A systematic review of the effectiveness of adalimumab

Assessment of response to DMARDs
Remission is not usually achieved in RA, but very
effective disease control is often possible. Modern
clinical trials rely on composite end-points such as
the American College for Rheumatology (ACR)
definition of improvement, preferred in US trials,
and the Disease Activity Score (DAS), preferred in
European studies. The ACR response, for example,
requires an improvement in counts of the number
of tender and swollen joints (using designated
joints) and at least three items from the following:
observer evaluation of overall disease activity,
patient evaluation of overall disease activity, patient
evaluation of pain, a score of physical disability;
and improvements in blood acute-phase responses
[e.g. erythrocyte sedimentation rate (ESR)
or C-reactive protein (CRP)]. Response is defined
as ACR20, ACR50 or ACR70, where the figures
refer to percentage improvement of these
clinical measures. This creates a dichotomous
outcome of responders and non-responders.
Achieving an ACR20 response has been
regarded as a low hurdle, but in clinical practice
patients who achieve this hurdle often gain a
worthwhile clinical improvement, especially in
early RA.
The DAS is calculated using a formula that
includes counts for tender and swollen joints, an
evaluation by the patient of general health (on a
scale of 0–100), and blood acute-phase responses
(usually ESR, but more recently using CRP).
Originally the DAS was based on an assessment of
53 joints for tenderness and 44 joints for swelling.
More recently DAS28, based on an evaluation of
28 joints, has been developed and proposed for
use in routine clinical practice. DAS28, like DAS,
is a continuous scale with a theoretical range from
0 to 10. Thresholds have been suggested for the
scale, such that a score greater than 5.1 is
regarded as indicating high disease activity, a score
of less than 3.2 low disease activity and a score of
less than 2.6 remission (for DAS28). 41,42 It is of
interest that these thresholds were originally
derived from actual decisions by physicians in
practice 43 and are now being proposed as
instruments for decision-making in practice.
Details of both scoring systems are provided in
Appendix 1.
Radiographic outcomes are believed by many to
be the most important outcome measure in RA. It
is acknowledged, however, that variation in joint
inflammation has a more profound and immediate
impact on disability compared with the slow and
cumulative effect of radiographic damage on
disability. 44 The most commonly used tools for
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Health Technology Assessment 2006; Vol. 10: No. 42
assessing joint damage are the Sharp and Larsen
methods and their modifications, which rely on
evaluations of plain radiographs (Appendix 1). As
indicated above, plain radiographs are rather
insensitive to change, but are cheap and widely
available. A majority of patients show only mild or
no progression on plain radiographs over periods
of 1–2 years, highlighting one of their limitations
in modern clinical trials. 45
Prognosis
The impact of RA on an individual can be viewed
from a variety of perspectives, including
employment status, economic costs to the
individual or society, quality of life, physical
disability, life expectancy, and medical
complications such as extra-articular disease and
joint deformity, radiographic damage or the need
for surgery. In general, persistent disease activity is
associated with poorer outcomes, although in the
first 5 years of disease physical function is
especially labile. Greater physical disability at
presentation is associated with greater disability
later in disease. Other factors linked with poorer
function include older age at presentation, the
presence of rheumatoid nodules, female gender,
psychological distress and degree of joint
tenderness. 46,47
Continued employment is related to type of work
and other aspects of the workplace, such as pace
of work, physical environment, physical function,
education and psychological status; work disability
is not necessarily linked to measures of disease
activity. 48,49 Radiographic damage in RA joints is
also influenced by rheumatoid factor status, age,
disease duration, extent of disease, and perhaps
genetic factors. Life expectancy in RA is reduced
and is related to age, disability, disease severity, comorbidity
and rheumatoid factor status, in
particular. 50–53 For example, a 50-year-old woman
with RA is expected to live for 4 years less than
one without RA. 54 This appears to be due,
principally, to increased cardiovascular disease,
particularly in those who are rheumatoid factor
positive.
Burden of illness
Early in disease indirect costs exceed costs due to
healthcare utilisation and medication (direct
costs), by two-fold. 55 It is also clear that informal
caregivers shoulder a considerable burden in
terms of forgone paid employment, leisure activity
and personal health. 56 Inevitably, in a disease
characterised by lifelong pain, discomfort and
physical impairment, the burden on individuals
and families is increased. Recent studies show that
7