Recombinant Human Interleukin-1 Receptor Antagonist Research Articles

A randomized controlled pilot trial of anakinra and pioglitazone for protein metabolism in patients on maintenance haemodialysis.

Chronic inflammation and insulin resistance are highly prevalent in patients on maintenance haemodialysis (MHD) and are strongly associated with protein energy wasting. We conducted a pilot, randomized, placebo-controlled trial of recombinant human interleukin-1 receptor antagonist (IL-1ra) and pioglitazone to explore the safety, feasibility and efficacy for insulin-mediated protein metabolism in patients undergoing MHD. Twenty-four patients were randomized to receive IL-1ra, pioglitazone or placebo for 12weeks. Changes in serum inflammatory markers and insulin-mediated protein synthesis, breakdown and net balance in the whole-body and skeletal muscle compartments were assessed using hyperinsulinaemic-hyperaminoacidemic clamp technique at baseline and Week 12. Among 24 patients, median (interquartile range) age was 51 (40, 61), 79% were African American and 21% had diabetes mellitus. All patients initiated on intervention completed the study, and no serious adverse events were observed. There was a statistically significant decrease in serum high-sensitivity C-reactive protein in the pioglitazone group compared with placebo, but not in the IL-1ra group. No significant differences in the changes of whole-body or skeletal muscle protein synthesis, breakdown and net balance were found between the groups. In this pilot study, there were no statistically significant effects of 12weeks of IL-1ra or pioglitazone on protein metabolism in patients on MHD. gov registration: NCT02278562.

Anakinra authorized to treat severe coronavirus disease 2019; Sepsis breakthrough or time to reflect?

The European Medicines Agency (EMA) and the United States Food and Drug Administration (FDA) announced conditions for using recombinant human interleukin-1 receptor antagonist (rhIL-1ra) to treat hospitalized patients with Coronavirus disease 2019 (COVID-19) and risk for progression. These decisions followed publication of the suPAR-guided Anakinra treatment for Validation of the risk and early Management OF seveRE respiratory failure by COVID-19 (SAVE- MORE) phase 3 clinical trial that yielded positive results. We conducted a literature review and theoretical analysis of IL-1 blockade as a therapy to treat COVID-19. Using a stepwise analysis, we assessed clinical applicability of the SAVE-MORE results and evaluated conceptual support for interleukin-1 suppression as a suitable approach to COVID-19 treatment. This therapeutic approach was then examined as an example of inflammation-suppressing measures used to treat sepsis. Anakinra use as a COVID-19 therapy seems to rely on a view of pathogenesis that incorrectly reflects human disease. Since COVID-19 is an example of sepsis, COVID-19 benefit due to anti-inflammatory therapy contradicts an extensive history of unsuccessful clinical study. Repurposing rhIL-1ra to treat COVID-19 appears to exemplify a cycle followed by inflammation-suppressing sepsis treatments. A landscape of treatment failures is interrupted by a successful clinical trial. However, subsequent confirmatory study fails to replicate the positive data. We suggest further experimentation is not a promising pathway to discover game-changing sepsis therapies. A different kind of approach may be necessary.

NLRP3 inflammasome and interleukin-1 contributions to COVID-19-associated coagulopathy and immunothrombosis.

Immunothrombosis-immune-mediated activation of coagulation-is protective against pathogens, but excessive immunothrombosis can result in pathological thrombosis and multiorgan damage, as in severe coronavirus disease 2019 (COVID-19). The NACHT-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome produces major proinflammatory cytokines of the interleukin (IL)-1 family, IL-1β and IL-18, and induces pyroptotic cell death. Activation of the NLRP3 inflammasome pathway also promotes immunothrombotic programs including release of neutrophil extracellular traps and tissue factor by leukocytes, and prothrombotic responses by platelets and the vascular endothelium. NLRP3 inflammasome activation occurs in patients with COVID-19 pneumonia. In preclinical models, NLRP3 inflammasome pathway blockade restrains COVID-19-like hyperinflammation and pathology. Anakinra, recombinant human IL-1 receptor antagonist, showed safety and efficacy and is approved for the treatment of hypoxaemic COVID-19 patients with early signs of hyperinflammation. The non-selective NLRP3 inhibitor colchicine reduced hospitalization and death in a subgroup of COVID-19 outpatients but is not approved for the treatment of COVID-19. Additional COVID-19 trials testing NLRP3 inflammasome pathway blockers are inconclusive or ongoing. We herein outline the contribution of immunothrombosis to COVID-19-associated coagulopathy, and review preclinical and clinical evidence suggesting an engagement of the NLRP3 inflammasome pathway in the immunothrombotic pathogenesis of COVID-19. We also summarize current efforts to target the NLRP3 inflammasome pathway in COVID-19, and discuss challenges, unmet gaps, and the therapeutic potential that inflammasome-targeted strategies may provide for inflammation-driven thrombotic disorders including COVID-19.

Correction of Immunological and Behavioral Parameters of Rats with Experimental Traumatic Brain Injury with a Preparation of Monoclonal Antibodies to the C3 Component of Complement

After traumatic brain injury (TBI), inflammation develops in the CNS, an active participant in which is the complement system. Activated complement fragments initiate inflammation, and subsequently significantly affect the processes of repair and regeneration. The aim of the work is to reduce neuroimmune disorders after experimental TBI by blocking excessive inflammation in the early stages of traumatic disease with monoclonal antibodies to the C3 component of complement. The work was carried out on 65 male Wistar rats using the “falling weight” model. To correct neuroinflammation, a preparation of a recombinant monoclonal antibody 3A8, specific for the C3 neodeterminant of the rat complement component, blocking the activation of the alternative complement pathway was administered (i.v., 100 mg/kg). As a reference drug, a recombinant human interleukin-1 receptor antagonist (rIL-1RA) was used, which was administered s.c. (dose of 50 mg/kg). Both drugs were administered once after 30 min of TBI (mode 1) or 24 hours after TBI (mode 2). We studied the levels of corticosterone in the blood, the cytotoxic and proliferative activity of lymphocytes, and behavioral responses in the “plus maze” test. The obtained data indicate that on the 7th day after TBI in rats treated with 3A8 antibodies in mode 1, post-traumatic weight loss was decreased, the natural cytotoxicity of splenocytes and their proliferative activity were increased, and motor and exploratory activity were increased with a significant decrease in the level of anxiety. The introduction of rIL-1RA in these regimens, as well as the combined use of both drugs, did not have a significant effect on the studied parameters.

Novel Pathophysiological, Diagnostic and Therapeutic Concepts in Acute and Recurrent Pericarditis

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models. More recently, following seminal clinical trials with colchicine and interleukin-1 (IL-1) blockers and a novel murine model of acute pericarditis using zymosan A, it has become clear that the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome/IL-1β axis plays a central role in driving acute pericardial inflammation and in sustaining this process during recurrences. Diagnostic management of pericarditis has been implemented with multimodality imaging including echocardiography, cardiac computed tomography, and cardiac magnetic resonance. These imaging modalities provide essential diagnostic and pathogenetic information, and are able to characterize pericardial inflammation, allowing to refine risk stratification and personalize treatment. Recent acquisitions yield relevant implications with regard to the therapeutic management of acute and recurrent pericarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are cornerstone therapies either for acute and recurrent pericarditis. However, the benefits of targeted agents, such as anakinra — a recombinant human IL-1 receptor antagonist — and rilonacept — an IL-1α/IL-1β trap, are being increasingly recognized. To this end, phenotyping patients with pericarditis and addressing such therapies to those presenting with auto-inflammatory features (elevated C-reactive protein, sustained pericardial and systemic inflammation, multiple recurrences) is of utmost importance to identify patients who might be more likely to benefit from NLRP3 inflammasome/IL-1β pathway blockade.

Anakinra as a potential treatment for COVID-19.

On November 8, 2022, the United States Food and Drug Administration (FDA) issued an emergency use authorization for the interleukin-1 (IL-1) inhibitor anakinra for the treatment of patients with COVID-19 pneumonia. The authorization was specifically intended for patients requiring supplemental oxygen who are at risk of progression to respiratory failure and are likely to have an elevated plasma soluble urokinase plasminogen activator receptor. Anakinra is a modified, recombinant human IL-1 receptor antagonist used to treat rheumatoid arthritis, neonatal-onset multisystem inflammatory disease and other inflammatory diseases. This manuscript examines what is known about the role of IL-1 receptor antagonism in the treatment of patients with COVID-19 and examines how anakinra may be used in the future to address the SARS-CoV-2 infection pandemic.

From Cytokine Storm to Cytokine Breeze: Did Lessons Learned from Immunopathogenesis Improve Immunomodulatory Treatment of Moderate-to-Severe COVID-19?

Complex immune response to infection has been highlighted, more than ever, during the COVID-19 pandemic. This review explores the immunomodulatory treatment of moderate-to-severe forms of this viral sepsis in the context of specific immunopathogenesis. Our objective is to analyze in detail the existing strategies for the use of immunomodulators in COVID-19. Immunomodulating therapy is very challenging; there are still underpowered or, in other ways, insufficient studies with inconclusive or conflicting results regarding a rationale for adding a second immunomodulatory drug to dexamethasone. Bearing in mind that a “cytokine storm” is not present in the majority of COVID-19 patients, it is to be expected that the path to the adequate choice of a second immunomodulatory drug is paved with uncertainty. Anakinra, a recombinant human IL-1 receptor antagonist, is a good choice in this setting. Yet, the latest update of the COVID-19 Treatment Guidelines Panel (31 May 2022) claims that there is insufficient evidence to recommend either for or against the use of anakinra for the treatment of COVID-19. EMA’s human medicines committee recommended extending the indication of anakinra to include treatment of COVID-19 in adult patients only recently (17 December 2021). It is obvious that this is still a work in progress, with few ongoing clinical trials. With over 6 million deaths from COVID-19, this is the right time to speed up this process. Our conclusion is that, during the course of COVID-19, the immune response is changing from the early phase to the late phase in individual patients, so immunomodulating therapy should be guided by individual responses at different time points.

Abstract P2043: Interleukin-1 Blockade Restores Exercise Capacity After Non-reperfused Acute Myocardial Infarction In The Mouse.

Background: Acute myocardial infarction (AMI) is associated with an intense inflammatory response promoting progression to heart failure (HF), characterized by dyspnea, fatigue, exercise intolerance. Interleukin-1 (IL-1) is the prototypical inflammatory cytokine increased in AMI. IL-1 injections reduce exercise capacity in healthy mice. Whether IL-1 reduces exercise capacity after AMI is unknown. Hypothesis: IL-1 blockade preserves exercise capacity in mice with experimental AMI. Methods: Ten-week-old male CD1 mice (N=45) were trained to run on a treadmill. Baseline exercise capacity was assessed. Based on the distance run, the mice were divided into tertiles. Mice in the middle tertile underwent surgical ligation of the coronary artery. Ten mice survived and were randomly assigned to treatment with daily intraperitoneal injections with anakinra, a recombinant human IL-1 receptor antagonist (10 mg/kg, 0.2 ml, N=4), or 0.9% NaCl vehicle (N=6). We measured exercise capacity at 1, 2, and 4 weeks. Data were analyzed using T-test for unpaired groups and are presented as mean and standard error of mean. Results: Baseline exercise capacity was 217±16 and 230±16 m in the anakinra and vehicle groups, respectively. Exercise capacity was significantly reduced 1 week after surgery in both groups (-57±9% vs -60±7%, P=0.80; P<0.01 vs respective baseline). By week 4, however, anakinra treatment significantly improved exercise capacity compared to the vehicle (+42±4% vs +8±7%, P<0.001) (Figure). Conclusion: Non-reperfused AMI leads to a severe reduction in exercise capacity that is reversed by IL-1 blockade. These data support IL-1 as a therapeutic target for preventing HF after AMI.

Rationale and design of interleukin-1 blockade in recently decompensated heart failure (REDHART2): a randomized, double blind, placebo controlled, single center, phase 2 study

BackgroundHeart 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.MethodWe 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 (VO2) measured at cardiopulmonary exercise testing (CPX) after 24 weeks of treatment, with placebo-corrected changes in peak VO2 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.DiscussionThe 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.

The Anti-Atherosclerosis Effect of Anakinra, a Recombinant Human Interleukin-1 Receptor Antagonist, in Apolipoprotein E Knockout Mice.

Interleukin (IL)-1β plays an important role in atherosclerosis pathogenesis. We aimed to investigate the effect of anakinra, a recombinant human IL-1 receptor antagonist, on the progression of atherosclerosis in apolipoprotein E knockout (ApoE–/–) mice. ApoE–/– mice (8-week male) were treated with saline (control), anakinra 10, 25, and 50 mg/kg, respectively (n = 10 in each group). Mice were fed a standard chow (4 weeks) followed by an atherogenic diet (35kcal% fat, 1.25% cholesterol, 12 weeks). Atheromatous plaques in ApoE–/– mice and the expression of inflammatory genes and signaling pathways in human umbilical vein endothelial cells (HUVECs), rat aortic smooth muscle cells (RAOSMCs), and 3T3-L1 adipocytes were assessed. Anakinra reduced the plaque size of the aortic arch (30.6% and 25.2% at the 25 mg/kg and 50 mg/kg doses, both p < 0.05) and serum triglyceride in ApoE–/– mice and suppressed inflammatory genes (IL-1β and IL-6) expressions in HUVECs and RAOSMCs (all p < 0.05). In RAOSMCs, anakinra reduced metalloproteinase-9 expression in a dose-dependent manner and inhibited cell migration. Anakinra-treated mice exhibited trends of lower CD68+ macrophage infiltration in visceral fat and monocyte chemoattractant protein-1 expression was reduced in 3T3-L1 adipocytes. Anakinra could be a useful component for complementary treatment with a standard regimen to reduce the residual cardiovascular risk.

Delayed Use of the Recombinant Human IL-1 Receptor Antagonist Anakinra in Five COVID-19 Patients with Pulmonary Fibrosis and Persistent Hypoxaemia: A Preliminary Report.

Up to one third of patients with severe COVID-19 pneumonia progress to acute respiratory distress syndrome (ARDS).Pulmonary fibrosis is a known consequence of ARDS.Our study shows promising results regarding the efficacy and safety of anakinra used in late-phase COVID-19 infection in patients with pulmonary fibrosis secondary to ARDS.

Systemic inflammation alters the neuroinflammatory response: a prospective clinical trial in traumatic brain injury

BackgroundNeuroinflammation following traumatic brain injury (TBI) has been shown to be associated with secondary injury development; however, how systemic inflammatory mediators affect this is not fully understood. The aim of this study was to see how systemic inflammation affects markers of neuroinflammation, if this inflammatory response had a temporal correlation between compartments and how different compartments differ in cytokine composition.MethodsTBI patients recruited to a previous randomised controlled trial studying the effects of the drug anakinra (Kineret®), a human recombinant interleukin-1 receptor antagonist (rhIL1ra), were used (n = 10 treatment arm, n = 10 control arm). Cytokine concentrations were measured in arterial and jugular venous samples twice a day, as well as in microdialysis-extracted brain extracellular fluid (ECF) following pooling every 6 h. C-reactive protein level (CRP), white blood cell count (WBC), temperature and confirmed systemic clinical infection were used as systemic markers of inflammation. Principal component analyses, linear mixed-effect models, cross-correlations and multiple factor analyses were used.ResultsJugular and arterial blood held similar cytokine information content, but brain-ECF was markedly different. No clear arterial to jugular gradient could be seen. No substantial delayed temporal associations between blood and brain compartments were detected. The development of a systemic clinical infection resulted in a significant decrease of IL1-ra, G-CSF, PDGF-ABBB, MIP-1b and RANTES (p < 0.05, respectively) in brain-ECF, even if adjusting for injury severity and demographic factors, while an increase in several cytokines could be seen in arterial blood.ConclusionsSystemic inflammation, and infection in particular, alters cytokine levels with different patterns seen in brain and in blood. Cerebral inflammatory monitoring provides independent information from arterial and jugular samples, which both demonstrate similar information content. These findings could present potential new treatment options in severe TBI patients, but novel prospective trials are warranted to confirm these associations.Graphical abstract

Inhalation of IL-1 Receptor Antagonist (ALTA-2530) Achieves Stable and Prolonged Pulmonary Exposure in Nonclinical Studies Supportive of Development for Bronchiolitis Obliterans Syndrome

Purpose ALTA-2530 is a novel inhaled formulation of recombinant human IL-1 receptor antagonist (rhIL-1Ra) in development for bronchiolitis obliterans syndrome (BOS). IL-1 overexpression in BOS drives chronic inflammation and fibroblast activation leading to airway remodeling and impaired oxygen transfer. Endogenous IL-1Ra is upregulated in response to IL-1 to limit cytokine signaling, but expression is inadequate to prevent BOS. Pharmacological IL-1 blockade is considered akin to restoration of physiologic immune regulation. Herein we determine if ALTA-2530 is stable during nebulization, achieves aerosol particle diameters consistent with distribution to distal airways, and pulmonary exposure commensurate with treatment of BOS. Methods Aerosolization and in vivo studies were performed with Aerogen Solo or Phillips InnospireGo vibrating mesh nebulizers. Rats (n=4/grp/timepoint) received ALTA-2530 by nose-only inhalation (0.63, 1.3, and 2.1mg/g lung). Serum and bronchioalveolar lavage (BAL) samples were collected for analysis by LC-MSMS. ALTA-2530 in lung epithelial lining fluid (ELF) was calculated using a BALF dilution factor. Results Nebulized ALTA-2530 delivered rhIL-1Ra particles with mass median aerodynamic diameters of ∼2.5-4 µm, consistent with delivery to small bronchioles. Impurity profiling by HPLC-UV and HPLC-SEC methods and an in vitro potency assay demonstrated rhIL-1Ra protein was stable during nebulization and retained full potency. ALTA-2530 achieved extensive and sustained exposure in lung ELF. The ratio of ELF to serum rhIL-1Ra was >2500X across all doses compared to 0.44X reported for lung tissue to plasma following a 5 hr IV infusion. Duration of lung exposure from a single inhaled dose exceeded 24 hr, in contrast to 1000X. Conclusion Nebulized ALTA-2530 delivers stable and active rhIL-1Ra protein, in a particle size for delivery to small airways of the lung and exposure duration predictive for once daily therapeutic dosing in BOS.

Inflammatory process as an etiological and prognostic factor of stroke and the goal of potential treatment strategies

Objective. Inflammation is the body’s natural defence mechanism against factors that damage its tissues. However, if it lasts chronically, it may adversely affect the body’s homeostasis. Inflammation is not only a long-known risk factor for the development of atherosclerosis and its complications, but also develops brain tissue damage in the course of ischemic stroke or intracerebral haemorrhage, leading to even greater damage. In addition, the immune system functions are impaired, which increases the risk of infection. Literature review. Drugs that can reduce the risk of stroke by inhibiting vascular damage and modifying the inflammatory process in the central nervous system, including counteracting the risk of infection, have become the subject of many experimental and clinical studies on strokes. Such drugs include canakinumab, human recombinant interleukin-1 receptor antagonist, colchicine, fingolimod, siponimod or natalizumab. Conclusions. Considering all available research results, the therapeutic pathway using anti-inflammatory drugs has a high potential; however, the complications associated with evoked immunosuppression in patients should be kept in mind. The paper presents a review of the literature on the role of the inflammatory process in the pathogenesis of stroke as well as related therapeutic options.

COVID-19 cytokine storm: targeting the appropriate cytokine.

As of January, 2021, nearly 2-million deaths worldwide have been attributed to COVID-19, which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Much of the mortality has been associated with a cytokine storm syndrome in patients admitted to hospital with COVID-19 pneumonia.1Henderson LA Canna SW Schulert GS et al.On the alert for cytokine storm: immunopathology in COVID-19.Arthritis Rheumatol. 2020; 72: 1059-1063Crossref PubMed Scopus (421) Google Scholar Defining the COVID-19 cytokine storm syndrome has been challenging, but early reports proposed combinations of clinical (eg, fever) and laboratory (eg, hyperferritinaemia) features in determining patients most likely to benefit from cytokine storm syndrome treatment.2Caricchio R Gallucci M Dass C et al.Preliminary predictive criteria for COVID-19 cytokine storm.Ann Rheum Dis. 2020; 80: 88-95Crossref PubMed Scopus (103) Google Scholar, 3Webb BJ Peltan ID Jensen P et al.Clinical criteria for COVID-19-associated hyperinflammatory syndrome: a cohort study.Lancet Rheumatol. 2020; 2: e754-e763Summary Full Text Full Text PDF PubMed Scopus (162) Google Scholar A vast array of anti-inflammatory therapies are being explored to dampen the cytokine storm syndrome to save lives. One of the first approaches to treat COVID-19 cytokine storm syndrome was targeting interleukin-6 (IL-6). Early during the pandemic, IL-6 concentrations were noted to be elevated, and IL-6-blocking therapies were available in China, whereas IL-1 inhibitors were not. Retrospective case series of monoclonal antibodies binding IL-6 or its receptor presented mixed results in potential benefit in treating COVID-19 cytokine storm syndrome; however, most randomised controlled trials have not documented improved survival with agents targeting IL-6.4Stone JH Frigault MJ Serling-Boyd NJ et al.Efficacy of tocilizumab in patients hospitalized with Covid-19.N Engl J Med. 2020; 383: 2333-2344Crossref PubMed Scopus (816) Google Scholar By contrast, targeting IL-1, another pro-inflammatory cytokine that has been targeted effectively in other cytokine storm syndromes,5Eloseily EM Weiser P Crayne CB et al.Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis.Arthritis Rheumatol. 2020; 72: 326-334Crossref PubMed Scopus (131) Google Scholar has been reported to be largely successful in improving COVID-19 survival based on retrospective cohort studies.6Huet T Beaussier H Voisin O et al.Anakinra for severe forms of COVID-19: a prospective cohort study.Lancet Rheumatol. 2020; 2: e393-e400Summary Full Text Full Text PDF PubMed Scopus (408) Google Scholar In The Lancet Rheumatology, Giulio Cavalli and colleagues compared the effectiveness of IL-1 and IL-6 inhibition in the treatment of COVID-19 cytokine storm syndrome.7Cavalli G Larcher A Tomelleri A et al.Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.Lancet Rheumatol. 2021; (published online Feb 3.)https://doi.org/10.1016/S2665-9913(21)00012-6Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar This single-centre, observational study of patients admitted to hospital with COVID-19, respiratory insufficiency, and hyperinflammation (elevated C-reactive protein ≥100 mg/L or ferritin ≥900 ng/mL) analysed mortality in those receiving an IL-1 receptor antagonist (anakinra; n=62) or one of two monoclonal antibodies binding the IL-6 receptor (tocilizumab or sarilumab; n=55) versus no interleukin inhibition (n=275). The study suffers from potential biases that are frequent in non-randomised studies, but the authors controlled for baseline clinical differences among groups using multivariable Cox regression analysis, as well as immortal bias by excluding early (within 24 h from enrolment) deaths and intensive care admissions. Moreover, many in the no interleukin inhibition group were offered one of the anti-cytokine interventions but chose not to receive them. As this cohort occurred before the reports of glucocorticoid benefits,8The RECOVERY Collaborative GroupDexamethasone in hospitalized patients with Covid-19—preliminary report.N Engl J Med. 2020; (published online July 17.)https://doi.org/10.1056/NEJMoa2021436Crossref Scopus (5223) Google Scholar very few patient outcomes were confounded by glucocorticoid therapy. With these caveats in mind, the 28-day survival (primary outcome) was 68% (95% CI 61–75) in the no interleukin inhibition population, 86% (74–100) for the patients who received the IL-1 inhibitor (lower mortality risk with a hazard ratio [HR] of 0·450, 95% CI 0·204–0·990; p=0·047), and 82% (69–97) for patients who received IL-6 inhibitors (0·900, 0·412–1·966; p=0·79). However, interaction tests revealed a lower mortality risk in the IL-6 inhibition group in those with increasing serum C-reactive protein concentrations. In addition, there was no evidence of adverse clinical outcome (a composite of death or mechanical ventilation) for either of the anti-cytokine treated groups compared with no interleukin inhibition. Thus, the recombinant human IL-1 receptor antagonist, anakinra, which blocks signalling of both IL-1α and IL-1β, significantly improved COVID-19 survival. Comparative effectiveness studies are uncommon trial designs for prospective randomised trials, particularly in the setting of a pandemic. Cohort studies, if properly analysed for various potential biases, can shed light on comparing possibly equivalent therapies (equipoise) for various conditions. Observational studies often suffer from lack of uniformity in treatment, but do allow for physician thoughtfulness and individualisation of care. For example, in this report, anakinra, which has a short half-life (about 4 h) was given at a high dose (10 mg/kg per day divided twice daily) and was not tapered until clinic benefit (defined respiratory and laboratory parameters) was achieved.7Cavalli G Larcher A Tomelleri A et al.Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.Lancet Rheumatol. 2021; (published online Feb 3.)https://doi.org/10.1016/S2665-9913(21)00012-6Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar This regimen differs substantially from that used in many randomised trials, which might use this treatment for 3–5 days at lower doses and then stop treatment irrespective of outcome. Why IL-1 blockade is proving more beneficial than IL-6 inhibition is unclear but might be related to the endotheliopathy associated with COVID-19 and the release of IL-1α, or the fact that IL-1 is frequently upstream of IL-6 expression, so blocking IL-1 signalling also indirectly blocks IL-6.9Crayne CB Albeituni S Nichols KE Cron RQ The immunology of macrophage activation syndrome.Front Immunol. 2019; 10: 119Crossref PubMed Scopus (314) Google Scholar Subsets of patients with COVID-19 might benefit from IL-6 blocking therapeutics, particularly early during the cytokine storm syndrome, as has been seen for IL-1 inhibition of cytokine storm syndrome.5Eloseily EM Weiser P Crayne CB et al.Benefit of anakinra in treating pediatric secondary hemophagocytic lymphohistiocytosis.Arthritis Rheumatol. 2020; 72: 326-334Crossref PubMed Scopus (131) Google Scholar However, such subsets have yet to be identified and might include those with low lactate dehydrogenase concentrations.7Cavalli G Larcher A Tomelleri A et al.Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.Lancet Rheumatol. 2021; (published online Feb 3.)https://doi.org/10.1016/S2665-9913(21)00012-6Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar Ultimately, a personalised medicine approach to treating various cytokine storm syndromes, COVID-19 and others, should result in improved survival. Trial design will be crucial, both in terms of selecting patients most likely to benefit (stricter criteria for cytokine storm syndrome) from cytokine-targeted treatments of COVID-19, as well as therapeutics approaches (eg, longer duration of treatment and combination treatment, such as cytokine blockade plus glucocorticoids, as seen in other cytokine storm syndromes10Henderson LA Cron RQ Macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis in childhood inflammatory disorders: diagnosis and management.Paediatr Drugs. 2020; 22: 29-44Crossref PubMed Scopus (52) Google Scholar). From the report of Cavalli and colleagues,7Cavalli G Larcher A Tomelleri A et al.Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort study.Lancet Rheumatol. 2021; (published online Feb 3.)https://doi.org/10.1016/S2665-9913(21)00012-6Summary Full Text Full Text PDF PubMed Scopus (105) Google Scholar and others, anakinra appears to be promising for saving the lives of patients with COVID-19 cytokine storm syndrome, and we all anxiously await prospective randomised controlled trails to confirm this optimism. I report grants and personal fees from Sobi, Novartis, and Pfizer during the conduct of the study. Interleukin-1 and interleukin-6 inhibition compared with standard management in patients with COVID-19 and hyperinflammation: a cohort studyIL-1 inhibition, but not IL-6 inhibition, was associated with a significant reduction of mortality in patients admitted to hospital with COVID-19, respiratory insufficiency, and hyperinflammation. IL-6 inhibition was effective in a subgroup of patients with markedly high C-reactive protein concentrations, whereas both IL-1 and IL-6 inhibition were effective in patients with low lactate dehydrogenase concentrations. Full-Text PDF

Anakinra: efficacy in the management of fever during neutropenia and mucositis in autologous stem cell transplantation (AFFECT-2)\u2014study protocol for a multicenter randomized double-blind placebo-controlled trial

BackgroundSince decades, fever and infections have been the most important complications of intensive chemotherapy and hematopoietic stem cell transplantation (HSCT) in the treatment of hematologic malignancies. Neutropenia has long been considered to be the most important risk factor for these complications. However, recent studies have shown that not neutropenia, but the development of mucositis is the most important cause of these complications. Currently, limited options for the prevention and treatment of mucositis are available, of which most are only supportive. The pro-inflammatory cytokine interleukin-1 (IL-1) plays a crucial role in the pathogenesis of mucositis. Pre-clinical studies of chemotherapy-induced mucositis have shown that recombinant human IL-1 receptor antagonist anakinra significantly ameliorated intestinal mucositis. In our pilot study AFFECT-1, we examined the safety and maximal tolerated dose of anakinra in patients with multiple myeloma, treated with high-dose melphalan (HDM) and autologous HSCT, selecting a dose of 300 mg daily for the phase IIb trial. The aim of the AFFECT-2 study is to determine the efficacy of anakinra in preventing fever during neutropenia (FN) and mucositis in this study population.Methods/designA multicenter, randomized, placebo-controlled, double-blind phase IIb trial will be conducted. Ninety patients with multiple myeloma scheduled for treatment with HDM and autologous HSCT will be included. Patients will be randomized between intravenous treatment with anakinra (300 mg) or placebo. Each group will be treated from day − 2 (day of HDM; day 0 is HSCT) up until day + 12. Outcome measures will be assessed at baseline, during admission, at discharge or day + 30, at day + 90, and + 1 year. The primary outcome will be reduction of FN. Secondary outcome measures include mucositis scores, bloodstream infections, citrulline levels, quality of life, and fatigue severity.DiscussionThe AFFECT-2 trial will examine the efficacy of anakinra in the management of fever during neutropenia and mucositis in patients with multiple myeloma treated with HDM and autologous HSCT. The results of this study may provide a new treatment option for these important complications. Also, this study will give us more insight in the pathophysiology of mucositis, including the role of IL-1 and the role of the microbiota in mucositis.Trial registrationClinicaltrials.gov NCT04099901. Registered on September 23, 2019. EudraCT: 2018-005046-10.

Preparation and Evaluation of Polymeric Microparticles of Human Recombinant IL-1 Receptor Antagonist by Spray Drying

Background: Formulating protein drugs into delivery systems with high drug loading is particularly challenging. Another major hurdle for formulation processes generally used for protein drugs is their scalability. In this article, we present the application of spray drying to prepare polymeric microparticles of human recombinant IL-1 receptor antagonist (IL-1 ra). Objective: The objective of this study was to formulate polymeric microparticles entrapping a therapeutic protein, human recombinant IL-1 ra using a spray drying process. Methods: IL-1 ra was formulated using three polymers viz. gelatin, pectin, and sodium alginate by using a spray drying process to produce polymer entrapped drug microparticles. A single drug to polymer ratio was used in the three drug-polymer formulation combinations. The prepared microparticles were evaluated for morphology by scanning electron microscopy, average particle size by dynamic light scattering and drug entrapment efficiency by ELISA. Results: Microparticles of three drug-polymer combinations were prepared using the Buchi B-90 spray dryer. The morphology of the three types of polymeric microparticles was found to be uniform by scanning electron microscopy. The average particle size for the three formulations ranged from 1 to 2.2 μ with a low standard deviation implying narrow particle size distribution. The drug loading efficiency ranged from 62 to 90 % W/W for the three formulations. Conclusion: The presented study demonstrates the feasibility of using spray drying to prepare morphologically uniform polymer entrapped protein drug microparticles with high drug entrapment efficiency.

IL-1Ra Protects Hepatocytes from CCl4-Induced Hepatocellular Apoptosis via Activating the ERK1/2 Pathway

AbstractInterleukin-1 receptor antagonist is an important acute-phase protein and an immune mediator, and its expression is associated with the development of hepatitis or acute liver failure. The aim of this study was to investigate whether recombinant human interleukin-1 receptor antagonist directly targets and improves cell survival in a carbon tetrachloride-induced hepatocyte injury model in vitro. A human hepatoma cell line and a mouse hepatocyte cell line were used to establish carbon tetrachloride-induced cell injury models in vitro, and cell viability, apoptosis, and reactive oxygen species level were determined to assess the degree of hepatocellular damage. Quantitative real-time polymerase chain reaction was used to analyze the level of interleukin-1β, interleukin-6, and tumor necrosis factor-α mRNA in cells; extracellular regulated protein kinases 1/2 phosphorylation in hepatocytes was analyzed using western blotting. Recombinant human interleukin-1 receptor antagonist could directly target hepatocytes, improve cell survival, and decrease carbon tetrachloride-induced cell apoptosis in vitro. In hepatocytes, recombinant human interleukin-1 receptor antagonist remarkably downregulated expression of interleukin-1β, interleukin-6, and tumor necrosis factor-α in hepatocytes exposed to carbon tetrachloride. It also decreased accumulation of reactive oxygen species and abrogated the suppression of extracellular regulated protein kinases 1/2 phosphorylation induced by carbon tetrachloride. However, stimulation of cells with an extracellular regulated protein kinases 1/2 inhibitor blocked the recombinant human interleukin-1 receptor antagonist-induced upregulation of extracellular regulated protein kinase1/2 activation and abrogated the improvement in hepatocyte survival following carbon tetrachloride treatment. Collectively, these findings provide new insights into the hepatocyte-protective mechanism of recombinant human interleukin-1 receptor antagonist.

The treatment of adult-onset Still's disease with anakinra, a recombinant human IL-1 receptor antagonist: a systematic review of literature

Adult-onset Still's disease (AOSD) is a rare, inflammatory disease of unknown aetiology, generally affecting young adults and requiring immunosuppressive treatment. In the last few years, bio- logic disease-modifying anti-rheumatic drugs (bDMARDs) have been successfully used in refractory cases, based on the pathogenic role of inflammatory cytokines in AOSD. Amongst bDMARDs, several observations confirmed the clinical usefulness of anakinra, a recombinant human non-glycosylated IL-1 receptor antagonist, in AOSD. At present, the treatment is still largely empirical and due to the possible fallacious aspects of clinical judgement, in this work, we performed a systematic review of literature (SRL) to summarise the evidence regarding the treatment with anakinra in AOSD, analysing rate of complete remission, corticosteroids (CCSs)-sparing effect, long-term retention rate, and safety. After screening titles, abstracts and analysis of full text, 15 manuscripts were analysed: 1 open randomised multicentre trial with two parallel groups and 14 observational single-arm retrospective studies. Collectively, results of the present SRL suggest the effectiveness of anakinra in the treatment of patients with AOSD. Furthermore, patients with AOSD are likely to achieve a good clinical response with anakinra and these outcomes are associated with a largely favourable safety profile. Furthermore, the majority of patients treated with anakinra may achieve a complete remission, also in monotherapy. Finally, the treatment with anakinra is associated with an important CCSs-sparing effect, and, a large percentage of these patients may stop CCSs, thus reducing predictable long-term CCSs side effects without the occurrence of new flares.

Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome.

ObjectiveThe objective of this study was to report the benefit of a therapeutic approach consisting of intravenous (IV) continuous anakinra (recombinant human interleukin‐1 receptor antagonist) infusions in treating severely ill adult patients with secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome (MAS).MethodsA retrospective chart review of five patients treated at Regions Hospital from 2016 to 2019 was conducted. Demographic, clinical, and laboratory characteristics and outcomes were recorded.ResultsContinuous IV anakinra infusions up to 2400 mg/d resulted in rapid serologic, then clinical response in 4 of 5 severely ill patients who were refractory to all other therapies, including subcutaneous anakinra. Subsequently, 3 of 5 patients have been maintained on anakinra or canakinumab, with no recurrence of MAS.ConclusionContinuous infusion of IV anakinra may result in rapid serologic and subsequent clinical improvement in adult patients with MAS. This method for treating cytokine storm should be considered in the current COVID‐19 pandemic in the subgroup of patients with severe disease who have a cytokine storm presentation.