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Article

Mediterranean Diet and Physical Activity Nudges versus Usual Care in Women with Rheumatoid Arthritis: Results from the MADEIRA Randomized Controlled Trial

by
Panos Papandreou
1,
Aristea Gioxari
2,†,
Efstratia Daskalou
3,†,
Maria G. Grammatikopoulou
4,
Maria Skouroliakou
5 and
Dimitrios P. Bogdanos
4,*
1
Department of Nutrition, IASO Hospital, 37 Chomatianou Str., Marousi, GR-15123 Athens, Greece
2
Department of Nutritional Science and Dietetics, School of Health Sciences, University of the Peloponnese, GR-24100 Kalamata, Greece
3
Department of Nutrition, General Hospital of Thessaloniki “G. Gennimatas”, 41 Ethnikis Aminis Str., GR-54635 Thessaloniki, Greece
4
Unit of Immunonutrition and Clinical Nutrition, Department of Rheumatology and Clinical Immunology, Faculty of Medicine, School of Health Sciences, University of Thessaly, Biopolis, GR-41110 Larissa, Greece
5
Department of Dietetics and Nutritional Science, School of Health Science and Education, Harokopio University, 70 Eleftheriou Venizelou Ave., GR-17676 Athens, Greece
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Nutrients 2023, 15(3), 676; https://doi.org/10.3390/nu15030676
Submission received: 30 December 2022 / Revised: 22 January 2023 / Accepted: 27 January 2023 / Published: 28 January 2023
(This article belongs to the Special Issue The Effect of Nutrition in Healthy and Unhealthy Immune System)
Browse Figure
Versions Notes

Abstract

:
In rheumatoid arthritis (RA), diet quality and nutritional status have been shown to impact the disease activity and adherence to the Mediterranean diet (MD) has been suggested as an anti-inflammatory regime to improve disease status and reduce cardiovascular risk. The Mediterranean DiEt In Rheumatoid Arthritis (MADEIRA) was a single-blind (statistician), two-arm randomized clinical trial, investigating the effects of a 12-week lifestyle intervention, including a personalized isocaloric MD plan with the promotion of physical activity (PA), supported through a clinical decision support systems (CDSS) platform, versus usual care in women with RA. Forty adult women with RA on remission were randomly allocated (1:1 ratio) to either the intervention or the control arm. The intervention group received personalized MD plans and lifestyle consultation on improving PA levels, whereas the controls were given generic dietary and PA advice, based on the National Dietary Guidelines. The primary outcome was that the difference in the MD adherence and secondary outcomes included change in disease activity (DAS28), anthropometric indices (BodPod), dietary intake, PA, vitamin D concentrations, and blood lipid profiles after 12 weeks from the initiation of the trial. At 3 months post-baseline, participants in the MD arm exhibited greater adherence to the MD compared with the controls (p < 0.001), lower DAS28 (p < 0.001), favorable improvements in dietary intake (p = 0.001), PA (p = 0.002), body weight and body composition (p < 0.001), blood glucose (p = 0.005), and serum 1,25(OH)2D concentrations (p < 0.001). The delivery of the MD and PA promotion through CDSS nudges in women with RA in an intensive manner improves the MD adherence and is associated with beneficial results regarding disease activity and cardiometabolic-related outcomes, compared with the usual care.

1. Introduction

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, inducing a systematic inflammatory state of the joints, gradually leading to bone resorption and cartilage erosion and the destruction of the affected joints [1,2]. Major symptoms include swelling of the joints, stiffness and pain, which negatively affect patients’ quality of life (QoL) [3]. Recent estimates of the prevalence of RA suggest a 1–2% global prevalence, with approximately two to three times more women being affected compared to the men [4,5]. In general, female patients tend to demonstrate worse outcomes than males. The treatment of RA aims in improving symptomatology, and reducing complications and lowering disease activity, allowing for the induction and sustainment of disease remission [3,6].
A plethora of genetic and environmental factors have been implicated in the pathogenesis of RA, with diet quality playing a significant role in the development of the entity, its pathophysiology, the manifestation of symptoms, and the management of RA [7,8,9]. Various dietary patterns, including the Mediterranean diet (MD), and individual nutrients including certain types of fatty acids and vitamin D, have been investigated for their potential associations with the development and prognosis of RA [10,11,12,13,14]. Dietary factors may interfere with several inflammatory pathways, influencing key pathophysiology features in RA [15]. For instance, a high-fat Western-type diet based on animal origin foods, which induces excess body weight and body fat, has been positively associated with the early onset of RA and a burdensome disease state [16,17]. A putative mechanism is the potential crosstalk between chronic obesity and RA inflammation, resulting in the upregulation of pro-inflammatory mediators, such as the tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and C-reactive protein (CRP) [18]. Furthermore, Western-type diets decrease the odds of achieving and sustaining disease remission, inducing greater disease activity scores [19].
The MD is a predominantly plant-based diet that includes a variety of fruits, vegetables, whole grains, seeds, legumes, olive oils, and fish, characterized by a moderate intake of dairy products and a low consumption of animal fats [20]. Adherence to the MD and its individual components entails a variety of anti-inflammatory effects, alleviating RA symptomatology [10,11,21,22,23]. In parallel, the MD has been shown to exert protective and beneficial effects against obesity and cardiovascular (CV) and metabolic disorders [24,25,26].
The risk for the development of cardiovascular diseases (CVD) is markedly increased in RA as a result of the chronic inflammation in various body systems, including the heart and the vascular system [27,28]. In particular, the risk of developing heart failure is double in RA compared with the unaffected population, with patients demonstrating a preserved ejection fraction >50%, without necessarily any clinical evidence of coronary artery disease (CAD) [28]. For this, the European League Against Rheumatism (EULAR) recommends the multiplication of traditional cumulative CV risk scores in RA by ×1.5 in order to reflect the increased CVD risk associated with RA. In RA, accumulative CV risk factors are associated with poorer outcomes [29] and reduced survival [30]. Recently, the EULAR recommended lifestyle modifications, including adherence to MD, regular exercise and smoking cessation, as protective measures against the development and progression of CVD [31].
With both RA and CVD being predominantly a “female challenge” [4,5], the need to address the efficacy of lifestyle modifications, including the MD in women with RA, becomes urgent. In this manner, the present randomized controlled trial (RCT) aimed to evaluate the effect of a personalized MD plan delivered through a clinical decisions support system (CDSS) platform versus usual care, in women with an RA diagnosis.

2. Materials and Methods

2.1. Study Design and Protocol

The Mediterranean DiEt In Rheumatoid Arthritis (MADEIRA) was a single-blind (statistician), two-arm randomized controlled trial, investigating the effects of a 12-week personalized lifestyle intervention including MD and PA promotion, versus usual care in women with RA. The study’s protocol was registered at the Center for Open Science Framework (OSF, https://www.shorturl.at/krW24, accessed on 22 January 2023). The reporting of the study follows the consolidated standards of reporting trials (CONSORT) statement [32].

2.2. Ethical Clearance

The Ethics Committee of Iaso Hospital (Athens, Greece) reviewed and approved the protocol of the study (Approval Code #d310519). All principles of the Helsinki Declaration and its later amendments were adhered to, and the terms of Good Clinical Practice were applied. Informed consent was obtained from all subjects involved in the study.

2.3. Participants

Adult women with a definite RA diagnosis based on the American College of Rheumatology (ACR)/EULAR 2010 classification criteria [33] were recruited from the outpatient clinic of Iaso Hospital (Athens, Greece) during 2021–2. Information on the study aim, protocol, and methodology were provided to all patients through a detailed leaflet before recruitment. Patients were advised to read the leaflet in detail and sign the informed consent in two copies, keeping one. The study took place from November 2021 until April 2022, at Iaso Hospital, in Athens. The inclusion and exclusion criteria for participation in the study are detailed in Table 1.

2.4. Randomization Procedure

Patients were randomly allocated to the intervention or the control arm, on blocks of 1, using an online random allocation software (https://stattrek.com/, accessed on 28 January 2023). Investigators and patients were aware of the allocation. An independent researcher was responsible for the randomization. The statistician was blinded to the allocation (single blind).

2.5. Procedures and Tools

2.5.1. Medical History and RA Specificities

A detailed medical history that included general information and disease-specific data (disease activity, symptoms, complications, treatment) was obtained by the attending rheumatologist specialist.
All women underwent clinical evaluation of RA through an objective physical articular examination, which was also used to calculate the Disease Activity Score of 28 joints (DAS28) [34] by the rheumatologist. The DAS28 combines data regarding the number of swollen and tender joints (based on 28 joints in total), perceived general health, and the acute phase response to the disease [34]. The score ranges between 0 to 9.4, with values exceeding 5.1 being indicative of an active disease and scores < 3.2 pointing to an inactive, well-controlled disease status [34].

2.5.2. Dietary Intake and MD Adherence

A semi-quantitative Food Frequency Questionnaire (FFQ), previously validated in Greek patients with CVD, was employed for the assessment of the usual dietary intake of participants [35]. Portion sizes estimations were facilitated with the demonstration of food replicas and real-size food photos.
The Diet Analysis Plus (version 6.1, Wadsworth 2003) software was used to analyze individual FFQs and previous day 24 h diet recalls (treatment adherence). The daily dietary intake of saturated fatty acids (SFA), monounsaturated fatty acids (MUFA), total fat, dietary fiber, and vitamin D were calculated for each participant.
Adherence to the MD was assessed using the Mediterranean Diet Score (MedDietScore) [36]. The score is based on the reported frequency of consumption of 11 food groups, which are either representative, or not, of the MD pattern [36]. The total score is calculated by summing the scores of each individual food group and ranges between 0–55 in a linear manner, with greater scores being indicative of increased adherence to the MD and a lower risk for the development of CVD [36].

2.5.3. Physical Activity (PA) Levels

The Greek version of the International Physical Activity Questionnaire (IPAQ) [37,38] for young and middle-aged adults was completed by all participants. The IPAQ measures health-related physical activity (PA) [38]. The IPAQ consists of 5 domains, each recording distinct activities, including (i) work-related PA; (ii) transportation PA; (iii) housework, house maintenance and caring for the family PA; (iv) recreation, sport and leisure PA; and (v) time spent sitting. The PA levels of each participant were expressed as metabolic equivalents of task (METs), in min per week.

2.5.4. Anthropometric Indices

Body weight (BW) was measured in kg, to the nearest g, using the Air Displacement Plethysmography method (Bodpod® Body Composition Tracking Systems, Life Measurement, Inc., Rome, Italy). Fat mass (FM) and fat-free mass (FFM) of participants were also estimated using the same device. For the Bodpod tests, participants did not perform any exercise or consume any foods and drinks for at least 2 h prior to the assessment, and were dressed in their underwear only [39], according to manufacturer guidelines.
Height was measured with a calibrated stadiometer to the nearest 0.1 cm (Seca 217, Seca, Hamburg, Germany).
Body mass index (BMI) of each participant was calculated as the ratio of BW (kg) to the square of height (m2). The BMI cutoffs for the classification of underweight (< 18.5 kg/m2), overweight (25 kg/m2 ≤ BMI < 30 kg/m2), and obesity (BMI ≥ 30 kg/m2) suggested by the World Health Organization (WHO) were applied [40] for the assessment of the BW status of participants.

2.5.5. Blood Samples: Collection and Assays

Each patient provided morning whole blood samples (20 mL) for the isolation of the serum and plasma after an overnight fast. Ethylenediamine tetra-acetic acid (EDTA) was used for the plasma isolation. For the isolation of serum, whole blood was previously allowed to clot at room temperature for 20 min. Whole blood samples were centrifuged at 3000 rpm for 10 min at 4 °C. For all assays, freshly drawn blood samples were used.
Serum glucose (Glu), total cholesterol (TC), high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides (TG), and CRP were quantified with an automatic biochemical analyser using manufacturer’s reagents (Cobas 8000 modular analyser, Roche Diagnostics GmbH, Mannheim, Germany).
An automated chemiluminescence system (Cobase 801 analytical module, Roche Diagnostics GmbH, Mannheim, Germany) was used to determine the concentrations of 1,25-dihydroxyvitamin D [1,25(OH)2D] in the serum of the participants, using manufacturer’s reagents.

2.6. Intervention and Comparator

2.6.1. Intervention

In the intervention arm, isocaloric personalized dietary plans according to the principles of the MD, patients’ energy expenditure requirements (EER), and food preferences were provided to the participants. In parallel, advice was also provided on increasing the PA levels according to the EULAR recommendations [31].
A CDSS platform was used for the delivery of the patient education, as previously detailed [41,42]. The specific CDSS was developed during 2016 and has been used in clinical practice as a complementary tool for the hospital’s dieticians and as a patient nudge tool [41,43]. CDSS platforms are employed to improve the delivery of healthcare interventions by facilitating medical decisions through the provision of targeted knowledge and health information [44]. Personalized login usernames and passwords were administered to all participating patients in the intervention arm, in order to have access to their personal CDSS database account, by which they could track their progress regarding BW, healthy eating, and PA levels.
The intervention lasted for a total of 12 weeks. During this time, two experienced registered dietitians (RDNs) communicated with participants on a biweekly basis through telephone calls to catch up, resolve possible queries, and provide support (A.G. and E.D.)

2.6.2. Comparator (Control Arm)

Participants in the control arm did not receive a personalized MD plan, nor did they have access to the CDSS platform. In contrast, they were given generic dietary advice and PA recommendations that were in line with the Greek National Dietary Guidelines for adults [45].

2.6.3. Treatment Adherence

According to the RDN’s instructions, all patients kept self-filled weekly food diaries that were evaluated remotely through CDSS (intervention group) or emails (control group). Unexpected phone calls were also made to participants to obtain 24 h diet recalls.

2.6.4. Study Timepoints

All measurements were performed at the baseline and at the end of the intervention period, at 12 weeks.

2.7. Primary and Secondary Outcomes

The primary outcome of the study was the difference (Δ) in the degree of adherence to the MD, assessed through the MedDietScore.
Secondary outcomes included differences (Δ) in disease activity (DAS28), dietary intake (SFA, MUFA, total fat, dietary fiber), as well as CV risk factors and inflammatory markers (BMI, FM, FFM, TC, HDL, LDL, TG, CRP levels), total PA levels, and 1,25(OH)2D concentrations.

2.8. Sample Size Calculation

A minimum sample size of 34 patients (17 per group) was deemed sufficient to result in a clinically important difference of 3.0 in the MedDietScore [standard deviation of mean (SD) = 3] using a two-tailed t-test with 80% power and a 5% level of significance (α).

2.9. Statistical Analyses

The Kolmogorov–Smirnov test was used to assess the normality of the distribution. Descriptive statistics were calculated for all parameters. Continuous data were expressed as mean ± standard deviation (SD), and dichotomous variables as counts (n) and proportions (%).
Differences between the two arms were assessed using Student’s t-test for normally distributed variables or the Mann–Whitney U test for those not normally distributed. For investigating possible intra-group differences, a paired samples t-test or the Wilcoxon test was applied. Correlations between the MedDietScore and dietary, anthropometric, and biochemical parameters were assessed using either the Pearson’s or the Spearman correlation coefficients for normally distributed and not normally distributed variables, respectively. All correlations were assessed at the end of treatment.
Statistical significance was set at p-value < 0.05. All analyses were performed with the Statistical Package for the Social Sciences (SPSS) (version 21.0, SPSS, Inc, ΙΒΜ, Chicago, IL, USA) and the Jamovi project (version 1.2.27.0) [46].

3. Results

3.1. Participants

The study sample comprised 40 women with RA meeting the inclusion criteria. All participants completed the trial and were incorporated in the final analyses, without any dropouts or patients lost-to-follow-up being recorded. The CONSORT diagram [32] of the study’s procedure is presented in Figure 1. All women inhabited the Attica region in Greece, were non-smokers, and reported consuming alcohol rarely or abstaining from alcohol.
Table 2 details the characteristics of the participants at the baseline. No differences were observed between the intervention and the control arm at the baseline regarding the participant age, anthropometric indices, body composition, dietary intake, blood markers, disease activity score, PA METs, and MedDietScore.

3.2. Mediterranean Diet Adherence and Dietary Intake

Table 3 presents the characteristics of the participants in each arm and pre-post intervention comparisons. Post-intervention, a significant increment was observed in the MD adherence among the participants in the intervention arm (p < 0.001), with a mean statistically significant increase of 3.75 units, while no change was observed among participants allocated to the control arm.

3.3. Disease Activity

DAS28 was significantly reduced at 3 months compared to the baseline among patients who received the intensive lifestyle intervention (p < 0.001). DAS28 correlated positively with the BMI (r = 0.330, p = 0.038) and dietary fat intake (r = 0.476, p = 0.002), and negatively with the MedDietScore (r = −0.452, p = 0.003).

3.4. Anthropometrics and PA Levels

At 12 weeks post-baseline, patients allocated in the intervention group exhibited a greater reduction in BW, BMI, and FM (p < 0.001) compared with the controls. PA levels were also improved in the intervention arm compared to the controls after 3 months (p = 0.002).

3.5. Dietary Intake

The post-intervention dietary intake of total fat, dietary cholesterol, and SFA were significantly lower in the intervention arm compared with the controls, while the consumption of MUFA and fiber were higher in the first compared with the latter (p ≤ 0.001). The MedDietScore correlated positively with the MUFA (r = 0.315, p = 0.047) and fiber intake (r = 0.477, p = 0.02), and negatively with the consumption of total fat (r = −0471, p = 0.002) and dietary cholesterol (r = −0.707, p = 0.001).

3.6. Blood Glucose, Serum Lipids, CRP and Vitamin D Concentrations

Both study groups exhibited greater serum vitamin D concentrations at 3 months after the initiation of the trial (p = 0.001), but, within the intervention arm, the mean increment was greater compared with that observed in the controls (p < 0.001). Serum vitamin D levels were negatively related to BW (r = −0.533, p < 0.001), FM as a percentage of BW (r = −0.363, p = 0.021), BMI (r = −0.560, p < 0.001), and the dietary intake of SFA (r = −0.348, p = 0.028). Vitamin D levels also correlated positively with the intake of MUFA (r = 0.436, p = 0.005) and dietary fiber (r = 0.510, p = 0.001).
No differences were noted with regard to the CRP and blood lipids levels between the intervention and comparator arms. On the other hand, blood glucose concentrations were improved among participants receiving the lifestyle intervention (p = 0.005).
Serum TG concentrations correlated negatively with the MedDietScore (r = −0.326, p = 0.004).

4. Discussion

The present study showed that a 12-week personalized MD plan, paired with PA promotion and delivered with the support of CDSS was successful in improving adherence to the MD, disease activity, PA levels, and a plethora of cardiometabolic outcomes among female patients with RA.
Adherence to the MD can be a useful tool to combat immune-mediated inflammatory diseases, including RA [23]. Results from other countries have shown a suboptimal adherence to the MD among patients with an RA diagnosis [47], with most patients adopting diets of poor quality in general, failing to meet the daily requirements for many nutrients [48,49,50,51]. A recent observational study conducted in Greece, suggested that female patients with RA demonstrated low-to-moderate adherence to the MD, with a mean MedDietScore equal to 29.55 [22]. In agreement with this, participants herein exhibited a mean baseline MedDietScore of 38.25, indicative of a moderate MD adherence and the adoption of a diet of mediocre quality. Among patients allocated to the intervention arm, adherence to the MD was further improved after 12 weeks of the intervention. In parallel, previous research has shown that adherence to the MD is associated with improved health perception regarding RA and general health [52]. Previous studies on the MD pattern have also shown improvements in the subjective measures of RA disease activity [28,29,30].
RCTs delivering traditional Cretan MD or other anti-inflammatory dietary interventions in patients with RA have revealed improvements regarding disease activity [53,54,55], whereas others suggested differences in the level of MD adherence between patients with low and high disease activity [22], suggesting that diet quality and composition might affect RA status. In the current trial, improvement in MD adherence was associated with ameliorated disease status, as evidenced by lower disease activity (DAS28 was negatively associated with MD adherence). This might have been the result of ameliorated dietary intake, with the observed improvements in the consumption of MUFA and fiber and the reduction in SFA intake being possible precipitating factors. The anti-inflammatory effects of MUFA in RA have been well-discussed in the context of the MD. In the TOMMOROW cohort [56], the dietary intake of MUFA was lower among patients with RA compared with healthy controls, while the ratio of the MUFA/SFA intake was positively associated with RA remission. The MD is considered as the ultimate anti-inflammatory dietary pattern, as it focuses on eating whole, plant-based foods that are rich in fiber and phytonutrients, while maintaining a stable glycemic response [57]. Dietary fiber is not digested in the small intestine, but upon fermentation by the colonic microflora, several microbial metabolites are produced that possess health-promoting effects. For instance, short chain fatty acids have been associated with improvements regarding microbial dysbiosis and the regulation of inflammatory biomarkers, such as plasma CRP, TNF-α, and IL-6, which are potent triggers of the RA disease activity [58]. There is evidence that a low-fiber dietary pattern may be linked to increased RA disease activity. For example, Elahi and associates showed that patients with RA on a low-fiber diet exhibited greater disease activity compared with those adhering to diets of higher-fiber contents [59].
In the present study, disease activity was also associated with BMI. The overall combined prevalence of overweight and obesity in the sample was high, namely 35% and 10%, respectively, and this observation is in accordance with previous studies indicating that excessive body weight is an important comorbidity in RA [22]. Patients with RA and comorbid obesity have been shown to exhibit greater DAS28 compared with the normoweight or overweight patients [60]. In RA, overweight and obesity consist of common results of long-term corticosteroid use and physical inactivity [61]. According to Padel, however [62], despite the seemingly worse disease activity, when imaging techniques are applied, patients with RA and obesity appear to have less inflammation and reduced rates of radiographic progression through time. A better diet quality in terms of adopting the MD pattern could be the possible route not only for managing RA symptoms, but also for maintaining a healthy BW and body composition [47]. Increased BW and body fat accumulation propels low-grade inflammation, thus, the adoption of the MD as an anti-inflammatory dietary pattern might induce a reduction in BW and tamper down inflammation. Herein, a 12-week MD intervention was effective at reducing BW, BMI, and FM among participants in the intervention arm compared with the controls.
RA, especially in the active disease state, is associated with considerable changes in blood lipids levels and insulin sensitivity, while metabolic changes, such as elevated TC, LDL, and TG concentrations, occur even in preclinical RA [63]. In the present study, TC, HDL, LDL, and TG remained unchanged in both study groups, but the TG levels were negatively associated with the MedDietScore, confirming the cardio-protective effects of the MD [24]. Additionally, the serum glucose levels were significantly lower among patients receiving personalized MD intervention compared with the controls, an observation that also implies the well-documented favorable effects of MD on glucoregulation [64].
There is evidence that the adoption of anti-inflammatory diets, including the MD, is negatively associated with inflammatory biomarkers in RA, such as CRP. In the randomized controlled study of Sköldstam and co-authors [53], patients with RA allocated to the MD arm exhibited significant reductions in CRP concentrations compared with the usual care group. Nevertheless, in the present study, CRP levels remained unchanged in both study arms, and this could be partially explained by the small sample size.
The role of vitamin D in immune-mediated inflammatory diseases, such as RA, has been extensively discussed in the literature. Vitamin D has been shown to exert immunomodulatory effects and downregulate pro-inflammatory agents [65]. Vitamin D deficiency is often observed in patients with RA [65,66], while hypovitaminosis is associated with the fastest disease progression, even in the early course of the disease [67]. A negative association between the serum vitamin D and RA disease activity has been reported, while vitamin D deficiency may be a potent contributor to CVD risk in RA [68]. In the present trial, 8 out of 40 patients with RA (20%) at the baseline had vitamin D insufficiency, with reference 1,25(OH)2D levels ranging between 20 to 68 ng/mL [69]. At the end of the trial, both study arms demonstrated a significant increase in the vitamin D serum levels, but the increment was sharper among participants in the intervention group than the control group at the end of the trial, with a mean concentration of 51.56 ng/mL vs. 40.36 ng/mL, respectively. The improvements noted in all study participants, irrespective of the treatment allocation, might be the result of the increased sunlight observed in the country during the summer months. Meta-analyses suggest that when vitamin D levels are improved (as in supplementation interventions), parallel improvements are also noted in the disease activity scores [66]. Thus, the ameliorated DAS28 observed at the end of the trial herein might well be the result of an overall improved vitamin D status.
Patients with RA tend to be inactive, in particular at the period following the diagnosis [70], with approximately 59% meeting the recommendations for PA [71]. In parallel, an RA diagnosis is reported as a persistent catalyst either for, or against, the performance of PA [72]. The use of nudges has been shown to increase PA levels and reduce sedentary behavior [73]. On the other hand, improvements in PA can also boost QoL and physical function [74], relieve pain, and increase aerobic capacity and CV fitness in RA [75,76]. In parallel, exercise is a known effector of circulating inflammatory markers [77] and an important contributor to cardiometabolic health [78]. In this manner, the improvements noted in the intervention arm herein might also be the result of greater PA among participants. In parallel, with improvements in PA and diet quality being parallel, it is also possible that they both consist of the result of nudging, or improved health-consciousness due to nudging.
Nudge policies aiming to modify health-related decisions, including dietary choices, are increasingly gaining popularity [79,80]. When nudge policies are delivered through CDSS platforms in particular, they can further improve the implementation of evidence [81]. According to a recent meta-analysis [82], a significant improvement in the proportion of patients receiving desired care is noted when CDSS are employed. Among patients with RA, previous studies have applied the CDSS for medication-related decisions [83] and for the incorporation of appropriate cultural contexts [84]. The present RCT consists of the first effort to use CDSS for improving lifestyle choices in RA.
Furthermore, the lifestyle intervention performed in the present RCT was carried out by experienced RDNs. Research has shown that when medical nutrition therapy (MNT) is applied by expert dietitians, patients tend to adhere to a greater degree and significant improvements are observed regarding their disease management [85,86,87,88]. In parallel, intensive lifestyle therapy, as performed herein, has also been shown to improve the health outcomes in comparison to standard care [85,89,90,91]. Furthermore, the use of CDSS for the delivery of interventions has been shown to improve clinical care [92]. Thus, it is possible that the additive effects of RDNs delivering the dietary intervention, the use of CDSS, and the more intensive meetings offered in the intervention arm may have corroborated for the observed improvements in the outcomes.
Patients with RA tend to underestimate the risk for developing CVD and are less concerned about the beneficial effects of protective lifestyle factors, such as the MD [93]. Therefore, personalized consultation sessions, as applied in the present trial, targeting improved MD adherence and higher levels of PA may have a beneficial impact not only with regard to the disease symptomatology, but also on the cardiometabolic and CV risk. There is evidence that increasing PA and/or exercise can simultaneously improve symptoms and reduce the impact of systemic RA manifestations [94]. A recent systematic review and meta-analysis revealed that the promotion of PA according to the public health recommendations improves CV fitness, muscle strength, and exercise behavior in patients with RA [76]. In the present trial, personalized lifestyle consultation sessions elevated the levels of PA of patients with RA at 12 weeks. Therefore, personalized nutrition and dietary guidance can promote diet quality and enhance disease management, serving as effective complementing treatment strategies for RA [95]. Such strategies can also enhance patient awareness on the value of lifestyle modification (healthy diet, regular exercise, smoking cessation, adequate sleep) on RA progression and remission. Based on the principles of the MD, Rondanelli and colleagues [96] have recently proposed a food pyramid adapted for patients with RA.
The small sample size and the possible bias that self-reported tools can cause comprise the limitations of the present study. For controlling these issues, a randomization protocol and validated questionnaires in Greek ample populations have been applied. In addition, the assigned RDNs were well experienced, and were able to detect unclear records and ask patients for proper clarifications.

5. Conclusions

In the present RCT, the delivery of a personalized diet plan based on the principles of the MD, paired with a lifestyle consultation for the promotion of PA for a total of 12 weeks, improved MD adherence in female patients with RA. Greater adherence to the MD was associated with an ameliorated dietary fat intake, BW, body composition, and lower disease activity state. Therefore, the adoption of the MD by patients with RA appears to be a feasible anti-inflammatory regime.

Author Contributions

Conceptualization, M.S. and D.P.B.; methodology, A.G., E.D. and M.G.G.; formal analysis, A.G. and E.D.; investigation, P.P., A.G. and E.D.; resources, M.S. and D.P.B.; data curation, A.G. and E.D.; writing—original draft preparation, P.P., A.G., E.D. and M.G.G.; writing—review and editing, M.S., D.P.B., P.P., A.G. and E.D.; visualization, E.D.; supervision, M.S. and D.P.B.; project administration, M.S. and D.P.B.; funding acquisition, M.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of Iaso Hospital (Approval Code #d310519).

Informed Consent Statement

Informed consent was obtained from all subjects involved in the study.

Data Availability Statement

All data are available upon request to the first author.

Acknowledgments

The research team would like to express their gratitude to all volunteers participating in the study.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Chauhan, K.; Jandu, J.S.; Goyal, A.; Al-Dhahir, M.A. Rheumatoid Arthritis; StatPearls Publishing: Tampa, FL, USA, 2022; ISBN 9781469889351. [Google Scholar]
  2. Fang, Q.; Zhou, C.; Nandakumar, K.S. Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis. Mediators Inflamm. 2020, 2020, 3830212. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Finckh, A.; Gilbert, B.; Hodkinson, B.; Bae, S.C.; Thomas, R.; Deane, K.D.; Alpizar-Rodriguez, D.; Lauper, K. Global epidemiology of rheumatoid arthritis. Nat. Rev. Rheumatol. 2022, 18, 591–602. [Google Scholar] [CrossRef] [PubMed]
  4. Kvien, T.K.; Uhlig, T.; Ødegård, S.; Heiberg, M.S. Epidemiological aspects of rheumatoid arthritis: The sex ratio. Ann. NY Acad. Sci. 2006, 1069, 212–222. [Google Scholar] [CrossRef]
  5. Gerosa, M.; De Angelis, V.; Riboldi, P.; Meroni, P.L. Rheumatoid arthritis: A female challenge. Womens Health 2008, 4, 195–201. [Google Scholar] [CrossRef] [Green Version]
  6. Bullock, J.; Rizvi, S.A.A.; Saleh, A.M.; Ahmed, S.S.; Do, D.P.; Ansari, R.A.; Ahmed, J. Rheumatoid Arthritis: A Brief Overview of the Treatment. Med. Princ. Pract. 2019, 27, 501. [Google Scholar] [CrossRef]
  7. Cutolo, M.; Nikiphorou, E. Nutrition and Diet in Rheumatoid Arthritis. Nutrients 2022, 14, 888. [Google Scholar] [CrossRef] [PubMed]
  8. Cassotta, M.; Forbes-Hernandez, T.Y.; Cianciosi, D.; Zabaleta, M.E.; Cano, S.S.; Dominguez, I.; Bullon, B.; Regolo, L.; Alvarez-Suarez, J.M.; Giampieri, F.; et al. Nutrition and Rheumatoid Arthritis in the ‘Omics’ Era. Nutrients 2021, 13, 763. [Google Scholar] [CrossRef]
  9. Alexandropoulou, I.; Grammatikopoulou, M.G.; Gkouskou, K.K.; Pritsa, A.A.; Vassilakou, T.; Rigopoulou, E.; Lindqvist, H.M.; Bogdanos, D.P. Ceramides in Autoimmune Rheumatic Diseases: Existing Evidence and Therapeutic Considerations for Diet as an Anticeramide Treatment. Nutrients 2023, 15, 229. [Google Scholar] [CrossRef]
  10. Gkiouras, K.; Grammatikopoulou, M.G.; Myrogiannis, I.; Papamitsou, T.; Rigopoulou, E.I.; Sakkas, L.I.; Bogdanos, D.P. Efficacy of n-3 fatty acid supplementation on rheumatoid arthritis’ disease activity indicators: A systematic review and meta-analysis of randomized placebo-controlled trials. Crit. Rev. Food Sci. Nutr. 2022, 1–15. [Google Scholar] [CrossRef]
  11. Gioxari, A.; Kaliora, A.C.; Marantidou, F.; Panagiotakos, D.P. Intake of ω-3 polyunsaturated fatty acids in patients with rheumatoid arthritis: A systematic review and meta-analysis. Nutrition 2018, 45, 114–124.e4. [Google Scholar] [CrossRef] [PubMed]
  12. 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? Nutrients 2020, 12, 1456. [Google Scholar] [CrossRef] [PubMed]
  13. Alwarith, J.; Kahleova, H.; Rembert, E.; Yonas, W.; Dort, S.; Calcagno, M.; Burgess, N.; Crosby, L.; Barnard, N.D. Nutrition Interventions in Rheumatoid Arthritis: The Potential Use of Plant-Based Diets. A Review. Front. Nutr. 2019, 6, 141. [Google Scholar] [CrossRef] [PubMed]
  14. Grammatikopoulou, M.G.; Marakis, G.; Gkiouras, K.; Athanatou, D.; Maraki, M.I.; Bogdanos, D.P. Fly me to the immune: Immunonutrition in rheumatic diseases. Mediterr. J. Rheumatol. 2023, 33. [Google Scholar]
  15. Romão, V.C.; Fonseca, J.E. Etiology and Risk Factors for Rheumatoid Arthritis: A State-of-the-Art Review. Front. Med. 2021, 8, 2383. [Google Scholar] [CrossRef] [PubMed]
  16. Mosalmanzadeh, N.; Jandari, S.; Soleimani, D.; Shadmand Foumani Moghadam, M.R.; Khorramrouz, F.; Araste, A.; Molavi, S.F.; Fakhlaie, R.; Jokar, M.; Rezvani, R. Major dietary patterns and food groups in relation to rheumatoid arthritis in newly diagnosed patients. Food Sci. Nutr. 2020, 8, 6477. [Google Scholar] [CrossRef] [PubMed]
  17. Nezamoleslami, S.; Ghiasvand, R.; Feizi, A.; Salesi, M.; Pourmasoumi, M. The relationship between dietary patterns and rheumatoid arthritis: A case-control study. Nutr. Metab. 2020, 17, 1–8. [Google Scholar] [CrossRef]
  18. Espinoza, G.; Maldonado, G.; Narvaez, J.; Guerrero, R.; Citera, G.; Rios, C. Beyond Rheumatoid Arthritis Evaluation: What are We Missing? Open Access Rheumatol. Res. Rev. 2021, 13, 45–55. [Google Scholar] [CrossRef]
  19. Badsha, H. Role of Diet in Influencing Rheumatoid Arthritis Disease Activity. Open Rheumatol. J. 2018, 12, 19–28. [Google Scholar] [CrossRef] [Green Version]
  20. Widmer, R.J.; Flammer, A.J.; Lerman, L.O.; Lerman, A. The Mediterranean diet, its components, and cardiovascular disease. Am. J. Med. 2015, 128, 229–238. [Google Scholar] [CrossRef] [Green Version]
  21. Forsyth, C.; Kouvari, M.; D’Cunha, N.M.; Georgousopoulou, E.N.; Panagiotakos, D.B.; Mellor, D.D.; Kellett, J.; Naumovski, N. The effects of the Mediterranean diet on rheumatoid arthritis prevention and treatment: A systematic review of human prospective studies. Rheumatol. Int. 2018, 38, 737–747. [Google Scholar] [CrossRef]
  22. Markaki, A.G.; Gkiouras, K.; Papakitsos, C.; Grammatikopoulou, M.G.; Papatsaraki, A.; Ioannou, R.; Tsagkari, A.; Papamitsou, T.; Bogdanos, D.P. Disease Activity, Functional Ability and Nutritional Status in Patients with Rheumatoid Arthritis: An Observational Study in Greece. Mediterr. J. Rheumatol. 2020, 31, 406. [Google Scholar] [CrossRef]
  23. Vranou, P.; Gkoutzourelas, A.; Athanatou, D.; Zafiriou, E.; Grammatikopoulou, M.G.; Bogdanos, D.P. Let Food Be Thy Medicine: The Case of The Mediterranean Diet in Rheumatoid Arthritis. Med. J. Rheumatol. 2020, 31, 20–24. [Google Scholar] [CrossRef]
  24. Papadaki, A.; Nolen-Doerr, E.; Mantzoros, C.S. The effect of the mediterranean diet on metabolic health: A systematic review and meta-analysis of controlled trials in adults. Nutrients 2020, 12, 1–21. [Google Scholar] [CrossRef] [PubMed]
  25. Klonizakis, M.; Bugg, A.; Hunt, B.; Theodoridis, X.; Bogdanos, D.P.; Grammatikopoulou, M.G. Assessing the Physiological Effects of Traditional Regional Diets Targeting the Prevention of Cardiovascular Disease: A Systematic Review of Randomized Controlled Trials Implementing Mediterranean, New Nordic, Japanese, Atlantic, Persian and Mexican Dietary Interventions. Nutrients 2021, 13, 3034. [Google Scholar] [CrossRef] [PubMed]
  26. Gioxari, A.; Grammatikopoulou, M.G.; Katsarou, C.; Panagiotakos, D.B.; Toutouza, M.; Kavouras, S.A.; Sidossis, L.S.; Maraki, M.I. A Modified Mediterranean Diet Improves Fasting and Postprandial Glucoregulation in Adults with Overweight and Obesity: A Pilot Study. Int. J. Environ. Res. Public Health 2022, 19, 15347. [Google Scholar] [CrossRef] [PubMed]
  27. Hansildaar, R.; Vedder, D.; Baniaamam, M.; Tausche, A.K.; Gerritsen, M.; Nurmohamed, M.T. Cardiovascular risk in inflammatory arthritis: Rheumatoid arthritis and gout. Lancet. Rheumatol. 2021, 3, e58–e70. [Google Scholar] [CrossRef]
  28. Crowson, C.S.; Liao, K.P.; Davis, J.M.; Solomon, D.H.; Matteson, E.L.; Knutson, K.L.; Hlatky, M.A.; Gabriel, S.E. Rheumatoid Arthritis and Cardiovascular Disease. Am. Heart J. 2013, 166, 622. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  29. Nicola, P.J.; Maradit-Kremers, H.; Roger, V.L.; Jacobsen, S.J.; Crowson, C.S.; Ballman, K.V.; Gabriel, S.E. The risk of congestive heart failure in rheumatoid arthritis: A population-based study over 46 years. Arthritis Rheum. 2005, 52, 412–420. [Google Scholar] [CrossRef]
  30. Chodara, A.M.; Wattiaux, A.; Bartels, C.M. Managing cardiovascular disease risk in rheumatoid arthritis: Clinical updates and three strategic approaches. Curr. Rheumatol. Rep. 2017, 19, 16. [Google Scholar] [CrossRef] [Green Version]
  31. Gwinnutt, J.M.; Wieczorek, M.; Balanescu, A.; Bischoff-Ferrari, H.A.; Boonen, A.; Cavalli, G.; de Souza, S.; de Thurah, A.; Dorner, T.E.; Moe, R.H.; et al. 2021 EULAR recommendations regarding lifestyle behaviours and work participation to prevent progression of rheumatic and musculoskeletal diseases. Ann. Rheum. Dis. 2022, 82, 48–56. [Google Scholar] [CrossRef]
  32. Schulz, K.F.; Altman, D.G.; Moher, D. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomized trials. Ann. Intern. Med. 2010, 152, 726–732. [Google Scholar] [CrossRef] [Green Version]
  33. Aletaha, D.; Neogi, T.; Silman, A.J.; Funovits, J.; Felson, D.T.; Bingham, C.O.; Birnbaum, N.S.; Burmester, G.R.; Bykerk, V.P.; Cohen, M.D.; et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010, 62, 2569–2581. [Google Scholar] [CrossRef] [PubMed]
  34. Prevoo, M.L.L.; Van’T Hof, M.A.; Kuper, H.H.; Van Leeuwen, M.A.; Van De Putte, L.B.A.; Van Riel, P.L.C.M. Modified disease activity scores that include twenty-eight-joint counts development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum. 1995, 38, 44–48. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Trichopoulou, A.; Bamia, C.; Trichopoulos, D. Mediterranean diet and survival among patients with coronary heart disease in Greece. Arch. Intern. Med. 2005, 165, 929–935. [Google Scholar] [CrossRef] [Green Version]
  36. Panagiotakos, D.B.; Pitsavos, C.; Stefanadis, C. Dietary patterns: A Mediterranean diet score and its relation to clinical and biological markers of cardiovascular disease risk. Nutr. Metab. Cardiovasc. Dis. 2006, 16, 559–568. [Google Scholar] [CrossRef]
  37. Papathanasiou, G.; Georgoudis, G.; Papandreou, M.; Spyropoulos, P.; Georgakopoulos, D.; Kalfakakou, V.; Evangelou, A. Reliability measures of the short International Physical Activity Questionnaire (IPAQ) in Greek young adults. Hell. J. Cardiol. 2009, 50, 282–294. [Google Scholar]
  38. Hagströmer, M.; Oja, P.; Sjöström, M. The International Physical Activity Questionnaire (IPAQ): A study of concurrent and construct validity. Public Health Nutr. 2006, 9, 755–762. [Google Scholar] [CrossRef] [PubMed]
  39. Collins, A.L.; McCarthy, H.D. Evaluation of factors determining the precision of body composition measurements by air displacement plethysmography. Eur. J. Clin. Nutr. 2003, 57, 770–776. [Google Scholar] [CrossRef] [Green Version]
  40. World Health Organization. Obesity: Preventing and Managing the Global Epidemic; World Health Organization: Geneva, Switzerland, 1998.
  41. Papandreou, P.; Gioxari, A.; Nimee, F.; Skouroliakou, M. Application of Clinical Decision Support System to Assist Breast Cancer Patients with Lifestyle Modifications during the COVID-19 Pandemic: A Randomised Controlled Trial. Nutrients 2021, 13, 2115. [Google Scholar] [CrossRef]
  42. Papandreou, P.; Gioxari, A.; Daskalou, E.; Vasilopoulou, A.; Skouroliakou, M. Personalized Nutritional Intervention to Improve Mediterranean Diet Adherence in Female Patients with Multiple Sclerosis: A Randomized Controlled Study. Diet 2022, 1, 25–38. [Google Scholar] [CrossRef]
  43. Papandreou, P.; Amerikanou, C.; Vezou, C.; Gioxari, A.; Kaliora, A.C.; Skouroliakou, M. Improving Adherence to the Mediterranean Diet in Early Pregnancy Using a Clinical Decision Support System; A Randomised Controlled Clinical Trial. Nutrients 2023, 15, 432. [Google Scholar] [CrossRef]
  44. Sutton, R.T.; Pincock, D.; Baumgart, D.C.; Sadowski, D.C.; Fedorak, R.N.; Kroeker, K.I. An overview of clinical decision support systems: Benefits, risks, and strategies for success. NPJ Digit. Med. 2020, 3, 1–10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Prolepsis Institute. National Nutritional Guide for Adults; Prolepsis Institute: Athens, Greece, 2014. [Google Scholar]
  46. Jamovi. The Jamovi Project; Jamovi: Sydney, Australia, 2020. [Google Scholar]
  47. Comee, L.; Taylor, C.A.; Nahikian-Nelms, M.; Ganesan, L.P.; Krok-Schoen, J.L. Dietary patterns and nutrient intake of individuals with rheumatoid arthritis and osteoarthritis in the United States. Nutrition 2019, 67–68, 110533. [Google Scholar] [CrossRef] [Green Version]
  48. Skoczyńska, M.; Swierkot, J. The role of diet in rheumatoid arthritis. Reumatologia 2018, 56, 259–267. [Google Scholar] [CrossRef]
  49. Berube, L.T.; Kiely, M.; Yazici, Y.; Woolf, K. Diet quality of individuals with rheumatoid arthritis using the Healthy Eating Index (HEI)-2010. Nutr. Health 2017, 23, 17–24. [Google Scholar] [CrossRef] [PubMed]
  50. Grimstvedt, M.E.; Woolf, K.; Milliron, B.J.; Manore, M.M. Lower Healthy Eating Index-2005 dietary quality scores in older women with rheumatoid arthritis v. healthy controls. Public Health Nutr. 2010, 13, 1170–1177. [Google Scholar] [CrossRef] [Green Version]
  51. Turesson Wadell, A.; Bärebring, L.; Hulander, E.; Gjertsson, I.; Lindqvist, H.M.; Winkvist, A. Inadequate Dietary Nutrient Intake in Patients With Rheumatoid Arthritis in Southwestern Sweden: A Cross-Sectional Study. Front. Nutr. 2022, 9, 915064. [Google Scholar] [CrossRef]
  52. Ingegnoli, F.; Schioppo, T.; Scotti, I.; Ubiali, T.; De Lucia, O.; Murgo, A.; Marano, G.; Boracchi, P.; Caporali, R. Adherence to Mediterranean diet and patient perception of rheumatoid arthritis. Complement. Ther. Med. 2020, 52, 102519. [Google Scholar] [CrossRef]
  53. Skoldstam, L.; Hagfors, L.; Johansson, G. An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis. Ann. Rheum. Dis. 2003, 62, 208–214. [Google Scholar] [CrossRef] [PubMed]
  54. Schönenberger, K.A.; Schüpfer, A.C.; Gloy, V.L.; Hasler, P.; Stanga, Z.; Kaegi-braun, N.; Reber, E. Effect of Anti-Inflammatory Diets on Pain in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. Nutrients 2021, 13, 4221. [Google Scholar] [CrossRef]
  55. McKellar, G.; Morrison, E.; McEntegart, A.; Hampson, R.; Tierney, A.; Mackle, G.; Scoular, J.; Scott, J.A.; Capell, H.A. A pilot study of a Mediterranean-type diet intervention in female patients with rheumatoid arthritis living in areas of social deprivation in Glasgow. Ann. Rheum. Dis. 2007, 66, 1239–1243. [Google Scholar] [CrossRef] [Green Version]
  56. Matsumoto, Y.; Sugioka, Y.; Tada, M.; Okano, T.; Mamoto, K.; Inui, K.; Habu, D.; Koike, T. Monounsaturated fatty acids might be key factors in the Mediterranean diet that suppress rheumatoid arthritis disease activity: The TOMORROW study. Clin. Nutr. 2018, 37, 675–680. [Google Scholar] [CrossRef]
  57. Ricker, M.A.; Haas, W.C. Anti-Inflammatory Diet in Clinical Practice: A Review. Nutr. Clin. Pract. 2017, 32, 318–325. [Google Scholar] [CrossRef] [PubMed]
  58. Häger, J.; Bang, H.; Hagen, M.; Frech, M.; Träger, P.; Sokolova, M.V.; Stéen, U.; Tascilar, K.; Sarter, K.; Schett, G.; et al. The Role of Dietary Fiber in Rheumatoid Arthritis Patients: A Feasibility Study. Nutrients 2019, 11, 2392. [Google Scholar] [CrossRef] [Green Version]
  59. Elahi, N.; Elahi, H.; Navashenaq, J.G.; Abdollahzad, H.; Mahaki, B.; Soleimani, D.; Mostafaei, R.; Samadi, M.; Bagheri, A.; Nachvak, S.M. The relationship between major dietary patterns and disease activity of rheumatoid arthritis. Clin. Nutr. ESPEN 2022, 51, 274–279. [Google Scholar] [CrossRef]
  60. Nikiphorou, E.; Norton, S.; Young, A.; Dixey, J.; Walsh, D.; Helliwell, H.; Kiely, P.; Davies, P.; Hill, L.; Gough, A.; et al. The association of obesity with disease activity, functional ability and quality of life in early rheumatoid arthritis: Data from the Early Rheumatoid Arthritis Study/Early Rheumatoid Arthritis Network UK prospective cohorts. Rheumatology 2018, 57, 1194–1202. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  61. Morgan, C.; Costello, R.E.; Ray, D.W.; Dixon, W.G. How Do Glucocorticoids Used in Rheumatic Disease Affect Body Weight? A Narrative Review of the Evidence. Arthritis Care Res. 2020, 72, 489–497. [Google Scholar] [CrossRef] [Green Version]
  62. Poudel, D.; George, M.D.; Baker, J.F. The Impact of Obesity on Disease Activity and Treatment Response in Rheumatoid Arthritis. Curr. Rheumatol. Rep. 2020, 22, 56. [Google Scholar] [CrossRef] [PubMed]
  63. Kerekes, G.; Nurmohamed, M.T.; González-Gay, M.A.; Seres, I.; Paragh, G.; Kardos, Z.; Baráth, Z.; Tamási, L.; Soltész, P.; Szekanecz, Z. Rheumatoid arthritis and metabolic syndrome. Nat. Rev. Rheumatol. 2014, 10, 691–696. [Google Scholar] [CrossRef]
  64. Esposito, K.; Maiorino, M.I.; Bellastella, G.; Chiodini, P.; Panagiotakos, D.; Giugliano, D. A journey into a Mediterranean diet and type 2 diabetes: A systematic review with meta-analyses. BMJ Open 2015, 5, e008222. [Google Scholar] [CrossRef] [Green Version]
  65. Heidari, B.; Hajian-Tilaki, K.; Babaei, M. Vitamin D Deficiency and Rheumatoid Arthritis: Epidemiological, Immunological, Clinical and Therapeutic Aspects. Mediterr. J. Rheumatol. 2019, 30, 94–102. [Google Scholar] [CrossRef]
  66. Guan, Y.; Hao, Y.; Guan, Y.; Bu, H.; Wang, H. The Effect of Vitamin D Supplementation on Rheumatoid Arthritis Patients: A Systematic Review and Meta-Analysis. Front. Med. 2020, 7, 596007. [Google Scholar] [CrossRef] [PubMed]
  67. Di Franco, M.; Barchetta, I.; Iannuccelli, C.; Gerardi, M.C.; Frisenda, S.; Ceccarelli, F.; Valesini, G.; Cavallo, M.G. Hypovitaminosis D in recent onset rheumatoid arthritis is predictive of reduced response to treatment and increased disease activity: A 12 month follow-up study. BMC Musculoskelet. Disord. 2015, 16, 53. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  68. Hollan, I.; Dessein, P.H.; Ronda, N.; Wasko, M.C.; Svenungsson, E.; Agewall, S.; Cohen-Tervaert, J.W.; Maki-Petaja, K.; Grundtvig, M.; Karpouzas, G.A.; et al. Prevention of cardiovascular disease in rheumatoid arthritis. Autoimmun. Rev. 2015, 14, 952–969. [Google Scholar] [CrossRef] [PubMed]
  69. Lagunova, Z.; Porojnicu, A.C.; Vieth, R.; Lindberg, F.A.; Hexeberg, S.; Moan, J. Serum 25-hydroxyvitamin D is a predictor of serum 1,25-dihydroxyvitamin D in overweight and obese patients. J. Nutr. 2011, 141, 112–117. [Google Scholar] [CrossRef] [Green Version]
  70. Gwinnutt, J.M.; Alsafar, H.; Hyrich, K.L.; Lunt, M.; Barton, A.; Verstappen, S.M.M. Do people with rheumatoid arthritis maintain their physical activity level at treatment onset over the first year of methotrexate therapy? Rheumatology 2021, 60, 4633–4642. [Google Scholar] [CrossRef]
  71. Bremander, A.; Malm, K.; Andersson, M.L. Physical activity in established rheumatoid arthritis and variables associated with maintenance of physical activity over a seven-year period—A longitudinal observational study. BMC Rheumatol. 2020, 4, 1–9. [Google Scholar] [CrossRef]
  72. Swärdh, E.; Opava, C.; Brodin, N. Physical activity in patients with rheumatoid arthritis—An agile lifelong behaviour: A qualitative meta-synthesis. RMD Open 2021, 7, e001635. [Google Scholar] [CrossRef]
  73. Forberger, S.; Wichmann, F.; Comito, C.N. Nudges used to promote physical activity and to reduce sedentary behaviour in the workplace: Results of a scoping review. Prev. Med. 2022, 155, 106922. [Google Scholar] [CrossRef]
  74. Björk, M.; Dragioti, E.; Alexandersson, H.; Esbensen, B.A.; Boström, C.; Friden, C.; Hjalmarsson, S.; Hörnberg, K.; Kjeken, I.; Regardt, M.; et al. Inflammatory Arthritis and the Effect of Physical Activity on Quality of Life and Self-Reported Function: A Systematic Review and Meta-Analysis. Arthritis Care Res. 2022, 74, 31–43. [Google Scholar] [CrossRef]
  75. Ye, H.; Weng, H.; Xu, Y.; Wang, L.; Wang, Q.; Xu, G. Effectiveness and safety of aerobic exercise for rheumatoid arthritis: A systematic review and meta-analysis of randomized controlled trials. BMC Sports Sci. Med. Rehabil. 2022, 14, 1–15. [Google Scholar] [CrossRef]
  76. Rausch Osthoff, A.K.; Juhl, C.B.; Knittle, K.; Dagfinrud, H.; Hurkmans, E.; Braun, J.; Schoones, J.; Vliet Vlieland, T.P.M.; Niedermann, K. Effects of exercise and physical activity promotion: Meta-analysis informing the 2018 EULAR recommendations for physical activity in people with rheumatoid arthritis, spondyloarthritis and hip/knee osteoarthritis. RMD Open 2018, 4, e000713. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Hejazi, K.; Wong, A. Effects of exercise training on inflammatory and cardiometabolic health markers in overweight and obese adults: A systematic review and meta-analysis of randomized controlled trials. J. Sports Med. Phys. Fitness 2022. [Google Scholar] [CrossRef] [PubMed]
  78. Batrakoulis, A.; Jamurtas, A.Z.; Metsios, G.S.; Perivoliotis, K.; Liguori, G.; Feito, Y.; Riebe, D.; Thompson, W.R.; Angelopoulos, T.J.; Krustrup, P.; et al. Comparative Efficacy of 5 Exercise Types on Cardiometabolic Health in Overweight and Obese Adults: A Systematic Review and Network Meta-Analysis of 81 Randomized Controlled Trials. Circ. Cardiovasc. Qual. Outcomes 2022, 15, E008243. [Google Scholar] [CrossRef] [PubMed]
  79. Laiou, E.; Rapti, I.; Schwarzer, R.; Fleig, L.; Cianferotti, L.; Ngo, J.; Rizos, E.C.; Wetle, T.F.; Kahlmeier, S.; Vigilanza, A.; et al. Review: Nudge interventions to promote healthy diets and physical activity. Food Policy 2021, 102, 102103. [Google Scholar] [CrossRef]
  80. Ensaff, H. A nudge in the right direction: The role of food choice architecture in changing populations’ diets. Proc. Nutr. Soc. 2021, 80, 195–206. [Google Scholar] [CrossRef]
  81. Chen, Y.; Harris, S.; Rogers, Y.; Ahmad, T.; Asselbergs, F.W. Nudging within learning health systems: Next generation decision support to improve cardiovascular care. Eur. Heart J. 2022, 43, 1296. [Google Scholar] [CrossRef]
  82. Kwan, J.L.; Lo, L.; Ferguson, J.; Goldberg, H.; Diaz-Martinez, J.P.; Tomlinson, G.; Grimshaw, J.M.; Shojania, K.G. Computerised clinical decision support systems and absolute improvements in care: Meta-analysis of controlled clinical trials. BMJ 2020, 370, m3216. [Google Scholar] [CrossRef]
  83. Hazlewood, G.S.; Marshall, D.A.; Barber, C.E.H.; Li, L.C.; Barnabe, C.; Bykerk, V.; Tugwell, P.; Hull, P.M.; Bansback, N. Using a Discrete-Choice Experiment in a Decision Aid to Nudge Patients Towards Value-Concordant Treatment Choices in Rheumatoid Arthritis: A Proof-of-Concept Study. Patient Prefer. Adherence 2020, 14, 829–838. [Google Scholar] [CrossRef]
  84. Umaefulam, V.; Fox, T.L.; Hazlewood, G.; Bansback, N.; Barber, C.E.H.; Barnabe, C. Adaptation of a Shared Decision-Making Tool for Early Rheumatoid Arthritis Treatment Decisions with Indigenous Patients. Patient 2022, 15, 233–243. [Google Scholar] [CrossRef]
  85. Vamvakis, A.; Gkaliagkousi, E.; Lazaridis, A.; Grammatikopoulou, M.G.; Triantafyllou, A.; Nikolaidou, B.; Koletsos, N.; Anyfanti, P.; Tzimos, C.; Zebekakis, P.; et al. Impact of intensive lifestyle treatment (Diet plus exercise) on endothelial and vascular function, arterial stiffness and blood pressure in stage 1 hypertension: Results of the Hintreat randomized controlled trial. Nutrients 2020, 12, 1326. [Google Scholar] [CrossRef]
  86. Franz, M.J.; Monk, A.; Barry, B.; McCllain, K.; Weaver, T.; Cooper, N.; Upham, P.; Bergerstall, R.; Mazze, R.S. Effectiveness of Medical Nutrition Therapy Provided by Dietitians in the Management of Non-Insulin-Dependent Diabetes Mellitus. A Randomized, Controlled Clinical Trial. J. Am. Diet. Assoc. 1995, 95, 1009–1017. [Google Scholar] [CrossRef] [PubMed]
  87. Briggs Early, K.; Stanley, K. Position of the Academy of Nutrition and Dietetics: The Role of Medical Nutrition Therapy and Registered Dietitian Nutritionists in the Prevention and Treatment of Prediabetes and Type 2 Diabetes. J. Acad. Nutr. Diet. 2018, 118, 343–353. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  88. Larson, E. Disease management, registered dietitians and medical nutrition therapy. J. Am. Diet. Assoc. 2002, 102, 190–191. [Google Scholar] [CrossRef]
  89. Johansen, M.Y.; Karstoft, K.; MacDonald, C.S.; Hansen, K.B.; Ellingsgaard, H.; Hartmann, B.; Wewer Albrechtsen, N.J.; Vaag, A.A.; Holst, J.J.; Pedersen, B.K.; et al. Effects of an intensive lifestyle intervention on the underlying mechanisms of improved glycaemic control in individuals with type 2 diabetes: A secondary analysis of a randomised clinical trial. Diabetologia 2020, 63, 2410–2422. [Google Scholar] [CrossRef] [PubMed]
  90. Johansen, M.Y.; Macdonald, C.S.; Hansen, K.B.; Karstoft, K.; Christensen, R.; Pedersen, M.; Hansen, L.S.; Zacho, M.; Wedell-Neergaard, A.S.; Nielsen, S.T.; et al. Effect of an intensive lifestyle intervention on glycemic control in patients with type 2 diabetes: A randomized clinical trial. JAMA 2017, 318, 637–646. [Google Scholar] [CrossRef]
  91. MacDonald, C.S.; Nielsen, S.M.; Bjørner, J.; Johansen, M.Y.; Christensen, R.; Vaag, A.; Lieberman, D.E.; Pedersen, B.K.; Langberg, H.; Ried-Larsen, M.; et al. One-year intensive lifestyle intervention and improvements in health-related quality of life and mental health in persons with type 2 diabetes: A secondary analysis of the U-TURN randomized controlled trial. BMJ Open Diabetes Res. Care 2021, 9, 1840. [Google Scholar] [CrossRef] [PubMed]
  92. Kawamoto, K.; Houlihan, C.A.; Balas, E.A.; Lobach, D.F. Improving clinical practice using clinical decision support systems: A systematic review of trials to identify features critical to success. Br. Med. J. 2005, 330, 765–768. [Google Scholar] [CrossRef] [Green Version]
  93. Alonso-Molero, J.; Prieto-Peña, D.; Mendoza, G.; Atienza-Mateo, B.; Corrales, A.; González-Gay, M.; Llorca, J. Misperception of the Cardiovascular Risk in Patients with Rheumatoid Arthritis. Int. J. Environ. Res. Public Health 2020, 17, 1–9. [Google Scholar] [CrossRef]
  94. Metsios, G.S.; Kitas, G.D. Physical activity, exercise and rheumatoid arthritis: Effectiveness, mechanisms and implementation. Best Pract. Res. Clin. Rheumatol. 2018, 32, 669–682. [Google Scholar] [CrossRef]
  95. Khanna, S.; Jaiswal, K.S.; Gupta, B. Managing Rheumatoid Arthritis with Dietary Interventions. Front. Nutr. 2017, 4, 52. [Google Scholar] [CrossRef] [PubMed]
  96. Rondanelli, M.; Perdoni, F.; Peroni, G.; Caporali, R.; Gasparri, C.; Riva, A.; Petrangolini, G.; Faliva, M.A.; Infantino, V.; Naso, M.; et al. Ideal food pyramid for patients with rheumatoid arthritis: A narrative review. Clin. Nutr. 2021, 40, 661–689. [Google Scholar] [CrossRef] [PubMed]
Nutrients 15 00676 g001 550
Figure 1. CONSORT [32] diagram of the study’s procedures.
Figure 1. CONSORT [32] diagram of the study’s procedures.
Nutrients 15 00676 g001
Table
Table 1. Inclusion and exclusion criteria for participation in the study.
Table 1. Inclusion and exclusion criteria for participation in the study.
Inclusion CriteriaExclusion Criteria
(1) Adult women (≥ 18 years of age)(1) Adolescent women
with an RA diagnosis according to the ACR/EULAR criteria [33] for >2 years(2) Patients with altered treatment regime ≤ 6 months before, or during the trial
(2) With mild-moderate disease activity based on the DAS28 (DAS28 < 3.2)(3) Women with RA with active disease (DAS28 > 5.1) [34]
(4) People unable to read and comprehend the consent form
(3) On an unchanged treatment regime for >6 months(5) Patients with psychiatric conditions
(4) Who provided consent for participation(6) Pregnant or lactating women
(7) Women on weight loss medication
(8) Women following a vegan diet ≤ 5 years prior to screening
(9) Those who did not consent or were unable to provide consent
(10) Women with allergies, food intolerances, serious or life-threating illness, e.g., malignancy; infections; heart, liver, or renal failure; congenital metabolic diseases; malabsorption; or cognitive disorders
(11) Alcoholism or drug addiction
(12) Women taking vitamin or mineral supplementation during or ≤6 months prior to screening
ACR—American College of Rheumatology; DAS28—disease activity score 28 [34]; EULAR—European League Against Rheumatism; RA—rheumatoid arthritis.
Table
Table 2. Characteristics of the participating women at baseline *.
Table 2. Characteristics of the participating women at baseline *.
CharacteristicsEnrolled
(N = 40)		Intervention Arm
(n = 20)		Control Arm
(n = 20)
Age (years)34.03 ± 5.4534.15 ± 5.9533.9 ± 5.06
Anthropometry:BW (kg)78.86 ± 19.4679.19 ± 21.3878.52 ± 17.88
BMI (kg/m2)25.76 ± 5.2226.13 ± 5.8925.40 ± 4.59
FM (% of BW)21.13 ± 12.0720.63 ± 11.8621.64 ± 12.56
FFM (% of BW)57.68 ± 11.9257.53 ± 13.3357.82 ± 10.66
Weight status:Normoweight/Overweight/Obese (n)22/14/412/6/210/8/2
Blood assays: Glucose (mg/dL)108.13 ± 17.16110.61 ± 7.34105.65 ± 23.19
TC (mg/dL)213.21 ± 50.11209.22 ± 53.02217.2 ± 48.07
HDL (mg/dL)69.33 ± 21.1671.78 ± 17.6266.88 ± 24.42
LDL (mg/dL)129.20 ± 42.31130.02 ± 45.87128.37 ± 39.61
TG (mg/dL)113.34 ± 67.12112.23 ± 75.76114.45 ± 59.20
CRP (mg/dL)0.74 ± 0.120.71 ± 0.110.77 ± 0.12
1,25(OH)2D (ng/mL)32.97 ± 4.1033.79 ± 3.9432.14 ± 4.19
Physical activity (IPAQ):METs-min/week647.46 ± 308.01580.78 ± 322.39714.14 ± 284.24
Adherence to the MD:MedDietScore 38.25 ± 3.2138.36 ± 3.4638.14 ± 3.03
Daily dietary intake:Total fat (g)68.76 ± 9.4967.02 ± 7.1570.50 ± 11.29
Dietary cholesterol (mg)199.19 ± 45.49188.94 ± 58.45209.44 ± 24.70
Fiber (g) 21.24 ± 4.8519.98± 4.2817.95 ± 4.24
SFA (g) 18.98± 3.6419.87 ± 2.1618.09 ± 4.58
MUFA (g) 29.63 ± 5.8530.84 ± 5.4728.42 ± 6.11
Disease activity:DAS282.82 ± 0.192.83 ± 0.192.81 ± 0.20
1,25(OH)2D—1,25-Dihydroxyvitamin D; BW—body weight; BMI—body mass index; CRP—C-reactive protein; DAS28—disease activity score 28 joints [34]; FFM—fat-free mass; FM—fat mass; HDL—high-density lipoprotein; IPAQ—International Physical Activity Questionnaire [37]; LDL—low-density lipoprotein; MD—Mediterranean diet; MedDietScore—Mediterranean Diet Score [36]; MET—metabolic equivalents of task; MUFA—mono-unsaturated fatty acids; NS—not significant; SFA—saturated fatty acids; TC—total cholesterol; TG—triglycerides; * Data are expressed as counts (n) or mean values ± standard deviation of mean (SD).
Table
Table 3. Characteristics of the participating women at baseline and end of treatment (12 weeks) *.
Table 3. Characteristics of the participating women at baseline and end of treatment (12 weeks) *.
CharacteristicsIntervention Arm
(n = 20)		p-Values
within
Timepoints †		Control Arm
(n = 20)		p-Values
within
Timepoints †		p-Values
between Groups †		p-Values
between Groups †
beforeafterbeforeafterBaseline12 WeeksΔ
Anthropometry:BW (kg)79.2 ± 21.477.1 ± 20.8<0.00178.5 ± 17.980.6 ± 18.3<0.0010.9160.576<0.001
BMI (kg/m2)26.13 ± 5.8925.42 ± 5.63<0.00125.40 ± 4.5926.04 ± 4.58<0.0010.6630.702<0.001
FM (% of BW)20.6 ± 11.920.3 ± 12.1<0.00121.6 ± 12.622.1 ± 12.10.0020.7940.665<0.001
FFM (% of BW)57.5 ± 13.356.7 ± 13.30.00157.8 ± 10.757.8 ± 11.10.9540.9400.7740.348
Blood assays: Glucose (mg/dL)110.6 ± 7.3104.8 ± 5.3<0.001105.7 ± 23.2104.7 ± 23.20.4010.3680.9640.005
TC (mg/dL)209.2 ± 53.0200.6 ± 56.50.183217.2 ± 48.1228.8 ± 53.00.2090.6210.1110.071
HDL (mg/dL)71.8 ± 17.669.7 ± 19.20.68066.9 ± 24.473.4 ± 27.30.1330.4720.6250.193
LDL (mg/dL)130.0 ± 45.9126.5 ± 52.00.637128.4 ± 39.6132.3 ± 45.30.6230.9040.7080.493
TG (mg/dL)112.2 ± 75.897.5 ± 57.70.057114.5 ± 59.2126.3 ± 83.60.3800.9180.2120.086
CRP (mg/dL)0.71 ± 0.110.72 ± 0.110.4080.77 ± 0.120.75 ± 0.110.3670.0840.4600.240
1,25(OH)2D (ng/mL)33.8 ± 3.951.6 ± 11.8<0.00132.1 ± 4.240.4 ± 6.4<0.0010.208<0.0010.001
Physical activity (IPAQ):METs (min/week)580.8 ± 322.4616.5 ± 315.90.002714.1 ± 284.2684.7 ± 251.10.0650.1740.4540.002
MD adherence:MedDietScore38.36 ± 3.4642.11 ± 2.48<0.00138.14 ± 3.0338.36 ± 2.740.3590.829<0.001<0.001
Daily dietary intake:Total fat (g)67.02 ± 7.1561.19 ± 7.90<0.00170.50 ± 11.2973.42 ± 11.57<0.0010.251<0.001<0.001
Cholesterol (mg)188.9 ± 58.5169.2 ± 50.3<0.001209.4 ± 24.7224.6 ± 28.3<0.0010.157<0.001<0.001
Fiber (g)19.98 ± 4.2826.09 ± 5.00<0.00117.95 ± 4.2423.73 ± 4.240.0670.1400.116<0.001
SFA (g)19.87 ± 2.1616.73 ± 3.120.00418.09 ± 4.5818.48 ± 4.770.1320.1250.1770.001
MUFA (g)30.84 ± 5.4736.98 ± 5.82<0.00128.42 ± 6.1128.73 ± 5.380.4330.195<0.001<0.001
Disease activity:DAS282.83 ± 0.192.71 ± 0.14<0.0012.81 ± 0.202.80 ± 0.170.8040.7440.054<0.001
1,25(OH)2D—1,25-Dihydroxyvitamin D; Δ—change from baseline to end of treatment; BW—body weight; BMI—body mass index; CRP—C-reactive protein; DAS28—disease activity score 28 joints [34]; FFM—fat-free mass; FM—fat mass; HDL—high-density lipoprotein; IPAQ—International Physical Activity Questionnaire [37]; LDL—low-density lipoprotein; MD—Mediterranean diet; MedDietScore—Mediterranean Diet Score [36]; MET—metabolic equivalents of task; MUFA—mono-unsaturated fatty acids; NS—not significant; SFA—saturated fatty acids; TC—total cholesterol; TG—triglycerides. * Data are expressed as mean values ± standard deviation of mean (SD); † p-value: significant differences between the control and the intervention group at baseline analyzed by independent sample t-test or the Mann–Whitney U test, where applicable.
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Papandreou, P.; Gioxari, A.; Daskalou, E.; Grammatikopoulou, M.G.; Skouroliakou, M.; Bogdanos, D.P. Mediterranean Diet and Physical Activity Nudges versus Usual Care in Women with Rheumatoid Arthritis: Results from the MADEIRA Randomized Controlled Trial. Nutrients 2023, 15, 676. https://doi.org/10.3390/nu15030676

AMA Style

Papandreou P, Gioxari A, Daskalou E, Grammatikopoulou MG, Skouroliakou M, Bogdanos DP. Mediterranean Diet and Physical Activity Nudges versus Usual Care in Women with Rheumatoid Arthritis: Results from the MADEIRA Randomized Controlled Trial. Nutrients. 2023; 15(3):676. https://doi.org/10.3390/nu15030676

Chicago/Turabian Style

Papandreou, Panos, Aristea Gioxari, Efstratia Daskalou, Maria G. Grammatikopoulou, Maria Skouroliakou, and Dimitrios P. Bogdanos. 2023. "Mediterranean Diet and Physical Activity Nudges versus Usual Care in Women with Rheumatoid Arthritis: Results from the MADEIRA Randomized Controlled Trial" Nutrients 15, no. 3: 676. https://doi.org/10.3390/nu15030676

APA Style

Papandreou, P., Gioxari, A., Daskalou, E., Grammatikopoulou, M. G., Skouroliakou, M., & Bogdanos, D. P. (2023). Mediterranean Diet and Physical Activity Nudges versus Usual Care in Women with Rheumatoid Arthritis: Results from the MADEIRA Randomized Controlled Trial. Nutrients, 15(3), 676. https://doi.org/10.3390/nu15030676

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