Inhibition of Interleukin 6 in Immune Inflammatory Rheumatic Diseases: Achievements, Prospects, and Hopes

Blockade of interleukin-6 (IL-6) is one of the most promising areas in the treatment of a number of immunoinflammatory diseases. Tocilizumab (TCZ), the first registered anti-IL-6 receptor monoclonal antibody, has been used effectively by rheumatologists since 2010. During this period, the spectrum of adverse reactions (ARs) of TCZ has been clearly defined. However, the multifaceted biological effects of IL-6 determine the probability of unexpected ARs. The article describes a clinical case of drug-induced encephalopathy with cognitive dysfunction during TCZ therapy.

Section: Discussionunclassified

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Drug-Induced Encephalopathy With Impaired Cognitive Functions During Tocilizumab Use

Шестерня

Прокопенко

Можейко

et al. 2019

“…[59]. Обсуждается снижение «пластичности» зрелых Th17-клеток в направлении формирования «патогенной» субпопуляции, связанной не с ИЛ23, а с другими «провоспалительными» цитокинами (например, механизма «транс-презентации» ИЛ6) [60,61].…”

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Il-23/Il-17 Inhibitors in Immunoinflammatory Rheumatic Diseases: New Horizons

Насонов

Коротаева²,

Дубинина³

et al. 2019

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Recently, more attention has been given to Th17 cells, the pathological activation of which plays a leading role in the development of a wide spectrum of human immunoinflammatory diseases (IID), including rheumatoid arthritis, psoriasis, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel diseases, etc. This has served as an incentive to design new biological agents and small molecules, the main mechanism of action of which is based on blocking the pathological effects of interleukin-17 (IL-17), others are associated with the activation of Th17 cells cytokines or signaling pathways that regulate the effects of these cytokines. The review discusses current ideas about the mechanisms regulating the formation and functional activity of IL-17 family cytokines, as well as evidence for the importance of these cytokines in the pathogenesis of IID.

“…В основе развития РА лежит активация В-клеток, которая приводит как к антителозависимым, обусловливающим образование ревматоидного фактора (РФ) и антител к циклическому цитруллинированному пептиду (АЦЦП), так и неантителозависимым реакциям, включающим стимуляцию артритогенных T-клеток и продукцию цитокинов [2][3][4]. Среди широкого спектра «провоспалительных» медиаторов, принимающих участие в патогенезе РА, важная роль принадлежит интерлейкину 6 (ИЛ6) [5,6]. ИЛ6 -плейотропный цитокин, который синтезируется многими клетками, включая В-лимфоциты [7], и проявляет широкий спектр «провоспалительных» биологических эффектов.…”

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B-lymphocyte subpopulations in patients with rheumatoid arthritis and the effect of an interleukin-6 receptor inhibitor on them.

Gerasimova¹,

Попкова²,

Алексанкин³

et al. 2019

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The clinical efficacy and safety of interleukin-6 (IL-6) receptor blockade have been well studied, but the data on the impact of therapeutic inhibition of IL-6 on B cells are scarce and contradictory. Preliminary reports have shown that B cell function and a humoral immune response may be modulated by an IL-6 receptor inhibitor.Objective: to assess the effect of 12-month tocilizumab (TCZ) therapy on B-cell phenotype and gene expression in RA and to analyze the association between B-cell subsets and RA activity.Subjects and methods. Examinations were made in 24 active RA patients (20 women and 4 men) (median age, 55 [49; 64] years; disease duration, 72 [24; 108] months; DAS28 5.8 [5.3; 6.3]; the patients were seropositive for rheumatoid factor (RF) (100%) and for anti-cyclic citrullinated peptide antibodies (87.3%). The patients received TCZ 8 mg/kg every 4 weeks. After 12 months of therapy, 54% of patients were categorized as good responders, 46% as moderate responders according to the EULAR response criteria. A control group consisted of 29 volunteers (21 women and 8 men; median age, 58.5 [53.0; 62.0] years). Peripheral blood lymphocytes were immunophenotyped at the time of enrollment and after 12 months. The absolute and relative counts of CD19+B lymphocytes, memory B cells (CD19+CD27+), non-switched memory B cells (CD19+IgD+CD27+), switched memory B cells (CD19+IgDCD27+), naive (CD19+IgD+CD27-), double-negative (CD19+IgD-CD27-), transitional (CD19+IgD+CD10+CD38++CD27) B cells, plasma cells (CD19+СD38+), and plasmablasts (CD19+СD38+++IgD-CD27+CD20-) were estimated using multicolor flow cytometry. Results and discussion. The relative and absolute counts of memory B cells (CD19+CD27+) (1.3 [0.9; 1.7]%, 0015 [0.001; 0.003]•109/l), switched memory B cells (CD19+IgD-CD27+) (6.8 [3.6; 11.6]%, 0.01 [0.005; 0.02]•109/l), and the absolute number of transitional B cells (CD19+CD38++CD10+IgD+CD27-) (0.00009 [0; 0.00028]•109/l) were found to be lower in RA patients than in donors: 2.2 [1.1; 3.0]%, 0.003 [0.001; 0.007]•109/l; 12.8 [9.3; 17.0]%, 0.02 [0.01; 0.04]•109/l; 0.0001 [0; 0.0003]•109/l, respectively (p<0.05 for all cases). After 12 months of TCZ therapy initiation, there were decreases in the relative and absolute counts of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) from 0.15 [0.1; 0.3] to 0.1 [0.01; 0.1]% and from 0.0003 [0.00007; 0.004]•109/l to 0.0001 [0; 0.0003]•109/l, respectively (p<0.05). At the same time, the relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) remained lower in RA patients than in donors: 1.0 [0.7; 1.2] and 2.2 [1.1; 3.0]%; 0.001 [0.006; 0.003]•109/l and 0.003 [0.001; 0.007]•109/l; 3.1 [1.1; 4.2] and 12.8 [9.3; 17.0]%; 0.003 [0.002; 0.006]•109/l and 0.02 [0.01; 0.04]•109/l, respectively (p<0.05 for all cases). Following 12 months of TCZ therapy, the numbers of other B-cell subpopulations were not considerably altered. When included in the study, the patients with RA showed correlations between the absolute count of memory B cells (CD19+CD27+) and the level of C-reactive protein (r=0.50; p<0.05); between the absolute count of plasmablasts (CD19+CD38+++CD27+IgD-CD20-) and the level of RF (r=0.41 and r=0.52; p<0.05). There were no correlations of B cell subsets with clinical and laboratory findings after 12 months of TCZ initiation.Conclusion. Immunophenotyping of peripheral blood B lymphocyte subsets showed the lower relative and absolute counts of memory B cells (CD19+CD27+) and switched memory B cells (CD19+CD27+IgD-) in RA patients than in healthy donors. The found correlations between the counts of memory B cells and plasmablasts and the values of laboratory parameters in patients with high RA activity may suggest that B lymphocytes are involved in the pathogenesis of RA. There was a decline in plasmablast levels after 12 months of TCZ therapy.