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

Abstract

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.

Figure

Suggested management framework for cytokine storm syndromes A cross-specialty management approach for cytokine storm syndromes is proposed. This includes switching off the cytokine storm, treating the underlying cause, and treating and preventing complications. To target the cytokine storm, immunosuppressants (often in combination) are used in an induction-maintenance treatment paradigm. Notably, higher doses of anakinra are often required in paediatric practice. Second-line therapies are added if inflammation is not controlled. A personalised approach for tapering (withdrawal) of therapy is recommended when inflammation is controlled. The figure illustrates the positioning of anakinra in a management framework for HLH and is not intended as a definitive treatment guideline for cytokine storm syndromes, and the various underlying drivers. AOSD=adult-onset Still's disease. CAR=chimeric antigen receptor. CRS=cytokine release syndrome. DMARDs=disease modifying anti-rheumatic drugs. EBV=Epstein-Barr virus. ECMO=extracorporeal membrane oxygenation. HHV8=human herpesvirus 8. HLH=haemophagocytic lymphohistiocytosis. HSCT=haematopoietic stem cell transplant. IV=intravenous. PO=oral administration. SC=subcutaneous. sJIA=systemic juvenile idiopathic arthritis. SLE=systemic lupus erythematosus.