Interleukin-1 Inhibitors and Vaccination Including COVID-19 in Inflammatory Rheumatic Diseases: A Nonsystematic Review.

Newly emerging variants of coronavirus 2 (SARS-CoV-2) raise concerns about the spread of the disease, and with the rising case numbers, the Coronavirus disease 2019 (COVID-19) remains a challenging medical emergency towards the end of the year 2021. Swiftly developed novel vaccines aid in the prevention of the spread, and it seems that a specific cure will not be at hand soon. The prognosis of COVID-19 in patients with autoimmune/autoinflammatory rheumatic diseases (AIIRD) is more severe when compared to the otherwise healthy population, and vaccination is essential. Evidence for both the efficacy and safety of COVID-19 vaccination in AIIRD under immunosuppression is accumulating, but the effect of Interleukin-1 on vaccination in general and in AIIRD patients is rarely addressed in the current literature. In light of the current literature, it seems that the level of agreement on the timing of COVID-19 vaccination is moderate in patients using IL-1 blockers, and expert opinions may vary. Generally, it may be recommended that patients under IL-1 blockade can be vaccinated without interrupting the anti-cytokine therapy, especially in patients with ongoing high disease activity to avoid disease relapses. However, in selected cases, after balancing for disease activity and risk of relapses, vaccination may be given seven days after the drug levels have returned to baseline, especially for IL-1 blocking agents with long half-lives such as canakinumab and rilonacept. This may help to ensure an ideal vaccine response in the face of the possibility that AIIRD patients may develop a more pronounced and severe COVID-19 disease course.

Early use of canakinumab to prevent mechanical ventilation in select COVID-19 patients: A retrospective, observational analysis.

INTRODUCTION: The fully-human monoclonal anti-interleukin (IL)-1ß antibody canakinumab may inhibit the production of inflammatory mediators in patients with coronavirus disease 2019 (COVID-19) and the hyperinflammatory response potentially leading to acute respiratory distress syndrome. OBJECTIVES: The goal of our retrospective, observational analysis was to evaluate the safety and efficacy of subcutaneous (s.c.) canakinumab in combination with our standard of care (SOC) treatment of selected patients with COVID-19 with respiratory failure and elevated reactive pro-inflammatory markers. METHODS: Eight participants received two doses of s.c. canakinumab 150 mg (or 2 mg/kg for participants weighing ≤40 kg) in addition to SOC. 12 patients received only SOC treatment. RESULTS: Canakinumab treatment reduced the need for mechanical ventilation and reduced proinflammatory markers, resulting in an amelioration of the final outcome, with respect to the control group who received SOC alone. The treatment was safe and well tolerated; no adverse events were reported. CONCLUSION: The use of canakinumab (300 mg, s.c.) in the early stage of COVID-19 with mild-to-moderate respiratory failure was superior to SOC at preventing clinical deterioration and may warrant further investigation as a treatment option for patients with COVID-19 who experience a hyperinflammatory response in the early stage of the disease.

A Novel Method for the Production of an Autologous Anti-Inflammatory and Anti-Catabolic Product (Cytorich) from Human Blood: A Prospective Treatment for the COVID-19-Induced Cytokine Storm.

BACKGROUND Autologous blood-derived products can target specific inflammatory molecular pathways and have potentially beneficial therapeutic effects on inflammatory pathologies. The purpose of this study was to assess in vitro the anti-inflammatory and anti-catabolic potential of an autologous blood product as a possible treatment for COVID-19-induced cytokine storm. MATERIAL AND METHODS Blood samples from healthy donors and donors who had recovered from COVID-19 were incubated using different techniques and analyzed for the presence of anti-inflammatory, anti-catabolic, regenerative, pro-inflammatory, and procatabolic molecules. RESULTS The highest concentrations of therapeutic molecules for targeting inflammatory pathways were found in the blood that had been incubated for 24 h at 37°C, whereas a significant increase was observed after 6 h of incubation in blood from COVID-19-recovered donors. Beneficially, the 6-h incubation process did not downregulate anti-COVID-19 immunoglobulin G concentrations. Unfortunately, increases in matrix metalloproteinase 9, tumor necrosis factor alpha, and interleukin-1 were detected in the product after incubation; however, these increases could be blocked by adding citric acid, with no effect on the concentration of the target therapeutic molecules. Our data allow for safer and more effective future treatments. CONCLUSIONS An autologous blood-derived product containing anti-inflammatory and anti-catabolic molecules, which we term Cytorich, has a promising therapeutic role in the treatment of a virus-induced cytokine storm, including that associated with COVID-19.

Immune response to intravenous immunoglobulin in patients with Kawasaki disease and MIS-C.

BACKGROUNDMultisystem inflammatory syndrome in children (MIS-C) is a rare but potentially severe illness that follows exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Kawasaki disease (KD) shares several clinical features with MIS-C, which prompted the use of intravenous immunoglobulin (IVIG), a mainstay therapy for KD. Both diseases share a robust activation of the innate immune system, including the IL-1 signaling pathway, and IL-1 blockade has been used for the treatment of both MIS-C and KD. The mechanism of action of IVIG in these 2 diseases and the cellular source of IL-1ß have not been defined.METHODSThe effects of IVIG on peripheral blood leukocyte populations from patients with MIS-C and KD were examined using flow cytometry and mass cytometry (CyTOF) and live-cell imaging.RESULTSCirculating neutrophils were highly activated in patients with KD and MIS-C and were a major source of IL-1ß. Following IVIG treatment, activated IL-1ß+ neutrophils were reduced in the circulation. In vitro, IVIG was a potent activator of neutrophil cell death via PI3K and NADPH oxidase, but independently of caspase activation.CONCLUSIONSActivated neutrophils expressing IL-1ß can be targeted by IVIG, supporting its use in both KD and MIS-C to ameliorate inflammation.FUNDINGPatient Centered Outcomes Research Institute; NIH; American Asthma Foundation; American Heart Association; Novo Nordisk Foundation; NIGMS; American Academy of Allergy, Asthma and Immunology Foundation.

Effect of Canakinumab vs Placebo on Survival Without Invasive Mechanical Ventilation in Patients Hospitalized With Severe COVID-19: A Randomized Clinical Trial.

Importance: Effective treatments for patients with severe COVID-19 are needed. Objective: To evaluate the efficacy of canakinumab, an anti-interleukin-1ß antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants: This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention: Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40-<60 kg, 600 mg for 60-80 kg, and 750 mg for >80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures: The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19-related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results: Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, -3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54; P = .29). COVID-19-related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of -2.3% (95% CI, -6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance: Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration: ClinicalTrials.gov Identifier: NCT04362813.

Efficacy of canakinumab in mild or severe COVID-19 pneumonia.

BACKGROUND: Clinicians all around the world are currently experiencing a pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Several therapeutic strategies have been used until now but, to date, there is no specific therapy to treat SARS-CoV-2 infection. In this study, we used canakinumab, a human monoclonal antibody targeting interleukin-1 beta to improve respiratory function and laboratory parameters compared with standard therapy (hydroxycloroquine plus lopinavir/ritonavir). METHODS: We enrolled 34 patients with mild or severe non intensive care unit (ICU) coronavirus disease 2019 (COVID-19): 17 patients treated with standard therapy and 17 patients treated with a subcutaneous single dose of canakinumab 300 mg. We collected data about oxygen supports and laboratory parameters such as inflammation indices and hemogasanalysis. We compared the data collected before the administration of canakinumab (T0), 3 days after T0 (T1) and 7 days after T0 (T2) with the same data from patients taking the standard therapy. RESULTS: We observed a reduction in inflammation indices and a significant and rapid increase in P/F ratio in canakinumab group, with improvement of 60.3% after the administration. We reported a significant reduction in oxygen flow in patients treated with canakinumab (-28.6% at T1 vs. T0 and -40.0% at T2 vs. T1). Conversely, the standard group increased the supply of high oxygen at T1 versus T0 (+66.7%), but reduced oxygen flows at T2 versus T1 (-40.0%). CONCLUSION: In hospitalized adult patients with mild or severe non ICU COVID-19, canakinumab could be a valid therapeutic option. Canakinumab therapy causes rapid and long-lasting improvement in oxygenation levels in the absence of any severe adverse events.

Case Report: Canakinumab for the Treatment of a Patient With COVID-19 Acute Respiratory Distress Syndrome.

Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1ß is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56 dim . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.

Blockage of interleukin-1ß with canakinumab in patients with Covid-19.

There is the urgent need to study the effects of immunomodulating agents as therapy for Covid-19. An observational, cohort, prospective study with 30 days of observation was carried out to assess clinical outcomes in 88 patients hospitalized for Covid-19 pneumonia and treated with canakinumab (300 mg sc). Median time from diagnosis of Covid-19 by viral swab to administration of canakinumab was 7.5 days (range 0-30, IQR 4-11). Median PaO2/FiO2 increased from 160 (range 53-409, IQR 122-210) at baseline to 237 (range 72-533, IQR 158-331) at day 7 after treatment with canakinumab (p < 0.0001). Improvement of oxygen support category was observed in 61.4% of cases. Median duration of hospitalization following administration of canakinumab was 6 days (range 0-30, IQR 4-11). At 7 days, 58% of patients had been discharged and 12 (13.6%) had died. Significant differences between baseline and 7 days were observed for absolute lymphocyte counts (mean 0.60 vs 1.11 × 109/L, respectively, p < 0.0001) and C-reactive protein (mean 31.5 vs 5.8 mg/L, respectively, p < 0.0001).Overall survival at 1 month was 79.5% (95% CI 68.7-90.3). Oxygen-support requirements improved and overall mortality was 13.6%. Confirmation of the efficacy of canakinumab for Covid-19 warrants further study in randomized controlled trials.

Identification of a novel orally bioavailable NLRP3 inflammasome inhibitor.

NLRP3 inflammasome mediated release of interleukin-1ß (IL-1ß) has been implicated in various diseases, including COVID-19. In this study, rationally designed alkenyl sulfonylurea derivatives were identified as novel, potent and orally bioavailable NLRP3 inhibitors. Compound 7 was found to be potent (IL-1ß IC50 = 35 nM; IL-18 IC50 = 33 nM) and selective NLRP3 inflammasome inhibitor with excellent pharmacokinetic profile having oral bioavailability of 99% in mice.

Targeting the NLRP3 Inflammasome in Severe COVID-19.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a member of the genus Betacoronavirus within the family Coronaviridae. It is an enveloped single-stranded positive-sense RNA virus. Since December of 2019, a global expansion of the infection has occurred with widespread dissemination of coronavirus disease 2019 (COVID-19). COVID-19 often manifests as only mild cold-like symptomatology, but severe disease with complications occurs in 15% of cases. Respiratory failure occurs in severe disease that can be accompanied by a systemic inflammatory reaction characterized by inflammatory cytokine release. In severe cases, fatality is caused by the rapid development of severe lung injury characteristic of acute respiratory distress syndrome (ARDS). Although ARDS is a complication of SARS-CoV-2 infection, it is not viral replication or infection that causes tissue injury; rather, it is the result of dysregulated hyperinflammation in response to viral infection. This pathology is characterized by intense, rapid stimulation of the innate immune response that triggers activation of the Nod-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome pathway and release of its products including the proinflammatory cytokines IL-6 and IL-1ß. Here we review the literature that describes the pathogenesis of severe COVID-19 and NLRP3 activation and describe an important role in targeting this pathway for the treatment of severe COVID-19.

Novel therapeutic targets for SARS-CoV-2-induced acute lung injury: Targeting a potential IL-1ß/neutrophil extracellular traps feedback loop.

Most COVID-19 infected individuals present with mild flu-like symptoms; however, 5-10% of cases suffer from life-threatening pneumonia and respiratory failure. The pathogenesis of SARS-CoV-2 and its pathology of associated acute lung injury (ALI), acute respiratory distress syndrome (ARDS), sepsis, coagulopathy and multiorgan failure is not known. SARS-CoV-2 is an envelope virus with S (spike), M (membrane), N (nucleocapsid) and E (envelop) proteins. In a closely related coronavirus (SARS-CoV), the transmembrane E protein exerts an important role in membrane-ionic transport through viroporins, deletion of which reduced levels of IL-1ß and a remarkably reduced lung edema compared to wild type. IL-1ß is generated by macrophages upon activation of intracellular NLRP3 (NOD-like, leucine rich repeat domains, and pyrin domain-containing protein 3), part of the functional NLRP3 inflammasome complex that detects pathogenic microorganisms and stressors, while neutrophils are enhanced by increasing levels of IL-1ß. Expiring neutrophils undergo "NETosis", producing thread-like extracellular structures termed neutrophil extracellular traps (NETs), which protect against mild infections and microbes. However, uncontrolled NET production can cause acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), coagulopathy, multiple organ failure, and autoimmune disease. Herein, we present arguments underlying our hypothesis that IL-1ß and NETs, mediated via NLRP3 inflammasomes, form a feed-forward loop leading to the excessive alveolar and endothelial damage observed in severe cases of COVID-19. Considering such assertions, we propose potential drug candidates that could be used to alleviate such pathologies. Considering that recent efforts to ascertain effective treatments of COVID-19 in severe patients has been less than successful, investigating novel avenues of treating this virus are essential.