Rheumatoid Arthritis

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Most common inflammatory joint disorder primarily characterised by symmetrical polyarticular synovitis. Affects up to 1-2% of population (incidence fairly similar globally, but China lower and Pima Indians in Arizona are higher). F 2-3x > M. Onset any age – more common 25 to 50 years (peak age of onset is 35-45 years). Associated with reduced life expectancy and increased disability. Generally considered as a systemic disease – but, in the early stages it is only an articular disease, with the systemic extra-articular manifestations not developing until late in the disease.

Unknown – probably multifactorial  inappropriate inflammatory response. Genetic predisposition (HLA-DR4 antigen increases risk by 5x)– localised to a pentapeptide in HLA-DRB1. Environmental agents, such as infectious agents (eg parvovirus, Mycoplasma, retrovirus, Epstein-Barr virus) may play a role in initiating immune response.

Other possible environmental risk factors include lower educational levels; cigarette smoking; psychological factors (eg emotional trauma); joint trauma. No relationship has been found between the risk of developing rheumatoid arthritis and diet or silicone breast implants.

Appears to be a negative association between gout and rheumatoid arthritis. A higher incidence in females may suggest role played by the sex hormones. Most females report a relief of rheumatoid symptoms during pregnancy.

Inciting agent activates immune system  immunological reactions  immune complexes in synovial fluid activate complement  inflammatory response  joint destruction.

Earliest change is inflammation and oedema of synovium with increased vascularity and increased production of synovial fluid – shows evidence of CD4+ T helper cells migrating into the joint. Next the synovial villi hypertrophy, synovial cells proliferation, increased vascularisation (angiogenesis) and pannus form (granulation tissue that grows across surface of articular cartilage from adjacent synovium). This is followed by destruction of cartilage by pannus – mediated by pro-inflammatory cytokines (eg TNF-alpha, interleukin-1-beta, interferon-gamma) and metalloproteases (eg collagenases). The muscles waste around the joint, hyperaemia develops and the joint capsule is distended. There is also destruction of unprotected bone at joint margin and subchondral bone by pannus, later leading to marked joint damage and capsular laxity, leading to deformity and fibrous ankylosis and eventually bony ankylosis of the joint.

Clinical features:
Early diagnosis crucial due to shift to earlier use of disease modifying drugs.
Onset insidious in 60-70% – sometimes abrupt with multiple joint involvement.
Often begins with insidious ache and morning stiffness (>30 mins)  gets better with motion; ‘Gel phenomenon’ – stiffness/ache after rest (due to accumulation of oedema fluid within tissue during rest/sleep). Most common presentation  polyarticular and symmetric – especially of small joint of feet and hands. Tenderness in all joints affected. Early afternoon fatigue and malaise also occur. Hands may be ‘puffy’. May be some slight muscle wasting around joints early.
Forefoot is presenting sight of symptoms in up to 20% (morning pain; pain when walking; pain on palpation) - but initial symptoms in this area may be more common, but tolerated by patients and they may not present until other symptoms (eg fingers) occur.
The early symptoms prior to diagnosis may be ‘normalised’ by the patients as being part of their age and activities and not part of a disease – 70% of patients with rheumatoid arthritis have been shown to do this – most also responded to their initial symptoms by taking no action or using self-treatment.

Typical radiographic changes in synovial joints are symmetrical – initially get soft tissue swelling and widening of joint space with some osteoporosis. Later get periarticular (juxta-articular) osteoporosis and uniform narrowing of joint space (as cartilage is destroyed), marginal cortical bone erosions (due to pannus destruction), subchondral bone erosions and cysts form, subluxations. In end stages may get bony ankylosis. Changes often first seen in fifth metatarsophalangeal joint.
Evidence of erosive damage to bone is seen in 45% patients on MRI within 4 months of symptom onset and 75% with 2 years .

Atypical initial presentations:
• rapid acute onset in 10-15% (usually in older age groups)
• systemic onset (non-articular features are predominant early)
• resembling polymyalgia rheumatica (but not as responsive to corticosteroids)

Later extra-articular involvement: Weight loss; malaise and fever; lymphadenopathy; skin (nodules – in 20%, at periarticular positions subject to high external pressure; inflammatory granulomatous lesions; vasculitis); eye (keratoconjunctitis, scleritis, episcleritis); respiratory (pleurisy, pleural effusions, interstitial/pulmonary fibrosis, rheumatoid nodules, bronchiolitis); cardiac (pericarditis, myocarditis, endocarditis, valvular heart disease); gastrointestinal (adverse effects from drugs); renal (amyloidosis, drug induced nephropathy, renal tubular acidosis); neurologic (entrapment syndromes – especially carpal tunnel, peripheral neuropathy from vasculitis – sensory and motor, mononeuritis multiplex); haematologic (anaemia, leucopoenia, lymphoma, thrombocytosis). Extra articular involvement is more likely in those who have RF factor and/or are HLA-DR4 positive.

Typical hand deformities (have significant impact on ADL’s) - fusiform swelling (PIP joint synovitis  spindle shape to fingers); Boutonniere deformity (PIP flexion and DIP hyperextension); Swan-neck deformity (flexion contracture of MCP with PIP hyperextension and DIP flexion); ulnar/lateral deviation of fingers. All these will affect foot hygiene and self-management ability.

Typical cervical spine involvement – up to 40% get atlantoaxial subluxation of C1-C2 with up to 20% having subaxial involvement.

Felty’s syndrome – more severe variant of rheumatoid arthritis with more sever extra-articular features, predominantly splenomegaly and granulocytopenia (these may precede arthritis); develops in 1-3% of those with RA; may be associated with chronic leg ulcers, bacterial infections (due to granulocytopenia) and a hyperpigmented skin; most are HLA-DR4 positive; F>M; joint damage is more severe.

Laboratory findings of RA:
Lab tests are not diagnostic.
• Blood – increased ESR in 90%; normochromic normocytic anaemia
• Synovial fluid – during active joint inflammation  cloudy, sterile, reduced viscosity, and increased white blood cells.
• Rheumatoid factor – present in 75% of those with rheumatoid arthritis – higher prevalence in those with extrarticular manifestations –not diagnostic test; good prognostic test, as those who are positive for rheumatoid factor have a poorer prognosis. Higher prevalence of other autoantibodies are also seen (antikeratin antibodies, antiperinuclear antibodies, anti-RA 33 antibodies)
• More severe radiographic changes have been associated with HLA-DRB1 and antikeratin antibodies .

Differential diagnosis:
Infectious arthritis, seronegative arthropathy (eg ankylosing spondylitis), crystal deposition arthropathy (eg gout), inflammatory phase of osteoarthritis, polymyalgia rheumatica, fibromyalgia, amyloidosis, arthritis associated with thyroid disease, chronic fatigue syndrome, glucocorticoid withdrawal syndrome, intermittent hydrarthrosis

Specific instruments for ongoing health status assessment of rheumatoid arthritis have been developed:
Stanford Health Assessment Questionnaire (SHAQ)
Functional Disability Index (FDI)
Arthritic Impact Measurement Scales (AIMS)
SF-36 Arthritic Specific Health Index (ASHI)
They are used to document the functional status of patients and the impact of the rheumatoid arthritis on them.

Criteria for Classification of Rheumatoid Arthritis – The American College of Rheumatology (1987):
Any four of the following criteria must be present to classify patients as having RA:
• morning stiffness (> 1 hr for more than 6 weeks)
• arthritis of three or more joints for greater than 6 weeks
• arthritis of hand joints for more than 6 weeks
• symmetrical arthritis for more than 6 weeks
• rheumatoid nodules
• serum rheumatoid factor
• radiographic changes (including erosions or bony decalcification)
The criteria have about a 90% sensitivity and specificity for rheumatoid arthritis compared to controls without rheumatoid arthritis.

Course of disease:
Rheumatoid arthritis can follow several unpredictable and variable courses – some have an acute rapid onset (10%) and up to 20% have a single episode of polyarthritis and have no further symptoms – for most the disease is progressive  disability and morbidity, but up to 20% respond well to disease modifying drug intervention. Pregnancy is usually associated with some clinical remission.

Factors associated with a poorer prognosis :
• older age at onset
• greater number of joints affected
• uncontrolled polyarthritis
• structural damage/deformity (eg presence of joint erosions on x-ray)
• functional disability
• presence of extra-articular features (especially vasculitis involving the lungs, heart and kidney)
• psychosocial problem (eg poverty, low educational achievement)
• high titre of rheumatoid factor
• presence of HLA-DR4

Involvement of foot:
• many cases start with symmetric involvement of metatarsophalangeal joints – presents as “metatarsalgia” - often also metacarpophalangeal joints.
• more likely to be lateral MPJ’s in early stage – can be tender to palpation - seen as MPJ oedema on dorsum and widening of forefoot – may be painful on compression
• plantar or interdigital bursitis and/or flexor tendonitis may be initial presenting complaint – can be detected by ultrasound, often before being symptomatic (Koski, 1997). This may present as ‘spreading’ of the toes. Three case reports on spreading of the toes as presenting feature of rheumatoid arthritis
• 40% of patients seen at one clinic that presented what was a diagnosis of Morton’s interdigital neuroma either had diagnosed rheumatoid arthritis at the time or later developed the disease (Awerbuch et al, 1980)
• rearfoot and ankle can also be an initial presentation of disease process
• radiologically – juxta articular demineralisation in affected joint; rarely get joint space enlargement at this stage; cysts, bony erosions are prime feature – occur at margin not covered by articular cartilage – usually on medial side of joint, except in fifth MPJ in which lateral side is affected early
• radiographic changes in the foot early in rheumatoid arthritis is indicative of a more aggressive form of the disease

• progressive foot deformities are invariably seen in all those with rheumatoid arthritis at later stages- most deformities due to inflammatory and biomechanical factors
• generally most have either a predominant involvement of forefoot or rearfoot
• pre-existing biomechanical/pathomechanical foot disorders will exacerbate foot symptoms
• forefoot:
• lateral deviation of toes, clawing of toes, subluxation of MPJ’s. MPJ deformities occur in almost all cases within 10 years  reduced foot function. Digital lesions develop from increased pressure. Abduction of forefoot due to pronated position of foot increases lever for extensor digitorum brevis muscle to pull the toes into a more lateral position (fifth toe often unaffected as no attachment to this toe)
• hallux valgus (may have pre-existed  made worse by rheumatoid arthritis). Incidence increases with increased duration of disease.
• anterior displacement of plantar fat pad  increased risk for plantar lesions and pain
• spread of forefoot (splaying) & plantar depression of metatarsal heads- due to peri artictular oedema and bursitis
• plantar hyperkeratosis and bursitis
• forefoot supinatus
• mid/rearfoot:
• the inflammatory process impairs the structures that stabilise the mid and rearfoot
• midfoot involvement  collapse of midfoot arch structure – can occur early with minimal symptomatic joint involvement – may be reason for higher incidence of plantar fasciitis in rheumatoid arthritis
• rearfoot pain common (but less common than forefoot involvement) – pain from involvement of joint or achilles tendonitis or retrocalcaneal bursitis (may get erosions on x-ray from bursitis)
• subtalar involvement  palpable swelling behind malleoli
• peroneal muscle  spasm may play a role in the rigid flatfoot deformity
• ankylosis of tarsal bones may occur late in the disease
• valgus rearfoot (can be very disabling) – initially flexible, then limited range of motion at subtalar joint  later may progress to ankylosis. The rearfoot going into valgus is most likely due to the disease process in the joint, a weakness and laxity in supporting structures and an inability of the foot to counter the normal early stance phase pronation.
• impingement of the calcaneo-fibular ligament has been suggested as the cause of lateral pain in the rearfoot
• tendon sheaths around rearfoot may become affected
• posterior tibial dysfunction (EMG studies have shown greater activity of the posterior tibial muscle – Keenan et al ). Tears of the posterior tibial tendon are common in those with ‘flat feet’ however it has been suggested that pathology in the sinus tarsi may be more important in the cause of flat foot in rheumatoid arthritis
• radiographically – talocalcaneal sclerosis; loss of joint space, osteophytes, angular changes associated with flat/pronated foot, erosions uncommon in midfoot & rearfoot
• other foot involvement:
• plantar heel pain – in 2-3% - calcaneal spurs more common (however, this may not be any more common than general population). Fibrosis of the plantar heel fat pad has been demonstrated
• changes in composition of fatty acids of heel pad have been shown  increased fat viscosity  decreased ability of heel to absorb shock .
• tarsal tunnel syndrome can occur at any stage – sometimes it occurs in initial stages
• subcutaneous nodules – most commonly plantar to central 3 metatarsal heads
• tenosynovitis of long flexors and extensors (tenosynovium produces proinflammatory cytokines and proteolytic enzymes that are important in tissue degradation – Jain et al )
• bursitis  Morton’s neuroma like symptoms
• atrophy of subcutaneous tissues (as part of disease process or secondary to corticosteroid use)
• longitudinal nail beading late in disease (may be due to vasculitis of nail bed)
• vasculitis  skin ulceration and digital ischaemia
• stress fractures (due to osteoporosis)
• gait changes  ‘shuffling’; no heel contact or propulsive phases of stance (due to avoidance of pain and muscle changes). Knees and hips tend to be flexed.
• ankle oedema (may be due to hypoalbuminaemia or lymphatic blockage from knee joint effusions)
• venous insufficiency
• mild sensory neuropathy
• wound healing difficulty (vasculitis affects wound oxygenation; patient may be on corticosteroids or immunosuppressives)
• leg and foot ulcers (most due to venous insufficiency and vasculitis, Oien , 2001)
• side effects of corticosteroids  skin problems, osteoporosis (may predispose to calcaneal stress fractures)
• radiographic:
• bilateral and symmetrical distribution of changes; periarticular osteoporosis (early) and generalised osteoporosis (late); uniform joint space narrowing; synovial cyst formation; central and marginal erosions; bony ankylosis; deformity; soft tissue swelling

Management of Rheumatoid Arthritis:
Aim of management is to relieve pain, decrease inflammation, preserve the integrity, structure and function of joints and maintain a normal lifestyle:
• Patient education and motivation (information on disease, treatment and prognosis – include spouses/caregivers) – many lay publications and organisations can help; may need psychological counselling; patient organisation have literature available
• Exercise (especially range of motion exercises and aerobic fitness) – complete rest may be needed in acute phases. A balance is needed between rest and exercise, depending on disease activity
• Physiotherapy (patient education, swelling reduction, heat, cold, exercise, joint mobility, electrotherapeutic modalities)
• Joint protection during activities of daily living – splinting and braces (especially during active phase)
• Occupational therapy – eg using alternative ways of performing tasks to reduce strain on joints; household and personal aids
• Good nutrition – especially for weight reduction if indicated and increased intake of omega-3 fatty acids has been suggested to be of benefit
• Complementary/alternative therapies – used by up to 80% of those with rheumatoid arthritis
• Surgical (eg fusion for cervical subluxation)

Pharmacological management:
As there is no cure for rheumatoid arthritis, the goal of pharmacological management is to relieve symptoms, prevent joint damage and put the disease into remission. NSAID’s are commonly used early, but disease-modifying agents are now being used earlier. More aggressive approaches are now being used than in the past – combination of drugs is common approach as many of them are not as effective if used as monotherapy. Delay of treatment  poorer outcome .

do not appear change natural history of disease, but are widely used as first line drug
control pain and inflammation  better joint function
patient’s vary in response
often only drug necessary in mild disease (but philosophy of more early aggressive management is altering this)

• role is constantly being debated
• suppress inflammation and immune response
commonly used, especially as a continuous oral background therapy
can use with anti-osteoporotic therapy (eg calcium supplements)
intra-articular injections may help settle a flare

Disease modifying antirheumatic drugs (DMARD’s)/Remission inducing drugs:
Pharmacological intervention with DMARD’s before joint erosion and permanent damage  prevents and/or retards joint damage  reduction in symptoms. DMARD’s are being used with increased frequency in combination and in an earlier stage of the disease process. A recent longer term study , has suggested that the benefits of DMARD’s shown in shorter term studies may be less than expected, but other studies (eg Choy et al , 2002) have shown the benefits of early aggrieve treatment in reduce extent of radiological progression.
Hydroxychloroquine is safe and effective in mild disease
have suppressive effect on disease – shown to be very effective
retinopathy is a common side effect  need opthamology screens every 6-12 months

• anti-inflammatory and modulates immune response
• common first choice drug – takes 6+ weeks for benefits to show
has been shown to reduce joint erosions
may be more effective in the seronegative spondyloarthropathies

• suppresses activity in a number of patients  prevents disease progression
• IM more effective than oral – usually weekly injections
• mechanism of action unclear
• associated with large number of side effects

• degradation product of penicillin
• shown to reduce inflammatory synovitis in 50%
• Not used much due to high toxicity (in 60% and can trigger a number of rare autoimmune diseases) and slow onset of action (often 6+ months to get effects)

• pyrimidine synthesis inhibitor
• shown to be as effective at methotrexate and more effective than sulfasalazine
• suppresses disease activity and delays radiological progression
• rapid onset (4 weeks) compared to methotrexate and sulfasalazine
• well tolerated (given orally)

Methotrexate (MTX):
• cytotoxic – shown to clearly control the inflammatory response
• most common first line agent – considered ‘gold-standard’ disease modifying agent
• long term efficacy is well documented, but rarely leads to a true/complete remission  often used in combination
• monotherapy with MTX is not often associated with sustained disease remissions
• only 50% of patients stay on it after 5 years due to toxicity

Anti-tumour necrosis factor (TNF) drugs (biologic agents):
• biological agents shown to reduce disease activity and halt joint damage
• the cytokine, TNF has a number of pro-inflammatory effects  plays a major role in inflammatory disease such as rheumatoid arthritis and is a key element in its pathogenesis  potential to block TNF
• eg Etanercept (soluble fusion protein given as a subcutaneous injection); Infliximab (monoclonal antibody given IV)  block activity of TNF-alpha;
• shown to have rapid improvement in joint pain and swelling – fast onset (1-2 weeks)
• used either alone or with methotrexate

Interleukin-1 receptor antagonist (IL-1Ra):
• eg anakinra (recently approved by FDA for use in rheumatoid arthritis)
• inhibits the pro-inflammatory cytokine IL-1

Management of the foot:
• patient education ie; proper foot care
• hyperkeratosis and dystrophic nail debridement
• skin hydration
• infection may be more difficult to manage due to use of immunosuppressants (may need to temporally come off these if using antibiotics)
• digital orthoses to maintain good digital alignment or protect lesions/pressure areas. Silicone orthodigital devices can be used serially to correct toe position – may also improve gait.
• Metatarsal pads for metatarsalgia and plantar hyperkeratosis
• footwear advice and prescription to accommodate foot deformity (extra depth and width) – there are compliance issue with the use of custom made footwear
• softer orthoses for accommodation of plantar lesions or painful joints. More rigid orthoses for realignment of rearfoot or prevention of development of hallux valgus. Rearfoot control may be vital to prevent calcaneus from going in to valgus (especially early in rearfoot disease) and for proper knee and hip function  devices may need to be more rigid to prevent the valgus rearfoot from developing (amount of rigidity needed will depend on supination resistance testing and body weight)
• ankle foot orthoses if valgus deformity is severe.
• shock absorption
• exercises to maximise range of motions

Functional foot orthoses to alter biomechanics have been shown to prevent the progression of hallux valgus but not in limiting pain and disability . Accommodative orthoses have been shown to reduce pain, reduce plantar pressures and improve gait parameters 45,46,47. More rigid orthoses in combination with supportive shoes where more effective at reducing forefoot pain than softer accommodative orthoses 45,46 showed that custom made functional foot orthoses used over a period of 30 months reduced foot pain by 19%, foot disability by 31% and functional limitation by 13% compared to a control group.

Increased use of knee replacement surgery  increased mobility  increased importance to protect feet.

Surgical management:
• indicated for severe pain, deformity and functional incapacity – not indicated if conservative treatment has a good chance
• early prophylactic surgery for deformity may be indicated if disease is not very destructive and involvement is localised
• metatarsal head resections are common
• rearfoot and midfoot joint fusions

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