Elsevier

The Lancet Neurology

Volume 9, Issue 3, March 2010, Pages 245-253
The Lancet Neurology

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Pulsed high-dose dexamethasone versus standard prednisolone treatment for chronic inflammatory demyelinating polyradiculoneuropathy (PREDICT study): a double-blind, randomised, controlled trial

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Summary

Background

Pulsed high-dose dexamethasone induced long-lasting remission in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in a pilot study. The PREDICT study aimed to compare remission rates in patients with CIDP treated with high-dose dexamethasone with rates in patients treated with standard oral prednisolone.

Methods

In eight neuromuscular centres in the Netherlands and one in the UK, patients aged 18 years or older who had newly diagnosed definite or probable CIDP were randomly assigned to a treatment regimen of either pulsed high-dose dexamethasone or standard oral prednisolone. Randomisation was done with a random number generator. The primary outcome measure was remission at 12 months, defined as improvement of at least three points on the Rivermead mobility index and improvement of at least one point on the inflammatory neuropathy cause and treatment disability scale. Analysis was by intention to treat. This trial is registered with Current Controlled Trials, number ISRCTN07779236.

Findings

Between December, 2003, and December, 2008, 40 patients were treated: 24 received dexamethasone and 16 received prednisolone. At 12 months, 16 patients were in remission: ten in the dexamethasone group and six in the prednisolone group (odds ratio [OR] 1·2, 95% CI 0·3–4·4). Most adverse events were minor and did not differ substantially between treatment groups; however, sleeplessness and Cushing's face occurred more often in the prednisolone group.

Interpretation

Pulsed high-dose dexamethasone treatment did not induce remission more often than prednisolone treatment. A substantial proportion of patients were in remission at 12 months in both treatment groups. High-dose dexamethasone could be considered as induction therapy in CIDP, but comparison with intravenous immunoglobulin treatment is needed.

Funding

The Prinses Beatrix Fonds (MAR01-0213) and the Department of Neurology, Academic Medical Center.

Introduction

Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is characterised by symmetric motor or sensory symptoms and signs, or both, in more than one limb, that develop over at least 2 months.1, 2, 3 CIDP can cause prolonged periods of disability, with 54% of patients becoming severely disabled at some point during the illness.4 More than 10% of patients with CIDP remain severely disabled despite treatment.4, 5, 6

Corticosteroids have been thought of as an effective treatment for CIDP since 1958.7 A placebo-controlled, unblinded, randomised clinical trial in 35 patients with CIDP showed a beneficial effect of corticosteroids.8 Open, uncontrolled studies have suggested that corticosteroid treatment improves impairment and disability in two-thirds to three-quarters of patients with CIDP.1, 9, 10, 11, 12, 13 A recent guideline recommended intravenous immunoglobulin and corticosteroids as possible first-line treatments in patients with sensory and motor CIDP who have significant disability.14 Which of these treatments should be tried first is a matter of debate and depends on various factors, such as availability, cost, and local facilities to administer intravenous immunoglobulin.

Both dexamethasone and prednisolone are corticosteroids with predominantly glucocorticoid activity. Prednisolone is the most commonly used corticosteroid for the treatment of CIDP. The anti-inflammatory potential of dexamethasone is about six-times higher than that of prednisolone.15, 16 Dexamethasone is usually classified as a long-acting corticosteroid (half-life 36–72 h) and prednisolone as an intermediate-acting corticosteroid (half-life 12–36 h).15, 16 Both drugs are rapidly and well absorbed from the gastrointestinal tract, bound to plasma proteins, and excreted in the urine.

The mechanism of the therapeutic effect of corticosteroid treatment in patients with CIDP is unknown. Glucocorticosteroids modulate the inflammatory process and the immune response by various mechanisms: transcriptional and post-transcriptional regulation of several genes that act through suppression of T-cell proliferation; reduced production of proinflammatory cytokines, chemokines, and adhesion molecules; induction of anti-inflammatory cytokines and cytokines receptors; and induction of apoptosis of T lymphocytes following CD3 downregulation.15, 16 These mechanisms are mediated through binding and saturation of the glucocorticoid receptor. Saturation of all glucocorticoid receptors is almost complete at a dose of 100 mg of prednisolone equivalent per day. During high-dose pulse therapies, additional effects occur such as interference with intracellular signal transduction, interaction with cell membranes affecting cell function, and the activity of membrane-associated proteins,15, 16 which might contribute to the therapeutic success of pulse therapies. For example, in one study on pharmacodynamics of intravenous methylprednisolone in patients with multiple sclerosis, patients with CIDP served as controls;17 in all patients methylprednisolone induced lymphocytopenia, primarily of CD4 T cells.

Type, dose, route, and duration of corticosteroid administration vary. Treatment schedules lasting as long as 2 years have been recommended.18 Long-term treatment with corticosteroids can cause serious side-effects. In three open-label studies, pulsed oral and intravenous corticosteroid treatment was effective and reduced steroid-related adverse events.11, 12, 19 Moreover, six cycles of pulsed high-dose oral dexamethasone given for 6 months induced remission in six of ten patients.19 Pulsed oral methylprednisolone induced remission in six of nine patients after a mean of 27 months of treatment.12 Inducing remission—defined as sustained improvement not needing maintenance treatment—would be beneficial in patients with chronic disease, particularly if long-term treatment is expensive or causes many side-effects.

We hypothesised that pulsed high-dose dexamethasone induces remission more often and more rapidly against minor short-lasting side-effects and with fewer serious or long-term side-effects compared with standard oral prednisolone treatment. We aimed to investigate this hypothesis in a multicentre, double-blind, randomised, controlled clinical trial.

Section snippets

Patients

Patients were enrolled in eight neuromuscular centres in the Netherlands and one in the UK. Patients were eligible if they were at least 18 years of age and had been newly diagnosed as having definite or probable CIDP according to the European neuromuscular centre diagnostic criteria.20 Patients had to have signs and symptoms sufficiently severe to warrant treatment and had to be treatment naive. Exclusion criteria were other diseases known to cause neuropathy (eg, diabetes mellitus,

Results

Between December, 2003, and December, 2007, 41 patients were randomly assigned and 40 started study medication (figure 1). One patient withdrew from the trial 1 day after assignment because of rapid disease progression and a change of diagnosis. This patient did not start trial medication, was not assessed for efficacy outcomes, and was excluded from all analyses. 24 patients were assigned to dexamethasone and 16 to prednisolone. All patients received at least one dose of their allocated

Discussion

This randomised trial did not show a difference in remission rate between pulsed high-dose dexamethasone treatment and continuous prednisolone treatment for 6 months in patients with CIDP. Both treatments were associated with a remission rate about 40% higher than baseline. The percentage of patients who reached remission after treatment for 6 months was less than we had hypothesised in the dexamethasone group, and higher than we had hypothesised in the prednisolone group. Although there was no

References (36)

  • PJ Dyck et al.

    Prednisone improves chronic inflammatory demyelinating polyradiculoneuropathy more than no treatment

    Ann Neurol

    (1982)
  • MM Mehndiratta et al.

    Corticosteroids for chronic inflammatory demyelinating polyradiculoneuropathy

    Cochrane Database Syst Rev

    (2002)
  • PA McCombe et al.

    Chronic inflammatory demyelinating polyradiculoneuropathy: a clinical and electrophysiological study of 92 cases

    Brain

    (1987)
  • G Lopate et al.

    Treatment of chronic inflammatory demyelinating polyneuropathy with high-dose intermittent intravenous methylprednisolone

    Arch Neurol

    (2005)
  • SA Muley et al.

    Treatment of chronic inflammatory demyelinating polyneuropathy with pulsed oral steroids

    Arch Neurol

    (2008)
  • A Sghirlanzoni et al.

    Chronic inflammatory demyelinating polyradiculoneuropathy: long-term course and treatment of 60 patients

    Neurol Sci

    (2000)
  • RAC Hughes et al.

    EFNS/PNS Guideline on management of chronic inflammatory demyelinating polyradiculoneuropathy: report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society

    Eur J Neurol

    (2006)
  • M Scudeletti et al.

    Immune regulatory properties of corticosteroids: prednisone induces apoptosis of human T lymphocytes following the CD3 down-regulation

    Ann NY Acad Sci

    (1999)
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