Использование метотрексата в лечении псориаза и псориатического артрита

Objective: To analyze the results of using methotrexate (MT) in the treatment of psoriasis and psoriatic arthritis (PsA). Results. The mechanism of action of MT, the historical aspects of its use in the treatment of psoriasis and PsA, and the data of clinical trials of the efficacy and safety of the drug are considered. MT therapy is shown to cause a high rate of adverse reactions, which requires measures to prevent and treat adverse events. MT has been found to be frequently used in different combinations, including with other disease-modifying antirheumatic drugs (sulfasalazine), prednisolone, and biological agents, such as tumor necrosis factor inhibitors. In accordance with the European S3-guidelines S3 on the systemic treatment of psoriasis, MT (15-22.5 mg weekly) should be recommended from the results of randomized clinical trials and the extensive clinical experience with this drug. In terms of the present-day views, the indications for immunosuppressive therapy for PsA may be expanded it should be initiated in the early stage of the disease, particularly in its severe forms, until there are destructive changes in the osteoarticular apparatus. Conclusion. MT is an effective drug to treat psoriasis and PsA. It is recommended for use in moderate and severe peripheral arthritis (Grade B) and skin lesions (Grade A).Цель исследования — анализ результатов применения метотрексата (МТ) в лечении псориаза и псориатического артрита (ПсА). Результаты исследования. Рассмотрены механизм действия МТ, исторические аспекты применения препарата в лечении псориаза и ПсА, данные клинических исследований эффективности и безопасности препарата. Показана высокая частота побочных реакций при проведении терапии МТ, что требует выполнения мероприятий, направленных на профилактику и лечение нежелательных явлений. Установлено, что МТ часто используется в разных комбинациях, в том числе с другими базисными противовоспалительными препаратами (сульфасалазин), преднизолоном и биологическими препаратами, такими как ингибиторы фактора некроза опухоли. В соответствии с Европейскими рекомендациями S3 по системному лечению псориаза МТ (15—22,5 мг в неделю) следует рекомендовать исходя из результатов рандомизированных клинических исследований и обширного клинического опыта применения этого препарата. С учетом современных представлений показания к иммуносупрессивной терапии при ПсА могут быть расширены — ее следует начинать в ранней стадии заболевания, особенно при тяжелых формах, до появления деструктивных изменений в костно-суставном аппарате. Заключение. МТ является эффективным лекарственным средством для лечения псориаза и ПсА. Он рекомендован к применению при периферическом артрите средней и тяжелой степени (степень доказательности В) и поражениях кожи (степень доказательности А)

THE EFFECT OF AN ANTI-TUMOR NECROSIS FACTOR-? AGENT ON DISEASE ACTIVITY,BLOOD RHEOLOGICAL PROPERTIES, AND THE ARTERIAL WALL IN PSORIATIC ARTHRITIS

Vascular dysfunction and inflammation in psoriatic arthritis (PsA) share the same pathogenetic mechanism wherein the proinflammatory cytokine tumor necrosis factor- (TNF-) plays a key role. Treatment with anti-TNF- agents is effective in inhibiting inflammation in PsA; however, their effect on the wall of large arteries has not been studied. Objective. To evaluate the effect of Adalimumab (ADA) on the arterial wall and blood rheological properties in PsA. Subjects and methods. Eighteen patients with PsA [12 women and 6 men; mean age 43.1±10.2 years; disease activity scores (DAS), 4.78 (4.0; 5.45)] were subcutaneously injected ADA, 40 mg/every two weeks, for 12 weeks. The investigators assessed the vascular wall, by measuring the mean and maximum common carotid intima-media thickness (IMT) by ultrasound duplex scanning, and arterial rigidity (AR), by determining the refraction index (RI,%) and the rigidity index by digital volume photoplethysmography and Doppler study measuring the aortic pulse wave velocity (PWV) in the carotid-femoral segment (Micromedical, UK), before and after treatment. Erythrocyte aggregation (EA) parameters [Т1 (sec), Kt (c.u.); (sec-1), I2,5 (%)] were measured recording the rate of inverse light scattering and the levels of blood lipids [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG)], and atherogenicity coefficient (AC) by routine methods on an automated Express plus analyzer (Bayer, Germany) at baseline, 4, and 12 weeks. The median and the interquartile range [Me (Q25; Q75)] were calculated; the changes in the parameters were estimated by the Wilcoxon test (Wt) and the Friedman test (Ft) for dependent samples;

Cytokine profile in psoriatic arthritis: search for relationships with inflammation and blood rheological properties

Objective. To estimate the serum levels of interleukins (IL) 6 and 10, tumor necrosis factor-α (TNF-α) and vascular endothelial growth factor (VEGF) in patients with psoriatic arthritis (PSA) and their relationship with the clinical and laboratory parameters of inflammation and with erythrocyte aggregation (EA). Material and methods. The authors measured the serum levels of C-reactive protein (CRP) by immunonephelometry (BN, ProSPEC, Siemens) and those of TNF-α, IL-6 and IL-10, and VEGF by X-MAP technology using a BioPlex-200 system (Panel Human 27-Plex Bio-Rad, USA) in 80 patients with PSA [45 women and 35 men; mean age 41.7±10.5 years, mean duration of PSA and psoriasis was 5.0 (2.0; 12,5) and 15 (4; 26) years, respectively; DAS 3.9 (3.09; 5.16)]. The blood samples from 16 healthy donors matched to the examinees for gender and age served as a control. The parameters of EA [Т1(с); Кt (arb. units); β (с-1), I2,5 (%)] were estimated, by recording the rate of back light scattering. The median (Me) and interquartile range [Q25; Q75], and mean and standard deviations (M±σ) were calculated; the indicators were compared by the Mann-Whitney test and Student's t test. Correlation analysis was made using the Spearman rank correlation coefficient (R); p < 0.05 was considered statistically significant. Results. There were significantly higher serum levels of IL-6 and IL-10, TNF-α, and VEGF in patients with PSA than in the controls, and impaired blood rheological properties. There were significant correlations of the level of most cytokines (IL-6 and IL-10, VEGF) with both the values of the clinical and laboratory activity of PSA (self-rated pain, the number of swollen and tender joints, a physician's assessment of disease activity, DAS, erythrocyte sedimentation rate, and fibrinogen) and most parameters of EA (Т1, Kt и I2.5). No significant relationships were found between VEGF and CRP. Conclusion. The enhanced clinical and laboratory activity of PSA is attended by the systemic activation of immunological mediators of inflammation and neoangiogenesis and by impaired blood rheological properties, which supports the interaction of these factors in the immunopathogenesis of the diseases

Secukinumab shows sustained efficacy and low structural progression in ankylosing spondylitis: 4-year results from the MEASURE 1 study.

Objectives:To evaluate the effect of secukinumab, a fully human anti-interleukin-17A monoclonal antibody, on efficacy, imaging outcomes, and safety through 4 years (208 weeks) in patients with ankylosing spondylitis. Methods:Patients opting to enrol had completed 2 years' treatment in the MEASURE 1 core study with subcutaneous secukinumab 150 or 75 mg every 4 weeks (q4Wk), following intravenous loading to Week (Wk) 4, or placebo treatment to Wk16/24. Up-titration from secukinumab 75-150 mg q4Wk was permitted following a protocol amendment. Efficacy is reported for patients originally randomized to secukinumab. Radiographic changes were assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and changes in MRI measures of inflammation using the Berlin scoring method. Safety and tolerability were evaluated. Results:Among 274 extension study participants, 89.7% (78/87) and 93.0% (93/100) originally randomized to secukinumab 150 and 75 mg, respectively, completed 208Wk. Through Wk208, Assessment of Spondyloarthritis International Society 20/40 (observed) were 79.7%/60.8% (150 mg), 71.0%/43.5% (75 mg) and 80.0%/76% (up-titrators; n = 25). Mean (s.d.) changes in mSASSS were 1.2 (3.91) (150 mg), 1.8 (4.32) (75 mg) and 1.6 (5.67) (up-titrators). No radiographic progression (mSASSS change from Baseline < 2) was observed in 79% of patients receiving either secukinumab dose. Exposure-adjusted incidence rates per 100 patient-years were: serious infections (1.0), Candida infections (0.4), Crohn's disease (0.6), ulcerative colitis (0.2), and malignant/unspecified tumours (0.5), with no new safety signals. Conclusion:Through 4 years, secukinumab provided sustained efficacy on signs and symptoms, and MRI outcomes, a low rate of radiographic progression and a consistent safety profile. Trial registration:NCT01863732

Long-term effectiveness and persistence of ustekinumab and TNF inhibitors in patients with psoriatic arthritis: final 3-year results from the PsABio real-world study

Objectives: To evaluate real-world persistence and effectiveness of the IL-12/23 inhibitor, ustekinumab or a tumour necrosis factor inhibitor (TNFi) for psoriatic arthritis over 3 years. Methods: PsABio (NCT02627768), a prospective, observational study, followed patients with PsA prescribed first-line to third-line ustekinumab or a TNFi. Persistence and effectiveness (achievement of clinical Disease Activity for PSA (cDAPSA) low disease activity (LDA)/remission and minimal disease activity/very LDA (MDA/VLDA)) were assessed every 6 months. Safety data were collected over 3 years. Analyses to compare the modes of action were adjusted on baseline differences by propensity scores (PS). Results: In 895 patients (mean age 49.8 years, 44.7% males), at 3 years, the proportion of patients still on their initial treatments was similar with ustekinumab (49.9%) and TNFi (47.8%). No difference was seen in the risk of stopping/switching; PS-adjusted hazard ratio (95% CI) for stopping/switching ustekinumab versus TNFi was 0.87 (0.68 to 1.11). In the overall population, cDAPSA LDA/remission was achieved in 58.6%/31.4% ustekinumab-treated and 69.8%/45.0% TNFi-treated patients; PS-adjusted ORs (95% CI) were 0.89 (0.63 to 1.26) for cDAPSA LDA; 0.72 (0.50 to 1.05) for remission. MDA/VLDA was achieved in 41.4%/19.2% of ustekinumab-treated and 54.2%/26.9% of TNFi-treated patients with overlapping PS-adjusted ORs. A greater percentage of TNFi-treated patients achieved effectiveness outcomes. Both treatments exhibited good long-term safety profiles, although ustekinumab-treated patients had a lower rate of adverse events (AEs) versus TNFi. Conclusion: At 3 years, there was generally comparable persistence after ustekinumab or TNFi treatment, but AE rates were lower with ustekinumab

Management of Peripheral Arthritis in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE We aimed to compile evidence for the efficacy and safety of therapeutic options for the peripheral arthritis domain of psoriatic arthritis (PsA) for the revised 2021 Group in Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations. METHODS A working group consisting of clinicians and patient research partners was convened. We reviewed the evidence from new randomized controlled trials (RCTs) for PsA treatment from February 19, 2013, to August 28, 2020. We used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE)-informed approach to derive evidence for the classes of therapeutic options for 3 patient groups: (1) naïve to treatment, (2) inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and (3) inadequate response to biologic DMARDs (bDMARDs). Recommendations were derived through consensus meetings. RESULTS The evidence review included 69 RCTs. We derived GRADE evidence for each class of therapeutic options and achieved consensus for the recommendations. For patients naïve to treatment, the working group strongly recommends csDMARDs (methotrexate, sulfasalazine, leflunomide) and phosphodiesterase 4 inhibitors, and emphasizes regular assessment and early escalation to achieve treatment target. bDMARDs (tumor necrosis factor inhibitors [TNFi], interleukin 17 inhibitors [IL-17i], IL-12/23i, IL-23i) and Janus kinase inhibitors (JAKi) are also strongly recommended. For patients with inadequate response to csDMARDs, we strongly recommend TNFi, IL-17i, IL-12/23i, IL-23i, and JAKi. For those who had prior experience with bDMARDs, we strongly recommend a second TNFi, IL-17i, IL-23i, and JAKi. The evidence supporting nonpharmacological interventions was very low. An expert panel conditionally recommends adequate physical activity, smoking cessation, and diet to control weight gain. CONCLUSION Evidence supporting optimal therapy for the peripheral arthritis domain of PsA was compiled for the revised 2021 GRAPPA treatment recommendations

Golimumab in the treatment of psoriatic arthritis: efficacy and safety

Tumor necrosis factor-α (TNF-α) holds a central position in the pathogenesis of autoimmune inflammatory diseases of the locomotor apparatus. A separate class of drugs, namely, TNF-α inhibitors, that are effective against multicomponent diseases, such as psoriatic arthritis (PsA), is now available to physicians. The paper reviews the results of clinical trials of the TNF-α inhibitor golimumab, a human TNF-α monoclonal antibody. Golimumab exerts a positive effect on all manifestations of PsA: arthritis, psoriatic skin and nail lesions, dactylitis, enthesitis, and quality of life. The drug is noted for its convenient route of administration – its standard dose is 50 mg injected subcutaneously once a month and for its low molecular immunogenicity. Recent data suggest that golimumab is an effective drug with a safety profile similar to that of the entire class of TNF-α inhibitors

Use of methotrexate in the treatment of psoriasis and psoriatic arthritis

Objective: To analyze the results of using methotrexate (MT) in the treatment of psoriasis and psoriatic arthritis (PsA). Results. The mechanism of action of MT, the historical aspects of its use in the treatment of psoriasis and PsA, and the data of clinical trials of the efficacy and safety of the drug are considered. MT therapy is shown to cause a high rate of adverse reactions, which requires measures to prevent and treat adverse events. MT has been found to be frequently used in different combinations, including with other disease-modifying antirheumatic drugs (sulfasalazine), prednisolone, and biological agents, such as tumor necrosis factor inhibitors. In accordance with the European S3-guidelines S3 on the systemic treatment of psoriasis, MT (15-22.5 mg weekly) should be recommended from the results of randomized clinical trials and the extensive clinical experience with this drug. In terms of the present-day views, the indications for immunosuppressive therapy for PsA may be expanded it should be initiated in the early stage of the disease, particularly in its severe forms, until there are destructive changes in the osteoarticular apparatus. Conclusion. MT is an effective drug to treat psoriasis and PsA. It is recommended for use in moderate and severe peripheral arthritis (Grade B) and skin lesions (Grade A)

Effect of the Pitot Tube on Measurements in Supersonic Axisymmetric Underexpanded Microjets

This paper describes the results of methodical investigations of the effect of the Pitot tube on measurements of gas-dynamic parameters of supersonic axisymmetric underexpanded real and model microjets. Particular attention is paid to distortions of Pitot pressure variations on the jet axis associated with the wave structure of the jet and to distortions of the supersonic core length. In experiments with model jets escaping from nozzles with diameters ranging from 0.52 to 1.06 mm into the low-pressure chamber, the measurements are performed by the Pitot tubes 0.05 to 2 mm in diameter. The results are analyzed together with the earlier obtained data for real microjets escaping from nozzles with diameters ranging from 10 to 340 &#181;m where the parameters of real microjets were determined by the Pitot microtube 12 &#181;m in diameter. Interaction of the Pitot tube with an unsteady jet in the laminar-turbulent transition region is investigated; the influence of this interaction on Pitot pressure measurements is determined, and a physical interpretation of this phenomenon is provided