Biomarker-Guided Treatment-And-Stop-Strategy for Recombinant IL-1Receptor Antagonist (anakinra) in Systemic Juvenile Idiopathic Arthritis

Bas Vastert, MD, PhD

Head of the department of pediatric rheumatology and immunology, Wilhelmina Children's Hospital Center for Translational Immunology, UMC Utrecht

sJIA treatment


• · Biological treatment targeting the IL1 (anakinra, canakinumab) and IL6 (tocilizumab) pathway
• · Improved prognosis and reduced need for steroids
• · Side-effects in children: osteoporosis, slowed growth, increased risk of infections, increased blood pressure, increased blood sugar, mood changes, cataract and cushingoid appearance (moon-face)
• · Biologicals are more effective when started early in the disease (Window of opportunity) 2

Utrecht protocol


Study design ESTIS


Cohort characteristics

Baseline cohort characteristics

Total number of participants

66

Number of participants intervention phase

45

Percentage of females (n)

54.6% (36/66)

Median age at start of symptoms in years (range)

8.86 (0.84- 15.71)

Trisomy 21

1/66 8.97 (0.93-16.61)

Median age at start of anakinra in years (range)

Median days onset symptoms to start anakinra (IQR)

23 (13-44)

Median Anakinra starting dose in mg/kg (range)

2 (1-5)

+/- 30% of patients without arthritis at start of rIL-1RA comparable to Ter Haar et al. A&R 2019


Improved taper-and-stop strategy

• · CID after 3 months of rIL-1RA mono-therapy
• · National multicenter setting = historic single center cohort
• · 73% vs. 71%
• · 45 patients entered the intervention cohort
• · 40: IL-18 under threshold within intervention time-frame
• · 80% success without restart
• · 4: IL-18 > threshold until t=8 months
• · 50% success without restart
• · Overall IL-18 with a cutoff of 1200pg/ml in the protocol significantly increases the percentage of patients with a successful taper-and-stop 1 year after rIL-1RA mono-therapy initiation compared to the historic cohort
• · 76% vs. 47% p=0.03
• · 97% of successful taper-and stop remains in remission up to 24 months

Conclusions

• · The Utrecht protocol, starting rIL-1RA early as first-line treatment in new-onset SJIA, is highly effective, also in a national multicenter setting
• · The addition of IL-18 with a cut-off value of 1200 pg/mL as a biomarker significantly increases the success of a tapering strategy of rIL-1RA in patients achieving CID at 3 months on rIL-1RA mono-therapy
• · Early taper and stop reduces the duration of treatment and amount of injections necessary
• · Our study also provide important information on the disease-course of non-mono phasic patients, with a higher chance for refractory disease
• UMC Utrecht · The down slope of IL-18 in the first months after treatment is associated with and predictive of refractory disease
• · Incidence of MAS seems not reduced!

2


IL-18 Levels at Baseline and 3 Months

Baseline Wilcoxon p-value: 0.679

3 Months Wilcoxon p-value: 0.159


2

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Days after start anakinra

Non-linear mixed effects modeling

AMCO3-001

AMCO3-003

AMCO3-004

AMCO3-006

AMCO3-007

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Days after start anakinra

400

Cytokine modeling


Macrophage Activation Syndrome


• · 17% (11/66) of patients developed MAS in the follow-up of ESTIS
• · >50% in the first 3 months after start of treatment


Remco Erkens





Acknowledgements

Dieneke Schonenberg-Meinema




Erika v Nieuwenhove

Dörte Hamann

Thomas Vogl

Sytze De Roock

Marc Jansen

Discussion



Anakinra side-effects: Local reaction at injection site (redness, itching) generally, appear within 2 weeks of therapy, disappear within 4-6 weeks (transient) liver enzyme elevations Potential increased risk of infections (mainly respiratory) Allergic reactions (anaphylaxis)