Giulio Cavalli, Italy
Vita-Salute San Raffaele University Immunology, Rheumatology, Allergy and Rare DiseasesPresenter of 2 Presentations
EFFECTIVENESS OF INTERLEUKIN-1 AND INTERLEUKIN-6 INHIBITION COMPARED TO STANDARD MANAGEMENT IN PATIENTS WITH COVID-19 AND HYPERINFLAMMATION: A COHORT STUDY
Abstract
Background and Aims
Patients with severe COVID-19 develop a life-threatening hyper-inflammatory response to the virus. Treatment with interleukin (IL)-1 or IL-6 inhibitors has been used to treat this patient population, but the comparative effectiveness of these different strategies remains undetermined.
Methods
Retrospective cohort study of in-hospital patients with COVID-19, respiratory insufficiency, and hyperinflammation, defined as serum C-reactive protein (CRP) ≥100 mg/L and/or ferritin ≥900 ng/ml. The primary endpoint was survival; secondary endpoint was a composite of death or mechanical ventilation. Multivariable Cox regression analysis and interaction tests were conducted.
Results
Of 392 included patients, 275 did not receive IL inhibitors, 62 received the IL-1 inhibitor anakinra, and 55 received an IL-6 inhibitor (tocilizumab, n=29; sarilumab, n=26). At multivariable analysis, patients treated with IL-1 inhibition, but not with IL-6 inhibition, had a significantly reduced mortality risk compared to patients who did not receive IL inhibitors (Hazard Ratios 0.45; 95% CI 0.20-0.99, p=0.04, and 0.90; 95% CI 0.41-1.97; p=0.8, respectively). At interaction tests IL-6 inhibition was effective in a subgroup of patients with markedly high CRP levels, whereas both IL-1 and IL-6 inhibition were more effective in patients with low LDH levels.
Conclusions
IL-1 inhibition, but not IL-6 inhibition, was associated with a significant reduction of mortality in hospitalized patients with COVID-19 and hyperinflammation. IL-6 inhibition was effective in a subgroup of patients with markedly high CRP levels, whereas both IL-1 and IL-6 inhibition were more effective in patients with low LDH levels.
INTERLEUKIN 1Α IN THE PATHOGENESIS AND TARGETED TREATMENT OF AUTOIMMUNE AND INFLAMMATORY DISEASES
Abstract
Background and Aims
The interleukin (IL)-1 family member IL-1α is a ubiquitous and pivotal pro-inflammatory cytokine. The IL‑1a precursor is constitutively present in nearly all cell types in health, but is released upon necrotic cell death as a bioactive mediator. IL‑1a is also expressed by infiltrating myeloid cells within injured tissues. The cytokine binds the IL-1 receptor 1 (IL-1R1), as does IL‑1β, and induces the same pro-inflammatory effects. Being a bioactive precursor released upon tissue damage and necrotic cell death, IL-1α is central to the pathogenesis of numerous conditions characterized by organ or tissue inflammation. This review illustrates the clinical relevance of IL-1α to the pathogenesis of inflammatory diseases, as well as the rationale for the targeted inhibition of this cytokine for treatment of these conditions.
Methods
Comprehensive review of the literature and expert opinion.
Results
IL-1α is involved in the pathogenesis of conditions affecting the lung and respiratory tract, dermatoses and inflammatory skin disorders, systemic sclerosis, myocarditis, pericarditis, myocardial infarction, coronary artery disease, inflammatory thrombosis, as well as complex multifactorial conditions such as COVID-19, vasculitis and Kawasaki disease, Behcet’s syndrome, Sjogren Syndrome, as well as cancer. Three biologics are available to reduce the activities of IL-1α; the monoclonal antibody bermekimab, the IL‑1 soluble receptor rilonacept, and the IL‑1 receptor antagonist anakinra.
Conclusions
Advances in mechanistic understanding and therapeutic management make it incumbent on physicians to be aware of IL-1α and of the opportunity for therapeutic inhibition of this cytokine across in a broad spectrum of diseases.