Improvements in quality-of-life dimensions through medium-chain triglyceride (MCT) supplementation in rheumatoid arthritis: updated findings from a randomised clinical trial

Abstract

Objective

To assess the impact of medium-chain triglycerides (MCTs) and fibre on health-related quality of life (QOL), morning stiffness and pain in rheumatoid arthritis (RA) patients.

Methods

A randomised, double-blind, placebo-controlled clinical trial enrolled 61 RA patients on stable drug treatment. Participants received twice-daily MCT supplementation (30 g/day) for 8 weeks, followed by 8 weeks of MCTs (30 g/day) combined with fibre (30 g/day). The control group received the same supplementation as the test group, with long-chain triglycerides instead of MCTs. QOL parameters, morning stiffness, pain intensity and lipid profile were assessed at baseline (T0), week 8 (T2) and week 16 (T4).

Results

After 16 weeks, the test group showed statistically and clinically significant improvements both in mental and physical health-related scores. MCT consumption significantly ameliorated mental health, emotional well-being, social behaviour and vitality (measured using 36-Item Short Form Survey) from baseline to T4 and relative to control. An increased motivation, as assessed with the Multidimensional Fatigue Inventory-20 questionnaire, was reported as well. Regular intake of MCTs significantly reduced the intensity and duration of morning stiffness and pain intensity (assessed using the Visual Analogue Scale) from baseline to T4 compared with control group. Reported effects were maintained after adding fibre to supplementation. Baseline blood lipid profile showed no significant differences.

Conclusions

Patients with RA supplemented with MCTs obtained significant improvements in several health-related QOL components compared to control, and fibre inclusion did not interfere with MCT efficacy. These results underscore the importance of targeted non-pharmacological approaches integrated to drug therapy in managing patients with RA.

Trial registration number

DRKS00025413.

WHAT IS ALREADY KNOWN ON THIS TOPIC

• Rheumatoid arthritis (RA) significantly impacts patients’ quality of life, despite ongoing drug therapy.

• Nutrition has gained significant attention as an integrative strategy for its potential to influence the disease activity.

WHAT THIS STUDY ADDS

• Medium-chain triglycerides (MCTs) were observed to enhance cognitive function, general fatigue and overall well-being in patients with RA, possibly by enhancing mitochondrial metabolism and improving overall energy levels.

• MCT-Induced Ketosis and Fiber in Rheumatoid Arthritis trial demonstrates how inclusion in the diet of specific nutrients can lead to significant patient outcomes.

HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

• Integrating targeted non-pharmacological strategies, such as specific dietary inclusion of nutrients, alongside drug therapy may offer additional benefits for patients with RA, particularly addressing comorbidities.

• Incorporating MCTs into the regular diet of patients with RA can significantly boost their mental and physical well-being.

Introduction

Rheumatic diseases represent a wide spectrum of pathologies typically affecting articular, periarticular and musculoskeletal systems. Beside their diverse clinical manifestations, all rheumatic disorders share a chronic inflammatory status, together with a breakdown of immune self-tolerance.¹ Among them, rheumatoid arthritis (RA) is one of the most common, with an estimated prevalence in Europe ranging from 1 to 6/1000 for men and 3 to 12/1000 for women and with an increasing trend from southern to northern countries.² Even if primarily involving joint structure, RA must be considered as a systemic disease, due to its extra-articular manifestations.³ In particular, cardiovascular disease (CVD) is the primary cause of death in RA, with these patients having a 60% increased risk of CVD mortality compared with the general population.⁴

The complex interplay of musculoskeletal symptoms and systemic comorbidities explains the major impact of RA on patients’ quality of life (QOL), which is severely affected in various dimensions, such as impairments in social relationships, mental well-being, lifestyle habits and economic status.⁵ Despite ongoing drug therapy, patients with RA mainly report fatigue, pain and morning stiffness as critical issues that impair their health-related QOL.^{6 7} For this reason, QOL assessments through different scales are increasingly employed in clinical practice to complement clinical examinations.⁸

RA comorbidities, patient’s reduced QOL and possible limitations of drug therapies are crucial factors when defining therapeutic goals. Following European Alliance of Associations for Rheumatology recommendations, remission should be considered as the primary therapeutic aim in RA.⁹ However, despite major breakthroughs in drug therapies, due to the complexity and the inter-individual variability of clinical manifestations, less than one-third are reported reaching long-term remission in real-world practice.¹⁰ This underlines the urgent need for holistic treatments in RA, combining pharmacological therapies with complementary approaches with the aim of positively impacting disease activity. Among integrative strategies, nutrition attracted considerable attention due to its potential in influencing the course of the disease.^{11 12} This interest is also shared by patients, who are often looking for self-management strategies for symptomatic improvements.¹³

Here, we aimed to understand the role of medium chain triglycerides (MCTs) and dietary fibre in supporting RA management. Unlike long-chain triglycerides (LCTs), MCTs are rapidly transported to the liver without being carried by chylomicrons, thus leading to a quick synthesis of ketone bodies such as beta-hydroxybutyrate (BHB).¹⁴ Interestingly, BHB has been described as a direct inhibitor of NLRP3 inflammasome, a protein complex involved in RA pathogenesis and progression, thus connecting MCTs to inflammatory pathways.¹⁵ Another noteworthy nutrient is represented by dietary fibre, which has been shown to correlate with an increased QOL.¹⁶ The positive impact of high fibre intake on perceived health status seems to be primarily due to its role in enhancing beneficial gut microbial activity.¹⁶ This, in turn, helps regulate inflammation, immune responses and metabolic function.¹⁶ Despite these mechanisms still requiring further examination to be confirmed, it has been observed that dietary fibre intake in patients with RA is often suboptimal compared with the general population and WHO recommendations.¹⁷

We conducted a randomised, double-blind, placebo-controlled clinical trial to investigate whether regular consumption of a formulation containing MCTs and fibre may be useful in RA patients’ dietary management. The main research question focused on comparing the change in the Simple Disease Activity Index (SDAI) from baseline to week 16 between the test group and the control group. In this update to our first publication,¹⁸ we present new findings on patients’ QOL, morning stiffness and pain, offering a comprehensive overview of how dietary management can significantly improve patient outcomes.

Methods

Clinical trial design and eligibility criteria

Clinical trial design and eligibility criteria have been conducted as described by Heidt et al.¹⁸ Briefly, this trial was designed as a randomised, double-blind, placebo-controlled, 16 weeks, single-centre study. Only patients with RA under regular follow-up at the Rheumatology Outpatient Practice in Bad Bocklet (Germany) and fulfilling inclusion and exclusion criteria (online supplemental table S1) were included in the study. The trial was conducted between August 2021 and October 2022.

Randomisation, sample size and intervention

Details about randomisation procedure, sample size and intervention have been previously reported.¹⁸ A stratified randomisation with a sex ratio of 2:1 between females and males was used to randomly assign patients with RA to either the test or control group. All investigators (rheumatologists, nurses and nutritionists) and patients were blinded to the group allocation until the trial ended. Sample size was calculated for a one-sided Mann-Whitney U (Wilcoxon) test, with a 1.0-point difference in decrease for the SDAI, a SD of 1.25, 90% power (d=0.8) and a 5% level of significance (α) being considered for a sample size of 58 patients. A study flowchart is shown in figure 1, reporting the primary endpoint, as well as the secondary endpoints analysed in this publication.

Figure 1. Summary of the study flow chart, presenting measurements related to the results included in this publication. Created in https://BioRender.com. LCTs, long-chain triglycerides; MCTs, medium-chain triglycerides; MFI-20, Multidimensional Fatigue Inventory; SDAI, Simple Disease Activity Index; SF-36, Short Form-36; VAS, Visual Analogue Scale.

As already described,¹⁸ the test group received a twice-daily formulation (once in the morning, before breakfast, once in the afternoon) containing MCTs (30 g/day) for 8 weeks followed by a second twice-daily regimen of MCTs (30 g/day) plus fibre (30 g/day) combination for an additional 8 weeks. In the control group, the dietary regimen contained LCTs instead of MCTs. Fibre was introduced in both study groups after 8 weeks of the dietary regimen. Patients could choose to consume each product as a cream or as a beverage, adding respectively 50 or 150 mL of water to the 50 g powder. Patient’s blood samples for lipid profile analysis and patient-reported outcome (PRO) measures were collected at baseline (T0), week 8 (T2) and week 16 (T4). All four interventions were provided by Dr. Schär AG/SPA, Postal, Italy. The four products were individually packaged in single-serving packets and provided in identical containers, each labelled with a unique batch number to ensure both blinding and accurate product assignment.

Study outcomes

The primary outcome of the study was set as a difference in SDAI from T0 to T4. Secondary outcomes, including PRO measures, morning stiffness, pain evaluation and patient’s lipid profile, were evaluated longitudinally from T0 to T2 to T4 between test and control groups.

Measurements

All measurements regarding the primary endpoint have been described in our previous publication.¹⁸ Disease activity was evaluated using the SDAI as measured using the arithmetic sum of tender and swollen 28-joint count, the patient’s and rheumatologist’s global assessment and C reactive protein in mg/dL.¹⁹ All standardised procedures were conducted by clinical laboratory staff at Hescuro Clinic Bad Bocklet, Germany. Clinically significant improvements were identified as changes from T0 that met or exceeded the minimal clinically important difference (MCID) for each of the mentioned outcome measures, except for morning stiffness duration and intensity due to an unknown MCID.²⁰

Adherence

The patients were asked to record the consumption of the formulation (date and time) and the ketone levels twice daily. According to the literature,²¹ the timing of BHB measurement was set at 30 min after ingestion as published.¹⁸ Telephone interviews were conducted weekly (or as needed) to clarify unanswered questions and check daily intake according to study protocol.

QOL assessment

Several scales have been validated to assess QOL in RA. German versions of the Short Form-36 (SF-36)²² and of the Multidimensional Fatigue Inventory (MFI-20)²³ were used to assess patients’ QOL, as described below.

The SF-36 consists of 36 items organised in eight dimensions: (1) physical functioning, (2) role limitations due to physical problems, (3) role limitations due to emotional problems, (4) vitality, (5) mental health, (6) social functioning, (7) body pain and (8) general health perception. Each item could have a score between 0 and 100, with 0 and 100 indicating worst and best health-related QOL, respectively.²⁴ Using different subscales, it is possible to provide a global measure of physical and mental functioning, both ranging from 0 to 100, with higher scores indicating better health.²² Changes of ≥5 points in domain scores were considered to represent MCID.²⁵

The MFI-20 is a 20-item self-report questionnaire developed to measure fatigue. It covers five different dimensions: general fatigue, physical fatigue, mental fatigue, reduced motivation and reduced activity. Patients use a scale ranging from 1 (‘yes, that is true’) to 5 (‘no, that is not true’) to indicate how items represent their feelings during the week preceding the measurement. A higher total score indicates higher fatigue levels.²³ MCID was defined as 8.5% of the value of the MFI-20 dimension for improvement.²⁶

Morning stiffness assessment

To investigate morning stiffness, its duration in minutes to maximum improvement and its perceived severity (intensity) on a Numeric Rating Scale were measured.

Pain assessment

The Visual Analog Scale for Pain (VAS) was used to measure pain intensity.²⁷ The VAS is a reliable and validated method to measure pain intensity. This scale consists of a line length of 10 cm of which lower (0) and higher (10) extremes indicate no pain and the greatest possible pain, respectively.²⁷ Patients should mark the spot on the line corresponding to their pain intensity. Then, the distance from 0 (absence of pain) and the marked spot is measured.²⁷ A ≥1-point decrease in pain from baseline was considered as MCID.²⁸ In our previous work,¹⁸ VAS score related to pain autonomously recorded by patients was presented (VAS patient), whereas VAS scores measured by the rheumatologist will be considered here (VAS physician).

Lipid profile

Blood samples were collected in a sterile manner after an overnight fast for serum triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) levels.

Statistical analysis

Statistical analyses were performed using SAS software V.9.4 (SAS Institute) and R studio V.4.3.2. All continuous variables were defined as mean±SD. Two-sided p values for comparison of the questionnaires’ continuous variables between placebo and test were derived via Wilcoxon-Mann-Whitney test using the SAS procedure npar1way. The Wilcoxon signed-rank test was used to compare lipid profile data coming from different time points among the same treatment group (control or test). The Wilcoxon-Mann-Whitney test was used to compare differences in lipid profile at the same time point between test and control group. A series of linear mixed-effects models was used to analyse changes over time (from T0 to T2 and from T0 to T4) among the two groups. Each model included fixed effects for group (control vs test), time point (T0, T2, T4) and their interaction (group × time point). A random intercept for each subject was included to account for repeated measures. Analysis was performed using the nlme package on R studio. Effect sizes were calculated using Cohen’s d and then interpreted according to conventional threshold. 95% CIs were reported to indicate the precision of the estimates. A p value <0.05 was considered statistically significant.

Results

Patient characteristics

61 patients with low to moderate disease activity as measured by SDAI were recruited in the study. Of them, 34 were randomly assigned to the test group and 27 to the control group, at a ratio of 2:1 (female/male). Baseline patients’ characteristics have been published previously¹⁸ and are here summarised in online supplemental table S2. Three female patients dropped out shortly after randomisation (2 in the test group and 1 in the control group), and 58 patients completed visit 2 (T2) (32 patients in the test group and 26 patients in the control group). At the end of the trial, 30 patients in the test group and 26 in the control completed visit T4 on week 16. The resulting test power still exceeded 89% with this sample size.

PRO measures

Analysis of PRO measures included comparison of results between the test and the control groups at baseline, week 8 and week 16 (longitudinal results). Differences in patient’s related outcomes in the same group over time, defined as T0 minus T4 and as T0 minus T2, were also analysed through mixed-effects modelling and used to compare the test group against the control.

Here, results from SF-36 and MFI-20 are presented.

Short Form-36

Longitudinal results from SF-36 are shown in online supplemental table S3. Compared with control group, a significant improvement from baseline to week 16 was observed in the test group across SF-36 mental health domain (p=0.0395, Cohen’s d=0.63, online supplemental table S3). No other statistically significant differences were observed when comparing patients belonging to the same study group at different time points.

Changes in SF-36 domains over time were also analysed by observing T0–T2 and T0–T4 variations through linear mixed effects modelling. Statistically significant improvements in role emotional, social functioning, mental health and vitality domains were highlighted when comparing control and test patients (table 1, figure 2). Specifically, mental health (p=0.0063; d=0.48) and vitality (p=0.0130; d=0.73) items showed a significant and robust amelioration in the test group from T0 to T2. A significant and robust improvement was also observed in role emotional (p=0.0087; d=0.49), mental health (p=0.0003; d=0.81), vitality (p=0.0056; d=0.60) and social functioning (p=0.0144; d=0.69) when considering variation from T0 to T4 in the test group. Moreover, statistically significant differences exceeded MCID in the test group (≥ 5 points). A significant amelioration was also noticed in the control group when comparing general health from T0 to T4 (p=0.0127; d=0.45), but this result was characterised by a not robust CI (95% CI 0.02 to 0.88), suggesting potential uncertainty. Similarly, physical functioning significantly improved in the control group from T0 to T2 (p=0.0234; d=0.38; 95% CI −0.04 to 0.79) and from T0 to T4 (p=0.0187; d=0.41; 95% CI −0.01 to 0.82), but both results were statistically uncertain due to CIs including zero.

Table 1. Differences in SF-36 domains between T0 and T2 and between T0 and T4, in control and test group.

		T0–T2				T0–T4
Item	Group	Mean±SD	P value	d	95% CI	Mean±SD	P value	d	95% CI
Physical functioning (n=54)	Ctrl	−7.86±22.05	0.0234	0.38	(−0.04 to 0.79)	−8.03±19.58	0.0187	0.41	(−0.01 to 0.82)
	Test	−5.67±15.47	0.5549	0.25	(−0.13 to 0.63)	−8.67±11.84	0.7196	0.65	(0.23 to 1.26)
Role physical (n=50)	Ctrl	−13.67±29.45	0.1496	0.43	(−0.01 to 0.83)	−7.29±42.66	0.3120	0.31	(−0.09 to 0.71)
	Test	−20.69±38.42	0.1692	0.64	(0.23 to 1.04)	−22.12±37.63	0.0612	0.61	(0.20 to 1.01)
Bodily pain (n=50)	Ctrl	−6.79±19.77	0.1408	0.35	(−0.08 to 0.78)	−7.21±21.17	0.1889	0.21	(−0.21 to 0.63)
	Test	−12.41±19.14	0.2276	0.81	(0.36 to 1.24)	−9.23±19.72	0.1712	0.68	(0.25 to 1.10)
General health (n=51)	Ctrl	1.76±17.77	0.8278	0.09	(−0.32 to 0.50)	−7.4±16.43	0.0127	0.45	(0.02 to 0.88)
	Test	−5.33±16.63	0.1616	0.42	(0.02 to 0.80)	−10.1±17.3	0.3534	0.68	(0.25 to 1.09)
Role emotional (n=50)	Ctrl	4.35±23.15	0.2043	−0.27	(−0.67 to 0.13)	6.94±36.75	0.1136	−0.23	(−0.63 to 0.17)
	Test	−2.30±37.72	0.1600	0.13	(−0.24 to 0.50)	−14.10±26.95	0.0087	0.49	(0.09 to 0.88)
Social functioning (n=51)	Ctrl	0±18.46	0.1545	0.22	(−0.18 to 0.62)	0.52±17.48	0.7521	0.11	(−0.28 to 0.50)
	Test	−9.27±16.76	0.5060	0.57	(0.16 to 0.97)	−13.89±20.31	0.0144	0.69	(0.26 to 1.10)
Mental health (n=53)	Ctrl	3.04±14.57	0.2295	−0.21	(−0.60 to 0.19)	3.35±19.12	0.2129	−0.15	(−0.54 to 0.25)
	Test	−6.13±14.24	0.0063	0.48	(0.07 to 0.87)	−9.33±11.74	0.0003	0.81	(0.37 to 1.24)
Vitality (n=53)	Ctrl	−0.4±16.71	0.8180	−0.03	(−0.43 to 0.37)	1.86±18.08	0.6714	−0.06	(−0.46 to 0.34)
	Test	−11.83±13.17	0.0130	0.73	(0.30 to 1.15)	−10.68±18	0.0056	0.60	(0.17 to 1.02)

Data are presented as mean±SD. P values refer to within-group changes over time. Cohen’s d indicates effect size, with corresponding 95% CIs. Statistically significant changes (p<0.05) are highlighted in bold.

SF-36, Short Form-36.

Figure 2. Radar chart illustrating average scores of SF-36 domains at T0 and T4, both in test and control groups. P values nominal. BP, bodily pain; GH, general health; MH, mental health; PF, physical functioning; RE, role-emotional; RP, role-physical; SF, social functioning; SF-36, Short Form-36; VIT, vitality.

Multidimensional Fatigue Inventory-20

No statistically significant differences were observed in MFI-20 when comparing test and control at T0, T2 and T4 (online supplemental table S4). However, linear mixed effect modelling revealed a significant and robust difference in the decrease of general fatigue from T0 to T2 (p=0.0163; d=−0.76) and from T0 to T4 (p=0.0004; d=−0.80) domain in the test group, compared with the control (table 2, figure 3). A significant change was also observed in reduced motivation from T0 to T4 in the test group, but the result was statistically uncertain due to the confidence interval (p=0.0042; d=−0.31; 95% CI −0.68 to 0.07). Differences observed in the test group exceeded MCID for both domains (≥1.02 and ≥0.70; respectively).

Table 2. Differences in MFI-20 domains between T0 and T2 and between T0 and T4, in control and test groups.

		T0–T2				T0–T4
Item	Group	Mean±SD	P value	d	95% CI	Mean±SD	P value	d	95% CI
General fatigue (n=52)	Ctrl	−0.14±4.09	0.9106	0.06	(−0.36 to 0.47)	−0.74±3.51	0.3868	0.19	(−0.23 to 0.61)
	Test	2.12±3.22	0.0163	−0.76	(−1.17 to 0.34)	2.93±3.67	0.0004	−0.80	(−1.21 to 0.37)
Physical fatigue (n=51)	Ctrl	0.22±3.18	0.7673	−0.07	(−0.48 to 0.34)	0.5±3.38	0.3352	−0.20	(−0.61 to 0.21)
	Test	1.5±3.73	0.1364	−0.51	(−0.89 to 0.12)	1.55±3.65	0.3955	−0.43	(−0.80 to 0.04)
Reduced activity (n=50)	Ctrl	−0.08±2.98	0.7071	0.13	(−0.28 to 0.54)	−0.52±3.38	0.8851	0.04	(−0.37 to 0.45)
	Test	1.19±3.01	0.0869	−0.56	(−0.95 to 0.17)	1.14±3.42	0.2247	−0.33	(−0.70 to 0.04)
Reduced motivation (n=52)	Ctrl	−0.26±2.11	0.9159	0	(−0.41 to 0.41)	−1.40±3.19	0.0273	0.38	(−0.05 to 0.80)
	Test	0.5±2.95	0.4307	−0.22	(−0.58 to 0.15)	0.96±3.11	0.0042	−0.31	(−0.68 to 0.07)
Mental fatigue (n=54)	Ctrl	0.33±3.18	0.4897	−0.14	(−0.54 to 0.26)	0.25±3.65	0.6594	−0.07	(−0.47 to 0.33)
	Test	0.97±3.06	0.5614	−0.34	(−0.71 to 0.03)	1.33±2.93	0.2554	−0.46	(−0.83 to 0.08)

Data are presented as mean±SD. P values refer to within-group changes over time. Cohen’s d indicates effect size, with corresponding 95% CIs. Statistically significant changes (p<0.05) are highlighted in bold.

MFI, Multidimensional Fatigue Inventory.

Figure 3. Radar chart illustrating average scores of MFI-20 domains at T0 and T4, both in test and control groups. P values nominal. MFI-20, Multidimensional Fatigue Inventory.

Morning stiffness

Morning stiffness was measured by its duration in minutes to maximum improvement and by its perceived severity on a numeric rating scale. Patients in the test group had a significant amelioration both in duration and intensity of morning stiffness from baseline to week 8 (p=0.0003, p=0.0002, respectively), as well as from baseline to week 16 (p=0.0004, p=0.0002, respectively) (online supplemental table S5, figure 4). When looking at the variation in morning stiffness values over time, measured from T0 to T2 and from T0 to T4 through linear mixed effects modelling, the test group showed a significant and robust improvement in morning stiffness duration from T0 to T2 (p=0.0129; d=0.75) and from T0 to T4 (p=0.0103; d=0.72). A consistent and meaningful amelioration was also observed in intensity values, which were significantly reduced in the test group from T0 to T2 (p=0.0081; d=0.81) and from T0 to T4 (p=0.0091; d=0.78) (online supplemental table S6).

Figure 4. Bar plots illustrating the mean and SD of morning stiffness duration in minutes (A) and intensity (B) of patients from both control and test groups, at different time points. Symbols indicate statistical significance within the same group, at different timepoints, as follows: *T0 versus T2; §T0 versus T4.

VAS physician

Pain score measured by physician (VAS physician) significantly improved in test group compared with control group, when looking at variation over time from T0 to T2 (p=0.0426; d=−0.91) and from T0 to T4 (p=0.0047; d=−1.18). A statistically significant variation was also observed in the control group from T0 to T4; however, it was considered as an uncertain result due to CI (p=0.0121; d=0.38; 95% CI −0.05 to 0.80) (table 3, online supplemental figures S1). Differences observed in the test group exceeded MCID both from T0 to T2 and from T0 to T4 (≥1 point). No other differences were observed when comparing test and control groups at different time points (online supplemental table S7).

Table 3. Differences in VAS physician pain score, defined as variation from T0 to T2 and T0 to T4.

	T0–T2 (n=58)				T0–T4 (n=56)
Group	Mean±SD	P value	d	95% CI	Mean±SD	P value	d	95% CI
Ctrl	0.44±1.39	0.0975	0	(−0.41 to 0.41)	0.67±1.73	0.0121	0.38	(−0.05 to 0.80)
Test	1.14±1.36	0.0426	−0.91	(−1.33 to 0.47)	1.72±1.45	0.0047	−1.18	(−1.64 to 0.71)

Data are presented as mean±SD. P values refer to within-group changes over time. Cohen’s d indicates effect size, with corresponding 95% CIs. Statistically significant changes (p<0.05) are highlighted in bold.

VAS, Visual Analogue Scale.

Lipid profile

The mean values for serum triglycerides, total cholesterol, HDL and LDL are presented in table 4. No statistically significant differences were observed when comparing lipid fractions among the two groups at different time points. However, some statistically significant variations were observed when looking at lipid profiles in patients from the same treatment group, at different time points. LDL values significantly decrease from T0 to T2 (p=0.0062) and from T0 to T4 (p=0.0129) in the control group. In the test group, HDL significantly decreased from T0 to T2 (p=0.0376) (data not shown).

Table 4. Patients’ lipid profile.

	Control group	Test group	P value	d	95% CI
Triglycerides
T0 (n=57)	133.83±54.78	137.06±74.22	0.8716	0.20	(−0.40 to 0.80)
T2 (n=55)	126.19±68.17	163.59±121	0.3408	0.44	(−0.17 to 1.04)
T4 (n=50)	139.58±78.77	156.50±87.68	0.264	0.26	(−0.34 to 0.86)
Total cholesterol
T0 (n=57)	218.33±50.93	224.79±39.19	0.8273	0.10	(−0.50 to 0.70)
T2 (n=55)	206.54±47.64	224.28±39.82	0.08394	0.67	(0.05 to 1.28)
T4 (n=50)	207.46±39.62	227.27±34.02	0.125	0.47	(−0.19 to 1.02)
HDL cholesterol
T0 (n=57)	64.95±20.11	66.12±15.48	0.5497	0	(−0.60 to 0.60)
T2 (n=55)	62.19±22.40	62.90±17.84	0.5493	−0.08	(−0.68 to 0.52)
T4 (n=50)	62.83±18.98	63.04±16.75	0.6408	−0.03	(−0.63 to 0.57)
LDL cholesterol
T0 (n=57)	126.54±43.16	131.27±37.18	0.821	0.05	(−0.55 to 0.65)
T2 (n=53)	118.92±41.81	127.48±35.82	0.3832	0.60	(−0.01 to 1.21)
T4 (n=50)	116.75±31.91	132.88±31.11	0.08922	0.37	(−0.23 to 0.98)

Data are presented as mean±SD.

HDL, high-density lipoprotein; LDL, low-density lipoprotein.

Discussion

More than one in three patients with RA under effective clinical control of their disease still experiences reduced health-related QOL due to pain, psychological and functional limitations,^{29 30} meaning that a holistic approach is urgently needed in RA, coupling pharmacological treatment to diet and to other complementary practices able to improve patients’ well-being.

In this study, we tested an innovative approach based on the addition of a food formula to patients’ regular diet, investigating whether and to which extent a food containing MCTs and fibre impacted on both clinical and PROs. Besides amelioration in the patient’s disease activity, already described by Heidt et al,¹⁸ data regarding QOL parameters, morning stiffness, pain intensity and lipid profile were analysed and discussed here.

In the present trial, clinical and disease activity measurements were paired with PRO analysis. The evaluation of PRO has become increasingly common in the clinical practice, due to the potential mismatch between patient’s actual disability (as measured with disease-related variables such as joint counts or blood biomarkers) and patient’s perception of disability.³¹ Measurement of PRO may help in characterising health outcomes of primary importance to patients, and which may affect their overall well-being. RA dramatically affects patients’ QOL, leading to physical and mental impairments which in turn negatively influence both therapeutical outcomes and the healthcare resources.²⁹ Here, various aspects of the patient’s QOL were considered, including mental and physical functioning, fatigue, morning stiffness and pain.

As expected, our cohort had lower scores of SF-36 emotional and physical domains of well-being at baseline, when compared with the general German population,^{32 33} thus confirming the substantial impact of RA on health-related QOL. Supplementation of regular diet with MCTs and fibre significantly ameliorated vitality, social functioning, emotional and mental health domains score when compared with control, as well as moved them closer to the values observed in the general healthy population.^{32 33} Moreover, changes observed in SF-36 domains reflected improvements which are considered as clinically meaningful in RA.²⁵ Since no amelioration was observed in the control group, we hypothesise that these differences may be related to the distinct metabolism of MCTs and LCTs. Compared with LCTs, MCTs are quickly converted into energy after ingestion, leading to a higher ketone production.³⁴ The remarkable ability of MCTs to induce ketosis more effectively than LCTs has also been confirmed by our previous publication, since only patients taking MCTs were shown to have a significant increase in BHB levels.¹⁸ Several pieces of evidence support the role of MCT-derived ketones in promoting cognitive health, as summarised in a narrative review from Shcherbakova et al.³⁵ MCTs may have beneficial effects by providing alternative and efficient fuel to our brain through ketone bodies, or by reducing oxidative stress and inflammation, both implicated in worsening brain function.³⁵ As with many other chronic inflammatory disorders, RA manifests in various neuropsychiatric symptoms that impact patients’ functional capacity and QOL, as well as their reactivity to pain and to drug therapy effectiveness.³⁶ Our current evidence suggests that MCTs have the potential to enhance cognitive function and overall well-being in these patients. Therefore, we propose that MCTs could serve as a promising dietary complementary intervention.

Beyond mental and psychological factors, physical impairments have a major impact on RA patients’ health-related QOL. Here, patients under regular assumption of MCTs showed a statistically significant amelioration in morning stiffness duration and intensity, pain and general fatigue, all of which represent key RA manifestations which are only marginally improved by conventional drug therapies.37,40 In addition to demonstrating statistical significance when compared with the control group, these improvements surpassed the MCID, thereby establishing their clinical relevance.^{25 26 28} Morning stiffness was an exception, as its clinical relevance could not be determined due to the absence of an established MCID.²⁰ As well as for mental health domains, described above, patients taking LCTs and fibre did not experience any improvement in their physical health components. Studies conducted on animal models reported that continuous intake of MCTs,⁴¹ as well as of their derivative octanoic acid,⁴² increases mitochondrial biosynthesis and metabolism. Dysfunction in these processes has been recently linked to the onset and the progression of RA,⁴³ thus justifying a possible beneficial effect of MCTs on general fatigue and physical vitality by enhancing mitochondrial metabolism and improving overall energy levels.⁴⁴

In addition to MCTs, fibre can also have played a significant role in improving patients’ perceived QOL through indirect mechanisms. Clinical evidence suggests that a high-fibre diet is associated with enhanced overall well-being, a reduced risk of CVDs and improved gut health.¹⁶ However, in the present trial, fibre was introduced after 8 weeks and given to both groups at the same time. Therefore, we cannot conclude that fibre alone exerted an additional or independent effect in mediating the positive outcomes observed. Rather, we can only infer that fibre co-supplementation did not attenuate or reverse the beneficial effects already achieved after 2 months of MCT-based regimen. Supporting the potential role of fibre, a randomised clinical trial from Latif et al⁴⁵ recently investigated the effects of high fibre multigrain supplementation in a cohort of patients with RA. Compared with the control group, those receiving the multigrain supplementation showed significant improvement in Disease Activity Score-28, morning stiffness, pain scale and a reduction in circulating inflammatory biomarkers as well.⁴⁵ Similarly, Kamal et al⁴⁶ reported that 49 patients with RA who consumed 30 g/day of water soluble gum Arabic powder experienced significant improvements in swollen joint count, tender joint count and VAS. Given the current study design, we hypothesise that MCTs and fibre combination may be compatible, but further studies are needed to disentangle the specific contribution of fibre.

Our previously published results demonstrated a significant improvement in disease activity in the test group consuming MCTs in combination with fibre, compared with the control group. We propose that SDAI could be significantly associated with PROs, as it provides distinct and complementary insights into the clinical characteristics of patients with RA. Consistent with previous data,⁴⁷ we suggest that RA activity could be a key predictor for QOL outcomes. Nonetheless, the complementary approach used in the present trial, integrating both clinical (SDAI) and QOL measurements, may be useful to improve current treatment strategies.

Given the high fat content in both test and control food products, we wanted to be sure that our intervention did not negatively influence blood lipid values, in particular triglycerides, total and LDL cholesterol values. This is of particular importance since RA as a chronic inflammatory disease is already associated with a 50% increase in CVDs and mortality comparable to that of diabetes.⁴⁸ This is why the European Society of Cardiology Guidelines identified RA as an independent CVD risk factor, mainly because of the systemic chronic low-grade inflammation and endothelial dysfunction related to this pathology.⁴⁹ Baseline blood lipid profile remained almost unchanged throughout the trial and no statistically significant differences were observed when comparing the two groups at different timepoints. A slight but statistically significant decrease in HDL was observed in the test group from T0 to T2, after taking MCTs with no fibre for 2 months. Our findings are consistent with a recent systematic review conducted by McKenzie et al,⁵⁰ according to which prolonged MCT supplementation does not affect total, LDL or HDL cholesterol. Based on this evidence, we can conclude that regular consumption of MCT-containing test product does not adversely affect patients’ lipid profile.

Several studies indicate that adopting a healthy and balanced diet would be ideal for patients with RA to help them manage their disease. However, in clinical practice, many patients face challenges in adhering to specific dietary changes consistently. The use of a targeted supplement as the one proposed in our study offers a controlled and practical approach to ensure the adequate intake of specific nutrients ie, MCTs and fibre, that may be difficult to obtain in comparable and adequate amounts through diet alone.

A strength of our clinical trial is its double-blinded and randomised design, with a statistical power ranging from 89% (n=56) to 90% (n=58), ensuring the robustness of our findings. Additionally, both the control and test groups exhibit a representative gender proportion, which enhances the validity of our results. A further strength lies in the familiarity of the patients with the rheumatologist and their prior experience with long-term treatment regimens, which contributed to high compliance rates and optimised the effectiveness of the intervention. Nonetheless, our study does present certain limitations. First of all, recruiting multiethnic patients in a multicentric trial would enhance the generalisability of our findings. Moreover, as the first trial exploring the supplementation of both high amounts of fats and fibre, additional clinical trials with similar settings are needed to further substantiate our results and validate the observed benefits. Particularly, future research should consider a dedicated study design to investigate the specific role of dietary fibre in driving some of the effects observed in this work. In this context, varying both the amount and the source of fibre could provide valuable insights into its individual contribution. Such trials would help distinguish the effects of fibre from other dietary components and clarify its potential therapeutic relevance. Also, while the short-term effects of MCTs and fibre supplementation on patients’ lipid profile are reassuring, more data should be collected to understand the role of the present regimen in terms of long-term sustainability and health impact.

In conclusion, our results demonstrated that patients with RA receiving regular supplementation of MCTs experienced a remarkable, clinically relevant improvement in their health-related QOL, compared with those on a control supplement. Despite the high-fat daily dose, no drastic changes were observed in patients’ lipid profile, and no side effects were reported by participants. The unique ability of MCTs in providing a rapid and efficient alternative energy source to the brain through ketone body production, along with their potential pro-cognitive effects, may explain the observed amelioration in different physical and mental PROs, including overall mental well-being, vitality, fatigue, morning stiffness duration and intensity and pain. These compelling findings, along with our previously published data, suggest that a holistic approach addressing comorbidities and the specific domains where patients with RA encounter complications might be more advantageous than drug therapy alone. In addition to general dietary recommendations, which have been validated but still require precise application, incorporating specific single nutrients into the diet of patients with RA could represent a practical approach to improve their mental and physical well-being.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information.