Interleukin-1 Inhibitors Research Articles

Rilonacept and Other Interleukin-1 Inhibitors in the Treatment of Recurrent Pericarditis.

Pericarditis is the commonest form of pericardial disease. Unfortunately, despite optimal treatment, approximately 15-30% of patients with acute pericarditis have recurrence. Many of these patients are refractory to colchicine, and become corticosteroid-dependent. Recurrent pericarditis severely impairs quality of life, and is associated with significant morbidity. Inflammasome formation and overproduction of interleukin (IL)-1 have been found to drive the systemic inflammatory response in recurrent autoinflammatory pericarditis. Several IL-1 inhibitors have been evaluated for their usefulness as therapeutic options. Rilonacept is a dimeric fusion protein that functions as a soluble decoy receptor that binds to both IL-1α and IL-1β, thereby inhibiting the IL-1 pathway. It is safe and efficacious in the treatment of recurrent pericarditis in the RHAPSODY II and III trials. Anakinra is a recombinant IL-1 receptor antagonist that blocks the action of circulating IL-1α and IL-1β. It has also been shown to be safe and efficacious in the AIRTRIP and IRAP studies. Canakinumab is a selective human monoclonal antibody against IL-1β, and data on its use in recurrent pericarditis is scarce. Several questions regarding IL-1 inhibitor therapy, such as the duration of treatment and the recommended tapering protocols, as well as their use in special populations like pregnant or lactating women, remain unanswered and need to be addressed in future studies.

Humoral immune response against BNT162b2 mRNA COVID-19 vaccine in patients with rheumatic disease undergoing immunosuppressive therapy: A Japanese monocentric study.

We investigated serum total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain after BNT162b2 mRNA vaccination against coronavirus disease 2019 (COVID-19) in Japanese patients taking various immunosuppressive medications for rheumatic disease. In 212 outpatients with rheumatic diseases at Kagawa University Hospital and 43 healthy volunteers (controls), all of whom had received 2 doses of BNT162b2 vaccine, serum antibody titers of SARS-CoV-2 spike protein were analyzed at least 14 days after the second dose. Many of the patients were taking immunosuppressive agents to manage their rheumatic disease. The antibody titers against SARS-CoV-2 spike protein in these patients were significantly lower than those in controls. The analysis of therapeutic agents revealed that the antibody titers in patients treated with rituximab were much lower than those in controls. In patients treated with tacrolimus, baricitinib, azathioprine, mycophenolate mofetil, abatacept, tumor necrosis factor inhibitors, cyclosporine, interleukin-6 inhibitors, methotrexate, or glucocorticoids, antibody titers were moderately lower than those of controls. Interleukin-17 and interleukin-23 inhibitors did not impair the humoral response. In addition, the combination of methotrexate with various immunosuppressive agents reduced titers, although not significantly. In Japanese patients with rheumatic disease, many immunosuppressants impaired the immune response to the BNT162b2 vaccine. The degree of decline in antibody titers differed according to immunosuppressant. When used concomitantly with other immunosuppressants, methotrexate may impair the immune response to the BNT162b2 vaccine. However, immunomodulatory treatments such as interleukin-17 and -23 inhibitors may not attenuate this response in patients with rheumatic disease.

The Use of Interleukin-6 Inhibitors in Patients with Coronavirus Disease 2019 Who Develop Acute Kidney Injury

The Use of Interleukin-6 Inhibitors in Patients with Coronavirus Disease 2019 Who Develop Acute Kidney Injury

Effects of interleukin-6 inhibition with ziltivekimab in patients at high risk of atherosclerotic events in Japan: results from the phase 2 RESCUE-2 trial

Abstract Introduction In the US phase 2 RESCUE trial, ziltivekimab, a fully human monoclonal antibody against the ligand of the pro-inflammatory cytokine interleukin-6, was shown to reduce biomarkers of inflammation in patients with chronic kidney disease (CKD) and elevated levels of high-sensitivity C-reactive protein (hsCRP), a marker of inflammation and cardiac risk.1 Here, we present outcomes from the phase 2 RESCUE-2 trial of ziltivekimab in a patient population from Japan. Purpose To evaluate the efficacy and safety of ziltivekimab 15 mg and 30 mg compared with placebo in Japanese patients with non-dialysis-dependent CKD (NDD-CKD). Methods We conducted a randomized, double-blind, placebo-controlled trial in 36 patients aged ≥20 years with stage 3–5 NDD-CKD and hsCRP ≥2 mg/L. Patients were randomly assigned to receive subcutaneous ziltivekimab 15 mg (n=11) or 30 mg (n=12), or placebo (n=13) at weeks 0, 4 and 8. The primary endpoint was percentage change in hsCRP levels from baseline to end of treatment (EOT) (average of week 10 and week 12 values); secondary endpoints included percentage change from baseline to EOT in levels of fibrinogen, serum amyloid A (SAA), N-terminal pro B-type natriuretic peptide (NT-proBNP) and lipids. Analysis of endpoints was performed using Wilcoxon two-sample test; differences between treatment groups were calculated using the Hodges–Lehmann estimator. Results Baseline characteristics are shown in the Table. At EOT, median hsCRP levels were reduced by 96% and 93% in the ziltivekimab 15 mg and 30 mg groups, respectively, compared with 27% for placebo (both p<0.001 vs placebo). At both doses, ziltivekimab provided rapid and sustained suppression of hsCRP over the 12-week treatment period (Figure). Statistically significant reductions in levels of the inflammatory markers SAA (15 mg: 71%; 30 mg: 58%; placebo: 30%; both p<0.01 vs placebo) and fibrinogen (38%; 34%; 2%; both p<0.0001 vs placebo) were also observed. Ziltivekimab was well tolerated, did not result in persistent neutropenia or thrombocytopenia, and had minimal effect on liver enzyme levels. There was a non-significant increase in low-density lipoprotein levels and a neutral effect on high-density lipoprotein levels. There was a limited, but statistically significant (p<0.05 vs placebo) increase in triglycerides, whereby levels increased in some patients and decreased in others. Conclusion Ziltivekimab effectively reduced inflammatory biomarkers associated with atherosclerosis in patients from Japan with CKD and residual inflammatory risk as measured by hsCRP. A significant reduction of more than 90% in hsCRP levels for both doses of ziltivekimab was demonstrated, with a safety profile similar to placebo. Overall, the results of the RESCUE-2 trial in Japan are consistent with the efficacy and safety results of the US-based RESCUE trial. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This study was funded by Novo Nordisk A/S. Medical writing support was provided by Johanna Scheinost PhD, PharmaGenesis Oxford Central, Oxford, UK, with funding from Novo Nordisk A/S.

PULMONARY ASPERGILLOSIS POST-TOCILIZUMAB TREATMENT IN A PATIENT WITH COVID-19 PNEUMONIA

PULMONARY ASPERGILLOSIS POST-TOCILIZUMAB TREATMENT IN A PATIENT WITH COVID-19 PNEUMONIA

Elucidating the anti-oxidant and anti-inflammatory potentials of Triticum aestivum against ulcerative colitis: An in vivo and in silico study

BackgroundUlcerative colitis has remained irremediable because of relapse and recurrence despite intake of conventional medicine, although natural products are seen to be a viable alternative. Triticum aestivum is high in antioxidants and anti-inflammatory compounds. PurposeAs a result, its anti-inflammatory activity was elucidated in experimentally induced colitis model to ascertains its anti-inflammatory both invivo and insilico. Study designThe animals (n = 5, 130–200 g) were categorized into four groups and given treatments for three weeks prior to ulcerative colitis induction: I (control), II (acetic acid induced colitis untreated (6% acetic acid), III (acetic acid induced colitis + mesalamine (400 mg/kg), and IV (aqueous extricate of common wheat (200 mg/kg). MethodsThe weight changes in the animal's body, the ratio of colon weight and length, the mass of the colon at 8 cm, the relative weight of the colon, the stool scoring, the ulcer score, and the gross morphology of the mucosa layer of the colon were assessed. Spectrophotometry approach was employed to determine the activities of superoxide dismutase and glutathione peroxidase as well as the levels of malondialdehyde, protein, and interleukin-6. A molecular docking investigation of Triticum aestivum compounds against interleukin-6 (IL-6) and cyclooxygenase-2 was then performed (COX-2). ResultsWhen liken with the gastric induced model, the administration of Triticum aestivum elevated the mass of the animals appreciably (p < 0.05) and decreased the weight of the colon at 8 cm, the mass-length ratio, the relative weight of the colon, stool scoring, ulcer score dropped considerably(p < 0.05). The gross morphology showed a significant (p < 0.05) decrease in the hyperemia, inflammation and ulceration after treatment with Triticum aestivum. When liken with the untreated group, MDA and IL-6 levels reduced glaringly (p < 0.05), while GSH and protein levels rose substantively (p < 0.05) after treatment with Triticum aestivum. With various docking outputs, Triticum aestivum compounds interacted with COX-2 and IL-6. Quercetin, protocatechuic acid 4-glucoside, and tricin were the most potent inhibitors of COX-2, whereas stachyose, allantoin, and tetrakis(2-benzimidazolylmethyl)-2‑hydroxy-1,3-diamino propane were the most effective inhibitors of IL-6. These chemicals interacted with key amino acid residues in these molecules' binding sites. ConclusionThe anti-oxidant and anti-inflammatory action of Triticum aestivum reported in this investigation suggest Triticum aestivum plant as a natural replacement and prospective source of a novel ulcerative colitis medication.

Regnase-1 Prevents Pulmonary Arterial Hypertension Through mRNA Degradation of Interleukin-6 and Platelet-Derived Growth Factor in Alveolar Macrophages.

Pulmonary arterial hypertension (PAH) is a type of pulmonary hypertension (PH) characterized by obliterative pulmonary vascular remodeling, resulting in right-sided heart failure. Although the pathogenesis of PAH is not fully understood, inflammatory responses and cytokines have been shown to be associated with PAH, in particular, with connective tissue disease-PAH. In this sense, Regnase-1, an RNase that regulates mRNAs encoding genes related to immune reactions, was investigated in relation to the pathogenesis of PH. We first examined the expression levels of ZC3H12A (encoding Regnase-1) in peripheral blood mononuclear cells from patients with PH classified under various types of PH, searching for an association between the ZC3H12A expression and clinical features. We then generated mice lacking Regnase-1 in myeloid cells, including alveolar macrophages, and examined right ventricular systolic pressures and histological changes in the lung. We further performed a comprehensive analysis of the transcriptome of alveolar macrophages and pulmonary arteries to identify genes regulated by Regnase-1 in alveolar macrophages. ZC3H12A expression in peripheral blood mononuclear cells was inversely correlated with the prognosis and severity of disease in patients with PH, in particular, in connective tissue disease-PAH. The critical role of Regnase-1 in controlling PAH was also reinforced by the analysis of mice lacking Regnase-1 in alveolar macrophages. These mice spontaneously developed severe PAH, characterized by the elevated right ventricular systolic pressures and irreversible pulmonary vascular remodeling, which recapitulated the pathology of patients with PAH. Transcriptomic analysis of alveolar macrophages and pulmonary arteries of these PAH mice revealed that Il6, Il1b, and Pdgfa/b are potential targets of Regnase-1 in alveolar macrophages in the regulation of PAH. The inhibition of IL-6 (interleukin-6) by an anti-IL-6 receptor antibody or platelet-derived growth factor by imatinib but not IL-1β (interleukin-1β) by anakinra, ameliorated the pathogenesis of PAH. Regnase-1 maintains lung innate immune homeostasis through the control of IL-6 and platelet-derived growth factor in alveolar macrophages, thereby suppressing the development of PAH in mice. Furthermore, the decreased expression of Regnase-1 in various types of PH implies its involvement in PH pathogenesis and may serve as a disease biomarker, and a therapeutic target for PH as well.

Giant Cell Arteritis: Focusing on Current Aspects From the Clinic to Diagnosis and Treatment.

Giant cell arteritis (GCA) is a granulomatous arteritis involving large arteries, particularly the aorta and its major proximal branches, including the carotid and temporal arteries. GCA involves individuals over 50years old. The etiopathogenesis of GCA may involve a genetic background triggered by unknown environmental factors (eg infections), the activation of dendritic cells as well as inflammatory and vascular remodeling. However, its pathogenetic mechanism still remains unclear, although progress has been made in recent years. In the past, inflammatory markers and arterial biopsy were considered as gold standard for the diagnosis of GCA. However, emerging imaging methods have been made more sensitive and specific for the diagnosis of GCA. Treatment includes biological and other modalities including interleukin-6 (IL-6) inhibitors.

Nosocomial Infections in COVID-19 Patients Treated with Immunomodulators: A Narrative Review

Nosocomial infections pose an imminent challenge to hospitalized Coronavirus disease-19 (COVID-19) patients due to complex interplay of dysregulated immune response combined with immunomodulator therapy. In the pre-pandemic era, immunomodulatory therapy has shown benefit in certain autoimmune conditions with untamed inflammatory response. Efforts to recapitulate these immunomodulatory effects in COVID-19 patients has gained impetus and were followed by NIH COVID-19 expert panel recommendations. The current NIH guideline recommends interleukin-6 inhibitors (tocilizumab and sarilumab) and Janus kinase inhibitors (baricitinib and tofacitinib). Several landmark research trials like COVAVTA, EMPACTA, REMDACTA, STOP-COVID and COV BARRIER have detailed the various effects associated with administration of immunomodulators. The historical evidence of increased infection among patients receiving immunomodulators for autoimmune conditions, raised concerns regarding administration of immunomodulators in COVID-19 patients. The aim of this review article is to provide a comprehensive update on the currently available literature surrounding this issue. We reviewed 40 studies out of which 37 investigated IL-6 inhibitors and 3 investigated JAK inhibitors. Among the studies reviewed, the reported rates of nosocomial infections among the COVID-19 patients treated with immunomodulators were similar to patients receiving standard of care for COVID-19. However, these studies were not powered to assess the side effect profile of these medications. Immunomodulators, by dampening the pyrogenic response and inflammatory markers may delay detection of infections among the patients. This underscores the importance of long-term surveillance which are necessary to discover the potential risks associated with these agents.

Olokizumab, a monoclonal antibody against interleukin-6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by tumour necrosis factor inhibitor therapy: efficacy and safety results of a randomised controlled phase III study

ObjectivesTo assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor...

Systemic interleukin-6 inhibition ameliorates acute neuropsychiatric phenotypes in a murine model of acute lung injury

Acute neuropsychiatric impairments occur in over 70% of patients with acute lung injury. Mechanical ventilation is a well-known precipitant of acute lung injury and is strongly associated with the development of acute delirium and anxiety phenotypes. In prior studies, we demonstrated that IL-6 mediates neuropathological changes in the frontal cortex and hippocampus of animals with mechanical ventilation-induced brain injury; however, the effect of systemic IL-6 inhibition on structural and functional acute neuropsychiatric phenotypes is not known. We hypothesized that a murine model of mechanical ventilation-induced acute lung injury (VILI) would induce neural injury to the amygdala and hippocampus, brain regions that are implicated in diverse neuropsychiatric conditions, and corresponding delirium- and anxiety-like functional impairments. Furthermore, we hypothesized that these structural and functional changes would reverse with systemic IL-6 inhibition. VILI was induced using high tidal volume (35 cc/kg) mechanical ventilation. Cleaved caspase-3 (CC3) expression was quantified as a neural injury marker and found to be significantly increased in the VILI group compared to spontaneously breathing or anesthetized and mechanically ventilated mice with 10 cc/kg tidal volume. VILI mice treated with systemic IL-6 inhibition had significantly reduced amygdalar and hippocampal CC3 expression compared to saline-treated animals and demonstrated amelioration in acute neuropsychiatric behaviors in open field, elevated plus maze, and Y-maze tests. Overall, these data provide evidence of a pathogenic role of systemic IL-6 in mediating structural and functional acute neuropsychiatric symptoms in VILI and provide preclinical justification to assess IL-6 inhibition as a potential intervention to ameliorate acute neuropsychiatric phenotypes following VILI.

A practical update on the management of patients with COVID–19

While vaccines against COVID-19 are being rolled out, an ongoing need remains for therapies to treat patients who have symptomatic COVID-19 before vaccination or in whom breakthrough infection develops. Dexamethasone and interleukin-6 inhibitors have been the mainstay of treatment for severe to critical COVID-19 requiring hospitalisation. However, in the previous few months, several therapies have been approved in the UK for hospitalised and non-hospitalised patients with COVID-19. In particular, the development of neutralising monoclonal antibodies and novel antivirals represents a welcome expansion in the armamentarium against COVID-19, not only therapeutically to reduce mortality but also because they can be used in mild or moderate disease to prevent hospitalisation. This update is based on guidance from NHS England as well as the World Health Organization, and provides practical support and guidance to all clinicians involved or interested in the management of COVID-19 patients, whether based in community, outpatient or inpatient settings.

A systematic literature review informing the consensus statement on efficacy and safety of pharmacological treatment with interleukin-6 pathway inhibition with biological DMARDs in immune-mediated inflammatory diseases

ObjectivesInforming an international task force updating the consensus statement on efficacy and safety of biological disease-modifying antirheumatic drugs (bDMARDs) selectively targeting interleukin-6 (IL-6) pathway in the context of immune-mediated inflammatory...

Molecular Modeling Guided Drug Designing for the Therapeutic Treatment of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic inflammatory disorder that can cause destructive joint disease, significant disability, and increased mortality. RA is the most frequent of all chronic inflammatory joint diseases, and its prevalence frequency in Pakistan is 1.6 per thousand people. Different cytokines and receptors were involved in the triggering of RA, including interleukin-6 (ILR-6), major histocompatibility complex (MHC) antigen human leukocyte (HLA-DR) receptor, and CD20. Several studies illustrated RA as an inherent immune response and triggered due to the “shared epitope.” Therefore, the involvement of all these receptors (IL-6, HLA-DR, and CD20) leads to the neurological, ocular, respiratory, cardiac, skin, and hematological manifestations that have been considered a potential therapeutic target for drug design. Various herbal, natural, and synthetic source inhibitors of interleukin-6 (IL-6), human leukocyte (HLA-DR), and CD20 were studied and reported previously. Reported inhibitors are compared to elucidate the best inhibitor for clinical trials, leading to the orally active drug. In this study, a computer-aided drug designing approach disclosed the potential inhibitors for all receptors based on their distinct binding affinity. Moreover, drug suitability was carried out using Lipinski’s rule by considering the adsorption, distribution, metabolism, and excretion (ADME) of ligands. Results elucidated “calycosin 7-O-glucoside” and “angeliferulate” as putative ligands for IL-6 and HLA-DR, respectively. However, the pharmacokinetic properties (ADMET) revealed angeliferulate as an effete ligand for the biological system compared to calycosin 7-O-glucoside. Based on docking, drug toxicity profiling or pharmacokinetics, and MD simulation stability, this study highlights orally active therapeutic inhibitors to inhibit the activity of pivotal receptors (IL6, HLA-DR, and CD20) of RA in humans. After clinical trials, the resultant inhibitors could be potential therapeutic agents in the drug development against RA.

Amitriptyline-Based Biodegradable PEG-PLGA Self-Assembled Nanoparticles Accelerate Cutaneous Wound Healing in Diabetic Rats.

The aim of this work was to study the healing activity of amitriptyline (Amitrip) in rat diabetic wounds. A nanoformula of the drug was prepared as Amitrip-based biodegradable PEG-PLGA self-assembled nanoparticles (Amitrip-NPs) with a mean particle size of 67.4 nm. An in vivo investigation was conducted to evaluate the wound-healing process of Amitrip-NPs in streptozotocin-induced diabetic rats. Wound contraction was accelerated in rats treated with Amitrip-NPs. Histological examinations confirmed these findings, with expedited remodeling and collagen deposition in the NPs-treated animals. The formula showed anti-inflammatory activities as demonstrated by inhibition of interleukin-6 (IL-6) expression and tumor necrosis factor-α (TNF-α) expression, as well as enhanced expression of interleukin-10 (IL-10). In addition, Amitrip-NPs protected against malondialdehyde (MDA) buildup and superoxide dismutase (SOD) and glutathione peroxidase (GPx) enzymatic exhaustion. The pro-collagen activity of Amitrip-NPs was confirmed by the observed enhancement of hydroxyproline wounded skin content, upregulation of Col 1A1 mRNA expression and immune expression of collagen type IV expression. Further, Amitrip-NPs significantly increased expression transforming growth factor-β1 (TGF-β1), vascular endothelial growth factor-A (VEGF-A), platelet-derived growth factor-B (PDGF-B) and cluster of differentiation 31 (CD31). In conclusion, the developed Amitrip-NPs expedited wound healing in diabetic rats. This involves anti-inflammatory, antioxidant, pro-collagen and angiogenic activities of the prepared NPs. This opens the gate for evaluating the usefulness of other structurally related tricyclic antidepressants in diabetic wounds.

Secondary Failure of Tocilizumab in Treating Elderly-Onset Rheumatoid Arthritis With Systemic Symptoms Complicated by Diverticulum Perforation

The treatment of rheumatoid arthritis (RA) has advanced from the use of steroids to disease-modifying anti-rheumatic drugs (DMARDs) and biologics such as tumor necrosis factor (TNF) and interleukin-6 (IL-6) inhibitors. Historically, steroids have been the mainstream in the clinical treatment of RA; however, the development of DMARDs has changed the RA treatment structure. In addition, biologics can alleviate RA symptoms. This case report describes the secondary failure of tocilizumab in treating RA with fatigue symptoms. Treatment with tocilizumab decreases C-reactive protein (CRP) levels, which may make detecting RA exacerbation difficult; therefore, obtaining the patient's precise history and thorough physical examinations are necessary. This case demonstrates the complexity of treating elderly-onset RA and reports practical methods for effective treatment.

The effects of glucocorticoids and immunosuppressants on cancer outcomes in checkpoint inhibitor therapy.

The emergence of checkpoint inhibitors has created a paradigm shift for the treatment of various malignancies. However, although these therapies are associated with improved survival rates, they also carry the risk of immune-related adverse events (irAEs). Moderate to severe irAEs are typically treated with glucocorticoids, sometimes with the addition of immunosuppressants as steroid-sparing therapy. However, it is unclear how glucocorticoids and immunosuppressants may impact cancer survival and the efficacy of immune checkpoint therapy on cancer. In this narrative review, we discuss the effects of glucocorticoids and immunosuppressants including methotrexate, hydroxychloroquine, azathioprine, mycophenolate mofetil, tumor-necrosis factor (TNF)-inhibitors, interleukin-6 inhibitors, interleukin-1 inhibitors, abatacept, rituximab, and Janus kinase inhibitors (JAKi) on cancer-specific outcomes in the setting of immune checkpoint inhibitor use.

Arsenic Induces GSK3β-Dependent p-Tau, Neuronal Apoptosis, and Cognitive Impairment via an Interdependent Hippocampal ERα and IL-1/IL-1R1 Mechanism in Female Rats.

Arsenic is an environmental contaminant with potential neurotoxicity. We previously reported that arsenic promoted hippocampal neuronal apoptosis, inducing cognitive loss. Here, we correlated it with tau pathology. We observed that environmentally relevant arsenic exposure increased tau phosphorylation and the principal tau kinase, glycogen synthase kinase-3 beta (GSK3β), in the female rat hippocampal neurons. We detected the same in primary hippocampal neurons. Because a regulated estrogen receptor (ER) level and inflammation contributed to normal hippocampal functions, we examined their levels following arsenic exposure. Our ER screening data revealed that arsenic down-regulated hippocampal neuronal ERα. We also detected an up-regulated hippocampal interleukin-1 (IL-1) and its receptor, IL-1R1. Further, co-treating arsenic with the ERα agonist, 4,4',4″-(4-Propyl-[1H]-pyrazole-1,3,5-triyl)trisphenol (PPT), or IL-1R antagonist (IL-1Ra) resulted in reduced GSK3β and p-tau, indicating involvement of decreased ERα and increased IL-1/IL-1R1 in tau hyperphosphorylation. We then checked whether ERα and IL-1/IL-1R1 had linkage, and detected that although PPT reduced IL-1 and IL-1R1, the IL-1Ra restored ERα, suggesting their arsenic-induced interdependence. We finally correlated this pathway with apoptosis and cognition. We observed that PPT, IL-1Ra and the GSK3β inhibitor, LiCl, reduced hippocampal neuronal cleaved caspase-3 and TUNEL+ve apoptotic count, and decreased the number of errors during learning and increased the saving memory for Y-Maze test and retention performance for Passive avoidance test in arsenic-treated rats. Thus, our study reveals a novel mechanism of arsenic-induced GSK3β-dependent tau pathology via interdependent ERα and IL-1/IL-1R1 signaling. It also envisages the protective role of ERα agonist and IL-1 inhibitor against arsenic-induced neurotoxicity.

КЛИНИКО-ГЕНЕТИЧЕСКАЯ ХАРАКТЕРИСТИКА БОЛЬНЫХ С TRAPS (ПЕРИОДИЧЕСКИЙ СИНДРОМ, АССОЦИИРОВАННЫЙ С РЕЦЕПТОРОМ ФАКТОРА НЕКРОЗА ОПУХОЛИ) ПО ДАННЫМ ФЕДЕРАЛЬНОГО РЕВМАТОЛОГИЧЕСКОГО ЦЕНТРА

The tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is a rare autosomal dominant disease associated with a mutation in the TNFRSF1A gene. It belongs to the group of monogenic autoinflammatory diseases (mAIDs) characterized by the repeated and prolonged episodes of fever, skin rashes, musculoskeletal, ophthalmic symptoms and an increase in the level of acute phase markers. The main targeted therapy is inhibitors of interleukin-1 (IL-1). The purpose of the study was to present the clinical and genetic characteristics of patients with TRAPS according to the data from the V.A. Nasonova Research Institute of Rheumatology (Moscow, Russia). The study included 28 patients from 2013 till 2021 with a clinical diagnosis of TRAPS from a selection of 162 (both pediatric and adult) patients with mAIDs: 17 females/11 males aged 2.5 to 65 years old (Me 9.0 y/o [7.9; 14.5]); 7 adults/21 children. All of them have underwent molecular genetic analysis for mutations in the TNFRSF1A gene. Results: the TRAPS was diagnosed in 28 (17.3%) among 162 patients with mAIDs. The age of onset ranged from 1 month till 28 years old (Me 4.0 y/o [1.0; 7.1]). Most patients fell ill prior to the age of 10 years old (89.3%), of which 8 (28.6%) before 1 year old, 7 (25%) from 1 to 5 years old, 1 (3.6%) from 5 to 10 years old, 10 (35.7%) from 10 to 18 years old and 2 (7.1%) from 21 to 28 years old. The duration of the disease and the delay in diagnosis at the time of inclusion ranged from 3 months till 59 years old. The diagnosis was made within the first year of illness in 4 (14.3%) of observed cases; within 1 to 10 years in 18 (64.3%); in 8 (28.6%) there was a delay in diagnosis of over 10 years; and in 4 (14.3%) the delay was more than 20 years of illness. The duration of attacks varied from 10 to 30 days, the intervals between the attacks ranged from 2 weeks till 6 months. The clinical manifestations were as follows: fever in 96.4% of cases, skin rashes in 71.4%, musculoskeletal symptoms in 18 (64.3%) cases, oligoarthritis in 9 (32.1%), polyarthritis in 2 (7.1% ), gastrointestinal manifestations in 18 (64.3%), lymphadenopathy of various groups in 10 (35.7%), ophthalmological manifestations in 8 (28.6%). The less often were the different nervous system manifestations, which accounted for 6% to 21% of cases, pharyngitis in 4 (14.3%) and stomatitis in 2 (7.1%). An increase in the sedimentation rate of erythrocytes was noted in 23 (82.1%), C-reactive protein in 20 (71.4%), leukocytosis in 11 (39.3%). The diagnosis in all patients was confirmed genetically. 10 patients had a low-penetrance mutation of р.Arg121Gln (р.Arg92Gln according to the old nomenclature). 5 familial cases were identified, the total number of sick family members was 12, from 2 to 4 in each family; 4 cases of amyloidosis (the all four were adults). Treatment: glucocorticoids in 19 (67.9%) cases, Cyclosporine A in 1, Colchicine in 5. 15 patients (53.6%) received genetically engineered biological preparations, the IL-1 (Canakinumab) was prescribed in 10 (35.7%) patients with the duration of admission from 1 to 9 years, Etanercept in 1, Adalimumab in 1 and Tocilizumab in 3. Conclusion: due to the similarity of clinical and laboratory symptoms with manifestations of rheumatic diseases, patients with TRAPS can be encountered in the rheumatologists’ practice. Most patients in the studied cohort had an early onset of the disease (prior to 10 years old), and the diagnosis delay of 10+ years was noted in 1/3 of patients. All patients had a specialized inflammatory phenotype coupled with genetic mutations. About half had required the appointment of biological drugs, IL-1 mainly. A complete response to the therapy in most patients and a good tolerability of treatment were noted, which allows the authors to consider this as the basis in the treatment and management of patients with TRAPS.

Anxiolytic-like effects of hochuekkito in lipopolysaccharide-treated mice involve interleukin-6 inhibition.

Hochuekkito (HET) is a Kampo medicine used to treat postoperative and post-illness general malaise and decreased motivation. HET is known to regulate immunity and modulate inflammation. However, the precise mechanism and effects of HET on inflammation-induced central nervous system disorders remain unclear. This study aimed to assess the effect of HET on inflammation-induced anxiety-like behavior and the mechanism underlying anxiety-like behavior induced by lipopolysaccharide (LPS). Institute of Cancer Research mice were treated with LPS (300 μg/kg, intraperitoneally), a bacterial endotoxin, to induce systemic inflammation. The mice were administered HET (1.0 g/kg, orally) once a day for 2 weeks before LPS treatment. The light-dark box test and the hole-board test were performed 24 h after the LPS injection to evaluate the effects of HET on anxiety-like behaviors. Serum samples were obtained at 2, 5, and 24 h after LPS injection, and interleukin-6 (IL-6) levels in serum were measured. Human and mouse macrophage cells (THP-1 and RAW264.7 cells, respectively) were used to investigate the effect of HET on LPS-induced IL-6 secretion. The repeated administration of HET prevented anxiety-like behavior and decreased serum IL-6 levels in LPS-treated mice. HET significantly suppressed LPS-induced IL-6 secretion in RAW264.7 and THP-1 cells. Similarly, glycyrrhizin, one of the chemical constituents of HET, suppressed LPS-induced anxiety-like behaviors. Our study revealed that HET ameliorated LPS-induced anxiety-like behavior and inhibited IL-6 release in vivo and in vitro. Therefore, we postulate that HET may be useful against inflammation-induced anxiety-like behavior.