adult - onset still 's disease ( aosd ) is a rare inflammatory disease of unknown etiology , which commonly affects young adults .
it is usually characterized by high spiking fevers , arthritis , and an evanescent , nonpruritic , macular and salmon coloured rash , appearing on the trunk and the extremities .
important laboratory findings include leukocytosis , with predominance of neutrophils , negative testing for rheumatoid factor ( rf ) , and antinuclear antibodies ( ana ) as well as high serum ferritin levels and low serum glycosylated ferritin levels [ 13 ] .
severe disease complications include pericarditis , endocarditis , haemolytic anaemia , and macrophage activation syndrome ( mas ) .
the latter is characterized by thrombocytopenia , markedly elevated ferritin levels , hypofibrinogenemia , and elevated aspartate amino - transferase ( ast ) .
aosd diagnosis can be safely established , after important mimickers including infections , malignancies , and autoimmune diseases are excluded .
treatment of patients with aosd includes nonsteroidal anti - inflammatory drugs ( nsaids ) , corticosteroids , and disease - modifying antirheumatic drugs ( dmards ) , while our better understanding of disease pathophysiology allowed the identification of biological agents as important targeted therapies [ 1 , 4 ] .  
recent studies have added valuable information in regard to the underlying pathogenetic mechanisms of aosd . besides , the exact pathogenesis remains largely elusive , with genetic , environmental , and immunologic contributors being implicated . in the present paper
, we aimed to summarize recent advances in pathophysiology and potential therapeutic strategies in the setting of aosd .
we also used rheumatology textbooks with chapters relevant to aosd and abstract database from acr and eular meetings at 2010 and 2011 .
 aosd or still 's disease pathophysiology ,   aosd or still 's disease therapy ,   still 's disease or aosd treatment ,   still 's disease or aosd and inflammasome . 
several small case studies have previously reported associations with distinct hla alleles in patients with aosd , with often conflicting results . in an early small study of 25 aosd patients ,
wouters et al . reported an increased frequency of the hla - dr4 allele in 29 patients with aosd compared to normal controls , with the presence of hla - drw6 being linked to root joint involvement .
in a subsequent study , a strong disease association with hla - b17 , b18 , b35 , and dr2 has been documented . in japanese populations ,
an association between a chronic articular form of aosd and hla - drb1 * 1501 ( dr2 ) , drb1 * 1201 ( dr5 ) , and dqb1 * 0602 ( dq1 ) was previously reported , while hla- and dqb1 * 0602 ( dq1 ) have been also associated with the systemic form of the disease .
data from a korean report , supported an association between hla - drb1 * 12 and drb1 * 15 and aosd , while hla - drb1 * 04 seemed to be protective . on the other hand , hla - drb1 *
14 alleles were more commonly present in patients with the monocyclic systemic type of aosd .  
the shared clinical and laboratory findings observed in aosd and infections are highly suggestive of a putative role of infectious agents in disease pathogenesis .
several anecdotal reports so far indicate a temporal relationship between bacterial and viral triggers prior to disease onset .
several viruses such as rubella , echovirus 7 , mumps , cytomegalovirus ( cmv ) , and others , as well as bacterial pathogens including yersinia enterocolitica , chlamydophila pneumoniae , brucella abortus , and borrelia burgdorferi , have been so far implicated in disease pathogenesis [ 1013 ] .
a hallmark of aosd is neutrophil and macrophage activation possibly under the effects of the proinflammatory interleukin-18 ( il-18 ) signalling .
neutrophil ( pmn ) cd64 a marker of neutrophil activation has been recently found to be upregulated in patients with active aosd .
a calcium - binding protein named calprotectin , secreted by activated neutrophils and macrophages , as well as macrophage migration inhibitory factor ( mif ) , is useful markers of disease activity and severity [ 15 , 16 ] .
intercellular adhesion molecule-1 ( icam-1 ) upregulated by il-18- has been also proposed as a potential clinical marker , as its expression typically reflects the level of disease activity .
furthermore , activation and differentiation of macrophages appears to be orchestrated by macrophage - colony stimulating factor ( m - csf ) , a cytokine which is substantially elevated in acutely ill aosd patients .  
the role of cd4 t helper ( th ) cells in the pathogenesis of aosd has been recently appreciated , with th1 subset predominating over that of th2 cd4 cells and being associated with disease activity .
accordingly , interferon - gamma ( ifn- ) mrna expression was found to be significantly higher than that of interleukin-4 ( il-4 ) in skin and synovial tissue biopsies .
the role of th17 lineage in aosd pathogenesis is also emerging , as evidenced by increased number of peripheral th17 cells in 24 patients with untreated and active aosd compared to healthy controls .
th17 cells are a subset of t helper cells , named after their ability to produce interleukin-17 ( il-17 ) .
this subset of cells is derived from the differentiation of naive cd4 t cells , under the influence of transforming growth factor  ( tgf ) , interleukin-1 ( il-1 ) , and interleukin-6 ( il-6 ) [ 20 , 21 ] .
interestingly , heightened levels of t - cell receptor -positive ( tcr+ ) t cells , mostly of the v9/v2 subset have been previously associated with active disease and correlated with inflammatory markers . since
, it has been recently appreciated that t/ cells are also represent an important source of il-17 production , the role of these cells in the pathogenesis of aosd requires further attention .  
interleukin-18 ( il-18 ) , interleukin-23 ( il-23 ) , and inteleukin-21 ( il-21)found to be elevated in active aosd patients  seem also to ensure the proliferation / maintenance of th17 cells . circulating th17 cells correlated with disease activity and ferritin as well as il-1 , il-6 , il-17 , il-18 , il-21 , and il-23 levels . of interest ,
additional t cell populations actively involved in aosd pathogenesis include the cd4 cd25 ( high ) t regulatory ( treg ) cells found to be low in these patients compared to healthy controls and inversely associated with disease activity .
furthermore , higher levels of cd4 cd25 ( high ) treg cells have been associated with a more favourable prognosis , as patients with monocyclic disease , a mild form of aosd , typically have higher concentrations of circulating cd4 cd25 ( high ) treg cells than those with polycyclic or chronic articular form .  
it should be , however , pointed out that according to recent findings , cytokine profile has not been proven useful in differentiating patients with aosd from those with sepsis , limiting their potential use in clinical practice .  
increased tnf- levels were detected in sera and tissues from aosd patients compared to healthy controls independently of disease activity . on the other hand , serum levels of soluble tumor necrosis factor - receptor-2 ( stnf - r2 ) correlated with serum crp levels , implying its potential use as a disease activity marker [ 8 , 26 , 30 ] .   
il-1 appears to be implicated in aosd pathogenesis as its serum concentration is elevated in these patients compared to healthy controls .
further evidence for the contribution of il-1 in aosd pathophysiology came from the pioneering work by pascual et al . reporting that incubated peripheral blood mononuclear cells ( pbmcs ) with serum from patients with systemic form of juvenile idiopathic arthritis ( sjia ) , led to increased expression of innate immunity genes and release of large amounts of il-1 .
however , plymorphisms in the il-1 and il-1 receptor ( il-1r ) genes have not been associated with aosd susceptibility , at least in a korean population .
recent findings suggest activation of the protein complex nucleotide - binding oligomerization - domain-(nod- ) like receptor family , pyrin domain containing 3 ( nlrp3 ) inflammasome , as an important source of il-1 ; this activation can occur by recognition of pathogen - associated molecular patterns ( pamps ) and danger - associated molecular patterns ( damps ) .
although it seems to contribute at least in one subset of sjia  the pediatric counterpart of aosd  with a favorable response to il-1 blockade , further studies are required to fully explore its exact role in the pathogenesis of aosd [ 3840 ] .
taken together , these observations may suggest that susceptibility to sjia and aosd might be conferred by an interplay with exogenous pathogens - triggers of inflammasome with genetically determined inflammasome responsiveness resulting in dysregulation of il-1 production .
heightened  sil-2r levels , a marker of t - cell activation , were also reported in two distinct studies of aosd patients , serving as a potential marker of disease activity [ 8 , 29 ] .  
il-6 levels have been found to be elevated in aosd patients compared to their healthy counterparts in association with disease activity , fever spikes , and crp levels . of interest , skin lesional biopsies from individuals presenting with the characteristic salmon coloured rash revealed heightened il-6 levels [ 2931 ] . in addition
, il-6 may contribute to the increased levels of ferritin as it stimulates its production along with crp and other acute - phase proteins by the liver .
finally , prolonged exposure to high levels of il-6 may be associated with severe growth impairment , especially in patients with sjia .
il-8 , a proinflammatory cytokine , which mobilizes , activates , and degranulates neutrophils at the site of inflammation has been also found to be raised in aosd patients compared to healthy controls , independently of activity status .
given that elevated levels of serum il-8 typically characterize the chronic articular form of aosd , they can be used as a marker to predict the persistence of arthritic complaints . as previously mentioned and in line with previous observations in other autoimmune diseases , serum il-17- proinflammatory cytokine derived by th17 cells was higher in patients with aosd and correlated with th17-circulating cells .
the fact that th17 cells and il-17 levels were both abated upon therapy administration implies a potential therapeutic role of th17 targeted therapies in the management of those diseases .
il-18- member of the il-1 family , which induces th1 cytokine production- , has been shown to be higher in the serum synovial tissue and lymph nodes in patients with aosd than in healthy individuals , serving as a marker of disease severity , possible response to corticosteroids and of aosd - related hepatitis [ 29 , 32 , 33 , 45 ] .
the latter is evidenced by the demonstrated association of il-18 serum levels with active liver disease .
locally rather than systematically produced il-18 by liver activated macrophages ( cd68 ) seems to contribute to this complication [ 30 , 34 ] .
associations of il-18 with serum ferritin , c - reactive protein ( crp ) , and neutrophil count have been also demonstrated [ 8 , 34 , 35 ] .
several polymorphisms of the il-18 gene have been associated with aosd in japanese and chinese populations [ 4648 ] .  
another function attributed to il-18 is that of lymphocyte apoptosis possibly through induction of fas ligand ( fasl ) and p53 pathways , both implicated in the programmed cell death .
this hypothesis is also supported by raised fas and fasl levels in untreated aosd patients compared to healthy controls .  
finally , in a more recent report , il-18 levels were found to be significantly elevated in patients of aosd complicated by mas compared to m - csf levels ; an opposite observation was made in patients with lupus - associated mas .  
although ifn- levels were also found to be raised in aosd patients compared to healthy individuals , no study so far demonstrated association of this cytokine with disease activity [ 26 , 29 ] .  
the contributory role of chemokines in the pathophysiology of aosd was supported by a recent study reporting elevated levels of cx3cl1 , cxcl8 , cxcl10 , ccl2 , and ccl3 in serum of aosd patients compared to healthy controls . of interest , only cx3cl could be used as a marker of disease activity as it was correlated well with serum crp , ferritin , il-18 , and sil-2r levels . furthermore , markedly elevated concentration of cx3cl1 and ferritin was able to predict the onset of mas , indicating its value in predicting aosd - related complications .
treatment of patients with aosd has been empirical for a long time , given the lack of solid data from well - designed double - blinded randomized clinical trials with the majority of evidence deriving from small case series and retrospective studies .
recent advances in better understanding of disease pathophysiology allowed the designation of targeted therapies leading to effective disease control .
conventional immunosuppressants and new biologics are the main agents included in our therapeutic armamentarium against aosd . while nonsteroidal anti - inflammatory drugs ( nsaids ) have been previously considered as a first - line medication for the treatment of aosd , they have been replaced by corticosteroids , as they are effective as monotherapy only in 715% of patients [ 66 , 68 ] .
the steroid therapy is efficacious in approximately two thirds of patients and more pronounced among those without chronic articular disease .
disease - modifying antirheumatic drugs ( dmards ) such as methotrexate ( mtx ) , cyclosporine , hydroxychloroquine , gold , penicillamine , and azathioprine , [ 7072 ] have been proven efficacious in steroid - resistant or -dependent aosd cases , with methotrexate being the most commonly used dmard in clinical practice with response rates up to 60% . in regard to sulfasalazine ,
reduced efficacy along with some previously raised safety issues given the reported associations with mas development discourages its use in aosd cases [ 7375 ] . in patients refractory to treatment with steroids and/or dmards ,
biological agents seem to achieve a better control of disease activity . despite the lack of solid evidence of tnf implication in the pathogenesis of aosd
as opposed to rheumatoid arthritis , anti - tnf agents have been used in aosd refractory cases with modest success , particularly in the chronic articular form of the disease lagging in efficacy behind il-1 and il-6 inhibitors . in a small case series of twelve aosd cases refractory to dmards , administration of etanercept , a soluble tnf receptor , led to arthritis improvement in 7 patients with nonsignificant adverse events .
infliximab , a monoclonal antibody against tnf , as a treatment of eight multidrug - resistant aosd cases led to full response in 87.5% ( 7/8 ) of patients .
five of these patients remained in remission even after the discontinuation of infliximab and one of them switched to etanercept due to infusion reactions .
only one of the responders required chronic therapy to control its arthritis and only one patient did not respond to these biological agents . in two
additional cases series , infliximab was administrated along with corticosteroids and dmards in a small number of patients with remission of systemic features , normalization of inflammatory markers , and without serious adverse reactions [ 52 , 55 ] .
further information regarding the safety and the efficacy of anti - tnf agents derives from a study published by fautrel et al .
in which infliximab or etanercept was administrated to twenty aosd patients , five with systemic and fifteen with polyarticular form , whose response to mtx and corticosteroids was considered inadequate .
the majority of patients responded partially to therapy ( 64% , or 16 of 25 patients ) and only five in twenty patients achieved complete remission .
anti - tnf--induced cutaneous adverse effects in the setting of sjia have been reported including cutaneous vasculitis and lichen planus , as well as psoriatic palmoplantar pustulosis accompanied by plaque - type psoriasis localized to the scalp . in view of the central role of il-1 in pathogenesis of aosd as previously reported , administration of interleukin-1 receptor antagonist ( anakinra ) in these patients
, it has been shown that patients ( 84% ) receiving anakinra either as monotherapy or as adjunct therapy responded completely within a few days and only one of them had its disease relapsed during the subsequent followup .
the remaining patients experience a partial clinical ( 12% ) and laboratory ( 16% ) response and only three patients discontinued the drug because of adverse effects . in general , the need for corticosteroids during treatment with anakinra greatly diminished in every patient .
the corticosteroid - sparing effect of anakinra along with its effectiveness was also noted in a case series reported by kalliolias et al . in 2007 .
furthermore , fitzgerald et al . demonstrated that anakinra is an effective agent to treat aosd patients refractory to corticosteroids , mtx and etanercept , as this drug rapidly resolves the inflammatory response and leads to normalization of laboratory markers .  
, in a study including both aosd and sjia patients , suggested anakinra as an effective alternative in the treatment of patients with aosd , with somewhat limited efficacy in sjia population .
in contrast , in a retrospective chart review of 46 sjia patients , receiving initially anakinra either as monotherapy or together with additional disease - modifying antirheumatic drugs revealed that in 60% of these patients the clinical activity resolved completely and laboratory markers were normalized .
the authors concluded that anakinra should be considered a safe and an effective way not only to treat systemic sjia but also to prevent the emergence of intractable arthritis .
in addition , according to a case report published by raffeiner et al . , anakinra could be successfully used in the treatment of a patient with aosd and myocarditis . on the other hand , ruiz et al . reported that anakinra could not prevent the progression of aosd - associated cardiac disease despite the excellent control of noncardiac symptoms of a patient , without excluding the possibility that anakinra may be implicated in cardiac events of this patient .
although anakinra seems to be an effective treatment of aosd patients regarding the rapid resolution of their clinical and laboratory markers , a recent case report published by lahiri and teng has shown that joint damage may progress despite the administration of this drug .
a second generation il-1 inhibitor , the il-1 trap rilonacept , has been used in 3 patients who had failed treatment with glucocorticoids , immunosuppressors , and biologics , including anakinra with promising results .
canakinumab , a fully human monoclonal antibody against il-1 with a long half - life , successfully controlled disease flares in aosd patients refractory to dmards , anakinra ( short - acting il-1 blockade ) , and rilonacept ( moderate - acting il-1 blockade ) .
in addition , the efficacy and safety of canakinumab in the treatment of sjia , the pediatric counterpart of aosd , has been demonstrated in a phase ii , multicenter , open - label study , with 60% of patients achieving an acr pediatric 50 response .
given the emerging role of t - cells in the pathogenesis of aosd , administration of abatacept , a t - cell costimulation modulator , in these patients seems to be a logical approach .
abatacept ( ctla4igfc ) , a fusion protein which consists of the extracellular domain of the cytotoxic t - lymphocyte antigen 4 ( ctla-4 ) and the fc portion of immunoglobulin g1 ( igg1 ) , inhibits t - cell activation by binding to cd80 and cd86 receptors on antigen - presenting cells ( apcs ) and preventing their interaction with cd28 receptor on t cells .
recent findings support a potential role of the latter in aosd cases refractory to conventional dmards , anti - tnf- agents , and even to il-1 receptor antagonists [ 81 , 82 ] .  
given that il-6 shares an important pathogenetic role in aosd , as mentioned above , the interleukin-6 ( il-6 ) antagonist , tocilizumab ( toc ) , has recently been proposed as a potential treatment for these patients .
indeed , it seems to be an effective drug even against aosd cases refractory to anakinra and tnf- antagonists in anecdotal cases , even as monotherapy [ 8391 ] .
tocilizumab was also able to control disease activity in a patient with diffuse intravascular coagulation ( dic ) and aosd , refractory to cyclosporine and high - dose glucocorticoids .
in addition , the dose of corticosteroids was greatly reduced as toc was added on maintenance therapy . on the other hand , mas seemed to follow toc administration in a patient with intractable aosd , implying that caution should be taken in very active forms of the disease . in the first case series of tocilizumab in fourteen patients with intractable aosd at a dose 58  mg / kg
every two or four weeks , eleven patients completed the 6-month followup and the remaining three discontinued the drug due to adverse effects , including necrotizing angiodermatitis , infusion - related chest pain , and systemic flare .
over the course of 6 months , the clinical activity resolved completely in 57% of patients ( 8/14 ) and corticosteroid maintenance dose was dramatically reduced , suggesting that toc may be an effective alternative treatment , when dealing with multidrug - resistant cases of aosd .
toc has also been approved for the treatment of sjia patients , as it is associated with substantial clinical and laboratory responses . of interest ,
administration of this drug in sjia patients led to improvement of reduced serum cartilage oligomeric matrix protein ( comp ) , further supporting the concept of contribution that high levels of il-6 in the suppression of growth cartilage turnover [ 42 , 94 ] .
taken together , these findings support the contributory role of several immune mediators in aosd pathogenesis allowing the determination of rational treatment approaches . while current evidence identifies il-1 blockade as a major therapeutic strategy in patients with refractory aosd , inhibition of il-6 , il-17 , or il-18 molecules holds significant promises .
given the complex and multifaceted nature of aosd , carefully designed clinical studies aimed to associate distinct clinical phenotypes with specific pathogenetic pathways would allow the designation of tailored therapies for distinct disease aspects .
 adult - onset still 's disease ( aosd ) is a systemic inflammatory disorder affecting primarily young individuals . 
 the diagnosis is primarily clinical and necessitates the exclusion of a wide range of mimicking disorders . given the lack of solid data in regard to the underlying pathogenetic mechanisms , treatment of aosd has been for years largely empirical . 
 recent advances have revealed a pivotal role of several proinflammatory cytokines such as tumor necrosis factor- ( tnf- ) , interleukin-1 ( il-1 ) , interleukin-6 ( il-6 ) , interleukin-8 ( il-8 ) , and interleukin-18 ( il-18 ) in disease pathogenesis , giving rise to the development of new targeted therapies aiming at optimal disease control . 