Adult-Onset Still’s Disease: Molecular Pathophysiology and Therapeutic Advances

Abstract

Adult-onset Still's disease (AOSD) is a rare inflammatory disorder of unknown etiology generally characterized by persistent high spiking fever, evanescent rash, and polyarthritis. The pathogenesis of AOSD is only partially known. The pivotal role of macrophage cell activation, which leads to T-helper 1 (Th1) cell cytokine activation, is now well-established in AOSD. Moreover, pro-inflammatory cytokines such as interleukin (IL)-1, -6, and -18 seem to play a key role in this disorder, giving rise to the development of new targeted therapies. For years, treatment of AOSD has been largely empirical, using nonsteroidal anti-inflammatory drugs, corticosteroids, and disease-modifying antirheumatic drugs. Patients with steroid- and methotrexate-refractory AOSD can now benefit from efficient and well-tolerated biologic agents such as IL-1, IL-6, and tumor necrosis factor-α antagonists.

Anakinra in Still’s disease: a profile of its use

“…Still’s disease is a serious inflammatory disorder that presents as adult-onset Still’s disease (AOSD) [ 1 – 5 ] or, in children aged ≤ 16 years, as systemic juvenile idiopathic arthritis (SJIA) [ 6 , 7 ]. The aetiology and pathogenesis of these conditions are largely unknown, with both presenting with heterogeneous non-specific symptoms, such as fever, skin rash and haematological disturbances, and both being associated with long-term disability, increased morbidity and mortality, and reduced health-related quality of life [ 1 , 3 – 6 , 8 ]. Results of gene-expression analyses suggest that AOSD and SJIA are expressions of a continuum of a single disease that differ by their time of onset, and that susceptibility to these disorders is associated with variations in certain genes [ 9 ].…”

“…Based on their signs and symptoms, patients with Still’s disease may have primarily systemic disease [associated with high fever, high levels of C-reactive protein (CRP), liver enzymes, ferritin, and interleukin (IL)-1 and IL-18, and elevated erythrocyte sedimentation rates (ESR)] or chronic articular disease [associated with arthritis, a lack of fever in some patients, and high levels of tumour necrosis factor (TNF)-α, and IL-6 and IL-17] [ 1 , 2 , 4 – 6 ]. Although arthritis may not be present for months or even years in patients with SJIA, the extent of joint involvement, as well as the persistence of the systemic symptoms, correlate with patients’ overall prognosis [ 6 ].…”

“…Empirical treatment of AOSD and SJIA has involved the use of NSAIDs, corticosteroids and disease-modifying anti-rheumatic drugs (DMARDs), such as methotrexate, ciclosporin, azathioprine, sulfasalazine, leflunomide and intravenous immunoglobulin (IVIg) [ 1 , 3 – 6 , 14 ]. With the discovery of the mediators of the inflammatory cascade underlying Still’s disease and the development of biological DMARDs (bDMARDs), it is now possible to target treatment against the key inflammatory cytokines involved.…”

“…With the discovery of the mediators of the inflammatory cascade underlying Still’s disease and the development of biological DMARDs (bDMARDs), it is now possible to target treatment against the key inflammatory cytokines involved. For example, patients with systemic AOSD or SJIA have a preferential response to IL-1 inhibitors, whereas those with chronic articular AOSD have a preferential response to TNF-α inhibitors, as these conditions are associated with high levels of the respective cytokines [ 1 , 2 , 6 ].…”

Development and Role in Therapy of Canakinumab in Adult-Onset Still’s Disease

“…The pathogenic mechanisms leading to AOSD and SoJIA are complex and not fully understood. An abnormal activation of the innate immune response is observed and several data sustain the pivotal role of inflammatory cytokines, in particular high levels of interleukin (IL)-1β, IL-6, IL-8, and tumour necrosis factor (TNF)-α ( Maria et al, 2014 ; Sfriso et al, 2018 ). Thus, in addition to the classic therapeutic options (non-steroidal anti-inflammatory drugs (NSAIDs), steroids, and immunosuppressive drugs), biologic agents targeting proinflammatory cytokines may be an effective approach.…”