A systematic review of the effectiveness of adalimumab

4
Background
Diagnosis may be obvious or may need specialist
assessment or a period of clinical observation.
Internationally agreed classification criteria for RA
are used widely in contemporary research studies.
The most recent criteria require patients to fulfil
four of the following: morning stiffness in joints
exceeding 1 hour, physician observed arthritis of
three or more areas with soft-tissue swelling,
arthritis involving hand joints, symmetrical
arthritis, rheumatoid skin nodules, a positive
blood test for rheumatoid factor and radiographic
changes typical of rheumatoid disease. 6 Such
criteria have limited utility in routine practice and
most clinicians diagnose RA without reference to
them. Indeed, many patients do not meet formal
disease classification criteria, at least early in their
disease. 7,8
Radiographic features of RA
Conventional radiographs may be normal or
may show soft-tissue swelling and reduced bone
density around affected joints, in early RA.
Later, there may be diffuse joint damage,
indicated by narrowing of the joint space, or focal
loss of bone and cartilage at the joint margin,
called erosions. Joint damage is assessed in clinical
trials using scores of both joint space narrowing
and joint erosions. Joint deformity or instability
may occur as damage progresses and in advanced
disease bony fusion occurs. More sensitive
imaging, for example with magnetic resonance
imaging (MRI), shows detailed anatomical and
pathological change. Some studies indicate that
erosions are seen on MRI up to 2 years before they
become visible on radiographs; 9 however, only a
quarter of erosions seen on MRI are eventually
also seen on X-rays. The clinical importance of
some MRI changes is debated but MRI remains,
potentially, an important and sensitive outcome
measure. 10
Epidemiology
RA affects around 0.5–1% of the population,
three times as many women as men, and has a
peak age of onset between the ages of 40 and
70 years. Prevalence of the disease at the age of
65 is six times that at the age of 25 years. Recent
estimates from England and Wales show an
annual incidence of 31 per 100,000 women and
13 per 100,000 men, suggesting a decline in
recent decades and a prevalence of 1.2% in
women and 0.4% in men. 11 There are
approximately 426,800 patients with RA in
England and Wales (population 52,793,000). 12
A primary care trust (PCT) with a population of
half a million, for example, has around
4000 patients with RA.
Aetiology
A specific cause for RA has not been identified; it
appears to have many contributory factors
including genetic and environmental influences.
Genetic influence is estimated at 50–60%. 13 The
occurrence of RA in both of a pair of monozygotic
twins is 12–15% and a family history of RA gives
an individual a risk ratio of 1.6, compared with
the expected population rate. 14 The human
leucocyte antigen HLA-DRB1 of chromosome 6
has been most clearly linked to RA, although this
accounts for less than half of the overall genetic
susceptibility of RA. 15 HLA plays a key role in
immune function and regulation. The only known
function of DR is in presentation of peptides to
T-cells for mounting an immune response to
particular antigens. Rheumatoid factor, an
autoantibody produced by B lymphocytes and
directed against immunoglobulin G (IgG), is also
an important feature of a proportion of patients
with RA and is implicated in disease. 16
Infectious agents have been suspected, but no
consistent relationship with an infective agent has
been shown. Sex hormones have also been
suspected because of the higher prevalence of RA
in women and a tendency for disease to improve
in pregnancy. However, a precise relationship has
not been identified. A causal link with lifestyle
factors such as diet, occupation or smoking has
not been shown.
Pathology
Synovial joints occur where the ends of two bones,
covered with hyaline cartilage, meet in a region
where free movement is desirable. This joint space
is encapsulated by a fibrous capsule lined, on the
inside, by a synovial membrane; which functions to
secrete fluid to lubricate and nourish hyaline
cartilage. The synovial layer of affected joints
becomes enlarged owing to increased cellularity, or
hyperplasia, infiltration by white blood cells and
formation of new blood vessels. This is
accompanied by increased fluid in the joint cavity,
which contains white blood cells and a high level of
protein (an exudate) contributing to the joint
swelling. Bony erosions of cartilage and bone occur
where synovial tissue meets cartilage and bone.
This occurs through the combined actions of
synovial tissue (pannus) and resident cartilage and
bone cells. Erosions, and loss of cartilage, are rarely
reversible. Such damage therefore compromises
the structure and function of a normal joint.
Role of TNF
TNF- and other cytokines such as interferon-,
interferon-, interleukin-1 (IL-1), interleukin-2