A systematic review of the effectiveness of adalimumab

Sensitivity analyses Results which include additional
patients treated with above the licensed dose
(6 mg kg –1 every eight weeks) in the ASPIRE trial
are summarised in Table 77 (Appendix 4). Data are
generally consistent with the primary analyses and
show a slightly increased effect size for efficacy
outcomes, except for the modified Sharp score.
When the above-licensed dose is included, the
combination of infliximab plus methotrexate is
associated with an increased risk of both serious
infection (RR 2.59, 95% CI 1.11 to 6.04) and
[Commercial-in-confidence information
removed]. [Commercial-in-confidence
information removed] patients developed
malignancy in the 6 mg kg –1 group compared with
[Commercial-in-confidence information
removed] in the 3 mg kg –1 group in ASPIRE.
Summary of effectiveness review
and additional evidence
Results of the primary meta-analyses (licensed
dose only) for the three TNF inhibitors for the key
outcomes are summarised in Table 17. A brief
description for each type of comparison is
provided below.
TNF inhibitors versus DMARDs
Volume of evidence
Only one adalimumab trial (PREMIER 102 , n = 531
in the relevant arms) and two etanercept trials
(ERA 123 , n = 424 and TEMPO 127 , n = 451) allow
head-to-head comparison between a TNF
inhibitor (at licensed dose) and methotrexate. No
trial compared a TNF inhibitor with other
conventional DMARDs.
Direction of effect
Adalimumab monotherapy was marginally less
effective than methotrexate monotherapy in
reducing RA symptoms and improving physical
function in early RA patients naïve to
methotrexate treatment, and did not offer better
tolerability over methotrexate. By contrast,
etanercept alone was slightly more effective than
methotrexate alone in early RA patients who were
naïve to methotrexate treatment and in patients
with longer disease duration who had no history
of treatment failure with methotrexate. Etanercept
was better tolerated than methotrexate in these
patients. Both adalimumab and etanercept were
significantly more effective than methotrexate in
slowing radiographic joint damage, but the clinical
relevance of these differences is unclear. No
significant differences between methotrexate and
adalimumab and etanercept were found for the
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Health Technology Assessment 2006; Vol. 10: No. 42
safety outcomes, including deaths, SAEs,
malignancy, serious infections and any infections.
However, this may be due to the relatively small
number of patients included in the analyses. Large
pragmatic trials and careful postmarketing
surveillance, including record linkage studies, are
needed to compare the relative safety of TNF
inhibitors compared with methotrexate and other
DMARDs.
TNF inhibitors versus placebo
Volume of evidence
The majority of RCTs included in this review
compared TNF inhibitors with placebo. Five
adalimumab trials 112–115,119 involving 1861
patients, eight etanercept
trials 103,104,121,122,125,126,129,130 involving 1715
patients, and two infliximab trials 105,133 involving
895 patients were included in the primary metaanalyses.
Direction of effect
All three TNF inhibitors were significantly more
effective in controlling the symptoms of RA,
improving physical function and retarding
radiographic joint damage and were associated with
few treatment withdrawals compared with placebo.
Use of above-licensed doses slightly increased the
treatment effect for adalimumab and infliximab,
but was associated with an increased risk of any
infection and serious infections. More patients
treated with adalimumab and infliximab had
cancer, but this did not reach statistical
significance. No increased risk of infection or
malignancy was found for etanercept compared
with placebo.
Combination of TNF inhibitor plus
methotrexate versus methotrexate
Volume of evidence
Four trials compared a TNF inhibitor (at licensed
dose) combined with methotrexate to methotrexate
alone in patients naïve to, or who had not
previously failed methotrexate: PREMIER 102
(n = 525) for adalimumab; TEMPO 127 (n = 459)
for etanercept; ASPIRE 135 (n = 665) for infliximab;
Quinn 2005 141 (n = 20) for infliximab.
Direction of effect
A TNF inhibitor combined with methotrexate was
significantly more effective than methotrexate
monotherapy in controlling RA symptoms,
improving physical function and slowing
radiographic joint damage for all three TNF
inhibitors. Fewer patients on combination therapy
withdrew from treatment, but the difference was
not statistically significant for the infliximab
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