Objective. To assess the efficacy and tolerability of canakinumab, a fully human anti-interleukin-1 monoclonal antibody, for the treatment of acute gouty arthritis.Methods. In this 8-week, single-blind, doubledummy, dose-ranging study, patients with acute gouty arthritis whose disease was refractory to or who had contraindications to nonsteroidal antiinflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg; n ؍ 143) or an intramuscular dose of triamcinolone acetonide (40 mg; n ؍ 57). Patients assessed pain using a 100-mm visual analog scale.Results. Seventy-two hours after treatment, a statistically significant dose response was observed for canakinumab. All canakinumab doses were associated with numerically less pain than triamcinolone acetonide; thus, a dose with equivalent efficacy to triamcinolone acetonide 72 hours after treatment could not be determined. The reduction from baseline in pain intensity with canakinumab 150 mg was greater than with triamcinolone acetonide 24, 48, and 72 hours after treatment (differences of ؊11.5 mm [P ؍ 0.04], ؊18.2 mm [P ؍ 0.002], and ؊19.2 mm [P < 0.001], respectively), and 4, 5, and 7 days after treatment (all P < 0.05). Canakinumab significantly reduced the risk of recurrent flares versus triamcinolone acetonide (P < 0.01 for all doses) (relative risk reduction 94% for canakinumab 150 mg versus triamcinolone acetonide). The overall incidence of adverse events was similar for canakinumab (41%) and triamcinolone acetonide (42%); most were mild or moderate in severity.Conclusion. Our findings indicate that canakinumab 150 mg provides rapid and sustained pain relief in patients with acute gouty arthritis, and significantly reduces the risk of recurrent flares compared with triamcinolone acetonide.Gout is a metabolic disease caused by monosodium urate monohydrate (MSU) crystal deposition and is one of the most common forms of inflammatory arthritis in adults (1,2). Its prevalence increases with age and is especially high in older men (2). Gouty arthritis commonly occurs in the lower extremities (3,4), and flares are characterized by rapid onset and build-up of pain, warmth, swelling, decreased range of motion, and redness of the involved joints (3,4). Initial flares last hours to weeks, whereas subsequent flares may be more prolonged. The frequency of flares often increases over time in patients who are inadequately treated (3,4).The goal of therapy in an acute gout flare is prompt and safe termination of pain and inflammation. Acute gouty arthritis is usually treated with nonsteroidal ClinicalTrials.gov identifier: NCT00798369.
IntroductionWe report the impact of canakinumab, a fully human anti-interleukin-1β monoclonal antibody, on inflammation and health-related quality of life (HRQoL) in patients with difficult-to-treat Gouty Arthritis.MethodsIn this eight-week, single-blind, double-dummy, dose-ranging study, patients with acute Gouty Arthritis flares who were unresponsive or intolerant to - or had contraindications for - non-steroidal anti-inflammatory drugs and/or colchicine were randomized to receive a single subcutaneous dose of canakinumab (10, 25, 50, 90, or 150 mg) (N = 143) or an intramuscular dose of triamcinolone acetonide 40 mg (N = 57). Patients assessed pain using a Likert scale, physicians assessed clinical signs of joint inflammation, and HRQoL was measured using the 36-item Short-Form Health Survey (SF-36) (acute version).ResultsAt baseline, 98% of patients were suffering from moderate-to-extreme pain. The percentage of patients with no or mild pain was numerically greater in most canakinumab groups compared with triamcinolone acetonide from 24 to 72 hours post-dose; the difference was statistically significant for canakinumab 150 mg at these time points (P < 0.05). Treatment with canakinumab 150 mg was associated with statistically significant lower Likert scores for tenderness (odds ratio (OR), 3.2; 95% confidence interval (CI), 1.27 to 7.89; P = 0.014) and swelling (OR, 2.7; 95% CI, 1.09 to 6.50, P = 0.032) at 72 hours compared with triamcinolone acetonide. Median C-reactive protein and serum amyloid A levels were normalized by seven days post-dose in most canakinumab groups, but remained elevated in the triamcinolone acetonide group. Improvements in physical health were observed at seven days post-dose in all treatment groups; increases in scores were highest for canakinumab 150 mg. In this group, the mean SF-36 physical component summary score increased by 12.0 points from baseline to 48.3 at seven days post-dose. SF-36 scores for physical functioning and bodily pain for the canakinumab 150 mg group approached those for the US general population by seven days post-dose and reached norm values by eight weeks post-dose.ConclusionsCanakinumab 150 mg provided significantly greater and more rapid reduction in pain and signs and symptoms of inflammation compared with triamcinolone acetonide 40 mg. Improvements in HRQoL were seen in both treatment groups with a faster onset with canakinumab 150 mg compared with triamcinolone acetonide 40 mg.Trial registrationclinicaltrials.gov: NCT00798369.
1 -ГБОУ ВПО "Московский государственный медико стоматологический университет им. А.И.Евдокимова" Минздрава России: 127473, Москва, ул. Делегатская, 20 / 1; 2 -ГБУЗ "Городская клиническая больница № 11" Департамента здравоохранения г. Москвы: 127018, Москва, ул. Двинцев, 6 РезюмеЦелью исследования явилось изучение клинико функциональных параметров и качества жизни (КЖ) больных хронической обструк тивной болезнью легких (ХОБЛ) c сопутствующим ожирением и метаболическими нарушениями с оценкой возможности их феноти пирования. На основании кластерного анализа, проведенного по методу k средних МакКуина, выделены 4 группы пациентов с отличи тельными особенностями течения ХОБЛ. Установлено, что наличие сопутствующего ожирения у больных ХОБЛ ассоциировано со значительным снижением легочной функции, переносимости физической нагрузки, показателей КЖ и выживаемости, частыми обост рениями, развитием инсулинорезистентности и активацией системных воспалительных реакций. Предполагается, что клинический вариант ХОБЛ с сопутствующим ожирением целесообразно рассматривать в качестве отдельного фенотипа заболевания, характеризу ющегося тяжелым течением. Ключевые слова: хроническая обструктивная болезнь легких, ожирение, инсулинорезистентность, фенотип, тяжелое течение, кластер ный анализ. Obesity and metabolic disorders in COPD patients: opportunities for phenotyping SummaryThe aim of the study was to compare clinical and functional features and health related quality of life (HRQoL) in patients with chronic obstructive pulmonary disease (COPD) regarding to co morbid obesity as a phenotypic sign. Methods. Patient classification was performed using K means clus tering analysis (MacQueen). It resulted in the classification of subjects into four clinical groups with marked differences in COPD symptoms. Results. Subjects with obesity had severe airflow limitation and dyspnoea, frequent exacerbations, severely impaired HRQoL, poor survival, decreased physical activity, insulin resistance and increased systemic inflammation. Conclusion. Thus, COPD with co morbid obesity could be con sidered as a distinct phenotype of COPD with severe symptoms.
Подагра является частой причиной воспалительного артрита, разрушения суставов, образования камней в почках и почечной недостаточности. Причиной воспаления в суставе является взаимодействие кристаллов мочевой кислоты (monosodium urate - MSU) и пирофосфата кальция (calcium pyrophosphate - СаРР) с макрофагами. Мы предположили, что подавлять кристалл-индуцированное воспаление мог бы М3 фенотип макрофагов, который увеличивает продукцию антивоспалительных цитокинов при действии воспалительных индукторов (АВ-М3 фенотип). Цель работы состояла в проверке этой гипотезы. Методы. Подагрическое воспаление моделировали с помощью добавления кристаллов MSU и СаРР к культуре макрофагов. Для программирования АВ-М3 фенотипа использовали ингибитор инфламмасомы MCC950 и IL-4. Воспалительную реакцию оценивали по продукции IL-1b и TGFb1. Результаты. Реакция нативных (M0) макрофагов и на кристаллы MSU, и на кристаллы CaPP воспроизвела острое подагрическое воспаление в форме 3-кратного увеличения продукции IL-1b (p < 0,05). При добавлении кристаллов MSU к АВ-М3 макрофагам содержание IL-1b в культуральной среде было меньше в 25 раз (p < 0,05), а содержание TGFb больше почти в 2 раза (p < 0,05) по сравнению со средой М0 макрофагов с кристаллами MSU. Аналогичный результат был получен при добавлении кристаллов CaPP к АВ-М3 макрофагам. Заключение. Таким образом, АВ-М3 фенотип отвечает на провоспалительное действие кристаллов MSU и CaPP снижением продукции IL-1b и усилением продукции TGFb1. Результаты работы подтвердили гипотезу о том, что АВ-М3 фенотип может ограничить кристалл-индуцированное воспаление. Соответственно, разработка клинической версии технологии АВ-М3 макрофагов представляется весьма перспективной. Gout is a common cause of inflammatory arthritis, joint damage, kidney stones, and kidney failure. Joint inflammation is induced by interaction of uric acid (monosodium urate, MSU) crystals and calcium pyrophosphate (CaPP) crystals with macrophages. We hypothesized that the crystal-induced inflammation could be suppressed by the M3 switch phenotype, which increases production of anti-inflammatory cytokines under the action of inflammation inducers (AB-M3 phenotype). The aim of the present study was to test this hypothesis. Methods. Gouty inflammation was modeled by adding MSU and CaPP crystals to cultured macrophages. The inflammasome inhibitor, MCC950, and IL-4 were used for programming the AB-M3 phenotype. The inflammatory response was evaluated by production of IL-1β and TGFβ1. Results. The response of native (M0) macrophages to either MSU crystals or CaPP crystals reproduced acute gouty inflammation in the form of a 3-fold increase in IL-1 β production (p < 0.05). When MSU crystals were added to AB-M3 macrophages, the IL-1β content in the culture medium became 25 times lower (p < 0.05), and the TGF-β1 content became almost twice higher (p < 0.05) than the respective values in the M0 macrophage medium with MSU crystals. A similar result was obtained when CaPP crystals were added to AB-M3 macrophages. Conclusion. The AB-M3 phenotype responds to the pro-inflammatory action of MSU and CaPP crystals by decreasing the IL-1β production and increasing the TGF-β1 production. These results confirmed the hypothesis that the AB-M3 phenotype restricts the crystal-induced production of inflammatory IL-1β and increases the production of anti-inflammatory TGF-β1. Therefore, development of a clinical version of the AB-M3 macrophage technology is very promising.
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