Cytokine Levels of Skin Lesions in Moderate and Severe Psoriasis as Predictors for the Type 4 Fosphodiesterase Inhibitor (Apremilast) Therapy Effectivness

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Background. Psoriasis is a widespread skin disorder characterized by cytokines as the main modulators of skin inflammation. A promising psoriasis therapy approach is targeted on cytokine networks by inhibiting the phosphodiesterase 4 (PDE-4). The efficacy and safety of the PDE-4 inhibitor apremilast in psoriasis confirmed in multicenter controlled studies, which, however, are accompanied by reports of unsuccessful therapy cases. Aims — to determine early immunological predictors for PDE-4 inhibitor (apremilast) therapy efficacy based on skin lesions cytokines analyzes in patients with moderate to severe psoriasis. Methods. An open, uncontrolled prospective clinical study was performed. Efficacy of apremilast was analyzed by PASI, BSA, sPGA and DLQI. The outcomes at 26 therapy week were compared with the cytokine levels in skin biopsies selected before starting therapy and analyzed using xMAP technology. The multiparameter prognostic model for apremilast therapy effectiveness was developed based on a heterogeneous sequential recognition procedure. Results. The 34 patients with moderate to severe psoriasis were included in the study. According to the clinical outcomes, two comparison groups were formed: high (75% reduction in PASI score or more; n = 14) and insufficient (50% reduction in PASI score or less; n = 20) apremilast efficiency. Cytokines analyses showed an inverse relationship between the initial anti-inflammatory IL-10 level and the PASI reduction (r = –0.37; p < 0.025). On the other hand, the relationships between pro-inflammatory cytokines IL-1β and IL-6 levels and PASI score at the 26th week of therapy were characterized by positive correlation: r = 0.31 (p < 0.05) and r = 0.37 (p < 0.025), respectively. Based on the data obtained, a predictive model for the apremilast therapy efficiency was developed. The expected predictive values of this model were 86% for a high therapy effectiveness and 60% for an insufficient effectiveness, respectively. Conclusions. The study results for the first time describe the cytokine profiles in the skin lesions in patients, who responded differently to PDE-4 inhibitor therapy. These dada allows to predict the treatment efficacy and give a chance to personalize apremilast usage for the moderate and severe psoriasis treatment.

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About the authors

Alexey A. Kubanov

State Research Centre of Dermatovenerology and Cosmetology

ORCID iD: 0000-0002-7625-0503
SPIN-code: 8771-4990

MD, PhD, Professor, Corresponding Member of the RAS 

Russian Federation, Moscow

Olga G. Artamonova

State Research Centre of Dermatovenerology and Cosmetology

Author for correspondence.
ORCID iD: 0000-0003-3778-4745
SPIN-code: 3308-3330
Russian Federation, Moscow

Arfenya E. Karamova

State Research Centre of Dermatovenerology and Cosmetology

ORCID iD: 0000-0003-3805-8489
SPIN-code: 3604-6491


Russian Federation, Moscow

Elena L. Vasileva

State Research Centre of Dermatovenerology and Cosmetology

ORCID iD: 0000-0002-3580-8398
SPIN-code: 9694-2253
Russian Federation, Moscow

Dmitry G. Deryabin

State Research Centre of Dermatovenerology and Cosmetology

ORCID iD: 0000-0002-2495-6694
SPIN-code: 8243-2537

MD, PhD, Professor

Russian Federation, Moscow


  1. Parisi R, Symmons DP, Griffiths CE, Ashcroft DM. Global epidemiology of psoriasis: a systematic review of incidence and prevalence. J Invest Dermatol. 2013;133(2):377–385. doi:
  2. Александрова Г.А., Мелехина Л.Е., Богданова Е.В., и др. Ресурсы и деятельность медицинских организаций дерматовенерологического профиля. Заболеваемость инфекциями, передаваемыми половым путем, заразными кожными болезнями и заболеваниями кожи за 2017–2018 гг. (cтатистические материалы). — М.: Департамент мониторинга, анализа и стратегического развития здравоохранения Минздрава России; ФГБУ «Центральный научно-исследовательский институт организации и информатизации здравоохранения» Минздрава России; ФГБУ «Государственный научный центр дерматовенерологии и косметологии» Минздрава России, 2019. [Aleksandrova GA, Melekhina LE, Bogdanova EV, et al. Resursi i deyatelnost’ medetsinskih organizatsii dermatovenerologicheskogo profilya. Zabolevaemost infektsiyami, peredavaemymi polovim putem, zaraznimi koznimi boleznyami i zabolevaniyami kozi za 2018–2018 gg. (statisticheskie materiali). Moscow: Departament monitoring, analiza i strategicheskogo razvitiya zdravoohraneniya Minzdrava Rossii; FGBU “Centralniy nauchno-issledovatelskiy institut organizacii I informatizacii zdravoohraneniya” Minzdrava Rossii; FGBU “Gosudarstvenniy nauchniy centr dermatovenerologii I kosmetologii” Minzdrava Rossii; 2019. (In Russ.)]
  3. Chiricozzi A, Romanelli P, Volpe E, et al. Scanning the immunopathogenesis of psoriasis. Int J Mol Sci. 2018;19(1):179. doi:
  4. Sbidian E, Chaimani A, Garcia-Doval I, et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev. 2017;12:CD011535. doi:
  5. Li H, Zuo J, Tang W. Phosphodiesterase-4 Inhibitors for the Treatment of Inflammatory Diseases. Front Pharmacol. 2018;9:1048. doi: 10.3389/fphar.2018.01048
  6. Pincelli C, Schafer PH, French LE, et al. Mechanisms Underlying the Clinical Effects of Apremilast for Psoriasis. J Drugs Dermatol. 2018;17(8):835–840.
  7. Keating GM. Apremilast: a review in psoriasis and psoriatic arthritis. Drugs. 2017;77(4):459–472. doi:
  8. Псориаз: клинические рекомендации / РОДВК. — М., 2016. [Psoriaz: Klinicheskie rekomendacii / RODVK. Moscow; 2016. (In Russ.)] Available from:
  9. Schafer PH, Truzzi F, Parton A, et al. Phosphodiesterase 4 in inflammatory diseases: effects of apremilast in psoriatic blood and in dermal myofibroblasts through the PDE4/CD271 complex. Cell Signal. 2016;28(7):753–763. doi:
  10. Schafer PH, Parton A, Capone L, et al. Apremilast is a selective PDE4 inhibitor with regulatory effects on innate immunity. Cell Signal. 2014;26(9):2016–2029. doi:
  11. Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83(12):1583–1590. doi:
  12. Papp K, Reich K, Leonardi CL, et al. Apremilast, an oral phosphodiesterase 4 (PDE4) inhibitor, in patients with moderate to severe plaque psoriasis: results of a phase III, randomized, controlled trial (Efficacy and Safety Trial Evaluating the Effects of Apremilast in Psoriasis [ESTEEM] 1). J Am Acad Dermatol. 2015;73(1):37–49. doi:
  13. Crowley J, Thaçi D, Joly P, et al. Long-term safety and tolerability of apremilast in patients with psoriasis: Pooled safety analysis for ≥ 156 weeks from 2 phase 3, randomized, controlled trials (ESTEEM 1 and 2). J Am Acad Dermatol. 2017;77(2):310–317. doi:
  14. Vujic I, Herman R, Sanlorenzo M, et al. Apremilast in psoriasis–a prospective real‐world study. J Eur Acad Dermatol Venereol. 2018;32(2):254–259. doi:
  15. Ighani A, Georgakopoulos JR, Shear NH, et al. Maintenance of therapeutic response after 1 year of apremilast combination therapy compared with monotherapy for the treatment of plaque psoriasis: A multicenter, retrospective study. J Am Acad Dermatol. 2018;79(5):953–956. doi:
  16. Кубанов А.А., Карамова А.Э., Артамонова О.Г. Возможности комбинированной терапии селективным ингибитором фосфодиэстеразы 4 (апремиласт) и ингибитором дигидрофолатредуктазы (метотрексат) у больных псориазом среднетяжелой и тяжелой степени тяжести и псориатическим артритом // Вестник РАМН. — 2019. — Т. 74. — № 5. — С. 292–298. [Kubanov AA, Artamonova OG, Karamova AE. Possibility of combined therapy with an oral phosphodiesterase-4 inhibitor (apremilast) and dihydrofolatereductase inhibitor (methotrexate) in patients with psoriatic arthritis plaque psoriasis. Annals of the Russian Academy of Medical Sciences. 2019:74(5):292–298. (In Russ.)] doi:
  17. Куликов А.Ю., Макарова Е.И. Оценка клинико-экономической эффективности применения лекарственного средства апремиласт в лечении псориатического артрита // Фармакоэкономика: теория и практика. — 2017. — Т. 5 — № 2. — С. 29–34. [Kulikov AY, Makarova EI. Assessment of clinical and economic effectiveness of apremilast in the treatment of psoriatic arthritis. Pharmacoeconomics: Theory and Practice. 2017;5(2):29–34. (In Russ.)]
  18. Medvedeva IV, Stokes ME, Eisinger D, et al. Large-scale Analyses of Disease Biomarkers and Apremilast Pharmacodynamic Effects. Sci Rep. 2020;10(1):605. doi:
  19. Garcet S, Nograles K, Correa da Rosa J, et al. Synergistic cytokine effects as apremilast response predictors in patients with psoriasis. J Allergy Clin Immunol. 2018;142(3):1010–1013. doi:
  20. Гублер Е.В., Генкин А.А. Применение непараметрических критериев статистики в медико-биологических исследованиях. — Ленинград: Медицина, 1973. [Gubler EV, Genkin AA. Primenenie neparametricheskih kriteriev statistiki v mediko-biologicheskih issledovanijah. Leningrad: Medicina; 1973. (In Russ.)]
  21. ГОСТ Р 53022.3-2008. Требования к качеству клинических лабораторных исследований. — Ч. 3. — М., 2010. [GOST R 53022.3-2008. Trebovanija k kachestvu klinicheskih laboratornyh issledovanij. Chast’ 3. Moscow; 2010. (In Russ.)]
  22. Paul C, Cather J, Gooderham M, Poulin Y., et al. Efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with moderate-to-severe plaque psoriasis over 52 weeks: a phase III, randomized controlled trial (ESTEEM 2). Br J Dermatol. 2015:173(6):1387–1399. doi:
  23. Shah BJ, Mistry D, Chaudhary N, Shah S. Real-world efficacy and safety of apremilast monotherapy in the management of moderate-to-severe Psoriasis. Indian Dermatol Online J. 2020:11(1):51–57. doi:
  24. Augustin M, Kleyn CE, Conrad C, Sator PG, et al. Characteristics and Outcomes of Patients Treated with Apremilast in the Real World: Results from the APPRECIATE Study. J Eur Acad Dermatol Venereol. 2020. doi:
  25. Tucker R. Interleukins in moderate to severe psoriasis. Hospital Pharmacy Europe. 2020. [Published on 9 January 2020.] Available from:https: //
  26. Chan TC, Hawkes JE, Krueger JG. Interleukin 23 in the skin: role in psoriasis pathogenesis and selective interleukin 23 blockade as treatment. Ther Adv Chronic Dis. 2018;9(5):111–119. doi:
  27. Kim HJ, Kim SH, Park J, et al. Up-regulation of receptor antagonist interleukin-1 family members in psoriasis and their regulation by pro-inflammatory cytokines. J Dermatol Sci. 2016;82(3):204–206. doi:
  28. Al-Robaee AA, Al-Zolibani AA, Al-Shobili HA, et al. IL-10 implication in psoriasis. Int J Health Sci (Qassim). 2008;2(1):53–58.
  29. Pușcaș AD, Cătană A, Pușcaș C, et al. Psoriasis: Association of interleukin-17 gene polymorphisms with severity and response to treatment (Review). Exp Ther Med. 2019;18(2):875–880. doi:
  30. Galluzzo M., D’Adamio S., Campione E., et al. Treating a Multidrug-Resistant Psoriatic HLA-C*18:01 Allele Carrier with Combination Ustekinumab Apremilast Therapy. Mol Diagn Ther. 2018;22(6):717–721. doi:

Supplementary files

Supplementary Files
1. Figure: 1. Design of a study aimed at finding early immunological predictors of the effectiveness of therapy with a PDE-4 inhibitor (apremilast)

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2. Figure: 2. Clinical efficacy of targeted therapy for moderate and severe psoriasis using a phosphodiesterase 4 inhibitor (apremilast): on the abscissa - weeks from the start of therapy; ordinate - the proportion of patients (%) with a change in PASI of 90% (PASI90), 75% (PASI75), 50% (PASI50) or less than 50% (<PASI50) of the initial value of this clinical index

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