Methotrexate for treatment of primary biliary cirrhosis
Authors: Peter A Bonis, Marshall Kaplan
Journal: Hepatology (2006)

To the editor: We congratulate Dr. Combes and colleagues for completing the PUMPS trial.1, 2 Although their negative results are disappointing, we hope that their study will not be a requiem for studies involving methotrexate in the treatment of PBC. The low event rate combined with the high dropout rate (30%) would have made it difficult to detect a favorable effect of any additional drug, particularly if it occurred in only a subset of individuals. Transplant-free survival was markedly higher than expected (94.5 vs. 83%). The authors comment that most of the dropouts were due to progression of disease but the data presented indicate that dropout was due to disease progression in only 10 of 88 patients. The trial was terminated early because of a stopping rule that indicated an extremely low probability that a statistically significant improvement would have been detected with its continuation. Nevertheless, the 95% confidence interval of the hazard ratio surrounding the main endpoint included a potentially clinically important treatment effect (up to a 56% reduction {or a 72% increase} in death or the need for transplant in the combination therapy group). Thus, at best, the study should be interpreted as excluding an extremely large treatment effect. We have observed striking variability in response to medical treatment among the more than 1200 patients with PBC we have cared for, an observation reported by others.3-5 The reasons for the variable responses are unknown. In particular, we have found that additional therapy benefits patients who had an incomplete biochemical response to UDCA alone and whose liver biopsies continue to showed prominent necroinflammation. Not all patients respond to additional therapy, and we continue it only in those who appear to be improving biochemically and histologically. By contrast, patients enrolled in the PUMPS trial may not have yet achieved a full biochemical and histologic benefit of UDCA before randomization and were continued on combination therapy regardless of their response. For patients who fail to respond to UDCA, we have little to offer other than transplantation when end stage liver disease develops. We have found that many of these patients respond to the addition of methotrexate and/or colchicine.6-8 Their symptoms improve or remit, blood tests become normal, liver biopsies improve and/or become normal, and they do not develop portal hypertension or end stage liver disease. We believe that these are good surrogate markers for improvement of PBC, just as they are for other liver diseases. The PUMPS trial illustrates the difficulties in designing studies in PBC that have sufficient power to demonstrate benefits of therapy (much less detect them in these subgroups of patients). The data regarding methotrexate in PBC are clearly heterogeneous. Although the PUMPS trial is an important negative study, it has limitations. We hope that it will not preclude continued investigation of combination therapy involving methotrexate in PBC considering the safety of methotrexate observed in the PUMPS trial (and other studies), the potential efficacy in some patients, and the lack of alternatives in patients who respond incompletely to UDCA. Peter A Bonis M.D.*, Marshall Kaplan M.D.*, * Gastroenterology Division Tufts New England Medical Center Boston, MA