Children with Steroid Dependent Nephrotic Syndrome: Rituximab or Tacrolimus? It’s All in the Timing

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Nephrotic syndrome (NS) is characterized by heavy proteinuria, hypoalbuminemia (2.5 g/dl), hypercholesterolemia, and generalized edema. Every year, an estimated 1.15 to 16.9 new children per 100,000 children are affected, with the number varying depending on race and geography.^1,2 Glucocorticoids are the mainstay of treatment, with most children responding to a 4- to 6-week course at the standard dose (so-called steroid-sensitive forms). However, of these, 40% to 70% experience further relapses, and within this group, a significant number develop steroid dependence,³ defined as relapse during or within 2 weeks of discontinuation of full-dose glucocorticoid therapy. For these difficult forms of steroid-sensitive NS, clinical practice guidelines suggest using steroid-sparing drugs such as calcineurin inhibitors, cyclophosphamide, levamisole, or mycophenolate mofetil (MMF).⁴ The use of rituximab (RTX) is suggested in those children who continue to relapse despite a course of at least one other steroid-sparing agent.

There is little evidence to choose one steroid-sparing agent over another, and selection of the first-line steroid-sparing agent must consider patient preferences, resources, and physician’s experience. The use of calcineurin inhibitors in steroid-dependent NS is hindered by the frequency of side effects over time, as it requires prolonged treatment. Tacrolimus is often preferred to cyclosporine because it has been shown to be more effective in pediatric kidney transplants and has fewer or no cosmetic side effects, although the use of tacrolimus can be associated with a higher chance of diabetes mellitus. However, retrospective studies have not shown a clear superiority of tacrolimus over cyclosporine.

RTX was first used in 2004 in a child with steroid-sensitive NS who developed idiopathic thrombocytopenic purpura and was found to be effective in maintaining remission of proteinuria.⁵ Thereafter, a vast number of studies have proven its efficacy in frequently relapsing and steroid-dependent forms of NS, including an randomized control trial versus placebo.^6,7 However, its benefit is mostly transient and few direct comparisons to oral steroid-sparing agents have been performed. Basu et al.⁵ performed the Rituximab for Relapse Prevention in Nephrotic Syndrome trial, a randomized control trial in which they compared a single course of RTX to tacrolimus, suggesting the superiority of RTX versus tacrolimus in maintaining remission at 12 months in children with steroid-dependent forms of NS.⁵ In the current issue of KI Reports, Basu et al.⁴ report on the longer follow-up of this study.

In this follow-up study, 117 children who completed Rituximab for Relapse Prevention in Nephrotic Syndrome were observed for another 24 months. Children who completed Rituximab for Relapse Prevention in Nephrotic Syndrome and had long-term data were included in this study except those with congenital NS, NS due to secondary cause (lupus nephritis, IgA nephropathy, amyloidosis, and known chronic infection like tuberculosis, HIV, or Hepatitis B or C). In case of relapse, remission was induced by oral prednisolone therapy (60 mg/m²/d) until 3 consecutive days of negative proteinuria followed by a taper. The RTX course consisted of 2 doses of RTX at 375 mg/m²/infusion, whereas tacrolimus was given orally at a dose to maintain trough levels at 5 to 7 ng/ml.

First and foremost, prolonging follow-up of an additional 24 months showed that the observed superiority of RTX versus tacrolimus at 12 months was not subsequently maintained. All 53 12-month relapse-free patients in the RTX arm relapsed in the subsequent year, with similar median relapse-free survival times in the 2 trial arms (62 vs. 59 weeks). This confirms that, as previously described in many studies, the effect of RTX in children with NS is most frequently transient, and as different B cell populations reconstitute, the vast majority of children inevitably relapse.⁶

In the present study, results of subsequent patient management are shown. In the RTX arm, patients who had relapsed within 52 weeks from the first course (early relapsers) received another course of RTX infusion (2 doses) and started on MMF (1200 mg/m²/d) at week 53. Those who relapsed between weeks 53 and 80 (intermediate relapsers) also received a second course of RTX along with MMF, whereas those who relapsed beyond 80 weeks from the first RTX course (late relapsers) received only a second RTX course without maintenance MMF. In the tacrolimus arm, a course of RTX was given following the first relapse, and tacrolimus was discontinued within 15 days. Moreover, 24 patients from the tacrolimus arm opted for a preventive RTX infusion and tacrolimus discontinuation while still in remission, to avoid a potential relapse. In case of a subsequent relapse, in both of these cases, an RTX course and MMF were given.

The decision to add MMF to RTX in more severe forms of NS (here, early and intermediate relapsers in the RTX arm, relapsers in the tacrolimus arm) is supported by a retrospective and prospective study, that demonstrated that this association significantly prolongs relapse-free survival post-RTX in children with complicated forms of NS.^8,9 These findings are confirmed in the present study, in which the 2-year relapse-free survival was 67% with maintenance MMF therapy as compared to 9% for the periods without post-RTX maintenance immunosuppression (P < 0.0001).

Interestingly, data from the tacrolimus arm patients also suggests that preemptive use of RTX may be advantageous in frequently relapsing or steroid-dependent NS, with electively switched patients tending toward a longer time to relapse following RTX compared to the patients switched postrelapse (P = 0.07).

In terms of total B cell recovery following RTX infusion, in this study B cell recovery was observed between 6 and 52 weeks, a cell count >270/μl at 6 months was a strong predictor of relapse within 12 months (sensitivity 100%, specificity 96%); and timing of total B cell reconstitution was similar when comparing a first and subsequent RTX courses. The use of RTX, apart from nonsevere infusion reactions, appeared safe at 36 months, with infections being slightly more frequent in the tacrolimus arm than in the RTX arm. In both arms, the use of second-line steroid-sparing agents led to a decrease in the cumulative prednisone dose and to a decrease in body mass index, reaching the overarching goal of minimizing glucocorticoid-related toxicity.

Taken altogether, though mostly confirmatory of other recent studies, the present study by Basu et al.⁵ nicely summarizes and exemplifies some key points of optimal management of children with complicated, frequently relapsing, or steroid-dependent NS:

• 1.Use of a calcineurin inhibitors or of RTX are both reasonable choices, allowing significant benefit in terms of achieving sustained remission off glucocorticoids. Their use should be started early, before significant morbidity from prolonged glucocorticoid use has been accrued.
• 2.In children who relapse on RTX alone, the use of a second RTX course combined with MMF is beneficial.
• 3.The vast majority of children with these forms of NS receiving RTX will relapse, therefore timing of RTX reinfusion is a crucial open question. Although most patients do not relapse in the first 12 months, total B cell reconstitution precedes relapse, therefore preemptive RTX reinfusion based on total B cells levels may be reasonable in patients who are at high risk of relapse.

It also leaves some open questions, which hopefully will be addressed by future studies:

• 1.In which patients should RTX be repeated preemptively, and in which reactively after a relapse?
• 2.What is the optimal timing of preemptive RTX redosing?
• 3.Which threshold of B cell count following RTX should be considered predictive of relapse, and is it possible to establish a unique threshold for all patients?

Reassuringly, in terms of the current International Pediatric Nephrology Association recommendations suggesting that RTX use should be delayed and used only in patients who have failed, that is, relapsed, despite at least 1 course of an oral steroid-sparing agent given at an adequate dose, the present study confirms this statement and provides a much needed longer follow-up that reveals opposite results from the initial findings at 12 months.⁵ Although RTX provides the great benefit of leaving patients off oral treatment, currently no therapeutic agent, including RTX, is disease modifying; that is, allows sustained remission for 24 to 36 months off treatment. The search for this type of therapeutic approach for children with difficult forms of NS continues (Figure 1).

Figure 1.

Rituximab or Tacrolimus in patient with steroid dependent nephrotic syndrome: recommendations and unasnswered questions. RTX, rituximab; SDNS, steroid dependent nephrotic syndrome.

Disclosure

MV has received consulting fees from Novartis, Roche, Apellis, Biocryst, Travere, Chinook, PureSpring, Bayer, and Chemocentrix and has given sponsored talks for Roche, Vifor, Glaxo, Novartis, WebMD, and Alexion. This has no influence on the content of this commentary. MAQ does not have any financial disclosure.