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Systemic inflammation is characterized by the induction of pro-inflammatory cytokines, the increased level of which in the blood of patients with chronic heart failure (CHF) correlates with unfavorable clinical outcomes. However, it is unclear whether pro-inflammatory cytokines are the cause or the consequence of the disease progression. CHF with preserved ejection fraction and CHF with reduced ejection fraction demonstrate different inflammatory features, which suggests different degrees of pro-inflammatory pathway activation. The review deals with participation of pro-inflammatory cytokines in pathophysiological processes of CHF development, emphasizing the role of interleukin-6 activation and the effects of accompanying diseases on the course of systemic inflammation. The search for new approaches to prevention and therapy of CHF remains actual. The review presents the results of clinical trials of targeted anti-cytokine therapy which have revealed difficulties in controlling inflammation under the conditions of CHF. Identification of specific pro-inflammatory pathways in CHF pathogenesis will allow one to control inflammatory cascades, thus providing a prospective therapeutic strategy.

Biological therapy in the treatment of immune-mediated conditions has changed their course, the quality of life of patients and the prognosis of diseases. The accumulated by mankind 20 years of experience with the use of genetically engineered drugs has led to a number of questions regarding, among other issues, safety in the long-term administration of biological therapy. Patients suffering from ulcerative colitis revealed changes in cell membranes, reflecting their structural and energy characteristics. Long-term administration of Infliximab leads to the stabilization of energy processes in the erythrocyte membrane and improves homeostatic function of the kidneys.The aim of the study was to evaluate the effect of long-term use of TNF-α blockers (Infliximab) on the structural and functional characteristics of cell membranes and the functional state of the kidneys in patients with moderate to severe ulcerative colitis.Materials and methods. We examined 103 patients with moderate to severe ulcerative colitis during the period of acute attack and remission, of which 28 patients received basic therapy using the drug Infliximab (IFX) for 10 years, 75 patients received standard basic treatment. The patients of the biological therapy group took the original drug Infliximab – Remicade. The comparison group consisted of 30 healthy volunteers, comparable by sex and age. The analysis of the state of erythrocyte membranes was carried out using a set of physicochemical methods: UV spectroscopy (SF-46m spectrophotometer), high-performance thin-layer reaction paper chromatography, membrane ultrafiltration, erythrocyte NMR spectroscopy on phosphoric (31P) and proton (1H) nuclei. The functional state of the kidneys was evaluated using a dynamic scintigraphic study (with the technemage –Tc-99m).Results. Prolonged use of anticytokine therapy with Infliximab for 10 years in patients with ulcerative colitis, upon reaching deep remission, improves endogenous intoxication, restores the structural and functional characteristics of cell membranes, normalizes cell energy metabolism and does not negatively affect the functional state of the kidneys.

Asthma is a heterogeneous inflammatory disease characterized by airflow obstruction, wheezing, eosinophilia and neutrophilia of the airways. Identification of distinct inflammatory patterns characterizing asthma endotypes led to the development of novel therapeutic approaches. Cytokine or cytokine receptor targeting by therapeutic antibodies, such as anti-IL-4 and anti-IL-5, is now approved for severe asthma treatment. However, the complexity of cytokine networks in asthma should not be underestimated. Inhibition of one pro-inflammatory cytokine may lead to perturbed expression of another pro-inflammatory cytokine. Without understanding of the underlying mechanisms and defining the molecular predictors it may be difficult to control cytokine release that accompanies certain disease manifestations. Accumulating evidence suggests that in some cases a combined pharmacological inhibition of pathogenic cytokines, such as simultaneous blockade of IL-4 and IL-13 signaling, or blockade of upstream cytokines, such as TSLP, are more effective than single cytokine targeting. IL-6 and TNF are the important inflammatory mediators in the pathogenesis of asthma. Preliminary data suggests that combined pharmacological inhibition of TNF and IL-6 during asthma may be more efficient as compared to individual neutralization of these cytokines. Here we summarize recent findings in the field of anti-cytokine therapy of asthma and discuss immunological mechanisms by which simultaneous targeting of multiple cytokines as opposed to targeting of a single cytokine may improve disease outcomes.

Asthma is a heterogeneous inflammatory disease characterized by airflow obstruction, wheezing, eosinophilia and neutrophilia of the airways. Identification of distinct inflammatory patterns characterizing asthma endotypes led to the development of novel therapeutic approaches. Cytokine or cytokine receptor targeting by therapeutic antibodies, such as anti-IL-4 and anti-IL-5, is now approved for severe asthma treatment. However, the complexity of cytokine networks in asthma should not be underestimated. Inhibition of one pro-inflammatory cytokine may lead to perturbed expression of another pro-inflammatory cytokine. Without understanding of the underlying mechanisms and defining the molecular predictors it may be difficult to control cytokine release that accompanies certain disease manifestations. Accumulating evidence suggests that in some cases a combined pharmacological inhibition of pathogenic cytokines, such as simultaneous blockade of IL-4 and IL-13 signaling, or blockade of upstream cytokines, such as TSLP, are more effective than single cytokine targeting. IL-6 and TNF are the important inflammatory mediators in the pathogenesis of asthma. Preliminary data suggests that combined pharmacological inhibition of TNF and IL-6 during asthma may be more efficient as compared to individual neutralization of these cytokines. Here we summarize recent findings in the field of anti-cytokine therapy of asthma and discuss immunological mechanisms by which simultaneous targeting of multiple cytokines as opposed to targeting of a single cytokine may improve disease outcomes. [ABSTRACT FROM AUTHOR]

Rapidly progressive periodontitis is a serious disease that leads to rapid degradation of periodontal tissues and can lead to tooth loss at a relatively young age. The purpose of this article is to study the effectiveness of various modern methods in the treatment of this disease on an experimental model. A model of the studied pathology was created - a rat with a destroyed circular ligament of the tooth and a ligature applied to the base of the teeth. 5 study groups were formed, where various treatment methods were used: the appointment of soft food, the combination of intramuscular administration of vitamin C and prednisolone, the combination of tocilizumab and dexamethasone, and the combination of photodynamic therapy and tocilizumab. Histological material was taken from experimental animals and evaluated. The best results were noted in the group of photodynamic therapy and tocilizumab, where there was a better histological picture with minimal signs of the inflammatory process and satisfactory indicators of clinical dynamics, this approach showed high efficiency in resolving inflammation in the area of the affected foci. The 2nd place was taken by the combination of tocilizumab and dexamethasone, in this group, accelerated positive dynamics were noted compared to other groups, but the results of histological examination were worse than in group 1. In 3rd place - the combination of ascorbic acid with dexamethasone and the appointment of soft food, where there were almost no differences in terms of histological results and clinical picture compared to the control group. The combination of tocilizumab with photodynamic therapy is promising in the treatment of patients with rapidly progressive periodontitis, but additional human studies are required to include this type of treatment in clinical guidelines., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Masson SAS. All rights reserved.)

In the available literature, little attention has been paid to the assessment of psoriasis and the biological therapy used for it and the nervous system. The purpose of this article is to discuss the relationship between psoriasis and the nervous system as well as to analyze the mechanisms that lead to neurological complications during anticytokine therapies in psoriasis. However, this connection requires further analysis. The use of biological drugs in psoriasis, although it yields positive therapeutic results, is not without numerous side effects. Serious neurological side effects of the therapy are most often visible with the use of anti-TNF-alpha, which is why patients should be monitored for their potential occurrence. Early detection of complications and rapid discontinuation of treatment with the drug may potentially increase the patient’s chances of a full recovery or improvement of his/her neurological condition. It also seems reasonable that, in the case of complications occurring during anti-TNF-alpha therapy, some of the drugs from other groups should be included in the therapy.

Objective. To assess efficacy and tolerability of infliximab in pts with rheumatoid arthritis (RA) in real clinical practice.Materials and methods. 75 RA pts with high disease activity according to DAS 28 in 80% who received previous antirheumatic drugs without proper effect were included in an open clinical trial. DAS 28 and ACR criteria were used as primary outcome measures.Results. Infliximab administration provided significant clinical improvement in most pts. Already in a week after the first infusion 20% ACR improvement was achieved in 74% of pts. Significant improvement of all the main treatment effect parameters was achieved after the second infusion. ESR and CRP mean values normalized after the third infusion. Rheumatoid factor decrease was noted after 6 weeks. Mean values of tender and swollen joint counts significantly decreased but arthritis signs remained in a part of pts. Clinical remission was achieved in 4 (19%) from 21 pts completed a year’s course of treatment and in 4 pts the treatment was not effective. Serious adverse events requiring infliximab withdrawal (including infectious arthritis, hand phlegmon and bronchitis) appeared in 7 ptsConclusion. These results show high efficacy of infliximab and prove advisability of its administration in RA

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease, in which systemic inflammation plays a key role. This 6-month randomized double-blinded placebo-controlled study evaluates the possible effect of natural preparation Inflaminat on clinical symptoms of COPD, indicators of respiratory function, and exacerbation frequency in 60 patients with moderate severity of COPD. Inflaminat is a combination of natural ingredients black elder (Sambucus nigra L.) berries, violet (Viola tricolor L.) herb, and calendula (Calendula officinalis L.) flowers. The preparation has been previously demonstrated to possess anticytokine and anti-inflammatory effects in experimental studies. In present study, COPD dynamics were evaluated by means of BCSS (Breathlessness, Cough, and Sputum Scale) and spirometry tests. It was shown that 6-months Inflaminat administration led to significant decrease of BCSS points from 3.0 ± 0.6 to 1.9 ± 0.7, (p = 0.002) as well as significant increase of FEV1 from 66 ± 18% to 73 ± 17%, (p = 0.042); there were no beneficial dynamics in placebo group. Side effects associated with preparation administration were not identified. The results of the study suggest that Inflaminat may be employed in treatment of patients with moderate severity of COPD, since it has a positive effect on COPD symptoms according BCSS and indicators of respiratory function FEV1.

Abstract. Prevalence of TNFα gene promoter polymorphism at -857 position was investigated in normal persons and among patients with rheumatoid arthritis. We detected a relation of this polymorphism to the levels of TNFα production by mononuclear cells of healthy donors. Changes in relative frequencies of the TNFα genotypes have been shown in rheumatoid arthritis. The -857С>T polymorphism of TNFα gene proved to be informative as a molecular marker reflecting efficiency of anti-TNFα therapy in rheumatoid arthritis.

Aim of investigation. To study potential of tumor necrosis factor-alpha inhibitor Remicade to prevent complications and unfavorable course of ulcerative colitis.Material and methods. Therapeutic role of Remicade was investigated in one of three compared groups (24 patients) with unfavourable prognosis (frequent relapses, continuous course, steroid-dependency, steroid resistance) and risk of complications.Results. Early onset of anticytokine therapy by Remicade has allowed to decrease frequency of unfavourable course from 83,3% (comparison group) and 78,3% (control group) to 12,5% and to prevent complications. Data of investigation prove, that so-called «top down» therapy with application of Remicade improves quality of life scores of patients in comparison to placebo (in 1 year) for over 18%, for 25,4% (in 2 years) and for 27,8% (in 3 years). Beneficial effect of anticytokine therapy in ulcerative colitis patients was revealed by parameters of general health, viability, mental health and social functioning.Conclusions. In cases of the prognosis of complications and unfavourable course of disease Remicade treatment should be started in maximally early terms.

Aim of investigation. To outline predictive model for unfavorable course of ulcerative colitis (UC).Material and methods. Overall 232 patients with UC were included in original study, 84 of them had favourable and 148 – unfavorable course of disease.Results. Prognostic system for various variants of course of UC and its complications, 27 most significant clinical signs of disease based on differentiated clinical and statistical evaluation was submitted. To define indications for «top down» therapy with application of TNF-α blockers clinically approved algorithm of prognostic decisions for development of favorable (uncomplicated, rarely relapsing) and unfavorable (frequently relapsing, continuous, steroiddependent) variants of disease, and its complications was stated. Basing on high scores of sensitivity (accuracy) and specificity of prognosis, that were received, data proving potential of indications for early anticytokine treat­ment by infliximab to avoid unfavorable course and complications of ulcerative colitis are presented.

Juvenil idyopatik artrit (JIA), psöriyatik artrit ve diğer spondiloartritler gibi hastalıkları da içine alan fakat juvenil romatoid artrit (JRA) spektrumu içinde bulunmayan hastalıklar grubunun genel adıdır. Geçmişten günümüze pek çok ajan kullanılmış olmakla beraber hastalığın kesin tedavisi sağlanamamıştır. Medikal tedavinin amaçları, eklem fonksiyonlarını korumak, semptomları iyileştirmek, normal büyüme ve gelişmenin devamını sağlamaktır. Bu amaçla metotreksat, sülfasalazin, hidroksiklorokin gibi temel etkili anti romatizmal ilaçlar, kortikosteroidler, non steroid anti enflamatuvar ilaçlar kullanılmıştır. Romatizmal hastalıkların tedavisinde biyolojik ajanların kullanımıyla birlikte bu ajanlar JIA tedavisinde de denenmiş, kısa ve orta vadede umut verici sonuçlar elde edilmiştir. Bu ajanlardan etanercept, adalimumab ve abatacept JIA tedavisinde Amerika Gıda ve İlaç Dairesi (FDA) tarafından onaylanmış üç ajandır. Bu ajanların JIA'de uzun vadeli sonuçları merakla beklenmektedir. Geliştirilmiş ajanların klinik etkilerinin araştırılmasında Amerikan Romatizma Cemiyeti'nin (ARC) cevap düzeylerinin değerlendirildiği 'core set data' denilen parametreler kullanılmaktadır. Hastalığın kesin tedavisinin olmaması nedeniyle yeni tedavi araştırmaları halen sürdürülmektedir.

Biological methods are widely used in the treatment of intestinal inflammation (II). The TNFalpha inhibitor infliximab can quickly correct recurrence, provide long-term remission and reduce hormone need in many patients with hormone-resistant and hormone-dependent forms of Crohn's disease (CD) and ulcerative colitis (UC). However, almost half of II patients fail anticytokine therapy. Some clinical trials of biological medicines were stopped because of toxicity and complications. One of promising approaches to II treatment is now transplantation of mesenchymal stromal cells (MSC). The trial with participation of 85 CD and UC patients demonstrates that intravenous injection of allogenic MSC significantly prolongs duration of remission, reduces recurrence risk and is indicated for patients with hormone-resistent, hormone-dependent forms of II. Cell therapy can be also used in combined treatment of other gastrointestinal diseases, hepatic cirrhosis, in particular. A clinical trial is initiated of efficacy of transplantation of bone marrow autologous cells CD133+ for stimulation of regeneration of the liver in its extensive resection and cirrhosis. The future of this method depends on the results of controlled, randomized clinical trials.

Biological therapy is a thriving area of research and development, and is well established for chronic forms of rheumatoid arthritis (RA) and ankylosing spondylitis (AS). However, there is no clinically validated biological therapy for osteoarthritis (OA). Chronic forms of OA are increasingly viewed as an inflammatory disease. OA was largely regarded as a “wear and tear disease”. However, the disease is now believed to involve “low grade” inflammation and the growth of blood vessels and nerves from the subchondral bone into articular cartilage. This realization has focused research effort on the development and evaluation of biological therapy that targets proinflammatory mediators, angiogenic factors and cytokines in articular cartilage, subchondral bone and synovium in chronic forms of OA. This review article provides an overview of emerging biological therapy for OA, and discusses recent molecular targets implicated in angiogenesis and neurogenesis and progress with antibody-based therapy, calcitonin, and kartogenin, the small molecule stimulator of chondrogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Cells are exposed to a large variety of cytokines that signal through corresponding cytokine receptors. In healthy tissues or tissues that respond properly to disturbed homeostasis, the cross-talk of a few conserved core signaling pathways downstream of the cytokine receptors is translated into an adequate cellular response. In chronic inflammatory diseases but also in cancer associated inflammation cytokine expression and the downstream signaling networks are dysregulated. Targeted therapies are aimed at the specific interference with dysregulated cytokine signaling. In this article some concepts of pharmacological intervention with cytokine signaling will be reviewed including biologics that target cytokines and cytokine receptors. Receptor fusion proteins consisting of the ligand-binding domains of cytokine receptors are highly specific and potent cytokine inhibitors and will be discussed in more detail. [Copyright &y& Elsevier]

Treatment with a combination of artrofoon and anaferon significantly reduced clinical and laboratory parameters of rheumatoid inflammation and significantly decreased the content of antiinflammatory cytokines in the blood. These findings attest to antiinflammatory and immunomodulating effects of these preparations. [ABSTRACT FROM AUTHOR]

In the available literature, little attention has been paid to the assessment of psoriasis and the biological therapy used for it and the nervous system. The purpose of this article is to discuss the relationship between psoriasis and the nervous system as well as to analyze the mechanisms that lead to neurological complications during anticytokine therapies in psoriasis. However, this connection requires further analysis. The use of biological drugs in psoriasis, although it yields positive therapeutic results, is not without numerous side effects. Serious neurological side effects of the therapy are most often visible with the use of anti-TNF-alpha, which is why patients should be monitored for their potential occurrence. Early detection of complications and rapid discontinuation of treatment with the drug may potentially increase the patient's chances of a full recovery or improvement of his/her neurological condition. It also seems reasonable that, in the case of complications occurring during anti-TNF-alpha therapy, some of the drugs from other groups should be included in the therapy. [ABSTRACT FROM AUTHOR]

Cytokine activation or dysregulation is implied in a variety of painful disease states. Numerous experimental studies provide evidence that proinflammatory cytokines induce or facilitate neuropathic pain. Cytokine levels are rapidly and markedly upregulated in the peripheral nerves, dorsal root ganglia, spinal cord and in particular regions of the brain, after peripheral nerve injuries. Direct receptor-mediated actions on afferent nerve fibers as well as cytokine effects involving further mediators have been reported. Whereas direct application of exogenous proinflammatory cytokines induces pain, blockade of these cytokines or application of anti-inflammatory cytokines reduces pain behavior in most experimental paradigms. Cytokine measurements may identify patients at risk of developing chronic pain associated with their neuropathic conditions, as in the examples of peripheral neuropathies and postherpetic neuralgia. Anticytokine agents currently on the market are effective for the treatment of mostly inflammatory pain conditions, and are starting to be introduced for neuropathic pain states; however, their use is limited by potential life-threatening complications. Owing to the pleiotropy and redundancy of the cytokine system, the successful approach may not be inhibition of one particular cytokine but strategies shifting the balance between pro- and anti-inflammatory cytokines in properly selected patients. Agents that specifically target downstream signaling molecules may provide hope for safer and more specific therapies. [ABSTRACT FROM AUTHOR]

Development of autoimmune process in the organism is mainly due to disturbances in cytokine production. Hyperproduction of cytokines can be induced by certain viruses, bacteria, genetic factors, and other triggers. Cytokines act in an interrelated immune cascade with interferon-γ (IFN-γ) playing a central role. Blocking IFN-γ is the safest and most effective method of treatment of TH1-mediated autoimmune diseases, although blocking other cytokines in the cascade may lead to some therapeutic effect as well. Disturbances in the synthesis of IFN-γ and, possibly, IFN-α may lead to autoantigen formation. Antibodies to IFN-γ have shown very pronounced therapeutic effect in multiple autoimmune conditions, especially in autoimmune skin diseases. Anticytokine therapy that we have pioneered may be the main pathogenetic method of treatment of a variety of autoimmune conditions. [ABSTRACT FROM AUTHOR]

We pioneered anticytokine therapy (ACT) in 1974 and 1989, proposing to remove interferon (IFN) and tumor necrosis factor (TNF)-α together with IFNs to treat various autoimmune diseases, including AIDS. This hypothesis was confirmed in different laboratories and opened a new line to produce and test different anticytokines. We have had good, sometimes striking results treating various Th1-mediated autoimmune diseases, including inflammatory skin diseases, using anti-IFN-γ and sometimes anti-TNF-α. Anti-IFN-γ may be a universal treatment for these conditions. Because TNF-α inhibitors, now successfully used in certain autoimmune disorders, have many severe side effects, there are opportunities for the development of other ACT and TNF-α antagonists with fewer side effects. [ABSTRACT FROM AUTHOR]

Systemic inflammation is characterized by the induction of pro-inflammatory cytokines, the increased level of which in the blood of patients with chronic heart failure (CHF) correlates with unfavorable clinical outcomes. However, it is unclear whether pro-inflammatory cytokines are the cause or the consequence of the disease progression. CHF with preserved ejection fraction and CHF with reduced ejection fraction demonstrate different inflammatory features, which suggests different degrees of pro-inflammatory pathway activation. The review deals with participation of pro-inflammatory cytokines in pathophysiological processes of CHF development, emphasizing the role of interleukin-6 activation and the effects of accompanying diseases on the course of systemic inflammation. The search for new approaches to prevention and therapy of CHF remains actual. The review presents the results of clinical trials of targeted anti-cytokine therapy which have revealed difficulties in controlling inflammation under the conditions of CHF. Identification of specific pro-inflammatory pathways in CHF pathogenesis will allow one to control inflammatory cascades, thus providing a prospective therapeutic strategy.

Chronic obstructive pulmonary disease (COPD) is a multifactorial disease, in which systemic inflammation plays a key role. This 6-month randomized double-blinded placebo-controlled study evaluates the possible effect of natural preparation Inflaminat on clinical symptoms of COPD, indicators of respiratory function, and exacerbation frequency in 60 patients with moderate severity of COPD. Inflaminat is a combination of natural ingredients black elder (Sambucus nigra L.) berries, violet (Viola tricolor L.) herb, and calendula (Calendula officinalis L.) flowers. The preparation has been previously demonstrated to possess anticytokine and anti-inflammatory effects in experimental studies. In present study, COPD dynamics were evaluated by means of BCSS (Breathlessness, Cough, and Sputum Scale) and spirometry tests. It was shown that 6-months Inflaminat administration led to significant decrease of BCSS points from 3.0 ± 0.6 to 1.9 ± 0.7, (p = 0.002) as well as significant increase of FEV1 from 66 ± 18% to 73 ± 17%, (p = 0.042); there were no beneficial dynamics in placebo group. Side effects associated with preparation administration were not identified. The results of the study suggest that Inflaminat may be employed in treatment of patients with moderate severity of COPD, since it has a positive effect on COPD symptoms according BCSS and indicators of respiratory function FEV1. [ABSTRACT FROM AUTHOR]