Reflections on therapeutic trials in primary biliary cirrhosis: A quality of life oriented counter-view


  • Potential conflict of interest: Nothing to report.

Reflections on Therapeutic Trials in Primary Biliary Cirrhosis: A Quality of Life Oriented Counter-View

To the editor:

A recent placebo-controlled, multi-center clinical trial, published in Hepatology, has reported that the addition of methotrexate to ursodeoxycholic acid (UDCA) therapy has no discernable effect on survival, or time to transplantation, in primary biliary cirrhosis (PBC).1 Although obviously disheartened by the efforts he and his colleagues have put in to what transpired to be a negative trial, we feel that the accompanying, rather pessimistic, editorial by Combes is far too narrow in its outlook.2 In this editorial Combes argues that it is difficult, if not impossible, to envisage future improvement in therapy in PBC. Whilst morbidity and mortality are of fundamental importance as goals in the treatment of any disease, we would argue that it is just as important that clinicians look to treat patients' symptoms and to improve their quality of life (QOL). This is particularly important in a condition such as PBC where significant impairment of QOL is recognised, typically resulting from symptoms such as fatigue, which are unrelated to disease severity.3–6 The importance of improvement in QOL as a goal of therapy in its own right, is made all the more pertinent by the observation, made so elegantly by Combes and colleagues, that outcomes in terms of survival are actually very good, almost regardless of therapy in young PBC patients with early disease (although it should be noted that the outcome in terms of survival may be less rosy in older patient groups).7 Whilst the Combes trial looked at end points including mortality, liver transplantation and clinical parameters, there is no mention of symptomatic and/or QOL assessment. In light of the low mortality demonstrated, and the likelihood that, if the patients are at all representative, they have substantial (but non-assessed) impairment of their QOL, it could be argued that the most important outcome measure was not studied.

The counter view to Combes is that what is needed in PBC is not pessimism but realism about the true nature of the impact that the disease has on patients and, accordingly, a paradigm shift in treatment goals. Although the search for novel additional pharmacological therapies able to stop disease progression continues, there is a persuasive argument that patients who progress on UDCA would do so with other agents, and that transplantation will be required by those patients who do progress in any case. However, even in patients in whom the disease is only slowly progressive, the symptoms of the disease can have a major impact on QOL. Ameliorating symptoms and improving QOL in such patients would be of major practical benefit to large numbers of patients. We have a duty of care as clinicians and researchers to look at QOL in our PBC patients and we would suggest that, in the future, at least as much effort be put in to clinical research and trial work in the area of improving QOL, as in to high concept, large scale and long term mortality-orientated trials which as Combes acknowledges have generated relatively little benefit to patients to date.

David E.J. Jones*, Neeraj Bhala*, Julia L. Newton*, * Liver Research Group, School of Clinical Medical Sciences, University of Newcastle, Newcastle-upon-Tyne, UK