Contemporary Clinical Trials Communications 17 (2020) 100524 Contents lists available at ScienceDirect Contemporary Clinical Trials Communications journal homepage: http://www.elsevier.com/locate/conctc Research paper Design of an anti-inflammatory diet (ITIS diet) for patients with rheumatoid arthritis Marta F. Bustamante a, Meritxall Agustín-Perez a, Francesca Cedola a, Roxana Coras a, c, Rekha Narasimhan a, Shahrokh Golshan b, Monica Guma a, c, * a Department of Medicine, University of California San Diego, San Diego, CA, USA b Department of Psychiatry, University of California San Diego, San Diego, CA, USA c Department of Medicine, Autonomous University of Barcelona, Plaça Cívica, 08193, Bellaterra, Barcelona, Spain A R T I C L E I N F O A B S T R A C T Keywords: Background: Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that affects synovial joints, Rheumatoid arthritis leading to inflammation, joint destruction, loss of function, and disability. Although recent pharmaceutical ad­ Diet design vances have improved treatment of RA, patients with RA often inquire about dietary interventions to improve RA Anti-inflammatory diet symptoms, as they perceive rapid changes in their symptoms after consumption of certain foods. There is evi­ ITIS diet Microbiome dence that some ingredients have pro- or anti-inflammatory effects. In addition, recent literature has shown a link between diet and microbiome changes. Both diet and the gut microbiome are linked to circulating metab­ olites that may modulate inflammation. However, evidence of the effects of an anti-inflammatory and probiotic- rich diet in patients with RA is scarce. There is also a need for biological data to support its anti-inflammatory effects. Methods: The main goal of this study is to delineate the design process for a diet tailored to our RA population. To achieve this goal, we collected information on diet, supplements, cooking methods, and intake of different in­ gredients for each patient. Different groups were interviewed, and their feedback was assessed to design a diet that incorporates suggested anti-inflammatory ingredients in a manner that was easy for patients to adopt based on their lifestyles and backgrounds. Results: We designed a diet that includes a high intake of potential anti-inflammatory ingredients. Feedback from highly motivated patients was critical in constructing an anti-inflammatory diet (ITIS diet) with elevated adherence. Conclusion: In order to tailor our diet, we surveyed our patients on several different parameters. We obtained important feedback on how feasible our ITIS diet is for RA patients. Using this feedback, we made minor im­ provements and finalized the design of the ITIS diet. This diet is being used in an on-going pilot study to determine their anti-inflammatory effect in pain and joint swelling in RA patients. Trial registration: Not applicable. 1. Background additional sources of relief and/or treatments with less side effects, and often inquire about dietary interventions to improve RA symptoms, as Rheumatoid arthritis (RA) is a systemic, debilitating, chronic in­ they perceive rapid changes in pain and/or swelling after consumption flammatory autoimmune disorder affecting approximately 1% of the of certain foods [2]. However, rheumatologists lack information to world population [1]. RA is a form of arthritis that causes pain, swelling, advise RA patients on nutrition. stiffness, and loss of function in joints. This disease severely impacts Diet might modulate RA symptoms by influencing the patient’s quality of life with increased morbidity and mortality. Although recent metabolic profile and increasing antioxidant levels, but also by altering pharmaceutical advances have improved the treatment of RA, most RA the microflora of the intestine. The gut microbiome is incredibly dy­ patients need lifelong pharmacological therapy. RA patients often seek namic and can change rapidly to dietary perturbations [3]. In addition, * Corresponding author. Division of Rheumatology, Allergy and Immunology, UCSD School of Medicine, 9500 Gilman Drive, La Jolla, CA, 92093-0656, USA. E-mail address: mguma@health.ucsd.edu (M. Guma). https://doi.org/10.1016/j.conctc.2020.100524 Received 26 September 2019; Received in revised form 1 January 2020; Accepted 11 January 2020 Available online 21 January 2020 2451-8654/© 2020 Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). M.F. Bustamante et al. Contemporary Clinical Trials Communications 17 (2020) 100524 the gut microbiome is also involved in the metabolism of some dietary Table 1 components and has the potential to modify circulating pro- or Strategies and recommendations in the ITIS diet. anti-inflammatory mediators [4]. For example, trimethylamine-N-oxide, Main recommendations Based on (WHY) Diet strategies (HOW) a pro-inflammatory metabolite that derives from choline and carnitine (WHAT/WHAT FOR) present in red meat, eggs, and dairy products, is produced by Prevotella � Lower the omega6/3 � A low omega 6/3 PUFA � The diet must contain copri among other bacteria [5,6]. An increased abundance of Prevotella PUFA ratio to 2:1 ratio reduces fatty fish such as copri was found in new-onset untreated RA patients suggesting P. copri � Increase intake of inflammation and sardines, tuna, twice may be pathogenic [7]. In general, bacteria that have an almost exclu­ MUFA improves per week, daily intake � Decrease intake of pro- autoimmunity of chia seeds and sive saccharolytic metabolism, such as lactobacilli and bifidobacterial, inflammatory FA such symptoms [28–32]. flaxseed oil. are considered potentially beneficial [8]. Both gut microbial species as trans-FA and satu­ � MUFA found in nuts, � Daily intake of nuts, produce a variety of tryptophan catabolites which are critical for in­ rated FA (present in avocado, sesame and avocado, and/or testinal homeostasis by decreasing intestinal permeability [9]. In addi­ dairy products, red olive oil have beneficial sesame seeds or tahini meat and processed effect in RA [33,34] � Avoid pre-cooked tion, some of these catabolites enter the bloodstream and have food) � Industrially produced food, red meat and anti-inflammatory and anti-oxidative effects [9]. Various dietary com­ trans-FA increase in­ processed meat. Cook ponents including miso and yogurt are a source of this beneficial flora. flammatory markers by baking, boiling or Daily yogurt was shown to reduce biomarkers of chronic inflammation and saturated FA in­ vapor. Avoid frying for in premenopausal women [10]. Dietary fiber, other complex carbohy­ crease inflammation long periods since it [15–17]. modifies PUFA to drates, and sugar alcohols present in fruits are prebiotics and might also trans-FA [60]. be beneficial by supporting healthy microbiome [11,12]. For instance, � High intake of � Dietary fiber, whole- � Daily green leafy microbial degradation of whole-grain complex carbohydrates increases prebiotics grain complex carbo­ vegetables (arugula, short chain fatty acids (SCFA), which were shown to be beneficial to � Daily intake of hydrates, and sugar al­ lettuce, broccoli, probiotics cohols present in fruits zucchini, Green beans) intestinal immune response [13]. are prebiotics that sup­ and fruits (prebiotic In addition, several foods have been identified as pro-inflammatory, port healthy micro­ source). including highly refined flours, gluten [14], trans- and saturated-fatty biome [11,12] and � Daily home-made acids (FA) [15–17], dairy products (milk and cheeses) [18], and red increases SCFA produc­ green juice (made of meat [19,20]. Some vegetables such as tomatoes, eggplants, and po­ tion improving immu­ fruits and green vege­ nity [13]. tables) (prebiotic tatoes contain solanine, a glycoalkaloid, which was suggested to in­ � Probiotics including source). crease intestinal permeability and be detrimental for arthritogenic yogurt reduce the levels � Promote whole grains pathologies [21–26]. In contrast, other nutrients have been suggested to of the pro- and avoid refined offer numerous health benefits [27], including long chain omega-3 inflammatory cytokines flours (prebiotic and improves disease source). polyunsaturated FA (PUFA) (chia seeds, flaxseeds, fatty fish) [28–32], activity in RA [10,52, � Daily yogurt (a brand monounsaturated FA (MUFA) (avocado, sesame) [33,34], antioxidants 53] that contains [35], phytochemicals [36], flavonoids [37,38], vitamin D [39], fruits Lactobacillus Casei with enzymatic proteins such as papain and bromelain (papaya, mango, among other species pineapple) [40–42], ginger [43], turmeric [44,45], black pepper [46, (Chobani) and miso (probiotic source). 47], green tea [48–50], and legumes [46,51]. However, only a few � Help digestion of large � Fiber consumption and � Daily enzymatic fruit: randomized double-blind placebo-controlled clinical trials have proteins in the gut and enzymatic fruits will pineapple, mango or attempted to determine whether supplementation with these in­ avoid unnecessary reduce colonic transit, papaya (source of gredients [31,34,35,37,38,43] or probiotics [52,53] are beneficial in RA fermentation and will help protein bromelain, papain and digestion other proteolytic patients. So far, most of the studies are pilot studies with small number � Bromelain and papain enzymes) of patients, studies on animal models, or in vitro studies. were shown to have an � Disassociate Despite a large number of publications on the effect of different in­ anti-inflammatory ef­ consumption of gredients and gut microbiome on inflammation, and reports showing an fect as well [40–42]. proteins from grains association between poor dietary quality and inflammation in RA pa­ � Large proteins in dairy � Increase fiber intake products are not � Substitute plant-based tients [54,55], only a few interventional studies have investigated completely digested milks (almond, rice, whether specific diet improves RA symptoms (for review [56,57]). The and can feed coconut) for dairy. effects of complete diet intervention (including vegetarian and Medi­ proteolytic bacteria, terranean diets) have shown positive effects in ameliorating RA symp­ resulting in the production of pro- toms. One of the studies showed that fasting first and then eating a inflammatory metabo­ vegetarian diet for one year was beneficial in RA, particularly in terms of lites [66]. number of swollen joints, stiffness, and C reactive protein (CRP) [58]. A � Condiment with anti- � Turmeric, black pepper � Condiment with diet trial with Mediterranean diet (MD) also showed a decrease in dis­ inflammatory spices and ginger have turmeric, black pepper ease activity (DAS28) of 0.56 (p < 0.001) and in quality of life compared � Eliminate salt antioxidant and anti- and ginger. inflammatory actions � Turmeric and black to control diet [59]. Yet, we could not find a trial using a diet that in­ [43–46] pepper should be used corporates and combines different potential anti-inflammatory � Black pepper increases at the same time. ingredients. bioavailability of � Low salt intake by Here, we will describe the steps taken to design our anti- curcuma [46,47] eliminating precooked inflammatory diet (ITIS diet) for a complementary therapy in RA pa­ � High salt intake is food associated with the risk tients. In Table 1, we summarized the strategies and ingredients of arthritis and has included in the ITIS diet. This diet is an omnivorous diet, based on a been related to Mediterranean diet but with several modifications. Our diet reinforces autoimmunity [67,68]. fast digestions by dissociating grains from proteins, suggests certain � Substitute vegetables � Solanaceae vegetables � Avoid the consumption with potential anti- contain glycoalkaloids. of eggplant, tomatoes cooking methods [60], is a diet low on gluten, and also includes enzy­ inflammatory Glycoalkaloids have and potatoes and matic fruits, whole grains, a very high consumption of omega 3 PUFA been reported to affect increase consumption and MUFA, and anti-inflammatory dressings and spices. It introduces (continued on next page) green juices in the morning to increase green leafy vegetables and fruit 2 M.F. Bustamante et al. Contemporary Clinical Trials Communications 17 (2020) 100524 Table 1 (continued ) was approved by the UCSD Institutional Review Board. We recruited Main recommendations Based on (WHY) Diet strategies (HOW) patients from the two most prevalent populations in our Arthritis (WHAT/WHAT FOR) Clinics: Hispanic and Caucasian RA patients. For one year, we worked properties for sol­ intestinal permeability of garlic, onion, carrot, with a total of 20 Hispanic and 14 Caucasian RA patients in collabora­ anaceae vegetables [21–26] pumpkin, zucchini or tion with a nutritionist to put together a 14-day ITIS diet that was � Vegetables with high green leafy vegetables. feasible and that included our proposed anti-inflammatory/probiotic content of components (Table 1). phytochemicals were Initial design of the diet: In order to design this first draft, we suggested to have anti- inflammatory proper­ examined the bibliography relating ingredients and inflammation, and ties (garlic, onion, diet intervention in RA patient. Once we decided the strategies and in­ pumpkin, zucchini, gredients we wanted to introduce, we designed a Mediterranean-based carrot, green leafy veg­ 7-day draft diet, which also included the main strategies described in etables) [36] � Decrease consumption � It contains high levels � Introduce legumes Table 1, and was structured as followed: daily green juices in the of red meat. of choline, which is the (red, white beans, morning, 3 main meals and 2 snacks. precursor of the lentils or garbanzo), Diet modifications with RA patients was conducted in four inflammatory poultry and white fish, phases: Since our main goal was to design a feasible diet, we worked metabolite TMAO [5,6] 2–3 days a week each. with several small groups of patients to tailor the diet for higher and saturated FA. Avoid red meat. � Reduce consumption � Gluten has been � Substitute whole adherence. The information gathered in the four phases of the study of gluten associated with grains such as rye, contributed to modify the draft until we built the final diet and in­ inflammatory states corn, oats or quinoa for structions. Different patients were recruited for each phase. In Phase I, [14]. refined wheat. we evaluated the dietary habits of each patient in the last year in order to Pseudocereals and gather information about their current diet habits. In Phase II, we � whole grains reduce inflammation [69,70] gathered information about patient knowledge, accessibility, afford­ � Avoid sugars, sugary � Sugary foods and � Substitute honey for ability, and taste preferences of our proposed ingredients. In phase III, foods and sugary beverages are sugar. Avoid soda and we designed a first draft of the diet with patient instructions and asked beverages associated to obesity, juices. for patient feedback to assess how accurately patients were able to un­ microbiome changes and low-grade inflam­ derstand and follow the diet. In phase IV, we conducted a 7-day trial matory state [71]. with patient feedback for final adjustments on the diet (Fig. 1). Macro � Substitute green tea for � Green tea contains � Daily green tea and micro-nutrient composition as well as more details of our ITIS diet is coffee polyphenols which available for interested parties. decrease pro- inflammatory cytokines in animal models and in 3. Results vitro models of RA) [48–50,72,73] 3.1. Phase I � Some studies suggest that coffee consumption may A representative sample of 5 Hispanic and 5 Caucasian patients were increase the risk of included in this phase. We constructed and distributed a diet habit developing RA [74]. questionnaire (Additional file 1) in order to elucidate dietary habits of � Increase the intake of Antioxidants, � Vegetables, fruits, the patients in the last year. The questionnaire contained questions � antioxidants, phytochemicals, apple cider vinegar, phytochemicals flavonoids and whole grains contain about how frequently (how many times per week) our patients had vitamins and vitamins were high amounts of flavonoids suggested to have anti- antioxidants, inflammatory proper­ phytochemicals ties [35–39]. vitamins, and flavonoids. � Daily home-made green juice (made of fruits and green vegetables) consumption, and daily yogurt and miso as probiotic. It also avoids consumption of processed and red meat, caffeine, dairy products (except yogurt), and vegetables from the solanaceae family. Of note, not all the ingredients and strategies proposed in our ITIS diet are based on inter­ ventional diet studies in RA patients. We wanted to introduce in­ gredients suggested to be beneficial in animal models or other inflammatory diseases as well. Therefore, the design of this diet is intended to give an alternative to non-vegetarian population with higher content of potential anti-inflammatory ingredients than the typical Mediterranean diet. Fig. 1. Flow chart showing the different phases of the design of the ITIS diet. From a draft that included potential anti-inflammatory ingredients described in 2. Methods the scientific literature, in phase I, we got information of current dietary habits, in phase II, we collected information about the ingredients that we wanted to Patients: Thirty-four adult patients with RA fulfilling the 2010 ACR/ include, in phase III, we requested feedback about the instructions and strate­ EULAR classification criteria for RA, were recruited from the Arthritis gies of our ITIS diet, and in phase IV, a few patients followed the ITIS diet for 7 Clinics at the University of California at San Diego (UCSD). The study days. The continuous feedback from our patients helped us make adjustments to the diet and build our final version of the ITIS diet. 3 M.F. Bustamante et al. Contemporary Clinical Trials Communications 17 (2020) 100524 consumed meat, eggs, fish, bread, grains, vegetables, mushrooms, le­ completely remove kefir, and substituted it with yogurt. Other in­ gumes, nuts, fruits, sauces, sweets, snacks, soups, and dairy products in gredients such as rye (contained in german bread), sweet potato, arugula the last year. In addition, patients were asked about their drinking habits shoots, quinoa, apple cider vinegar, and tofu were made optional (but and food preparation practices, including time invested in cooking. The recommended). Ingredient that we deemed critical were left as a questionnaire took approximately 1 h to complete, and RA patients filled mandatory ingredient in the ITIS diet: miso, turmeric, flaxseed oil, and the questionnaires individually in a designated room at the clinical tahini. facilities. We also asked patients if they were willing to avoid some products Average frequency of consumption of the ingredients (times per and/or substitute them for others. Of the patients surveyed, one did not week) of these 10 RA patients are shown in additional file 2. Patient respond to this question, and 9 out of 10 patients agreed to substitute: consumption of vegetables, fruits, meat, eggs, fish, grains, legumes and refined cereals for integral cereals, solanaceae vegetables for green nuts did not differ from our ITIS diet. Of note, red meat was consumed vegetables, trans fatty acids and saturated fatty acids for omega 3 PUFA less than once a week among these RA patients. Leeks, onion, peppers, and MUFA, sugar for stevia or honey, soda drinks for home-made juices, and lettuce were the most consumed vegetables; berries and avocados and dairy products for vegetable extracts. 8 out of 10 patients were were the most consumed fruits followed by peaches, nectarines, apri­ willing to substitute alcoholic drinks and coffee for green tea, and 6 out cots, oranges, apples, and pears. Enzymatic fruits and ginger were not of 10 patients agreed to reduce gluten consumption. frequently consumed. Alcohol consumption was low, but they had daily Finally, patients were asked if they had access to a blender to coffee. Patients also reported a high consumption of simple carbohy­ determine if they were able to prepare smoothies. All Hispanic patients drates such as cookies and cakes, added sugar, and consumed dairy and 3 of the 4 Caucasian patients had one available at home. Average products almost daily. They did consume yogurt but not miso. They did available time to cook per day was 1.5 h (�1.03), with a range from 30 not frequently add seeds, anti-inflammatory dressings or anti- min to 3 h. All but one patient responded that they were willing to learn inflammatory spices in their food. They used olive oil followed by new recipes, and subjects assigned themselves an average of 8.6/10 in canola oil. Patients mainly steamed or boiled their food, but also fried their resolution to follow the diet. for longer than 5 min. Though patients mainly prepared their meals at home, pre-cooked food was used frequently. 3.3. Phase III 3.2. Phase II 9 Hispanic and 6 Caucasian patients were included in phase III. We asked patients for feedback on a final version of the 14-day diet (which A total of 6 Hispanic and 5 Caucasian patients were included in this included both the diet and pertinent instructions). We focused on phase. The objective of this phase was to gather information about pa­ whether the diet could be easily understood and completed by patients. tient knowledge and assess the affordability and accessibility of the Patients were shown the diet and instructions, and after providing products included in the ITIS diet. We designed a questionnaire that necessary clarifications, we asked patients to answer the diet-related assessed the following categories: familiarity with ingredients, previous questions shown in additional file 4A. Patients responded individually consumption of ingredients, knowledge of food and preparation in a designated room at the clinical facilities. methods, knowledge of where to buy the ingredients, and affordability The feedback from this phase is shown in additional file 4B. All pa­ of the ingredients. The questionnaire took around 30 min to complete tients understood the instructions and overall were not worried about and RA patients answered it individually in a designated room at the satiety and time to prepare the meals. When patients were asked about clinical facilities. the diet schedule, all but 3 indicated that they could adhere to it. 12 After the questionnaire was administered, we assigned a numeric patients reported that they would be satiated with the diet, while three value based on patient responses: if the response was negative, we patients expressed doubt. We also observed that most patients had suf­ assigned 0. If the response was positive, we assigned 100, and if it was ficient time to prepare breakfast correctly. Though most of the ques­ doubtful, we assigned 50. Finally, we averaged patient responses for tioned patients did not indicate their cooking habits, those who did, each ingredient and analyzed feasibility of patient use. Responses indicated that they often steam, bake, or grill. We did encounter a few regarding patient knowledge and accessibility to consumption were complaints on certain aspects of the diet plan. Some patients complained averaged for individual ingredients (Additional file 3). We also calcu­ about elimination of dairy products, coffee, and alcohol. Yet, we lated two final scores: accessibility was calculated as the average of the strongly believe that these products would detrimentally affect inflam­ following questions: ‘do you know where to buy it?’, ‘can you buy it near mation and decided to eliminate them from the 14-day diet. We sug­ your home?’, ‘do you know the price?’ and ‘can you afford it?’. Knowl­ gested substituting dairy products with nut extracts like almond milk, edge was calculated as the average of the following questions: ‘do you and coffee with green tea. Finally, patients asked for more recipe ex­ know what it is?’, ‘do you consume it?’ and ‘do you know how to cook amples to facilitate diet completion. it?’. If final averages fell below 50 for any category, this was interpreted as poor knowledge or accessibility for that ingredient, and we recon­ 3.4. Phase IV sidered introducing the ingredient and/or reevaluated our strategy for introducing the ingredient. We conducted a pilot trial of a 7-day ITIS diet on 5 Hispanic and 3 Additional file 3 shows the results of this questionnaire. Most of the Caucasian patients in order to get their feedback about following the ingredients that we intended to include in our ITIS diet were well-known diet. Patients were provided with turmeric, black pepper, powder and easily accepted. All of the fruits, most vegetables, chicken, and nuts, ginger, flaxseed oil, apple vinegar, tahini, sesame seeds, miso, chai were well-known and accessible. Of note, knowledge and accessibility seeds, flaxseeds, rye bread, oatmeal, almond milk, and olive oil to correlated well for each product; this possibly reflects a relationship facilitate their consumption. We had 1-h session with groups of two to between knowing how to use an ingredient and knowing where to buy it three patients to explain the diet and instructions in detail. Sessions were at the best price. Notably, products that have been promoted recently in conducted in English or Spanish depending on patient preferences. Pa­ the media, such as ginger and chia seeds, were well-known and acces­ tients were instructed to keep a diet diary and were given instructions on sible to patients. how to contact us in case of questions. Several ingredients had a value of <50 in knowledge or accessibility. We obtained feedback from 4 Hispanic patients; one patient dropped These ingredients were: rye, tahini, kefir, arugula, turmeric, quinoa, out of the trial. All 3 Caucasian patients completed the 7-diet trial. The miso, tofu, flaxseed oil, omelets, apple cider vinegar, and sweet potato. Hispanic patients surveyed, except for some exceptions attributed to Among the ingredients that were poorly accepted, we decided to personal tastes, were able to follow the diet and had no critical 4 M.F. Bustamante et al. Contemporary Clinical Trials Communications 17 (2020) 100524 difficulties. Among Caucasian patients, two patients asked for a shop­ their habits since they had been diagnosed, either after getting infor­ ping list to help with the menu and struggled to accomplish the timings mation from nutrition websites, or eliminating some foods they thought and the cooking expectations for the diet. We plan to give more flexi­ were triggering their symptoms. We hope that this will increase the bility in the diet schedule for the interventional study. patient adherence to the ITIS diet. Of note, one study showed an asso­ Final diet design: Table 2 shows the final version of the ITIS diet. ciation between specific foods and symptoms in RA patients, and they For lunch and dinner, three recommended options were given, and pa­ reported that blueberries, fish, and spinach improved RA symptoms, tients were able to distribute those throughout the week. These options while soda containing sugar and desserts aggravated their symptoms and guidelines for the patient are described in additional file 5. Macro [2]. and micro-nutrient composition as well as more details of our ITIS diet is In phase II, we collected patient feedback about the ingredients that available to interested parties. were part of the ITIS diet. To increase the feasibility of our diets, the ingredients that were poorly known or too expensive were either 4. Discussion removed, made optional, given more information or provided. Inter­ estingly, some studies have suggested that low socio-economic status Though there is some evidence that several foods might be pro- has been associated with increased RA morbidity, poorer clinical out­ inflammatory while other foods might have anti-inflammatory proper­ comes, decreased functional ability and reduced quality of life [63]. ties, there are few interventional studies to show their effect in patients Although people from lower socio-economic are more likely to smoke, affected with diseases whose main symptoms are pain and swelling such which is a known environmental risk factor for RA, they are also more as RA. Although Mediterranean and vegetarian diets are beneficial for deficient in certain micronutrients. Of interest, a study from Harvard those suffering from RA, these diets do not include several ingredients School of Public Health found that eating a healthy diet (rich in fruits, shown to be anti-inflammatory in some randomized clinical trials or vegetables, fish, and nuts) cost about $1.50 more per day per person animal models of arthritis or in vitro experiments. Given the complexity than eating an unhealthy diet (the kind full of processed foods and and severity of RA, it seems doubtful that a single change in diet, by refined grains) [64]. In phase III, we received feedback about our diet adding or eliminating one ingredient, would be sufficient to diminish instructions and guideline, and we improved the text for clarity and systemic inflammation. Some metanalyses of individual ingredients or included more recipes. Finally, in phase IV, a 7-day feasibility trial probiotics in RA reflect contradictory results or mild effects of those helped us with the last version of our ITIS diet. Overall, patients were supplements [44,45,61,62]. Instead, a diet that combines several of the highly motivated and open to trying most of the suggested ingredients. suggested strategies to decrease inflammation may represent a more Managing chronic diseases in self-motivated patients with diet and realistic dietician approach for those suffering from the disease. Yet, the lifestyle changes was shown to be critical to achieve treatment goals in patients might adhere better to a small change or addition of just sup­ other diseases [65]. plements than a complete change in their diet. Thus, our goal was to The strength of this study is the continuous feedback we got from the design a diet that introduced patient’s feedback to increase their community we are planning to treat to build our ITIS diet. Although we adherence and feasibility for a future interventional trial. expected differences between Hispanic and Caucasian patients given Patient feedback in the different phases helped us adjust the diet their different socioeconomic status, lifestyle, and accessibility to some based on knowledge and accessibility of ingredients, and to improve the stores, our perception was that the diet habits of Hispanic and Caucasian quality of the instructions. In phase I, we learned that the strategies our patients were very similar. Additionally, both Caucasians and Hispanics ITIS diet contemplated did not differ drastically from the current diet had similar knowledge about ingredients included in the diet. Unfortu­ habits of our patients. Our patients mentioned that they had adjusted nately, we were unable to conduct statistical analyses given the small Table 2 Final version of the ITIS diet. Monday Tuesday Wednesday Thursday Friday Saturday Sunday 7–8 am SMOOTHIE Coconut milk, Pear, lemon, Grapes, celery, Almond or oat milk, Spinach, ginger, Papaya, spinach, Parsley, mango, papaya, yogurt, vanilla, spinach, spinach, turmeric, almond milk, pineapple, pineapple water cucumber, lime, strawberries, pear, papaya, turmeric, chia strawberries, water ginger, chia seeds, flaxseeds, seeds, honey water cinnamon banana, water 7–8 am BREAKFAST 1-2 spoonful of oats 1-2 corn tortillas, 1 -2 corn tortillas 1-2 spoons of oat 1-2 corn 1 -2 corn tortillas 1-2 corn tortillas, with non-dairy spread with with tahini with non-dairy milk tortillas, spread with tahini spread with milk (oat milk, avocado, sesame (sesame seed (oat, almond or rice with avocado, (sesame seed avocado, sesame almond milk or rice seeds, and flaxseed extract) with ¼ milk. Add berries sesame seeds, extract) with ¼ seeds, and milk). Add berries oil. teaspoon of (optional). and flaxseed oil. teaspoon of linseed oil. (optional). Green tea infusion. honey. Green tea infusion. Green tea honey. Green tea Green tea infusion. Green tea infusion. Green tea infusion. infusion infusion 10–11 SNACK Plain yogurt Plain yogurt Plain yogurt Plain yogurt Plain yogurt Plain yogurt Plain yogurt a.m. (Chobani Brand, no (Chobani Brand, no (Chobani Brand, (Chobani Brand, no (Chobani Brand, (Chobani Brand, no (Chobani sugar added) sugar added) no sugar added) sugar added) no sugar added) sugar added) Brand, no sugar added) 12-1 LUNCH OPTION 1: Salad (generous plate) pm OPTION 2: Grains with vegetables OPTION 3: Legumes with vegetables 4 p.m. SNACK Mango, papaya, Mango, Mango, papaya, Mango, papaya, Mango, papaya, Mango, papaya, Mango, papaya, pineapple, apple, papaya, pineapple, apple, pineapple, apple, pineapple, pineapple, apple, pineapple, apple, pear or banana þ4 pineapple, pear or banana þ4 pear or banana þ4 apple, pear or pear or banana pear or banana walnuts apple, pear or walnuts walnuts banana þ4 þ4 walnuts þ4 walnuts banana þ4 walnuts walnuts 6–7 DINNER OPTION 1: Vegetable soup/cream þ protein pm OPTION 2: Miso soup þ baked/steamed/grilled vegetables þ protein OPTION 3: Salad þ protein 5 M.F. Bustamante et al. Contemporary Clinical Trials Communications 17 (2020) 100524 number or patients in each phase. Second, we provided groceries. Par­ References ticipants received around $100 in specific ingredients that help their consumption. Finally, we also provided detailed instructions and dietary [1] G.S. Firestein, Evolving concepts of rheumatoid arthritis, Nature 423 (2003) 356–361. counseling for the participants at the phase IV which together with [2] S.K. Tedeschi, M. Frits, J. Cui, Z.Z. Zhang, T. Mahmoud, C. Iannaccone, T.C. Lin, groceries being provided increased adherence and positive feedback in K. Yoshida, M.E. Weinblatt, N.A. Shadick, D.H. Solomon, Diet and rheumatoid this pilot phase. This diet is being used in an on-going pilot study to arthritis symptoms: survey results from a rheumatoid arthritis registry, Arthritis Care Res. 69 (2017) 1920–1925. determine their anti-inflammatory effect in pain and joint swelling in RA [3] M. Derrien, P. Veiga, Rethinking diet to aid human-microbe symbiosis, Trends patients. Microbiol. 25 (2017) 100–112. [4] B.O. Schroeder, F. Backhed, Signals from the gut microbiota to distant organs in physiology and disease, Nat. Med. 22 (2016) 1079–1089. Ethical approval and consent to participate [5] R.A. Koeth, Z. Wang, B.S. Levison, J.A. Buffa, E. Org, B.T. Sheehy, E.B. Britt, X. Fu, Y. Wu, L. Li, et al., Intestinal microbiota metabolism of L-carnitine, a nutrient in red Ethical approval was granted by the Institutional Review Board (IRB) meat, promotes atherosclerosis, Nat. Med. 19 (2013) 576–585. [6] Z. Wang, E. Klipfell, B.J. Bennett, R. Koeth, B.S. Levison, B. Dugar, A.E. Feldstein, at University of California at San Diego. E.B. Britt, X. Fu, Y.M. Chung, et al., Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease, Nature 472 (2011) 57–63. [7] J.U. Scher, A. Sczesnak, R.S. Longman, N. Segata, C. Ubeda, C. Bielski, T. Rostron, Consent for publication V. Cerundolo, E.G. Pamer, S.B. Abramson, et al., Expansion of intestinal Prevotella copri correlates with enhanced susceptibility to arthritis, Elife 2 (2013) e01202. Not applicable. [8] F. Gaucher, S. Bonnassie, H. Rabah, P. Marchand, P. Blanc, R. Jeantet, G. Jan, Review: adaptation of beneficial propionibacteria, lactobacilli, and bifidobacteria improves tolerance toward technological and digestive stresses, Front. Microbiol. Availability of supporting data 10 (2019) 841. [9] H.M. Roager, T.R. Licht, Microbial tryptophan catabolites in health and disease, Nat. Commun. 9 (2018) 3294. Not applicable. [10] R. Pei, D.M. DiMarco, K.K. Putt, D.A. Martin, Q. Gu, C. Chitchumroonchokchai, H. M. White, C.O. Scarlett, R.S. Bruno, B.W. Bolling, Low-fat yogurt consumption Funding reduces biomarkers of chronic inflammation and inhibits markers of endotoxin exposure in healthy premenopausal women: a randomised controlled trial, Br. J. Nutr. 118 (2017) 1043–1051. Funding sources: Research reported in this publication was sup­ [11] M. Lyte, A. Chapel, J.M. Lyte, Y. Ai, A. Proctor, J.L. Jane, G.J. Phillips, Resistant ported by Krupp Endowed Foundation to MG and by grant from the starch alters the microbiota-gut brain Axis: implications for dietary modulation of behavior, PloS One 11 (2016) e0146406. Spanish Society of Rheumatology to RC. This work was also supported in [12] J. Slavin, Fiber and prebiotics: mechanisms and health benefits, Nutrients 5 (2013) part by the Erickson Family. 1417–1435. [13] K.E. Bach Knudsen, Microbial degradation of whole-grain complex carbohydrates and impact on short-chain fatty acids and health, Adv. Nutr. 6 (2015) 206–213. Authors’ contributors [14] A. Lerner, T. Matthias, Rheumatoid arthritis-celiac disease relationship: joints get that gut feeling, Autoimmun. Rev. 14 (2015) 1038–1047. [15] A.B. Oteng, S. Kersten, Mechanisms of action of trans fatty acids, Adv. Nutr. (2019 Study conception and design: MFB, MAP, RN, SG, and MG. Patients Nov 29), https://doi.org/10.1093/advances/nmz125 [Epub ahead of print]. recruitment: FC, RC and MG. Analysis and interpretation of data. MFB, [16] B. Li, J.C.K. Leung, L.Y.Y. Chan, W.H. Yiu, S.C.W. Tang, A global perspective on the MAP, RC, SG and FC. MG supervised the overall project. crosstalk between saturated fatty acids and Toll-like receptor 4 in the etiology of inflammation and insulin resistance, Prog. Lipid Res. 77 (2019) 101020. [17] N.T. Bendsen, S. Stender, P.B. Szecsi, S.B. Pedersen, S. Basu, L.I. Hellgren, J. Authors’ information W. Newman, T.M. Larsen, S.B. Haugaard, A. Astrup, Effect of industrially produced trans fat on markers of systemic inflammation: evidence from a randomized trial in women, J. Lipid Res. 52 (2011) 1821–1828. MFB, MAP, FC, RC, RN and MG are of the Department of Medicine [18] E. Demmer, M.D. Van Loan, N. Rivera, T.S. Rogers, E.R. Gertz, J.B. German, A. University of California San Diego, San Diego, CA, USA; RC and MG are M. Zivkovic, J.T. Smilowitz, Consumption of a high-fat meal containing cheese also of the Department of Medicine, Autonomous University of Barce­ compared with a vegan alternative lowers postprandial C-reactive protein in overweight and obese individuals with metabolic abnormalities: a randomised lona, Plaça Cívica, Spain; SG is of the Department of Psychiatry Uni­ controlled cross-over study, J. Nutr. Sci. 5 (2016) e9. versity of California San Diego, San Diego, CA, USA. [19] A.N. Samraj, O.M. Pearce, H. Laubli, A.N. Crittenden, A.K. Bergfeld, K. Banda, C. J. Gregg, A.E. Bingman, P. Secrest, S.L. Diaz, et al., A red meat-derived glycan promotes inflammation and cancer progression, Proc. Natl. Acad. Sci. U. S. A. 112 Declaration of competing interest (2015) 542–547. [20] S.H. Ley, Q. Sun, W.C. Willett, A.H. Eliassen, K. Wu, A. Pan, F. Grodstein, F.B. Hu, Associations between red meat intake and biomarkers of inflammation and glucose The authors report no conflict of interest. metabolism in women, Am. J. Clin. Nutr. 99 (2014) 352–360. [21] M. Friedman, Potato glycoalkaloids and metabolites: roles in the plant and in the diet, J. Agric. Food Chem. 54 (2006) 8655–8681. Acknowledgments [22] A.M. El-Tawil, Prevalence of inflammatory bowel diseases in the Western Nations: high consumption of potatoes may be contributing, Int. J. Colorectal Dis. 23 (2008) Not applicable. 1017–1018. [23] T.T. Mensinga, A.J. Sips, C.J. Rompelberg, K. van Twillert, J. Meulenbelt, H.J. van den Top, H.P. van Egmond, Potato glycoalkaloids and adverse effects in humans: List of abbreviations an ascending dose study, Regul. Toxicol. Pharmacol. 41 (2005) 66–72. [24] C. Bemeur, P. Desjardins, R.F. Butterworth, Antioxidant and anti-inflammatory effects of mild hypothermia in the attenuation of liver injury due to azoxymethane RA Rheumatoid arthritis toxicity in the mouse, Metab. Brain Dis. 25 (2010) 23–29. SCFA Short chain fatty acids [25] B. Patel, R. Schutte, P. Sporns, J. Doyle, L. Jewel, R.N. Fedorak, Potato CRP C reactive protein glycoalkaloids adversely affect intestinal permeability and aggravate inflammatory bowel disease, Inflamm. Bowel Dis. 8 (2002) 340–346. FA Fatty acids [26] V. Iablokov, B.C. Sydora, R. Foshaug, J. Meddings, D. Driedger, T. Churchill, R. PUFA polyunsaturated FA N. Fedorak, Naturally occurring glycoalkaloids in potatoes aggravate intestinal MUFA monounsaturated FA inflammation in two mouse models of inflammatory bowel disease, Dig. Dis. Sci. 55 (2010) 3078–3085. [27] B. Sears, Anti-inflammatory diets, J. Am. Coll. Nutr. 34 (Suppl 1) (2015) 14–21. Appendix A. Supplementary data [28] S. Lorente-Cebrian, A.G. Costa, S. Navas-Carretero, M. Zabala, L.M. Laiglesia, J. A. Martinez, M.J. Moreno-Aliaga, An update on the role of omega-3 fatty acids on inflammatory and degenerative diseases, J. Physiol. Biochem. 71 (2015) 341–349. Supplementary data to this article can be found online at https://doi. org/10.1016/j.conctc.2020.100524. 6 M.F. Bustamante et al. Contemporary Clinical Trials Communications 17 (2020) 100524 [29] A.A. Berbert, C.R. Kondo, C.L. Almendra, T. Matsuo, I. Dichi, Supplementation of [52] B. Zamani, H.R. Golkar, S. Farshbaf, M. Emadi-Baygi, M. Tajabadi-Ebrahimi, fish oil and olive oil in patients with rheumatoid arthritis, Nutrition 21 (2005) P. Jafari, R. Akhavan, M. Taghizadeh, M.R. Memarzadeh, Z. Asemi, Clinical and 131–136. metabolic response to probiotic supplementation in patients with rheumatoid [30] A. Gioxari, A.C. Kaliora, F. Marantidou, D.P. Panagiotakos, Intake of omega-3 arthritis: a randomized, double-blind, placebo-controlled trial, Int. J. Rheum. Dis. polyunsaturated fatty acids in patients with rheumatoid arthritis: a systematic 19 (2016) 869–879. review and meta-analysis, Nutrition 45 (2018) 114–124, e114. [53] B. Alipour, A. Homayouni-Rad, E. Vaghef-Mehrabany, S.K. Sharif, L. Vaghef- [31] C. Dawczynski, M. Dittrich, T. Neumann, K. Goetze, A. Welzel, P. Oelzner, Mehrabany, M. Asghari-Jafarabadi, M.R. Nakhjavani, J. Mohtadi-Nia, Effects of S. Volker, A.M. Schaible, F. Troisi, L. Thomas, et al., Docosahexaenoic acid in the Lactobacillus casei supplementation on disease activity and inflammatory treatment of rheumatoid arthritis: a double-blind, placebo-controlled, randomized cytokines in rheumatoid arthritis patients: a randomized double-blind clinical trial, cross-over study with microalgae vs. sunflower oil, Clin. Nutr. 37 (2018) 494–504. Int. J. Rheum. Dis. 17 (2014) 519–527. [32] M. Abdulrazaq, J.K. Innes, P.C. Calder, Effect of omega-3 polyunsaturated fatty [54] L. Barebring, A. Winkvist, I. Gjertsson, H.M. Lindqvist, Poor dietary quality is acids on arthritic pain: a systematic review, Nutrition 39–40 (2017) 57–66. associated with increased inflammation in Swedish patients with rheumatoid [33] Y. Matsumoto, Y. Sugioka, M. Tada, T. Okano, K. Mamoto, K. Inui, D. Habu, arthritis, Nutrients (2018) 10. T. Koike, Monounsaturated fatty acids might be key factors in the Mediterranean [55] S.K. Tedeschi, J.M. Bathon, J.T. Giles, T.C. Lin, K. Yoshida, D.H. Solomon, diet that suppress rheumatoid arthritis disease activity: the TOMORROW study, Relationship between fish consumption and disease activity in rheumatoid Clin. Nutr. 37 (2018) 675–680. arthritis, Arthritis Care Res. 70 (2018) 327–332. [34] B. Helli, M.M. Shahi, K. Mowla, M.T. Jalali, H.K. Haghighian, A randomized, triple- [56] S. Khanna, K.S. Jaiswal, B. Gupta, Managing rheumatoid arthritis with dietary blind, placebo-controlled clinical trial, evaluating the sesamin supplement effects interventions, Front. Nutr. 4 (2017) 52. on proteolytic enzymes, inflammatory markers, and clinical indices in women with [57] J. Grygielska, F. Raciborski, A. Klak, J. Owoc, The impact of nutrition and rheumatoid arthritis, Phytother Res. 33 (2019) 2421–2428. generally available products such as nicotine and alcohol on rheumatoid arthritis - [35] M. Batooei, A. Tahamoli-Roudsari, Z. Basiri, F. Yasrebifar, M. Shahdoust, review of the literature, Reumatologia 56 (2018) 121–127. A. Eshraghi, M. Mehrpooya, S. Ataei, Evaluating the effect of oral N-acetylcysteine [58] J. Kjeldsen-Kragh, M. Haugen, C.F. Borchgrevink, E. Laerum, M. Eek, P. Mowinkel, as an adjuvant treatment on clinical outcomes of patients with rheumatoid K. Hovi, O. Forre, Controlled trial of fasting and one-year vegetarian diet in arthritis: a randomized, double blind clinical trial, Rev. Recent Clin. Trials 13 rheumatoid arthritis, Lancet 338 (1991) 899–902. (2018) 132–138. [59] L. Skoldstam, L. Hagfors, G. Johansson, An experimental study of a Mediterranean [36] F. Zhu, B. Du, B. Xu, Anti-inflammatory effects of phytochemicals from fruits, diet intervention for patients with rheumatoid arthritis, Ann. Rheum. Dis. 62 vegetables, and food legumes: a review, Crit. Rev. Food Sci. Nutr. 58 (2018) (2003) 208–214. 1260–1270. [60] K.H. Wagner, I. Elmadfa, Chemical and biological modulations of food due to the [37] F. Javadi, A. Ahmadzadeh, S. Eghtesadi, N. Aryaeian, M. Zabihiyeganeh, A. Rahimi frying process, Int. J. Vitam. Nutr. Res. 82 (2012) 163–167. Foroushani, S. Jazayeri, The effect of quercetin on inflammatory factors and [61] Y. Liu, J.J. Alookaran, J.M. Rhoads, Probiotics in autoimmune and inflammatory clinical symptoms in women with rheumatoid arthritis: a double-blind, disorders, Nutrients (2018) 10. randomized controlled trial, J. Am. Coll. Nutr. 36 (2017) 9–15. [62] A.T. Mohammed, M. Khattab, A.M. Ahmed, T. Turk, N. Sakr, A. Mk, [38] M. Ghavipour, G. Sotoudeh, E. Tavakoli, K. Mowla, J. Hasanzadeh, Z. Mazloom, M. Abdelhalim, B. Sawaf, K. Hirayama, N.T. Huy, The therapeutic effect of Pomegranate extract alleviates disease activity and some blood biomarkers of probiotics on rheumatoid arthritis: a systematic review and meta-analysis of inflammation and oxidative stress in Rheumatoid Arthritis patients, Eur. J. Clin. randomized control trials, Clin. Rheumatol. 36 (2017) 2697–2707. Nutr. 71 (2017) 92–96. [63] S.M.M. Verstappen, The impact of socio-economic status in rheumatoid arthritis, [39] A. Lo Gullo, G. Mandraffino, G. Bagnato, C.O. Aragona, E. Imbalzano, A. D’Ascola, Rheumatology 56 (2017) 1051–1052. F. Rotondo, A. Cinquegrani, E. Mormina, C. Saitta, et al., Vitamin D status in [64] M. Rao, A. Afshin, G. Singh, D. Mozaffarian, Do healthier foods and diet patterns rheumatoid arthritis: inflammation, arterial stiffness and circulating progenitor cell cost more than less healthy options? A systematic review and meta-analysis, BMJ number, PloS One 10 (2015) e0134602. Open 3 (2013) e004277. [40] S. Muller, R. Marz, M. Schmolz, B. Drewelow, K. Eschmann, P. Meiser, Placebo- [65] D.A. Nadeau, Management of type 2 diabetes mellitus in self-motivated patients: controlled randomized clinical trial on the immunomodulating activities of low- optimized diet, exercise, and medication for weight loss and cardiometabolic and high-dose bromelain after oral administration - new evidence on the fitness, Physician Sportsmed. 42 (2014) 49–59. antiinflammatory mode of action of bromelain, Phytother Res. 27 (2013) 199–204. [66] G. Boudry, M.K. Hamilton, M. Chichlowski, S. Wickramasinghe, D. Barile, K. [41] L.P. Hale, M. Chichlowski, C.T. Trinh, P.K. Greer, Dietary supplementation with M. Kalanetra, D.A. Mills, H.E. Raybould, Bovine milk oligosaccharides decrease gut fresh pineapple juice decreases inflammation and colonic neoplasia in IL-10- permeability and improve inflammation and microbial dysbiosis in diet-induced deficient mice with colitis, Inflamm. Bowel Dis. 16 (2010) 2012–2021. obese mice, J. Dairy Sci. 100 (2017) 2471–2481. [42] S. Pandey, P.J. Cabot, P.N. Shaw, A.K. Hewavitharana, Anti-inflammatory and [67] E. Salgado, M. Bes-Rastrollo, J. de Irala, L. Carmona, J.J. Gomez-Reino, High immunomodulatory properties of Carica papaya, J. Immunot. 13 (2016) 590–602. sodium intake is associated with self-reported rheumatoid arthritis: a cross [43] N. Aryaeian, F. Shahram, M. Mahmoudi, H. Tavakoli, B. Yousefi, T. Arablou, Jafari sectional and case control analysis within the SUN cohort, Medicine (Baltim.) 94 Karegar S: the effect of ginger supplementation on some immunity and (2015) e924. inflammation intermediate genes expression in patients with active Rheumatoid [68] K. Sharif, H. Amital, Y. Shoenfeld, The role of dietary sodium in autoimmune Arthritis, Gene 698 (2019) 179–185. diseases: the salty truth, Autoimmun. Rev. 17 (2018) 1069–1073. [44] J.W. Daily, M. Yang, S. Park, Efficacy of turmeric extracts and curcumin for [69] S.M. Vanegas, M. Meydani, J.B. Barnett, B. Goldin, A. Kane, H. Rasmussen, alleviating the symptoms of joint arthritis: a systematic review and meta-analysis C. Brown, P. Vangay, D. Knights, S. Jonnalagadda, et al., Substituting whole grains of randomized clinical trials, J. Med. Food 19 (2016) 717–729. for refined grains in a 6-wk randomized trial has a modest effect on gut microbiota [45] B. Chandran, A. Goel, A randomized, pilot study to assess the efficacy and safety of and immune and inflammatory markers of healthy adults, Am. J. Clin. Nutr. 105 curcumin in patients with active rheumatoid arthritis, Phytother Res. 26 (2012) (2017) 635–650. 1719–1725. [70] H.M. Roager, J.K. Vogt, M. Kristensen, L.B.S. Hansen, S. Ibrugger, R.B. Maerkedahl, [46] J.S. Bang, D.H. Oh, H.M. Choi, B.J. Sur, S.J. Lim, J.Y. Kim, H.I. Yang, M.C. Yoo, D. M.I. Bahl, M.V. Lind, R.L. Nielsen, H. Frokiaer, et al., Whole grain-rich diet reduces H. Hahm, K.S. Kim, Anti-inflammatory and antiarthritic effects of piperine in body weight and systemic low-grade inflammation without inducing major human interleukin 1beta-stimulated fibroblast-like synoviocytes and in rat arthritis changes of the gut microbiome: a randomised cross-over trial, Gut 68 (2019) models, Arthritis Res. Ther. 11 (2009). R49. 83–93. [47] Y. Panahi, M.S. Hosseini, N. Khalili, E. Naimi, M. Majeed, A. Sahebkar, Antioxidant [71] H. Tilg, N. Zmora, T.E. Adolph, E. Elinav, The intestinal microbiota fuelling and anti-inflammatory effects of curcuminoid-piperine combination in subjects metabolic inflammation, Nat. Rev. Immunol. 20 (1) (2020 Jan) 40–54, https://doi. with metabolic syndrome: a randomized controlled trial and an updated meta- org/10.1038/s41577-019-0198-4. analysis, Clin. Nutr. 34 (2015) 1101–1108. [72] K. Sharif, A. Watad, N.L. Bragazzi, M. Adawi, H. Amital, Y. Shoenfeld, Coffee and [48] A.H. Alghadir, S.A. Gabr, E.S. Al-Eisa, Green tea and exercise interventions as autoimmunity: more than a mere hot beverage!, Autoimmun. Rev. 16 (2017) nondrug remedies in geriatric patients with rheumatoid arthritis, J. Phys. Ther. Sci. 712–721. 28 (2016) 2820–2829. [73] S.C. Bae, Y.H. Lee, Coffee consumption and the risk of rheumatoid arthritis and [49] T. Ohishi, S. Goto, P. Monira, M. Isemura, Y. Nakamura, Anti-inflammatory action systemic lupus erythematosus: a Mendelian randomization study, Clin. Rheumatol. of green tea, Anti-Inflammatory Anti-Allergy Agents Med. Chem. 15 (2016) 74–90. 37 (2018) 2875–2879. [50] S. Sung, D. Kwon, E. Um, B. Kim, Could polyphenols help in the control of [74] M. Heliovaara, K. Aho, P. Knekt, O. Impivaara, A. Reunanen, A. Aromaa, Coffee rheumatoid arthritis? Molecules (2019) 24. consumption, rheumatoid factor, and the risk of rheumatoid arthritis, Ann. Rheum. [51] A. Salehi-Abargouei, S. Saraf-Bank, N. Bellissimo, L. Azadbakht, Effects of non-soy Dis. 59 (2000) 631–635. legume consumption on C-reactive protein: a systematic review and meta-analysis, Nutrition 31 (2015) 631–639. 7