A diet including intake of only fruits and vegetables, eliminating any animal product or by-products is vegan diet. This has been repeatedly reported to be clinically beneficial for disease remission in RA patients (44–46, 57). Studies conclude that the improvements in disease activity might have been a result of reduction in immune-reactivity to certain food antigens in the gastrointestinal tract that were eliminated by changing the diet (45, 46). Furthermore, Hafström et al. (76) observed that during fasting there was decrease in duration of morning stiffness, ESR, articular index, concentrations of acute-phase reactants including orosomucoid, C3 and haptoglobin and an increase in hemoglobin. Moreover, the release of lysozyme by neutrophils was reduced in RA patients, the components of which are known to cause inflammation and destruction of joints. Leukotriene B4 (LTB4) is a pro-inflammatory mediator, involved in activation of neutrophils, eosinophils, and monocytes, production of pro-inflammatory cytokines, which further leads to tissue inflammation and neutrophil-mediated tissue damage (77). It was reported that the release of LTB4 from neutrophils was markedly reduced at completion of the fasting week (76).

Furthermore, it has been reported that during starvation, ketone bodies, including β-hydroxybutyrate (BHB), increase and serve as an alternate source of ATP in mammals (78). NLRP3 inflammasome regulates release of IL-18 and IL-1β (pro-inflammatory cytokines) in macrophages and gets activated on receiving damage-associated molecular patterns (79). Yun-Hee Youm et al. reported inhibition of activation of NLRP3 inflammasomes by BHB in response to various NLRP3 activators. BHB also reduced NLRP3-mediated release of IL-1β and IL-18 from human monocytes. Thus, the study concludes that starvation or ketogenic diets may play an anti-inflammatory role through inflammasome inhibition in BHB-mediated manner (79). This has been as well reported in the review by Tedeschi and Costenbader (80).

Müller et al. conducted a meta-analysis in order to find the effect of fasting followed by vegetarian diet in patients with RA. The study reports clinically and statistically significant beneficial long-term effect on RA patients, which may be used as a treatment for the disease (81).

Therefore, fasting followed by vegan diet or vegan diet alone can potentially reduce symptoms and disease activity in RA patients independent of changes in intestinal microflora. Improvements observed can be attributed to reduced exposure to potential antigens contributed by the omnivorous diet of RA patients.

Mediterranean diet is rich in oleic acid, omega-3 fatty acids, unrefined carbohydrates, and phytochemicals (82). MD and particularly the Cretan MD involve high consumption of olive oil, cereals, fruits, vegetables, fish, and legumes; less red meat; and inclusion of moderate amount of red wine in diet. A study conducted by Sköldstam et al. concluded that on administration of Cretan MD to RA patients, inflammation was reduced, vitality and physical functions were improved (48). An important component of MD is olive oil which has antioxidant properties, is rich in oleic acid (18:1n-9), is metabolized to form eicosatrienoic acid (20:3n-9), and has anti-inflammatory effects similar to those of n-3 polyunsaturated fatty acids from fish oils (48). Studies have also shown that incorporation of olive oil in diet decreases the risk of developing RA (83). Rosillo et al. (84) have shown that administration of extra virgin olive oil in CIA mice (type II collagen-induced arthritis) reduced the serum levels of cartilage oligomeric matrix protein (COMP) and metalloproteinase-3 (MMP-3) that are the predictive markers of cartilage and joint damage in RA. The expression of pro-inflammatory cytokines including IL-1β, TNF-α, and IL-17, involved in progression of the disease, was also reduced. STAT-3 transcription factor promotes abnormal growth and prolonged survival of synovial cells (85) as well as in Th17 cell differentiation (86) in RA. Rosillo et al. also concluded that olive oil diet interfered with STAT-3 signaling by suppressing phosphorylation of STAT-3 and thus repressing IL-17 production (84). MAPKs induce pro-inflammatory gene expression, thereby promoting inflammatory processes (87). On investigating the effect of dietary olive oil on MAPKs (JNK and p38) signaling pathway in mice fed with olive oil, they found reduced levels of phosphorylated JNK and p38 proteins. They also observed reduced translocation of p65 to nucleus thus reducing NF-κβ mediated activation of various pro-inflammatory genes including TNF-α, IL-17, IL-6, and IL-1β within arthritic joint microenvironment where they can influence osteoclast differentiation thus promoting joint destruction. Therefore, reduction in NF-κβ mediated activation of pro-inflammatory cytokines will minimize joint destruction in patients. The study concluded that mice fed with olive oil had reduced cartilage destruction, joint edema, and arthritis development, and thus, olive oil may be beneficial in preventing RA (84).

Elemental diet provides food in simplest form consisting of glucose, vitamins, trace elements, and essential amino acids, is hypoallergenic, contains all nutrients for daily requirements, and is thought to be less immunogenic (71). In the clinical trial conducted by Podas et al. (70), RA patients were given an elemental diet (E028) providing 86 kcal and 2.5 g protein/100 ml liquid elemental diet for 2 weeks. A large proportion of patients (72%) taking this elemental diet had more than 20% improvement in pain [on a 10 cm visual analog scale (VAS)], early morning stiffness, and the Ritchie articular index (RAI). The study concluded that this diet was as effective as 15 mg/day of oral prednisolone. However, no improvement was visible in the laboratory parameters including ESR, CRP, hemoglobin and a relapse of symptoms on discontinuation of this elemental diet pointed toward food antigens playing a possible role in pathogenesis and progression of RA (70). Similarly, Kavanagh et al. (69) and Holst-Jensen et al. (71) reported effects of different elemental diets with improvement in clinical and symptomatic parameters helping patients with food-aggravated disease conditions. Patients treated with elemental diet showed reduced symptoms of RA but relapsed on discontinuation (69). These studies further indicate that aggravation in symptoms of RA may be an effect of certain food allergens that are absent in elemental diet.

Certain food and food components may worsen the disease conditions in RA (69, 70). Thus, an elimination diet plan may as well be considered wherein we eliminate those food related antigens that may possibly aggravate the disease symptoms (72). Intestinal epithelium is an interface between mucosal immune system and external environment, and it is the interaction between intestinal epithelial cells and mucosal immune system which determines the resultant immune response to various food antigens (88). There are many evidences that show food as a potential antigen for humans which pass through the gastrointestinal tract’s epithelium and further interact with mucosal immune system and move into circulation (89). It has been shown that the intestinal mucosa is more permeable to allergens in RA patients on administration of non-steroid anti-inflammatory drugs (90). A study conducted by Van de Laar and Van der Korst (72), included seropositive RA patients divided into two groups of which one was administered diet free of additives, allergens, and preservatives and other was on allergen restricted diet containing yellow dyes and lactoproteins. No difference was observed in clinical effects on RA patients taking any of these diets (72). A study conducted by Karatay et al. enrolled 18 RA patients who gave a positive skin prick test (SPT) (PPG) response to at least one food and 17 RA patients with completely negative SPT (PNG) results. All patients were kept on elimination diet where patients in PPG were given prick positive food and PNG patients were given corn (most allergenic to RA patients) along with rice (not allergenic) in increased amount for 12 days. This phase was then followed by re-elimination phase. In PPG, ESR, CRP, pain, tender and swollen joints, RAI score, TNF-α, and IL-1β increased during the challenge phase and after re-elimination phase. Thus, these studies concluded that food allergens are potential triggers of the immune system leading to inflammation by the activation of macrophage and other effector cells.

Treatment of RA includes inhibition of TNF-α and IL-1, and these inflammatory mediators are observed to be increased with the intake of allergenic food hence excluding some of these food from RA patient’s diet may benefit them as well as help them to reduce their requirement of recombinant human IL-1 receptor antagonist and anti-TNF-α antibodies (73).

Most of the staple food consumed all over the world are comprised of dietary fibers and whole grains. A definitive explanation for dietary fibers can be put as remnants of food not digested in small intestine, which then moves to large intestine and gets fermented by the microflora and induces several health promoting effects (92). Insoluble fibers such as cellulose and lignin are found in fruits, vegetables, and whole grains; and soluble fibers include pectin, guar gum, and mucilage (93). Earlier studies have found an inverse relationship between intake of dietary fiber and inflammatory biomarkers such as plasma fibrinogen, hs-CRP, TNF-α, IL-6 levels which are indicators of RA (94). However, contradictory reports were published as well by Hu and the group (95).

When germ, endosperm, and bran are present in same proportions as in intact grains, they are regarded as whole grains. Whole wheat, whole rice, oats, corn, rye, barley, millets, sorghum, canary seed, fonio, and wild rice are generally included in the category of common whole grains (96). Whole grains provide rich amounts of antioxidants, phytic acid, vitamin E and selenium, and these components are known to be involved in anti-inflammatory processes (97).

Even if no conclusive evidences are found about the role of dietary fibers and whole grains in RA, Food and Drug Administration (FDA) has approved their health promoting claims (98). As per Dietary Reference Intakes recommendations, daily consumption of dietary fibers within the limit of 14 g per 1,000 kcal intake or 25 and 38 g for an adult women and men, respectively (93) has health benefits.

Apart from the botanic definition, fruits are the pulpy seeded tissues with sweet and tart taste (99). Bioactive components and phytochemicals, the non-nutrient plant compounds, present in fruits and vegetables are the key players and have been shown to diminish the symptoms of several chronic diseases such as atherosclerosis, arthritis, diabetes, asthma, AIDS, neoplasia, and cardiovascular diseases (100–102). Dietary phytochemicals are generally categorized into main groups as nitrogen-containing compounds, phenolics, organosulfur compounds, alkaloids, phytosterols, and carotenoids (103).

Regular consumption of fresh fruits rich in important phytochemicals can reduce oxidative stress and inflammation (104). Several cohort studies have also reported that repeated and high consumption is not only associated with downregulation of disease progression but also may provide protective effects against RA (105–107).

In patients suffering from RA, osteoclastogenesis (the process of bone tissue destruction by osteoclast cells) has been identified as a clinical phenomenon (108). Dried plums are rich source of polyphenols, when consumed can suppress osteoclastogenesis by inhibiting the activity of TNF-α and nitric oxide (NO) synthase and downregulate the transcription factor-nuclear factor for activated T cells (NFATc1) (109).

Anthocyanins have proved themselves as potent antioxidants and are more abundant in black rice, eggplant, and black soybean. These have properties to reduce oxidative stress by increasing superoxide dismutase (SOD) and decreasing serum malondialdehyde (MDA). It has been reported in mouse models of RA that the uptake of anthocyanins can bring down TNF-α levels (110), thereby reducing disease activity. Resveratrol from black grapes has been found to exert protective effect in rat model of RA (111). It was reported that resveratrol can lower down specific RA biomarkers such as serum RF, COMP, and MMP-3; immunological biomarkers as IgG and antinuclear antibody; immunomodulatroy cytokines (TNF-α) and oxidative stress (111). Mangiferin, a polyphenolic compound found in mangoes, used in an in vivo study on RA-induced DBA-1/J male mice reported downregulation of IL-1β, IL-6, and TNF-α, inhibited NF-κβ signaling, and activated extracellular signal regulated kinase 1/2 (ERK1/2) (112). In another study with mangiferin, it was observed that mangiferin prevented joint destruction in RA by inducing proapoptotic effects on human synovium-derived synoviocytes (113).

Kaempferol, an important phytochemical found in grapefruits, can bring down the level of inflammatory cytokine IL-1β, inhibiting the cell signaling pathways like phosphorylation of ERK1/2, p38, and JNK and activation of NF-κβ (114). Several enzymes inducing oxidative stress such as MMPs, COX-2, and PGE-2 in RA-derived synoviocytes were lowered down on administration of kaempferol (114). These molecules are reported in destruction of bone and articular cartilage leading to pathogenesis of RA (115, 116). A mixture of polyphenols composed of epigallocatechin, gallate, catechin, tannic acid, and querectin when injected at intra-articular region of rat model of RA, prevented cartilage destruction while reducing inflammation (117).

p-Coumaric acid is largely present in grapes, oranges, apples, tomatoes, spinach, and potatoes. In an in vivo study using rat model of adjuvant-induced arthritis, p-coumaric acid intake significantly reduced the expression of TNF-α (118). Genistein, an important isoflavone present in soybeans maintained a perfect balance between T helper cell, Th1 and Th2, and inhibited IFN-γ and IL-4 production which ultimately brings down the inflammation (119). Freshly prepared orange juice has high content of beta-cryptoxanthin and its intake reduces the risk of RA in humans (120). Pineapple stem are rich source of proteolytic enzyme called as bromelain. In a study, bromelain was consumed orally by RA patients in dosages of 20 or 40 mg for 3–4 times daily up to 13 months. About 72% of the total patients involved in the study came up with promising results, and there were no side effects detected. In spite of promising results obtained, significance of the study cannot be explained due to lack of control groups (121).

Ginger has been known for its therapeutic properties due to the presence of pungent phenolics such as shogaols and gingerols (122). Turmeric, rich in phenolic curcuminoids, has also proved its beneficial effects against several malignancies (123). In a study, a perfect mixture of blended ginger and turmeric were given to the adjuvant-induced arthritic rats. This mixture showed protective effects against extra-articular complications of RA (122). In another study conducted by the same group, they found that ginger and turmeric administered at a dose of 200 mg/kg body weight could independently lower down the signs and symptoms of RA in the adjuvant-induced arthritic male Wistar albino rats. The results were significant with a p-value <0.05 as compared to the control group receiving only indomethacin (123).

Curcumin has also presented itself as a potent anti-inflammatory spice by blocking the expression of IL-1 and IL-6 in an in vitro study with RA patient-derived fibroblast-like synoviocytes (124). Methotrexate is a widely prescribed antirheumatic drug for the treatment of RA but it increases oxidative stress, decreases NO levels, and leads to vascular endothelial dysfunction (124, 125). Curcumin and folic acid co-administration was found to lower down methotrexate-induced vascular endothelial dysfunctions in male Wistar rats (126).

Bark of Cinnamomum zeylanicum (Cinnamon bark) is widely used in South-East Asian dishes. Rathi et al. treated RA animal models involving male Swiss albino mice and Wistar rats with polyphenolic fraction of cinnamon barks and found inhibitory effects on secretion of cytokines IL-2, IL-4, and IFN-γ and reduction in levels of TNF-α (127).

Omega-3 or omega-6 fatty acids have shown their potential as immunosuppressants and anti-inflammatory agents (128–131). Borage seed oil provides high amount of omega-6 fatty acid or gamma-linolenic acid (GLA) (132). A double-blind trial was conducted on 37 patients with active RA, and they were assigned to consume borage seed oil containing 1.4 g of GLA per day while placebo group was given cottonseed oil. After 24 weeks of consumption, the group which received GLA had significantly reduced tender and swollen joint scores, whereas placebo group did not show any change (133).

Gamma-linolenic acid and omega-3 fatty acid alpha-linolenic and stearidonic acid from black currant seed oil (BCSO) has also been investigated for their therapeutic activity. About 10.5 g of BCSO were given to RA patients in double-blind fashion and soybean oil as placebo for 24 weeks continuously. BCSO treated group, when compared with placebo group came up with significant positive effects in pain relieving and joint tenderness (134).

Fish oils provide high amount of omega-3 fatty acids, and their efficacy to treat RA has been checked in several controlled trials. RA patients were provided with fish oil with 3.6 g of omega-3 fatty acids per day in double-blind fashion, and placebo group were treated with mixture of fatty acids for 12 weeks, which was very much similar in amount found in average diet. The group which received fish oil had reduced morning stiffness, significant increase in grip strength compared to the placebo group (135). Eicosapentaenoic and docosahexaenoic acids are ethyl ester derivatives of omega-3 fatty acids, and their capability to reduce severity of RA has been assessed. When RA patients consumed these derivatives in an amount of 130 mg/kg body weight/day for 26–30 weeks, a significant decrease in pain, morning stiffness, and tender joints was observed in comparison with the placebo group that received only corn oil (136).

Synbiotics are composed of probiotics and prebiotics (the non-digestible food products beneficial for growth of helpful bacteria in large intestine and provides health promoting effects) (137). Several reports have confirmed the reduction of oxidative stress in human body by consumption of synbiotics (138–141). As per FDA, probiotics are “live microorganisms which, when administered in adequate amounts, confer a health benefit on the host” (142). Bifidobacterium and Lactobacillus are the key strains widely used as probiotics in commercial, pharmaceutical, and nutraceutical products (143, 144). Many reports have frequently stated that the population of gut microbes gets altered in a person affected with RA (56, 145–147), and several animal studies have already proved that any alteration in gut microbiota corresponds to initiation of RA (148).

In several animal and human studies, the health promoting benefits of probiotics has been extensively assessed. When RA-induced animal models were fed Lactobacillus casei, it led to improvised health conditions by reduction in levels of pro-inflammatory cytokines such as IL-1β, IL-2, IL-6, IL-12, and IL-17, IFN-γ, and TNF-α, while upregulating the secretion of regulatory cytokines like IL-10 and TGF-β (149–152).

When yogurts fermented with live or heat killed Lactobacillus rhamnosus GG (LGG) and L. bulgaricus were fed to arthritis induced Lewis rats, it significantly reduced arthritis clinical scores (153). Anti-inflammatory effects of methotrexate was enhanced, when the medicine combined with Escherichia coli strain O83 (Colinfant) was administered on adjuvant-induced arthritis models (154).

Different strains of probiotics have also been used for human studies with reports of health conditions improvements (63, 67, 68). Oxidative stress generated during metabolism has also been held as culprit for pathogenesis of RA and selective strains with high antioxidant activity may be employed to lower down disease progression. In a study, female RA patients were given L. casei 01 supplement capsules containing about 10⁸ colony-forming unit (CFU)/capsule and the placebo group maltodextrin for 8 weeks. After treatment, a significant decrease was observed in number of tender or swollen joints, VAS scores, hs-CRP levels, disease activity score (DAS), TNF-α, and IL-12 in the probiotic group with a significant increase in serum IL-10 levels. Alteration of gut microbiota is known in case of early RA disease, and probiotics normalize the gut fauna toward a normal healthy microbiota and show anti-inflammatory activity. At the end of the study, several oxidative stress indices were also measured wherein MDA level decreased insignificantly, total antioxidant capacity levels and catalase activity increased in probiotics groups while there were no changes observed in SOD and glutathione peroxidase activity (62).

In a pilot study conducted on 21 RA patients, the effect of LGG on their health condition has been assessed. Patients from test group were prescribed to take two capsules of LGG twice a day (Gefilus, Valio Ltd.; ≥5 × 10⁹ CFU/capsule), and the placebo group took the same capsule without bacteria for 12 months and finally several inflammatory parameters were measured. The number of tender and swollen joints reduced from 8.3 to 4.4, as compared to an increase from 5.5 to 5.6 in placebo group, mean serum IL-1β decreased in placebo group but no significant change in levels of TNF-α, IL-6, IL-10, IL-12, and myeloperoxiedase was observed (63).

Consumption of alcohol with pathogenesis of RA is still under debate. While some studies point that alcohol consumption leads to progression of RA (155–158), others have concluded that no such relationship exists (159, 160).

In a recent case–control study on Scandinavian population, alcohol consumption led to decrease in RA risk in a dose-dependant manner when alcohol consuming subjects were compared with non-drinkers despite of their gender, age, and CCP status difference (161).

Another study focused on frequency of alcohol consumption not the amount, by RA patients of Caucasian ethnicity and reported similar results. All measures of RA severity such as CRP, DAS28 score, modified health assessment questionnaire, and pain VAS were found to be in inverse relation with increased frequency of alcohol uptake (80, 162).

Epigallocatechin-3-gallate (EGCG) has proved its therapeutic potential and has been of particular interest among natural products for its use as a nutraceutical (163). It is a main phytochemical present in green tea that is obtained from dried leaves of Camellia sinensis and C. assamica of Theacease family (164). The protective effects exerted by green tea have been well proved in neurodegenerative disease, inflammatory disease, cardiovascular disease, and several types of cancer (165, 166).

In RA, the resistance of synovial fibroblasts against apoptosis has been set as a trademark, and this characteristic is enhanced by constitutive expression of proteins like AKT and NF-κβ and overexpression of Mcl-1 and Bcl-2 (anti-apoptotic proteins) (167). EGCG treatment has successfully shown its ability to downregulate Mcl-1 in synovial fibroblasts and increases the susceptibility toward apoptosis (167). The reports also conclude that EGCG successfully suppresses the production of MMP-1, MMP-2, and MMP-3 in synovial fibroblasts and prevents bone and cartilage destruction (168, 169). EGCG treatment in RA patients inhibits IL-1β induced IL-6 production by synovial fibroblasts and can upregulate an inhibitor, i.e., soluble gp130 receptor, which in turn suppresses IL-6 trans signaling (170).

Plants with effective health promoting effects are known as herbs, and these have a long history of being used as medicine to cure several diseases. Synthetic drugs used in arthropathies have been associated with numerous side effects on health, which in return has led the focus toward medicines of botanical origin (171).

Sallaki (Boswellia serrata) is widely recommended as an anti-inflammatory herb as prescribed in Ayurveda (172). The phytochemical which act as key player is boswellic acid from pentacyclic triterpene family (173). Boswellic acid inhibits the expression of lipoxygenase-5 and eventually lowering down leukotriene synthesis and leukotreines are well known for their role in inflammation (174–176). These have also proved their potency to block NF-κβ activation and brought down the levels of pro-inflammatory cytokines like TNF-α, IL-1, IL-2, IL-4, IL-6, and IFN-γ and also prevented classical complement pathway by restricting the cleavage of C3 to C3b (177).

Ashwagandha (Withania somnifera) is one of the plants being described in Ayurveda as a potent anti-inflammatory plant (178). It is rich in Withaferin A, a steroidal phytochemical which can prevent proceeding of NF-κβ signaling pathway (179). In vitro studies with ashwagandha extract suppressed release of pro-inflammatory cytokines as TNF-α, IL-12, and IL-1β from synoviocytes of RA patients but it failed to stop synthesis and subsequent release of IL-6 (180). Rats with induced arthritis when treated with powder of ashwagandha roots showed less destruction of bone collagen (181). Moreover, in a double-blind placebo-controlled study aqueous extract significantly reduced stiffness, disability to move knee and joints, and pain score (182).