Long-term tacrolimus therapy safe, effective in lupus nephritis

Maintenance treatment with tacrolimus in patients with lupus nephritis (LN) over 5 years is effective and well tolerated in the real-world clinical setting, results of a postmarketing surveillance (PMS) study in Japan have shown.

“Maintenance therapy with prolonged immunosuppressive treatment is very important in LN, owing to the high relapse rate even after successful induction treatment,” the researchers said.

This open-label, noncomparative, observational PMS study was conducted across 275 sites in Japan, with a follow-up of 10 years. Data relating to 5 years of tacrolimus maintenance therapy at the interim cutoff in August 2016 were reported.

A total of 1,395 patients were registered, of which 1,355 received tacrolimus maintenance therapy for LN and had available safety data. Pneumonia (1.1 percent) was the most common serious adverse drug reaction (ADR), followed by herpes zoster (1.0 percent), diabetes mellitus (1.0 percent), and cellulitis (1.0 percent). ADR occurred primarily within the first 28 weeks of treatment, with no significant increase seen during the follow-up period. [J Rheumatol 2021;48:74-81]

In subgroup analyses, the following risk factors were observed for tacrolimus-related ADR: inpatient management, LN disease severity, increasing age, abnormal renal or hepatic function, and comorbid or previous disease. The cumulative rates of progression to renal failure based on the attending physician’s assessment were 0.8 percent and 6.6 percent at years 1 and 5, respectively. The corresponding cumulative relapse rates were 7.8 percent and 30.6 percent.

Furthermore, tacrolimus treatment initiation significantly improved urine protein:creatinine ratio, serum anti-dsDNA antibody levels, complement C3 levels, and steroid-sparing effects at 4 weeks (p<0.001) and persisted over 5 years.

“There is increasing evidence to suggest that the immunosuppressant tacrolimus may be an effective and well-tolerated treatment option for LN as both induction and maintenance therapy,” the researchers said, noting that these data were based on short-term treatment and small patient populations. [Mod Rheumatol 2009;19:606-615; Lupus 2012;21:944-952; Clin Nephrol 2009;72:430-437; Am J Kidney Dis 2011;57:235-244; Nephrol Dial Transplant 2012;27:1467-1472; Kidney Int 2005;68:813-817]

The discontinuation rate for tacrolimus was 37.3 percent, which was comparable to that observed with other immunosuppressive agents. The main reason for discontinuation in the early treatment period (up to week 28) was adverse events (AE). This finding suggested that physicians should take care to assess whether discontinuation due to AE is warranted, taking into consideration the duration of therapy.

The current study was limited by the incorrect completion of report forms, lack of protocol-defined definitions for effectiveness variables, and its open-label and noncomparative observational design, with the attendant potential for bias.

“The final report of the ongoing PMS study at 10 years will shed further light on the clinical value and characterization of tacrolimus therapy in patients with LN,” the researchers said. “Comparative studies against other immunosuppressive therapies are also required to determine the clinical utility and role of tacrolimus in this setting.”