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Nutrients, foods and dietary patterns in the management of autoimmune rheumatic diseases

Open AccessPublished:June 18, 2022DOI:https://doi.org/10.1016/j.nutos.2022.06.002

      Summary

      Background

      Rheumatic disease (RD) represents a broad spectrum of systemic conditions characterized by inflammation and pain in muscles or joints with a significant burden on quality of life. Increasing evidence suggests that diet could play a modulatory role in RD by influencing cardiovascular diseases (CVD) risk factors frequently present in these patients as well as inflammation and antioxidant defence.

      Objectives

      This review aims to summarize the available evidence on the effect of nutrients, foods and dietary patterns on the most common autoimmune inflammatory RD including rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus and systemic sclerosis.

      Results

      We documented that MUFAs and PUFAs seem to have positive effects in modulating the inflammatory process. Regarding the dietary interventions, low-calorie diets, Mediterranean diet and fasting appear to be effective in reducing the symptoms of the most common RD. Positive results were also obtained in some cases with gluten-free, low-fat, vegan, elimination or anti-inflammatory diets.

      Conclusion

      Although further and specific studies are needed, the fact that people obtained an improvement in clinical outcomes after almost all these dietary patterns suggests that a healthy diet could play a pivotal role in the RD management.

      Keywords

      1. Introduction

      Rheumatic diseases (RD) represent a broad spectrum of systemic conditions characterized by inflammation and pain in muscles or joints with a significant burden on quality of life. Rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus and systemic sclerosis are among the most common autoimmune RD. The RD aetiology and pathogenesis are highly complex and characterized by auto-reactive immune responses that cause immune-mediated organ damage, which, in turn, is associated with increased morbidity and mortality [
      • Hedar A.M.
      • Stradner M.H.
      • Roessler A.
      • Goswami N.
      Autoimmune rheumatic diseases and vascular function: the concept of autoimmune atherosclerosis.
      ]. It has been estimated that one third of the mortality associated with autoimmune diseases is due to cardiovascular diseases (CVD). Indeed, a complex interaction between traditional and disease-specific traits leads to a premature atherosclerotic process in RD patients [
      • Amaya-Amaya J.
      • Montoya-Sánchez L.
      • Rojas-Villarraga A.
      Cardiovascular involvement in autoimmune diseases.
      ].
      In this scenario, increasing evidence suggests that diet could play an important modulatory role in RD by influencing the traditional CVD risk factors frequently present in these patients – i.e., obesity, insulin resistance, dyslipidaemia, or diabetes mellitus – as well as inflammation and antioxidant defense [
      • Alunno A.
      • Carubbi F.
      • Bartoloni E.
      • Grassi D.
      • Ferri C.
      • Gerli R.
      Diet in Rheumatoid Arthritis versus Systemic Lupus Erythematosus: Any Differences?.
      ]. Recent evidence suggests that gut microbiota (GM) could be involved in the RD pathogenesis, thus suggesting that a diet that could influence the GM might influence disease activity [
      • Macfarlane T.V.
      • Abbood H.M.
      • Pathan E.
      • Gordon K.
      • Hinz J.
      • Macfarlane G.J.
      Relationship between diet and anky-losing spondylitis: A systematic review.
      ]. Furthermore, diet is able to influence the pharmacological treatment efficacy so it is gaining interest among healthcare providers.
      Even if nutritional care appears promising, current nutritional information in the RD management is extremely scarce and varies according to the different diseases. A recent survey by Pham and colleagues [
      • Pham T.
      • Sokol H.
      • Halioua B.
      • Pourcel G.
      • Brun M.
      • Pain E.
      • et al.
      Immune-mediated inflammatory diseases and nutrition: results from an online survey on patients' practices and perceptions.
      ] revealed that only a small percentage of people diagnosed with RD received nutritional advice and that most of them were rather dissatisfied with information and service provided. RD patients frequently ask their doctors about which diets to follow, and even in the absence of advice, most of them are undertaking different dietary choices since its own experience.
      It is therefore clear that the question of whether diet plays a role in the progression of rheumatic diseases is a crucial issue for many patients and healthcare providers. Thus, the aim of our review is to summarize the current available evidence regarding the ideal dietary approach for the management of the most common RD to decrease the counteracting inflammation and the symptomatology, in order to improve the life quality of patients.

      2. Nutrients, foods, dietary patterns and rheumatoid arthritis

      Rheumatoid arthritis (RA) is a systemic chronic immune-mediated inflammatory disease characterized by joint swelling and tenderness, bone and cartilage damage, and production of autoantibodies such as anti-citrullinated protein and rheumatoid factor. RA is the most common of inflammatory arthritis, affecting about 1% of the global population with profound impact on patients' quality of life, causing severe disability [
      • Smolen J.S.
      • Aletaha D.
      • Barton A.
      • Burmester G.R.
      • Emery P.
      • Firestein G.S.
      • et al.
      Rheumatoid arthritis.
      ]. Extra-articular manifestations affecting internal organs occur frequently and lead premature mortality, mainly due to an increased atherosclerosis leading to cardiovascular events that are independent of traditional risk factors and are associated with systemic inflammation [
      • del Rincón I.D.
      • Williams K.
      • Stern M.P.
      • Freeman G.L.
      • Escalante A.
      High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors.
      ]. Joint inflammation and synovial hyperplasia are caused by the influx of activated inflammatory cells, abnormal activation of fibroblast-like synoviocytes, and induction of angiogenesis thus inhibiting several apoptotic pathways. Moreover, several proinflammatory cytokines (e.g. TNF-α, IL-1, IL-6, IL-17, and IL-12p70) play a pivotal role in RA pathogenesis. Although the disease etiology remains unknown, an increased risk for developing RA has been associated with HLA-DRB1 alleles. As with many autoimmune illnesses, the risk is major in the women with a female-male ratio of 3:1. Several triggering factors that could lead to the onset or promote progression of RA have been identified including infections, smoking, pollution, diet, oral hygiene, periodontitis, and imbalance in the gastrointestinal microbiota. Although numerous new drugs, particularly biologic agents, are now available for RA treatment, morbidity and mortality remain high [
      • Smolen J.S.
      • Aletaha D.
      • Barton A.
      • Burmester G.R.
      • Emery P.
      • Firestein G.S.
      • et al.
      Rheumatoid arthritis.
      ].
      The RA is certainly the most studied RD; detailed studies in humans on the relationship between nutrients or food intake and disease progression in RA patients are still lacking (Fig. 1 and Table 1). Most of the studies investigating the effects on RA of fat intake – especially omega-3 and omega-6 – use dietary supplements. However, one study reported that MUFAs, as part of a Mediterranean diet, were associated with disease severity in RA since high MUFAs intake resulted to be an independent predictor of remission, and the ratio of daily consumption of MUFAs to saturated fatty acids was inversely associated with disease severity [
      • Matsumoto Y.
      • Sugioka Y.
      • Tada M.
      • Okano T.
      • Mamoto K.
      • Inui K.
      • et al.
      Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study.
      ]. In a survey by Tedeschi et al., 24% of patients reported a diet influence on RA symptomatology; 15% reported positive effects of some foods, especially spinach or berries, while 19% observed negative effects of sweets and sugary drinks [
      • Tedeschi S.K.
      • Frits M.
      • Cui J.
      • Zhang Z.Z.
      • Mahmoud T.
      • Iannaccone C.
      • et al.
      Diet and rheumatoid arthritis symptoms: survey results from a rheumatoid arthritis registry.
      ]. In addition, daily vegetable consumption resulted to be significantly associated with more favorable arterial function in RA patients [
      • Crilly M.A.
      • McNeill G.
      Arterial dysfunction in patients with rheumatoid arthritis and the consumption of daily fruits and daily vegetables.
      ]. Finally, there are contrasting data regarding the effect of alcohol on RA disease activity, with some studies pointing that alcohol consumption leads to worsening of inflammation, disease activity or radiographic damage [
      • Lu B.
      • Rho Y.H.
      • Cui J.
      • Iannaccone C.K.
      • Frits M.L.
      • Karlson E.W.
      • et al.
      Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis.
      ] and some others reporting decrease in self-reported tender joint count and pain in drinkers with respect to non-drinkers [
      • Bergman S.
      • Symeonidou S.
      • Andersson M.L.
      • Söderlin M.K.
      BARFOT Study Group
      Alcohol consumption is associated with lower self-reported disease activity and better health-related quality of life in female rheumatoid arthritis patients in Sweden: Data from BARFOT, a multicenter study on early RA.
      ].
      Figure 1
      Fig. 1Summary of the evidence about the effect of nutrients, foods and dietary patterns on RD.
      Table 1Nutrients, foods, dietary patterns and rheumatoid arthritis
      Author, yearCountryType of studyPopulation, nAge, yrsSexDurationNutrient/food/dietary patternOutcomesFindings
      Matsumoto et al., 2018 [
      • Matsumoto Y.
      • Sugioka Y.
      • Tada M.
      • Okano T.
      • Mamoto K.
      • Inui K.
      • et al.
      Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study.
      ]
      JapanCase-control208 RA patients;

      205 healthy controls
      61 (51–70) RA;

      60 (50–67) controls
      84% FNAMUFA, SFA, alcohol, pulses, seafood, grains, tubers and roots, fruits, vegetables, meat, milk and dairy productsDAS28-ESR, MHAQDAS28-ESR inversely correlated with MUFA/SFA intake
      Tedeschi et al., 2017 [
      • Tedeschi S.K.
      • Frits M.
      • Cui J.
      • Zhang Z.Z.
      • Mahmoud T.
      • Iannaccone C.
      • et al.
      Diet and rheumatoid arthritis symptoms: survey results from a rheumatoid arthritis registry.
      ]
      USCross-sectional217 RA patients65 (53–71)83% FNAMilk, cheese, red meat, tomato, eggplant, white potatoes, bell or hot peppers, diet soft drinks, beer, fish, spinach, blueberries, strawberries, chocolate, red wine, soft drinks with sugar, coffee, teaRADAI, MHAQ, DAS28-CRP, CDAIBlueberries and spinach were the foods most often reported to improve RA symptoms, while soda with sugar and desserts were most often reported to worsen RA symptoms
      Crilly et al., 2012 [
      • Crilly M.A.
      • McNeill G.
      Arterial dysfunction in patients with rheumatoid arthritis and the consumption of daily fruits and daily vegetables.
      ]
      UKCross-sectional114 RA patients54 ± 6.681% FNAFruits, vegetablesPWADaily vegetable consumption, but not daily fruit consumption, was independently associated with more favourable arterial function in patients with RA
      Lu et al., 2014 [
      • Lu B.
      • Rho Y.H.
      • Cui J.
      • Iannaccone C.K.
      • Frits M.L.
      • Karlson E.W.
      • et al.
      Associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis.
      ]
      USCohort662 RA patients54.6 ± 14.383% F7 yearsAlcoholDAS28-CRP3, MHAQModerate alcohol consumption was associated with a better functional status in RA
      Bergman et al., 2013 [
      • Bergman S.
      • Symeonidou S.
      • Andersson M.L.
      • Söderlin M.K.
      BARFOT Study Group
      Alcohol consumption is associated with lower self-reported disease activity and better health-related quality of life in female rheumatoid arthritis patients in Sweden: Data from BARFOT, a multicenter study on early RA.
      ]
      SwedenCross-sectional1,238 RA patients65 ± 1370% FNAAlcoholHRQL, DAS28There was an association between alcohol consumption and both lower self-reported disease activity and higher HRQL in female, but not in male, RA patients
      Kjeldsen-Kragh et al., 1991 [
      • Kjeldsen-Kragh J.
      • Haugen M.
      • Borchgrevink C.F.
      • Laerum E.
      • Eek M.
      • Mowinkel P.
      • et al.
      Controlled trial of fasting and one- year vegetarian diet in rheumatoid arthritis.
      ]
      NorwayRCT53 RA patients53 (26–63)89% F1 yearFasting followed by vegetarian dietPain, morning stiffness, functional ability, MHAQ, joint count, grip strength, haemoglobin, ESR, platelet count, WBC, CRP, albuminDiet group showed a significant improvement in number of tender joints, swollen joints, pain score, morning stiffness, grip strength, ESR, CRP, WBC, and MHAQ
      Mc Dougall et al., 2002 [
      • Mc Dougall J.
      • Bruce B.
      • Spiller G.
      • Westerdahl J.
      • Mc Dougall M.
      Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis.
      ]
      USDietary intervention trial24 RA patients56 ± 1192% F4 weeksHypocaloric low-fat vegan dietCRP, rheumatoid factor, ESR, body weight, joint count, pain, ability function, morning stiffnessPatients with moderate-to-severe RA experienced significant reductions in RA symptoms, body weight, CRP and rheumatoid factor
      Elkan et al., 2008 [
      • Elkan A.C.
      • 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.
      ]
      SwedenRCT66 RA patients49.9 (46.6–53.3)93% F1 yearGluten-free vegan dietDAS28, HAQ, CRP, albumin, cholesterol, triglycerides, HDL, LDL, oxLDL, anti-PCsA gluten-free vegan diet in RA induces atheroprotective and anti-inflammatory changes, including decreased LDL and oxLDL levels and raised anti-PC IgM and IgA levels
      Panush et al., 1983 [
      • Panush R.S.
      • Carter R.L.
      • Katz P.
      • Kowsari B.
      • Longley S.
      • Finnie S.
      Diet therapy for rheumatoid arthritis.
      ]
      USRCT26 RA patients53.646% F10 weeksDiet free of additives, preservatives, fruit, red meat, herbs, and dairy productsPain, morning stiffness, joint count, grip strength, CBC, rheumatoid factor, antinuclear antibodies, C3, C4, stool occult blood tests ESRNo clinically important differences among rheumatologic, laboratory, immunologic, radiologic, or nutritional findings between patients on experimental and placebo diets
      Darlington et al., 1986 [
      • Darlington L.
      • Ramsey N.
      • Mansfield J.
      Placebo-controlled, blind study of dietary manipulation therapy in rheumatoid arthritis.
      ]
      UKRCT53 RA patientsNA81% F6 weeksElimination diet with the exclusion of food which often cause intolerancePain, morning stiffness, joint count, grip strength, physical function, haemoglobin, absolute eosinophil count, platelet count, ESR, antinuclear antibodies, rheumatoid factor, C3, cryoglobulins, fibrinogenElimination diet in RA patients led to a significant improvement during periods of dietary therapy compared with periods of placebo treatment, particularly among “good responders”
      Van De Laar et al., 1992 [
      • Van De Laar A.M.
      • Van Der Korst J.K.
      Food intolerance in rheumatoid arthritis I. A double blind, controlled trial of the clinical effects of elimination of milk allergens and azo dyes.
      ]
      NetherlandRCT94 RA patients5870% F4 weeksElimination diet with the exclusion of allergensMorning stiffness, joint count, grip strength, physical function, haemoglobin, % eosinophils, ESR, leucocytes, thrombocytes, body weightComparison between baseline and subsequent periods showed only subjective improvements. No differences were seen between the clinical effects of the tested diet
      Sarzi-Puttini et al., 2000 [
      • Sarzi-Puttini P.
      • Comi D.
      • Boccassini L.
      • Muzzupappa S.
      • Turiel M.
      • Panni B.
      • et al.
      Diet therapy for rheumatoid arthritis. A controlled double-blind study of two different dietary regimens.
      ]
      ItalyRCT50 RA patients49.6 (32-6478% F6 monthsElimination diet with the exclusion of allergens, high in unsaturated fats, low in saturated fatsMorning stiffness, joint count, pain, HAQ, BMI, body weight, CBC, rheumatoid factor, urinalysis, CRP, C3, C4, immunoglobulins, ESR, cholesterol, HDL, triglyceridesThe elimination diet did better for all the variables considered but only four variables (Ritchie's index, tender and swollen joints, and ESR) reached a statistical difference by multivariate analysis
      Scrivo et al., 2017 [
      • Scrivo R.
      • Massaro L.
      • Barbati C.
      • Vomero M.
      • Ceccarelli F.
      • Spinelli F.R.
      • et al.
      The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus.
      ]
      ItalyRCT14 RA patients58.5 (50–67)93% F3 weeksLow-sodium dietTh17, Treg, cytokinesA trend toward a reduction in the frequencies of Th17 cells, TGFβ and IL-9 over the low-sodium diet regimen was observed, while Treg cells exhibited the opposite trend
      Vadell et al., 2020 [
      • Vadell A.K.E.
      • Bärebring L.
      • Hulander E.
      • Gjertsson I.
      • Lindqvist H.M.
      • Winkvist A.
      Anti-inflammatory diet in rheumatoid arthritis (adira) – a randomized, controlled crossover trial indicating effects on disease activity.
      ]
      SwedenRCT50 RA patients61 ± 1277% F10 weeksAnti-inflammatory dietDAS28-ESR, DAS28-CRPDAS28-ESR significantly decreased during the intervention period, while no significant differences in the components were observed
      McKellar et al., 2007 [
      • McKellar G.
      • Morrison E.
      • McEntegart A.
      • Hampson R.
      • Tierney A.
      • Mackle G.
      • et al.
      A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid arthritis living in areas of social deprivation in Glasgow.
      ]
      UKRCT130 RA patients58 (47–64)100% F6 monthsMediterranean dietjoint count, pain, morning stiffness, DAS28, HAQ, ESR, CRP, IL-6Significant benefit in pain score, morning stiffness and HAQ was shown in the intervention group
      anti-PCs: natural atheroprotective antibodies against phosphorylcholine; CBC: Complete Blood Count; CDAI: Clinical Disease Activity Index; CRP: C-reactive protein; DAS28: Disease Activity Score in 28 Joints; DAS28-CRP: Disease Activity Score in 28 Joints and C-reactive protein; DAS28-ESR: disease activity scores in 28 joints and erythrocyte sedimentation rates; ESR: erythrocyte sedimentation rates; HRQL: health related quality of life; MHAQ: modified Health Assessment Questionnaire; MUFA: mono-unsaturated fatty acids; oxLDL: blood lipids oxidized low-density lipoprotein; PWA: pulse wave analysis; RADAI: RA Disease Activity Index; RCT: Randomized Controlled Trial; SFA: saturated fatty acids; Th17: T helper 17 cells; Treg: regulatory T cells; WBC: white blood cell.
      To date, several studies on RA progression and different dietary patterns have been performed (Fig. 1 and Table 1). Fasting followed by a vegetarian diet may be useful in the RA treatment by reducing inflammation and pain [
      • Kjeldsen-Kragh J.
      • Haugen M.
      • Borchgrevink C.F.
      • Laerum E.
      • Eek M.
      • Mowinkel P.
      • et al.
      Controlled trial of fasting and one- year vegetarian diet in rheumatoid arthritis.
      ] as confirmed by Muller and colleagues that reviewed all the available evidence on fasting and disease progression in RA [
      • Muller H.
      • de Toledo F.W.
      • Resch K.L.
      Fasting followed by vegetarian diet in patients with rheumatoid arthritis: a systematic review.
      ], even if long-term effects on RA symptoms are still controversial [
      • Gioia C.
      • Lucchino B.
      • Tarsitano M.G.
      • Iannuccelli C.
      • Di Franco M.
      Dietary habits and nutrition in rheumatoid arthritis: can diet influence disease development and clinical manifestations?.
      ]. A 4-week hypocaloric very low-fat vegan diet led to a reduction of body weight and RA symptoms in 24 RA patients [
      • Mc Dougall J.
      • Bruce B.
      • Spiller G.
      • Westerdahl J.
      • Mc Dougall M.
      Effects of a very low-fat, vegan diet in subjects with rheumatoid arthritis.
      ]. In addition, 1-year gluten-free, vegan diet rich in whole cereals was associated with a significant reduction of oxidized LDL levels, anti-beta-lactoglobulin and anti-gliadin antibodies levels, as well as a reduction of disease severity [
      • Elkan A.C.
      • 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.
      ,
      • El-Chammas K.
      • Danner E.
      Gluten-free diet in nonceliac disease.
      ]. Other studies intervened with allergen-free diets by eliminating certain foods that commonly cause allergies such as eggs, wheat, dairy products, and spice, finding improvements in specific patient subgroups, but no significant differences were found overall between the intervention and control groups [
      • Panush R.S.
      • Carter R.L.
      • Katz P.
      • Kowsari B.
      • Longley S.
      • Finnie S.
      Diet therapy for rheumatoid arthritis.
      ,
      • Darlington L.
      • Ramsey N.
      • Mansfield J.
      Placebo-controlled, blind study of dietary manipulation therapy in rheumatoid arthritis.
      ,
      • Van De Laar A.M.
      • Van Der Korst J.K.
      Food intolerance in rheumatoid arthritis I. A double blind, controlled trial of the clinical effects of elimination of milk allergens and azo dyes.
      ,
      • Sarzi-Puttini P.
      • Comi D.
      • Boccassini L.
      • Muzzupappa S.
      • Turiel M.
      • Panni B.
      • et al.
      Diet therapy for rheumatoid arthritis. A controlled double-blind study of two different dietary regimens.
      ]. Low-sodium diet seems to have some anti-inflammatory potential, indeed, a decrease in TGFβ, IL-9 and Th17 cell after a 3-week low-sodium diet and their increase after 2 weeks of normal-sodium diet was observed, whereas an opposite trend was observed for Treg cells [
      • Scrivo R.
      • Massaro L.
      • Barbati C.
      • Vomero M.
      • Ceccarelli F.
      • Spinelli F.R.
      • et al.
      The role of dietary sodium intake on the modulation of T helper 17 cells and regulatory T cells in patients with rheumatoid arthritis and systemic lupus erythematosus.
      ]. Furthermore, a low-inflammatory diet rich in omega-3 fatty acids, dietary fiber and probiotics compared to a typical Swedish diet high in saturated fats showed a mild symptomatic improvement in RA patients, but no significant changes in disease activity were observed [
      • Vadell A.K.E.
      • Bärebring L.
      • Hulander E.
      • Gjertsson I.
      • Lindqvist H.M.
      • Winkvist A.
      Anti-inflammatory diet in rheumatoid arthritis (adira) – a randomized, controlled crossover trial indicating effects on disease activity.
      ]. Finally, a paper by McKellar and colleagues examined the effects of Mediterranean diet in patients with RA, concluding that it has beneficial effects in people living with RA in reducing pain and improving physical function [
      • McKellar G.
      • Morrison E.
      • McEntegart A.
      • Hampson R.
      • Tierney A.
      • Mackle G.
      • et al.
      A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid arthritis living in areas of social deprivation in Glasgow.
      ], as also confirmed by a recent systematic review [
      • Forsyth C.
      • Kouvari M.
      • D’Cunha N.M.
      • Georgousopoulou E.N.
      • Panagiotakos D.B.
      • Mellor D.D.
      • et al.
      The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: a systematic review of human prospective studies.
      ].

      3. Nutrients, foods, dietary patterns and Sjogren's syndrome

      Sjogren's syndrome (SS) is one of the most common autoimmune disease, typically associated with the production of antinuclear autoantibodies (including an-ti-Ro60, anti-Ro52/SSA and anti-La/SS) and characterized by lymphocytic infiltration. SS affects the exocrine glands, mainly the lacrimal and salivary glands, as well as extra-glandular epithelial tissues [
      • Brito-Zerón P.
      • Baldini C.
      • Bootsma H.
      • Bowman S.J.
      • Jonsson R.
      • Mariette X.
      • et al.
      Sjögren syndrome.
      ]. Principal symptoms associated with SS include frequent dryness of eyes (xeropthalmia) and mouth (xerostomia), however in most cases (50–70% of patients) these symptoms are also associated with severe extra-glandular manifestations (e.g., arthritis, vasculitis, bronchiectasis, nephritis, autonomic nervous system dysfunction and peripheral neuropathy). The prognosis is mainly conditioned by the extra-glandular involvement. Unfortunately, SS is oftentimes misdiagnosed and undertreated, and although it is considered a benign condition, patients have an in-creased risk to develop lymphoma. SS may occur in any age, but primarily affects middle-aged women, with a 9:1 female: male ratio and a prevalence ranging from 0.04 to 0.17%. Its pathogenesis is thought to be a multistep process, triggered by an environ-mental factor, most likely viral, in genetically predisposed individuals [
      • Seror R.
      • Nocturne G.
      • Mariette X.
      Current and future therapies for primary Sjögren syndrome.
      ].
      Regarding dietary habits, a study on 24 SS women evidenced a lower intake of omega-3 fatty acids and vitamin C, and a greater intake of calcium with respect to healthy control [
      • Cermak J.M.
      • Papas A.S.
      • Sullivan R.M.
      • Dana M.R.
      • Sullivan D.A.
      Nutrient intake in women with primary and secondary Sjögren's syndrome.
      ]. To date, evidence on dietary patterns, foods, or nutrients' intake in patients with SS is extremely scarce (Fig. 1 and Table 2). A letter by Peen et al. [
      • Peen E.
      • Haga H.J.
      • Haugen A.J.
      • Kahrs G.E.
      • Haugen M.
      The effect of a liquid diet on salivary flow in primary Sjögren's syndrome.
      ] showed the efficacy of a 4-week period of liquid diet on salivary and lacrimal flow in 23 SS patients. A case report on 5 SS children (5 months–8 years) reported no effects on SS symptoms after a low-fat diet supplemented with medium-chain fatty acids [
      • Maaswinkel-Mooij P.D.
      • Brouwer O.F.
      • Rizzo W.B.
      Unsuccessful dietary treatment of Sjögren-Larsson syndrome.
      ]. Finally, a case report on a 42-year-old woman with SS and premature ovarian failure showed a reversal of her premature ovarian failure and restoration of normal menses using an elimination diet with the exclusion of gluten, refined sugars, beef, dairy products, eggs, nightshade vegetables, and citrus fruit for 4 months [
      • Feuerstein J.
      Reversal of premature ovarian failure in a patient with Sjögren syndrome using an elimination diet protocol.
      ].
      Table 2Nutrients, foods, dietary patterns and Sjögren's syndrome
      Author, yearCountryType of studyPopulation, nAge, yrsSexDurationNutrient/food/dietary patternOutcomesFindings
      Peen et al., 2008 [
      • Peen E.
      • Haga H.J.
      • Haugen A.J.
      • Kahrs G.E.
      • Haugen M.
      The effect of a liquid diet on salivary flow in primary Sjögren's syndrome.
      ]
      NorwayRCT23 SS patients56.6 (34–73)91% F4 weeksLiquid dietUWSC, Schirmer I test, CRP, ESR, fatigue, joint painUWSC and the sum of Schirmer I (both eyes) increased significantly even in the pSS patients with no lacrimal flow at the start of the study
      Maaswinkel-Mooij et al., 1994 [
      • Maaswinkel-Mooij P.D.
      • Brouwer O.F.
      • Rizzo W.B.
      Unsuccessful dietary treatment of Sjögren-Larsson syndrome.
      ]
      NetherlandCase series5 SS patients5 months -8 yearsNANALow-fat diet supplemented with medium-chain fatty acidsPlasma octadecanol levels, skin lesions, neurologic symptomsPlasma octadecanol levels remained unchanged, and skin lesions and neurologic symptoms did not abate
      Feuerstein et al., 2010 [
      • Feuerstein J.
      Reversal of premature ovarian failure in a patient with Sjögren syndrome using an elimination diet protocol.
      ]
      USCase report1 SS patient42100% F4 monthsElimination diet with the exclusion of gluten, refined sugars, beef, dairy products, eggs, nightshade vegetables, and citrusFSH, ESR, rheumatological symptomsElimination diet led to a drop in FSH and ESR. Menses resumed and rheumatological symptoms significantly improved
      CRP: C-reactive protein; ESR: erythrocyte sedimentation rates; FSH: follicle-stimulating hormone; UWSC: unstimulated whole salivary collection.

      4. Nutrients, foods, dietary patterns and systemic lupus erythematosus

      Systemic lupus erythematosus (SLE) is a severe, chronic autoimmune disease of unknown etiology that can affect virtually any organ, leading to significant morbidity and mortality. It is characterized by immune-dysregulation with the production of autoantibodies (anti-nuclear, anti-double-stranded DNA and anti-Smith), immune complex formation and deposition in tissues resulting in local and systemic inflammation [
      • Lisnevskaia L.
      • Murphy G.
      • Isenberg D.
      Systemic lupus erythematosus.
      ]. The SLE pathogenesis remains unclear, however, it is widely considered as multifactorial with a combination of genetic susceptibilities, environmental factors (such as infections, UV exposure, stress, pollution, or diet) and epigenetic modifications that may impact the disease in terms of triggering or altering its course. SLE is most prevalent in females of childbearing age, with a female: male ratio of 9:1. Estimated incidence rate is 1–25 per 100,000 people in Europe, with a prevalence of about 0.04%. Clinical features vary widely, overlap with other illnesses, and are often initially subtle. They range from mild skin and joint involvement to life-threatening manifestations in the kidney, lung, components of the blood, central nervous system, and heart. SLE may be associated with the presence of lupus anticoagulant and antiphospholipid antibodies leading to a severe thrombophilic state, increasing the risk for thrombosis, or disseminated intravascular coagulation. Gastrointestinal manifestations are frequent in SLE patients and may be caused either by the disease itself or by the highly aggressive treatments [
      • Kaul A.
      • Gordon C.
      • Crow M.K.
      • Touma Z.
      • Urowitz M.B.
      • van Vollenhoven R.
      • et al.
      Systemic lupus erythematosus.
      ].
      Very few studies examined the effect of nutrients or single foods on SLE progression (Fig. 1 and Table 3). One observational study investigated the association between dietary habits and disease severity, blood lipids and atherosclerosis showing that lower omega-3 intakes and higher carbohydrate intakes among SLE patients appeared to be related with increased disease severity, adverse serum lipids and plaque presence [
      • Elkan A.C.
      • Anania C.
      • Gustafsson T.
      • Jogestrand T.
      • Hafström I.
      • Frostegård J.
      Diet and fatty acid pattern among patients with SLE: associations with disease activity, blood lipids and atherosclerosis.
      ]. Regarding dietary proteins, Milovanov and colleagues [
      • Milovanov I.S.
      • Lysenko L.V.
      • Milovanova L.I.
      • Dobrosmyslov I.A.
      The role of balanced low-protein diet in inhibition of predialysis chronic kidney disease progression in patients with systemic diseases.
      ] reported that a protein-restricted diet (0.6 g/kg/die) had a beneficial effect on nutritional status and glomerular filtration rate in SLE patients with chronic kidney disease. Furthermore, excessive protein intake has been linked to bone mineral loss in patients with juvenile SLE [
      • Caetano M.C.
      • Ortiz T.T.
      • Terreri M.T.
      • Sarni R.O.
      • Silva S.G.
      • Souza F.I.
      • et al.
      Inadequate dietary intake of children and adolescents with juvenile idiopathic arthritis and systemic lupus erythematosus.
      ]. Finally, a study on 279 SLE women investigating the association between dietary intake of vitamin B6 and B12, folate, and dietary fiber and the risk of active disease and atherosclerotic events, showed an inverse association between vitamin B6 and dietary fiber intake and occurrence of active disease in SLE [
      • Minami Y.
      • Hirabayashi Y.
      • Nagata C.
      • Ishii T.
      • Harigae H.
      • Sasaki T.
      Intakes of vitamin B6 and dietary fiber and clinical course of systemic lupus erythematosus: a prospective study of Japanese female patients.
      ].
      Table 3Nutrients, foods, dietary patterns and systemic lupus erythematosus
      Author, yearCountryType of studyPopulation, nAge, yrsSexDurationNutrient/food/dietary patternOutcomesFindings
      Elkan et al., 2012 [
      • Elkan A.C.
      • Anania C.
      • Gustafsson T.
      • Jogestrand T.
      • Hafström I.
      • Frostegård J.
      Diet and fatty acid pattern among patients with SLE: associations with disease activity, blood lipids and atherosclerosis.
      ]
      SwedenCase-control114 SLE patients; 122 controls47.9 (45.5–50.4) SLE; 49.1 (46.8–51.4) controls88% FNADietary fiber, carbohydrate, protein, total fat, SFA, MUFA, PUFA, Omega-3, Omega-6SLAM, SLEDAI, SLICC, CRP, ESR, blood lipids, lipoproteins, carotid plaque, fatty acid contentThe higher intake of carbohydrate, lower fibre intake and lower intake of omega-3 and omega-6 in SLE patients appear to be associated with worse disease activity, adverse serum lipids and plaque presence
      Milovanov et al., 2009 [
      • Milovanov I.S.
      • Lysenko L.V.
      • Milovanova L.I.
      • Dobrosmyslov I.A.
      The role of balanced low-protein diet in inhibition of predialysis chronic kidney disease progression in patients with systemic diseases.
      ]
      RussiaRCT33 SLE patientsNANA24–48 monthsLow-protein dietRenal functionProtein-restricted diet had a beneficial effect on nutritional status and glomerular filtration rate in SLE patients with chronic kidney disease
      Caetano et al., 2009 [
      • Caetano M.C.
      • Ortiz T.T.
      • Terreri M.T.
      • Sarni R.O.
      • Silva S.G.
      • Souza F.I.
      • et al.
      Inadequate dietary intake of children and adolescents with juvenile idiopathic arthritis and systemic lupus erythematosus.
      ]
      BrazilCross-sectionalNA16.5NANACarbohydrate, protein, total fatDisease activityExcessive protein intake has been linked to bone mineral loss in patients with juvenile SLE
      Minami et al., 2011 [
      • Minami Y.
      • Hirabayashi Y.
      • Nagata C.
      • Ishii T.
      • Harigae H.
      • Sasaki T.
      Intakes of vitamin B6 and dietary fiber and clinical course of systemic lupus erythematosus: a prospective study of Japanese female patients.
      ]
      JapanCohort412 SLE patients40 ± 13100% F46 monthsVitamin B6, vitamin B12, folate, dietary fiberLACC, SLICC, atherosclerotic vascular eventsInverse association between vitamin B6 and dietary fiber intake and the risk of active disease
      Davies et al., 2012 [
      • Davies R.J.
      • Lomer M.C.
      • Yeo S.I.
      • Avloniti K.
      • Sangle S.R.
      • D'Cruz D.P.
      Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids.
      ]
      UKRCT23 SLE patients44 ± 12100% F6 weeksLow glycaemic index diet,

      Calorie-restricted diet
      Body weight, BILAG, SLEDAI, ECLAM, SLICC, FSS, PSQI, cholesterol, LDL, HDL, glycaemia, triglyceride, lipoprotein A, homocysteine, fibrinogen, hsCRP, uric acid, ketonesA statistically significant reduction in weight and perceived fatigue after both interventions, while no changes in disease activity, total cholesterol, HDL, LDL and glycaemia were observed.
      Shah et al., 2002 [
      • Shah M.
      • Kavanaugh A.
      • Coyle Y.
      • Adams-Huet B.
      • Lipsky P.E.
      Effect of a culturally sensitive cholesterol lowering diet program on lipid and lipoproteins, body weight, nutrient intakes, and quality of life in patients with systemic lupus erythematosus.
      ]
      USRCT17 SLE patients44.1 ± 9.3100% F12 weeksLow-fat dietBlood lipids, lipoproteins, body weight, quality of lifeAn increase in quality of life as well as a significant decrease in weight and total cholesterol but no changes in LDL, HDL, and triglyceride levels were observed.
      Pocovi-Gerardino et al., 2021 [
      • Pocovi-Gerardino G.
      • Correa-Rodríguez M.
      • Callejas-Rubio J.L.
      • Ríos-Fernández R.
      • Martín-Amada M.
      • Cruz-Caparros M.G.
      • et al.
      Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: A cross-sectional study.
      ]
      SpainCross-sectional280 SLE patients46.9 ± 12.990,4% FNAMediterranean dietCRP, homocysteine, SLEDAI, SLICC, lipid profile, body weight, C3, C4, homocysteineGreater adherence to the Mediterranean diet was significantly associated with better anthropometric profiles, fewer cardiovascular disease risk factors, and lower disease activity and damage accrual scores
      Goharifar et al., 2015 [
      • Goharifar H.
      • Faezi S.T.
      • Paragomi P.
      • Montazeri A.
      • Banihashemi A.T.
      • Akhlaghkhah M.
      • et al.
      The effect of Ramadan fasting on quiescent systemic lupus erythematosus (SLE) patients’ disease activity, health quality of life and lipid profile: A pilot study.
      ]
      IranCase-control40 SLE patients (21 cases; 19 controls)39.7 ± 13.4 SLE; 40.2 ± 11.2 controls100% F12 weeksRamadan fastingSLEDAI, lipid profile, quality of life, C3, C4, anti-ds DNA, CBC, ESR, BMIRamadan fasting led to a significant reduction in total cholesterol and a significant increase of anti-dsDNA antibodies, while no changes in disease activity and patients' quality of life were observed
      BILAG: British Isles Lupus Assessment Group; BMI: Body Mass Index; CBC: Complete Blood Count; CRP: C-reactive protein; ECLAM: European Community Lupus Activity Measure; ESR: erythrocyte sedimentation rates; FSS: Fatigue Severity Scale; HDL: High-density Lipoprotein; hsCRP: high sensitivity C-reactive protein; LACC: Lupus Activity Criteria Count; LDL: Low-density Lipoprotein; MUFA: Mono-unsaturated Fatty Acids; PSQI: Pittsburgh Sleep Quality Index; PUFA: Poli-unsaturated Fatty Acids; SFA: Saturated fatty Acids; SLAM: Systemic Lupus Activity Measure; SLEDAI: Systemic Lupus Erythematosus Disease Activity Index; SLICC: Systemic Lupus International Collaborating Clinics.
      More than half of the SLE patients present three or more CVD risk factors and obesity, dyslipidaemia and diabetes are certainly the most common [
      • Alunno A.
      • Carubbi F.
      • Bartoloni E.
      • Grassi D.
      • Ferri C.
      • Gerli R.
      Diet in Rheumatoid Arthritis versus Systemic Lupus Erythematosus: Any Differences?.
      ]. Davies and colleagues [
      • Davies R.J.
      • Lomer M.C.
      • Yeo S.I.
      • Avloniti K.
      • Sangle S.R.
      • D'Cruz D.P.
      Weight loss and improvements in fatigue in systemic lupus erythematosus: a controlled trial of a low glycaemic index diet versus a calorie restricted diet in patients treated with corticosteroids.
      ] compared a hypoglycemic diet with a calorie-restricted diet and observed a statistically significant reduction in weight and perceived fatigue after both interventions, while no changes in disease activity, total cholesterol, HDL-cholesterol, LDL-cholesterol, and glycaemia were observed. Shah et al. [
      • Shah M.
      • Kavanaugh A.
      • Coyle Y.
      • Adams-Huet B.
      • Lipsky P.E.
      Effect of a culturally sensitive cholesterol lowering diet program on lipid and lipoproteins, body weight, nutrient intakes, and quality of life in patients with systemic lupus erythematosus.
      ] investigated the effectiveness of a low-fat diet to lose weight and cholesterol levels in a restricted group of SLE patients, showing an increase in quality of life as well as a significant decrease in weight and total cholesterol but no changes in LDL-cholesterol, HDL-cholesterol, and triglyceride levels were observed. Only one study explored the effects of the Mediterranean diet in 280 SLE patients, revealing that subjects with higher adherence to this dietary pattern reported lower disease severity and disease damage scores, lower BMI and fat mass and fewer CVD risk factors [
      • Pocovi-Gerardino G.
      • Correa-Rodríguez M.
      • Callejas-Rubio J.L.
      • Ríos-Fernández R.
      • Martín-Amada M.
      • Cruz-Caparros M.G.
      • et al.
      Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: A cross-sectional study.
      ]. In addition, higher consumption of fish, vegetables, fruits and olive oil, and lower consumption of red meat and meat products and sugars resulted to be associated with lower disease activity and damage [
      • Pocovi-Gerardino G.
      • Correa-Rodríguez M.
      • Callejas-Rubio J.L.
      • Ríos-Fernández R.
      • Martín-Amada M.
      • Cruz-Caparros M.G.
      • et al.
      Beneficial effect of Mediterranean diet on disease activity and cardiovascular risk in systemic lupus erythematosus patients: A cross-sectional study.
      ]. In addition, another study assessed the effects of the Ramadan fasting in a cohort of SLE patients reporting, after 24 days of fasting, a significant reduction in total cholesterol and a significant increase of anti-dsDNA antibodies that remained stable and significant after 3 months [
      • Goharifar H.
      • Faezi S.T.
      • Paragomi P.
      • Montazeri A.
      • Banihashemi A.T.
      • Akhlaghkhah M.
      • et al.
      The effect of Ramadan fasting on quiescent systemic lupus erythematosus (SLE) patients’ disease activity, health quality of life and lipid profile: A pilot study.
      ]. However, no changes in disease activity and patients' quality of life were observed [
      • Goharifar H.
      • Faezi S.T.
      • Paragomi P.
      • Montazeri A.
      • Banihashemi A.T.
      • Akhlaghkhah M.
      • et al.
      The effect of Ramadan fasting on quiescent systemic lupus erythematosus (SLE) patients’ disease activity, health quality of life and lipid profile: A pilot study.
      ]. Finally, a study highlighted the importance of personalized nutrition counselling which resulted to be effective in initiating dietary changes in SLE patients [
      • Everett S.T.
      • Wolf R.
      • Contento I.
      • Haiduc V.
      • Richey M.
      • Erkan D.
      Short-term patient-centered nutrition counseling impacts weight and nutrient intake in patients with systemic lupus erythematosus.
      ].

      5. Nutrients, foods, dietary patterns and systemic sclerosis

      Systemic sclerosis (SSc) is a rare and complex connective tissue disorder with high mortality rate. It is characterized by widespread fibrosis, early micro-vasculopathy, and immune-system dysregulation with production of autoantibodies (anti-nuclear, and the more specific anti-centromere and anti-ScL-70). The distinguishing SSc hallmark is represented by a progressive fibrosis of skin and internal organ owing to a maladaptive repair process characterized by excessive production of collagen and other components [
      • Allanore Y.
      • Simms R.
      • Distler O.
      • Trojanowska M.
      • Pope J.
      • Denton C.P.
      • et al.
      Systemic sclerosis.
      ]. The SSc aetiology remains quite obscure, and the pathogenesis may encompass multiple genetic and environmental factors such as infections, drugs, diet, and lifestyle. The disease onset is earlier in women than in men, generally occurring between 40 and 50 years of age, with a male to female ratio of 3–4:1. SSc is an unpredictable disease that may have different clinical features at onset as well as a heterogeneous course with time [
      • Varga J.
      • Trojanowska M.
      • Kuwana M.
      Pathogenesis of systemic sclerosis: recent insights of molecular and cellular mechanisms and therapeutic opportunities.
      ]. The early disease diagnosis is very problematic in the oligosymptomatic phase because initial symptoms, such as Raynaud's phenomenon and puffy fingers, are not specific signs. Consequently, delays in diagnosis may lead to progression of the disease up to the point that important organ damage and SSc-related vasculopathy complications (i.e., interstitial lung disease and pulmonary arterial hypertension) ensue [
      • Bellando-Randone S.
      • Matucci-Cerinic M.
      Very early systemic sclerosis.
      ].
      Since oesophageal dysmotility and abnormalities of intestinal function are important manifestations in SSc, several dietary guidelines for the SSc management have been published to date, even if evidence on dietary patterns, food or nutrients' intake in these patients is extremely unusual [
      • Smith E.
      • Pauling J.D.
      The efficacy of dietary intervention on gastrointestinal involvement in systemic sclerosis: A systematic literature review.
      ] as reported in Fig. 1 and Table 4. A study performed thirty years ago evaluated the dietary habits of 30 SSc patients finding a lower intake of dietary fiber, fruit, and vegetables with respect to healthy controls [
      • Lundberg A.C.
      • Akesson A.
      • Akesson B.
      Dietary intake and nutritional status in patients with systemic sclerosis.
      ]. Few years later Gough and colleagues [
      • Gough A.
      • Sheeran T.
      • Bacon P.
      • Emery P.
      Dietary advice in systemic sclerosis: the dangers of a high fibre diet.
      ] – based on a small case series – suggested that a high-fiber diet may exacerbate gastrointestinal symptoms in SSc. Another study explored the effect of a vitamin C-deficient diet on 11 SSc patients to determine whether lack of this substance would impair collagen synthesis and consequently improve the lesions of SSc, but none of the signs or SSc symptoms improved in any of the patients [
      • Lazarus R.J.
      • Kaplan D.A.
      • Diamond H.S.
      • Emmanuel G.
      Treatment of scleroderma patients with a scorbutic diet: negative result.
      ]. In two subsequent works, Marie et al. hypothesized that fructose and lactose malabsorption – reported in 40% and 44% of the patients, respectively – may play a critical role in the onset of gastrointestinal symptoms in these patients, showing that low-fructose diet resulted in a marked decrease of gastrointestinal clinical manifestations in SSc patients with fructose malabsorption [
      • Marie I.
      • Leroi A.M.
      • Gourcerol G.
      • Levesque H.
      • Ménard J.F.
      • Ducrotte P.
      Fructose Malabsorption in Systemic Sclerosis.
      ,
      • Marie I.
      • Leroi A.M.
      • Gourcerol G.
      • Levesque H.
      • Menard J.F.
      • Ducrotte P.
      Lactose malabsorption in systemic sclerosis.
      ].
      Table 4Nutrients, foods, dietary patterns and systemic sclerosis
      Author, yearCountryType of studyPopulation, nAge, yrsSexDurationNutrient/food/dietary patternOutcomesFindings
      Gough et al., 1998 [
      • Gough A.
      • Sheeran T.
      • Bacon P.
      • Emery P.
      Dietary advice in systemic sclerosis: the dangers of a high fibre diet.
      ]
      UKCase series4 SSc46–71100% FNADietary fiberGastrointestinal symptomsHigh-fiber diet seems to exacerbate gastrointestinal symptoms in SSc
      Lazarus et al., 1970 [
      • Lazarus R.J.
      • Kaplan D.A.
      • Diamond H.S.
      • Emmanuel G.
      Treatment of scleroderma patients with a scorbutic diet: negative result.
      ]
      USDietary intervention trial11 SSc patientsNANANALow-vitamin C dietCollagen sysntesis, scleroderma lesionsLow-vitamin C diet did not impair collagen synthesis and consequently did not improve the lesions of SSc
      Marie et al., 2015 [
      • Marie I.
      • Leroi A.M.
      • Gourcerol G.
      • Levesque H.
      • Ménard J.F.
      • Ducrotte P.
      Fructose Malabsorption in Systemic Sclerosis.
      ]
      FranceDietary intervention trial80 SSc patients52.5 (22–79)82.5% F4 weeksLow-FODMAPs dietDigestive symptoms, BMI, ESR, CRP, albumin, prealbumin, ferritin, folic acid, vitamin B12, magnesium, zinc, selenium, 25OHvitamin DLow-FODMAPs diet resulted in a marked decrease of gastrointestinal clinical manifestations in SSc patients with fructose malabsorption
      Marie et al., 2016 [
      • Marie I.
      • Leroi A.M.
      • Gourcerol G.
      • Levesque H.
      • Menard J.F.
      • Ducrotte P.
      Lactose malabsorption in systemic sclerosis.
      ]
      FranceDietary intervention trial99 SSc patients53.5 (21–79)82% F4 weeksLactose-free dietDigestive symptoms, BMI, ESR, CRP, albumin, prealbumin, ferritin, folic acid, vitamin B12, magnesium, zinc, selenium, 25OHvitamin DIn SSc patients with symptomatic lactose malabsorption, digestive symptoms were lower after initiation of lactose-free diet
      Ortiz-Santamaria et al., 2014 [
      • Ortiz-Santamaria V.
      • Puig C.
      • Soldevillla C.
      • Barata A.
      • Cuquet J.
      • Recasens A.
      Nutritional support in patients with systemic sclerosis.
      ]
      SpainRCT9 SSc patients62.6 ± 11.789% F1 yearIndividualized balanced dietBody weight, BMI, quality of lifeNo significant improvements in body weight, food intake, nutritional biochemical parameters, and quality of life were observed after individualized balanced diet intervention
      Doerfler et al., 2017 [
      • Doerfler B.
      • Allen T.S.
      • Southwood C.
      • Brenner D.
      • Hirano I.
      • Sheean P.
      Medical nutrition therapy for patients with advanced systemic sclerosis (MNT PASS): A pilot intervention study.
      ]
      USDietary intervention trial18 SSc51.3 ± 11.089% F6 weekMedical nutrition therapyBody weight, BMI, body composition, sarcopeniaIndividually tailored medical nutrition therapy improved symptom burden and sarcopenia in patients with SSc involving the gastro-intestinal tract.
      Guillen-Del Castillo et al., 2013 [
      • Guillen-Del Castillo A.
      Coeliac disease in scleroderma—clinical features, frequency and impact of screening in scleroderma.
      ]
      UKDietary intervention trial4 SScNANANAGluten-free dietGastrointestinal symptomsAfter gluten-free diet all SSc-CD patients had an improvement of small bowel symptoms.
      Luchetti et al., 2016 [
      • Luchetti M.M.
      • Festa A.
      • Schnitzler T.
      • Benfaremo D.
      • Bagnati R.
      • Rossini M.
      • et al.
      Gastrointestinal disease and microbial translocation in patients with systemic sclerosis: an observational study on the effect of nutritional intervention and implications for the role of the microbioma in the pathogenesis of the disease.
      ]
      ItalyCase-control38 SSc; 25 controlsNANA24 weeksMediterranean dietI-FABP, LPS, CD14, clinical symptomsMediterranean diet significantly improves the clinical symptoms and the gastro-intestinal damage (I-FABP), thus reducing microbial

      translocation (LPS) and immune system activation (CD14)
      BMI: Body Mass Index; CRP: C-reactive protein; ESR: erythrocyte sedimentation rates; I-FABP: intestinal-type fatty acid-binding protein; LPS: lipopolysaccharide.
      To date there are only two small RCTs testing the effect of different dietary patterns in the SSc management. The first one investigated the effect of a one-year individualized balanced diet intervention on 9 SSc patients at risk for malnutrition, finding no significant improvements in body weight, food intake, nutritional biochemical parameters, and quality of life of these patients [
      • Ortiz-Santamaria V.
      • Puig C.
      • Soldevillla C.
      • Barata A.
      • Cuquet J.
      • Recasens A.
      Nutritional support in patients with systemic sclerosis.
      ]. The second one investigated the effect of a 6-week medical nutrition therapy (MNT) intervention on 18 SSc subjects with gastrointestinal involvement and unintentional weight loss, reporting an improvement in the symptom burden and in the sarcopenia, defined as appendicular lean height (ALH) [
      • Doerfler B.
      • Allen T.S.
      • Southwood C.
      • Brenner D.
      • Hirano I.
      • Sheean P.
      Medical nutrition therapy for patients with advanced systemic sclerosis (MNT PASS): A pilot intervention study.
      ]. Finally, two abstracts (which have never been published as complete papers) showed an improvement in gastrointestinal symptoms in 4 subjects with SSc and coeliac disease by following a gluten-free diet and in 38 SSc subjects after a 6-month intervention with Mediterranean diet [
      • Guillen-Del Castillo A.
      Coeliac disease in scleroderma—clinical features, frequency and impact of screening in scleroderma.
      ,
      • Luchetti M.M.
      • Festa A.
      • Schnitzler T.
      • Benfaremo D.
      • Bagnati R.
      • Rossini M.
      • et al.
      Gastrointestinal disease and microbial translocation in patients with systemic sclerosis: an observational study on the effect of nutritional intervention and implications for the role of the microbioma in the pathogenesis of the disease.
      ].

      6. Conclusions

      Emerging data suggest that diet plays a crucial role in the treatment of RD, through management of inflammation, nutritional status, and oxidative stress. Considering that a specific diet can be a helpful support for patients suffering from RD, we have summarized and discussed all the available evidence on the effect of nutrients, foods, and dietary patterns on the most common RD, including rheumatoid arthritis, Sjogren's syndrome, systemic lupus erythematosus and systemic sclerosis.
      Although only few studies on single food or food components are available in the literature, dietary fats seem to have a pivotal role in the RD progression. Saturated fats showed a negative effect on disease progression – probably due to their pro-inflammatory effects – while omega-3 and MUFAs seem to have a positive effect in modulating the inflammatory process. The role of dietary fiber remains controversial with some evidence suggesting a positive effect on inflammation and disease severity and some others reporting a worsening of gastrointestinal symptoms – especially in some predisposed subjects with gastrointestinal dysfunction – due to the increase of fermentable substrates. Regarding the dietary interventions, low-calorie diets, Mediterranean diet and fasting appear to be effective in reducing the symptomatology of the most common RD. Indeed, most of the included studies showed a significant improvement in chronic pain, inflammation, and gastrointestinal symptoms. Furthermore, weight loss in most of the included RD (except for SSc, in which patients are at high risk for malnutrition) seems to be associated with both reduced inflammation and improved quality of life, thus suggesting that body weight could have a functional repercussion in these patients. Positive results were also obtained in some cases with gluten-free diets, low-fat diets, vegan, elimination or anti-inflammatory diets. As reported in our previous study [
      • Pagliai G.
      • Giangrandi I.
      • Dinu M.
      • Sofi F.
      • Colombini B.
      Nutritional interventions in the management of fibromyalgia syndrome.
      ], all these diets are generally regarded as healthy dietary models, rich in plant foods and antioxidants and poor in animal products and saturated fats, so the fact that people reported an improvement in clinical outcomes after almost all these dietary patterns, suggests that a healthy diet could play a pivotal role in the RD management.
      However, it is important to note that most of the investigated diets were hypocaloric diets, so we cannot exclude that the beneficial effects could be exclusively due to the weight loss, that is directly linked to a reduced inflammatory state. In addition, in many cases, elimination diets have led to positive results because subjects with some food intolerances were considered. In these patients, we expect an improvement, but this doesn't mean that these benefits are valid and extendable to the entire population with no food intolerances. Furthermore, these results should be interpreted with caution since the available studies have several biases that limit the robustness of the findings. First, the limited sample size with no possibility of blinding could affect the results. Secondly, outcomes are often analysed without considering possible confounding factors such as drugs' treatments. In addition, different methods to collect dietary data are frequently used, with most of them reporting several bias i.e. recall bias. Finally, a follow-up is almost never carried out to determine whether the positive effects are maintained over time or are only transient.
      In conclusion, although nutritional therapy could be a promising way to approach RD, further research should be conducted to understand the specific mechanisms that interconnect the regulation of immunity, inflammation, oxidative stress, and nutrition in order to reduce clinical symptoms and ameliorate the quality of life of the patients with autoimmune RD.

      Author Contributions

      G.P., B.C. and S.B.R. wrote the article. A.A., S.G. and F.S. participated in the critical revision and final approval. All authors have read and agreed to the published version of the manuscript.

      Funding and sponsorship

      This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

      Conflicts of interest

      The authors declare no conflict of interest.

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