The recent insights into the pathophysiological mechanisms in SJIA have led to major changes in the management of this disease. Until recently, the treatment algorithms in SJIA included mainly steroids and methotrexate [61
]. Since their introduction in the late 90s, TNF- inhibiting agents have also been frequently used in these patients. Thalidomide [62
], Cyclosphosphamide [63
] or even autologous stem cell transplantation [64
] have been used in patients with a particularly severe disease. However, Methotrexate, the first choice second line agent in JIA, is now recognized to be less effective for both the systemic and articular manifestations of SJIA [65
]. TNF-inhibiting agents also show significantly lower response rates in SJIA compared to other JIA subtypes [68
In contrast, the preliminary experience with new biologics blocking IL-1β and IL-6 looks very promising. Initially, in uncontrolled studies in patients with refractory SJIA resistant to methotrexate and TNFα-blockade, the treatment with Kineret led to a rapid and sustained remission within a few days [10
]. However, the initial optimism for this treatment has been somewhat diminished by more recent reports suggesting that not all the patients with SJIA respond to the treatment and the response is not always sustained 73
]. These observations suggest that there might be different subsets within the disease [39
] and studies aimed at the identification of biologic markers that would predict response are in progress. Another possible reason for the poor response to Kineret in some patients is that the utilization of the naturally occurring IL-1 receptor antagonists may not be the best strategy to inhibit IL-1 activity [75
]. Indeed, it may be difficult to occupy the large number of IL1 receptors expressed on many different cell types. In addition, IL-1 receptor antagonists are rapidly excreted by the kidney, while new IL-1Rs are being generated every day. These problems are likely to be overcome with the new long-acting agents that block IL-1 more efficiently. One of these new agents, Rilonacept (or IL-1 Trap) is a fusion protein consisting of the two human IL1 receptor extracellular domains and the Fc portion of human IgG1. It incorporates in a single molecule the extracellular domains of both receptor chains required for IL-1 signaling: the IL-1 type I receptor and the IL-1 receptor accessory protein. Because of this, the IL-1 Trap molecule might be a more efficient inhibitor of in vivo IL-1 signalling than Kineret. Recently, Rilonacept has been proven to be effective in a phase II trial in familial cold autoinflammatory syndrome [76
], and a Phase III trial of this agent in SJIA is in progress. A fully human anti-interleukin-1β (anti-IL-1β) monoclonal antibody is another new IL-1 inhibiting agent currently studied in SJIA in the USA and Europe. The preliminary experience with the anti-IL-6 receptor antibody (Toculizumab) in two independent Phase II studies [77
] in SJIA shows even greater promise. However, the safety profiles of these agents still need to be determined.
Currently in clinical practice, the increasing enthusiasm for the IL-1 and IL-6 inhibiting agents has led to a rapid decrease in the use of Methotrexate and TNF-inhibitors in SJIA while early administration of the IL-1 and IL-6 inhibiting agents is becoming more and more common. There is a hope that the early administration of the IL-1 and IL-6 inhibiting agents will also allow to decrease or even avoid the use of steroids in at least some of the patients with SJIA.
In conclusion, similarly to the autoinflammatory syndromes such as FMF, and NOMID, the abnormalities in the innate rather than adaptive immunity play a major role in the pathophysiology of SJIA. Based on this, the emerging consensus is that SJIA should be viewed as an auto-inflammatory syndrome. The utilization of the new IL-1 and IL-6 blocking agents is likely to become the main treatment of SJIA and, perhaps, change the long term outcome in this still often devastating disease.