Intravenous anakinra for cytokine storm syndromes
Authors: Yvan Jamilloux, Mathieu Gerfaud-Valentin, Pascal Sève
Journal: The Lancet Rheumatology (2020)

In their Viewpoint on cytokine storm syndromes, Puja Mehta and colleagues1Mehta P Cron R Hartwell J Manson JJ Tattersall RS Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome.Lancet Rheumatol. 2020; 2: e358-e367Summary Full Text Full Text PDF PubMed Scopus (177) Google Scholar stated that "there is a critical need and growing call for unified nomenclature (such as cytokine storm syndromes)". Although we agree that a multidisciplinary effort is needed to analyse and classify these conditions, we have concerns about unifying them all under a single umbrella. Indeed, cytokine storm syndromes currently encompass several different conditions with extremely varied causes, pathophysiological processes, or prominant cytokines. Although they manifest with similar symptoms, they might have only one truly common feature: hypercytokinaemia. For instance, haemophagocytic lymphohistiocytosis might be the consequence of deficient cytotoxic cells (primary and some virally-induced haemophagocytic lymphohistiocytosis),2Carter SJ Tattersall RS Ramanan AV Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment.Rheumatology (Oxford). 2019; 58: 5-17Crossref PubMed Scopus (153) Google Scholar hyperactivation of the inflammasome pathway (NLRC4-associated macrophage activation syndrome),3Canna SW de Jesus AA Gouni S et al.An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome.Nat Genet. 2014; 46: 1140-1146Crossref PubMed Scopus (521) Google Scholar or a yet-to-be-defined combination of these factors (eg, Still's disease spectrum). All of these conditions are characterised by elevated plasma concentrations of IL-1 family cytokines (IL-1β and IL-18) and tissue haemophagocytosis. Alternatively, cytokine release syndrome secondary to chimeric antigen receptor T-cell therapy has been linked to high IFN-γ release, whereas the involvement of the IL-1 family cytokines seemed less prominent.4Dholaria BR Bachmeier C Locke F Mechanisms and management of chimeric antigen receptor T-cell therapy related toxicities.BioDrugs Clin Immunother Biopharm Gene Ther. 2019; 33: 45-60Google Scholar Lastly, it is noteworthy that cytokine storm has attracted great interest, as a result of its description as a major determinant of COVID-19 outcomes. Yet, despite there being no definitive understanding of its immunopathology, a hallmark of COVID-19-associated cytokine storms seems to be prominent IL-6 elevation, with only 25% of patients showing evidence for IL-1-driven macrophage activation or haemophagocytosis.5Giamarellos-Bourboulis EJ Netea MG Rovina N et al.Complex immune dysregulation in COVID-19 patients with severe respiratory failure.Cell Host Microbe. 2020; 27: 992-1000Summary Full Text Full Text PDF PubMed Scopus (1462) Google Scholar In the remaining 75% of patients, the disease has been compared with complex immune dysregulation seen in patients with sepsis (ie, prominent role for IL-6, low HLA-DR expression, and lymphopenia). These considerations are important because the clinicians' armamentarium is now large enough to offer the best targeted therapies in these different contexts (ie, inhibitors of IL-1, IFN-γ, or IL-6). Defining criteria for choosing one treatment over the other, or instead of a less-targeted therapy (eg, corticosteroids or Janus kinase inhibitors) will certainly be one of the challenges of clinical trials in the near future. Overall, we suggest that if an international, multidisciplinary effort is mounted to unify cytokine storm syndromes within one spectrum, this nomenclature will have to be subdivided on the basis of the cause, the supposed pathophysiology, and the pivotal cytokines involved. In daily practice, the availability of rapid immune monitoring tests (eg, cytokine multiplex assays) would therefore be of utmost interest. We declare no competing interests. Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndromeThe term cytokine storm syndromes describes conditions characterised by a life-threatening, fulminant hypercytokinaemia with high mortality. Cytokine storm syndromes can be genetic or a secondary complication of autoimmune or autoinflammatory disorders, infections, and haematological malignancies. These syndromes represent a key area of interface between rheumatology and general medicine. Rheumatologists often lead in management, in view of their experience using intensive immunosuppressive regimens and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome [sHLH/MAS]). Full-Text PDF Intravenous anakinra for cytokine storm syndromes – Authors' replyWe appreciate the interest in our Viewpoint1 on the use of intravenous anakinra in cytokine storm syndromes. Yvan Jamilloux and colleagues contribute to continuing discussions regarding the terminology of hyperinflammatory disorders;2 we suggest a unifying umbrella term of cytokine storm syndromes. We feel that it is the concept of hyperinflammation that is crucial; the conditions characterised by hyperinflammation overlap, and we endorse shared clinical and scientific learning. Full-Text PDF Intravenous anakinra for cytokine storm syndromesWe read with interest the Viewpoint by Puja Mehta and colleagues1 on the use of intravenous anakinra in secondary haemophagocytic lymphohistiocytosis or macrophage activation syndrome (sHLH/MAS), in which they suggest a framework for the management of cytokine storm syndromes. Full-Text PDF