Introduction

Still’s disease was described in children in 1897 by Sir George Frederick Still and is today called systemic juvenile idiopathic arthritis (sJIA).1 One century later, in the early 1970s, Eric Bywaters described a similar inflammatory condition in young adults, called adult-onset Still’s disease (AOSD).2 Indeed, according to his study of 14 women aged 17–35 years, clinical features were identical to those of patients with sJIA. The cut-off of 16 years to discriminate between the two conditions was subsequently instituted but was arbitrary and related to the organisation of care structures (different inpatient units for children and adults with ‘rheumatism’ because of different care requirements).3

Many arguments support that sJIA and AOSD may correspond to the same rare non-familial (sporadic) systemic inflammatory disorder occurring at different ages.4 sJIA and AOSD are characterised by inappropriate activation of innate immunity, with typical features of autoinflammatory disease, particularly at onset, and by subsequent abnormalities in adaptive immunity during the chronic phase. Clinically, both entities are characterised by four cardinal symptoms: high fever, typically spiking and lasting several days or weeks; arthralgia and arthritis; skin rash, typically coloured salmon pink and macular or maculopapular; and increased leucocyte and neutrophil counts.5 6 Besides these cardinal features, the two conditions share many other clinical manifestations, including hepatomegaly, splenomegaly, lymphadenopathy and serositis. Furthermore, they exhibit common laboratory abnormalities, including increased erythrocyte sedimentation rate (ESR) and C reactive protein (CRP) level and hyperferritinaemia. In addition, the disease course and prognosis are comparable.5 6 Historically, the clinical course has been divided into three different phenotypes, described on the basis of the evolution of symptoms over time: monocyclic, polycyclic and chronic.4

For both sJIA and AOSD, a phenotypic dichotomy has been recognised: a more systemic inflammatory phenotype and a more chronic articular phenotype, with or without residual systemic features.4 Additionally, both are associated with a predisposition to life-threatening complications, such as macrophage activation syndrome (MAS), hepatitis and interstitial lung disease.5 6 MAS is a hyperinflammatory condition that should be suspected in patients with sJIA/AOSD with fever, cytopenia and hyperferritinaemia. Diagnostic scores (MAS/sJIA (MS) score or HScore)7 8 and classification criteria (2016 MAS criteria)9 are available to help clinicians in the early diagnosis. Early immunosuppressive treatment is associated with reduced mortality, both in adults and children. At present, MAS mortality remains approximately 10%,10 so identifying biomarkers related to the pathway involved in the development of MAS could be useful for targeted therapy and to improve management.

In addition, several data suggest that sJIA and AOSD are very similar in terms of the pathophysiology because the innate immune system plays a prominent role in both conditions.5 11 12 The overexpression of inflammatory cytokines, such as interleukin-1 (IL-1), IL-6, IL-18 and calcium-binding proteins, as well as the striking response to IL-1 and IL-6 inhibition have led to considering the conditions as complex, polygenic autoinflammatory syndromes.5 11 12 The finding of similar associations with human leucocyte antigen (HLA) alleles and cytokine gene polymorphisms indicates that sJIA and AOSD may be indistinguishable on a genetic level.13 While these patients do not exhibit classical features of autoimmunity, the adaptive immunity seems involved, particularly in patients with a chronic articular course.

According to the compelling evidence of their similarity, many experts believe that sJIA and AOSD are the same disease occurring at different ages.4 However, there has never been a formalised consensus, and most scientific studies have addressed sJIA and AOSD separately. As a result, the classification criteria used for clinical research purposes differ, and therapeutic strategies and clinical practice guidelines have been defined independently for sJIA and AOSD, thus reducing the power of clinical trials, limiting the dissemination of knowledge and hampering the implementation of optimal strategies in daily practice. Several Still’s disease experts have expressed the view that sJIA and AOSD should be considered a single disease, but evidence has been lacking for the case and to reach consensus.

The European Alliance of Associations for Rheumatology (EULAR) and the Paediatric Rheumatology European Society (PReS) decided to homogenise the perspective of rheumatologists of paediatric and adult disease and set up a task force to draft joint recommendations for the diagnosis and management of sJIA and AOSD. A systematic review (SR) of the literature was undertaken to inform the task force. The objectives of this study were to analyse the similarity of the diseases in terms of the prevalence of clinical manifestations (including complications) and the diagnostic value of biomarkers in both diseases. Finding that the diseases are similar in this SR would help demonstrate that sJIA and AOSD are the same disease occurring at different ages.

ResultsSR1: prevalence of manifestations

The search identified 515 records. After removing 191 duplicates, 324 reports were screened, and one article, published immediately after the date of search, was included after a secondary search. Nine articles were assessed for detailed eligibility, and all but one were finally included (n=1010 participants). Online supplemental figure 1 describes the selection process.

Table 1 summarises the main characteristics of the included studies. Except for one cross-sectional study, the design of the studies was longitudinal; only one was prospective. The risk of bias was moderate in six studies and high in two (mean score 5 on the adapted Hoy scale for prevalence studies). In two studies, the authors clearly stated they were from referral centres; such information was missing for the others. The systemic/articular pattern was reported in only two studies, and the disease course was described in five. ILAR criteria were the most used for the diagnosis of sJIA (six studies, five using the 2001 second Edmonton revision and one the previous first 1997 Durban revision), followed by the ACR 1972 criteria (two studies) and PRINTO criteria (one study). Only three studies strictly applied the ILAR criteria for patient inclusion. Two studies used them as a diagnostic aid, but the final diagnosis was by physician opinion.28 29 For AOSD, the use of Yamaguchi criteria was more consensual: they were used in all eight studies. In addition to the Yamaguchi criteria, the Medsger and Christy and Fautrel criteria were used in one study each. As for sJIA, the final diagnosis of AOSD was retained by the physician in the same two studies. The Pouchot systemic score (original or modified by Rau et al) was available for four studies; disease activity was high.

Table 1

Main characteristics of the included studies in SR1: prevalence of manifestations

Table 2 summarises the main demographic characteristics of the samples as well as the patterns and clinical courses and criteria fulfilment by age group. Descriptors are provided as weighted average percentages or means. The female distribution was similar, about 50% in each group. The duration of follow-up was 6 months longer in the sJIA than AOSD group. The groups were comparable in distribution of patterns and courses.

Table 2

Demographic characteristics of the samples, patterns and courses, and criteria fulfilled, by group (SR1: prevalence of manifestations)

The two groups did not differ in pooled prevalence of clinical manifestations, except for the three features, myalgia, sore throat and weight loss, which were more frequent in AOSD than sJIA (figure 1, online supplemental figure 2). Similarly, the groups did not differ in pooled prevalence of biological features, including leucocytosis, serum CRP level and ferritin level. The only exception was anaemia when defined by the cut-off of haemoglobin <120 g/L, which is more appropriate for adults. Indeed, during childhood, normal values change with age, and in several age groups, a value of 120 is well within normal limits (figure 2, online supplemental figure 3). Indeed, the difference was not evident when a threshold relevant for both children and adults was used (ie, haemoglobin <100 g/L). Other biological features were reported differently across studies, so obtaining a pooled mean was not possible.

Figure 1

Prevalence (pooled estimates) of clinical manifestations in patients with sJIA and AOSD (SR1: prevalence of manifestations). Values are pooled estimates of prevalence (95% CI). For each parameter, prevalence is represented in black for sJIA and grey for AOSD. 1Heterogenity is summarised visually by asterisks: *low heterogeneity (I2<50%); **moderate heterogeneity (50<I2<75%); ***high heterogeneity (I2>75%). For details of the I2 and p values of each group, please refer to the online supplemental material. 2Heterogeneity between groups is statistically different at p<0.05. For details of p values, please refer to the online supplemental material. The line "arthritis bis" gives the arthritis pooled estimate prevalence without the study by Inoue et al 12 because it had a very low rate of arthritis in both age groups, accounting for the large part of variability when taken into account. sJIA, systemic juvenile idiopathic arthritis; AOSD, adult-onset Still’s disease.

Figure 2

Prevalence (pooled estimates) of modified biological features in sJIA and AOSD (SR1: prevalence of manifestations). Values are pooled estimates of prevalence (95% CI). For each parameter, prevalence is represented in black for sJIA and grey for AOSD. 1Heterogenity is summarised visually by asterisks: *low heterogeneity (I2<50%); **moderate heterogeneity (50<I2<75%; there were no studies with moderate heterogeneity in this figure); ***high heterogeneity (I2>75%). For details of the I2 and p values of each group, please refer to the online supplemental material. 2Heterogeneity between groups is statistically different at p<0.05. For details of p values, please refer to the online supplemental material. ANA, antinuclear antibody; AOSD, adult-onset Still’s disease; CRP, C reactive protein; ESR, erythrocyte sedimentation rate; Hb, haemoglobin; RF, rheumatoid factor; sJIA, systemic juvenile idiopathic arthritis.

Except for AA amyloidosis, the two groups did not differ in pooled prevalence of complications (figure 3, online supplemental figure 4). Although mortality was slightly higher in the AOSD than sJIA group (with high heterogeneity in the studies), the difference did not reach statistical difference. Regarding MAS, we found heterogeneity within groups, but not between groups. Of note, only one study reported on the frequency of thrombotic microangiopathy, tamponade, myocarditis or pulmonary hypertension, and, therefore, meta-analysis was not performed for these complications.29 Two studies reported the frequency of amyloidosis. Although numbers were very low, AA amyloidosis was less frequent in AOSD than sJIA, and the difference between groups was statistically significant (p=0.009).

Figure 3

Prevalence (pooled estimates) of complications in patients with sJIA and AOSD (SR1: prevalence of manifestations). Values are pooled estimates of prevalence (95% CI). For each parameter, prevalence is represented in black for sJIA and grey for AOSD. 1In Neau et al 29, the details of macrophage activation syndrome (MAS), thrombotic microangiopathy, tamponade, myocarditis and interstitial lung disease for each group (sJIA and AOSD) were obtained directly from the authors (not published data). 2Heterogenity is summarised visually by asterisks: *low heterogeneity (I2<50%); **moderate heterogeneity (50<I2<75%); ***high heterogeneity (I2>75%). For details of the I2 and p values of each group, please refer to the online supplemental material. 3Heterogeneity between groups is statistically different at p<0.05. For details of p values, please refer to the online supplemental material. 4Note that for Neau et al [29], the authors reported a total n=26 in the published data, but in their Excel file n=24 (12 in sJIA group, 12 in AOSD group), so we considered n=24 for our meta-analysis. 5Only one study 29 reported on the frequency of thrombotic microangiopathy, tamponade, myocarditis or pulmonary hypertension, and so meta-analysis was not performed for these complications. AOSD, adult-onset Still’s disease; sJIA, systemic juvenile idiopathic arthritis.

Table 3 provides the weighted frequency of articular involvement in sJIA and AOSD by joint. Only two papers provided the n/N.30 31 A third provided a sentence with the order of frequency of the involvement but without the n/N.32 The difference in frequency between groups was not present, except in the following joints: knees, ankle, elbow, hip and cervical spine, clinically higher in sJIA than AOSD.

Table 3

Weighted frequency of articular involvement in sJIA and AOSD by joint

The weighted percentages of treatments used in included studies are found in online supplemental table 6. Non-steroidal anti-inflammatory drugs were more used in sJIA, and glucocorticoids and conventional synthetic disease-modifying antirheumatic drugs (DMARDs; methotrexate) were more used in AOSD. A greater percentage of children received biologic DMARDs than adults.

SR2: diagnostic biomarkers for sJIA and AOSD

The search identified 1099 records. After removing 120 duplicates, 972 reports were screened, 118 were assessed for eligibility and 33 were finally included. Online supplemental figure 5 describes the selection process.

The SR retrieved many different potential diagnostic biomarkers (online supplemental figure 6 and online supplemental table 10). Only three were analysed in several studies of both sJIA and AOSD: ferritin/glycosylated ferritin, the S100 protein group (S100A8/A9/A12) and IL-18. Table 4 summarises each of these studies and the cut-offs for biomarkers and accuracy data. Online supplemental table 11 provides the QUADAS-2 evaluation of risk of bias of the retrieved studies; most were at moderate to high risk of bias. We did not pool the results in a meta-analysis because of the variability in populations compared and the definition of a gold standard.

Table 4

Main serum diagnostic biomarkers in sJIA and AOSD and their performance (SR2: diagnostic biomarkers for sJIA and AOSD)

SR3: diagnostic biomarkers for MAS

From the 979 articles retrieved, we finally selected 10 articles that fulfilled the eligibility criteria described (online supplemental figure 7). Eight articles concerned sJIA and two AOSD. Among the biomarkers identified, some were ‘classical’ (ie, standard laboratory measurements) and others ‘novel’ (ie, non-standard laboratory measurements of inflammation related to pathogenic pathways of MAS). High sensitivity/specificity was defined as values >70% and moderate sensitivity/specificity as 50–70%.

Classical biomarkers for MAS

Seven articles evaluated the classical biomarkers of MAS33–39: two studies included adults, and five studies included children. Online supplemental table 12 summarises the main data and the risk of bias for each study. Two studies before the development of the 2016 MAS classification criteria were included because from an analysis of the articles we could establish that the patients satisfied the 2016 MAS criteria.

Ferritin level was the most frequently reported diagnostic biomarker for MAS. It showed high sensitivity but moderate specificity to differentiate sJIA/AOSD-related MAS and active sJIA/AOSD without MAS or infections. The cut-off values differed depending on the population (adult or paediatric) and the controls used. The ratio or ferritin level to ESR showed high sensitivity and specificity to differentiate sJIA-related MAS and infections. Only one study evaluated the glycosylated ferritin fraction in AOSD-related MAS versus AOSD without MAS; it showed very high sensitivity but low specificity.

CRP level was tested as a diagnostic biomarker to differentiate sJIA-related MAS and virus-associated or familial haemophagocytic lymphohistiocytosis (HLH) but showed moderate sensitivity and specificity. It was the only biomarker tested as a prognostic biomarker for MAS in one study in which high CRP level predicted mortality in AOSD-related MAS versus AOSD without MAS, with moderate sensitivity and low specificity. Other inflammatory/tissue damage biomarkers (albumin, aspartate aminotransferase, soluble CD25, fibrinogen, lactate dehydrogenase, neutrophil, platelet count and white cell count) were evaluated as diagnostic biomarkers for sJIA-related MAS versus active sJIA or other forms of HLH. All showed moderate sensitivity and specificity.

Novel biomarkers for MAS

Four studies investigated the accuracy of novel biomarkers as potentially diagnostic for MAS.33 40–42 Table 5 summarises their main data and risk of bias. These studies included only paediatric patients with sJIA-related MAS. Patients with sJIA without MAS or with other (primary or secondary) forms of HLH were used as control group.

Table 5

Novel diagnostic biomarkers for MAS: characteristics of the studies and parameters of accuracy (SR3: diagnostic biomarkers for MAS)

Total IL-18 level was used as a diagnostic biomarker of MAS alone or combined with C-X-C motif ligand (CXCL9 or CXCL10). High levels of total IL-18 had high sensitivity and specificity for distinguishing sJIA-related MAS from sJIA without MAS but not the other forms of secondary HLH (sHLH). Increased IL-18/CXCL9 and IL-18/CXCL10 ratios had moderate sensitivity and specificity for distinguishing sJIA-related MAS from sHLH but with good sensitivity and specificity for distinguishing sJIA-MAS from primary HLH (pHLH). S100A12, alone or combined with CXCL9 or CXCL10, had high sensitivity and specificity for distinguishing sJIA-related MAS from pHLH or sHLH. CXCL9 alone (ie, not combined with IL-18 or S100A12) yielded high sensitivity and specificity for distinguishing sJIA-MAS from sJIA without MAS. High levels of adenosine deaminase 2 (ADA2) activity presented high sensitivity and specificity for distinguishing sJIA-related MAS from sJIA without MAS. High CD38high/HLA-DR+CD8+ T-cell count and CD4dimCD8+ T-cell count distinguished sJIA-MAS from active sJIA without MAS with high sensitivity and specificity. Finally, a high TNFR-I/TNFR-II ratio showed high sensitivity and moderate specificity for differentiating patients with sJIA-MAS and patients with sJIA receiving tocilizumab.

Discussion

To our knowledge, this study is the first SR of comparative cohorts and meta-analysis examining the prevalence of clinical manifestations (including complications) and laboratory findings in sJIA and AOSD. We found a globally similar prevalence of clinical and biological manifestations for sJIA and AOSD, including complications. This is a strong argument supporting a continuum between the two entities.

The differences in prevalence were few and not substantial and can be easily explained by confounding factors. Myalgia and sore throat were more frequent in adults than children. These are symptoms that are difficult for young children to report, leading to a possible reporting bias. Furthermore, sore throat is one of the items required in the Yamaguchi criteria and thus recorded/noted by rheumatologists caring for adults but is not present in ILAR criteria; therefore, paediatricians may be less likely to look for it,4 43 while it is not in the criteria used in the paediatric age. Weight loss was more frequently mentioned in adults than children, who rather have a growth curve break. The conditions did not differ in the frequency of anaemia with a haemoglobin cut-off of <100 g/L, which was more appropriate, because children physiologically have lower levels of haemoglobin compared with adults.44 The authors of these comparative studies should probably have used different standards for this factor for paediatric and adult populations. The same remark can be applied to leucocytosis; however, no statistically significant difference was noted whatever the threshold. Children have more prolonged exposure to the uncontrolled inflammatory process than do adults, because the disease starts earlier in life.45 However, the two studies reporting AA amyloidosis were older (1995 and 2006),30 31 performed prior to the widespread use of biologics, which may have greatly reduced the prevalence of AA amyloidosis in recent years.46 47 Notably, AA amyloidosis was not reported in the retrieved articles that were more recent than 2006. One last difference is a potential different distribution of the affected joints between children and adults (table 3). The small number of studies (two papers) requires caution in generalising these results. Other comparative series have shown a higher similarity in the topography of affected joints between sJIA and AOSD.48 This observation seems consistent with the results of a third study we retrieved,32 in which the authors reported that ‘the affected joints were the knees, ankles, wrists, elbows, proximal interphalangeal joints and metacarpophalangeal joints (in order of frequency) in children and adults alike’. However, this study could not be included in our meta-analysis because the n/N for each joint involvement were not provided.

We did not find any difference between sJIA and AOSD in terms of sex in that the weighted average of women was about 50% in each group. Although the sex ratio is 1:1 in the paediatric-onset forms, some authors have suggested that the adult form may more frequently affect women (70% vs 30%).4 However, these data were mostly from rheumatological series with small numbers (61–104 patients) and included mainly chronic joint forms. More recent series have reported a more balanced sex ratio, although the number of patients is still limited.49 50

Although many paediatricians often consider ILAR 2001 criteria too stringent because they require at least one joint with arthritis persisting for at least 6 weeks, we found a globally similar prevalence of arthritis between sJIA and AOSD in our meta-analysis. This observation could be explained in part by only three studies strictly applying the ILAR 2001 criteria for including paediatric patients, and one applied the previous 1997 Durban revision of the ILAR criteria, which are looser because they take into account the possibility of developing arthritis only after 6 months of systemic illness. In fact, the need for arthritis, which is mandatory in the ILAR 2001 classification, is debated among paediatricians because many young patients do not have arthritis (but rather arthralgia) and yet have all the other classic manifestations of Still’s disease.43 Thus, a revision of the classification criteria for the paediatric form has recently been proposed,18 and the presence of persistent arthritis may no longer be considered mandatory in the future.

Concluding that sJIA and AOSD are the same disease occurring at different ages of life would eventually imply the need to use the same classification criteria. Indeed, in the current configuration, rheumatologists of children and adults may use different or even contradictory terms when referring to the same disease.51 Indeed, a common disease name and classification criteria would allow for homogenising the diagnosis and management of paediatric and adult patients and would open the door to joint clinical research and trials. The question remaining is whether new common criteria should be established or whether already existing classification criteria can be used interchangeably in children and adults. For instance, the Yamaguchi criteria may be useful for classifying sJIA.52

Our SR retrieved many different potential diagnostic biomarkers (online supplemental figure 6 and online supplemental table 10). However, only three were analysed in several studies in both sJIA and AOSD: ferritin/glycosylated ferritin, the protein S100 group (S100A8/A9/A12) and IL-18. The controls used between the different studies were very different, so generalising results is impossible. Therefore, sensitivity, specificity, cut-offs and AUC values provided in table 4 must be interpreted with caution. Nevertheless, these diagnostic biomarkers look promising, and research should start using them in a more standardised way. One potential limitation of our SR on diagnostic biomarkers is that we included only studies that had accuracy data (ROC, AUC, sensitivity and specificity values). Hence, it misses more descriptive studies with only correlations, but this would have led to a high number of studies and lower scientific pertinence. Other biomarkers have been proposed but only in small cohorts, without replication in another population (online supplemental figure 6 and online supplemental table 10).

The same limitations (accuracy parameters, controls and missing descriptive studies with only correlations) apply to SR3 on diagnostic biomarkers for MAS (table 5 and online supplemental table 12). MAS occurring during sJIA and AOSD is a hyperinflammatory condition with significant morbidity and mortality. Early recognition and diagnosis can be challenging, and remission is often achieved with the association of multiple therapies. Clinical scores and classification criteria have recently been developed to help clinicians diagnose MAS. In sJIA, the 2016 classification criteria for MAS have shown high specificity (99%) and sensitivity (73%).9 In patients with AOSD, these criteria were useful to identify MAS with high specificity (100%) and sensitivity (70%) and helped identify patients at high risk of mortality.53 54 Two diagnostic scores for MAS have been developed, the MS score7 and the HScore8: they have high sensitivity (both 91.3%) and specificity (83.8% and 90.2%).55 The MS score was developed in sJIA and the HScore was developed in adults with various forms of sHLH, which included only a few patients with AOSD. All these scores and criteria include variable combinations of elevated ferritin levels, inappropriately low cell counts, elevated liver function test results and signs of intravascular activation of coagulation, all known to be part of the clinical and laboratory pattern associated with hyperinflammation.56 Our SR3 yielded several papers confirming ferritin level as a diagnostic biomarker for MAS with high sensitivity. However, we found scarce data, or no data, concerning the other laboratory factors (CRP, albumin, aspartate aminotransferase, soluble CD25, fibrinogen, lactate dehydrogenase, neutrophil, platelet count and white cell count), which are part of these criteria and scores. To improve the early recognition of MAS, studies examining the predictive value of each of these laboratory measurements are warranted. In addition, validation of the MAS 2016 criteria in populations of different ages and the establishment of cut-offs for age are needed.

With the progressive recent understanding of the pathogenesis of MAS, novel diagnostic biomarkers have been investigated to improve the diagnosis of MAS (ie, with earlier identification with higher sensitivity and specificity). Our SR3 retrieved only paediatric studies of these potential novel biomarkers for MAS. No studies involving adults could be linked to our inclusion criteria, which required diagnosis by the MAS 2016 classification criteria, which are more frequently used by paediatricians than physicians for adults. Therefore, we may have missed some studies of AOSD-related MAS using other criteria. Also, although MAS 2016 criteria are the most rigorous to classify MAS, they have been recently developed and so would appear to bias against older studies. In any case, the first novel biomarker identified is IL-18. It is an interferon-γ (IFN-γ)-inducing cytokine that has been involved in the pathogenesis of MAS in the context of sJIA/AOSD. It is present in the blood as a free molecule or bound to IL-18-binding protein (IL-18BP), total IL-18 being a combination of both.57 Free IL-18 is biologically active. Markedly elevated levels of total IL-18 are suggestive of predisposition to the development of MAS in the sJIA population.58 59 Elevated total IL-18 level seems to distinguish MAS from active sJIA with high sensitivity and specificity.33 One study reported significantly higher free IL-18 levels in sJIA-MAS than sJIA without MAS and other forms of HLH, with no relevant differences in level of IL-18BP between MAS and other forms of HLH.57 Because the assay for free IL-18 is not widely available and levels of free IL-18 are highly related total IL-18 level,57 measurement of total IL-18 is routine, and clinically graded tests are becoming available. Consistent with the activation of the IFN-γ pathway, high CXCL9 level and ADA2 activity, both induced by IFN-γ, have been reported in MAS in both children and adults.33 57 60 61 Indeed, CXCL9 level and ADA2 activity also seem good diagnostic biomarkers able to differentiate MAS and active sJIA, with high sensitivity and specificity (table 5). Furthermore, ADA2 activity is highly related to total ADA activity, whose detection is more convenient.62 Hence, total ADA activity may be a MAS biomarker.62 In addition, serum levels of total IL-18 and S100A12 differentiate MAS and other forms of HLH (primary and secondary) with high sensitivity and specificity.40 This may be particularly helpful in the context of MAS presenting at the onset of Still’s disease when the diagnosis of the disease itself is not yet clear. Markedly elevated populations of activated CD8 T cells (CD38high/HLA-DR+CD8+ T cells and CD4dimCD8+ T cells) are present in MAS versus active sJIA.41 CD8 T lymphocytes have been found pathogenic in some HLH models, and their count is elevated in primary (p)HLH and infection-associated HLH.63 64 Activated CD8 T lymphocytes, identified by CD38high/HLA-DR+ positivity, are also able to distinguish HLH (primary and infection associated) from sepsis.64 They appear to differentiate MAS and active sJIA with high specificity and sensitivity. Both populations are similarly increased in all forms of sHLH, which demonstrates that they do not differentiate MAS in Still’s disease and other forms of sHLH.

Overall, these observations with the various potential diagnostic biomarkers are reported in a limited number of studies, and therefore, confirmation in larger series is needed. Moreover, to allow widespread use of these novel biomarkers in clinical practice, cross-validation between different laboratories is needed as is the identification of standardised international cut-off values. An international project involving North American and European centres is ongoing. No data about prognostic biomarkers have been reported, except one study reporting high CRP level as a predictor of mortality in MAS during AOSD, with high sensitivity and low specificity.34 Taking into account the previous considerations and their increasing availability, IFN-γ-related biomarkers (CXCL9 and IL-18) seem to be novel biomarkers that could improve the diagnosis and management of MAS. Moreover, activated T cells are also promising because they can be easily evaluated with a simple flow cytometry protocol and seem to help in the differential diagnosis of MAS versus active sJIA/AOSD but also many forms of ppHLH and sHLH.

Our study has some limitations. The studies retrieved were of medium to low quality (medium to high risk of bias), which is inherent to studies of rare diseases and retrospective study designs (SR1 on comparative cohorts) and diagnostic biomarker studies (SR2 and SR3). In SR1, we included only cohorts that compared children and adults. Including all single cohorts would have been cumbersome and could have been a source of bias in reporting (reporting is more homogeneous in comparative cohorts). We chose the cut-off of ≥20 patients in each group for two reasons: sJIA/AOSD is a rare disease, so cohorts comparing children versus adults with a high number of patients in each group are rare; it would have been difficult to have any prevalence below at least 20 patients in each group. Of note, we had originally planned to collect information on biomarkers in these comparative studies. Unfortunately, the data were almost non-existent in these studies and therefore not usable, which justified the second SR specifically dedicated to diagnostic biomarkers and focusing on single cohorts. We also initially planned to examine the different definitions used to define some manifestations such as fever and musculoskeletal and skin involvement because these items often lack a consensual definition in the literature. Unfortunately, most of the selected articles did not provide definitions of these features, so we could not meet our objective. Complications were reported only by a few studies. Some (thrombotic microangiopathy, tamponade, myocarditis or pulmonary hypertension) were reported in only one study, so meta-analysis could not be performed.

Our data provide strong and robust arguments favouring the similarity of sJIA and AOSD (ie, a continuum between the two entities). They validate the rationale to produce joint recommendations for the diagnosis and management of sJIA and AOSD, as planned by EULAR and PReS. It is the first step for future work aimed at proposing a unique name for sJIA and AOSD, as well as a common and consensual set of classification criteria. The present work will also open the way to common research to validate diagnostic and prognostic biomarkers and establish new therapeutic strategies for the disease and its complications.

Protocol and registration

The protocol for SR1 was registered in PROSPERO (CRD42022374240, https://www.crd.york.ac.uk/prospero).

In the initial protocol, we had planned to include only studies whose participants met the ILAR criteria for patients with sJIA and the Yamaguchi or Fautrel criteria for patients with AOSD. However, because some of the selected studies were published before 2004, when the ILAR criteria were revised for the second time, the protocol was secondarily amended to include studies that used at least one of the earlier historical classification criteria (ACR 1972 or Durban’s first revision of ILAR criteria for sJIA; Medsger and Christy criteria for AOSD) or the PRINTO criteria. Similarly, we decided to have a tolerance for retaining studies that used classification criteria, but in which the final diagnosis was from the physician.

The protocol for SR3 was registered in PROSPERO (CRD42024534021, https://www.crd.york.ac.uk/prospero).