Windows of Opportunity for Preclinical Rheumatoid Arthritis

Doctor holding and assessing the hand of a patient, explaining the early onset triggers of rheumatoid arthritis and how functional medicine can help slow disease progression.
Read time: 4 minutes

Rheumatoid arthritis (RA) affects an estimated 17.6 million people worldwide, with one forecast suggesting the disease will impact 31.7 million individuals by 2050.1 In the US alone, the combined direct and indirect costs associated with rheumatoid arthritis has been estimated at $46 billion annually.2 Genetic, environmental, and lifestyle risk factors and their complex interplay contribute to RA development.1,3,4 Disease progression includes several changes in the synovial fluid of RA patients, leading to the increase of cytokines that promote a pro-inflammatory state.3 Asymptomatic joint inflammation and the presence of autoimmune antibodies can occur years before clinical symptoms begin.3 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 well before RA can be diagnosed.5 In one study of patients with musculoskeletal complaints, those patients with the highest levels of autoantibodies at baseline had a 62% increased likelihood of RA diagnosis at five years.6 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.7 This “preclinical” stage8 offers opportunities to intervene early.9

For those patients at higher risk of RA development, early detection is vital, and lifestyle risk factors such as smoking, dental hygiene, and gut health are suggested areas that may modify disease risk and progression.1,10,11 What factors tip the scale to cause or prevent RA? In the following video, IFM’s Director of Medical Education Initiatives Robert Luby, MD, IFMCP, describes some of the known precursors to the development of RA.

(Video Time: 02:00)

Risk Factors: Environmental and Lifestyle-Factor Contributions

Exposure to traffic exhaust is one environmental factor correlated with the development of RA, suggesting that small particulate air pollution may play a role.4 Ozone particles have also been implicated.12,13 A 2019 review article states that both innate and adaptive immune responses play a role in the mechanism connecting air pollution with RA.14

Smoking is a modifiable lifestyle factor that contributes to RA risk.1 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.15 The increased likelihood of periodontitis in smokers may explain some of that association.16 Oral infection with P. gingivalis may be a trigger for RA in a subset of patients.17 Underlying bacterial infections and lipopolysaccharides (LPS) are also suspected to play a role in RA.18

Obesity may also be associated with an increased risk of RA and contribute to the progression of the disease.19 However, when counseling patients with RA 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.20 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.20 Since women with RA have a three-fold increased risk of death when compared to healthy peers,20 weight loss recommendations should be personalized and monitored. In addition, focusing interventions on building muscles may also be appropriate for a patient 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.21

Regarding nutrition, a highly processed and inflammatory diet contributes to ongoing immune activation, yet many patients with RA consume highly processed, low-nutrient-value diets.22 Yet helping these patients improve their diet can be an important point of leverage. Studies indicate that following an anti-inflammatory diet such as the Mediterranean diet may be an effective adjunctive treatment to not only reduce systemic inflammation associated with RA but also to help reduce pain while increasing physical function.23,24 In addition to a healthy diet, specific nutrients may benefit patients with RA. A 2023 meta-analysis (n=539 total patients) found that curcumin improved inflammation levels and clinical symptoms in patients with RA.25 Another 2023 meta-analysis (n=47 randomized controlled trials) suggested that dietary polyphenols (e.g., cinnamon extract, garlic extract, quercetin, resveratrol, tea polyphenols, etc.) may improve disease activity scores, inflammation levels, or oxidative stress markers in patients with RA.26

IFM’s expansive toolkit offers multiple avenues to determine lifestyle-based RA risk factors, from toxicant exposures to dietary patterns and ways to work with patients to improve eating patterns, including therapeutic food plans and take-home customizable handouts for patients. Learn more about the functional medicine approach to autoimmune diseases, such as RA, and those clinical interventions that help patients optimize their immune health at IFM’s upcoming Immune Advanced Practice Module (APM).

Learn More About Immune Imbalance

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  1. GBD 2021 Rheumatoid Arthritis Collaborators. Global, regional, and national burden of rheumatoid arthritis, 1990-2020, and projections to 2050: a systematic analysis of the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(10):e594-e610. doi:1016/S2665-9913(23)00211-4
  2. Hochberg MC, Cisternas MG, Watkins-Castillo SI. Rheumatoid arthritis. In: Weinstein S, Watkins-Castillo SI, Yelin E, et al. The Burden of Musculoskeletal Diseases in the United States: Prevalence, Societal and Economic Costs (BMUS). 4th ed. United States Bone and Joint Initiative; 2020. Accessed December 11, 2023.
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  6. Rakieh C, Nam JL, Hunt L, et al. Predicting the development of clinical arthritis in anti-CCP positive individuals with non-specific musculoskeletal symptoms: a prospective observational cohort study. Ann Rheum Dis. 2015;74(9):1659-1666. doi:1136/annrheumdis-2014-205227
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  16.  Eke PI, Borgnakke WS, Genco RJ. Recent epidemiologic trends in periodontitis in the USA. Periodontol 2000. 2020;82(1):257-267. doi:1111/prd.12323
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