AOSD is a rare systemic inflammatory disorder of unknown aetiology [16]. Most studies on the prognosis of AOSD focused on the long-term risk of systemic relapse and/or chronic polyarthritis [5,6,7,8]. SJIA and AOSD are currently considered the same diseases at different ages [1]. In the past decade, AOSD has been shown to be a potentially life-threatening disease [9, 10, 17, 18]. As with SJIA, the complication that has attracted most attention is sHLH [9, 10, 19,20,21]. A variety of organ complications can occur, such as myocarditis, cardiac tamponade, respiratory failure and non-cardiogenic shock [1, 17]. We recently reported a multicentre series of 20 patients that required ICU admission due to AOSD complication-related organ failure, and reviewed 79 published cases [11]. Strikingly, complications mostly occurred at disease onset, resulting in a considerable diagnostic delay, with sepsis as the key misleading working hypothesis.
The main objective of the present study was to determine if CAOSD is a consequence of therapeutic delay or could represent a peculiar disease subset. We found that CAOSD patients tended to have a shorter delay between disease onset and AOSD treatment initiation, which was mainly due to a faster referral to the hospital. Both supervised and unsupervised statistical analyses demonstrated that even before organ failure occurred, these AOSD cases that would subsequently become life-threatening had peculiar characteristics, including a younger age and a shorter interval between disease onset and hospital admission. Furthermore, these CAOSD patients exhibited a peculiar phenotype, with more frequent cardio-pulmonary manifestations, hepato-splenomegaly, higher inflammatory markers and less frequent arthralgia and/or arthritis, when compared to other AOSD patients. Interestingly, these findings are reminiscent of how the heterogeneity of AOSD and SJIA has been delineated in recent years, by opposing arthritis on one side to systemic features and/or macrophage activation on the other [22, 23]. Several pro-inflammatory cytokines play a key role in SJIA/AOSD, including TNF-α, IFN-γ, IL-1, IL-6, IL-17 and IL-18. Ten years ago, Gattorno et al. showed that children with SJIA that responded to IL-1 receptor antagonist (anakinra) had less arthritis and higher neutrophilic leucocytosis than others [24]. In 2014, Ichida et al. reported that non-arthritic AOSD patients had more frequent splenomegaly, higher ferritin levels and higher IL-18 level and occasionally suffered organ complications (serositis, acute respiratory distress, sHLH, disseminated intravascular coagulation), which were not seen in arthritic patients [25]. More recently, Shimizu et al. described 2 cytokine profiles in SJIA: the IL-6-dominant subset had more arthritis, whereas the IL-18-dominant one was more susceptible to sHLH [26]. The same group subsequently made similar observations in patients with AOSD, where IL-18-dominant patients had higher ferritin levels but a lower frequency of arthritis as compared to IL-6-dominant patients [27]. A recent study demonstrated how arthritic versus systemic manifestation of AOSD predicted response to IL-6 and IL-1 blockade, respectively [28].
Overall, our data suggest that CAOSD patients, i.e. AOSD patients who develop life-threatening complications at disease onset, represent a distinct clinical subset characterised by a more rapid and more severe systemic inflammatory response syndrome. This life-threatening cytokine storm might be driven mostly by IL-1 and IL-18. Hyperferritinaemia, hepato-splenomegaly and haemophagocytosis also point to macrophage activation as a key driving force of CAOSD. Our finding that these patients are significantly younger suggests that some genetic susceptibility may play a role.
Importantly, the overwhelming majority of patients who developed life-threatening manifestations did so before the diagnosis of AOSD was made [11]. AOSD is a well-known cause of sHLH, an entity most intensivists are more familiar with. However, key manifestations of most malignancy, immunodeficiency and/or infection-related sHLH include cytopenias. By contrast, despite several features are reminiscent of macrophage activation (fever, hyperferritinaemia, hepato-splenomegaly, coagulopathy and haemophagocytosis), CAOSD present with marked neutrophilic leukocytosis with or without moderate anaemia and/or thrombocytopenia, which likely contribute to misguide clinician [11]. Thus, the main area of improvement is to increase awareness of this peculiar entity among non-specialists (hospitalists, intensivists, respiratory physicians, cardiologists, etc.), who have to be aware of CAOSD being a sepsis mimicker in critically ill adult patients with fever of unknown origin (FUO). Despite the diversity of organ complications that CAOSD patients may present with, the overall picture of AOSD, including the simple clues to its diagnosis, remains the classical ones (salmon rash, sore throat, neutrophil leukocytosis, hyperferritinaemia, etc.). Early recognition of those may avoid pointless investigations, diagnostic delay and deaths of young adult patients.
The exact burden of CAOSD remains unclear in recently published series and discrepancies between them suggest that CAOSD may be underdiagnosed in FUO patients presenting with life-threatening complications. In a large retrospective series from an Italian rheumatological network including 245 AOSD patients, no data were available regarding organ manifestations or deaths, and only 7 patients (2.6%) were considered to have sHLH [2]. In a recent nationwide Japanese series, none of the 169 patients had a fatal outcome [29, 30]. In another French series, patients were seen mainly in internal medicine departments and as many as 33% presented with organ complications (with a heterogeneous spectrum, in line with our own observations [7]). Two recent retrospective AOSD series reported an unexpectedly high mortality rate, which suggests better recognition of CAOSD, but that therapeutic management still needs to be improved. Ahn et al. studied 64 Korean patients diagnosed with AOSD at a Seoul Hospital over a 10-year period, of whom 36 (56%) were classified as having sHLH and 12 (18.7%) died [9]. Death occurred within 3 months in all cases (within 1 month in 10 cases), due to AOSD-related multiorgan failure in 8 cases, and superimposed infection in 4. In a recent Italian series of 119 AOSD patients, 19 (16%) patients died due to AOSD: 12 deaths were attributed to AOSD-related sHLH, 5 to AOSD-related MOF and 2 to infection [10]. To date, limited data are available to define the optimum therapeutic strategy beyond corticosteroids. Most published experience reports the promising efficacy of cyclosporin and IL-1 receptor antagonist (anakinra). Intravenous immunoglobulins are an appealing immunomodulatory strategy when infection is a key concern. Unfortunately, they have limited efficacy and may even delay the recourse to more potent therapies [9, 11]. Further studies are needed to clarify the benefit/risk of sHLH-targeting chemotherapy (etoposide) [31], pleiotropic immunosuppressants (e.g. cyclophosphamide) and IL-6 targeted therapies [32] Other candidate drugs will hopefully appear in the near future [32, 33].
Our study has several limitations, owing to its retrospective nature and the rarity of AOSD. Unfortunately, the methodology of case–control collection and the rarity of CAOSD in our single-centre AOSD cohort (5/46, 11%) did not allow us to build a scoring system to predict CAOSD. Thus, the potential red flags we point at should be taken with caution. Another limitation of our study is that we focused on data gathered at first presentation. However, AOSD early clinico-biological course is heterogeneous. Further studies are needed to determine if the dynamics of blood cell counts, liver tests and ferritin levels can predict short-term outcome. Comparing a multicentre case series to a single-centre control group may be a source of bias. However, cases were collected from centres that were very similar to ours (internal medicine department of non-tertiary university or non-teaching hospitals) and 5 were from our own cohort. Further multicentre matched case–controlled studies are warranted to identify red flags for CAOSD.