To “Lump” or to “Split” in Macrophage Activation Syndrome and Hemophagocytic Lymphohistiocytosis

Nikiforow, Sarah; Berliner, Nancy

doi:10.1002/art.41106

Cited by 10 publications

(9 citation statements)

References 32 publications

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“…Although there has been progress in understanding the mechanistic basis for the initation and propogation of cytokine storm syndromes, there remains a considerable unmet need for effective therapies, better understanding of the aetiopathogenesis, and identification of biomarkers to predict treatment response and prognosis, to enable a stratified and ultimately precision medicine treatment approach. 76,77 Prospective research and comprehensive data capture, with deep phenotyping and biobanking, is crucial. The heterogenity and perceived rarity of cytokine storm syndromes, coupled with a reticence to conduct clini cal trials in critically ill patients, has hampered the develop ment of novel therapies.…”

Section: Discussionmentioning

confidence: 99%

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome

Mehta

Cron

Hartwell

et al. 2020

The Lancet Rheumatology

240

223

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The 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]). Interleukin (IL)-1 is pivotal in hyperinflammation. Anakinra, a recombinant humanised IL-1 receptor antagonist, is licenced at a dose of 100 mg once daily by subcutaneous injection for rheumatoid arthritis, systemic juvenile idiopathic arthritis, adult-onset Still's disease, and cryopyrin-associated periodic syndromes. In cytokine storm syndromes, the subcutaneous route is often problematic, as absorption can be unreliable in patients with critical illness, and multiple injections are needed to achieve the high doses required. As a result, intravenous anakinra is used in clinical practice for sHLH/MAS, despite this being an off-licence indication and route of administration. Among 46 patients admitted to our three international, tertiary centres for sHLH/MAS and treated with anakinra over 12 months, the intravenous route of delivery was used in 18 (39%) patients. In this Viewpoint, we describe current challenges in the management of cytokine storm syndromes and review the pharmacokinetic and safety profile of intravenous anakinra. There is accumulating evidence to support the rationale for, and safety of, intravenous anakinra as a first-line treatment in patients with sHLH/MAS. Intravenous anakinra has important clinical relevance when high doses of drug are required or if patients have subcutaneous oedema, severe thrombocytopenia, or neurological involvement. Cross-speciality management and collaboration, with the generation of international, multi-centre registries and biobanks, are needed to better understand the aetiopathogenesis and improve the poor prognosis of cytokine storm syndromes.

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Section: Discussionmentioning

confidence: 99%

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome

Mehta

Cron

Hartwell

et al. 2020

The Lancet Rheumatology

240

223

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“…Earlier treatment with anakinra, in the first 5 days of hospitalization, was associated with a statistically significant reduction in mortality. Although promising, there is some hesitation about broad application of IL‐1 blockade in cases of secondary HLH not due to underlying autoimmune disease (36) because secondary HLH remains a very heterogenous disease. As further divisions in clinical, serologic, and genetic profiles of patients with secondary HLH are established, targeted therapy algorithms for different phenotypes may be established.…”

Section: Discussionmentioning

confidence: 99%

“…Current data do not support a carte blanche approach to hyperinflammatory syndromes using anakinra. (36). Interestingly, however, a reanalysis of data from a phase 3 randomized controlled trial of IL‐1 blockade (anakinra) in sepsis showed significant survival benefit in patients with hyperinflammation, without increased adverse events.…”

Section: Discussionmentioning

confidence: 99%

Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome

Monteagudo

Boothby

Gertner

2020

ACR Open Rheumatology

167

149

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Objective The objective of this study was to report the benefit of a therapeutic approach consisting of intravenous (IV) continuous anakinra (recombinant human interleukin‐1 receptor antagonist) infusions in treating severely ill adult patients with secondary hemophagocytic lymphohistiocytosis or macrophage activation syndrome (MAS). Methods A retrospective chart review of five patients treated at Regions Hospital from 2016 to 2019 was conducted. Demographic, clinical, and laboratory characteristics and outcomes were recorded. Results Continuous IV anakinra infusions up to 2400 mg/d resulted in rapid serologic, then clinical response in 4 of 5 severely ill patients who were refractory to all other therapies, including subcutaneous anakinra. Subsequently, 3 of 5 patients have been maintained on anakinra or canakinumab, with no recurrence of MAS. Conclusion Continuous infusion of IV anakinra may result in rapid serologic and subsequent clinical improvement in adult patients with MAS. This method for treating cytokine storm should be considered in the current COVID‐19 pandemic in the subgroup of patients with severe disease who have a cytokine storm presentation.

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“…ytokine storm syndromes (CSS) such as secondary hemophagocytic lymphohistiocytosis (HLH) (sHLH) are life-threatening disorders associated with bacterial and viral infections and have recently been considered a cause for mortality in persons infected with SARS-CoV-2 (1)(2)(3)(4). Also known as macrophage activation syndrome (5,6), sHLH is associated with hyperactivated macrophages that adopt a hemophagocytic phenotype and thus aberrantly engulf other healthy hematopoietic-lineage cells such as RBCs, leukocytes, and platelets, often leading to consumptive cytopenias (i.e., anemia, leukopenia, and thrombocytopenia) (7)(8)(9). The underlying mechanism driving macrophages to become hemophagocytic under inflammatory conditions, however, has yet to be clearly determined (10).…”

mentioning

confidence: 99%

Inflammation Unrestrained by SIRPα Induces Secondary Hemophagocytic Lymphohistiocytosis Independent of IFN-γ

Kidder

Bian

Shi

et al. 2020

The Journal of Immunology

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A hallmark of secondary hemophagocytic lymphohistiocytosis (sHLH), a severe form of cytokine storm syndrome, is the emergence of overactivated macrophages that engulf healthy host blood cells (i.e., hemophagocytosis) and contribute to the dysregulated inflammation-driven pathology. In this study, we show that depleting SIRPα (SIRPα−/−) in mice during TLR9-driven inflammation exacerbates and accelerates the onset of fulminant sHLH, in which systemic hemophagocytosis, hypercytokinemia, consumptive cytopenias, hyperferritinemia, and other hemophagocytic lymphohistiocytosis hallmarks were apparent. In contrast, mice expressing SIRPα, including those deficient of the SIRPα ligand CD47 (CD47−/−), do not phenocopy SIRPα deficiency and fail to fully develop sHLH, albeit TLR9-inflamed wild-type and CD47−/− mice exhibited hemophagocytosis, anemia, and splenomegaly. Although IFN-γ is largely considered a driver of hemophagocytic lymphohistiocytosis pathology, IFN-γ neutralization did not preclude the precipitation of sHLH in TLR9-inflamed SIRPα−/− mice, whereas macrophage depletion attenuated sHLH in SIRPα−/− mice. Mechanistic studies confirmed that SIRPα not only restrains macrophages from acquiring a hemophagocytic phenotype but also tempers their proinflammatory cytokine and ferritin secretion by negatively regulating Erk1/2 and p38 activation downstream of TLR9 signaling. In addition to TLR9 agonists, TLR2, TLR3, or TLR4 agonists, as well as TNF-α, IL-6, or IL-17A, but not IFN-γ, similarly induced sHLH in SIRPα−/− mice but not SIRPα+ mice. Collectively, our study suggests that SIRPα plays a previously unappreciated role in sHLH/cytokine storm syndrome pathogenesis by preventing macrophages from becoming both hemophagocytic and hyperactivated under proinflammation.

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To “Lump” or to “Split” in Macrophage Activation Syndrome and Hemophagocytic Lymphohistiocytosis

Cited by 10 publications

References 32 publications

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome

Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome

Continuous Intravenous Anakinra Infusion to Calm the Cytokine Storm in Macrophage Activation Syndrome

Inflammation Unrestrained by SIRPα Induces Secondary Hemophagocytic Lymphohistiocytosis Independent of IFN-γ

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