A systematic review of the effectiveness of adalimumab

experiencing these events was not reported, the
number of patients who experienced infections
that were classified as SAEs was used instead.
Figures of serious infection reported by study
investigators without a clear definition were also
included if the above information was not
available.
Additional exploratory analyses on death, any
infections, non-melanoma skin cancer and all
cancer excluding non-melanoma skin cancers were
carried out.
Approach for meta-analysis
Each TNF inhibitor was meta-analysed separately.
The primary analysis compared each TNF
inhibitor at the licensed dose (or its equivalent)
with placebo or other active comparators using the
latest follow-up data available from the
randomised, controlled period of each trial. The
doses included in the primary analysis are:
● adalimumab: 40 mg every other week (may be
increased to every week if response is
inadequate) or 20 mg every week
● etanercept: 25 mg twice weekly, 50 mg once
weekly or 16 mg m –2 twice weekly
● infliximab: 3 mg kg –1 at 0, 2 and 6 weeks, and
then every 8 weeks.
Sensitivity analyses included TNF inhibitors at
licensed doses and above, and at all doses
including sublicensed doses. Studies in which
single injections or infusions were administered
are not included in the primary analysis, but are
included in the all-dose sensitivity analyses.
Duration of follow-up for each trial is displayed on
the forest plots of primary analysis for
comparison. Additional analyses of results at
1 month, 3, 6 and 12 months and beyond are also
conducted for ACR20 response.
For each TNF inhibitor three comparisons were
made:
1. TNF inhibitor versus conventional DMARD:
this head-to-head comparison is most relevant
for clinical practice. A fair head-to-head
comparison requires that patients should not
have previously tried any of the drugs being
compared, or at least not be selected as
responders/non-responders.
2. TNF inhibitor versus placebo (with or without
concomitant, ongoing DMARDs): trials that
were included in this comparison typically
recruited patients whose disease had been
inadequately controlled by conventional
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Health Technology Assessment 2006; Vol. 10: No. 42
DMARDs. The DMARDs that the patients had
been taking before study entry (if any) were
either stopped or continued during the trial
and a TNF inhibitor or placebo was given to
patients. In both cases a TNF inhibitor is
compared with placebo but the scenarios
behind the comparisons are different. The
former represents a comparison of stopping
DMARDs versus replacing a DMARD with a
TNF inhibitor. The latter represents a
comparison of continuing a DMARD (which is,
at best, partially effective) versus adding a TNF
inhibitor to that DMARD.
To explore whether treatment effects differ
between these two scenarios, the primary
analyses of trials are displayed in the forest
plots according to concomitant DMARD
treatment. Studies in which patients stopped all
concomitant DMARDs are placed on top of the
plots and are labelled with a (–) sign. These are
followed by studies in which patients continued
their existing DMARD treatment, which are
labelled with a (+) sign. In a few studies the
patients continued their ongoing antirheumatic
therapy, which may have included DMARDs.
These studies are labelled with a (±) sign.
3. Combination (TNF inhibitor plus newly
initiated conventional DMARD) versus newlyinitiated
conventional DMARD alone: this
analysis reports trials in which patients were
naïve to, or had not previously failed treatment
with the TNF inhibitor and the DMARD being
compared. The only comparator DMARD used
in such trials to date has been methotrexate.
The effect size in these trials represents the
additional treatment benefit (or harm) of the
combination over the newly initiated
methotrexate alone. In these trials there is a
greater benefit to patients in the control arm
than seen in trials where the comparator is an
established ongoing DMARD. It is thus
necessary to distinguish between this analysis
and that in (2), above, and the authors feel that
it is inappropriate to cite a summary statistic
combining these two different types of
comparisons. However, for illustrative purpose,
the forest plots of the primary analyses give
both comparisons (2) and (3) on the same plot
to illustrate the overall heterogeneity between
these two types of ‘placebo versus TNF
inhibitor’ comparison.
Although most trials contributed data to only one
of the three comparisons described above, a few
trials contributed to more than one. For example,
the PREMIER trial compared adalimumab alone,
methotrexate alone, and the combination of
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