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<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="other" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Vestnik dermatologii i venerologii</journal-id><journal-title-group><journal-title xml:lang="en">Vestnik dermatologii i venerologii</journal-title><trans-title-group xml:lang="ru"><trans-title>Вестник дерматологии и венерологии</trans-title></trans-title-group></journal-title-group><issn publication-format="print">0042-4609</issn><issn publication-format="electronic">2313-6294</issn><publisher><publisher-name xml:lang="en">Rossijskoe Obschestvo Dermatovenerologov i Kosmetologov</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">343</article-id><article-id pub-id-type="doi">10.25208/0042-4609-2017-93-5-89-96</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>DRUG TREATMENT IN DERMATOVENEROLOGY</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>ФАРМАКОТЕРАПИЯ В ДЕРМАТОВЕНЕРОЛОГИИ</subject></subj-group><subj-group subj-group-type="article-type"><subject></subject></subj-group></article-categories><title-group><article-title xml:lang="en">Signaling Рathway Blockers: Action Mechanism, Efficacy, Safety of Therapy for Patients with Psoriasis and Psoriatic Arthritis</article-title><trans-title-group xml:lang="ru"><trans-title>Блокаторы сигнальных путей: механизм действия, эффективность, безопасность терапии у больных псориазом и псориатическим артритом</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><name-alternatives><name xml:lang="en"><surname>Bakulev</surname><given-names>A. A.</given-names></name><name xml:lang="ru"><surname>Бакулев</surname><given-names>А. Л.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>Bolshaya Kazachia str, 112, 410012</p></bio><bio xml:lang="ru"><p>д.м.н., профессор кафедры кожных и венерических болезней</p></bio><email>al_ba05@mail.ru</email><xref ref-type="aff" rid="aff1"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">Saratov State Medical University named after V. I. Razumovsky of the Ministry of Health of Russian Federation, Saratov</institution></aff><aff><institution xml:lang="ru">Саратовский государственный медицинский университет им. В. И. Разумовского Минздрава России 410012, Российская Федерация, г. Саратов</institution></aff></aff-alternatives><pub-date date-type="pub" iso-8601-date="2017-10-04" publication-format="electronic"><day>04</day><month>10</month><year>2017</year></pub-date><volume>93</volume><issue>5</issue><issue-title xml:lang="en"/><issue-title xml:lang="ru"/><fpage>89</fpage><lpage>96</lpage><history><date date-type="received" iso-8601-date="2018-01-04"><day>04</day><month>01</month><year>2018</year></date><date date-type="accepted" iso-8601-date="2018-01-04"><day>04</day><month>01</month><year>2018</year></date></history><permissions><copyright-statement xml:lang="en">Copyright ©; 2017, Bakulev A.A.</copyright-statement><copyright-statement xml:lang="ru">Copyright ©; 2017, Бакулев А.Л.</copyright-statement><copyright-year>2017</copyright-year><copyright-holder xml:lang="en">Bakulev A.A.</copyright-holder><copyright-holder xml:lang="ru">Бакулев А.Л.</copyright-holder><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/><license><ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/">https://creativecommons.org/licenses/by/4.0</ali:license_ref></license></permissions><self-uri xlink:href="https://vestnikdv.ru/jour/article/view/343">https://vestnikdv.ru/jour/article/view/343</self-uri><abstract xml:lang="en"><p>In the literature review, contemporary data on immune pathogenesis of psoriasis and the emergence of comorbid states against the background of systemic chronic inflammation among patients is discussed. On the example of the apremilast medical preparation, the information on a new class of therapeutic agents for the treatment of psoriasis and psoriatic arthritis – “small molecules” is given, including their physicochemical properties and action mechanism, as well as on the key differences from immune-suppressive and genetically engineered biological preparations. Data on large-scale international randomised clinical trials of the efficacy and safety of the PDE4 inhibitor of apremilast among patients with moderate to severe psoriasis and psoriatic arthritis is presented. The published international clinical recommendations on the use of apremilast among patients with psoriasis and psoriatic arthritis, the criteria for evaluating the response to therapy, as well as the potential profile of patients for the use of apremilast in real clinical practice are discussed.</p></abstract><trans-abstract xml:lang="ru"><p>В обзоре обсуждаются современные данные иммунопатогенеза псориаза и возникновения коморбидных состояний на фоне системного хронического воспаления в организме пациентов. На примере лекарственного препарата апремиласт приводятся сведения о новом классе терапевтических средств для лечения псориаза и псориатического артрита – «малых молекулах», в том числе их физико-химических свойствах и механизме действия, ключевых отличиях от других иммуносупрессивных и генно-инженерных биологических препаратов. Представлены данные масштабных международных рандомизированных клинических исследований по эффективности и безопасности ингибитора ФДЭ4 апремиласта при лечении больных среднетяжелым и тяжелым псориазом, а также псориатическим артритом. Обсуждаются опубликованные международные клинические рекомендации по применению апремиласта у больных псориазом, псориатическим артритом, критерии оценки ответа на терапию, а также потенциальный профиль пациентов для применения апремиласта в условиях реальной клинической практики. </p></trans-abstract><kwd-group xml:lang="en"><kwd>psoriasis</kwd><kwd>psoriatic arthritis</kwd><kwd>immune system</kwd><kwd>pathogenesis</kwd><kwd>comorbid states</kwd><kwd>therapy</kwd><kwd>small molecules</kwd><kwd>aprimilast</kwd><kwd>soriasis</kwd><kwd>psoriatic arthritis</kwd><kwd>immune system</kwd><kwd>pathogenesis</kwd><kwd>comorbid states</kwd><kwd>therapy</kwd><kwd>small molecules</kwd><kwd>aprimilast</kwd><kwd>efficiency</kwd><kwd>recommendations for use</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>псориаз</kwd><kwd>псориа сориаз</kwd><kwd>псориатический артрит</kwd><kwd>иммунная система</kwd><kwd>па тический артрит</kwd><kwd>иммунная система</kwd><kwd>патогенез</kwd><kwd>к тогенез</kwd><kwd>коморбидные состояния</kwd><kwd>терапия</kwd><kwd>морбидные состояния</kwd><kwd>терапия</kwd><kwd>малые молекулы</kwd><kwd>апремиласт</kwd><kwd>эффективность</kwd><kwd>рек алые молекулы</kwd><kwd>апремиласт</kwd><kwd>эффективность</kwd><kwd>рекомендации по применению</kwd></kwd-group><funding-group/></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><mixed-citation>1. Langley R. G. Exploring new concepts in the successful management of psoriasis. J EADV. 2012. Vol.26. March. 2012.</mixed-citation></ref><ref id="B2"><label>2.</label><mixed-citation>2. Coimbra S., Catarino C., Santos-Silva A. The triad psoriasisobesity-adipokine profile. J Eur Acad Dermatol Venereol. 2016. Nov;30(11):1876–1885.</mixed-citation></ref><ref id="B3"><label>3.</label><mixed-citation>3. Gerdes S., Mrowietz U. Comorbidities and psoriasis. Impact on clinical practice]. Hautarzt. 2012. Mar;63(3):202–213.</mixed-citation></ref><ref id="B4"><label>4.</label><mixed-citation>4. Onumah N., Kircik L. H. Psoriasis and its comorbidities. J Drugs Dermatol. 2012. May;11(5 Suppl):5–10.</mixed-citation></ref><ref id="B5"><label>5.</label><mixed-citation>5. Lotti T., Hercogova J., Prignano F. The concept of psoriatic disease: can cutaneous psoriasis any longer be separated by the systemic comorbidities? Dermatol Ther. 2010. Mar–Apr;23(2):119–122.</mixed-citation></ref><ref id="B6"><label>6.</label><mixed-citation>6. Gisondi P., Ferrazzi A., Girolomoni G. Metabolic comorbidities and psoriasis. Acta Dermatovenerol Croat. 2010;18(4):297–304.</mixed-citation></ref><ref id="B7"><label>7.</label><mixed-citation>7. Lynch M., Ahern T., Sweeney C. M., Malara A., Tobin A. M., O'Shea D., Kirby B. Adipokines, psoriasis, systemic inflammation, and endothelial dysfunction. Int J Dermatol. 2017. Aug 1. doi: 10.1111/ijd.13699.</mixed-citation></ref><ref id="B8"><label>8.</label><mixed-citation>8. Takeshita J., Grewal S., Langan S. M., Mehta N. N., Ogdie A., Van Voorhees A. S., Gelfand J. M. Psoriasis and comorbid diseases: Implications for management. J Am Acad Dermatol. 2017. Mar; 76(3):393–403.</mixed-citation></ref><ref id="B9"><label>9.</label><mixed-citation>9. Lichtman A. H., Binder C. J., Tsimikas S., Witztum J. Adaptive immunity in atherogenesis: new insights and therapeutic approaches. The Journal of Clinical Investigation. 2013;№1:27–36.</mixed-citation></ref><ref id="B10"><label>10.</label><mixed-citation>10. Gelfand J. M., Troxel A. B., Lewis J. D., Kurd S. K., Shin D. B., Wang X., Margolis D. J., Strom B. L. The risk of mortality in patients with psoriasis: results from a population-based study. Arch Dermatol. 2007. Dec;143(12):1493–1499.</mixed-citation></ref><ref id="B11"><label>11.</label><mixed-citation>11. Kim J., Krueger J. G. The immunopathogenesis of psoriasis. Dermatol Clin. 2015. Jan;33(1):13–23.</mixed-citation></ref><ref id="B12"><label>12.</label><mixed-citation>12. Bos J. D., de Rie M. A., Teunissen M. B., Piskin G. Psoriasis: dysregulation of innate immunity. Br J Dermatol. 2005. Jun; 152(6):1098– 1107.</mixed-citation></ref><ref id="B13"><label>13.</label><mixed-citation>13. Zhang Z., Fan W., Yang G., Xu Z., Wang J., Cheng Q., Yu M. Risk of tuberculosis in patients treated with TNF-Į antagonists: a systematic review and meta-analysis of randomised controlled trials. BMJ Open. 2017. Mar22;7(3):e012567.</mixed-citation></ref><ref id="B14"><label>14.</label><mixed-citation>14. Бакулев А. Л. Селективное внутриклеточное ингибирование сигнальных путей – новое направление системной терапии больных псориазом. Вестник дерматол. 2017;№ 5:55–62 [ Bakulev A. L. Selektivnoe vnutrikletochnoe ingibirovanie signal'nyh putej – novoe napravlenie sistemnoj terapii bol'nyh psoriazom. Vestnik dermatol. 2017;(5):55–62]</mixed-citation></ref><ref id="B15"><label>15.</label><mixed-citation>15. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis.Biochem Pharmacol. 2012. Jun15; 83(12):1583–1590. Epub 2012 Jan 10.</mixed-citation></ref><ref id="B16"><label>16.</label><mixed-citation>16. Schafer P. H., Parton A., Gandhi A. K., Capone L., Adams M., Wu L., Bartlett J. B., Loveland M. A., Gilhar A., Cheung Y.F. et al. Apremilast, a cAMP phosphodiesterase-4 inhibitor, demonstrates anti-inflammatory activity in vitro and in a model of psoriasis. Br J Pharmacol. 2010. Feb;159(4):842– 855. Epub 2009 Dec 24.</mixed-citation></ref><ref id="B17"><label>17.</label><mixed-citation>17. Кубанова А. А., Кубанов А. А., Насонов Е. Л., Соколовский Е. В., Знаменская Л. Ф., Рахматулина М. Р., Бакулев А. Л., Хобейш М. М., Чикин В. В., Коротаева Т. В., Логинова Е. Ю., Корсакова Ю. Л. Псориатический артрит. Клинические рекомендации РОДВК и Ассоциации ревматологов России. М., 2015. [Kubanova A. A., Kubanov A. A., Nasonov E. L., Sokolovskij E. V., Znamenskaya L. F., Rahmatulina M. R., Bakulev A. L., Hobejsh M. M., CHikin V. V., Korotaeva T. V., Loginova E. YU., Korsakova YU. L. Psoriaticheskij artrit. Klinicheskie rekomendacii RODVK i Associacii revmatologov Rossii. M., 2015]</mixed-citation></ref><ref id="B18"><label>18.</label><mixed-citation>18. Houslay M. D., Schafer P., Zhang K. Y. Keynote review: phosphodiesterase-4 as a therapeutic target. Drug Discov Today. 2005;10:1503–1519.</mixed-citation></ref><ref id="B19"><label>19.</label><mixed-citation>19. Wright L. C., Seybold J., Robichaud A. et al. Phosphodiesterase expression in human epithelial cells. Am J Physiol Lung Cell Mol Physiol. 1998;275(4 Pt 1):L694–700.</mixed-citation></ref><ref id="B20"><label>20.</label><mixed-citation>20. Shepherd M. C., Baillie G. S., Stirling D. I., Houslay M. D. Remodelling of the PDE4 cAMP phosphodiesterase isoform profile upon monocyte-macrophage differentiation of human U937 cells. Br J Pharmacol. 2004;142:339–351.</mixed-citation></ref><ref id="B21"><label>21.</label><mixed-citation>21. Bjorgo E., Tasken K. Role of cAMP phosphodiesterase 4 in regulation of T-cell function. Crit Rev Immunol. 2006;26:443–451.</mixed-citation></ref><ref id="B22"><label>22.</label><mixed-citation>22. Heystek H. C., Thierry A. C., Soulard P., Moulon C. Phosphodiesterase 4 inhibitors reduce human dendritic cell inflammatory cytokine production and Th1-polarizing capacity. Int Immunol. 2003;15:827– 835.</mixed-citation></ref><ref id="B23"><label>23.</label><mixed-citation>23. Schett G., Sloan V. S., Stevens R. M., Schafer P. Apremilast: a novel PDE4 inhibitor in the treatment of autoimmune and inflammatory diseases. Ther Adv Musculoskelet Dis. 2010;2:271–278.</mixed-citation></ref><ref id="B24"><label>24.</label><mixed-citation>24. Tenor H., Hedbom E., Hauselmann H. J. et al. Phosphodiesterase isoenzyme families in human osteoarthritis chondrocytes–functional importance of phosphodiesterase 4. Br J Pharmacol. 2002;135:609–618.</mixed-citation></ref><ref id="B25"><label>25.</label><mixed-citation>25. Papp K., Reich K., Leonardi C. L. et al. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (ESTEEM 1). J Am Acad Dermatol. 2015;73:37–49.</mixed-citation></ref><ref id="B26"><label>26.</label><mixed-citation>26. Paul С., Cather J., Gooderham M. at al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderateto-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). BJD. 2015;173:1387–1399.</mixed-citation></ref><ref id="B27"><label>27.</label><mixed-citation>27. Rich P., Gooderham M., Bachelez H., Goncalves J., Day R. M., Chen R., Crowley J. Apremilast, an oral phosphodiesterase 4 inhibitor, in patients with difficult-to-treat nail and scalp psoriasis: Results of 2 phase III randomized, controlled trials (ESTEEM 1 and ESTEEM 2). J Am Acad Dermatol.2016;74:134–142.</mixed-citation></ref><ref id="B28"><label>28.</label><mixed-citation>28. Kavanaugh A., Mease P.J., Gomez-Reino J.J., Adebajo A.O., Wollenhaupt J., Gladman D.D., Hochfeld M., Teng L.L., Schett G., Lespessailles E., Hall S. Longterm (52-week) results of a phase III randomized, controlled trial of apremilast in patients with psoriatic arthritis. J Rheumatol. 2015. Mar;42(3):479–488.</mixed-citation></ref><ref id="B29"><label>29.</label><mixed-citation>29. Gladman D., Kavanaugh A., Adebajo A. O. et al. Apremilast, an Oral Phosphodiesterase 4 Inhibitor, Is Associated with Long-Term (104-Week) Improvements in Enthesitis and Dactylitis in Patients with Psoriatic Arthritis: Pooled Results from Three Phase III, Randomized, Controlled Trials. ACR/ ARHP Annual Meeting, 2015. Abstract 2888.</mixed-citation></ref><ref id="B30"><label>30.</label><mixed-citation>30. Reich K., Gooderham M., Green L., Bewley A., Zhang Z., Khanskaya I., Day R. M., Goncalves J., Shah K., Piguet V., Soung J. The efficacy and safety of apremilast, etanercept and placebo in patients with moderate-to-severe plaque psoriasis: 52-week results from a phase IIIb, randomized, placebo-controlled trial (LIBERATE). J Eur Acad Dermatol Venereol. 2017. Mar;31(3):507–517.</mixed-citation></ref><ref id="B31"><label>31.</label><mixed-citation>31. Papp K., Chen R., Day R., Paul C., Shah K., Sobell J. Safety and Tolerability of Apremilast Up to 182 Weeks: Pooled Analyses From Phase 3 Clinical Trials. 74th Annual Meeting AAD. Washington, 2016. Poster 2347.</mixed-citation></ref><ref id="B32"><label>32.</label><mixed-citation>32. Инструкция по медицинскому применению препарата Отесла. 2016. [Instrukciya po medicinskomu primeneniyu preparata Otesla. 2016]</mixed-citation></ref><ref id="B33"><label>33.</label><mixed-citation>33. Apremilast for treating moderate to severe plaque psoriasis. NICE Guideline, 2016:TA419.</mixed-citation></ref><ref id="B34"><label>34.</label><mixed-citation>34. Gossec J., Smolen J. S., Ramiro S. at al. Eurupean League Against Rheumatism (EULAR) recommendations for the management of psoriatic artritis with pharmacological therapies: 2015 update. Ann Rheum Dis. 2015:0;1–12.</mixed-citation></ref><ref id="B35"><label>35.</label><mixed-citation>35. Contes L., Kavanaugh A., Mease P. J. et al. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis 2015 Treatment Recommendations for Psoriatic Arthritis. Arthritis &amp; Rheumatology. 2016;Marth:1–12.</mixed-citation></ref><ref id="B36"><label>36.</label><mixed-citation>36. Apremilast for treating active psoriatic arthritis. NICE Guideline, 2017:TA433. 37. Псориаз. Проект клинических рекомендаций. М, 2016. http:// cr.rosminzdrav.ru/schema.html?id=866#/text</mixed-citation></ref></ref-list></back></article>
