Causes and Risk Factors of Rheumatoid Arthritis

Smoking and obesity add to the burden of inflammation

In This Article

Rheumatoid arthritis (RA) is caused by your immune system attacking parts of your own body as if they were dangerous germs. Among other tissues, the immune system targets membranes surrounding your joints, which are called the synovium. That leads to inflammation that can damage and even destroy the joints' bone and cartilage.

As in other autoimmune disorders, such as lupus and psoriasis, the underlying cause of rheumatoid arthritis is not well understood. What doctors do know is that certain factors—including smoking and obesity—can place you at higher risk of not only getting the disease, but having more severe symptoms.

rheumatoid arthritis causes and risk factors
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Common Causes

Rheumatoid arthritis, like all autoimmune diseases, is defined by an immune system that has gone awry. Under normal circumstances, the body produces defensive proteins (called antibodies) that are "programmed" to target and attack a specific disease-causing agent (called an pathogen).

For reasons unknown, the body will sometimes produce autoantibodies ("auto" meaning "self") that mistake normal cells and tissues for pathogens. Depending on the disorder, the autoimmune assault may be generalized (affecting multiple organs) or specific (preferentially targeting one or more organ systems).

With rheumatoid arthritis, the joints are specifically targeted, suggesting that a part of the immune system is "misprogramming" the antibodies in a very specific way. Variants in the human leukocyte antigen (HLA) system, the genetic site that controls the immune response, are believed to be at the center of this anomaly.

Genes That May Play a Role

Certain variants in other genes may also contribute, including:

  • STAT4, a gene that plays an important role in the regulation and activation of the immune response
  • TRAF1 and C5, two genes associated with chronic inflammation
  • PTPN22, a gene associated with both the development and progression of rheumatoid arthritis

It is possible that a specific combination of gene variants and/or genetic mutations may be enough to trigger the disease. Even so, not all people with these gene variants develop rheumatoid arthritis, and not all people with rheumatoid arthritis have these gene variants.

That means it's likely other factors can trigger the autoimmune response, especially (but not only) a genetic predisposed to the disease. One theory is that certain bacteria or viruses may inadvertently "confuse" the immune system. Four infections suspected of triggering rheumatoid arthritis in some people are:

Scientists believe that there may be cross-reactivity between these antigens and certain normal cells of the body. If so, antibodies produced in response to EBV, for example, may see EBV and a normal cell as the same thing. Even if the EBV infection eventually resolves, the body will remain on "high alert," ready to pounce on any cell it believes to be EBV.

Other factors may also cause the immune system to malfunction. Some of these factors may be modifiable, meaning we can change them, while others may not.

Non-Modifiable Risk Factors

Rheumatoid arthritis affects some groups of people more than others. The three non-modifiable factors commonly linked to the disease are:

  • Age
  • Gender
  • Family history of rheumatoid arthritis (genetics)

Age

While rheumatoid arthritis can strike at any age, the onset of symptoms usually begins between the ages of 40 and 60. Moreover, the risk increases as you get older.

Overall, the odds of developing rheumatic arthritis will more than triple between the ages of 35 and 75, increasing from 29 new cases per 100,000 people per year to 99 new cases per 100,000 people per year, according to research from the Mayo Clinic.

Gender

Women are two to three times likely to get rheumatoid arthritis than men. While the explanation for this disparity is far from definitive, hormones are believed to play a role.

This is evidenced in part by research showing women often develop the disease after major shifts in their hormones. This sometimes happens immediately after pregnancy or with the onset of menopause. Estrogen, or specifically the depletion of estrogen, is believed to be the culprit.

Accordingly, estrogen replacement may offer a protective benefit to older women who may otherwise be vulnerable to the disease.

The same benefit may be extended to younger women who take a combination oral contraceptive (birth control pills). According to researchers at the Karolinska Institute in Stockholm, women who have used an estrogen-containing contraceptive for longer than seven years had a nearly 20% decreased risk of the most common type of rheumatoid arthritis compared to women who never took the pill.

Genetics

If you have a parent or sibling with rheumatoid arthritis, your risk of developing the disease is three to five times greater than the general population. Having second-degree relatives with the disease more or less doubles your risk. These figures help illustrate the central role that genetics play in the development of the autoimmune disorder.

According to a 2016 study published in The Lancet, between 40% and 60% of your risk of developing rheumatoid arthritis is genetic. While the exact genetic permutations have yet to be identified, people with autoimmune diseases are believed to have one or more mutations that alter the way their immune system recognizes and targets disease-causing agents.

One of the primary suspects is HLA-DR4, a gene variant linked to other autoimmune diseases, such as lupus, polymyalgia rheumatica, and autoimmune hepatitis. Research from the University of Michigan has further concluded that people with a specific genetic marker called the HLA shared epitope have a five-fold greater chance of developing rheumatoid arthritis than people without the marker.

Lifestyle Risk Factors

Lifestyle risk factors are those that are modifiable. Changing these factors may not only reduce the severity of your illness, but they may also even reduce your risk of getting the disease in the first place.

Smoking

Smoking has a cause-and-effect relationship with rheumatoid arthritis. Not only do cigarettes increase your risk of getting the disease, they can accelerate the progression of your symptoms, sometimes severely.

A comprehensive review of clinical studies conducted by researchers at the Kobe University Graduate School of Medicine concluded that being a heavy smoker (defined as smoking a pack of cigarettes a day for more than 20 years) nearly doubles your risk of rheumatoid arthritis. The risk is greatly amplified if you also have the HLA shared epitope marker.

Moreover, smokers who test positive for rheumatoid factor (RF) are three times more likely to get rheumatoid arthritis than their non-smoking counterparts, whether they're current or past smokers. As its own independent risk factor, smoking is known to promote cell death, increase inflammation, and stimulate the production of free radicals that further damage already inflamed joint tissue.

If you take medications to treat the disease, smoking can interfere with their activity and make them less effective. This includes such foundational medications as methotrexate and newer TNF-blockers like Enbrel (etanercept) and Humira (adalimumab).

Obesity

Rheumatoid arthritis is characterized by chronic inflammation that gradually degrades and destroys bone and joint tissue. Anything that adds to this inflammation will only make things worse.

Obesity is one condition that can trigger systemic inflammation, caused by the accumulation of adipose (fat) cells and the hyperproduction of inflammatory proteins known as cytokines. The more adipose cells you have in your body, the higher the concentration of certain cytokines. Moreover, increased body weight adds stress to the affected joints, particularly of the knees, hips, and feet, resulting in greater loss of mobility and pain.

Obesity can rob you of your ability to achieve remission, which is a state of low disease activity in which inflammation is more or less under control. According to research from the Weill Cornell Medical College, people with a body mass index (BMI) of over 30—the clinical definition of obesity—are 47% less like to achieve remission compared to people with a BMI under 25.

Physical and Emotional Stress

While rheumatoid arthritis symptoms can often flare up for no apparent reason, certain things may trigger a sudden worsening of symptoms.

Physical overexertion is one of these things. While the mechanism for this is poorly understood, it's believed that the sudden and excessive release of stress hormones, such as cortisol and adrenaline, may cause changes that indirectly intensify the autoimmune response. While this doesn't in any way undermine the enormous benefits of exercise in treating rheumatoid, it does suggest that physical activity needs to be appropriate, particularly insofar as the joints are concerned.

The body's response to physical stress may be mirrored by its response to emotional stress. While scientists have yet to find a clear association between stress and rheumatoid arthritis symptoms, people living with the disease often report that flare-ups come right after moments of extreme anxiety, depression, or fatigue.

Other common triggers include infections, including the cold or flu, which are associated with immune activation; and eating certain foods that trigger an allergic response in some people, causing the immune system to react abnormally.

All of these factors place varying degrees of stress on the body which the immune system responds to, sometimes adversely.

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