present or history of$ 5%body surface area) or psoriatic arthritis, were compared to age- and sex-matchedcontrols with benign nevi, warts, or acne not treated with oral medications. MetS wasdefined by the presence of at least 3 of the following criteria: triglycerides $ 100mg/dL, HDL-C\50 mg/dL for females or\45 mg/dL for males, fasting blood glucose$ 110 mg/dL, waist circumference[75th percentile for age and sex, and systolic ordiastolic blood pressure[90th percentile for age, sex and height. Serum lipid profileswere obtained after a 12-hour fast. Secondary endpoints included high-sensitivity C-reactive protein (hs-CRP), flow-mediated dilation (FMD), and peripheral arterytonometry (PAT). Results Thirty percent (6/20) of pediatric psoriasis subjects metcriteria for MetS versus 5% (1/20) in the control group (P \ .05). Subjects withpsoriasis had higher mean fasting blood glucose levels, 91.1 mg/dL (95% CI,87.8-94.3), compared to the control group, 82.9 mg/dL (95% CI, 77.4-87.4), P ¼.01. Differences between the other 4 individual components of MetS (all P[.1), BMIand BMI percentile for age and sex, hs-CRP, and markers of endothelial dysfunction,including FMD and PAT, did not show statistical significance. Although there was adifference between the BMI percentiles of psoriasis subjects with MetS compared totheir age- and sex-matched controls, with percentiles of 88.0 and 56.4, respectively,this was not found to be statistically significant (P ¼ .1).

Limitations: This study is limited by its small sample size and lack of control forcigarette smoke exposure.

Conclusion: Results of this trial demonstrate that children with psoriasis have higherrates of MetS compared to age- and sex-matched controls. It will therefore beimportant to evaluate pediatric psoriasis patients for components of MetS to preventfuture CVD morbidity and mortality.

d by Amgen.

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J AM ACAD DERMATOL AB193