A systematic review of the effectiveness of adalimumab

(IL-2) and interleukin-6 (IL-6), produced by
macrophages and activated lymphocytes,
promote inflammation. In early RA TNF- is
expressed in abundance in synovial tissues and,
locally, promotes growth of new blood vessels,
orchestrates inflammation and other cytokine
production, and induces migration of white blood
cells into the joint, which release potentially
harmful enzymes. Systemically, TNF- is an
important mediator of cachexia, fever, bone
resorption and cardiovascular collapse (as in septic
or endotoxic shock).
TNF- has a half-life of a few minutes and its
production can comprise as much as 1–2% of
protein released by activated macrophages. Newly
produced TNF- spans the cell membrane and
may be active in this membrane-bound form,
especially in T lymphocytes. More usually, TNF-
is released as a soluble molecule by cleavage of the
intracellular tail by an enzyme known as TNF-converting
enzyme (TACE). 17 Three soluble
molecules combine together, forming a trimer,
and signal to cells by binding to one of two
possible cell receptors: a 55-kDa (TNF-R1) or a
75-kDa TNF (TNF-R2) receptor. Receptor binding
induces a pair of receptors to combine and
triggers biological activity. TNF- has a greater
affinity for TNF-R1 than for TNF-R2; the latter
appears to capture TNF- and pass it on to TNF-
R1. Mice lacking TNF-R1 have poorly developed
lymphoid organs, are highly susceptible to
infection by mycobacteria and Listeria
monocytogenes, and are particularly prone to
chronic inflammation and to endotoxic shock
induced by TNF-. Expression of TNF-R2 is
restricted to endothelial cells (lining cells in blood
vessels) and white blood cells. TNF-R1 is
expressed by virtually all cell types. 18
The extracellular sections of TNF receptors on
cells are shed by proteolysis and these soluble
TNF receptors (sTNFRs) are natural inhibitors of
TNF and a means of regulating TNF- activity, 19
although it has also been suggested that sTNFRs
stabilise circulating TNF- and function as TNF
agonists. Levels of sTNFR are raised in RA and
other conditions causing inflammation. Defective
shedding of the TNF-R1 can be caused by rare
autosomal recessive gene defects; known as
familial periodic syndromes or TNF-receptorassociated
periodic syndromes (TRAPs). People
with these conditions experience episodic fever,
inflammation and deposition of amyloid but may
also have a survival advantage in terms of a more
effective host defence against certain bacterial
infections. 20,21
© Queen’s Printer and Controller of HMSO 2006. All rights reserved.
Health Technology Assessment 2006; Vol. 10: No. 42
Goals of management
Physicians treating RA aim to control symptoms of
joint pain and stiffness and to minimise loss of
function and improve the quality of life of their
patients. Reducing the risk of disability associated
with joint damage and deformity and treating any
extra-articular manifestations are also key
objectives. Since RA is a heterogeneous disease,
which may vary over time, a long-term plan with
regular clinical evaluation to assess disease status,
co-morbidity, patient preferences and psychosocial
factors is essential, and is aided by well-informed
and satisfied patients and carers. 22,23
Current drug therapy for RA
Non-steroidal anti-inflammatory drugs (NSAIDs)
and analgesics are commonly used for symptom
relief in RA. These drugs do not modify the
disease process and, in severe disease, are often
insufficiently effective for symptom control.
Corticosteroids may produce dramatic and rapid
improvements in RA symptoms, including
systemic features such as fatigue and weight loss,
and may be given by mouth, as intramuscular
injections, intravenously or as joint injections.
Steroid injections provide only short-term benefits,
but oral steroids may provide prolonged benefits.
In clinical practice a significant proportion of
patients take steroids for years and experience
difficulty when therapy is withdrawn.
Some RA patients are managed solely with oral
steroids, NSAIDs and analgesics, in varying
combinations. Corticosteroids are also commonly
used for short-term management of acute
symptoms, or as bridge therapy, to allow rapid
control of disease while awaiting the effects of
slower acting drugs such as DMARDs, which
reduce the risk of joint damage. Drugs used
commonly in the UK and regarded as DMARDs
include azathioprine, etanercept, ciclosporin A,
hydroxychloroquine, infliximab, leflunomide,
sulfasalazine, methotrexate and injectable
gold. 24–26
Glucocorticoids may be regarded as DMARDs, as
their use appears to reduce the risk of joint
damage. 27 Steroids were not included in the
baseline clinical pathway of the economic model in
this review, for the following reasons. First,
glucocorticoids are used widely as an adjunct to
other antirheumatic therapy whether that
therapy includes conventional DMARDs or TNF
inhibitors. For example, in clinical trials in
established RA 50% or more of adalimumab- or
placebo-treated patients were on glucocorticoids.
Secondly, practice with regard to steroid use varies
5