Windows of Opportunity for Preclinical Rheumatoid Arthritis

Doctor examining woman's arthritic hands
Read time: 4 minutes

Rheumatoid arthritis (RA) affects more than 1.5% of the world’s population,1 with one forecast suggesting that the rates of practitioner-diagnosed arthritis will increase by 49% by 2040 due to an aging population.2 One in four US adults are projected to have rheumatoid arthritis by 2040.2

Genetic and environmental factors play a role in the development and the progression of the disease. Heritability estimates for RA range from 53-65%.3,4 There are close to 60 genetic loci associated with susceptibility to RA across multiple populations.4 These loci are at least partially shared across ethnicities.3 Several changes in the synovial fluid of RA patients seem to increase cytokines and promote a pro-inflammatory state.5 Before the condition emerges, patients enter a pro-inflammatory state in part due to this genetic predisposition. Other factors, including diet, lifestyle, and toxic exposures, contribute to and exacerbate systemic inflammation, which may trigger the onset or accelerate the progression of RA. Chronic states of inflammation are present long before a formal diagnosis; as a functional medicine clinician, how can you identify the windows of opportunities in a patient’s diagnostic workup?

Preclinical Autoantibodies

The preclinical phase of RA often involves increased production of autoantibodies, which are detectable more than 10 years before RA can be diagnosed.6,7 In one study of patients with musculoskeletal complaints, those patients with the highest levels of antibodies at baseline had a 62% increased likelihood of RA diagnosis at five years.8 In a cohort study of healthy relatives of those suffering from arthritis, anticyclic citrullinated peptide (anti-CCP) antibody levels at baseline had positive predictive value of 68% for RA diagnosis at five years.9 This “preclinical” stage10 offers opportunities to intervene early.11

One review article has emphasized that early intervention may at least delay and might sometimes prevent the onset of rheumatoid arthritis.12 This highlights the need to help susceptible patients modify their lifestyle to reduce the risk of disease progression.13 As an inflammation-mediated disease, rheumatoid arthritis is preceded by systemic autoimmunity, and then, as the hypothesis goes, a trigger causes synovial inflammation that begins the RA-specific disease process.14

What factors tip the scale to cause or prevent RA? In the following video, IFM Executive Director of Medical Education Robert Luby, MD, describes some of the known precursors to the development of RA.

(Video Time: 02:00)

Risk Factors: Environmental Contributions

Environmental factors may exacerbate a pro-inflammatory state, acting as mediators that can speed up the development of RA. What lifestyle factors contribute to this process?

No contributing environmental factor is quite as established as smoking to predispose an individual to autoimmune conditions.15-17 Chronic inflammation due to smoking leads to production of the aforementioned anti-CCP autoantibodies, which can set the stage for RA in individuals with a genetic predisposition.18 The increased likelihood of periodontitis in smokers, specifically P. gingivalis infection, may explain some of that association.3,16 Oral infection with P. gingivalis may be a trigger for RA in a subset of patients.19 Underlying bacterial infections and lipopolysaccharides (LPS) are also suspected to play a role in RA.20

Obesity is also correlated with an increased risk of RA. In a large cohort study, women under the age of 55 who were obese for a decade were also 37% more likely to have RA.21 The earlier in life that a woman becomes obese, the higher the likelihood of later RA development.22

However, when counseling patients to lose weight, it is important to emphasize that weight loss must be healthy and monitored; in one prospective study over 40 years, women with preclinical RA or healthy controls who lost more than 30 pounds during the study had an increased risk of death.22 On the other hand, in those with RA or healthy controls, weight gain during the timeframe had no effect on mortality when compared with stable weight.22 Since women with RA have a three-fold increased risk of death when compared to healthy peers,22 weight loss recommendations should be personalized and monitored. There is a known trend for RA patients to lose muscle mass, and that loss of muscle mass is correlated with increased joint destruction.23 Focusing interventions on building muscles may have greater impact than weight loss protocols. This may be especially helpful because individuals with RA are more likely to be sedentary than their peers without RA, and inflammation due to the disease may reduce skeletal muscle mass.24

A highly processed and inflammatory diet contributes to ongoing immune activation, yet many patients with RA consume highly processed, low-nutrient-value diets.25 This is likely in part due to functional limitations and pain, but helping these patients improve their diet can be an important point of leverage.

Exposure to traffic exhaust is also correlated with the development of RA, suggesting that small particulate air pollution may play a role.26 Ozone particles have also been implicated.27,28 A 2019 review article states that both innate and adaptive immune responses play a role in the mechanism connecting air pollution with RA.29

In all of these instances, increased inflammation occurs. An inflammatory milieu likely plays a major role in the development of RA. Further study is needed to understand more about the other environmental factors that contribute to RA.4

Protective Factor: Nutrition

Is an ounce of prevention worth a pound of cure?30

In addition to cigarette smoking reduction, a healthy diet has been suggested by both a 2019 meta-review31 and a 2020 randomized controlled crossover trial32 as a potentially powerful public health intervention to reduce rheumatoid arthritis. As it is for many other chronic conditions, an anti-inflammatory diet rich in fruits and vegetables may be protective—especially if it includes mushrooms and citrus and reduces red meat.31

Omega-3 fatty acids may be protective and reduce the risk of RA,3,31,33 and a healthy eating pattern that includes whole grains, fruits, and vegetables has also been correlated with decreased diagnosis.13,34 Curcumin has also been suggested as a supplement that may not only reduce inflammation in RA patients but may also help the P. gingivalis infection seen in so many of these patients.35

IFM’s food plans (available in the IFM Toolkit) offer one way to work with patients to improve eating patterns, including take-home handouts for patients that can be customized for their specific condition(s) and preferences. This may be especially important as a recent study found that patients at risk of rheumatoid arthritis are more likely to undertake preventative interventions if the risk of side effects is low; the authors explain that they predict highest uptake of convenient treatments offering low-to-moderate reductions in risk of developing RA and low risks of serious side-effects.11 Nutrition interventions not only offer risk reduction but often have beneficial side effects and may prevent other chronic conditions.

As a prototypical autoimmune condition, prevention strategies for RA may have a large impact. While many autoimmune diseases tend to be viewed as separate entities, a broader perspective may reveal that shared mechanisms are the underlying cause of these maladies. Functional medicine takes the perspective that immune imbalance, while often resulting from a genetic disposition, will generally arise in the context of one or more of the following: the habitual consumption of a pro-inflammatory diet, food allergies and intolerances, microbial infections, hormonal imbalances, nutritional insufficiencies, and xenobiotic exposure. For further reading on the topic of immune dysfunction, please visit the following links:

Learn More About Immune Imbalance

Learn to Recognize and Reverse Immune Dysfunction

Improve Immune Function With Diet & Lifestyle Change

Understanding the Psychoemotional Roots of Immune Disease


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  2. Hootman JM, Helmick CG, Barbour KE, Theis KA, Boring MA. Updated projected prevalence of self?reported doctor?diagnosed arthritis and arthritis?attributable activity limitation among US adults, 2015–2040. Arthritis Rheumatol. 2016;68(7):1582-1587. doi:10.1002/art.39692.
  3. MacGregor AJ, Snieder H, Rigby AS, et al. Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum. 2000;43(1):30-37. doi:10.1002/1529-0131(200001)43:1<30::AID-ANR5>3.0.CO;2-B.
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