key: cord-0896639-h4tnz9x4 authors: Mehta, Puja; Cron, Randy Q; Hartwell, James; Manson, Jessica J; Tattersall, Rachel S title: Silencing the cytokine storm: the use of intravenous anakinra in haemophagocytic lymphohistiocytosis or macrophage activation syndrome date: 2020-05-04 journal: Lancet Rheumatol DOI: 10.1016/s2665-9913(20)30096-5 sha: 02981925fc9330abbf43819272523df61ebdc7d6 doc_id: 896639 cord_uid: h4tnz9x4 Summary 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. Haemophagocytic lymphohistiocytosis (HLH) is a poten tially lifethreatening, underrecognised, hyper inflam ma tory syndrome characterised by immune dysregula tion leading to an uncontrolled, selfsustaining cytokine storm and multiorgan damage. Different terms are used to describe the clinical presentations of HLH; in this Viewpoint, we use cytokine storm syndromes. Cytokine storm syndromes represent a key interface between rheumatology and general internal medicine. Rheuma tologists often lead in management, in view of their experience with immunosuppressive therapies and managing cytokine storm syndromes in the context of rheumatic disorders or infection (known as secondary haemo phagocytic lymphohistiocytosis or macrophage activa tion syndrome [sHLH/MAS]). However, these patients might present to any medical specialty. Cytokine storm syndromes confer a high mortality rate, with an allcause mortality of approximately 40% in adults; 1 early recognition and initiation of treat ment is crucial to improve patient out comes. 2 Interleukin (IL)1 is pivotal to the aetio pathogenesis of these syn dromes. Offlicence anakinra, a recombinant human ised IL1 receptor antag onist, is recommended (if available) in treatment algo rithms for HLH, 2-5 but guid ance regarding the route of administration is absent. Subcutaneous dos ing could be difficult in patients with cytokine storm syndromes due to unreliable absorption in the context of critical illness and the fact that multiple daily injections are needed to achieve highdoses. Addi tionally, subcutan eous dosing can be painful and might be contraindicated in patients with thrombocytopenia and coagulopathy. Therefore, intra venous anakinra is already used in clinical practice for some cases of cytokine storm syndrome, including sHLH/MAS, although it is an offlicence indication and route of administration and little evidence exists to support its efficacy in this context. In this Viewpoint, we describe current challenges in manag ing patients with cytokine storm syndromes and our experience using intravenous anakinra in patients with sHLH/MAS in three international tertiary centres. We review the pharma cokinetic and safety profile of intrave nous anakinra, define potential indications for intra venous dos ing in patients with cytokine storm syndromes, and outline strate gies to improve outcomes in these rapidly fatal and complex conditions. Classification, epidemiology, and aetiopathogenesis of cytokine storm syndromes HLH was originally classified in a binary manner as either primary (genetic) or secondary (acquired) HLH, although this classification might not be appropriate given evidence from contemporary modelling suggesting a continuum of genetic risk. 6 In clinical practice, multiple diagnostic labels assigned to manifestations of cytokine storm syndromes, falling under the remit of various specialties with differing diagnostic and manage ment priorities and approaches, Viewpoint might have impeded progress. Hence, there is a critical need and growing call for unified nomenclature (such as cytokine storm synd romes) 4 and crossspecialty collabora tion to pool resources and expertise. Primary or familial HLH usually presents in infancy or early childhood and is considered a genetic disease of impaired perforindependent cytotoxic function. sHLH can present at any age and can be triggered by infec tion (commonly EpsteinBarr virus), haematological malignancy, autoimmune or autoinflammatory disorders, or iatrogenic causes, including haematopoietic stem cell transplantation. 3 Hyperinflammation has a prevalence of 3·7-4·3% in patients with sepsis (macrophage activation like syndrome). 7 Severe cytokine release syndrome also occurs in some patients following chimeric antigen receptor (CAR) Tcell therapy for haematological malig nancies, and this manifestation might also reside on an HLH spectrum. 8 sHLH/MAS associated with rheuma tological disorders is most com mon in paediatric and adolescent patients with systemic juvenile idiopathic arthritis and in patients with adultonset Still's disease. Subclinical MAS occurs in 30-40% of children with systemic juvenile idiopathic arthritis, 9,10 whereas fulminant MAS has a prevalence of 10% in this population and of 10-15% in patients with adultonset Still's disease. [11] [12] [13] Systemic juvenile idiopathic arthritis and adultonset Still's disease lie on a continuum of a single disease entity, 14,15 with MAS representing the underlying autoinflammatory disease activity at the severe end of the spectrum rather than a separate condition. Infection is a common inciting event for MAS, both in patients with systemic juvenile idiopathic arthritis (approximately one third of patients) 16 and those with adultonset Still's disease. 11,12 MAS occurs in 0·9-9% of patients with systemic lupus erythematosus, 13,17-19 and indeed might be a complication of most rheumatic con ditions, including rheumatoid arthritis, and vasculitis. Simultaneous infection and immunosuppression is likely to be culpable in triggering disease. 1, 12, 13 sHLH is associated with a very high acute allcause mortality of approximately 40% in adults, 1 which rises to 85% in the context of malignancy. 20 In a multicentre study 21 of 68 patients with sHLH, the median overall survival was 4 months (95% CI 0·0-10·2 months); prognosis was worse in patients with a malignancy than in those without (median survival of 2·8 vs 10·7 months; p=0·007). MAS in patients with systemic juvenile idiopathic arthritis has a reported mor tality of 8-22%. 16, 22, 23 The threshold model of cytokine storm syndrome is a useful concept and refers to the combination of genetic pre disposition, underlying inflammation (eg, adultonset Still's disease or malignancy), and trigger ing insults (eg, infection) that culminate in hyperinflammation 3 (eg, hetero zygous familial HLH gene mutations [PRF1 and LYST] in adult patients with influenzaassociated HLH). 24 The aetiopathogenesis of cytokine storm syndromes is not fully understood but is thought to involve a failure of the normal perforindependent cytolytic function of natural killer cells and cytotoxic CD8 T cells, which regulate inflammation and maintain homoeostasis in the con text of infection or inflammation by inducing apoptosis of antigen present ing cells. 3 In cytokine storm syn dromes, defective clear ance of antigenic stimuli results in con tinuous activation and pro liferation of macrophages (histiocytes), haemophagocytosis, and an autocrine loop of proinflammatory cytokines (cytokine storm), including IL1β, IL6, IL8, IL18, interferon gamma (IFNγ), and tumor necrosis factor, resulting in clinical sequelae includ ing unremitting fever (the cardinal feature of cytokine storm syndromes). 25 The main challenges in cytokine storm syndromes include lack of recognition (limited awareness) of the disease, difficulties with diagnosis in view of contested clini cal criteria and potential confounders, and selection of treatment, which is largely based on expert consensus and extrapolated from familial HLH. Initiation of treat ment is time sensitive, but missed and delayed diagnoses are common. Recognition of cytokine storm syndromes is challenging because the hyperinflammatory spectrum ranges from an innocuous and indolent state to a fulminant and fatal hypercytokinaemia, with nonspecific overlapping features of many systemic illnesses, including the potential underlying drivers themselves (eg, sepsis, malignancy, and rheumatic disease). Diagnostic criteria have been developed for familial HLH (HLH2004 guidelines), 26 MAS associated with sys temic juvenile idiopathic arthritis, 10 and sHLH (HScore; 27 table 1). Diagnostic criteria for sHLH have not been universally agreed nor adopted, and current strategies (using HLH2004 guidelines and HScore) have sub stantial limitations. The HScore has been shown to be more accurate for diagnosis than the HLH2004 criteria if used at the time of presentation (sensitivity of 90%, but specificity of only 79%), 28 although it is not widely used by haematooncologists in clinical practice. Use of the HLH2004 criteria in adults is questionable, as the criteria have only been validated in children and include specialist tests (eg, soluble CD25) that are expensive, often difficult to access, and associated with long turnaround times for results in some centres, resulting in delays in diagnosis and treatment. Hyperferritinaemia is a key laboratory feature in both paediatric and adult practice. Ferritin levels within the normal range (<500 ng/mL) have a high negative predictive value for HLH, and this parameter has been incorporated in diagnostic algo rithms, given the wide availability and low cost of the ferritin test. 4,6 Ferritin levels of more than 10 000 mg/L are diagnostic of HLH in children, with 96% specificity and 90% sensi tivity. 29 Ferritin level correlates with disease activity, and serial measurements are useful to monitor the response to treatment and relapse. 3,30 Both peak ferritin levels and a fall of less than 50% after treatment are associated with Viewpoint higher mortality. 30 Hyperferritinaemia is less specific for HLH in adults, 31, 32 as it can have other causes including liver failure. Different specialties might prioritise some features for diagnostic confirmation, adding further complexity. Tissue haemophagocytosis is probably the most conten tious criteria for HLH diag nosis, although technically it is not considered essential for diagnosis. Haemophagocytosis has limited sensi tivity and specificity, might be absent in the early stages of disease, and might be present in critical illness with out sHLH. 7 In adults, the diagnostic criteria are often only strictly fulfilled in the advanced stages when initiating treatment might already be futile. Withholding potentially life saving treatment until criteria are met could result in a missed window of opportunity before a patient tips into an accelerated, unsalvageable state. A better approach to identify the spectrum of cytokine storm syndromes early is to be hypervigilant in sick patients with unexplained fever and cytopenias, especially in those at risk (eg, with underlying rheumatic disease), by monitor ing trends (rather than absolute values) in laboratory para meters (eg, decreasing platelet counts or erythro cyte sedimentation rate, and increasing ferritin levels). The benefits of potentially lifesaving treatments must be balanced against potential risks of immunosuppress ion. There are validated protocols for treating cytokine storm syndromes secondary to familial HLH 26 or CAR Tcell therapy; 33 however, there is a distinct absence of validated treatment protocols or randomised controlled trials of sHLH treatment in adults. Recently published manage ment algorithms in adults with sHLH 2,3 are based on consensus expert opinion and clinical experience, largely extrapolated from the paediatric literature. Cytokine storm syndromes require an indi vidualised manage ment approach with crossspecialty input, including from rheu matology, haema tology, infec tious diseases, and critical care, especially since the intensive immunosuppressive regimens required often appear counterintuitive in crit ically ill patients with putative infection and apparent sepsis. Contemporaneous access to experts in hyper inflammation outside of formal meetings is vital, as urgent action is required to successfully treat these patients. A suggested framework for management is proposed in the figure, with concurrent strategies to inhibit the cytokine storm using immunosuppression (including selective blockade of pivotal cytokines, steroids, or chemotherapy with etoposide), treat the underlying driver of inflamma tion (eg, chemotherapy for malignancy), and prevent or treat complications. An inductionmaintenance treatment paradigm aims to rapidly terminate the hypercytokinaemia and hyperinflam mation with induction therapies, followed by maintenance therapy to control inflammation and prevent relapse. Maintenance treatment can then be gradually with drawn fHLH 26 Adult HScore However, a steroidfree regimen is excep tionally difficult to achieve in patients with severe cytokine storm syndromes. Anakinra has established efficacy in patients with systemic juvenile idiopathic arthritis and the associated MAS [36] [37] [38] [39] and might also improve survival in patients with MAS associated with other rheumatic disorders, 40 including systemic lupus erythematosus. 38 A retrospective review of 44 paediatric patients (aged 10 years; range 1- 19) with sHLH with various underlying causes showed that earlier initia tion of anakinra (within 5 days of hospital admission) was associated with reduced mortality, espe cially in nonmalignancyassociated HLH. 41 Anakinra was associated with a better outcome in patients with under lying rheumatic disease, with 100% survival in patients with MAS associated with systemic juvenile idiopathic arthritis. 41 Overall survival of paediatric patients treated with anakinra in that study was higher (73% [32 of 44] survival) 41 compared with etoposidebased protocols in a report of patients with primary and sHLH (56% [63 of 113]) survival, among whom 78% [88 of 113] had sHLH). 26 Anakinra has a favourable nonmyelosuppressive safety profile 4 com pared with other available treatments for cytokine storm syndromes, for example etoposide 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. 42 and other therapies in development for HLH, such as Janus kinase (JAK) inhibitors (eg, ruxolitinib). 43 Notably, there is emerging evidence that IL1 blockade might also have some efficacy in cytokine release syndrome after CAR Tcell therapy, 44, 45 although random ised controlled trials are pending. When treating sHLH in the context of infections (eg, coronavirus disease 2019 [COVID19]), 46 anakinra could be pref erable to tocilizumab from a safety per spective, as anakinra is likely to be less myelosuppressive and hepato toxic, has a shorter halflife (and therefore faster washout if discontinued), and does not mask indicators of infection (eg, IL6 blockade might suppress Creactive protein and fever as a mechanistic effect). The potential efficacy of JAK inhibitors (along with their associated advantages of oral formulation and short halflife), might be offset by safety concerns around poten tially deleterious effects of simul taneous (versus selective) blockade of multiple cytokines. Notably, serum IL1β is not a reliable biomarker of disease activity nor is it useful for predicting treatment response. IL1β levels might be in the normal range in patients with active sHLH (although might be elevated at local sites of inflammation) and often do not correlate with outcomes following treatment with anakinra. Serum IL1β levels might be technically difficult to measure due to assay variability and might not be comparable between laboratories. Other firstline treatments for cytokine storm syndromes include steroids and intravenous immuno globulin. Intra venous immunoglobulin might need to be repeated after 14 days due to its halflife of 14-21 days. With regard to steroids, rheumatologists usually elect for pulsed intra venous methylprednisolone, but dexameth asone is pre ferred if there is neurological involvement. Secondline therapies for refractory cytokine storm syndromes include etoposide and intrathecal meth o trexate, which are usually prescribed by haematologists. Etoposide requires dose adjustment if there is renal dysfunction, liver impair ment, or previous or current neutropenia. Intravenous ciclosporin, if given at induc tion, is usually swapped for the oral formulation for maintenance. Specific treatments are indicated for particular under lying causes of cytokine storm syndrome. Tocilizumab is licensed for cytokine release syndrome after CAR Tcell therapy 33, 42 and is also used for multi centric Castleman's disease. 47 Adjunctive Bcell depletion with rituximab (antiCD20 monoclonal antibody [mAb]) has been shown to reduce viral load and serum ferritin levels, and to improve overall clinical outcomes in patients with EpsteinBarr virusdriven HLH. 48 Chemotherapy and etoposidebased pro tocols are more commonly used for cytokine storm syndromes associated with lymphoproliferative disorders, where the prognosis is usually very poor. Emapalumab (antiIFNγ mAb) was approved by the US FDA in November, 2018, for familial HLH; 49 however, this drug is not licenced for use in adults. Identification of genetic muta tions characteristic of familial HLH facilitate eligi bility for haematopoietic stem cell transplantation, which might be curative. Subcutaneous anakinra, 100 mg once daily, is licenced for rheumatoid arthritis, systematic juvenile idiopathic arthri tis, adultonset Still's disease, and cryopyrinassociated periodic syndromes. Anakinra is recommended offlicence for management of sHLH/MAS, starting with at least 1-2 mg/kg per day, increasing to a maximum of 8 mg/kg per day 3 (paediatric doses are often higher). Notably, refractory cases of sHLH/MAS have been reported to require 100 mg anakinra four times per day; 50 as such, some clinicians choose to start at higher doses and down titrate the dose when the inflammation is controlled. Anakinra is also used intravenously in clinical practice for patients with cytokine storm syndromes, and the intra venous route was endorsed in a recent multidisciplinary consensus guideline, 4 despite limited rationale and sup portive evidence. It is unclear when or why the practice of intravenous administration of anakinra first started; its use might have originated from a desire to achieve a rapid onset of action in critically unwell patients with high mortality, limited treatment options, and purported poor peripheral absorption. Safety data from clinical trials of intravenous anakinra (24-48 mg/kg per day) in sepsis might have provided reassurance for its wider use in patients with cytokine storm syndromes, in whom secondary infections are almost universal, although the maximal treatment duration in these sepsis trials was only 72 hours. 51 Longterm safety data for anakinra is reassur ing in rheumatoid arthritis (3 years) 52,53 and cryopyrin associated periodic syndromes (5 years); 54 steroids and comorbidities could increase the risk of infections. 53 The true frequency of intravenous anakinra use, compared with subcutaneous delivery, for patients with cytokine storm syndromes in current clinical practice is unknown; however, from our own experience in three international tertiary referral centres for cytokine storm syndromes, a substantial number of patients receive intra venous dosing. Among patients who received anakinra in hospital between January, 2019, and December, 2019, the intravenous route was used in 33% (10 of 30 children; aged between 15 months and 18 years) treated at the Children's of Alabama Hospital (AL, USA); in 67% (6 of 9) of adults treated at the University College London Hospital (UK); and in 29% (2 of 7) of adults treated at the Sheffield Teaching Hospital NHS Foundation Trust (UK). In total, the intravenous route was used in 39% (18 of 46) of patients who received anakinra in hospital for cytokine storm syndromes in our three centres over 12 months. Additionally, we are contacted regularly (approximately 1-4 times per month across sites) by physicians in the USA Viewpoint and UK, requesting remote management advice for sick patients with cytokine storm syndromes. Anakinra is a large polypeptide (17 kDa) with a small initial volume of distribution. The absolute bioavailability of anakinra after a 70 mg subcutaneous injection in healthy individuals is 95% 55 according to the summary of product characteristics; bioavailability was recently reported as between 80% and 92%, 56 independent of body weight and bodymass index (BMI). Anakinra exhibits flipflop kinetics after sub cutaneous administration; the absorption process rep resents the terminal phase of the concentrationtime profile because subcutaneous absorp tion is rate limiting in the disposition. Studies have shown a similar area under the curve (reflecting exposure to the drug after administration) for a single dose of anakinra using both subcutaneous (100 mg) and intravenous (1 mg/kg) bolus injections in healthy volunteers (table 2) . 57 The terminal halflife of ankinra is longer when delivered subcutaneously (5·24 h) than intravenously (2·64 h), with similar clearance, indicating that absorp tion is slower than elimination. 56, 57 After subcutaneous administration, the halflife increases significantly (3·63−7·62 h; p<0·05) with both body weight and BMI, 56 suggesting that the absorption rate constant decreases as these variables increase. The drug has longer halflives in more obese individuals, suggesting that those with greater adipose tissue have slower anakinra transport and consequently less rapid systemic subcutaneous absorption. 56 The maximum plasma concentration (Cmax) of anakinra is higher with intravenous dosing compared with subcutan eous dos ing (24-29 times higher). 56, 57 Furthermore, the time to achieve maximum plasma concentration (Tmax) after sub cutaneous injection ranged from 3·7 h to 4·3 h 56 in healthy volunteers (3-7 hours in patients with rheumatoid arthritis). 55 Taken together these findings suggest that intravenous dosing of anakinra enables a higher and faster maximal plasma concentration (ie, higher Cmax and shorter Tmax) to be achieved, compared with subcutaneous delivery. To our knowledge, pharmacokinetic studies have not been done in patients with subcutaneous oedema, but given the influence of adiposity on the absorption rate of sub cutaneous anakinra, it is plausible that intraveous dosing might be preferable in patients with peripheral oedema and anasarca. If administered intravenously, as per con vention for other biologics, anakinra should be used in a dedicated line. 58 Anakinra can cross the blood brain barrier when given intravenously, despite being a large protein with very low (4%) penetration into cerebrospinal fluid. 58, 59 Subcutaneous delivery of anakinra is neuroprotective in rats, although very high doses are required. 60 It could be inferred that intravenous administration of anakinra could be favoured in patients with cytokine storm syndromes and neurological manifestations. Clearance of anakinra is directly related to renal function. 57 Dose adjustment is not recommended for subcutaneous administration in patients with mildtomoderate renal impairment, 55 but dose reduction is warranted if there is moderate-severe renal impairment or if haemofiltration is required, as anakinra is only minimally removed by dialysis. 57 There fore, there might be a risk of anakinra accumulation and toxicity in critically ill patients with cytokine storm syndromes receiving renal replacement therapy; strategies employed in clinical practice to over come this include administering intravenous anakinra after dialysis sessions and avoiding continuous intra venous infusions. Most publications on cytokine storm syndromes describe subcutaneous use of anakinra; however, intravenous dos ing has been reported in eight patients (table 3, appendix pp 1-3) with equal gender distribution and a mean age of 22 years (range 22 months to 71 years). 41, [61] [62] [63] [64] [65] [66] The reported underlying driver of cytokine storm in these patients included autoimmune or autoinflammatory diseases in three patients (one each with adultonset Still's disease, systemic juvenile idiopathic arthritis, and systemic lupus erythematosus). Underlying infection was diagnosed in three patients (one each with cytomegalovirus, septic arthritis, and human herpesvirus 8); one patient had both underlying auto immunity (vasculitis) and infection (cyto megalovirus); and another had underlying haema tological disease (myelodysplastic syndrome). Anakinra was used intra venously at induction in all patients and was converted to subcutaneous maintenance in four of six survivors. Seven of eight patients also received corticosteroids. One patient (4yearold female) with systemic juvenile idiopathic arthritis was treated with a combination of anakinra and abatacept (CTLA4Ig) therapy. There were three deaths associated with multiorgan failure, of which two were associated with fungemia. No adverse events were directly attributed to anakinra. The length of follow In a phase 3 randomised, doubleblind trial 67 of 893 patients with sepsis comparing anakinra (1 or 2 mg/kg per h) with placebo, anakinra failed to meet the primary endpoint of improved 28day survival but resulted in improved survival in a subset of patients with poor prognosis (n=563; p=0·009). Based on these results, a confirmatory phase 3 trial was done in 696 patients with severe sepsis compar ing intravenous anakinra (100 mg bolus followed by a 72 h continuous infusion at 2 mg/kg per h; n=350) and placebo (n=346). 68 Safety data for the anakinra and placebo groups were comparable. This study 68 was discontinued following an interim analysis, in which no survival benefit of anakinra could be shown. In a retrospective review 20 years after the original phase 3 trial 67 was completed, 43 (5·6%) of 763 patients with available data could be classified as having hyper inflammation at enrolment, based on deranged liver function and coagulopathy as proxy markers. 26 (60%) of these patients received intravenous anakinra and 17 (40%) received placebo, with a 28day mortality of 35% and 65%, respectively (p=0·0006). 69 These posthoc results suggest that a subgroup of patients with sepsis and inflammation (macrophage activationlike syndrome) might respond to anakinra and potentially other immunotherapy drugs. The PROVIDE trial (NCT03332225) is a doubleblind randomised trial of personalised immunotherapy in sepsis, in which patients were randomly assigned to receive either 200 mg of intravenous anakinra three times daily, subcutaneous recombinant human IFNγ (rhIFNγ), or placebo for 7 days, based on a panel of biomarkers and laboratory tests to identify a hyperinflammatory profile (treated with anakinra) or hypoinflammatory profiles (treated with rhIFNγ). Although clinical trials of anakinra in sepsis have so far shown equivocal efficacy, they have not raised any safety concerns in the anakinra groups. The results of the PROVIDE trial are awaited. Anakinra was given by a continuous intravenous infusion (400-3200 mg/day) for 7 days to 17 patients with steroidresistant acute graftversushost disease. 70 No safety signals were reported except for a reversible rise of liver transaminases seen in two (12%) patients. In two studies of patients with subarachnoid haemorrhage, 67,71 intra venous anakinra was given as a 500 mg bolus followed by a 10 mg/kg per h infusion for 24 h (six patients) 71 or a 100 mg bolus followed by a 2 mg/kg per h infusion for 24 hours (eight patients). 59 No adverse or serious adverse events attributed to anakinra were reported. In a randomised phase 2 study, 72 34 patients with acute stroke were randomly assigned to anakinra (100 mg intravenous loading bolus, followed by a 2 mg/kg per h infusion over 72 h) or placebo. No adverse events were attributed to anakinra. The subcutaneous (licenced) route of anakinra is recom mended in guidelines based on consensus expertopinion for sHLHlike cytokine storm syndromes. However, in a The optimal dosing regimen for intravenous anakinra in patients with cytokine storm syndrome is unclear. Reported regimens include intravenous loading boluses to supplement continuous intravenous infusions 58, 59, 68, 71, 72 or subcutaneous injections (eg, in ulcerative colitis ISRCTN43717130). 73 Use of an intravenous loading bolus or a continuous intravenous infusion could enable steady state plasma concentrations to be rapidly attained and main tained, avoiding potentially subtherapeutic troughs. 58, 59, 73 Given the shorter halflife of intravenous anakinra (relative to subcutaneous delivery), we suggest administration using split dosing (eg, twice daily intra venous boluses) or a continuous infusion. Cytokine storm syndromes can rapidly lead to critical illness and death if not promptly treated, and anakinra is increasingly recognised as an important treatment. Evidence is accumulating to support the safety of intra venous anakinra, which is preferable to the licenced subcutaneous route in critically unwell patients; the small number of published cases of intravenous anakinra in patients with cytokine storm syndromes is undoubtedly a marked underrepresentation of real world use, and it is imperative that clinical experience and outcomes are shared. Anakinra is a key drug used in the firstline management of patients with cytokine storm syndromes, and as such there are ongoing national initiatives in the UK to improve early access to this potentially lifesaving treatment, similar to the existing comission ing policies for anakinra in patients with systemic juve nile idiopathic arthritisassociated MAS 74 and adultonset Still's disease. 75 A systematic approach is needed to optimise recogni tion, diagnosis, and management of cytokine storm syn dromes, acknowledging that there are likely to be differ ent triggers of hyperinflammation in individual patients. Crossspecialty collaborative working models are increas ingly being used in both adult and paediatric settings. 4 In the UK, the national HLH acrossspeciality collaboration working group, endorsed by the Histio UK patient group, was established to improve clinical, edu cational, and aca demic outcomes and has supported the development of a national UK HLH registry and bioresource. 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. However, the optics are changing and momentum is building, with the recent US FDA approval of the antiIFNγ mAb emapalumab for famil ial HLH, 49 and an openlabelled pilot trial of ruxolitinib in patients with sHLH. 43 There is a pressing need to improve prognosis for patients with cytokine storm syndromes. This requires increased awareness and recognition of cytokine storm syndromes, with crossspecialty collaboration, interna tional multicentre registries, and controlled trials that will facilitate the generation of evidencebased, validated guidelines to improve the prognosis of patients with cyto kine storm syndromes. Rheumatologists are well placed to lead and coordinate this continued effort. 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