Causes and Risk Factors of Rheumatoid Arthritis

Smoking and obesity add to the burden of inflammation

Show Article Table of Contents

rheumatoid arthritis causes and risk factors
© Verywell, 2018 

People sometimes think that rheumatoid arthritis and osteoarthritis are the same thing. While osteoarthritis is caused by the long-term wear-and-tear of a joint, rheumatoid arthritis is a much more complex and confusing disease in which the immune system attacks its own cells and tissues, including those of the joints, skin, and other organs. Like other autoimmune disorders, such as lupus and psoriasis, the underlying cause of rheumatoid arthritis is not well understood.

What we do know is that certain factors—including smoking and obesity—can place you at higher risk of not only getting the disease, but experiencing worse symptoms.

Common Causes

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

For reasons unknown, the body will sometimes produce autoantibodies that mistake normal cells for harmful ones. 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.

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. With that being said, not all people with these genes develop rheumatoid arthritis, and not all people with rheumatoid arthritis have these gene variants.

What this tells us is that there are likely other factors that can trigger the autoimmune response, especially (but not only) if you are genetically predisposed to the disease. One theory is that certain bacteria or viruses may inadvertently "confuse" the immune system. Four infections that might trigger rheumatoid arthritis in some people are:

  • Epstein-Barr virus (EBV)
  • Escherichia coli (E. coli)
  • Hepatitis C virus (HCV)
  • Mycobacterium

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 more than others. The three non-modifiable factors commonly linked to the disease are age, gender, and a 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 will increase the older you get older. Overall, the odds of developing rheumatic arthritis will more than triple between the ages of 35 and 75, increasing from 29 cases per 100,000 people to 99 cases per 100,000, according to research from the Mayo Clinic.

Gender

Women are 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 that has shown that women will often develop the disease after major shifts in their hormones. This sometimes happens immediately after pregnancy or in tandem with the onset of menopause. Estrogen, or specifically the depletion of estrogen, is believed to be the culprit.

On the other hand, 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 (a.k.a. "the Pill"). 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 percent 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 times greater than the general population. Having second-degree relatives with the disease more or less doubles your risk. These figures help to illustrate the central role that genetics play in the development of the autoimmune disorder.

According to a 2016 study published in The Lancet, genetics plays a part in between 40 percent and 65 percent of all confirmed cases. 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 that the 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 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, they may 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 are 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.

Even 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 such 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 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 also rob you of your ability to achieve remission, the 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 percent 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, there are conditions that may trigger a sudden worsening of symptoms.

Physical overexertion is one of these. While the mechanism for this is poorly understood, it is believed that the sudden and excessive release of stress hormones, such as cortisol and adrenaline, may have a knock-on effect that intensifies 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 will often report that flare-ups are immediately preceded by moments of extreme anxiety, depression, or fatigue.

Other common triggers include infections, including the cold or flu, which are associated with immune activation. Flare-ups may also occur in response to certain foods you eat that trigger an allergic response in which the immune system reacts abnormally.

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

View Article Sources