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Background A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. Methods In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day − 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. Results Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) ( p  = 0.0002), ferritin ( p  = 0.009), and temperature ( p  = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature ( p  = 0.03), white blood cell counts ( p  = 0.02), and plasma levels of ferritin ( p  = 0.003), procalcitonin ( p  = 0.001), creatinine ( p  = 0.01), and bilirubin ( p  = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. Conclusions Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.

The expression of interleukin-1–receptor antagonist is reduced in pancreatic islets in type 2 diabetes, and high glucose concentrations induce interleukin-1β production in human pancreatic beta cells, suggesting that the interleukin-1 pathway may be a treatment target. This randomized trial showed that the interleukin-1–receptor antagonist anakinra (100 mg) improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation, as compared with placebo. This randomized trial showed that the interleukin-1–receptor antagonist anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic inflammation, as compared with placebo. Type 2 diabetes mellitus occurs when beta-cell function fails to compensate for insulin resistance. 1 , 2 Beta-cell function progressively deteriorates with an increasing duration of diabetes, 3 partly because of beta-cell demise through apoptosis. 4 – 6 Interleukin-1β, a proinflammatory cytokine 7 implicated as an effector molecule of inflammatory beta-cell destruction leading to type 1 diabetes, 8 inhibits the function and promotes the apoptosis of beta cells. 9 Beta cells producing interleukin-1β have been observed in pancreatic sections obtained from patients with type 2 diabetes. 10 Depending on culture conditions, high glucose levels increase beta-cell production and the release of interleukin-1β, followed by functional impairment and apoptosis. 10 – . . .

Fatigue is a major cause of disability in primary Sjögren's syndrome (pSS). Fatigue has similarities with sickness behaviour in animals; the latter mediated by pro-inflammatory cytokines, in particular interleukin (IL)-1, acting on neuronal brain cells. We hypothesised that IL-1 inhibition might improve fatigue in pSS patients; thus, we examined the effects and safety of an IL-1 receptor antagonist (anakinra) on fatigue. Twenty-six pSS patients participated in a double-blind, placebo-controlled parallel group study. Patients were randomised to receive either anakinra or a placebo for four weeks. Fatigue was evaluated by a fatigue visual analogue scale and the Fatigue Severity Scale. The primary outcome measure was a group-wise comparison of the fatigue scores at week 4, adjusted for baseline values. Secondary outcome measures included evaluation of laboratory results and safety. The proportion of patients in each group who experienced a 50% reduction in fatigue was regarded as a post-hoc outcome. All outcomes were measured at week 4. There was no significant difference between the groups in fatigue scores at week 4 compared to baseline after treatment with anakinra. However, six out of 12 patients on anakinra versus one out of 13 patients on the placebo reported a 50% reduction in fatigue VAS (p = 0.03). There were two serious adverse events in each group. This randomised, double-blind, placebo-controlled trial of IL-1 blockade did not find a significant reduction in fatigue in pSS in its primary endpoint. A 50% reduction in fatigue was analysed post-hoc, and significantly more patients on the active drug than on placebo reached this endpoint. Although not supported by the primary endpoint, this may indicate that IL-1 inhibition influences fatigue in patients with pSS. ClinicalTrials.gov NCT00683345.

Background Heart failure (HF) is a global leading cause of mortality despite implementation of guideline directed therapy which warrants a need for novel treatment strategies. Proof-of-concept clinical trials of anakinra, a recombinant human Interleukin-1 (IL-1) receptor antagonist, have shown promising results in patients with HF. Method We designed a single center, randomized, placebo controlled, double-blind phase II randomized clinical trial. One hundred and two adult patients hospitalized within 2 weeks of discharge due to acute decompensated HF with reduced ejection fraction (HFrEF) and systemic inflammation (high sensitivity of C-reactive protein > 2 mg/L) will be randomized in 2:1 ratio to receive anakinra or placebo for 24 weeks. The primary objective is to determine the effect of anakinra on peak oxygen consumption (VO 2 ) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO 2 at CPX after 24 weeks (or longest available follow up). Secondary exploratory endpoints will assess the effects of anakinra on additional CPX parameters, structural and functional echocardiographic data, noninvasive hemodynamic, quality of life questionnaires, biomarkers, and HF outcomes. Discussion The current trial will assess the effects of IL-1 blockade with anakinra for 24 weeks on cardiorespiratory fitness in patients with recent hospitalization due to acute decompensated HFrEF. Trial registration: The trial was registered prospectively with ClinicalTrials.gov on Jan 8, 2019, identifier NCT03797001.

Fibroblast growth factor-21 (FGF21) is elevated in patients with the metabolic syndrome. Although the exact underlying mechanisms remain ill-defined, chronic low-grade inflammation with increased Interleukin-(IL)-1β expression may be responsible. The aim of this study was to investigate effects of two different anti-inflammatory treatments (IL-1 antagonism or high-dose corticosteroids) on FGF21 in patients with the metabolic syndrome. This is a secondary analysis of two interventional studies in patients with obesity and features of the metabolic syndrome. Trial A was an interventional trial (n = 73) investigating short-term effects of the IL-1 antagonist anakinra and of dexamethasone. Trial B was a randomized, placebo-controlled, double-blinded trial (n = 67) investigating longer-term effects of IL-1 antagonism. In total, 140 patients were included in both trials. Median age was 55 years (IQR 44–66), 26% were female and median BMI was 37 kg/m 2 (IQR 34–39). Almost half of the patients were diabetic (45%) and had increased c-reactive protein levels of 3.4 mg/L. FGF21 levels correlated with fasting glucose levels, HOMA-index, C-peptide levels, HbA1c and BMI. Short-term treatment with anakinra led to a reduction of FGF21 levels by − 200 pg/mL (95%CI − 334 to − 66; p = 0.004). No effect was detectable after longer-term treatment (between-group difference: − 8.8 pg/mL (95%CI − 130.9 to 113.3; p = 0.89). Acute treatment with dexamethasone was associated with reductions of FGF21 by -175 pg/mL (95%CI − 236 to − 113; p < 0.001). Anti-inflammatory treatment with both, IL-1 antagonism and corticosteroids reduced FGF21 levels at short-term in individuals with the metabolic syndrome. Trial registration: ClinicalTrials.gov Identifiers NCT02672592 and NCT00757276.

Background Cytokine disturbances have been suggested to be associated with the Chronic Fatigue Syndrome/Myalgic encephalomyelitis (CFS/ME) for decades. Methods Fifty female CFS patients were included in a study on the effect of the interleukin-1-receptor antagonist anakinra or placebo during 4 weeks. EDTA plasma was collected from patients before and directly after treatment. At baseline, plasma samples were collected at the same time from 48 healthy, age-matched female neighborhood controls. A panel of 92 inflammatory markers was determined in parallel in 1 μL samples using a ‘proximity extension assay’ (PEA) based immunoassay. Since Transforming growth factor beta (TGF-β) and interleukin-1 receptor antagonist (IL-1Ra) were not included in this platform, these cytokines were measured with ELISA. Results In CFS/ME patients, the ‘normalized protein expression’ value of IL-12p40 and CSF-1 was significantly higher (p value 0.0042 and 0.049, respectively). Furthermore, using LASSO regression, a combination of 47 markers yielded a prediction model with a corrected AUC of 0.73. After correction for multiple testing, anakinra had no effect on circulating cytokines. TGF-β did not differ between patients and controls. Conclusions In conclusion, this study demonstrated increased IL-12p40 and CSF-1 concentrations in CFS/ME patients in addition to a set of predictive biomarkers. There was no effect of anakinra on circulating cytokines other than IL-1Ra. Trial Registration : ClinicalTrials.gov Identifier: NCT02108210 , Registered April 2014

In the clinic, chimeric antigen receptor–modified T (CAR T) cell therapy is frequently associated with life-threatening cytokine-release syndrome (CRS) and neurotoxicity. Understanding the nature of these pathologies and developing treatments for them are hampered by the lack of appropriate animal models. Herein, we describe a mouse model recapitulating key features of CRS and neurotoxicity. In humanized mice with high leukemia burden, CAR T cell–mediated clearance of cancer triggered high fever and elevated IL-6 levels, which are hallmarks of CRS. Human monocytes were the major source of IL-1 and IL-6 during CRS. Accordingly, the syndrome was prevented by monocyte depletion or by blocking IL-6 receptor with tocilizumab. Nonetheless, tocilizumab failed to protect mice from delayed lethal neurotoxicity, characterized by meningeal inflammation. Instead, the IL-1 receptor antagonist anakinra abolished both CRS and neurotoxicity, resulting in substantially extended leukemia-free survival. These findings offer a therapeutic strategy to tackle neurotoxicity and open new avenues to safer CAR T cell therapies. IL-1 blockade prevents cytokine-release syndrome and neurotoxicity by CAR T cells.

Cytokine release syndrome (CRS), commonly known as cytokine storm, is an acute systemic inflammatory response that is a significant global health threat. Interleukin-6 (IL-6) and interleukin-1 (IL-1) are key pro-inflammatory cytokines involved in CRS and are hence critical therapeutic targets. Current antagonists, such as tocilizumab and anakinra, target IL-6R/IL-1R but have limitations due to their long half-life and systemic anti-inflammatory effects, making them less suitable for acute or localized treatments. Here we present the de novo design of small protein antagonists that prevent IL-1 and IL-6 from interacting with their receptors to activate signaling. The designed proteins bind to the IL-6R, GP130 (an IL-6 co-receptor), and IL-1R1 receptor subunits with binding affinities in the picomolar to low-nanomolar range. X-ray crystallography studies reveal that the structures of these antagonists closely match their computational design models. In a human cardiac organoid disease model, the IL-1R antagonists demonstrated protective effects against inflammation and cardiac damage induced by IL-1β. These minibinders show promise for administration via subcutaneous injection or intranasal/inhaled routes to mitigate acute cytokine storm effects. Here, the authors computationally designed and produced small protein antagonists to target IL-6 and IL-1β signaling to develop modulators of CRS.

Diabetes mellitus (DM) encompasses a multitude of secondary disorders, including heart disease. One of the most frequent and potentially life threatening disorders of DM-induced heart disease is ventricular tachycardia (VT). Here we show that toll-like receptor 2 (TLR2) and NLRP3 inflammasome activation in cardiac macrophages mediate the production of IL-1β in DM mice. IL-1β causes prolongation of the action potential duration, induces a decrease in potassium current and an increase in calcium sparks in cardiomyocytes, which are changes that underlie arrhythmia propensity. IL-1β-induced spontaneous contractile events are associated with CaMKII oxidation and phosphorylation. We further show that DM-induced arrhythmias can be successfully treated by inhibiting the IL-1β axis with either IL-1 receptor antagonist or by inhibiting the NLRP3 inflammasome. Our results establish IL-1β as an inflammatory connection between metabolic dysfunction and arrhythmias in DM. Ventricular arrhythmia is a leading cause of death in patients with diabetes. Here the authors show that inflammasome activation and ILK-1β production in cardiac macrophages cause arrhythmia in diabetic mice, which can be successfully treated using agonists to IL-1β receptor or NLRP3 inhibitors.

Severe coronavirus disease 2019 (COVID-19) is characterized by systemic hyper-inflammation, acute respiratory distress syndrome, and multiple organ failure. Cytokine storm refers to a set of clinical conditions caused by excessive immune reactions and has been recognized as a leading cause of severe COVID-19. While comparisons have been made between COVID-19 cytokine storm and other kinds of cytokine storm such as hemophagocytic lymphohistiocytosis and cytokine release syndrome, the pathogenesis of cytokine storm has not been clearly elucidated yet. Recent studies have shown that impaired response of type-1 IFNs in early stage of COVID-19 infection played a major role in the development of cytokine storm, and various cytokines such as IL-6 and IL-1 were involved in severe COVID-19. Furthermore, many clinical evidences have indicated the importance of anti-inflammatory therapy in severe COVID-19. Several approaches are currently being used to treat the observed cytokine storm associated with COVID-19, and expectations are especially high for new cytokine-targeted therapies, such as tocilizumab, anakinra, and baricitinib. Although a number of studies have been conducted on anti-inflammatory treatments for severe COVID-19, no specific recommendations have been made on which drugs should be used for which patients and when. In this review, we provide an overview of cytokine storm in COVID-19 and treatments currently being used to address it. In addition, we discuss the potential therapeutic role of extracorporeal cytokine removal to treat the cytokine storm associated with COVID-19.