The Skeletal System
Rheumatoid arthritis (RA) is the commonest form of chronic inflammatory
joint disease. In its typical form RA is a symmetrical, destructive and
deforming polyarthritis affecting small and large peripheral joint with
associated systemic disturbances, a variety of extra-articular features and
the presence of circulating autoantibodies that target the Fc portions of
normal IgG antibodies (rheumatoid factors). Rheumatoid factors bind with their
target self-antigens in blood and joint synovial membranes, forming immune
complexes that initiate an inflammatory reaction.
Rheumatoid arthritis occurs throughout the world and in all ethnic groups.
Climate, altitude and geography do not appear to influence its prevalence. The
overall prevalence of RA in Caucasian populations is about 1% with female to
male of 3:1. The disease starts most commonly between the third and fifth
Although the cause of rheumatoid arthritis remains unknown, there is
increasing evidence that the disease is triggered by T lymphocyte activation
in genetically predisposed individuals with defined HLA Class II tissue types
(HLA-DR4 is the major susceptibility type). However it is not known which
antigen (exogenous or endogenous) initiates and perpetuates the disease, but
certain retroviruses and parvoviruses might be responsible, at least in
initial stages of the disease. Alternatively, it has been suggested that
sensitisation to self antigens could be a consequence of enzymatic or free
radical damage to proteins such as immunoglobulin (IgG) or collagen, which
results in minor structural abnormality.
Whatever the initiating stimulus, RA is characterised by persistent
activation of immune cells and the presence of immune complexes at sites of
articular and extra-articular lesions. Thus rheumatoid arthritis is both an
extravascular immune complex disease and a disorder of cell-mediated immunity.
The severity of tissue damage is related to joint movement and physical stress
as well as the activity of the inflammatory disease indicating that mechanical
factors are also important in its pathogenesis.
The earliest change is swelling and hyperaemia (redness) of the synovial
membrane and the underlying connective tissues, which become infiltrated with
lymphocytes (especially CD4 T helper cells responsible for starting an
inflammatory response), plasma cells and macrophages (macrophages secrete
cytokines such as tumour necrosis factor now through to play an important role
in tissue inflammation). Damage of joint tissues appears to be the result of
action of released lysosomal enzymes from macrophages and neutrophils
Accumulation of inflammatory fluid (exudate) in the joint space takes place
during active phases of the disease. Thickening of the synovial membrane
occurs with the formation of lymphoid aggregates resembling an immunologically
active lymph node. Hyperplastic and oedematous synovial inflammatory tissue
(pannus) is formed, spreading over and under the articular cartilage, which is
progressively eroded and destroyed, but some damage of articular capsule and
ligaments also occurs. Later, fibrous adhesions may form between the layers of
pannus across the joint space. These adhesions can undergo partial
calcification eventually forming fibrous or bony ankylosis (joint immobility).
Clinical features: < BACK TO TOP >
- In the majority of patients the onset is insidious with joint pain,
stiffness and symmetrical swelling f a number of peripheral joints, usually
first small joints of the fingers and toes.
- Swelling of proximal, but not distal, interphalangeal joint gives the
fingers a characteristic 'spindled' appearance, and swelling of the
metatarsophalangeal joints results in 'broadening' of the forefoot (patients
may need to buy bigger shoes).
- Rest pain in the joints and especially early morning stiffness are
characteristic features, and the pain seems to improve on joint movement
(exercise or mild work).
- In time the disease spreads to involve the wrists, elbows, shoulders,
ankles, knees, other foot joints, cervical spine with neck pain and
- The temporomandibular, acromioclavicular and sternoclavicular joints are
sometimes involed, hip joints also but only in very advanced disease.
- As the disease advances tendon sheath and joint destruction result in
limitation of joint motion with consequent muscle atrophy, instability,
subluxation (incomplete dislocation) and deformities such as very
characteristic ulnar drift (deviation) of the fingers.
- Hyperextension of the proximal interphalangeal joint with fixed flexion at
the distal interphalangeal joint leads to 'swan neck' deformity.
- Fixed flexion of the proximal interphalangeal joint and extension of the
distal interphalangeal joint forms 'button-hole' (boutonniere) deformity.
- In the foot hyperextension of the toes ('clawing') develop as well exposed
metatarsal heads with a painful sensation of 'walking on pebbles'.
- Subcutaneous rheumatoid nodules develop in 20% of patients at sites of
pressure or friction such as dorsal side of the hands, elbow area, sacrum
and Achilles tendon: they are composed of central area of tissue necrosis
surrounded by the layers of lymphocytes and connective tissue.
- Extra-articular features are various: fever, weight loss, fatigue,
susceptibility to infection, muscle wasting, tenosynovitis, osteoporosis,
anaemia, lymphadenopathy, splenomegaly, episcleritis and
keratoconjunctivitis, peripheral vasculitis, pericarditis, myocarditis,
conduction defects in the heart (various types of heart block), pleurisy
with pleural effusions and peripheral neuropathy (the patient may complain
of burning sensation or numbness).
- Characteristically the course of the disease is prolonged with
exacerbations and remissions, but resulting in significant disability in
Diagnosis: < BACK TO TOP >
- Diagnosis of rheumatoid arthritis can be established if any four or more
of the follwing criteria are identified:
- morning stiffness lasting more that 1 hour (duration of six weeks or
- arthritis f 3 or more joint areas - polyarthritis (duration of six weeks
- arthritis of hand joints (duration of six weeks or more)
- rheumatoid subcutaneous nodules
- positive rheumatoid factor
- characteristic X ray changes (loss of bine cartilage, bone erosions,
subluxations, deformations, ankylosis)
- Markers of active inflammatory disease in blood are important supportive
- normochromic-normocytic anaemia of chronic disease (not iron
- thrombocytosis (increased platelet count)
- increased erythrocyte sedimentation rate (found in 90% of cases)
- C reactive protein (more sensitive than ESR) which is an abnormal
protein produced in the liver, that resembles immunoglobulins in
- Serological tests can detect rheumatoid factors by testing the ability
of the patient's serum to agglutinate certain carrier particles coated
with IgG, and they readily demonstrate IgM rheumatoid factors (IgM
molecules are composed of 5 units that can bind different particles).
- Polystyrene plastic beads coated with human IgG are used in the latex
fixation test and IgM rheumatoid factors readily agglutinate these
- Sheep or human erythrocytes coated with rabbit anti-erythrocyte
antibodies are used in the Rose Waaler sheep-cell agglutination test
(SCAT) and the human erythrocyte agglutination test (HEAT).
- The latex fixation test is simple and sensitive but less specific so
that it is frequently used as a screening test. The erythrocyte tests
are less sensitive but more specific to rheumatoid arthritis, and
therefore are carried out after the latex test has returned a positive
- The agglutination tests are positive in 70% of patients with
rheumatoid arthritis but may not become so for 1-2 years, However,
positive tests are also found in other autoimmune diseases (e.g.,
systemic lupus erythematosus) and chronic infections (e.g., chronic
- Rheumatoid factor, including IgG type, can be identified by
nephelometry technique that measures the turbidity of the patient's
serum after IgG has been added that serves as an antigen (turbidity is
due to formed immune complexes).
- Up to 30% of patients with RA have positive tests for antinuclear
factor (antibodies against various nuclear components), which is more
commonly associated with systemic lupus erythematosus.
Management < BACK TO TOP >
- Because the aetiology of rheumatoid arthritis is unknown the treatment is
empirically directed towards relief of symptoms, suppression of active and
progressive disease and conservation and restoration of function in affected
- This can be achieved by combining treatment of the patient (drugs, rest,
physiotherapy, surgery) with modification of the environment (appropriate
aids, appliances, housing, occupation, statutory social benefits etc).
- NSAIDs (non-steroidal anti-inflammatory drugs) provide important
symptomatic relief but they do not appear to alter the lomg-term course of
the disease. Drugs commonly given are ibuprofen [Brufen, Nurofen],
ketoprofen [Orudis, Oruvail], naproxen[Naprosyn, Naprogesic], indomomethacin
[ Indocid], piroxicam [Feldene], diclofenec [Voltaren], tenoxicam [Tilcotil].
- Currently available NSAIDs frequently cause side effects such as
gastrointestinal disturbances, bleeding or even peptic ulcer disease, and
impairment of kidney function known as analgesic nephropathy (roughly in 25%
of treated patients).
- New NSAIDs such as celecoxib [Celebrex] have highly selective anti-COX-2
activity (most NSAIDs mentioned earlier block both types of cyclo-oxygenase
COX-1 and COX-2) and much less incidence of gastrointestinal and renal side
effects have been approved.
- Recent studies have suggested that more aggressive therapy started early
can delay the crippling portion of rheumatoid factor and has been diagnosed
as new rheumatoid arthritis, the drug of choice currently may be immuno-suppressive
drug methotrexate [Methotrexate, Ledertrexate, Methoblastin], usually once a
week, when a response occurs in about 1 month.
- Recently a new immunosuppressive/immuno modulatory drug leflunomide [Arava]
has been approved for treatment of rheumatoid arthritis. It is gived orally
once a day and its results are comparable to methotrexate, although it
appears to be better tolerated.
- Other drugs that might be considered are:
- oral and parenteral gold compounds such as auranofin [Ridaura],
aurothioglucose [Gold-50] and autothiomalate [Myocrisin]
- immuno-suppressant azathioprine [Imuran]
- penicillamine [D-Penamine]
- corticosteroid drugs in low doses, usually prednisolone [Delta-Cortef,
Panafcortelone, Solone] or prednisone [Panafcort, Sone]
- sulfasalazine [Salazopyrin]
- Recently monoclonal antibodies against TNF (tumour necrosis factor)
such as etanercept and infliximab have been approved for in USA (not yet
available in Australia) and they act as anti-inflammatory agents (given
Prognosis < BACK TO TOP >
- The course and prognosis in rheumatoid arthritis is very variable. Review
after ten years show that:
- 25% will have almost complete remission of symptoms and remain fit for
all normal activities.
- 40% will have only moderate impairment of function despite
exacerbations and remissions of disease
- 25% will be more severely disabled.
- 10% will be severely crippled
- A poor prognosis may be associated with:
- high concentrations of rheumatoid factor
- insidious onset of disease
- more than a year active disease without remission despite treatment
- early development of subcutaneous and bone erosions
- extra articular manifestations
Juvenile Rheumatoid Arthritis
Juvenile rheumatoid arthritis is similar to adult RA. There
are three main clinical patterns:
- Systemic onset (also known as Still's disease) occurs in about 20%
of patients with high fever, macular rash (usually seen when fever is
present), splenomegaly, generalised lymphadenopathy, pleurisy, pericarditis,
with myalgia, arthralgia and eventually polyarthritis. This pattern most
common between the ages of 1 and 5 years. There is usually weight loss and
retardation of growth. Rheumatoid factor and antinuclear antibodies are
- Pauciaticular onset occurs in about 40% of patients, usually young
girls, involving four or less joints and usually no systemic features.
Antinuclear antibodies are found in up to 75% of affected children.
- Polyarticular onset occurs in the remaining 40% of patients and
often is similar to adult RA Rheumatoid factor is usually negative, but in
adolescent girls it can be positive.
The overall prognosis for juvenile rheumatoid arthritis is generally better
than for adult one, with complete remissions developing in 50-75% of patients.
Patients with polyarticular onset and positive rheumatoid factor have less
Therapy is similar to adult RA. Various non-steroidal anti-inflammatory
drugs are given, but in contrast to adult RA corticosteroids are reserved for
children with severe systemic disease only. Immunosuppressants may be
necessary for managing more serious polyarticular disease. Other measures such
as hydrotherapy in a warm pool, exercises, and other physiotherapy measures
are also useful.
Dr Zoran Pletikosa)