The Committee further considered the DMARD-IR ICERs from the DSU's 2011 exploratory analysis. It noted that although tocilizumab appeared cost effective as the first biological treatment (£5,700 per QALY gained), this sequence had rituximab as the third biological treatment in the sequence, rather than the second. The Committee raised concerns that this was counterintuitive because the total drug treatment cost of rituximab is approximately half that of either tocilizumab or etanercept. On the basis of previous discussions (see section 4.11) the Committee was not convinced that the clinical effectiveness of etanercept or tocilizumab would be sufficiently superior to rituximab such that a sequence in which rituximab was third would be more cost effective than 1 in which rituximab was second. The Committee noted that a sequence in which tocilizumab was the first biological treatment, followed by rituximab, followed by etanercept, had not been included in either the manufacturer's or the DSU's 2011 analyses. It was aware that in clinical practice this sequence would involve off-licence use of rituximab because the marketing authorisation restricts rituximab to use after an inadequate response or intolerance to other DMARDs including 1 or more TNF‑alpha inhibitors. However, the Committee considered that to understand the impact on the cost effectiveness of placing tocilizumab first in the sequence, it was important to consider all possible treatment sequences. It noted that in their exploratory incremental analysis from 2011, the DSU had incorporated an alternative baseline sequence of tocilizumab followed by rituximab. The Committee accepted this sequence as a proxy for tocilizumab, followed by rituximab, followed by etanercept. It noted that when this alternative baseline sequence was included in the exploratory analysis, 3 sequences were extendedly dominated (see section 3.49) leaving the baseline sequence of tocilizumab followed by rituximab, and the sequence of etanercept, followed by rituximab, followed by tocilizumab. Comparing these 2 sequences, tocilizumab as the third biological in the sequence had an ICER of £28,400 per QALY gained, compared with tocilizumab as the first biological treatment in the sequence. It accepted that some uncertainty around the point estimates of the ICERs was likely. However, the conclusion to this analysis was consistent with the reasoning in section 4.18. The Committee concluded that tocilizumab should be recommended as an option when used in the same way as the TNF‑alpha inhibitors etanercept, adalimumab, infliximab, golimumab and certolizumab pegol recommended in NICE's technology appraisal guidance on adalimumab, etanercept and infliximab; certolizumab pegol; and golimumab. The Committee understood that its recommendation would apply to people whose rheumatoid arthritis has a DAS28 score of greater than 5.1. It also understood that treatment should normally be initiated with the least expensive drug (taking into account administration costs, required dose and product price per dose) and this may need to be varied in individual cases because of differences in the mode of administration and treatment schedules.