Dietary Intervention in Connective Tissue Diseases: Comparison
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Please note this is a comparison between Version 3 by Vicky Zhou and Version 2 by Francesca Oliviero.

Dietary intervention and nutritional counseling might have an important role as adjuvant therapy in patients with connective tissue diseases, particularly in the light of the comorbidities which characterize these conditions. 

  • dietary intervention
  • autoimmunity
  • inflammation
  • connective tissue diseases
  • systemic lupus erythematosus
  • idiopathic inflammatory myopathies
  • vasculitis
  • Sjögren’s syndrome
  • systemic sclerosis

1. Introduction

Nutritional status and dietary intake have long been recognized to affect health and disease. Increasing evidence shows how nutrient and non-nutrient (i.e., bioactive) compounds, which are being more frequently used according to a dietary lifestyle, are capable to modify disease risk factors, genetic and epigenetic pathways, inflammatory mediators and, therefore, clinical outcomes.
With respect to rheumatic diseases, much work has been conducted in an attempt understand the pathogenic molecular mechanisms that can be affected by specific dietary substances. However, despite the encouraging experimental results, clinical studies evaluating their effect on disease activity or progression are still limited and mostly regard rheumatoid arthritis.

2. Evidence from Randomized Clinical Trials

2.1. Systemic Lupus Erythematosus

2.1.1. Omega-3 Polyunsaturated Fatty Acids

Omega (n)-3 polyunsaturated fatty acids are among the most studied of dietary interventions in SLE. The first RCTs conducted on these nutrients date back to the 1990s, when the beneficial clinical immunological and biochemical effect of fish oil was demonstrated in several animal disease models [1,2][1][2]. The epidemiological observation of a very low incidence of autoimmune and inflammatory disorders in Eskimo populations compared with matched European individuals, in addition to the association between higher intakes of the n-3 fatty acids (eicosapentaenoic acid, EPA, and docosahexaenoic acid, DHA) and lower risk of developing cardiovascular disease, pushed the research in this direction [3]. Since then, an impressive number of experimental and clinical studies have been conducted [4].
The first two RCTs have been performed in patients with active SLE over a period of six months [5,6][5][6]. In both studies, n-3 fatty acids were administered through MaxEPA capsules at 0.2 g/kg/die [5] or 20 g/die [6] according to a crossover design. While the first study showed a limited and short-lived clinical benefit, the second showed a significant benefit on patients’ clinical state. Interestingly, an increase in red blood cell EPA concentration was observed in patients receiving MaxEPA [6].
Another crossover trial conducted in patients with SLE and nephritis [7] aimed at investigating the effect of EPA and DHA in renal function. No significant changes in clinical scores and renal function measures were observed in this study, including for proteinuria, glomerular filtration rate, urinary IgG, and serum creatine. However, supplementation with fish oil caused a reduction in values for a few lipid parameters, such as triglycerides and VLDL levels. Despite the crossover design, a small sample size and the lack of validated measures of disease activity characterized and represent limitations of the mentioned studies. Furthermore, the choice of olive oil as a control has been supposed to represent a potential source of error due to its possible underestimated active effect [7].
      Flaxseeds have been used in patients with documented hematuria and proteinuria to evaluate the effect of alpha-linolenic acid, the precursor of n-3 fatty acids, in renal function [8][7]. A two-year crossover non-placebo-controlled trial demonstrated that 30 g of flaxseeds administered daily induced a renoprotective effect in lupus but were difficult to tolerate in the long term, leading to poor adherence to the intervention and thus affecting the results of the study. A larger cohort of patients has been included in another study evaluating the effect of 3 g/die of MaxEPA and 3 mg copper in patients with active disease [9][8]. This six-month trial that had a double placebo design showed a significant reduction in disease activity assessed by the SLAM-R (Systemic Lupus Activity Measure, revised) scoring system but no significant therapeutic benefit from copper supplementation. Contrary to the previous studies, this trial used a validated index for determining lupus activity considering different clinical and laboratory domains and is the first showing a potential beneficial role of n-3 fatty acids in SLE [9][8]. With the introduction of validated disease activity scores, other interventional trials on n-3 supplementation have been concluded. The benefit on disease activity has been confirmed in a placebo-controlled RCT conducted in 60 patients [10][9]. After a period of six months of fish oil administration, the patients showed a significant reduction in SLAM-R and BILAG indices and, importantly, an improvement in endothelial function as measured by vascular indices including flow-mediated dilation of the brachial artery and diastolic shear stress. Using different concentrations of n-3 EPA and DHA, other authors did not find any significant benefit on disease activity and fatigue in a population of 50 patients with SLE [11][10]. However, they developed an improved version of the physician global disease assessment. Regarding inflammatory circulating markers, the supplementation with n-3 fatty acids showed no impact on serum concentrations of the cytokines IL-6 and IL-10, and adipokines leptin and adiponectin [12][11], whereas it exhibited a small effect on IL-13 [11][10].

2.2. Idiopathic Inflammatory Myopathies

Contrary to SLE, only a few RCT studies have examined the role of dietary intervention on the outcome of other connective tissue diseases. Indeed, idiopathic inflammatory myopathies (IIM), which are characterized, among other features, by systemic and muscle inflammation with an increase in cytokine levels, might benefit from an anti-inflammatory diet or supplementation. Some clinical studies demonstrated, for instance, that vitamin E reduces levels of cell damage markers and the concentration of exercise-induced cytokines in hypoxia, suggesting a possible protective effect against hypoxia-induced inflammation [30][12]. Polyphenols were demonstrated to protect muscle inflammation and atrophy in a mouse model of chronic inflammation [31][13], while n-3 fatty acids were shown to prevent lipotoxicity and inflammation through the regulation of muscle lipid and glucose metabolism [32][14]. An association between dermatomyositis (DM) and celiac disease was documented in children [33][15] and adults [34][16], where a strict gluten-free diet can lead to disease resolution [34][16]. With respect to dietary interventional trials, three RCTs have been carried out in idiopathic inflammatory myopathies. The first is the largest as it involved patients with both polymyositis (PM) and dermatomyositis (DM) that were assigned to receive a loading followed by a maintenance dose of creatine in combination with home exercise [35][17]. Compared to the placebo group (exercise alone), patients has improved muscle performance assessed as by a composite measure and endurance work after six months of treatment. The choice of creatine in IIM found its rationale in the reduced levels of intramuscular phosphocreatine in patients with IIM and increased creatine excretion, which was shown to be correlated with global disease damage in juvenile DM [36][18].

2.3. Vasculitis

Only a proof-of-concept clinical study has addressed the possible influence of diet in vasculitis and concerns Behçet’s disease. In this disease, the depletion of some strains of microorganisms in the gut microbiota is observed. Therefore, the decreased production of anti-inflammatory short-chain fatty acids (SCFA) was demonstrated [39][19]. These metabolites, including butyrate, acetate, and propionate, have been shown to possess positive immune-modulating activity by modifying the cytokine production profile of T helper cells, promoting intestinal epithelial barrier integrity, resolving intestinal inflammation, and regulating the acetylation of lysine residues, a covalent modification that affects proteins involved in a variety of signaling and metabolic processes [40][20].
The effects of two butyrate-rich diets on blood redox status, fibrin degradation, and clinical modifications were assessed in patients with Behçet disease. After an intervention period of three months, both diets lead to a significant reduction in leukocyte ROS production and plasma lipid peroxidation and an increase in plasma total antioxidant capacity. Although disease activity significantly improved, the results were not associated with modified SCFA production, which presumably occurs after longer periods of nutritional intervention [41,42][21][22].

2.4. Sjögren’s Syndrome

As a complex autoimmune condition with a wide range of disruptive symptoms, SS might benefit from a diet rich in immunomodulatory substances, including polyunsaturated fatty acids and bioactive compounds. An association between adherence to the Mediterranean diet and a lower likelihood of having primary SS has been observed [43][23]. In support of the role of nutrition in SS, it has been shown that a lifelong gluten-free diet reduced the infiltration of monocytes/macrophages and T cells in salivary glands in diabetic mice developing sialadenitis [44][24]. Although still partial, this evidence sustains the multifaceted relation between immunopathological features of different autoimmune diseases and the capacity of specific dietary compounds in modulating disease onset as well as expression in SS.
Randomized clinical trials are still scarce in SS. The deficiency of vitamin B6 in patients with SS and its association with altered T helper cells and IL-2 production has prompted some researchers to investigate the role of pyridoxine in IL-2 release from cultured T lymphocytes collected from SS and healthy subjects randomized to receive the vitamin or the placebo. Although no effect was evidenced at the end of the three-month study, the authors did not exclude the influence of pyridoxine at a different molecular level [45][25].

2.5. Systemic Sclerosis (SSc)

Very few studies have been conducted on the effect of dietary supplementation in SSc. Most of these were performed on the comorbidities related to this autoimmune condition. Gastrointestinal symptoms are a frequent comorbidity in SSc and represent one of the most important risk factors for malnutrition in the disease. It was shown that the combined assessment of nutritional parameters, including pre-albumin and disease activity, improves the evaluation of mortality risk in SSc [47][26]. Consequently, nutritional assessment and, more importantly, dietary intervention should be pursued in these patients. Recently, SSc was found to be associated with altered intestinal microbiota, but the relationship between dysbiosis and the pathogenesis and features of the disease are not completely clear [48][27]. Starting from the above observations, probiotics have been tested for their known modulatory action on microbiota and immune system in patients with SSc and gastrointestinal involvement. An 8-week RCT showed that probiotic supplementation did not have any effect in reducing gastrointestinal symptoms but led to a decrease in Th17 cell levels, indicating an immunomodulatory capacity of the probiotic strains used in the study [49][28]. Significant findings have been evidenced in another trial, where the efficacy of probiotics in systemic sclerosis-associated gastrointestinal disease was positively evaluated regarding gastrointestinal reflux. The SSc clinical outcomes were not, however, evaluated in that study [50][29].

3. Conclusions

Connective tissue diseases encompass different complex disorders with an autoimmune background and a broad variety of clinical manifestations. Besides the involvement of connective tissue, these diseases share features, such as fatigue, and comorbidities mainly affecting the cardiovascular system.
Although anti-inflammatory dietary habits have long been recognized to influence these comorbidities, it is not clear how much diet or dietary supplementation might affect the clinical course of patients with connective tissue diseases.
As outlined in this review, most of the RCTs were conducted in SLE and often show varying results. Certainly, some benefit on disease activity indices were obtained using n-3 fatty acids and VitD, even if the different dosages and intervention period make it difficult to compare the various studies [9,10,11][8][9][10].
Fatigue, which is a common feature in connective tissue disorders, seems to be affected by healthy nutritional intervention and VitD [14,20][30][31]. Creatine supplementation showed some benefit on muscle performance and metabolism in IIM [35,38][17][32] while interesting results for Behçet disease were achieved with a butyrate-enriched diet [42][22].
Promising data regarding both renal function and disease activity in SLE were obtained for the use of polyphenols. Although the evidence is still limited, the wide range of favorable effects of these compounds already been demonstrated in many chronic diseases support their use as adjuvant therapy in SLE patients.
Finally, although most dietary supplements do not require a medical prescription and supervision, it is always recommended that a doctor be consulted for specific nutritional indications and contraindications.
The results from RCTs conducted on connective tissue diseases are still too limited to draw firm conclusions on the clinical benefit of dietary intervention under these conditions. Notwithstanding, the results are encouraging and deserve to be explored upon in depth and with larger cohorts of patients.

References

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