Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease that primarily affects the joints, though its effects can extend to other organs and bodily systems. The most commonly affected joints are those in the hands and feet. Other areas that may be affected include the knees, hips, skin, heart, lungs, eyes and vascular system.

RA is estimated to affect ~1% of the population and is the second most common form of arthritis in Australia. Age of onset is typically between 30 and 50 years.

Symptoms & Diagnosis

The most common symptoms of RA include:

  • Swelling, pain and warmth in the joints;
  • Joint stiffness, particularly in the morning or after extended periods of inactivity;
  • Fatigue and weakness;
  • Fever.

There are no specific diagnostic criteria for RA. Diagnosing RA typically involves a combination of symptom presentation, blood test and imaging test results:

  • Blood test results such as an elevated erythrocyte sedimentation rate (ESR) and/or C-reactive protein (CRP) may indicate increased inflammatory activity in the body.
  • X-rays are commonly used to assess bony abnormalities such as joint erosion. Ultrasound and magnetic resonance imaging (MRI) are capable of detecting abnormalities of bone, soft tissue and fluid-filled structures, allowing for assessment of joint inflammation and oedema (swelling). These are useful for diagnosing early RA.

What Causes Rheumatoid Arthritis?

RA is an autoimmune inflammatory disease, meaning it involves dysregulation of the immune system (i.e. autoantibody production) and chronic inflammation. Autoantibodies are proteins produced by immune cells that are directed towards the body’s own cells or tissues. In autoimmune diseases, they cause the immune system to attack its own healthy cells or tissues. In RA, it is the synovial membrane that lines many joints that is targeted, and this leads to joint inflammation. Chronic inflammation causes further damage to the joints, and may also affect other structures and organs.

Numerous risk factors contribute to the development of RA. It is generally a combination and interaction of genetic factors and environmental or lifestyle factors that activates RA and determines the severity of the disease.

Genetic Factors

Studies estimate approximately 65% of the risk of developing RA is genetic. Many autoimmune diseases are associated with genetic variations in Human Leukocyte Antigen (HLA) alleles (each of our genes consists of 2 alleles – one from each parent). HLA genes encode cell surface proteins that regulate the immune response, allowing the immune system to differentiate between self and foreign cells/substances. They differ from person to person and basically determine our “tissue type”. A specific shared genetic sequence in the HLA-DR4 allele is most strongly associated with RA.

Numerous other genes and genetic variations have been associated with RA, though they are of much smaller effect. This includes differences in gene expression; i.e. which genes are “switched on” in order to make proteins. This differs amongst our cells depending on what the cell needs, its environment, hormones, and so forth. Gene expression is also affected by external environmental and lifestyle factors.

Environmental / Lifestyle Factors

The risk of developing RA increases with age and is slightly higher in females. Cigarette smoking or exposure is the strongest environmental trigger for RA.

Other risk factors include:

  • Obesity – consumption of sugar-sweetened drinks may be associated;
  • Infection / poor hygiene – i.e. microbial infections, periodontal disease such as gingivitis;
  • Gastrointestinal disturbances – i.e. imbalance in gut microbiome;
  • Comorbid conditions – i.e. diabetes 1 & 2, inflammatory lung disease;
  • Stress.

It is important to note that many of the environmental risk factors for RA are pro-inflammatory. They may stimulate RA development by initiating or propagating the immune response and/or worsen the secondary inflammation associated with RA and thus increase the severity of the disease.

Current Treatment Options

RA requires long term treatment and management. If insufficiently or poorly treated, RA can progressively affect other joints, organs and/or systems, and can lead to the development of additional serious conditions, such as vasculitis, cardiovascular disease, lung disease, lymphoma and osteoporosis.

While there is currently no cure for RA, effective and early treatment can slow the progression of the disease and send it into remission.

Pharmacotherapy

Non-steroidal anti-inflammatory drugs (NSAIDs – i.e. ibuprofen, diclofenac, naproxen, celecoxib) reduce inflammation and may provide relief from pain and joint stiffness, however they do not treat the underlying disease mechanisms.

Corticosteroids (i.e. cortisone, prednisone) may reduce inflammation and offer acute, significant pain relief, however, they too fail to treat the underlying condition. Furthermore, corticosteroids are associated with worse side effects and particularly serious adverse effects if used long-term.

Disease-modifying antirheumatic drugs (DMARDs) are the recommended primary treatment for RA. They are effective at treating inflammation and slowing disease progression. DMARDs are classed as either synthetic (conventional or targeted) or biological:

  • The conventional synthetic DMARD methotrexate, an immune system suppressant, is recommended as the first-line treatment for RA.
  • Targeted DMARDs are those that have been developed to target intracellular signalling molecules (i.e. tofacitinib).
  • Biological DMARDs target specific molecules or cells involved in the inflammatory response. They include inhibitors of tumor necrosis factor (TNF; i.e. etanercept, infliximab), inhibitors of immune cells (i.e. rituximab: anti-B-cell; abatacept: anti-T-cell) and inhibitors of pro-inflammatory interleukins (i.e. tocilizumab). Their level of effectiveness appears to be similar.

Combinations of different classes of DMARDs may be prescribed for RA. Targeted and biological DMARDs are associated with more side effects than conventional DMARDs, particularly an increased risk and incidence of serious infections, and must be used with caution.

Physical Therapy

Clinical trials support exercise programs as an effective and safe therapeutic option for patients with RA. Exercise programs have been shown to improve quality of life and restore muscle strength.

Surgery

Joint replacement surgery may be performed in cases of severe joint damage and medically uncontrolled symptoms. The most commonly replaced joints are the knees and hips.

New & Emerging Treatments

Treatment of RA has come a long way since the introduction of DMARDs, however, there is much room for improvement as remission rates remain low and a cure has yet to be found. A better understanding of what exactly is causing RA, which likely involves multiple mechanisms, would significantly aid the development of potentially curative treatments.

There are numerous pharmaceutical agents and therapies currently in early development and testing phases. Some examples are:

  • New biologic DMARDs – i.e. more pro-inflammatory cytokine inhibitors, new cell-targeting agents, new antibodies;
  • New targeted synthetic DMARDs;
  • Agents that target molecules involved in regulation of gene expression;
  • Cellular therapies – i.e. restoration of immune cells to a state of “immune tolerance” which are then transferred to the patient (i.e. stem cells and dendritic cells).

Clinical Trials

Genesis Research Services is currently recruiting participants with rheumatoid arthritis who are currently taking methotrexate. To register your interest and see if you qualify for this study, click here or call us on (02) 4985 1860.


References:

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  14. Image courtesy of stockdevil at FreeDigitalPhotos.net
October 19th, 2017|
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