First Use of Oral Histone Deacetylase Inhibitor (Givinostat) in Systemic Onset Juvenile Idiopathic Arthritis (Sojia)
Jelena Vojinovic
Department Pediatric Rheumatology, University Clinical Center, Faculty of Medicine, Nis Serbia, Bul dr Zoran Djindjic 48 18000 Nis, Serbia
Abstract:
Objective: Low concentrations of histone deacetylase inhibitors (HDACi) exhibit anti-inflammatory properties including animal models of arthritis. Here we present results of first use of an orally active HDACi Givinostat (ITF2357) to influence cytokine network and affect rheumatic arthritis, in children with SOJIA.
Methods: Givinostat was orally administered for up to 12 weeks at a dose of 1.5 mg/kg/day in 17 SOJIA patients with average disease duration of 59.53±49.16 months and duration of active disease of 14.19±24.41 months. Clinical assessment of disease activity was performed using ACR Pedi 30, 50 or 70 and a systemic feature score. The primary objective was safety and primary endpoint was number of responders who completed 12 weeks of treatment. Cytokines were measured in hole blood lysates using R&D Systems (MosaicTM ELISA) human cytokine panel.
Results: Givinostat was safe and well tolerated with adverse events being mild or moderate, of short duration and self-limiting. Out of 17 patients who entered the study, ten completed the 12 weeks of treatment (58.8%). At week 4,the mean systemic feature score significantly decreased from 5.24 ± 0.37 to 2.59 ± 0.33 and the ACR Pedi 30, 50 or 70 improvement was 77.8%, 55.6% and 22.2%. At week 12, the ACR scores increased further to 77.8%, 77.8% and 66.7%, respectively. The most consistent finding was the reduction in the number of active joints and/or joints with limited range of motion. At week 4, in patients with baseline WBC of 12,000 or greater (N=11), there was a significant decrease (p<0.01) in the total WBC and absolute numbers of neutrophils (-30.6 and – 29.8 D% from baseline, respectively). Cytokines in whole blood lysates were elevated at baseline but after 2 and 4 weeks of Givinostat, CD40L (p<0.05), IL‑1a (p<0.001) and IFNg normalised.
Conclusion: HDAC inhibition by Givinostat was safe and resulted in significant improvement in the arthritic component as well as normalized cytokine and hematological parameters of the disease.
