We do not feel that further studies of methotrexate in PBC need be precluded by the results of the PUMPS trial.1 Our only request is that any future trials be adequately controlled, contain a sufficient number of patients, and be aimed at demonstrating an effect on hard endpoints of the disease such as preventing complications; the need for transplantation; or delaying time to death. In lieu of this, the quality of life should be improved by treatment.
We are not surprised that a uniform response to one therapy is not observed in PBC. Clearly, the effects of many polymorphisms are being observed in both the pathogenesis and the response to tissue injury in many diseases, and this undoubtedly applies to PBC as well.
In their recent review of PBC,2 Drs. Kaplan and Gershwin proposed an untested form of therapy, i.e., the addition of colchicine to ursodiol, if 1 year of therapy with the latter was deemed inadequate; then the addition of methotrexate after an additional year if the previously combined therapy was inadequate. An adequate response was said to consist of resolution of pruritus, a decrease in serum alkaline phosphatase activity to less than 50% above normal, and improvement in liver histological findings. Yet, to date, none of these latter responses, individually or collectively, has served as an adequate surrogate for the hard endpoints of prevention of complications of liver disease, of preventing the need for liver transplantation, for prolongation of survival free of liver transplantation, or for improving the quality of life.