Page 18 / SA ORTHOPAEDIC JOURNAL Autumn 2010 CLINICAL ARTICLE
C L I N I C A L A RT I C L E
MMTM Ally MBChB, FCP
Rheumatologist, Department of Internal Medicine, Head: Division of Rheumatology, University of Pretoria
and Steve Biko Academic Hospital
CC Visser MBChB
Rheumatologist, Department of Orthopaedics, Pain Clinic, Steve Biko Academic Hospital
Prof MMTM Ally
University of Pretoria & Pretoria Academic Hospital
Faculty of Health Sciences
School of Medicine
Department of Internal Medicine
Head: Division of Rheumatology
PO Box 667
Pretoria, South Africa
Tel: 27 (0)12 354-2112
Fax: 27 (0)12 354-4168
RA is a chronic inflammatory disease resulting in severe morbidity and premature mortality. This review explores
in a series of two articles, the current developments in the pathogenesis, diagnosis, monitoring and management of
patients with RA. The diagnosis of early as well as established disease is discussed, including the diagnostic crite-
ria. Particular emphasis is placed on the pitfalls and benefits of early diagnosis and early intervention.
Prevention and limitation of comorbidity from the disease is highly important. This can be achieved following a
paradigm shift in RA management. The emphasis is now on early introduction of disease-modifying
anti-rheumatic drugs, including timely use of highly efficacious pharmacological innovations. Side effects,
including peri-operative implications of pharmacological therapy, are discussed.
Current therapeutic strategy to manage this disease should also be applied in resource-poor settings and develop-
ing countries. These therapies are cost effective if used early and judiciously, giving hope to many patients with RA.
Review of the pathogenesis, clinical features, utility of special investigations
and measures of disease activity in patients with rheumatoid arthritis
Introduction Rheumatoid arthritis in the developing
Rheumatoid arthritis (RA) is the commonest type of world
inflammatory arthritis and often has a progressive and A major problem in developing countries is a significant
destructive course. RA not only significantly affects func- delay in the diagnosis of RA and the initiation of appropri-
tion and quality of life, but is also associated with signif- ate treatment. This delay leads to a poor outcome and the
icant comorbidity and premature death. With the revolu- loss of working ability. For instance, in manual labourers,
tionary advances in the development of new and more most patients are unable to work within two years of disease
effective therapies, it is now possible to dramatically alter onset with devastating social consequences.1,2 There is
the course of the disease, especially when treatment is limited data available on the epidemiology of RA in South
started early. This review focuses on the diagnosis of early Africa. A recent review of data from developing countries
RA, assessment of disease activity, and principles of man- suggests a prevalence of approximately 1%, which is simi-
agement. lar to that seen in developed countries.1,3
CLINICAL ARTICLE SA ORTHOPAEDIC JOURNAL Autumn 2010 / Page 19
RA is also associated with an increased risk of infection, Clinical diagnosis
related to both the disease and to immunosuppressive
Early rheumatoid arthritis
therapy. Of particular concern in developing countries are
Early diagnosis and treatment of RA is of paramount impor-
viral hepatitis, HIV and tuberculosis.
tance. The window of opportunity to halt or retard the
inflammatory process is the first two to three years. Studies
Pathogenesis of rheumatoid arthritis have shown that the rate of radiographic progression is the
In recent years tremendous advances have been made in fastest during this window period, with early intervention
the understanding of human immune and inflammatory significantly altering the course of the disease and the
responses in the pathogenesis of RA. However, despite degree of joint destruction in later years.12-14
concerted research efforts, the triggering factor for RA In clinical trials, early RA is often defined as a disease dura-
still remains an elusive mystery. tion of less than two years, but more recent studies have
Genetic factors certainly have a role to play in the patho- been using one year or even six months as a cut-off point.
genesis of RA. The ‘shared epitope’ is a common Presenting symptoms are usually insidious, with arthritis
sequence of amino acids on the HLA-DR4 antigen seen in developing over weeks to months, although an acute onset
the vast majority of patients with RA.4 Certain antigen is seen in up to 15% of patients. Non-specific constitutional
subtypes have been associated with more aggressive dis- symptoms such as fatigue and malaise rather than arthritis,
ease while other subtypes confer a protective effect.4-6 predominate in some patients. Less commonly, extra-articu-
The innate immune system, responsible for the initial lar manifestations such as scleritis, sicca syndrome (dry
non-specific response to foreign antigens, seems to be eyes and dry mouth) and rheumatoid nodules are found,
involved early in RA.7,8 The antigens which trigger the reflecting more aggressive disease.
innate immune system response have not yet been identi- The presence of four or more of the American College of
fied, but probably resemble or mimic synovial tissue anti- Rheumatology (ACR) classification criteria is often used to
gens. Antigen stimulation leads to a cascade of events in diagnose RA.15 These criteria include clinical, serological
a genetically predisposed individual in the presence of and radiological features:
certain hormonal and environmental factors. • Morning stiffness for ≥1 hour
Thereafter, the adaptive immune system (antigen-specific • Arthritis of ≥3 joint areas
immune responses) launches a sustained and specific • Arthritis of wrist/metacarpal phalangeal/proximal
attack on synovial tissue, which is now perceived as ‘for- interphalangeal joints
eign’. • Symmetric arthritis
The immune response leads to the characteristic histo- • Rheumatoid nodules
logical features of RA. This is characterised by synovial • Serum rheumatoid factor (IgM)
proliferation, new blood vessel formation and infiltration • Radiographic changes: peri-articular osteopaenia, mar-
of the synovium by T-cells, B-cells, macrophages and ginal erosions
fibroblasts. This process is eventually followed by local
joint destruction.9 New criteria currently under review
The inflammatory infiltrate secretes numerous Newer diagnostic methods such as magnetic resonance
cytokines, of which TNF-α, IL-1 and IL-6 are the pivotal imaging (MRI), ultrasound and the cyclic citrullinated pep-
cytokines in the pathogenesis of RA. Cytokines are gly- tide (CCP) antibody tests have become available increasing
coproteins that act via cell surface receptors to regulate the sensitivity and specificity of diagnosing RA, especially
cellular function by either promotion or suppression of in early disease.15-20 It is important to look for features that
inflammation. This balance between pro-inflammatory would suggest persistent inflammation or erosive disease
versus anti-inflammatory cytokines is disturbed in RA. (Table I).
Cytokines are also responsible for local and systemic Synovitis may be subtle, with only mild joint swelling, a
effects seen in RA. TNF-α plays an important role in syn- soft ‘doughy’ feel and tenderness along the joint line. It
ovial proliferation and activation of osteoclasts resulting commonly involves the wrist, metacarpophalangeal (MCP),
in erosive joint destruction and functional impairment.9
The systemic effects include not only extra-aerticular dis-
ease but accelerated atheroscelerosis and consequent Table I: Risk factors for persistent inflamma-
increased cardiovascular morbidity and mortality. tion or erosive disease18,21
Cytokines such as TNF-α, IL-1 and IL-6 have become
important targets in the management of RA. Other new • Morning stiffness > 30 minutes
treatment modalities target B-cell depletion and inhibition • Metacarpal or metatarsal squeeze tenderness
of T-cell stimulation.10,11 There may possibly be a role for
• Arthritis of three or more joint areas
bisphosphonates to prevent erosive disease by inhibiting
• Symmetrical arthritis
• Radiographic erosions
Page 20 / SA ORTHOPAEDIC JOURNAL Autumn 2010 CLINICAL ARTICLE
proximal interphalangeal (PIP), knee and metatarsopha- Lower limb
langeal (MTP) joints. Clinicians should be aware that ini- • Hip: This joint is less frequently involved, and is
tially the joint involvement can be asymmetrical. classically associated with axial migration of the
Other possible differentials in the diagnosis of patients femoral head. This can be complicated by protrusio
with early arthritis need to be considered. Features such as acetabuli.
Raynaud’s phenomenon, malar rash, photosensitivity, oral • Knees: The knees are commonly involved in RA.
ulceration, alopecia and dysphagia may suggest an underly- Progressive disease often results in fixed flexion
ing connective tissue disorder. deformities, varus or valgus angulation. Synovial or
Baker’s cysts may also develop. If these cysts rupture,
Established rheumatoid arthritis they can cause severe pain and swelling of the calf and
With progressive disease, typical articular and extra-articu- resemble a deep venous thrombosis.
lar manifestations develop. • Ankle and foot: Involvement of the ankle is less com-
mon than hindfoot and midfoot arthritis, which often
Articular manifestations leads to pronation and valgus deformity of the hind-
The articular deformities result as a consequence of both the foot.22 Classical forefoot changes include hallux val-
synovitis, as well as bony, ligament and tendon pathology. gus, lateral deviation and upward subluxation of the
These deformities are especially distinctive in the hands and second to fifth toes. MTP subluxation leads to painful
feet. pressure areas over the metatarsal heads and may be
complicated by protrusion of the metatarsal heads
Upper limb through the plantar skin.
• The hand: Involvement predominantly involves the
MCP and PIP joints, resulting in the classical rheuma- Other
toid swan-neck deformities, boutonniere deformities or • Cervical spine: Involvement is often asymptomatic
Z-deformities of the thumb. Palmar subluxation and and should be suspected in all patients with erosive
ulnar deviation of the fingers occur at the MCP joints. If disease in the hands, as this correlates with cervical
the finger deformities are reducible, the possibility of involvement. Rarely patients may present with fea-
systemic lupus erythematosus should be considered. tures of vertebro-basilar insufficiency related to
Severe erosive disease and resorptive changes of the increased tortuosity of the vertebral arteries. Tilting of
phalanges result in the telescoping digits seen in arthri- the head to one side may occur and is a result of col-
tis mutilans. With more aggressive treatments, arthritis lapse of the lateral mass of C1. Basilar invagination
mutilans is now seen far less frequently. and C1-C2 subluxation are serious complications that
Tendon ruptures may be caused by pressure or friction could result in severe cord impingement or sudden
over bony prominences, or by weakening of the tendon death.23
due to tenosynovitis. Triggering of fingers may be relat- • Cricoarytenoid joint: Involvement is seen in 30% of
ed to either tenosynovial fibrinous thickening or to nod- patients and usually presents with hoarseness or local
ule formation within the tendon. discomfort. Very rarely it may be associated with res-
Radial deviation and palmar subluxation are character- piratory symptoms.
istic features in the wrist. The presence of a ballottable • Temporomandibular joint: Radiological involvement
ulnar styloid prominence is known as the ‘piano key is seen in almost 80% of patients with RA and is clin-
sign’, an important risk factor for extensor tendon rup- ically involved in approximately 50% of patients.
ture.15 • Ossicles in the ear: Erosive disease and shortening of
• Elbow: Involvement results in limitation of extension, the ossicles may result in conductive hearing loss
pronation and supination. Olecranon bursitis may occur, • Sternoclavicular and manubriosternal joints: These
but this can also occur with gout, trauma or infections. joints are commonly involved but often asympto-
• Shoulder and acromioclavicular joint: These joints are matic.
commonly involved in RA. Bursal involvement may
cause impingement of the rotator cuff and could con- Extra-articular manifestations
tribute to the typical resorption of the distal clavicle. Extra-articular manifestations are associated with a poor-
Rotator cuff tendinitis or tears can eventually lead to er prognosis. Nodules typically occur over the extensor
rotator cuff arthropathy. areas of the forearm but could also be seen in other areas
such as the ischial and sacral prominences, finger joints,
Achilles tendon and the occipital region. Nodules may
also occur in the larynx, heart, lungs and sclera.
Other possible differentials in the diagnosis of
Interestingly, although methotrexate is used to treat RA, it
patients with early arthritis need to be considered
may cause rapid development and growth of nodules that
affect the digits in particular.24,25
CLINICAL ARTICLE SA ORTHOPAEDIC JOURNAL Autumn 2010 / Page 21
Ocular involvement occurs mostly secondary to There are numerous chronic infective and inflammatory
Sjögren’s syndrome and presents with dry eyes and causes of false positive results. There is no need to repeat
mouth. Episcleritis is usually noninflammatory; it mani- the test once positive, as it has no role in the monitoring
fests as patchy scleromalacia, with scleromalacia per- of disease activity.
forans a rare complication.
Pleural effusion is the most common lung manifestation, Cyclic Citrullinated Peptide Antibodies (CCP)
with an exudative effusion typically low in glucose. The recent identification of an antibody to a chemically
Interstitial lung disease is seen in a third of patients but altered synovial protein (a process called citrullination)
may also be a complication of therapy. In patients with has increased the sensitivity and specificity of diagnosing
occupational exposure to coal mining, development of RA, especially if used in combination with the rheuma-
pulmonary nodulosis is known as ‘Caplan’s syndrome’. toid factor. This antibody has been implicated in the pos-
Anaemia related to chronic disease is common in sible aetiology of RA, especially in smokers. Smoking in
patients with active disease. Iron deficiency anaemia may patients with the HLA-DR4 antigen seems to act as an
result from gastrointestinal bleeding related to nons- important risk factor for citrullination of synovial protein,
teroidal anti-inflammatory drugs (NSAIDs). The presence thus resulting in anti-CCP antibodies. These antibodies
of leg ulcers, splenomegaly or leucopaenia may signify have been found in patients preceding the onset of RA
Felty’s syndrome. This is seen in about 1% of patients and and may have a predictive role. As with RF, the presence
is characterised by severe articular and extra-articular of CCP antibodies has been shown to be associated with
involvement. a poorer prognosis.16,17
Structural cardiac disease is not common. However, RA The presence of both RF and CCP have a specificity of
is associated with a significantly increased risk for car- >98% for the diagnosis of RA.
diovascular morbidity and mortality, similar to that seen
in type 2 diabetes. Inflammation is now considered an
important independent risk factor for atherosclerosis, with Imaging
studies in RA showing a significant relationship between
CRP and cardiovascular disease.26-29 This risk for acceler-
Plain X-rays are usually normal in early disease, but can
ated atherosclerosis emphasises the need to manage the
be useful if characteristic marginal erosions are seen,
whole patient, to look for traditional risk factors of car-
sometimes as early as three months after the onset of dis-
diovascular disease, and also to control the inflammatory
ease (only 10% of patients). Most patients (70%) develop
erosive disease within three years, most commonly in the
RA patients are at increased risk of malignancy, with a
feet. Positive RF and baseline radiographic score are the
two- to three-fold increase in susceptibility to develop
best predictors of radiographic progression. Juxta-articu-
lymphomas.30 With the advent of newer therapies, partic-
lar osteopaenia, often regarded as an early feature of RA,
ularly TNF-α blockers, theoretical concerns were raised
has been shown to be unreliable in longitudinal studies
that this risk would increase but these concerns have not
involving multiple centres. Numerous different scoring
been validated to date. Atypical presentations or onset in
systems exist, with the Larson and Sharp scores used in
the elderly could be a paraneoplastic manifestation of an
most clinical trials.33
Special investigations Musculoskeletal ultrasound allows for real-time evalua-
General tion of joints and has become a useful extension of the
Acute-phase markers like the erythrocyte sedimentation clinical examination. Synovitis and effusions are readily
rate (ESR) and C-reactive protein (CRP) may be normal seen and Doppler ultrasound measurement of vascular
in early RA. If the CRP is elevated together with anaemia flow can be used to assess severity of the inflammation
this usually signifies a poorer prognosis. and to monitor treatment response.19 Erosions can be
detected earlier on ultrasound than on plain X-rays but
Antibodies this modality is very operator-dependent.
Rheumatoid factor (RF)
As RA is an autoimmune disease, the presence of circulat- Magnetic resonance imaging
ing antibodies may assist with the diagnosis. RF is an anti- Magnetic resonance imaging (MRI) is more expensive
body against the Fc component of immunoglobulins. Its and not as readily available as ultrasound. Extremity MRI
presence is associated with a poorer prognosis.16,17 RF is not units will make musculoskeletal MRI more accessible in
essential for the diagnosis of RA, as around 40% of patients future. MRI provides an objective and sensitive tool to
test negative in early disease. About 20% of patients detect synovitis, effusions, erosions and bone marrow
remain negative throughout the course of their disease. inflammatory changes consistent with RA.19,20
Page 22 / SA ORTHOPAEDIC JOURNAL Autumn 2010 CLINICAL ARTICLE
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SA O RT H O PA E D I C S J O U R N A L
( PA S T AND PRESENT)
Ally M Prof Erasmus P J Dr Lukhele M Prof Snowdowne R B Prof
Biddulph S Prof Erken E H W Prof Malan M M Dr Snyckers C Dr
Birkholtz F F Dr Erlank E Dr Marais K Dr Snyckers H M Dr
Bosman M Prof Ferreira A P Dr Maraspini C Dr Sparks L T Dr
Burger D Mnr Ferreira M Dr Maritz N G J Prof Stiglingh W Dr
Close V M Dr Flemming J Prof Mennen E Dr Swart J Prof
Coetzee C Prof Frantzen D J M Dr Mennen U Prof Sweet M B E Prof
Coetzee E Dr Franz R C Prof McCarthy E Dr (USA) Theron F de V Dr
Colyn H J S Dr George J A Prof Molteno R G Dr van der Westhuizen J Dr
Conradie A Dr Goga I E Prof Motsitsi N S Dr van Niekerk J J Dr
Daneel P J Dr Golele R Prof Muller E W Dr van Papendorp D Prof
de Beer G J E Dr Govender S Prof Myburgh J G Dr van Wingerden J Dr
de Beer J F Dr Gräbe J C Dr Naude M C Dr van Wyk L Dr
de Beer M A Dr Gräbe R P Prof Olivier C J Dr van Zyl A A Dr
de Jongh A G V Dr Grobbelaar C J Dr Peach A Dr Venter J A Dr
de Kock W J Dr Hastings C J Dr Pelser E Dr Venter P J Dr
de la Harpe A Dr Hoffman T B Prof Pettifor J M Prof Vermaak H Prof
de Lange L J Dr Hough S Prof Potgieter D Dr Visser C C Dr
de Vos J N Dr Janse v Rensburg Prof Potgieter J Dr Vlok G J Prof
Dove M G Prof Koekemoer D Dr Pretorius J A Dr Wade W J Dr
Dreyer G Prof Kohnke W Dr Rasool M N Dr Walters J Prof
du Plessis D C Dr Kruger J Dr Rösch T G Dr Webber L Prof
du Plessis D Prof Lautenbach E E G Dr Schepers A Dr Weber F A Dr
du Toit G T Dr Le Roux T L B Prof Schnitzler C M Prof Zondagh I Dr
Dunn R N Dr Lindeque B G P Prof Shipley J A Prof
Eisenstein S Prof Louw J A Dr Smit J P J Dr