Seminars in Arthritis and Rheumatism 51 (2021) 858
874

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Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit

Adult-onset Still’s disease in focus: Clinical manifestations, diagnosis,

treatment, and unmet needs in the era of targeted therapies
Petros Efthimioua,*, Apostolos Kontziasb, Peter Hurc, Kavita Rodhad, G S Ramakrishnad,
Priscila Nakasatoc
a
Internal Medicine and Rheumatology, New York Rheumatology Care and Ross University School of Medicine, NY, United States
b
Division of Rheumatology, Allergy and Immunology, Stony Brook University School of Medicine, Stony Brook, NY, United States
c
Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States
d
Value and Access, Novartis Healthcare Pvt Ltd, Hyderabad, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder of unknown etiology,
Adult-onset still's disease characterized by a clinical triad of high spiking fever, arthralgia (§ arthritis), and evanescent skin rash. Man-
AOSD agement of AOSD poses several challenges, including difficulty in diagnosis and limited therapeutic options.
Diagnosis In this review, we examined whether AOSD and systemic juvenile idiopathic arthritis (SJIA) represent a con-
Biologics
tinuum of the same disease. We also explored the latest available evidence related to prevalence, clinical and
Novel biomarkers
laboratory manifestations, complications, diagnostic challenges, novel biomarkers, and treatment options in
Unmet needs
the era of biologics and identified the unmet needs of patients with AOSD.
Methods: A comprehensive systematic literature search was performed in the Embase and MEDLINE (via
PubMed) literature databases. The search was limited to human studies published in English from inception
up to March 2020. Additionally, abstracts presented at various conferences were screened and hand searches
were performed. Publications were processed according to the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses (PRISMA) guidelines.
Results: A total of 123 publications were identified through the literature search, majority of which were case
series and retrospective observational studies. AOSD and SJIA are widely considered part of the same disease
spectrum owing to similarities in their clinical and biological features. The clinical presentation of AOSD is
highly variable, accompanied by a broad spectrum of disease manifestations. Recent evidence suggests that
the AOSD disease course can be classified into two distinct categories: “systemic” and “articular.” Further-
more, AOSD patients may experience various life-threatening complications, such as macrophage activation
syndrome — reported in as high as 23% of AOSD patients and considered to be the most severe complication
characterized by a high mortality rate.
The ambiguity in presentation and lack of serologic markers make the diagnosis of AOSD difficult, often lead-
ing to a delay in diagnosis. Given these limitations, the Yamaguchi and Fautrel criteria are the most widely
used diagnostic tools in clinical practice. It has been observed that a clinical diagnosis of AOSD is generally
reached by exclusion while investigating a patient with fever of unknown origin. Recent advances have dem-
onstrated a major role of proinflammatory cytokines, such as interleukin (IL)-1, IL-6, IL-18, and IL-37, and
other biomarkers in the pathogenesis and management of AOSD.
Owing to the rarity of the disease, there are very limited clinical trials evaluating management strategies for
AOSD. The current AOSD treatment paradigm includes non-steroidal anti-inflammatory drugs (NSAIDs) and
glucocorticoids initially, conventional synthetic disease-modifying anti-rheumatic drugs in steroid-refractory
patients, and biologics in those resistant to conventional treatment. Only a few country-specific guidelines
for the management of AOSD have been published, and a treat-to-target approach, as previously recom-
mended for SJIA, is still lacking. Canakinumab is the only FDA
approved biologic for the treatment of AOSD.

Abbreviations: ACR, American College of Rheumatology; ANA, antinuclear antibody; AOSD, adult-onset still’s disease; CRP, C-reactive protein; Cyr61, cysteine-rich angiogenic
inducer 61; DMARD, disease-modifying antirheumatic drug; ESR, erythrocyte sedimentation rate; FDA, Food and Drug Administration; FUO, fever of unknown origin; HLA, human
leukocyte antigen; HLH, hemophagocytic lymphohistiocytosis; HO-1, heme oxygenase; IL, interleukin; IFN, interferon; JAK, Janus kinase; LRG, leucine-rich a2-glycoprotein; MAS,
macrophage activation syndrome; NLR, neutrophil-to-lymphocyte ratio; NSAID, nonsteroidal anti-inflammatory drug; PRISMA, Preferred Reporting Items for Systematic Reviews
and Meta-Analyses; RA, rheumatoid arthritis; RF, rheumatoid factor; RCT, randomized controlled trial; SJIA, systemic juvenile idiopathic arthritis; SLE, systemic lupus erythemato-
sus; SLR, systematic literature review; USA, United States of America; US, United States
* Corresponding author.
E-mail address: [email protected] (P. Efthimiou).

https://doi.org/10.1016/j.semarthrit.2021.06.004
0049-0172/© 2021 Novartis Pharmaceuticals Corporation. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)
 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874 859

Conclusion: Emerging evidence supports that AOSD and SJIA represent a continuum of the same disease
entity. Despite advancements in the understanding of AOSD, it continues to pose a substantial burden on
patients and the healthcare systems, and substantial unmet needs exist across key domains such as the path-
way to diagnosis, use of biomarkers in clinical practice, and standardized treatment strategies. Further
research and collaboration is crucial for optimizing the diagnosis and management of AOSD patients.
© 2021 Novartis Pharmaceuticals Corporation. Published by Elsevier Inc. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)

Introduction No ethical approval was required because no individual patient

identifiers were disclosed in the publications included in this SLR.
Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory
disease of unknown etiology usually affecting young adults. AOSD Results
was first described as a distinct clinical entity in the early 1970s by
Eric Bywaters [1]. It is typically characterized by a triad of spiking Continuum of sjia to AOSD
fever, arthritis, and salmon-colored skin rash and closely resembles
childhood-onset Still’s disease, commonly known as systemic juve- AOSD is a systemic inflammatory disorder analogous to SJIA. Both
nile idiopathic arthritis (SJIA), which was first described by George conditions encompass many common clinical and biological features,
Still in 1897 [2]. Although the exact pathogenic mechanisms of the including the occurrence of macrophage activation syndrome (MAS;
disease are unknown, substantial advances have been made support- Table 1). Specifically, cohort studies across the spectrum depict that
ing the concept of a Still’s disease spectrum, wherein SJIA and AOSD both AOSD and SJIA appear to affect a similar distribution of joints
would be part of a continuum, delimited by the age at onset of dis- and are similarly associated with a constellation of systemic manifes-
ease presentation [3]. Several factors have been proposed to be tations, including fever; a very characteristic salmon-colored, evanes-
involved in the etiology of this disease, including genetics (associa- cent cutaneous eruption; splenomegaly; lymphadenopathy; myalgia;
tion with human leukocyte antigen [HLA] DRB1*1201 and 1501, B35, hepatomegaly; pericarditis; pneumonitis; and renal dysfunction. Col-
DR2 and DR5), infections (from viral and bacterial pathogens), and a lectively, these findings show that AOSD patients have a disease
dysregulated immune system [4
7]. Stressful life events related to onset and course undistinguishable from that of SJIA patients, sug-
work, family and health have also been suggested to be a potential gesting that these diseases represent a continuum of a single disease
trigger for AOSD [8]. With the advantage of understanding the role of entity.
the inflammasome in its childhood counterpart SJIA and in mono-
genic autoinflammatory diseases, there is growing evidence that Epidemiology
AOSD is an autoinflammatory disorder [9,10].
In this systematic literature review (SLR), we focused on the epi- AOSD is a rare multisystem disease; it is a relatively recently
demiology, clinical picture, complications, diagnosis, and possible described condition and therefore lacks robust epidemiological data.
treatment strategies for AOSD in the era of biologics. We also Most of the information is based on data from retrospective observa-
explored the relationship between AOSD and SJIA and new diagnostic tional studies or case series. The annual incidence of AOSD is esti-
biomarkers available for AOSD patients. mated to be between 0.16 and 0.62 per 100,000 individuals
worldwide, independent of ethnicity [18
20]. The estimated preva-
Methods lence is between 0.73 and 6.77 per 100,000 individuals [18,19,21]. In
two recent studies, the prevalence was reported to be 3.9 per
This SLR was conducted following the Preferred Reporting 100,000 individuals in Japan and 6.77 per 100,000 individuals in Tur-
Items for Systematic Reviews and Meta-Analyses (PRISMA) guide- key [18,21]. Owing to an increased awareness about AOSD over the
lines [11]. Comprehensive searches were conducted in March 2020 last 2 decades, incidence and prevalence rates were observed to be
using the Embase and MEDLINE (via PubMed) literature databases higher in recent studies compared with those reported before 2000
as well as abstracts presented at various conferences. We also per- (Table 2).
formed hand searches for relevant additional references. The main
search terms included “Adult Onset Still Disease,” “AOSD,” “Still’s Disease patterns
disease,” “Wissler Fanconi syndrome,” “epidemiology,” “diagno-
sis,” “clinical and laboratory manifestations,” “disease continuum,” Conventionally, three major disease patterns have been observed
“disease burden,” “diagnostic biomarkers,” and “treatment” (see in AOSD patients: monocyclic, polycyclic, and chronic articular
Supplementary Material for the complete list of search terms). The (Table 3). The monocyclic pattern is characterized by a single sys-
search was limited to human studies published in English from temic episode completely resolving within months; the polycyclic
inception up to March 2020. Two reviewers independently (also called intermittent) pattern is associated with one or more dis-
screened all the identified studies, and any disagreement was dis- ease flares and characterized by complete remissions that can last up
cussed and resolved. to a couple of years, and the chronic articular pattern is usually asso-
The search identified 2178 articles, of which 2107 were assessed ciated with long-lasting polyarthritis.
for eligibility after removal of duplicates and 123 publications fulfill- Maria et al. have proposed a dichotomous view of AOSD, distin-
ing the requirements were selected for the present SLR (Fig. 1). A guishing the AOSD subtypes according to the dominant clinical
majority of the retrieved articles were case series, case reports, and expression. Thus, it is possible to discriminate two different subsets
retrospective observational studies; therefore, to ensure reliable data of patients—those with predominant systemic clinical features, such
assessment, we included only those articles reporting data from 30 as fever and skin rash, and those with predominant articular involve-
patients. Well-designed prospective studies in AOSD patients are ment, more similar to the classic features of rheumatoid arthritis
very limited owing to the rarity of the disease. Furthermore, as the (RA) [22]. Approximately 50
70% of patients develop a chronic poly-
number of randomized controlled trials (RCTs) in AOSD patients is cyclic form of the disease or chronic polyarthritis, which can eventu-
very limited, we included all available RCTs irrespective of the num- ally induce joint destruction [21,23
25]. Similarly, Ichida et al. have
ber of patients. described two subsets of patients with AOSD—the “non-RA subtype,”
860 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874

Fig. 1. Summary of search results: PRISMA flow diagram.

Abbreviations: PKPD: pharmacokinetic-pharmacodynamic; PRISMA: preferred reporting items for systematic reviews and meta-analyses.

characterized by severe systemic inflammation, and the “RA-like sub- Clinical manifestations
type,” characterized by severe, sometimes erosive, arthritis [26]. AOSD patients generally present with the following triad of symp-
In regard to disease progression, Colina et al. demonstrated that toms: a spiking fever (>39 °C), maculopapular salmon-colored rash,
persistence of high ferritin levels after adequate treatment may be a and arthritis or arthralgia. The most common features of AOSD are
predictor of the chronic articular course [27]. Furthermore, data listed below:
from a large multicenter study suggested that a delayed diagnosis
was an important factor associated with the development of chronic  Fever: Fever is the most prominent symptom, occurring in
disease. Relapses or chronic articular patterns were found to be 46
100% of patients, and usually precedes other manifestations.
more common when the diagnosis had been delayed for >6 months The fever is typically a high spiking quotidian fever (39 °C),
[25
27]. which occurs daily or occasionally peaks twice daily, resolving
within a few hours. In a large cohort of AOSD patients, the fever
Clinical and laboratory manifestations pattern was usually intermittent in most cases, and was remittent
in up to 20% of the cases [37]. The diagnosis is often reached by
Age at diagnosis exclusion while investigating a patient with a fever of unknown
The disease occurs worldwide, usually affecting young adults with origin (FUO) [23,35,46]. Thus, awareness of this characteristic
a mean age at diagnosis of approximately 38 years (range: 33.3
45.0 fever pattern can be a valuable clue to early recognition of the dis-
years); however, delayed diagnosis is common considering the non- ease and to differentiate among other conditions such as lym-
specific symptoms and the lack of awareness among patients and phoma (Pel-Ebstein fever) and infections (tertian and quartan
within the medical community. AOSD shows a bimodal age distribu- malarial infections and undulant fever in brucellosis).
 Musculoskeletal manifestations: Joint involvement is a common
tion with two peaks of onset—the first affecting people in the age
group of 16
25 years and the second affecting people in the age sign in AOSD patients (approximately 40
100%), with arthralgia
group of 36
46 years. Most patients (45
80%) had disease onset and arthritis being the most frequently reported manifestations.
between 16 and 35 years of age. Although onset after the age of 60 is Arthritis, which is usually mild and localized at the beginning, can
rare, some case series have identified adult onset in patients aggravate through the course of the disease, becoming more
>60 years of age as well, which constituted around 7
10% of the severe and polyarticular. The most commonly involved joints are
cases [23,35,37,44,45]. The sex ratio was almost balanced in some the knees, wrists, ankles, elbows, and proximal interphalangeal
studies, while in some of the largest case series, a female predomi- joints [35,37,38,41,44,47]. AOSD often spares the distal interpha-
nance was observed (Table 4). langeal joints of the hands and shoulders. Narrowing of the
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Table 1
Similarities and differences between AOSD and SJIA.

Publication No. of patients Similarities Differences

AOSD SJIA

Inoue_2016 [12] 33 77 Clinical features: rash, lymphadenopathy, hepato- Significant female predominance among patients
megaly, splenomegaly, and arthritis with AOSD (p < 0.05)
Laboratory findings: hyperleukocytosis and eleva- Significantly increased serum ferritin levels, hepa-
tion of transaminase and ferritin levels tomegaly, and splenomegaly were observed more
MAS reported in both frequently with AOSD (p < 0.05)
Similar cytokine release patterns in both clinical Arthritis was more common among SJIA patients
entities than among AOSD patients (p < 0.05)
Markedly elevated serum IL-18 levels in patients
with AOSD and SJIA during the active and inactive
phases of the disease
Elevated levels of serum neopterin, IL-6, IL-18,
sTNF-RI, and sTNF-RII were observed in patients
with AOSD and SJIA during the active phase; how-
ever, all these cytokine levels normalized once
patients achieved clinical remission
Significant increases in serum neopterin, IL-18,
sTNF-RI, and sTNF-RII were observed during the
MAS phases of both diseases
Feist_2018 [13] 29 216 children; 56 young adolescents Canakinumab had a similar efficacy in older adoles-

cents/young adults and children and young adoles-
cents, i.e., both diseases were highly responsive to
IL-1b inhibition
Lin_2000 [14] 21 24 All children and adults with Still’s disease had fever More AOSD patients vs SJIA patients presented with a
Affected joints were similar—the knees, ankles, sore throat (81% vs 46%; p = 0.03)
wrists, elbows, proximal interphalangeal joints, AOSD patients had a significantly higher serum fer-
and metacarpophalangeal joints (in order of fre- ritin concentration than SJIA patients during the
quency) active disease phase (p < 0.01)
The clinical and laboratory features were similar
All children and adults received therapeutic dos-
ages of NSAIDs (aspirin or naproxen) Chronic
arthritis was comparable
Pay_2006 [15] 95 25 There were no significant differences in the pattern of The frequency of fever (98.9% vs 84%; p < 0.05), skin
fever and the type of skin rash or its localization rash (82.1% vs 64%; p < 0.05), myalgia (69.5% vs
between the groups 20%; p < 0.001), weight loss (17.9% vs 0%; p < 0.05),
and sore throat (66.3% vs 24%; p < 0.001) was
found to be significantly higher in patients with
AOSD compared with patients with SJIA
The most commonly affected joints were the
wrists, knees, and ankles (in order of frequency) in
adult patients with AOSD and the ankles, knees,
and wrists in patients with SJIA
Liver dysfunction and neutrophilia were more
common among adults
A majority of the adult patients had an unclassified
course in AOSD vs SJIA patients (21.1% vs 8.3%;
p < 0.05), whereas children predominantly had a
polycyclic disease pattern (41.7% vs 16.8%;
p < 0.001)
Uppal_1995 [16] 31 23 The clinical picture, disease course, and outcomes in AOSD had a significantly lower time interval from
AOSD were similar to those in SJIA disease onset to remission compared with SJIA
Yang_2018 [17] 132 - There was a fair concordance between the Yamaguchi

and ILAR criteria for SJIA in patients with AOSD
Abbreviations: AOSD: adult-onset Still’s disease; IL: interleukin; ILAR: International League of Associations for Rheumatology; MAS: macrophage activation syndrome; NSAID:
nonsteroidal anti-inflammatory drug; SJIA: systemic juvenile idiopathic arthritis; sTNF-RI: soluble tumor necrosis factor receptor I; sTNF-RII: soluble tumor necrosis factor recep-
tor II.

intercarpal or carpometacarpal joint spaces was observed in up to [27,35]. The Koebner phenomenon (the appearance of new lesions
75% of patients, being more characteristic of AOSD and unlikely in on areas of cutaneous injury or trauma, in otherwise healthy skin)
other inflammatory joint diseases of young adults, such as sys- was also observed in almost all patients in one case series [37].
temic lupus erythematosus (SLE) [35,37].  Sore throat/pharyngitis: This condition is commonly reported in
 Rash: The characteristic rash in Still’s disease is transient, non- up to 91.9% of patients. It usually coincides with the fever spike
pruritic, salmon-colored, and with macular or maculopapular and subsides as the body temperature returns to normal [44,48].
lesions, which are often observed during febrile episodes, pre-  Lymph node enlargement and hepatosplenomegaly: These condi-
dominantly in the late afternoon or evening. The typical rash tions are also very common. Lymphadenopathy develops in
appears mainly on the trunk and proximal extremities, occasion- around 42.8
56.3% of AOSD patients, frequently involving the
ally on the palms and soles, and tends to accompany fever [46], in cervical region, and may raise a suspicion of lymphoma initially.
some occasions being misdiagnosed as a drug eruption. Another Hepatomegaly may present in 6.6
71% of patients and is usually
common finding in many AOSD patients is an exaggerated urticar- accompanied with splenomegaly in up to 44% of the cases. Spleno-
ial response to cutaneous stimuli, which is referred to as derma- megaly alone was found in up to 83.7% of patients. Lymph node
tographism (reported in as high as 31% and 59% of patients) biopsy in AOSD patients may reveal reactive hyperplasia or
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Table 2
Incidence and prevalence of AOSD.

Publication Country Study type N Annual incidence (per 100,000) Prevalence (per 100,000)

Asanuma_2015 [21] Japan Retrospective 169 NR 3.9

Balci_2015 [18] Turkey Retrospective 42 0.62 6.77
Wakai_1997 [19] Japan Retrospective 146 0.22 (M), 0.34 (F) 0.73 (M), 1.47 (F)
Magadur-Joly_1995 [20] France Retrospective 62 0.16 NR
Abbreviations: AOSD: adult-onset Still’s disease; F: female; M: male; NR: not reported.

Table 3
Clinical course in AOSD patients.

Publication N Disease pattern (% of patients)

Monocyclic systemic/self-limited (%) Polycyclic systemic/intermittent (%) Chronic articular (%)

Kalyoncu_2016 [25] 356 45.9 36.1 18.0

Sfriso_2016 [28] 245 23.9 40.8 35.3*
Asanuma_2015 [21] 169 39.7 34.2 26.1
Kim_2012 [29] 141
44.4 55.6
Colafrancesco_2017 [30] 140
74.2** 25.8
Kim_2013 [31] 137 27.0 49.6 23.4
Ruscitti_2018 [32] 119 30.3 31.1 22.7
Ruscitti_2016 [33] 100 29.0 22.0 33.0
Pay_2006 [15] 95 21.1 16.8 41.1
Cagatay_2009 [34] 84 33.3 33.3 27.4***
Chen_2004 [35] 82 34.0 45.0 21.0
Kim_2014 [36] 82 40.2 40.2 17.1
Colina_2011 [27] 76 26.0 30.0 44.0
Franchini_2010 [37] 66 20.0 40.0 40.0
Pouchot_1991 [6] 62 33.9 24.2 35.5
Magadur-Joly_1995 [20] 62 44.0 32.0 24.0
Zeng_2009 [38] 61 44.3 29.5 16.4x
Gerfaud-Valentin_2014 [24] 57 30.0 44.0 26.0
Kim_2012 [39] 54 53.7 9.3 27.7
Franchini_2010 [40] 45
64.0** 36.0
Balci_2015 [18] 42 64.3 23.8 11.9
Riera_2011 [41] 41 44.0 26.0 30.0
Mitamura_2009 [42] 34 50.0 35.0 15.0
Tejera_2013 [43] 30 50.0 50.0

Lin_2000 [14] 45 57.0 43.0

Overall range 21.1
64.3% 9.3
50.0% 11.9
55.6%
* Chronic articular monocyclic pattern in 4.6% and chronic articular polycyclic pattern in 30.7% of patients.
** Systemic disease pattern.
*** Chronic articular monocyclic systemic pattern in 6% and chronic articular polycyclic systemic pattern in 21.4% of patients.
x
Chronic articular monocyclic pattern in 4.9% and chronic articular polycyclic pattern in 11.5% of patients.
Please note that a specific percentage was not mentioned for some subtypes in the actual publication, which is presented as “-” in the above table.
Abbreviations: AOSD: adult-onset still’s disease.

nonspecific chronic inflammation [44,46,48]. Lymphoma is always Overall, AOSD is a multisystem disorder, and although considered
a differential diagnosis since fever is a key symptom in both dis- a benign condition, it can present with life-threatening complications
eases in addition to splenomegaly. Mild, transient elevations in and lead to chronic disabilities.
liver enzyme levels are commonly observed, with a few cases of
liver dysfunction being reported [37,44,45]. Laboratory manifestations
 Other manifestations: In different case series, myalgia was present A typical laboratory panel of a patient with AOSD presents leuko-
in 13
95% of patients and was often associated with temperature cytosis with neutrophilia, elevated levels of acute-phase reactants
elevation. Several other manifestations such as weight loss such as C-reactive protein (CRP) and erythrocyte sedimentation rate
(11.5
66.1%), serositis (7.2
29%), pericarditis (2.6
37.1%), and (ESR), elevated liver enzymes, and markedly elevated ferritin levels
pleuritis (2.9-53.2%) were also reported in the literature. Other in the absence of rheumatoid factor (RF) and antinuclear antibodies
relatively rare manifestations reported in few case series are (ANAs) (Table 5).
interstitial pneumonia (1.0
15.0%), abdominal pain (1.2
24.0%), CRP was elevated in 70
100% of patients and ESR was 40 mm/h
pulmonary arterial hypertension (2.9%) [49], myocarditis (14%) in 68.9
100% of patients. Neutrophilic leukocytosis was found in
[49], encephalopathy (8.8%) [49], asthenia (35.3%) [50], gastroin- 73
100% of AOSD patients. Ferritin levels were found to be elevated
testinal symptoms (26.8%) [36], and peritonitis (2.7%) [44]. Rare in a majority of AOSD patients, with 34.0
97.6% of patients having
presentations related to lung disease have been observed to be serum ferritin levels 1000 ng/mL and 19.5
60.0% of patients having
more frequent in SJIA patients compared with AOSD patients serum ferritin levels 3000 ng/mL. It is not clear whether ferritin
[51,52]. only reflects an acute-phase reaction or if it has a role in the patho-
genesis of the disease. An elevated ferritin level is a nonspecific but
General characteristics and disease manifestations reported in common finding in AOSD and could be useful in helping make the
most recent and published series with largest number of patients are diagnosis, particularly in the presence of other typical signs and
compared in Table 4. symptoms. Abnormal liver function and anemia of chronic disease
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Table 4
Characteristics of AOSD patients among the largest published series in the last 5 years.

Asanuma_2015 [21] Hu_2019 [47] Kalyoncu_2016 [25] Nakamura_2020 [53] Sfriso_2016 [28] Zhang_2016 [54]

Country/Nationality Japan China Turkey Japan Italy China

N 169 517 356 178 245 305
General characteristics
Infant onset: Adult onset 4.8%: 95.2% NR NR NR NR NR
Age at onset, median, years 46 37.7 30 42 38.8 33.2
Female (%) 72.0 72.0 59.0 70.0 47.3 71.7
Clinical characteristics (%)
Fever >39.0 °C 91.6 91.3 95.8 96.0 92.6 100.0
Arthralgia 83.1 73.1 94.9 74.0 93.0 47.2
Arthritis 50.7
64.6



Typical rash 62.2 79.9 66.9 63.0 67.7 73.1
Sore throat 59.3 60.5 63.5 39.0 62.0 31.8
Lymphadenopathy 44.7 51.1 28.1 37.0 60.4* 33.4
Splenomegaly 32.3 34.4 25.0 37.0** 60.4* 43.3
Pericarditis 3.1 14.1 6.2
17.3

Myalgia 25.9 32.5 52.8

25.6
Laboratory findings
Leukocytosis (>10,000/mL) 79.4 85.6 84.9 55.0 81.0

Leukocytosis (>15,000/mL)
60.8

70.3

Neutrophils >80% 71.5 78.4 66.7



Anemia <10 g/dL 40.2 27.3 65.4

68.9
Thrombocytopenia (platelets <15 £ 104) 13.6



0
Thrombocytosis

37.6
46.0

(platelets >40,000/mm3)
Elevated ESR 68.9 91.9 98.2
87.0 97.0
Elevated CRP 91.5 93.8 98.2
97.0
Hyperferritinemia 88.5 95.8 96.7
56.4 94.8
Serum ferritin >3000 ng/mL 60.0 78.8 NR
80.1

Abnormal liver function/raised ALT and/or AST
61.6 50.4 54.0 53.5 56.1
* Lymphadenopathy/splenomegaly.
** Hepatosplenomegaly.
Abbreviations: ALT: alanine aminotransferase; AOSD: adult-onset Still’s disease; AST: aspartate aminotransferase; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate;
N: total number of patients; NR: not reported.

are usually reversible once the disease subsides. Hypoalbuminemia Table 5

(albumin 3.5 mg/dL) was also commonly observed. Laboratory manifestations.

Laboratory manifestations Frequency range (%)

Elevated CRP 70
100

Clinical complications
Elevated ESR (40 mm/h) 68.9
100
Similar to SJIA, inadequate control of inflammatory activity is Hyperferritinemia
associated with a risk of serious complications in AOSD patients [55]. Ferritin > normal range 43.1
100
MAS is one of the most serious and potentially life-threatening com- Ferritin 1000 ng/mL or >5 times normal level 34.0
97.6
Ferritin 3000 ng/mL (severe) 19.5
60.0
plications among AOSD patients, with a reported mortality rate rang-
Leukocytosis/increased WBCs
ing between 20% and 42% [55
57]. MAS represents an acute systemic WBC 10,000/mm3 23.6
96.8
inflammatory response caused by a cytokine release syndrome; its WBC 15,000/mm3 31.7
93.5
occurrence has been associated with a significant reduction in sur- Leukocytosis + neutrophilia 73
100
vival rate in patients with AOSD (p < 0.0001) [32,56,57]. In a retro- Neutrophils 80% 32.0
98
Abnormal liver function/liver dysfunction 10.4
91.2
spective hospital-based study, overall survival was significantly
Anemia (hemoglobin 10 g/dL) 13.0
74.5
lower in patients with MAS than in those without MAS (67% vs 100%; ANA negative 9.0
100
p < 0.001) [58]. MAS is also known as hemophagocytic syndrome ANA positive 2.9
25.8*
and is considered to be a form of secondary hemophagocytic lympho- Glycosylated ferritin (20%) 72.2
79.5
histiocytosis (HLH) [59]. Hypoalbuminemia (albumin 3.5 mg/dL) 41
72
PMN cells (80%) 69.4
78.0
The incidence of MAS in patients with AOSD has been reported to Proteinuria 2.9
11.0
be as high as 23% in some studies [49]. AOSD patients may present Raised LDH 69.0
81.5
with MAS at the time of diagnosis or during the disease course [32]. RF positive 0
20.1*
Almost all AOSD patients with MAS were reported to have fever. A RF negative 56.5
100
Thrombocytosis (platelets 400,000/mL) 8.0
48.4
change in the typical pattern of fever occurs in patients with Still’s
disease who develop MAS (from intermittent to nonremittent fever), * In some case series, a small proportion of patients reported positive RF and
ANA. Thus, although AOSD is considered as a seronegative disorder (as per the
and this change can help to differentiate between underlying disease
Yamaguchi criteria), it should also be taken into consideration in seropositive
flare-ups and MAS. A diagnosis of MAS should be increasingly sus- patients with typical clinical presentation and other compatible findings.
pected in patients presenting with continuous high fever, lymphade- Abbreviations: ANA: antinuclear antibody; AOSD: adult-onset Still’s disease;
nopathy, hepatosplenomegaly, liver dysfunction, significantly CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; LDH: lactate dehy-
elevated levels of serum ferritin, and elevated triglycerides but low drogenase; PMN: polymorphonuclear; RF: rheumatoid factor; WBC: white blood
cell.
number of platelets or neutrophils [32,55,56,60]. In patients with
AOSD who develop MAS, a greater risk of aggressive disease symp-
toms, therapeutic recalcitrance, and mortality was noted Other complications of AOSD reported in >10% of patients
[32,56
58,61]. Thus, a clinician’s suspicion is critical for early detec- included multiple relapses, myocarditis, pericardial effusion, cardiac
tion and proper management. tamponade, cardiopulmonary shock, fulminant hepatitis, multiple
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874

Table 6 Table 7
Clinical complications of AOSD. AOSD patients presenting with initial complaint of FUO.

Clinical complications Frequency range (%) Publication Country Number of Final AOSD
patients diagnosis
MAS 1.7
23.5 with FUO (N) in patients
Hemophagocytic syndrome/HLH* 7.0
83.3 with initial
Multiple relapses 35.3 complaint of
Myocarditis 1.9
21.1 FUO (%)
Pericardial effusion 21.0
Cardiac tamponade 15.8 Bilgin_2019 [65] Turkey 106 18.9
Cardiopulmonary shock 10.5 Bosilkovski_2016 [66] Republic of 123 4.9
Fulminant hepatitis 10.5 North
Multiple organ failure 10.5 Macedonia
Disseminated intravascular coagulation 0.9
7.0 Bosilkovski_2019 [67] Republic of 106 7.6
Interstitial lung disease 1.9 North
Joint deformities 14.7 Macedonia
Acute respiratory distress syndrome 3.0
21.1 Crispin_2005 [68] Mexico 161 16.1
Pancytopenia 5.7 Goto_2007 [69] Japan 51 11.8
Renal dysfunction 6.6 Hung_2017 [70] Taiwan 58 3.4
Secondary amyloidosis 1.0 Pedersen_2011 [71] Denmark 31 16.1
Thrombotic thrombocytopenic purpura 1.0 Kim_2013 [72] Korea 77 5.2
Kucukardali_2008 [73] Turkey 154 13.6
* HLH is a hyperinflammatory condition characterized by inap-
Mert_2003 [74] Turkey 130 15.4
propriate survival of histiocytes and cytotoxic T lymphocytes. HLH
Mir_2014 [75] India 66 3.0
may be familial (fHLH) or secondary/acquired (sHLH); sHLH is
Saltoglu_2004 [76] Turkey 87 4.6
termed as MAS when associated with rheumatological disease [62].
Schonau_2017 [77] Germany 72 15.3
Abbreviations: AOSD: adult-onset Still’s disease; HLH: hemophago-
Sethi_2014 [78] India 101 13.9
cytic lymphohistiocytosis; MAS: macrophage activation syndrome.
Shoji_1994 [79] Japan 80 7.5
Tabak_2003 [80] Turkey 117 11.1
Vanderschueren_2012 [81] Belgium 447 4.9
organ failure, joint deformities, and acute respiratory distress syn- Zhai_2018 [82] China 215 17.2
drome (Table 6). Zhiyong_2003 [83] China 158 11.4
Abbreviations: AOSD: adult-onset Still’s disease; FUO: fever of unknown origin.

Disease journey of patients with AOSD

presence of arthralgia, hyperferritinemia, sore throat, and neutro-
philia strongly favors AOSD in patients presenting with FUO.
Primary diagnosis of patients with AOSD Similarly, Crispin et al. proposed a scale to identify patients with
As observed across multiple case series, AOSD patients were pri- AOSD (Table 8). The scale comprises five criteria—arthritis, pharyngi-
marily diagnosed by rheumatologists, as patients commonly com- tis, Still’s rash, splenomegaly, and neutrophilia—to differentiate AOSD
plain of arthralgia as the initial symptom; however, no substantial from other causes of FUO. The presence of each of these criteria con-
data are available [24,47,63]. Considering the appearance of skin fers a different number of points, and the points are added to obtain a
rashes and joint pain along with fever in AOSD, many patients might total score. If the score equals 30, a diagnosis of AOSD may be con-
first seek dermatologic treatment, given that their skin lesions are firmed [68]. This scale appears to be highly specific (~98%), with pre-
clearly visible and thus have a more immediate impact on their daily dictive values greater than 90% and ease of use in clinical practice.
lives [64]. Thus, if dermatologists are familiar with the associated Since the nonspecific clinical features of AOSD may pose a diag-
rheumatological manifestations, they can help in early diagnosis of nostic challenge, several criteria have been developed for the identifi-
AOSD. Other specialists, such as those treating infectious diseases cation of AOSD patients (Table 9). The Yamaguchi and Fautrel
and hematologists, are frequently consulted to opine on the possibil- classification criteria are the most widely used criteria for AOSD
ity of an underlying infection or hematologic malignancy. Rarely, [86,87]. The diagnosis of AOSD depends largely on a combination of
patients initially present with MAS requiring hospitalization and major and minor criteria, requiring the exclusion of other clinical
extensive workup before rendering an AOSD diagnosis. conditions that may mimic AOSD, including infection, malignancy,
and other rheumatologic disorders such as autoimmune diseases and
Diagnosis of AOSD systemic vasculitis (Table 9). The sensitivity of the Yamaguchi criteria
(96.2%) is hampered by a large number of clinical conditions that
Diagnostic tools used in clinical practice. The diagnosis of AOSD is should be excluded, whereas the Fautrel diagnostic criteria require
highly dependent on the physician’s judgment. A diagnosis of AOSD measurement of glycosylated ferritin, which may not be available in
is usually made based on a thorough clinical evaluation, assessment many healthcare facilities. Additionally, these criteria were designed
of patient history, identification of characteristic findings, and exclu- based on retrospective data, and none of them have been compared
sion of other possible and more common disorders (i.e., a diagnosis or validated using an appropriate “gold standard” control group,
of exclusion). Affected individuals present with a high spiking fever, which raises questions on their diagnostic capabilities. Results from a
maculopapular rash, arthralgia or arthritis, and pharyngitis and often retrospective study by Bilgin et al. [88] demonstrated that when the
have elevated levels of acute-phase reactants such as ESR and CRP, current Yamaguchi criteria were applied to patients with AOSD,
serum ferritin, neutrophils, leukocytes, and/or platelets. 93.5% met the criteria for AOSD. However, when “neutrophilia >
The clinical diagnosis of AOSD is generally reached by exclusion upper normal limit” was used instead of “leukocytosis with neutro-
while investigating a patient with FUO. From the publications philia >80%,” all patients met the revised criteria for AOSD. Conse-
retrieved on FUO and Still’s disease that met the criteria for our quently, using “neutrophilia > upper normal limit” as a criterion
review, almost all AOSD patients presented with fever at the initial instead of “leukocytosis with neutrophilia >8000 may be more appro-
stage, and approximately 10-20% of patients evaluated for FUO had a priate for the diagnosis of AOSD in real-life settings. Thus, specialists
diagnosis of AOSD per data from different cohort studies (Table 7). have not yet reached a consensus as to what would be the most effec-
Bilgin et al. have proposed an algorithm to differentiate AOSD tive diagnostic pathway for AOSD, and a robust diagnostic tool is still
patients from patients with other causes of FUO [84,85] (Fig. 2). The a major unmet need for this clinical condition.
 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874 865

Fig. 2. Algorithm for differentiating AOSD from FUO [85].

Abbreviations: AOSD: adult-onset Still’s disease; FUO: fever of unknown origin; PPV: positive predictive value; UNL: upper normal limit.
Reprinted by permission from Bilgin E, et al. Clin Rheumatol. 2019;38(4):1193
1194. Copyright Ó 2019, International League of Associations for Rheumatology (ILAR).

Table 8 Novel biomarkers

Clinical scale for the diagnosis of AOSD in the setting of FUO proposed by Crispin et al. To date, the serum levels of nonspecific acute-phase reactants,
[68].
including CRP, ESR, and ferritin, have been useful biomarkers for
Criterion Description Points AOSD in daily practice, as part of a bigger clinical picture composed
of a characteristic combination of signs, symptoms, and laboratory
Arthritis Presence of synovitis 10
Pharyngitis Present at the beginning of the disease 7 findings. Nevertheless, recent advances have demonstrated a major
Still’s rash Macular or maculopapular pink-salmon rash that 5 role of proinflammatory cytokines, such as interleukin (IL)
1, IL-6,
accompanies the fever IL-18, and IL-37, and other biomarkers in the diagnosis and manage-
Splenomegaly Detected clinically or by imaging studies (>11 cm) 5
ment of AOSD.
Neutrophilia Total neutrophil count higher than 9.5 £ 103/mL 18
Total 45
Glycosylated ferritin. Hyperferritinemia has been observed in cases of
If a patient with FUO has 30 points, the diagnosis of AOSD can be established with-
out further diagnostic workup, with a high specificity (~98%).
AOSD (refer Table 5) and may serve as an indicator of disease activity.
Abbreviations: AOSD: adult-onset Still’s disease; FUO: fever of unknown origin. However, ferritin has poor predictive value when used to diagnose
AOSD in the absence of characteristic clinical features, regardless of
the threshold used [91,92]. In addition, increased levels of ferritin
have been noted in other diseases, such as infectious, liver, and kid-
In a study that investigated the characteristic pathologic findings ney diseases, as well as malignancies, which can complicate the dif-
from the skin, lymph nodes, liver, and bone marrow to assist in ferential diagnosis process. Some studies suggest the use of ferritin as
proper diagnosis of AOSD, the relatively specific findings with respect a predictive factor for disease progression to the chronic form. A
to cutaneous manifestations of AOSD were mild inflammatory cell potentially more useful biomarker might be glycosylated ferritin,
infiltration in the upper dermis, basal vacuolization, keratinocyte which has comparatively higher sensitivity and specificity (Table 10).
necrosis, presence of karyorrhexis, and mucin in the dermis. In all In healthy adults, 50
80% of ferritin is glycosylated. A decrease in the
cases, the pathologic findings in the lymph nodes included paracorti- percentage of ferritin glycosylation can be observed in inflammatory
cal hyperplasia with vascular and immunoblastic proliferation. Skin diseases, malignancies, infections, or liver disease but is rarely less
and lymph node pathology along with clinical findings can aid in the than 20%. Levels of glycosylated ferritin below 20% have been
diagnosis of AOSD [64], in particular by excluding other more com- described in patients with AOSD and HLH. A retrospective multicen-
mon diseases. Kikuchi-Fujimoto disease, also known as histiocytic ter study evaluated the concordance of ferritin and glycosylated ferri-
necrotizing lymphadenitis and characterized by subacute necrotizing tin levels with a final diagnosis of AOSD (using the Yamaguchi
regional lymphadenopathy, and Castleman disease, a poorly under- criteria). The sensitivity and specificity of the glycosylated ferritin
stood lymphoproliferative disease, are rare conditions that can be dif- test in the diagnosis of AOSD was found to be 80% and 66%, respec-
ferentiated from AOSD based on a lymph node biopsy [89,90]. tively, when tested alone, and 43% and 93%, respectively, when
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874

Table 9
Most commonly used classification criteria for AOSD.

Yamaguchi et al. classification criteria for AOSD [86] Fautrel et al. classification criteria for AOSD [87]

Sensitivity: 96.2% Sensitivity: 80.6%

Specificity: 92.1% Specificity: 98.5%
Major criteria: Major criteria:
1. Fever 39 °C lasting at least 1 week 1. Spiking fever 39 °C
2. Arthralgia or arthritis for 2 weeks 2. Arthralgia
3. Typical nonpruritic salmon-pink skin rash 3. Transient erythema
4. Leukocytosis 10,000/mm3 with 80% polymorphonuclear cells 4. Pharyngitis
5. Polymorphonuclear cells 80%
6. Glycosylated ferritin 20%
Minor criteria: Minor criteria:
1. Sore throat 1. Maculopapular rash
2. Lymph node enlargement 2. Leukocytes 10,000/mm3
3. Hepatomegaly or splenomegaly
4. Abnormal liver function tests
5. Negative ANA and RF tests
Exclusion criteria:
1. Infections (especially, sepsis and infectious mononucleosis)
2. Malignancy (mainly malignant lymphoma)
3. Other rheumatic disorders (mainly polyarteritis nodosa and rheumatoid vas-
culitis with extraarticular features)
For diagnosis of AOSD, patient should meet “5 or more criteria, of which at least 2 For diagnosis of AOSD, patient should meet “4 or more major criteria OR 3 major
should be major” criteria + 2 minor criteria”.
Abbreviations: ANA: antinuclear antibody; AOSD: adult-onset Still’s disease; RF: rheumatoid factor.

combined with a total ferritin level greater than five times the normal comparable between patients who had a chronic articular pattern
value [91]. and those who had a systemic pattern [98]. IL-37 inhibits the expres-
sion of proinflammatory cytokines in peripheral blood mononuclear
Heme-oxygenase 1 (HO-1). In a recent retrospective study conducted cells (PBMCs) from patients with SJIA/AOSD, indicating the potential
in Japan, serum ferritin and HO-1 levels were assessed in 110 AOSD anti-inflammatory role of IL-37 in AOSD [101]. Furthermore, a recent
patients and 46 disease controls. Results revealed that serum ferritin study demonstrated that IL-37 acts as a regulator of trained immu-
and HO-1 levels were significantly higher in active and relapsed nity, emerging as a potential therapeutic target in immune-mediated
AOSD cases compared with the disease controls and were reduced by pathologies [102]. Thus, IL-37 plays a promising role as novel disease
the treatment. Serum ferritin level >819 ng/mL showed a sensitivity activity biomarker as well as therapy for AOSD [98,103].
of approximately 80% and specificity of 71% for AOSD, whereas serum
HO-1 level >30.2 ng/mL yielded a sensitivity of 86% and specificity of Other potential biomarkers. Serum levels of calprotectin (a hetero-
83% [93]. Thus, typical skin rash and high-grade fever, neutrophilia, dimer of the S100A8 and S100A9 proteins), leucine-rich a2-glycopro-
RF/ANA negativity, sore throat, and serum HO-1 with serum ferritin tein (LRG), and cysteine-rich angiogenic inducer 61 (Cyr61) could be
can serve as strong indicators for AOSD diagnosis and predictors of useful biomarkers for monitoring disease activity and might play a
disease relapse. key role in the pathogenesis of AOSD [97,104
106].
In a study of 164 patients with suspected AOSD, clinical symptoms
Interleukins. High levels of serum cytokines such as IL-1, IL-6, IL-18, and blood test results were retrospectively assessed. Of these, 127
and IL-37 have been detected in AOSD patients. Several studies have had a final diagnosis of AOSD. The neutrophil-to-lymphocyte ratio
shown that serum levels of free IL-18 are extremely high in AOSD (NLR) was compared between AOSD patients and non-AOSD patients
patients (up to 1000-fold higher) as well as SJIA patients with active and was found to be higher in AOSD patients than in non-AOSD
disease and clearly correlated with other biomarkers of disease activ- patients. Thus, NLR can be a potential diagnostic tool and a marker
ity [94
97]. Additionally, normalization of IL-18 serum levels was for evaluation of disease activity [104]. NLR showed a sensitivity of
observed in the remission stage [96]. Findings suggest that IL-18 91.7% and specificity of 68.4% as a diagnostic tool for AOSD, which
could be helpful as a diagnostic biomarker for AOSD as well as a dif- were significantly higher than those of other inflammatory markers
ferential diagnosis marker with respect to other inflammatory disor- such as ESR, CRP, and ferritin. Multivariate analysis also revealed the
ders such as RA and ankylosing spondylitis [94
97]. Also, IL-18 can utility of the NLR in differential diagnosis of HLH [107]. The NLR was
be used as an indicator of disease activity because serum IL-18 levels significantly higher in patients with MAS than in patients with HLH.
are known to be associated with disease severity and serum ferritin
levels in AOSD patients [95,97].
IL-37 is a unique IL-1 family member functioning as a regulatory Delay in diagnosis
cytokine which can help in differentiating AOSD patients from Although early diagnosis tends to lead to a better prognosis, diag-
healthy controls [98,99]. A recent study of 62 patients demonstrated nosis is often delayed, with most patients being diagnosed only after
that upregulation of IL-37 serum levels positively correlated with the the appearance of relapsing symptoms. Long delays in the diagnosis
systemic score and laboratory features that represented AOSD dis- of AOSD patients have been reported across multiple studies
ease activity. IL-37 levels decreased when disease activity reduced in (Table 11). The median interval between onset of symptoms and a
follow-up patients [98]. Thus, increased expression of IL-37 and its definite diagnosis of AOSD ranged between 1 and 4.1 months across
positive correlation with disease activity suggest its involvement in studies (Table 11). Owing to the heterogeneity in clinical presenta-
AOSD pathogenesis [98,99,100]. Several studies have demonstrated tion, the lack of a specific diagnostic test, and the rarity of the disease,
that IL-18, interferon (IFN)-g , IL-10, and IL-4 are associated with sys- a delayed diagnosis is common among AOSD patients.
temic AOSD, whereas IL-6, IL-17, and IL-23 are associated with Some of the causes for the delay in diagnosis of AOSD are summa-
arthritic AOSD [27,100]. However, serum levels of IL-37 were rized below:
 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874 867

Table 10
Novel biomarkers in AOSD.

Publication Future diagnostic biomarkers Sensitivity (%) Specificity (%) Overall remarks

Chi_2018 [98] Serum IL-37 Serum IL-37 levels were dramatically higher in patients with
AOSD than in healthy controls, and levels of IL-37 positively
correlated with the systemic score and laboratory features that
represented AOSD disease activity
Serum IL-37 protein levels also correlated with expression of
the proinflammatory cytokines IL-1b and IL-18 as well as with
the anti-inflammatory cytokine IL-10
Serum levels of IL-37 were comparable between patients who
had a chronic articular pattern and those who had a systemic
pattern
Fautrel_2001 [91] Ferritin > normal limit (N) 67.3 35.8 Glycosylated ferritin level 20% appears to be a better diagnostic
Ferritin >5N 40.8 80 marker of AOSD than an elevated level of serum ferritin, and the
Glycosylated ferritin 20% 79.5 66.4 combination of both abnormalities can be especially helpful for
Ferritin > N and glycosylated ferritin 20% 70.5 83.2 the differential diagnosis of AOSD
Ferritin >5 N and glycosylated ferritin 20% 43.2 92.9 The specificity of ferritin levels greater than the upper normal
limit (35.8%) is too unspecific to be helpful in clinical practice
Girard_2016 [94] Serum IL-18 Free IL-18 serum levels were significantly higher in AOSD patients
(median 8.89 pg/mL) than in healthy and disease controls (other
inflammatory disorders; 1.37 pg/mL; p < 0.01)
Free IL-18 serum levels correlated with clinical and biological
markers of AOSD activity
Guo_2016 [104] Serum calprotectin 63.0 80.1 Calprotectin is considered to be “good” or “fair” at differentiating
AOSD patients from patients with other rheumatic diseases and
healthy controls
Ha_2015 [105] Serum LRG 92.3 97.9 Serum LRG levels were significantly elevated in patients with
AOSD (128.8 § 40.8 ng/mL) compared to those in patients with
RA and in healthy controls (p < 0.001)
Elevated serum LRG levels correlated well with disease activity
measures
Jung_2014 [96] IL-18 85.0 97.0 Serum IL-6, IFN-g , IL-18, IL-18BP, and free IL-18 levels were ele-
vated in
AOSD patients compared with RA and AS patients
Free IL-18 86.0 97.0 IL-18 is an efficient marker for diagnosis and follow-up in AOSD
patients and may be a useful predictive marker of remission,
especially in the inactive stage
Kim_2012 [97] S100A8/A9 69.4 98 Serum S100A8/A9 correlates with leukocyte count, ESR, CRP, ferri-
tin, and systemic disease score
IL-18 91.7 99.1 Serum levels of S100A8/A9 and IL-18 in patients with AOSD were
significantly higher than those in patients with RA and healthy
controls
Kirino_2018 [93] Serum ferritin 76.1 73.8 Serum ferritin and HO-1 may serve as highly specific and sensitive
HO-1 84.8 83.3 biomarkers for AOSD
Kudela_2019 [95] IL-18 63.3 96.9 IL-18 levels were significantly increased in patients with active
AOSD compared with patients in remission. For diagnosis of SJIA
in children, a cutoff value of 10,000 pg/mL was chosen, with a
specificity of 100% and a sensitivity of 60%
Lian_2012 [92] Combined Yamaguchi criteria and hyperferritinemia 83.5 98.8 Ferritin level 2500 mg/L appeared to be highly specific for a
Ferritin 750 mg/L diagnosis of AOSD
Ferritin 1250 mg/L 70.9 99.3 When the Yamaguchi criteria and hyperferritinemia were com-
Ferritin 2500 mg/L 43.0 99.9 bined, they helped in better AOSD diagnosis
Su_2019 [106] Cyr61 Serum levels of Cyr61 were inversely correlated with disease
activity in AOSD patients, i.e., significantly increased serum lev-
els of Cyr61 were observed in inactive AOSD patients than those
in active patients and healthy controls
Can be a potential biomarker of AOSD disease activity
Abbreviations: AOSD: adult-onset Still’s disease; AS: ankylosing spondylitis; CRP: C-reactive protein; Cyr61: cysteine-rich angiogenic inducer 61; ESR: erythrocyte sedimentation
rate; HO-1: heme oxygenase-1; IFN: interferon; IL: interleukin; IL-18BP: interleukin 18 binding protein; LRG: leucine-rich a2-glycoprotein; RA: rheumatoid arthritis; SJIA: sys-
temic juvenile idiopathic arthritis.

 Diagnostic difficulty: The initial symptoms of AOSD are similar to children and adults with Still’s disease have fever at disease onset,
those of other diseases such as infections, malignancies, and other while arthritis may not be evident during the initial stages of the
inflammatory conditions. Bacterial infection and FUO have been disease [14
16]
the most common misdiagnoses at the time of investigation, fol-
lowed by allergy, including drug eruption, and autoimmune dis- Burden of disease
eases, including either SLE or RA [23,27,35,47,108,109] The burden of AOSD is not well documented in the literature. In
 Absence of specific clinically available biomarkers for diagnosis of one of the largest nationwide studies of AOSD in the United States
AOSD [108] (US), 5-year retrospective data of AOSD patients hospitalized
 All known clinical and laboratory features of AOSD may not be between 2009 and 2013 revealed an inpatient mortality of 2.6%. Inpa-
present at the same time as the disease presents itself; thus, diag- tient mortality was reported to be significantly higher among Asian
nosis could be delayed for several weeks or months, especially in patients compared with White patients [111]. As observed across
patients with a polycyclic disease course [37,39,110]. Virtually all multiple studies, AOSD was associated with significant morbidity and
868 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874

Table 11
Time to diagnosis of AOSD.

Publication Sample size (N) Time to diagnosis/delay in diagnosis

Mean SD Median SD Range

Chen_2004 [35] 82 3.3 mo


(10 d to 4 y)

Colina_2011 [27] 76 21 mo 25 mo



Dwivedi_2017 [110] 34 12.24 mo




Ekbote_2018 [49] 34 3.5 mo


0.5
5.5 mo
Franchini_2010 [37] 66

4 mo
1 mo to 20 y
Gerfaud-Valentin_2014 [24] 57

4 mo
0
312 mo/26 y
Hu_2019 [47] 517

4.6 mo
0.5
96 mo
Iliou_2013 [23] 44 3.5 mo


0.5
6 mo
Kim_2012 [39] 54 41.1 d 87.5 d



Kim_2014 [36] 82

1 mo 46 mo 0.2
336 mo
Lin_2000 [14] 21 4.6 mo 2.3 mo



Pay_2006 [15] 95

3 mo
0.5
84 mo
Tamai_2017 [108] 51 50.4 d




Tamai_2019 [109] 65 21 d




Uppal_1995 [16] 31 4.34 y 4.04 y 3y


Abbreviations: AOSD: adult-onset Still’s disease; d: days; mo: months; SD: standard deviation; y: years.

Table 12 involvement is not an absolute contraindication, but continuous

Mortality rates among AOSD patients. monitoring of transaminase is warranted [114,115].
Publication Country Type of study Total patients Mortality (%) Other conventional DMARDs such as cyclosporine A, azathioprine,
leflunomide, and hydroxychloroquine have been shown to be benefi-
Balci_2015 [18] Turkey Retrospective 42 2.3
cial in AOSD patients, but methotrexate is still the preferred choice as
Ekbote_2018 [49] India Retrospective 34 8.8
Gerfaud-Valen- France Retrospective 57 5.2 a first-line steroid-sparing treatment [116].
tin_2014 [24]
Kim_2012 [39] Korea Retrospective 54 9.3 Biologics
Kim_2014 [36] Korea Retrospective 82 2.4
Treatment with biologics is recommended in AOSD patients
Mehta_2019 [111] USA Retrospective 5820 2.6
Ruscitti_2016 [33] Italy Retrospective 100 16
refractory to conventional corticosteroid and DMARD therapy [116].
Ruscitti_2018 [32] Italy Retrospective 119 16 Currently, both IL-1 inhibitors canakinumab and anakinra are
Wang_2020 [56] China Retrospective 447 4.5 approved in Europe, and only canakinumab is approved in the USA,
Zeng_2009 [38] China Retrospective 61 9.8 for the treatment of AOSD. Rilonacept, tumor necrosis factor-a block-
Abbreviations: AOSD: adult-onset still’s disease. ers, and tocilizumab are used off-label.
Most patients achieved partial response rather than remission
with tumor necrosis factor-a blockers. Patients with arthritis lacking
mortality and life-threatening manifestations and hence impacted systemic manifestations, lower IL-18 levels, and lower serum ferritin
the health-related quality of life of patients (Table 12). are more likely to respond to tumor necrosis factor-a blockers
Data on the economic burden of AOSD are very scarce. Only one [116,117,118]. Switching from one tumor necrosis factor-a blocker
study conducted in the US reported the mean cost of hospitalization to another does not provide any additional effect [116,118].
due to AOSD as USD 30,857 [111]. Treatment with anti
IL-1 agents is significantly effective in
patients with AOSD refractory to conventional treatment
Treatment pattern [30,40,118,120]. First-line biologic therapy for AOSD with canakinu-
mab resulted in rapid and marked efficacy, ultimately leading to full
Nonsteroidal anti-inflammatory drugs and corticosteroids clinical remissions [121]. Prompt initiation of IL-1-blocking therapies
Most AOSD patients in the identified literature were treated with was reported to be associated with better disease outcomes, and
glucocorticoids. While patients presenting with the monocyclic pat- optimal retention rates [122,123,124].
tern easily achieve remission with the use of nonsteroidal anti- Response to IL-1 inhibitors is rapid and sustained and allows
inflammatory drugs (NSAIDs) and corticosteroids, patients presenting patients to reduce their dependence on corticosteroids. Failure of one
with the polycyclic systemic pattern or chronic arthritis are relatively IL-1 inhibitor does not preclude the achievement of a therapeutic
difficult to treat and may require further treatment with conventional response with another IL-1 inhibitor. IL-1 inhibitors are generally
immunosuppressants and/or biologic drugs [46]. Studies showed that safe [30,125]. In an RCT among AOSD patients, treatment of active
>80% of AOSD patients did not achieve remission with NSAIDs and AOSD with canakinumab led to improvements in several outcome
approximately 20% suffered from adverse events [3,46,112,113]. Sys- measures, with two-thirds of patients on canakinumab achieving the
temic corticosteroid therapy (prednisone, dexamethasone, and meth- primary outcome, defined as the proportion of patients with a clini-
ylprednisolone) led to remission in approximately 65% of the cally relevant reduction in disease activity at week 12 [119,120].
patients, showing greater efficacy in resolving systemic symptoms Other biologics including tocilizumab, abatacept, rituximab, and
(as opposed to articular symptoms) [113]. tofacitinib have also been investigated in AOSD. A randomized, dou-
ble-blind, placebo-controlled phase III trial suggested that tocilizu-
Conventional disease-modifying antirheumatic drugs mab is effective in AOSD, although the primary endpoint was not
A majority of AOSD patients were treated with at least one dis- met, and solid conclusion was not drawn [126]. Tocilizumab should
ease-modifying antirheumatic drug (DMARD), with methotrexate be considered as an alternative to IL-1 antagonists, particularly when
being the most commonly used DMARD. In a chart review, metho- joint involvement is present [115,127]. Abatacept (a modulator of T-
trexate was found to be effective for disease control in systemic and lymphocyte activation) and rituximab (a monoclonal anti-CD20 anti-
chronic articular AOSD, particularly in 40
70% of steroid-dependent body) have been assessed in refractory AOSD patients with very little
AOSD patients [24]. Methotrexate use in AOSD patients with liver benefit [125]. A recent case report concluded that application of the
 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874 869

Table 13
AOSD treatment options (24,112,115
119).

Line of treatment Treatment Pros Cons

First line NSAIDs and corticosteroids  Monocyclic pattern  Polycyclic systemic pattern or chronic arthritis
 Systemic corticosteroids achieve remission in  NSAIDs do not achieve remission in >80% of
65% of patients patients
 Corticosteroids are the first line of treatment  Steroid dependency occurs in approximately
for AOSD 45% of cases
 Steroid dependence was associated with
splenomegaly, low glycosylated ferritin, an
elevated ESR, and young age at onset of AOSD
First line Methotrexate  First-line steroid-sparing treatment in AOSD  Slow to induce remission, especially of sys-
 Systemic and chronic articular AOSD, espe- temic symptoms
cially steroid dependent  Can cause severe adverse events, including
liver toxicity and pneumonitis
 Blood count, renal function, and liver enzymes
should be monitored
Second line IL-1 inhibitors* including anakinra and  Patients refractory to conventional corticoste-  Patients receiving anakinra are more likely to
canakinumab roid and DMARD therapy relapse as soon as treatment is stopped com-
 Polycyclic or chronic AOSD pared with those receiving canakinumab due
 Canakinumab and anakinra are the only to a shorter half-life (4
6 h vs 26 days)
approved biologics**  Injection site reactions are more frequent with
 Are relatively safe anakinra

* Rilonacept is currently not approved.

** Canakinumab is the only approved biologic for AOSD in the US, while in Europe, both canakinumab and anakinra are approved for AOSD.
Abbreviations: AOSD: adult-onset Still’s disease; DMARD: disease-modifying antirheumatic drug; ESR: erythrocyte sedimentation rate; IL: interleukin; NSAID: nonsteroidal anti-
inflammatory drug.

Janus kinase (JAK) inhibitor tofacitinib in refractory AOSD patients Table 14

contributes to disease remission and decrease in corticosteroid dose Clinical management recommendations for AOSD [132,133].

in those with polyarthritis [126,128]. Reference Country Key recommendations

Summary of treatment options available for AOSD patients is pro-
Mimura_2018 Japan Systemic glucocorticoids ameliorate clinical
vided in Table 13.
symptoms and manifestations of AOSD-
High-dose intravenous pulse glucocorti-
Efficacy and safety outcomes coids ameliorate clinical symptoms and
Efficacy data in AOSD were mostly reported from case reports manifestations of AOSD in patients with
severe organ damage
and case series. There were only two RCTs conducted in AOSD
 It is recommended to concomitantly use
patients on tocilizumab and canakinumab versus placebo methotrexate for the management of clini-
[119,120,126]. The primary efficacy outcome reported in the toci- cal symptoms and manifestations, which
lizumab trial was the American College of Rheumatology (ACR) has a glucocorticoid-sparing effect in glu-
50 response at week 4, while the primary efficacy outcome cocorticoid-resistant refractory AOSD
 Tocilizumab and canakinumab are useful
reported in the canakinumab trial was the proportion of patients
for the improvement of symptoms and
with a clinically relevant reduction in disease activity at week 12 disease states, and they have an effect in
[119,120,126,129]. reducing the glucocorticoid dose. They
A significant improvement in systemic manifestations (systemic also improve growth in SJIA cases that
feature score) was reported in patients on tocilizumab at week 4 and show resistance to conventional therapy
Colafrancesco_2019 Italy AOSD and SJIA may be considered as the
week 12 compared with patients on placebo [126]. Patients on ana- same disease
kinra achieved remission in systemic manifestations (fever, rash, and Data from SJIA suggest that early treatment
raised inflammatory markers) and corticosteroid tapering [23]. The with IL-1 inhibitors is associated with a
Pouchot score was significantly reduced at 3 months compared with better therapeutic response
IL-1 inhibitors (anakinra, canakinumab,
baseline among patients on anakinra as well as among patients on
and rilonacept) are significantly effective in
canakinumab [30]. A higher ACR response was reported among patients with AOSD refractory to conven-
patients on canakinumab in a pooled analysis of RCTs [129]. Very few tional treatment
studies reported serious adverse events among AOSD patients on bio- Abbreviations: AOSD: adult-onset Still’s disease; IL: interleukin; SJIA: systemic juve-
logics [113,119,120,126-131]. In a randomized, placebo-controlled nile idiopathic arthritis.
trial, the safety profile of canakinumab in AOSD was similar to that
reported in SJIA patients, with no unexpected safety issues observed
[120]. severe organ involvement. For steroid-refractory patients, metho-
trexate was strongly recommended. The main limitation of the guide-
Clinical management in AOSD line was that owing to the rarity of AOSD, only a few global reports
with high-quality evidence were available [132].
To date, there are no internationally recognized guidelines for the A panel of experts from Italy developed recommendations based
management of AOSD. on the Delphi process for the management of patients with AOSD
The first clinical practice guidelines for AOSD (as part of a Still’s with IL-1 inhibitors (Table 14). The panel concluded that the litera-
disease continuum that encompasses SJIA) were developed in Japan ture is consistent in demonstrating a beneficial effect of IL-1 inhibi-
in 2017 by the Ministry of Health [132]. They recommended systemic tors, with a high proportion of patients achieving rapid and sustained
glucocorticoids for improving clinical symptoms with high-dose remission of systemic symptoms and normalized inflammatory
intravenous pulse glucocorticoid therapy for AOSD patients with markers [133].
870 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874

Fig. 3. Treatment algorithm for AOSD.

Abbreviations: AOSD: adult-onset Still’s disease; CR: complete response; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; F: failure; IL: interleukin; MDR: multidis-
ciplinary round; NSAID: nonsteroidal anti-inflammatory drug; PR: partial response; TNF: tumor necrosis factor.
Reprinted by permission from Feist E, et al. Nat Rev Rheumatol. 2018;14(10):603
618. Copyright Ó 2018, Springer Nature Limited.

The management of AOSD varies widely depending on various prevention of complications and chronic, irreversible disabil-
clinical presentations of the disease. Feist et al. proposed a treatment ity.
algorithm showing a targeted strategy with early use of biologics for
AOSD (Fig. 3) [134]. Discussion

AOSD is a rare systemic inflammatory condition that is poorly rec-

Unmet needs and research agenda ognized. Significant advances have been made in the understanding
of the pathogenesis of the disease (i.e., key cytokines involved and
The understanding of AOSD has advanced considerably over the the role of the inflammasome), but important unmet needs related to
past 10
15 years; however, there are still very important unmet diagnosis and optimal management still remain.
needs to be addressed. There is a paucity of robust epidemiological data on AOSD, and the
true disease burden is difficult to estimate owing to the lack of
 Early detection of AOSD. national disease registries and prospective databases and considering
 Lack of understanding of the patient journey; due to the diverse that most of the published data are retrospective in nature. Moreover,
presentation of AOSD, some patients might have to undergo a there are no studies that have evaluated the direct or indirect health-
long journey before any suspicion of AOSD. care costs associated with AOSD at the country level.
 Limited information about the disease burden of AOSD in terms of AOSD poses many diagnostic challenges as it presents with a com-
mortality, and a lack of data about the direct economic burden of bination of nonspecific symptoms that can be caused by a wide vari-
the disease. ety of other diseases. Diagnostic delays and disease complications are
 The role of genetics and/or biomarkers for accurate and timely exacerbated by the lack of pathognomonic serologic or clinical dis-
diagnosis and to monitor disease progression and treatment ease markers. However, the key point to remember is that for
response. patients who present with prolonged and unexplained fever com-
 A targeted treatment approach, aiming for a comprehensive bined with musculoskeletal symptoms and evanescent rash, the dif-
disease control (articular and systemic manifestations) and ferential diagnoses should include AOSD.
 P. Efthimiou et al. / Seminars in Arthritis and Rheumatism 51 (2021) 858
874 871

Advances in immunology have enhanced our knowledge on the prospective studies is very challenging in the context of rare diseases,
role of cytokines in disease pathogenesis. To date, many biomarkers, nationwide registries, and good-quality RCTs with a smaller number
including calprotectin, ILs (IL-6, IL-18, and IL-37), Cyr61, soluble of patients can be helpful to fill the knowledge gap that still exists.
S100A12, neutrophils (CD64+), and CXCL-10(+)/CXCL-13(+) cells,
have been evaluated to monitor AOSD disease activity. However, Funding
their utilities in clinical practice have not been validated adequately
owing to technical or economic reasons. Furthermore, MAS is a rare The work was supported by the funding from Novartis Pharma-
life-threatening syndrome that can complicate the course of AOSD. ceuticals Corporation, East Hanover, NJ, USA.
Early recognition of MAS in AOSD patients still remains diagnostically
challenging as there is no diagnostic test or even a set of uniform dis- Author contributions
ease diagnostic criteria to differentiate MAS from the underlying sys-
temic inflammatory condition. Future research in this disease area All authors contributed to researching data for the article, discus-
should aim for the identification and validation of tools for the early sion of content, writing and reviewing and/or editing the manuscript
diagnosis of AOSD and optimized treatment to prevent chronic artic- before submission.
ular inflammation as well as irreversible joint damage.
For AOSD management, glucocorticoids are suggested initially,
Declaration of Competing Interest
while methotrexate is recommended for steroid-refractory patients.
For patients resistant to conventional therapy, biologics are recom-
Dr. Petros Efthimiou has served on the advisory board of Novartis and
mended. The treatment response to biologics may depend on disease
Kiniksa.
phenotype: arthritis and a chronic articular phenotype have been
Dr. Apostolos Kontzias has served on the advisory board of Novartis
associated with a substantial response to IL-6 inhibition, whereas the
and Kiniksa.
systemic phenotype has been associated with a substantial response
Peter Hur and Priscila Nakasato are employees of Novartis Pharma-
to IL-1 inhibition [135].
ceuticals Corporation.
In SJIA, the primary target for treatment is recommended as clini-
Kavita Rodha and GS Ramakrishna are employees of Novartis Health-
cal remission [136]. In SJIA, use of biologics as the first line of therapy
care Pvt Ltd.
has demonstrated rapid attainment of inactive disease compared
with conventional therapy and has also led to the avoidance of gluco-
corticoids [137]. AOSD management can possibly emulate that of SJIA Supplementary materials
and incorporate early treatment with biologics. Further studies are
needed to assess if early treatment with biologics leads to better Supplementary material associated with this article can be found,
patient outcomes and a change in the natural history of the disease in the online version, at doi:10.1016/j.semarthrit.2021.06.004.
process.
There are only a few guidelines on the clinical management of References
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