REVIEW

published: 10 September 2019

doi: 10.3389/fnut.2019.00141

Nutrition Interventions in
Rheumatoid Arthritis: The Potential
Use of Plant-Based Diets. A Review
Jihad Alwarith 1*, Hana Kahleova 1 , Emilie Rembert 1 , Willy Yonas 1 , Sara Dort 1 ,
Manuel Calcagno 1 , Nora Burgess 1 , Lee Crosby 1 and Neal D. Barnard 1,2
1
Physicians Committee for Responsible Medicine, Washington, DC, United States, 2 Adjunct Faculty, George Washington
University School of Medicine and Health Sciences, Washington, DC, United States

Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease, affects roughly

1% of the world’s population. RA pathogenesis remains unclear, but genetic factors
account for 50–60% of the risk while the remainder might be linked to modifiable factors,
such as infectious diseases, tobacco smoking, gut bacteria, and nutrition. Dietary triggers
may play an inciting role in the autoimmune process, and a compromised intestinal
barrier may allow food components or microorganisms to enter the blood stream,
triggering inflammation. In addition, excessive body weight may affect pharmacotherapy
response and the likelihood of disease remission, as well as the risk of disease mortality.
Edited by: Evidence suggests that changes in diet might play an important role in RA management
Lidia Santarpia, and remission. Several studies have shown improvements in RA symptoms with diets
University of Naples Federico II, Italy
excluding animal products. Studies have also shown that dietary fiber found in these
Reviewed by:
Ulkan Kilic, plant-based foods can improve gut bacteria composition and increase bacterial diversity
University of Health Sciences, Turkey in RA patients, thus reducing their inflammation and joint pain. Although some of the
Javaid Alam,
National University of
trigger foods in RA patients are individualized, a vegan diet helps improve symptoms by
Malaysia, Malaysia eliminating many of these foods. This review examines the potential role of a plant-based
*Correspondence: diet in mediating RA symptoms. Further research is needed to test the effectiveness of
Jihad Alwarith plant-based diets on joint pain, inflammation, and quality of life in patients with RA.
jalwarith@pcrm.org
Keywords: autoimmune, diet, inflammation, plant-based, vegan, vegetarian, rheumatoid arthritis
Specialty section:
This article was submitted to
Clinical Nutrition, INTRODUCTION
a section of the journal
Frontiers in Nutrition Rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease, affects roughly 1% of the
Received: 06 November 2018 world’s population (1). Hands, wrists, and knees are most commonly bilaterally affected causing
Accepted: 13 August 2019 inflammation, pain, and eventually permanent joint damage (2). Genetic factors may account for
Published: 10 September 2019 a portion of risk (3–5), while the rest might be linked to environmental factors or a combination
Citation: of genetic and environmental factors. Infectious diseases, tobacco smoking, and gut bacteria have
Alwarith J, Kahleova H, Rembert E, all been considered to play a role in the development or progression of RA (6). Medications are a
Yonas W, Dort S, Calcagno M, mainstay of treatment, but have unwanted side effects or are often expensive (7). Thus, changes in
Burgess N, Crosby L and Barnard ND
diet might be an easy and economical intervention in the management of RA.
(2019) Nutrition Interventions in
Rheumatoid Arthritis: The Potential
Several studies have shown a correlation between modifiable risk factors and improvement of
Use of Plant-Based Diets. A Review. symptoms and outcomes in RA patients. Excessive body weight and diets that include animal
Front. Nutr. 6:141. products (e.g., dairy and red meat) tend to impair RA management efforts and exacerbate
doi: 10.3389/fnut.2019.00141 symptoms, presumably due to their pro-inflammatory effects (8). In contrast, diets rich in

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Alwarith et al. Nutrition Interventions in Rheumatoid Arthritis

vegetables, fruits, and fiber are associated with lower BMI (9– Accumulating scientific evidence supports the health
11), have anti-inflammatory properties and help reduce pain advantages of vegetarian diets (22). Vegetarian diets are
and inflammation in these patients (12). Specifically, a 4-weeks characterized by reduced or eliminated consumption of animal
low-fat vegan diet has been shown to significantly improve RA products but may include dairy products and/or eggs, while
symptoms such as joint pain, stiffness, swelling and limitation in vegan diets contain only plant foods. Both vegetarian and vegan
function (13). Likewise, a 1-year intervention tested the effects of diets typically emphasize vegetables, fruits, grains, legumes, and
a 7–10 day fast, followed by 3.5 months of a gluten-free vegan diet nuts. This paper summarizes the associations between diet and
and gradual adoption of a vegetarian diet for the remainder of RA and makes a case for the potential benefits of a vegan diet in
the study period. Significant improvements in several RA disease RA management.
activity variables were observed after 1 month, including: number
of tender joints, Ritchie’s articular index, number of swollen
joints, pain score, duration of morning stiffness, grip strength,
PATHOGENESIS OF RHEUMATOID
erythrocyte sedimentation rate, C-reactive protein, white blood ARTHRITIS
cell count, and a health assessment questionnaire score. These
improvements were maintained after 1 year (14). Rheumatoid arthritis is an autoimmune disorder characterized
Several studies have reported lower risk of autoimmune by inflammation of the synovial lining. Inflammation results in
diseases with a vegan diet. A 2013 study, using data from an increase in the number of synoviocytes and immune cells. As
the Adventist Health Study-2 (AHS-2) cohort (n = 65,981), a result, the synovial membrane becomes hyperplastic, resulting
described a lower incidence and prevalence of hypothyroidism in eventual cartilage and bone erosion (23). The pathogenesis of
in people following vegan diets, compared to omnivorous, rheumatoid arthritis is illustrated in Figure 1.
lacto-ovovegetarian, semi-vegetarian, and pesco-vegetarian diets Studies have suggested that RA risk is influenced by a genetic
even after controlling for BMI and demographic variables. predisposition, environmental factors, or a combination of both.
The researchers speculated that the inflammatory properties of It is clear that immune cells, such as lymphocytes, neutrophils,
animal products could explain the lower risk in vegans (15). and macrophages, play an important role in the pathophysiology
Tonstad et al. also examined the correlation between dietary of RA (24). Within the synovium of RA patients are macrophages
patterns and hyperthyroidism in the AHS-2 study population. and T cells that produce cytokines which promote inflammation
Noting that the most common cause of hyperthyroidism and cell migration. Cytokines tumor necrosis factor-α (TNF-α),
is Graves’ Disease, an autoimmune disorder, the researchers interleukin-1 (IL-1), and interleukin-6 (IL-6), produced by
observed a 52% lower risk of hyperthyroidism with those macrophages, and cytokine interleukin-17 (IL-17), produced by
consuming a vegan diet when compared to omnivores (16). CD4+ T cells, are commonly involved in the inflammatory
Compared to non-vegetarians and lacto-ovovegetarians, vegans response and subsequent cartilage destruction.
reported the lowest intake of saturated and trans fats, the highest These cytokines activate synoviocytes and cause them to
intake of fiber, and displayed the lowest mean BMI (16), all of proliferate, creating proteases in the synovial fluid, which lead
which could be relevant for the risk of hyperthyroidism. Potential to the breakdown of cartilage and hypertrophied synovial tissue,
down-regulation of insulin-like growth factor (IGF-1) (17) and known as pannus (25). Pannus can be further exacerbated by
higher consumption of polyphenols (18) in vegans are other angiogenesis. The additional blood supply to invaded cartilage
possible protective mechanisms against hyperthyroidism. and bone allows immune cells to infiltrate the joints, worsening
Lauer et al. examined risk factors for multiple sclerosis, an the synovial hyperplasia (24). Cytokines also combine with
autoimmune disease of the central nervous system, in male receptor activator of nuclear factor kappa-β ligand (RANKL) to
World War II veterans using the 1993 nationwide case-control stimulate osteoclast activity, which leads to bone erosion. The
study (n = 10,610) (19, 20). In the U.S, meat and dairy sales expression of RANKL is also affected by T cells (26).
were significantly correlated with multiple sclerosis risk, while Synovial dendritic cells stimulate immune response by
inverse associations were found with fruit and vegetable sales. attracting T lymphocytes and activating antigen-specific T cells
Affluence was also positively associated with multiple sclerosis and, in turn, B cells. In this positive feedback loop, activated B
risk, corresponding with increased meat and dairy consumption cells stimulate CD4+ T cells, producing more cytokines (27, 28).
with higher socioeconomic status. B cell proliferation can also lead to the creation of plasma cells,
These results suggest that a vegan diet, with a high which produce autoantibodies, including rheumatoid factor (RF)
intake of fruits and vegetables and the elimination of animal and anti-citrullinated protein antibodies (ACPAs) (29). These
products, could protect against the development of autoimmune autoantibodies infiltrate the joint through newly developed blood
conditions. In contrast, diets high in animal products and vessels and are currently used in the diagnosis and prognosis of
low in fiber might increase the risk of developing these RA (30).
autoimmune conditions.
Intestinal gut health might play a role in the observed anti- WEIGHT CONTROL AND RA
inflammatory effects of dietary fiber. Studies have shown that
dietary fiber can alter the composition of gut bacteria and Studies show that excessive body weight increases the risk for
increase the bacterial diversity, which is oftentimes lacking in RA developing RA (31). A 2011 report defined obesity as having
patients, thus preventing intestinal damage (21). higher than normal levels of all triglycerides found in adipose

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Alwarith et al. Nutrition Interventions in Rheumatoid Arthritis

FIGURE 1 | RA pathogenesis. Angiogenesis: Reproduced from Sitox / E+ via Getty Images (https://www.gettyimages.com/detail/photo/vascular-system-veins-
royalty-free-image/155351346). RA Hand: Reproduced from BSIP / Universal Images Group via Getty Images (https://www.gettyimages.com/detail/news-photo/
illustration-of-a-hand-suffering-from-rheumatoid-arthritis-news-photo/586117004?adppopup=true).

tissue, which can contribute to negative health outcomes such as by excess body weight further exacerbates inflammation in these
increased inflammation, type 2 diabetes, insulin resistance, and patients; therefore, weight loss could be an effective therapy for
cardiovascular disease (32). Excessive adipose tissue secretes pro- individuals diagnosed with RA.
inflammatory cytokines (adipokines) into circulation, which can Multiple studies have concluded that RA patients who are
increase adipose tissue growth, leading to a positive feedback overweight have worse outcomes than those with a normal body
cycle of adipokine secretion and tissue inflammation (33). mass index (BMI≤24.9) (34, 35). The Canadian Early Arthritis
Adipose tissue stores energy in the form of fat, which Cohort (CATCH) study (n = 982) showed that being overweight
helps regulate several physiological processes such as insulin or obese were independently associated with a decreased chance
sensitivity, metabolism, and inflammation. However, having for achieving sustained RA remission. Overweight patients were
excess fat in adipose tissue and non-adipose tissue cells can 25 and 47% less likely to achieve sustained remission within 3
hinder these physiological processes. Recent studies have found years, respectively (36). Similarly, the Nurses’ Health Study I and
that increased fat inside cells is related to increased inflammation II, two prospective cohort studies including a total of 239,131 U.S.
(32). In addition, the extra stress placed on weight-bearing joints female nurses, reported that being overweight at 18 years of age

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Alwarith et al. Nutrition Interventions in Rheumatoid Arthritis

was associated with a 35% increased risk of developing RA and a ASSOCIATIONS BETWEEN DIET AND RA
50% risk of developing seropositive RA in adulthood (33).
Weight loss could be useful for alleviating the effects of Diet and Inflammation
inflammation and obesity in RA patients. A 2018 retrospective A 2015 study (n = 50) observed reductions in inflammatory
analysis (n = 174) evaluated the association between weight loss scores in overweight or obese, otherwise healthy, participants
and RA disease activity, and found that overweight individuals randomized to a 2-month vegan, vegetarian, or pesco-vegetarian
who lost ≥5 kg had a three-fold increased odds of disease dietary intervention (p < 0.05) compared to those placed on a
activity improvement compared to those who lost <5 kg. The semi-vegetarian or omnivorous diet. Subjects in all five groups
clinical disease activity scale quantifies RA disease activity from were counseled to choose low-fat foods, but only the vegan
0 to 76 (higher scores indicating higher disease activity) by participants met the mean percentage energy from fat and
measuring the number of tender and swollen joints as well as saturated fat (≤30% energy from fat and ≤7% energy from
a physician and patient global assessment on a 0–10 scale. The saturated fat) recommendations. The researchers attributed this
study concluded that each kilogram of weight lost was associated observation to the elimination of the leading sources of fat in
with a clinical disease activity index improvement of 1.15 (p = the western diet (beef, cheese, milk, and poultry; 8). Diets high
0.0026) (37). Sparks et al. investigated the effect of weight loss in fat and processed meat have been positive associated with
in RA patients after bariatric surgery (n = 53) and had similar inflammatory markers C-reactive protein (CRP), interleukin-
findings. At a 12-month, post-surgery follow-up, 6% of patients 6 (IL-6), and homocysteine, while diets high in whole grains
had moderate/high disease activity compared to 57% at baseline. and fruit have been inversely associated with these biomarkers
At the most recent follow-up (mean 5.8 years after surgery) (50). Likewise, vegetarian diets are negatively associated with
74% of patients were in remission compared to 26% at baseline. CRP levels (p < 0.000) (51). Furthermore, a 3-week vegan
Furthermore, inflammatory markers were significantly lower at lifestyle intervention resulted in a 33% reduction in CRP levels
the 6-, 12-month, and most recent follow up visits of 5.8 ± 3.2 (p < 0.001), which was attributed to the anti-inflammatory
years following surgery (p < 0.05, p < 0.001, and p < 0.001, components of the vegan diet, such as high fiber intake (>49
respectively) (38). Weight loss may be a key non-pharmacologic g/day) (12).
approach in reducing inflammation and RA disease activity. Research has found that a low-fat vegan diet improves
In addition to the importance of weight management, a 2015 RA symptoms, such as the degree of pain, joint tenderness,
nested case-control study (n = 33,456) found an association and joint swelling (13). A randomized clinical trial found
between elevated serum cholesterol and the subsequent that a gluten-free vegan diet decreases immunoglobulin G
development of RA. Women diagnosed with RA at follow- (IgG) in RA patients, an oftentimes elevated pro-inflammatory
up had higher total cholesterol levels at baseline compared antibody (52). A Cretan Mediterranean Diet, rich in olive
with healthy controls (OR 1.42; 95% CI 1.08–1.87). However, oil, cereals, vegetables, fruits, and legumes, also resulted in
this relationship was not observed in men (39). The positive significant improvements in Disease Activity Score (DAS28),
association between total cholesterol levels and RA development Health Assessment Questionnaire (HAQ), C-Reactive Protein
in women suggests a possible mechanism related to female (CRP), and swollen joint counts in patients with RA (53).
sex hormones. A low-fat, vegan diet, which reduces plasma However, further investigation is needed as previous research has
cholesterol and has a hormone-stabilizing effect (40–42), also shown that a high-fat diet may change the composition of
may therefore help protect against the development of RA in the gut bacteria and be linked to inflammation (54–56).
women (39). The naturally low-fat, fiber-rich components of a vegan
Vegetarian and vegan diets have been consistently shown diet might mediate the pathways that alleviate joint
to be effective weight loss and cholesterol-lowering strategies inflammation and pain, as observed through reduced CRP
compared with other conventional calorie-restricted diets. Two levels and improved inflammatory scores. These findings
meta-analyses of randomized clinical trials showed a benefit of highlight the need for a randomized study that objectively
vegetarian, especially vegan, diets on body weight, compared measures biomarkers of inflammation related to plant-based
with other diets (43, 44). The strong evidence is supported dietary changes.
by observational studies (9–11). Likewise, the evidence for the
effectiveness of vegetarian, particularly vegan, diets in lowering Relationship Between Inflammation and Protein
total and LDL-cholesterol in clinical trials is consistent (45, Quantity and Source
46) and is further supported by observational studies (47, 48). Rheumatoid arthritis is a type of inflammatory polyarthritis,
Elkan et al. (n = 66) observed reductions in BMI, LDL, and characterized by inflammation in more than four joints (57).
total cholesterol after both 3 and 12 months of a gluten- Higher red meat intake has been positively associated with
free vegan diet (p < 0.01). These results correspond with the inflammatory polyarthritis (p = 0.04). Participants consuming
improvements in Disease Activity Score of 28 joints, Health the highest levels of red meat (OR 1.9, 95% CI 0.9–4.0), total meat
Assessment Questionnaires, and CRP levels (p ≤ 0.008) after 12 (OR 2.3, 95% CI 1.1–4.9), and total protein (OR 2.9, 95% CI 1.1–
months (49). These findings suggest that by improving weight 7.5), displayed a higher risk for inflammatory polyarthritis when
loss and lowering serum cholesterol levels, plant-based diets compared to participants with lower meat and protein intakes
might improve RA symptoms and decrease the risk of developing (58). These findings suggest that meat intake increases the risk
the disease. of inflammatory arthritis.

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Gögebakan et al. (n = 932) examined the effects of weight products has been shown to reduce adiposity and improve CRP
loss from varying dietary compositions on high sensitivity C- and adiponectin levels (61).
reactive protein (hsCRP) using data from the Diet, Obesity, These findings highlight some of the potential mechanisms
and Genes study (DiOgenes) (59). After an initial weight loss by which vegan diets could improve inflammation in RA
of at least 8%, participants were randomized to 1 of 5 dietary patients. Apart from eliminating leading triggers, reducing
interventions for 26 weeks. These interventions included: (1) animal protein has been linked to lower inflammatory markers
low protein, low glycemic index; (2) low protein, high glycemic and increased insulin sensitivity. Research also suggests that the
index; (3) high protein, low glycemic index; (4) high protein, low-glycemic index and high fiber content of the diet could
high glycemic index; and (5) control diet based on national reduce inflammatory gene expression. Thus, a naturally anti-
dietary guidelines. The initial calorie-restricted period resulted inflammatory vegan diet could improve RA symptoms.
in a significant improvement of hsCRP, which is likely due to
calorie restriction-stimulated activation of protective metabolic
pathways, thus reducing inflammatory markers. Low-glycemic Fat Intake and Inflammation
index diets resulted in a further decrease of hsCRP of −0.46 mg/L A 3-month Mediterranean dietary intervention which
greater than in the high-glycemic-index groups. Similarly, hsCRP significantly increased the ratio of monounsaturated
values decreased −0.25 mg/L more in the low-protein groups fats:saturated fats improved rheumatoid arthritis symptoms
than in the high-protein groups. Gögebakan et al. postulate as measured by pain score and physical function (62). These
that the lower post-prandial glucose levels on low-glycemic findings suggest that saturated fat might be linked to poorer
index diets decrease inflammatory gene expression, resulting in rheumatoid arthritis symptoms, while monounsaturated fats are
reduced hsCRP levels (59). associated with improved outcomes (63).
A high-protein diet (28% protein, 43% carbohydrate, 13 g A 2013 study (n = 15) examined the acute antioxidant and
fiber) reduced insulin sensitivity by 12% while a high cereal fiber inflammatory response following a high-fat meal in overweight
diet (17% protein, 52% carbohydrate, 43 g fiber) improved insulin participants over an 8 h period. Pro-inflammatory TNF-α and IL-
sensitivity by 13% in 111 overweight and obese participants 6 concentrations increased significantly in response to the meal.
(60). Participants assigned to the high fiber diet displayed 25% TNF-α levels increased by 12 pg/mL (p < 0.001) in the first
higher insulin sensitivity than those on the high protein diet hour and remained significantly above fasting values throughout
after the 6-week intervention (p = 0.008). These results indicate the 8 h. IL-6 levels constantly rose after the meal, doubling
that high dietary protein (≥25–30% of energy) induces insulin its basal value after 2 h (+0.3 pg/mL, p < 0.05) and reached
resistance. Interestingly, insulin sensitivity was not significantly a maximum concentration after 8 h. Likewise, total cholesterol
altered after 6 weeks of a mixed diet (23% protein, 44% levels increased throughout the post-meal study period and
carbohydrate, 26 g fiber). While dietary proteins are normally peaked at the 8 h point (+7 mg/dl; p < 0.01) (64).
degraded by enzymes in the upper gut, these results indicate High-fat meal ingestion also increased endogenous
that cereal fibers may impede protein absorption in the small antioxidants, uric acid and thiols, indicating the presence
intestine. Thus, a low-glycemic, high-fiber and low-protein diet of oxidative stress. The area under the curve of both uric acid
could mediate inflammation by decreasing pro-inflammatory and thiols was significantly correlated with the triglycerides area
gene expression and improving insulin sensitivity, even after under the curve (Pearson coefficient 0.923). This concomitant
significant reductions in inflammatory markers due to weight loss antioxidant response to high-fat meal ingestion highlights the
(59, 60). Ley et al. (n = 3,690) sought to examine the association pronounced impact of dietary-induced inflammation, due to a
between red meat intake and inflammatory biomarkers. Cross- single meal (64).
sectional data from the Nurses’ Health Study was analyzed and A moderate (3.68–13.67 g) or high (>13.67 g) reduction in
the association between total, unprocessed, and processed meat saturated fatty acid consumption has been shown to reduce
intake with CRP and adiponectin were measured. Greater total, leptin, a pro-inflammatory adipokine, and increase adiponectin,
unprocessed, and processed red meat intakes were associated an anti-inflammatory adipokine, in obese adolescents. Likewise
with significantly higher plasma CRP concentrations and lower a decrease in the pro-inflammatory leptin/adiponectin (L/A)
adiponectin levels for participants in the highest quintiles of and an increase in the anti-inflammatory adiponectin/leptin
these groups. Similarly, lower CRP values were associated with (A/L) ratio was observed after the reduction in saturated fatty
substituting a serving of total red meat with a combination of acid consumption. A negative correlation between the change
alternative protein sources (including poultry, fish, legumes, or in SFA and adiponectin as well as A/L ratio (p < 0.05 for
nuts) (β = −0.106, p ≤ 0.02). However, these associations were both) was observed. Participants with the greatest reduction
no longer significant after adjustment for BMI, as well as medical of SFA increased their adiponectin levels by 50%, followed by
and lifestyle variables (61). 20% and 23% in the moderate and low SFA reduction groups,
BMI accounted for a statistically significant proportion of respectively (p ≤ 0.05) (65). This study demonstrates that a
associations with these biomarkers. The results of this study moderate change in SFA intake can yield significant changes in
indicate that while greater red meat intake is associated with inflammatory measures.
higher plasma concentrations of inflammatory biomarkers in The primary source of saturated fat in the U.S. is dairy
diabetes-free women, adiposity accounted for a statistically products, followed by meat, eggs, and various processed foods
significant proportion of these associations. Excluding animal (66). A low-fat, vegan diet is naturally free of animal products

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Alwarith et al. Nutrition Interventions in Rheumatoid Arthritis

and low in SFA, potentially improving RA symptoms by up- remain speculative (77). Some studies suggest a connection
regulating anti-inflammatory markers and down-regulating pro- between intestinal inflammation and joint inflammation (78).
inflammatory adipokines. Kim et al. observed that a vegan diet lowers the relative
abundance of Enterobacteriaceae in the gut, which in turn
Complex Carbohydrates, Fiber Intake, and reduces fecal lipocalin-2 (Lcn-2), a sensitive biomarker of
Inflammation intestinal inflammation, within 28 days (54). Table 1 lists the
A 2009 systematic review (n = 554) sought to determine type of correlation between bacterial species, dietary factors,
the influence of dietary fiber on CRP values in clinical trials and inflammation.
(67). Increased fiber consumption, with corresponding altered
fat intake and weight loss, was associated with lower CRP Elimination Diets in the Treatment of RA
concentrations of 25–54% (p = 0.05) in six of the seven reviewed As explored throughout this review, a growing body of research
studies. The use of psyllium fiber supplementation in the seventh suggests that RA may have a gastrointestinal component and may
study did not result in lower CRP values, indicating that the even originate in the gut, at least for some individuals. In addition
effects of psyllium do not replicate those of a high-fiber diet to other dietary considerations, antigenic load and sensitivities to
(68). A significant decrease in inflammatory marker levels follows specific foods may contribute to both the onset and severity of
decreased fat intake (69), increased fiber consumption (70–72), RA (81).
and weight loss (69). Thus, a vegan diet, structured around low- An early review by van de Laar et al. revealed that arthritic
glycemic foods and naturally high in fiber, has potential to lower symptoms are associated with multiple gut-related conditions,
inflammatory markers. including celiac disease, intestinal bypass, and inflammatory
Dietary fiber is fermented by gut microbiota to produce bowel disease. Moreover, mast cells, which are activated in
short chain fatty acids (SCFAs), which have a beneficial effect response to foreign antigens, often in a process mediated by
on colonocytes (21, 73). Damage to colonocytes can result in immunoglobulin E (IgE), are present in elevated numbers in the
intestinal permeability, endotoxemia, and inflammation. Thus, synovial tissues of patients with RA (82, 83). Even more telling,
a diet rich in fiber provides an abundant energy source cross-reactive antibodies to various foods are found in the small
to colonocyte, reducing the risk of pathogens entering the intestine of those with RA at markedly higher levels than in
bloodstream and inducing an inflammatory response. healthy individuals (84).
These findings suggest that dietary fiber can reduce local and Multiple studies have found improvements in RA patients
systemic inflammation, and that modulating effects on the gut placed on an elemental diet in which all antigenic proteins are
bacteria composition, SCFA production, and intestinal barrier eliminated from the patient’s diet. The individual is given, as
integrity could be involved. a sole source of nutrition, a complete formula in which all
proteins have been broken down into free amino acids. A study
Microbiome and Inflammation conducted by Podas et al. found that placing patients with RA
The gut may play a key role in the pathophysiology of on an elemental diet was as effective as 15 mg/day of oral
RA. Permeability of the intestinal barrier allows for food prednisolone over a 2-week period (81). However, symptoms
components or bacterial endotoxins to enter the bloodstream. returned upon cessation of the elemental diet, just as for cessation
Absorption of endotoxins into circulation can trigger a of prednisolone. Similar benefits were not seen for patients on
systemic inflammatory response (74). This process may help a peptide diet containing protein fragments 3–6 amino acids in
explain the oftentimes elevated self-reactive antibodies and pro- length (85).
inflammatory T lymphocytes in RA patients (13, 21, 75). The Elimination diets, which remove one or more foods likely
maintenance of the intestinal barrier is largely dependent on the to trigger symptoms, have also been shown to induce clinical
composition of the gut microbiome. As discussed in the previous improvement in RA patients in clinical trials (52, 86). These
section, particular microbes ferment dietary fiber into the short improvements disappear when patients resume their normal
chain fatty acids (SCFAs) that serve as the primary energy diet (86).
source for colonocytes. Certain SCFAs, particularly butyrate, However, response to elimination diets is highly
have also been shown to ameliorate colonocyte DNA damage individualized. Darlington et al. reported that some RA patients
(21, 73). A microbiome lacking in diversity can result in were “good responders.” These individuals, who reported feeling
lower concentrations of these SCFAs, and therefore, impair the “better” or “much better” after an elimination diet (75% of
intestinal barrier, allowing pathogens to enter the bloodstream, respondents), showed profound improvements in all or nearly
and inducing an inflammatory response (74). Previous research all measures of disease activity. Interestingly, after analyzing
has shown that the microbiomes of RA patients not only lack a number of personal attributes, the only factor significantly
microbial diversity but are dominated by Prevotella copri (75, associated with a good response to the elimination diet was a
76). This bacterial species appears to lower the abundance of family history of atopy (86).
other beneficial species and thrive in untreated RA patients (75). One challenge in studying elimination diets for RA is that,
Thus, the gut microbiome and dietary fiber intake might have a as for food allergies, trigger foods are often unique to each
significant impact on RA disease activity. individual (87). Multiple methods have been tried to identify
The gut microbiome could mediate the connection between individual food sensitivities, with varying degrees of success. Skin
diet, inflammation, and RA, although these relationships prick testing (SPT) is a tool used to identify IgE antibody response

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Alwarith et al. Nutrition Interventions in Rheumatoid Arthritis

TABLE 1 | Microbiota and inflammatory associations.

Genus Dietary association Association with inflammation/RA References

Ruminococcus ↑Fruit and vegetables ↓Endotoxemia (79)

↑Non-digestible carbohydrates ↓Colorectal adenomas (80)
Roseburia ↓High protein/low carbohydrate diet ↓Inflammatory Bowel Disease (80)
↑Mediterranean diet ↓Colorectal adenomas
↓Animal protein
Bifidobacterium ↑Non-digestible carbohydrates ↓hs-CRP (80)
↑Plant polyphenols ↑Immune-modulation
↑Low fat diet ↑Gut mucosal barrier
↑Unsaturated fat
↑Date fruits
↑Mediterranean diet
↓Western diet
↓Beef
Lactobacillus ↑Non-digestible carbohydrates ↑Anti-inflammatory activities (80)
↑Plant polyphenols ↓hs-CRP
↑Unsaturated fat ↓Intestinal dysbiosis
↑Mediterranean diet ↓Inflammatory Bowel Disease
↓High fat diet
↓Western diet

↑Increase.
↓Decrease.

to a stimulus, but does not consistently correspond with reactions

TABLE 2 | Foods inducing symptoms in food-reactive RA patients (n = 41).
to offensive foods (88).
However, SPT and oral food challenges have both identified Food Percent of Food Percent of
foods capable of worsening RA symptoms in some individuals. patients affected patients affected
For example, SPT was used to identify corn, wheat, coffee,
Corn 57 Malt 27
soybeans, and other foods as possible triggers in 20 RA patients
Wheat 54 Cheese 24
who demonstrated reactivity in SPT (Note: the researchers did
Bacon/pork 39 Grapefruit 24
not test dairy products or red meat due to bovine spongiform
Oranges 39 Tomato 22
encephalopathy concerns). Of the 18 patients who subsequently
underwent an elimination period wherein they omitted common Milk 37 Peanuts 20

food allergens, followed by a challenge with foods they reacted Oats 37 Sugar (cane) 20

to in SPT, 13 (72%) experienced worsening symptoms after Rye 34 Butter 17

reintroduction of SPT-positive foods (89). Eggs 32 Lamb 17

Darlington et al. used elimination and oral food challenge Beef 32 Lemons 17
to identify foods capable of inducing symptoms in RA patients. Coffee 32 Soy 17
Forty-eight patients undertook a 6-week elimination diet; forty- From Darlington and Ramsey (90).
one were found to have foods that triggered symptoms. Foods
triggering symptoms for reactive patients are described in
Table 2 (90). challenge studies, one trial found strikingly higher levels of
Serum levels of food-specific antibodies and even rectal antibodies to milk, egg, pork, and codfish antigens, along with
food protein challenge have also been tried; however, these wheat, oat, and soy antigens, in the jejunal fluid of RA patients
methods have largely failed to identify a reliable link between when compared to controls. Given evidence suggesting these
specific foods and clinical symptoms (87). Additional foods results were not due to increased intestinal permeability from
have been implicated in some individuals using these and other NSAID exposure, study authors concluded that mucosal immune
methodologies. For example, the level of antibodies specific activation in the intestine could play a role in the pathogenesis of
to Saccharomyces cerevisiae (baker’s or brewer’s yeast) in the RA (84).
blood of RA patients strongly correlates with C-reactive protein However, a 2009 Cochrane review found “uncertain” effects
levels and erythrocyte sedimentation rate, both markers of of elimination and vegan diets as a result of inadequate data
inflammation (91). reporting (92); little if any research has since been published
Animal foods, including milk, eggs, and dairy, have also on the effects of elimination diets on RA. The lack of recent
been found to be particularly problematic for RA patients, as research on this topic is concerning, since emerging research has
evidenced by studies showing symptomatic improvement with shown that diets eliminating specific foods can be effective for
a vegan diet (13, 52). Certain cereals may also pose problems other inflammatory and autoimmune conditions, such as Crohn’s
in addition to animal products. Confirming findings from food disease (93, 94) and eosinophilic esophagitis (95–98). Eliminating

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Alwarith et al. Nutrition Interventions in Rheumatoid Arthritis

gluten has also been found to not only ameliorate intestinal and increase the bacterial diversity in RA patients, potentially
signs and symptoms in celiac disease (CD) but also to improve reducing inflammation and joint pain. Moreover, although
arthritis/arthralgia in some CD patients (99, 100). some of the trigger foods in RA patients are individualized,
The relationship between diet and RA is complex, and a vegan diet comprised of fruits, whole grains, legumes,
foods that trigger reactions in patients are individualized and and vegetables, can improve symptoms by eliminating many
therefore can be challenging to detect. However, a vegan common trigger foods. Elimination of additional food triggers
diet comprised of fruits, grains, legumes, and vegetables can may be necessary depending on the individual food sensitivities.
be a beneficial start for RA patients. In addition to being Further research is needed to test the effectiveness of plant-based
associated with lower BMI and greater fiber intake, this diet may diets on joint pain, inflammation, and quality of life in patients
help improve symptoms by eliminating many common trigger with RA.
foods. Further elimination may be beneficial depending on
the individual. AUTHOR CONTRIBUTIONS

CONCLUSION JA and HK contributed organization of the manuscript. MC

drafted the manuscript and composed the outline. JA, HK, ER,
Several studies have shown that joint pain and other RA WY, SD, MC, NBu, and LC wrote sections of the manuscript.
symptoms may be modified by dietary factors. Excessive body NBa reviewed and approved the submitted version. All authors
weight and diets that include animal products (e.g., dairy, red had full access to data and revised and approved the manuscript
meat) exacerbate the RA symptoms likely due to their pro- for publication.
inflammatory effects. In contrast, diets rich in vegetables, fruits,
and fiber are associated with lower BMI, have anti-inflammatory FUNDING
properties and help reduce pain and inflammation in these
patients. Studies have shown that dietary fiber found in these This work was funded by the Physicians Committee for
plant-based foods can improve the gut bacteria composition Responsible Medicine.

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eosinophilic esophagitis. Clin Gastroenterol Hepatol. (2017) 15:1698-707.e7. Conflict of Interest Statement: The authors declare that the research was
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98. Reed CC, Fan C, Koutlas NT, Shaheen NJ, Dellon ES. Food elimination be construed as a potential conflict of interest.
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100. Jericho H, Sansotta N, Guandalini S. Extraintestinal manifestations of celiac copyright owner(s) are credited and that the original publication in this journal
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