Dr. Maharaj is Instructor, Clinical Foundations, Ross University School of Medicine, Barbados, West Indies.
Dr. Selfridge is Professor, Clinical Foundations Department, Ross University School of Medicine, Barbados, West Indies.
• An autoimmune inflammatory process underlies the pathogenesis of rheumatoid disease.
• Certain dietary patterns and profiles have proven pro- and anti-inflammatory effects.
• Dietary habits influence gastrointestinal physiology, including the gut microbiome, and systemic inflammatory cascades.
• Dietary modifications, when integrated into holistic management of patients with rheumatoid arthritis, can mitigate disease activity, modify pharmacological intervention, and reduce disease morbidity.
SYNOPSIS: An extensive systematic review of research exploring the relationship between diet and the risk of rheumatoid arthritis as well as disease activity concludes that some dietary patterns and supplements may be protective enough to be recommended as part of the holistic management of rheumatoid disease.
SOURCE: Gioia C, Lucchino B, Tarsitano M, et al. Dietary habits and nutrition in rheumatoid arthritis: Can diet influence disease development and clinical manifestations? Nutrients 2020;12:1456.
Chronic autoimmune inflammatory diseases, such as rheumatoid arthritis (RA), cardiovascular diseases, and adiposity-based chronic diseases, such as type 2 diabetes mellitus, constitute a global healthcare burden of pandemic proportions. They all share systemic inflammation in their pathophysiology and environmental factors, such as diet, as potentially enabling conditions.1 RA has a global age-adjusted prevalence of 0.24%, is twice as prevalent in females compared to males, and is ranked as the 42nd-highest contributor to global disability.2 Higher prevalence has been noted in Australia, Western Europe, and North America and lower prevalence noted in Eastern Asia, Southeast Asia, North Africa, and the Middle East. Higher prevalence also has been associated with high income.2 Global variation in disease burden and association of RA with higher income support the premise that environment and diet may play a role in this disease risk and disease severity.
Gioia et al offer a systematic review of more than 200 publications (from 1979-2020) exploring the relationship between diet and RA in the following categories:
- pro- and anti-inflammatory influences of specific dietary constituents;
- diet as an epigenetic risk factor for RA development, disease activity, and outcomes;
- dietary effects on the gut microbiome and subsequent effect on inflammatory cascade;
- the influence of specific nutrients on disease activity in established RA;
- dietary recommendations for RA patients.
Studies included in the review encompass bench in vitro and animal research on food and nutrient biochemistry and immunology, epidemiologic studies, longitudinal cohort studies, cross-sectional studies, randomized controlled trials, and systematic reviews and meta-analyses.
The ability to measure inflammatory markers, such as C-reactive protein, interleukin-6, and tumor necrosis factor-alpha, has enabled the assessment of the proinflammatory and anti-inflammatory effects of dietary patterns and individual nutrients. Given the geographic differences in the prevalence of RA, comparison between the standard Western diet and the Mediterranean diet (MD) and their inflammatory potential seems intuitive. The former, characterized by relatively high intake of red meat, saturated/trans fats, refined sugars, and high glycemic index carbohydrates and low omega-3/omega-6 fatty acid ratios, has been associated with increased RA risk through documented pro-inflammatory marker responses and induction of insulin-resistance and obesity.
Trans-fatty acids found in manufactured (hydrogenated) cooking oils and margarines have demonstrated pro-inflammatory effects when compared to polyunsaturated fatty acids (PUFAs), such as omega-3 fatty acids, found in fish oils, nuts, and eggs. The Mediterranean Diet emphasizes consumption of plant-based unprocessed foods and PUFAs, and its nutrient-dense profile has been associated with reduced overall mortality, reduced cardiovascular mortality, and reduced incidence of cancer as well as reduced incidence of Alzheimer’s and Parkinson’s disease. Biochemical analyses of components of the MD have identified the antioxidative properties of polyphenols and lycopenes in red wine and tomatoes, respectively, and the anti-inflammatory influences of flavonoids and carotenoids found in fruits and vegetables.
The proven immunomodulatory effects of the active metabolite of vitamin D are well known and highlight the challenges of connecting this metabolite with disease processes.3 Vitamin D deficiency has been observed in patients with autoimmune conditions, but its actual role has not been well defined because of confounding variables within studies, such as sunlight exposure, and an absence of global consensus on defined deficiency levels. Table 1 (online at https://bit.ly/3q6HMi1) summarizes findings from two large prospective cohort studies (EPIC-Norfolk and NHS) and a cross-sectional multicenter study
examining diet and the risk of developing RA. Results from these studies are conflicting and inconclusive despite what is known about the pro-inflammatory and anti-inflammatory potentials of the listed foods and nutrients.
Studies of milk consumption and the risk of RA have been similarly mixed and inconclusive. The association between fruit and vegetable consumption and RA risk also has been inconclusive. Despite the abundant anti-
inflammatory and antioxidant components of plant-based foods, it is possible that consumption of “nightshade” vegetables (potatoes, tomatoes, and eggplant) and their known association with increased RA risk confounds study results. These vegetables contain solanine, an alkaloid that increases intestinal permeability. Some evidence suggests that “excessive” consumption of red meat (more than two servings/month) has been associated with an increased risk of inflammatory polyarthritis in rat models possibly mediated through the pro-inflammatory metabolite trimethylamine-N-oxide found in blood and synovial samples.
Sound biochemical evidence exists to implicate the pro-inflammatory additive effects of salt and smoking through the induction of glucocorticoid kinase-1 and anti-citrullinated protein antibodies. High-caloric diets resulting in obesity, increased body mass index (BMI), and waist circumference are established risk factors for RD development. The authors posit that white adipose tissue is an “endocrine organ” able to release inflammatory mediators, thus promoting the development of autoimmune and other inflammatory diseases. A population-based study of more than 500,000 subjects found an association between increased waist circumference (even after BMI correction) and heightened risk of RA development. Similar associations were found in a Danish cohort, which showed an increased risk of RA development and higher total body fat and waist circumference, especially in women. Consumption of sugary drinks appears to increase the risk of RA development, as does consumption of > 4 cups of coffee daily, although when cigarette smoking was considered as a confounding factor in coffee consumption, the association was lost.
Alternatively, omega-3 fatty acid intake and consumption of fatty fish appear to confer protection, as does olive oil and drinking tea. Moderate alcohol consumption (three to five drinks/week) also appears to confer protection, although studies have been hampered by confounders and other limitations. Green tea appears to suppress inflammation in mouse models of arthritis. Disruption of normal gut microbiota may be associated with the pathogenesis of RA, via alteration of gut epithelial integrity with increased intestinal mucosal permeability, allowing immunogenic substances from ingested food to trigger a systemic inflammatory cascade. Studies suggest that RA is associated with significant modification of gut microbiota and that specific bacteria may directly influence the development of the disease. MD may have a beneficial effect on the gut microbiota in RA, if maintained for longer than three months.
Calorie restriction, fasting, and a ketogenic/low carbohydrate diet have shown anti-inflammatory effect with reduction in inflammatory markers, although these interventions have not been studied for effects on RA disease activity and symptoms. Studies of antioxidant supplementation (selenium, ascorbic acid, vitamin A, vitamin E, zinc) in RA have been mixed, with clinical disease activity corresponding poorly to any salubrious changes in measured oxidative stress. Although genistein, a compound found in soybeans, has demonstrated in vitro and in vivo ability to inhibit inflammatory cytokines and growth factor expression, its clinical efficacy is unknown. Gluten has known immunogenic properties. Elimination of gluten (plus a vegan diet) was associated with decreased RA disease activity and athero-protection. Alcohol consumption has shown mixed effects on RA symptoms. Probiotic supplementation appears to consistently reduce pro-inflammatory cytokines in patients with RA but has demonstrated mixed effects on patient symptoms and disease activity.
The authors conclude that dietary patterns influence both the risk of developing RA and disease activity in patients diagnosed with RA. Current research supports a MD for primary prevention and for adjunctive treatment for RA. Additional reduction in red meat, refined sugar, gluten, salt, trans fatty acids, and coffee, as well as solanine-containing “nightshade” family vegetables is advised. Dietary substances to be encouraged include omega-3 fatty acids (fatty fish), mono-unsaturated fats (olive oil), fruits and vegetables, and probiotics. Figure 1 (online at https://bit.ly/3j4MPOH) illustrates the effects of various foods and nutrients on joint health and rheumatoid arthritis and their complex interactions.
COMMENTARY
Although in-vitro and rodent-model studies reveal compelling biochemistry supporting the pro- and anti-inflammatory effects of a wide variety of foods and nutrients, the clinician’s challenge lies in determining how well these effects translate into in vivo ecosystems and associated complex homeostatic processes toward creating recommendations for patient dietary practices and interventions.
Strengths of this analysis include its comprehensive database, wide thematic scope, and types of studies reviewed. Although incredibly edifying, this broad spectrum of information simultaneously limits the ability to arrive at consistent data-supported specific clinical recommendations for dietary interventions for RA. No reasonable statistical meta-analysis of the research data was possible, given the diversity of study designs. Additional large clinical controlled trials of dietary interventions are technically difficult but necessary to amass the practical data needed to support inclusion of dietary and nutritional advice in therapeutic guidelines. Nonetheless, clinicians may consider the following advice in caring for their RA patients, based upon this review:
- An MD can be recommended to confer beneficial effects on risk, related comorbidities, and RA disease activity.
- Limited consumption of salt, sweetened drinks, alcohol, milk, and red meat and avoidance of smoking tobacco may help reduce the harmful pathophysiological processes of inflammation in RA.
- Maintenance of optimum vitamin D levels via dietary intake or ultraviolet exposure is important for RA management.
- Regulation of body weight as an imperative because of its demonstrated adverse effect on disease activity.
REFERENCES
- Mechanick J, Hurley D, Garvey T. Adiposity-based chronic disease as a new diagnostic term: The American Association of Clinical Endocrinologists and American College of Endocrinology position statement. Endocr Pract 2017;23;371-378.
- Cross M, Smith E, Hoy D, et al. The global burden of rheumatoid arthritis: Estimate from the Global Burden of Disease 2010 study. Ann Rheum Dis 2014;73:1316-1322.
- Skrobot A, Demkow U, Wachowska M. Immunomodulatory role of vitamin D: A review. Adv Exp Med Biol 2018;1108:13-23.
