A systematic review of the effectiveness of adalimumab

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Discussion
heterogeneity found between the studies in any of
the outcomes being meta-analysed. Subgroup
analyses within TEMPO also indicated that
treatment effects do not vary substantially between
early RA and late RA patients.
TEMPO was unique in that it was the only trial
that allowed head-to-head comparison between a
TNF inhibitor and methotrexate, in a population
that included both early RA and established RA.
While it provides useful insight in many aspects,
the generalisability of the results, at least in the
UK, is not clear. In this trial half of the patients
were reported as having previously received
methotrexate without toxicity or lack of efficacy
and yet these patients had not been treated with
methotrexate for at least 6 months before the
study. Such patients are uncommon in real
practice. Consequently, the use of results from this
trial in the economic model to give an estimate of
improvement with the use of the combination of
etanercept plus methotrexate in established RA,
would exaggerate the treatment benefit as most
real patients would have failed treatment with
methotrexate at this stage.
TNF inhibitors versus placebo
The majority of RCTs included in this review
compared TNF inhibitors with placebo.
Adalimumab, etanercept and infliximab are all
effective treatments, compared with placebo, in
terms of improving symptoms of the disease and
preventing radiographic damage due to disease.
The relative risk for ACR20 for etanercept versus
placebo showed a decreasing pattern in trials in
which patients: (1) were not receiving any
concurrent DMARDs; (2) were receiving
concurrent DMARDs which had failed to provide
adequate disease control; and (3) were receiving
concurrent, newly initiated methotrexate (see
Figure 24, p. 48). This reflects increasing response
rates in the control (placebo) arms rather than
differential response rates in the intervention
(etanercept) arms. Statistically significant
differences were found in most of the efficacy
outcomes (but not necessarily safety outcomes)
between (3) and the other two analyses. This
confirmed the importance of separating
comparisons in which newly initiated methotrexate
was involved. The difference between (1) and (2),
however, was only marginal (test for heterogeneity
p = 0.10). This is consistent with the suggestion
that the presence or absence of concurrent
DMARDs that had failed to provide adequate
control of disease activity does not have a
significant influence on the treatment effect of
adalimumab or etanercept. Further observations
from direct comparison within etanercept trials, in
Codreanu 103 (replacing ongoing sulfasalazine with
etanercept or adding etanercept to ongoing
sulfasalazine) and ADORE 107 (replacing ongoing
methotrexate with etanercept or adding etanercept
to ongoing methotrexate) are also consistent with
this interpretation: there were generally no
significant differences between etanercept-alone
arms and combination arms in efficacy and safety
outcomes in these two trials. No adalimumab trial
allowed such observation, and the current licence
stipulates that adalimumab should be given in
combination with methotrexate unless it is not
tolerated, possibly on the basis that the absolute
improvement observed in adalimumab trials was
larger when adalimumab was given with
methotrexate.
The pooled risk of malignancies for adalimumab
compared with placebo approached statistical
significance in the meta-analysis. Malignancies
were also observed more frequently in infliximabtreated
patients in placebo-controlled trials. While
these findings were based on a small number of
cases and do not appear to be supported by
observational studies, continuous vigilance
regarding this potential adverse effect is
warranted. Observational studies published to date
have compared the incidence of malignancies for
TNF inhibitor-treated patients with either the
incidence observed in general population or that
observed in cohorts of RA patients. Comparisons
have ignored the well-known ‘healthy patient’
effect of trials and, indeed, patients who entered
trials of TNF inhibitors or who received TNF
treatment in practice were a subgroup of RA
patients in which patients with risk factors
associated with malignancies (such as past history
of malignancy; chronic obstructive pulmonary
disease, viral hepatitis and HIV infection) were
excluded. The patients who received TNF
inhibitors in observational studies were therefore
likely to have a lower risk of malignancies (with
the exception of lymphoma) compared with
general population or general RA population.
Future observational studies should attempt to
adjust for such potential confounding.
TNF inhibitor plus methotrexate versus
methotrexate
Four trials 102,127,135,141 compared the combination
of a TNF inhibitor plus methotrexate with
methotrexate alone in patients naïve to
methotrexate or patients who did not have a
history of treatment failure with methotrexate.
The combinations were significantly more effective
than methotrexate alone for all three TNF