title: Adult onset Still's disease (AOSD) in the era of biologic therapies: dichotomous view for cytokine and clinical expressions.
abstract: Adult onset Still's disease (AOSD) is a rare inflammatory disorder characterized by hectic spiking fever, evanescent rash and joint involvement. Prognosis is highly variable upon disease course and specific involvements, ranging from benign and limited outcome to chronic destructive polyarthritis and/or life-threatening events in case of visceral complications or reactive hemophagocytic lymphohistiocytosis (RHL). AOSD remains a debatable entity at the frontiers of autoimmune diseases and autoinflammatory disorders. The pivotal role of macrophage cell activation leading to a typical Th1 cytokine storm is now well established in AOSD, and confirmed by the benefits using treatments targeting TNF-α, IL-1β or IL-6 in refractory patients. However, it remains difficult to determine predictive factors of outcome and to draw guidelines for patient management. Herein, reviewing literature and relying on our experience in a series of 8 refractory AOSD patients, we question nosology and postulate that different cytokine patterns could underlie contrasting clinical expressions, as well as responses to targeted therapies. We therefore propose to dichotomize AOSD according to its clinical presentation. On the one hand, 'systemic AOSD' patients, exhibiting the highest inflammation process driven by excessive IL-18, IL-1β and IL-6 production, would be at risk of life-threatening complications (such as multivisceral involvements and RHL), and would preferentially respond to IL-1β and IL-6 antagonists. On the other hand, 'rheumatic AOSD' patients, exhibiting pre-eminence of joint involvement driven by IL-8 and IFN-γ production, would be at risk of articular destructions, and would preferentially respond to TNF-α blockers.
authors.affiliation: Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France; Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France.
authors.forename: Alexandre Thibault Jacques
authors.initials: AT
authors.lastname: Maria
authors.affiliation: Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France.
authors.forename: Alain
authors.initials: A
authors.lastname: Le Quellec
authors.affiliation: Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France; Clinical Immunology and Osteoarticular Diseases Therapeutic Unit, Lapeyronie Hospital, 191 Avenue du Doyen Gaston Giraud, F-34295 Montpellier, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Jorgensen
authors.affiliation: Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France; Auto-Inflammatory Diseases Unit, Genetic Laboratory, Arnaud De Villeneuve Hospital, 191 Avenue du Doyen Gaston Giraud, F-34295 Montpellier, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Touitou
authors.affiliation: Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Rivière
authors.affiliation: Department of Internal Medicine-Multiorganic Diseases, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, F-34295 Montpellier, France; Inserm, U 844, Saint-Eloi Hospital, 80 Avenue Augustin Fliche, Montpellier F-34295, France. Electronic address: p-guilpain@chu-montpellier.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Guilpain
mesh_terms: D000328:Adult; D001691:Biological Therapy; D016207:Cytokines / Q000627:therapeutic use*; D006801:Humans; D008262:Macrophage Activation; D016706:Still's Disease, Adult-Onset / Q000628:therapy*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines
keywords: Adult-onset Still's disease; Autoinflammatory disorder; Biologic agents; Cytokines; Macrophage activation syndrome; Reactive hemophagocytic lymphohistiocytosis