Background/Purpose:

Systemic Juvenile Idiopathic Arthritis (SJIA) is a severe disabling subtype of Juvenile Idiopathic Arthritis characterized by arthritis plus systemic symptoms, such as high fever, rash, serositis, and lymphadenopathy. Among others, interleukin (IL)-1β is an inflammatory cytokine that plays a dominant role in SJIA and several other autoinflammatory conditions, with anti-IL-1β therapy showing good efficacy in many of these settings. Canakinumab (CAN) is a high-affinity selective human monoclonal antibody targeted against IL-1β. Levels of inflammatory biomarkers and gene expression profiles of patients with active SJIA before and during canakinumab treatment were studied from patients aged 2 to <20 years participating in 2 phase III trials.

Methods:

Serial measurements of levels of cytokines and proteins involved in inflammation (IL6; IL18; S100A8, A9 and A12) were made at baseline and at Days 3 and 29 after initiation of CAN treatment.  Whole blood samples and DNA microarrays were used to characterize the early (Day 3) transcriptional response to CAN treatment and to predict efficacy.

Results:  

Protein markers: The median levels of IL-6 were strongly reduced; 7.2 fold reduction in the first trial (p=0.012) and 4.9 fold in the second trial (p=0.000046) by Day 29, while IL-18 levels remained largely unchanged by Day 29. Among the S100 proteins, median S100A9 levels were reduced by 3.4 fold in the first trial (p=0.0078) and 4.3 fold in the second trial (p=0.016). S100A8 and S100A9 proteins did not show consistent behaviors across the two trials.

Gene Expression:

For all comparisons, the number of down regulated genes was much larger than the number of upregulated genes upon treatment, suggesting that the active disease state was mainly characterized by transcriptional activation of “disease genes”. Transcriptional changes upon CAN treatment at Day 3 were highly consistent between the two trials. Subjects who showed strong transcriptional changes (primarily down regulation, >2x, p=0.05) also showed a strong adapted pediatric ACR response (≥ACR50) at Day 15, while subjects that did not reach ACR50 by Day 15 showed a much weaker transcriptional response at Day 3. Strongly responsive genes included many known inflammation and neutrophil-related genes, including IL-1β, encoding the CAN target.  A set of transcripts was identified for which baseline expression levels predicted a subgroup of strong (≥ACR70) responders at Day 15. However, another subgroup of strong responders was indistinguishable from weak responders (

Conclusion:

CAN treatment resulted in a strong reduction of elevated baseline IL6 protein levels in patients with active SJIA, while IL18 protein levels remained largely unchanged until Day 29 of the treatment period. Many patients who showed a strong clinical benefit already at Day 15 were characterized by high baseline expression levels of inflammatory and neutrophil associated genes which were repressed after 3 days of CAN treatment. A second, smaller, group of patients showing good clinical response did, however, not show this pattern, suggesting the existence of mechanistically different subpopulations in this disease.