Impact of adding tacrolimus to initial treatment of interstitial pneumonitis in polymyositis/dermatomyositis: a single-arm clinical trial

Kazuki Takada, Yoshinori Katada, Satoshi Ito, Taichi Hayashi, Jun Kishi, Kenji Itoh, Hiroyuki Yamashita, Michito Hirakata, Kimito Kawahata, Atsushi Kawakami, Norihiko Watanabe, Tatsuya Atsumi, Yoshinari Takasaki, Nobuyuki Miyasaka, Kazuki Takada, Yoshinori Katada, Satoshi Ito, Taichi Hayashi, Jun Kishi, Kenji Itoh, Hiroyuki Yamashita, Michito Hirakata, Kimito Kawahata, Atsushi Kawakami, Norihiko Watanabe, Tatsuya Atsumi, Yoshinari Takasaki, Nobuyuki Miyasaka

Abstract

Objective: Interstitial pneumonia is common and has high short-term mortality in patients with PM and DM despite glucocorticoid (GC) treatment. Retrospective studies suggested that the early use of immunosuppressive drugs with GCs might improve its short-term mortality.

Methods: A multicentre, single-arm, 52-week-long clinical trial was performed to test whether the initial combination treatment with tacrolimus (0.075 mg/kg/day, adjusted for the target whole-blood trough levels between 5 and 10 ng/ml) and GCs (0.6-1.0 mg/kg/day of prednisolone followed by a slow taper) improves short-term mortality of PM/DM-interstitial pneumonia patients. The primary outcome was overall survival. We originally intended to compare, by using propensity-score matching, the outcome data of clinical trial patients with that of historical control patients who were initially treated with GCs alone.

Results: The 52-week survival rate with the combination treatment (N = 26) was 88.0% (95% CI, 67.3, 96.0). Safety profiles of the combination treatment were consistent with those known for tacrolimus and high-dose GCs individually. Serious adverse events occurred in 11 patients (44.0%), which included four opportunistic infections. Only 16 patients, including only 1 deceased patient, were registered as historical controls, which precluded meaningful comparative analysis against the clinical trial patients.

Conclusion: Our study provided findings which suggest that initial treatment with tacrolimus and GCs may improve short-term mortality of PM/DM-interstitial pneumonia patients with manageable safety profiles. This was the first prospective clinical investigation conducted according to the Good Clinical Practice Guideline of the International Conference on Harmonization for the treatment of this potentially life-threatening disease.

Trial registration: ClinicalTrials.gov, https://ichgcp.net/clinical-trials-registry/NCT00504348" title="See in ClinicalTrials.gov">NCT00504348.

Keywords: dermatomyositis; interstitial lung disease; interstitial pneumonia; polymyositis; tacrolimus.

© The Author(s) 2019. Published by Oxford University Press on behalf of the British Society for Rheumatology.

Figures

Fig . 1
Fig. 1
Overall and progression-free survival in prospective investigation group patients (A) Overalla and (B) progression-free survivalb. aOne patient died 92 days after the end of 52-week tacrolimus treatment due to the exacerbation of interstitial pneumonitis that developed during the study period (on the 172nd day of the study), although it is not reflected in this figure. bKaplan–Meier estimates of time to death or ‘progression’ up to the end of the 52nd week in 25 prospective investigation group patients.
Fig . 2
Fig. 2
Changes in FVC (% of predicted) in prospective investigation group patients Points and bars represent the mean and s.d., respectively. †P < 0.001, paired t-test, compared against baseline. FVC: forced vital capacity; LOCF: the end-of-the-study data for all patients using the last-observation-carried-forward method.

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