Update on Tacrolimus in Patients With Interstitial Pneumonia Associated With Polymyositis or Dermatomyositis: 3-Year Postmarketing Surveillance Follow-Up in Japan

To the Editor:

In 2013, tacrolimus was approved in Japan for the treatment of interstitial lung disease (ILD) in patients with polymyositis (PM)/dermatomyositis (DM).¹ Subsequently, Kuwana et al² reported the 2-year interim prospective results of a postmarketing surveillance study, which found that tacrolimus-containing immunosuppressive regimens were well tolerated in patients with PM/DM-associated ILD.² As the maximum 3-year surveillance period has been completed, we now report the safety and efficacy results beyond 2 years to further highlight the long-term clinical utility of tacrolimus in these patients. Detailed study procedures have been described previously.²

Case report forms were available for 174 patients at 3 years, with 4 additional DM patients vs the 2-year interim report. The underlying disease was PM in 46 patients and DM in 128 patients, including 64 with clinically amyopathic DM (CADM) and 64 patients with classic DM. Patient demographic and clinical characteristics at 3 years were similar to the 2-year data² (Supplementary Table S1, available with the online version of this article).

From 2 to 3 years, mean tacrolimus daily dose and trough concentrations remained consistent. The 3-year mean (SD) tacrolimus daily dose and trough concentrations were 0.06 (0.03) mg/kg/day and 6.6 (2.7) ng/mL, respectively (Supplementary Figure S1, available with the online version of this article). At 3 years, 10.5% of patients (n/N = 6/57) had trough concentration > 10 ng/mL. The majority of patients (64.9%, n/N = 37/57) had a trough blood concentration within the target of 5 to 10 ng/mL, as per the Japanese prescribing information,³ indicating there was minimal intrapatient variability in tacrolimus concentrations and tacrolimus was generally used as per the prescribing information.

The overall survival (OS) rate remained consistent from 2 to 3 years (90% vs 89%). The 3-year OS was similar between patients with different underlying disease, except patients with CADM, in whom survival rates were lower (PM, 94%; overall DM, 87%; classic DM, 95%; CADM, 79%; Figure 1A). In patients stratified by antimelanoma differentiation-associated gene 5 (MDA5) and antiaminoacyl tRNA synthetase (ARS) antibodies, survival remained broadly consistent from 2 to 3 years (Supplementary Figures 2A and 2C, available with the online version of this article), supporting our observations from the interim report.²

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Figure.

Kaplan-Meier curves of (A) overall survival, and (B) overall progression-free survival during the 3-year follow-up period (COAP). CADM: clinically amyopathic dermatomyositis; COAP: clinical outcome analysis population; DM: dermatomyositis; PM: polymyositis.

The progression-free survival (PFS) rate decreased from 63% at 2 years to 51% at 3 years. The 3-year PFS rate was similar regardless of underlying disease (PM, 53%; overall DM, 51%; classic DM 48%; CADM, 52%; Figure 1B). The decrease in PFS from 2 to 3 years further highlights the need for the close monitoring of these patients even though they are receiving ongoing treatment. From 2 to 3 years, the PFS rate in anti-MDA5 antibody–negative patients decreased and was similar to that in anti-MDA5 antibody–positive patients (Supplementary Figure 2B, available with the online version of this article). A similar trend was observed between patients who were positive and negative for anti-ARS antibody (Supplementary Figure 2D). Although these differences appear less pronounced compared with what we had previously reported,² the number of patients with available PFS data decreased over the 3-year follow-up period, which may have affected these results.

Overall, from 2 to 3 years, mean serum ferritin, Krebs von den Lungen 6, and surfactant protein D levels remained broadly consistent, whereas percent forced vital capacity decreased somewhat between timepoints (Supplementary Table S2, available with the online version of this article).

There were no changes in adverse drug reactions (ADRs) or serious ADRs at the 3-year follow-up in the 113 patients with ongoing cases at 2 years. There were no substantial increases in previously reported ADRs after 2 years. From 2 to 3 years, the most common ADRs were infections (6.2%), renal impairment (3.5%), impaired glucose tolerance (1.8%), and psychiatric and nervous system disorders (1.8%; Table). From 2 to 3 years, 2 patients died, from interstitial pneumonia (PM, n = 1) and suicide (CADM, n = 1). Overall, there were no new safety concerns with the use of tacrolimus-containing immunosuppressive regimens at 3 years of follow-up. Further, these results are in agreement with a recent metaanalysis, which found that in patients with PM/DM-associated ILD, tacrolimus has an acceptable safety profile compared with conventional therapy.⁴

The limitations of this study have been reported previously,² including its observational, open-label, and noncomparative design. Additionally, the 3-year data for some clinical outcomes were not available due to a substantial decrease in patient numbers; missing data likely arose from their omission in routine laboratory tests.

In conclusion, the final 3-year surveillance results of this study were in line with the previously reported 2-year interim report² and provide additional evidence for the continued long-term use of tacrolimus-containing immunosuppressive regimens in real-world clinical practice in patients with PM/DM-associated ILD.

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