Long-Term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis in Japan: 10-Year Analysis of the Real-World TRUST Study.

OBJECTIVE: To assess the long-term safety and effectiveness of tacrolimus as maintenance therapy in patients with lupus nephritis (LN) receiving treatment in real-world clinical settings in Japan. METHODS: An open-label, noncomparative, observational, prospective postmarketing surveillance study was conducted in 1395 patients with LN receiving maintenance treatment with tacrolimus at 278 medical institutions across Japan over a period of 10 years. Tacrolimus continuation rate and cumulative incidence of adverse drug reactions (ADRs), relapse, progression to renal failure, and progression to dialysis were calculated using Kaplan-Meier analysis. RESULTS: Safety data were available for 1355 patients, almost half (49.3%) of whom remained on tacrolimus for the full 10 years of follow-up. A significant reduction in mean (SD) daily oral corticosteroid dose was observed from 16.0 (9.7) mg/day at 4 weeks after initiation of tacrolimus treatment to 7.2 (4.4) mg/day at year 10 (P < 0.001). The most frequently reported serious ADRs were infections (reported for 131 [9.7%] patients). Except for infections, no marked increase in the incidence of any other ADRs was seen over time, including renal impairment, malignant tumors, and cardiac dysfunction. Renal function was generally well maintained over the 10 years of follow-up. At year 10, cumulative rates of relapse, renal failure, and dialysis were 44.5%, 12.2%, and 4.5%, respectively. CONCLUSION: Tacrolimus was effective and generally well tolerated as maintenance therapy for LN in a large cohort of patients in Japan followed for 10 years, almost half of whom remained on therapy for the entire duration of follow-up. (ClinicalTrials.gov: NCT01410747).

Tacrolimus use and renal function in pregnancy with lupus nephritis: Analysis of post-marketing surveillance data in Japan.

OBJECTIVES: Tacrolimus may be administered to pregnant women with lupus nephritis in Japan if considered therapeutically beneficial, but supporting data are limited. We assessed the safety and effectiveness of tacrolimus before, during, and after pregnancy in women with lupus nephritis receiving tacrolimus. METHODS: This was an ad hoc analysis of data from a post-marketing surveillance study of tacrolimus in patients with lupus nephritis in Japan. Pregnancy outcomes, nephritis status, and adverse events were assessed for up to 2 years postpartum. RESULTS: Data were available for 23 births in 21 patients (two patients had two births each). Tacrolimus for lupus nephritis was continued during 11 births in nine patients (during and after pregnancy) and discontinued in 12 patients (when pregnancy was known or when approaching delivery). Renal function was generally maintained in patients who gave birth while receiving tacrolimus; however, there were cases of increased urine protein and decreased renal function over 2 years. There were no unexpected adverse events/safety concerns. CONCLUSIONS: These data from clinical practice suggest that tacrolimus is a valid treatment option for lupus nephritis in fertile women in Japan and, with careful monitoring, pregnant women with lupus nephritis may continue their tacrolimus treatment.

Tacrolimus in Patients With Interstitial Pneumonia Associated With Polymyositis or Dermatomyositis: Interim Report of Postmarketing Surveillance in Japan.

OBJECTIVE: The calcineurin inhibitor tacrolimus has been approved in Japan for the treatment of interstitial pneumonia (IP) in patients with polymyositis (PM) and dermatomyositis (DM). Postmarketing surveillance was initiated to examine long-term outcomes of immunosuppressive regimens containing tacrolimus in real-world settings. METHODS: Observational, prospective, postmarketing surveillance is ongoing in 179 patients with PM/DM-associated IP initiating treatment with tacrolimus. We report interim findings after 2 years of follow-up. Cumulative overall survival was assessed using Kaplan-Meier analysis. Potential prognostic factors for mortality were assessed by univariate Cox proportional hazards analysis. RESULTS: A total of 170 patients were included in this analysis. At the time of starting treatment with tacrolimus, almost all patients were receiving corticosteroids (98.8%), and cyclophosphamide was additionally used in 42 patients (24.7%). Forty-nine patients (28.8%) discontinued tacrolimus during follow-up, mainly due to loss to follow-up, patient death, and adverse events. Mean (SD) oral corticosteroid dose decreased from 32.4 (21.6) mg/day at baseline to 7.6 (4.2) mg/day at 2 years. Overall survival at 2 years was 90.3%; corresponding progression-free survival was 62.5%. Factors found to be associated with all-cause mortality included diagnosis of clinically amyopathic DM (hazard ratio [HR] 9.04, 95% CI 1.18-69.51 vs PM), ferritin level 500 to < 1500 ng/mL (HR 8.61, 95% CI 2.51-29.45 vs < 500 ng/mL), and presence of antimelanoma differentiation-associated gene 5 antibodies (HR 8.16, 95% CI 1.03-64.47 vs absence). CONCLUSION: Immunosuppressive regimens containing tacrolimus appear useful for the management of IP in patients with PM/DM. [ClinicalTrials.gov: NCT02159651].

Long-term Safety and Effectiveness of Tacrolimus in Patients With Lupus Nephritis: 5-year Interim Postmarketing Surveillance Study in Japan (TRUST).

OBJECTIVE: To assess the long-term safety and effectiveness of tacrolimus for treating lupus nephritis (LN) in the real-world clinical setting. METHODS: This is an ongoing, open-label, noncomparative, observational, postmarketing surveillance study conducted across 275 sites in Japan. Registered patients with LN were followed for 10 years. Here we report data relating to 5 years of tacrolimus maintenance therapy at the interim data cutoff in August 2016. RESULTS: Of 1395 registered patients, 1355 received tacrolimus maintenance therapy for LN and provided safety data. The most common serious adverse drug reactions (ADR) included pneumonia (1.1%), herpes zoster (1.0%), cellulitis (1.0%), and diabetes mellitus (1.0%). ADR occurred mainly within the first 28 weeks of tacrolimus treatment, and no marked increase was observed during the follow-up period. Subgroup analyses suggested that risk factors for commonly observed ADR associated with tacrolimus included inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rate of progression to renal failure (based on the attending physician's assessment) was 0.8% at Year 1 and 6.6% at Year 5. Cumulative relapse rates were 7.8% and 30.6%, respectively. Urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects were all significantly improved from 4 weeks after tacrolimus treatment initiation (P < 0.001) and were sustained over 5 years. CONCLUSION: Long-term tacrolimus maintenance treatment over 5 years in the real-world clinical setting was well tolerated and effective in a large population of patients with LN (www.ClinicalTrials.gov: NCT01410747).