番茄社区

The immunosuppressive agent tacrolimus, commonly used for solid organ transplantation, may have a therapeutic role in systemic lupus erythematosus (SLE), particularly for lupus nephritis, European researchers reported.

In a study that included 29 patients, partial clinical improvement was seen at 3 months in 72.4% and complete resolution of disease activity in 31%, according to Marta Mosca, MD, PhD, of the University of Pisa in Italy, and colleagues.

In addition, proteinuria had declined by more than 50% in 62.5% at 3 months, the researchers reported online in .

Aside from its immunosuppressive effects, tacrolimus also had antiproteinuric effects, and in a mouse model was protective of podocytes from apoptosis and injury to the actin cytoskeleton. It has been used for various kidney disorders and, , has shown efficacy as remission induction for patients with lupus nephritis. Few data are available, however, for patients of other ethnicities.

To examine the experience in European patients, Mosca and colleagues retrospectively analyzed data from three referral centers in Italy, Spain, and France where patients with lupus had been given tacrolimus.

Most patients were white females, mean age was 38, and mean disease duration was 13 years. Almost all patients had renal and joint involvement, and the majority also had skin and hematologic disease manifestations. All were positive for antinuclear antibodies.

Previous immunosuppressive therapies included cyclophosphamide in 72%, azathioprine in 66%, rituximab (Rituxan) in 41%, and mycophenolate mofetil (CellCept) and methotrexate each in 17%. Concomitant medications given with the tacrolimus included glucocorticoids in 93%, hydroxychloroquine in 83%, mycophenolate mofetil in 28%, azathioprine in 10%, belimumab (Benlysta) in 14%, and rituximab in 7%.

At baseline, the median SLE Disease Activity Index was 8, decreasing to 4 at 3 months and to 3 at 12 months (P<0.001). The median level of C3 complement was 74 mg/dL at baseline, rising to 81 at 3 months and 84 at 12 months (P=0.02). Anti-dsDNA antibodies were present at baseline in 75%, in 70% at 3 months, but only 25% at 12 months, while median 24-hour proteinuria declined from 1,425 mg to 380 mg (P<0.001).

Renal response was defined as a reduction of more than 50% in proteinuria and stabilization or improvement of creatinine, while complete response also required proteinuria below 0.5 g and inactive urinary sediment.

At 3 months, renal response was seen in 65.2% and complete response in 34.7%, and at 6 months, the corresponding numbers were 76.2% and 42.8%, respectively.

Eight patients had extrarenal manifestations such as arthritis, serositis, and cutaneous or hematologic involvement. Complete or partial resolution of these symptoms was observed in 62.5%, most often within the first 3 months.

Tacrolimus was discontinued in nine patients, because of intolerance in three, a lack of efficacy in four, and disease remission in two. Adverse effects included gastrointestinal intolerance, headache, and cognitive impairment, and one patient who was also taking glucocorticoids and belimumab had recurrent mild infections.

Infections are an important concern with any immunosuppressive treatment, the authors cautioned. In , fewer serious infections were seen with tacrolimus than with high doses of glucocorticoids and cyclophosphamide. However, long-term safety is uncertain with calcineurin inhibitors such as tacrolimus, particularly because of nephrotoxicity, hypertension, and diabetes.

Limitations of the study included its small numbers, retrospective analysis, and brief follow-up.

Nonetheless, the authors concluded that "our data support the role of tacrolimus as a useful immunosuppressive drug, with a high rate of success when added to previous therapy to refractory lupus patients with renal and non-renal disease."

Comment