A Brief Review of the Mediterranean Diet’s Role in Mediating Inflammation and in Management of Rheumatoid Arthritis

Abstract

The Mediterranean diet (MD) is a dietary pattern for which the health benefits in prevention of cardiovascular disease, cancer, and metabolic disorders have been well-substantiated. However, emerging clinical literature has shown its promise in reducing risk and disease activity in many autoimmune diseases. This review focuses on literature about components of the MD and their role in modulating inflammatory pathways implicated in autoimmune disease. This review also focuses on literature assessing the MD’s associations with clinical outcomes in rheumatoid arthritis (RA), a systemic autoimmune condition primarily affecting one’s joints. The core components of the MD (such as whole grains, fish, olive oil, yogurt, cheese, and moderate red wine consumption) have been seen to reduce laboratory and clinical markers of inflammation through a number of mechanisms. Recent population-based cohort studies and randomized clinical trials have been more equivocal in their findings. This suggests that although the MD may have statistically significant impacts on RA risk and symptom severity, these effects are of uncertain clinical significance. This highlights the ongoing need for high-quality clinical research on lifestyle interventions in RA and other autoimmune diseases, along with the continued importance of emphasizing lifestyle-based interventions in the management of chronic disease.

Introduction

The Mediterranean diet (MD) is a dietary pattern characterized by preferential consumption of fish protein, whole grains, vegetables, and olive oil, with moderate consumption of other animal proteins and red wine. ¹ It has been gaining traction among both the general population and the medical establishment for decades. During this time, there has been research showing its promise in reducing the chances of developing cardiovascular disease (CVD), cancer, and metabolic disorders. ^2,3 Simultaneously, a growing body of clinical research has investigated its possible role in prevention and management of autoimmune inflammatory diseases, from inflammatory bowel disease to systemic lupus erythematosus. ^4,5

Among these diseases is rheumatoid arthritis (RA), a condition characterized by arthritis via immune-mediated destruction of bone and cartilage. ⁶ Cornerstone medical therapies for RA traditionally involve systemic immunosuppression, with the goal of lowering global immune system activity or targeting specific immune cell types or signaling pathways to reduce disease burden. Ongoing clinical research has also found that modifiable risk factors (eg, smoking, periodontal disease, adiposity, physical activity, diet, and gut microbiome) likely play crucial roles in mediating the chances of developing RA and overall symptom burden among those already with RA. Although interest in nonpharmacological interventions is high among patients living with autoimmune disease, these interventions are less commonly prioritized in clinical practice. ⁷

With the burgeoning promise of diet-based therapies playing an adjunctive role alongside traditional medical therapy in the management of inflammatory arthritis, it is necessary to first critically appraise the available evidence. This narrative review will first provide an overview of the MD’s individual components and the physiology behind their touted anti-inflammatory effects. The review will then appraise recent clinical literature evaluating the MD’s use in prevention and management of RA.

The Mediterranean Diet and Inflammatory Pathways

The physiology mediating the association between the MD and systemic inflammation is multifactorial due to the diverse nature of the MD’s components. The high proportion of long-chain polyunsaturated fatty acids (PUFAs) in ingredients such as olive oil and fish protein is thought to play a role in the MD’s anti-inflammatory effects. ⁸ In humans, fatty acids from endogenous adipose tissue and exogenous saturated fat intake are metabolized by enzymatic pathways to lipid-derived pro-inflammatory cytokines such as prostaglandins and leukotrienes. ⁹ These cytokines mediate activation and recruitment of leukocytes that drive symptoms seen in inflammatory arthritis. ¹⁰ However, PUFAs such as those from fish and olive oil have been noted to have inhibitory effects on these pathways, resulting in lower production of pro-inflammatory, lipid-derived cytokines. ¹¹ PUFAs have also been shown to modulate synthesis of pro-inflammatory cytokines produced by other enzymatic pathways as well. A study on inflammatory colitis in a mouse model found that fish oil supplementation led to statistically significant reductions in IL-1β, IL-6, TNF-α, and MCP-1. ¹² These mechanisms also may translate to clinically significant effects in humans, as meta-analyses show significant associations between therapeutic doses of fish oil and positive RA outcomes, including reduced tender joint count, morning stiffness duration, and use of nonsteroidal anti-inflammatory drugs. ¹³

Whole grains are another prominent component of the MD. They are defined as grain products consumed in their unprocessed state, without removal of components such as the bran or germ that contain important micronutrients and fiber. ¹⁴ In the MD, these can include (but are not limited to) farro, quinoa, barley, and brown or wild rice. ¹ Their effects on the inflammatory response are multifactorial and likely involve both direct anti-inflammatory properties of fibers and phytochemicals, especially polyphenolic compounds, that are found in whole grains, as well as the downstream anti-inflammatory effects associated with metabolites of these compounds. ¹⁵ Meta-analyses have shown that whole-grain intake is associated with lower chances of developing CVD and cancer, but evidence of its association with autoimmune disease is currently limited. ^2,3 Future research should seek to explore possible relationships between whole-grain consumption and autoimmune disease.

Fermented dairy products (FDPs), such as Greek yogurt and certain cheeses, are also parts of the MD. They are thought to benefit overall health through a variety of mechanisms. FDPs contain metabolically active lactic acid bacteria, which produce lactic acid via fermentation of carbohydrates. ¹⁶ Some lactic acid bacteria have proteolytic capabilities that allow them to produce peptide molecules that are shown to have immune-mediating effects. ¹⁷ However, the directionality of these effects on inflammation seems to be mixed. Research in animal models has shown some FDP-derived peptides to have pro-inflammatory effects, such as stimulating lymphocyte proliferation or macrophage activation and phagocytosis. ¹⁸ However, in vitro research on human endothelial cells also demonstrates other FDP-derived peptides to have anti-inflammatory effects via attenuating expression of immune signaling molecules, such as ICAM-1 and NF-kB. ¹⁹ Despite these conflicting immunomodulatory effects seen in animal and in vitro models, a systematic review of clinical trials has shown an overall attenuating effect of FDPs on inflammatory activity in humans, with a substantial anti-inflammatory signal seen only in fermented, as opposed to nonfermented, dairy products. ²⁰ This suggests that although FDPs have variable activating and inhibiting effects on immune system activation, they may be clinically associated with overall attenuation of clinical inflammatory markers.

Moderate red wine consumption (less than 2 glasses per day) is considered a part of the MD. ¹ Alcohol intake is known to be associated with a number of adverse outcomes, including increased cancer and CVD risk. ²¹ However, literature has shown that moderate alcohol consumption (2 drinks per day for males or 1 drink per day for females) is associated with reduced chances of developing inflammatory arthritis such as RA and other autoimmune diseases, including systemic lupus erythematosus. ^22–24 Red wine is thought to reduce inflammation through polyphenols, similar to those found in whole grains, which result in increased expression of antioxidant enzymes responsible for clearing pro-inflammatory free radical species. ²⁵ In addition, direct effects of alcohol and downstream impacts of its metabolites have been shown to have various immunomodulatory effects, such as attenuation of B cell proliferation and maturation, as well as inhibition of helper T cell subtypes and subsequently reduced cytokine production. ^26,27 It should be noted that research has largely only shown benefits associated with moderate alcohol consumption in reducing RA risk. Heavy alcohol consumption is not conclusively shown to mitigate the probability of developing RA and is known to be associated with many health consequences such as cirrhosis, diabetes, and CVD. ²¹

Clinical Research on the Mediterranean Diet and Rheumatoid Arthritis

The literature behind the MD’s association with improved outcomes in CVD, obesity, and diabetes is well-known. However, emerging clinical research has found that it may also have benefits in prevention and management of autoimmune conditions like RA. ^28–30 Recent, large, population-based cohort and case-control studies in the United States and Europe (France, Greece, Sweden) have sought to elucidate associations between the MD and chances of developing RA.

Johansson et al (2018) ³¹ was a case-control study among a large population of Swedish patients with RA that aimed to determine associations between rates of RA development and adherence to the MD. It found that higher MD adherence was associated with decreased chances of developing RA. However, this effect was only observed in males and those with seropositive RA. There may be reasons for this selectivity. Regarding seropositivity, there are potential etiologic differences between seropositive (rheumatoid factor and/or anti–cyclic citrullinated peptide antibodies positive) and seronegative (rheumatoid factor and anti–cyclic citrullinated peptide antibodies negative) RA, with research showing that dietary factors such as coffee intake are associated with seropositive but not seronegative disease. ³² Regarding sex differences, prior retrospective and prospective studies with all-female cohorts did not find an association between the MD and RA risk, which was similar to the findings of Johansson et al. ^33,34 Taken together , this research suggests sex as a possible factor mediating the relationship between diet and RA risk and highlights this as an area for future inquiry.

However, not all studies were able to observe such differences between the MD and RA risk. A large prospective cohort study done among patients in the United States showed that among patients at the end of the study period who had developed RA, lower MD adherence was not associated with development of either seropositive or seronegative disease. ³³ The heterogeneity of results observed in these studies might have been due to diverse patient characteristics among the global patient populations they investigated, as well as methodological differences in measurement of MD adherence.

There are few randomized clinical trials (RCTs) investigating nutritional interventions among patients with RA and even fewer investigating the MD specifically. However, the past few years have seen 2 high-quality RCTs in this field (Table). The Mediterranean Diet in Rheumatoid Arthritis trial randomized patients with RA to a Mediterranean diet plan and lifestyle consultation aiming to promote physical activity or usual standard of care. ³⁵ At the end of the study period, those in the intervention group had significantly lower RA symptom severity scores. However, due to the experimental arm of the intervention, including both a dietary intervention (the MD) and a lifestyle counseling intervention, it is difficult to state which of these contributed more to the positive effects observed in this arm. Additionally, postintervention RA symptom severity scores between the intervention and control groups trended toward, but did not ultimately achieve, statistical significance.

Table:

Comparison of randomized clinical trials on the Mediterranean diet and disease activity in rheumatoid arthritis

Clinical trial	MADEIRA (2023)	ADIRA (2020)	Sköldstam et al (2003)
Population description	40 female patients with well-controlled RA.	50 patients (77% female) with well-controlled RA.	51 patients (80% female) with well-controlled RA.
Notable exclusion criteria	Changes in treatment regimen within the past 6 mo. Presence of active disease (DAS28 a > 5.1).	Changes in treatment regimen within the past 8 wk.	Changes in disease-modifying antirheumatic drugs within the past 3 mo, steroids within the past 4 wk, or NSAIDs within the past 10 d.
Intervention(s)	Personalized dietary plans according to principles of the MD (without premade meals). Web platform to provide patient education and to facilitate MD adherence.	Combination of premade meals and patient-prepared meals. Recipe books based on the MD to facilitate dietary adherence. Prominently featuring food with possible anti-inflammatory associations (including salmon, whole-grain cereals, yogurt, pomegranate, and juice shots with probiotics).	3 wk of premade meals adherent with the MD and dietary lessons on the MD, followed by participants preparing their own meals in accordance with the MD.
Comparison	Generic dietary advice and physical activity recommendations without use of the web platform.	Premade meals and dietary recommendations corresponding to the average Swedish diet.	3 wk of ordinary hospital food, followed by participants preparing their own meals per their usual preferences.
Measurement of RA disease activity	DAS28. a	DAS28. a	DAS28. a
Measurement(s) of MD adherence	Standardized questionnaire.	Dietary history interview.	Standardized questionnaire and dietary history interviews.
Outcome	Significantly lower post- (2.83 ± 0.19) vs pre-intervention (2.71 ± 0.14) DAS28 a a scores in the intervention group (P < .001). Postintervention DAS28 scores between the intervention and control groups trending toward significance (P = .054).	Significantly lower post- (3.39 [2.66–4.41]) vs pre-intervention (2.71 [2.41–3.79]) DAS28 a a scores in the intervention group (P = .012). No significant difference in postintervention DAS28 scores, tender or swollen joint count, ESR/CRP between intervention and control groups.	Significantly lower post- vs pre-intervention DAS28 a scores (P = .047), swollen joint count (P = .006), and CRP (P = .001) in the intervention group. No significant changes in the aforementioned metrics in the control group.

^a Disease activity score 28, a composite score used to measure overall disease activity among patients with RA.

ADIRA, Anti-Inflammatory Diet in Rheumatoid Arthritis; CRP, c-reactive protein; ESR, erythrocyte sedimentation rate; MADEIRA, Mediterranean Diet in Rheumatoid Arthritis; MD, Mediterranean diet; NSAID, nonsteroidal anti-inflammatory drug; RA, rheumatoid arthritis.

Also notable is the recent Anti-Inflammatory Diet in Rheumatoid Arthritis trial. ³⁶ This crossover trial among Swedish patients with RA randomized participants to an experimental group of an anti-inflammatory diet vs a control group of a typical Swedish diet. It then had participants switch groups after a washout period. The anti-inflammatory diet in this study, although not explicitly labeled as the MD, did have many features consistent with the MD, including exclusively fish-based animal protein intake, whole grains, yogurt and other FDPs, and vegetables. Similar to the Mediterranean Diet in Rheumatoid Arthritis trial, although this study found a reduction in RA symptom severity scores postdietary intervention compared to pre-intervention, it did not find substantial differences in RA symptom severity between its control and experimental groups at the end of the study period. Taken together, the findings of these recent RCTs may imply that although their dietary interventions may have had some statistically significant impact on RA disease activity, the magnitude of the effect was not sufficient to meet clinical significance. This could be due to the smaller sample size of the studies and insufficient statistical power. It could also be due to the fact that their population of patients with RA was overall less symptomatic at baseline, with lower symptom severity scores, than those in earlier clinical trials. ³⁷

A glance at the aforementioned literature seems to suggest that clinical evidence supporting the MD’s use in management of RA does exist. However, there are still inconsistencies with which substantial population-level benefits are seen with MD-based dietary interventions. This observation is also noted by several meta-analyses in this field. ^38,39

Conclusion

Nonpharmacologic interventions in autoimmune disease are topics of great interest for both clinical research and patients. Dietary interventions, like the MD, show promise in reducing the chances of developing RA and mitigating symptom severity in those living with these diseases. Available RCTs among patients already with RA signal that MD interventions may lead to statistically significant reductions in self-reported RA symptoms. However, they do not conclusively show that these effects are of clinical significance. Despite this, the robust body of evidence pointing to its beneficial effects in CVD, cancer, and metabolic disorders still makes it a valuable dietary pattern to promote in clinical practice. ^2,3 Furthermore, its benefits in CVD risk reduction make it an appealing dietary pattern for patients with RA, particularly due to higher CVD morbidity and mortality seen in this patient population. ¹¹ Future research should seek to better explain relationships between the MD or other dietary patterns and RA, as well as the efficacy of exercise and other lifestyle-based interventions in management of RA and other autoimmune conditions. Future RCTs should also seek to investigate the MD’s potential efficacy in reducing the chances of developing RA. This hypothesis has been supported by prospective cohort studies. However, it has not yet been studied in current clinical trials, which have focused on assessing the MD’s ability to ameliorate symptoms in individuals already with RA. Finally, the authors encourage current and future efforts to educate general practitioners and rheumatologists on lifestyle-based interventions in management of chronic disease. These might take the form of in-person (eg, journal clubs; lectures at professional society meetings; or seminars from dieticians, physical therapists, and other allied health personnel) and online (eg, nutrition modules in continuing medical education and online webinars) interventions.