Anakinra In Patients Research Articles

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

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

Abstract 4134949: Effect of anakinra in patients with ST-elevation myocardial infarction according to the renal function

Introduction: Interleukin(IL)-1 blockade with anakinra dampens the inflammatory response and prevents heart failure (HF) events in patients with ST-elevation myocardial infarction (STEMI). The efficacy of anakinra according to the baseline renal function in STEMI has not been addressed. Hypothesis: The efficacy of anakinra is independent of the baseline renal function. Aim: To determine the effect of anakinra according to the baseline renal function in patients with STEMI. Methods: We pooled patients with STEMI from 3 double-blind randomized clinical trials. Patients with estimated glomerular filtration rate (eGFR) <15 mL/min/1.73m2 were excluded. We divided the cohort based on the median baseline eGFR using the modified 2021 CKD-EPI equation (≥ or < 86 mL/min/1.73m2). We analyzed the area-under-the-curve for C-reactive protein (AUC-CRP) at 14 days, and the incidence of the composite outcome of all-cause death or new-onset HF at 1 year using the Log-rank test. We also evaluated the creatinine changes at 48-72 hours after percutaneous coronary intervention (PCI). Results: We analyzed 139 patients, 110 (79%) males, 52 (37%) Black or African-American, with a median age of 56 [49–63] years. The AUC-CRP at 14 days was significantly higher in patients receiving placebo vs. anakinra both in those with eGFR <86 mL/min/1.73m2 (250.5[131.4-512.0] vs. 66.4[42.3-126.5] mg●day/L, p<0.001) and those with eGFR ≥86 mL/min/1.73m2 (214.2[113.6-303.4] vs. 86.4[35.9-194.3] mg●day/L, p<0.01). Anakinra significantly reduced the composite outcome of all-cause death or new-onset HF in patients with baseline eGFR <86 mL/min/1.73m2 (4/41 [9.8%] vs. 9/27 [33.3%], Log-rank p=0.024) as well as in patients with baseline eGFR ≥86 mL/min/1.73m2 (3/43 [6.9%] vs. 7/28 [25%], Log-rank p=0.038)(p=0.97 for interaction)(Figure). No differences in creatinine changes 48-72 hours after PCI were observed (0.01 [-0.10 to 0.15] mg/dL in anakinra vs. 0.01[-0.08 to 0.14] mg/dL in placebo; p=0.80). Conclusion: In a cohort of patients with STEMI and mainly preserved or mildly reduced renal function, IL-1 blockade with anakinra blunts the acute inflammatory response and prevents all-cause death or new-onset HF at 1 year independent of baseline renal function.

Intravenous high-dose anakinra drops venous thrombosis and acute coronary syndrome in severe and critical COVID-19 patients: a propensity score matched study

In our study, we aimed to evaluate the effect of high-dose intravenous anakinra treatment on the development of thrombotic events in severe and critical COVID-19 patients. This retrospective observational study was conducted at a tertiary referral center in Aksaray, Turkey. The study population consisted of two groups as follows; the patients receiving high-dose intravenous anakinra (anakinra group) added to background therapy and the patients treated with standard of care (SoC) as a historical control group. Age, gender, mcHIS scores, and comorbidities such as diabetes mellitus, hypertension, and coronary heart disease of the patients were determined as the variables to be matched. We included 114 patients in SoC and 139 patients in the Anakinra group in the study. Development of any thromboembolic event (5% vs 12.3%, p = 0.038; OR 4.3) and PTE (2.9% vs 9.6%, p = 0.023; OR 5.1) were lower in the Anakinra group than SoC. No patient experienced cerebrovascular accident and/or clinically evident deep venous thrombosis both in two arms. After 1:1 PS matching, 88 patients in SoC and 88 patients in the Anakinra group were matched and included in the analysis. In survival analysis, the development of any thromboembolic event, pulmonary thromboembolism, and acute coronary syndrome (ACS) were higher in SoC compared to Anakinra. Survival rate was also lower in patients with SoC arm than Anakinra in patients who had any thromboembolic event as well as ACS. In our study, the development of thrombosis was associated with hyperinflammation in patients with severe and critical COVID-19. Intravenous high-dose anakinra treatment decreases both venous and arterial events in patients with severe and critical COVID-19.

Real-life use of High-Dose Anakinra in Patients with COVID-19 Treated with Remdesivir

Aim: Aim of this study was to evaluate the effect of anakinra (ANK) addition to remdesivir (RDV) on all-cause 28-day mortality in patients hospitalized with COVID-19. Patients & methods: ANK was administered intravenously at a dose of 5 mg/kg every 12 h in patients with severe respiratory failure and pronounced inflammatory status. 58 patients were treated with RDV + ANK, 219 patients with RDV. Results: The estimate of mortality at 28 days was 17.2% in the RDV + ANK group and 21.4% in the RDV group. Median time to death was 14 days in the RDV + ANK group and 19 in the RDV group. Conclusion: Despite severe respiratory failure and pronounced inflammatory status, patients who received RDV + ANK had similar mortality compared with patients who received RDV.

A Phase II Trial of Prophylactic Anakinra to Prevent Neurotoxicity in Patients Receiving Anti-CD19 CAR T-Cell Therapy for Relapsed or Refractory Lymphoma: Final Results from Cohort 2

Background: Whilst tocilizumab is effective in the management of chimeric antigen receptor T-cell (CAR-T) associated cytokine release syndrome (CRS), there are no targeted therapies for immune effector cell-associated neurotoxicity syndrome (ICANS). Rates of severe (≥ grade 3) ICANS remain high with axicabtagene (axi-cel) and brexucabtagene (brexu-cel) at > 30%. Preclinical models have shown that anakinra, an IL-1 receptor antagonist, reduced CAR-mediated immune toxicities without affecting efficacy. Based on these data, we conducted a phase 2 trial of prophylactic anakinra in patients receiving commercial anti-CD19 CAR-T for r/r B-cell lymphoma (NCT04148430). The study had sequential enrollment in 2 independent cohorts. We recently reported results from cohort 1 in which patients received subcutaneous (SC) anakinra from day 2 until at least day 10 post-CAR infusion and showed that prophylactic anakinra reduced the rate of severe ICANS to 9.7% (Park, Nat Med, 2023). Herein, we report results from cohort 2 of the study where we utilized anakinra as a complete prophylactic strategy. Methods: Adult patients with a diagnosis of r/r large B-cell lymphoma (LBCL), high-grade B-cell lymphoma (HGBCL), follicular lymphoma (FL) or mantle cell lymphoma (MCL) receiving commercial anti-CD19 CAR-T were enrolled. Patients received SC anakinra 100 mg daily from day 0 for at least 7 d. The frequency of anakinra could be increased up to 100 mg every 6 h, and the duration beyond 7 d for persistent or progressive CRS and ICANS. Tocilizumab and steroid use were allowed for the management of persistent or progressive CRS and ICANS. A baseline and day 5 lumbar puncture were performed for CSF analysis. The primary endpoint was the rate of severe ICANS, graded per the ASTCT criteria. Secondary endpoints included rates of severe CRS, all grade CRS and ICANS, overall response rate (ORR), survival outcomes, and serum and CSF biomarker levels. Results: 37 patients were screened, 31 enrolled, and 30 treated (LBCL=13, HGBCL=6, FL=6, MCL=5). 1 enrolled patient did not proceed with treatment due to COVID-19 infection. The median age of the cohort was 65yrs (range: 24 - 81yrs) and patients received axi-cel (19 pts; 63%), brexu-cel (5 pts; 17%), lisocabtagene (4 pts; 13%) and tisagenlecleucel (2 pts; 7%). Patients received a median 3 prior lines of therapy (range: 1 - 7); 22 (73%) were refractory to their immediate prior therapy; 17 (57%) received bridging therapy and 3 (10%) had active CNS disease at CAR infusion. Pretherapy tumor burden as measured by the median sum of the products of diameters was 1638mm 2 (range: 0 - 21,570mm 2). All patients started anakinra on day 0. Anakinra administration was increased in 24 patients (80%) during CRS; it was increased to a maximum of 100mg q12h in 1 patient and 100mg q6h in 23 patients. The median duration of anakinra administration was 9.5 d (IQR 8 - 13). No patient stopped anakinra due to an adverse event. A total of 3 patients (10%) experienced severe ICANS, all of which were grade 3 only. 9 patients (30%) experienced any grade ICANS (Fig 1A). The median time to ICANS onset was 6.5 d (range: 4 - 10 d). All-grade CRS occurred in 24 patients (80%). Most CRS events were grade 1 or 2 except for 3 grade 3 events (10%) (Fig 1A). Of the 24 patients who received CD28-containing CARs (axi-cel and brexu-cel), all-grade and severe ICANS rate was 29% and 12.5%, respectively (Fig 1B). In the 3 patients with active CNS disease, there was 1 grade 2, and 1 grade 3 ICANS event. 23 patients (77%) received tocilizumab and 18 (60%) received steroids for CRS and/or ICANS. The median follow-up was 5.8mo. The best ORR by day 100 was 83% (95% CI 65-94%) with a CR rate of 73% (95% CI 54-89%). The estimated progression-free and overall survival at 6mo was 72% (95% CI 50-93%) and 81% (95% CI 66-86%), respectively. Conclusion: Early use of prophylactic anakinra was safe, feasible and reduced the rate of severe ICANS without affecting efficacy in adult patients receiving anti-CD19 CAR-T for r/r B-cell lymphoma. Rates of severe ICANS were very similar between cohorts 1 and 2; at 9.7% and 10% in the entire cohorts, respectively, and 11% and 12.5% in patients treated with CD28-containing CARs, respectively. The risk-adapted dosing of anakinra likely contributed to the low rates of severe ICANS in this study. Detailed comparison of results from cohort 1, analysis of the anakinra dose-relationship on efficacy, and serum and CSF biomarkers will be presented at the meeting.

Impact of C-reactive protein levels and role of anakinra in patients with ST-elevation myocardial infarction

BackgroundInterleukin-1 blockade with anakinra reduces C-reactive protein (CRP) levels and prevents heart failure (HF) events after ST-segment myocardial infarction (STEMI). The effectiveness of anakinra according to the degree of systemic inflammation in STEMI has not been addressed. MethodsWe analyzed 139 patients from three Virginia Commonwealth University Anakinra Response Trial randomized clinical trials to assess whether CRP levels predicted HF hospitalization or death in patients with STEMI, and if CRP levels influenced the effects of treatment with anakinra. ResultsCRP cut-off levels for prediction of the composite of death or HF hospitalization for CRP at admission, 3 and 14 days were, respectively 6.45 mg/L (100% of sensitivity and 66.1% specificity), 26 mg/L (100% of sensitivity and 78% specificity) and 9.56 mg/L (100% of sensitivity and 80% specificity). More patients with elevated CRP levels died or had a HF hospitalization (5/47 [11%] vs 0/82 [0%], p = 0.004 for CRP at admission; 5/32 [15.6%] vs 0/92 [0%], p < 0.001 for day 3 and 5/26 [19%] vs 0/89 [0%], p < 0.001 for day 14). A greater number of patients treated with anakinra had low CRP levels at 3 and 14 days compared to placebo (Odds Ratio 0.11 [95% IC 0.04–0.28], p < 0.0001 and OR 0.35 [95% CI 0.14–0.86], p = 0.02, respectively). Anakinra significantly prevented death or HF hospitalization in patients with high inflammatory burden (p = 0.04 for admission, p = 0.24 for day 3, and p = 0.05 for day 14). ConclusionPatients with elevated CRP had higher incidence of HF hospitalization or death. Anakinra reduced the number of patients with elevated CRP levels and prevented death or HF hospitalization in patients with elevated CRP levels.

Single center experience of using Anakinra prophylactically at Day 0 to reduce CD19 CART toxicities.

e19503 Background: Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 is an effective line of the treatment for relapsed/refractory CD19 B cell cancers, however navigating Cytokine Release Syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity (ICANS) still remains a challenging task. Corticosteroids and Tocilizumab are currently the mainstay treatment for toxicities but Anakinra, an IL-1 receptor antagonist has also been successfully used to treat patients receiving CART who develop CRS/ICANS. In this study we set out to describe the utility of prophylactic use of Anakinra in patients receiving CART. Methods: We conducted a single center retrospective analysis of patients who received Anakinra for CRS and ICANS prophylaxis per institutional protocol. Patient data including demographics, cancer history, CRS &amp; ICANS American Society for Transplantation and Cellular Therapy Grades, toxicity treatment history and outcomes during their hospitalization were extracted from our medical records. Institutional review board approval was obtained for this review. Results: A total of 19 patients {Diffuse Large B Cell Lymphoma = 10, Follicular = 2,Mantle cell = 2 and Acute Lymphoblastic Leukemia (ALL) = 5} were enrolled in our cohort. The median age of the patients at the time of T cell infusion was 63 years (range, 26-75). CD19 CAR products included Axicabtagene ciloleucel (8 pts; 42.1%), Brexucabtagene autoleucel (6 pts; 31.5%) and Tisagenlecleucel (5 pts; 26.3%). CRS of all grades was observed in 13 patients (68.4%) with severe CRS (grade 3-4) observed in 1 patient (5.2%) (grade 4;12 days). Median CRS duration was 3 days (range, 1-18). Median max CRS grade was observed for 2 days (range, 1-12). Median time to CRS was 5 days (range; 1-8). ICANS of all grades was observed in 12 patients (63.1%), with severe ICANS (grade3-4) in 5 patients (26.3%) {1 patient with grade 4 for 12 days; 4 patients with grade 3 for a median of 2 days (range;1-4)}. Median time to ICANS was 6 days (range, 1-11). Tocilizumab and corticosteroids were used in 9 patients (47.3%) and 11 patients (57.8%), respectively. Median starting day of Tocilizumab and steroid was on day 4(range, 1-6) and day4 (range, 1-21) respectively. Median dose of Tocilizumab was 2 (range, 1-3). Median dose of total Dexamethasone and Methylprednisolone use was 125mg (range, 10-276) and 3.92 g (range, 3-7.4) respectively for a median of 6 cumulative days (range, 1-22). Three patients (15.7%) required ICU transfer with a median stay of 5 days (range, 4-16). 1 patient died of Neurotoxicity on Day 27(Mantle cell) and 2 ALL patients died due to progression after discharge on Day61 and 256. Conclusions: We observed that prophylactically starting Anakinra at Day 0 appeared to improve CRS and ICANS toxicities in patients receiving CART. Further prospective investigations with larger population pools would be required to better understand its role in CAR T toxicity suppression.

OP33 Results of a randomised controlled trial to evaluate Interleukin 1 blockade with anakinra in patients with acute severe ulcerative colitis (IASO)

Abstract Background Acute severe ulcerative colitis (ASUC) is a severe manifestation of ulcerative colitis (UC) that requires hospitalisation. Despite significant advances in therapeutic options for UC and in the medical management of steroid-refractory ASUC, the initial treatment paradigm for ASUC has not changed since the 1950s and is based on the use of intravenous (IV) corticosteroids. Approximately 50% of patients do not respond and require further medical or surgical therapy. Interleukin 1 (IL-1) has been identified as a key mediator of colonic inflammation and plays a pivotal role in local activation of neutrophils and a number of downstream inflammatory mediators. The IL-1 axis has been repeatedly identified as a therapeutic target in UC. The Interleukin 1 (IL-1) blockade in Acute Severe Colitis (IASO) trial investigated whether antagonism of IL-1 signalling could improve outcomes in patients with ASUC. Methods We performed a phase II, multicentre randomised (1:1), placebo-controlled, double-blinded trial of IL-1 blockade with short-duration anakinra, given alongside IV corticosteroids to adult patients hospitalised with suspected or confirmed ASUC. The primary outcome was the incidence of medical (ie infliximab/ciclosporin) or surgical rescue therapy (colectomy) within 10 days following the commencement of IV corticosteroid therapy. Secondary outcomes included disease activity, time to clinical response, time to rescue therapy, colectomy incidence by day 98 post IV corticosteroids and safety. The trial aimed to recruit 214 patients across 20 sites in the UK. Prespecified analyses were performed for feasibility and for futility. Results At the time of the prespecified interim futility analysis, 113 patients had been randomised, 55 to placebo, and 58 to anakinra (figure 1). The incidence of medical or surgical rescue therapy by day 10 was higher in the anakinra group than in the placebo group (43% vs 26%). The incidence of colectomy by day 98 was higher in the anakinra group (11% vs 4%). These differences were not statistically significant. Logistic models containing a mixture of baseline stratification factors did not suggest that the need for rescue therapy would be reduced with anakinra treatment and on the advice of the independent data monitoring committee, the trial was terminated for futility. There was a higher incidence of adverse event in the placebo group, the most common was worsening of ulcerative colitis. Conclusion This trial shows that adding anakinra to current standard care with IV corticosteroids in patients with ASUC did not reduce the need for rescue therapy or colectomy. This suggests that IL-1 blockade is not a therapeutic target in ASUC. There were no safety concerns with anakinra treatment.

Anakinra for patients with COVID-19: an updated systematic review and meta-analysis

Severe COVID-19 patients can develop a maladaptive immune response with hyper-production of cytokines and chemokines which lead to alveolar damage, endothelial activation, coagulopathy and thromboembolic events. We performed a meta-analysis which included any study performed on COVID-19 patients with respiratory hypoxemic failure who received anakinra versus any comparator. Primary endpoint was mortality. Secondary endpoints were intubation rate, superinfection and thromboembolic events. Subgroups analyses included patients in general ward, with hyperinflammation and/or baseline ratio of arterial oxygen partial pressure (PaO2) to fractional inspired oxygen (FiO2) &gt;200. Twenty-four studies were included. Mortality in anakinra patients was significantly lower than mortality of controls (19% vs. 28%; p &lt; 0.0001). Anakinra patients had significantly lower risk of intubation (16% vs. 33%; p &lt; 0.001). Mortality reduction was confirmed in general ward settings, in patients with hyperinflammation and with PaO2/FiO2 &gt;200, but not when selecting randomized studies only. A trend towards increased mortality in more severe patients was observed.

Protective effect of anakinra on audiovestibular function in a murine model of endolymphatic hydrops.

Ménière's disease (MD), a common disease in the inner ear, is characterized by an increase in endolymph in the cochlear duct and vestibular labyrinth. The pathophysiology of the condition appears to be the immune response. Studies have shown that basal levels of the IL-1β increased in some MD patients. Here, we used a murine model of endolymphatic hydrops (EH) to study the effect of anakinra on auditory and vestibular function. Mice were intraperitoneal injected with anakinra or saline before LPS by postauricular injection. Weight and disease severity were measured, histologic changes in auditory were assessed, and inflammation state was evaluated. We found that anakinra therapy reduced LPS-induced EH, alleviated LPS-induced hearing loss and vestibular dysfunction, and inhibited the expression of the inflammatory cytokines and macrophage infiltration in the cochlea of mice. We further demonstrated that anakinra ameliorated the disorganization and degeneration of myelin sheath, and reduced the neuron damage in cochlea of EH mice. Consequently, anakinra contributes to a promising therapeutic approach to MD, by restricting EH, alleviating auditory and vestibular function, inhibiting inflammation of the inner ear and protecting the cochlear nerve. Further investigations are needed to assess the potential therapeutic benefits of anakinra in patients with MD.

Treatment Experiences with Intravenous Immunoglobulins, Ixekizumab, Dupilumab, and Anakinra in Netherton Syndrome: A Case Series

Background: Netherton syndrome (NS) is a rare potential life-threatening disorder that causes severe defects to the skin barrier. No effective treatment options are available for patients with NS and current therapy is mostly supportive. The effects of intravenous immunoglobulins (IVIGs), ixekizumab, and dupilumab have scarcely been reported. Additionally, the role of anakinra in patients with NS has never been investigated. Objectives: The objective was to report our experiences of treatment with IVIG, ixekizumab, dupi­lumab, and anakinra in patients with NS. Methods: A retrospective case series, including 5 patients with NS, was performed in a tertiary referral hospital between 2016 and 2021. Patients were treated with IVIG, ixekizumab, dupilumab, and/or anakinra. Long-term experiences with treatment regimens and adverse events requiring medical attention were reported. Results: IVIG, ixekizumab, dupilumab, and anakinra were well tolerated with no severe adverse events. The 2 patients that received IVIG showed clinical response for 6 months and 2.5 years. Ixekizumab was effective in 1 of our patients for 3.5 years, while in another patient ixekizumab lost its effect after 1.5 years. Dupilumab treatment did not result in persistent improvement of NS-related skin symptoms in 1 patient. Anakinra showed physician-assessed clinical response during the first months of treatment in 4 patients with NS. During anakinra treatment, no changes in blood levels of IL-1β, IL-6, and TNF-α levels were measured at routine blood examinations. Conclusions: This case series suggests that the use of IVIG, ixekizumab, dupilumab, and anakinra in NS is safe and moderately effective on the short term. On the long term, a decline in effect was observed. Our experiences may help clinicians and researchers to provide adequate care and develop treatment for these severely affected patients. More international research, especially on the long term, is needed to determine if and which patients benefit most from the emerging therapies for NS.

Efficacy and safety of anakinra in adults presenting deteriorating respiratory symptoms from COVID-19: A randomized controlled trial.

We aimed to investigate whether anakinra, an interleukin-1receptor inhibitor, could improve outcome in moderate COVID-19 patients. In this controlled, open-label trial, we enrolled adults with COVID-19 requiring oxygen. We randomly assigned patients to receive intravenous anakinra plus optimized standard of care (oSOC) vs. oSOC alone. The primary outcome was treatment success at day 14 defined as patient alive and not requiring mechanical ventilation or extracorporeal membrane oxygenation. Between 27th April and 6th October 2020, we enrolled 71 patients (240 patients planned to been enrolled): 37 were assigned to the anakinra group and 34 to oSOC group. The study ended prematurely by recommendation of the data and safety monitoring board due to safety concerns. On day 14, the proportion of treatment success was significantly lower in the anakinra group 70% (n = 26) vs. 91% (n = 31) in the oSOC group: risk difference-21 percentage points (95% CI, -39 to -2), odds ratio 0.23 (95% CI, 0.06 to 0.91), p = 0.027. After a 28-day follow-up, 9 patients in the anakinra group and 3 in the oSOC group had died. Overall survival at day 28 was 75% (95% CI, 62% to 91%) in the anakinra group versus 91% (95% CI, 82% to 100%) (p = 0.06) in the oSOC group. Serious adverse events occurred in 19 (51%) patients in the anakinra group and 18 (53%) in the oSOC group (p = 0·89). This trial did not show efficacy of anakinra in patients with COVID-19. Furthermore, contrary to our hypothesis, we found that anakinra was inferior to oSOC in patients with moderate COVID-19 pneumonia.

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Anticoagulation as secondary prevention of massive lung thromboses in hospitalized patients with COVID-19

Timely Recognition and Early Multi-Step Antinflammatory Therapy May Prevent ICU Admission of Patients With MIS-C: Proposal for a Severity Score.

In this observational study, we report the clinical, therapeutics and outcome features of 23 patients with multisystem inflammatory syndrome (MIS-C) who have been treated in Gaslini Children Hospital (Genoa, Italy) with a multistep antinflammatory treatment protocol, based on disease severity at admission. Patients were initially assigned to four severity classes on admission and treated accordingly. The therapeutic options ranged from IV immunoglobulin alone to a combination of IVIG plus pulses of methylprednisolone plus anakinra for patients with marked cardiac function impairment or signs of macrophage activation syndrome, with rapid treatment escalation in case of inadequate therapeutic response. With the application of this therapeutic strategy, no patient required admission to Intensive Care Unit (ICU) or invasive mechanical ventilation, and no inotropic drugs administration was required. Early aggressive treatment of MIS-C, with therapeutic interventions modulated based on the severity of clinical manifestations may help to prevent the progression of the inflammatory process and to avoid the need of admission to the ICU. A timely intervention with anti-IL-1 blockers can play a pivotal role in very severe patients that are at risk to have an incomplete response to immunoglobulins and steroids.

A randomized controlled clinical trial on efficacy and safety of anakinra in patients with severe COVID-19.

IntroductionHyperinflammatory state has a role in the pathogenesis of COVID‐19. Anakinra could reduce inflammation and help to combat the condition. In this study, we aimed to assess the safety and efficacy of anakinra (PerkinRA®) in severe COVID‐19.MethodThe study was an open‐label, randomized, controlled trial conducted in Imam Hossein Medical Center from May to July 2020. Patients with a confirmed diagnosis of COVID‐19 were included in this study. We administered anakinra 100 mg daily intravenously. All patients received COVID‐19 pharmacotherapy based on the represented national guideline. The need for invasive mechanical ventilation is considered the primary outcome.ResultsThirty patients were included in this study, and 15 of them received Anakinra. Nineteen patients were male (63.3%), and 11 were female (36.7%). The mean age of patients was 55.77 ± 15.89 years. In the intervention group, the need for invasive mechanical ventilation was significantly reduced compared to the control group (20.0% vs. 66.7%, p = .010). Also, these patients had a significantly lower length of hospital stay (p = .043). No significant higher rate of infection was recorded.ConclusionAnakinra as an immunomodulatory agent has been associated with the reduced need for mechanical ventilation in patients admitted to intensive care units because of severe COVID‐19. The medication reduced the hospital length of stay. Furthermore, no increased risk of infection was observed. Further randomized placebo‐controlled trials with a larger sample size are needed to confirm these findings.

OP0164 LONG-TERM SAFETY OF ANAKINRA IN PATIENTS WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS FROM THE PHARMACHILD REGISTRY

OP0164 LONG-TERM SAFETY OF ANAKINRA IN PATIENTS WITH SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS FROM THE PHARMACHILD REGISTRY

A single center, double blind, randomized, placebo controlled trial of anakinra in adult patients with features of Cytokine Storm Syndrome in COVID-19

Abstract Methods: (ClinicalTrials.gov, NCT04362111) Adult inpatients were recruited with PCR confirmed SARS-CoV-2 infection, radiographic confirmation of COVID-19 pneumonia, new or increasing oxygen requirement, ferritin ≥700 ng/mL, and any 3 of the following: D-dimer ≥500 ng/mL, platelet count &amp;lt;130,000/mm3, white blood cell count &amp;lt;3500/mm3 or lymphocyte count &amp;lt;1000/mm3, AST or ALT &amp;gt;2X the upper limit of normal (ULN), LDH &amp;gt;2X the ULN, C-reactive protein &amp;gt;100 mg/L. Eligible patients were randomly assigned (1:1) to standard of care (SoC) plus anakinra (100 mg subcutaneous every 6 hours for 10 days) or SoC plus placebo. Primary outcome was survival and discharge from the hospital without need for intubation/mechanical ventilation at day 10. Analyses were done on a modified intention-to-treat basis. Results: Between August 2020 and January 2021, 32 patients (235 screened) were recruited: 15 assigned to anakinra group and 17 to placebo group. 2 patients in the placebo group withdrew in the initial 48 hours and were excluded from analysis. Median age was 63 years (IQR 56 – 70.3), 20 (66.7%) were men, and 20 (66.7%) Caucasian. At day 10, 1 (6.7%) patient in the anakinra group had died and 2 (13.3%) in the placebo group had died (p=0.54). At hospital discharge, 4 (26.7%) patients in the anakinra group and 4 (26.7%) in the SoC group had died. Confirmed infections occurred in 4 (anakinra) and 2 (placebo), respectively (p=0.36). Conclusion: Anakinra added to SoC with dexamethasone did not significantly impact outcomes in study patients with clinical lab features of early cytokine storm syndrome and mild-to-moderate COVID-19 pneumonia. Additional studies are needed to assess efficacy and optimal dosing duration of anakinra in patients with more severe COVID-19.

Interleukin-1 and interleukin-6 inhibition in patients with COVID-19 and hyperinflammation - Authors' reply.

Interleukin-1 and interleukin-6 inhibition in patients with COVID-19 and hyperinflammation - Authors' reply.

Anakinra for patients with COVID-19: a meta-analysis of non-randomized cohort studies.

IntroductionSevere COVID-19 cases have a detrimental hyper-inflammatory host response and different cytokine-blocking biologic agents were explored to improve outcomes. Anakinra blocks the activity of both IL-1α and IL‑1β and is approved for different autoinflammatory disorders, but it is used off-label for conditions characterized by an excess of cytokine production. Several studies on anakinra in COVID-19 patients reported positive effects. We performed a meta-analysis of all published evidence on the use of anakinra in COVID19 to investigate its effect on survival and need for mechanical ventilation. MethodsWe searched for any study performed on adult patients with acute hypoxemic failure related to 2019-nCoV infection, receiving anakinra versus any comparator. Primary endpoint was mortality at the longest available follow-up. Adverse effects, need for mechanical ventilation and discharge at home with no limitations were also analysed. ResultsFour observational studies involving 184 patients were included. Overall mortality of patients treated with anakinra was significantly lower than mortality in the control group (95% CI 0.14-0.48, p<0.0001). Moreover, patients treated with anakinra had a significantly lower risk of need for mechanical ventilation than controls (95% CI 0.250.74, p=0.002). No difference in adverse events and discharge at home with no limitations was observed. The Trial Sequential Analysis z-cumulative line reached the monitoring boundary for benefit and the required sample size. ConclusionsAdministration of anakinra in COVID-19 patients was safe and might be associated with reductions in both mortality and need for mechanical ventilation. Randomized clinical trials are warranted to confirm these findings.

PIH4 An Economic Comparison of Treatment Strategies with Anakinra in Systemic Juvenile Idiopathic Arthritis (SJIA)

Systemic juvenile idiopathic arthritis (sJIA) is a rare, complex autoinflammatory disease with substantial morbidity. Since the turn of the century, biologic agents (such as anakinra) have been successfully used to treat patients internationally, but their usage in some regions is limited to those that have failed to achieve clinically-inactive disease with corticosteroids and conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). Use of anakinra in the first line leads to better clinical outcomes, but longer-term costs for this strategy have not been established. This study aims to compare the economic implications of alternative treatment strategies with anakinra for patients with sJIA. Data for patients treated with first-line anakinra were identified from a single-centre, prospective study conducted in the Netherlands and compared to a combination of published clinical trials and economic evaluation information, as well as clinical expert input to facilitate a comparison to later-line anakinra (i.e. following corticosteroids + csDMARDs). Costs were estimated for product acquisition and medical resource use (MRU), including planned outpatient visits and unplanned hospital admissions. Total costs (in Euros) over a 5-year horizon were compared. Total 5-year product acquisition costs for the first-line anakinra strategy were €24,021, versus €20,471 for later-line anakinra. The corresponding MRU costs were €19,197 (first-line) versus €25,425 (later-line). Overall 5-year costs (product acquisition and MRU) were lower for the first-line strategy (€43,218 versus €45,896). A comparison of economic outcomes in the management of sJIA with anakinra is challenging, yet the findings of this study support the expectation that earlier use may lead to cost savings through reduced medical expenditure. Further research is required to fully establish the differences in costs associated with alternative treatment strategies in sJIA, including costs related to the avoidance of additional downstream costs, such as steroid-related complications, osteoarthritis, and macrophage activation syndrome.