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In the first part of this study, we set the bases for the anti-inflammatory diet we would use in the second part of the work. Thus, we performed an exhaustive search to identify anti-inflammatory diets and nutrients described in the academic literature; we also performed a search for pro-inflammatory foods. The search was conducted from 1 November 2020 to 30 January 2021 using “anti-inflammatory diet,” “chronic pain,” and “rheumatic diseases” as the key words, although other key words were also used to better understand certain foods or nutrients such as glutenin or casein thought to be involved in inflammation. We only considered articles written in English and studies carried out on humans aged over 45 years.

Forty-five patients were recruited from different Valencian Rheumatoid Patient Associations, with permission of the presidents of each association. All the patients had previously been diagnosed by rheumatologists and were all treated after signing their informed written consent to participation in this work. This study was reviewed and approved by the Institutional Review Board (IRB) at the CEU Cardenal Herrera University (CEEI20/095, approval date: 31 March 2021) and was compliant with the European General Data Protection Regulation (RGPD) and Organic Law 3/2018 on the Protection of Personal Data and the Guarantee of Digital Rights which guarantees data protection and data security, confidentially, and use for the purpose for which the participants were properly informed. Moreover, the study complied with the principles of the Declaration of Helsinki.

We conducted a 4-month nutritional intervention study with an anti-inflammatory, supplemented, MD (AnMeD-S) in which pro-inflammatory foods such as gluten products, cow’s milk, red meat, alcohol, sugar, and processed foods were removed. We also recommended an increase in anti-inflammatory foods such as blue fish, EVOO, nuts, fruits, vegetables, legumes, plain yogurt and kefir, and turmeric. Additionally, each month we provided the patients with a container of Curcuma Latte (Baïa Food^®) which contains curcuma and black pepper to enhance curcumin absorption. The curcuma powder was given to the patients because it is not usually consumed as part of the MD. The study consisted of 5 face-to-face and 5 telematic visits with in-person visits scheduled once a month and the first telematic visit being scheduled 15 days after the first in-person visit and monthly thereafter. Moreover, Zoom^® meetings (Zoom Video Communications, Inc.) were also programmed every month to provide dietary education (Figure 1).

Different questionnaires were used to evaluate the nutritional status of each patient. First, an adaptation of the Predimed FFQ was used at the beginning and end of the study to determine the evolution of the participants and frequency of the foods consumed (32). In addition, the MNA questionnaire (24) was used to rate the patients’ risk of malnutrition.

We used the OSQ (25) to assess sleep disorders. Perceived pain was evaluated with a numeric rating scale (NRS) (33), patient disability was estimated with the HAQ (27, 28), and depression with the GDS (26). Moreover, the same NRS was employed to measure stress in order to compare the participant’s perceptions of pain, rest, and stress (33).

A cognition screening was performed at the beginning and end of the 4-month intervention using the Memory Impairment Screening (MIS) (29), Short Portable Mental State Questionnaire (SPMSQ) (30), and Semantic Verbal Fluency (SFV) (31) tests. The characteristics of the 9 validated questionnaires used to measure nutrition status, cognitive impairment, pain, insomnia, and depression are shown in Table 1.

To evaluate adhesion to our proposed anti-inflammatory diet, a modified version of the ITIS diet score (34) created by the University of California San Diego was adjusted to the AnMeD-S. A total score of 156 points was possible using our scoring system. Negative points being assigned if refined grains, red meat, more than 4 eggs per week, saturated fats, milk, flavored yogurts, more than 3 coffees per day, alcohol, sweetened beverages, sugar, pastries, or cakes, or sauces such as ketchup and mayonnaise, etc. had been ingested. From among the remaining foods evaluated, the most important ones such as turmeric, EVOO, blue fish, nuts, dark chocolate, fruits, and plain yogurt or kefir received more points. Table 2 shows the overall scoring system and how it was calculated based on how the patients answered the FFQ.

We separated the vegetable score into three groups. The first group was greens and included lettuce, spinach, chard, endive, green beans, and other types of green leafy vegetables. The second group was of non-greens and included tomato, asparagus, celery, peppers, artichoke, mushrooms, and carrots. The third group contained every other vegetable including cauliflower, broccoli, aubergine/eggplant, courgette/zucchini, cucumber, brussels sprouts, and other commonly used vegetables. In addition, the fruits were also separated into three groups. The first group contained berries including strawberries, grapes, fruits of the forest (raspberries, blackberries, and blueberries, etc.), and cherries. The second group contained enzymatic fruits including orange, tangerine, grapefruit, pineapple, kiwi, and banana. The last group included other fruits such as apple, pear, peach, melon, and watermelon. After evaluating the score, we rated them as percentages.

To evaluate the therapeutic effect of the AnMeD-S we collected the following data:

Likewise, we also calculated some new variables to rank the patients into different groups. For each monitored food, the first group were patients already following the recommendations at the start and end of the study (“maintain”). The second group were patients that improved their diet to meet our recommendations (“meet”). The third group were the patients who improved their diet but did not meet our recommendations (“improve”). The last group were patients who maintained their habits and did not meet our recommendations or whose diet had worsened (“worsen”).

The classification remained as followed: consumption of a healthy diet, consumption of anti-inflammatory foods, consumption of pro-inflammatory foods, and finally, overall consumption of an anti-inflammatory diet (“low”: [0–50%]; “moderate”: [50–75%]; and “high”: [75–100%]).

The sample size was calculated to ensure that the work would be able to detect a change in the food consumption based on the score and a reduction in the degree of pain after the dietary intervention. Therefore, the sample size was determined to maximize these two conditions as follows:

To detect the effect of increased consumption of the AnMeD-S with a confidence of 95% and statistical power of 80%, taking a mean increase of 17% and a standard deviation of 20% as reference values, a sample size with more than 11 individuals was required.

To determine the effect of a reduction in the degree of pain by a mean of 1 point and a standard deviation of 2 points, with a confidence of 95% and a statistical power of 80%, a sample size exceeding 27 participants was needed.

Finally, we recruited a total of n = 45 participants to this study, which therefore exceeded the required sample size of at least 27 individuals. All the baseline and follow-up variable data described above was stored in an Excel spreadsheet which was designed ad hoc. These metrics were: consumption of the AnMeD-S, physical and QoL characteristics at the beginning and end of the study; we also recorded whether there was an improvement for each of the characteristics for each individual participant. The advanced statistics software R was used for the statistical analyses. The qualitative variables were described as the sample sizes and percentages (n [%]); quantitative variables were described as the mean and standard deviation (x̄ ± s). To analyze the association between qualitative variables, Chi-squared or Fisher exact tests were used; statistical significance is indicated with an * if the p-value was <0.05; ** for <0.01, and *** for <0.001.

The difference in the scores achieved before and after the AnMeD-S intervention was used to determine the increase in consumption of the corresponding food group. Spearman rank correlations were calculated to evaluate if changes in consumption toward the diet recommendations given to participants were associated with the numerical indicators of QoL. Correlation tests and their corresponding p-values were also used to determine significant associations. In contrast with the methodology proposed in the previous paragraph, this procedure evaluated changes in these scores rather than dividing the individuals according to their adherence to the AnMeD-S consumption recommendations.

The key information upon which the AnMeD-S anti-inflammatory nutritional trial conducted in this work was based was extracted from the academic literature. We designed the guide based on the MD according to the grade and accuracy of the available evidence. We chose the MD because it has been proven to reduce inflammation and oxidative stress and consequently, to increase cellular metabolism and promote stem cell-based regeneration. However, we also prohibited some foods included in the MD because they are considered pro-inflammatory (red meat, gluten, and cow’s milk), while also adding other anti-inflammatory foods such as curcumin and coffee.

Regarding the anti-inflammatory foods mentioned above, it is well known that polyphenols can effectively prevent and alleviate the symptoms of rheumatic diseases. This is because of their antioxidant and anti-inflammatory actions, which are mediated by inhibiting the transcription and expression of pro-inflammatory cytokines (35). Some important polyphenols are flavonols, anthocyanins, proanthocyanins, and resveratrol, which are present in many fruits and legumes. Moreover, carotenoids are known to have antioxidant properties because they inhibit reactive oxygen species (ROS), meaning they have a protective effect in rheumatic diseases. These carotenoids can be found in fruits and vegetables such as sweet potatoes, carrots, red peppers, squash, avocado, and watermelon.

At the same time, monounsaturated fatty acids (MUFAs), found in foods such as nuts, also have antioxidant activity which can mitigate chronic pro-inflammatory processes. Indeed, the function of polyunsaturated fatty acids (PUFAs) in the improvement of mitochondrial function, inhibition of inflammatory mediators such as interleukins (ILs) and tumor necrosis factor alpha (TNF-α), and decrease in oxidative stress is well-known. Importantly, there are different PUFAs known as ω-3 and ω-6, with both being involved in the inflammatory response and their ratio being of key importance. The ω-3 PUFAs are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which both help in the regulation of antioxidant signaling pathways. In turn, the amount of the ω-6 PUFA, arachidonic acid (AA) released from cells determines the intensity of inflammation. When less AA is found in cell membranes, less AA is released and therefore, fewer eicosanoids are formed (36).

AA can mainly be found in the fatty parts of meats, especially red meat, while ω-3 is mainly found in EVOO, fish, and fish oil supplements. An increase in postprandial lipopolysaccharides (LPSs) and toll-like receptor-4 (TLR4) is associated with increased levels of inflammatory cytokines such as IL-6, IL-17, and TNF-α which, in turn, activate oxidative bursts. Many epidemiological studies have provided a solid rationale for the health benefits of diets based on foods of vegetable origin (36). Of note, an important aspect of vegetable consumption is mixing at least 2 or 3 vegetables with different colors in every meal to ensure the intake of different micronutrients. In this line, several studies have revealed that curcuminoids act to inhibit the expression of IL-1, IL-8, and IL-6, and TNF-α, thereby decreasing the severity of rheumatic disease. Moreover, these molecules also help to downregulate the production of NO, COX₂, iNOS, lipoxygenase activator protein-1, and NF-kB in a wide range of cells, with the latter simultaneously increasing the levels of cytokines (IL-10).

Beta-casomorphin is a peptide with opioid activity which is produced by the incomplete degradation of the protein from cow’s milk (casein) in the intestine. Furthermore, increased intestinal permeability could lead to impairment of the intestinal barrier with the subsequent passage of such peptides into the bloodstream, thereby triggering a systemic immune response (37). Even though beta-casomorphin is mainly found in cow’s milk, consuming fermented foods such as plain yogurt and some cheeses has been shown to have a positive effect because of its impact on gut microbiota diversity (38). Thus, our nutritionist made the subjective decision of what foods to include in the AnMeD-S and the recommended frequency of their consumption, as shown in Table 2.

Forty-five patients with an illness accompanied by CP were included in this study. Forty of the participants were women (89%) and the average age was 59 ± 7 years. Twenty patients had a background of cognitive impairment (44%), 40 patients claimed to have memory loss (89%), and possible cognitive impairment had been identified in 5 of them (11%). Finally, 28 patients had a diagnosis of depression (62%). The results from the cognitive impairment questionnaires were not statistically significant. This may have been because of our small sample size or because the participants were too young to be diagnosed. Moreover, it is important to note that following a new dietary routine for 4-months was insufficient to see any changes in the cognitive test results.

Table 3 details the three main food groups. The first groups comprised foods that are part of a healthy diet. The second group defines foods with an anti-inflammatory effect. Finally, the last group contains foods with a pro-inflammatory effect. We also describe the consumption levels recommended for each food in order to achieve an anti-inflammatory therapeutic effect. To evaluate the diet, each food received a different score based on the recommended consumption frequency and its anti-inflammatory effect. We established a maximum score for each food, regardless of higher intake levels. A 100% consumption of healthy foods was graded with 60 points and a 100% consumption of anti-inflammatory foods was scored with a maximum of 96 points. Thus, the gold standard for this diet, if the patient followed the diet perfectly, was a total of 156 points.

Table 4 shows the number of patients and their percentage adherence for each food, classified into four categories. Firstly, patients that already followed the recommendations and were able to maintain their habits (maintain column). Secondly, patients that did not follow the recommendations before starting the study but were able to meet them while completing the work (meet column). Thirdly, patients that improved their consumption habits without reaching the intake goal (improve column). Finally, patients that did not meet the required consumption recommendations or whose habits became worse (worsen column). It is worth noting that the consumption of healthy foods and anti-inflammatory foods is desirable, hence we considered an improvement to be an increase their consumption. Nevertheless, it is the other way around for pro-inflammatory foods, meaning that an improvement meant a decrease their consumption.

From the beginning of the work, many of the patients were already eating some of the foods at the recommended frequencies. In the healthy foods group, 67 and 76% of the patients met this criteria for white meat and eggs, respectively. For the anti-inflammatory foods, 73% of the patients already met the EVOO consumption recommendation. Lastly, in the pro-inflammatory food category, 80% of the patients were already following the recommendations for wine and sweet beverages and 73% were following the coffee recommendation. In other words, the consumption of these foods was not responsible for any physical or QoL changes in this work because their consumption did not change during the course of the study. However, there was an improvement in the intake for several different foods including legumes (47%), greens (47%), non-greens (36%), blue fish (44%), and cow’s milk (51%). These improvements could have been involved in physical and QoL changes in the study participants. Furthermore, its seemed to be more complicated for participants to introduce certain foods into the diet such as gluten-free foods (47%), other vegetables (49%), enzymatic fruits (51%), plain yogurt or kefir (53%), and dark chocolate (60%), or for them to restrict refined grains (40%) and alcohol use (56%).

The number of participants and percentages that maintained adequate consumption according to our recommendations from the start of follow-up (Maintain), improved until complying with the recommendations (Meet), that improved but did not adhere to the recommendations (Improve), or whose consumption did not improve or worsened (Worsen).

In terms of foods associated with healthy diets, the consumption of poultry and eggs seemed to be easier for the participants to maintain. The patients met the established dietary requirements for legumes (47%) and greens (47%) and it was easier for them to improve their consumption of non-greens (36%), although not sufficiently to meet our recommendations. The anti-inflammatory food most easily maintained by almost all the patients was EVOO (73%). Blue fish was consumed in adequate levels in 44% of the participants and the ingestion of nuts was improved in only 31%.

For each food group, the participant consumption percentages were calculated at the beginning and end of the study. Patients were classified into three groups. The first group had the participants with a low consumption (0–50%); the second group comprised those with a moderate consumption (50–75%); and the last group was made up of patients with a high consumption (75–100%). Table 5 shows how the consumption levels contributed to each patient at the beginning (table rows) and end (table columns) of the study; it is divided into four groups: healthy foods, anti-inflammatory foods, pro-inflammatory foods, and overall diet. As we can observe, 27 patients consumed healthy foods sparingly; the consumption worsened to low consumption by the end of the study for 2 of participants; 11 patients maintained moderate consumption levels; and 14 patients improved to register high consumption.

If we compare the evolution of the patients, we can see that 38 of them improved their consumption of pro-inflammatory foods compared to 29 patients in the anti-inflammatory foods group and 27 in the healthy diet group. This information indicates that, a priori it is easier for patients to abandon unhealthy habits in their diet than to incorporate healthy habits. On the one hand, healthy and anti-inflammatory foods were assessed positively; therefore, to achieve a good score for the AnMeD-S it was advisable to consume high amounts of them. On the other hand, pro-inflammatory foods were assessed negatively and hence, it was advisable to consume the lowest amount of them possible. In accordance with this scenario, to easily pinpoint each patient in each group that had improved or worsened, in Table 5 we highlighted them in green or red, respectively; the amber color was used only in the healthy food group for patients who had maintained their consumption. For instance, the consumption of healthy foods worsened in 7 patients, stayed moderate in 11, and improved in 27.

Physical characteristics and the improvement or worsening of the patient metrics recorded are shown in the rows in Table 6. An improvement was considered a decrease in the variable, except for the MNA, corporal water content, and muscular mass. In turn, the columns represent an improvement or worsening in each food group. As discussed, changes in the consumption of healthy foods were not statistically associated with the physical condition of the participants. Nevertheless, a reduction in the consumption of anti-inflammatory foods was positively associated with a decrease in BMI, BF, and AC and WC. Likewise, improvements in pro-inflammatory food consumption was positively associated with decreased weight, BMI, BF, MA, VF, and WC and HC.

Finally, on the one hand, the overall diet was positively associated with a decreased BMI, BF, VF, AC, WC, HC, and WHI. It was also associated with an increase in BW and MM. On the other hand, having chronic pain disease was not associated with any improvements in physical characteristics. Table 7 shows the anthropometric measurements recorded for the participants before and after the nutritional intervention.

Table 8 shows the changes in QoL characteristics among our participants. The patients improved when the value for each characteristic had decreased at the end of the study, with the exception of rest and sleep satisfaction in which an improvement was an increase in the value. The columns in the table indicate the changes for each food group and for the overall diet. No statistically significant associations were observed between an increase in the consumption of healthy foods and improvement in any of the QoL characteristics. However, equal, or greater consumption of anti-inflammatory foods was associated with decreased pain and stress. In addition, reduced consumption of pro-inflammatory foods was associated with positive changes in sleep satisfaction. At the end of the study, an improvement in the overall diet was positively correlated a decrease in pain, HAQ score, and hypersomnia.

To analyze data from a different perspective, we calculated Spearman rank correlations for the changes in nutritional scores and the scales measuring QoL characteristics. Firstly, these tests did not indicate any association between QoL characteristics and the general consumption of a healthy diet. Secondly, the correlations suggested an association between pain and the anti-inflammatory score (Spearman’s rho = −0.32, p = 0.0315), pain and the pro-inflammatory score (Spearman’s rho = −0.42, p = 0.0045), pain and the overall score (Spearman’s rho = −0.42, p = 0.0043), stress and an anti-inflammatory diet (Spearman’s rho = −0.51, p = 0.0003), and stress and the overall score (Spearman’s rho = −0.48, p = 0.0010). Figure 2 graphically represents the Spearman correlations for all the score/QoL characteristic pairs as a grid, with a higher correlation intensity with an improvement in QoL shown in green. The numerical values of the Spearman correlations and outcomes of each test are provided in Supplementary Table S1.

The Spearman rank correlation between food groups and QoL characteristics was not presented in Figure 3. These correlation tests indicated some associations between pain and food groups, especially with gluten-free foods (Spearman’s rho = −0.49, p = 0.0006), refined grains (Spearman’s rho = 0.46, p = 0.0014), and berries (Spearman’s rho = −0.3341, p = 0.02492). The correlations for the other groups were not so clear and so were graphically represented with a heatmap in Figure 3; their Spearman rank correlation values and p-values are shown in Supplementary Table S2. In Figure 2, higher correlations with a deterioration in QoL were shown as a higher intensity red color, while higher intensity green shows a greater improvement in the QoL characteristics. A diagnosis of chronic disease was not associated with improvements in QoL attributes. Of note, even though we found a significant positive association between improved food consumption and better QoL metrics, this does not inherently imply a cause–effect relationship.

Pain can reduce or condition well-being in the daily lives of patients. We analyzed the association between pain and changes in their everyday anthropometric characteristics. As shown in Table 9, decreased pain was positively associated with improved stress, HAQ, hypersomnia, and insomnia.

The limitations of the study were that the follow-up time was only 4 months and so it was impossible to know if the patients maintained their modified eating habits once the intervention period had finished and the difficulty in obtaining a routine assessment of blood chemistry parameters and inflammation markers of the participants. However, the modifications and restrictions in the AnMeD-S were relatively easy for patients to apply and follow, which should have helped ensure that they did not easily abandon it.