Windows of Opportunity for Preclinical Rheumatoid Arthritis
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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?
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.
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 to Recognize and Reverse Immune Dysfunction
Improve Immune Function With Diet & Lifestyle Change
Understanding the Psychoemotional Roots of Immune Disease
- Verma MK, Sobha K. Understanding the major risk factors in the beginning and the progression of rheumatoid arthritis: current scenario and future prospects. Inflamm Res. 2015;64(9):647-659. doi:10.1007/s00011-015-0843-8.
- 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.
- 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.
- Araki Y, Mimura T. The mechanisms underlying chronic inflammation in rheumatoid arthritis from the perspective of the epigenetic landscape. J Immunol Res. 2016;2016:6290682. doi:10.1155/2016/6290682.
- Glant TT, Mikecz K, Rauch TA. Epigenetics in the pathogenesis of rheumatoid arthritis. BMC Med. 2014;12:35. doi:10.1186/1741-7015-12-35.
- Nielen MMJ, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum. 2004;50(2):380-386. doi:10.1002/art.20018.
- Tracy A, Buckley CD, Raza K. Pre-symptomatic autoimmunity in rheumatoid arthritis: when does the disease start? Semin Immunopathol. 2017;39(4):423-435. doi:10.1007/s00281-017-0620-6.
- 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:10.1136/annrheumdis-2014-205227.
- Ramos?Remus C, Castillo?Ortiz JD, Aguilar?Lozano L, et al. Autoantibodies in prediction of the development of rheumatoid arthritis among healthy relatives of patients with the disease. Arthritis Rheumatol. 2015;67(11):2837-2844. doi:10.1002/art.39297.
- Deane KD, Demoruelle MK, Kelmenson LB, Kuhn KA, Norris JM, Holers VM. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol. 2017;31(1):3-18. doi:10.1016/j.berh.2017.08.003.
- Harrison M, Spooner L, Bansback N, et al. Preventing rheumatoid arthritis: preferences for and predicted uptake of preventive treatments among high risk individuals. PLoS One. 2019;14(4):E216075. doi:10.1371/journal.pone.0216075.
- Hunt L, Emery P. Defining populations at risk of rheumatoid arthritis: the first steps to prevention. Nat Rev Rheumatol. 2014;10(9):521-530. doi:10.1038/nrrheum.2014.82.
- Paul BJ, Kandy HI, Krishnan V. Pre-rheumatoid arthritis and its prevention. Eur J Rheumatol. 2017;4(2):161-165. doi:10.5152/eurjrheum.2017.16006.
- Gerlag DM, Norris JM, Tak PP. Towards prevention of autoantibody-positive rheumatoid arthritis: from lifestyle modification to preventive treatment. Rheumatology. 2016;55(4):607-614. doi:10.1093/rheumatology/kev347.
- Silman AJ, Newman J, Macgregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis: results from a nationwide study of disease-discordant twins. Arthritis Rheum. 1996;39(5):732-735. doi:10.1002/art.1780390504.
- Stolt P, Bengtsson C, Nordmark B, et al. Quantification of the influence of cigarette smoking on rheumatoid arthritis: results from a population based case-control study, using incident cases. Ann Rheum Dis. 2003;62(9):835-841. doi:10.1136/ard.62.9.835.
- Hutchinson D, Shepstone L, Moots R, Lear JT, Lynch MP. Heavy cigarette smoking is strongly associated with rheumatoid arthritis (RA), particularly in patients without a family history of RA. Ann Rheum Dis. 2001;60(3):223-227. doi:10.1136/ard.60.3.223.
- Anderson R, Meyer PW, Ally MM, Tikly M. Smoking and air pollution as pro-inflammatory triggers for the development of rheumatoid arthritis. Nicotine Tob Res. 2016;18(7):1556-1565. doi:10.1093/ntr/ntw030.
- Kharlamova N, Jiang X, Sherina N, et al. Antibodies to Porphyromonas gingivalis indicate interaction between oral infection, smoking, and risk genes in rheumatoid arthritis etiology. Arthritis Rheumatol 2016;68(3):604-613. doi:10.1002/art.39491.
- Pretorius E, Akeredolu O-O, Soma P, Kell DB. Major involvement of bacterial components in rheumatoid arthritis and its accompanying oxidative stress, systemic inflammation and hypercoagulability. Exp Biol Med. 2017;242(4):355-373. doi:10.1177/1535370216681549.
- Lu B, Hiraki LT, Sparks JA, et al. Being overweight or obese and risk of developing rheumatoid arthritis among women: a prospective cohort study. Ann Rheum Dis. 2014;73(11):1914-1922. doi:10.1136/annrheumdis-2014-205459.
- Sparks JA, Chang SC, Nguyen US, et al. Weight change during the early rheumatoid arthritis period and risk of subsequent mortality in women with rheumatoid arthritis and matched comparators. Arthritis Rheumatol. 2018;70(1):18-29. doi:10.1002/art.40346.
- Baker JF, Von Feldt J, Mostoufi?Moab S, et al. Deficits in muscle mass, muscle density, and modified associations with fat in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2014;66(11):1612-1618. doi:10.1002/acr.22328.
- Hanaoka BY, Ithurburn MP, Rigsbee CA, et al. Chronic inflammation in rheumatoid arthritis and mediators of skeletal muscle pathology and physical impairment: a review. Arthritis Care Res (Hoboken). 2019;71(2):173-177. doi:10.1002/acr.23775.
- Bärebring L, Winkvist A, Gjertsson I, Lindqvist HM. Poor dietary quality is associated with increased inflammation in Swedish patients with rheumatoid arthritis. Nutrients. 2018;10(10):1535. doi:10.3390/nu10101535.
- Essouma M, Noubiap JJ. Is air pollution a risk factor for rheumatoid arthritis? J Inflamm (Lond). 2015;12:48. doi:10.1186/S12950-015-0092-1.
- Jung C-R, Hsieh H-Y, Hwang B-F. Air pollution as a potential determinant of rheumatoid arthritis: a population-based cohort study in Taiwan. Epidemiology. 2017;28(Suppl 1):S54-S59. doi:10.1097/EDE.0000000000000732.
- Shin J, Lee J, Lee J, Ha E-H. Association between exposure to ambient air pollution and rheumatoid arthritis in adults. Int J Environ Res Public Health. 2019;16(7):1227. doi:10.3390/ijerph16071227.
- Sigaux J, Biton J, André E, Semerano L, Boissier MC. Air pollution as a determinant of rheumatoid arthritis. Joint Bone Spine. 2019;86(1):37-42. doi:10.1016/j.jbspin.2018.03.001.
- Zaccardelli A, Friedlander HM, Ford JA, Sparks JA. Potential of lifestyle changes for reducing the risk of developing rheumatoid arthritis: is an ounce of prevention worth a pound of cure? Clin Ther. 2019;41(7):1323-1345. doi:10.1016/j.clinthera.2019.04.021.
- He J, Wang Y, Feng M, et al. Dietary intake and risk of rheumatoid arthritis—a cross section multicenter study. Clin Rheumatol. 2016;35(12):2901-2908. doi:10.1007/s10067-016-3383-x.
- Vadell AKE, Bärebring L, Hulander E, Gjertsson I, Lindqvist HM, Winkvist A. Anti-inflammatory diet in rheumatoid arthritis (ADIRA)–a randomized, controlled crossover trial indicating effects on disease activity. Am J Clin Nutr. 2020;111(6):1203-1213. doi:10.1093/ajcn/nqaa019.
- Philippou E, Nikiphorou E. Are we really what we eat? Nutrition and its role in the onset of rheumatoid arthritis. Autoimmun Rev. 2018;17(11):1074-1077. doi:10.1016/j.autrev.2018.05.009.
- Gioia C, Lucchino B, Tarsitano MG, Iannuccelli C, Di Franco M. Dietary habits and nutrition in rheumatoid arthritis: can diet influence disease development and clinical manifestations? Nutrients. 2020;12(5):1456. doi:10.3390/nu12051456.
- Asteriou E, Gkoutzourelas A, Mavropoulos A, Katsiari C, Sakkas LI, Bogdanos DP. Curcumin for the management of periodontitis and early ACPA-positive rheumatoid arthritis: killing two birds with one stone. Nutrients. 2018;10(7):908. doi:10.3390/nu10070908.