MD, PhD, FMedSci, FSB, FRCP, FRCPEd

eczema

One of the best-selling supplements in the UK as well as several other countries is evening primrose oil (EPO). It is available via all sorts of outlets (even respectable pharmacies – or is that supposedly respectable?), and is being promoted for a wide range of conditions, including eczema. The NIH website is optimistic about its efficacy: “Evening primrose oil may have modest benefits for eczema.” Our brand-new Cochrane review was aimed at critically assessing the effects of oral EPO or borage oil (BO) on the symptoms of atopic eczema, and it casts considerable doubt on this somewhat uncritical view.

Here is what we did: We searched six databases as well as online trials registers and checked the bibliographies of included studies for further references to relevant trials. We corresponded with trial investigators and pharmaceutical companies to identify unpublished and ongoing trials. We also performed a separate search for adverse effects. All RCTs investigating oral intake of EPO or BO for eczema were included.

Two experts independently applied eligibility criteria, assessed risk of bias, and extracted data. We pooled dichotomous outcomes using risk ratios (RR), and continuous outcomes using the mean difference (MD). Where possible, we pooled study results using random-effects meta-analysis and tested statistical heterogeneity.

And here is what we found: 27 studies with a total of 1596 participants met our inclusion criteria: 19 studies tested EPO, and 8 studies assessed BO. A meta-analysis of results from 7 studies showed that EPO failed to improve global eczema symptoms as reported by participants and doctors. Treatment with BO also failed to improve global eczema symptoms. 67% of the studies had a low risk of bias for random sequence generation; 44%, for allocation concealment; 59%, for blinding; and 37%, for other biases.

Our conclusions were clear: Oral borage oil and evening primrose oil lack effect on eczema; improvement was similar to respective placebos used in trials. Oral BO and EPO are not effective treatments for eczema.

The very wide-spread notion that EPO is effective for eczema and a range of other conditions was originally promoted by the researcher turned entrepreneur, D F Horrobin, who claimed that several human diseases, including eczema, were due to a lack of fatty acid precursors and could thus be effectively treated with EPO. In the 1980s, Horrobin began to sell EPO supplements without having conclusively demonstrated their safety and efficacy; this led to confiscations and felony indictments in the US. As chief executive of Scotia Pharmaceuticals, Horrobin obtained licences for several EPO-preparations which later were withdrawn for lack of efficacy. Charges of mismanagement and fraud led to Horrobin being ousted as CEO by the board of the company. Later, Horrobin published a positive meta-analysis of EPO for eczema where he excluded the negative results of the largest published trial, but included results of 7 of his own unpublished studies. When scientists asked to examine the data, Horrobin’s legal team convinced the journal to refuse the request.

The evidence for EPO is negative not just for eczema. To the best of my knowledge, there is not a single disease or symptom for which it demonstrably works. Our own review of the data concluded ” EPO has not been established as an effective treatment for any condition”

Our new Cochrane review might help to put this long saga to rest. In my view, it is a fascinating tale of a scientist being blinded by creed and ambition. The results of such errors can be dramatic. Horrobin misled all of us: patients, health care professionals, scientists, regulators, decision makers, businessmen. This caused unnecessary expense and set back research efforts in a multitude of areas. I find the tale also fascinating from other perspectives; for instance, it begs the question why so many ‘respectable’ manufacturers and retailers are still allowed to make money on EPO. Is it not time to debunk the EPO-myth and say it as clearly as possible: EPO helps only those who financially profit from misleading the public?

During the last decade, Professor Claudia Witt and co-workers from the Charite in Berlin have published more studies of homeopathy than any other research group. Much of their conclusions are over-optimistic and worringly uncritical, in my view. Their latest article is on homeopathy as a treatment of eczema. As it happens, I have recently published a systematic review of this subject; it concluded that “the evidence from controlled clinical trials… fails to show that homeopathy is an efficacious treatment for eczema“. The question therefore arises whether the latest publication of the Berlin team changes my conclusion in any way.

Their new article describes a prospective multi-centre study which included 135 children with mild to moderate atopic eczema. The parents of the kids enrolled in this trial were able to choose either homeopathic or conventional doctors for their children who treated them as they saw fit. The article gives only scant details about the actual treatments administered. The main outcome of the study was a validated symptom score at 36 months. Further endpoints included quality of life, conventional medicine consumption, safety and disease related costs at six, 12 and 36 months.

The results showed no significant differences between the groups at 36 months. However, the children treated conventionally seemed to improve quicker than those in the homeopathy group. The total costs were about twice higher in the homoeopathic compared to the conventional group. The authors conclude as follows: “Taking patient preferences into account, while being unable to rule out residual confounding, in this long-term observational study, the effects of homoeopathic treatment were not superior to conventional treatment for children with mild to moderate atopic eczema, but involved higher costs“.

At least one previous report of this study has been available for some time and had thus been included in my systematic review. It is therefore unlikely that this new analysis might change my conclusion, particularly as the trial by Witt et al has many flaws. Here are just some of the most obvious ones:

Patients were selected according to parents’ preferences.

This means expectations could have played an important role.

It also means that the groups were not comparable in various, potentially important prognostic variables.

Even though much of the article reads as though the homeopaths exclusively employed homeopathic remedies, the truth is that both groups received similar amounts of conventional care and treatments. In other words, the study followed a ‘A+B versus B’ design (here is the sentence that best gives the game away “At 36 months the frequency of daily basic skin care was… comparable in both groups, as was the number of different medications (including corticosteroids and antihistamines)…”). I have previously stated that this type of study-design can never produce a negative result because A+B is always more than B.

Yet, at first glance, this new study seems to prove my thesis wrong: even though the parents chose their preferred options, and even though all patients were treated conventionally, the addition of homeopathy to conventional care failed to produce a better clinical outcome. On the contrary, the homeopathically treated kids had to wait longer for their symptoms to ease. The only significant difference was that the addition of homeopathy to conventional eczema treatments was much more expensive than conventional therapy alone (this finding is less than remarkable: even the most useless additional intervention costs money).

So, is my theory about ‘A+B versusB’ study-designs wrong? I don’t think so. If B equals zero, one would expect exactly the finding Witt et al produced:  A+0=A. In turn, this is not a compliment for the homeopaths of this study: they seem to have been incapable of even generating a placebo-response. And this might indicate that homeopathy was not even usefull as a means to generate a placebo-response. Whatever interpretation one adopts, this study tells us very little of value (as children often grow out of eczema, we cannot even be sure whether the results are not simply a reflection of the natural history of the disease); in my view, it merely demonstrates that weak study designs can only create weak findings which, in this particular case, are next to useless.

The study was sponsored by the Robert Bosch Stiftung, an organisation which claims to be dedicated to excellence in research and which has, in the past, spent millions on researching homeopathy. It seems doubtful that trials of this caliber can live up to any claim of excellence. In any case, the new analysis is certainly no reason to change the conclusion of my systematic review.

To their credit, Witt et al are well aware of the many weaknesses of their study. Perhaps in an attempt to make them appear less glaring, they stress that “the aim of this study was to reflect the real world situation“.Usually I do not accept the argument that pragmatic trials cannot be rigorous – but I think Witt et al do have a point here: the real word tells us that homeopathic remedies are pure placebos!

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