anti-IL-6 Research Articles

Review article: Novel therapies in inflammatory bowel disease - An update for clinicians.

Several new treatments including small molecules and biologics have been approved for the treatment of inflammatory bowel diseases in recent years. Clinicians and patients now have a wide variety of therapeutic options to choose from and these novel therapies provide several advantages including oral administration, lower immunogenicity, better selectivity and arguably better safety profiles. An increase in treatment options has increased the complexity of decision-making. Both patients and clinicians have had to become rapidly familiar with efficacy of new medications balanced against a range of pre-initiation requirements, dosing schedules and adverse event profiles. To provide a simple guide to practising clinicians on recently approved and emerging therapies and address key challenges around treatment strategies such as optimal sequencing and timing of treatment. We comprehensively searched the published literature and major conference abstracts to identify phase III placebo-controlled and active comparator trials for Crohn's disease and ulcerative colitis. Data for recently approved therapies including selective Janus kinase inhibitors, sphingosine-1 receptor modulators and p19 interleukin (IL)-23 inhibitors have demonstrated improved patient outcomes in both Crohn's disease and ulcerative colitis. Further comparative head-to-head studies have improved our understanding of when and how to optimally use newer therapies, specifically for IL-23 inhibitors. Data for emerging treatment options and novel treatment strategies such as early effective treatment, combinations of treatments and implications for sequencing are continuing to transform IBD care continually. Recently approved novel therapies have expanded the range of medical options available to treat IBD. However, further data from long-term extension studies, real-world studies and head-to-head trials are warranted to better inform the long-term safety and optimal sequencing of treatments for patients living with IBD.

Urticarial vasculitis.

Urticarial vasculitis is a rare condition manifesting with a variety of clinical presentations ranging from skin limited lesions to life-threatening systemic illnesses. This review aims to highlight the recent findings on the etiology, diagnostic modalities, and therapeutic strategies and course of urticarial vasculitis. In addition to well established triggers, urticarial vasculitis (UV) cases associated with severe acute respiratory syndrome coronavirus 2 (SARS-Cov2) disease and COVID-19 vaccines, vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome, and adenosine deaminase (ADA) deficiency have been reported. A clinical-dermoscopic model for differentiating urticarial vasculitis has been developed with purpuric patches and globules favoring UV diagnosis and thus diminishing the need for histopathology. The efficacy of treatment modalities has been reviewed, and antihistamines, systemic corticosteroids, omalizumab, cyclophosphamide, tocilizumab, anti-interleukin (IL)-1 agents, and rituximab were shown to have the highest success rates. Regarding the durability of remission, rituximab, dapsone, and MMF were related to long-lasting treatment free responses. The course of hypocomplementemic urticarial vasculitis was investigated in an epidemiological study, revealing 5- and 10-year survival rates of 92% and 83%, respectively. Chronic obstructive pulmonary disease, septicemia, and end-stage renal disease were identified as causes of mortality. With the aid of dermoscopy, a noninvasive tool, differentiation from chronic spontaneous urticaria can be made, and the need for histopathological examination can be diminished. Although clear definitions and consensus criteria for performing disease severity are lacking, careful screening is needed to tailor the treatment on an individual basis. Emerging infections like SARS-CoV 2, vaccines, and autoinflammatory disorders like VEXAS syndrome and ADA deficiency are new associations. The optimal use of well established agents like systemic corticosteroids and immunomodulators are mainstay treatment modalities, whereas IL-1 inhibitors, omalizumab, rituximab and Janus Kinase inhibitors may represent viable alternatives in selected cases.

Methotrexate promotes the release of granulocyte–macrophage colony-stimulating factor from rheumatoid arthritis fibroblast-like synoviocytes via autocrine interleukin-1 signaling

BackgroundActivated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators.MethodsPrimary RA-FLS were activated by stimulation with interleukin-1β (IL-1β) or platelet-derived growth factor + IL-1β in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations.ResultsSix thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on ‘Molecular mechanisms of cancer’ and TOFA on ‘Interferon signaling’. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte–macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages.ConclusionsMTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.

Anakinra-Dependent Recurrent Pericarditis: The Role of the R202Q Variant of the MEFV Gene.

Background: the role of the R202Q (c.605G>A, p.Arg202Gln) missense variant of the MEFV gene has been debated as either a benign polymorphism or a potentially pathogenic mutation. We report and discuss here the case of a young female with corticosteroid-dependent recurrent pericarditis carrying the homozygous R202Q variant, exhibiting distinctive clinical features possibly influenced by this genetic variant. Methods: a 30-year-old woman with a previous diagnosis of cancer and recent respiratory infection presented with severe pleuritic chest pain, hypotension, tachycardia, and fever. Initial diagnostic evaluation indicated cardiac tamponade, and emergent pericardiocentesis was performed. Despite initial treatment with NSAIDs, colchicine, and corticosteroids, the patient experienced multiple recurrences. Genetic testing identified homozygous R202Q variant in the MEFV gene. Given the corticosteroid dependency and recurrent nature of her condition, IL-1 inhibitor anakinra was introduced, leading to significant improvement, although tapering below 150 mg per week failed to prevent recurrences. Results: the introduction of anakinra resulted in rapid symptom relief and resolution of pericardial effusion. However, attempts to taper or discontinue anakinra led to pericarditis recurrences. Ultimately, a maintenance dose of 50 mg every three days was established, which maintained remission for 18 months without recurrence. Despite multiple tapering attempts, further reduction in anakinra dosage was unsuccessful without triggering relapses. Conclusions: the R202Q variant, although typically considered benign, may contribute to an autoinflammatory phenotype resembling familial Mediterranean fever. This case underscores the potential pathogenicity of the homozygous R202Q variant in recurrent pericarditis and its responsiveness to IL-1 inhibition. In patients with corticosteroid-dependent recurrent pericarditis, genetic testing for the R202Q variant should be considered when anti-IL-1 drugs cannot be withdrawn. Further studies are warranted to elucidate the variant's role in pericardial inflammation and guide personalized treatment strategies.

Infection and infestation-related adverse events of biologics in psoriasis: insights from the Food and Drug Administration Adverse Event Reporting System (FAERS)

ABSTRACT Objective The study aims to thoroughly assess the adverse events related to infections and infestations associated with biological agents used for psoriasis using the U.S. Food and Drug Administration’s Adverse Event Reporting System (FAERS) database. Methods We analyzed FAERS data from the first quarter of 2004 to the fourth quarter of 2023. The study included TNF-α inhibitors (etanercept, infliximab, adalimumab), IL-12/23 inhibitors (ustekinumab), IL-23p19 inhibitors (guselkumab), and IL-17 inhibitors (secukinumab, ixekizumab). We used disproportionality analysis and Bayesian methods to quantify the related adverse event (AE) signals. Results Most AEs related to infections and infestations are already listed on the drug packaging labels. Notably, TNF-α inhibitors are associated with a significantly higher incidence of tuberculosis-related diseases compared to other biological agents. In contrast, IL-17 inhibitors show a greater variety and number of fungal infection-related AEs than their counterparts. Furthermore, our study has identified new potential AEs that require the attention of clinicians. Conclusion In clinical practice, it is advisable to monitor the risks of infections and infestations in patients receiving biological agents for psoriasis to enable early detection and intervention. Our findings highlight the need for further epidemiological investigations to establish causality and guide clinical practice in managing these risks effectively.

The Association of Interleukin-36 Staining Intensity and Response to Biologic Therapy in Patients With Psoriasis: A Retrospective Immunohistochemical and Chart Review Pilot Study.

There are limited surrogate biomarkers to identify the active inflammatory pathway in psoriasis to direct treatment with targeted biologic therapies. We investigated the association of interleukin (IL)-36 epidermal expression, a diagnostic marker of psoriasis, with response to biologic therapy in patients with psoriasis. Retrospective immunohistochemical and chart review pilot study. Patients with psoriasis with low (scores 0-2) vs. high (scores 3-4) IL-36 expression did not have significantly different response rates to tumor necrosis factor α (TNFα), IL-17, and IL-12/23 or IL-23 inhibitors; and similarly, mean IL-36 expression scores did not significantly differ among responders vs. non-responders to each treatment mechanism. However, in patients with psoriasis treated with IL-12/23 or IL-23 inhibitors, there was a marked absolute difference in response rates in those with high vs. low IL-36 (84% vs. 50%, p = 0.12) and in mean IL-36 scores in responders vs. non-responders (3.35 vs. 2.57, p = 0.19). Patients with psoriasis with high IL-36 expression were more likely to respond to IL-12/23 and IL-23 inhibition than those with low IL-36, though these findings were not statistically significant. Additional studies with larger sample sizes are needed to validate and expand upon these findings.

Superior effect of adalimumab versus secukinumab on ultrasound-confirmed synovitis in psoriatic arthritis: comprehensive evidence from musculoskeletal ultrasound and clinical assessments

Background and objectives: Psoriatic arthritis (PsA) is a chronic inflammatory musculoskeletal disorder affecting 30% of psoriatic patients. Effective treatment, especially with biologics like IL-17 and TNF inhibitors, is vital for improving patient outcomes. This study aimed to compare the efficacy of secukinumab and adalimumab in PsA patients through clinical and ultrasonographic evaluations.Materials and methods: We enrolled 116 PsA patients, with 58 patients receiving secukinumab and 58 receiving adalimumab. Regular follow-ups were conducted at weeks 4, 12, 24, and 52. The primary outcome was the proportion of patients achieving at least a 20% improvement in the ACR response (ACR20) at week 12, with additional evaluations for axial arthritis, enthesitis, skin involvement, minimal disease activity, health assessment questionnaire, and ultrasound changes.Results: There was no significant difference in ACR20 response between the two groups at week 12 (OR: 0.59, 95% CI: 0.26–1.37, p = 0.22). However, secukinumab demonstrated superior efficacy in achieving Psoriasis Area and Severity Index (PASI)90 (OR: 2.25, 95%CI: 1.07–4.74, p = 0.03), while adalimumab showed better improvement in ultrasound synovitis count (β: 0.94, 95%CI: 0.09–1.79, p = 0.03) and synovitis PD signal (β: 0.20, 95%CI: 0.03–0.36, p = 0.02).Conclusions: In conclusion, both treatments were highly effective for PsA, with secukinumab being more suitable for severe skin involvement and adalimumab for significant ultrasound-confirmed synovitis.

Distinctive CD39+CD9+ lung interstitial macrophages suppress IL-23/Th17-mediated neutrophilic asthma by inhibiting NETosis.

The IL-23-Th17 axis is responsible for neutrophilic inflammation in various inflammatory diseases. Here, we discover a potential pathway to inhibit neutrophilic asthma. In our neutrophil-dominant asthma (NDA) model, single-cell RNA-seq analysis identifies a subpopulation of CD39+CD9+ interstitial macrophages (IMs) suppressed by IL-23 in NDA conditions but increased by an IL-23 inhibitor αIL-23p19. Adoptively transferred CD39+CD9+ IMs suppress neutrophil extracellular trap formation (NETosis), a representative phenotype of NDA, and also Th17 cell activation and neutrophilic inflammation. CD39+CD9+ IMs first attach to neutrophils in a CD9-dependent manner, and then remove ATP near neutrophils that contribute to NETosis in a CD39-dependent manner. Transcriptomic data from asthmatic patients finally show decreased CD39+CD9+ IMs in severe asthma than mild/moderate asthma. Our results suggest that CD39+CD9+ IMs function as a potent negative regulator of neutrophilic inflammation by suppressing NETosis in the IL-23-Th17 axis and can thus serve as a potential therapeutic target for IL-23-Th17-mediated neutrophilic asthma.

LC–MS coupled with diagnostic ion strategy facilitated the discovery of 5-methylcoumarin meroterpenoids from Gerbera piloselloides

Plant-derived natural products remain crucial in drug development. However, the identification of undescribed natural products is becoming increasingly challenging. A comprehensive strategy combining LC–MS with diagnostic ions was proposed for the discovery of undescribed 5-methylcoumarin meroterpenoids. Thirteen undescribed 5-methylcoumarin meroterpenoids, including five pairs of enantiomers (1a/1b and 5a/5b–8a/8b), were isolated from the whole plant of Gerbera piloselloides. Their structures and absolute configurations were unambiguously determined based on their spectroscopic data, calculated and experimental ECD data and X-ray diffraction analysis. Bioassays conducted on scopolamine-induced injury PC12 cells revealed that compounds 5a/5b, 7a/7b and 8a/8b possessed mild protective effects. Additionally, compounds 2 and 8 showed notable IL-6 inhibition in lipopolysaccharide-induced BEAS-2B cells.

A Review of Interleukin-23/Interleukin-17 Inhibitor Exposure during Pregnancy in Patients with Psoriasis

Psoriasis is an immune cell-mediated chronic relapsing inflammatory skin disease that often develops during the reproductive years of women. The treatment of psoriasis during pregnancy is challenging as remarkable changes occur in the maternal body, and it requires the selection of therapy which is safe for both mother and fetus. The use of interleukin-23 (IL-23)/IL-17 inhibitors has been growing in psoriasis disease management and so the risk of their exposure during pregnancy is increasing too. However, human safety data in pregnancy are limited. This article aims to review pregnancy outcomes associated with IL-23/IL-17 inhibitor exposure in psoriasis patients and to see possible therapeutic options for psoriasis treatment during pregnancy. A search of the PubMed database up to June 2023 for articles was performed. The search strategy included a combination of terms as (pregnancy) AND (psoriasis) AND (Ustekinumab)/(Secukinumab)/(ixekizumab)/(brodalumab)/(guselkumab)/(tildrakizumab)/(risankizumab)/IL-23 inhibitors/IL-17 inhibitors. Resulted articles were reviewed manually for case reports, exposures from registries, and clinical trials. Most of the exposures to IL-23/IL-17 inhibitors were inadvertent, and therapy was suspended upon the detection of pregnancy. No signals on miscarriages, spontaneous abortions, and adverse developmental outcomes have been reported with first-trimester exposures to IL-23/IL-17 inhibitors. However, benefit–risk profile cannot be extrapolated based on first-trimester exposure as the transfer of these biologics across the placenta occurs in the later stage of pregnancy. More safety data from large cohorts of full-term exposure are required for IL-23/IL-17 inhibitors to consider them safe therapeutic options during pregnancy.

Long-term Effectiveness and Safety of Risankizumab in Patients with Crohn’s Disease

Background and AimsRisankizumab is a selective IL23 inhibitor approved for the treatment of Crohn’s disease (CD). We report a large long-term real-world experience with risankizumab in CD. MethodsWe performed a prospective monitoring of clinical outcomes in patients in our center who started treatment with risankizumab. Patients with active luminal disease who had at least 12 weeks of follow-up were included in the effectiveness analysis. Harvey-Bradshaw Index (HBI) as well as C-reactive protein (CRP) and fecal calprotectin (FCP) were used to monitor disease activity. Primary outcomes were clinical remission and steroid-free clinical remission rates at weeks 12, 26, and 52. Univariate analysis followed by a multivariate analysis using a logistic regression model was performed to identify predictors of steroid-free clinical remission at one year. All patients who started treatment with risankizumab for any indication were included in the safety analysis. Results134 patients were included in the effectiveness analysis. 70 (52%) were ustekinumab-experienced. Clinical remission rates were 69%, 64%, and 54% at weeks 12, 26, and 52, respectively. Steroid-free clinical remission rates at 12, 26, and 52 weeks were 58%, 58%, and 50% respectively. Remission rates in ustekinumab-experienced patients were not statistically lower compared to naïve patients, and in a multivariate analysis, prior ustekinumab treatment was not associated with lower odds of achieving steroid-free clinical remission at one year. Adverse effects were assessed in 243 patients and were consistent with previous literature. ConclusionsThis large real-world experience with risankizumab with long-term follow-up demonstrates effectiveness and safety in patients with CD; there was comparable effectiveness in ustekinumab-naïve and ustekinumab-experienced patients.

Tocilizumab plus Nintedanib for progressive interstitial lung disease in systemic sclerosis: a one-year observational study.

Randomized controlled trials have recently shown that both the IL-6 inhibitor Tocilizumab and the antifibrotic Nintedanib are efficacious for Systemic Sclerosis (SSc)-associated progressive interstitial lung disease (ILD). Since real-world clinical data on Tocilizumab/Nintedanib combination are lacking, we report on their long-term safety and efficacy. Consecutive patients who received off-label Tocilizumab for SSc plus Nintedanib for progressive ILD were retrospectively studied. Adverse events, and changes in Forced Vital Capacity (FVC), Diffucing Capacity for Carbon Monoxide (DLCO) and high resolution chest tomography (HRCT) between baseline and 6 and 12 months were assessed. Tocilizumab/Nintedanib combination was well tolerated by all 20 patients [aged 52 ± 13 years (mean ± SD), 14 women, 15 diffuse SSc, disease duration of 5.7 ± 4.9 years]; 7 of 20 patients received concomitant mycophenolate mofetil safely. No serious adverse events or laboratory abnormalities were noted. Five patients developed persistent diarrhea and 2 of them reduced dosage of Nintedanib. Baseline FVC (74%±12%) and DLCO (45%±10%) remained overall stable both at 6 months (73.5%±13% and 46%±11%, respectively) and 12 months (73%±14% and 45%±11%, respectively), regardless of disease duration. The extent of fibrotic reticular pattern in available pairs of HRCTs (n = 12) remained also stable at 12 months, whereas proportion (%) of ground glass opacities decreased from 29%±16to21%±14% (p = 0.048); improvement in HRCTs by almost 75% was noted in 2 of these12 patients. Tocilizumab/Nintedanib combination for one year was safe and stabilized lung function in real-world SSc patients with progressive ILD. Additional studies of this combination treatment in SSc-ILD are warranted.

Regulatory Role of IL6 in Immune-Related Adverse Events during Checkpoint Inhibitor Treatment in Melanoma

The landscape of clinical management for metastatic melanoma (MM) and other solid tumors has been modernized by the advent of immune checkpoint inhibitors (ICI), including programmed cell death-1 (PD-1), programmed cell death-ligand 1 (PD-L1), and cytotoxic T lymphocyte antigen 4 (CTLA-4) inhibitors. While these agents demonstrate efficacy in suppressing tumor growth, they also lead to immune-related adverse events (irAEs), resulting in the exacerbation of autoimmune diseases such as rheumatoid arthritis (RA), ulcerative colitis (UC), and Crohn’s disease (CD). The immune checkpoint inhibitors offer promising advancements in the treatment of melanoma and other cancers, but they also present significant challenges related to irAEs and autoimmune diseases. Ongoing research is crucial to better understand these challenges and develop strategies for mitigating adverse effects while maximizing therapeutic benefits. In this manuscript, we addressed this challenge using network-based approaches by constructing and analyzing the molecular and signaling networks associated with tumor-immune crosstalk. Our analysis revealed that IL6 is the key regulator responsible for irAEs during ICI therapies. Furthermore, we conducted an integrative network and molecular-level analysis, including virtual screening, of drug libraries, such as the Collection of Open Natural Products (COCONUT) and the Zinc15 FDA-approved library, to identify potential IL6 inhibitors. Subsequently, the compound amprenavir was identified as the best molecule that may disrupt essential interactions between IL6 and IL6R, which are responsible for initiating the signaling cascades underlying irAEs in ICI therapies.

Efficacy and safety of targeted therapies in VEXAS syndrome: retrospective study from the FRENVEX

ObjectivesVacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and...

Diminished expression of the ubiquitin-proteasome system in early treatment-naïve patients with rheumatoid arthritis and concomitant type 2 diabetes may be linked to IL-1 pathway hyper-activity; results from PEAC cohort

ObjectiveBased on the recent evidence of IL-1 inhibition in patients with rheumatoid arthritis (RA) and concomitant type 2 diabetes (T2D), we evaluated the synovial tissue expression of IL-1 related genes in relationship to the ubiquitin–proteasome system and the effects of insulin on ubiquitinated proteins in fibroblast-like synoviocytes (FLSs).MethodsThe synovial expression of IL-1 pathway genes was compared in early (< 1 year) treatment-naïve RA patients with T2D (RA/T2D n = 16) and age- and sex-matched RA patients without T2D (n = 16), enrolled in the Pathobiology of Early Arthritis Cohort (PEAC). The synovial expression of ubiquitin in macrophages and synovial lining fibroblasts was also assessed by Immunohistochemistry/immunofluorescence and correlated with synovial pathotypes. Finally, FLSs from RA patients (n = 5) were isolated and treated with human insulin (200 and 500 nM) and ubiquitinated proteins were assessed by western blot.ResultsSynovial tissues of RA/T2D patients were characterised by a consistent reduced expression of ubiquitin–proteasome genes. More specifically, ubiquitin genes (UBB, UBC, and UBA52) and genes codifying proteasome subunits (PSMA2, PSMA6, PSMA7, PSMB1, PSMB3, PSMB4, PSMB6, PSMB8, PSMB9, PSMB10, PSMC1, PSMD9, PSME1, and PSME2) were significantly lower in RA/T2D patients. On the contrary, genes regulating fibroblast functions (FGF7, FGF10, FRS2, FGFR3, and SOS1), and genes linked to IL-1 pathway hyper-activity (APP, IRAK2, and OSMR) were upregulated in RA/T2D. Immunohistochemistry showed a significant reduction of the percentage of ubiquitin-positive cells in synovial tissues of RA/T2D patients. Ubiquitin-positive cells were also increased in patients with a lympho-myeloid pathotype compared to diffuse myeloid or pauci-immune-fibroid. Finally, in vitro experiments showed a reduction of ubiquitinated proteins in RA-FLSs treated with a high concentration of insulin (500 nM).ConclusionsA different IL-1 pathway gene expression was observed in the synovial tissues of early treatment-naïve RA/T2D patients, linked to decreased expression of the ubiquitin–proteasome system. These findings may provide a mechanistic explanation of the observed clinical benefits of IL-1 inhibition in patients with RA and concomitant T2D.

Discovery and In Vivo Exploration of 1,3,4-Oxadiazole and α-Fluoroacrylate Containing IL-17 Inhibitors.

IL-17, a pro-inflammatory cytokine produced mainly by Th17 cells, is involved in the immune response to fungal and bacterial infections, whereas its aberrant production is associated with autoimmune and inflammatory diseases. IL-17 blocking antibodies like secukinumab (Cosentyx) have been developed and are used to treat conditions like psoriasis, psoriatic arthritis, and ankylosing spondylitis. Recently, the low molecular weight IL-17 inhibitor LY3509754 entered the clinic but was discontinued in Phase 1 due to adverse effects. In this study, we explored the replacements of furazan moiety posing a potential toxicology risk in LY3509754. By exploring replacements such as heterocycles as amide-isosteres as well as α-F-acrylamides, two compounds (18 and 26) were identified. Both compounds effectively reduced knee swelling in a rat arthritis model. However, early rat and dog toxicity studies revealed adverse findings, preventing their further development and indicating that furazan might not be responsible for the adverse effects of LY3509754.

Features of diagnostics and therapy of familial Mediterranean fever

The purpose of this work is to attempt to provide an overview of current recommendations for the diagnosis and treatment of familial Mediterranean fever, as well as to present our own clinical observation of this pathology. A selective analysis of the literature over the past 5 years (2020-2024) was carried out in the scientometric databases PubMed (https://pubmed.ncbi.nlm.nih.gov) and the Russian Science Citation Index (www.elibrary.ru). Current data on the autoinflammatory disease familial Mediterranean fever are reviewed. It is important to understand the fact that this pathological condition can be combined with a wide range of autoimmune diseases. The lack of therapy is dangerous for the development of serious complications (systemic amyloidosis). Attention is drawn to the use of colchicine, as well as in the case of colchicine resistance and insufficient effectiveness of colchicine – IL-1 inhibitors. We present our own clinical observation of this disease with an emphasis on the features of the course and stages of therapy for this pathology. A young man, Armenian, was treated for 3 years due to acute conditions with an increase in body temperature to febrile levels, severe abdominal pain and moderate arthralgia. The conditions were accompanied by leukocytosis and increased CRP, but no signs of acute surgical disease were detected. After a molecular genetic study, the diagnosis of familial Mediterranean fever was verified. Colchicine was prescribed, which helped stop many manifestations of the disease; she has been taking it regularly for 5 years. Currently, episodes of exacerbations have become significantly less frequent, laboratory markers of acute inflammation have normalized, but the use of colchicine in the maximum daily dose causes abdominal discomfort. Rare episodes of exacerbations during treatment suggest insufficient effectiveness of this drug. An option to achieve results in such a situation is to use a class of genetically engineered biological drugs such as IL-1 inhibitors. Familial Mediterranean fever is a rare pathological condition, but doctors of various clinical specialties should be wary of its detection. Achieving treatment success requires constant monitoring of the patient’s condition, prescribing therapy with colchicine or IL-1 inhibitors from the moment of diagnosis.

The role of cellular senescence in the pathogenesis of Rheumatoid Arthritis: Focus on IL-6 as a target gene

BackgroundRheumatoid arthritis is a chronic autoimmune disease. However, the specific role of senescence in rheumatoid arthritis (RA) is unknown. This study aimed to identify potential aging-related genes that have diagnostic and therapeutic value for RA. MethodsThe GSE89408 dataset was downloaded from the Gene Expression Omnibus (GEO). Aging-related genes were downloaded from the HAGR database. Differentially expressed genes (DEGs) were subsequently identified with the “edgeR” tool. Next, hub genes were identified with a PPI network and CytoHubba analysis. Receiver operating characteristic (ROC) curves were used to evaluate the diagnostic value of these hub genes. Immune infiltration analysis was performed with the CIBERSORT algorithm. Additionally, molecular docking was performed with CB-Dock2. Finally, correlation experiments were performed to validate the bioinformatics and molecular docking results. ResultsA total of 22 ADEGs were identified. Combined PPI network and CytoHubba analyses identified a total of 7 hub genes, including IL-6, IL7R, IL2RG, CDK1, PTGS2, and LEP, which are associated mainly with inflammation and immune responses. ROC analysis revealed that the hub genes were highly predictive of RA. Analysis of immune infiltration revealed that the 6 hub genes were positively associated with M1 macrophages. Validation experiments revealed that the inhibition of IL-6 significantly decreased the degree of synovial fibroblast (FLS) senescence. Furthermore, molecular docking and validation experiments revealed that IL-6 is a potential target for drug therapy. ConclusionThis study demonstrated that RA-FLS senescence may promote the development of RA via inflammatory and immune mechanisms. Seven hub genes were identified, of which IL-6 is a reliable biomarker for the diagnosis and treatment of RA.

Biological therapy for psoriatic arthritis: current state and future perspectives.

Psoriatic arthritis is a medical condition that lies at the intersection of various fields of medicine, and its therapy always requires a comprehensive, holistic approach. Biological disease-modifying antirheumatic drugs (bDMARDs) constitute an extremely effective treatment method for PsA, provided that appropriate principles for patient qualification for the drug are followed, along with subsequent monitoring of the response to treatment. Based on their mechanisms of action, four main groups of bDMARDs used in PsA can be distinguished (TNF inhibitors, IL-12/23 and IL-23 inhibitors, IL-17 inhibitors, CTLA4 agonists). Clinical trials are ongoing in search of registration for additional bDMARDs, and the tasks for doctors and scientists worldwide include patient education, increasing treatment accessibility, and optimizing its costs.

A mouse model of overexpression of human IL-6 by tissue-resident macrophages in the context of LPS-induced inflammation

Chronic inflammation caused by overexpression of IL-6 underlies a number of pathological conditions Mouse models of systemic chronic inflammation with overexpression of human IL-6 (hIL-6) are in demand not only in the context of studying the molecular mechanisms of inflammation, but also in assessing the effectiveness of clinically approved or newly developed IL-6 inhibitors. One experimental approach in addressing such models in mice relies on the induction of systemic acute inflammation in response to lipopolysaccharide (LPS) administration. This work describes mice with tamoxifen-dependent overexpression of human IL-6 in CX3CR1+ myeloid cells in the context of systemic inflammation induced by LPS administration. Our study demonstrates that the highest expression of the transgene carrying IL6 was observed in the heart, while high production of this cytokine was detected in the blood serum. In response to LPS administration, the production of hIL-6 in the blood increased in transgenic mice, while the production of mIL-6 also increased and was comparable to that in wild-type mice. The consequences of high systemic production of hIL-6, which in our model originates from CX3CR1+ tissue-resident macrophages, were noticeable even in the organs in which these cells are not present. Thus, significant amounts of hIL-6 were detected in tissue lysates of the lungs of transgenic mice after LPS administration. Evaluation of the expression of genes encoding cytokines and markers of tissue remodeling upon injury using quantitative real-time PCR showed significant changes in their expression in the context of LPS-induced systemic inflammation. Thus, this work demonstrates the feasibility of using a mouse model with tamoxifen-dependent transgene activation in CX3CR1+ tissue-resident macrophages to study the effects of systemic overexpression of IL-6 and pharmacological blockade of this cytokine with clinically approved or newly developed inhibitors in the context of experimentally induced diseases.