Factors influencing the SARS-CoV-2 infection and vaccination induced immune response in rheumatoid arthritis.

Background: To investigate the factors that have significant impact on the Severe Acute Respiratory Syndrome Corona Virus 2 (SARS-CoV-2) infection and vaccination induced immune response in rheumatoid arthritis (RA). Methods: Serological response was measured by quantifying anti-SARS-CoV-2 specific antibodies, while the cell-mediated response was measured by a whole-blood test quantifying the interferon (IFN)-γ response to different SARS-CoV-2-specific domains. Results: We prospectively enrolled 109 RA patients and 43 healthy controls. The median time (IQR) between the confirmed infection or the last vaccination dose and the day when samples were taken ("sampling interval") was 3.67 (2.03, 5.50) months in the RA group. Anti-Spike (anti-S) specific antibodies were detected in 94% of RA patients. Among the investigated patient related variables, age (p<0.004), sampling interval (p<0.001), the brand of the vaccine (p<0.001) and targeted RA therapy (TNF-inhibitor, IL-6 inhibitor, anti-CD20 therapy) had significant effect on the anti-S levels. After covariate adjustment TNF-inhibitor therapy decreased the anti-S antibody concentrations by 80% (p<0.001). The same figures for IL-6 inhibitor and anti-CD20 therapy were 74% (p=0.049) and 97% (p=0.002), respectively. Compared to subjects who were infected but were not vaccinated, the RNA COVID-19 vaccines increased the anti-S antibody levels to 71.1 (mRNA-1273) and 36.0 (BNT162b2) fold (p<0.001). The corresponding figure for the ChAdOx1s vaccine is 18.1(p=0.037). Anti-CCP (anti-cyclic citrullinated peptides) positive patients had 6.28 times (p= 0.00165) higher anti-S levels, than the anti-CCP negative patients. Positive T-cell response was observed in 87% of the healthy volunteer group and in 52% of the RA patient group. Following vaccination or infection it declined significantly (p= 0.044) but more slowly than that of anti-S titer (6%/month versus 25%). Specific T-cell responses were decreased by 65% in patients treated with anti-CD20 therapy (p=0.055). Conclusion: Our study showed that the SARS-CoV-2-specific antibody levels were substantially reduced in RA patients treated with TNF-α-inhibitors (N=51) and IL-6-inhibitor (N=15). In addition, anti-CD20 therapy (N=4) inhibited both SARS-CoV-2-induced humoral and cellular immune responses. Furthermore, the magnitude of humoral and cellular immune response was dependent on the age and decreased over time. The RNA vaccines and ChAdOx1s vaccine effectively increased the level of anti-S antibodies.

Largely Accelerated Arterial Aging in Rheumatoid Arthritis Is Associated With Inflammatory Activity and Smoking in the Early Stage of the Disease.

Background: Rheumatoid arthritis (RA) patients have a shorter life expectancy than the general population primarily due to cardiovascular comorbidities. Objectives: To characterize arterial aging in RA. Patients and Methods: Coronary calcium score (CCS) were available from 112 RA patients; out of these patients, follow-up CCS were measured for 54 randomly selected individuals. Control CCS were obtained from the MESA database (includes 6,000 < participants); arterial age was calculated from CCS. Results: RA patients were significantly older (10.45 ± 18.45 years, p < 0.001) in terms of the arterial age than the age-, gender-, and race-matched controls. The proportion of RA patients who had zero CCS was significantly less (p < 0.01) than that of those in the MESA reference group. Each disease year contributed an extra 0.395 years (p < 0.01) on the top of the normal aging process. However, the rate of the accelerated aging is not uniform, in the first years of the disease it is apparently faster. Smoking (p < 0.05), previous cardiovascular events (p < 0.05), and high blood pressure (p < 0.05) had additional significant effect on the aging process. In the follow-up study, inflammatory disease activity (CRP > 5 mg/L, p < 0.05) especially in smokers and shorter than 10 years of disease duration (p = 0.05) had the largest impact. Conclusion: Arterial aging is faster in RA patients than in control subjects, particularly in the first 10 years of the disease. Inflammation, previous cardiovascular events, and smoking are additional contributing factors to the intensified coronary atherosclerosis progression. These data support that optimal control of inflammation is essential to attenuate the cardiovascular risk in RA.

AM-251, A Cannabinoid Antagonist, Modifies the Dynamics of Sleep-Wake Cycles in Rats.

Study Objectives: (a) To describe the microarchitecture of wakefulness and sleep following administrations of 5- and 10-mg/kg AM-251 in rats. (b) To develop a new statistical method to follow bout-to-bout dynamics. Method: Wistar rats (n = 6) had been equipped with electroencephalography (EEG) and electromyography (EMG) electrodes. Following their recovery and habituation after the surgery, the animals were injected with vehicle and 5- and 10-mg/kg AM-251 intraperitoneally and EEG, EMG, and motor activity were analyzed for the subsequent 3 h. Results: AM-251 induced a dose- and time-dependent increase in the number of bouts in active wake (AW), and it decreased this number in all other vigilance states except in passive wake (PW). In contrast, the bout duration in PW compensatory decreased. The effect of AM-251 on the sleep transition dynamics was monitored with a new tool we call "transition heatmap." The analysis of bout trajectories with transition heatmaps reveals a highly organized pattern. Conclusion: AM-251 selectively influences the frequency of vigilance state transitions, but it has no direct impact on the state lengths. AM-251 markedly changed the state transition dynamics, which was visualized with the help of state transition heatmaps.

Additive effect of 5-HT2C and CB1 receptor blockade on the regulation of sleep-wake cycle.

BACKGROUND: Previous data show that serotonin 2C (5-HT2C) and cannabinoid 1 (CB1) receptors have a role in the modulation of sleep-wake cycle. Namely, antagonists on these receptors promoted wakefulness and inhibited rapid eye movement sleep (REMS) in rodents. The interaction of these receptors are also present in other physiological functions, such as the regulation of appetite. Blockade of 5-HT2C receptors modulat the effect of CB1 receptor antagonist, presumably in consecutive or interdependent steps. Here we investigate, whether previous blockade of 5-HT2C receptors can affect CB1 receptor functions in the sleep-wake regulation. RESULTS: Wistar rats were equipped with electroencephalography (EEG) and electromyography (EMG) electrodes. Following the recovery and habituation after surgery, animals were injected intraperitoneally (ip.) with SB-242084, a 5-HT2C receptor antagonist (1.0 mg/kg) at light onset (beginning of passive phase) followed by an injection with AM-251, a CB1 receptor antagonist (5.0 or 10.0 mg/kg, ip.) 10 min later. EEG, EMG and motor activity were analyzed for the subsequent 2 h. Both SB-242084 and AM-251 increased the time spent in active wakefulness, while decreased the time spent in non-REMS and REMS stages in the first 2 h of passive phase. In combination, the effect of the agents were additive, furthermore, statistical analysis did not show any interaction between the effects of these drugs in the modulation of vigilance stages. CONCLUSIONS: Our results suggest that 5-HT2C receptor blockade followed by blockade of CB1 receptors evoked additive effect on the regulation of sleep-wake pattern.

Determinants of biological drug survival in rheumatoid arthritis: evidence from a Hungarian rheumatology center over 8 years of retrospective data.

OBJECTIVE: To compare drug survival of biological therapies in patients with rheumatoid arthritis (RA), and analyze the determinants of discontinuation probabilities and switches to other biological therapies. MATERIALS AND METHODS: Consecutive RA patients initiating first biological treatment in one rheumatology center between 2006 and 2013 were included. Log-rank test was used to analyze the differences between the survival curves of different biological drugs. Cox regression was applied to analyze the discontinuation due to inefficacy, the occurrence of adverse events, or to any reasons. RESULTS: A total of 540 patients were included in the analysis. The most frequently used first-line biological treatments were infliximab (N=176, 33%), adalimumab (N=150, 28%), and etanercept (N=132, 24%). Discontinuation of first tumor necrosis factor-alpha (TNF-α) treatment was observed for 347 (64%) patients, due to inefficacy (n=209, 60%), adverse events (n=103, 30%), and other reasons (n=35, 10%). Drug survival rates for TNF-α and non-TNF-α therapies were significantly different, and were in favor of non-TNF-α therapies. Every additional number of treatment significantly increased the risk of inefficacy by 27% (p<0.001) and of adverse events by 35% (p=0.002). After the discontinuation of the initial TNF-α treatment, switching to rituximab and tocilizumab was associated with significantly longer treatment duration than switching to a second TNF-α. The non-TNF-α therapies resulted in significantly longer treatment duration, due to both less adverse events and longer maintenance of effectiveness. CONCLUSION: Non-TNF-α therapies resulted in significantly longer treatment duration, and lost their effectiveness later. Increase in the number of switches significantly increased the risk of discontinuation of any biological therapy.

Immunosuppressants increase the levels of natural autoantibodies reactive with glycosaminoglycans in myasthenia gravis.

Increasing number of evidences support the role of glycosylation in the evolution of autoimmunity. We examined carbohydrate-reactive natural autoantibodies systematically for the first time in patients with autoimmune myasthenia gravis. Antibodies reactive to glycosaminoglycans were measured with CovaLink ELISA in the sera of 59 myasthenia patients as well as in 54 healthy controls. We used the GlycoChip carbohydrate array to characterize individual carbohydrate recognition patterns. Chondroitin-sulphate C and anti-α-mannose-specific IgG levels were significantly elevated in myasthenia patients. Unexpectedly, we found that immunosuppressants increased the levels of the protective IgM glycosaminoglycan-reactive natural antibodies demonstrating a new role for these agents in immunoregulation.

Prolonged effect of endorphin treatment during pregnancy in the rat on the histamine content of immune cells of F1 and F2 offspring generations.

Female rats were treated with beta-endorphin on the 19th day of pregnancy and the histamine content of immune cells (blood lymphocytes; peritoneal lymphocytes, monocyte-macrophage-granulocyte group, mast cells; thymic lymphocytes) of the 7-week-old progenies (F1 generation) was studied using a flow-cytometric immunocytochemical technique. In an other group, female F1 progenies of endorphin-treated mothers were mated with control males and the F2 generation was monitored for histamine content similar to the F1. In the F1 generation each cell type, except peritoneal and blood lymphocytes, contained significantly more histamine than the control cells. In the F2 generation only mast cells contained significantly more histamine relative to the appropriate control. This means that the effect of endorphin (hormonal) imprinting is transmitted transgenerationally, but with decreasing intensity however. Mast cells retained the effect of imprinting for longer than the other cells. The results are compared with the levels of serotonin in similarly treated animals, studied in earlier experiments. As the endorphin level can be elevated during pregnancy (by pain, traumatization, or other stress conditions) this can the set biogenic amine content of adult immune cells.