Polyphenols for improvement of inflammation and symptoms in rheumatic diseases: systematic review

ABSTRACT BACKGROUND: Rheumatic diseases (RDs) are a group of pathological conditions characterized by inflammation and functional disability. There is evidence suggesting that regular consumption of polyphenols has therapeutic effects capable of relieving RD symptoms. OBJECTIVE: To synthesize data from randomized controlled trials on administration of polyphenols and their effects on RD activity. DESIGN AND SETTING: Systematic review conducted at Universidade Federal de Ouro Preto, Minas Gerais, Brazil. METHODS: A systematic search was conducted in the databases PubMed (Medline), LILACS (BVS), IBECS (BVS), CUMED (BVS), BINACIS (BVS), EMBASE, Web of Science and Cochrane Library and in the grey literature. The present study followed a PRISMA-P checklist. RESULTS: In total, 646 articles were considered potentially eligible, of which 33 were then subjected to complete reading. Out of these, 17 randomized controlled trials articles were selected to form the final sample. Among these 17 articles, 64.71% assessed osteoarthritis (n = 11), 23.53% rheumatoid arthritis (n = 4), 5.88% rheumatoid arthritis and fibromyalgia (n = 1) and 5.88% osteoarthritis and rheumatoid (n = 1). Intake of polyphenol showed positive effects in most of the studies assessed (94.12%): it improved pain (64.70%) and inflammation (58.82%). CONCLUSION: Polyphenols are potential allies for treating RD activity. However, the range of polyphenol sources administered was a limitation of this review, as also was the lack of information about the methodological characteristics of the studies evaluated. Thus, further primary studies are needed in order to evaluate the effects of polyphenol consumption for reducing RD activity. SYSTEMATIC REVIEW REGISTER: PROSPERO - CRD42020145349.


INTRODUCTION
Rheumatic diseases (RDs) belong to a group of chronic musculoskeletal pathological conditions characterized by joint damage, inflammation, pain, functional disability and impact on individuals' quality of life. [1][2][3][4] Rheumatic diseases include chronic clinical conditions of multicausal etiopathogenesis characterized by disruption of immunological tolerance, production of autoantibodies, production of a number of substances accounting for lesions in many body structures, 4 mechanical stress in the joints and changes to the alignment of bones, cartilage and other structures necessary for joint stability. 5 They give rise to a heterogeneous group of clinical conditions, such as rheumatoid arthritis, osteoarthritis, scleroderma, systemic sclerosis, ankylosing spondylitis, fibromyalgia, osteoporosis, tendinitis, gout and lupus, among others. Osteoarthritis (OA) and rheumatoid arthritis (RA) are the most common RDs. 3 OA is the first chronic, inflammatory and degenerative disease that arises through joint cartilage wear or loss. 2 RA is an inflammatory disease that mainly affects joints without being degenerative. Instead, it causes structural damage and joint inflammation, which result in progressive structural and functional losses. 4 RDs are more common in developed countries and in women. In Europe and North America, their prevalence is 0.5%-1.0%. 6 OA is the most common form of arthritis, affecting approximately etanercept, certolizumab pegol, golimumab, adalimumab, tocilizumab, abatacept, rituximab, tofacitinib, baricitinib, upadacitinib, secukinumab, ustekinumab, ixekizumab, guselkumab and belimumab. However, these can be costly and can have side effects like abdominal pain, back pain, chest pain and nausea. 8 Diet therapy can be used to assist RD therapies, since it helps to reduce pain and inflammation effects. 9 The Nurses' Health Study cohort showed lower RA incidence among individuals who followed healthy dietary patterns (as assessed using the Healthy Eating Index, HEI-2010) than among individuals who followed inadequate dietary patterns. 10 Regular consumption of fresh fruits, vegetables and spices rich in phytochemicals can mitigate oxidative stress and inflammation, and relieve symptoms. 11 The therapeutic effects of phytochemicals, especially polyphenols, on RDs have been studied, given their antioxidant, anti-inflammatory and immunomodulatory properties. 3 Polyphenols are metabolites found in plants that are produced in metabolic pathways triggered by plant interactions with environmental factors. They are involved in plant reproduction and in communication between plants, as well as in their defense against pathogens. Polyphenols are found in vegetables, fruits, cocoa and nuts, and also in their derivatives, such as juices and teas. 12 Epidemiological studies have presented associations between polyphenol intake and RDs, [13][14][15] and experimental studies on animal models and in vitro investigations about the role played by polyphenols in RDs have been conducted. Diets rich in bioactive compounds are associated with improvement of disease activity, since these substances act as protective factors against inflammatory processes and against endothelial dysfunction linked to development of worsening of clinical signs and symptoms. 3 A systematic review of the literature showed that total flavonoids and specific subclasses of flavonoids such as flavanols, flavanones, flavones, isoflavones and anthocyanins (but without addressing total polyphenols in diets) are associated with low risk of developing diabetes, cardiovascular events and mortality. 16 However, to the best of our knowledge, no systematic review has been conducted with the aim of evaluating the association between administration of polyphenols and RD symptoms.

OBJECTIVE
The aim of the present article was to review the effects of polyphenols on RD activity, based on information available in the literature (randomized clinical trials).

Protocol and registration
The present systematic review was conducted in accordance with the "Preferred Reporting Items for Systematic Reviews and Meta-Analysis" guidelines (PRISMA-P  The descriptors used were previously defined in the MeSH, DECS and Emtree databases. These related to "Rheumatic Diseases" or "Disease, Rheumatic" or "Rheumatic Disease" or "Rheumatism" and "Polyphenols" or "Provinols".

Inclusion and exclusion criteria
Only double-blind randomized controlled trials (RCTs) analyzing outcomes from interventions consisting of polyphenol administration to improve disease activity were included in this study. No restrictions on the date of publication or language used were imposed in relation to article selection.
The exclusion criteria encompassed duplicates, in vitro studies, reviews, cross-sectional or observational studies, case reports, case series, ecological studies, studies about other morbidities or studies on pregnant women, children or teenagers.

Data collection process
The references retrieved through the search strategies were exported to an Endnote file (Clarivate Analytics, Philadelphia, United States), and duplicates were removed. Two independent researchers (HNC and APD) selected titles and abstracts; potential texts were evaluated to check their eligibility based on the criteria described above. A third researcher (NSG) resolved any discrepancies resulting from disagreements between HNC and APD. In addition, the grey literature, such as monographs, dissertations, theses and conference proceedings, was assessed based on references in the articles selected.

Data extraction
Two independent researchers (HNC and APD) extracted data on features such as study design, name of the first author, publication year, participants, participants' age and sex, intervention features, placebo groups (sample, age, sex), intervention types (polyphenol use), sample size and outcomes (rheumatic disease activity: pain, functional capacity, inflammatory markers, laboratory markers, antioxidant activity and quality of life).

Evaluation of the methodological quality of the studies included
The quality of the RCT methodology was assessed through the Cochrane tool for risk of bias in Cochrane randomized studies (RoB 2.0, London, England), which classifies studies as having high or low risk of bias. The methodological quality was assessed by two independent researchers (HNC and APD), and a third researcher (NSG) resolved any score divergences.

RESULTS
The search in the databases and in the grey literature resulted in 646 studies. In total, 641 publications were evaluated after duplicate removal (n = 5). From among these, 542 articles were  The analysis on the studies included in this review was demonstrated through three tables that were organized according to the pathological conditions found. The lack of information about the methodological characteristics of the studies evaluated in the present review made it difficult to classify the quality of evidence, as shown in Figure 2. Eight studies did not mention any method of randomization. [19][20][21][22][23][24][25][26] Among all the articles, five did not mention the allocation method. 18,19,22,23,27 Nine studies had a high risk of bias because the study participants were not blinded to either the intervention or the placebo groups. 20,21,24,25,29,30 In six studies, an imbalance in either the number of or the reasons for missing data, between the experimental and control groups, was observed. 18,20,25,26,28,30 Lastly, just four authors described all the outcomes targeted and measured. 20,26,28,30

DISCUSSION
We found out that polyphenols are capable of helping to treat RDs, with reductions of inflammation and pain. Therefore, their use in treatments for RDs can impact the quality of life of the individuals affected.
To the best of our knowledge, the present systematic review was a pioneer in assessing the association between polyphenol administration and mitigation/improvement of rheumatic disease activity in humans.
Positive effects from polyphenol intake on the improvement/ RD improvement was mostly identified by means of biochemical markers that indicate normal or pathological functioning. 34 Inflammatory biomarker levels are increased in RDs, and are associated with the pain and other symptoms of the disease. 6 They can be divided into the following categories: pro-inflammatory cytokines, anti-inflammatory cytokines, adipokines and chemokines.
Pro-inflammatory cytokines are mainly produced by adipocytes: the main ones are IL-6, IL-8, IL-1β and TNF-α. 34 Specific biomarkers of RD, such as MMP, stand out among them. These biomarkers belong to a family of enzymes that account for the extracellular degradation of cartilage matrix components, including collagen type II and aggrecan; they change bone metabolism, cartilage and the synovial membrane, which leads to joint destruction. 35 There is a specific treatment for each clinical condition in RDs.
These treatments can range from medication to secondary therapies such as individualized diet therapy. 6,36 Overall, drug therapy involves use of non-steroidal anti-inflammatory drugs (NSAIDs) such as diclofenac and meloxicam, but these substances lead to      Given the lack of consensus on the best doses and types of polyphenols in the studies assessed in this review, the results should be interpreted with caution and attention. There is a need to conduct primary studies that focus on the minimum dose necessary to achieve the protective effects of polyphenols on the health of patients with RDs. Accordingly, for better guidance for healthcare professionals and patients, future research must focus on, and align with, daily recommendations for foods that are known to be source of polyphenols that are capable of preventing and protecting health and helping in treating RDs, due to the importance of consuming such bioactive compounds.
Despite the bias in the primary data sources that is reported here, this review produced promising results, considering that, overall, the dietary intake from polyphenol-rich sources had positive effects with regard to reducing both inflammation and the symptoms of RDs. Shep et al. 22 Wong et al. 20 Schell et al. 18 Panahi et al. 33 Naderi et al. 27 Nakagawa et al. 32 Khojah et al. 23 Javadi et al. 19 Du et al. 28 Hussain et al. 21 Hänninen et al. 31 Chandran and Goel 24 Haroyan et al. 25 Henrotin et al. 17 Bitler et al. 29 Thimóteo et al. 26 Schumacher et al. 30 Low risk of bias Uncertain risk of bias Higher risk Figure 2. Assessment of the quality of randomized clinical trials selected to form part of the present review, 2020.