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Multitarget induction therapy superior over short term for lupus nephritis

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Promising, but longer follow-up needed

During the last decades, trials in lupus nephritis have been blessed by the publication of large studies involving hundreds of patients. While this is certainly a major achievement, yet it has not been paralleled by long-enough follow-ups. Experience has shown that in lupus nephritis, a large number of patients is “silver” but long-term follow-up is “gold.”

The very good 6-month results of Dr. Liu and colleagues’ study is an example of this aphorism. The importance of this finding is emphasized by data showing that early (within 3-6 months) response to immunosuppressive treatment has good positive predictive value for long-term (10 years) preservation of renal function (Arthritis Rheum. 2004;50:3934-40).

So, should multitarget therapy with combination of tacrolimus with mycophenolate become the new “standard of care” in lupus nephritis?

The authors of this commentary are painfully aware of the unmet needs in the treatment of lupus nephritis and certainly welcome these data. However, our enthusiasm is tempered by the following concerns.

First, there are some methodology issues to be considered such as the fact that six patients randomized to cyclophosphamide for unknown reasons did not receive the treatment and were excluded from the study, or that there were 80 missing visits in the cyclophosphamide group and 38 in the multitarget group. Nonetheless, the researchers handled these issues by data imputation and sensitivity analyses, which confirmed their findings.

Second, the results of this trial may not be generalized to all patients with lupus nephritis. As the authors discuss in the paper, this study was performed in Chinese patients who tend to respond favorably to calcineurin inhibitors. Previous lupus nephritis trials have suggested differences in the efficacy of immunosuppressive agents across patients from different ethnic backgrounds (Rheumatology [Oxford] 2010;49:128-40). Furthermore, included patients had median disease duration of 2 months, only 20.7% had glomerular filtration rate < 60 mL/min per 1.73m2, and most of them did not have high-risk histological features in kidney biopsy (median activity index of 7, chronicity index of 1). Further studies will be required to determine the efficacy of multitarget therapy in patients with adverse prognostic factors such as moderate or severe impairment of renal function, or presence of crescents.

The current study was an induction-only trial. The podocyte-preserving and anti-proteinuric effects of calcineurin inhibitors may account for the higher and faster rates of resolution of proteinuria and complete renal remission in the multitarget group. The clinical significance of this finding, especially in view of the slow-mode of action of cyclophosphamide, remains to be seen. In fact, several studies have shown that in spite of the lower rates of renal remission with cyclophosphamide, the majority of patients maintain their renal function if proteinuria is less than 2 g/day (Ann. Intern. Med. 2001;135:248-57). Whether there is a benefit of the multitarget therapy in terms of renal flares and long-term stabilization of the renal function remains to be seen. To this end, the authors do not indicate how the renal remission in these patients will be maintained and the optimal dosage and duration of immunosuppressive treatment. This is of particular importance considering also the potential nephrotoxic effects of calcineurin inhibitors when used for long time periods.

Thus, at this point, while the use of multitarget therapy from the beginning may increase the rates of complete renal remission, it increases the cost and the complexity of lupus nephritis treatment. One may consider adding calcineurin inhibitors if the patient does not reach partial renal response after 3-6 months. Meanwhile, we are eagerly awaiting longer follow-up of this most valuable cohort of patients and information of how this remission can be maintained, how durable it is, and more importantly, whether after 5 years of therapy there is a difference in the preservation of renal function.

Dr. George Bertsias is with the department of rheumatology, clinical immunology, and allergy at the University of Crete Medical School, Heraklion, Greece. Dr. John Boletis is with the nephrology department and renal transplant unit at Laiko General Hospital, University of Athens. Dr. Dimitrios T. Boumpas is with the fourth department of internal medicine, Attikon Hospital, University of Athens. They had nothing to disclose.


 

FROM ANNALS OF INTERNAL MEDICINE

References

A multitarget therapy of mycophenolate mofetil and tacrolimus for lupus nephritis induction therapy led to almost twice as many complete remissions as did intravenous cyclophosphamide in an open-label, randomized, controlled trial.

“Because immune dysregulation is fundamental to pathogenesis of lupus nephritis, with both B and T cells involved in the development of the disease, it may be necessary to target multiple aspects of the immune response using combined immunosuppressants,” wrote Dr. Zhi-Hong Liu of Nanjing (China) University and her colleagues (Ann. Intern. Med. 2014 Nov. 11 [doi:10.7326/M14-1030]).

Dr. Zhihong Liu

Dr. Zhihong Liu

Between April 2009 and June 2011, 368 adults aged 18-65 years from 26 renal centers in China were randomized to receive mycophenolate mofetil (MMF) and tacrolimus with a steroid or IV cyclophosphamide with a steroid for 24 weeks. A total of 362 received medication (6 did not receive their assigned cyclophosphamide treatment for unknown reasons), and 310 completed the whole 24-week course of treatment. All participants in the study had biopsy-proven lupus nephritis diagnosed within the previous 6 months and had not been previously treated with MMF, cyclophosphamide, tacrolimus, or high-dose methylprednisolone, nor had they had renal replacement therapy, plasmapheresis, or IV gamma globulin therapy in the previous 12 weeks.

All patients began by receiving IV methylprednisolone pulse therapy (0.5 g/day) for 3 days and then oral prednisone (0.6 mg/kg) daily for 4 weeks, with prednisone tapering to 10 mg/day for the remainder of the study period. Following methylprednisolone pulse therapy, the multitarget group received MMF (0.5 g twice daily) and tacrolimus (2 mg twice daily) while the comparison group received IV cyclophosphamide (initially 0.75 g/m2 body surface area, then adjusted to 0.5-1.0 g/m2).

Nearly half – 45.9% – of patients in the multitarget group achieved full remission, whereas 25.6% of patients receiving IV cyclophosphamide showed complete remission (P < .001). The investigators defined complete remission as a 24-hour urinary protein excretion of 0.4 g or less, the absence of active urine sediments, a serum albumin level of 35 g/L or greater, and normal serum creatinine.

Results on secondary endpoints also favored multitarget therapy. The percentage of patients who had an overall response to treatment (complete and partial remissions) was 83.5% for multitarget therapy and 63% for cyclophosphamide (P < .001). Multitarget therapy patients responded to treatment at a median of 8.9 weeks, compared with cyclophosphamide-treated patients at 13 weeks. The investigators defined partial response as a 50% or greater reduction in proteinuria and urine protein less than 3.5 g/24 hours, a serum albumin level of 30 g/L or higher, and a normal or 25% or lower increase in serum creatinine level from baseline.

After treatment, patients in the multitarget therapy group also had significantly better results on other secondary endpoints, including changes in urine protein, serum albumin, systemic lupus erythematosus disease activity score, and C3 levels.

Adverse events occurred among 50.3% of multitarget recipients and 52.5% of cyclophosphamide recipients. More patients who received multitarget therapy had a serious adverse event (7.2% vs. 2.8%, respectively), and more patients withdrew from the multitarget therapy group (5.5% vs. 1.7%), but there were no statistically significant differences between the groups for either comparison.

The study was supported by the National Basic Research Program of China and the National Key Technology R&D Programs. Information on disclosures was unavailable at the time of publication.

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