Ketogenic diet improves disease activity and cardiovascular risk in psoriatic arthritis: A proof of concept study

Roberta Ramonda; Francesca Ometto; Giovanni Striani; Giacomo Cozzi; Daniela Basso; Filippo Evangelista; Mariagrazia Lorenzin; Laura Scagnellato; Ada Aita; Marta Favero; Filippo Brocadello; Andrea Doria

doi:10.1371/journal.pone.0321140

. 2025 Apr 22;20(4):e0321140. doi: 10.1371/journal.pone.0321140

Ketogenic diet improves disease activity and cardiovascular risk in psoriatic arthritis: A proof of concept study

Roberta Ramonda ^1,^☯,^*, Francesca Ometto ^2,^☯,^*, Giovanni Striani ^1,^☯,^*, Giacomo Cozzi ¹, Daniela Basso ³, Filippo Evangelista ¹, Mariagrazia Lorenzin ¹, Laura Scagnellato ¹, Ada Aita ³, Marta Favero ^1,⁴, Filippo Brocadello ⁵, Andrea Doria ¹

Editor: Luca Navarini⁶

PMCID: PMC12013891 PMID: 40261944

Abstract

Objectives

Very low-calorie ketogenic diet (VLCKD) is a low-carbohydrate, low-calorie regimen that leads to rapid weight loss and may reduce inflammation. This study assessed the impact of VLCKD on anthropometric measurements, inflammatory biomarkers, metabolic health, and cardiovascular risk in psoriatic arthritis (PsA) patients moderately overweight or in class I obesity.

Methods

A proof-of-concept single-arm monocentric study involved PsA patients undergoing a 9-week VLCKD treatment. Patients with Body Mass Index (BMI) ≥27 and <35, in stable (≥6 months) remission or low disease activity, as defined by Disease Activity in PSoriatic Arthritis (DAPSA) score, were included and underwent nutritional evaluations every 3 weeks. The study analyzed changes after the VLCKD intervention and the association between changes of anthropometric parameters and clinical and laboratory variables.

Results

Twenty patients were enrolled since April 2022 and completed the study in May 2023. Median baseline BMI was 30.9 (interquartile range 29.1–33) kg/m². All participants exhibited low baseline disease activity, which correlated with BMI (Spearman’s correlation coefficient (r_s)=0.59,p=0.007). Following VLCKD, significant improvements were observed in all anthropometric measures (BMI -3.5[-4;-2.6]), PsA activity (DAPSA -6.1[-16.8;3.7]), cardiovascular parameters (SCORE2 index -0.2[-0.7;0.1]), insulin resistance (Homeostatic Model Assessment-Insuline Resistance -2.1[-1.1;-3.0]), and lipid profile. Most inflammatory biomarkers remained within normal limits. BMI reduction correlated with changes in DAPSA scores (r_s=0.52,p=0.020). Patients with higher baseline weight or clinical activity experienced more pronounced improvements.

Conclusions

VLCKD significantly improved PsA activity and metabolic health. Patients with a higher BMI and less controlled disease are particularly motivated and could benefit more from VLCKD compared to those with lower BMI or better disease control.

Introduction

Diet may influence both the onset and management of rheumatic diseases, contributing to the complex interplay between genetic and environmental factors. Specific nutrients can impact the balance between anti-inflammatory and pro-inflammatory cytokines: omega-3 polyunsaturated fatty acids (PUFAs) are known for their anti-inflammatory properties [1,2,3,4] whereas sugars and high-calorie foods may increase risk of rheumatic diseases [5]. Although few studies have investigated the influence of specific diets in rheumatic conditions, there is growing evidence of the importance of diet in patients with psoriatic arthritis (PsA) and spondyloarthritis, particularly the Mediterranean diet [6–10]. Furthermore, PsA patients have an elevated risk of overweight and should be routinely monitored for metabolic and cardiovascular disease [11–13,14]. A healthy and balanced diet is particularly recommended in rheumatic patients to achieve and maintain normal weight, as well as mitigate biomechanical joint stress [15,16].

The ketogenic diet (KD) is a low-carbohydrate, high-fat regimen that induces ketosis in the body and has become widely recognized as an effective tool for weight loss [17]. The very-low-calorie KD (VLCKD) is an extremely restrictive regimen providing very few grams of carbohydrates, low calorie intake and a minimal protein intake necessary to preserve lean mass [18]. The VLCKD and KD have been investigated for various clinical conditions beyond their established use in severe obesity and drug-resistant epilepsy [19,20], including cardiovascular disease [21], osteoarthritis [22], fibromyalgia [23], psoriasis [24,25], rheumatoid arthritis [26], and gout [27].

A series of intricate processes triggered by the KD suggests that this dietary approach could be an effective tool in reducing both inflammation and pain [20,28]. Beta hydroxybutyrate (BHB), the main ketone body, may exert inhibitory effects on various pro-inflammatory cytokines such as interleukins (IL)-1β, IL-17, IL-18. These cytokines have been shown to decrease with KD in various inflammatory conditions, including rheumatoid arthritis [19,29,30]. The KD and VLCKD also improve insulin resistance, which in turn inhibits the production of IL-1α, IL-1β, IL-6, tumor necrosis factor α (TNF-α), and leptin [31,32]. These mechanisms, besides downregulating pro-inflammatory cytokines produced by the adipose tissue, suggest that the anti-inflammatory effect of KD and VLCKD may be superior to that observed with other hypocaloric diets [33,34].

Therefore, we aimed to conduct a single-arm, proof-of-concept monocentric study to evaluate the effectiveness of a 9-week VLCKD on disease activity measured with Disease Activity in PSoriatic Arthritis (DAPSA) index in patients with PsA and moderate overweight status or class I obesity. Secondary endpoints were to measure the efficacy of VLCKD on anthropometric measurements, other measures of PsA activity, inflammatory indices, lipid profile, insulin resistance, and cardiovascular risk.

Methods

Study design

We conducted a single-arm, prospective, single-center proof-of-concept study at the Spondyloarthritis outpatient clinic of Padova University Hospital, Italy. Moderately overweight or class I obesity patients with PsA who underwent a 9-week VLCKD regimen were enrolled. Patients were evaluated every 3 weeks by a dietitian, who provided guidance to patients, and by a rheumatologist at baseline (W0) and at the end of the study (W9).

Patients

Inclusion criteria were: (I) diagnosis of PsA according to the Classification Criteria for Psoriatic Arthritis (CASPAR) [35] with disease duration <10 years; (II) age ≥18 years; (III) body mass index (BMI) ≥27 and <35; (IV) stable treatment with conventional synthetic disease-modifying anti-rheumatic drugs (DMARDs) or biological/targeted DMARDs in the 6 months prior to enrollment; (V) remission or stable low disease activity (LDA) as defined by Disease Activity in Psoriatic Arthritis (DAPSA) index in the 6 months prior to enrollment. Exclusion criteria were: (I) concomitant musculoskeletal diseases; (II) patients unable to follow nutritional indications; (III) ongoing corticosteroid treatment; (IV) patients on a specific diet or regularly taking nutraceuticals or nutritional supplements; (V) contraindications to VLCKD [36].

Diet protocol

Patients were assessed every three weeks by a nutritionist who inquired about their diet, provided nutritional guidance, and offered alternatives in cases of difficulty adhering to the nutritional protocol. A very low carbohydrate content (<20 g/day) was allowed. Protein and lipid intake were approximately 1–1.4 g/kg of ideal body weight/day and 15–30 g/day, respectively. Total caloric intake was between 450 and 800 kcal/day based on calculated ideal body weight.

Collected data

A complete list of variables included in the study may be found in S1 Table. Sociodemographic data were collected at W0. At W0 and W9 the main variables collected were:

- Anthropometric measurements: body weight (to the nearest 0.1 kg), standing height (to the nearest 0.5 cm); abdominal circumference; BMI was calculated accordingly.
- Measures of PsA activity (including patient-reported outcomes): tender joint count (TJC) and swollen joint count (SJC), dactylitis; DAPSA, Disease Activity Score-28 – C Reactive Protein (DAS28-CRP), ASDAS-CRP (Ankylosing Spondylitis Disease Activity Score – C Reactive Protein), Psoriasis Area Severity Index (PASI), Spondyloarthritis Research Consortium of Canada score (SPARCC); physician- and patient-reported outcomes: lost work hours according to the Work Productivity and Activity Impairment Questionnaire (WPAI), VAS (Visual Analogue Scale) pain; patient and physician global assessment measured on a VAS scale (PtGA and PGA).
- Blood and urine samples: Samples were collected after an overnight fast and analyzed at the Laboratory Medicine facility of Padova University Hospital for inflammatory indices (hsCRP [high-sensitivity C-reactive protein], Erythrocyte Sedimentation Rate [ESR], IL-1α, IL-1β, IL-6, TNF-α, fecal calprotectin [f-CPT]), and for hematology and biochemistry parameters (lipid profile, insulinemia, hepatic, renal, and thyroid function, blood glucose, azotemia, protein electrophoresis, uricemia, intestinal permeability test; urinary ketones [as an indicator of adherence to the VLCKD]). The Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index was calculated using the formula: fasting glucose (mg/dL) × fasting insulin (mU/L)/ 405. Due to reduced levels of IL-1α, IL-1β, IL-6, and f-CPT, these variables were converted into binary categorical variables for statistical analysis, using the upper limit of the normal range specified by the laboratory test company as the cut-off. The cut-offs were: 3.9 ng/L for IL-1α, 5.0 ng/L for IL-1β, 7.0 ng/L for IL-6, and 70 μg/g for f-CPT.
- Nutritional questionnaires: PREDIMED (PREvención con DIeta MEDiterránea, Mediterranean diet adherence questionnaire) and FFQ (Food Frequency Questionnaire).
- Cardiovascular parameters: SBP (Systolic Blood Pressure), DBP (Diastolic Blood Pressure), SCORE2 index (Systematic COronary Risk Evaluation 2 index). The SCORE2 index [37] was calculated using the appropriate calculators for individuals aged over 75 and those with type 2 diabetes. Subjects under 40 years of age were excluded from SCORE2 as per definition. Subsequently, the scores were adjusted by multiplying by 1.5, as recommended by the EULAR cardiovascular risk guidelines for arthritis [14].

Medical records were retrieved by a single investigator and recorded anonymously in an electronic database on a password-protected computer. The data were last accessed on January 8, 2024. All enrolled patients provided written informed consent to participate in the study in accordance with the principles of the Declaration of Helsinki, and for the anonymous use of personal data, in compliance with Italian Legislative Decree 196/2003. Ethical approval for the study was obtained on December 12, 2011 (Approval No. 2438P).

Statistical analysis

The study analysis was structured into four phases: (I) association between variables at W0 that could impact the analysis of the effect of VLCKD; (II) changes in parameters between W0 and W9 to identify significant modifications following VLCKD; (III) association between changes in anthropometric parameters and other variables during the study to assess the impact of weight, BMI and abdominal circumference modifications on PsA disease activity; (IV) association of variables at W0 with modifications during the study to identify baseline predictors of a better response to the VLCKD.

Continuous variables were tested for normality using the Shapiro-Wilk test, revealing a non-normal distribution for all variables, necessitating non-parametric tests. The analysis of the changes in continuous variables between W0 and W9 was conducted using the Wilcoxon test. Associations between categorical variables were evaluated using either the Chi-square test or Fisher’s exact test, as appropriate. The Kruskal-Wallis test was employed to assess the association between categorical and continuous variables. Spearman’s correlation coefficient was utilized for continuous variables. All tests were considered statistically significant at the alpha level of p<0.05. Continuous variables are expressed as median and interquartile range (IQR). SPSS Version 25.0 was used for statistical analysis.

Results

Characteristics of patients at W0

Twenty patients were included starting from April 27, 2022, with the last patient completing the study on May 31, 2023. None of the patients dropped out of the study or reported adverse events. The characteristics of the patients and assessments at W0 are reported in Table 1 and 2 and in S2–S5 Tables. The patients were 9 (45.0%) male with a median age of 55.5 (50–59.3) years, BMI 30.9 (29.1–33) kg/m². Seven patients (70%) presented with cardiovascular comorbidity and 2 (6.6%) had type-2 diabetes. Thirteen patients (65%) were treated with biological DMARDs. At W0, all patients were in PsA remission or low disease activity according to DAPSA: 11.5 (5.2;23.8). ASDAS-CRP was 1.5 (0,5;1,7) and PASI 0 (0;1.8). All inflammatory biomarkers tested in the study revealed no detectable inflammation at W0, except for 4 (21.1%) patients who had slightly elevated IL-6 levels (Table 2). Cardiovascular risk score was 6.9 (3.8;14), according to SCORE2 (expressed as 10-year risk of cardiovascular events).

Table 1. Characteristics of the patients at W0.

Subjects	20
Male, n (%)	9 (45.0)
Age, years, median (IQR)	55.5 (50;59.3)
Height, cm, median (IQR)	173 (164;177.3)
Smoke ever, n (%)	6 (30.0)
Cardiovascular comorbidity, n (%)	7 (35.0)
Type 2 diabetes, n (%)	2 (10.0)
Disease duration, years, median (IQR)	8.8 (4.2;14.3)
Current csDMARD, n (%)	6 (30.0)
Current b/tsDMARD, n (%)	14 (70.0)

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Categorical variables are reported as number and percentage, continuous variables are reported as median and interquartile range.

IQR, interquartile range; csDMARDs conventional synthetic disease modifying antirheumatic drugs; b/tsDMARDs biological/targeted synthetic disease-modifying antirheumatic drugs.

Table 2. Characteristics of the patients and modification during the study.

	W0	W9	Δ (W9-W0)	p*
Weight, kg, median (IQR)	91 (81.8;99.7)	83.6 (70,5;88,5)	-10.2 (-12.6;-7.7)	<0.001
Height, cm, median (IQR)	173 (164;177.3)	173 (164.8;177.3)	0 (0;0)	NA
BMI, kg/m2, median (IQR)	30.9 (29.1;33)	27.2 (25.8;29.7)	-3.5 (-4;-2.6)	<0.001
Abdominal circumference, cm, median (IQR)	106 (103.8;115.3)	96 (91;106)	-11.8 (-14;-10)	<0.001
Tender joints count (0–68), median (IQR)	3 (1;6)	0 (0;2.5)	-1 (-2;0)	0.007
Swollen joints count (0–68), median (IQR)	0 (0;2)	0 (0;0.3)	0 (-1.3;0)	0.033
DAPSA, median (IQR)	11.5 (5.2;23.8)	8.6 (2.1;13.5)	-6.1 (-16.8;3.7)	0.006
DAS28-CRP, median (IQR)	2.6 (2.1;3.7)	2.4 (1.8;2.8)	-0.9 (-1.8;0.7)	0.068
ASDAS-CRP, median (IQR)	1.5 (0,5;1,7)	0.9 (0.4;1.4)	-0.4 (-0.7;0)	0.016
SPARCC, median (IQR)	1.5 (0;4.5)	0 (0;4.3)	0 (-3.5;2.5)	0.072
PASI, median (IQR)	0 (0;1.8)	0 (0;0.2)	0 (-1.2;0)	0.027
Patient global assessment (0–10 cm), median (IQR)	4 (2;5.3)	3 (1;4.3)	-0.5 (-4;1.5)	0.103
Physician Global Assessment (0–10 cm), median (IQR)	3.5 (2;5)	2.5 (0.8;4)	-0.5 (-4;1.3)	0.038
WPAI – Lost work hours, median (IQR)	0 (0;0)	0 (0;0)	0 (0;0)	0.196
hsCRP, mg/L, median (IQR)	0.2 (0.1;0.4)	0.2 (0.1;0.7)	0 (-0.1;0.1)	0.777
ESR, mm/h, median (IQR)	14 (7.8;30.8)	19 (8.8;42.5)	4 (-0.3;12)	0.055
IL-1α ≥ 3,9 ng/L^°, n (%)	0 (0)	0 (0)	0 (0)	NA
IL-1β ≥ 5,0 ng/L^°, n (%)	4 (21.1)	1 (5.3)	-3 (-15.8)	0.582
IL-6≥7,0 ng/L^°, n (%)	4 (21.1)	4 (21.1)	0 (0.0)	0.110
TNFα, ng/L^°, median (IQR)	12.8 (7.3;92.9)	12.5 (6.6;63.5)	-1.7 (-14.4;0.4)	0.227
Fecal calprotectin ≥70 μg/g ^{^}, n (%)	7 (38.9)	4 (27.8)	-3 (15.8)	0.001
Total cholesterol, mg/dl, median (IQR)	194 (165;233)	185 (135.3;209.5)	-23 (-41.5;-4)	0.007
HDL cholesterol, mg/dl, median (IQR)	51.5 (46.3;62.5)	52.5 (42.3;64.5)	-3.5 (-9.3;2.3)	0.150
LDL cholesterol, mg/dl, median (IQR)	114 (96.5;152.3)	110 (68.3;136)	-10 (-31.3;-2.5)	0.037
Triglyceride, mg/dl, median (IQR)	103.5 (81.5;128.5)	79 (65;89.5)	-25 (-50.3;-3.8)	0.004
Uricemia, mmol/L, median (IQR)	0.4 (0.3;0.4)	0.4 (0.3;0.4)	0 (0;0)	0.861
Blood glucose, mg/dl, median (IQR)	100 (87.5;115.5)	95 (89.5;102.8)	-7 (-16.3;2.5)	0.076
Insulinemia, mU/L^°, median (IQR)	15.4 (11;21.8)	9.2 (6.6;63.5)	-5.6 (-9.7;-3.9)	<0.001
HOMA-IR, median (IQR)	3.7 (2.4;5.8)	2.3 (1.4;3.4)	-2.1(-1.1;-3.0)	<0.001
Lactulose/mannitol ratio, median (IQR)	0 (0;0)	0 (0;0)	0 (0;0)	0.035
Ketones, g/L, median (IQR)	0 (0;0)	0 (0;0.1)	0 (0;0.1)	0.035
PREDIMED score, median (IQR)	7 (7;9)	8.5 (6.8;10)	0.5 (-2.3;2)	0.761
Systolic blood pressure, mmHg, median (IQR)	140 (130;145)	130 (120;140)	0 (-6.3;0)	0.246
Diastolic blood pressure, mmHg, median (IQR)	85 (80;90)	80 (80;90)	0 (0;5)	0.674
SCORE2, 10-year risk percentage^°§, median (IQR)	6.9 (3.8;14)	7.4 (4.1;12.3)	-0.2 (-0.7;0.1)	0.009

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°Data calculated from 19 patients; ^ data calculated from 18 patients.

IQR, interquartile range; BMI, body mass index; DAPSA, disease activity in psoriatic arthritis; DAS28-CRP, disease activity score on 28 joints with C-reactive protein; ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score – C-Reactive Protein; SPARCC, Spondylarthritis Research Consortium of Canada; PASI, Psoriasis Area Severity Index; WPAI, Work Productivity and Activity Impairment questionnaire; hsCRP, High Sensitivity CRP, ESR, Erythrocyte Sedimentation Rate; IL, interleukin, TNFα, Tumor Necrosis Factor alpha; HDL, High Density Lipoprotein; LDL, Low Density Lipoprotein; HOMA-IR Homeostatic model assessment for insulin resistance; PREDIMED, PREvención con DIeta MEDiterránea; SCORE2 (Systematic Coronary Risk Evaluation 2).

Association between variables at W0

The analysis of the association between measurements at W0 was conducted using different types of tests and is comprehensively detailed in S3–S5 Tables. At W0, the anthropometric measurements (weight, BMI, abdominal circumference) were significantly correlated with each other and male subjects had a significantly higher weight. BMI positively correlated with DAPSA and DAS28-CRP, indicating that greater disease severity at W0 was present in subjects with a higher BMI (r_s=0.59, p=0.007 and r_s=0.47, p=0.035, respectively). No significant associations were observed between the anthropometric measurements and inflammatory biomarkers. Measures of peripheral and axial PsA, and patient-reported measures, correlated with each other, except for SPARCC (S4 Table). As expected, DAS28-CRP correlated with ESR and hsCRP, while peripheral joint-related indices (SJC) and PGA were significantly associated only with IL-6 levels, which were elevated in those with a more active disease (S3 Table). Conversely, at W0, TNFα levels correlated negatively with joint disease indices, DAPSA and DAS28-CRP, with higher levels in those with less active disease (r_s=0.48, p=0.034 and r_s=0.45, p=0.047, respectively).. As, expected, fasting insulinemia, glucose and HOMA-IR positively correlated with weight, BMI and abdominal circumference, being higher in individuals with increased measurements (S4 Table). At W0, anthropometric measurements no significant associations with the lipid profile or the cardiovascular indices (S4 Table).

Changes between W0 and W9 (identification of significant modifications following VLCKD)

The modification of the variables throughout the study is reported in Table 2 and is fully provided in S6–S11 Tables and S1 Fig. All anthropometric variables were significantly reduced with a median weight reduction of -10.2 (-12.6;-7.7) kg, a BMI reduction of -3.5 (-4;-2.6), and an abdominal circumference reduction of -11.8 (-14;-10) cm. Also, most domains of PsA (peripheral, axial, skin disease and patient-reported outcomes), significantly improved except for enthesitis (SPARCC). In particular, the DAPSA was reduced by a median of -6.1 (-16.8;3.7).

Inflammatory biomarkers remained stable following VLCKD, except for f-CPT levels which decreased significantly (Table 2). Among the laboratory variables, insulin levels significantly decreased by -5.6 (-9.7;-3.9) mU/L and accordingly HOMA-IR (-2.[-1.1;-3.0]). The lipid profile overall improved: total cholesterol (TC), Low Density Lipoprotein (LDL)-cholesterol, and triglycerides significantly decreased [by -23 (-41.5;-4), -10 (-31.3;-2.5) and -25 (-50.3;-3.8) mg/dL, respectively] with non-significant reduction in High Density Lipoprotein (HDL). As anticipated in the context of a ketogenic diet, urinary ketones increased significantly (Table 2). Lactulose/mannitol ratio increased due to a non-significant decrease in mannitol while lactulose and sucrose remained stable (Table 2, S9 Table and S1 Fig).

Nutritional questionnaires revealed a significant reduction in the consumption of cereal derivatives and processed cereal products, fresh fruit, legumes, dairy products, sweets, sodas, and alcoholic beverages. Conversely, the consumption of nuts, seafood, and eggs significantly increased (Fig 1). Adherence to the Mediterranean diet, measured by PREDIMED, remained stable (Table 2).

Fig 1 — Significance refers to the Wilcoxon test, * p < 0.05, **p < 0.01. W0 week 0; W9 week 9. Although SBP and DBP were not significantly reduced, improvement in cardiovascular risk was significant: -0.2 (-0.7;0.1) units in SCORE2 10-year risk percentage.

Association between changes in anthropometric measurements and changes in other variables during the study (assessing the impact of weight, BMI and abdominal circumference modification on PsA disease activity)

The results of the associations between the modification of anthropometric measures and modification of inflammatory and disease indices are reported in Fig 2. For full details, see S12–S18 Tables.

Fig 2 — Values displayed refer to Spearman’s correlation coefficient r_s, negative correlations are in red, positive correlations are in blue. * p < 0.05, **p < 0.01, BMI, body mass index, DAPSA, disease activity in psoriatic arthritis; DAS28-CRP, disease activity score 28 with C reactive protein; ASDAS-CRP, Ankylosing Spondylitis Disease Activity Score – CRP; SPARCC, Spondyloarthritis Research Consortium of Canada; PASI, Psoriasis Area Severity Index; Physician Global Assessment; WPAI, Work Productivity and Activity Impairment questionnaire; hsCRP, High sensitivity CRP, ESR, Erythrocyte Sedimentation Rate; IL-1α; TNFα, Tumor Necrosis Factor alpha.

The reduction in BMI significantly correlated with a reduction of PsA activity measures, specifically peripheral arthritis (DAPSA, r_s =0.52, p=0.020), and WPAI lost work hours (r_s =0.26, p=0.022). The reduction in abdominal circumference correlated with the reduction of TJC (r_s =0.48, p=0.033). No significant correlation between changes in anthropometric measures and inflammation indices was observed, except for a modest and inverse association between the change in abdominal circumference and the change in hsCRP (r_s=0.50, p=0.046) (S14 and S18 Tables). Similarly, the improvement in anthropometric measures was not associated with a consistent change in the lipid profile, while a reduction of weight and BMI correlated with reduction of blood glucose (r_s=0.60, p=0.005 and r_s =0.62, p=0.003, respectively) and HOMA-IR (BMI only, r_s=0.46, p=0.046) (S15 Table). As expected, both weight and BMI reduction correlated with the increase in urinary ketones (r_s=-0.56, p=0.012 and r_s =-0.51, p=0.025, respectively) and also with the reduction in urinary mannitol (r_s=0.540, p=0.014 and r_s=0.498, p=0.026, respectively) (S15 Table).

FFQ showed that the reduction in abdominal circumference was significantly associated with a decrease in the consumption of cereals and derivatives and processed meats (r_s=0.51, p=0.022 and r_s=0.52, p=0.020, respectively). Weight and BMI reduction correlated with blood pressure reduction: r_s=0.52, p=0.020 and r_s=0.53, p=0.017 with SBP and r_s=0.48, p=0.031 weight with DBP), but no significant associations were found with cardiovascular indices modification (S17 Table).

Association of variables at W0 with modifications during the study (identifying predictors of better response to VLCKD)

The results of the associations between variables at W0 and variable improvement during the study are provided in Fig 3 and in detail in S19–S27 Tables.

Individuals with greater weight at W0 lost more weight during the study (S25 Table). Also, participants with higher disease activity at W0, as measured by DAPSA and DAS28-CRP, showed greater improvements in all anthropometric measures. Subjects with elevated IL-6 at W0, who also had higher disease activity at W0, exhibited greater improvements in weight and abdominal circumference (S19 Table); on the contrary, individuals with higher TNF-α at W0, who also presented lower disease activity at W0, showed a significantly smaller reduction in weight and BMI during the study (S25 Table). Subjects with higher activity and higher ESR and hsCRP at W0, experienced significantly greater improvements in almost all disease activity measures (S25 Table).

Discussion

Our preliminary study showed that a 9-week VLCKD, a strict low-calorie, and low-carbohydrate nutritional regimen, is feasible for overweight and obese patients with PsA. Furthermore, the VLCKD was very effective in reducing weight, with >10% weight loss observed in our patients, and it improved most domains of PsA activity. A strict adherence to the diet improved insulin resistance, lipid profiles, and blood pressure parameters, thus reducing cardiovascular risk. Considering that disease activity in all patients in the study was low at baseline, no significant modifications of inflammatory parameters were observed.

All patients adhered to the carbohydrate restriction protocol, as indicated by the increased levels of urinary ketones, demonstrating the effectiveness of the nutritional approach which included evaluations every three weeks. Additionally, ketosis effectively suppresses hunger and enhances satiety, which may therefore constitute an advantage over the hypocaloric Mediterranean diet and improve adherence [38]. Patients with higher baseline weights showed greater motivation and achieved more significant weight loss suggesting that individuals with obesity, rather than overweight, may be more suitable candidates for VLCKD.

The study revealed improvements across nearly all indices of PsA activity, including peripheral arthritis, axial involvement, and psoriasis. DAPSA score decreased significantly, especially in those who exhibited more substantial BMI reductions. These changes did not stem from reduced biohumoral markers, but from the significant improvement in tender joint count, pain scores, and patient-reported outcomes. Improved functionality was also evidenced by fewer lost working hours, which also correlated with BMI reduction. The primary aim of a VLCKD is to induce significant weight loss, which reduces mechanical stress on the joints and, in turn, decreases pain and inflammation [39]. Consequently, disease activity is diminished even in the absence of a reduction in inflammatory mediators, as observed in our study, where patients exhibited normal levels of inflammatory biomarkers. This finding explains the lack of association between disease activity modification and changes in biohumoral markers. Nonetheless, although VLCKD lacks specific food component intake indications, it may exert putative anti-inflammatory and immunomodulatory effects on mediators not analyzed in this study. Notably, VLCKD and KD have also been observed to improve skin disease in psoriatic patients [24,25].

Despite evidence of anti-inflammatory biological pathways associated with VLCKD and previous reports indicating reduced levels of TNFα and IL-6 following the diet [19,28,29,30,31,32,40,41], only a few changes in inflammatory biomarkers were observed in this study. Likewise, the sole previous study in the literature that examined the implementation of KD in PsA patients, demonstrated that KD specifically reduced levels of IL-6, IL-17 and IL-23, but not other inflammatory biomarkers [34]. The lack of significant changes in serological inflammation should be interpreted in the context of the baseline characteristics of our study population, which consisted of subjects with well-controlled disease. Most were receiving bDMARDs, and baseline inflammatory cytokine levels were below the measurable limits for many subjects.

High baseline TNF-alpha levels were predictive of less significant weight loss, while high baseline IL-6 levels appeared predictive of more significant weight loss. A possible explanation for this finding is that the study may have lacked sufficient statistical power to detect significant changes in specific biomarkers, given the heterogeneous nature of the population. Indeed, different disease pattern may be present at W0: those with high TNF-α levels, associated with low disease activity indices and lower BMI, and those with high IL-6 levels, correlated with high disease activity indices, particularly in relation to joint involvement and higher BMI. Patients with elevated TNF-α levels and lower BMI at W0 may exhibit a different pattern of psoriatic disease, characterized by milder joint involvement and potentially a reduced benefit from VLCKD.

Changes in the intestinal transcellular pathway may affect the intestinal permeability, measured by the lactulose/mannitol ratio which appeared to worsen — i.e., increased urinary mannitol — though it remained within the reference range. This phenomenon has been previously described in obese patients undergoing VLCKD but requires further investigation [42].

The lipid and metabolic profiles improved significantly in all patients, as expected with KD [43]. Notably, we also noted a significant reduction in insulin resistance — over 50% vs. baseline — as assessed by the HOMA-IR index, in line with previous reports in the literature and reinforcing the beneficial metabolic effects of this dietary approach [44].

A major strength of our study is that we assessed cardiovascular risk over a short time period after implementing VLCKD, whereas such effects were typically expected to manifest over a longer period [45]. Cardiovascular risk indices showed a slight albeit significant improvement overall. This is particularly noteworthy as these indices do not incorporate anthropometric measurements; the improved lipid profiles and blood pressure correlated with weight and BMI reduction.

Despite a drastic reduction in carbohydrates (including legumes and fresh fruit), the VLCKD did not reduce the adherence to the Mediterranean diet because of an increased intake of fish and nuts. This is important given the known benefits of the Mediterranean diet constituents for rheumatic patients and those at higher cardiovascular risk.

We would be remiss if we did not mention some of the limitations of our study. The small sample size and short observation period may have limited the statistical power and generalizability of our findings. Furthermore, the absence of a control arm prevents a comprehensive analysis of confounders which makes it difficult to determine whether the observed effects are attributable to weight loss itself or specifically to the VLCKD protocol compared to other dietary interventions. Nonetheless, given the highly restrictive nature of this diet—intended for short-term use under clinical supervision— and the high likelihood of dropouts, a proof-of-concept study was deemed appropriate to evaluate the potential benefits of this dietary approach. These findings provide a foundation for future investigations. We did not measure additional inflammatory cytokines involved in PsA, such as IL-17, which could have helped detect subtle improvements in the serological profile and inflammatory state of patients. A larger-scale study will also allow for a more thorough analysis of confounders, particularly in relation to DMARD treatment and patients with high disease activity.

Our study demonstrated that VLCKD was effective in improving anthropometric measures, PsA activity, and metabolic and cardiovascular parameters in overweight and obese patients, with the degree of improvement correlating with BMI reduction. Further trials are necessary to investigate the combination of the VLCKD with nutritional regimens that could sustain these short-term benefits over time, gradually transitioning the patient back to a Mediterranean dietary pattern, which should remain the reference model for chronic inflammatory arthritis. Additionally, the study underscores the importance of diet as an adjunct to pharmacological treatments, with the potential to reduce the cardiovascular and metabolic burden in patients with PsA.

Supporting information

S1 Table. Full list of variables included in the study.

(PDF)

pone.0321140.s001.pdf^{(122.6KB, pdf)}

S2 Table. Characteristics of the patients at W0.

(PDF)

pone.0321140.s002.pdf^{(85.6KB, pdf)}

S3 Table. Association between continuous and categorical variables at W0.

(PDF)

pone.0321140.s003.pdf^{(217.4KB, pdf)}

S4 Table. Association between continuous variables at W0.

(PDF)

pone.0321140.s004.pdf^{(264.6KB, pdf)}

S5 Table

Association between categorical variables at W0.

(PDF)

pone.0321140.s005.pdf^{(125.2KB, pdf)}

S6 Table. Modification of anthropometric measurements during the study.

(PDF)

pone.0321140.s006.pdf^{(94.2KB, pdf)}

S7 Table. Modification of clinical variables during the study.

(PDF)

pone.0321140.s007.pdf^{(97.8KB, pdf)}

S8 Table. Modification of inflammatory biomarkers during the study.

(PDF)

pone.0321140.s008.pdf^{(92.9KB, pdf)}

S9 Table. Modification of laboratory variables during the study.

(PDF)

pone.0321140.s009.pdf^{(116.5KB, pdf)}

S10 Table. Modification of nutritional questionnaires during the study.

(PDF)

pone.0321140.s010.pdf^{(90.8KB, pdf)}

S11 Table. Modification of cardiovascular parameters during the study.

(PDF)

pone.0321140.s011.pdf^{(95.5KB, pdf)}

S12 Table. Correlation between the modification of anthropometric measurements during the study.

(PDF)

pone.0321140.s012.pdf^{(99.6KB, pdf)}

S13 Table. Correlation between the modification of anthropometric measurements and the modification of clinical variables during the study.

(PDF)

pone.0321140.s013.pdf^{(112.1KB, pdf)}

S14 Table. Correlation between the modification of anthropometric measurements and the modification of inflammatory biomarkers during the study.

(PDF)

pone.0321140.s014.pdf^{(100.9KB, pdf)}

S15 Table. Correlation between the modification of anthropometric measurements and the modification of laboratory variables during the study.

(PDF)

pone.0321140.s015.pdf^{(136.5KB, pdf)}

S16 Table. Correlation between the modification of anthropometric measurements and the modification of food frequencies during the study.

(PDF)

pone.0321140.s016.pdf^{(107.6KB, pdf)}

S17 Table. Correlation between the modification of anthropometric measurements and the modification of cardiovascular parameters during the study.

(PDF)

pone.0321140.s017.pdf^{(113.1KB, pdf)}

S18 Table. Association between the modification of anthropometric measurements and the modification of categorical variables during the study.

(PDF)

pone.0321140.s018.pdf^{(109.6KB, pdf)}

S19 Table. Analysis of the association between categorical variables at W0 and the modification of continuous anthropometric measurements during the study.

(PDF)

pone.0321140.s019.pdf^{(131.1KB, pdf)}

S20 Table. Analysis of the association between categorical variables at W0 and the modification of continuous clinical variables during the study.

(PDF)

pone.0321140.s020.pdf^{(183.1KB, pdf)}

S21 Table. Analysis of the association between categorical variables at W0 and the modification of inflammatory biomarkers during the study.

(PDF)

pone.0321140.s021.pdf^{(126.1KB, pdf)}

S22 Table. Analysis of the association between categorical variables at W0 and the modification of continuous laboratory variables during the study.

(PDF)

pone.0321140.s022.pdf^{(224.4KB, pdf)}

S23 Table. Analysis of the association between categorical variables at W0 and the modification of nutritional questionnaires during the study.

(PDF)

pone.0321140.s023.pdf^{(151.8KB, pdf)}

S24 Table. Analysis of the association between categorical variables at W0 and the modification of cardiovascular parameters during the study.

(PDF)

pone.0321140.s024.pdf^{(141.5KB, pdf)}

S25 Table. Association between continuous variables at W0 and the modification of continuous variables during the study.

(PDF)

pone.0321140.s025.pdf^{(320.3KB, pdf)}

S26 Table. Association between categorical variables at W0 and the modification of categorical variables (clinical, inflammatory biomarkers, and cardiovascular parameters).

(PDF)

pone.0321140.s026.pdf^{(145.6KB, pdf)}

S27 Table. Association between continuous variables at W0 and the modification of categorical variables during the study.

(PDF)

pone.0321140.s027.pdf^{(149.1KB, pdf)}

S1 Figure. Simple Boxplots of permeability tests during the study.

(PDF)

pone.0321140.s028.pdf^{(763.4KB, pdf)}

Acknowledgments

The authors would like to thank nurses Nicoletta Pedron and Federica Delon for their invaluable contributions that led to the amelioration of the study.

Data Availability

All relevant data are within the manuscript and its Supporting Information files.

Funding Statement

The author(s) received no specific funding for this work.

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PLoS One. 2025 Apr 22;20(4):e0321140. doi: 10.1371/journal.pone.0321140.r001

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PLoS One. doi: 10.1371/journal.pone.0321140.r002

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Luca Navarini

21 Jan 2025

PONE-D-24-38756Ketogenic diet improves disease activity and cardiovascular risk in psoriatic arthritis: a proof of concept studyPLOS ONE

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Reviewer #1: The manuscript addresses an important aspect of PsA management by focusing on a very low-calorie ketogenic diet, that has been suggested to have anti-inflammatory effects. The article is well-written and organized, although correction for minor typos is encouraged. I have a few comments on the paper.

1) The authors state that the VLCKD is associated with an improvement of disease activity, which correlates with BMI reduction. However, this improvement is not associated with changes in IL-6 and TNFα levels. How do the authors explain this result?

2) Authors say that individuals with higher TNFα at W0 showed greater weight and BMI reduction if they had low disease activity. Why according to the authors are TNFα levels inversely correlated with disease activity?

3) Although there are only two patients with diabetes, did the authors find any differences in the effectiveness of the VLCKD compared to the remaining study cohort?

4) The authors affirm that patients with higher disease activity at W0 according to DAPSA and DAS28-CRP showed greater improvements in blood glucose levels and HOMA-IR. What correlation do the authors think there is between DAPSA/DAS28 and blood glucose concentration/HOMA-IR?

It will be interesting in the future to include patients with high disease activity at baseline, as well as to evaluate variations in IL17 in patients undergoing a VLCKD.

Reviewer #2: This manuscript presents data from PSA patients undergoing a very low calories ketogenic diet (VLCKD). Changes in anthropometric measures, BMI, and lipid profile are correlated with changes in disease activity. Major issues to be addressed include the following:

1. The main limitation is the lack of a control arm, preventing any consideration about the efficacy of the VLKD itself. Only correlations between weight loss/ diet adherence and disease activity parameters can be examined, but it is impossible to understand whether observed changes are due to the specific type of diet, or to weight loss in general. In fact, similar results have been obtained with different types of diet, in studies with similar limitations (Klingberg E, et al. Arthritis Res Ther. 2019;21(1):17; Klingberg E, et al. Arthritis Res Ther. 2020;22(1):254)

2. Sample size is also quite small (n=20) without specific considerations as to why this was considered to be adequate.

3. The heterogeneity of the included population, e.g. in terms of background treatment, poses a challenge in controlling for potential confounders. In fact, as the authors note, inflammatory biomarkers were significantly lower in the bDMARDs group vs csDMARDs only. This observation would suggest it would be more appropriate to include patients with a more similar background treatment, or at least to control for therapy, which seems to be an important confounder, in the analyses. Nonetheless, this is a very difficult task with a sample size of 20 patients.

4. A high number of analyses have been carried out, some without a real objective (e.g in figure 2 correlation between changes in BMI and anthropometric measures, or in figure 3 correlations between various disease activity indexes, both quite expected and without an added value to existing knowledge), increasing significantly type I error. I would suggest removing these kind of analysis and focusing on the correlations between changes in BMI/anthropometric measures/ketones on one side, and disease activity or inflammatory indexes on the other side.

In summary the topic of the manuscript is potentially relevant, however, the limited sample size, the lack of a control arm and control for confounders, significantly limit the impact of results.

**********

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Reviewer #1: No

Reviewer #2: No

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PLoS One. 2025 Apr 22;20(4):e0321140. doi: 10.1371/journal.pone.0321140.r003

Author response to Decision Letter 1

30 Jan 2025

Reviewer #1

The manuscript addresses an important aspect of PsA management by focusing on a very low-calorie ketogenic diet, that has been suggested to have anti-inflammatory effects. The article is well-written and organized, although correction for minor typos is encouraged. I have a few comments on the paper.

> We thank the reviewer for highlighting this important issue. The intricate relationship between BMI modification, disease activity, and inflammatory indices is indeed complex and deserves further explanation. We have elaborated on our hypotheses and revised a relevant paragraph in the discussion section to provide greater clarity as follows:

“The primary aim of a VLCKD is to induce significant weight loss, which reduces mechanical stress on the joints and, in turn, decreases pain and inflammation. Consequently, disease activity is diminished even in the absence of a reduction in inflammatory mediators, as observed in our study, where patients exhibited normal levels of inflammatory biomarkers. This finding explains the lack of association between disease activity modification and changes in biohumoral markers. Nonetheless, although VLCKD lacks specific food component intake indications, it may exert putative anti-inflammatory and immunomodulatory effects on mediators not analyzed in this study. Notably, VLCKD and KD have also been observed to improve skin disease in psoriatic patients.”

> We thank the reviewer for highlighting this issue and encouraging us to clarify this observation and improve our text. In response, we have included a new paragraph in the discussion section, adding further clarification as follows:

“High baseline TNF-alpha levels were predictive of less significant weight loss, while high baseline IL-6 levels appeared predictive of more significant weight loss. A possible explanation for this finding is that the study may have lacked sufficient statistical power to detect significant changes in specific biomarkers, given the heterogeneous nature of the population. Indeed, different disease pattern may be present at W0: those with high TNF-α levels, associated with low disease activity indices and lower BMI, and those with high IL-6 levels, correlated with high disease activity indices, particularly in relation to joint involvement and higher BMI. Patients with elevated TNF-α levels and lower BMI at W0 may exhibit a different pattern of psoriatic disease, characterized by milder joint involvement and potentially a reduced benefit from VLCKD.”

3. Although there are only two patients with diabetes, did the authors find any differences in the effectiveness of the VLCKD compared to the remaining study cohort?

> We thank the reviewer for drawing attention to this observation. Two patients with diabetes were included in the study; however, their data were excluded due to a lack of significant findings and the redundancy of the information already provided by insulin levels and HOMA-IR. For completeness, we have included the data (with no significant association observed) between diabetes and changes in anthropometric measures in Supplementary Table S21.

4. The authors affirm that patients with higher disease activity at W0 according to DAPSA and DAS28-CRP showed greater improvements in blood glucose levels and HOMA-IR. What correlation do the authors think there is between DAPSA/DAS28 and blood glucose concentration/HOMA-IR?

>We appreciate the reviewer for highlighting this issue. Higher activity indices at W0 were associated with higher weight, and these patients exhibited greater improvements in anthropometric measures compared to those with lower activity indices. Anthropometric improvement, in turn, was linked to an amelioration of insulin resistance, which explains the observed association between high activity indices at W0 and improved insulin resistance. Nonetheless, this effect is likely attributable to weight loss. To avoid confounding and redundancy, as suggested by Reviewer #2, we have focused on the most relevant findings and removed this information from the last paragraph of the results section. Data, however, remain available in the supplementary information.

5. It will be interesting in the future to include patients with high disease activity at baseline, as well as to evaluate variations in IL17 in patients undergoing a VLCKD.

> We thank the reviewer for highlighting this issue. These limitations were already addressed in the discussion and have now been further emphasized as follows:

“We did not measure additional inflammatory cytokines involved in PsA, such as IL-17, which could have helped detect subtle improvements in the serological profile and inflammatory state of patients.”

Reviewer #2

This manuscript presents data from PSA patients undergoing a very low calories ketogenic diet (VLCKD). Changes in anthropometric measures, BMI, and lipid profile are correlated with changes in disease activity. Major issues to be addressed include the following:

>We thank the reviewer for highlighting this important limitation. We have added this point to the limitation paragraph in the discussion and rephrased the entire paragraph as follows:

"The small sample size and short observation period may have limited the statistical power and generalizability of our findings. Furthermore, the absence of a control arm prevents a comprehensive analysis of confounders which makes it difficult to determine whether the observed effects are attributable to weight loss itself or specifically to the VLCKD protocol compared to other dietary interventions. Nonetheless, given the highly restrictive nature of this diet—intended for short-term use under clinical supervision— and the high likelihood of dropouts, a proof-of-concept study was deemed appropriate to evaluate the potential benefits of this dietary approach. These findings provide a foundation for future investigations. We did not measure additional inflammatory cytokines involved in PsA, such as IL-17, which could have helped detect subtle improvements in the serological profile and inflammatory state of patients. A larger-scale study will also allow for a more thorough analysis of confounders, particularly in relation to DMARD treatment and patients with high disease activity.”

Also references were added in the text in the discussion section:

Reference number 40:

“The primary aim of a VLCKD is to induce significant weight loss, thereby reducing mechanical stress on the joints, which leads to decreased pain and inflammation40.”

40. Klingberg E, Bilberg A, Björkman S, Hedberg M, Jacobsson L, Forsblad-d'Elia H, Carlsten H, Eliasson B, Larsson I. Weight loss improves disease activity in patients with psoriatic arthritis and obesity: an interventional study. Arthritis Res Ther. 2019;21(1):17.

Reference number 46:

“A major strength of our study is that we assessed cardiovascular risk over a short time period after implementing VLCKD, such effects were typically expected to manifest over a longer period46”

46. Klingberg E, Björkman S, Eliasson B, Larsson I, Bilberg A. Weight loss is associated with sustained improvement of disease activity and cardiovascular risk factors in patients with psoriatic arthritis and obesity: a prospective intervention study with two years of follow-up. Arthritis Res Ther. 2020;22(1):254.

2. Sample size is also quite small (n=20) without specific considerations as to why this was considered to be adequate.

>We thank the reviewer for pointing out this issue. As discussed above, the study is a proof-of-concept study which is adequate for a very restrictive diet. The issue has been addressed in the limitations paragraph, specifically as follows:

“The small sample size and short observation period may have limited the statistical power and generalizability of our findings. […] Nonetheless, given the highly restrictive nature of this diet—intended for short-term use under clinical supervision— and the high likelihood of dropouts, a proof-of-concept study was deemed appropriate to evaluate the potential benefits of this dietary approach.”

>We thank the reviewer for pointing out this issue. We agree with their observation and have emphasized this point in the limitations section:

“A larger-scale study will also allow for a more thorough analysis of confounders, particularly in relation to DMARD treatment and patients with high disease activity.”

> We thank the reviewer for contributing to the improvement of the clarity of our findings. We agree with their observation and have summarized findings that were less relevant and could limit the comprehension of the main results. Information regarding activity indices, inflammatory biomarkers, and anthropometric measures has been highlighted, while redundant information and details about laboratory tests and questionnaires have been summarized as follows:

In section “Association between variables at W0” the following sentences were removed or rephrased:

“Notably, higher TNFα levels also associated with higher f-CPT levels, and both of them displayed significantly lower levels in subjects treated with bDMARDs. As, expected, fasting insulinemia, glucose and HOMA-IR positively correlated with weight, BMI and abdominal circumference, being higher in individuals with increased measurements : HOMA-IR rs=0.50, p=0.042; rs=0.54, p=0.001 and rs=0.66, p=0.49, p=0.028, respectively” (Supplementary Table S4b). At W0, anthropometric measurements showed no significant associations with the lipid profile or the cardiovascular indices (Supplementary Tables S4b and S4c).”

In section “Changes between W0 and W9 (identification of significant modifications following VLCKD)” the following sentence was removed:

“Notably, WBC and platelet count significantly decreased (Supplementary Table S9).”

In section“Association between changes in anthropometric measurements and changes in other variables during the study (assessing the impact of weight, BMI and abdominal circumference modification on PsA disease activity)” the following sentences were removed or additional information was included:

“No significant correlation between changes in anthropometric measures and inflammation indices was observed, except for a modest and inverse association between the change in abdominal circumference and the change in hsCRP (rs=0.50, p=0.046) (Supplementary Tables S15 and S19)”

“Greater weight reduction was also associated with a decrease in neutrophils, and BMI with WBC (Supplementary Table S16)”

“Weight and BMI reduction correlated with blood pressure reduction (rs=0.52, p=0.020 and rs=0.53, p=0.017, respectively with SBP and rs=0.48, p=0.031 weight with DBP), but no significant associations were found with cardiovascular indices modification (Supplementary Table S18)

In section “Association of variables at W0 with modifications during the study (identifying predictors of better response to VLCKD)” the following paragraphs were removed or rephrased:

“Furthermore, those with greater weight and abdominal circumference at W0 also experienced a greater reduction in TJC and weight decrease correlated with the reduction of WPAI lost work hours. Subjects with higher ESR and hsCRP at W0, who also presented higher DAS28-CRP, showed significantly greater improvements in TJC, SJC, and axial disease measures (ASDAS-CRP) (Supplementary Table S27a).” ).

“Subjects with higher activity and higher ESR and hsCRP at W0, experienced significantly greater improvements in almost all disease activity measures (Supplementary Table S27a and S27b).”

Participants with higher disease activity at W0 according to DAPSA and DAS28-CRP showed greater improvements in blood glucose levels and HOMA-IR. Participants with higher BMI and weight at W0 showed more significant reductions in WBC, lymphocytes, blood glucose and HOMA-IR. Subjects with elevated IL-6 at W0 more frequently showed improvement in HDL cholesterol; subjects with elevated TNF-α levels more frequently presented a reduction in TC and LDL cholesterol and those with elevated f-CPT had a more frequent reduction in LDL cholesterol (Supplementary Table S23). Subjects with higher cardiovascular risk at W0, according to SCORE2, improved more in the same index. Participants with higher BMI and weight at W0 showed more significant reductions in SBP and DBP.”

In the discussion section the following sentence was removed:

Notably, IL-6 levels, as well as platelet and white blood cell counts were decreased as observed previously

Figures 2 and 3 have also been summarized as suggested. Cardiovascular indices and laboratory tests were removed. Information regarding anthropometric measures, disease activity, and inflammatory biomarkers has been retained and organized to improve clarity.

6. In summary the topic of the manuscript is potentially relevant, however, the limited sample size, the lack of a control arm and control for confounders, significantly limit the impact of results.

>We further thank the reviewer for their interest in our paper. We have followed the reviewer’s suggestion and modified substantially the result section by removing less relevant information and highlighting the major findings. Furthermore, we are aware that the study population is small, nonetheless being the diet very restrictive a proof-of-concept study was deemed necessary in PSA patients before a larger-scale study was conducted. We also discussed the limitations of our study more comprehensively in the discussion section, as outlined above (points 1, 2 and 3).

Attachment

Submitted filename: Response to Reviewers 0128 01.docx

pone.0321140.s030.docx^{(6.2MB, docx)}

PLoS One. doi: 10.1371/journal.pone.0321140.r004

Decision Letter 1

Luca Navarini

2 Mar 2025

Ketogenic diet improves disease activity and cardiovascular risk in psoriatic arthritis: a proof of concept study

PONE-D-24-38756R1

Dear Dr. Ramonda,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

Reviewer #1: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

Reviewer #1: Yes

**********

6. Review Comments to the Author

Reviewer #1: thanks to the authors for the modifications and clarifications which have allowed an improvement of the paper.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean? ). If published, this will include your full peer review and any attached files.

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Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy .

Reviewer #1: No

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PLoS One. doi: 10.1371/journal.pone.0321140.r005

Acceptance letter

Luca Navarini

PONE-D-24-38756R1

PLOS ONE

Dear Dr. Ramonda,

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

S1 Table. Full list of variables included in the study.

(PDF)

pone.0321140.s001.pdf^{(122.6KB, pdf)}

S2 Table. Characteristics of the patients at W0.

(PDF)

pone.0321140.s002.pdf^{(85.6KB, pdf)}

S3 Table. Association between continuous and categorical variables at W0.

(PDF)

pone.0321140.s003.pdf^{(217.4KB, pdf)}

S4 Table. Association between continuous variables at W0.

(PDF)

pone.0321140.s004.pdf^{(264.6KB, pdf)}

S5 Table

Association between categorical variables at W0.

(PDF)

pone.0321140.s005.pdf^{(125.2KB, pdf)}

S6 Table. Modification of anthropometric measurements during the study.

(PDF)

pone.0321140.s006.pdf^{(94.2KB, pdf)}

S7 Table. Modification of clinical variables during the study.

(PDF)

pone.0321140.s007.pdf^{(97.8KB, pdf)}

S8 Table. Modification of inflammatory biomarkers during the study.

(PDF)

pone.0321140.s008.pdf^{(92.9KB, pdf)}

S9 Table. Modification of laboratory variables during the study.

(PDF)

pone.0321140.s009.pdf^{(116.5KB, pdf)}

S10 Table. Modification of nutritional questionnaires during the study.

(PDF)

pone.0321140.s010.pdf^{(90.8KB, pdf)}

S11 Table. Modification of cardiovascular parameters during the study.

(PDF)

pone.0321140.s011.pdf^{(95.5KB, pdf)}

S12 Table. Correlation between the modification of anthropometric measurements during the study.

(PDF)

pone.0321140.s012.pdf^{(99.6KB, pdf)}

S13 Table. Correlation between the modification of anthropometric measurements and the modification of clinical variables during the study.

(PDF)

pone.0321140.s013.pdf^{(112.1KB, pdf)}

S14 Table. Correlation between the modification of anthropometric measurements and the modification of inflammatory biomarkers during the study.

(PDF)

pone.0321140.s014.pdf^{(100.9KB, pdf)}

S15 Table. Correlation between the modification of anthropometric measurements and the modification of laboratory variables during the study.

(PDF)

pone.0321140.s015.pdf^{(136.5KB, pdf)}

S16 Table. Correlation between the modification of anthropometric measurements and the modification of food frequencies during the study.

(PDF)

pone.0321140.s016.pdf^{(107.6KB, pdf)}

S17 Table. Correlation between the modification of anthropometric measurements and the modification of cardiovascular parameters during the study.

(PDF)

pone.0321140.s017.pdf^{(113.1KB, pdf)}

S18 Table. Association between the modification of anthropometric measurements and the modification of categorical variables during the study.

(PDF)

pone.0321140.s018.pdf^{(109.6KB, pdf)}

S19 Table. Analysis of the association between categorical variables at W0 and the modification of continuous anthropometric measurements during the study.

(PDF)

pone.0321140.s019.pdf^{(131.1KB, pdf)}

S20 Table. Analysis of the association between categorical variables at W0 and the modification of continuous clinical variables during the study.

(PDF)

pone.0321140.s020.pdf^{(183.1KB, pdf)}

S21 Table. Analysis of the association between categorical variables at W0 and the modification of inflammatory biomarkers during the study.

(PDF)

pone.0321140.s021.pdf^{(126.1KB, pdf)}

S22 Table. Analysis of the association between categorical variables at W0 and the modification of continuous laboratory variables during the study.

(PDF)

pone.0321140.s022.pdf^{(224.4KB, pdf)}

S23 Table. Analysis of the association between categorical variables at W0 and the modification of nutritional questionnaires during the study.

(PDF)

pone.0321140.s023.pdf^{(151.8KB, pdf)}

S24 Table. Analysis of the association between categorical variables at W0 and the modification of cardiovascular parameters during the study.

(PDF)

pone.0321140.s024.pdf^{(141.5KB, pdf)}

S25 Table. Association between continuous variables at W0 and the modification of continuous variables during the study.

(PDF)

pone.0321140.s025.pdf^{(320.3KB, pdf)}

S26 Table. Association between categorical variables at W0 and the modification of categorical variables (clinical, inflammatory biomarkers, and cardiovascular parameters).

(PDF)

pone.0321140.s026.pdf^{(145.6KB, pdf)}

S27 Table. Association between continuous variables at W0 and the modification of categorical variables during the study.

(PDF)

pone.0321140.s027.pdf^{(149.1KB, pdf)}

S1 Figure. Simple Boxplots of permeability tests during the study.

(PDF)

pone.0321140.s028.pdf^{(763.4KB, pdf)}

Attachment

Submitted filename: Response to Reviewers 0128 01.docx

pone.0321140.s030.docx^{(6.2MB, docx)}

Data Availability Statement

All relevant data are within the manuscript and its Supporting Information files.

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PERMALINK

Ketogenic diet improves disease activity and cardiovascular risk in psoriatic arthritis: A proof of concept study

Roberta Ramonda

Francesca Ometto

Giovanni Striani

Giacomo Cozzi

Daniela Basso

Filippo Evangelista

Mariagrazia Lorenzin

Laura Scagnellato

Ada Aita

Marta Favero

Filippo Brocadello

Andrea Doria

Roles

Abstract

Objectives

Methods

Results

Conclusions

Introduction

Methods

Study design

Patients

Diet protocol

Collected data

Statistical analysis

Results

Characteristics of patients at W0

Table 1. Characteristics of the patients at W0.

Table 2. Characteristics of the patients and modification during the study.

Association between variables at W0

Changes between W0 and W9 (identification of significant modifications following VLCKD)

Fig 1. Food frequency modification during the study according to the food frequency questionnaire.

Fig 2. Correlation matrix between modification of anthropometric measurements and modification of other variables during the study.

Association of variables at W0 with modifications during the study (identifying predictors of better response to VLCKD)

Fig 3. Correlation matrix between variables at W0 and the modification of main variables during the study.

Discussion

Supporting information

Acknowledgments

Data Availability

Funding Statement

References

Author response to Decision Letter 0

Transfer Alert

Decision Letter 0

Luca Navarini

Roles

Author response to Decision Letter 1

Decision Letter 1

Luca Navarini

Roles

Acceptance letter

Luca Navarini

Roles

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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