Interleukin-6 Receptor Inhibitor Research Articles

A Systematic Overview of Contraindications and Special Warnings for Biologic and Targeted Synthetic Disease Modifying Antirheumatic Drugs: Establishing a Framework to Create a "Safety Checklist".

The purpose of this review is to provide an overview of the contraindications, special warnings, and boxed warnings with the aim to establish a framework to create a prescription safety checklist for a class of drugs or disease indication. This study covers biologic disease modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs). We identified contraindications, boxed warnings, and special warnings provided by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). The study included b/tsDMARDs approved for treating rheumatoid arthritis (RA), psoriatic arthritis (PsA), axial spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA) within the drug-classes anti-CD20, tumor necrosis factor inhibitors (TNFi), interleukin-1 inhibitors (IL-1i), cytotoxic T-lymphocyte-associated protein (CTLA) 4, interleukin-12/23 inhibitors (IL-12/23i), interleukin 6 receptor inhibitors (IL-6Ri), Janus kinase inhibitors (JAKi), phosphodiesterase 4 inhibitors (PDE4i), interleukin-17 inhibitors (IL-17i), and interleukin-23 inhibitors (IL-23i). All drug classes, except PDE4i, had contraindications and/or warnings related to infections, including tuberculosis. A warning about herpes zoster was listed for anti-CD20, IL-1i, IL-6Ri, and JAKi, while a warning about hepatitis reactivation was listed for anti-CD20, TNFi, IL-1i, CTLA4-Ig, IL-6Ri, and JAKi. Malignancy risk was mentioned for all drug classes except PDE4i, IL-17i, and IL-23i. Other warnings included demyelinating disease (TNFi, CTLA4-Ig, and IL-6Ri), heart failure (anti-CD20 and TNFi), major adverse cardiac events (JAKi and IL-12/23) and venous thromboembolism (JAKi), hyperlipidemia (IL-6Ri and JAKi), liver impairment (TNFi, IL-1i, IL-6Ri, and JAKi), kidney impairment (IL-1i, JAKi, and PDE4i), inflammatory bowel disease (IL-17i), gastrointestinal perforation (IL-6Ri, JAKi), cytopenia (anti-CD20, TNFi, IL-1i, IL-6Ri, JAKi), and depression (PDE4i). Contraindications and warnings appeared to increase with the passage of time since the drug's approval. This review provides an overview to establish the framework to create an easily accessible and actionable prescription safety checklist from individual medical product prescription information provided by regulatory medical authorities.

Could tocilizumab be used in familial Mediterranean Fever? A systematic review.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease characterized by recurrent fever and serosal inflammation. Although colchicine is the primary treatment, around 10% of FMF patients do not respond to it, necessitating alternative therapies. Biologic treatments, such as interleukin-1β (IL-1β), TNF-α, and interleukin-6 (IL-6) inhibitors, have been considered. However, the accessibility and cost of IL-1β inhibitors may limit their use in certain regions. Tocilizumab (TCZ), an IL-6 receptor inhibitor, offers an alternative, but its efficacy in FMF is not well-documented. To evaluate the efficacy and safety of tocilizumab in the treatment of FMF. Following PRISMA guidelines, we identified 237 articles on the use of TCZ in FMF. After selection, 14 articles were included: 2 double-blind RCTs, 2 retrospective studies, and 10 case reports. Multicentre double-blind RCTs reported mixed results in FMF patients without AA amyloidosis due to genetic/classification heterogeneity of the available studies, possible misdiagnosed FMF patients and study design. Retrospective studies suggest that TCZ may benefit FMF patients with established renal AA amyloidosis, potentially preventing progression and managing flares more effectively. TCZ showed a safe profile with no specific adverse events, but data on its use during pregnancy or breastfeeding are lacking. There was no available data on the use of TCZ in pediatric FMF. This review summarizes the current state of research, safety and efficacy of TCZ in FMF. While IL1β inhibitors remain the first choice for colchicine-resistant or intolerant FMF patients, TCZ might be of interest in some selected FMF patients with established AA amyloidosis and resistance to colchicine and interleukin 1 inhibitors.

Current management of giant cell arteritis and its complications.

This review provides an update on current management strategies for giant cell arteritis (GCA), emphasizing the need for alternative therapies to reduce disease relapses and mitigate glucocorticoid (GC)-related morbidity. The standard of care for GCA has traditionally involved prolonged use of GC, and recent studies are exploring faster GC tapering regimens in an effort to reduce adverse effects while maintaining disease control. Randomized clinical trials have highlighted the efficacy of tocilizumab (TCZ), an interleukin-6 receptor inhibitor, in reducing disease flares and sparing GCs. However, the optimal treatment duration with TCZ is unknown and patients remain at risk of relapse after treatment discontinuation. An unmet therapeutic need persists for patients who are not candidates for TCZ, and for those who have inadequate response to this biologic. Therefore, investigations into alternative therapies such as targeting interleukin-17A, blocking T-cell activation or inhibiting the Janus kinase-signal transducer and activator of transcription pathway, showcase potential avenues for tailored treatments. While GCs remain the cornerstone of therapy, TCZ emerges as a promising GC-sparing agent. Ongoing research targeting different pathways implicated in GCA pathogenesis have led to encouraging results. However, the preliminary nature of these findings necessitates larger randomized controlled trials to establish their efficacy conclusively.

Comparison of anti-IL-6 receptor and JAK inhibitors in patients with rheumatoid arthritis from the real-world practice FIRST study.

A molecular-targeted drug that is suitable as the second choice for patients with rheumatoid arthritis (RA) who show an inadequate response to the first biological disease-modifying antirheumatic drug (bDMARD) is unknown. This study aimed to analyze the efficacy and safety of interleukin-6 receptor (IL-6Ri) and Janus kinase inhibitors (JAKis), often selected as molecular-targeted drugs for second or subsequent treatments. The efficacy and safety of JAKis and IL-6Ri were compared using propensity score-based inverse probability of treatment weighting (PS-IPTW) using propensity scores after 26 weeks of therapy in patients with RA. The remission rate at week 26, determined by the clinical disease activity index (CDAI), and the incidence of infection were higher in the JAKis than in the IL-6Ri group. The CDAI trajectories were divided into four according to the growth mixture modeling. IL-6Ri demonstrated greater efficacy in RA patients with ineffective to single bDMARD therapy compared with those with multiple ineffective bDMARDs. In patients who failed to respond to one bDMARD, there was no significant difference in the CDAI remission rate at week 26 between the JAKis (29.1%) and IL-6Ri (21.8%) groups (p= 0.21). However, for patients who did not respond to at least two bDMARDs, the CDAI remission rate at week 26 was higher in the JAKis than in the IL-6Ri group. IL-6Ri offers a superior balance of efficacy and safety compared with JAKis for RA patients unresponsive to one bDMARD. However, JAKis may suit patients who do not respond to multiple bDMARDs.

Five-year follow-up of patients with difficult-to-treat rheumatoid arthritis.

To elucidate the long-term outcomes of patients with difficult-to-treat rheumatoid arthritis (D2T RA). We collected data on the clinical course of patients who had been identified as D2T RA in 2018 until 2023. We stratified the patients according to outcomes at the last visit: resolved D2T RA, persistent D2T RA, and mortality. We compared their clinical characteristics and investigated the predictive factors for the resolution of D2T RA or mortality. Furthermore, we investigated the impact of the causes of D2T RA identified in 2018, multidrug resistance, comorbidities, and socioeconomic factors on outcomes in 2023. Of 173 patients identified as D2T RA in 2018, 150 were included in the analysis. Among them, D2T RA was resolved in 67 (45%), 75 (50%) remained as D2T RA, and 8 (5%) died. Patients with resolved D2T RA were significantly younger at the latest visit (p= 0.02), had a higher proportion of treatment changes during five years (p= 0.002), and had a higher proportion of interleukin-6 receptor inhibitors use in 2023 (p= 0.04) than those in patients with persistent D2T RA or those who died. D2T RA resolved in 38% of patients with multidrug resistance, mainly with treatment changes. Rheumatic disease comorbidity index and glucocorticoid dose escalation were independent risk factors for mortality (odds ratio [OR], 3.50; p= 0.02 and OR, 31.9; p= 0.002, respectively). Further modifications in RA treatment are useful for resolving D2T RA. Multiple comorbidities and glucocorticoid use are associated with mortality.

Phase II trial of weekly or bi-weekly tocilizumab with ipilimumab and nivolumab in advanced melanoma: Clinical outcomes and biomarker analysis.

9553 Background: Combination immune-checkpoint inhibitors (ICIs) improved outcomes in a plethora of cancer subtypes. However, up to 60% of patients (pts) receiving ipilimumab (ipi) plus nivolumab (nivo) experience grade 3/4 (G 3/4) immune-related adverse events (irAEs), often leading to treatment discontinuation. We evaluated two therapeutic strategies targeting interleukin-6 receptor (IL-6R) to reduce irAEs while enhancing ICls efficacy. Methods: Phase Il trial (NCT04940299) investigating safety/efficacy of frontline tocilizumab (toci; IL-6R inhibitor) combined with ipi 3mg/kg + nivo 1mg/kg Q3 weeks (wks) for 12 wks in advanced melanoma. Initially, toci was given as 162 mg subcutaneously (SQ) bi-weekly for 6 doses (regular dosing regimen; RD). Then, we escalated to a dose dense (DD) regimen (162 mg SQ weekly for 6 wks then bi-weekly for 6 wks; 9 doses total). Primary objective was rate of G 3/4 irAEs. Secondary objectives were objective response rates (ORR) and disease control rate (DCR) per RECIST 1.1. Exploratory objectives involved immune analysis (gene expression, CyTOF, cytokine analysis) on longitudinal blood and tissue samples to identify drivers of auto- vs antitumor immunity. Results: As of Feb 2024, 35 pts were enrolled (25 pts to RD regimen; 10 pts to DD regimen). In RD group, median follow-up is 18 months (6 - 25 months). By 12 wks, 44% of pts developed G 3/4 irAEs including colitis (20%), hepatitis (16%), pancreatitis (12%), type I diabetes and serum sickness (4% each) and 20% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 7.4 wks. 16% of pts discontinued ICIs due to irAEs. ORR was 56% at 12 wks including 40% in pts with high LDH and DCR was 80%. Gene expression analysis showed a trend towards higher expression of IL-17 pathway genes in pts who developed G 3/4 irAEs, suggesting IL-6/Th17 pathway was not sufficiently inhibited. Thus, we enrolled 10 pts into the DD regimen aiming to achieve better inhibition of the IL-6/Th17 pathway. In DD group, median follow-up is 7 months (3 - 13 months). By 12 wks, 40% of pts developed G 3/4 irAEs, including colitis (10%), hepatitis (20%), and uveitis (10%) and 30% of pts required hospitalization due to irAEs. Median time to G 3/4 irAEs onset was 4.9 wks. 30% of pts discontinued ICIs due to irAEs. ORR was 70% at 12 wks including 75% in pts with high LDH and DCR was 80%. Conclusions: To our knowledge, this is the first study to investigate toci in combination with high dose ipi3/nivo1. Although our cohort is small, preliminary data suggests IL-6R blockade using the DD regimen could decrease the rate of G 3/4 irAEs while maintaining antitumor responses of ipi3/nivo1. A randomized phase ll trial investigating this strategy is underway. Ongoing immune analysis comparing treatment regimens aims to identify distinct pathways involved in auto- vs antitumor immunity and IL-6/Th17 independent pathways of toxicity. Clinical trial information: NCT04940299 .

Genetically Proxied IL-6 Receptor Inhibition and Coronary Artery Disease Risk in a Japanese Population

Genetically Proxied IL-6 Receptor Inhibition and Coronary Artery Disease Risk in a Japanese Population

Exercise-induced changes in left ventricular strain are affected by interleukin-6 activity: An exploratory analysis of a randomised-controlled trial in humans with abdominal obesity.

Whilst the exercise-induced myokine interleukin-6 (IL-6) plays a beneficial role in cardiac structural adaptations, its influence on exercise-induced functional cardiac outcomes remains unknown. We hypothesised that IL-6 activity is required for exercise-induced improvements in left ventricular global longitudinal strain (LV GLS). In an exploratory study 52 individuals with abdominal obesity were randomised to 12weeks' high-intensity exercise or no exercise in combination with IL-6 receptor inhibition (IL-6i) or placebo. LV strain and volume measurements were assessed by cardiac magnetic resonance. Exercise improved LV GLS by -5.4% [95% CI: -9.1% to -1.6%] (P=0.007). Comparing the change from baseline in LV GLS in the exercise + placebo group (-4.8% [95% CI: -7.4% to -2.2%]; P<0.0004) to the exercise + IL-6i group (-1.1% [95% CI: -3.8% to 1.6%]; P=0.42), the exercise + placebo group changed -3.7% [95% CI: -7.4% to -0.02%] (P=0.049) more than the exercise + IL6i group. However, the interaction effect between exercise and IL-6i was insignificant (4.5% [95% CI: -0.8% to 9.9%]; P=0.09). Similarly, the exercise + placebo group improved LV global circumferential strain by -3.1% [95% CI: -6.0% to -0.1%] (P=0.04) more compared to the exercise + IL-6i group, yet we found an insignificant interaction between exercise and IL-6i (4.2% [95% CI: -1.8% to 10.3%]; P=0.16). There was no effect of IL-6i on exercise-induced changes to volume rates. This study underscores the importance of IL-6 in improving LV GLS in individuals with abdominal obesity suggesting a role for IL-6 in cardiac functional exercise adaptations.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45–60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09–0.61), IL-6Ri: 0.34 (0.14–0.81), CTLA-4-Ig: 0.36 (0.15–0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Genetically proxied interleukin-6 receptor inhibition increases risk of atopic dermatitis

BackgroundDermatitis has been reported after initiation of IL-6 receptor inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signalling. However, causality remains unclear. As indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD. ObjectiveTo examine the association between IL-6Ri and risk of AD. MethodsTo genetically mimic IL-6Ri, we selected single nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein (CRP) at genome-wide significance among 343,524 individuals. Genetic data for AD were obtained from 10,788 cases and 30,047 controls of European ancestry. We used the inverse-variance weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated using 13,473 AD Finnish cases and 2,385 East Asian cases. Results from three independent analyses were pooled by meta-analysis. ResultsGenetically proxied IL-6Ri was associated with increased risk of AD (OR 1.78 per 4.4 mg/l reduction in CRP; 95%CI 1.28, 2.48; p=6.5x10-4). Results were replicated using Finnish outcome data (OR 2.07; 95%CI 1.58, 2.72; p=1.57x10-7), and Eastern Asian datasets (OR 1.68; 95%CI 1.12, 2.54; p=0.013). Meta-analysis of three independent populations (OR 1.89; 95%CI 1.57, 2.28; p=2.68x10-11) showed no statistical evidence of heterogeneity (p=0.65). We found no statistical evidence for pleiotropy or genetic confounding. ConclusionThis genetic investigation provides consistent evidence, across independent multi-ancestry populations, that IL-6R signalling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases.

Potential cellular intravesical therapy for non-muscle invasive bladder cancer: Nectin-4 targeted CAR-T cell therapy

Bladder cancer poses a significant global health challenge, particularly with its prevalence in males and the increasing incidence rates in Europe. While non-muscle invasive bladder cancer can be managed with localized treatments, its recurrence remains a concern. Intravesical Bacillus Calmette-Guérin therapy triggers an immune response against cancer cells, yet recurrences post- transurethral resection of bladder tumor persist. Thus, innovative strategies are needed. We propose the use of Nectin-4 targeted chimeric antigen receptor T cell therapy to prevent non-muscle invasive bladder cancer recurrence and progression. Nectin-4 is expressed in non-muscle invasive bladder cancer, making it an ideal target. CAR-T cells engineered with Nectin-4 receptors can specifically eliminate cancer cells. By directly applying these cells intravesically, the limitations of CAR-T cell access to solid tumors are circumvented. However, challenges persist, such as the immunosuppressive microenvironment of bladder cancer. This can be addressed by combining intravesical Bacillus Calmette-Guérin with CAR-T therapy or utilizing immune checkpoint inhibitors. CAR-T therapy-related toxicities, like cytokine release syndrome, can be managed with IL-6 and IL-1 receptor inhibitors. Our hypothesis suggests that Nectin-4 targeted CAR-T cells have the potential to revolutionize bladder cancer treatment. This therapy could not only eliminate cancer cells but also prevent recurrence and progression by inducing immune memory. Although further research is needed, this innovative approach shows promise in the treatment of non-muscle invasive bladder cancer.

Tocilizumab in chronic active antibody-mediated rejection: rationale and protocol of an in-progress randomized controlled open-label multi-center trial (INTERCEPT study)

BackgroundChronic active antibody-mediated rejection (caAMR) in kidney transplants is associated with irreversible tissue damage and a leading cause of graft loss in the long-term. However, the treatment for caAMR remains a challenge to date. Recently, tocilizumab, a recombinant humanized monoclonal antibody directed against the human interleukin-6 (IL-6) receptor, has shown promise in the treatment of caAMR. However, it has not been systematically investigated so far underscoring the need for randomized controlled studies in this area.MethodsThe INTERCEPT study is an investigator-driven randomized controlled open-label multi-center trial in kidney transplant recipients to assess the efficacy of tocilizumab in the treatment of biopsy-proven caAMR. A total of 50 recipients with biopsy-proven caAMR at least 12 months after transplantation will be randomized to receive either tocilizumab (n = 25) added to our standard of care (SOC) maintenance treatment or SOC alone (n = 25) for a period of 24 months. Patients will be followed for an additional 12 months after cessation of study medication. After the inclusion biopsies at baseline, protocol kidney graft biopsies will be performed at 12 and 24 months. The sample size calculation assumed a difference of 5 ml/year in slope of estimated glomerular filtration rate (eGFR) between the two groups for 80% power at an alpha of 0.05.The primary endpoint is the slope of eGFR at 24 months after start of treatment. The secondary endpoints include assessment of the following at 12, 24, and 36 months: composite risk score iBox, safety, evolution and characteristics of donor-specific antibodies (DSA), graft histology, proteinuria, kidney function assessed by measured GFR (mGFR), patient- and death-censored graft survival, and patient-reported outcomes that include transplant-specific well-being, adherence to immunosuppressive medications and perceived threat of the risk of graft rejection.DiscussionNo effective treatment exists for caAMR at present. Based on the hypothesis that inhibition of IL-6 receptor by tocilizumab will reduce antibody production and reduce antibody-mediated damage, our randomized trial has a potential to provide evidence for a novel treatment strategy for caAMR, therewith slowing the decline in graft function in the long-term.Trial registrationClinicalTrials.gov NCT04561986. Registered on September 24, 2020

Disease-modifying anti-rheumatic drug selection in Japanese patients with rheumatoid arthritis treated with biologics or JAK inhibitors without methotrexate: A retrospective hospital-based administrative claims database study.

We evaluated the medication selection and clinical characteristics of rheumatoid arthritis (RA) patients who started treatment with/without methotrexate (using biologic disease-modifying antirheumatic drugs or Janus kinase inhibitors [JAKi] instead) in Japan. Using a Japanese hospital-based administrative claims database, RA patients who received treatment (abatacept, interleukin-6 receptor inhibitor [IL-6Ri], tumor necrosis factor inhibitor, or JAKi) between 1/January/2015 and 31/December/2019 were enrolled. In total 19,301 patients were included (10,530 receiving methotrexate; 8,771 not receiving methotrexate within 60 days of the first treatment). Mean ages at diagnosis were 60.7 and 65.9 years in the methotrexate and non-methotrexate groups (p <0.0001). The non-methotrexate group had higher proportions of patients with Charlson Comorbidity Index ≥1 (p <0.0001), and higher comorbidity rates. Abatacept was the most frequently used drug among patients with infectious/parasitic, circulatory, and respiratory diseases at baseline. IL-6Ri had the highest use rate among patients with neoplasms; blood, gastrointestinal, and genitourinary diseases; and abnormal clinical/laboratory findings. Abatacept had the highest persistence probability from 6 months onward. Methotrexate is used less frequently among older Japanese RA patients or those with comorbidities. Abatacept is the most frequently used drug, followed by IL-6Ri, in patients not using methotrexate at the treatment start.

Dynamics of modified cardiovascular risk factors in patients with rheumatoid arthritis on the background of 5-year therapy with an interleukin 6 receptor inhibitor

The effect of an inhibitor of interleukin (IL) 6 receptors on the state of the cardiovascular system in patients with rheumatoid arthritis (RA) remains poorly understood, especially with its long-term use.The aim – to study the effect of therapy with the IL-6 receptor inhibitor tocilizumab (TCZ) on the dynamics of modifiable risk factors (RF), total cardiovascular risk (CVR), structural changes in the carotid arteries (CA) and the incidence of cardiovascular complications (CVC) in patients with rheumatoid arthritis during the 260-week follow-up period.Material and methods. The study included 37 patients with active RA (32 women and 5 men) with ineffectiveness and/or intolerance to disease modifying anti-rheumatic drugs (DMARDs); median age was 56 [48; 68] years, disease duration was 92 [49; 158] months; DAS28 (Disease Activity Score 28) – 6.2 [5.5; 6.7] points; all patients were seropositive for rheumatoid factor (RF), 86% – for antibodies to cyclic citrullinated peptide (ACCP). Patients received TCZ therapy 8 mg/kg intravenously every 4 weeks; after 192 [176; 210] weeks, 60% of patients switched to subcutaneous administration of the drug at a dose of 162 mg once a week. In 51% of patients with RA, TCZ monotherapy was performed, in 49% – combination therapy of TCZ with DMARDs. Statins were received by 17 (46%) patients, including 7 patients before and 10 after inclusion in the study. All patients underwent an assessment of traditional risk factors, the total cardiovascular risk was calculated using the mSCORE scale, atherosclerotic vascular lesions were assessed by the detection of atherosclerotic plaques (ASP) of CA. The observation period was 260.4 [251.5; 283.4] weeks.Results. After 260 weeks of TCZ therapy, RA remission was observed in 32 (86%) patients, low activity – in 5 (14%) patients. During the observation period, the frequency of modified RF and the total CVR did not change significantly, an increase in body mass index (BMI) by 11% was recorded, the number of patients with hypercholesterolemia and a reduced level of HDL cholesterol (C) decreased. In patients without statin therapy, there were no significant changes in the blood lipid spectrum. In the group of patients receiving statins, there was an increase in HDL-C by 43%, a decrease in cholesterol levels by 15%, atherogenic index (AI) by 56% (p&lt;0.01 in all cases) and associations between the dynamics of ∆cholesterol and ∆CRP (r=0.35; p=0.04), ∆LDL-C and ∆CRP (r=0.41; p=0.03). Significant structural changes in CA in RA patients by the end of 260 weeks of TCZ therapy were not identified. Initially, intima-media thickness (IMT) CA positively moderately correlated with age (r=0.7; p&lt;0.01), BMI (r=0.37; p&lt;0.01), systolic blood pressure (SBP) (r=0.62; p&lt;0.01) and weakly with lipid spectrum parameters – cholesterol (r=0.29; p&lt;0.01), LDL-C (r=0.36; p&lt;0.01). No new associations of IMT CA by the end of the observation, as well as the relationship of the IMT CA value with the indicators of RA activity and the ongoing therapy, were identified. By the end of the study, the distribution of patients by mSCORE value and CVR level did not change significantly. The incidence of CVC was 0,54 per 100 patient-years over a 260-week period of TCZ use. Conclusion. Against the background of long-term TCZ therapy in RA patients, there was no increase in CVR and significant structural changes in CA. It is necessary to dynamically monitor the blood lipid profile and CVR in RA patients receiving TCZ therapy. Statin therapy can successfully control dyslipidemia in RA patients who receive long-term TCZ.

Immune Checkpoint Inhibitor-Induced Inflammatory Arthritis: Overview of Therapies and a Personalized Approach to Optimized Combined Therapy.

Immune checkpoint inhibitors (ICIs), including anti-cytotoxic T lymphocyte antigen 4, anti-programmed cell death 1, and anti-programmed cell death ligand 1 (PD-L1) antibodies, are currently widely used in oncology clinical practice, achieving considerable success in improving disease outcomes. New checkpoint targets are being discovered and investigated through basic science research and clinical trials. ICI remove negative regulatory immune signals on T cells, leading to immune activation and induction of antitumor immunity. Patients who receive ICI, however, are at risk for developing immune-related adverse events (irAEs), which are attributed to increased T cell activity against antigens in both tumors and in healthy tissues, to increased inflammatory cytokine levels, to increased levels of preexisting autoantibodies, and to enhanced complement-mediated inflammation. Arthritis is one of the most common irAEs. ICI-induced rheumatic irAEs are categorized by levels of severity which guide the choice of treatment options. Management of ICI-induced rheumatic irAEs includes the use of glucocorticoids, disease-modifying antirheumatic drugs (mainly methotrexate), and biological agents (e.g., tumor necrosis factor, interleukin-6 receptor, and CD20 inhibitors). This review aims to summarize the current ICI subtypes, their role in rheumatic irAEs development, and therapies currently used in clinical practice to manage irAEs. In addition, we propose to use an ex vivo personalized diagnostic assay for the selection of the most effective ICI with antirheumatic drugs combinations that will inhibit the advancement of ICI-induced adverse events.

Effect of Anti-Interleukin-6 Agents on Psychopathology in a Sample of Patients with Post-COVID-19 Syndrome: An Observational Study.

Interleukin 6 (IL-6) receptor inhibitors tocilizumab and sarilumab have recently been approved for severe coronavirus disease 2019 (COVID-19). They also affect mood, even though their effect on the post-COVID-19 syndrome-related psychopathology still has to be investigated. The aim of this study was to investigate their effect on psychopathology in a sample of patients with post-COVID-19 syndrome. We included 246 patients (34% female, 66% male) aged 18-75 years who had been hospitalized for COVID. Patients were split into those who received anti-IL-6 receptor agents (Anti-IL-6-R, N = 88) and those who did not (Ctrl, N = 158). The former group was further split into those receiving tocilizumab (TOC, N = 67) and those receiving sarilumab (SAR, N = 21). Groups were compared based on clinical characteristics before and during COVID-19 as well as on physical and psychiatric symptoms after COVID-19. Ctrl had less psychiatric and physical symptoms during hospitalization and more post-COVID-19 diarrhea, headache, cough, and dyspnea upon exertion than those receiving IL-6-receptor inhibitors. Ctrl also showed greater difficulties in emotion regulation. These differences were driven by TOC vs. Ctrl, whereas differences between SAR and Ctrl or TOC did not reach significance. IL-6 receptor inhibitors are related to a lower post-COVID-19 illness burden and seem to be effective in emotion regulation. Further research is needed to confirm these findings.

Gp130-HIF1α axis-induced vascular damage is prevented by the short-term inhibition of IL-6 receptor signaling.

Protection against endothelial damage is recognized as a frontline approach to preventing the progression of cytokine release syndrome (CRS). Accumulating evidence has demonstrated that interleukin-6 (IL-6) promotes vascular endothelial damage during CRS, although the molecular mechanisms remain to be fully elucidated. Targeting IL-6 receptor signaling delays CRS progression; however, current options are limited by persistent inhibition of the immune system. Here, we show that endothelial IL-6 trans-signaling promoted vascular damage and inflammatory responses via hypoxia-inducible factor-1α (HIF1α)-induced glycolysis. Using pharmacological inhibitors targeting HIF1α activity or mice with the genetic ablation of gp130 in the endothelium, we found that inhibition of IL-6R (IL-6 receptor)-HIF1α signaling in endothelial cells protected against vascular injury caused by septic damage and provided survival benefit in a mouse model of sepsis. In addition, we developed a short half-life anti-IL-6R antibody (silent anti-IL-6R antibody) and found that it was highly effective at augmenting survival for sepsis and severe burn by strengthening the endothelial glycocalyx and reducing cytokine storm, and vascular leakage. Together, our data advance the role of endothelial IL-6 trans-signaling in the progression of CRS and indicate a potential therapeutic approach for burns and sepsis.

Proteogenomic Data Integration Reveals CXCL10 as a Potentially Downstream Causal Mediator for IL-6 Signaling on Atherosclerosis.

Genetic and experimental studies support a causal involvement of IL-6 (interleukin-6) signaling in atheroprogression. Although trials targeting IL-6 signaling are underway, any benefits must be balanced against an impaired host immune response. Dissecting the mechanisms that mediate the effects of IL-6 signaling on atherosclerosis could offer insights about novel drug targets with more specific effects. Leveraging data from 522 681 individuals, we constructed a genetic instrument of 26 variants in the gene encoding the IL-6R (IL-6 receptor) that proxied for pharmacological IL-6R inhibition. Using Mendelian randomization, we assessed its effects on 3281 plasma proteins quantified with an aptamer-based assay in the INTERVAL cohort (n=3301). Using mediation Mendelian randomization, we explored proteomic mediators of the effects of genetically proxied IL-6 signaling on coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease. For significant mediators, we tested associations of their circulating levels with incident cardiovascular events in a population-based study (n=1704) and explored the histological, transcriptomic, and cellular phenotypes correlated with their expression levels in samples from human atherosclerotic lesions. We found significant effects of genetically proxied IL-6 signaling on 70 circulating proteins involved in cytokine production/regulation and immune cell recruitment/differentiation, which correlated with the proteomic effects of pharmacological IL-6R inhibition in a clinical trial. Among the 70 significant proteins, genetically proxied circulating levels of CXCL10 (C-X-C motif chemokine ligand 10) were associated with risk of coronary artery disease, large artery atherosclerotic stroke, and peripheral artery disease, with up to 67% of the effects of genetically downregulated IL-6 signaling on these end points mediated by decreases in CXCL10. Higher midlife circulating CXCL10 levels were associated with a larger number of cardiovascular events over 20 years, whereas higher CXCL10 expression in human atherosclerotic lesions correlated with a larger lipid core and a transcriptomic profile reflecting immune cell infiltration, adaptive immune system activation, and cytokine signaling. Integrating multiomics data, we found a proteomic signature of IL-6 signaling activation and mediators of its effects on cardiovascular disease. Our analyses suggest the interferon-γ-inducible chemokine CXCL10 to be a potentially causal mediator for atherosclerosis in 3 vascular compartments and, as such, could serve as a promising drug target for atheroprotection.

A rare complication of acute lower limb ischemia post coronavirus disease 2019 infection in a healthy pediatric patient: case report

BackgroundCoronavirus Disease 2019 (COVID-19) is a novel respiratory disease that first emerged in 2019. Patients infected with this disease present with a myriad of symptoms. Limb ischemia and hypercoagulability are complications identified in adults. COVID-19-related vasculitis is a known but seldom reported complication in pediatric patients, and the treatment approach is still not well established.Case presentationWe report the case of a healthy four-year-old female with a history of COVID-19 who developed acute lower limb ischemia. This was initially treated as a case of acute snake envenomation by administering snake antivenom with no improvement. She eventually developed lower limb acrocyanosis with an inability to ambulate. The patient was started on interleukin-6 receptor inhibitors (tocilizumab), anticoagulants, and pulse steroid therapy. The patient had complete resolution with the loss of only one toe.ConclusionIdentification of thromboembolic complications in pediatric patients with no comorbidities and a history of COVID-19 can be difficult. Early recognition and treatment have a major impact on morbidity and can increase the likelihood of limb salvage.

Comparative effectiveness of biological disease-modifying antirheumatic drugs and Janus kinase inhibitor monotherapy in rheumatoid arthritis.

To examine the effectiveness and drug tolerability of biological disease-modifying antirheumatic drugs (bDMARDs) and Janus kinase inhibitor (JAKi) monotherapy in patients with rheumatoid arthritis (RA) in a multicentre cohort study. Patients with RA initiated with bDMARD/JAKi monotherapy without conventional synthetic DMARDs were included. Monotherapy regimens were categorised as interleukin-6 receptor inhibitors (IL-6Ri), cytotoxic T-lymphocyte-associated protein 4 immunoglobulin (CTLA4Ig), JAKi, or tumour necrosis factor inhibitors (TNFi). Multiple propensity score-based inverse probability weighting (IPW) was used to reduce selection bias. Linear mixed-effect models with IPW were used to examine changes in the disease activity score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR) at 24 weeks, and drug retention was compared among monotherapy using IPW Cox proportional hazards models. A total of 849 treatment courses from 635 patients were included (IL-6Ri, 218; CTLA4Ig, 183; JAKi, 92; TNFi, 356). The difference in change in DAS28-ESR at week 24 as the primary outcome was -0.93 (95% CI: -1.20 to -0.66) lower in the IL-6Ri group than TNFi, while that of CTLA4Ig and JAKi was similar with that of TNFi (-0.20 [-0.48 to 0.08], -0.25 [-0.67 to 0.16], respectively). IL-6Ri use was associated with significantly lower overall drug discontinuation than TNFi use (hazard ratio = 0.55 [0.39-0.78], P = 0.001). Similar retention rates were identified among CTLA4Ig and JAKi compared to TNFi. In the analysis with IPW to reduce selection bias, IL-6Ri monotherapy was superior to TNFi monotherapy in terms of effectiveness and drug retention. No significant differences were identified between CTLA4Ig, JAKi, and TNFi monotherapy.