Rheumatoid Arthritis

What is rheumatoid arthritis (RA)?

Rheumatoid arthritis is a chronic inflammatory disease that is mainly characterised by peripheral small joint arthritis. It is not just a local infection- it is systemic, and affects many areas of the body. It is fairly common and has a heterogeneous presentation, so it has been hypothesised that what we think of as "rheumatoid arthritis" is actually a number of different diseases lumped together.

Aetiology

The aetiology of rheumatoid arthritis is not fully understood, but is thought to be multifactorial. A whole range of factors may lead to an autoimmune condition in which there is a loss of tolerance of self that cannot be recovered.

Genetics

There is strong evidence for a genetic basis for RA. A positive family history increases RA risk by 3-5 times. The heritability of seropositive (i.e. can detect rheumatoid factor (RF) and/or autoantibodies against citrullinated peptides (ACPAs)) is around 40-65%, whereas the heritability of seronegative disease is only around 20%.

There are over 100 loci associated with RA risk, but possibly the most well-studied loci have been MHC/HLA loci. In particular, HLA DRB1 molecules are more common in people with RA. Some of these molecules have a "shared epitope" sequence, which seems to determine which antigens bind. The actual role of this "shared epitope" is unknown, but it is associated with the presence of serological markers such as RF and ACPAs. RF is an antibody directed against the Fc component of IgG, whereas ACPA are antibodies against citrullinated peptides. (RF and ACPAs are present in around 50-70% of patients, and are associated with a poorer prognosis.) Other loci associated with RA risk are likely to be involved with co-stimulatory pathways, such as cytokine signalling and lymphocyte receptor activation.

Environmental

The main environmental factors implicated in RA are gender, low socioeconomic status, smoking, antigens and infections. Females are 3x as likely to get RA than males, especially in the three months after giving birth. Smoking is very strongly linked to RA- it increases the risk 5x in individuals with only one copy of shared epitope or ACPA, and increases the risk 25x in those with two copies of shared epitope or ACPA. Smoking induces citrullination, forming citrullinated peptides that ACPAs act against. Infections that might increase risk of RA include mycoplasma, periodontal disease, EBV, parvovirus and herpes (though some of these links are ill-defined). The microbiome may also play a role- gastrointestinal dysbiosis is implicated in rheumatoid arthritis. Antigens that may play a role in RA include heat-shock proteins and type II collagen.

Pathogenesis

The pathogenesis of RA is still poorly understood, but it is thought that it begins with the formation of immune complexes between ACPAs and antigens. RF then binds, leading to complement activation. Over time, the concentration and epitope diversity of ACPAs increases, as does the concentration of serum cytokines.

ACPAs, which are produced by B-cells, are present for up to 10 years before diagnosis. They have an altered glycosylation status that enhances their Fc-receptor and citrullinated antigen binding. ACPAs may activate macrophages and/or osteoclasts.

Epidemiology

RA affects around 1% of the global adult population. As mentioned earlier, it affects more women than men. The peak age of onset is between the ages of 45 and 65 years.

Clinical presentation and course

As mentioned earlier, RA is fairly heterogeneous, so different patients will present differently. It is mostly progressive, but early diagnosis and treatment can reduce the damage. The main symptoms are swelling of small peripheral joints with morning stiffness and diffuse aching. Joints have inflammatory infiltrate, synovial hyperplasia, increased vascularity and formation of pannus (abnormal granulation tissue). Sometimes deformities, such as "swan necking" and Boutonniere deformities, may result. These symptoms may be preceded by fatigue, malaise and depression.

As also mentioned earlier, RA is systemic and therefore doesn't only affect the joints. It can also cause cardiovascular problems such as pericarditis, pulmonary problems such as pulmonary nodules and pleuritis, eye problems such as conjunctivitis, and haematologic problems such as granulocytopenia (decrease in white blood cells).

Brief management

The main aims of treatment are to deal with pain and prevent joint destruction. The main drugs used are simple analgesics, anti-inflammatory drugs, disease-modifying anti-rheumatoid drugs (DMARDs) such as methotrexate, leflunomide and sulfasalazine, and biologics and small molecules such as antibodies. Biologics are relatively expensive, so they are generally used in more treatment- resistant cases. The aim is to have a DAS (disease activity score) less than 2.4.