Determination of Heterogeneous Proteomic and Metabolomic Response in anti-TNF and anti-IL-6 Treatment of Patients with Rheumatoid Arthritis.

Reduction in tumor necrosis factor (αTNF) and interleukin-6 (IL-6) activities is a widely utilized strategy for the treatment of rheumatoid arthritis (RA) with a high success rate. Despite both schemes targeting the deprivation of inflammatory reactions caused by the excessive activity of cytokines, their mechanisms of action and the final output are still unequal. This was a comparative longitudinal study that lasted for 24 weeks and aimed to find the answer to why the two schemes of therapy can pass out of proportion in attitude of their efficiency. What are the differences in metabolic and proteomic responses among patients who were being treated by either the anti-TNF or anti-IL-6 strategy? We found increased levels of immunoglobulins A and G (more than 2-fold in anti-IL-6 and more than 4-5-fold in anti-TNF groups) at the final stage (24 weeks) of monitoring but the most profound increase was determined for µ-chains of immunoglobulins in both groups of study. Metabolomic changes displayed main alterations with regard to arginine metabolism and collagen maintenance, where arginine increased 8.86-fold (p < 0.001) in anti-TNF and 5.71-fold (p < 0.05) in anti-IL-6 groups but patients treated by the anti-TNF scheme suffered a higher depletion of arginine before the start of therapy. Some indicators of matrix and bone tissue degradation also increased 4-hydroxyproline (4-HP) more than 6-fold (p < 0.001) in anti-TNF and more than 2-fold (p < 0.05) in the anti-IL-6 group, but the growth dynamics in the anti-IL6 group was delayed (gradually raised at week 24) compared to the anti-TNF group (raised at week 12) following a smooth reduction. The ELISA analysis of IL-6 and TNFα concentration in the study population supported proteomic and metabolomic data. A positive correlation between ΔCDAI and ΔDAS28 indicators and ESR and CRP was established for the majority of patients after 24 weeks of treatment where ESR and CRP reduced by 20% and 40% finally, respectively. A regression model using the Forest Plot was estimated to elucidate the impact of the most significant clinical, biochemical, and anthropometric indicators for the evaluation of differences between considered anti-TNF and anti-IL-6 schemes of therapy.

Calcification of coronary arteries in early rheumatoid arthritis prior to anti-rheumatic therapy.

Accelerated coronary atherosclerosis is common in patients with rheumatoid arthritis (RA). To examine coronary artery calcification (CAC) frequency and severity, its correlation with traditional risk factors (TRF) of cardiovascular diseases (CVD) and inflammatory markers in patients with early RA prior to anti-rheumatic therapy. RA adult patients (ACR/EULAR criteria, 2010, duration ≤ 12 months, without prior administration of disease-modifying anti-rheumatic drugs, glucocorticoids) underwent 32-row scanning for CAC scoring. Agatston, volume and mass calcium scores were calculated. Additionally, we used calculators on the website of the Multi-Ethnic Study of Atherosclerosis. 74 RA patients (women n = 54 (73%), median age 56 years, median RA duration 6 months) with moderate/high RA activity (median DAS28 [ESR] 5.4) were enrolled within the framework of the observational study. Most of the patients had multiple TRFs of CVD and subclinical organ damage. CAC has been detected in 34 (46%) early RA patients. Calcification severity was significantly higher in men and in patients with ischemic heart disease (IHD). In patients younger than 45 years (n = 16) CAC was not detected. Among patients older than 45 years (n = 58), the frequency of CAC was 59%: asymptomatic patients-n = 46 (48%), IHD patients-n = 12 (100%). Among asymptomatic patients the presence of CAC associated with a significantly higher frequency of arterial hypertension (1.6 fold) compared with cases without CAC. Coronary age in asymptomatic patients with CAC and IHD patients was significantly greater than their actual age. More than half of early RA patients older 45 years had CAC. The presence and severity of CAC correlated positively with TRFs, but not with lipid levels and RA activity.

The Effects of Rituximab on Lipids, Arterial Stiffness and Carotid Intima-Media Thickness in Rheumatoid Arthritis.

The aim of the study was to examine lipid profiles, arterial stiffness (AS), carotid intima-media thickness (cIMT), in 55 women with RA without overt cardiovascular disease (СVD) treated with rituximab (RTX).The following parameters were recorded before and 24 weeks after RTX therapy (2 infusions of 500 or 1,000 mg RTX intravenously, fortnightly): plasma total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides, DAS 28-ESR, serum C-reactive protein (CRP), RF IgM, AS (SI - stiffness index, RI - reflection index) by digital volume pulse contour analysis (Micro Medical, UK), and common cIMT by high-resolution B-mode carotid ultrasound. Based on the European League Against Rheumatism (EULAR) criteria, patients were divided into two groups: 1) moderate/good response to RTX therapy after 24 weeks (41 patients, 75%), 2) no response to RTX therapy (14 patients, 25%). Effective RTX therapy resulted in 9% increase in TC, 23% increase in HDL-C and 14% decrease in atherogenic index, 57% decrease in SI and 24% decrease in RI. We observed a 9% decrease of cIMTmax at 24 weeks. The improvement of cardiovascular parameters was accompanied by statistically significant decreases of CRP, ESR, RF IgM and DAS 28 in group 1 (P < 0.05). There were not significant changes in lipid profile, AS parameters, and cIMT in group 2. Two infusions of RTX in case of moderate/good EULAR effect of therapy exerted favorable effects on lipid profile, AS and cIMT in women with RA without overt CVD.