Interleukin-6 Blockade Research Articles

Abstract 4117731: Interleukin-1 Blockade in Patients With ST-Segment Elevation Myocardial Infarction Across the Spectrum of Coronary Artery Disease Complexity.

Background: Patients with ST-segment elevation myocardial infarction (STEMI) and complex coronary artery disease (CAD) face a poor prognosis, including increased heart failure (HF) risk. Interleukin-1 (IL-1) blockade with Anakinra inhibits the acute inflammatory response and prevent HF after STEMI, but data on its effects based on CAD complexity are lacking. Aims: To assess the effects of Anakinra in patients with STEMI, across the spectrum of CAD complexity. Methods: We performed a pooled secondary analysis of 139 patients with STEMI from three randomized clinical trials (VCUART studies) comparing Anakinra (N=84) versus placebo (N=55). Multivessel CAD was defined as the presence of at least one ≥70% stenosis in a non-culprit vessel of >2.5 mm diameter, not stented during index coronary intervention. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), SYNTAX II and Gensini scores were calculated, and patients were divided by the median. We evaluated a composite endpoint of new-onset HF, HF hospitalization, or all-cause death at 1-year follow-up using Kaplan-Meier survival curves, Cox regression analysis for Hazard Ratios, and calculated interactions between groups. Results: We included 139 patients with STEMI, 85 (61%) with single vessel CAD and 54 (39%) with multivessel CAD. According to the spectrum of CAD complexity, 60 (43%) presented a SYNTAX score >9, 59 (42%) a SYNTAX II score >24 and 65 (47%) a Gensini score >32. New-onset HF, HF hospitalization, or all-cause death occurred in a total of 23 patients: 7 among the 84 subjects in the Anakinra group and 16 within the 55 patients in the placebo group. We found no statistically significant interactions between CAD complexity and allocation to Anakinra or placebo for the composite endpoint (Figure). Conclusions: Among patients with STEMI, IL-1 blockade with Anakinra significantly reduced the risk of new-onset HF, HF hospitalization, or all-cause death compared to placebo, regardless of the number of vessels affected and the spectrum of CAD complexity.

Interleukin-1 Blockade in Patients With ST-Segment Elevation Myocardial Infarction Across the Spectrum of Coronary Artery Disease Complexity.

Patients with ST-segment elevation myocardial infarction (STEMI) and complex coronary artery disease (CAD) face a poor prognosis, including increased heart failure (HF) risk. Phase 2 clinical trials of anakinra have shown inhibition of the acute inflammatory response and prevention of HF after STEMI, but data on its effects based on CAD complexity are lacking. We performed a pooled secondary analysis of 139 patients with STEMI. The SYNTAX (Synergy Between Percutaneous Coronary Intervention with Taxus and Cardiac Surgery), SYNTAX II and Gensini scores were calculated, and patients were divided into two groups below and above the median. We evaluated the effect of anakinra on the area-under-the-curve of high-sensitivity C-reactive protein (hsCRP-AUC) at 14 days, and the composite endpoint of new-onset HF, HF hospitalization, or all-cause death at 1-year follow-up using Kaplan-Meier survival curves, Cox regression analysis for Hazard Ratios (HR), and tested interactions between subgroups. All three CAD complexity scores (SYNTAX, SYNTAX II and Gensini) were associated with an increased risk of adverse events (HR 1.02 to 1.06, all p-values ≤0.025). We found no statistically significant interactions between CAD extent, measured as single-vessel or multi-vessel CAD, SYNTAX score ≤9 or >9, SYNTAX II score ≤24 or >24, Gensini score ≤32 or >32, and treatment effect of anakinra on hsCRP-AUC or the composite clinical endpoint (all p-values for interaction >0.05). In conclusion, among patients with STEMI, IL-1 blockade with anakinra significantly attenuated the acute inflammatory response and reduced the risk of HF-related events regardless of the spectrum of CAD complexity.

IL-1 Blockade Mitigates Autism and Cerebral Palsy Traits in Offspring In-Utero Exposed to Group B Streptococcus Chorioamnionitis.

Group B Streptococcus (GBS) is one of the most common bacteria responsible for placental and neonatal infection and inflammation resulting in lifelong neurobehavioral impairments. In particular, GBS-induced chorioamnionitis is known in preclinical models to upregulate inflammatory pathways, primarily through the activation of the interleukin-1 (IL-1) pathway, leading to brain injury and subsequent neurodevelopmental issues. Previous studies from our laboratory using Lewis rat pups have shown that male offspring exposed in utero to GBS chorioamnionitis develop brain injuries leading to neurobehavioral impairments such as autistic traits. In the present study, we aimed to explore whether blocking the IL-1 pathway could prevent or mitigate these neurodevelopmental impairments in adulthood. Using our established preclinical model, we administered IL-1 receptor antagonist (IL-1Ra) to dams with GBS-induced chorioamnionitis. Here, we show that IL-1Ra administration to dams reversed autistic and cerebral palsy traits in male adult offspring exposed in utero to GBS. Hence, IL-1 blockade could serve as a therapeutic intervention against pathogen-induced neurodevelopmental disorders. This research supports the need for future human randomized controlled trials to assess IL-1 blockade administered during pregnancy or in newborns as a strategy to reduce the long-term neurobehavioral consequences of prenatal infections, such as autism, cerebral palsy, learning disabilities, and other neurodevelopmental disorders.

Novel use of Siltuximab in a patient with VEXAS Syndrome.

VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) is an increasingly recognized disorder that occurs due to somatic mutations of a ubiquitin-activating enzyme encoded by ubiquitin-like modifier activating enzyme 1 gene, UBA1. Clinical findings associated with VEXAS syndrome include recurrent fevers, polychondritis, periorbital edema, pleural effusions, myocarditis and/or pericarditis, hepatosplenomegaly, myelodysplastic syndrome, cytopenias, inflammatory arthritis, neutrophilic dermatosis, and deep venous thrombosis. Novel renal manifestations like interstitial nephritis are infrequent, and to our knowledge, acute renal failure due to C3 glomerulonephritis (C3GN) has not yet been reported. Overwhelming systemic inflammation can result in morbid end-organ damage and death. While there is no formal guideline or established protocol for its management, treatment of VEXAS syndrome with tocilizumab, an interleukin-6 (IL-6)-directed therapy, has been described in the literature. Here, we report a case of a 71-year-old male patient presenting with C3GN as an initial manifestation of VEXAS syndrome and explore the rationale for our approach to treatment with IL-6 blockade. Our patient was initially treated with two inpatient doses of tocilizumab with successful transition to siltuximab in the outpatient setting. He continues to benefit from ongoing siltuximab treatment for more than one year to date without any safety issues or relapse of VEXAS syndrome.

Interleukin-1 blockade with RPH-104 (goflikicept) in patients with ST-segment elevation myocardial infarction (STEMI): secondary endpoints from an international, double blind, randomized, placebo-controlled, phase IIa study.

In a randomized double-blinded clinical trial of patients with ST segment elevation myocardial infarction (STEMI), goflikicept, an Interleukin-1 (IL-1) blocker, significantly reduced systemic inflammation, measured as the area-under-the-curve (AUC) for high-sensitivity C reactive protein (hsCRP) at 14 days. We report secondary analyses of biomarkers at 28 days, and cardiac function and clinical endpoints at 1 year. Patients received a single administration of goflikicept 80 mg (n=34), goflikicept 160 mg (n=34), or placebo (n=34). Both doses of goflikicept significantly reduced the AUC for hsCRP at 28 days compared with placebo, without statistically significant differences between the doses. There we no statistically significant differences between groups in the AUC for natriuretic peptides at 28 days. There were no significant differences between placebo, goflikicept 80 mg and 160 mg groups in deaths (2.9%, 2.9% and 0%), hospitalization for cardiovascular reasons (9.1%, 5.9%, and 0%), new-onset or progression of heart failure (9.1%, 5.9%, and 5.9%), and new or increased use of loop diuretics (24.2%, 14.7%, and 17.6%), nor in the number of patients with treatment emergent adverse events, with no treatment-related serious adverse events in any group. In conclusion, in patients with STEMI, IL-1 blockade with goflikicept 80 mg or 160 mg was well tolerated and associated with significant reduction of systemic inflammation. Further adequately powered studies are warranted to determine whether the reduction in systemic inflammation with goflikicept translates into a clinical benefit in patients with STEMI.

345.1: Interleukin-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation.

345.1: Interleukin-6 blockade prevents costimulation blockade-resistant allograft rejection by promoting intragraft regulation.

Interleukin-1 blockade in patients with Wiskott-Aldrich syndrome: a retrospective multinational case series

AbstractUp to 70% of patients with Wiskott-Aldrich syndrome (WAS) develop autoimmune and inflammatory manifestations. Dysregulation of interleukin 1 (IL-1) may be involved in their pathogenesis, yet there is little evidence on treatment with anti–IL-1 agents in these patients. We conducted a multicenter retrospective analysis of 9 patients with WAS treated with anti–IL-1 agents (anakinra or canakinumab). All patients had prominent inflammatory manifestations, including systemic, cutaneous, articular, and intestinal symptoms; 3 patients presented with a severe systemic inflammatory syndrome since the first months of life. Corticosteroid therapy was associated with partial or no response, whereas treatment with anakinra or canakinumab resulted in prompt, often dramatic, responses in all patients, allowing bridging to gene therapy (4 patients) or hematopoietic stem cell transplantation (HSCT; 5 patients). Treatment was overall well tolerated. Low donor myeloid chimerism developed in 4 patients after HSCT and was associated with the appearance or the recurrence of inflammatory manifestations. A second HSCT was performed in 2 patients, achieving full-donor chimerism and resolution of inflammatory manifestation, whereas the other 2 patients were treated with prolonged therapy with anti–IL-1 agents. Our experience demonstrates that some inflammatory manifestations of WAS are dependent on IL-1 and respond well to its pharmacologic blockade.

TAFRO Syndrome: Guidance for Managing Patients Presenting Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly

TAFRO syndrome is an inflammatory disorder of unknown etiology characterized by thrombocytopenia, anasarca, fever, reticulin fibrosis, renal insufficiency, and organomegaly. Despite great advancements in research on the TAFRO syndrome in the last decade, its diagnosis and treatment are still challenging for most clinicians because of its rarity and severity. Since the initial proposal of the TAFRO syndrome as a distinct disease entity in 2010, two independent diagnostic criteria have been developed. Although these are different in the concept of whether TAFRO syndrome is a subtype of idiopathic multicentric Castleman disease or not, they are similar except for the magnitude of lymph node histopathology. Because there have been no specific biomarkers, numerous diseases must be ruled out before the diagnosis of TAFRO syndrome is made. The standard of care has not been fully established, but interleukin-6 blockade therapy with siltuximab or tocilizumab and anti-inflammatory therapy with high-dose corticosteroids are the most commonly applied for the treatment of TAFRO syndrome. The other immune suppressive agents or combination cytotoxic chemotherapies are considered for patients who do not respond to the initial treatment. Whereas glowing awareness of this disease improves the clinical outcomes of patients with TAFRO syndrome, further worldwide collaborations are warranted.

Safety and efficacy of interleukin-6 blockade for immune-related adverse events: A systematic review and meta-analysis.

e24149 Background: Interleukin-6 blockade (IL-6) - tocilizumab and sarilumab - have shown promising results for steroid-refractory immune-related adverse events (irAEs) in cancer patients treated with immune-checkpoint inhibitors (ICI). However, the ideal scenario for IL-6 therapy use is not well established. Hence, we conducted a systematic review and meta-analysis to investigate the safety and efficacy of IL-6 blockade for patients with ICI-associated irAEs. Methods: PubMed, Embase, and Cochrane databases were searched for studies including at least five patients with ICI-associated irAEs treated with IL-6 blockade. The main outcomes were safety and efficacy, measured as clinical improvement (resolution or improvement of irAEs or steroid taper to < 10mg daily), C-reactive protein (CRP) level changes, and elevated IL-6 levels. Analyses using random-effects model were done in R Software. Heterogeneity was assessed using I2. Results: Eight studies with 202 patients were included: 1 clinical trial, 3 multicenter, and 4 single-center observational studies. The median age was 63 years (30-81), and 59% were male. Melanoma was the predominant tumor type (n = 78, 38.6%), followed by lung (n = 67, 33%), renal cell carcinoma (n = 21, 10%), bladder cancer (n = 12, 6%), and others. Monotherapy with ICI, targeting PD-1, PD-L1, or CTLA-4, was given to 77% of patients, while 23% had combination ICI therapy. Follow-up ranged from 6 to 23 months. Most patients received prior steroids (85%) or steroid-sparing immunosuppression (24%). Pooled analysis of all patients showed an overall clinical improvement rate of 87.9% (95%CI 78.7 to 95.1, I2= 44%). Clinical improvement with IL-6 blockade was significantly higher in patients with cytokine release syndrome (CRS, 100%) and rheumatic irAEs (88%) compared to other irAEs (p < 0.01, Table 1). At the time of irAEs, the median CRP level was 109.3 (11.5 to 233), which decreased to 17 (1 to 60) after IL-6 blockade. The frequency of baseline elevated IL-6 level was 90.6% (95%CI 68 to 100, I2= 80%). Grade 3 or 4 IL-6-related adverse events were reported in 11% (17/151) of patients and included neutropenia (n = 6), increased liver transaminase levels (n = 4), and gastrointestinal perforation (n = 2). Conclusions: This systematic review and meta-analysis provides evidence for the use of IL-6 blockade for steroid-treating refractory irAEs associated with ICI. The vast majority of patients with steroid-refractory CRS and rheumatic irAEs were successfully treated with anti-IL6 therapy.[Table: see text]

Interleukin-6 receptor blockade with tocilizumab to reduce immune-related toxicity with ipilimumab and nivolumab in metastatic melanoma.

9538 Background: Interleukin-6(IL-6) blockade has reversed steroid-refractory immune-related toxicity in patients receiving immune checkpoint blockade (ICB). IL-6 and its downstream acute phase reactants are also associated with short survival and therapeutic resistance in patients receiving single agent or combination ICB. We undertook a phase II trial of IPI, NIVO and the IL-6 receptor blocking antibody tocilizumab (TOCI) in unresectable melanoma. Methods: In a phase II, Simon-design two-stage trial, 70 patients with untreated metastatic melanoma received IPI at 1 mg/kg and NIVO at 3 mg/kg for 4 induction doses to week 12, and TOCI at 4 mg/kg every 6 weeks up to week 24. Maintenance NIVO was administered at 240 mg intravenously (IV) from weeks 12 to 24, then at a dose of 480 mg IV every 4 weeks for up to 2 years of treatment. To proceed past the first stage of 18 patients, 12/18 RECIST responses or more and/or a grade 3-5 treatment related immune-related adverse event (irAE) rate of ≤5/18 were required. Those criteria were both fulfilled, and in the second stage 49 patients were treated, with 3 additional patients accrued. Serum and peripheral blood samples were collected for biomarker assays at baseline and week 7. Results: There were 40/70 RECIST responders with a 57% best overall response rate (BORR), (exact 95% confidence interval (CI) of 44-68%) of partial response (PR) or complete response (CR); 6 patients had stable disease (SD), 24 with progression, at a median of 2.4 years of follow-up. A total of 46 patients had clinical benefit (CR+PR+SD) = 65% (exact 95% CI 37-81%). Median progression-free survival was 13 months. The expected BORR was 47% in the randomized Checkmate-511 trial at the same doses of IPI/NIVO. There have been 16 cases of grades 3-4 irAE including 3 episodes of colitis for a total of 16/71 patients eligible for toxicity = 22% (exact 95% CI: 12-31%), all grade 3/4; the expected rate of grades 3-5 TRAEs was 34% per Checkmate-511. The rate of irAE leading to discontinuation was 14%; it was 25% for CheckMate 511. Twenty-one deaths (30%) occurred, all due to progression. All grade 3-4 irAES were reversible and no grade 5 toxicity was seen. Osteopontin+IL6+CD45RAnegclassical monocytes were associated with response, and higher levels of naive CD8 T cells were associated with progression. CD16+CD56+CD57+ mature natural killer cells were significantly lower in patients with grade 3-4 immune-related toxicity. Conclusions: Prophylactic TOCI resulted in a low rate of grade 3-4 irAEs by week 24 in patients with stage IV melanoma receiving induction IPI 1 mg/kg and NIVO 3 mg/kg while maintaining a favorable overall response rate and survival. Novel biomarkers of response and toxicity including NK cells and monocytes as well as naïve and effector memory CD8 T cells were defined by high-resolution flow cytometry. Additional correlative data will be presented. Clinical trial information: NCT03999749 .

Sequential administration of paricalcitol followed by IL-17 blockade for progressive refractory IgA nephropathy patients

There is no established treatment for progressive IgA nephropathy refractory to steroids and immunosuppressant drugs (r-IgAN). Interleukin 17 (IL-17) blockade has garnered interest in immune-mediated diseases involving the gut-kidney axis. However, single IL-17A inhibition induced paradoxical effects in patients with Crohn’s disease and some cases of de novo glomerulonephritis, possibly due to the complete Th1 cell response, along with the concomitant downregulation of regulatory T cells (Tregs). Seven r-IgAN patients were treated with at least six months of oral paricalcitol, followed by the addition of subcutaneous anti-IL-17A (secukinumab). After a mean follow-up of 28 months, proteinuria decreased by 71% (95% CI: 56–87), P < 0.001. One patient started dialysis, while the annual eGFR decline in the remaining patients [mean (95% CI)] was reduced by 4.9 mL/min/1.73 m2 (95% CI: 0.1–9.7), P = 0.046. Circulating Th1, Th17, and Treg cells remained stable, but Th2 cells decreased, modifying the Th1/Th2 ratio. Intriguingly, accumulation of circulating Th17.1 cells was observed. This novel sequential therapy appears to optimize renal advantages in patients with r-IgAN and elicit alterations in potentially pathogenic T helper cells.

Combined Blockade of Interleukin-6 and β-Catenin Inhibits Breast and Colon Tumor Growth In Vitro

Background: As the primary regulator of tumor activities, the tumor microenvironment contains several factors contributing to tumor progression and metastasis. Interleukin 6 (IL-6) and β-catenin are two key factors in the tumor microenvironment, which are effective in tumor progression in primary studies. This study aimed to evaluate the impact of IL-6 and β-catenin blockade on tumor growth and progression in vitro. Methods: In this study, small interfering RNA (siRNA) technology was used to target IL-6 and β-catenin using two murine cell lines, 4T1 (breast cancer) and CT26 (colon cancer). The target gene expression was analyzed by applying quantitative real-time polymerase chain reaction assays. The MTT assay was used to measure how a treatment could affect the cells’ survival ability. All data were analyzed by GraphPad Prism 9, and P-values less than 0.05 were considered significant. Results: Both cell lines demonstrated downregulation in the expression patterns of genes involved in apoptosis, metastasis, proliferation, and angiogenesis. Both cell lines showed significantly decreased IL-6 secretion following IL-6 targeting. Moreover, simultaneous targeting of IL-6 and β-catenin factors significantly reduced the survival of cancer cells. Conclusion: These results revealed that targeting β-catenin and IL-6 simultaneously may be a useful treatment strategy for colon and breast cancers. Further investigations are required to determine the effectiveness of these interventions and adjust their safety.

IL-6 Blockade in Cytokine Storm Syndromes.

Interleukin-6 (IL-6) is a pro-inflammatory cytokine elevated in cytokine storm syndromes, including hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS). It is also elevated in cytokine release syndrome (CRS) after immune activating cancer therapies such as chimeric antigen receptor (CAR) T-cells or bispecific T-cell engagers (BITEs) and in some patients after infection with SARS-CoV-2. The interaction of IL-6 with its receptor complex can happen in several forms, making effectively blocking this cytokine's effects clinically challenging. Fortunately, effective clinical agents targeting the IL-6 receptor (tocilizumab) and IL-6 directly (siltuximab) have been developed and are approved for use in humans. IL-6 blockade has now been used to safely and effectively treat several cytokine storm syndromes (CSS). Other methods of investigation in effective IL-6 blockade are underway.

Is Interleukin-6 blockade a viable strategy to prevent progression of acute respiratory distress syndrome in non-COVID viral pneumonia?

Is Interleukin-6 blockade a viable strategy to prevent progression of acute respiratory distress syndrome in non-COVID viral pneumonia?

Acute necrotizing encephalopathy of childhood secondary to parainfluenza infection: A review of two cases

IntroductionAcute necrotizing encephalopathy (ANE) of childhood is a rare inflammatory syndrome, classically associated with preceding febrile illness and followed by fulminant neurological deterioration including encephalopathy, seizures, and focal neurological deficits with multifocal lesions of the thalami, rostral brainstem, and cerebral and cerebellar gray and white matter. ANE is distinctly associated with significant rates of neurological sequelae and death. Multiple infectious and parainfectious etiologies have been associated with ANE, notably influenza A. Case ReportWe report two cases of ANE associated with parainfluenza infection. Both children were treated with high-dose methylprednisolone and intravenous immunoglobulin, and one treated with tocilizumab. However, both patients suffered rapid neurological deterioration and death despite aggressive intervention. ConclusionWe present two cases of ANE with rapid neurological deterioration and death despite aggressive medical therapy. Rapid treatment with immunomodulatory treatments can lead to symptomatic recovery of variable degree in some patients. While high-dose steroids, intravenous immunoglobulin, and plasma exchange are common therapies for ANE, some case reports have suggested interleukin-6 (IL-6) blockade with tocilizumab can be beneficial. We report the nineteenth documented child in pediatric literature treated for ANE with tocilizumab, who did not respond to treatment, suggesting the response is heterogeneous and warrants additional investigation.

Chronic Active Antibody-mediated Rejection: Opportunity to Determine the Role of Interleukin-6 Blockade.

Chronic active antibody-mediated rejection (caAMR) is arguably the most important cause of late kidney allograft failure. However, there are no US Food and Drug Administration (FDA)-approved treatments for acute or chronic AMR and there is no consensus on effective treatment. Many trials in transplantation have failed because of slow and/or inadequate enrollment, and no new agent has been approved by the FDA for transplantation in over a decade. Several lines of evidence suggest that interleukin-6 is an important driver of AMR, and clazakizumab, a humanized monoclonal antibody that neutralizes interleukin-6, has shown promising results in phase 2 studies. The IMAGINE trial (Interleukin-6 Blockade Modifying Antibody-mediated Graft Injury and Estimated Glomerular Filtration Rate Decline) (NCT03744910) is the first to be considered by the FDA using a reasonably likely surrogate endpoint (slope of estimated glomerular filtration rate decline >1 y) for accelerated approval and is the only ongoing clinical trial for the treatment of chronic rejection. This trial offers us the opportunity to advance the care for our patients in need, and this article is a call to action for all transplant providers caring for patients with caAMR.

Diabetes mellitus and response to IL-1 blockade with Anakinra after ST-elevation myocardial infarction: a pooled analysis of the VCU-ART studies

Abstract Background ST segment elevation myocardial infarction (STEMI) elicits an intense inflammatory response which is thought to contribute to subsequent maladaptive myocardial healing and remodeling, ultimately leading to heart failure (HF). The interleukin-1 (IL-1) blocker anakinra administered during the first 14 days after STEMI patients has been shown to effectively dampen the inflammatory response and reduce the incidence of HF events in pilot randomized controlled trials. Diabetes mellitus is a condition of enhanced systemic inflammation. Purpose To assess the role of diabetes mellitus as a modulating factor in respect to the efficacy of anakinra treatment during the first 14 days after STEMI. Methods We conducted a pooled analysis of three previous proof of principle trials on anakinra in STEMI. Diabetes mellitus was defined based on clinical history, use of glucose-lowering medications, or elevated hemoglobin A1c &amp;gt;6.5% at time of enrollment and further characterized as type I or type II based on the available clinical assessment. The area-under-the-curve for C reactive protein (AUC-CRP) at 14 days was used as a measure of the systemic inflammatory response during STEMI. The clinical endpoint was composite of death, hospitalizations for HF and urgent HF visits. Results The study population included 139 patients, of whom 39 (28%) had a diagnosis of diabetes mellitus at time of enrolment, all with type II. Median age was 56 [49-63] and 56 [49-63] years in patients with and without diabetes, respectively (p=0.652). There were 29 (21%) female and 52 (37%) Black-African American patients among those with diabetes compared to 29 (21%) female and 52 (37%) Black-African American patients in those without diabetes (p=0.69 and p=0.16, respectively). Treatment with anakinra (N=84) significantly dampened acute inflammation associated with STEMI in patients with diabetes (AUC-CRP 223 [117-399] vs 76 [42-148] mg•day/L, p&amp;lt;0.001) and in those without diabetes (AUC-CRP 223 [117-399] vs 76 [42-148] mg•day/L, p&amp;lt;0.001 – Figure 1). No statistically significant interaction between diabetes status and treatment with anakinra on outcomes was detected (pint=0.92): treatment with anakinra was associated with a hazard ratio [HR] 0.28 [0.09-0.84](p=0.02) in non-diabetic patients and HR 0.26 [0.11-1.32](p=0.10) in diabetic patients – Figure 2. Conclusion In this pooled analysis of the VCU-ART trials, the presence of type II diabetes mellitus showed no interaction with the efficacy of the treatment with anakinra early after STEMI in reducing the systemic inflammatory response or preventing new onset heart failure, hospitalization for HF or death.Figure 1.Figure 2

Differential response to interleukin-1 blockade with anakinra on cardiorespiratory fitness in patients with heart failure with preserved ejection fraction stratified according to ejection fraction

Abstract Background Patients with heart failure with preserved ejection fraction (HFpEF) are a heterogeneous clinical population and might respond differently to pharmacologic therapies based on their baseline left ventricular EF (LVEF) (50-59% vs. ≥60%). Interleukin-1 (IL-1) is a key pro-inflammatory cytokine being explored as a therapeutic target in HFpEF for its effects on numerous outcomes including cardiorespiratory fitness (CRF). Purpose Our aim was to examine changes in CRF and C-reactive protein (CRP), a surrogate for IL-1 activity, in patients with HFpEF treated with the IL-1 recombinant human receptor antagonist anakinra, stratified according to resting LVEF. Methods We analyzed data from 32 patients (median age 55 [51-64] years, 24 (75%) female) with HFpEF, defined as a presence of HF symptoms, LVEF≥50%, and evidence of left ventricular diastolic dysfunction or elevated filling pressures. All patients were treated with anakinra 100 mg subcutaneously daily for 12 [2-12] weeks. Patients were stratified into two groups: LVEF 50-59% and LVEF ≥60%. At baseline and during treatment, patients underwent cardiopulmonary exercise testing and venipuncture to measure changes in peak oxygen consumption (peak VO2) and CRP. Categorical and continuous variables are expressed as N (%) and median (interquartile range) and were compared with the chi-square and Mann-Whitney test, respectively. The within-group paired differences were compared using the Wilcoxon signed-rank test. Results The cohort included 15 patients with LVEF 50-59% and 17 with LVEF ≥60%, without significant differences in age and sex between groups. In patients with LVEF 50-59% and ≥60%, baseline peak VO2 was 14.1 [13.1–17.3] and 13.8 [11.8-18.6] mLO2·kg-1·min-1, respectively (p = 0.82), and CRP was 6.2 [3.4-15.9] and 6.1 [3.7-17.6] mg/L, respectively (p = 0.74). A significant increase in peak VO2 (from 13.8 [11.8-18.6] to 15.8 [12.7-19.9] mLO2·kg-1·min-1, p = 0.033) and decrease in CRP (from 6.2 [3.4-15.9] mg/L to 3.4 [1.0-6.7] mg/L, p = 0.003) was seen in patients with LVEF ≥60%; whereas in those with LVEF 50-59% there were no significant changes in peak VO2 (from 14.1 [13.1–17.3] to 14.1 [11.0–17.3] mLO2·kg-1·min-1, p = 0.25) despite a significant reduction in CRP (from 6.1 [3.7-17.6] mg/L to 1.4 [0.8-11.4] mg/L, p = 0.016). We found a difference in the interval changes in peak VO2 (0 [from -1.1 to +0.3] vs +1.7 [from -0.7 to +2.3] mLO2·kg-1·min-1 in patients with LVEF 50-59% and ≥60%, respectively, p = 0.01), without differences in the interval change in CRP levels (–3.5 [from -6 to -2.1] vs –3.0 [from -11.4 to -2.1] mg/L, respectively, p = 0.91). Figure 1. Conclusions Patients with HFpEF demonstrate differential peak VO2 response to anakinra treatment based on resting LVEF, with those with a LVEF ≥60% showing greater improvement in CRF. Further randomized control trials are needed to validate these data and explore the potential underlying mechanisms.

Abstract 16312: Sex-Based Differences in Response to Interleukin-1 Blockade With Anakinra in Patients With ST-Segment Elevation Myocardial Infarction

Introduction: Interleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra in this setting. Methods: We analyzed sex-based differences in the systemic inflammation (CRP levels) and composite end-point of new-onset HF or death in patients with STEMI from three different Virginia Commonwealth University Anakinra Response Trial (VCU-ART) randomized clinical trials. Data are reported as median and interquartile range [IQR] or number and percentage (%). Kaplan-Meier curves for event-free survival were constructed for the time-dependent composite endpoint and compared using the log-rank analysis. Results: We analyzed 139 patients from three VCU-ART trials, 29 (21%) were women while 110 (79%) were men. Baseline CRP was higher in women compared to men (8.9 [5.2-13.5] vs 4.2 [2.1-7.7] mg/L, P&lt;0.001). Twenty-two (75%) women and 62 (56%) men were treated with anakinra. Area under the curve (AUC)-CRP at 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs 223 [119-374] mg day/L) and in women (73 [46-313] vs 242 [102-988] mg day/L) (P&lt;0.001 at ANOVA for multiple groups, P for interaction 0.22) Figure A . The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs 14 [29.1%]) and in women (3 [13.6%] vs 2 [28.5%]) (P=0.019 at ANOVA, P for interaction 0.44) Figure B . There were no statistically significant differences between women and men in AUC-CRP and HF events when comparing separately the anakinra and placebo groups (all P&gt;0.05). Conclusions: Women were underrepresented in the VCU-ART trials, they appeared to have higher CRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.

Response to interleukin-1 blockade with anakinra in women and men with ST-segment elevation myocardial infarction.

Interleukin-1 blockade with anakinra reduces high-sensitivity C-reactive protein (hsCRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). Sex-based differences in STEMI patients have been reported, but no data are available regarding response to anakinra. We analyzed the systemic inflammation and composite end-point of new-onset HF or death in women and men with STEMI treated with anakinra from three different Virginia Commonwealth University Anakinra Response Trial (VCUART) randomized clinical trials. We analyzed 139 patients, 29 (21%) were women while 110 (79%) were men. Baseline hsCRP was higher in women compared to men (8.9 [5.2-13.5] vs. 4.2 [2.1-7.7] mg/L, P<0.001). Eighty-four patients were treated with anakinra (22 [75%] women and 62 [56%] men). The area under the curve of hsCRP (hsCRP-AUC) after 14 days was numerically lower in patients receiving anakinra versus placebo both in men (86 [37-130] vs. 223 [119-374] mg day/L) and in women (73 [46-313] vs. 242 [102-988] mg day/L) (P<0.001 for multiple groups, P for interaction 0.22). The incidence of the composite endpoint was also numerically lower in the anakinra group compared to placebo, both in men (4 [6.4%] vs. 14 [29.1%]) and in women (3 [13.6%] vs. 2 [28.5%]) (P=0.019 for multiple groups, P for interaction 0.44). There were no statistically significant differences between women and men in hsCRP-AUC and death or HF events when comparing separately the anakinra and placebo groups (all P>0.05). Women were underrepresented in the VCUART trials, they appeared to have higher hsCRP levels at time of presentation, yet to benefit similar to men by treatment with anakinra in STEMI.