Background/Purpose: To evaluate the long-term safety of tocilizumab (TCZ) for the treatment of rheumatoid arthritis (RA) in a real-world clinical setting in Japan.

Methods: In this long-term extension of the single-arm, observational postmarketing surveillance study of TCZ, patients who received at least 1 dose of intravenous TCZ (8 mg/kg) between April 2008 and August 2010 were observed for 3 years. Patient characteristics and the incidences of mortality, serious infection, malignancy, GI perforation and serious cardiac dysfunction were evaluated during observation period. The analyses included the adverse events (AEs) after discontinuation of TCZ. Data were summarized as the proportion (95% CI) of patients experiencing each event or as incidence rates presented as the number of patients per 100 patient-years (PY).

Results: In total, 5573 patients were enrolled, with a total observation of 15,106 PY. Excluding patients who died, transferred hospitals, or were lost to follow-up, a total of 5327 patients (95.59%) completed 1 year, 4850 (87.03%) completed 2 years, and 4527 (81.23%) completed 3 years of observation. The mean and median treatment duration was 2.1and 2.9 years, respectively. The overall mortality rate during the observation period was 2.58% (144/5573 patients). The most common cause of death was infection (28.47%), followed by respiratory disease (15.97%), malignancy (14.58%), and cardiac dysfunction (9.03%). The standardized mortality ratio (SMR) in comparison with the general Japanese population was 1.27 (95% CI, 1.08–1.50), which is comparable to the SMR reported in a large observational cohort of Japanese patients with RA (all-patient mortality between 1.46 [95% CI, 1.32–1.60] and 1.90 [95% CI, 1.75–2.07]).¹ The incidence rate of malignancy during the observation period was 2.24% (0.83/100 PY), and the standardized incidence ratio (SIR) was 0.79 (95% CI, 0.66–0.95), which was stable over time. Only malignant lymphoma had a significantly higher incidence compared to the general Japanese population, with a SIR of 3.13 (95% CI, 1.82–5.39) which is comparable to that of all RA patients compared with the general population (SIR, 6.07; 95% CI, 3.71–9.37).² There was no increase in rate of any AEs with prolonged observation, while incidence of fatal events, serious infection, GI perforation and serious cardiac dysfunction decreased over time. (Table).

Conclusion: The safety profile of TCZ was consistent over time with respect to mortality, serious infections, malignancy, gastrointestinal perforation, and serious cardiac dysfunction. These data confirm the long-term safety of TCZ use in patients with RA in a real-world clinical setting in Japan.

Ref 1; Nakajima et. al. Scand J Rheumatol. 2010;39(5):360-367.

Ref 2; Yamada et. al. Rheumatol Int. 2011;31(11):1487-1492

Table. Changes in the incidence of fatal events, serious infections malignancy GI perforation and serious cardiac dysfunction during observation period

Incidence rate [95%CI]	0-52 wk (n=5573)	53-104 wk (n=5168)	105-156wk (n=4721)
Mortality	1.18 [0.92-1.50]	0.85 [0.62-1.14]	0.47 [0.29-0.70]
Malignancy	0.68 [0.48-0.93]	0.81 [0.59-1.10]	0.66 [0.45-0.93]
Serious infections	5.67 [5.08-6.31]	3.25 [2.78-3.77]	2.16 [1.77-2.62]
Gastrointestinal perforation	0.36 [0.22-0.55]	0.15 [0.07-0.30]	0.15 [0.06-0.31]
Serious cardiac dysfunction	0.61[0.42-0.85]	0.41 [0.25-0.62]	0.11 [0.03-0.25]

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/first-confirmation-data-of-long-term-safety-for-tocilizumab-in-real-world-setting-3-year-follow-up-postmarketing-surveillance-of-5573-patients-with-rheumatoid-arthritis-in-japan/