T CELLS AS THERAPEUTIC TARGETS

Much of our experience with biological agents in autoimmune disease has been derived from studies of T cell directed therapy in rheumatoid arthritis (RA) (box 1). Data from these studies have provided substantial insight into study design, product development, and T cell biology. Initial studies entailed targeting of CD4 T cells with murine monoclonal antibodies (mAb) of differing isotypes directed at a variety of epitopes on the CD4 molecule. Between 1989–1994, eight short-term open label trials yielded promising results with clinical responses in 60%–75% of patients (reviewed in Strand and Keystone¹). In 1996, seven years after the initial studies were published, the first randomised placebo controlled trial (RCT) of murine anti-CD4 mAb showing no clinical benefit was reported.² A similar discrepancy in clinical outcome between early uncontrolled trials and placebo RCTs was also observed with a murine anti-CD5 immunotoxin conjugate,³ as well as the chimeric anti-CD4 mAb, cM412.^4,5 This difference probably reflects both expectation bias on the part of the investigator and patient with “new and innovative therapy” as well as a placebo effect. In studies of anti-CD5 immunotoxin conjugate, for example a placebo rate as high 50% was observed. A review of the problem by Epstein suggested that the results reflect more of an expectation bias than a placebo effect.⁶ His conclusion is based on an analysis of several trials involving chimeric anti-CD4 mAb in which the clinical benefit observed in the experimental group of the RCT was significantly lower than that observed in the open label groups. A placebo effect would be expected to yield comparable clinical responses between the two groups. The discrepancy between open label and RCT responses emphasises the magnitude of experimental bias in open label studies and as well as the need for vigorous blinding in RCTs. The …