Mechanisms, biomarkers and targets for adult-onset Still's disease

Abstract

Adult-onset Still's disease (AoSD) is a rare but clinically well-known, polygenic, systemic autoinflammatory disease. Owing to its sporadic appearance in all adult age groups with potentially severe inflammatory onset accompanied by a broad spectrum of disease manifestation and complications, AoSD is an unsolved challenge for clinicians with limited therapeutic options. This Review provides a comprehensive insight into the complex and heterogeneous nature of AoSD, describing biomarkers of the disease and its progression and the cytokine signalling pathways that contribute to disease. The efficacy and safety of biologic therapeutic options are also discussed, and guidance for treatment decisions is provided. Improving the approach to AoSD in the future will require much closer cooperation between paediatric and adult rheumatologists to establish common diagnostic strategies, treatment targets and goals.

Fig. 1. Pathogenic pathways in AoSD.

Danger signals (pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), such as infections or environmental chemical factors) are transmitted to macrophages and neutrophils through Toll-like receptors (TLRs), which excessively activate the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome in patients with a predisposing genetic background. This excessive activation of NLRP3 seems to be central and leads to intense production of IL-1β and IL-18. These cytokines intensely stimulate innate immune cell activation, as well as adaptive immune cells, leading to overproduction of several pro-inflammatory cytokines including IL-6, IL-8, IL-17 and TNF, as well as further production of IL-1β and IL-18. Several factors actively contribute to this amplified inflammatory response, which is often referred to as the cytokine ‘burst’ or ‘storm’. In addition to IL-1β itself conferring retrograde activation of macrophages and neutrophils, alarmins such as the S100 proteins and advanced glycation end products (AGEs) are involved. Aside from the amplification mechanisms, deficiency or failure in regulatory or anti-inflammatory mechanisms might be involved in the pathogenesis of autoinflammatory diseases, including deficiency in regulatory T (T_reg) cells or natural killer (NK) cells, insufficient IL-10 production and deficiency in production of resolving lipid mediators, soluble receptors of AGEs (sRAGEs) or other resolution-associated molecular patterns (RAMPs). Hence, adult-onset Still’s disease (AoSD) pathogenesis is related to an imbalance between inflammation and resolution. DC, dendritic cell; ER, endoplasmic reticulum; PMN, polymorphonuclear neutrophil; ROS, reactive oxygen species; TGFβ, transforming growth factor-β; T_H1, T helper 1; T_H17, T helper 17.

Fig. 2. Signs of AoSD.

The schematic shows the major clinical symptoms for diagnosis of adult-onset Still’s disease (AoSD), as well as other manifestations and life-threatening complications. CRP; C-reactive protein; DIC, disseminated intravascular coagulation; ESR, erythrocyte sedimentation rate; GF, glycosylated ferritin; TMA, thrombotic microangiopathy.

Fig. 3. Managing patients with AoSD.

The schematic shows a therapeutic strategy to manage patients with adult-onset Still’s disease (AoSD), providing instruction on how to proceed in case of failing any given therapy. CR, complete response; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; F, failure; MDR, multidisciplinary round; PR, partial response.