Очень ранний клинический ответ при лечении ингибитором янус-киназ тофацитинибом у больных активным ревматоидным артритом: динамика боли и элементов центральной сенситизации

Janus kinase (JK) inhibitors block the intracellular signaling pathways that are responsible for the synthesis of proinflammatory cytokines and mediators, which in turn cause the activation of pain receptors and central sensitization (CS). It is suggested that JK inhibitors can rapidly eliminate pain and reduce the severity of CS.Objective: to evaluate the effect of the JK inhibitor tofacitinib (TOFA) on the intensity of pain and the signs of CS in patients with active rheumatoid arthritis (RA) at 7 and 28 days after therapy initiation.Patients and methods. A study group consisted of 39 patients (79.5% female) (mean age 50.9±11.1 years) with RA (DAS28 5.8±0.6). Of these, 89.7% were seropositive for rheumatoid factor; 82.0% took methotrexate and 18.0% received leflunomide. All the patients were prescribed TOFA 5 mg twice daily due to the inefficacy or intolerance of biological agents. The investigators estimated pain intensity using a Brief Pain Inventory (BPI), rated the presence of a neuropathic pain component (NPC) with the PainDETECT questionnaire, and assessed the signs of CS with the Central Sensitization Inventory (CSI) during the first 4 weeks after TOFA administration.Results and discussion. The patients initially experienced moderate or severe pain (the mean scores of 5.33±2.51 on the numerical rating scale (NRS) included in BPI); 53.8% had signs of CS (CSI scores of ≥40); 17.9% had signs of a NPC (PainDETECT scores of >18). Already on day 7 after the start of TOFA administration, there was a statistically significant decrease in the mean NRS pain intensity scores to 4.06±2.2 (p=0.01) and by 29.4±17.9%, as shown by the patient's assessment of the analgesic effect of therapy (BPI), as well as the severity of CS, namely a decrease in the mean NRS pain score to 35.9±11.2 (p=0.01). On 28 days, the effect became better: there was a reduction in the level of NRS pain to 2.32±1.57 (p<0.001), in pain according to the patient's assessment of the analgesic effect of therapy to 43.6±29.6%; in the median PainDETECT score to 2.5 [0; 8.7] (p<0.001); and in CSI scores to an average of 26.4±13.9 (p <0.001). No serious adverse reactions were noted.TOFA has a rapid analgesic effect, which allows it to be considered as a chooser for pathogenetic therapy in patients with active RA and severe pain, especially in the presence of CS signs and secondary fibromyalgia. Undoubtedly, large-scale, long-term controlled studies with a wider range of estimated parameters are required to clarify the therapeutic potential of TOFA in this patient category. The limitation of this investigation was its open observer design pattern.Conclusion. The use of the JK inhibitor TOFA can achieve a rapid analgesic effect, inter alia due to its effect on CS and NPC.Ингибиторы янус-киназ (ЯК) блокируют внутриклеточные сигнальные пути, отвечающие за синтез провоспалительных цитокинов и медиаторов, которые, в свою очередь, вызывают активацию болевых рецепторов и развитие центральной сенситизации (ЦС). Предполагается, что ингибиторы ЯК могут быстро устранять боль и уменьшать выраженность ЦС.Цель исследования – оценить влияние ингибитора ЯК тофацитиниба (ТОФА) на выраженность боли и признаки ЦС у больных активным ревматоидным артритом (РА) через 7 и 28 дней после начала терапии.Пациенты и методы. Исследуемую группу составили 39 больных РА (средний возраст 50,9±11,1 года, 79,5% женщин), DAS28 – 5,8±0,6. Из них 89,7% были серопозитивными по ревматоидному фактору, 82,0% получали метотрексат и 18,0% – лефлуномид. Всем пациентам был назначен ТОФА 5 мг 2 раза в день в связи с неэффективностью или непереносимостью генно-инженерных биологических препаратов. Оценивались выраженность боли с помощью опросника BPI (Brief Pain Inventory), наличие невропатического компонента боли (НКБ) с помощью опросника PainDETECT и признаков ЦС с помощью опросника CSI (Central Sensitization Inventory) в первые 4 нед после назначения ТОФА.Результаты и обсуждение. Пациенты исходно испытывали умеренную или выраженную боль (в среднем 5,33±2,51 по числовой рейтинговой шкале – ЧРШ, включенной в BPI), 53,8% имели признаки ЦС (CSI ≥40), 17,9% – признаки НКБ (PainDETECT >18). Уже через 7 дней после начала приема ТОФА отмечалось статистически значимое снижение интенсивности боли в среднем до 4,06±2,2 по ЧРШ (р=0,01) и на 29,4±17,9% по оценке анальгетического эффекта терапии пациентом (BPI), а также выраженности ЦС – уменьшение значения CSI в среднем до 35,9±11,2 (р=0,01). Через 28 дней эффект усилился: наблюдалось снижение уровня боли по ЧРШ до 2,32±1,57 (р<0,001), боли по оценке анальгетического эффекта терапии пациентом до 43,6±29,6%, медианы значения PainDETECT до 2,5 [0; 8,7] (р<0,001), показателя CSI в среднем до 26,4±13,9 (р<0,001). Серьезных неблагоприятных реакций не отмечено. ТОФА обладает быстрым анальгетическим эффектом, что позволяет рассматривать его как средство выбора при проведении патогенетической терапии у больных активным РА с выраженной болью, особенно при наличии признаков ЦС и вторичной фибромиалгии. Несомненно, требуются большие по масштабу длительные контролируемые исследования с более широким кругом оцениваемых параметров для уточнения лечебного потенциала ТОФА у этой категории пациентов. Ограничением настоящего исследования явился его открытый наблюдательный характер.Заключение. Использование ингибитора ЯК ТОФА позволяет достичь быстрого анальгетического эффекта, в том числе за счет влияния на ЦС и НКБ

ANALYSIS OF THE RESULTS OF TOFACITINIB THERAPY IN REAL CLINICAL PRACTICE ACCORDING TO THE ALL-RUSSIAN ARTHRITIS REGISTRY (OREL)

Objective: to analyze the results of tofacitinib (TOFA) therapy in real clinical practice according to the All-Russian Arthritis Registry (OREL). Subjects and methods. The OREL Registry included 347 patients (286 (82%) women and 61 (18%) men) with rheumatoid arthritis (RA) who initiated TOFA therapy. The male:female ratio was 1:4.7. The patients’ median age at onset of the disease was 42 years; its duration was 8 years. Most of the patients included in the registry had extended- (n=171 (52%)) or late- (n=148 (45%)) stage of RA. Results and discussion. Prior to initiation of TOFA therapy, RA activity according to DAS28 was high and moderate in 91 (64.5%) and 40 (28.4%) patients, respectively; the median DAS28 value was 5.5 [4.6; 6.2]; SDAI – 30.5 [21.4; 42.9], and CDAI – 28.2 [20.0; 37.1]. The use of TOFA was accompanied by significant decrease of disease activity. After 12 weeks, high RA activity was persistent in 32 (22.7%) patients; the number of patients with moderate activity increased to 77 (54.6%), that of those with low activity rose to 15 (10.6%); remission was observed in 17 (12.1%) patients. 216 (62.6%) and 76 (22%) patients received TOFA as first- and second-line therapy, respectively. TOFA was most frequently prescribed when tumor necrosis factor-á inhibitors (19.6%), rituximab (7.8%), tocilizumab (4.3%), and abatacept (5.2%) were insufficiently effective or poorly tolerated. Conclusion. The results of using TOFA in real clinical practice may suggest that the drug has high efficacy in patients with RA. TOFA can be used at a dose of 5 or 10 mg twice daily as both alone and in combination with disease-modifying anti-rheumatic drugs. TOFA showed similar efficacy in patients who had earlier taken biological agents and in those who had not

A very early clinical response to treatment with the Janus kinase inhibitor tofacitinib in patients with active rheumatoid arthritis: the dynamics of pain and central sensitization elements

Janus kinase (JK) inhibitors block the intracellular signaling pathways that are responsible for the synthesis of proinflammatory cytokines and mediators, which in turn cause the activation of pain receptors and central sensitization (CS). It is suggested that JK inhibitors can rapidly eliminate pain and reduce the severity of CS.Objective: to evaluate the effect of the JK inhibitor tofacitinib (TOFA) on the intensity of pain and the signs of CS in patients with active rheumatoid arthritis (RA) at 7 and 28 days after therapy initiation.Patients and methods. A study group consisted of 39 patients (79.5% female) (mean age 50.9±11.1 years) with RA (DAS28 5.8±0.6). Of these, 89.7% were seropositive for rheumatoid factor; 82.0% took methotrexate and 18.0% received leflunomide. All the patients were prescribed TOFA 5 mg twice daily due to the inefficacy or intolerance of biological agents. The investigators estimated pain intensity using a Brief Pain Inventory (BPI), rated the presence of a neuropathic pain component (NPC) with the PainDETECT questionnaire, and assessed the signs of CS with the Central Sensitization Inventory (CSI) during the first 4 weeks after TOFA administration.Results and discussion. The patients initially experienced moderate or severe pain (the mean scores of 5.33±2.51 on the numerical rating scale (NRS) included in BPI); 53.8% had signs of CS (CSI scores of ≥40); 17.9% had signs of a NPC (PainDETECT scores of >18). Already on day 7 after the start of TOFA administration, there was a statistically significant decrease in the mean NRS pain intensity scores to 4.06±2.2 (p=0.01) and by 29.4±17.9%, as shown by the patient's assessment of the analgesic effect of therapy (BPI), as well as the severity of CS, namely a decrease in the mean NRS pain score to 35.9±11.2 (p=0.01). On 28 days, the effect became better: there was a reduction in the level of NRS pain to 2.32±1.57 (p<0.001), in pain according to the patient's assessment of the analgesic effect of therapy to 43.6±29.6%; in the median PainDETECT score to 2.5 [0; 8.7] (p<0.001); and in CSI scores to an average of 26.4±13.9 (p <0.001). No serious adverse reactions were noted.TOFA has a rapid analgesic effect, which allows it to be considered as a chooser for pathogenetic therapy in patients with active RA and severe pain, especially in the presence of CS signs and secondary fibromyalgia. Undoubtedly, large-scale, long-term controlled studies with a wider range of estimated parameters are required to clarify the therapeutic potential of TOFA in this patient category. The limitation of this investigation was its open observer design pattern.Conclusion. The use of the JK inhibitor TOFA can achieve a rapid analgesic effect, inter alia due to its effect on CS and NPC

RHEUMATOID ARTHRITIS IN THE RUSSIAN FEDERATION ACCORDING TO RUSSIAN ARTHRITIS REGISTRY DATA (COMMUNICATION I)

The paper presents the materials of the Russian Arthritis Registry (OREL) that includes 3276 patients from 11 Russian Federation's largest research-and-practical centers situated in Moscow, Saint Petersburg, Novosibirsk, Kazan, Tula, Yaroslavl, Tyumen. It discusses the main goals of setting up registries, compares the results of an analysis of the data available in the Russian Registry OREL and registries of European countries and the USA. The findings suggest that there is non-uniform information on clinical, laboratory, and instrumental parameters in the national registers of a number of European countries and the USA. According to its basic characteristics, the Russian Registry OREL compares favorably with a number of other registries in the completeness of data collection, which allows a general idea of rheumatoidarthritis (RA) patients in Russia. For further development of the OREL Registry, it is necessary to concentrate our attention on the following main areas: to improve the quality of filling out documents; to follow-up patients receiving different RA therapy regimens according to the guidelines of the Association of Rheumatologists of Russia for the treatment of RA; to conduct in-depth studies of comorbidity, primarily depressive disorders; to analyze adverse reactions that make RA therapy difficult; to actively use modules for patients' self-rating of their condition; to develop nursing care, etc

Orientation-Induced Redox Isomerism in Planar Supramolecular Systems

In this work, a previously undescribed phenomenon of orientation-induced redox isomerism in a Langmuir monolayer is revealed in the case of cerium bis-[tetra-(15-crown-5)-phthalocyaninate]-(Ce[(15C5)4Pc]2). It was established that intramolecular electron transfer (IET) from the electronic system of phthalocyanine to the 4f-orbital of cerium atom occurs upon spreading of a (Ce[(15C5)4Pc]2) chloroform solution onto the air?water interface (3D -> 2D IET). This process is related to the transformation of Ce4+ cation in the solution to Ce3+ in the monolayer. It was also found that reversible Ce3+ Ce4+ IETs occur upon compression (π1 -> π2) and expansion (π2 -> π1) of monolayer (2Dπ1 2Dπ2 IET, π-surface pressure). The mechanism of genuine redox isomerism was confirmed by the results of in situ UV?vis spectral measurements performed on monolayers and Langmuir?Blodgett films, AFM, and XPS studies of Langmuir?Blodgett films transferred at different surface pressures. The understanding of this reversible IET mechanism is especially important due to possible applications of such redox-isomeric systems in the development of nanoscale multibit information storage devices