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editorial

Indian Pediatr 2017;54: 815-816

Levamisole: Standard or Intensive Therapy?


Aditi Sinha and *Arvind Bagga

From Department of Pediatrics, ICMR Center for Advanced Research in Nephrology, AIIMS, New Delhi, India. Email: [email protected] 

 

Nephrotic syndrome has an estimated prevalence of 12-16 children per 100000 child population [1]. Almost one-half of these patients have frequent relapses or steroid dependence, which require management to prevent complications due to relapses as well as toxicity of corticosteroid therapy [2]. The initial management of patients with frequent relapses is with long-term prednisolone, which while effective, is associated with risks of steroid toxicity, particularly impaired growth and bone mineralization, and visual and metabolic complications. The use of steroid-sparing agents that enable reduction or cessation of corticosteroid therapy is therefore recommended [3,4]. Medications accepted for this purpose include levamisole, cyclophosphamide, mycophenolate mofetil (MMF), calcineurin inhibitors and rituximab. Evidence for their use is based on retrospective or prospective case series, few randomized placebo-controlled studies and even fewer comparative trials [5]. Guidelines from professional organizations recommend the use of steroid-sparing agents, but the order of therapy is not defined [3,4].

For more than three decades, levamisole has been considered effective and safe for preventing relapses of steroid-sensitive nephrotic syndrome [2-4]. The medication is available in Asia and marketed in few countries in Europe, but not in North- and South-Americas, and Africa. Data from multiple case series and meta-analysis of trials confirm that 1-2 year therapy with levamisole is steroid-sparing and results in about 50% reduction in relapses [5]. Despite clinical effectiveness, there is a limited evidence to explain the mechanisms of levamisole action. Some studies suggest that therapy results in upregulation of specific cytokines, including interleukin (IL)-8, IL-24 and those involving Th1-lymphocytes [6]. Glucocorticoid receptor expression and signaling on podocytes may be modulated by levamisole, and contribute to the response [7].

Two recent trials (available as conference abstracts) emphasize the efficacy of levamisole in relapsing nephrotic syndrome [8,9]. A study from our center compared the efficacy of alternate-day therapy with levamisole (n=73) to daily MMF (n=76) in reducing the frequency of relapses [8]. Over next 12 months, there were similar number of relapses in the two groups; relative relapse rate 1.27 relapses/person-year (95%CI 0.94, 1.74; P=0.12). The respective relapse rates were significantly reduced compared to the year preceding randomization in both levamisole (mean difference 2.1 relapses/person-year) and MMF (mean difference 2.4 relapses/person-year) (both P<0.0001) groups. The second is a double-blind placebo-controlled study that evaluated the efficacy of one year levamisole versus placebo therapy in 99 patients [9]. During follow-up, the time to relapse was increased in patients receiving levamisole compared to placebo (hazard ratio 0.22; 95% CI 0.11, 0.43; P=0.001). After 12-month treatment, 6% patients receiving placebo and 26% receiving levamisole were in remission (P=0.012). Moderate neutropenia, which reversed on discontinuation of treatment, occurred in 8%. Other side effects of prolonged therapy included elevation of transaminases and rare occurrence of small vessel vasculitis.

In this issue of Indian Pediatrics, Samuel, et al. [10] report a retrospective experience with levamisole in 95 patients with frequently-relapsing (n=62) and steroid-dependent (n=33) nephrotic syndrome. Therapy with alternate-day levamisole (2-2.5 mg/kg) was effective in 70 (73.7%). Out of 25 patients where alternate-day therapy with levamisole was not successful, a switch to daily levamisole administration at similar doses resulted in additional success in 14 patients. Therapy with standard alternate-day and the novel daily-therapy thus resulted in an overall benefit in 84 (88.4%) patients. Similar to others, results were better in the frequent relapsers than those with steroid-dependence [5,8,9]. No side effects were observed, although there is a possibility of under-reporting in the retrospective review. The effect of therapy was not sustained; one-half of patients showed frequent relapses on stopping levamisole.

The above observations are interesting and similar to recent reports that show promising results of daily therapy, should administration of alternate-day levamisole fail [11]. However, the literature is limited , and includes retrospective and prospective case series with significant risk of selection, performance and detection-bias; all of which might result in overestimation of effect-size by 20-35%. A placebo-controlled, multicenter double-blind randomized trial, stratified for steroid dependence, is required to examine if daily administration of levamisole is superior to alternate-day therapy. Given the observed effect, the study would require 130 patients per arm at 90% power, two-tailed alpha error of 5% and assumed attrition of ~10%. A careful prospective monitoring for adverse events would be necessary.

A note of caution! Five decades ago, the ISKDC empirically recommended 8 weeks of prednisone treatment for the initial episode of nephrotic syndrome; this increased to 12 weeks based on a randomized study by the APN [12]. Over the next 25 years, multiple open-label randomized studies (some with significant bias) showed that further prolongation of therapy was even better, resulting in meta-analysis based guidelines for ~7-month initial therapy, despite risks of steroid toxicity [13]. Over the past 4 years, the wheel has come ‘full circle’ with four high-quality multicenter double-blind trials affirming that 8-12 week initial therapy was enough with prolongation having no long-term benefits [14,15].

We need not follow the same path for levamisole. Multiple randomized trials affirm the satisfactory role of levamisole, administered on alternate days, as a steroid-sparing agent in patients with relapsing nephrotic syndrome. Until results from placebo-controlled studies confirm the benefits and safety of daily over alternate-day levamisole therapy, we suggest that pediatricians continue to follow standard guidelines for treatment.

Funding: None; Competing interests: None stated.

References

1. El Bakkali L, Rodrigues Pereira R, Kuik DJ, Ket JC, van Wijk JA. Nephrotic syndrome in The Netherlands: a population-based cohort study and a review of the literature. Pediatr Nephrol. 2011;26:1241-6.

2. Bagga A, Mantan M. Nephrotic syndrome in children. Indian J Med Res. 2005;122:13-28.

3. Management of steroid sensitive nephrotic syndrome: revised guidelines. Indian Pediatric Nephrology Group, Indian Academy of Pediatrics. Indian Pediatr. 2008;45:203-14.

4. Lombel RM, Gipson DS, Hodson EM; Kidney Disease: Improving Global Outcomes. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr Nephrol. 2013;28:415-26.

5. Pravitsitthikul N, Willis NS, Hodson EM, Craig JC. Non-corticosteroid immunosuppressive medications for steroid-sensitive nephrotic syndrome in children. Cochrane Database Syst Rev. 2013;10:CD002290.

6. Fu Y, Wang T, Xiu L, Shi X, Bian Z, Zhang Y, et al. Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo. Int Immunopharmacol. 2016;31:57-65.

7. Jiang L, Dasgupta I, Hurcombe JA, Colyer HF, Mathieson PW, Welsh GI. Levamisole in steroid-sensitive nephrotic syndrome: usefulness in adult patients and laboratory insights into mechanisms of action via direct action on the kidney podocyte. Clin Sci (Lond). 2015;128:883-93.

8. Sinha A, Puraswani M, Rawat M, Hari P, Bagga A. RCT comparing mycophenolate mofetil and levamisole in frequently relapsing nephrotic syndrome. Pediatr Nephrol. 2014;29(S10):2434.

9. Gruppen M, Davin JC, Bouts A. Levamisole increases the time to relapse in children with steroid-sensitive idiopathic nephrotic syndrome: Results of a multi-center, double-blind, placebo-controlled, randomized clinical trial. Pediatr Nephrol. 2016;31:1753.

10. Samual EMK, Krishnamurthy S, Bhanudeep S, Muske S. Levamisole in frequently-relapsing and steroid-dependent nephrotic syndrome. Indian Pediatr. 2017; 54:831-34.

11. Ekambaram S, Mahalingam V, Nageswaran P, Udani A, Geminiganesan S, Priyadarshini S. Efficacy of levamisole in children with frequently relapsing and steroid-dependent nephrotic syndrome. Indian Pediatr. 2014;51:371-3.

12. Ehrich JH, Brodehl J. Long versus standard prednisone therapy for initial treatment of idiopathic nephrotic syndrome in children. Arbeitsgemeinschaft fur Padiatrische Nephrologie. Eur J Pediatr. 1993;152:357-61.

13. Hodson EM, Willis NS, Craig JC. Corticosteroid therapy for nephrotic syndrome in children. Cochrane Database Syst Rev. 2007;4:CD001533.

14. Larkins N, Kim S, Craig J, Hodson E. Steroid-sensitive nephrotic syndrome: an evidence-based update of immunosuppressive treatment in children. Arch Dis Child. 2016;101:404-8.

15. Webb N, Wooley R, Brettell E, Cummins C, Trompeter R, Barsoum E, et al.; on behalf of the PREDNOS investigators. Standard vs. extended course prednisolone therapy for the presenting episode of steroid sensitive nephrotic syndrome: PREDNOS Study. Pediatr Nephrol. 2017;32:1647.

 

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