Editorial: How Publication Bias May Harm Treatment Guidelines

The treatment of rheumatoid arthritis (RA) is an attractive field for systematic literature research and meta-analysis. Several factors may explain this popularity. RA is the most common inflammatory rheumatic disease, at least 15 different disease-modifying antirheumatic drugs (DMARDs) with proven efficacy but uncertain priority are available, and the availability of all of these effective DMARDs has motivated many investigators to test strategies with different timing, intensity, and combinations of DMARDs in order to further optimize treatment outcome. These reasons may also explain why RA treatment has become such a highly competitive arena with vivid scientific debate, conflicting personal opinions, and immense commercial interests. An investigator conducting systematic literature research has to find his way in this arena of prejudices, strong opinions, and marketing strategies. Often such a researcher is told by “experts” that a rather limited literature search will suffice, since the experts already know the data very well. Multiple experiences have convinced me of the contrary. While the expert’s memory may be a fruitful source to check for inconsistencies in the search results, it is obvious that expert opinion in fact is only a compilation of recent and remarkable but often incidental observations published in high-impact journals by famous authors, rather than a balanced interpretation of all available literature. In 2009, most experts in the European League Against Rheumatism task force for recommendations for the management of RA were convinced of the virtues of DMARD combination therapy because of one or two “eye-catching” trials. But a careful and extensive systematic literature search made the experts finally conclude that there was actually insufficient evidence to claim that DMARD combination therapy in RA is better than DMARD monotherapy (1). Superior efficacy in the trials with combination DMARD therapy could be ascribed to the effects of glucocorticoids rather than to the DMARD combinations themselves. Such a conclusion would not have been reached if only single trials were interpreted, or if expert opinion was followed. Systematic literature research and meta-analysis are powerful tools to get a scientifically robust impression of the state of the art regarding the treatment of diseases. Electronic bibliographic databases, such as PubMed, Cochrane, and Embase, that can be easily accessed, have proven to be indispensable, and the contribution of this type of meta-research to the body of current medical knowledge is substantial. There is one important proviso. Before the results of a trial can be retrieved for systematic literature research, they should appear in the public domain. Publication of trial results is the sole responsibility of the investigators. Not all investigators take this responsibility very seriously. An unknown percentage of completed clinical trials will never be published. While this behavior of deliberately keeping completed trials outside the public domain is widely considered unethical, there is no legal way to force investigators to publish their results. In fact, that is a strange omission in a world where to date particular emphasis has been laid on detecting and preventing scientific fraud. Just as with fraud, deliberate refusal to publish unsatisfactory trial results does not give justice to the altruistic contribution of patients who voluntarily consent to participate in a trial. Reasons not to publish the results of trials are rather intransparent. Investigators may lose interest when confronted with the absence of an anticipated positive effect, or they may be discouraged by consecutive rejections by journals. Alternatively, investigators may be hindered by industry sponsors from publishing commercially unprofitable results. Whatever the reasons, deliberately refraining from publication of completed trials will always lead to a Robert B. M. Landewé, MD: Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and Atrium Medical Center, Heerlen, The Netherlands. Address correspondence to Robert B. M. Landewé, MD, Academic Medical Center, University of Amsterdam, Department of Clinical Immunology and Rheumatology, Meibergdreef 9, PO Box 22660, 1100 DD Amsterdam, The Netherlands. E-mail: landewe@rlandewe.nl. Submitted for publication June 24, 2014; accepted in revised form July 10, 2014.