New frontiers in the treatment of systemic juvenile idiopathic arthritis

Canny, Susan; Mellins, Elizabeth

doi:10.12688/f1000research.11327.1

Cited by 14 publications

(15 citation statements)

References 82 publications

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“…Recent advances in the pathology of SJIA draw attention to other possible therapeutic biologic targets such as IL-18, IL-17, signaling molecules such as enzymes in the JAK family, and interferon-γ in MAS in resistant, difficult-to-treat patients. 18 , 71 …”

Section: Future Perspectives – the Role Of Early Il-1 Blockade And Pomentioning

confidence: 99%

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

Toplak¹,

Blazina²,

Avčin³

2018

DDDT

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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.

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Section: Future Perspectives – the Role Of Early Il-1 Blockade And Pomentioning

confidence: 99%

“… 13 – 17 Recent advances in the pathogenesis of SJIA have revealed new possible biologic targets for the treatment of resistant cases, including IL-18, IL-17, and signaling molecules such as enzymes of the Janus kinase (JAK) family. 18 …”

Section: Introductionmentioning

confidence: 99%

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

Toplak¹,

Blazina²,

Avčin³

2018

DDDT

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“…Brodalumab is another biologics (anti-IL-17 receptor A antibody) drug that was recently approved by the FDA for the treatment of severe-to-moderate psoriasis and psoriatic arthritis [30]. Since IL-17 signaling is also implicated in the pathophysiology of Crohn's disease (CD) [31] and systemic juvenile idiopathic arthritis (SJIA) [32], we evaluated brodalumab repositioning potential for these diseases. The results of ml-SOM confirmed the action of brodalumab in psoriasis that includes inhibition of keratinization in epidermal cells and leveraging immune response at the site of psoriatic lesions [33,59].…”

Section: Discussionmentioning

confidence: 99%

“…Brodalumab (anti-IL-17 receptor A antibody) was approved for the treatment of severe-to-moderate psoriasis and psoriatic arthritis [30]. We chose Crohn's disease (CD) and systemic juvenile idiopathic arthritis (SJIA) as repositioning targets since IL-17 signaling is implicated in these diseases [31,32].…”

Section: Experiments Design and Datasetsmentioning

confidence: 99%

Transcriptome-Guided Drug Repositioning

et al. 2019

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Drug repositioning can save considerable time and resources and significantly speed up the drug development process. The increasing availability of drug action and disease-associated transcriptome data makes it an attractive source for repositioning studies. Here, we have developed a transcriptome-guided approach for drug/biologics repositioning based on multi-layer self-organizing maps (ml-SOM). It allows for analyzing multiple transcriptome datasets by segmenting them into layers of drug action- and disease-associated transcriptome data. A comparison of expression changes in clusters of functionally related genes across the layers identifies “drug target” spots in disease layers and evaluates the repositioning possibility of a drug. The repositioning potential for two approved biologics drugs (infliximab and brodalumab) confirmed the drugs’ action for approved diseases (ulcerative colitis and Crohn’s disease for infliximab and psoriasis for brodalumab). We showed the potential efficacy of infliximab for the treatment of sarcoidosis, but not chronic obstructive pulmonary disease (COPD). Brodalumab failed to affect dysregulated functional gene clusters in Crohn’s disease (CD) and systemic juvenile idiopathic arthritis (SJIA), clearly indicating that it may not be effective in the treatment of these diseases. In conclusion, ml-SOM offers a novel approach for transcriptome-guided drug repositioning that could be particularly useful for biologics drugs.

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“…Among auto-inflammatory syndromes, AOSD shows greatest similarity to our hIL-1 cTg mice, although our mice do not exhibit all phenotypes seen in patients with AOSD. Still’s disease is also an arthritis disease first described by Still in 1897 55 and currently known as systemic juvenile idiopathic arthritis 56 . In 1971, Bywaters described 14 children with pediatric Still’s disease resembling AOSD 57 .…”

Section: Discussionmentioning

confidence: 99%

IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

Oike

Kanagawa

Sato

et al. 2018

Sci Rep

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Auto-inflammatory syndrome, a condition clinically distinct from rheumatoid arthritis, is characterized by systemic inflammation in tissues such as major joints, skin, and internal organs. Autonomous innate-immune activation is thought to promote this inflammation, but underlying pathological mechanisms have not been clarified nor are treatment strategies established. Here, we newly established a mouse model in which IL-1 signaling is conditionally activated in adult mice (hIL-1 cTg) and observed phenotypes similar to those seen in auto-inflammatory syndrome patients. In serum of hIL-1 cTg mice, IL-6 and IL-17 levels significantly increased, and signal transducer and activator of transcription 3 (Stat3) was activated in joints. When we crossed hIL-1 cTg with either IL-6- or IL-17-deficient mice or with Stat3 conditional knockout mice, phenotypes seen in hIL-1 cTg mice were significantly ameliorated. Thus, IL-6, IL-17 and Stat3 all represent potential therapeutic targets for this syndrome.

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New frontiers in the treatment of systemic juvenile idiopathic arthritis

Cited by 14 publications

References 82 publications

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

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

Transcriptome-Guided Drug Repositioning

IL-6, IL-17 and Stat3 are required for auto-inflammatory syndrome development in mouse

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