Adult-onset Still’s disease (AOSD) is a rare autoinflammatory disorder of unknown etiology, which was initially described in adults by Eric Bywaters in 1971. During the first forty years, the pathophysiology of the disease had remained largely obscure and only recently was our understanding of the disease enhanced by the description of the autoinflammatory syndromes. The term “autoinflammatory” has been ascribed to a group of disorders characterized by frequent attacks of inflammation without any indication that this process is related to auto-antigen stimulus. These disorders are associated with defective interleukin-1 processing, regulation of nuclear factor-B transcription factor, and likely abnormal cellular apoptosis. Mutations in genes encoding the tumor necrosis factor (TNF) receptor and pyrin superfamilies of molecules may result in the endurance of leukocytes that would customarily go through apoptosis. As a result, relatively minor proinflammatory triggers may lead to an exaggerated, and potentially harmful, inflammatory response. Patients with autoinflammatory syndromes, including the classic hereditary periodic fever syndromes, may share certain genetic traits; the MEFV gene mutation M694V, associated with familial mediterranean fever (FMF) and IL-1 hypersecretion was seen with increased frequency in turkish children with sJIA. Furthermore, macrophage activating syndrome (MAS), a severe, life-threatening complication that is particularly frequent in patients with AOSD and sJIA has been associated with mutations in the perforin and the MUNC13-4 genes.
Clinical Manifestation and Diagnosis
The diagnosis of AOSD continues to be a clinical one and, in the absence of a definitive diagnostic test, often necessititates the arduous exclusion of potential mimickers, that is, infectious, neoplasmatic, autoimmune, and other autoinflammatory diseases and can be facilitated by the use of one of several validated diagnostic criteria, that is Yamaguchi’s (see below), Cush’s, or Fautrel’s.
Disease severity varies significantly among affected individuals and, even, within the same individual. In certain cases, a single or infrequent recurrent flares, usually dominated by systemic symptoms (fever, rash) that can mask the concurrent inflammatory polyarthritis, may resolve spontaneously or require a short course of systemic corticosteroids. On the more severe end of the spectrum, multiple flares of debilitating frequency or continously active disease, often associated with chronic progressive arthritis and disability, require continous, aggressive immunomodulatory treatment and are associated with complications that carry significant morbidity and mortality.
Systemic corticosteroid therapy is still touted as the primary treatment, especially targeting systemic manifestations, despite concerns regarding the risks associated with their long-term use and their efficacy in preventing radiographic progression of chronic inflammatory arthritis. Tradiitional disease modifying antirheumatic drugs (DMARDs), especially methotrexate (MTX), have shown efficacy in inducing remission in refractory cases and are frequently used as steroid sparing drugs and, also, for prevention of arthritis progression, ankylosis, and disability. However, many cases prove to be refractory and their management remains a challenge; clinicians find themselves combating a disease with protean manifestations with limited evidence-based guidance caused by a paucity of controlled studies. Moreover, there is a growing number of published reports describing rare, albeit life-threatening, multisystemic complications of AOSD. Elevated levels of proinflammatory cytokines such as IL-1β, IL-6, IL-17, IL-8, IL-18, and TNF-a were previously described in AOSD patients, often in association with disease activity and/or distinct clinical phenotypes and serological feaures such as hepatic involvement, arthritic complaints, salmon rash, and hyperferittinimia among others. Given these findings, available biologic agents targeting IL-1, IL-6, and TNF-a for other rheumatologic conditions led to their off-label use in AOSD, with variable success.
While antiTNF agents have been proved moderately efficacious in AOSD refractory cases particularly in the chronic articular form of the disease, IL-1 inhibition is currently considered the mainstay of treatment for AOSD leading to significant improvement in both clinical and laboratory terms. Preliminary results from case series also support a role for IL-6 blockade in the management of refractory disease forms, given the implication of this cytokine in disease pathogenesis. Finally, and since the contributory role of T-cell compartment has been increasingly recognized in AOSD pathophysiology, abatacept—a T-cell costimulation stimulator—has been succesfully used in refractory AOSD cases.
International Journal of Inflammation Volume 2012 (2012), Article ID 964751, 4 pages http://dx.doi.org/10.1155/2012/964751