Peroxisome proliferator-activated receptors α (PPARα) agonists, or fibrates, are used in the treatment for dyslipidemia. Experimental data suggest that fibrates have anti-inflammatory properties, and PPARα is essential for the differentiation of endothelial progenitor cells (EPC) which diminished pool in rheumatoid arthritis (RA) contributes to accelerated atherosclerosis. The data on fibrates' effects in patients with RA are limited. The aim of this study was to investigate changes in disease activity, inflammatory markers, lipid profile, and circulating EPC in active RA patients treated with fenofibrate. Twenty-seven patients with active RA taking traditional disease-modifying antirheumatic drugs (DMARDs) were prescribed fenofibrate (145 mg/day) for 3 months. All patients received background traditional DMARDs in stable doses. The outcomes measured were clinical disease activity variables, circulating cytokines, adipokines, lipids, and EPC. Twenty-five patients completed the study. At the end of treatment, there was a significant reduction in DAS28, all individual DAS28 components except tender joint count, the duration of morning stiffness, and in the patient's assessment of disease activity. Fifteen (60 %) patients achieved good/moderate EULAR response, while 10 (40 %) patients satisfied ACR20 response criteria. Treatment with fenofibrate resulted in significant decrease in CRP and IL-6 concentrations and improvement in lipid profile. There was no change in the concentrations of circulating EPC. In conclusion, fenofibrate treatment is associated with reduced inflammation and improved lipid profile in RA patients. Large randomized controlled studies are needed to confirm these results and to define the role of fibrates in the treatment for RA.

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Background Several epidemiological studies have shown the existence of diabetes (type II) - associated osteoarthritis (T2D-associated OA). Currently there is a lack of data about special features of this OA phenotype. Objectives To explore the proinflammatory serum cytokine levels and the clinical features in patients with knee OA and T2D and compare with patients with knee OA without T2D. Methods Patients (n=78) were divided into two groups. Group 1 (n=52) had bilateral knee OA according to ACR criteria and T2D diagnosed one year before the start of joint disease. Group 2 (n=26) had bilateral knee OA according to ACR criteria without T2D. We assessed serum cytokine levels (IL-6, IL-18) using ELISA. Pain, general health, stiffness, physical functions, quality of life (QoL) and mental health disorders were measured by visual analog scale (VAS),Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Knee injury and Osteoarthritis Outcome Score (KOOS), short form 36 (SF-36), patient health questionnaire-9 (PHQ-9). Statistical data are presented as median and 25/75 percentiles. We used U-Mann-Whitney test to detect differences between groups. Correlation was assessed using Spearman correlation coefficient (rs). Results Median age of group 1 (n=52) were 63 (interquartile range (IQR)): 58.25-69) 80.7% were women. At the group 2 (n=26) median ages were 66 (IQR: 54-70) 84.6% were women. Serum cytokine levels of IL-6 and IL-18 were significantly higher in patients of group 1 than the group 2 (p=0.0006 and p=0.0012 respectively). Statistically significant differences between two groups were found in such scales and indices as VAS, WOMAC, KOOS and SF-36 (certain data performed in Table). Also, mental health disorders in groups had statistically significant differences (SF-36 MH p=0.0137, PHQ-9 p=0.0424). Significant correlation was found between serum cytokines concentrations (IL-6 and IL-18) and most parameters of KOOS, SF-36 in both groups. Conclusions According to this study results, plasma cytokine concentrations were elevated and observed high intensity of pain, significant impairment of physical functions, mental health and QoL in T2D-associated OA patients. Also this study suggests that serum cytokines concentrations are linked with the severity of knee T2D-associated OA. A positive association between IL-6, IL-18 and T2D-associated OA may assume participation of this proinflammatory factors in the pathogenesis of this OA phenotype. These data should be verified by larger studies. Disclosure of Interest : None declared DOI 10.1136/annrheumdis-2014-eular.4932

Адрес для переписки:Ширинский Иван Валерьевич ФГБНУ «Научно-исследовательский институт фундаментальной и клинической иммунологии» 630099, Россия, г. Новосибирск, ул. Ядринцевская, 14. Тел.: 8 (383) 228-25-47. Факс: 8 (383) 228-25-47. Е-mail: ishirinsky@mail.ru Address for correspondence : Shirinsky Ivan V. Research Institute of Fundamental and Clinical Immunology 630099, Russian Federation, Novosibirsk, Yadrintsevskaya str., Образец цитирования: И.В. Ширинский, О.В. Сазонова, Н.Ю. Калиновская, В.С. Ширинский, «Коморбидность, метилирование ДНК и аутоиммунитет при диабет-ассоциированном остеоартрите: поисковое исследование» // Медицинская иммунология, 2015. Т. 17, № 4. С. 327-334. doi: 10.15789/1563-0625-2015-4-327-334 © Ширинский И.В. и соавт., 2015 For citation: I.V. Shirinsky, O.V. Sazonova, N.Yu. Kalinovskaya, V.S. Shirinsky, "Comorbidity, DNA methylation and autoimmunity in diabetesassociated osteoarthritis: an exploratory study", Medical Immunology (Russia)/Meditsinskaya Immunologiya, 2015, Vol. 17, no. 4, pp. 327-334. doi: 10.15789/1563-0625-2015 Резюме. Остеоартрит (ОА) является одной из актуальных проблем клинической медицины не толь-ко вследствие большой распространенности, но и повышенной частоты коморбидной патологии. Ранее нами был описан клинический фенотип ОА в сочетании с СД 2 типа (ОАСД), являющийся субтипом ОА и характеризующийся большей тяжестью ОА, сниженным уровнем качества жизни. В настоящее время в литературе отсутствуют данные о биомаркерах ОАСД. Исходя из современных знаний о механизмах развития СД 2 типа и ОА, предполагается, что ключевым молекулярным звеном патогенеза этих заболеваний могут быть нарушения процессов метилирования ДНК. Ряд факторов (хроническое системное воспаление, повышение содержания конечных продуктов гликирования) может приводить к усилению деградации хряща при ОА, ассоциированном с СД 2 типа. Как ОА, так и СД 2 характеризуются высоким бременем коморбдной патологии, что позволяет предположить адди-тивный эффект сочетания этих заболеваний на индексы коморбидности. Таким образом, в поисковом исследовании у больных ОАСД изучалось глобальное метилирование ДНК в мононуклеарах перифе-рической крови (МНК ПК), биомаркеры деструкции в хрящевой ткани и показатели коморбидности. Уровень глобального метилирования ДНК в МНК ПК оценивался как содержание 5-метилцитозина с помощью проточной цитометрии. Определение содержания аггрекана и антител к коллагену II типа в сыворотке ПК проводили методом ИФА. Показатели коморбидности оценивались с помощью шка-лы CIRS-G (Cumulative Illness Rating Scale). Обследовано 78 больных генерализованным ОА. Опыт-ную группу составили 52 больных, у которых клиническим проявлениям ОА не менее года предше-ствовал СД 2 типа. В контрольную группу были включены 26 больных ОА без СД. Установлено, что, помимо тяжелых клинических проявлений суставного синдрома и наличия системного воспаления, у больных ОАСД определяется высокий уровень тяжести коморбидности, обусловленный не только СД, но и другими сопутствующими заболеваниями. Различи...

Background Anti-inflammatory and antiatherogenic properties of peroxisome proliferator-activated α (PPARα) receptor agonists (fibrates) suggest their utility in the treatment of various inflammatory rheumatic disorders associated with accelerated atherosclerosis. They include osteoarthritis (OA), particularly its erosive phenotype (EOA) characterized by pronounced synovial inflammation. Putative EOA biomarkers reflecting extent of chronic inflammation and increased risk of atherosclerosis are serum cytokines and adipokines. Another candidate biomarker for cardiovascular morbidity in OA is number of circulating endothelial progenitor cells (EPC). There have been no published studies evaluating fenofibrate efficacy and its effects on systemic cytokine and adipokine production and EPC concentrations in patients with erosive OA. Objectives To assess the influence of fenofibrate treatment on clinical efficacy parameters, in vivo cytokine and adipokine production and concentrations of EPC in patients with EOA. Methods EOA patients received treatment with 145 mg of fenofibrate per day for 12 weeks. The studied efficacy outcomes were pain levels (100 mm VAS), functional index for hand OA (FIHOA), Cochin index, patient and physician global assessment (100 mm VAS), tender and swollen joint count, duration of morning stiffness, and ESR. Response was assessed in accordance with OMERACT-OARSI criteria. Serum was obtained from each patient and peripheral blood mononuclear cells were isolated on baseline and at week 12 of the treatment. TNF-α, IL-6, IL-1, IL-17, IFN-γ, IL-10, apiponectin and resistin were measured in sera using specific ELISA. Endothelial progenitor cell (EPC) counts in peripheral blood were evaluated by flow cytometry as CD34+/CD144+/CD3- cells within the lymphocyte gate. Results Fifteen patients (all women, median age 61 years, IQR 57-63) were enrolled in the study. Fenofibrate treatment was associated with significant decreases in pain score, TJC, morning stiffness, disease activity score, Cochen index, and ESR (Table). Eight (53%) patients developed OMERACT-OARSI response at the end of treatment. Serum IL-10 concentrations significantly (p=0.03) decreased while no changes in other studied cytokines and adipokines were detected. There were also no differences in circulating EPC numbers before and after the treatment. Fenofibrate was well tolerated, no patient experienced disease flare during the treatment. Table 1. Efficacy parameters at baseline and after the treatment (median and IQR are presented) Week 0Week 12p Pain (100 mm VAS)28 (20-50)20 (10-36)0.0008 TJC8 (5-16)5 (4-8)0.007 SJC7 (3-10)4 (1-7)0.175 Morining stiffness60 (20-130)20 (0-30)0.0035 Disease activity (100 mm VAS)51 (45-60)20 (18-40)<0.0001 Patient’s global assessment (100 mm VAS)50 (38-64)31 (21-43)0.0141 Cochen index8 (4-12)4 (0-14)0.0182 ESR, mm/h21 (7.75-28.5)10.5 (7.25-18.5)0.0195 Conclusions In EOA patients, treatment with fenofibrate is associated with decreased pain, improved hand function and ESR reduction but has no effect on pr...