The Open Rheumatology Journal




ISSN: 1874-3129 ― Volume 12, 2018
REVIEW ARTICLE

Role of Diet in Influencing Rheumatoid Arthritis Disease Activity



Humeira Badsha*
Dr. Humeira Badsha Medical Center, Beach Park Plaza, Jumeira Road, Dubai, UAE

Abstract

Background:

Patients with Rheumatoid Arthritis (RA) frequently ask their doctors about which diets to follow, and even in the absence of advice from their physicians, many patients are undertaking various dietary interventions.

Discussion:

However, the role of dietary modifications in RA is not well understood. Several studies have tried to address these gaps in our understanding. Intestinal microbial modifications are being studied for the prevention and management of RA. Some benefits of vegan diet may be explained by antioxidant constituents, lactobacilli and fibre, and by potential changes in intestinal flora. Similarly, Mediterranean diet shows anti-inflammatory effects due to protective properties of omega-3 polyunsaturated fatty acids and vitamins, but also by influencing the gut microbiome. Gluten-free and elemental diets have been associated with some benefits in RA though the existing evidence is limited. Long-term intake of fish and other sources of long-chain polyunsaturated fatty acids are protective for development of RA. The benefits of fasting, anti-oxidant supplementation, flavanoids, and probiotics in RA are not clear. Vitamin D has been shown to influence autoimmunity and specifically decrease RA disease activity. The role of supplements such as fish oils and vitamin D should be explored in future trials to gain new insights in disease pathogenesis and develop RA-specific dietary recommendations.

Conclusion:

Specifically more research is needed to explore the association of diet and the gut microbiome and how this can influence RA disease activity.

Keywords: Diet, Rheumatoid arthritis, Microbiome, Inflammation, Dysbiosis, Disease.


Article Information


Identifiers and Pagination:

Year: 2018
Volume: 12
First Page: 19
Last Page: 28
Publisher Id: TORJ-12-19
DOI: 10.2174/1874312901812010019

Article History:

Received Date: 16/12/2017
Revision Received Date: 6/1/2018
Acceptance Date: 21/01/2018
Electronic publication date: 08/02/2018
Collection year: 2018

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 2144
Abstract HTML Views: 904
PDF Downloads: 747
ePub Downloads: 711
Total Views/Downloads: 4506

Unique Statistics:

Full-Text HTML Views: 1379
Abstract HTML Views: 395
PDF Downloads: 330
ePub Downloads: 194
Total Views/Downloads: 2298
Geographical View

© 2018 Humeira Badsha.

open-access license: This is an open access article distributed under the terms of the Creative Commons Attribution 4.0 International Public License (CC-BY 4.0), a copy of which is available at: (https://creativecommons.org/licenses/by/4.0/legalcode). This license permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


* Address correspondence to this author at the Dr. Humeira Badsha Medical Center, Beach Park Plaza, Jumeira Road, Dubai, UAE, Tel: +9714 385 6009, E-mail: doctorbadsha@gmail.com




1. INTRODUCTION

Despite advances in the treatment of Rheumatoid Arthritis (RA), remission rates are still low [1Hetland ML, Christensen IJ, Tarp U, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010; 62(1): 22-32.[http://dx.doi.org/10.1002/art.27227] [PMID: 20039405] ]. Approximately 50% of patients were experimented with unorthodox treatments and diets in the recent 6 months probably in an attempt to gain better disease control [2Darlington LG, Ramsey NW, Mansfield JR. Placebo-controlled, blind study of dietary manipulation therapy in rheumatoid arthritis. Lancet 1986; 1(8475): 236-8.[http://dx.doi.org/10.1016/S0140-6736(86)90774-9] [PMID: 2868255] ]. There are clear links between diet and celiac disease but it is more difficult to prove these links in RA and osteoarthritis. Patients look to their rheumatologists for advice regarding dietary modifications and what they are told is that there is limited scientific proof regarding the effectiveness of a dietary approach aimed to help RA [3Smedslund G, Byfuglien MG, Olsen SU, Hagen KB. Effectiveness and safety of dietary interventions for rheumatoid arthritis: A systematic review of randomized controlled trials. J Am Diet Assoc 2010; 110(5): 727-35.[http://dx.doi.org/10.1016/j.jada.2010.02.010] [PMID: 20430134] ]. However, our recent understanding of the role of the gut microbiome in influencing RA disease activity has increased, leading to postulations that diet can influence the gut bacteria and hence RA disease activity.

The link between the gastrointestinal microbiome and immune system is well established and one can influence the activity of the other [4Duerkop BA, Vaishnava S, Hooper LV. Immune responses to the microbiota at the intestinal mucosal surface. Immunity 2009; 31(3): 368-76.[http://dx.doi.org/10.1016/j.immuni.2009.08.009] [PMID: 19766080] -6Mazmanian SK, Kasper DL. The love-hate relationship between bacterial polysaccharides and the host immune system. Nat Rev Immunol 2006; 6(11): 849-58.[http://dx.doi.org/10.1038/nri1956] [PMID: 17024229] ]. Gut microbiota plays an important part in the pathogenesis of systemic inflammatory diseases like RA. The influence is potentially mediated by altered epithelial and mucosal permeability and immune tolerance to the indigenous microbiota. Studies have shown that there is trafficking of activated immune cells to the

joints and altered expression of antigenic foci in the joints [7Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S. The role of the microbiome in rheumatic diseases. Curr Rheumatol Rep 2013; 15(3): 314.[http://dx.doi.org/10.1007/s11926-012-0314-y] [PMID: 23378145] ]. Filamentous bacteria in the gut have been reported to drive autoimmune arthritis through their influence on the T helper 17 cells [8Wu H-J, Ivanov II, Darce J, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 2010; 32(6): 815-27.[http://dx.doi.org/10.1016/j.immuni.2010.06.001] [PMID: 20620945] ]. Faecal microbiota has been characterized in (RA) and evidence supports the participation of intestinal microbes in the pathogenesis of RA [9Vaahtovuo J, Munukka E, Korkeamäki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol 2008; 35(8): 1500-5.[PMID: 18528968] , 10Sandhya P, Danda D, Sharma D, Scaria V. Does the buck stop with the bugs?: An overview of microbial dysbiosis in rheumatoid arthritis. Int J Rheum Dis 2016; 19(1): 8-20.[http://dx.doi.org/10.1111/1756-185X.12728] [PMID: 26385261] ]. Changes in the microbiome due to changing lifestyle and dietary habits have led to immunological imbalances. This dysbiosis can influence the immunological damage in conditions like RA and inflammatory bowel disease [11Actis GC. The gut microbiome. Inflamm Allergy Drug Targets 2014; 13(4): 217-23.[http://dx.doi.org/10.2174/1871528113666140623113221] [PMID: 24953716] ].In patients with obesity, gut microbiota enhance autoimmune conditions by both direct and indirect mechanisms. The former are mediated by endotoxin-induced inflammation and the latter by regulatory B and T cells and T helper 17 cells [12Daïen CI, Sellam J. Obesity and inflammatory arthritis: Impact on occurrence, disease characteristics and therapeutic response. RMD Open 2015; 1(1): e000012.[http://dx.doi.org/10.1136/rmdopen-2014-000012] [PMID: 26509048] ]. The gut microbiota has been reported to influence immunological homeostasis due to its proximity to the host’s intestinal immunity and the ability to influence the immune responses. Dysbiosis impacts the innate immunological pathways which lead to the production of pro-inflammatory cytokines IL-1, IL-18, IL-17, IFNϒ, TNF, and others. The signalling pathways involve an array of molecules, e.g. serum amyloid A, CC-chemokine ligand 5, and others that are produced by autoreactive T cells. The autoreactive T cells also migrate to the peripheral immune compartments to activate the B cells to form antibody producing plasma cells. The antibodies and the plasma cells then migrate to the synovial tissues to initiate an inflammatory cascade. Macrophages, fibroblasts, osteoclasts, and proteinases are the key components of the synovial inflammatory processes [13Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011; 7(10): 569-78.[http://dx.doi.org/10.1038/nrrheum.2011.121] [PMID: 21862983] ].

Chronic inflammation promotes endothelial cell activation and vascular dysfunction that can induce atheroma formation in patients with RA. The putative mediators of atherogenic mechanisms include cytokines like TNF, IL-1, IL-17 and acute phase reactants like C reactive protein and serum amyloid P-component. These mechanisms potentially explain the higher risk of cardiovascular diseases in patients with RA [14Kaplan MJ. Cardiovascular complications of rheumatoid arthritis: Assessment, prevention, and treatment. Rheum Dis Clin North Am 2010; 36(2): 405-26.[http://dx.doi.org/10.1016/j.rdc.2010.02.002] [PMID: 20510241] ]. Another shared inflammatory mechanism in vascular dysfunction and RA include the increased numbers of platelets and high levels of platelet microparticles (PMPs). The PMPs induce synovial fibroblast cytokine response to amplify the inflammation in RA [15Boilard E, Nigrovic PA, Larabee K, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327(5965): 580-3.[http://dx.doi.org/10.1126/science.1181928] [PMID: 20110505] ].

With the increased understanding of microbiome in systemic inflammatory diseases like RA, dietary interventions and probiotics may find application in the management of such conditions. Dietary changes can impact the human intestinal microbiome leading to local inflammation and increased permeability. This can cause a systemic spread of pro-inflammatory lymphocytes and cytokines leading to inflammation in distant sites such as the joints [16van der Meulen TA, Harmsen H, Bootsma H, Spijkervet F, Kroese F, Vissink A. The microbiome-systemic diseases connection. Oral Dis 2016; 22(8): 719-34.[http://dx.doi.org/10.1111/odi.12472] [PMID: 26953630] ]. Diet and weight loss are said to alleviate the disease burden in RA [17Li S, Micheletti R. Role of diet in rheumatic disease. Rheum Dis Clin North Am 2011; 37(1): 119-33.[http://dx.doi.org/10.1016/j.rdc.2010.11.006] [PMID: 21220091] ]. Microbial manipulation by dietary modifications, probiotics, antibiotics, and disease-modifying agents seems to modulate the disease process and progression in RA. In this review, the available evidence is evaluated for the potential role of diet in RA.

2. DIET IN RA

2.1. Mediterranean Diet and RA

Mediterranean diet is largely based on consumption of foods derived from plant sources with limited meat consumption. The main source of fats is small amounts of wine and olive oil. The role of Mediterranean diet in rheumatic diseases derives from anti-inflammatory and protective properties of omega-3 polyunsaturated fatty acids and vitamins. Constituents of olive oil such as oleic acid and olecanthal have natural anti-inflammatory properties [18Sales C, Oliviero F, Spinella P. The mediterranean diet model in inflammatory rheumatic diseases. Reumatismo 2009; 61(1): 10-4.[PMID: 19370182] ].

There is conflicting evidence for the benefits of Mediterranean diet in RA. Some studies have reported a decrease in pain and disease activity with Mediterranean diet in RA [19González Cernadas L, Rodríguez-Romero B, Carballo-Costa L. Importance of nutritional treatment in the inflammatory process of rheumatoid arthritis patients; a review. Nutr Hosp 2014; 29(2): 237-45.[PMID: 24528339] ]. In a 12 week randomised trial in 51 patients with RA, Mediterranean diet intervention demonstrated reduction in disease activity (measured by the 28 joint count Disease Activity Score (DAS28)), improvement in physical function (Health Assessment Questionnaire (HAQ)) and increased vitality [20Sköldstam L, Hagfors L, Johansson G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62(3): 208-14.[http://dx.doi.org/10.1136/ard.62.3.208] [PMID: 12594104] ]. These results can partly be attributed to antioxidant-rich foods during the Mediterranean diet [21Hagfors L, Leanderson P, Sköldstam L, Andersson J, Johansson G. Antioxidant intake, plasma antioxidants and oxidative stress in a randomized, controlled, parallel, Mediterranean dietary intervention study on patients with rheumatoid arthritis. Nutr J 2003; 2: 5.[http://dx.doi.org/10.1186/1475-2891-2-5] [PMID: 12952549] ].

During 3511050 person-years of follow-up in 83,245 and 91,393 women from the Nurses' Health Study (NHS; 1980-2008) and the NHS II (1991-2009), respectively, 913 participants developed RA. There was no significant association between the adherence to Mediterranean dietary pattern and the risk of RA [22Hu Y, Costenbader KH, Gao X, et al. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am J Clin Nutr 2014; 100(3): 959-67.[http://dx.doi.org/10.3945/ajcn.114.086918] [PMID: 25030783] ]. In 208 patients from the TOMORROW study, high Monounsaturated Fatty Acids (MUFA) intake was an independent predictor of remission in the RA group with borderline boundary significance (odds ratio, 1.97; 95% CI, 0.98-3.98; P = 0.057) [23Matsumoto Y, Sugioka Y, Tada M, et al. Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study. ClinNutr 2017. Feb 21 17)30061-4].

2.2. Flavanoids/Isoflavones and RA

Flavonoids are a group of phenolic compounds that are widely distributed in plants and fungus. The antioxidant, antimicrobial, and anti-inflammatory properties of flavanoids explain the role of these agents in atherosclerosis, rheumatoid arthritis, and other inflammatory conditions. The exact mechanisms for benefits of flavanoids in RA are unclear [24Yu N, Han F, Lin X, Tang C, Ye J, Cai X. The association between serum selenium levels with rheumatoid arthritis. Biol Trace Elem Res 2016; 172(1): 46-52.[http://dx.doi.org/10.1007/s12011-015-0558-2] [PMID: 26581918] ]. Genistein, the major active compound from soybean, has anti-inflammatory, anti-angiogenesis, anti-proliferative, antioxidant, immunomodulatory, pain relief, and joint protection properties. In vitro and in vivo studies suggest genistein to be a promising agent for the treatment of RA [25Li J, Gang D, Yu X, et al. Genistein: The potential for efficacy in rheumatoid arthritis. Clin Rheumatol 2013; 32(5): 535-40.[http://dx.doi.org/10.1007/s10067-012-2148-4] [PMID: 23307323] ]. Genistein is shown to inhibit IL-1β, TNF-α or EGF-induced proliferation and MMP-9 expression in fibroblast-like synoviocytes of RA [26Zhang Y, Dong J, He P, et al. Genistein inhibit cytokines or growth factor-induced proliferation and transformation phenotype in fibroblast-like synoviocytes of rheumatoid arthritis. Inflammation 2012; 35(1): 377-87.[http://dx.doi.org/10.1007/s10753-011-9365-x] [PMID: 21792602] ]. Additionally, genistein is shown to inhibit pro-inflammatory cytokines in human mast cell activation through the inhibition of the ERK pathway [27Kim DH, Jung WS, Kim ME, et al. Genistein inhibits proinflammatory cytokines in human mast cell activation through the inhibition of the ERK pathway. Int J Mol Med 2014; 34(6): 1669-74.[http://dx.doi.org/10.3892/ijmm.2014.1956] [PMID: 25319548] ] and improve the serum paraoxonase activity and lipid profiles in rats [28Mohammadshahi M, Haidari F, Saei AA, Rashidi B, Mahboob S, Rashidi MR. Soy protein, genistein, and daidzein improve serum paraoxonase activity and lipid profiles in rheumatoid arthritis in rats. J Med Food 2013; 16(2): 147-54.[http://dx.doi.org/10.1089/jmf.2012.2509] [PMID: 23342971] ].

2.3. Gluten Free Diets in RA

Gluten, a gut-derived antigen, is an immunological trigger in coeliac disease and RA. The systemic immune response in celiac disease may be directed towards sites other than the gut. Gut-derived antigens are the key initiators and drivers of dysimmunity in RA. These shared immunological mechanisms explain the concomitant occurrence of celiac disease and RA [29Warjri SB, Ete T, Beyong T, et al. Coeliac disease with rheumatoid arthritis: An unusual association. Gastroenterol Res 2015; 8(1): 167-8.[http://dx.doi.org/10.14740/gr641w] [PMID: 27785291] ]. Gluten-free diet has been associated with benefits in patients with RA though the existing evidence is inconclusive. Gluten-free vegan diet for 1 year has been shown to significantly reduce levels of antibodies to β-lactoglobulin and gliadin and disease activity in patients with RA [30El-Chammas K, Danner E. Gluten-free diet in nonceliac disease. Nutr Clin Pract 2011; 26(3): 294-9.[http://dx.doi.org/10.1177/0884533611405538] [PMID: 21586414] ]. In a randomized study in 66 patients with RA, a gluten-free vegan diet demonstrated potentially atheroprotective and anti-inflammatory changes, including decreased LDL and oxLDL levels and raised natural atheroprotective antibodies against phosphorylcholine [31Elkan AC, Sjöberg B, Kolsrud B, Ringertz B, Hafström I, Frostegård J. Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: A randomized study. Arthritis Res Ther 2008; 10(2): R34.[http://dx.doi.org/10.1186/ar2388] [PMID: 18348715] ].

2.4. Elemental Diet and RA

An elemental diet contains amino acids (no whole proteins), mono/di-saccharides and medium/long-chain triglycerides. These are supplemented with vitamins and trace elements. In a pilot study, 30 patients with active rheumatoid arthritis were randomly allocated to 2 weeks of treatment with an elemental diet (n = 21) or oral prednisolone 15 mg/day (n = 9). In this study, elemental diet was as effective as a course of oral prednisolone 15 mg daily in improving subjective clinical parameters in RA except the swollen joint score. An improvement of greater than 20% in early morning stiffness, pain (VAS score) and the Ritchie articular index occurred in 72% of the elemental diet group and 78% of the prednisolone group [32Podas T, Nightingale JM, Oldham R, Roy S, Sheehan NJ, Mayberry JF. Is rheumatoid arthritis a disease that starts in the intestine? A pilot study comparing an elemental diet with oral prednisolone. Postgrad Med J 2007; 83(976): 128-31.[http://dx.doi.org/10.1136/pgmj.2006.050245] [PMID: 17308218] ]. However, not all patients benefit with elemental diet and this may be reserved for only select patients with RA [33Haugen MA, Kjeldsen-Kragh J, Førre O. A pilot study of the effect of an elemental diet in the management of rheumatoid arthritis. Clin Exp Rheumatol 1994; 12(3): 275-9.[PMID: 8070160] ].

2.5. Vegan and Elimination Diets and RA

Some studies have demonstrated benefits of vegan diet in RA [34Stamp LK, James MJ, Cleland LG. Diet and rheumatoid arthritis: A review of the literature. Semin Arthritis Rheum 2005; 35(2): 77-94.[http://dx.doi.org/10.1016/j.semarthrit.2005.05.001] [PMID: 16194694] ] The benefits of vegan diet may be explained by antioxidant constituents, lactobacilli and fibre [35Hänninen , Kaartinen K, Rauma AL, et al. Antioxidants in vegan diet and rheumatic disorders. Toxicology 2000; 155(1-3): 45-53.[http://dx.doi.org/10.1016/S0300-483X(00)00276-6] [PMID: 11156742] ] and by potential changes in intestinal flora [36Toivanen P, Eerola E. A vegan diet changes the intestinal flora. Rheumatology (Oxford) 2002; 41(8): 950-1.[http://dx.doi.org/10.1093/rheumatology/41.8.950] [PMID: 12154219] ] In a single-blind dietary intervention study, 24 patients with moderate-to-severe RA reported significant reductions in symptoms with a 4-week, very low-fat (approximately 10%), vegan diet. At 4 weeks, weight (p < 0.001) and all measures of RA symptomatology decreased significantly (p < 0.05), except for duration of morning stiffness (p > 0.05). There were no significant reductions in C-reactive protein and RA factor while erythrocyte sedimentation rate remain unchanged (p > 0.05) [37McDougall J, Bruce B, Spiller G, Westerdahl J, McDougall M. Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis. J Altern Complement Med 2002; 8(1): 71-5.[http://dx.doi.org/10.1089/107555302753507195] [PMID: 11890437] ].

In a study by Kjeldsen-Kragh (1999) [38Kjeldsen-Kragh J. Rheumatoid arthritis treated with vegetarian diets. Am J Clin Nutr 1999; 70(3)(Suppl.): 594S-600S.[PMID: 10479237] ], patients were assigned to fasting followed by a vegan diet; 12 of the 27 patients in the experimental diet group showed significant clinical improvement compared with only 2 of the 26 patients in the control group (P < 0.003, Fisher's exact test). After the study, patients were evaluated after 1 year. The diet responders continued to be statistically better than the non-responders in clinical variables.

There is insufficient evidence for absolute elimination of dairy products in the diet of patients with RA given the established benefits of dairy products for health [39Rozenberg S, Body JJ, Bruyère O, et al. Effects of dairy products consumption on health: Benefits and beliefs--A commentary from the belgian bone club and the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases. Calcif Tissue Int 2016; 98(1): 1-17.[http://dx.doi.org/10.1007/s00223-015-0062-x] [PMID: 26445771] ]. Total elimination of dairy from diet is not recommended for control of symptoms in RA [40Gossec L, Pavy S, Pham T, et al. Nonpharmacological treatments in early rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine 2006; 73(4): 396-402.[http://dx.doi.org/10.1016/j.jbspin.2006.01.008] [PMID: 16626995] ]. However, there is conflicting evidence for continued use of dairy products. Panush (1991) [41Panush RS. Does food cause or cure arthritis? Rheum Dis Clin North Am 1991; 17(2): 259-72.[PMID: 1862237] ] demonstrated temporary improvement in the signs and symptoms of RA with diet elimination and modification in a controlled study where the symptoms associated with food sensitivities were studied. During this study, when the patients were fasting or on a severely restricted diet, the patients’ symptoms improved significantly. However, when the patients had milk reintroduced into the diet, episodes of pain, swollen and tender joints and stiffness were experienced.

2.6. Polyunsaturated Fatty Acids and RA

Long-term intake of fish and other sources of long-chain n-3 polyunsaturated fatty acids (n-3 PUFAs) have been reported to be protective for development of RA. In a prospective study in 205 women with RA, dietary intake of long-chain n-3 PUFAs (>0.21 g/day) was associated with a 35% decreased risk of developing RA (multivariable adjusted relative risk (RR) 0.65; 95% CI: 0.48 to 0.90) compared with a lower intake. Long-term intake of consistently >0.21 g/day was associated with a 52% (95% CI: 29% to 67%) decreased risk and consistent long-term consumption (fish ≥1 serving per week compared with<1) was associated with a 29% decrease in risk (RR 0.71; 95% CI: 0.48 to 1.04) [42Di Giuseppe D, Wallin A, Bottai M, Askling J, Wolk A. Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: A prospective cohort study of women. Ann Rheum Dis 2014; 73(11): 1949-53.[http://dx.doi.org/10.1136/annrheumdis-2013-203338] [PMID: 23940215] ].

Some studies support the role of ω-3 PUFAs supplementation as a valuable therapeutic option to improve symptoms, tender joint count, duration of morning stiffness, and the requirement of NSAIDs in RA [43Navarini L, Afeltra A, Gallo Afflitto G, Margiotta DP. Polyunsaturated fatty acids: Any role in rheumatoid arthritis? Lipids Health Dis 2017; 16(1): 197.[http://dx.doi.org/10.1186/s12944-017-0586-3] [PMID: 29017507] ]. In a recent meta-analysis of 20 randomized control trials (n=717), ω-3 polyunsaturated fatty acids reduced the level of leukotriene B4 (five trials, Standardized Mean Difference [SMD], -0.440; 95% confidence interval [CI], -0.676 to -0.205; I2=46.5%; P <0.001) and blood triacylglycerol levels (three trials, SMD, -0.316; 95% CI: -0.561 to -0.070; I2=0.0%; P=0.012) in RA [44Schorpion A, Kolasinski SL, Marantidou F, Panagiotakos DP. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: A systematic review and meta-analysis. Nutrition. 2018 Jan;45:114-124.e4. Curr Rheumatol Rep 2017; 19(11): 73.[http://dx.doi.org/10.1007/s11926-017-0696-y] [PMID: 29094223] ].

2.7. Probiotics and RA

Current evidence supports the role of probiotics as adjunctive therapy in RA [45Wang P, Tao JH, Pan HF. Probiotic bacteria: A viable adjuvant therapy for relieving symptoms of rheumatoid arthritis. Inflammopharmacology 2016; 24(5): 189-96.[http://dx.doi.org/10.1007/s10787-016-0277-0] [PMID: 27581587] ]. In a randomized double-blind clinical trial, 60 women with established RA received Lactobacillus casei 01 or placebo for 8 weeks. This study confirmed the role of Lactobacillus casei 01 as an adjunct therapy to help alleviate symptoms and improve inflammatory cytokines in RA. The probiotic supplementation decreased serum high-sensitivity C-reactive protein levels, tender and swollen joint counts, global health score, and DAS28 (P < 0.05). At the end of the study, a significant difference was observed between the intervention and placebo groups for IL-10, IL-12 and TNF-α changes (P <0.05) in favour of the probiotic group. Probiotic treatment was not associated with any adverse effects [46Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: A randomized double-blind clinical trial. Int J Rheum Dis 2014; 17(5): 519-27.[PMID: 24673738] ].

However, clinical trials have not demonstrated any consistent and appreciable impact on patient reported or laboratory outcome measures [47Schorpion A, Kolasinski SL. Can probiotic supplements improve outcomes in rheumatoid arthritis? Curr Rheumatol Rep 2017; 19(11): 73.[http://dx.doi.org/10.1007/s11926-017-0696-y] [PMID: 29094223] ]. In a randomized double-blind placebo-controlled clinical trial in 60 patients with RA, daily supplementation with Lactobacillus casei 01 demonstrated no improvement in serum lipids [48Vaghef-Mehrabany E, Vaghef-Mehrabany L, Asghari-Jafarabadi M, Homayouni-Rad A, Issazadeh K, Alipour B. Effects of probiotic supplementation on lipid profile of women with rheumatoid arthritis: A randomized placebo-controlled clinical trial. Health Promot Perspect 2017; 7(2): 95-101.[http://dx.doi.org/10.15171/hpp.2017.17] [PMID: 28326290] ]. In another study, Lactobacillus casei 01 demonstrated no significant impact on the oxidative status in patients with RA characterized by serum malondialdehyde, total antioxidant capacity, erythrocyte superoxide dismutase, and catalase [49Vaghef-Mehrabany E, Homayouni-Rad A, Alipour B, Sharif SK, Vaghef-Mehrabany L, Alipour-Ajiry S. Effects of probiotic supplementation on oxidative stress indices in women with rheumatoid arthritis: A randomized double-blind clinical trial. J Am Coll Nutr 2016; 35(4): 291-9.[http://dx.doi.org/10.1080/07315724.2014.959208] [PMID: 25856220] ].

A meta-analysis of 9 studies (n=361), established a reduction in levels of pro-inflammatory cytokines IL-6 with probiotics vs. placebo in RA (standardized mean difference: - 0.708; 95% CI: - 1.370 to 0.047, P=0.036). However, there was no difference between probiotics and placebo in disease activity score (mean difference 0.023; 95% CI - 0.584 to 0.631, P=0.940). The clinical effect of probiotics in RA remained unclear. The authors concluded that high-quality randomized controlled trials were needed to prove the effect [50Mohammed AT, Khattab M, Ahmed AM, et al. The therapeutic effect of probiotics on rheumatoid arthritis: A systematic review and meta-analysis of randomized control trials. Clin Rheumatol 2017; 36(12): 2697-707.[http://dx.doi.org/10.1007/s10067-017-3814-3] [PMID: 28914373] ]. Probiotics make an appealing therapeutic strategy in RA due to possible interactions with the microbiome but the effects need to be confirmed in interventional studies [51Bedaiwi MK, Inman RD. Microbiome and probiotics: Link to arthritis. Curr Opin Rheumatol 2014; 26(4): 410-5.[http://dx.doi.org/10.1097/BOR.0000000000000075] [PMID: 24841227] ].

Recent studies show that specific bacteria may benefit RA patients. In a study in VDQ8 mice treatment with P. histicola in prophylactic or therapeutic protocols exhibited significantly decreased incidence and severity of arthritis compared to controls [52Marietta EV, Murray JA, Luckey DH, et al. Suppression of Inflammatory Arthritis by Human Gut-Derived Prevotella histicola in Humanized Mice. Arthritis Rheumatol 2016; 68(12): 2878-88.[http://dx.doi.org/10.1002/art.39785] [PMID: 27337150] ]. The microbial mucosal modulation of arthritis was dependent on regulation by CD103+ dendritic cells and myeloid suppressors (CD11b+Gr-1+ cells) and by generation of Treg cells (CD4+CD25+FoxP3+) in the gut, resulting in suppression of antigen-specific Th17 responses and increased transcription of interleukin-10. Treatment with P. histicola led to reduced intestinal permeability by increasing expression of enzymes that produce antimicrobial peptides as well as tight junction proteins (zonulaoccludens 1 and occludin).However, the innate immune response via Toll-like receptor 4 (TLR-4) and TLR-9 was not affected in treated mice.

There is evidence for alteration in gut microbiome with diets. In an analysis of stool samples from [53Peltonen R, Kjeldsen-Kragh J, Haugen M, et al. Changes of faecal flora in rheumatoid arthritis during fasting and one-year vegetarian diet. Br J Rheumatol 1994; 33(7): 638-43.[http://dx.doi.org/10.1093/rheumatology/33.7.638] [PMID: 8019792] ] RA patients, significant alteration in the intestinal flora was observed when the patients changed from omnivorous to vegan diet and for periods with vegan and lactovegetarian diets. The faecal flora from patients with high and low improvement indices differed significantly from each other at 1 and 13 months during the diet [53Peltonen R, Kjeldsen-Kragh J, Haugen M, et al. Changes of faecal flora in rheumatoid arthritis during fasting and one-year vegetarian diet. Br J Rheumatol 1994; 33(7): 638-43.[http://dx.doi.org/10.1093/rheumatology/33.7.638] [PMID: 8019792] ]. This finding of an association between intestinal flora and disease activity may have implications for our understanding of how diet can affect RA.

2.8. Alcohol and RA

Increased frequency of alcohol consumption is associated with severity of disease in RA. Alcohol has unfavourable effects on CRP, DAS28-CRP, pain VAS, modified HAQ, and radiographic damage (Larsen score) in RA [54Maxwell JR, Gowers IR, Moore DJ, Wilson AG. Alcohol consumption is inversely associated with risk and severity of rheumatoid arthritis. Rheumatology (Oxford) 2010; 49(11): 2140-6.[http://dx.doi.org/10.1093/rheumatology/keq202] [PMID: 20667949] ]. Similar associations were reported in a prospective observational study in 615 patients of RA [55Lu B, Rho YH, Cui J, et al. Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis. J Rheumatol 2014; 41(1): 24-30.[http://dx.doi.org/10.3899/jrheum.130074] [PMID: 24293566] ]. On the contrary, in 386 patients from the Västerbotten Intervention Program (VIP) cohort, alcohol was not associated with a risk of RA [56Sundström B, Johansson I, Rantapää-Dahlqvist S. Diet and alcohol as risk factors for rheumatoid arthritis: A nested case-control study. Rheumatol Int 2015; 35(3): 533-9.[http://dx.doi.org/10.1007/s00296-014-3185-x] [PMID: 25428595] ].

The risks for hepatotoxicity due to alcohol may be increased in patients with RA who are treated with methotrexate [57Kremer JM, Weinblatt ME. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis 2017.]. However, weekly alcohol consumption of <14 units does not appear to be associated with an increased risk of transaminitis in these patients [58Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis 2017; 76(9): 1509-14.[http://dx.doi.org/10.1136/annrheumdis-2016-210629] [PMID: 28341765] ]. The current evidence suggests that patients with RA should eliminate or limit alcohol consumption to very small quantities. The benefit and safety of moderate alcohol intake needs to be evaluated in clinical studies.

2.9. Vitamin D Supplements and RA

The relationship of vitamin D and RA is complex as the vitamin has a proven role in the immunological milieu in the pathophysiology of RA. Deficiency of vitamin D is common in patients with RA [59Bellan M, Sainaghi PP, Pirisi M. Role of Vitamin D in Rheumatoid Arthritis. Adv Exp Med Biol 2017; 996: 155-68.[http://dx.doi.org/10.1007/978-3-319-56017-5_13] [PMID: 29124698] ]. The COMORA Study confirmed the low levels of vitamin D in RA (n=1413, 15 countries) in different countries and in different latitudes. Low levels of vitamin D were associated with increased disease activity and corticosteroid dosage, and comorbidities in RA [60Hajjaj-Hassouni N, Mawani N, Allali F, et al. Evaluation of vitamin D status in rheumatoid arthritis and Its association with disease activity across 15 countries: "The COMORA Study". Int J Rheumatol 2017. 2017: 5491676]. However, vitamin D supplementation does not have a disease modifying effect in RA. In a 12 week randomized, double-blind, placebo-controlled trial of 25-hydroxy vitamin D 50,000 IU weekly vs. placebo (n=117) in RA, supplementation with vitamin D did not affect the disease activity in RA [61Salesi M, Farajzadegan Z, Jeffery LE, et al. Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint. Rheumatol Int J Autoimmun 2012; 32(7): 2129-3358. Oct 21. pii: S0896-8411(17) 30420-1.[http://dx.doi.org/10.1007/s00296-011-1944-5] ].

Vitamin D has potent anti-inflammatory effects possibly due to suppression of IL-17 + and IFNγ+ T cells implicated in RA. However, the T cells in synovial fluid in RA have demonstrated a reduced sensitivity to vitamin D. Restoration of response to vitamin D in the memory T cells in synovial fluid represents a possible treatment strategy to be explored in RA [61Salesi M, Farajzadegan Z, Jeffery LE, et al. Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint. Rheumatol Int J Autoimmun 2012; 32(7): 2129-3358. Oct 21. pii: S0896-8411(17) 30420-1.[http://dx.doi.org/10.1007/s00296-011-1944-5] ]. Patients with active RA under steroid treatment may need supplementation with calcium and vitamin D to prevent osteoporosis [62Keysser G. Are there effective dietary recommendations for patients with rheumatoid arthritis?. Z Rheumatol 2001; 60(1): 17-27.[PMID: 11263011] ]. and to alleviate the symptoms of anxiety and depression [63Pu D, Luo J, Wang Y, et al. Prevalence of depression and anxiety in rheumatoid arthritis patients and their associations with serum vitamin D level. Clin Rheumatol 2017. Epub ahead of print[http://dx.doi.org/10.1007/s10067-017-3874-4] [PMID: 29063463] ].

2.10. Other Supplements and RA

Iron has an important role in maintaining normal immune function and deficiency of iron and anaemia may hamper the immunological balance in RA [64Baker JF, Ghio AJ. Iron homoeostasis in rheumatic disease. Rheumatology (Oxford) 2009; 48(11): 1339-44.[http://dx.doi.org/10.1093/rheumatology/kep221] [PMID: 19628641] ]. Complex interactions of the pro-inflammatory cytokine, interleukin-6, the iron regulatory hormone, hepcidin, and the iron exporter, ferroportin underlie the impaired iron homeostasis in anaemia associated with inflammation [65Fraenkel PG. Anemia of Inflammation: A Review. Med Clin North Am 2017; 101(2): 285-96.[http://dx.doi.org/10.1016/j.mcna.2016.09.005] [PMID: 28189171] ]. Correction of anaemia can help improve the physical activity and quality of life in patients with rheumatic diseases [66Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol 2013; 9(4): 205-15.[http://dx.doi.org/10.1038/nrrheum.2012.183] [PMID: 23147894] ].

2.11. Anti Oxidants and RA

There is a marked increase in oxidative stress in RA. Patients with RA show marked increase in the formation of reactive oxygen species, lipid peroxidation, protein oxidation, DNA damage and decrease in the activity of antioxidant defence systems [67Mateen S, Moin S, Shahzad S, Khan AQ. Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species. PLoS One 2017; 12(6): e0178879.[http://dx.doi.org/10.1371/journal.pone.0178879] [PMID: 28594861] ]. However, there is conflicting evidence in literature for the benefits of anti-oxidant supplementation in RA.

In a study in 40 women with RA, daily supplementation with 50 μg selenium, 8 mg zinc, 400 μg vitamin A, 125 mg vitamin C, and 40 mg vitamin E improved clinical outcomes and alleviated oxidative stress in RA. In this study, there was a significant improvement in disease activity but not in the number of painful and swollen joints. The antioxidant levels in erythrocytes were increased [68Jalili M, Kolahi S, Aref-Hosseini SR, Mamegani ME, Hekmatdoost A. Beneficial role of antioxidants on clinical outcomes and erythrocyte antioxidant parameters in rheumatoid arthritis patients. Int J Prev Med 2014; 5(7): 835-40.[PMID: 25104994] ]. In another study, supplementation with the anti-oxidant vitamins such as vitamin A and C, or with trace elements like selenium and zinc had no proven influence on the disease activity in RA [62Keysser G. Are there effective dietary recommendations for patients with rheumatoid arthritis?. Z Rheumatol 2001; 60(1): 17-27.[PMID: 11263011] ].

There is a significant association of low serum selenium levels and RA [24Yu N, Han F, Lin X, Tang C, Ye J, Cai X. The association between serum selenium levels with rheumatoid arthritis. Biol Trace Elem Res 2016; 172(1): 46-52.[http://dx.doi.org/10.1007/s12011-015-0558-2] [PMID: 26581918] ]. Serum copper levels are reported to be positively correlated with disease activity in RA. Low serum concentrations of albumin, zinc, and selenium were independently related to disease activity index in an evaluation of trace elements in 110 patients with RA [69Sahebari M, Ayati R, Mirzaei H, et al. Serum trace element concentrations in rheumatoid arthritis. Biol Trace Elem Res 2016; 171(2): 237-45.[http://dx.doi.org/10.1007/s12011-015-0501-6] [PMID: 26450515] ].

2.12. Fasting in RA

A well balanced diet is important to meet the nutritional requirements in RA. Reduction of pain and inflammation in RA has been established with fasting [70Longo VD, Mattson MP. Fasting: Molecular mechanisms and clinical applications. Cell Metab 2014; 19(2): 181-92.[http://dx.doi.org/10.1016/j.cmet.2013.12.008] [PMID: 24440038] ] although reversal of remission is also known following resumption of regular dietary habits [71Müller H, de Toledo FW, Resch KL. Fasting followed by vegetarian diet in patients with rheumatoid arthritis: A systematic review. Scand J Rheumatol 2001; 30(1): 1-10.[http://dx.doi.org/10.1080/030097401750065256] [PMID: 11252685] ]. The benefits with fasting in RA, if any, are transient and may not have long-term implications in disease activity [72Sköldstam L, Larsson L, Lindström FD. Effect of fasting and lactovegetarian diet on rheumatoid arthritis. Scand J Rheumatol 1979; 8(4): 249-55.[http://dx.doi.org/10.3109/03009747909114631] [PMID: 534318] ].

2.13. Obesity and RA

Obesity has been reported to decrease the odds of achieving and sustaining remission in RA. When compared to the non-obese, obese patients with RA have worse Disease Activity Scores or Disease Activity Scores in 28 joints, tender joint counts, inflammatory markers, patient global evaluation scores, pain scores, and physical function scores. Though obesity has not been associated with increased mortality in RA, interventions to prevent and reverse obesity can help to improve the outcomes and quality of life in RA [73Liu Y, Hazlewood GS, Kaplan GG, Eksteen B, Barnabe C. Impact of obesity on remission and disease activity in rheumatoid arthritis: A systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2017; 69(2): 157-65.[http://dx.doi.org/10.1002/acr.22932] [PMID: 27159376] ]. Foods linked with obesity such as sweetened soda have been associated with an increased risk of RA. When compared to no consumption of sugar-sweetened soda or <1 soda per month, consumption of ≥1 sugar-sweetened soda per day has 63% increased risk of developing seropositive RA. [74Hu Y, Costenbader KH, Gao X, Hu FB, Karlson EW, Lu B. Mediterranean diet and incidence of rheumatoid arthritis in women. Arthritis Care Res (Hoboken) 2015; 67(5): 597-606.[http://dx.doi.org/10.1002/acr.22481] [PMID: 25251857] ]

3. CONCLUSION

Studies of dietary interventions for RA are limited and not of high quality. Most have heterogeneity in interventions and outcomes, baseline imbalance and inadequate data reporting [75Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G. Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev 2009; (1): CD006400.[PMID: 19160281] ].

Clinical trials of dietary treatments are difficult to design and implement due to problems associated with recruitment, compliance, and drop-outs. Recruitment in trials with dietary interventions is difficult, as it requires patients to change their lifestyles. Adherence to diet for a prolonged period may be difficult and trials with dietary interventions have a high dropout rate. Education about the diet and follow up in such trials requires dedicated efforts of a dietician. Challenges in design of dietary interventions include the process of blinding. Studies with long-term follow up (beyond 1 year) are difficult to implement and are lacking for diet in RA. [76Kjeldsen-Kragh J. Mediterranean diet intervention in rheumatoid arthritis. Ann Rheum Dis 2003; 62(3): 193-5.[http://dx.doi.org/10.1136/ard.62.3.193] [PMID: 12594101] ] Studies should be planned and adequately powered to control for variables that can influence disease activity in RA including medications. Adjustments for confounding factors like smoking, physical activity, socioeconomic status, and obesity is important for validity of study results.

Additionally there is heterogeneity in tools used for assessments of dietary patterns in RA. Studies have reported the use of different questionnaires like the Brief Self-administered Diet History Questionnaire (BDHQ) [23Matsumoto Y, Sugioka Y, Tada M, et al. Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study. ClinNutr 2017. Feb 21 17)30061-4] and the validated food frequency questionnaires [22Hu Y, Costenbader KH, Gao X, et al. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am J Clin Nutr 2014; 100(3): 959-67.[http://dx.doi.org/10.3945/ajcn.114.086918] [PMID: 25030783] ]. Comparisons across studies may be difficult due to these trends. Dietary records for dietary intake are difficult to maintain and are subject to recall bias.

3.1. Gaps in Understanding and Directions for Future Research

There is currently a lack of understanding for nutritional requirements in RA. Specific dietary recommendations have not evolved due to variability in the clinical course of RA. In 386 patients from the Västerbotten Intervention Program (VIP) cohort, diet was not associated with a risk of RA. [55Lu B, Rho YH, Cui J, et al. Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis. J Rheumatol 2014; 41(1): 24-30.[http://dx.doi.org/10.3899/jrheum.130074] [PMID: 24293566] ] In a recent feasibility trial, individualized counselling did not significantly improve the dietary habits in patients with inflammatory RA (n=31) of <1 year duration [77Garner S, Fenton T, Martin L, Creaser C, Johns C, Barnabe C. Personalized diet and exercise recommendations in early rheumatoid arthritis: A feasibility trial. Musculoskelet Care 2017. Epub ahead of print[http://dx.doi.org/10.1002/msc.1214] [PMID: 28967710] ].

Future trials may evaluate specific dietary modifications, e.g. the association with moderate intake of alcohol and the role of probiotics and antibiotics in RA. There is a potential role of adipokines in mediating the association of RA and obesity. If studied in future trials, this can help to understand newer molecular targets for management of RA [12Daïen CI, Sellam J. Obesity and inflammatory arthritis: Impact on occurrence, disease characteristics and therapeutic response. RMD Open 2015; 1(1): e000012.[http://dx.doi.org/10.1136/rmdopen-2014-000012] [PMID: 26509048] ] Studies that link diet with RA and specific pathways of inflammation and immune regulation offer the possibility of identifying new therapeutic approaches in select patients. Better understanding of dietary factors in RA can contribute to developing new insights in disease pathogenesis and RA-specific recommendations.

The effects of ω-3 PUFAs supplementation on radiographic progression and synovial histopathology in RA remain to be evaluated in future studies. The role of polyunsaturated fatty acids in early arthritis and in combination with biologics should also be explored in well-designed trials in RA patients [43Navarini L, Afeltra A, Gallo Afflitto G, Margiotta DP. Polyunsaturated fatty acids: Any role in rheumatoid arthritis? Lipids Health Dis 2017; 16(1): 197.[http://dx.doi.org/10.1186/s12944-017-0586-3] [PMID: 29017507] ].

In summary, although we tell our patients there is a limited role for diet in RA, certain diets may help some groups of patients. However, the available evidence does not establish dietary interventions as a substitute for pharmacotherapy in RA. Limited or cyclical fasting, vegan, Mediterranean diets or elimination of dairy and gluten, all seem to play a role but it is hard to sustain these diets long term. Dysbiosis is a key factor in RA and diet can influence the gut microbiome and perhaps RA disease activity be manipulated through diet and alteration of gut bacteria. Probiotics could have a role although evidence for this is limited. Supplements with vitamin D, calcium, or fish oils could be useful where indicated.

DISCLOSURE

Dr. Humeira Badsha Medical Center, Dubai, provided funding for financial support.

CONSENT FOR PUBLICATION

Not applicable.

CONFLICT OF INTEREST

The author declares no conflict of interest, financial or otherwise.

ACKNOWLEDGEMENTS

The author acknowledge MediCeption Science Pvt Ltd (http://www.mediception.com) for providing medical writing support.

REFERENCES

[1] Hetland ML, Christensen IJ, Tarp U, et al. Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry. Arthritis Rheum 2010; 62(1): 22-32.[http://dx.doi.org/10.1002/art.27227] [PMID: 20039405]
[2] Darlington LG, Ramsey NW, Mansfield JR. Placebo-controlled, blind study of dietary manipulation therapy in rheumatoid arthritis. Lancet 1986; 1(8475): 236-8.[http://dx.doi.org/10.1016/S0140-6736(86)90774-9] [PMID: 2868255]
[3] Smedslund G, Byfuglien MG, Olsen SU, Hagen KB. Effectiveness and safety of dietary interventions for rheumatoid arthritis: A systematic review of randomized controlled trials. J Am Diet Assoc 2010; 110(5): 727-35.[http://dx.doi.org/10.1016/j.jada.2010.02.010] [PMID: 20430134]
[4] Duerkop BA, Vaishnava S, Hooper LV. Immune responses to the microbiota at the intestinal mucosal surface. Immunity 2009; 31(3): 368-76.[http://dx.doi.org/10.1016/j.immuni.2009.08.009] [PMID: 19766080]
[5] Macpherson AJ, Harris NL. Interactions between commensal intestinal bacteria and the immune system. Nat Rev Immunol 2004; 4(6): 478-85.[http://dx.doi.org/10.1038/nri1373] [PMID: 15173836]
[6] Mazmanian SK, Kasper DL. The love-hate relationship between bacterial polysaccharides and the host immune system. Nat Rev Immunol 2006; 6(11): 849-58.[http://dx.doi.org/10.1038/nri1956] [PMID: 17024229]
[7] Yeoh N, Burton JP, Suppiah P, Reid G, Stebbings S. The role of the microbiome in rheumatic diseases. Curr Rheumatol Rep 2013; 15(3): 314.[http://dx.doi.org/10.1007/s11926-012-0314-y] [PMID: 23378145]
[8] Wu H-J, Ivanov II, Darce J, et al. Gut-residing segmented filamentous bacteria drive autoimmune arthritis via T helper 17 cells. Immunity 2010; 32(6): 815-27.[http://dx.doi.org/10.1016/j.immuni.2010.06.001] [PMID: 20620945]
[9] Vaahtovuo J, Munukka E, Korkeamäki M, Luukkainen R, Toivanen P. Fecal microbiota in early rheumatoid arthritis. J Rheumatol 2008; 35(8): 1500-5.[PMID: 18528968]
[10] Sandhya P, Danda D, Sharma D, Scaria V. Does the buck stop with the bugs?: An overview of microbial dysbiosis in rheumatoid arthritis. Int J Rheum Dis 2016; 19(1): 8-20.[http://dx.doi.org/10.1111/1756-185X.12728] [PMID: 26385261]
[11] Actis GC. The gut microbiome. Inflamm Allergy Drug Targets 2014; 13(4): 217-23.[http://dx.doi.org/10.2174/1871528113666140623113221] [PMID: 24953716]
[12] Daïen CI, Sellam J. Obesity and inflammatory arthritis: Impact on occurrence, disease characteristics and therapeutic response. RMD Open 2015; 1(1): e000012.[http://dx.doi.org/10.1136/rmdopen-2014-000012] [PMID: 26509048]
[13] Scher JU, Abramson SB. The microbiome and rheumatoid arthritis. Nat Rev Rheumatol 2011; 7(10): 569-78.[http://dx.doi.org/10.1038/nrrheum.2011.121] [PMID: 21862983]
[14] Kaplan MJ. Cardiovascular complications of rheumatoid arthritis: Assessment, prevention, and treatment. Rheum Dis Clin North Am 2010; 36(2): 405-26.[http://dx.doi.org/10.1016/j.rdc.2010.02.002] [PMID: 20510241]
[15] Boilard E, Nigrovic PA, Larabee K, et al. Platelets amplify inflammation in arthritis via collagen-dependent microparticle production. Science 2010; 327(5965): 580-3.[http://dx.doi.org/10.1126/science.1181928] [PMID: 20110505]
[16] van der Meulen TA, Harmsen H, Bootsma H, Spijkervet F, Kroese F, Vissink A. The microbiome-systemic diseases connection. Oral Dis 2016; 22(8): 719-34.[http://dx.doi.org/10.1111/odi.12472] [PMID: 26953630]
[17] Li S, Micheletti R. Role of diet in rheumatic disease. Rheum Dis Clin North Am 2011; 37(1): 119-33.[http://dx.doi.org/10.1016/j.rdc.2010.11.006] [PMID: 21220091]
[18] Sales C, Oliviero F, Spinella P. The mediterranean diet model in inflammatory rheumatic diseases. Reumatismo 2009; 61(1): 10-4.[PMID: 19370182]
[19] González Cernadas L, Rodríguez-Romero B, Carballo-Costa L. Importance of nutritional treatment in the inflammatory process of rheumatoid arthritis patients; a review. Nutr Hosp 2014; 29(2): 237-45.[PMID: 24528339]
[20] Sköldstam L, Hagfors L, Johansson G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann Rheum Dis 2003; 62(3): 208-14.[http://dx.doi.org/10.1136/ard.62.3.208] [PMID: 12594104]
[21] Hagfors L, Leanderson P, Sköldstam L, Andersson J, Johansson G. Antioxidant intake, plasma antioxidants and oxidative stress in a randomized, controlled, parallel, Mediterranean dietary intervention study on patients with rheumatoid arthritis. Nutr J 2003; 2: 5.[http://dx.doi.org/10.1186/1475-2891-2-5] [PMID: 12952549]
[22] Hu Y, Costenbader KH, Gao X, et al. Sugar-sweetened soda consumption and risk of developing rheumatoid arthritis in women. Am J Clin Nutr 2014; 100(3): 959-67.[http://dx.doi.org/10.3945/ajcn.114.086918] [PMID: 25030783]
[23] Matsumoto Y, Sugioka Y, Tada M, et al. Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study. ClinNutr 2017. Feb 21 17)30061-4
[24] Yu N, Han F, Lin X, Tang C, Ye J, Cai X. The association between serum selenium levels with rheumatoid arthritis. Biol Trace Elem Res 2016; 172(1): 46-52.[http://dx.doi.org/10.1007/s12011-015-0558-2] [PMID: 26581918]
[25] Li J, Gang D, Yu X, et al. Genistein: The potential for efficacy in rheumatoid arthritis. Clin Rheumatol 2013; 32(5): 535-40.[http://dx.doi.org/10.1007/s10067-012-2148-4] [PMID: 23307323]
[26] Zhang Y, Dong J, He P, et al. Genistein inhibit cytokines or growth factor-induced proliferation and transformation phenotype in fibroblast-like synoviocytes of rheumatoid arthritis. Inflammation 2012; 35(1): 377-87.[http://dx.doi.org/10.1007/s10753-011-9365-x] [PMID: 21792602]
[27] Kim DH, Jung WS, Kim ME, et al. Genistein inhibits proinflammatory cytokines in human mast cell activation through the inhibition of the ERK pathway. Int J Mol Med 2014; 34(6): 1669-74.[http://dx.doi.org/10.3892/ijmm.2014.1956] [PMID: 25319548]
[28] Mohammadshahi M, Haidari F, Saei AA, Rashidi B, Mahboob S, Rashidi MR. Soy protein, genistein, and daidzein improve serum paraoxonase activity and lipid profiles in rheumatoid arthritis in rats. J Med Food 2013; 16(2): 147-54.[http://dx.doi.org/10.1089/jmf.2012.2509] [PMID: 23342971]
[29] Warjri SB, Ete T, Beyong T, et al. Coeliac disease with rheumatoid arthritis: An unusual association. Gastroenterol Res 2015; 8(1): 167-8.[http://dx.doi.org/10.14740/gr641w] [PMID: 27785291]
[30] El-Chammas K, Danner E. Gluten-free diet in nonceliac disease. Nutr Clin Pract 2011; 26(3): 294-9.[http://dx.doi.org/10.1177/0884533611405538] [PMID: 21586414]
[31] Elkan AC, Sjöberg B, Kolsrud B, Ringertz B, Hafström I, Frostegård J. Gluten-free vegan diet induces decreased LDL and oxidized LDL levels and raised atheroprotective natural antibodies against phosphorylcholine in patients with rheumatoid arthritis: A randomized study. Arthritis Res Ther 2008; 10(2): R34.[http://dx.doi.org/10.1186/ar2388] [PMID: 18348715]
[32] Podas T, Nightingale JM, Oldham R, Roy S, Sheehan NJ, Mayberry JF. Is rheumatoid arthritis a disease that starts in the intestine? A pilot study comparing an elemental diet with oral prednisolone. Postgrad Med J 2007; 83(976): 128-31.[http://dx.doi.org/10.1136/pgmj.2006.050245] [PMID: 17308218]
[33] Haugen MA, Kjeldsen-Kragh J, Førre O. A pilot study of the effect of an elemental diet in the management of rheumatoid arthritis. Clin Exp Rheumatol 1994; 12(3): 275-9.[PMID: 8070160]
[34] Stamp LK, James MJ, Cleland LG. Diet and rheumatoid arthritis: A review of the literature. Semin Arthritis Rheum 2005; 35(2): 77-94.[http://dx.doi.org/10.1016/j.semarthrit.2005.05.001] [PMID: 16194694]
[35] Hänninen , Kaartinen K, Rauma AL, et al. Antioxidants in vegan diet and rheumatic disorders. Toxicology 2000; 155(1-3): 45-53.[http://dx.doi.org/10.1016/S0300-483X(00)00276-6] [PMID: 11156742]
[36] Toivanen P, Eerola E. A vegan diet changes the intestinal flora. Rheumatology (Oxford) 2002; 41(8): 950-1.[http://dx.doi.org/10.1093/rheumatology/41.8.950] [PMID: 12154219]
[37] McDougall J, Bruce B, Spiller G, Westerdahl J, McDougall M. Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis. J Altern Complement Med 2002; 8(1): 71-5.[http://dx.doi.org/10.1089/107555302753507195] [PMID: 11890437]
[38] Kjeldsen-Kragh J. Rheumatoid arthritis treated with vegetarian diets. Am J Clin Nutr 1999; 70(3)(Suppl.): 594S-600S.[PMID: 10479237]
[39] Rozenberg S, Body JJ, Bruyère O, et al. Effects of dairy products consumption on health: Benefits and beliefs--A commentary from the belgian bone club and the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases. Calcif Tissue Int 2016; 98(1): 1-17.[http://dx.doi.org/10.1007/s00223-015-0062-x] [PMID: 26445771]
[40] Gossec L, Pavy S, Pham T, et al. Nonpharmacological treatments in early rheumatoid arthritis: clinical practice guidelines based on published evidence and expert opinion. Joint Bone Spine 2006; 73(4): 396-402.[http://dx.doi.org/10.1016/j.jbspin.2006.01.008] [PMID: 16626995]
[41] Panush RS. Does food cause or cure arthritis? Rheum Dis Clin North Am 1991; 17(2): 259-72.[PMID: 1862237]
[42] Di Giuseppe D, Wallin A, Bottai M, Askling J, Wolk A. Long-term intake of dietary long-chain n-3 polyunsaturated fatty acids and risk of rheumatoid arthritis: A prospective cohort study of women. Ann Rheum Dis 2014; 73(11): 1949-53.[http://dx.doi.org/10.1136/annrheumdis-2013-203338] [PMID: 23940215]
[43] Navarini L, Afeltra A, Gallo Afflitto G, Margiotta DP. Polyunsaturated fatty acids: Any role in rheumatoid arthritis? Lipids Health Dis 2017; 16(1): 197.[http://dx.doi.org/10.1186/s12944-017-0586-3] [PMID: 29017507]
[44] Schorpion A, Kolasinski SL, Marantidou F, Panagiotakos DP. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: A systematic review and meta-analysis. Nutrition. 2018 Jan;45:114-124.e4. Curr Rheumatol Rep 2017; 19(11): 73.[http://dx.doi.org/10.1007/s11926-017-0696-y] [PMID: 29094223]
[45] Wang P, Tao JH, Pan HF. Probiotic bacteria: A viable adjuvant therapy for relieving symptoms of rheumatoid arthritis. Inflammopharmacology 2016; 24(5): 189-96.[http://dx.doi.org/10.1007/s10787-016-0277-0] [PMID: 27581587]
[46] Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: A randomized double-blind clinical trial. Int J Rheum Dis 2014; 17(5): 519-27.[PMID: 24673738]
[47] Schorpion A, Kolasinski SL. Can probiotic supplements improve outcomes in rheumatoid arthritis? Curr Rheumatol Rep 2017; 19(11): 73.[http://dx.doi.org/10.1007/s11926-017-0696-y] [PMID: 29094223]
[48] Vaghef-Mehrabany E, Vaghef-Mehrabany L, Asghari-Jafarabadi M, Homayouni-Rad A, Issazadeh K, Alipour B. Effects of probiotic supplementation on lipid profile of women with rheumatoid arthritis: A randomized placebo-controlled clinical trial. Health Promot Perspect 2017; 7(2): 95-101.[http://dx.doi.org/10.15171/hpp.2017.17] [PMID: 28326290]
[49] Vaghef-Mehrabany E, Homayouni-Rad A, Alipour B, Sharif SK, Vaghef-Mehrabany L, Alipour-Ajiry S. Effects of probiotic supplementation on oxidative stress indices in women with rheumatoid arthritis: A randomized double-blind clinical trial. J Am Coll Nutr 2016; 35(4): 291-9.[http://dx.doi.org/10.1080/07315724.2014.959208] [PMID: 25856220]
[50] Mohammed AT, Khattab M, Ahmed AM, et al. The therapeutic effect of probiotics on rheumatoid arthritis: A systematic review and meta-analysis of randomized control trials. Clin Rheumatol 2017; 36(12): 2697-707.[http://dx.doi.org/10.1007/s10067-017-3814-3] [PMID: 28914373]
[51] Bedaiwi MK, Inman RD. Microbiome and probiotics: Link to arthritis. Curr Opin Rheumatol 2014; 26(4): 410-5.[http://dx.doi.org/10.1097/BOR.0000000000000075] [PMID: 24841227]
[52] Marietta EV, Murray JA, Luckey DH, et al. Suppression of Inflammatory Arthritis by Human Gut-Derived Prevotella histicola in Humanized Mice. Arthritis Rheumatol 2016; 68(12): 2878-88.[http://dx.doi.org/10.1002/art.39785] [PMID: 27337150]
[53] Peltonen R, Kjeldsen-Kragh J, Haugen M, et al. Changes of faecal flora in rheumatoid arthritis during fasting and one-year vegetarian diet. Br J Rheumatol 1994; 33(7): 638-43.[http://dx.doi.org/10.1093/rheumatology/33.7.638] [PMID: 8019792]
[54] Maxwell JR, Gowers IR, Moore DJ, Wilson AG. Alcohol consumption is inversely associated with risk and severity of rheumatoid arthritis. Rheumatology (Oxford) 2010; 49(11): 2140-6.[http://dx.doi.org/10.1093/rheumatology/keq202] [PMID: 20667949]
[55] Lu B, Rho YH, Cui J, et al. Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis. J Rheumatol 2014; 41(1): 24-30.[http://dx.doi.org/10.3899/jrheum.130074] [PMID: 24293566]
[56] Sundström B, Johansson I, Rantapää-Dahlqvist S. Diet and alcohol as risk factors for rheumatoid arthritis: A nested case-control study. Rheumatol Int 2015; 35(3): 533-9.[http://dx.doi.org/10.1007/s00296-014-3185-x] [PMID: 25428595]
[57] Kremer JM, Weinblatt ME. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis 2017.
[58] Humphreys JH, Warner A, Costello R, Lunt M, Verstappen SM, Dixon WG. Quantifying the hepatotoxic risk of alcohol consumption in patients with rheumatoid arthritis taking methotrexate. Ann Rheum Dis 2017; 76(9): 1509-14.[http://dx.doi.org/10.1136/annrheumdis-2016-210629] [PMID: 28341765]
[59] Bellan M, Sainaghi PP, Pirisi M. Role of Vitamin D in Rheumatoid Arthritis. Adv Exp Med Biol 2017; 996: 155-68.[http://dx.doi.org/10.1007/978-3-319-56017-5_13] [PMID: 29124698]
[60] Hajjaj-Hassouni N, Mawani N, Allali F, et al. Evaluation of vitamin D status in rheumatoid arthritis and Its association with disease activity across 15 countries: "The COMORA Study". Int J Rheumatol 2017. 2017: 5491676
[61] Salesi M, Farajzadegan Z, Jeffery LE, et al. Efficacy of vitamin D in patients with active rheumatoid arthritis receiving methotrexate therapy. Decreased sensitivity to 1,25-dihydroxyvitamin D3 in T cells from the rheumatoid joint. Rheumatol Int J Autoimmun 2012; 32(7): 2129-3358. Oct 21. pii: S0896-8411(17) 30420-1.[http://dx.doi.org/10.1007/s00296-011-1944-5]
[62] Keysser G. Are there effective dietary recommendations for patients with rheumatoid arthritis?. Z Rheumatol 2001; 60(1): 17-27.[PMID: 11263011]
[63] Pu D, Luo J, Wang Y, et al. Prevalence of depression and anxiety in rheumatoid arthritis patients and their associations with serum vitamin D level. Clin Rheumatol 2017. Epub ahead of print[http://dx.doi.org/10.1007/s10067-017-3874-4] [PMID: 29063463]
[64] Baker JF, Ghio AJ. Iron homoeostasis in rheumatic disease. Rheumatology (Oxford) 2009; 48(11): 1339-44.[http://dx.doi.org/10.1093/rheumatology/kep221] [PMID: 19628641]
[65] Fraenkel PG. Anemia of Inflammation: A Review. Med Clin North Am 2017; 101(2): 285-96.[http://dx.doi.org/10.1016/j.mcna.2016.09.005] [PMID: 28189171]
[66] Weiss G, Schett G. Anaemia in inflammatory rheumatic diseases. Nat Rev Rheumatol 2013; 9(4): 205-15.[http://dx.doi.org/10.1038/nrrheum.2012.183] [PMID: 23147894]
[67] Mateen S, Moin S, Shahzad S, Khan AQ. Level of inflammatory cytokines in rheumatoid arthritis patients: Correlation with 25-hydroxy vitamin D and reactive oxygen species. PLoS One 2017; 12(6): e0178879.[http://dx.doi.org/10.1371/journal.pone.0178879] [PMID: 28594861]
[68] Jalili M, Kolahi S, Aref-Hosseini SR, Mamegani ME, Hekmatdoost A. Beneficial role of antioxidants on clinical outcomes and erythrocyte antioxidant parameters in rheumatoid arthritis patients. Int J Prev Med 2014; 5(7): 835-40.[PMID: 25104994]
[69] Sahebari M, Ayati R, Mirzaei H, et al. Serum trace element concentrations in rheumatoid arthritis. Biol Trace Elem Res 2016; 171(2): 237-45.[http://dx.doi.org/10.1007/s12011-015-0501-6] [PMID: 26450515]
[70] Longo VD, Mattson MP. Fasting: Molecular mechanisms and clinical applications. Cell Metab 2014; 19(2): 181-92.[http://dx.doi.org/10.1016/j.cmet.2013.12.008] [PMID: 24440038]
[71] Müller H, de Toledo FW, Resch KL. Fasting followed by vegetarian diet in patients with rheumatoid arthritis: A systematic review. Scand J Rheumatol 2001; 30(1): 1-10.[http://dx.doi.org/10.1080/030097401750065256] [PMID: 11252685]
[72] Sköldstam L, Larsson L, Lindström FD. Effect of fasting and lactovegetarian diet on rheumatoid arthritis. Scand J Rheumatol 1979; 8(4): 249-55.[http://dx.doi.org/10.3109/03009747909114631] [PMID: 534318]
[73] Liu Y, Hazlewood GS, Kaplan GG, Eksteen B, Barnabe C. Impact of obesity on remission and disease activity in rheumatoid arthritis: A systematic review and meta-analysis. Arthritis Care Res (Hoboken) 2017; 69(2): 157-65.[http://dx.doi.org/10.1002/acr.22932] [PMID: 27159376]
[74] Hu Y, Costenbader KH, Gao X, Hu FB, Karlson EW, Lu B. Mediterranean diet and incidence of rheumatoid arthritis in women. Arthritis Care Res (Hoboken) 2015; 67(5): 597-606.[http://dx.doi.org/10.1002/acr.22481] [PMID: 25251857]
[75] Hagen KB, Byfuglien MG, Falzon L, Olsen SU, Smedslund G. Dietary interventions for rheumatoid arthritis. Cochrane Database Syst Rev 2009; (1): CD006400.[PMID: 19160281]
[76] Kjeldsen-Kragh J. Mediterranean diet intervention in rheumatoid arthritis. Ann Rheum Dis 2003; 62(3): 193-5.[http://dx.doi.org/10.1136/ard.62.3.193] [PMID: 12594101]
[77] Garner S, Fenton T, Martin L, Creaser C, Johns C, Barnabe C. Personalized diet and exercise recommendations in early rheumatoid arthritis: A feasibility trial. Musculoskelet Care 2017. Epub ahead of print[http://dx.doi.org/10.1002/msc.1214] [PMID: 28967710]

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


SCImago Journal Ranking

SCImago Journal & Country Rank

Browse Contents



Advertisements


Webmaster Contact: info@benthamopen.com
Copyright © 2018 Bentham Open