Oral tacrolimus noninferior to intravenous cyclophosphamide for lupus nephritis

1. Oral tacrolimus was noninferior to intravenous cyclophosphamide for lupus nephritis disease measures with lower toxicity.

Evidence Rating Level: 1 (Excellent)

Study Rundown: Lupus nephritis is a common complication of systemic lupus erythematosus, occurring in a majority of patients (as many as 60%). The existing standard of care includes intravenous cyclophosphamide, carry significant adverse effects and cytotoxic risk. Tacrolimus, a calcineurin inhibitor that prevents T-cell activation and downstream autoantibody production, has demonstrated efficacy in randomized controlled trials with lower toxicity. Despite this evidence, it has not been compared with cyclophosphamide in any large-scale trials. This phase 3 multicenter randomized controlled trial randomized 157 patients in China to a tacrolimus group and 142 to receive IV cyclophosphamide. The primary outcome was the number of patients who received a complete or partial response in kidney function at week 24. Secondary outcomes included the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, immune parameters and kidney function parameters. Tacrolimus resulted in a complete or partial response rate comparable to the IV cyclophosphamide group, while adverse effects were less frequent in the tacrolimus group.

Click here to read the study in JAMA

Relevant Reading: Efficacy and safety of tacrolimus for lupus nephritis: A placebo-controlled double-blind multicenter study

In-Depth [Randomized controlled trial]: This study recruited patients aged 18 to 60 years with systemic lupus erythematosus and lupus nephritis classes III to V from 35 centers in China. The study ran from March 10, 2015 to September 13, 2018. Eligible and willing patients were recruited from outpatient settings. Inclusion criteria included body mass indices of 18.5 to 27, 24-hour urine protein greater than 1.5 g and serum creatinine of less than 260 μmol/L. In terms of the treatment, all patients received intravenous methylprednisolone 0.5 g/d for 3 days prior to starting study treatment, followed by oral prednisone at 0.8 mg/kg/d for 4 weeks tapered to a maintenance dose of 10 mg/d until 24 weeks.Tacrolimus dosing was initiated at 4 mg/d while IV cyclophosphamide was initiated at 0.75 mg/² body surface area followed by 0.5 to 1.0 g/m² every 4 weeks. Patients were assessed at weeks 1,2,4,8,12,16,20 and 24. During the trial, 7 patients withdrew due to adverse effects while 7 withdrew their consent. Tacrolimus resulted in a complete or partial response rate comparable to the IV cyclophosphamide group (83.0% and 75.0%, respectively); difference, 7.1% (2-sided 95% CI -2.7% to 16.9). The SLEDAI was -8.6 with tacrolimus at 24 weeks and -6.4 with IV cyclophosphamide (difference, -2.2; 95% CI, -3.1 to -1.3). Treatment-emergent adverse events (TEAEs) were recorded and considered serious if they resulted in threats to a patient’s life, disability, or hospitalization. The most common TEAEs were upper respiratory tract infection (n=37, 23.6%) in the tacrolimus group and leukopenia (n=16, 11.3%) in the IV cyclosporine group. Adverse effects were less frequent in the tacrolimus group (18.5%, compared to 24.6%). Serious TEAEs were reported in18.5% and 24.6% of patients in either group, respectively. In total, there were 2 treatment-related deaths while 7 patients withdrew from the study following adverse effects.

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