Catch-up growth during tocilizumab therapy for systemic juvenile idiopathic arthritis: 2-year data from a phase 3 clinical trial

Abstract

Introduction: Systemic JIA (sJIA), characterized by chronic arthritis associated with prominent systemic features, has a significant impact on the growing skeleton, resulting in impaired linear growth and systemic osteoporosis. A phase 3 trial (TENDER) demonstrated that the IL-6 receptor inhibitor tocilizumab (TCZ) is effective in the treatment of patients with sJIA. Long-term growth responses for children in the TENDER trial (up to week 104) are presented. Method: The TENDER trial enrolled 112 patients (ages 2-17 years) with active, refractory sJIA (> 6 months duration with inadequate response to previous NSAIDs and oral corticosteroids). After a 12-week, randomized, placebo-controlled phase, patients received open-label TCZ in the long-term extension. Height parameters, laboratory data and clinical assessments of disease activity were compared at baseline and through year 2 of the study in patients who never received growth hormone. Results: At enrolment in the TENDER trial, the height measurements of study patients revealed profound growth failure (mean WHO height standard deviation score [SDS] of -2.0; n=103). During treatment, the majority of patients had greater than normal height velocities, with 84% of female patients and 72% of male patients demonstrating catch-up growth (Figure 1). The height SDS increased significantly from baseline to year 2 of the study, with a mean improvement of 0.56 (P<0.0001, paired t-test). Additional growth analysis was performed for patients with Tanner stage <4 at baseline. Although the mean corticosteroid dose was higher in the first year (0.14 mg/kg/day compared with 0.05 mg/kg/day in the second year), mean height velocities in the first and second years of the study were comparable at 6.7 and 7.1 cm/y, respectively. During TCZ treatment, a significant increase in insulin-like growth factor 1 (IGF-1) levels was observed, suggesting a normalization of growth hormone axis function [mean baseline IGF-1 SDS of -0.9 (n=70) compared with year 2 mean IGF-1 SDS of -0.2 (n=56); P=0.0015, paired t-test on n=56]. The osteocalcin/c-telopeptide of type 1 collagen (OC/CTX-1) ratio increased significantly (P=0.0082, paired t-test), suggesting an increase in osteoblast activity relative to osteoclast activity. At year 1, JADAS-71 score correlated with height velocity during that year (Spearman rank r=-0.36, P=0.0010; n=81). Conclusion: TCZ therapy for sJIA resulted in catch-up growth of study patients. Additionally, TCZ therapy resulted in increased IGF-1 levels and OC/CTX-1 ratios, suggesting beneficial effects on the growth hormone axis and on bone metabolism. Improvement in JADAS scores correlated with increased height velocity. Continued data collection (for a total of 5 years) will allow a comprehensive analysis of growth outcomes in the TENDER study. (Figure Presented).