The role of IL-1 inhibition in systemic juvenile idiopathic arthritis: current status and future perspectives

Abstract

The pathogenesis, clinical course, and response to treatment in systemic juvenile idiopathic arthritis (SJIA) differ from other types of juvenile idiopathic arthritis and are similar to other interleukin-1 (IL-1)-mediated diseases. The main cytokine involved in the pathogenesis of SJIA is IL-1β, which can be neutralized by targeted anti-IL-1 therapy. In SJIA, no antibodies have been found and there is growing evidence that it is mainly an autoinflammatory and not an autoimmune disease. Before the era of biologic therapy, treatment of SJIA was primarily based on long-term treatment with high doses of glucocorticosteroids (GCS). The side effects of GCS could have a significant impact on the outcome of the disease and could cause long-term damage. Treatment with anti-IL-1 agents early in the disease course has revolutionized the management principles of SJIA. However, not all SJIA patients respond equally well to anti-IL-1 therapy, and it has been shown that age at the onset of disease, duration of the disease, number of affected joints, neutrophil count, and ferritin level can predict the response to anti-IL-1 therapy. In particular, an elevated ferritin level should prompt testing for macrophage activation syndrome (MAS), the most severe complication of SJIA. Anti-IL-1 therapy has been shown to be effective also in patients with MAS. Although anti-IL-1 agents are currently not recommended as first-line treatment, there is growing evidence that anti-IL-1 agents introduced at the beginning of SJIA could enable lower doses and a shorter duration of GCS therapy, change the long-term disease outcome, and even influence molecular disease patterns. There are currently three anti-IL-1 agents available: anakinra, canakinumab, and rilonacept. In this review, we present the current knowledge on the pathogenesis of SJIA, the rational for anti-IL-1 treatment, and future perspectives on the treatment of SJIA.

Plasma interleukin-37 is increased and inhibits the production of inflammatory cytokines in peripheral blood mononuclear cells in systemic juvenile idiopathic arthritis patients

“…Previous studies have demonstrated that pro-inflammatory cytokines IL-1β, IL-6, TNF-α and IFN-γ markedly increased in sJIA patients and were closely related to the inflammation of sJIA [ 3 , 28 ]. Clinical trials showed that antibodies of these pro-inflammatory cytokines could effectively alleviate the disease severity in patients with sJIA [ 7 , 34 – 36 ]. Therefore, blocking these cytokines expression is a promising strategy for the development of novel anti-sJIA therapies.…”

“…Abundant evidences have suggested that pro-inflammatory cytokines, such as interleukin (IL)-6, IL-17 and tumor necrosis factor-α (TNF-α), were significantly increased in the peripheral blood of sJIA patients, which are related to the pathogenesis of sJIA [ 3 – 5 ]. Interestingly, although IL-1β serum levels in sJIA patients were as low as those of healthy controls (HCs), neutralization of IL-1β with anti-IL-1β agents could effectively and sustainably block the inflammatory response in sJIA [ 6 , 7 ]. Accumulating clinical trials demonstrated that therapies targeting these cytokines or their receptors could partially alleviate the inflammatory symptoms and reduce disease activity in sJIA [ 8 – 10 ].…”

Biologics in uveitis: An update

“…[57][58] Authors have reported its effectiveness in the management of severe uveitic cases. 7,[57][58][59][60][61][62][63][64][65] Interleukin (IL)-1 has shown to be a key proinflammatory cytokine in many autoimmune diseases and its inhibition might have a promising future among other novel therapeutic opportunities. 58…”

Pneumococcal Vaccine in Patients with Systemic Juvenile Idiopathic Arthritis Receiving Biologic Therapy: International Practice Review

“…Канакинумаб -человеческое моноклональное антитело к IL1␤, блокирующее связывание цитокина с рецептором, IL1␤-индуцированную активацию генов и синтез медиаторов воспаления [57]. Препарат был одобрен в США в 2013 г. в качестве монотерапии или в комбинации с метотрексатом для пациентов старше 2 лет с активным сЮИА и неадекватным ответом на терапию нестероидными противовоспалительными препаратами или системными глюкокортикостероидами [58].…”