One of the target drugs for plaque psoriasis treatment is apremilast, which is a selective phosphodiesterase 4 (PDE4) inhibitor. In this study, 34 moderate-to-severe and severe plaque psoriasis patients from Russia were treated with apremilast for 26 weeks. This allowed us to observe the effectiveness of splitting patient cohorts based on clinical outcomes, which were assessed using the Psoriasis Area Severity Index (PASI). In total, 14 patients (41%) indicated having an advanced outcome with delta PASI 75 after treatment; 20 patients indicated having moderate or no effects. Genome variability was investigated using the Illumina Infinium Global Screening Array. Genome-wide analysis revealed apremilast therapy clinical outcome associations at three compact genome regions with undefined functions situated on chromosomes 2, 4, and 5, as well as on a single single-nucleotide polymorphism (SNP) on chromosome 23. Pre-selected SNP sets were associated with psoriasis vulgaris analysis, which was used to identify four SNP-associated targeted therapy efficiencies: IL1β (rs1143633), IL4 (IL13) (rs20541), IL23R (rs2201841), and TNFα (rs1800629) genes. Moreover, we showed that the use of the global polygenic risk score allowed for the prediction of onset psoriasis in Russians. Therefore, these results can serve as a starting point for creating a predictive model of apremilast therapy response in the targeted therapy of patients with psoriasis vulgaris.

A new approach to the problem of significant youthification of arterial hypertension and its fast progression in non-indigenous populations of the polar and arctic regions has been presented. The hypertension progression in high latitudes is combined with influence of climate change biological stressful pace in the Arctic area and influence of adverse space, geophysical, weather, chronobiologi-cal factors. Research scientists of the Russian polar and arctic regions have identified a number of leading elements of the northern climatic-geographic chronic stress which make the main contribution to formation and progression of hypertension in the North. The most characteristic manifestations of climatic-geographic stress in uncomfortable and extreme regions of the North and Siberia are reactions of the central nervous and endocrine systems, metabolic changes and development of "oxidative stress". In addition to these manifestations the polisindromatic climatic stress may include: deficit of detoxification processes and barrier organs, northern metabolic type disorders, northern tissue hypoxia, immune deficiency, blood hypercoagulation, multiple endocrine disorders, regenerative and plastic failure, violation of electromagnetic homeostasis, functional dissymmetry of interhemispheric relations, desynchronosis, emotional stress, meteopathies. Obviously, creation of advanced innovative preventive and therapeutic technologies to reduce spread of hypertension among population in the polar and arctic regions require active study of the northern stress mechanisms' role in progression of this severe cardiovascular pathology.

Objective — Assessment of phosphodiesterase-4 inhibitor (apremilast) therapy’s influence on skin cytokine levels in patients with moderate-to-severe and severe psoriasis. Material and Methods — An open, uncontrolled study was conducted. 16 patients with plaque psoriasis (13 men, 3 women; mean ± standard deviation (SD) age 35.1±9.7 years, range 21-60) were enrolled. The mean Psoriasis Area and Severity Index (PASI) was 20.7±8.93 (range 10-47). All patients were prescribed apremilast 30 milligrams (mg) per os (PO) Bis In Die (BID). The efficacy of therapy was evaluated by PASI at 14 and 26 weeks of therapy. Lesional skin samples were collected at baseline and weeks 14 and 26. Levels of interleukin (IL)-1β, IL-4, IL-6, IL-10, IL-17A, IL-17F, IL-21, IL-22, IL-23, IL-25, IL-31, IL -33, interferon (INF)-γ, Soluble CD40-ligand (sCD40L), tumor necrosis factor (TNF)-α were measured by microsphere-based suspension array technology (Luminex® xMAP™ system). Results — Levels of cytokines (except IL-4 and IL-33) in lesional skin samples were found to have decreased at week 14 compared with those at baseline. Similar decreases were seen for IL-23, IL-25, IL-31, sCD40L at week 26. In contrast, the levels of other cytokines increased again at week 26, in comparison with baseline. Levels of IL-4 and IL-33 rose throughout the follow-up period. Cytokine levels in lesional skin samples were compared with those of healthy controls both at baseline and during therapy. Conclusion — The results of our study show that administering apremilast therapy to patients with psoriasis can bring the levels of cytokines involved in the IL-23/IL-17 axis in the lesional skin to the level of cytokine in non-lesional skin and to the levels in the skin of healthy individuals.

Background: Data on the possible combinations of apremilast with other types of psoriasis therapy is limited. Description of clinical cases: We present the data on the efficacy and safety of combination therapy of the selective phosphodiesterase 4 inhibitor and dihydrofolatereductase inhibitor (methotrexate) for the treatment of psoriasis and psoriatic arthritis in patients with moderate-to-severe plaque psoriasis and active psoriatic arthritis with lack of efficacy of methotrexate in the anamnesis. The selective phosphodiesterase 4 inhibitor (apremilast) was administered according to the prescription. The severity psoriatic arthritis of was estimated by PASI. The effectiveness of therapy was evaluated at week 14. Due to the lack of effect, methotrexate was added subcutaneously at week 14. The effectiveness of combination therapy was assessed at week 26. In both cases, the significant clinical improvement was reached (patients reached PASI 75 and PASI 90), a decrease of the psoriatic arthritis activity according to the DAS28 and DAPSA. Conclusion: These clinical cases demonstrate the efficacy and safety of combined therapy with methotrexate and apremilast inpatients with active psoriatic arthritis and moderate to severe plaque psoriasis.

Objective:to evaluate the efficacy and safety of a selective phosphodiesterase type 4 inhibitor in patients with psoriasis and psoriatic arthritis (PsA).Subjects and methods.An open uncontrolled study was conducted, which enrolled 20 patients (12 men, 8 women); their mean age was 39.2±14.3 years, the mean duration of psoriasis and PsA was 20.2±12.2 and 10.4±10.2 years, respectively. All the patients included in the study had previously received phototherapy, systemic drugs (methotrexate, aromatic retinoids) with an insufficient effect. Apremilast was administered according to the standard regimen: dose titration during the first 5 days, then 30-mg tablets twice daily for 26 weeks. The efficiency of the therapy was evaluated from changes in PASI, BSA, and sPGA and according to the American College of Rheumatology (ACR) criteria at 14 and 26 weeks and from those in DAS28 at 26 week.Results and discussion.There were 50 and 75% decreases in PASI respectively in 12 (60%) and 5 (25%) patients, at week 14 of therapy and in 14 (70%) and 7 (35%) patients at week 26. Fourteen (81.2%) patients achieved 20% ACR improvement at week 14. DAS28 decreased on an average by 1.8 at week 26. Adverse events (severe headache, tachycardia) were observed in two patients who were excluded from the study.Conclusion.Apremilast is an effective and safe agent for the treatment of psoriasis and PsA in patients who have received another systemic therapy proven to be ineffective or they tolerated the latter poorly.

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; p0.025). On the other hand, the relationships between pro-inflammatory cytokines IL-1 and IL-6 levels and PASI score at the 26th week of therapy were characterized by positive correlation: r=0.31 (p0.05) and r=0.37 (p0.025), 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.

Псориаз - хроническое воспалительное заболевание кожи мультифакториальной природы с доминирующим значением в развитии генетических факторов, характеризующееся ускоренной пролиферацией эпидермоцитов и нарушением их дифференцировки, дисбалансом между провоспалительными и противовоспалительными цитокинами. Накапливающиеся данные ассоциативных исследований предрасположенности к заболеванию обнаружили значительное количество однонуклеотидных полиморфизмов, расположенных в участках генома, связанных с функционированием иммунной системы. Систематический обзор вариабельности SNP в исследованиях предрасположенности к развитию псориаза позволил сформировать панель 84 SNP маркеров, потенциально значимых для возникновения псориаза и в развития заболевания. Исследование SNP проведено сочетанием высокопроизводительного генотипирования на микрочипах Illumina и компьютерного импьютинга. В подгруппах пациентов с различной эффективностью терапии селективным ингибитором клеточного фосфорилирования «апремиласт» обнаружены различия для трех SNP rs12307915, rs2227473 и rs744166, что открывает возможности прогнозирования эффективности терапии этим препаратом. Psoriasis is a chronic inflammation skin disease with complex genetic architecture that affects approximately 2% of the world population. The condition is characterized by abnormal keratinocyte hyperproliferation and differentiation related to a dysregulated immune system governed by a pro-inflammatory cytokine network. The accumulating data of psoriasis associative studies reveals significant number of SNPs located in genome sites related with immune system. A review of sources available allowed the selection of potentially significant for psoriasis occurrence and development SNP set, includes 84 markers. SNP determination has been carried out by a combination of high-performance genotyping on Illumina microchips and computer imputing. The differences in three SNPs rs12307915, rs2227473 and rs744166 were found in patient groups with different apremilast therapy outcome, paving the way to the development of predictive psoriasis therapy approaches.

Diffuse cutaneous leishmaniasis is a rare form of cutaneous leishmaniasis characterized by an inadequate immune response of the host cells to parasitic invasion (weak T-helper (Th)1 response or Th2 response with the production of interleukin (IL)-4 and IL-10). The characteristic features of the disease include diffuse nodular eruption, masquerading as leprosy and a frequent association with immunosuppression (HIV co-infection, for example). The Russian Federation is a non-endemic country for leishmaniasis, but this disease can be brought into the country by tourists, immigrants, refugees and military personnel. A clinical case of diffuse cutaneous leishmaniasis and HIV co-infection is presented. The patient was a citizen of Uzbekistan, a country endemic for leishmaniasis. The authors were unable to find domestic scientific publications describing cases of diffuse cutaneous leishmaniasis detected in the Russian Federation. The presented clinical case of diffuse cutaneous leishmaniasis in a patient with HIV is the first in the Russian literature.