A systematic review of the effectiveness of adalimumab

disease between clinic appointments, before being
eligible for therapy. A majority of patients (94%)
registered in the BSRBR are recorded as having
met this standard, although the veracity of
recorded data is unclear – it is not audited and
there is an incentive for clinicians, who judge that
thresholds inappropriately control access to
therapy, to state that patients have met the
criteria.
Guidance also recommends that, in order to
continue therapy with TNF inhibitors, disease
activity needs to decrease by a DAS28 of 1.2, or be
at or below 3.2 after 3 months of treatment. The
BSR submission to NICE indicates that this may
have been a typing error as a good DAS response
is defined as a change of greater than 1.2 and a
score below 3.2. 85 DAS28 thresholds scores were
derived originally from actual decisions taken in
practice 43 and their principal role is as outcome
measures in clinical trials. Although these may be
useful hurdles and good instruments for
monitoring therapy, it has been argued that
unthinking application of such thresholds devalues
clinical judgements, especially since the DAS28
has some properties that undermine confidence in
its value for individual decision-making. 90–93 In
the BSRBR 41% of patients classified as nonresponders
on DAS thresholds continued with
TNF inhibitors, indicating that clinicians and
patients clearly felt that the modest improvement
in DAS (mean improvement 0.3) and other health
gains 85 were sufficient to warrant continued drug
use.
Sequential use of TNF inhibitors, where patients
fail to respond or experience an adverse reaction
to one agent, was not recommended in previous
guidance on the basis that there was no evidence
supporting this practice. Since then, many
practising clinicians have noted benefits for
patients when switching agents. Some experiences
have been published and demonstrate potential
benefits for patients switching from any one of the
three agents to another of these agents. 94,95 BSR
guidance (2005) cites some of this evidence
without making any specific recommendations.
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Health Technology Assessment 2006; Vol. 10: No. 42
Data from the BSRBR indicate that this practice is
prevalent, despite current guidance.
Updated BSR guidance considers, briefly, the use
of dose changes and increased frequency of dosing
for infliximab and adalimumab. A significant
proportion of patients receiving infliximab
experience increased disease activity after an
initial good response. Clinicians have responded,
in some cases, by reducing the interval between
infusions such that patients are given 3 mg kg –1 of
infliximab every 6 weeks instead of every 8 weeks,
or by increasing the dose of infliximab to
5mgkg –1 at 8-week intervals. 96,97 Published
observations indicate effective disease control by
doing this, but at significantly increased drug
costs. A large series from Belgium, for example,
showed that nearly one-quarter of treated patients
had dose increases, 74 whereas a US study showed
that over 60% of patients had dose increases. 98 In
addition, the licence for adalimumab allows for
increasing the dose from 40 mg every other week
to once a week, effectively doubling the cost of
therapy. It is unclear how commonly this is done
in practice. By contrast, increasing etanercept
beyond a total of 50 mg per week (as one or two
injections) does not appear to improve efficacy. 99
Degree of diffusion and
anticipated costs
By the end of 2004, 8455 patients with RA and
1081 with other rheumatic diseases were treated
with TNF inhibitors and were registered with the
BSRBR. New patients were being added to the
registry at a rate of 450 per month, in early
2004. 62,85 If one estimates that currently around
8000–10,000 patients with RA are being treated
with TNF inhibitors, at approximately £10,000 per
annum each, then the annual national costs of
TNF inhibitors for RA is in the region of
£80–100 million. These figures are rising and,
given that only around 2% of patients with RA are
currently on TNF inhibitors, there is the potential
for future increases to be substantial.
11