“Never go to excess, but let moderation be your guide” Cicero

“Too much of a good thing is wonderful” Mae West

The approval of the monoclonal anti-tumour necrosis factor antibody, infliximab, for the treatment of rheumatoid arthritis (RA) in 1999, occurring almost simultaneously with that of etanercept, marked an important event in the history of rheumatology. The possibility of providing good disease control to patients with the disease, while preventing structural damage, increased dramatically, and rheumatology would never be the same.

From the time of its first approval, a peculiar feature of infliximab was uncertainty about optimal dosing. The original observations made at the Kennedy Institute in London with the antibody then known as cA2, later as “avakine”, and later still as infliximab, suggested that 1 mg/kg was too little to provide meaningful responses. On the other hand, 3 mg/kg, 10 mg/kg and even 20 mg/kg were found to have beneficial effects in RA.1^–4 The single pivotal phase III clinical trial carried out with infliximab, the ATTRACT study, tested four possible combinations of dosage and dosing interval: 3 mg/kg or 10 mg/kg, every 4 or every 8 weeks.4 5 It should perhaps be noted that in that trial each of these dosage/frequency combinations was preceded by the—now standard—“loading” regimen of three infliximab infusions given over 6 weeks (at 0, 2, and 6 weeks). There is, to the best of my knowledge, no clear pharmacological rationale for such a loading dose, but it certainly has made it more difficult accurately to assess and interpret the results with the various dosage/frequency combinations. For example, the 24-week results in the ATTRACT trial were very similar for the four different infliximab dosage/frequency groups (and, of course, much better than placebo); but was this evidence that each of these options was …