Interleukin-1 Inhibitors Research Articles

Immunization With Recombinant Haemonchus contortus Y75B8A.8 Partially Protects Local Crossbred Female Goats From Haemonchus contortus Infection.

Haemonchus contortus Y75B8A.8 (Hc8) derived from H. contortus excretory–secretory (ES) products was identified as a functional inhibitor of goat interleukin 2 (IL-2). It may act as a vaccine candidate for the development of therapeutic strategies against H. contortus infection. In this research, recombinant Hc8 (rHc8) and goat anti-rHc8 polyclonal antibodies were employed to evaluate the protective capacities of Hc8 antigen against H. contortus infections via active and passive immunization trials, respectively. In both trials, local crossbred female goats aged 9–12 months old were randomly divided into three groups, five in each group, respectively. Parasitological examinations, including fecal egg counts (FEC), cumulative FEC (cFEC), and worm burdens, were performed. In addition, antibody levels in mucosal homogenate (MH) samples and hematological and immunological parameters were detected. In the passive trial, goats were intravenously immunized with 5 mg total IgG containing anti-rHc8 goat polyclonal antibodies. After twice immunization, compared with the challenged control group, cFEC was reduced by 39%. In addition, there was a 46% reduction of worm burdens compared with the challenged controls. In the active immunization trials, 500 μg of recombinant Hc8 protein was given subcutaneously twice to 9–12-month-old local crossbred female goats with a 2-week interval, resulting in the generation of high levels of antigen-specific circulating antibodies. Besides, cFEC and abomasal worm burden were reduced by 70 and 55%, respectively, compared with the challenged control group. In addition, immunized goats had higher mucosal homogenate IgA and hemoglobin levels than the challenged controls in both passive and active immunization trials. These preliminary results demonstrated the immunoprophylactic effects of Hc8 antigen and will inform new studies on ES proteins in developing subunit recombinant vaccines against H. contortus.

Modulatory effect of IL-1 inhibition following lipopolysaccharide-induced neuroinflammation in neonatal microglia and astrocytes.

Inflammation-induced white matter injury (WMI) in preterm infants is characterized by microglia activation, astrogliosis, oxidative stress and neurodevelopmental impairments. Microglia and astrocytes activation can be described under a broad spectrum of activation profile with extremes described as pro-inflammatory/neurotoxic (M1 microglia or A1 astrocyte) or anti-inflammatory/neuroprotective (M2 microglia or A2 astrocyte) in response to stimuli including lipopolysaccharide (LPS) and interleukin 1 (IL-1). As IL-1 signalling pathway has been posited as a major driver of inflammation-induced perinatal WMI, our aim was to evaluate the contribution of IL-1 modulation in LPS-induced microglia and astrocyte activation. Primary neonatal cell co-cultures of astrocytes and microglia were treated with LPS (100 ng/ml) for 8h or 24 h. Two distinct IL-1 receptor antagonists, Rytvela or Kineret (1μg/ml), were added simultaneously with LPS to respectively modulate or block IL-1 receptor. Medium was collected to measure levels of IL-1β. Expression of markers related to pro- and anti-inflammatory microglia and astrocyte activation profiles and antioxidant genes were assessed. At 8h, LPS exposure induced pro- (M1/A1) and anti-inflammatory (M2/A2) marker expression and inhibited antioxidant gene expression in microglia and astrocytes. By 24 h, continuous LPS exposure increased pro-inflammatory and neurotoxic microglial and astrocytic markers (M1/A1), as well as antioxidant genes. Administration of IL-1 antagonists Rytvela and Kineret with continuous LPS exposure had no significant effect on modulation of specific microglia and astrocyte activation pathways. We show that LPS effects on in vitro neonatal microglia and astrocytes co-cultures are time dependent eliciting a number of pro- and anti-inflammatory responses during the acute phase of inflammation (8h), which shift towards pro-inflammatory and neurotoxic factors by 24 h. Although LPS-induced inflammation led to abundant IL-1 expression, IL-1 inhibition had no significant impact on in vitro modulation of microglia and astrocyte activation pathways towards M2 and A2 activation profile.

Case Report: Cardiac Tamponade in Association With Cytokine Release Syndrome Following CAR-T Cell Therapy

Chimeric antigen receptor T (CAR-T) cell therapy has been shown to have substantial efficacy against refractory hematopoietic malignancies. However, it frequently causes cytokine release syndrome (CRS) as a treatment-specific adverse event. Although cardiovascular events associated with CAR-T cell therapy have been increasingly reported recently, pericardial disease is a rare complication and its clinical course is not well characterized. Here, we report a case of acute pericardial effusion with cardiac tamponade after CAR-T cell therapy.Case SummaryA 59-year-old man with refractory diffuse large B-cell lymphoma underwent CAR-T cell therapy. Grade 2 CRS was observed on day 0; it progressed to grade 4 on day 7 and was accompanied by a fever over 39°C, hypoxia requiring intubation, hypotension requiring the use of a vasopressor agent, and supraventricular tachycardia. Although cardiac function was preserved, marked pericardial effusion with the collapse of the right heart was detected on echocardiography. Since pericardiocentesis was considered to have a high complication risk due to severe myelosuppression, medications for CRS were prioritized. Tocilizumab, an interleukin-6 inhibitor, and high-dose methylprednisolone (1 g/day for 3 days) were administered for the management of severe CRS. On day 8, the pericardial effusion decreased, and the hemodynamic status markedly stabilized. CRS did not exacerbate after the steroid dose was reduced. Further, lymphoma size reduced after the induction of CAR-T cell therapy, and tumor regrowth was not noted at 3 months after CAR-T cell infusion.ConclusionInterleukin-6 pathway inhibitors and corticosteroid therapy should be considered in the context of CRS for significant pericardial effusion after CAR-T cell therapy in the acute phase.

Clinical and economic analysis of biologic agents and targeted synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: cost per responder model

AIM. To compare the cost per responder (CPR) between different groups of biologic agents and targeted synthetic disease-modifying antirheumatic drugs in patients with rheumatoid arthritis (RA). Materials and Methods. A total of 320 patients with RA were included in the study. Patients were divided into 4 groups (n=80 in each group): group 1 received B cell-depleting agent (rituximab), group 2 – TNF-alpha (α) inhibitors, group 3 –interleukin-6 inhibitor (tocilizumab), and group 4 – Janus kinase inhibitor (tofacitinib). The effectiveness of therapy was assessed using the generally accepted index of rheumatoid arthritis activity DAS28 and the dynamics of this index after 12 months of therapy. A good response on DAS28 (current DAS28 scores of 3.2 or less with reductions in DAS28 of more than 1.2) was accepted as a response to therapy. For the leading CPR-DAS28 drugs, an ad- ditional CPR study was performed using the SDAI, CDAI, and RAPID-3 indices. Results. A good response on DAS28 was observed more frequently in group 3 (56.3%) and group 4 (6.3%) compared to group 1 (11.5%, p<0.05 in both cases) and group 2 patients (22.5%, p<0.05 in both cases). CPR-DAS28 in group 3 was RUB 1094772.6, in group 4 – RUB 1089201.3; and that was 3.3 times lower than in group 1 (RUB 3587662.2, p<0.05 in both cases) and 2.3 times lower than in group 4 (RUB 2545747.3, p<0.05 in both cases). In group 3 (tocilizumab) CPR-SDAI was RUB 786867.9, CPR-CDAI – RUB 774285.7, and CPR-RAPID-3 – RUB 786867.9. In group 4 (tofacitinib) CPR-SDAI was RUB 1048831.2, CPR-CDAI – RUB 1088379.9, and CPR-RAPID – RUB 915730.8. Conclusion. CPR were lower with interleukin-6 inhibitor and Janus kinase inhibitor therapy than with B cell-depleting agent and TNF-α inhibitors therapy. Determination of CPR by SDAI, CDAI, and RAPID-3 indices revealed an advantage of interleukin-6 inhibitor therapy over Janus kinase inhibitor therapy.

Fengreqing Oral Liquid Exerts Anti-Inflammatory Effects by Promoting Apoptosis and Inhibiting PI3K/AKT and NF-κB Signaling Pathways.

Fengreqing oral liquid (FOL), a Chinese patent drug frequently used in clinical practice in China, is effective in treating inflammatory diseases of the upper respiratory tract such as colds and flu. However, its anti-inflammatory effects and mechanisms remain to be elucidated. In this study, the anti-inflammatory effects of FOL and its mechanisms on PI3K/AKT and NF-κB signaling pathways in LPS-induced RAW264.7 cells were explored, as well as the regulatory effect of FOL on apoptosis. In addition, the potential of FOL for the treatment of acute lung injury was explored in LPS-induced ALI mice. The results showed that treatment with FOL significantly reduced the levels of interleukin 1β (IL-1β), interleukin 6 (IL-6), nitric oxide (NO), and tumor necrosis factor α (TNF-α) in the supernatant of LPS-induced RAW264.7 cells, and also significantly reduced the phosphorylated protein levels of PI3K and AKT in the PI3K/AKT signaling pathway and also protein levels of NF-κB p50, phosphorylated NF-κB p65, and IκBα in the NF-κB signaling pathway. In addition, the results showed that FOL induced apoptosis in LPS-induced RAW264.7 cells at the level of 80%–90%, and significantly increased the protein expression levels of the pro-apoptotic Bax and cleaved-caspase-3. In LPS-induced ALI mice, FOL administration showed inhibition of IL-1β, IL-6, and TNF-α in Bronchoalveolar lavage fluid (BALF) and decreased protein expression levels of PI3K, AKT, NF-κB p50, and NF-κB p65, and elevated protein expression levels of Bax and cleaved-caspase-3 significantly. These results suggest that FOL may exert anti-inflammatory effects by inhibiting the PI3K/AKT signaling pathway to promote apoptosis and leading to attenuated activation of the NF-κB signaling pathway.

Antibody responses to inactivated and mRNA SARS-CoV-2 vaccines in familial Mediterranean fever patients treated with interleukin-1 inhibitors.

Antibody responses to inactivated and mRNA SARS-CoV-2 vaccines in familial Mediterranean fever patients treated with interleukin-1 inhibitors.

Evaluating the structural and immune mechanism of Interleukin-6 for the investigation of goat milk peptides as potential treatments for COVID-19

The function of Immune control, haematopoiesis, and inflammation all depend on the cytokine Interleukin 6 (IL-6), and higher expression of IL-6 is seen in COVID-19 and other diseases. The immune protein IL-6 activation is dependent on binding interactions with IL-6Rα, mIL-6R, and sIL-6R for its cellular function. Termination of these reaction could benefit for controlling the over-expression in COVID-19 patients and that may arise as inhibitors for controlling COVID-19. Traditionally, the goat milk has been prescribed as medicine in ayurvedic practice and through this work, we have explored the benefits of peptides from goat milk as IL-6 inhibitors, and it have the potential of inhibiting the over expression of IL-6 and control the COVID-19 disease. Computational experiments have shown that goat peptides had strong interactions with IL-6, with higher scoring profiles and energy efficiency ranging from −6.00 kcal/mol to −9.00 kcal/mol in docking score and −39.00 kcal/mol in binding energy. Especially the YLGYLEQLLR, VLVLDTDYK and AMKPWIQPK peptides from goat milk holds better scoring and shows strong interactions were identified as the most potential IL-6 inhibitor candidates in this study. Peptides from Goat proteins, which are capable of binding to the IL-6 receptor with strong binding conformations, have no negative effects on other immune system proteins.

Drug Investigation to Dampen the Comorbidity of Rheumatoid Arthritis and Osteoporosis via Molecular Docking Test.

At present, most rheumatoid arthritis (RA) patients are at risk of osteoporosis (OP), which is increased by 1.5 times compared to non-RA individuals. Hence, we investigated overlapping targets related directly to the occurrence and development of RA and OP through public databases (DisGeNET, and OMIM) and literature. A total of 678 overlapping targets were considered as comorbid factors, and 604 out of 678 were correlated with one another. Interleukin 6 (IL-6), with the highest degree of value in terms of protein–protein interaction (PPI), was considered to be a core target against comorbidity. We identified 31 existing small molecules (< 1000 g/mol) as IL-6 inhibitors, and 19 ligands were selected by the 3 primary criteria (Lipinski’s rule, TPSA, and binding energy). We postulated that MD2-TLR4-IN-1 (PubChem ID: 138454798), as confirmed by the three criteria, was the key ligand to alleviate comorbidity between RA and OP. In conclusion, we described a promising active ligand (MD2-TLR4-IN-1), and a potential target (IL-6) against comorbidity of RA and OP, providing scientific evidence for a further clinical trial.

Ibrutinib reverses IL-6-induced osimertinib resistance through inhibition of Laminin \u03b15/FAK signaling

Osimertinib, a 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is the first-line standard-of-care for EGFR-mutant non-small cell lung cancer (NSCLC) patients, while acquired drug resistance will inevitably occur. Interleukin-6 (IL-6) is a keystone cytokine in inflammation and cancer, while its role in osimertinib efficacy was unknown. Here we show that clinically, plasma IL-6 level predicts osimertinib efficacy in EGFR mutant NSCLC patients. Highly increased IL-6 levels are found in patients with acquired resistance to osimertinib. Addition of IL-6 or exogenous overexpression of IL-6 directly induces osimertinib resistance. Proteomics reveals LAMA5 (Laminin α5) and PTK2, protein tyrosine kinase 2, also called focal adhesion kinase (FAK), are activated in osimertinib-resistant cells, and siRNA knockdown of LAMA5 or PTK2 reverses IL-6-mediated osimertinib resistance. Next, using a large-scale compound screening, we identify ibrutinib as a potent inhibitor of IL-6 and Laminin α5/FAK signaling, which shows synergy with osimertinib in osimertinib-resistant cells with high IL-6 levels, but not in those with low IL-6 levels. In vivo, this combination inhibits tumor growth of xenografts bearing osimertinib-resistant tumors. Taken together, we conclude that Laminin α5/FAK signaling is responsible for IL-6-induced osimertinib resistance, which could be reversed by combination of ibrutinib and osimertinib.

Dynamics of T- and B-lymphocytes in patients with rheumatoid arthritis, receiving biological disease-modifying antirheumatic drugs

Objective: assessment of the dynamics of T- and B-lymphocytes subpopulations in rheumatoid arthritis (RA) during therapy with synthetic disease-modifying antirheumatic drugs (sDMARDs) and biological disease-modifying antirheumatic drugs (bDMARDs): inhibitors of tumor necrosis factor α (iTNFα) and an inhibitor of interleukin 6 receptors (iIL6R ).Patients and methods. The study included 77 patients with RA who met the 2010 ACR/EULAR criteria (mean age 56 [44; 62] years). Group 1 included 30 (27 women and 3 men) patients with early RA who had not previously received therapy. Group 2 included 20 (14 women and 6 men) patients on sDMARD therapy who were prescribed iTNFα for the first time. The 3rd group is represented by retrospective data of 27 (23 women and 4 men) patients who previously used sDMARDs (MT – 85%, leflunomide – LEF – 15%), in whom iIL6R therapy was initiated for the first time. All study participants initially and 6 months later underwent immunophenotyping of T- and B-lymphocytes by flow cytofluorometry according to the standard method.Results and discussion. In all groups, there were no significant changes in the studied T-lymphocyte profile during 6 months of follow-up. When comparing the immunogram data of patients treated with sDMARDs and iTNFα, no significant differences in subpopulations of B-lymphocytes were found. At baseline, the iIL6R group had higher levels of naive B-lymphocytes and plasmablasts and low concentrations of «switched» B-cells. For all methods of treatment, the number of «switched» B-cells decreased, while plasmablasts and plasma cells increased.Conclusion. From the data obtained, it follows that the simultaneous decrease in the levels of memory B-cells and their «switched» forms, plasmablasts and plasma cells can be used as a marker for the early administration of drugs that disrupt the differentiation of B-lymphocytes, in particular, iIL6R.

Timeline Approach for the Treatment of COVID-19 - An Overview

The outbreak of novel CORONA virus has taken many lives since the onset of the pandemic. On December 31, 2019, the World Health Organization received reports of pneumonia with an unknown aetiology in the Chinese city of Wuhan. Chinese officials discovered a new coronavirus as the source of the outbreak on 7 January 2020, provisionally named "2019-nCoV." The World Health Organisation has recorded 4,215,966 confirmed cases and 79,758 fatalities by the end of December 2020, both of which have been raised quickly. The main symptoms of this disease that were recorded so far include fever in 85% of patients, dyspnoea in 70–80%, cough in 40–80%, smell and taste dysfunction in 50%, myalgia in 30%, and gastrointestinal problems in 10–30%. To reduce the count of patients entering into severity phase many diagnostic criteria were employed that includes Reverse Transcriptase Polymerase Chain Reaction test, High Resolution Computed Tomography scan, measuring the levels of Creatinine Reactive Protein, Domain Dimer, Serum Ferritin to assess the level of inflammation. Nevertheless, of all the treatment strategies employed by various researchers, doctors, scientists, and vast number of organizations and institutions, this review article provides the treatment strategies to treat Covid-19 according to the timeline progression of the disease, gleaning the information from various sources. The treatment protocol includes the right time diagnosis and starting the treatment with remdesivir, corticosteroids, anti-platelet agents and Interleukin-6 inhibitors, Janus Kinase inhibitors basing on the severity of the disease. But the crucial part to treat Covid-19 lies in establishing the right therapy at the right time. Keywords: Remdesivir; Corticosteroids; Anti-platelet agents; Cytokine storm; C-reactive protein; D-Dimer; Serum ferritin; RT-PCR, Janus kinase inhibitors.

Design, molecular Docking, synthesis and evaluation of xanthoxylin hybrids as dual inhibitors of IL-6 and acetylcholinesterase for Alzheimer's disease

Interleukin-6 (IL-6) and acetylcholinesterase (AChE) are two important targets implicated in progression of Alzheimer's Disease (AD). Simultaneous inhibition of both IL-6 and AChE by a molecule presents an effective strategy for the treatment of AD. In this study, the pharmacophores for inhibition of IL-6 and AChE are identified, and coupled to design novel molecules capable of acting as dual inhibitors of IL-6 and AChE. Literature review reveals that xanthoxylin and a disubstituted or a carbamoyl amine are pharmacophore for IL-6 and AChE inhibition, respectively. Therefore, xanthoxylin is coupled with various disubstituted amines or carbamoyl amines through alkyl linkers of different lengths (1–4 carbon atoms) to design two series of 80 compounds. All designed compounds are docked in AChE. Based on their docking score, 15 compounds are selected for synthesis and evaluation of AChE inhibitory activity. The compounds showing > 45% inhibition of EeAChE are selected for evaluation of IL-6 and butyrylcholinesterase (BuChE) inhibitory activities. Compound Y13g is found to be the most potent inhibitor of EeAChE, BuChE and IL-6. It is further evaluated in vivo using STZ-induced amnesia model in mice at three doses (0.2, 0.4 and 0.8 mg/kg), wherein it shows dose-dependent effects. At 0.8 mg/kg, it reverses the STZ-induced memory deficit, and shows histopathology similarly as in normal animals. The findings suggest that compounds derived from coupling of xanthoxylin with piperazine through a 3-carbon chain provides a useful template for the development of new chemical entities effective against AD.

Isoxanthanol has protective and anti-inflammatory effects on subchondral bone deterioration in experimental osteoarthritic rat model.

In the present study isoxanthanol was investigated for treatment of monosodium iodoacetate (MIA)-induced osteoarthritis (OA) in vivo. The study demonstrated that isoxanthanol inhibited excessive release of interleukin-6, NO and PGE2 in RAW264.7 cells treated with LPS in dose dependent manner. The effects of isoxanthanol were examined in a rat model of osteoarthritis (OA) and observed to amelio-rate inflammatory damage and protect against OA. Moreover, in vivo data also confirmed inhibition of interleukin-6, NO and PGE2 levels in LPS-induced OA-rats. Deterioration of knee subchondral bone in LPS-induced OA-rats was also prevented effectively by isoxanthanol-treatment. Therefore, isoxanthanol prevents subchondral bone deterioration in OA rats via targeting inflammatory processes.

Improved anti-inflammatory and anticancer properties of celecoxib loaded zinc oxide and magnesium oxide nanoclusters: A molecular docking and density functional theory simulation

Present study offers great prospects for the adsorption of anti-inflammatory celecoxib molecule (CXB) over the surface of zinc oxide (Zn12O12) and magnesium oxide (Mg12O12) nanoclusters in several environments by performing robust theoretical calculations. Density functional theory (DFT), time-dependent density functional theory (TDDFT) and molecular docking calculations have been extensively carried out to predict the foremost optimum site of CXB adsorption. It has been observed that the CXB molecule prefers to be adsorbed by its SO2 site on the Zn-O and Mg-O bonds of the Zn12O12 and Mg12O12 nanoclusters instead of NH2 and NH sites, where electrostatic interactions dominate over the bonding characteristics of the conjugate complexes. Furthermore, the presence of interactions between the CXB molecule and nanoclusters has also been evidenced by the UV–Vis absorption spectra and IR spectra. Molecular docking analysis has revealed that both adsorption states including CXB/Zn12O12 and CXB/Mg12O12 have good inhibitory potential against protein tumor necrosis factor alpha (TNF-α) and Interleukin-1 (IL-1), and human epidermal growth factor receptor 2 (HER2). Hence they might be explored as efficient TNF-α, IL-1, and HER2 inhibitors. Hence from the study, it can be anticipated that these nanoclusters can behave as an appropriate biomedical carrier for the CXB drug delivery.

The synergistic antitumor effect of IL-6 neutralization with NVP-BEZ235 in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) still ranks among the top cancers worldwide with high incidence and mortality. Due to abnormal activation of the PI3K/AKT/mTOR signalling pathway in HCC, targeting this pathway represents a potential therapeutic strategy. NVP-BEZ235 is a novel dual-targeted ATP-competitive PI3K/mTOR inhibitor that has shown effective antitumor effects. In this study, we found that interleukin-6 (IL-6) was significantly increased after exposure to NVP-BEZ235, and we proposed a treatment in which an anti-IL-6 antibody was combined with NVP-BEZ235 for HCC. In vitro results revealed that targeted inhibition of IL-6 potentiated the antitumor effects of NVP-BEZ235 in HCC cells. The mechanism might be attributed to their synergistic inhibitory activity on the PI3K/AKT/mTOR signalling pathway. Furthermore, an in vivo study demonstrated that combined administration of NVP-BEZ235 and anti-IL-6 Ab reduced HCC tumour load more effectively than either NVP-BEZ235 or anti-IL-6 Ab treatment alone. These findings add guidance value to the analysis of HCC and provide a reference for clinical treatment.

Phase Ib/II trial of siltuximab and spartalizumab in patients in metastatic pancreatic cancer.

TPS626 Background: Interleukin-6 (IL-6) is associated with carcinogenesis, immune suppression, and poor prognosis in pancreatic adenocarcinoma (PDAC). Preclinical data demonstrated dual inhibition of IL-6 and (programmed death ligand-1) PD-L1 facilitates CD8+ T cell migration into pancreatic tumors and was effective in controlling tumor growth in syngeneic and genetically engineered PDAC mouse models. Siltuximab is a chimeric monoclonal antibody which targets the IL-6 molecule specifically and spartalizumab is a high-affinity ligand-blocking humanized IgG4 antibody against the PD-1 receptor. Based on this preclinical rationale, we developed a phase Ib/II trial to determine the recommended phase II dose (RP2D), evaluate the safety, toxicity profile, preliminary antitumor activity, and immunogenicity of the siltuximab and spartalizumab in patients with previously treated metastatic PDAC. Methods: The phase Ib trial design is standard 3+3. Primary endpoint is to determine RP2D. Siltuximab is administered intravenously (IV) in three dose levels of 6 mg/kg (DL1), 11 mg/kg (DL2), 9 mg/kg (only if 2 DLTs observed on DL2) every 3 weeks with spartalizumab at 300 mg IV every 3 weeks. Eligible patients must have stage IV PDAC who have failed at least one prior therapy age ≥18 years, ECOG PS 0-1, no prior anti PD-1 or anti-PD-L1 agent. After RP2D is established, an expansion phase will enroll 24 patients with PDAC. Pre and on-treatment biopsy will be performed in 24 patients in the expansion cohort for correlative analysis. Pre-treatment and on-treatment peripheral blood samples will be collected from all patients. In the expansion phase patients will receive initial cycle (every 3 weeks) treatment with either spartalizumab or spartalizumab plus siltuximab and then starting cycle 2 all patients receive the combination following the on-treatment research biopsy. This design will enable us to evaluate the immunological effects of spartalizumab alone versus the combination in the tumor microenvironment and peripheral blood. This study was activated in January 2020 and to date 12 patients were enrolled in dose escalation phase. The dose expansion phase has recently started accrual. Clinical trial information: NCT04191421.

A comparative analysis of autologous conditioned serum (ACS) &amp; platelet‐rich plasma (PRP) in early osteoarthrosis of knee

Osteoarthrosis represents a failure of the diarthrodial, synovial lined joint. Among the elderly, knee osteoarthrosis is the most frequent cause of chronic disability. The prevalence of osteoarthrosis is rising in the Indian population because of the increased life span. Platelet rich plasma (PRP) is defined as a volume of plasma with a platelet concentration more than that in the peripheral blood. Many basic, preclinical and even clinical case studies and trails report PRP’s efficacy to improve musculoskeletal conditions including osteoarthrosis. Autologous conditioned serum (ACS) is an autologous blood product eNRIched with interleukin-1 receptor antagonist (il-1ra), a naturally occurring inhibitor of interleukin-1 (il-1). Our study on ACS &amp; platelet rich plasma has thrown up an exciting choice of treatment modality in knee osteoarthrosis, and it has proved efficient in observation period of two years.

Interleukin-1 Inhibitors and Vaccination Including COVID-19 in Inflammatory Rheumatic Diseases: A Nonsystematic Review.

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.

Assessment of Clinical Efficacy of Dexamethasone in Patients with Moderate COVID-19

The host immune response, primarily manifested by hypercytokinemia, obviously plays a key role in the development of severe novel coronavirus disease, COVID-19. Currently, numerous therapies aimed at suppressing the hyperinflammatory response and the "cytokine storm" are being investigated. One of these methods is the use of corticosteroids, particularly dexamethasone.The aim was to assess the clinical efficacy of dexamethasone in patients with moderate bilateral multifocal pneumonia caused by SARS CoV-2 virus.Material and methods. Sixty-nine patients aged from 31 to 88 years hospitalized in Almazov National Research Center and the Semashko City Hospital No 38 with SARS CoV-2 coronavirus infection complicated by moderate (semiquantitative visual pulmonary lesion grading system CT 2-3 corresponding to 25-50% and 50-75% parenchymal involvement, respectively) community-acquired bilateral multifocal pneumonia were retrospectively studied. Group 1 included 39 patients with moderate coronavirus infection who received therapy according to the current version of the temporary guidelines (TG) of the Ministry of Health of the Russian Federation, including dexamethasone. The drug was administered parenterally twice daily in a dosage of 12 mg in the morning and 8 mg in the evening for the first three days, then the dose was gradually reduced over 5-7 days. No Interleukin-6 inhibitors were administered to patients in this group. Group 2 was composed of 30 patients who received therapy according to the current version of TG, including a parenteral interleukin-6 inhibitor (tocilizumab, olokizumab, or sarilumab) following the standard regimen. Patients in this group were not administered with dexamethasone.Results. CT scans corresponding to severity grade 3 and 4 (50-75% and &gt;75% involvement, respectively) lung lesions on Day 7 were found in 35.89% of group 1 patients, while similar CT scans were found in 50% of patients who received interleukin-6 inhibitors (P=0.33). On Day 14 no significant differences in this parameter were revealed as well. Duration of fever in the dexamethasone group was 3.69 (0.62;6.76) days, while in the control group it was 3.95 (0.61;7.29) days (P=0.98). There was a tendency to decreased blood Creactive protein (CRP) values in the dexamethasone group on days 5 and 7. The frequency of transfer of patients to the ICU and hospital stay duration did not differ significantly between the groups.Conclusion. Dexamethasone has comparable clinical efficacy with IL-6 antagonists in the comprehensive treatment of patients with moderate COVID-19 disease, which is confirmed by the chest CT evolution, duration of fever, and changes in serum CRP.

Efficacy and safety of biologic agents for the treatment of osteoarthritis: a meta-analysis of randomized placebo-controlled trials.

Background:We aimed to evaluate the efficacy and safety of biologic agents targeting three main cytokines, that is, nerve growth factor (NGF), interleukin-1 (IL-1), and tumor necrosis factor-α (TNF-α), for osteoarthritis (OA) treatment.Methods:Databases (PubMed, Embase, and Cochrane Library) and ClinicalTrials.gov were systematically searched for randomized placebo-controlled trials (RCTs) of biologic agents from inception to November 15, 2020. The outcomes were the mean change in pain, function scores, and the risk of adverse effects (AEs).Results:Out of the 28 studies with 29 RCTs (8555 individuals) included, biologic agents were superior to placebo in pain relief (standardized mean difference [SMD] = 0.28, 95% confidence interval [CI] = 0.17–0.38, p < 0.001) and function improvement (SMD = 0.30, 95% CI = 0.18–0.43, p < 0.001). The incidence of any AEs (risk ratio [RR] = 1.09, 95% CI = 1.05–1.14, p < 0.001) and discontinuations due to AEs (RR = 1.39, 95% CI = 1.05–1.83, p = 0.021) were higher following treatment with biologic agents while no significant difference was found in serious AEs. Subgroup analyses showed that NGF inhibitors provided superior pain relief (SMD = 0.36, 95% CI = 0.26–0.47, p < 0.001) and function improvement (SMD = 0.41, 95% CI = 0.30–0.51, p < 0.001), whereas IL-1 inhibitors and TNF-α inhibitors did not. Meanwhile, NGF inhibitors increased the incidence of any AEs (RR = 1.12, 95% CI = 1.07–1.17, p < 0.001) and discontinuations due to AEs (RR = 1.48, 95% CI = 1.07–2.06, p = 0.018). IL-1 inhibitors and TNF-α inhibitors showed no difference in safety compared with placebo.Conclusions:The efficacy and safety of biologic agents vary by mechanism of action. NGF inhibitors can relieve OA-related pain and improve function but involve safety concerns. IL-1 inhibitors and TNF-α inhibitors are relatively safe options but with limited efficacy.