A systematic review of the effectiveness of adalimumab

combination, which was associated with nearly a
three-fold increase in withdrawal owing to adverse
events (RR 2.99, 95% CI 1.49 to 6.03) and serious
infections (RR 2.74, 95% CI 1.12 to 6.70).
Adalimumab combined with methotrexate was
associated with a slight, but significant increase in
[Commercial-in-confidence information
removed]. Risks of serious infection (RR
[Commercial-in-confidence information
removed]) and withdrawal owing to adverse events
(RR = 1.62, 95% CI 0.94 to 2.77) were also
increased, compared with methotrexate alone, but
these did not reach statistical significance. No
significant differences in safety outcomes were
found between etanercept combined with
methotrexate and methotrexate alone. More
malignancy occurred in the combination group
but this did not reach statistical significance. All
three TNF inhibitors, when combined with
methotrexate, showed a trend towards increased
SAEs, but again this was not statistically
significant.
Additional information on effectiveness
and safety
This section summarises additional evidence that
is not included in the meta-analyses. Information
cited in this section is collated from FDA reports,
published reviews and observational studies,
summaries of product characteristics, and
submissions from the BSR and manufacturers of
TNF inhibitor to NICE. Lack of appropriate,
unbiased comparison groups is a major problem
for the validity of comparative results from
non-RCTs. This should be borne in mind
when interpreting observational data. Issues
related to tuberculosis and blood monitoring were
discussed in the section ‘Special precautions for
use of TNF inhibitors’ (p. 9) and are not
described here.
Mortality
Mortality data from long-term follow-up
programmes for patients treated with adalimumab
and etanercept were reviewed by the FDA in
2003. 146 The observed death rates in the follow-up
programmes, adjusted for age and gender, were
lower than would be expected among US general
populations and do not indicate a higher death
rate with TNF inhibitor treatments.
Malignancies including lymphomas
A significant increase in the incidence of
lymphoma compared with the general population
was noted for all three TNF inhibitors in the 2003
FDA review. 146 Controversy remains with regard to
whether the observed higher incidences indicate
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Health Technology Assessment 2006; Vol. 10: No. 42
additional risk due to TNF treatment, or whether
they are in line with the increased risk of
lymphoma observed in RA patients with high
inflammatory activity. 147–151 In general, the
incidence of other types of malignancies in TNF
inhibitor-treated patients was found to be similar
to, or lower than that observed in the general
population 146,152,153 and other RA
populations. 85,151
Congestive heart failure
Adalimumab and infliximab are contraindicated in
moderate to severe heart failure (New York Heart
Association class III or IV). Two RCTs (not
included in this systematic review) that evaluated
the use of etanercept in the treatment of
congestive failure were terminated early owing to
lack of efficacy, and data from one of these trials
suggested a possible tendency towards worsening
of congestive heart failure and increased all-cause
mortality in patients treated with etanercept. 154,155
In another trial that evaluated the use of
infliximab in congestive heart failure, no clinical
benefit was observed and high-dose infliximab
(10 mg kg –1 at 0, 2 and 6 weeks) was associated
with an increased risk for a composite outcome
that included death from any cause and
hospitalisation for heart failure (hazard ratio 2.84,
95% CI 1.01 to 7.97). 156
Pulmonary fibrosis
In an investigation of pulmonary fibrosis and
associated death, BSRBR found that there was a
two- to three-fold increase in mortality for patients
with pulmonary fibrosis at baseline compared with
those without it among all patients (including
TNF-treated and control group) with 6 months’
follow-up data. 85 As the vast majority of the
patients with pulmonary fibrosis at baseline were
in the TNF-treated groups and only one death
associated with pulmonary fibrosis occurred in the
control group, it was not possible to conclude
whether there is a potential association between
TNF treatment and death associated with
pulmonary fibrosis.
Combination of TNF inhibitors with anakinra
Results from an RCT (not included in this
systematic review, see Appendix 3) by Genovese
and colleagues 157 suggest that combination
therapy with etanercept plus anakinra provided no
treatment benefit over etanercept alone, and was
associated with an increased risk of serious
infections (0% for etanercept alone and 3.7–7.4%
for combination therapy). The combination of
TNF inhibitors and anakinra is therefore not
recommended.
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