Patients diagnosed with COVID-19 and treated with anakinra: a real-world study in the USA

Summary Anakinra, a recombinant, non-glycosylated human interleukin (IL)-1 receptor antagonist, has been used in real-world clinical practice to manage hyperinflammation in COVID-19. This retrospective, observational study analyses USA hospital inpatient data of patients diagnosed with moderate/severe COVID-19 and treated with anakinra between 1 April and 31 August 2020. Of the 119 patients included in the analysis, 63.9% were male, 48.6% were of black ethnicity and the mean (standard deviation [SD]) age was 64.7 (12.5) years. Mean (SD) time from hospital admission to anakinra initiation was 7.3 (6.1) days. Following anakinra initiation, 73.1% of patients received antibiotics, 55.5% received antithrombotics, and 91.0% received corticosteroids. Overall, 64.7% of patients required intensive care unit (ICU) admittance, and 28.6% received mechanical ventilation following admission. Patients who did not require ICU admittance or who were discharged alive experienced a significantly shorter time between hospital admission and receiving anakinra treatment compared with those admitted to the ICU (5 vs 8 days; p = 0.002) or those who died in hospital (6 vs 9 days; p = 0.01). Patients with myocardial infarction or renal conditions were six times (p < 0.01) and three times (p = 0.01), respectively, more likely to die in hospital than be discharged alive. A longer time from hospital admission until anakinra treatment was associated with significantly higher mortality (p = 0.01). Findings from this real-world study suggest that a shorter time from hospital admission to anakinra treatment is associated with significantly lower ICU admissions and mortality among patients with moderate/severe COVID-19.

Anakinra Treatment for Refractory Cerebral Autoinflammatory Responses

BackgroundRefractory cerebral autoinflammatory-autoimmune diseases are often associated with dysregulated innate immunity, which are targeted by anakinra, an interleukin-1 receptor antagonist. Here, we analyzed the therapeutic effect of anakinra in refractory cerebral autoinflammatory response (CAIR).MethodsWe analyzed single institutional patients treated with anakinra for CAIR from January 2017 to May 2021. Anakinra was sympathetically used for patients with intractable CAIR at 100 mg/day subcutaneously. A good response was defined as any improvement of the modified Rankin Scale, Clinical Assessment Scale in Autoimmune Encephalitis, or Expanded Disability Status Scale.ResultsA total of twelve patients with various diagnostic etiologies were treated with anakinra (mean age=45.1; male=7). Four patients showed good responses, and eight patients had unclear responses. Among the good responders, 75% of the patients had pathologically demonstrated CAIR. The two very good responders had primary progressive multiple sclerosis and cerebral granulomatosis with polyangiitis in each, and microglia/macrophage infiltration was prominent in their brain biopsies. No patient had a serious adverse effect.ConclusionsAnakinra may be a therapeutic option for refractory cerebral autoinflammatory diseases with microglia and macrophage infiltrations.

AB0785 TREATING IDIOPATHIC RECURRENT PERICARDITIS WITH INTERLEUKIN-1 INHIBITORS - A SINGLE CENTER EXPERIENCE

Background:Pericarditis is a common disease with significant morbidity (1). Idiopathic pericarditis, where an underlying cause cannot be identified, makes up for 80% of cases in the Western World (1). Up to 30% of these patients experience recurrence despite optimal treatment (2). Idiopathic recurrent pericarditis (IRP) is thought to represent an auto-inflammatory process rather than a reinfection (3). 2015 European Society of Cardiology (ESC) guidelines have outlined treatment of acute episodes and first recurrence with nonsteroidal anti-inflammatory drugs (NSAID), acetyl salicylic acid (ASS) and Colchicine as first line and Glucocorticoids (GC) as second line treatment (3). However GC treatment increases the risk of relapse, dependence and toxicity (2). Interleukin-1 (IL-1) inhibitors have been proposed as possible treatments in IRP (3, 4).Objectives:The aim of this case study is to outline our first experiences treating IRP with the IL-1 inhibitor anakinra in our Rheumatologic clinic.Methods:All patients referred to our department in 2018/2019 with pericarditis were physically seen in our outpatient clinic. All patients were screened for malignancy, infection or rheumatologic disease as possible cause by clinical measures. Following ESC guideline, patients who suffered either the third recurrence under optimal treatment or significant side effects or dependency from GC were considered for anakinra treatment. Daily injection of anakinra (100mg) were given continuously over at least three months with gradual tapering over at least three months afterwards. Physical emergency department contacts, days hospitalized, colchicine- and GC use, the year prior to Anakinra treatment was recorded retrospectively. During follow up the same data was prospectively recorded.Results:Over the course of two years 20 patients were referred to our clinic. All fulfilled ESC diagnostic criteria for pericarditis at index episode. In none of the patients could a rheumatologic, infectious or malignant cause be identified. 16 patients could be treated according to 2015 ESC guidelines with first or second line agents. Four patients were aligned to anakinra-treatment. Prior to referral, duration of symptoms was 5 - 120 months (mean 61 months). Further relevant patient- characteristics are outlined in Table 1.After initiation of anakinra patients were afterwards regularly followed up in scheduled visits every 3 months.Table 1.Characteristics of the four patients aligned to anakinra prior to anakinra-initiation.PatientNumber of recurrencesNumber emergency hospital contacts related to IRP the year prior to nakinraDays hospitalized related to IRP the year prior to anakinraGC dose prior to anakinraotherI2237.5 mgsteroidglaucomaII72410 mgIII472220 mgIV731220 mgFollow-up after start of anakinra was 6-15 months (mean 11.5 months). No patient was admitted to hospital or emergency department in that period. All four patients could taper and stop GC without recurrence. One patient experienced a mild relapse after discontinuing anakinra and was restarted on a low dose with complete remission. No patient had elevated CRP values at the end of follow-up and no patient experienced tamponade or clinical signs of constriction. No significant side effects were noted, no patient had to stop anakinra-treatment during follow up.Conclusion:Implementation of anakinra treatment in cases of complicated IRP was both secure and successful in our rheumatologic outpatient department. In our small sample we could confirm findings from bigger trials regarding effect- and side effect rates of anakinra treating IRP.References:[1]Klein A et al. Cardiol Rev. 2020 Epub ahead of print. PMID: 32956167.[2]Cremer P et al. J Am Coll Cardiol. 2016;68(21):2311-2328[3]Adler Y et alEuropean Heart Journal, 2015;36(42):2873–2885[4]Imazio M et al Eur J Prev Cardiol. 2020;27(9):956-964Disclosure of Interests:None declared

Early Anakinra Treatment for COVID-19 Guided by Urokinase Plasminogen Receptor

Background In a previous open-label trial, early anakinra treatment guided by elevated soluble urokinase plasminogen activator receptor (suPAR) prevented progression of COVID-19 pneumonia into respiratory failure. Methods In the SAVE-MORE multicenter trial, 594 hospitalized patients with moderate and severe COVID-19 pneumonia and plasma suPAR 6 ng/ml or more and receiving standard-of-care were 1:2 randomized to subcutaneous treatment with placebo or 100 mg anakinra once daily for 10 days. The primary endpoint was the overall clinical status of the 11-point World Health Organization ordinal Clinical Performance Scale (WHO-CPS) at day 28. The changes of the WHO-CPS and of the sequential organ failure assessment (SOFA) score were the main secondary endpoints. Results Anakinra-treated patients were distributed to lower strata of WHO-CPS by day 28 (adjusted odds ratio-OR 0.36; 95%CI 0.26-0.50; P<0.001); anakinra protected from severe disease or death (6 or more points of WHO-CPS) (OR: 0.46; P: 0.01). The median absolute decrease of WHO-CPS in the placebo and anakinra groups from baseline was 3 and 4 points respectively at day 28 (OR 0.40; P<0.0001); and 2 and 3 points at day 14 (OR 0.63; P: 0.003); the absolute decrease of SOFA score was 0 and 1 points (OR 0.63; P: 0.004). 28-day mortality decreased (Hazard ratio: 0.45; P: 0.045). Hospital stay was shorter. Conclusions Early start of anakinra treatment guided by suPAR provides 2.78 times better improvement of overall clinical status in moderate and severe COVID-19 pneumonia. (Sponsored by the Hellenic Institute for the Study of Sepsis ClinicalTrials.gov identifier, NCT04680949)

Effect of anakinra on mortality in COVID-19: a patient level meta-analysis

SummaryBackgroundAnakinra may represent an important therapy to improve the prognosis of COVID-19 patients. This meta-analysis using individual patient data was designed to assess the efficacy and safety of anakinra treatment in patients with COVID-19.MethodsBased on a pre-specified protocol (PROSPERO: CRD42020221491), a systematic literature search was performed in MEDLINE (PubMed), Cochrane, medRxiv.org, bioRxiv.org and clinicaltrials.gov databases for trials in COVID-19 comparing administration of anakinra with standard-of-care and/or placebo. Individual patient data from eligible trials were requested. The primary endpoint was the mortality rate and the secondary endpoint was safety.FindingsLiterature search yielded 209 articles, of which 178 articles fulfilled screening criteria and were full-text assessed. Aggregate data on 1185 patients from 9 studies were analyzed and individual patient data on 895 patients from 6 studies were collected. Most studies used historical controls. Mortality was significantly lower in anakinra-treated patients (38/342 [11·1%]) as compared with 137/553 (24·8%) observed in patients receiving standard-of-care and/or placebo on top of standard-of-care (137/553 [24·8%]); adjusted odds ratio (OR), 0·32; 95% CI, 0·20 to 0·51; p <0·001. The mortality benefit was similar across subgroups regardless of diabetes mellitus, ferritin concentrations, or baseline P/F ratio. The effect was more profound in patients exhibiting CRP levels >100 mg/L (OR 0·28,95%CI 0·27-1·47). Safety issues, such as increase of secondary infections, did not emerge.InterpretationAnakinra may be a safe anti-inflammatory treatment option in patients hospitalized with moderate-to-severe COVID-19 pneumonia to reduce mortality, especially in the presence of hyperinflammation signs such as CRP>100mg /L.FundingSobi.Research in contextEvidence before this studySince the emergence of the COVID-19 pandemic, numerous drugs have been tried in an effort to prevent major detrimental consequences, such as respiratory and multiorgan failure and death. Early during the pandemic, it was realized that drugs aiming to regulate the immune host reaction may play an important role in the treatment of COVID-19. Evidence from a small number of patients with moderate or severe COVID-19 treated with anakinra, and interleukin-1 receptor antagonist, has suggested therapeutic efficacy. We systematically searched all available literature and aimed to present cumulative evidence of anakinra treatment in COVID-19 and the related effect on mortality.Added value of this studyThis is the first patient-level analysis on the effect of anakinra treatment in COVID-19 patients, which, on the one hand, suggests a significant benefit in the reduction of mortality and on the other hand, reassures safety of the treatment. Most importantly, the current study identifies a subgroup of patients with CRP>100mg/L, that may benefit most from treatment with anakinra. Confirmation of these effects in larger randomized clinical trials (RCTs) is urgently needed.Implications of all the available evidenceAnakinra may be an effective and safe immunomodulatory treatment in moderate-to-severe cases of pneumonia due to COVID-19 to prevent unfavorable outcomes. Anakinra may be helpful to avoid adverse events, such as breakthrough infections observed often with dexamethasone use, and may be considered an alternative in specific subgroups of patients e.g. diabetics. Larger trials, summarized in the Table, are ongoing and their results are urgently needed to investigate anakinra’s best place in the treatment of COVID-19.

IL-1 Mediates Tissue Specific Inflammation and Severe Respiratory Failure In Covid-19: Clinical And Experimental Evidence

ABSTRACTBackgroundAcute respiratory distress syndrome (ARDS) in COVID-19 has been associated with dysregulated immune responses leading to catastrophic inflammation. The activation pathways remain to be fully elucidated. We investigated the ability of circulating to induce dysregulated immune responses.Materials & MethodsCalprotectin and high mobility group box 1 (HMGB1) were associated with ARDS in 60 COVID-19 patients. In a second cohort of 40 COVID-19 patients calprotectin at hospital admission was associated with serum levels of soluble urokinase plasminogen activator receptor (suPAR). A COVID-19 animal model was developed by intravenous injection of plasma from healthy volunteers or patients with COVID-19 ARDS into C57/BL6 mice once daily for 3 consecutive days. In separate experiments, mice were treated with a) the IL-1 receptor antagonist Anakinra or vehicle and b) Flo1-2a anti-murine anti-IL-1α monoclonal antibody or the specific anti-human IL-1α antibody XB2001, or isotype controls. Mice were sacrificed on day 4. Cytokines and myeloperoxidase (MPO) in tissues were measured.ResultsCalprotectin, but not HMGB1, was elevated ARDS. Higher suPAR readouts indicated higher calprotectin levels. CHallenge of mice with COVID-19 plasma led to inflammatory reactions in murine lung and intestines as evidenced by increased levels of TNFα, IL-6, IFNγ and MPO. Anakinra treatment brought these levels down. Similar decrease was found in mice treated with Flo1-2a but not with XB2001.ConclusionCirculating alarmins, specifically calprotectin, of critically ill COVID-19 patients induces tissue-specific inflammatory responses through an IL-1α mediated mechanism. This could be attenuated through inhibition of IL-1 receptor or specific inhibition of IL-1α.

Inhibition of IL-6 in the LCWE Mouse Model of Kawasaki Disease Inhibits Acute Phase Reactant Serum Amyloid A but Fails to Attenuate Vasculitis

ObjectiveKawasaki disease (KD) is the most common cause of acquired pediatric heart disease in the developed world. 10% of KD patients are resistant to front-line therapy, and no interventions exist to address secondary complications such as myocardial fibrosis. We sought to identify proteins and pathways associated with disease and anti-IL-1 treatment in a mouse model of KD.MethodsVasculitis was induced via Lactobacillus casei cell wall extract (LCWE) injection in 5-week-old male mice. Groups of mice were injected with LCWE alone, LCWE and IL-1 receptor antagonist anakinra, or saline for controls. Upper heart tissue was assessed by quantitative mass spectrometry analysis. Expression and activation of STAT3 was assessed by immunohistochemistry, immunofluorescence and Western blot, and IL-6 expression by RNA-seq and ELISA. A STAT3 small molecular inhibitor and anti-IL-6R antibody were used to evaluate the role of STAT3 and IL-6 in disease development.ResultsSTAT3 was highly expressed and phosphorylated in cardiac tissue of LCWE-injected mice, and reduced following anakinra treatment. Il6 and Stat3 gene expression was enhanced in abdominal aorta of LCWE-injected mice and reduced with Anakinra treatment. IL-6 serum levels were enhanced in LCWE-injected mice and normalized by anakinra. However, neither inhibition of STAT3 nor blockade of IL-6 altered disease development.ConclusionProteomic analysis of cardiac tissues demonstrates differential protein expression between KD-like, control and anakinra treated cardiac tissue. STAT3 and IL-6 were highly upregulated with LCWE and normalized by anakinra treatment. However, both STAT3 and IL-6 were dispensable for disease development indicating they may be bystanders of inflammation.

An open label trial of anakinra to prevent respiratory failure in COVID-19

Background It was studied if early suPAR-guided anakinra treatment can prevent severe respiratory failure (SRF) of COVID-19.Methods 130 patients with suPAR ≥6 ng/ml were assigned to subcutaneous anakinra 100mg once daily for 10 days. Primary outcome was SRF incidence by day 14 defined as any respiratory ratio below 150 mmHg necessitating mechanical or non-invasive ventilation. Main secondary outcomes were 30-day mortality and inflammatory mediators; 28-day WHO-CPS was explored. Propensity-matched standard-of care comparators were studied.Results 22.3% with anakinra treatment and 59.2% comparators (hazard ratio, 0.30; 95%CI, 0.20-0.46) progressed into SRF; 30-day mortality was 11.5% and 22.3% respectively (hazard ratio 0.49; 95% CI 0.25-0.97). Anakinra was associated with decrease in circulating interleukin (IL)-6, sCD163 and sIL2-R; IL-10/IL-6 ratio on day 7 was inversely associated with SOFA score; patients were allocated to less severe WHO-CPS strata.Conclusions Early suPAR-guided anakinra decreased SRF and restored the pro-/anti-inflammatory balance.Trial Registration: ClinicalTrials.gov, NCT04357366