P13 Real-life single-centre experience of tocilizumab-associated neutropenia in children with JIA
Authors: Foley Charlene , Sadik Tara , Obaidi Muthana Al 
Published: September 2019

Abstract

Background
Tocilizumab, approved for treatment of children >2years with SoJIA and polyarticular JIA (pJIA) is efficacious and well-tolerated. Transient neutropenia as a side-effect of treatment has been reported. Our aim was to perform a retrospective chart review of children treated with Tocilizumab and report our experience of tocilizumab-associated neutopenic episodes.

Methods
Retrospective review of patients receiving tocilizumab (January 2010-January 2019) performed and baseline demographics recorded. Patients with a diagnosis of extended-oligoarticular JIA (ExO-JIA), pJIA and SoJIA were reviewed in more detail to ascertain frequency of neutropenia and related-factors. For the purpose of analysis, ExO-JIA and pJIA were combined to create an ExO/pJIA group. Neutropenia was defined as neutrophils<1.5 and severe neutropenia as < 1.0. Statistical analysis was performed using the Mann-Whitney-U and Chi-Square tests.

Results
Sixty-eight children (60% female) attending the rheumatology department at GOSH are receiving tocilizumab. Of these, 53 (78%) have a diagnosis of ExO-JIA (n = 10), pJIA (n = 12) or SoJIA (n = 31). Median age at diagnosis was 4.4years (0.2–14.7). Disease duration pre-commencement of tocilizumab was 2.9years (0.1–11).
Children with SoJIA were commenced on tocilizumab significantly (p < 0.001) earlier in their disease course than children with ExO/pJIA (1.5 years, 0.1–7.4 versus 6.5 years, 0.4-11 respectively). However, there was no significant difference in number of alternative treatments received pre-tocilizumab between groups. Concurrent methotrexate administration was similar between groups. In contrast, concurrent use of steroids in SoJIA (27/31, 87%) was significantly more frequent (p < 0.00001) than in ExO/pJIA (2/22, 9%).
All children commenced on tocilizumab had a normal preceding white cell and neutrophil count. Median time to first episode of neutropenia was 0.5years (0.1-3.2). No significant pattern in time from commencing tocilizumab to developing first episode of neutropenia was observed (40% developed neutropenia after >6months on tocilizumab).
Recurrent neutropenia (i.e. >2 episodes of neutropenia) was observed in 38% (20/53) and was significantly more common in children with SoJIA compared to ExO/pJIA (p < 0.05). All children with ExO/pJIA experienced a total of 2-3 neutropenic episodes, significantly less (p < 0.05) than the recurrence rate in children with SoJIA (median 7 episodes, 2-17).
Severe neutropenia was observed in 65% (n = 13), occurring significantly (p < 0.001) more frequently in SoJIA (n = 11, 85%) than ExO/pJIA. In those with recurrent neutropenia, no significant correlation was identified between risk of neutropenia and interval between doses, dose (mg/kg) received, concurrent administration of methotrexate, duration on tocilizumab or number of alternative treatments received pre-tocilizumab.
Finally, 17 children (32%) taking tocilizumab had a documented infection, but no relationship between neutropenia and risk of infection was identified.

Conclusion
Tocilizumab-associated neutropenia is more frequently observed, more severe and more often recurrent in children with SoJIA. Neutropenia can occur at any stage in the treatment course, therefore clinicians should consider continuing blood-monitoring pre-tocilizumab long-term, with particular attention paid to those diagnosed with SoJIA.

Conflicts of Interest
The authors declare no conflicts of interest.