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Psoriatic arthritis
Short report
Sex differences in cytokines and adipokines in obese patients with PsA and controls undergoing a weight loss intervention
  1. Anton Jonatan Landgren1,2,
  2. Charlotte A Jonsson1,
  3. Annelie Bilberg3,4,
  4. Björn Eliasson5,
  5. Linda Torres1,4,
  6. Mats Dehlin1,4,
  7. Lennart Jacobsson1,
  8. Inger Gjertsson1,4,
  9. Ingrid Larsson5,6 and
  10. Eva Klingberg1,4
  1. 1Department of Rheumatology and Inflammation Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  2. 2Region Västra Götaland, Research and Development Primary Health Care, Södra Bohuslän, Gothenburg, Sweden
  3. 3Institute of Neuroscience and Physiology, Section of Health and Rehabilitation, Physiotherapy, Sahlgrenska Academy, Gothenburg, Sweden
  4. 4Department of Rheumatology, Sahlgrenska University Hospital, Gothenburg, Sweden
  5. 5Department of Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden
  6. 6Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
  1. Correspondence to Dr Anton Jonatan Landgren; anton.landgren{at}rheuma.gu.se

Abstract

Objective In this post hoc analysis of a previously published study, we compared cytokines and adipokine levels in women and men with psoriatic arthritis (PsA) at baseline (BL) and 6 months (M6) following a weight loss intervention.

Methods Patients with PsA (n=41) between 25 and 75 years of age, with body mass index (BMI)≥33 kg/m2 were included in a weight loss intervention with a very low energy diet (VLED) for 12 or 16 weeks depending on BL BMI<40 or ≥40 kg/m2. As controls (n=39), obese individuals, already planned for VLED treatment were recruited and matched for sex, age and weight to the patients with PsA. Cytokines and adipokines were measured at BL and M6.

Results At BL, serum levels of interleukin (IL)-23, leptin and high molecular weight-adiponectin were higher in women with PsA compared with men, whereas serum levels of interferon (IFN)-γ, IL-12/IL-23 p40 and IL-13 were significantly lower in women. Serum IL-23 was significantly reduced at M6 compared with BL in women but not in men with PsA. In women with PsA, the reduction in IL-23 at M6, ∆IL-23, were positively correlated with ∆Disease Activity Score 28 C reactive protein (CRP) (Spearman’s correlation (rS)=0.486, p=0.016), ∆CRP (rS=0.468, p=0.021), ∆leptin (rS=0.683, p<0.001) and negatively correlated with ∆total-adiponectin (rS=−0.433, p=0.035). Also in women, ∆Disease Activity in Psoriatic Arthritis was positively correlated with ∆tumour necrosis factor-α (rS=0.417, p=0.034), ∆IL-1β (rS=0.550, p=0.034), ∆IFN-γ (rS=0.414, p=0.035) and ∆leptin (rS=0.410, p=0.038). None of these correlations were significant in men with PsA.

Conclusions Women and men with PsA differed with regard to serum levels of cytokines and adipokines before and after weight loss.

  • Arthritis, Psoriatic
  • Cytokines
  • Inflammation
http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/rmdopen-2023-003821

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    WHAT IS ALREADY KNOWN ON THIS TOPIC

    • Obesity is over-represented in psoriatic arthritis (PsA), weight loss is associated with improved disease activity, improved response to treatment and reduced levels of proinflammatory cytokines and adipokines.

    • Women with PsA frequently report worse pain, fatigue and poorer response to treatment.

    • Previous studies have found sex differences in cytokines and adipokines, however, no study has assessed sex differences in cytokines and adipokines in PsA.

    WHAT THIS STUDY ADDS

    • In this study, we found significantly reduced serum interleukin (IL)-23 levels in women, but not in men with PsA after a weight loss intervention.

    • Reductions in IL-23, ∆IL-23, were positively correlated with ∆Disease Activity Score 28 C reactive protein (CRP), ∆CRP, ∆leptin and negatively correlated with ∆total-adiponectin, in women but not in men.

    HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY

    • This study identifies differences in cytokine and adipokine levels in women and men with PsA, that may have an impact on sex differences regarding patient-reported outcome measures and treatment response.

    Introduction

    Obesity is associated with increased levels of several proinflammatory cytokines and adipokines, including tumour necrosis factor (TNF)-α, interleukin (IL)−1, IL-6, IL-17, IL-23, C reactive protein (CRP) and leptin.1 2 Weight loss in obese individuals often results in lowered levels of proinflammatory cytokines, CRP and adipokines.3 Obesity is a known risk factor for developing psoriatic arthritis (PsA).4 Obesity in PsA is associated with higher disease activity and reduced response to treatment,5 whereas weight loss has been shown to improve disease activity in obese patients with PsA.6 PsA has a similar sex distribution between women and men, although important sex differences relating to disease characteristics, pain, fatigue and response to treatment7 8 have been reported. Others have reported sex differences in proinflammatory cytokines,9 10 although not assessing patients with PsA. To our knowledge no previous study has investigated sex differences in cytokine levels in PsA. We have previously reported on the effects of weight loss by a very low energy diet (VLED) on cytokine levels in obese patients with PsA and matched controls that underwent a weight loss intervention.11 Here we report on sex differences in cytokine levels at baseline (BL) and at 6 months (M6) from the same study, in which 41 patients with PsA (26 women and 15 men) and 39 controls (28 women and 11 men), matched by sex, age and weight, were followed-up to M6.

    Methods

    The 12-month weight loss intervention and study design have been described in detail previously.6 11 Patients with PsA between 25 and 75 years of age, with body mass index (BMI)≥33 kg/m2 and meeting the ClASsification criteria for Psoriatic ARthritis criteria12 were eligible. Exclusion criteria for both patients and controls were epilepsy, pregnancy, porphyria, type 1 diabetes, severe kidney, heart or catabolic disease, binge eating disorder, current treatment with lithium, phenytoin or warfarin, having mental imbalance affecting participation or a history of stroke, myocardial infarction, major surgery or trauma during the last 3 months or cancer treatment during the last 5 years. Treatment with conventional synthetical or biological disease-modifying anti-rheumatic drugs was held unchanged from 3 months before BL until M6. Patients with PsA and controls were given VLED (640 kcal/day) for 12 or 16 weeks, depending on BL BMI<40 or ≥40 kg/m2. Food was gradually reintroduced thereafter and every patient was given an individual diet advise and followed during 12 months at the obesity department. As controls, obese individuals, already planned for VLED treatment were recruited from the Regional Obesity Centre at Sahlgrenska University Hospital and matched for sex, age and weight to the patients with PsA. In addition to the exclusion criteria for patients with PsA, controls with a diagnosis of psoriasis, PsA or any inflammatory rheumatic disease were not eligible for the study. Serum levels of cytokines and adipokines were analysed at BL and M6 using Human Magnetic Luminex Assays (R&D Systems). The analysis and quantification were performed using a Bio-Plex 200 system (Bio-Rad) with five-parameter logistic standard curves. Samples with analyte levels below the detection level were excluded from the analysis.

    Statistical analyses

    Descriptive statistics are presented as numbers (%), median and IQR.

    The Mann-Whitney U test was used for comparisons of continuous variables between groups. The χ2 test was used for categorical variables. Wilcoxon signed-rank test was used to compare continuous-related samples. Correlations were calculated using Spearman’s correlation (rS). Two-tailed tests were used and p≤0.05 was considered statistically significant. Statistical analyses were made using SPSS Statistics V.29 (IBM, Chicago, USA).

    Results

    At BL, women versus men with PsA had higher BMI, Disease Activity in Psoriatic Arthritis (DAPSA) score, Disease Activity Score 28 joints using CRP (DAS28-CRP), Health Assessment Questionnaire (HAQ) scores and also higher Visual Analogue Scales for patient’s global disease activity, pain and fatigue. Serum IL-23, leptin and high molecular weight (HMW)-adiponectin were also higher in women with PsA, whereas serum levels of interferon (IFN)-γ, IL-12/IL-23 p40 and IL-13 were significantly lower in women compared with men table 1. In controls, serum levels of IL-23 and leptin were also higher in women, whereas BMI, TNF-α, IL-12/IL-23 p40 and IFN-γ were lower in women than in men (table 2).

    View this table:
    Table 1

    Cytokines and adipokines in women and men with psoriatic arthritis at baseline and at 6 months (M6) of follow-up

    View this table:
    Table 2

    Cytokines and adipokines in controls, stratified by sex, at baseline and at 6 months of follow-up

    Serum IL-23 was significantly reduced at M6 compared with BL in women but not in men with PsA (table 1). In female controls, significant reductions in TNF-α, IL-6, IL-12/IL-23 p40, IL-13, IL-23, IFN-γ, leptin and significant increases in HMW-adiponectin and total-adiponectin at M6 compared with BL were observed (table 2). In male controls, IL-23 and leptin were significantly reduced whereas HMW-adiponectin and total-adiponectin were significantly increased at M6 compared with BL. Changes in cytokines and adipokines comparing BL and M6 in women and men with PsA are further displayed in figure 1. In women with PsA, the reduction in IL-23 at M6, ∆IL-23, was positively correlated with ∆DAS28CRP (rS=0.486, p=0.016), ∆CRP (rS=0.468, p=0.021), ∆leptin (rS=0.683, p<0.001) and negatively correlated with ∆total-adiponectin (rS=−0.433, p=0.035). In addition, in women, ∆DAPSA was positively correlated with ∆TNF-α (rS=0.417, p=0.034), ∆IL-1β (rS=0.550, p=0.034), ∆IFN-γ (rS=0.414, p=0.035) and ∆leptin (rS=0.410, p=0.038). In men with PsA, these correlations were weaker and non-significant.

    Figure 1
    Figure 1

    Boxplots for cytokines and adipokines, showing the distribution of change (median and IQR) in %, comparing BL and M6. (A) Baseline (BL) to month 6 (M6) change (%) in women with psoriatic arthritis (PsA), n=26; number of patients with missing data values (cytokine or adipokine levels below detection limit); IL- 1β, n=11; IL- 12/IL- 23 p40, n=5; IL- 13, n=1; IL- 17, n=18; IL- 23, n=2. (B) BL to M6 change (%) in men with PsA, n=15; number of patients with missing data values (cytokine or adipokine levels below detection limit); IL- 1β, n=3; IL- 12/IL- 23 p40, n=1; IL-17, n=8; IL- 23, n=4; leptin, n=1. HMW, high molecular weight; IFN, interferon; IL, interleukin; TNF tumour necrosis factor; Tot total.

    Discussion

    Sex differences in serum cytokines levels in patients with PsA have not previously been studied. However, previous studies have reported higher levels of leptin and adiponectin in healthy women compared with men,10 but higher levels of IL-1β, IL-6 and TNF-α in healthy men compared with healthy women.9 The worse HAQ, pain and fatigue scores in women with PsA in the current study are consistent with a recent review by Coates et al.8 Although hampered by a small sample size, multiple testing and fewer men, as well as differences in BMI between women and men, the results from the current study suggest that there are sex differences in cytokine levels in patients with PsA and obesity. This should be further explored in a larger study. These sex differences may play a role in the sex-specific differences in patient-reported outcomes and in treatment response.

    Ethics statements

    Patient consent for publication

    Ethics approval

    The study was approved by the Regional Ethics Committee in Gothenburg (approval number 901–15). Participants gave informed consent to participate in the study before taking part.

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    Footnotes

    • Contributors AJL participated in interpretation of data and was responsible for statistical analyses and drafting of the article. CAJ was responsible for the serum analyses of cytokines and adipokines and participated in interpretation of the data and drafting of the article. AB participated in the study design, recruitment and examination of patients, collection, analysis and interpretation of data. BE participated in the study design, recruitment and examination of patients, collection and interpretation of data and was responsible for the weight loss treatment and follow-up. LT participated in interpretation of data and drafting of the article. MD participated in interpretation of data and drafting of the article. LJ participated in interpretation of data and drafting of the article. IG participated in the study design, in interpretation of data and drafting of the article. IL participated in the study design, recruitment and examination of patients, collection and interpretation of data and was responsible for the weight loss treatment and follow-up. EK was responsible for the study design, recruitment of patients, rheumatological evaluations, data collection, interpretation of data and participated in drafting of the article. All authors have critically reviewed the manuscript, approved the final version to be published and agreed to be accountable for all aspects of the work.

    • Funding The study was financed by grants from the Swedish state under the agreement between the Swedish government and the county councils, the ALF-agreement (ALFGBG-970322 and ALFGBG-966169), the Gothenburg Society of Medicine, Inger Bendix foundation for medical research, Rune and Ulla Amlövs foundation for Rheumatology Research, Stiftelsen Psoriasisfonden, the Swedish Rheumatology Association research grant in collaboration with Roche and the Swedish Rheumatology Association research grant in collaboration with Galapagos/Biopharma. The sponsors of the study had no role in the design and conduct of the study; collection, management, analysis and interpretation of the data; or the preparation, review or approval of the manuscript.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.