Sex differences in the association between plasma polyunsaturated fatty acids levels and moderate-to-severe plaque psoriasis severity: a cross-sectional and longitudinal study
Journal of Translational Medicine volume 21, Article number: 834 (2023)
Psoriasis is a chronic inflammatory skin disease with metabolic abnormalities serving as important contributors for pathogenesis and progression. Polyunsaturated fatty acids (PUFAs) have been found to be associated with human diseases, including psoriasis. However, differences and controversies exist regarding their content and roles.
Plasma PUFAs concentrations were measured in 296 patients with moderate-to-severe plaque psoriasis from the Shanghai Psoriasis Effectiveness Evaluation CoHort. Disease severity was assessed using Clinician-Reported Outcomes (ClinROs), including Psoriasis Area and Severity Index (PASI), Body Surface Area (BSA) and Physician Global Assessment (PGA), as well as Patient-Reported Outcomes (PROs), including Patient Global Assessment (PtGA) and Dermatology Life Quality Index (DLQI). Multivariate generalized linear regression models (GLMs), subgroup and interaction analysis, and restricted cubic spline were used to estimate the cross-sectional associations between PUFAs concentrations and disease severity. Longitudinal assessments of PASI scores and PASI response were conducted at a 12-week follow-up. Associations between baseline plasma PUFAs levels and prospective PASI scores or PASI response were assessed using multivariate GLMs or logistic regression models.
Males suffered severer psoriasis and presented lower plasma docosahexaenoic acid (DHA) and arachidonic acid (ARA) levels compared to females. Among males, plasma eicosadienoic acid (EDA) level was positively associated with PASI, BSA and PGA scores, while total Omega-3 PUFAs and/or eicosapentaenoic acid (EPA) levels exhibited non-linear associations with PASI and/or BSA scores. α-Linolenic acid (ALA) was negatively, whereas ARA was positively, associated with DLQI scores. In females, Omega-3 PUFAs, including EPA, DHA, and total Omega-3 PUFAs, showed inverse associations with PASI and BSA scores. Longitudinally, plasma total Omega-6 PUFAs were positively associated with the likelihood of achieving PASI 100 at 12 weeks in males. In females, concentrations of dohomo-γ-linolenic acid were prospectively associated with an increase in PASI scores, and DHA was associated with the likelihood of achieving PASI 75 and PASI 90 decline.
Sex differences cross-sectionally exist in disease severity and plasma PUFAs levels. The association between PUFAs and psoriasis severity also varies cross-sectionally and longitudinally between males and females. Sex differences should be considered when studying the function and clinical application of PUFAs in psoriasis.
Psoriasis is a common, chronic, immune-mediated skin disease that presents at any age [1, 2]. It occurs worldwide and affects over 6 million people in China [1, 2]. Psoriasis has been regarded as a systemic inflammatory disease, with metabolic abnormalities serving as important contributors for pathogenesis and progression [3,4,5]. Decades ago, researchers investigated the composition and metabolism of fatty acids (FAs) in psoriasis, revealing a close association with the disease, particularly in terms of their composition and metabolism [6,7,8]. However, with changes in dietary habits, the composition, metabolism, and roles of FAs in the human body will change significantly. Thus, it is meaningful to analyze the latest FAs composition and metabolism of FAs in psoriasis patients and their relationship with the disease, in order to provide reference for clinical treatment.
Polyunsaturated fatty acids (PUFAs) refer to unsaturated fatty acids with two or more carbon–carbon double bonds . Omega-3 PUFAs and Omega-6 PUFAs are common PUFAs widely investigated and have been reported to be associated with many human diseases . However, due to populational differences, existing reports have shown differences in the content and changes of Omega-3 and Omega-6 PUFAs in human diseases, leading to controversies over their roles and the necessity of dietary supplementation [9, 10]. Differences and controversies also appear in research on skin diseases, such as atopic dermatitis, acne, and psoriasis, mainly due to considerations of population and individual genetic differences . To date, only one epidemiologic study with a small sample size (85 patients) has explored the association between FAs and psoriasis, and found that PASI scores were associated with low levels of serum docosahexaenoic acid (DHA) and Omega-3 PUFAs . Therefore, it is essential to investigate the latest PUFAs status in psoriasis patients and their relationship with the disease.
In this cross-sectional and longitudinal study, we aimed to observe disease severity and determine the PUFAs profiles of psoriasis patients, as well as examine the associations between PUFAs status and the severity of psoriasis. We identified significant sex differences and conducted sex-based analysis and discussion.
Study design and participants
The present analysis used a cross-sectional study design and was nested in the Shanghai Psoriasis Effectiveness Evaluation CoHort (SPEECH), which was reported in our previous publication . In brief, patients (≥ 18 years old) were recruited if:  had a diagnosis of chronic moderate-to-severe plaque psoriasis (based on Psoriasis Area and Severity Index (PASI) scores);  did not receive the treatment of phototherapy, conventional systemic medications (acitretin or methotrexate) in the preceding month, or biologics within the last 3 months. Among 2515 patients with moderate-to-severe plaque psoriasis recruited in the SPEECH (up to July, 2023), this study included 296 patients who were enrolled between 2021 and 2023 and whose PUFAs were measured. After enrollment, patients received different treatments, including phototherapy, conventional systemic medications (acitretin or methotrexate) or biological agents (adalimumab, ustekinumab, secukinumab or ixekizumab). Data, encompassing demographic information and clinical outcomes, were collected at the 12-week mark (Fig. 1) .
The registry (Chinese Clinical Trial Registry ChiCTR 2000036186) was performed following the principles of the Declaration of Helsinki. Ethical approvals for SPEECH project were previously described in our publication  and were obtained from the following institutions: Shanghai Tenth People’s Hospital (#20KT110); Ruijin Hospital (#2020821); Huashan Hospital (#KY2021-733); Changhai Hospital (#2020-27); Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (#2020-KY-047); and Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (#2021-129). Informed consents were obtained from all participants.
Plasma fatty acids detection
Plasma of the venous peripheral blood was collected from the patients at baseline upon their enrollment in the SPEECH study, following a standardized protocol. Subsequently, the collected samples were centrifuged and stored at − 80 °C until analysis. The extraction and esterification of lipids were performed on 100 µL of plasma using a standard methodology with some modifications [14, 15]. Nonadecanoic acid (Sigma, USA) was used as the internal standard. Fatty acid methyl esters (FAME) (37 Component FAME Mix CDAA-252,795, ANPEL Laboratory Technologies (Shanghai) Inc.) were separated on a capillary column (30 m × 0.25 mm × 0.25 μm) (DB-wax, Agilent Technologies Inc., USA) using gas chromatography-mass spectrometry (7890B-5977B, Agilent Technologies Inc., USA). Data acquisition and processing were performed with Mass Hunter Software (Agilent Technologies Inc., USA). The proportions of PUFAs were expressed as molar proportions (mol %) of the total fatty acids. During the detection process, plasma samples were organized in batches of up to 22, which included two samples from a standard pool for quality control (QC). Coefficient of variation of QC were 4.63% for linoleic acid (LA, 18:2n6-cis), 8.01% for α-linolenic acid (ALA, 18:3n3), 9.89% for eicosadienoic acid (EDA, 20:2n6), 8.56% for dohomo-γ-linolenic acid (DGLA, 20:3n6), 10.85% for arachidonic acid (ARA, 20:4n6), 6.08% for eicosapentaenoic acid (EPA, 20:5n3) and 7.59% for DHA (22:6n3).
Data collection and outcomes
For each patient, demographics and effectiveness outcomes including Clinician-Reported Outcomes (ClinROs) and Patient-Reported Outcomes (PROs) were collected at baseline. ClinROs included PASI (gold standard for assessing psoriasis severity, from 0 to a theoretical maximum of 72, with higher scores indicating worse disease), Physician Global Assessment [PGA, 5-point scale, from 0 (clear) to 4 (severe)] and Body Surface Area (BSA, 0–100%), and PROs included Patient Global Assessment (PtGA, 11-point scale, from 0 to 10, with higher scores indicating more severe psoriasis) and Dermatology Life Quality Index (DLQI, 30-point scale, from 0 to 30, the higher the score, the greater the impairment of quality of life) [16, 17]. After 12 weeks, PASI scores were re-assessed, and PASI 75 (defined as 75% reduction of PASI scores from baseline), PASI 90 and PASI 100 were calculated.
The characteristics of patients were summarized using the mean with standard deviation (SD) or median with inter-quartile range (IQR) for continuous variables and number and percentage for categorical variables. The Shapiro–Wilk test was used to evaluate the normality of the data distributions. Differences between males and females were assessed using the Mann–Whitney U test for non-normally distributed data, and the chi-squared test for categorical data.
To examine the associations between plasma PUFAs levels and patients’ ClinROs or PROs scores at baseline, multivariate generalized linear regression models were performed. To determine the relationships of plasma PUFAs levels, PASI scores or PASI response at week 12, multivariate logistic regression models and multivariate generalized linear regression models were conducted. The continuous variable of PUFAs concentrations including LA, ALA, EDA, DGLA, ARA, EPA, DHA, Omega-3 PUFAs (the pool of ALA, DHA and EPA), Omega-6 PUFAs (the pool of LA, EDA, DGLA and ARA), and Omega-6/Omega-3 PUFAs ratio. Based on the literature, age, education (“high school or lower”, “college or above”), smoking history (“yes” or “no”) and alcohol using history (“yes” or “no”) were considered as potential confounders in cross-sectional study [18, 19]; while in longitudinal study, in addition to those variables mentioned above, various treatment, including acitretin, methotrexate, phototherapy, and biologics, were adjusted in statistical models . Except for age, the remaining selected covariates were modeled as categorical variables. Multiple imputation was used for covariates with missing values. The number (proportion) of covariates’ missing values are shown as follows: 1 (0.34%) for Body Mass Index (BMI), 1 (0.34%) for alcohol using history, 2 (0.68%) for age, and 10 (3.38%) for education levels.
To identify the potential dose-response associations between plasma PUFAs levels and clinical scores, we used restricted cubic spline (RCS) models with four knots (5th, 35th, 65th, and 95th quantiles) to estimate Poverall and Pnonlinear. Both p-values lower than 0.05 indicated a non-linear relationship between plasma PUFAs levels and clinical scores. β-Coefficients (β) with their corresponding 95% confidence intervals (CIs) and odd ratios (ORs) with 95% CI were used to report the change in clinical scores and PASI response, respectively. Besides, stratified by age (20–60, > 60 years old), BMI (< 23.99, 23.99–28, ≥ 28 kg/m2) in both sexes, and drinking history (no and yes), and alcohol using history (no and yes) in males and interaction analyses between various stratification factors and plasma PUFAs levels were performed.
Finally, we also conducted several sensitivity analyses to confirm the robustness of our major findings . In our analysis, we found the non-linear relationships between PUFAs levels and disease severity in male patients. In order to better evaluate the stability and reliability of our results, we performed subgroup analysis (total males, without obese and/or overweight males);  Considering that there were some missing values of the covariates (e.g., age, education levels), we utilized missing indicator method to impute information and performed additional analysis .
All analyses were conducted using SAS 9.4 software (SAS Institute Inc., Cary, NC, USA) and R (version 4.3.1, R Development Core Team). We used the R packages “rms” for RCS analysis. The level of significance was two-sided p-value < 0.05.
Patient baseline characteristics
The characteristics of the moderate-to-severe plaque psoriasis patients in this study are shown in Table 1. Of the 296 participants, there were 228 (77%) males (age 50.88 ± 15.23 years) and 68 (23%) females (age 52.00 ± 16.25 years). Notably, there were no statistically significant differences between the sexes in terms of age and the duration of psoriasis. In comparison with females, males exhibited a higher BMI, a greater proportion with a higher level of education (college or above), and a higher prevalence of smoking and drinking history.
Sex differences in psoriasis severity and plasma PUFAs concentrations at baseline
As shown in Table 2, there were evident sex differences in the ClinROs and plasma PUFAs concentrations: males had higher PASI, BSA and PGA scores, whereas females had higher levels of DHA and ARA. No significant differences were observed in PROs scores between male and female patients.
Associations of plasma PUFAs levels with psoriasis severity at baseline
In males, EDA levels were positively associated with PASI scores (β = 7.10, 95% CI 0.61, 13.60), BSA scores (β = 14.90, 95% CI 0.56, 29.24), and PGA scores (β = 0.88, 95% CI 0.26, 1.51) (Table 3). ALA levels were positively associated with DLQI scores (β = 1.20, 95% CI 0.52, 1.89), whereas ARA levels were negatively associated with DLQI scores (β = − 0.35, 95% CI − 0.58, − 0.11) (Table 3).
In females, no significant relationship was found between Omega-6 PUFAs levels and the severity scores of psoriasis patients (Table 4). Among Omega-3 PUFAs, EPA, DHA, and total Omega-3 PUFAs levels presented negative associations with PASI scores (β = − 2.67, 95% CI − 5.21, − 0.14; β = − 0.92, 95% CI − 1.72, − 0.12; β = − 0.65, 95% CI − 1.28, − 0.02), and BSA scores (β = − 5.84, 95% CI − 10.86, − 0.81; β = − 2.02, 95% CI − 3.61, − 0.44; β = − 1.42, 95% CI − 2.67, − 0.17), respectively (Table 4).
To further study the roles of potential confounders in the associations of plasma PUFAs levels with the severity of psoriasis, we stratified male or female patients into subgroups based on age and BMI. Additionally, we also stratified males based on smoking history and alcohol use. In the subgroups analysis of males, ALA was negatively associated with PASI scores in the 20–60 years age group (β = − 2.34, 95% CI − 3.94, − 0.73, p-interaction < 0.05), and EDA was positively associated with PASI scores in individuals with a BMI ranging from 23.99 to 28 kg/m2 (β = 11.97, 95% CI 1.86, 22.07), and with a history of alcohol use (β = 11.42, 95% CI 6.11, 22.73) (Additional file 1: Tables S1, S2). DGLA showed significantly positive association with PASI scores in males with smoking history (β = 63.73, 95% CI 10.18, 117.28) (Additional file 1: Table S2). In the subgroup analysis of females with a BMI lower than 23.99 kg/m2, a negative association was found between EPA and PASI scores (β = − 2.59, 95% CI − 5.15, − 0.03), while a positive relationship was observed with LA (β = 0.55, 95% CI 0.05, 1.05) and the Omega-6/3 ratio (β = 1.00, 95% CI 0.18, 1.81) (Additional file 1: Tables S3, S4).
Dose-response associations between Omega-3 PUFAs levels and clinical scores at baseline
In males, we did not find a linear association between Omega-3 PUFAs and clinical scores as expected, so we further explored whether there were non-linear relationships. After adjusting for covariates, we identified non-linear associations between PASI scores and EPA and Omega-3 PUFA levels in male patients (Fig. 2). In total males, within the range of Omega-3 PUFAs increasing from 6.03 to 8.92%, the β-coefficients (95% CI) of PASI scores decreased from 1.23 (0.10, 2.37) to − 1.31 (− 2.95, 0.32), which indicated an inverse association between the PASI scores and Omega-3 PUFAs levels within this specific range. However, both below or above this range, the association was positive, resulting in a distinctive N-shaped curve (Fig. 2A). Notably, even in subgroup analyses that excluded individuals obesity or overweight, these non-linear associations still existed (Fig. 2A). Furthermore, EPA exhibited similar non-linear relationship curves with PASI scores in males, whether they had obesity or not (Fig. 2B). In the case of BSA scores, among all men and when excluding individuals with obesity, EPA levels were also associated with BSA scores in a non-linear, N-shape pattern. However, we did not find significant relationships between total Omega-3 PUFAs and BSA scores (Fig. 3).
Associations between plasma PUFAs levels and PASI scores/response at week 12
Initially, we did not observe any difference in achieving PASI 75, PASI 90 or PASI 100 between males and females (Fig. 4). However, compared with females, males had higher PASI scores in biologic treatment group (Fig. 4). To observe the association between plasma PUFAs levels and PASI response, we found that Omega-6 PUFAs were positively associated with the probability of achieving PASI 100 at 12 weeks (OR = 1.14, 95% CI 1.03, 1.27) in males (Table 5). In females, we found that plasma DGLA levels were positively associated with PASI scores at 12 weeks (β = 34.82, 95% CI 7.24, 62.40) (Table 6). Surprisingly, DHA was negatively associated with possibility of achieving PASI 75 or PASI 90 (OR = 0.55, 95% CI 0.31, 0.99; OR = 0.38, 95% CI 0.17, 0.84, respectively) (Table 6).
In this cross-sectional study, we observed that males experienced severer psoriasis and presented lower plasma DHA and ARA levels than females. Besides, we explored the associations between PUFAs and psoriasis severity based on sex. Among males, plasma EDA was associated with increased scores of ClinROs including PASI, BSA, and PGA. Moreover, total Omega-3 PUFAs and/or EPA were associated with PASI and/or BSA scores in a non-linear manner. In terms of PROs, ALA was negatively, whereas ARA was positively associated with DLQI scores. However, these relationships were not found in females. Plasma Omega-3 PUFAs, including EPA, DHA, and total Omega-3 PUFAs, were identified to be inversely associated with PASI and BSA scores in women. Longitudinally, plasma total Omega-6 PUFAs were positively associated with the possibility of achieving a PASI 100 response at 12 weeks in males. In females, concentrations of DGLA were prospectively associated with an increase in PASI scores, while DHA was associated with a decreased likelihood of achieving PASI 75 and PASI 90 responses (Additional file 1: Fig. S1).
In this study, we found that male patients had higher scores of PASI, BSA and PGA than their female counterparts. Although the prevalence of psoriasis is generally considered to be balanced between sexes [21, 22], the severity of psoriasis may be modified by sex due to the “nature” (e.g., different body structure, endocrine and metabolism), daily lifestyle (e.g., smoking and alcohol intake), and treatment expectations [23,24,25]. Previous studies have reported sex differences in psoriasis severity [26, 27]. These distinctions can also be observed in many other inflammatory conditions, such as asthma , myocarditis , atherosclerosis , inflammatory bowel disease , etc. For psoriasis, Hägg et al. demonstrated significant differences in psoriasis severity based on gender in a Swedish population of 5438 patients . Another cross-sectional study enrolled 3023 Roman patients found that male sex was associated with severe or very severe PGA scores and PASI scores ≥ 10 . These findings correspond with our results that men had more severe psoriasis than women. To figure out the explanations for these disparities, we also compared the duration of psoriasis, treatment approaches, and comorbidities between males and females (data not shown). However, we only found a higher prevalence of stroke (p = 0.030), and coronary artery disease (p = 0.039) in females. Considering the sex differences in psoriasis severity, dermatologists should treat and manage psoriasis patients with a sex perspective.
In addition to disease severity, we observed sex differences in plasma PUFAs profiles, with women exhibiting higher DHA and ARA levels compared to men. To our knowledge, none of the existing publications has reported sex differences in PUFAs levels among moderate-to-severe psoriasis patients. Previously cumulative observational studies have reported sex differences in Omega-3 PUFAs levels (e.g., EPA, DHA) among healthy adults, even after controlling dietary intake [32,33,34,35,36]. Recently, in a massive clinical population (n = 1,169,621) from the United States, females had higher median levels of DHA (+ 11.40%) and ARA (+ 4.34%) than males . The underlying mechanism involved in mediating these differences may be sex hormones, presumably estrogens [33, 38, 39]. For example, estrogens regulate the expression of Delta-6 desaturase, a key enzyme in the metabolism of Omega-3 and Omega-6 fatty acids, and this hypothesis has been further supported by in vitro and in vivo studies [33, 40]. Besides, studies have documented that women tend to maintain healthier lifestyles and dietary habits compared to men [41, 42]. Thus, when exploring the association between PUFAs profiles and psoriasis severity, sex differences should be taken into consideration.
In our study, we do not find a significant difference in PROs between males and females. However, a recent cross-sectional study conducted in Dalian, China, reported an association between sex and the quality of life (QoL). The disparity between our two studies could be attributed to differences in study design, such as variations in sample size (228 males and 68 females in our study; 125 males and 60 females in Zhang’s study) and the distinct geographic locations where the research was conducted (Shanghai in our study; Dalian in Zhang’s study). Besides, patients from Zhang’s study had higher DLQI scores (mean ± SD: 11.74 ± 6.74) than our patients (9.37 ± 6.32), which underscores the individual differences among patients and the incommensurability between these two studies. Although males in our present study displayed higher ClinROs scores than females, they did not exhibit worse PROs. This discrepancy might be due to the fact that disease severity does not necessarily correlate with the quality of life .
The current literature suggests that psoriasis patients may have abnormal lipid metabolism, and supplementation with Omega-3 PUFAs hope to be beneficial for the management of psoriasis by diminishing inflammatory processes [11, 44]. Although previous evidence is sparse, our findings are supported by a cross-sectional study involving 85 patients, that which revealed an inverse correlation between total Omega-3 PUFAs levels and PASI scores (p = 0.048) . However, our study boasts a relatively larger sample size, and we took into account sex differences in the analysis, which emphasizing the significance of our research. In females, we observed negative associations between EPA, DHA levels and ClinROs assessments (PASI and BSA). It is well established that psoriasis is a chronic inflammatory disease and anti-inflammation is vital important in the treatment of psoriasis . Many studies have unveiled the various beneficial effects of Omega-3 PUFAs such as EPA and DHA on inflammatory diseases, as they are involved in the synthesis of anti-inflammatory metabolites . They also show anti-inflammatory activities in inflammatory skin diseases, including psoriasis . In psoriasis, in vivo and in vitro experiments have confirmed that Omega-3 PUFA metabolites influence multiple inflammatory signaling axis and cytokines on immune and epithelial cells, whereas the impact of dietary supplementation on psoriasis population is currently unclear [48,49,50].
Epidemiological studies have consistently reported a relationship between increased body weight and psoriasis , and a mendelian randomization study also provided compelling evidence indicating a positive association between BMI and psoriasis . Thus, we performed RCS analysis to delve deeper into the impact of PUFAs on psoriasis severity, specifically considering patients with varying BMIs. Specifically, our study found a likely N-shape relationship between plasma Omega-3 PUFAs levels and the severity of psoriasis in all males, as well as in subgroups excluding those with obesity or overweight both. Among all males, plasma Omega-3 PUFAs levels below 6.03% or above 8.92% exhibited positive associations with psoriasis severity, suggesting that Omega-3 nutrient status and psoriasis action is intricate and dose-dependent. In addition, our study also found positive associations between EDA and ClinROs outcomes in males, which was consistent in subgroup analysis among overweight patients. Although this PUFA has been reported to have anti-inflammatory functions in other diseases [53, 54], the functional roles and underlying mechanisms of this PUFA in psoriasis remain largely unknown and need to be further investigated.
In addition, our study suggests that ALA levels were positively, whereas ARA levels were negatively, associated with DLQI scores. DLQI reflects the QoL during treatment, which is a subjective score of the patient [17, 55]. Till now, only a few studies have reported the roles of PUFAs in improving QoL in other diseases, such as inflammatory bowel disease and Alzheimer’s disease [56, 57]. While in the context of psoriasis, there isa dearth of relevant reports. The relevant mechanism is unclear and may be related to the impact of PUFAs on brain cognitive function [55, 56]. Collectively, based on our results from cross-sectional study, Omega-3 PUFAs was negatively associated with severity of psoriasis, while Omega-6 PUFAs had the opposite effects, indicating that taking fish oil supplements (rich in Omega-3 PUFAs) could be beneficial for the management of psoriasis. Nevertheless, this hypothesis still needs high-quality randomized controlled trials to support. Additionally, our longitudinal study did not yield consistent results regarding Omega-3 PUFAs, which could be attributed to the limited sample size and variations in treatment effects.
Our study possesses several notable strengths. First, we collected high-quality clinical data including ClinROs and PROs on psoriasis severity and QoL, which increased the reliability of our findings . The consistent results from the three ClinROs outcomes substantially reduce the likelihood of false discoveries. Second, while previous studies predominantly focused on alterations in fatty acid composition in psoriasis patients compared to the general population, few explored the relationship between fatty acid levels and disease severity in psoriasis. Our study addresses this gap in the literature. Third, in this study, we used the molar percentage of PUFAs for statistical analysis. This statistical approach helps to minimize individual differences in the total amount of PUFAs, making our findings more robust. Fourth, we assessed the PUFAs status of psoriatic patients using plasma samples, a known ideal and noninvasive method that is easily accessible and highly sensitive for reflecting the PUFAs status in individuals . Furthermore, we utilized standard detection assays with advanced equipment and rigorous quality control measures, which bolsters the reliability and generalizability of our study. Finally, this study conducted a sex-based analysis and found linear relationships in women as well as both linear and nonlinear relationships in men between PUFAs and disease severity. These data emphasize the importance of considering gender when studying the function and clinical application of PUFAs.
Nonetheless, our study does have several limitations. First, although a set of confounders were adjusted based on the literatures [18, 19], residual or unmeasured confounders could still exist, which might influence our findings. Second, it’s worth noting that all the psoriasis patients in our study were of Chinese ethnicity, and therefore, the generalizability of our findings to other populations may be limited. Thirdly, as with any cross-sectional epidemiologic study, the statistical associations observed in the present study cannot imply any causality. Finally, despite our study’s longitudinal design, we did not obtain consistent results when compared to the cross-sectional study. This discrepancy could be attributed to the limited sample size, variations in treatment effects, and the fact that plasma PUFAs levels at baseline may not be representative of the long-term PUFAs status of psoriatic patients. To gain a more comprehensive understanding, further research with more extensive data collection and a larger sample size, incorporating data at various time points, is required to explore factors that may modulate the effects of these fatty acids.
In this cross-sectional study, we identified sex differences in both the disease severity and plasma PUFAs levels among psoriasis patients. Moreover, we cross-sectionally and longitudinally observed variations in the association between plasma PUFAs levels and psoriasis severity between men and women. Sex differences should be considered when studying the function and clinical application of PUFAs in psoriasis.
Availability of data and materials
Data described in the manuscript, code book, and analytic code will be made available upon reasonable request.
Body Mass Index
Body Surface Area
Dermatology Life Quality Index
Fatty acid methyl esters
Generalized linear regression models
Psoriasis Area and Severity Index
- PASI 75:
75% Reduction of PASI scores from baseline
- PASI 90:
90% Reduction of PASI scores from baseline
- PASI 100:
100% Reduction of PASI scores from baseline
Physician Global Assessment
Patient Global Assessment
Polyunsaturated fatty acids
Quality of life
Restricted cubic spline
Shanghai Psoriasis Effectiveness Evaluation CoHort
Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, Griffiths CEM, Ashcroft DM, et al. National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study. BMJ. 2020. https://doi.org/10.1136/bmj.m1590.
Griffiths CEM, Armstrong AW, Gudjonsson JE, Barker J. Psoriasis. Lancet. 2021;397(10281):1301–15. https://doi.org/10.1016/S0140-6736(20)32549-6.
Friis NU, Hoffmann N, Gyldenlove M, Skov L, Vilsboll T, Knop FK, et al. Glucose metabolism in patients with psoriasis. Br J Dermatol. 2019;180(2):264–71. https://doi.org/10.1111/bjd.17349.
Schett G, Rahman P, Ritchlin C, McInnes IB, Elewaut D, Scher JU. Psoriatic arthritis from a mechanistic perspective. Nat Rev Rheumatol. 2022;18(6):311–25. https://doi.org/10.1038/s41584-022-00776-6.
Quaranta M, Knapp B, Garzorz N, Mattii M, Pullabhatla V, Pennino D, et al. Intraindividual genome expression analysis reveals a specific molecular signature of psoriasis and eczema. Sci Transl Med. 2014;6(244):244ra90. https://doi.org/10.1126/scitranslmed.3008946.
Studnitsin AA, Igoshin IUM. Disorders of lipid metabolism in psoriasis (literature survey). Vestn Dermatol Venerol. 1976;9:40–4.
Voorhees JJ. Pathophysiology of psoriasis. Annu Rev Med. 1977;28:467–73. https://doi.org/10.1146/annurev.me.28.020177.002343.
Yardley HJ, Summerly R. Lipid composition and metabolism in normal and diseased epidermis. Pharmacol Ther. 1981;13(2):357–83. https://doi.org/10.1016/0163-7258(81)90006-1.
Dyall SC, Balas L, Bazan NG, Brenna JT, Chiang N, da Costa Souza F, et al. Polyunsaturated fatty acids and fatty acid-derived lipid mediators: recent advances in the understanding of their biosynthesis, structures, and functions. Prog Lipid Res. 2022;86: 101165. https://doi.org/10.1016/j.plipres.2022.101165.
Schulze MB, Minihane AM, Saleh RNM, Riserus U. Intake and metabolism of omega-3 and omega-6 polyunsaturated fatty acids: nutritional implications for cardiometabolic diseases. Lancet Diabetes Endocrinol. 2020;8(11):915–30. https://doi.org/10.1016/S2213-8587(20)30148-0.
Balic A, Vlasic D, Zuzul K, Marinovic B, Bukvic Mokos Z. Omega-3 versus Omega-6 polyunsaturated fatty acids in the Prevention and treatment of inflammatory skin diseases. Int J Mol Sci. 2020;21(3): 741. https://doi.org/10.3390/ijms21030741.
Mysliwiec H, Baran A, Harasim-Symbor E, Mysliwiec P, Milewska AJ, Chabowski A, et al. Serum fatty acid profile in psoriasis and its comorbidity. Arch Dermatol Res. 2017;309(5):371–80. https://doi.org/10.1007/s00403-017-1748-x.
Yu N, Peng C, Zhou J, Gu J, Xu J, Li X, et al. Measurement properties of the patient global assessment numerical rating scale in moderate-to-severe psoriasis. Br J Dermatol. 2023. https://doi.org/10.1093/bjd/ljad188.
Folch J, Lees M, Sloane Stanley GH. A simple method for the isolation and purification of total lipides from animal tissues. J Biol Chem. 1957;226(1):497–509.
Yang K, Chen C, Yan Q, Shen X, Jiang L, Ma R, et al. Combined association of early exposure to long-chain n-3 polyunsaturated fatty acids, mercury and selenium with cognitive performance in 1-year-old infants. Environ Res. 2022;207(112186): 112186. https://doi.org/10.1016/j.envres.2021.112186.
Puzenat E, Bronsard V, Prey S, Gourraud PA, Aractingi S, Bagot M, et al. What are the best outcome measures for assessing plaque psoriasis severity? A systematic review of the literature. J Eur Acad Dermatol Venereol. 2010;24(Suppl 2):10–6. https://doi.org/10.1111/j.1468-3083.2009.03562.x.
Finlay AY, Khan GK. Dermatology Life Quality Index (DLQI)—a simple practical measure for routine clinical use. Clin Exp Dermatol. 1994;19(3):210–6. https://doi.org/10.1111/j.1365-2230.1994.tb01167.x.
Ruan Z, Lu T, Chen Y, Yuan M, Yu H, Liu R, et al. Association between psoriasis and nonalcoholic fatty liver disease among outpatient US adults. JAMA Dermatol. 2022;158(7):745–53. https://doi.org/10.1001/jamadermatol.2022.1609.
Joel MZ, Fan R, Cohen JM. Association between psoriasis and celiac disease: a cross-sectional study in the all of US research program. J Am Acad Dermatol. 2023;88(6):1386–8. https://doi.org/10.1016/j.jaad.2023.02.004.
Ma R, Yang K, Chen C, Mao X, Shen X, Jiang L, et al. Early-life exposure to aluminum and fine motor performance in infants: a longitudinal study. J Expo Sci Environ Epidemiol. 2021;31(2):248–56. https://doi.org/10.1038/s41370-021-00294-9.
Burshtein J, Strunk A, Garg A. Incidence of psoriasis among adults in the United States: a sex- and age-adjusted population analysis. J Am Acad Dermatol. 2021;84(4):1023–9. https://doi.org/10.1016/j.jaad.2020.11.039.
Nazir Z, Strunk A, Garg A. Age- and sex-adjusted prevalence estimates among adults with psoriasis in the United States. J Am Acad Dermatol. 2022;86(3):703–5. https://doi.org/10.1016/j.jaad.2021.03.020.
Wei J, Zhu J, Xu H, Zhou D, Elder JT, Tsoi LC, et al. Alcohol consumption and Smoking in relation to psoriasis: a Mendelian randomization study. Br J Dermatol. 2022;187(5):684–91. https://doi.org/10.1111/bjd.21718.
Kearney N, Kirby B. Alcohol and psoriasis for the dermatologist: know, screen. Intervene Am J Clin Dermatol. 2022;23(6):881–90. https://doi.org/10.1007/s40257-022-00713-z.
Maul JT, Navarini AA, Sommer R, Anzengruber F, Sorbe C, Mrowietz U, et al. Gender and age significantly determine patient needs and treatment goals in psoriasis—a lesson for practice. J Eur Acad Dermatol Venereol. 2019;33(4):700–8. https://doi.org/10.1111/jdv.15324.
Hagg D, Sundstrom A, Eriksson M, Schmitt-Egenolf M. Severity of psoriasis differs between men and women: a study of the clinical outcome measure psoriasis area and severity index (PASI) in 5438 Swedish register patients. Am J Clin Dermatol. 2017;18(4):583–90. https://doi.org/10.1007/s40257-017-0274-0.
Napolitano M, Mastroeni S, Fania L, Pallotta S, Fusari R, Uras C, et al. Sex- and gender-associated clinical and psychosocial characteristics of patients with psoriasis. Clin Exp Dermatol. 2020;45(6):705–11. https://doi.org/10.1111/ced.14218.
Rossi A, Roviezzo F, Sorrentino R, Riemma MA, Cerqua I, Bilancia R, et al. Leukotriene-mediated sex dimorphism in murine asthma-like features during allergen sensitization. Pharmacol Res. 2019;139:182–90. https://doi.org/10.1016/j.phrs.2018.11.024.
Di Florio DN, Sin J, Coronado MJ, Atwal PS, Fairweather D. Sex differences in inflammation, redox biology, mitochondria and autoimmunity. Redox Biol. 2020;31(101482): 101482. https://doi.org/10.1016/j.redox.2020.101482.
Man JJ, Beckman JA, Jaffe IZ. Sex as a biological variable in atherosclerosis. Circ Res. 2020;126(9):1297–319. https://doi.org/10.1161/CIRCRESAHA.120.315930.
Xu L, Huang G, Cong Y, Yu Y, Li Y. Sex-related differences in inflammatory bowel diseases: the potential role of sex hormones. Inflamm Bowel Dis. 2022;28(11):1766–75. https://doi.org/10.1093/ibd/izac094.
Crowe FL, Skeaff CM, Green TJ, Gray AR. Serum n-3 long-chain PUFA differ by sex and age in a population-based survey of New Zealand adolescents and adults. Br J Nutr. 2008;99(1):168–74. https://doi.org/10.1017/S000711450779387X.
Giltay EJ, Gooren LJ, Toorians AW, Katan MB, Zock PL. Docosahexaenoic acid concentrations are higher in women than in men because of estrogenic effects. Am J Clin Nutr. 2004;80(5):1167–74. https://doi.org/10.1093/ajcn/80.5.1167.
Bakewell L, Burdge GC, Calder PC. Polyunsaturated fatty acid concentrations in young men and women consuming their habitual diets. Br J Nutr. 2006;96(1):93–9. https://doi.org/10.1079/bjn20061801.
Metherel AH, Armstrong JM, Patterson AC, Stark KD. Assessment of blood measures of n-3 polyunsaturated fatty acids with acute fish oil supplementation and washout in men and women. Prostaglandins Leukot Essent Fatty Acids. 2009;81(1):23–9. https://doi.org/10.1016/j.plefa.2009.05.018.
Walker CG, Browning LM, Mander AP, Madden J, West AL, Calder PC, et al. Age and sex differences in the incorporation of EPA and DHA into plasma fractions, cells and adipose tissue in humans. Br J Nutr. 2014;111(4):679–89. https://doi.org/10.1017/S0007114513002985.
Diffenderfer MR, Rajapakse N, Pham E, He L, Dansinger ML, Nelson JR, et al. Plasma fatty acid profiles: relationships with sex, age, and state-reported heart disease mortality rates in the United States. J Clin Lipidol. 2022;16(2):184–97. https://doi.org/10.1016/j.jacl.2021.12.005.
Pender-Cudlip MC, Krag KJ, Martini D, Yu J, Guidi A, Skinner SS, et al. Delta-6-desaturase activity and arachidonic acid synthesis are increased in human breast cancer tissue. Cancer Sci. 2013;104(6):760–4. https://doi.org/10.1111/cas.12129.
Childs CE, Romeu-Nadal M, Burdge GC, Calder PC. Gender differences in the n-3 fatty acid content of tissues. Proc Nutr Soc. 2008;67(1):19–27. https://doi.org/10.1017/S0029665108005983.
Kitson AP, Marks KA, Shaw B, Mutch DM, Stark KD. Treatment of ovariectomized rats with 17beta-estradiol increases hepatic delta-6 desaturase enzyme expression and docosahexaenoic acid levels in hepatic and plasma phospholipids. Prostaglandins Leukot Essent Fatty Acids. 2013;89(2–3):81–8. https://doi.org/10.1016/j.plefa.2013.05.003.
Wielsoe M, Berthelsen D, Mulvad G, Isidor S, Long M, Bonefeld-Jorgensen EC. Dietary habits among men and women in West Greenland: follow-up on the ACCEPT birth cohort. BMC Public Health. 2021;21(1):1426. https://doi.org/10.1186/s12889-021-11359-7.
Vari R, Scazzocchio B, D’Amore A, Giovannini C, Gessani S, Masella R. Gender-related differences in lifestyle may affect health status. Ann Ist Super Sanita. 2016;52(2):158–66. https://doi.org/10.4415/ANN_16_02_06.
Wojtyna E, Lakuta P, Marcinkiewicz K, Bergler-Czop B, Brzezinska-Wcislo L. Gender, body image and social support: biopsychosocial determinants of depression among patients with psoriasis. Acta Derm Venereol. 2017;97(1):91–7. https://doi.org/10.2340/00015555-2483.
Nowowiejska J, Baran A, Flisiak I. Aberrations in lipid expression and metabolism in psoriasis. Int J Mol Sci. 2021;22(12): 6561. https://doi.org/10.3390/ijms22126561.
Korman NJ. Management of psoriasis as a systemic disease: what is the evidence? Br J Dermatol. 2020;182(4):840–8. https://doi.org/10.1111/bjd.18245.
Kalupahana NS, Goonapienuwala BL, Moustaid-Moussa N. Omega-3 fatty acids and adipose tissue: inflammation and browning. Annu Rev Nutr. 2020;40:25–49. https://doi.org/10.1146/annurev-nutr-122319-034142.
Sawada Y, Saito-Sasaki N, Nakamura M. Omega 3 fatty acid and skin diseases. Front Immunol. 2020;11:623052. https://doi.org/10.3389/fimmu.2020.623052.
Ariel A, Serhan CN. Resolvins and protectins in the termination program of acute inflammation. Trends Immunol. 2007;28(4):176–83. https://doi.org/10.1016/j.it.2007.02.007.
Xu J, Duan X, Hu F, Poorun D, Liu X, Wang X, et al. Resolvin D1 attenuates imiquimod-induced mice psoriasiform dermatitis through MAPKs and NF-kappaB pathways. J Dermatol Sci. 2018;89(2):127–35. https://doi.org/10.1016/j.jdermsci.2017.10.016.
Melo CPB, Saito P, Martinez RM, Staurengo-Ferrari L, Pinto IC, Rodrigues CCA, et al. Aspirin-triggered resolvin D1 (AT-RvD1) protects mouse skin against UVB-induced inflammation and oxidative stress. Molecules. 2023;28(5): 2417. https://doi.org/10.3390/molecules28052417.
Snekvik I, Smith CH, Nilsen TIL, Langan SM, Modalsli EH, Romundstad PR, et al. Obesity, waist circumference, weight change, and risk of incident psoriasis: prospective data from the HUNT study. J Invest Dermatol. 2017;137(12):2484–90. https://doi.org/10.1016/j.jid.2017.07.822.
Budu-Aggrey A, Brumpton B, Tyrrell J, Watkins S, Modalsli EH, Celis-Morales C, et al. Evidence of a causal relationship between body mass index and psoriasis: a mendelian randomization study. PLoS Med. 2019;16(1): e1002739. https://doi.org/10.1371/journal.pmed.1002739.
Baker EJ, Valenzuela CA, van Dooremalen WTM, Martinez-Fernandez L, Yaqoob P, Miles EA, et al. Gamma-linolenic and pinolenic acids exert anti-inflammatory effects in cultured human endothelial cells through their elongation products. Mol Nutr Food Res. 2020;64(20): e2000382. https://doi.org/10.1002/mnfr.202000382.
Chen SJ, Chuang LT, Liao JS, Huang WC, Lin HH. Phospholipid incorporation of non-methylene-interrupted fatty acids (NMIFA) in murine microglial BV-2 cells reduces pro-inflammatory mediator production. Inflammation. 2015;38(6):2133–45. https://doi.org/10.1007/s10753-015-0196-z.
Mattei PL, Corey KC, Kimball AB. Psoriasis area severity index (PASI) and the dermatology life quality index (DLQI): the correlation between disease severity and psychological burden in patients treated with biological therapies. J Eur Acad Dermatol Venereol. 2014;28(3):333–7. https://doi.org/10.1111/jdv.12106.
Ajabnoor SM, Thorpe G, Abdelhamid A, Hooper L. Long-term effects of increasing omega-3, omega-6 and total polyunsaturated fats on inflammatory bowel disease and markers of inflammation: a systematic review and meta-analysis of randomized controlled trials. Eur J Nutr. 2021;60(5):2293–316. https://doi.org/10.1007/s00394-020-02413-y.
Nolan JM, Power R, Howard AN, Bergin P, Roche W, Prado-Cabrero A, et al. Supplementation with carotenoids, Omega-3 fatty acids, and vitamin E has a positive effect on the symptoms and progression of Alzheimer’s disease. J Alzheimers Dis. 2022;90(1):233–49. https://doi.org/10.3233/JAD-220556.
Katan MB, Deslypere JP, van Birgelen AP, Penders M, Zegwaard M. Kinetics of the incorporation of dietary fatty acids into serum cholesteryl esters, erythrocyte membranes, and adipose tissue: an 18-month controlled study. J Lipid Res. 1997;38(10):2012–22.
This study was supported by funding from Clinical Research Plan of SHDC (No. SHDC2020CR1014B), China Postdoctoral Science Foundation (2023M732651), the National Natural Science Foundation of China (82203907, 82273510, 82003334, 82103712, 82103707), the Innovation Program of Shanghai Municipal Education Commission (2019-01-07-00-07-E00046), Program of Shanghai Academic Research Leader (20XD1403300), Talent Plan of Shanghai Municipal Health Commission (No. 2022YQ057), and Clinical Research Plan of Shanghai Municipal Health Commission (No. 20214Y0337).
Ethics approval and consent to participate
The Ethical approvals for SPEECH were: Shanghai Tenth People’s Hospital (#20KT110); Ruijin Hospital (#2020821); Huashan Hospital (#KY2021-733); Changhai Hospital (#2020-27); Shanghai Jiao Tong University Affiliated Sixth People’s Hospital (#2020-KY-047); and Yueyang Hospital of Integrated Traditional Chinese and Western Medicine (#2021-129). Informed consents were obtained from all participants.
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Subgroup and interaction analysis between plasma Omega-3 PUFAs levels (mol %) and PASI scores in males. Table S2. Subgroup and interaction analysis between plasma Omega-6 PUFAs levels (mol %) and PASI scores in males. Table S3. Subgroup and interaction analysis between plasma Omega-3 PUFAs levels (mol %) and PASI scores in females. Table S4. Subgroup and interaction analysis between plasma Omega-6 PUFAs levels (mol %) and PASI scores in females. Figure S1. Study design and major results of the study.
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Wang, X., Ma, R., Shi, R. et al. Sex differences in the association between plasma polyunsaturated fatty acids levels and moderate-to-severe plaque psoriasis severity: a cross-sectional and longitudinal study. J Transl Med 21, 834 (2023). https://doi.org/10.1186/s12967-023-04726-y