Predictors of disease flare after discontinuation of concomitant methotrexate in Japanese patients with rheumatoid arthritis treated with tocilizumab - 20/06/20

Doi : 10.1016/j.jbspin.2020.06.001

Shuji Asai ^a, Nobunori Takahashi ^a, Masatoshi Hayashi ^b, Masahiro Hanabayashi ^c, Yasuhide Kanayama ^d, Toki Takemoto ^e, Yuichiro Yabe ^f, Tomone Shioura ^g, Hisato Ishikawa ^h, Yutaka Yoshioka ⁱ, Takefumi Kato ^j, Yuji Hirano ^k, Takayoshi Fujibayashi ^l, Yosuke Hattori ^m, Tomonori Kobayakawa ⁿ, Masahiko Ando ^o, Yachiyo Kuwatsuka ^o, Takuya Matsumoto ^a,^g, Nobuyuki Asai ^a,^m, Yasumori Sobue ^a, Tsuyoshi Nishiume ^a, Mochihito Suzuki ^a, Naoki Ishiguro ^a, Toshihisa Kojima ^a,⁎
^a Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan
^b Department of Rheumatology, Nagano Red Cross Hospital, 5-22-1 Wakasato, Nagano, Nagano 380-8582, Japan
^c Department of Rheumatology, Ichinomiya Municipal Hospital, 2-2-22 Bunkyo, Ichinomiya, Aichi 491-8558, Japan
^d Department of Rheumatology, Toyota Kosei Hospital, 500-1 Ibobara, Josui-cho, Toyota, Aichi 470-0396, Japan
^e Department of Orthopedic Surgery, Anjo Kosei Hospital, 28 Higashihirokute, Anjo-cho, Anjo, Aichi 446-8602, Japan
^f Department of Rheumatology, Tokyo Shinjuku Medical Center, 5-1 Tsukudo-cho, Shinjuku-ku, Tokyo 162-8543, Japan
^g Department of Rheumatology, Shizuoka Kosei Hospital, 23 Kitaban-cho, Aoi-ku, Shizuoka, Shizuoka 420-8623, Japan
^h Department of Rheumatology, Japanese Red Cross Nagoya Daiichi Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya, Aichi 453-8511, Japan
ⁱ Department of Rheumatology, Handa Municipal Hospital, 2-29 Toyo-cho, Handa, Aichi 475-8599, Japan
^j Kato Orthopedic Clinic, 8-4 Minamimyodaiji-cho, Okazaki, Aichi 444-0852, Japan
^k Department of Rheumatology, Toyohashi Municipal Hospital, 50 Aotake-cho, Toyohashi, Aichi 441-8570, Japan
^l Department of Orthopedic Surgery, Konan Kosei Hospital, 137 Omatsubara, Takaya-cho, Konan, Aichi 483-8704, Japan
^m Department of Orthopedic Surgery and Rheumatology, Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya, Aichi 460-0001, Japan
ⁿ Department of Rheumatology, Chutoen General Medical Center, 1-1 Shobugaike, Kakegawa, Shizuoka 436-8555, Japan
^o Department of Advanced Medicine, Nagoya University Hospital, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan

^⁎Corresponding author.

Sous presse. Épreuves corrigées par l'auteur. Disponible en ligne depuis le Saturday 20 June 2020
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Highlights

•	Of RA patients with sustained low disease activity receiving tocilizumab plus methotrexate, 69.4% maintained low disease activity at 52weeks after methotrexate discontinuation.
•	Male patients and those receiving tocilizumab at an extended dosing interval were at high risk of disease flare after discontinuation of concomitant methotrexate.
•	Methotrexate discontinuation reduced the prevalence of gastroesophageal reflux disease in RA patients.

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Abstract

Objective

To investigate predictors of disease flare after methotrexate discontinuation in Japanese rheumatoid arthritis (RA) patients with sustained low disease activity undergoing tocilizumab plus methotrexate combination therapy.

Methods

Participants of this multicenter, open-label, uncontrolled, prospective study were RA patients maintaining low disease activity (Clinical Disease Activity Index [CDAI]≤10) for≥12weeks with tocilizumab plus methotrexate. Methotrexate was discontinued after 12weeks of biweekly administration while continuing tocilizumab therapy. Disease flare was defined as either a CDAI score>10 or intervention with rescue treatments for any reason even if the CDAI score was≤10. The impact of baseline characteristics on disease flare at week 64 (52weeks after methotrexate discontinuation) was assessed with logistic regression models.

Results

Efficacy analyses were performed in 49 patients, of whom 15 had a disease flare by week 64. The proportion (95% confidence interval [CI]) of patients who maintained low disease activity without a flare at week 64 was 69.4% (54.6–81.8%). The dosing interval of tocilizumab was longer than that described on the drug label in Japan (i.e., intravenously every 4weeks, or subcutaneously every 2weeks) in 27% and 6% of patients with and without a flare, respectively. Multivariate analysis revealed that male sex (odds ratio [OR]: 18.00, 95% CI: 2.80–115.56) and extended dosing interval of tocilizumab (OR: 12.00, 95% CI: 1.72–83.80) were independent predictors of disease flare.

Conclusion

Male patients and those receiving tocilizumab at an extended dosing interval are at high risk of disease flare after discontinuation of concomitant methotrexate.