adult - onset still 's disease ( aosd ) is a systemic autoinflammatory disorder characterized by daily high - spiking fevers , evanescent maculopapular rash , sore throat , polyarthritis , myalgia , lymphadenopathy , and hepatosplenomegaly [ 1 , 2 ] . however , a growing number of experimental evidences supports the hypothesis that a disregulation of inflammasome complex and a related overproduction of the proinflammatory cytokine interleukin 1 ( il-1 ) is a pivotal event in the pathogenesis of this disorder , in analogy with other autoinflammatory diseases that share with aosd clinical and biological characteristics . in this paper , we discuss the biology and the role of il-1 in aosd pathogenesis and we review the current literature about the utilization of anti - il-1 agents in clinical practice . il-1 is a pleiotropic mediator of the response to infection and injury , which affects nearly all cell types , either alone or in combination with other cytokines . the components of the latter do not express constitutively this protein whose availability is over the control of the innate immunity which acts as a sophisticated system for detecting signals of  danger  such as pathogenetic microbes or host - derived signals of cellular stress . recognition occurs through a limited group of pathogen - recognition receptors ( prrs ) like the toll - like receptors ( tlrs ) and the nod - like receptors ( nlrs ) . for instance , the interaction of tlr with its ligand triggers pro - il1 gene expression and synthesis . the conversion of pro - il1 into active il1 is mediated by caspase 1 which requires nlr activation and subsequent inflammasome complex organization to exert its action . once secreted , il-1 binds and activates the single transmembrane domain type i il-1 receptor ( il-1ri ) on a variety of cell types . the following step is the recruitment of il-1 receptor accessory protein ( il-1rap ) to the il-1ri / il-1 complex . the signal pathway initiated leads ultimately to nuclear factor b ( nfb ) translocation in the nucleus and finally to the expression of an array of inflammatory genes [ 57 ] ( figure 1 ) . interestingly , recent advances suggest that caspase-1 may not be the only responsible of il-1 activation . neutrophil serine proteases , mast cell chymase , and metalloproteinases may also be able to proteolytically cleaving pro - il-1 [ 8 , 9 ] . il-1 upregulates cytokines , acute phase proteins , and tissue remodeling enzymes . as a key mediator of innate immunity is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into inflamed tissues , which are key aosd manifestations . in the periphery , il-1 , in synergy with tnf , is recognised as an important factor in driving bone and cartilage erosion . of more , it increases platelet production , which results in thrombocytosis , and promotes the production of il-6 , which in turns stimulates hepatocytes to synthesize several acute phase proteins [ 10 , 11 ] ( figure 2 ) . il-1 also plays an important role in the adaptive immune response acting directly on nave and memory t cells to promote their expansion and survival and instructing b cells to enhance antibody production . moreover , it has recently been discovered that il-1 drives the development of th17 cells , which are now known to be a key t - cell subset mediating many autoimmune and chronic inflammatory diseases . the frequency of circulating th17 cells is elevated and positively correlated with disease activity in aosd patients [ 1216 ] . as it plays a critical role in host defence eliciting a wide range of effects , the activity of il-1 needs to be tighltly controlled to avoid tissue damage resulting in autoreactive response . the regulation takes place on several levels , including transcription , mrna stability , translation , maturation , secretion , receptor expression , and release of soluble receptors , as well as il-1rii , a decoy receptor and il-1ra , a naturally expressed inhibitor of il-1 receptor occupancy [ 17 , 18 ] . the complexity of il-1 biology explains well why the aberrant activation of the innate immunity system can lead to a multitude of chronic diseases , like aosd ( figure 1 ) . aosd is a member of the expanding group of the  autoinflammatory disorders  . in contrast with autoimmunitary diseases that are primarily caused by dysregulation of adaptive immune responses , autoinflammatory diseases are caused by disorders in the innate inflammatory pathways and the usual hallmarks of autoimmunity such as high titers of antigen - specific t lymphocytes and autoantibodies are characteristically absent . one of the major events in the pathogenesis in these syndromes is an increased release of active il-1. cytokine profile in aosd sera is characterized by the presence of il-6 , ifn , il-18 , and , of note , il-1 [ 21 , 22 ] . the identification of the critical role of nlrp3 inflammasome in the maturation of il-1 motivated the study of its role in the pathogenesis of autoinflammatory syndromes . mutations of the inflammasome related genes have been identified in the cryopyrin - associated periodic syndromes ( capss ) , in familial mediterranean fever ( fmf ) and in the pyogenic arthritis , pyoderma gangrenosum , and acne syndrome ( papa ) . the primum movens of the pathogenetic sequence seems to be an infectious agent , as suggested by the temporal relationship between disease onset and viral syndromes . other pathogenic organisms ( bacteria , parasites , or chemical events ) may also be involved . anyway , infection alone is unlike to be sufficient to trigger aosd , and a predisposing genetic background is probably required even if no consistent associations with hla aplotypes have been individuated . youm et al . have studied 83 aosd patients to investigate whether il-1 and il-1ra gene polymorphisms are associated with the development and clinical features of aosd , but no differences were observed between patients and healthy controls . a potent il-1 production - inducer is il-18 , a member of the il-1 family that growing evidences are demonstrating to be pivotal in promoting the systemic inflammatory process of aosd . it exerts pleiotropic effects such as the stimulation of neutrophil migration and activation , the polarization of t - cell response versus the th1 phenotype , the expression of adhesion molecules and the activation of natural killer cells . it synergizes with il-6 in the production of ferritin from macrophage - lineage cells   and with il-23 in the induction of th17 cells . il-18 serum levels are higher in aosd patients compared to other autoinflammatory diseases   and correlate with disease activity , serum ferritin levels , and neutrophil count . the local expression of il-18 may be responsible for tissue damage in some target organs such liver   and synovial membranes . however , actually the most convincing case supporting the central role of il-1 in aosd pathogenesis is the dramatic and sustained efficacy of il1-blockade on aosd symptoms , even in refractory forms of the disease . it is a recombinant , nonglycosylated form of human il-1 receptor that acts as a pure receptor antagonist binding tightly to the il-1ri and preventing activation of this receptor by either il-1 or il-1. it is administered subcutaneously once daily , due to its short half - life . approved by the fda in 2001 for treating patients with rheumatoid arthritis , its use validated the importance of il-1 in a broad spectrum of inflammatory diseases , aosd included . a growing number of reports describe a rapid response to anakinra characterized by impressive reduction in disease activity , fever resolution , and normalization of hematologic and biochemical parameters within hours to days after the first injection in patients affected from aosd refractory to other synthetic or biological treatment [ 3 , 22 , 3034 ] . these effects are likely to be sustained over a long treatment period and allow tapering and withdrawal of concomitant glucocorticoids and dmards and finally anakinra administration in monotherapy [ 3436 ] . such a long - lasting effect was not described with tnf - blockers , whose efficacy seems to decrease over time . our group has observed that in some patients that achieved a complete and stable remission was possible not only a discontinuation or reduction of treatment associated , but also of anakinra itself , without relapse . these data seem to be confirmed by the retrospective study of laskari et al . . the possibility of dose reduction may enhance compliance and drug adherence and highlights the potential cost - effectiveness of anakinra . moreover , according to our observations , the most impressive results were obtained in patients with systemic forms . we can argue that the proinflammatory cytokine il-1 could have a more prominent role in systemic forms of aosd for whom anakinra use can be reserved . in these cases , anakinra may be efficacious not only to induce remission , but also to prevent new relapses in polycyclic forms and the amyloidosis development associated with long - standing elevated inflammatory markers . another open question is whether anakinra must be introduced early in the course of aosd or only after other conventional treatment failure to avoid the adverse effects of a prolonged corticotherapy and to limit the social impact of a poorly controlled disease . to support the necessity of an earlier introduction of anakinra , moulis et al . have reported two cases of dramatic side effects secondary to conventional treatment that later had an immediate and remarkable response after anakinra starting . the most frequent adverse event reported in the clinical trials is injection - site reaction which is generally mild to moderate and rapidly resolutive . some infections have been reported ; however , it has not been associated with the development of tuberculosis or other fungal infections , demyelinating syndromes or worsening of congestive heart failure . a recent systematic review of literature conducted by singh et al . on 163 randomized controlled trials with 50,010 participants and 46 extension studies with 11,954 participants that included indirect comparisons between anakinra and other biological agents revealed that anakinra is associated with a significantly lower risk of serious adverse events compared to most other biologic treatments . anecdotally , we report a severe systemic inflammatory response syndrome after anakinra introduction   and an episode of thrombocytopenia , which appeared one week after anakinra introduction and resolved soon after its discontinuation . immunization against anakinra has been described , but the appearance of potentially neutralizing antibodies is transient and has never been associated with anakinra failure subsequently do not preventing chronical anakinra administration . in conclusion , even if more studies are needed , all the evidences actually available strongly support the importance of anakinra as new safe and effective therapeutic option in aosd treatment . although anakinra has been demonstrated effective and safe , its short half - life demanding daily injections often associated with painful local adverse reactions limits its usefulness in the clinical practice . this has represented an incentive to the development of new anti - il1 antagonists with different pharmacokinetic properties . recently , soluble receptors for il-1 ( rilonacept ) and human mabs to il-1 ( canakinumab and gevokizumab ) have been used to neutralize il-1 specifically ( table 1 ) . rilonacept ( regeneron ) is a construct of 2 extracellular chains of the il-1r complex ( il-1r plus il-1rap ) fused to the fc portion of human igg1 . since it contains both receptor components , rilonacept is able to bind il-1 and il-1 with high affinity . it has an half - life is longer that  anakinra , and it is administrated once weekly . henderson et al . investigated the use of rilonacept in a small cohort of refractory aosd patients observing a good clinical and biological response . interestingly , they reported that high levels of il-18 at baseline were predictors of a successful response . this evidence suggests this biomarker as a useful tool to predict response to treatment . canakinumab ( ilaris ) is a human monoclonal igg1 antibody targeted against il-1 , thus preventing its binding to the receptor complex . generated by a transgenic mouse strain , it offers a high specificity for il-1. among il-1 antagonists , canakinumab is the agent with the longest half - life . of more , it has been demonstrated that its clinical efficacy is prolonged beyond what expected based on its half - life . subsequently , pharmacokinetic modelings have shown a positive feedback of il-1 on its own production . this explains why the effectiveness of the drug is greater than its half - life , thus permitting its administration once every two months [ 48 , 49 ] . in clinical trials , canakinumab and rilonacept the rate of injection site injections was 34% versus 27% in rilonacept versus placebo and 9% versus 14% in canakinumab versus placebo [ 50 , 51 ] . actually , canakinumab and rilonacept are indicated only for the treatment of the caps , but they could represent a new therapeutic option for aosd [ 52 , 53 ] . gevokizumab ( xoma 052 ) is an igg2-humanized mab against human il-1. xoma has completed a successful proof - of - concept phase 2 trial of gevokizumab in patients with behet 's uveitis , types 1 and 2 diabetes , and rheumatoid arthritis . it belongs the potential to treat patients with a wide variety of inflammatory diseases , including autoinflammatory diseases [ 54 , 55 ] . the development of il-1 blockers with higher affinity and longer half - life could improve patient management and also favor patient compliance .
interleukin 1 ( il-1 ) is emerging as a master mediator of adult onset still 's disease ( aosd ) pathogenesis . 
 this pleiotropic cytokine , whose expression is under the control of the inflammasome pathway , has a wide type of effects . as a key mediator of innate immunity is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues , which are key aosd manifestations . 
 the study of proinflammatory cytokines profiles in sera and pathological tissues of aosd patients has shown elevated levels of il-1 , these levels being highly correlated with disease activity and severity . 
 these experimental evidences and the analogy with other autoinflammatory diseases that share with aosd clinical and biological characteristics have suggested the blockade of il-1 as a possible new therapeutic option for the aosd , especially in conventional therapy resistant cases . 
 anakinra , the first anti - il-1 agent put on the market , has demonstrated capable to induce a rapid response sustained over time , especially in systemic forms , where anti - tnf failed to control symptoms . while a growing number of evidences supports the utilisation of anakinra in aosd , a new generation of anti - il1 antagonists is developing . 
 canakinumab and rilonacept , thanks to their higher affinity and longer half - life , could improve the management of this invalidating disease .