Presentation and diagnosis of adult-onset Still’s disease: the implications of current and emerging markers in overcoming the diagnostic challenge

Abstract

Adult-onset Still’s disease (AOSD) is a known cause of fever of unknown origin. It is characterized by a triad of symptoms: spiking fever (>39°C), salmon-colored rash and arthritis/arthralgia. On a predisposing genetic background, several conditions may act as trigger for disease and among these, infectious agents are the most important. Nowadays, a dichotomous view of AOSD has been introduced which distinguishes this entity in two subsets according to the clinical features and laboratory aspects: systemic or articular. As AOSD is a diagnosis of exclusion, specific biomarkers able to facilitate differential diagnosis are needed. A number of possible biomarkers have been proposed that will be discussed in detail in this review: ferritin, IL-18, procalcitonin, s100 proteins and sCD163.

Keywords:

• adult-onset Still’s disease
• AOSD
• CD163
• ferritin
• interleukin-18
• procalcitonin
• s100A12
• s100A8/9

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

Key issues

• A dichotomous view of adult-onset Still’s disease (AOSD) has been recently introduced, distinguishing two subtypes of disease according to the dominant clinical expression and laboratory features: a systemic pattern and a chronic articular pattern.

• According to the major diagnostic criteria, AOSD is considered a diagnosis of exclusion and the identification of specific serological biomarkers, possibly useful also to evaluate disease activity, is essential.

• Over the past years several serological biomarkers have been proposed and the following are the most commonly recognized: ferritin, glycosylated ferritin, IL-18, procalcitonin, sCD163, S100A8/A9 and S100A12.

• To diagnose AOSD, a fivefold increase in ferritin serum level has been suggested; moreover, the presence of glycosylated ferritin lower than 20% is considered a more specific marker of disease.

• sCD163 is a marker of macrophage activation that is overexpressed during AOSD course. Its serum levels are correlated with ferritin, suggesting a possible role of macrophages in ferritin production.

• A new possible function for ferritin in the pathogenesis of different autoimmune and autoinflammatory conditions has been recently hypothesized and a pathogenic role in AOSD has been speculated too.

• IL-18 represents one of the main cytokines in course of AOSD. Indeed, in this condition, this cytokine seems to plays a pivotal role, being overexpressed not only into the serum of patients but also at tissue level.

• Procalcitonin serum levels are raised in course of AOSD; however, in this specific condition, its ability to discriminate patients with or without infection is still controversial.

• S100A8/A9 and S100A12 are new emerging serologic markers that appear not only overexpressed during AOSD but also correlate with disease activity.