ARTHRITIS & RHEUMATOLOGYVol. 66, No. S3, March 2014, pp S23–S24DOI 10.1002/art.38430© 2014, American College of Rheumatology

A14: Neutropenia With Tocilizumab TreatmentIs Not Associated With Increased Infection Risk inPatients With Systemic Juvenile Idiopathic Arthritis

Fabrizio De Benedetti,1 Nicolino Ruperto,2 Eileen Baildam,2 Ruben Burgos-Vargas,2

Gerd Horneff,2 Hans Iko Huppertz,2 Kirsten Minden,3 Barry L. Myones,4 Karen Onel,5

Jianmei Wang,6 Kamal N. Bharucha,7 Daniel J. Lovell,4 Alberto Martini,2

and Hermine Brunner8

Background/Purpose: In the phase 3 TENDERtrial of tocilizumab (TCZ) in patients with systemicjuvenile idiopathic arthritis (sJIA), decreases in neutro-phil count were commonly observed. The purpose of thisstudy was to determine whether neutropenia was asso-ciated with increased risk for infection and to investigatevariables associated with the development of neutrope-nia in patients treated with TCZ for up to 2 years inTENDER.

Methods: One hundred twelve children with ac-tive, persistent sJIA were randomly assigned 2:1 toreceive TCZ based on body weight (12 mg/kg �30 kg or8 mg/kg �30 kg) or placebo intravenously every 2 weeksfor 12 weeks and continued in an ongoing, TCZ open-label extension (1). Worst Common Toxicity Criteria(CTC) neutropenia grade (grade 1, �1.5 and �2.0 �109/L; grade 2, �1.0 and �1.5 � 109/L; grade 3, �0.5and �1.0 � 109/L; grade 4, �0.5 � 109/L) and lowestobserved neutrophil count (109/L) were identified foreach patient. Univariate linear regression analysis wasperformed to investigate the association of patient char-acteristics with lowest observed neutrophil count. Ratesof infection and serious infection (per 100 patient-years[PY]) in periods �15 days around grade 1–2 neutro-penia (22.9 PY) and around grade 3–4 neutropenia(5.5 PY) were compared with corresponding rates inperiods with normal neutrophil count (173.6 PY).

Results: Up to week 104, 64 of 112 patients

(57.1%) had at least 1 episode of grade 1–4 neutropenia;worst grade: 1 (n � 2), 2 (n � 34), 3 (n � 26), and 4 (n �2). Rates of infection and serious infection duringperiods of normal neutrophil counts (276.5/100 PY [95%CI: 252.3, 302.3] and 11.5/100 PY [95% CI: 7.0, 17.8],respectively) were comparable with those observed �15days around grade 1–2 neutropenia (226.7/100 PY [95%CI: 169.3, 297.3]; 8.7/100 PY [95% CI: 1.1, 31.5]) andgrade 3–4 neutropenia (292.5/100 PY [95% CI: 167.2,475.0]; 0/100 PY), with no trend toward increased riskwith higher grade neutropenia. Methotrexate use (Yes/No) was significantly associated with lowest observedneutrophil count (difference: �0.575 [95% CI: �1.02,�0.13], p � 0.012), with 62% of 77 patients receivingmethotrexate versus 46% of 35 patients not receivingmethotrexate having grade 1–4 neutropenia. Youngerage was borderline associated with lowest observedneutrophil count (� � 0.04661; p � 0.047). Concurrentuse of glucocorticoids and TCZ exposure were notassociated with lowest observed neutrophil count (p �0.3).

Conclusion: No trend for association betweenneutropenia and increased risk for infection was ob-served in the TENDER trial. Background methotrexate,and somewhat younger age, was associated with in-creased risk for neutropenia, whereas TCZ exposureand concurrent glucocorticoid use were not.

REFERENCE

1. De Benedetti F et al. N Engl J Med 2012;367:2385.

Disclosure: F. De Benedetti, Abbott, Pfizer, BMS, Roche, Novimmune, Novartis,SOBI, 2; N. Ruperto, Abbott, AstraZeneca, BMS, Centocor, Eli Lilly, FrancescoAngelini, GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer, Regen-eron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, 2, Abbott,

1IRCCS Ospedale Pediatrico Bambino Gesu, Rome, Italy,2PRINTO, Genoa, Italy, 3Children’s University Hospital Charite/German Rheumatism Research Centre Berlin, Berlin, Germany,4PRCSG, Cincinnati, OH, 5University of Chicago Hospitals, Chicago,IL, 6Roche Products Ltd., Welwyn Garden City, United Kingdom,7Genentech, South San Francisco, CA, 8Cincinnati Children’s HospitalMedical Center, Cincinnati, OH.

S23

AstraZeneca, BMS, Centocor, Eli Lilly, Francesco Angelini, GlaxoSmithKline,Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis,Schwarz Biosciences, Xoma, Wyeth, 5, Abbott, Boehringer, BMS, Novartis,Astellas, Italfarmaco, MedImmune, Pfizer, Roche, 8; E. Baildam, None; R.Burgos-Vargas, AbbVie, 2, AbbVie, BMS, Pfizer, 5, AbbVie, BMS, Janssen,Pfizer, Roche, 8; G. Horneff, Abbott, Pfizer, 2; H. I. Huppertz, Abbott, Chugai,Pfizer, Roche, Swedish Orphan, 5; K. Minden, Pfizer, Abbvie, 2, Pfizer, Abbvie,Roche, Chugai, Medac, 5; B. L. Myones, None; K. Onel, None; J. Wang, RochePharmaceuticals, 3; K. N. Bharucha, Genentech and Biogen IDEC Inc., 3; D. J.Lovell, Astra-Zeneca, Centocor, Janssen, Wyeth, Amgen, Bristol-Myers Squibb,

Abbott, Pfizer, Regeneron, Hoffmann-La Roche, Novartis, Genentech, 5, Genen-tech, Roche, 8; A. Martini, Abbott, AstraZeneca, BMS, Centocor, Eli Lilly,Francesco Angelini, GlaxoSmithKline, Italfarmaco, Merck Serono, Novartis, Pfizer,Regeneron, Roche, Sanofi Aventis, Schwarz Biosciences, Xoma, Wyeth, 2, Abbott,AstraZeneca, BMS, Centocor, Eli Lilly, Francesco Angelini, GlaxoSmithKline,Italfarmaco, Merck Serono, Novartis, Pfizer, Regeneron, Roche, Sanofi Aventis,Schwarz Biosciences, Xoma, Wyeth, 5, Abbott, BMS, Astellas, Boehringer,Italfarmaco, MedImmune, Novartis, Pfizer, 8; H. Brunner, Novartis, Genentech,MedImmune, EMD Serono, AMS, Pfizer, UCB, Janssen, 5, Genentech and BiogenIDEC Inc., 8.

S24 THURSDAY, APRIL 3, 2014; 8:30 AM–6:00 PM