A systematic review of the effectiveness of adalimumab

10
Background
infliximab if a patient has had an adverse effect to
methotrexate, since the licence for infliximab
stipulates combined therapy with methotrexate.
Physicians also favour drugs with which they are
familiar – etanercept and infliximab have been
around longer than adalimumab – and also based
on their personal experiences, or perceived
efficacy, in individual circumstances. Often a
choice is made for practical reasons such as
convenience of self-administered injections against
a need to attend hospital for intravenous
infusions 80 or the availability of resources to
deliver timely infusions. Preliminary data for
infliximab administered as subcutaneous injections
compared with intravenous infusions have recently
been presented. 81
Patients starting DMARDs are most concerned
about drug toxicity 82 and commonly have a fear of
giving their own injections; but clinical experience
shows that a majority, even those with markedly
impaired hand dexterity, cope very well. Patients
may prefer adalimumab to etanercept, as fewer
injections are needed, and also because
adalimumab is available as a prefilled syringe,
whereas etanercept needs to be prepared from a
powdered formulation. However, a prefilled
syringe of etanercept was approved in the USA
late in 2004, but at the time of writing is not
available in Europe. Personal experience also
suggests that some elderly patients prefer to
receive intravenous infusions rather than
contemplate administrating their own injections.
Current NICE guidance for use of
TNF inhibitors
Treatment of RA with etanercept and infliximab
was considered in a previous NICE appraisal and
the guidance published in 2002 83 mirrors that
proposed earlier by a committee of the BSR. 84 A
brief commentary on aspects of this guidance is
given below.
A key feature of the guidance is a requirement to
register treated patients, with their consent, in a
national register, the BSR Biologics Register
(BSRBR). The aim of the BSRBR is to establish
the long-term safety of a variety of biological
agents (including TNF inhibitors) in adult patients
with RA and other rheumatic diseases. In
particular, the BSRBR is interested in mortality,
malignancy and serious adverse events (SAEs) and
its sample size was based on being able to detect a
two-fold increase in risk of lymphoma over
5 years. There are two cohorts: a group of patients
with rheumatic disorders newly exposed to
biological agents, mainly TNF inhibitors, and a
comparison group with similar disease
characteristics being treated with other nonbiological
DMARDs. It is proposed that patients
are monitored for 5 years or more. 85 The target
for recruiting patients treated with etanercept was
met recently and clinicians are no longer required
to register patients being treated with this drug.
Clinicians have described their difficulties finding
funding for TNF inhibitors and also meeting the
demands of current guidance in terms of BSRBR
registration and patient evaluations. 63
It is recommended that neither etanercept nor
infliximab is used unless a patient has failed to
respond to two DMARDs, including methotrexate.
Other eligibility criteria, dose ranges and desired
duration of previously tried therapies were as
proposed by the BSR. Since 2002 evidence of the
use of TNF inhibitors before other DMARDs has
accumulated and this is considered in this review.
The BSR, in their updated guidance, state that
circumstances leading to first line use of TNF
inhibitors would be rare. 86 Data from the BSRBR
show that the median number of previous
DMARDs used by registered patients was four,
indicating conservative use of these new drugs. 87
The BSR, endorsed by NICE in 2002,
recommended that patients should only be eligible
for TNF inhibitors if they fulfil the 1987 American
Rheumatism Association (ARA) criteria for the
classification of RA. 88 As indicated earlier,
clinicians rarely apply criteria for diagnosis in
practice. Around 10% of patients in the BSRBR
with a clinical diagnosis of RA appeared not to
meet disease classification criteria. 85 The criteria,
especially the list version, have important
limitations. 89 Moreover, patients may take several
years after disease onset to fulfil these criteria, 7
and it is possible that, as TNF inhibitors are used
earlier in disease, some patients suitable for TNF
inhibitors do not meet formal classification
criteria.
Current guidance stipulates that patients should
have active disease determined by a DAS28 of
greater than 5.1 and that disease activity should be
assessed at two time-points 1 month apart, before
therapy. Funding agreements between some
hospital trusts and PCTs require that these
thresholds must be met before funding is agreed.
Inevitably, this influences the DAS scores recorded
in busy clinics. Some argue that it is unreasonable
for patients to have to continue with active disease
for a month, having already tolerated active