Safety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series.
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ABSTRACT:
SUBMITTER: Clark KEN
PROVIDER: S-EPMC7454860 | biostudies-literature | 2020
REPOSITORIES: biostudies-literature
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Safety of intravenous anakinra in COVID-19 with evidence of hyperinflammation, a case series.
Clark Kristina E N KEN Collas Oliver O Lachmann Helen H Singh Animesh A Buckley Jim J Bhagani Sanjay S
Rheumatology advances in practice 20200804 2
<h4>Objectives</h4>Anakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the s.c. form, previous anecdotal reports have emphasized its utility when given i.v. Our aim is to report our experience on the beneficial effects of anakinra i.v. in patients with SARS-CoV-2 and evidence of hyperinflammation.<h4>Methods</h4>We report four patients with severe COVID-19 infection requiring intensive care admissi ...[more]
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Project description:BackgroundNetherton 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.ObjectivesThe objective was to report our experiences of treatment with IVIG, ixekizumab, dupi-lumab, and anakinra in patients with NS.MethodsA 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.ResultsIVIG, 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.ConclusionsThis 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.
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Project description:Despite the progressing knowledge in COVID-19 management, remdesivir is the only agent that got approval to inhibit viral replication. However, there are limited data about effective immunomodulatory agents to prevent cytokine release in COVID-19. Cytokine release syndrome in COVID-19 resembles secondary hemophagocytic lymphohistiocytosis, in which interleukin-1 (IL-1) plays a key role. Anakinra is the first recombinant IL-1 receptor antagonist studied for off-label use in COVID-19 treatment. This study reviews the current clinical evidence on the role of interleukin-1 in COVID-19-related cytokine storm, therapeutic effects, significant clinical concerns, and pros and cons of anakinra administration in the management of COVID-19 patients. In this review, four items are shown to be important for achieving the optimal therapeutic effects of anakinra in COVID-19 patients. These items include duration of treatment ≥ 10 days, doses ≥ 100 mg, intravenous administration, and early initiation of therapy. Also, anakinra might be more beneficial in the early stages of the disease when higher levels of cytokines are yet to be observed, which could prevent progression to severe illness and mechanical ventilation. Further studies are required to address the SARS-CoV-2 induced cytokine release syndrome and the role of anakinra in identifying ideal treatment approaches for COVID-19 patients based on their clinical status.
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Project description:BackgroundGout is the most common type of inflammatory arthritis. Nonsteroidal anti-inflammatory drugs, corticosteroids, and colchicine are the first-line agents, although they are contraindicated in many patients. Blockade of IL-1 with anakinra can be an alternative.ObjectiveTo present a case series of 10 difficult-to-treat gout patients treated with anakinra and perform a scoping review of the effectiveness and safety of anakinra in gout patients.MethodsA total of 1,519 citations were screened. The reviewers ran a two-stage screening process by title/abstract and full-text reading. Thirty-eight articles finally met the selection criteria and were included for data extraction and synthesis. Experience in difficult-to treat and complex clinical scenarios, such as active infection, hemodialysis, and transplantation, were specifically described.ResultsThe study sample comprised 551 patients, from whom 648 flares were finally analyzed. The mean age was 57.9 years, and 82.9% were men. The clinical presentation was polyarticular in 47.5% and tophaceous in 66.9%. Sixty-five patients with an active infection, 41 transplanted patients and 14 in haemodyalisis treated with anakinra are described. More than half of the patients had >1 associated comorbidity. Anakinra was effective both for flares (94%) and for long-term treatment (91%) and well tolerated. In the case of flares, 34 (6.7%) adverse effects were registered. Adverse events were more prevalent in long-term treatment.ConclusionAnakinra was effective and safe for management of gout flares in difficult-to-treat patients. It has been used in multiple complex scenarios, such as active infections, dialysis, transplantation, chronic kidney disease, and polyarticular gout. Anakinra has also proven effective as long-term treatment, although there are more concerns about its safety.
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Project description:BackgroundAnakinra is a recombinant interleukin-1 (IL-1) receptor antagonist used in systemic juvenile idiopathic arthritis (sJIA), refractory Kawasaki disease (KD) and cryopyrin-associated autoinflammatory syndrome (CAPS). Anakinra associated hepatotoxicity, while rare, has been described in several cases in daily practice. In this case series the authors describe three pediatric patients with this side effect in the setting of severe macrophage activation syndrome (MAS) in KD and sJIA.Case presentationThe first patient was a 12-year-old boy who presented with fever, maculo-papular exanthema and polyarthralgia. Tonsillitis, distal limb induration and tender cervical lymph nodes were observed. Erythrocyte-sedimentation rate (ESR), C-reactive protein (CRP), ferritin (11,975 ng/mL), D-dimers (5,98 mg/L FEU) and soluble CD25 (3645 pg/mL) levels were elevated. Exclusion of sepsis / toxic shock syndrome warranted introduction of IV methylprednisolone and immunoglobulin (IG IV), with partial response. A MAS secondary to KD was assumed, and anakinra 2 mg/kg/day was introduced. Twenty days later he developed new-onset nausea and severe cyto-cholestasis, normalizing after 2 months of drug discontinuation. Posterior onset of polyarthritis and evanescent lead to a final diagnosis of sJIA. The second patient was a 2-year-old boy with a 10-day history of fevers, generalized rash, hepatosplenomegaly and strawberry tongue. Leucocytosis with neutrophilia and elevated CRP were observed. Initial treatment with IVIG in the setting of incomplete KD was ineffective. Mild anaemia, leukopenia and very high serum ferritin (maximum 26,128 ng/mL) ensued. Presumptive sJIA associated MAS was treated with IV methylprednisolone and anakinra 2 mg/kg/day, with prompt response. Four weeks later transaminitis was detected, and temporary anakinra suspension led to normalisation of laboratorial values. The third case related to a 4-year-old boy presenting with fever, maculopapular rash and cervical lymphadenopathy. CRP and ESR were elevated, and KD was diagnosed. IVIG and methylprednisolone were initiated with clinical worsening, warranting for anakinra introduction at 2 mg/kg/day. After three weeks, liver enzymes progressively elevated, resolving on 2 weeks of anakinra discontinuation.ConclusionsTo the best of our knowledge, this is the first case series describing anakinra associated hepatotoxicity in pediatric patients with rheumatic diseases other than sJIA, bringing additional insight to therapeutic monitoring in patients undergoing this treatment.
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Project description:BackgroundMortality of patients with coronavirus disease 2019 (COVID-19), acute respiratory distress syndrome (ARDS), and systemic inflammation is high. In areas of pandemic outbreak, the number of patients can exceed maximum capacity of intensive care units (ICUs), and, thus, these individuals often receive non-invasive ventilation outside of the ICU. Effective treatments for this population are needed urgently. Anakinra is a recombinant interleukin-1 receptor antagonist that might be beneficial in this patient population.MethodsWe conducted a retrospective cohort study at the San Raffaele Hospital in Milan, Italy. We included consecutive patients (aged ≥18 years) with COVID-19, moderate-to-severe ARDS, and hyperinflammation (defined as serum C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both) who were managed with non-invasive ventilation outside of the ICU and who received standard treatment of 200 mg hydroxychloroquine twice a day orally and 400 mg lopinavir with 100 mg ritonavir twice a day orally. We compared survival, mechanical ventilation-free survival, changes in C-reactive protein, respiratory function, and clinical status in a cohort of patients who received additional treatment with anakinra (either 5 mg/kg twice a day intravenously [high dose] or 100 mg twice a day subcutaneously [low dose]) with a retrospective cohort of patients who did not receive anakinra (referred to as the standard treatment group). All outcomes were assessed at 21 days. This study is part of the COVID-19 Biobank study, which is registered with ClinicalTrials.gov, NCT04318366.FindingsBetween March 17 and March 27, 2020, 29 patients received high-dose intravenous anakinra, non-invasive ventilation, and standard treatment. Between March 10 and March 17, 2020, 16 patients received non-invasive ventilation and standard treatment only and comprised the comparison group for this study. A further seven patients received low-dose subcutaneous anakinra in addition to non-invasive ventilation and standard treatment; however, anakinra treatment was interrupted after 7 days because of a paucity of effects on serum C-reactive protein and clinical status. At 21 days, treatment with high-dose anakinra was associated with reductions in serum C-reactive protein and progressive improvements in respiratory function in 21 (72%) of 29 patients; five (17%) patients were on mechanical ventilation and three (10%) died. In the standard treatment group, eight (50%) of 16 patients showed respiratory improvement at 21 days; one (6%) patient was on mechanical ventilation and seven (44%) died. At 21 days, survival was 90% in the high-dose anakinra group and 56% in the standard treatment group (p=0·009). Mechanical ventilation-free survival was 72% in the anakinra group versus 50% in the standard treatment group (p=0·15). Bacteraemia occurred in four (14%) of 29 patients receiving high-dose anakinra and two (13%) of 16 patients receiving standard treatment. Discontinuation of anakinra was not followed by inflammatory relapses.InterpretationIn this retrospective cohort study of patients with COVID-19 and ARDS managed with non-invasive ventilation outside of the ICU, treatment with high-dose anakinra was safe and associated with clinical improvement in 72% of patients. Confirmation of efficacy will require controlled trials.FundingNone.
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