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Indian Pediatr 2017;54: 815-816 |
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Levamisole: Standard or Intensive Therapy?
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Aditi Sinha and *Arvind
Bagga
From Department of Pediatrics, ICMR Center for
Advanced Research in Nephrology, AIIMS, New Delhi, India. Email:
[email protected]
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N ephrotic 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.
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