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