Background/Purpose: Systemic juvenile idiopathic arthritis (sJIA), characterized by chronic arthritis associated with prominent systemic and laboratory features, also has a significant impact on the growing skeleton, resulting in impaired linear growth and systemic osteoporosis. A phase 3 trial (TENDER) demonstrated that the interleukin-6 (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.

Methods: The TENDER trial enrolled 112 patients (ages 2-17 years) with active, refractory sJIA (≥6-month duration with inadequate response to previous nonsteroidal anti-inflammatory drugs 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.

Results: At enrollment in the TENDER trial, the height measurements of study patients revealed profound growth failure (mean height standard deviation score [SDS] of –2.1; n = 107). During treatment, the majority of patients had greater than normal height velocities, with 85% of female patients and 73% of male patients demonstrating catch-up growth (Figure). The height SDS increased significantly from baseline to year 2 of the study, with a mean improvement of 0.61 (p < 0.0001, paired t-test). Although the mean corticosteroid dose was higher in the first year (0.13 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 5.8 and 6.3 cm/y, respectively (p = 0.32, paired t-test). 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 –1.1 [n = 95] compared with year 2 mean IGF-1 SDS of 0.0 [n = 91]; p < 0.0001, paired t-test). The osteocalcin/c-telopeptide of type 1 collagen (OC/CTX-1) ratio increased significantly (p = 0.0045, paired t-test), suggesting an increase in osteoblast activity relative to osteoclast activity. Patients with greater improvement in JADAS-71 scores during the first year had greater height velocities during that year (r = –0.35, p = 0.0002; mean decrease in JADAS-71 of 29.2 [n= 107]).

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.