Rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic, autoimmune disorder that is predominantly characterised by synovial inflammation leading to inflammatory arthritis. It affects around 1% of the UK population - more commonly women aged 40-60 years old.

Pathophysiology

The exact cause of RA is still undetermined. Its aetiology is considered multifactorial as it involves environmental triggers, immunological and genetic factors:

• Environmental triggers
• Smoking - this is single most important modifiable risk factor. This is because smoking is associated with the production of rheumatoid factor (RF) and anti- citrullinated protein antibodies (ACPA) which both increase the likelihood of RA development. The risk is proportional to the duration and quantity of smoking.
• Infections - autoimmunity may form due to molecular mimicry after certain infections. For example, Porphyromonas gingivalis, which is implicated in periodontitis and is highly associated with RA development.
• Hormones - RA disproportionately affects women. This may suggest a hormonal role in its aetiology.
• Immunological factors - autoantibodies are often detectable many years prior to presentation of symptoms. Specifically RF and ACPA. We shall discuss these in more depth below.
• Genetic factors - HLA-DR1 and HLA-DR4 are strongly associated with the disease. Other genes implicated include PTPN22 and STAT4.

Autoantibodies in RA:

As mentioned, RF and ACPA are 2 central autoantibodies in the pathogenesis of RA.

1. Rheumatoid factor (RF)

Rheumatoid factor is an autoantibody that targets the fragment crystallisable (Fc) region of IgG antibodies. The Fc portion corresponds with the heavy chain on the antibody. It binds to the IgG which then activates the complement cascade to recruit inflammatory cells and amplify the inflammatory process.

It is present in 70-80% of RA cases and is a sensitive marker, however, it is not a specific marker as it can be found sometimes in Sjögren’s syndrome and some infections.

2. Anti-citrullinated protein antibodies (ACPA)

As implied in the name, ACPA antibodies target citrullinated proteins. These are proteins that have had arginine residues converted into citrulline through the enzyme peptidylarginine deiminase (PAD). Citrullination (also known as deimination) is a normal process that occurs in our bodies for regulating protein function, tissue remodelling (such as in wound healing) and also some immune functions (such as neutrophil extracellular traps to defend against infections). However, dysregulation leads to neo-antigen formation that triggers the immune response seen in RA.

ACPA are more specific for RA and are associated with more aggressive disease courses.

RF and ACPA are diagnostic and prognostic markers but RA may develop without them (this is known as seronegative RA).

So how does RA develop?

Individuals with HLA-DR1 or HLA-DR4 may be predisposed and as such are more likely to recognise citrullinated proteins as foreign antigens

Often environmental triggers such as smoking, infections, molecular mimicry begin the process of citrullination which then leads to the development of ACPA and RF. These autoantibodies form immune complexes that get deposited in the synovium of joints. Macrophages and dendritic cells in the joints activate CD4+ T-cells which stimulate additional immune cells to release pro-inflammatory cytokines. The most notable cytokines as TNF-α, IL-1 and IL-6. VEGF is also released which causes angiogenesis. This angiogenesis promotes further infiltration of inflammatory cells into the synovium.

The immune response causes hyperplasia of fibroblast-like synoviocytes (FLS) which then form a pannus. A pannus is a thickened layer of inflamed synovium. This pannus destroys adjacent bone and cartilage. Matrix metalloproteinases (MMPs) are released by FLS and macrophages and this also destroys the cartilage. RANKL is also released which activates osteoclasts and leads to bony erosions.

Some of these inflammatory mediators may enter the systemic circulation which can lead to the systemic symptoms of RA and may increase the cardiovascular risk.

⚠️ Risk factors

• Family history
• HLA-DR4 and HLA-DR1
• Female sex
• Aged 40-60 years old
• Smoking
• Obesity
• Porphyromonas gingivalis

😷 Presentation

The typical presentation of rheumatoid arthritis is:

1. Symmetrical distal polyarthritis in the hands and feet - typically the metacarpophalangeal (MCP), proximal interphalangeal (PIP), metatarsophalangeal (MTP) and wrist joints.
2. Morning stiffness that improves with use and worsens with inactivity.
3. Swelling of joints due to inflammation as well as synovial thickening.

Hand deformities in RA - these occur in late stage RA and are not typically present in newly diagnosed patients.

1. Swan neck - hyperextension of the PIP and flexion of the DIP joints.
2. Boutonnière deformity - flexion of the PIP and hyperextension of the DIP
3. Ulnar deviation/drift - deviation of the fingers towards the ulna (away from the thumb) at the MCP joint.
4. Rheumatoid nodules - firm swellings found on the extensor surfaces predominantly.
5. Z-deformity - hyperextension of the IP joint

Associated systemic symptoms of RA include:

• Fatigue
• Malaise
• Weight loss

Let’s also take a look at the extra-articular features of RA as well:

• Eyes - around 25% of patients with RA end up with some ocular manifestations.
• Keratoconjuctivitis sicca - dryness of the eyes.
• Episcleritis
• Scleritis
• Corneal ulceration
• Skin - associated with severe disease.
• Skin rash - vasculitic lesions.
• Leg ulcers - may occur with Felty syndrome
• Cardiovascular
• Pericarditis
• Valvulitis
• Myocardial fibrosis
• Pulmonary
• Pleuritis
• Pulmonary nodules
• Pulmonary fibrosis
• Bronchiolitis obliterans
• Caplan’s syndrome - a rare pulmonary manifestation of RA. It is also known as rheumatoid pneumoconiosis. It occurs in RA patients who are exposed to silica, asbestos, coal and other inorganic dust. It manifests as intrapulmonary nodules ranging in size from 0.5cm to 5cm.
• Renal
• Amyloidosis
• Nephropathy
• Hepatic
• Hepatomegaly
• Neurological
• Carpal tunnel syndrome and peripheral nerve entrapment
• Atlantoaxial subluxation - this is due to damage to the C2’s odontoid peg and the ligaments surrounding it. It results in shifting of C1. Such shifts may result in spinal cord compression.
• Mononeuritis multiplex
• Polyneuropathy
• Haematological
• Anaemia of chronic disease
• Neutropenia
• Lymphadenopathy

Felty syndrome

A rare but severe manifestation of extra-articular RA. It only affects ~1% of RA patients (most commonly middle-aged or elderly).

It is characterised by a triad of:

1. Rheumatoid arthritis - usually long-standing and severe RA.
2. Splenomegaly - sequestration of neutrophils in the spleen results in spleen enlargement and neutrophil destruction.
3. Neutropenia - due to an overactive immune response which leads to neutrophil destruction.

Of course the low neutrophil count makes patients more susceptible to opportunistic infections.

Palindromic rheumatism

A rare form of episodic inflammatory arthritis that is characterised by sudden and recurrent flares that affect a few joints. There is a sudden onset of pain, swelling and stiffness that sometimes has soft tissue swelling and systemic features. However, it resolves spontaneously and leaves no permanent joint damage. It is sometimes considered a precursor to RA itself.

🔍 Investigations

The diagnosis of RA is essentially a clinical diagnosis. If someone is suspected of having RA through clinical assessment (persistent synovitis of undetermined cause), they require referral to rheumatology (within 3 weeks). Investigations can be done to aid the diagnosis and to obtain some baseline information but these should not delay a referral.

An urgent referral (within 3 days) needs to be made if any of the following are present:

• Small joints of the hands or feet affected
• More than one joint affected
• Delay of ≥3 months between onset and medical attention

Patients can be offered the lowest effective dose of an NSAID while waiting for a referral. It should be co-prescribed with a PPI. However, glucocorticoids should not be prescribed until a specialist assessment has been conducted.

What investigations can be done to aid the diagnosis?

• Rheumatoid factor - positive in 60-70% of patients.
• Anti-CCP antibodies - positive in about 80% of patients.
• X-rays of hands and feet - help determine disease severity.

We also need to obtain some baseline investigations to monitor severity:

• FBC, LFT and U&Es
• CRP and ESR
• Ultrasound or MRI of joints

🔢 Scoring

NICE recommends using the Health Assessment Questionnaire (HAQ) to measure functional ability. A baseline score should be obtained at diagnosis which can be compared with follow-up scores to assess treatment response.

The Disease Activity Score 28 (DAS28) is a score used to measure the activity of RA.

It looks at 4 variables:

1. Tender joint count
2. Swollen joint count
3. CRP level
4. Global health on a visual analogue scale

🧰 Management

In the management of RA, we follow a treat-to-target (T2T) approach. This focuses on achieving remission (complete absence of disease activity) or low disease activity if remission is not possible. This may be achieved through conventional disease-modifying anti-rheumatic drugs (cDMARDS) or biological agents or targeted synthetic DMARDS.

🚨 Complications

• TNF-alpha side effects
• TB reactivation
• Malignancy
• Ischaemic heart disease
• Depression
• Extra-articular manifestations

🔮 Prognosis

Certain features may indicate a poor prognosis:

1. Anti-CCP positive
2. RF positive
3. Higher HAQ score at presentation
4. X-ray changes
5. Extra-articular features
6. HLA-DR4
7. Female gender

✍️ Referral guidelines

RA patients should be referred for surgical opinion early on if any of the following occur:

• Persistent pain as a result of joint damage or soft tissue changes
• Worsening function
• Progressive deformity
• Persistent localised synovitis
• Imminent/actual tendon rupture
• Nerve compression
• Stress fracture
• Septic arthritis

Surgery offers benefits of pain relief, prevented further deterioration as well as deformity.