A systematic review of the effectiveness of adalimumab

6
Background
greatly, such that some physicians prefer high-dose
oral therapy while initiating a DMARD, 28 others
prefer intramuscular 29 or even intravenous
steroids, others low oral prednisolone given for
prolonged periods 27 (with or without DMARDs)
and yet others may rely on intra-articular therapy
wherever possible. Thirdly, patients with
established RA also differ in their preferences for
how glucocorticoids are used and many,
particularly those experiencing adverse effects
such as weight gain or osteoporosis, prefer to
avoid them altogether.
DMARDs rarely induce complete disease
remission, although effective disease control can
be achieved and may also lead to other benefits
such as reduced cardiovascular mortality. 30 The
mode of action of most DMARDs is incompletely
understood. It is recommended that patients with
active RA should be treated soon after diagnosis
with DMARDs, since delayed use appears to lead
to worse clinical outcomes. 31 This has led to the
concept of a ‘window of opportunity’ in the
treatment of RA; that is, delayed use of DMARDs
reduces the prospect of benefits in the future.
Appropriate concerns have been expressed about
data supporting this idea. 32 Indeed, the ‘window
of opportunity’ concept risks creating a
therapeutic imperative for DMARD use when
clinicians and patients face newly diagnosed
inflammatory polyarthritis: this may be misplaced
since early inflammatory polyarthritis commonly
remits. Thus, careful evaluation and appropriate
clinical judgements are needed in choosing
therapies. 33
Effective disease control with DMARDs commonly
leads to successful withdrawal of NSAIDs,
analgesics and corticosteroids. Some DMARDs,
such as azathioprine and hydroxychloroquine, are
probably less effective than other agents, such as
methotrexate, sulfasalazine and leflunomide.
Toxicity of DMARDs also differs, and each drug
has a specific dosing and monitoring schedule.
Unfortunately, discontinuation of therapy is
common with these agents; for example, the
proportion of people still taking gold after 5 years
is 20%, sulfasalazine 35% and methotrexate 57%. 34
Such data highlight the limitations of the available
agents; that is, relatively short-term drug ‘survival’
for a disease with a lifelong course.
DMARDs may be discontinued because of toxicity,
inadequate disease control, disease relapse, patient
or physician preferences, complicating comorbidity
or a combination of these. Toxicity
varies from relatively minor reactions to life-
threatening events such as bone-marrow
suppression. 35 Hydroxychloroquine and
methotrexate appear to have the most favourable
risk–benefit profile. 36 Methotrexate is widely
regarded as the standard against which other
drugs should be judged, and treatment is more
likely to be sustained with this drug.
DMARDs are used in a variety of ways: several
agents, often with corticosteroids added, may be
combined early in disease (combination
therapy 18,37 ), which may then be continued or
some drugs gradually withdrawn (step-down
treatment 28 ); DMARDs may be used singly and
agents added (step-up); or withdrawn and
replaced (sequential monotherapy), if disease
control is judged to be inadequate. 31,38 In the UK
monotherapy with sulfasalazine or methotrexate,
in newly diagnosed patients, is currently the
preferred initial strategy. Preferred DMARD
combinations include methotrexate and
sulfasalazine given together, or ciclosporin A or
hydroxychloroquine given with methotrexate. 25 It
appears that as successive DMARDs are tried to
control disease the likelihood of sustained drug
use declines, regardless of the choice of initial
DMARD; that is, the second DMARD tried is likely
to be used for a shorter time than the first and the
third shorter than the second, and so on. 26
Patients achieving good disease control, or
remission, with a DMARD are at risk of relapse if
treatment is discontinued, and current guidelines
advocate sustained long-term therapy. 23 Nearly
a quarter of patients on long-term therapy,
however, are consistently non-compliant with
DMARDs. 39
Non-drug treatments
With advanced joint damage surgical intervention
such as joint replacement arthroplasty, joint fusion
or osteotomy may be necessary. Long-term
observations show that around a quarter of
patients with RA undergo a total joint
arthroplasty. 40 It cannot, of course, be assumed
that all such surgery is directly attributable to RA,
especially as osteoarthritis is the most prevalent
form of arthritis. Other surgical interventions,
such as removal of synovial tissues and rheumatoid
nodules, peripheral nerve decompression (such as
in carpal tunnel syndrome), or soft-tissue
procedures such as tendon release or repair may
be necessary at any stage of disease. Patients often
also need advice and support from a
multidisciplinary team, including specialist nurses,
podiatrists, physiotherapists and occupational
therapists in contemporary rheumatology
practice.