In a case-control study which retrospectively assessed the diet consumed 5 years before disease onset based on the Chinese population, RA patients consumed more carbohydrates than healthy controls. Increased carbohydrates intake might make excessive energy absorption, lead to increased body weight and elevate the risk of RA (15, 16).

More pieces of evidence were in the case of monosaccharide. An observational study indicated that the intake of sugar-sweetened soda increased the risk of RA (17). Researchers also found an association between the consumption of high-fructose soft drinks and the onset of RA (18). The background mechanism may be that elevated glucose and fructose ingestion promote the production of advanced glycation end products (AGEs) and enhance autophagy and NETosis (19). Whereas, a recent cohort study based on the French population found no correlation between sugar-sweetened soft drinks and RA risk, but indicated that artificially-sweetened soft drinks increased RA risk (20).

Glutamine, which is a non-essential amino acid relatively abundant in beef, eggs, tofu and other protein-rich foods, is another source of energy in addition to glucose. Glutamine is consumed at the highest rate by neutrophils compared with other immune cells (21). As the substrate of NADPH, glutamine participants in increasing superoxide generation through NADPH oxidase in neutrophils (22). Besides, glutamine is involved in the synthesis of O-linked beta-N-acetylglucosamine (O-GlcNAc), which is increased in activated neutrophils and promotes cellular mobility via the MAPK pathway (23). However, there were rare publications focused on the association of glutamine supplementation and RA, except for one study conducted 17 years ago which showed that supplementation with beta-hydroxy-beta-methylbutyrate, glutamine and arginine had no benefit in reversing cachexia in RA patients (24).

Red meat may exacerbate inflammation through saturated fatty acids and nitrites. But whether red meat intake can increase the risk of RA is still under debate. In a case-control study, a high red meat intake was associated with an increase in the risk of inflammatory polyarthritis (25). Compared to a meat-rich diet, people consuming a vegan diet experienced a decrease in total neutrophil counts (26). In RA patients who underwent a 3-month diet excluding meat, gluten and lactose, the circulating neutrophils were significantly decreased, together with a relief of inflammation symptoms (27). And in a recent cross-sectional study with 707 RA patients recruited, a high intake of red meat was associated with earlier disease onset, especially in those with smoking habits or overweight problems (28). Nevertheless, there were also lots of studies suggesting no effect red meat consumption laid on the risk of RA (29, 30). A recent meta-analysis analyzed 7 cohorts and 6 case-control studies also found no significant association between red meat consumption and the risk of RA (31).

Omega-3 polyunsaturated fatty acid was considered as a protective factor against RA. Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which are rich in deep-sea fishes, have been shown to be able to inhibit NF-κB signal, thus reducing the production of pro-inflammatory cytokines (32). With the suppression of chemotaxis, the recruitment and infiltration of leucocytes were also inhibited (33). The metabolic product of omega-3, resolvin, was also found able to attenuate inflammation and relieve joint pain via the inhibition of neutrophil recruitment in RA (34). A prospective cohort study showed that a more than 0.21 g per day dietary consumption of long-chain omega-3 polyunsaturated fatty acids was associated with a 35% decline in the risk of RA (35). In a cross-sectional study, fish consumption no less than 2 times per week was able to attenuate the disease severity of RA patients (36).

Previous reports have found that RA patients experience significantly lowered levels of 25-hydroxyvitamin D [25(OH)D] (37, 38). And the deficiency of 25(OH)D was thought to be associated with a higher disease severity (39). The seasonal fluctuation of disease performance might be related to the seasonal variation of the serum 25(OH)D levels (40).

In fact, vitamin D (vit D) took part in the amelioration of inflammation by reducing the synthesis of pro-inflammatory mediators, inhibiting the release of ROS, and decreasing NETosis (41, 42). In mouse models, supplementation of Vitamin D3 was able to promote ATP degradation and revert E-ADA activity in neutrophils, thus ameliorating the joint symptoms (43). And in RA patients with vit D deficiency, supplementation of vit D could rapidly improve the disease activity (44). Moreover, five years of vit D supplementation could reduce the incidence of autoimmune disease by 22% (45).

The serum zinc level is also decreased in RA, probably because of the increased zinc import to the cell under the exposure of pro-inflammatory cytokines (46). As a result, the deficiency of zinc will further promote inflammation by increasing the release of pro-inflammatory mediators and ROS by epigenetic mechanisms (47).

In mice models, supplementation of zinc by injection could decrease the recruitment and activity of neutrophils, thus ameliorating inflammation and tissue damage (48). A meta-analysis of clinical trials indicated that with the increase of serum zinc, neutrophil levels decreased, and so was circulating CRP, hs-CRP, TNF-α and IL-6 (49). However, as for the effect zinc supplementation laid on NETosis, there remains a controversy. Some reports suggested that zinc could inhibit NETosis by inhibiting histone citrullination (48, 50). While some others found an increase in the NETs formation and release after the treatment of zinc (51, 52).

Selenium is another trace element in the human body and showed remarkable anti-inflammation and antioxidant potential in RA. Compared to normal controls, patients with RA presented with significantly lower serum selenium levels (53). Moreover, RA patients with higher serum selenium concentration seemed to have milder inflammation, indicated by lower levels of CRP and ESR (54). Animal studies proposed that selenium-treated RA mice presented with reduced neutrophil counts, decreased NETs production, downregulated pro-inflammatory cytokines, and improved disease severity (55). Additionally, selenium also caused a reduction of ROS and alleviated oxidative stress (56).

Iron plays an important role both in the recruitment and in the physical functions of neutrophils. Compared to normal controls, the serum iron level was significantly lower and the level of soluble transferrin receptor was elevated in RA patients (57). RA aggravated iron redistribution, making a decrease of iron in the blood and an increase in the synovium, and amplifying local inflammation (58). Iron imbalance contributed to RA inflammation. On the one hand, a deficiency of iron might promote the formation of NETs, which could be reversed by iron supplementation. On the other hand, when it came to iron overload, free iron would participate in NETosis and increase inflammation, which was able to be rescued by iron chelators (59).

N-acetylcysteine (NAC) is the acetylated form of L-cysteine. The supplementation of NAC is widely utilized in chronic obstructive pulmonary disease and acetaminophen intoxication, but has not been recommended in RA (60). NAC could remove ROS and inhibit the synthesis of pro-inflammation cytokines, thus reducing the recruitment of neutrophils and other immune cells (61). Up to now, studies about the correlation between NAC and RA are still rare. A clinical trial conducted recently showed that NAC supplementation could reduce the levels of several mediators involved in oxidative stress, but could not reduce disease activity or improve the symptoms of RA patients (62).

Quercetin is an ingredient widely existing in various plants. It has been proven to have numerous protective effects such as antioxidation, reducing inflammation and preventing cancer (63). Recently, a clinical study demonstrated the function of quercetin in ameliorating inflammation and improving symptoms in RA patients (64). Experiments based on animal models further confirmed this and uncovered the fundamental mechanisms (63). Firstly, quercetin could reduce chemokines and pro-inflammation cytokines, thus inhibiting neutrophil infiltration. In addition, quercetin could also increase apoptosis and inhibit the release of pro-inflammatory cytokines by macrophages. Moreover, quercetin could inhibit autophagy and reduce the production of NETs (65–68).

Resveratrol is another ingredient extracted from numerous plants. Animal studies suggested that resveratrol was able to reduce ROS and alleviate RA (69). A meta-analysis of preclinical models showed that resveratrol could decrease the level of several pro-inflammatory cytokines including IL-1, IL-6 and TNF-α (70). The beneficial effect of resveratrol in RA patients was also verified by a clinical trial, where those accepted daily resveratrol supplementation showed improved clinical symptoms and serum inflammation indicators (71).

Icariin is the major ingredient of epimedium, a traditional herb in China. Evidence accumulates that icariin is able to alleviate inflammation and regulate immunology (72). Experiments based on arthritis rat models showed that it could decrease the levels of pro-inflammatory mediators, reduce the density of neutrophils and suppress joint degradation (73).

Moreover, Tetrandrine, a kind of alkaloid separated from Stephania tetrandra S. Moore, was able to mitigate the symptoms of RA in arthritis murine models. Not only could it decrease serum IL-6 level, but it was also capable to inhibit NETs formation (74). Cedrol, which can be found in ginger, was also considered able to attenuate inflammation in RA. It was verified by animal models that cedrol could inhibit the phosphorylation of JAK3 protein, thus inhibiting the secretion of pro-inflammatory cytokines, and decreasing the neutrophil count (75).