Etiology

Adult-onset Still disease (AOSD) is a multisystem autoinflammatory disorder with a presumed polygenic basis but the precise etiology remains unclear.[1][5][6] It is postulated that an external - in most cases infectious - trigger is required to provoke an aberrant inflammatory response in genetically susceptible individuals, leading to the development of the disease.[1][4][5] AOSD and systemic juvenile idiopathic arthritis (sJIA) are commonly considered to represent a continuum of the same disease entity, distinguished by their differing age of onset.[3][5][6]

Genetic factors are believed to predispose the individual to an aberrant and sustained inflammatory response to the trigger, although there is no clear evidence of a familial pattern to AOSD.[1][4][5] Research has found a link between human leukocyte antigen (HLA) gene polymorphisms and susceptibility to AOSD, suggesting an important role for the adaptive immune system.[6] The reported associations between AOSD and HLA antigens include HLA-B17, HLA-B18, HLA-B35, HLA-DR2, and HLA-DR4 and, in addition, an association has been noted with both HLA-DRB1*12 and HLA-DRB1*15.[1][4][5] Other genetic factors postulated to predispose individuals to AOSD include polymorphisms affecting the genes for interleukin (IL)-18 and macrophage migration inhibitory factor (MIF).[1] Furthermore, a proportion of patients with AOSD carry at least one genetic variant associated with certain of the prototypic monogenic autoinflammatory conditions.[6]

No single pathogenic trigger for the aberrant immune response has been defined, suggesting the possibility that multiple environmental triggers may be relevant.[1] Suggested infectious triggers include:[1][4]

  • Viruses: for example, adenovirus, human immunodeficiency virus (HIV), parvovirus B19, Epstein-Barr virus (EBV), rubella virus, measles virus, hepatitis virus, cytomegalovirus, and influenza virus

  • Bacteria: for example, Mycoplasma pneumoniae, Chlamydia pneumoniae, Yersinia enterocolitica.

Case reports of both primary diagnosis of AOSD and flares in patients with known AOSD have been noted in temporal association with COVID-19 vaccination or natural infection.[2][13][14][15]

Pathophysiology

The pathophysiology of AOSD remains poorly understood, although recent advances indicate the importance of a systemic inflammatory process involving dysregulated activation of both the innate and adaptive immune system, leading to the production of proinflammatory cytokines.[1][6]​​ Neutrophils and macrophages are the main effector cells of this dysregulated immune response; neutrophil activation is a characteristic feature of the disease with over 80% of patients having neutrophilic leukocytosis during acute flares of the condition.​[4][5]​​​[6] 

Cytokines associated with driving the proinflammatory cascade in AOSD include interleukin(IL)-1, IL-6, IL-8, IL-18, and IL-37; interferon-gamma; and tumor necrosis factor (TNF)-𝛂.[1][3][5][6] It is postulated that IL-1𝛃 and IL-18 are primarily responsible for systemic symptoms such as fever, rash, and multiorgan involvement, whereas TNF-𝛂 and IL-6 are more closely associated with joint symptoms.[4][6] IL-1 and IL-6 inhibition have become important management strategies via the development of biologic medications.[1][4]

Along with an intensified inflammatory cascade, it has been proposed that inadequate resolution of inflammation is a further contributory factor to the “cytokine storm” associated with AOSD, perhaps linked to the hyperferritinemia that is characteristic of AOSD.[1][4]

Classification

Categorization based on clinical course

Conventionally, the clinical course of AOSD has been observed to follow one of three patterns:[1][4][5]

  • Monocyclic systemic: typically one systemic episode lasting a few months followed by remission

  • Polycyclic systemic: intermittent episodes or flares with remissions lasting from weeks to several years

  • Chronic articular: persisting symptoms, usually affecting multiple joints and with the potential to develop to joint destruction.

More recently, two subtypes of AOSD with distinct serologic profiles have been proposed based on the predominant symptoms:[3] [4][5]

  • Systemic manifestation - predominant symptoms of fever and skin rash, with possible multiorgan involvement

  • Chronic articular manifestation - predominant joint symptoms.

It is postulated that the proinflammatory cytokines involved differ between these two subtypes.[4][6]

Use of this content is subject to our disclaimer