The Systemic‐Onset Variant of Juvenile Idiopathic Arthritis Needs to Be Recorded as an Autoinflammatory Syndrome: Comment on the Review by Nigrovic

We read with interest the recent review article by Nigrovic (1) describing the uniqueness of systemic juvenile idiopathic arthritis (JIA) among the different subtypes of JIA, because it is characterized by systemic features during the initial phase and severe articular signs during the later phase of disease. As discussed by Nigrovic, there is increasing evidence that initiating cytokine blockade early during the systemic phase might alter disease pathophysiology to avoid chronic inflammation and even the arthritic manifestations of systemic JIA. The umbrella-term “JIA” still identifies a heterogeneous group of inflammatory joint diseases. In particular, according to the International League of Associations for Rheumatology classification (2), JIA refers to all forms of arthritides of unknown etiology beginning before age 16 years and persisting for at least 6 weeks, supposing that all other known causes of arthritis have been ruled out. The results of previous studies have indicated that systemic JIA is associated with abnormalities of the innate immune system rather than the classic autoimmune system, because neither autoantibodies nor strong HLA genetic associations can be demonstrated (3). Indeed, systemic JIA does not behave as an articular disease, and many investigators have shown how its manifestations closely mimic those of autoinflammatory syndromes, with an exaggerated innate immune response leading to recurrent sterile inflammation, phagocyte activation, and oversecretion of proinflammatory cytokines such as interleukin-1β (IL-1β), in synergy with endogenous Toll-like receptor ligands, resulting in significant long-term morbidity (4). Although many investigators agree that the systemic inflammation in systemic JIA is driven mostly by up-regulated innate immune pathways, including IL-1, it remains unestablished whether this is attributable to intrinsic abnormalities in caspase 1 activation or environmental triggers. Pascual et al (5) showed that different innate immunity genes were overworking in patients with active systemic JIA. Moreover, different studies have also revealed the dramatic impact of IL-1 blockade, in the form of either the IL-1 receptor antagonist anakinra or the anti–IL-1β blocker canakinumab, in the induction of clinical remission in a substantial subset of patients with systemic JIA. Although we believe that reconsidering the nomenclature of JIA should be approached with caution and global consensus, the newer insights into the pathogenesis and treatment of systemic JIA suggest that this disorder should be drawn away from the group of juvenile arthritides and definitely included in the group of acquired autoinflammatory syndromes, which day after day continues to enlarge and includes nonhereditary periodic fever syndromes, vascular diseases, and metabolic diseases.