Thursday January 17 2008
Photographs showing responses to etanercept treatment. Picture courtesy of the NEJM. Copyright ©2008 Massachusetts Medical Society. All rights reserved.
New research has found that an arthritis drug could significantly reduce psoriasis symptoms in children, reported The Daily Telegraph today. The paper described a study of 211 patients from four to 17-years-old with the severest form of the condition that causes widespread red scaly skin patches. The newspaper report said that a three-month course of weekly injections of the drug etanercept, sold under the name Enbrel in Britain, cleared at least three quarters of the patches in more than half of patients.
Etanercept is in a class of drugs known as “soluble tumour necrosis factor receptor fusion proteins” (anti-TNF) which already treat adults with rheumatoid arthritis and ankylosing spondylitis (a disease causing progressive stiffening of the spine) when these conditions have been unresponsive to other medicines. The paper stated that this trial is the first to show that etanercept is safe and effective in children, pointing out that existing treatments for psoriasis in children and adolescents are limited and can have serious side-effects.
This study was designed to assess the safety of the drug, as well as how well it cleared this debilitating skin condition. The drug was effective in reducing symptoms and signs of psoriasis (more than half of the patients improved by 75%). The trial ran for a short time and, according to the researchers, four patients experienced “serious adverse events”. Although these resolved without any consequences, further trials are needed to assess the long-term safety of the drug. Clinical judgment, taking into account the views of those affected, will be required to assess if these risks are acceptable to young patients with moderate to severe psoriasis.
Where did the story come from?
The research was conducted by Dr Amy Paller from the Children’s Memorial Hospital and Northwestern University Medical School in association with other colleagues in Chicago and the US. The study was supported by Amgen and by Wyeth Pharmaceuticals, the manufacturers of etanercept.
The study was published in the peer-reviewed: The New England Journal of Medicine.
What kind of scientific study was this?
This was a double-blind, placebo controlled, randomised controlled trial. The study ran for 48-weeks, in three phases. Initially 211 patients with psoriasis (aged between four and 17) were randomly allocated to receiving 12 weekly injections of a placebo (inactive, dummy injections) or to a group who received 12 weekly injections of etanercept. Those who were given the drug were given 0.8 mg of etanercept per kilogram of body weight (to a maximum of 50 mg). This was a double-blinded phase where neither the researchers nor the patients knew who was receiving the drug.
This phase was followed by a further 24 weeks of weekly etanercept injections, but this time both the experimental and the placebo group received etanercept, and the researchers and the patients knew who was taking the drug.
At week 36, 138 patients were randomly allocated to either having their etanercept treatment withdrawn or to continue with treatment. This third phase lasted for a further 12 weeks, until the end of the study.
The researchers assessed the extent and severity of psoriasis with a recognised scale - the psoriasis area and severity index (PASI) - and carefully defined measures of the quality of life and adverse events, including serious adverse events, infectious reactions at the injection sites, cancers and laboratory values from blood tests.
The PASI scale rates three aspects of psoriasis - redness, scale, and skin thickening in four body areas; the head and neck area, arms, legs, and trunk. After adjustments for the relative sizes of these areas, the maximum theoretical score is 72. A score of 10 or less indicates mild psoriasis. The researchers in this study defined success as 75% or greater improvement from baseline in the PASI score (PASI 75) at week 12.
What were the results of the study?
At week 12, 57% of patients receiving etanercept had improved by 75% (PASI 75) compared to 11% of those receiving the placebo injections. Significantly more patients in the etanercept group than in the placebo group had improved by 90%, i.e. had improved even more.
When the etanercept patients were assessed by a doctor, about half were clear (their psoriasis had resolved) or almost clear compared to 13% of those on placebo injections. When all the patients were given etanercept between weeks 12 and 36, the rates of PASI 75 were similar (68% and 65%) for patients in the etanercept and placebo groups respectively.
During the withdrawal period from weeks 36 to 48, contact was lost with 29 of the 69 patients (42%) who were randomly assigned to having the drug withdrawn for the third phase of the trial. Four serious adverse events (including three infections) occurred in three patients during treatment with open-label etanercept. All these resolved without consequences.
What interpretations did the researchers draw from these results?
The researchers concluded that etanercept significantly reduces disease severity in children and adolescents with moderate-to-severe plaque psoriasis.
What does the NHS Knowledge Service make of this study?
This drug company sponsored study has been designed in a way that allowed everyone who took part the opportunity to receive the active drug. This was done by having the open label part to the study where everyone was given the treatment. This added some complexity to the study, but this has been carefully and transparently explained in the journal article. The results are not only statistically significant, but also clinically important and provide a useful benefit to the majority of patients suitable for the drug.
The researchers acknowledged minor limitations that could have affected the results, including the fact that heavier children received higher doses of the drug according to a weight-based dosing schedule and the children who continued to receive etanercept treatment in the third phase were on average 6kg heavier than the placebo group. This imbalance between groups may account for some of the difference in response.
In addition to the four serious adverse events reported (which included the removal of an ovarian cyst, and three infections of gastroenteritis, or pneumonia) there were three cases where tests showed that the patient’s blood had high haemoglobin levels. Although all were recorded as toxic effects, one occurred before the etanercept therapy began, therefore it can be assumed that this event was not due to the drug.
A new effective treatment for moderate to severe psoriasis in children and adolescents will be welcomed by families and those treating the condition. Further information to define the ideal dose and dosing schedules along with more information on the drug’s long-term safety are needed.
Sir Muir Gray adds...
It will be important to see other trials and to have a systematic review of these trials, not only to assess the beneficial effects, but also to identify harms. Because harms are less common than benefits, bigger numbers of patients are needed to spot them; the lesson of vioxx remains a warning.