Baseline IL-6 Levels Research Articles

Comparison of IL-6, IL-10, and TNFα levels between PLWHIV with and without Kaposi Sarcoma and healthy controls.

Kaposi sarcoma (KS) is an angioproliferative disease caused by human herpesvirus 8 (HHV-8) and is mediated by cytokines in an immunodeficient environment. This study aimed to compare IL-6, IL-10, and TNFα levels among AIDS patients with disseminated KS (DKS), treatment naïve patients living with HIV (PLWHIV) without DKS, and healthy controls. Secondary outcomes were to compare cytokines levels in patients with DKS and unfavorable outcomes, as well as an analysis of the behavior of cytokines over time. This cohort study was performed at two centers in Mexico City. Three groups were included. Group 1: HIV+ treatment naïve with DKS, Group 2: HIV+ treatment naïve without KS, and Group 3: HIV negative, healthy controls. Plasmatic IL-6, IL-10, and TNFα levels were measured at baseline and over time in Groups 1 and 2. Seventy-six patients were included: 39 (52%) in Group 1, 17 (22%) in Group 2, and 20 (26%) in Group 3. The median baseline IL-6, IL-10, and TNFα levels were significantly higher in group 1. In group 1, baseline IL-6 was higher in patients who died than in survivors (14.4 vs 5.8 pg/mL p=0.048). Patients with severe immune reconstitution inflammatory syndrome due to KS (S-IRIS-KS) had higher IL-6 values than those without it (14.4 vs 5.8 pg/mL p=0.004). In the repeated-measures model in group 1, IL-10 levels were higher in patients who died (p<0.001) and developed IRIS-KS (p=0.01). IL-6, IL-10, and TNF α levels were markedly higher in patients with DKS. IL-6 and IL-10 levels were higher in patients with unfavorable outcomes.

Abstract 4134249: Cardiovascular Risk Factors and Associations of Chronic Inflammatory-Related Disease in the Multi-Ethnic Study of Atherosclerosis

Background: Inflammation plays a role in the development of cardiovascular disease (CVD). We have defined various non-cardiovascular and non-cancer conditions, both infectious and non-infectious, with a common basis of inflammation; collectively termed Chronic Inflammatory-Related Disease (ChrIRD). We have previously described that ChrIRD is common, associated with baseline inflammatory marker levels, associated with high mortality, and has a bidirectional association with CVD. The clinical implications of these data require further study. Aims: We hypothesize that many traditional risk factors for CVD are also associated with ChrIRD and that ChrIRD has additional unique risk factors. We also hypothesize that the treatment of traditional CVD risk factors is associated with a decreased likelihood of ChrIRD. Methods: We studied MESA participants free of overt CVD or significant illness at baseline. ChrIRD was determined based on review of ICD codes for hospitalizations and deaths. Incident CVD was adjudicated by review of medical records. We performed proportional hazards regression (time-dependent for CVD) to identify factors associated with a first diagnosis of ChrIRD. All variables were simultaneously entered into the model. Results: Participants (n=6155) had mean age 62±10 years and 47% male gender. ChrIRD was observed in 24% and CVD in 18%; including 8% with both conditions. Participants with a diagnosis of CVD, older age, higher heart rate, higher BMI, current or ever smoking status, higher HDL, higher baseline IL6 and GlycA levels, and NSAID use had increased likelihood of ChrIRD. Whereas those with female sex, higher total cholesterol, and statin use had a decreased likelihood of ChrIRD. Participant race/ethnicity, blood pressure, diabetes status, antihypertensive use, aspirin use, baseline CRP level, and baseline D-dimer level were not associated with ChrIRD. Regression results are summarized in Table 1. Conclusions: ChrIRD shares some risk factors with CVD, while other risk factors are opposite. Better understanding of ChrIRD could eventually lead to improved patient care.

Trajectories and predictive significance of inflammatory parameters for clinical outcome in COVID-19 patients treated with tocilizumab.

The IL-6 receptor inhibitor tocilizumab reduces mortality and morbidity in severe cases of COVID-19 through its effects on hyperinflammation and was approved as adjuvant therapy. Since tocilizumab changes the levels of inflammatory markers, we aimed to describe these changes in patients treated with tocilizumab, analyse their value in predicting death and bacterial superinfection and determine their influence on mortality rates. A retrospective analysis of 76 patients who were treated with tocilizumab for severe COVID-19 in 2020 and 2021 was conducted. Inflammatory markers (IL-6, C-reactive protein (CRP), procalcitonin) were documented before and up to seven days after tocilizumab administration. The overall mortality was 25% and 53.8% in patients who required invasive respiratory support. Deceased patients had higher baseline IL-6 (p = 0.026) and peak IL-6 levels after tocilizumab vs those who survived (p < 0.0001). A peak IL-6 value > 1000pg/dl after tocilizumab administration was a good predictor of mortality (AUC = 0.812). Of the deceased patients 41.1% had a renewed CRP increase after an initial decrease following tocilizumab administration, compared to 7.1% of the surviving patients (p = 0.0011). Documented bacterial superinfections were observed in 35.5% (27/76) of patients, of whom 48.1% (13/27) died. CRP-decline and IL-6 increase after tocilizumab treatment occurs regularly. An increase of IL-6 levels exceeding tenfold of baseline IL-6 levels, an absolute peak of 1000pg/ml or a renewed increase of CRP are associated with higher mortality. Suppressed CRP synthesis can impede the diagnosis of bacterial superinfections, thus increasing the risk for complications.

Association between PPARγ polymorphisms and neurological functional disability of ischemic stroke.

Peroxisome proliferator-activated receptor-γ (PPARγ) plays a protective role against brain injury after stroke in mice. However, the relationship between PPARγ gene polymorphisms and the functional outcome of acute ischemic stroke (AIS) remains unknown. 8822 patients from The Third China National Stroke Registry (CNSR-III) after whole-genome sequencing, two functional single nucleotide polymorphisms(SNPs) in PPARγ, rs1801282 C > G and rs3856806 C > T, were further analysed. The primary outcome was neurological functional disability at three months. Of the 8822 patients, 968 (11.0%) and 3497 (39.6%) were carriers of rs1801282 and rs3856806, respectively. Carriers of rs3856806 showed reduced risks for three-month neurological functional disability (OR, 0.84; 95% CI, 0.73-0.98; p = 0.02) and reduced risks for higher infarct volume (OR 0.90, 95% CI, 0.81-0.99, p = 0.04). They also had a reduced risk of neurological functional disability only in case of lower baseline IL-6 levels (OR 0.64, 95% CI 0.48-0.84, Pinteraction = 0.01). Carriers of rs1801282 had a reduced risk for three-month neurological functional disability (OR 0.77, 95% CI, 0.61-0.99, p = 0.04). Our study suggested that PPARγ polymorphisms are associated with a reduced risk for neurological functional disability and higher infarct volume in AIS. Therefore, PPARγ can be a potential therapeutic target in AIS.

Early On-Treatment Assessment of T Cells, Cytokines, and Tumor DNA with Adaptively Dosed Nivolumab + Ipilimumab: Final Results from the Phase 2 ADAPT-IT Study.

The Adaptively Dosed ImmunoTherapy Trial (ADAPT-IT;NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared with conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate at Week 12. Plasma was assayed for circulating tumor DNA and 10 cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. Among the treated patients, expansion of proliferating T-cell populations was observed in responders and nonresponders. Baseline IL6 levels were low in patients achieving an objective radiographic response (median 1.30 vs. 2.86 pg/mL; P = 0.025). High baseline IL6 levels were associated with short progression-free survival [PFS; HR = 1.24, 95% confidence interval (CI), 1.01-1.52; P = 0.041]. At Week 6, patients with response had lower average tumor variant allele fractions than nonresponders (median 0.000 vs. 0.019; P = 0.014). Greater increases in average variant allele fractions from baseline to Week 6 correlated with short PFS (HR = 1.11, 95% CI, 1.01-1.21; P = 0.023). Week 12 overall response rate was 47% (95% CI, 35%-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI, 10-not reached); 76% of responses (95% CI, 64%-91%) persisted at 36 months. Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL6 and circulating tumor DNA changes during treatment warrant further study as biomarkers of nivo-ipi response.

Predictive Value of Interleukin 6 and Interleukin 8 in Response to Treatment of Hepatitis C Virus.

Chronic hepatitis C (CHC) infection is a major public health problem in many low- and middle-income countries. The study aimed to find out how interleukin IL-6 and IL-8 levels in the blood affect the virological response to directacting antivirals (DAAs) and to find useful clinical or immunological markers for the response to HCV treatment. CHC patients from a real Egyptian population (n = 4,300), who were treated during the Egyptian national initiative to eliminate HCV at the Sherbin Central Hospital, Dakahlia Governorate, Ministry of Health, Egypt, were enrolled in our study. They were all patients who did not obtain a sustained virological response (SVR) (n = 75; non-responder; the response rate was 98.26%), and a total of 100 patients were randomly selected from patients who obtained SVR (responder) and were age- and gender-matched (p > 0.05) with non-responder patients. Serum levels of IL-6 and IL-8 were measured by commercial ELISA kits. Non-responder patients were associated with significantly high levels of ALT, AST, ALP, and total bilirubin. Non-responders had significantly (p < 0.05) higher baseline IL-6 (16.7 ± 4.92 pg/mL) and IL-8 (37.81 ± 10.55 pg/mL) levels compared to responders (12.68 ± 2.06, 29.06 ± 5.94 pg/mL, respectively). There was a substantial (p < 0.05) association between the combination of two cytokines and a high likelihood of treatment failure, as indicated by all parameters examined, with the highest correlation values seen. The present study showed that increased IL-6 and IL-8 were associated with HCV treatment failure. Also, IL8 was associated with hepatic fibrosis.

Germline Determinants of Toxicity and Efficacy in Patients with Large B-Cell Lymphoma Treated with Anti-CD19 Autologous CAR T-Cell Therapy

Background. Increasing data have demonstrated that acquired genetic aberrations, including TP53 mutations in the tumor cells and clonal hematopoiesis, can impact the efficacy and/or toxicity of anti-CD19 autologous CAR T-cell therapy (CART) in patients with large B-cell lymphoma (LBCL). Recent data have suggested that germline genetic aberrations, including polymorphisms in CD19, ABCB1, MISP and CPVL (Strati P et al, Leukemia 2022) and deleterious germline variants in STXBP2, can also affect outcomes in these patients. However, a comprehensive analysis of germline determinants of response and toxicity after CART in this patient population has not yet been described. Methods. Genome-wide genotyping using the Illumina Genome Screening Array (GSAv2.0) was performed in 170 patients with relapsed or refractory LBCL treated with standard of care axicabtagene ciloleucel in third line and beyond. Response was assessed according to 2014 Lugano criteria. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded according to ASTCT criteria, and cytopenia according to CTCAE v5. Polygenic risk score (PRS) instruments for blood cell traits and inflammatory markers were obtained from the PGS Catalog and analyzed using PRSice. Risk of poor response and toxicity was estimated using logistic regression models with standardized PRS scores as a continuous variable adjusting for age at diagnosis, gender, and bridging therapy (yes/no). Exploratory genome-wide association study (GWAS) analyses were also performed. Results. The median age was 58 years, 116 (68%) were male, and 91 (54%) received bridging therapy. Interestingly, increasing PRS for baseline IL-6 levels was associated with decreased risk of CRS grade (G) 2-4 (β: -0.15, 95% CI: -0.30 to -0.013, p=0.030) and ICANS G3-4 (β: -0.21, 95% CI: -0.37 to -0.066, p=0.005). Similarly, increased genetically-predicted monocyte levels decreased risk of ICANS G3-4 (β: -0.16, 95% CI: -0.31 to -0.018, p=0.027). Baseline genetically-predicted monocyte levels were also associated with increased probability of a CR at D90 (β: 0.19, 95% CI: 0.041 to 0.34, p=0.011). For prolonged cytopenia (defined as G3-4 cytopenia ongoing at day 30), risk was increased with increasing PRS for reticulocyte levels (β: 0.29, 95% CI: 0.10 to 0.48, p=0.002). No genome-wide significant (p&amp;lt;5x10 -8) variants were identified in the exploratory GWAS analyses, however, several loci at p=10 -5 were located within/near potential biologically-relevant candidate genes. This included an association with prolonged cytopenia for rs111940551 located upstream of IKZF1, a regulator of lymphocyte differentiation, and serving as a putative expression quantitative trait loci (eQTL) for this gene. An intragenic variant identified for ICANS G3-4 (rs1149927) was in high linkage disequilibrium (D'=0.97) with a variant previously shown to be associated with brain morphology. Conclusion. PRS representing baseline levels of several key blood cell traits, particularly monocytes, and inflammatory markers may impact toxicities and efficacy of CART in patients with LBCL. The intriguing finding of an inverse association for IL-6 with both high-grade CRS and ICANS was unexpected and needs further investigation. Larger studies are warranted to confirm these observations and better understand how relevant germline genetic determinants may influence efficacy and toxicity after CART therapy. Elucidating such determinants may help in improving patient selection and in developing strategies to enhance the therapeutic index of CART.

Abstract 12958: Temporal Association of Systemic Inflammatory Biomarkers With Incidence of Postoperative Atrial Fibrillation After Botulinum Toxin Type A Administration in Epicardial Fat Pads

Background: A one-time injection of botulinum toxin type A (BoNT/A) in epicardial fat pads was evaluated for post-operative atrial fibrillation (POAF) in patients undergoing open-chest cardiac surgery in the Ph2 NOVA trial. Treatment with 125U BoNT/A numerically reduced the incidence of POAF in the mITT (36.5% vs 46.1%) and CABG populations (28.4% vs 40.0%), with statistical significance observed in the CABG + ≥65 years subgroup (27.5% vs 56.4%; P &lt;0.01). No significant reduction was observed in the 250U group vs placebo. Purpose: Explore systemic inflammatory biomarker changes after treatment with BoNT/A and the temporal relation to incidence of POAF. Methods: This analysis included 308 patients who received 125U BoNT/A (n=103), 250U BoNT/A (n=103), or placebo (n=102). Subgroup analysis was done for CABG (n=198), age ≥65 years (n=185), and CABG + ≥65 years (n=118). Serum samples were collected preoperatively prior to dosing on Day 1, then post-treatment on Days 2-4 to test for IL-6, IL-10, and hsCRP. A 2-sample t test was used for mean concentrations and a linear mixed model was used for fold change (FC) from baseline. Results: Baseline levels of IL-6, IL-10, and hsCRP were similar between treatment groups. Reduction of IL-6 (45.7 ± 4.4 vs 62.4 ± 5.8 pg/mL, P &lt;0.05; 10.8 vs 15.9 FC, P &lt;0.01) and IL-10 (1.49 ± 0.13 vs 2.04 ± 0.24 pg/mL, P &lt;0.05; 1.96 vs 2.66 FC, P &lt;0.01) was most significant on Day 2 in CABG patients treated with 125U vs placebo, which aligns with the highest rate and risk of POAF (Figure 1). Mean hsCRP was most significantly reduced on Day 4 in the 250U group among CABG patients (193 ± 8 vs 227 ± 10 mg/dL, P &lt;0.01) followed by 125U vs placebo (196 ± 10 vs 227 ± 10 mg/dL, P &lt;0.05); a similar dose-dependent reduction was observed by FC analysis. Conclusions: Treatment with 125U BoNT/A in cardiac surgery patients lowered the incidence of POAF vs placebo and reduced postoperative systemic IL-6 and IL-10 on Day 2, most significantly in the CABG population.

Diagnostic Impact of Hs-CRP and IL-6 for Acute Coronary Syndrome in Patients Admitted to the ED with Chest Pain: Added Value to the HEART Score?

To investigate whether hs-CRP and IL-6 provide additional diagnostic value beyond that achieved by the HEART score in patients with chest pain suggestive of acute coronary syndrome (ACS) admitted to the emergency department (ED). This was a post hoc analysis using data from the RACING-MI study. Baseline data, including hs-CRP and IL-6 levels, were analyzed using the plasma from the biobank. A total of 818 patients with chest pain suggestive of ACS were included in this analysis. Of these, 98 were diagnosed with ACS (12%). Logistic regression was used to identify the independent predictors of ACS development in patients with chest pain. hs-CRP levels >2 mg/L were observed in 50% of all ACS cases. IL-6 levels >1.3 pg/mL were observed in 71% of all ACS cases. hs-CRP had a sensitivity of 50% and specificity of 51% for the diagnosis of ACS, whereas IL-6 had a sensitivity of 71% and specificity of 29%. The diagnostic likelihood ratios for ACS was 1.0 for hs-CRP>2 mg/L and IL-6 > 1.3 pg/mL, respectively. Logistic regression analysis revealed that age, male gender, and ongoing smoking were associated with ACS in patients with acute chest pain. No association was found between IL-6 or hs-CRP level and ACS. This was observed for both IL-6 and hs-CRP, whether assessed on a continuous scale or using prespecified cut-off values. Among the 818 patients admitted to the ED with chest pain suggestive of ACS, neither hs-CRP nor IL-6 provided an independent added diagnostic value. Our results suggest that inflammatory markers have limited diagnostic value in detecting patients with ACS in the ED.

Effect of guselkumab on serum biomarkers in patients with active psoriatic arthritis and inadequate response to tumor necrosis factor inhibitors: results from the COSMOS phase 3b study

BackgroundGuselkumab is a selective interleukin (IL)-23 inhibitor targeting the IL-23p19 subunit. In the phase 3b COSMOS trial, guselkumab demonstrated efficacy in treating participants with active psoriatic arthritis (PsA) and inadequate response (IR; lack of efficacy or intolerance) to tumor necrosis factor inhibitors (TNFi).MethodsAdults with active PsA (≥ 3 swollen joints, ≥ 3 tender joints) and IR to one or two TNFi (TNFi-IR) were randomized 2:1 to guselkumab at Weeks 0, 4, then every 8 weeks (Q8W) or placebo➔guselkumab Q8W at Week 24 with possible early escape at Week 16. Levels of serum cytokines, including interferon γ (IFNγ), IL-10, and tumor necrosis factor α (TNFα); T helper 17 (Th17) effector cytokines IL-17A, IL-17F, and IL-22; and acute phase proteins C-reactive protein (CRP), IL-6, and serum amyloid A (SAA), were assessed and compared with demographically matched healthy controls; guselkumab pharmacodynamics through Week 24 were also assessed. Associations between baseline biomarker levels and 1) baseline disease activity (28-joint disease activity score using CRP [DAS28-CRP], psoriasis area and severity index [PASI], and % body surface area [BSA] affected by psoriasis) and 2) clinical response (including ≥ 20% improvement in American College of Rheumatology criteria [ACR20] response) at Week 24 were assessed.ResultsBaseline serum levels of IL-6, IL-10, IL-17A, IL-17F, IL-22, TNFα, and IFNγ were significantly higher in COSMOS TNFi-IR participants than in healthy controls. Baseline IL-6, CRP, and SAA levels were associated with baseline DAS28-CRP. IL-17A and IL-17F levels were associated with baseline PASI score and psoriasis BSA. Baseline swollen or tender joint counts did not associate with baseline biomarker levels. At Week 24, significant decreases from baseline in CRP, SAA, IL-17A, IL-17F, and IL-22 levels were seen in guselkumab-, but not placebo-, treated participants. IL-17F and IL-22 levels at Week 24 in guselkumab-treated participants did not significantly differ from those of healthy controls. Guselkumab-treated participants achieving ACR20 response at Week 24 exhibited higher baseline IL-22 and IFNγ levels versus nonresponders.ConclusionsResults from COSMOS participants with active, TNFi-IR PsA suggest guselkumab reduces levels of effector cytokines associated with the IL-23/IL-17 pathway, including those associated with baseline arthritis and skin disease activity.Trial registrationClinicalTrials.gov: NCT03796858.

High plasma IL-6 levels may enhance the adverse effects of mouse allergen exposure in urban schools on asthma morbidity in children

Few data on the relationships between environmental exposures, asthma morbidity, and systemic IL-6 inflammation exist. We sought to determine whether baseline plasma IL-6 level is associated with increased asthma morbidity in children exposed to mouse allergen in inner-city classrooms. Data from the longitudinal School Inner-City Asthma Studies of 215 children with asthma, aged 4 to 14 years and recruited from urban elementary schools, were analyzed. Given the unknown threshold of IL-6 risk levels and skewness of the distribution, the children were stratified into tertiles as follows: low baseline IL-6 level (<0.013 pg/mL), moderate baseline IL-6 level (0.013-0.302 pg/mL), and high baseline IL-6 level (>0.302 pg/mL). Relationships between plasma IL-6 level and body mass index (BMI) percentile, inflammatory markers, lung function, mouse allergen exposure, and asthma outcomes were assessed. Cross-sectional analysis demonstrated that increasing IL-6 level was associated with higher BMI percentile (P< .0001), C-reactive protein level (P= .0006), and blood neutrophil count (P= .0024). IL-6 was not associated with type 2 inflammatory markers, including blood eosinophil count, allergic sensitization, or fractional exhaled nitric oxide level. Longitudinal analysis showed that children with high IL-6 levels had a higher number of days with asthma symptoms than did those children with moderate (incidence rate ratio= 1.74 [95% CI= 1.10-2.77]; P= .0187) or low (incidence rate ratio=1.83 [95% CI= 1.21-2.77]; P= .0043) IL-6 levels. Children with high IL-6 levels who were exposed to increasing levels of mouse allergen exhibited lower ratios of FEV1 value to forced vital capacity than did children with moderate IL-6 levels (β= -0.0044 [95% CI= -0.0073 to -0.0015]; pairwise interaction P= .0028) or low IL-6 levels (β= -0.0042 [95% CI= - 0.0070 to -0.0013]; pairwise interaction P= .0039). Inner-city children with asthma and high plasma IL-6 levels are more likely to have an increased BMI, elevated C-reactive protein level, elevated blood neutrophil count, and greater asthma symptoms. High IL-6 level appears to increase susceptibility to the effects of classroom exposure to mouse allergen on lung function in urban children.

Cytopenia after CAR‑T cell therapy: Analysis of 63patients with relapsed and refractory B‑cell non‑Hodgkin lymphoma.

The present study aimed to determine the clinical characteristics of cytopenia in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (B-NHL) who were treated with chimeric antigen receptor T-cell (CAR-T) therapy. Thus, a total of 63 patients with relapsed and refractory B-NHL who underwent CAR-T therapy between March 2017 and October 2021 were retrospectively selected for analysis. Neutropenia, anemia and thrombocytopenia at grade ≥3 occurred in 48 (76.19%), 16 (25.39%) and 15 (23.80%) cases, respectively. The results of a multivariate analysis demonstrated that the baseline absolute neutrophil count (ANC) and hemoglobin concentration were independent risk factors for grade ≥3 cytopenia. A total of 3 patients died early and were therefore excluded from the present study. Furthermore, cell recovery was examined at day +28 after infusion; 21 patients (35%) did not recover from cytopenia and 39 patients (65%) recovered. A multivariate analysis demonstrated that the baseline ANC <2.29×109/l, baseline hemoglobin <114.50 g/l and baseline IL-6 >21.43 pg/l were independent risk factors affecting hemocyte recovery. In conclusion, patients with relapsed and refractory B-NHL exhibited an increased incidence of grade ≥3 hematologic toxicity following CAR-T cell therapy, while baseline blood cell and IL-6 levels are independent risk factors for hemocyte recovery.

Serum and Urinary Biomarkers in COVID-19 Patients with or without Baseline Chronic Kidney Disease

In a prospective, observational, non-interventional, single-center study, we assessed various plasma and urinary biomarkers of kidney injury (neutrophil gelatinase-associated Lipocain [NGAL], kidney-injury molecule-1 [KIM-1], and interleukin-18 [IL-18]); inflammation (IL-6, C-reactive protein [CRP]); plus angiotensin converting enzyme 2 (ACE2) in 120 COVID-19 patients (of whom 70 had chronic kidney disease (CKD) at emergency-department (ED) admission). Our aim was to correlate the biomarkers with the outcomes (death, acute kidney injury [AKI]). All patients had received a chest-CT scan at admission to calculate the severity score (0-5). Biomarkers were also assessed in healthy volunteers and non-COVID-19-CKD patients. These biomarkers statistically differed across subgroups, i.e., they were significantly increased in COVID-19 patients, except for urinary (u)KIM1 and uIL-18. Amongst the biomarkers, only IL-6 was independently associated with mortality, along with AKI and not using remdesivir. Regarding the prediction of AKI, only IL-6 and uKIM1 were significantly elevated in patients presenting with AKI. However, AKI could not be predicted. Having high baseline IL-6 levels was associated with subsequent ventilation requirement and death. The mortality rate was almost 90% when the chest CT-scan severity score was 3 or 4 vs. 6.8% when the severity score was 0-2 (p < 0.0001).

Correlation of high serum interleukin-6 with clinical outcome and T cell response in patients with unresectable hepatocellular carcinoma treated with atezolizumab and bevacizumab.

596 Background: We elucidated the clinical and immunologic implications of serum interleukin (IL)-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). Methods: We prospectively enrolled 165 patients with unresectable HCC (Discovery cohort: 84 patients from three centers; Validation cohort: 81 patients from one center). Baseline blood samples were analyzed using a flow cytometric bead array. The tumor immune microenvironment was analyzed using RNA sequencing. Results: In the Discovery cohort, clinical benefit (CB) was defined as a complete or partial response or stable disease for ≥ 6 months. Among various blood-based biomarkers, the serum IL-6 level was significantly higher in patients without CB than in those with CB (mean 11.56 vs. 5.05 pg/mL, P=0.02). The optimal cutoff value for high IL-6 was determined as 18.49 pg/mL using maximally selected rank statistics, and 15.2% of patients were identified to have high IL-6 levels at baseline. In both the Discovery and Validation cohorts, patients with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev compared with that of patients with low IL-6 levels. In the multivariable Cox regression analysis, the clinical implication of high IL-6 levels persisted even after adjustment for various confounding factors. Patients with high IL-6 levels showed reduced interferon-γ and tumor necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and CD8+ T-cell proliferation. Finally, patients with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumor microenvironment. Conclusions: High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment.

High serum IL-6 correlates with reduced clinical benefit of atezolizumab and bevacizumab in unresectable hepatocellular carcinoma

We elucidated the clinical and immunologic implications of serum IL-6 levels in patients with unresectable hepatocellular carcinoma (HCC) treated with atezolizumab and bevacizumab (Ate/Bev). We prospectively enrolled 165 patients with unresectable HCC (discovery cohort: 84 patients from three centres; validation cohort: 81 patients from one centre). Baseline blood samples were analysed using a flow cytometric bead array. The tumour immune microenvironment was analysed using RNA sequencing. In the discovery cohort, clinical benefit 6 months (CB6m) was defined as complete or partial response, or stable disease for ≥6 months. Among various blood-based biomarkers, serum IL-6 levels were significantly higher in participants without CB6m than in those with CB6m (mean 11.56 vs. 5.05pg/ml, p= 0.02). Using maximally selected rank statistics, the optimal cut-off value for high IL-6 was determined as 18.49pg/ml, and 15.2% of participants were found to have high IL-6 levels at baseline. In both the discovery and validation cohorts, participants with high baseline IL-6 levels had a reduced response rate and worse progression-free and overall survival after Ate/Bev treatment compared with those with low baseline IL-6 levels. In multivariable Cox regression analysis, the clinical implications of high IL-6 levels persisted, even after adjusting for various confounding factors. Participants with high IL-6 levels showed reduced interferon-γ and tumour necrosis factor-α secretion from CD8+ T cells. Moreover, excess IL-6 suppressed cytokine production and proliferation of CD8+ T cells. Finally, participants with high IL-6 levels exhibited a non-T-cell-inflamed immunosuppressive tumour microenvironment. High baseline IL-6 levels can be associated with poor clinical outcomes and impaired T-cell function in patients with unresectable HCC after Ate/Bev treatment. Although patients with hepatocellular carcinoma who respond to treatment with atezolizumab and bevacizumab exhibit favourable clinical outcomes, a fraction of these still experience primary resistance. We found that high baseline serum levels of IL-6 correlate with poor clinical outcomes and impaired T-cell response in patients with hepatocellular carcinoma treated with atezolizumab and bevacizumab.

Can Baseline IL-6 Levels Predict Long COVID in Subjects Hospitalized for SARS-CoV-2 Disease?

The immune response to infection plays a crucial role in the pathogenesis of COVID-19, but several patients develop a wide range of persistent symptoms, which is becoming a major global health and economic burden. However, reliable indicators are not yet available to predict the persistence of symptoms typical of the so-called long COVID. Our study aims to explore an eventual role of IL-6 levels as a marker of long COVID. Altogether, 184 patients admitted to the COVID Medicine Unit of the University Hospital in Palermo, Italy, from the 1st of September 2020, were analyzed. Patients were divided into two groups according to the IL-6 serum levels (normal or elevated), considering the serum IL-6 levels measured during the first four days of hospitalization. In our study, higher serum IL-6 levels were associated with a doubled higher risk of long COVID (OR = 2.05; 95% CI: 1.04-4.50) and, in particular, they were associated with a higher incidence of mobility decline (OR = 2.55; 95% CI: 1.08-9.40) and PTSD (OR = 2.38; 95% CI: 1.06-8.61). The analysis of our case series confirmed the prominent role of IL-6 levels in response to SARS-CoV-2 infection, as predictors not only of COVID-19 disease severity and unfavorable outcomes, but also long COVID development trends.

Canakinumab Effects on Erythropoiesis, Cardiovascular Risk, and Clonal Hematopoiesis: Proteogenomic Analysis of the Cantos Randomized Clinical Trial

Canakinumab is a monoclonal antibody that directly neutralizes interleukin (IL)-1β. In the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) - a randomized, double-blind, placebo-controlled trial that enrolled 10,061 patients with previous myocardial infarction and high-sensitivity C-reactive protein (hsCRP) levels ≥2 mg/L - canakinumab prevented recurrent cardiovascular (CV) events (Ridker et al. NEJM 2017). Anemia of inflammation (AI) presents with mild to moderate anemia in the setting of systemic inflammatory conditions. The pathogenesis of AI involves deregulation of iron homeostasis via hepcidin and inflammatory cytokines such as IL-1β, IL-6, and TNF-α, resulting in skewed myeloid differentiation and decreased erythrocyte lifespan via enhanced erythrophagocytosis (Ganz et al. NEJM 2019). A CANTOS exploratory study revealed that canakinumab reduces the incidence of anemia and improves hemoglobin levels (Vallurupalli et al. Ann Intern Med. 2020). Among mutations associated with clonal hematopoiesis (CH), patients with TET2 variants had fewer major adverse CV events than those without CH mutations (Svensson et al. JAMA Cardiol. 2022). CH mutations in TET2 were associated with higher IL-1β levels (Bick et al. Nature 2020), generating the hypothesis that inhibition of IL-1β may provide preferential benefits to patients with CH mutations. To determine the association between CH mutations and clinical response to canakinumab and evaluate the underlying molecular mechanisms of anemia response, a proteogenomic study was performed in 13080 plasma samples from 4595 CANTOS participants, including highly multiplexed proteomics (4785 proteins) and targeted deep sequencing of CH mutations with variant allele fraction≥ 2% (Figure A). Longitudinal and cross-sectional analyses were performed in pre- and post-treatment samples from patients with at least one pre-treatment sample (baseline). CH mutations were associated with older age, anemia at baseline, and higher baseline IL-6 and TNF-α levels (all OR's >1.4 and p<0.003). Among patients without baseline anemia, canakinumab treatment prevented incidental anemia, compared to those treated with a placebo (without CH mutation: HR=0.72; 95% CI=0.61-0.84; P < 0.001, with CH mutations: HR=0.77; 95% CI=0.49-1.19; P =0.24). In individuals treated with canakinumab, however, those with CH mutations were more likely to develop incidental anemia compared to patients without CH mutations (HR=1.56; 95% CI=1.18-2.07; P=0.002). Conversely, among patients with baseline anemia, canakinumab treatment significantly improved hemoglobin levels in patients with CH mutations compared to a placebo (P< 0.001), whereas a significant difference was not found in hemoglobin levels of patients without CH mutations (Figure B). Enhanced hemoglobin response over time to canakinumab was observed in patients with concurrent baseline anemia and CH mutations, particularly in DNMT3A and TET2, compared to no CH mutations (all CH mutations, DNMT3A and TET2,P = 0.022, 0.004, 0.078 respectively). We observed that canakinumab treatment reversed multiple nodes of abnormal erythropoiesis associated with AI. Canakinumab treatment was associated with lower hepcidin and inflammatory cytokines (IL-6 and TNF-α) and down-regulation of pathways for complement activation and phagocytosis, which may prolong RBC lifespan and promote erythropoiesis. Higher odds of having both an increase in hemoglobin and a decrease in hepcidin (OR=1.88; 95% CI=1.62 - 2.17; P<0.001 ) and both an increase in hemoglobin and a decrease in IL-6 (OR=3.46; 95%CI=3.00 - 4.00; P<0.001) were observed with canakinumab treatment compared to placebo. The characterization of proteomic profiles in patients with CH mutations revealed novel biological links in dysregulation of RBC homeostasis, cardiovascular risk biomarkers, inhibitory immune molecules, and bone morphogenetic protein antagonists, which were reversed by canakinumab treatment more significantly in patients with TET2 mutations. Collectively this data provides direct clinical evidence that patients with concurrent anemia and CH mutations can benefit from canakinumab treatment by suppressing CH-mediated activation of the IL-1β/IL-6 axis and reversing ineffective erythropoiesis via multiple mechanisms, and the type of CH mutations may be associated with distinct clinical and biological response. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Baseline CRP and Ferritin Identify Patients at High Risk of Poor Outcomes after Axicabtagene Ciloleucel Despite Corticosteroid Prophylaxis

Introduction: We and others have reported the role of cytokines and the tumor microenvironment on the development of severe grade >3 toxicities and CAR T resistance in recipients of CD19 targeted therapy. However, these analyses are not readily available outside of research settings. Early intervention and prophylactic strategies with cytokine blocking agents and/or steroids to mitigate severe toxicity have been explored. In a recent analysis of cohort 6 of the ZUMA-1 trial, investigators reported improved rates of severe toxicity with the prophylactic use of dexamethasone (Oluwole OO, Br J Haematol 2021). There is limited data on which patients benefit the most from such strategies. Methods: This is a study to evaluate factors associated with the development of severe immune mediated toxicities and treatment resistance in patients with R/R DLBCL treated with standard of care axicabtagene ciloleucel (axi-cel) at Moffitt Cancer Center. Baseline samples of CRP, LDH and ferritin were collected within one week prior to lymphodepleting chemotherapy. Cytokine analyses were performed as previously described (Faramand R, CCR 2020). Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded based on ASTCT criteria. Patients were stratified into three risk groups based on baseline CRP and ferritin; low risk (CRP <4gm/dL and ferritin <400ng/dL), intermediate (not meeting criteria for high risk or low risk), and high risk (CRP >4gm/dL and ferritin >400ng/dL). During the study period, institutional clinical standards were revised to administer prophylactic corticosteroids consecutively to all patients meeting high risk criteria. Patient survival outcomes were compared using Kaplan-Meier curves and subsequent log-rank tests. Multivariable Cox proportional hazards regression model with adjustment for clinical covariates was used to estimate hazard ratios for survival outcomes. Results: 136 patients with R/R DLBCL treated with axi-cel (>2 lines of therapy) are included in this study. Baseline patient characteristics and outcomes are summarized in Table 1. Most patients developed CRS (n=126) with 10.3% developing severe (gr. >3) CRS. Eighty-three patients (61%) developed ICANS with 28% having severe gr. >3 toxicity. The median overall survival (OS) was 34.9 months with a median progression free survival (PFS) of 12.2 months. We previously reported association of baseline elevated IL6 levels with poor clinical outcomes. Baseline IL6 levels correlated (p<0.0001, Fig. 1A) with risk category based on CRP and ferritin. Rates of severe CRS (25.9 vs. 1.61%, p=0.001) and ICANS ( 51.9 vs. 16.1%, p=0.002) were significantly higher in the high-risk (HR) group in comparison to the low risk group. Median PFS was 3 months, 7.9 and not reached in the high, intermediate and low risk groups respectively (p=0.0001) (Fig. 1B). The median OS was significantly inferior in the HR group at 6.9 months compared to 14.9 months and not reached in the intermediate and low groups respectively (p<0.0001) (Fig. 1C). Based on the above risk stratification, ten additional patients met HR criteria and were treated with prophylactic dexamethasone for three days starting on the day of CAR T cell infusion. Although most patients (90%) developed CRS, none developed severe CRS in the prophylactic steroids group which compares favorably to 25.9% observed in historical HR patients who did not receive prophylactic steroids (p=0.16). Severe ICANS was lower (30%) in the prophylactic cohort as compared to 52% in historical HR patients (p=0.29). The median PFS and OS were 2.9 and 5.9 months respectively in recipients of prophylactic steroids. Discussion: We establish that baseline elevated levels of CRP and Ferritin are associated with severe toxicity, and significantly inferior PFS and OS. Patients in the low risk group have excellent outcomes in terms of toxicity and efficacy using standard treatment paradigms negating the need for steroid prophylaxis and may be considered for outpatient treatment. In this report, prophylactic steroids were only used in 10 patients meeting high risk criteria. While there were no cases of severe CRS, efficacy outcomes remained poor in this high-risk cohort despite steroid prophylaxis. High risk patients can be easily identified prior to treatment with CAR T using standard labs and are encouraged to enroll on clinical trials to improve outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

CSF IL-8 Associated with Response to Gene Therapy in a Case Series of Spinal Muscular Atrophy

Gene therapies have greatly changed the outlook in spinal muscular atrophy (SMA), and this disorder provides a rare opportunity to study longitudinal biomarker changes correlated with reduced disease burden and improved clinical outcomes. Recent work suggests clinical response to correlate with declining cerebrospinal fluid (CSF) levels of the neurodegenerative marker neurofilament light chain (NfL) in children receiving serial anti-sense oligonucleotide therapy. However, change in CSF NfL levels is no longer a practical biomarker as more children undergo single-dose gene replacement therapy. Here we leverage serial CSF samples (median of 4 per child) collected in 13 children with SMA undergoing anti-sense oligonucleotide therapy to characterize the longitudinal profiles of NfL as well as inflammatory and neuronal proteins. In contrast to neurodegeneration in adults, we found NfL levels to first decrease following initiation of treatment but then increase upon further treatment and improved motor functions. We then examined additional CSF inflammatory and neuronal markers for linear association with motor function during SMA treatment. We identified longitudinal IL-8 levels to inversely correlate with motor functions determined by clinical examination (F(1, 47) = 12.903, p = 0.001) or electromyography in the abductor pollicis brevis muscle (p = 0.064). In keeping with this, lower baseline IL-8 levels were associated with better longitudinal outcomes, even though this difference diminished over 2 years in the younger group. We thus propose CSF IL-8 as a biomarker for baseline function and short-term treatment response in SMA, and a candidate biomarker for future treatment trials in other neurodegenerative disorders.

TNF-α, IL-6 and hsCRP in patients with melancholic, atypical and anxious depression: an antibody array analysis related to somatic symptoms

BackgroundThe association between inflammation and major depressive disorder (MDD) remains poorly understood, given the heterogeneity of patients with MDD.AimsWe investigated inflammatory markers, such as interleukin (IL)-6, high-sensitivity C reactive protein...