For the clinician it is important to know whether a new drug works, and how the new drug performs against other drugs. However, new drugs are typically tested in placebo-controlled trials without active comparison. New drugs are often tested in a population with high levels of disease activity. Clinicians, however, may also seek the optimal treatment for patients with persistent moderate levels of disease activity. An answer may come from clinical trials that compare two effective drugs in patients with moderate disease activity. A main consequence, however, is that trial endpoints are needed that can detect small but relevant differences in efficacy. An ideal endpoint for trials in rheumatic diseases may be a marker that continually follows short-term changes in the disease process. The levels of the marker should be strongly associated with long-term outcome, thus prognosticating the future. When it can be measured truly and feasible, the marker would be useful as an endpoint in trials and for supporting treatment decisions in clinical practice.