Targeting the Metabolic-Inflammatory Axis in Psoriasis and Psoriatic Arthritis: Evidence From Diet, Glucagon-like Peptide-1 Receptor Agonists, and Patient Perspectives

Dietary changes in clinical trials

The intestinal microbiota is increasingly recognized as a central regulator of host homeostasis through the production of metabolites that modulate both innate and adaptive immunity, as well as key host metabolic pathways.⁹ Although microbial metabolites have been implicated in systemic immune-metabolic disorders, their role in localized conditions such as joint diseases remains less well defined. Previous evidence suggests that gut dysbiosis¹⁰ and distinct circulating metabolite profiles¹¹ can play important roles in patients with PsD. However, the observed associations between gut dysbiosis and circulating metabolite profiles remain largely correlational, and a direct functional link along the gut-joint axis has yet to be demonstrated. Among microbial metabolites, bile acids (BAs) are of particular interest, as they not only participate in lipid digestion but also act as signaling molecules.¹² Of interest, a recent paper described a novel gut-joint axis mediated by GLP-1 in osteoarthritis, modulated by the intestinal microbiome and secondary BAs.¹³ This axis may play a role in regulating joint inflammation in PsD and other arthritides, offering new insights into BA metabolism and signaling. These findings open up novel therapeutic avenues that complement conventional symptomatic treatments by targeting the microbiota-metabolite-joint axis.¹³

In clinical trials of antiinflammatory diets in patients with rheumatoid arthritis (RA), Coras et al reported that clinical improvement correlated with distinct metabolomic changes, particularly within the plasma BA pool, which was independent of weight loss.¹⁴ In animal models of RA, such dietary interventions reduced disease activity scores and markedly altered both the metabolome and BA composition. In vitro, GLP-1RAs decreased IL-6 secretion in TNF-stimulated synovial fibroblasts, indicating a direct antiinflammatory effect (M. Guma, MD, PhD, unpublished data, 2025). Collectively, these preliminary findings suggest that dietary interventions and GLP-1RAs may act as synergistic strategies targeting the microbiome, metabolome, and joint inflammation.

Obesity has emerged as a key modifiable risk factor in PsD. Its prevalence is higher among people with PsO and PsA compared with the general population, and it has been linked to both disease onset and increased severity.¹⁵ Weight reduction, particularly through lifestyle interventions, has been associated with clinical improvement and with a higher likelihood of achieving minimal disease activity in PsA.¹⁵ Moreover, Western diet–induced gut dysbiosis may further exacerbate inflammation by disrupting the mucosal barrier, altering microbial balance, and promoting aberrant metabolite production, including BAs.¹⁶

Eder et al emphasized the importance of obesity and diet in PsA, with specific reference to the preliminary findings of the Dietary Interventions in Psoriatic Arthritis (DIPSA) clinical trial.⁵ The DIPSA trial, designed as a randomized controlled study, compared the effects of a Mediterranean diet and a hypocaloric Dietary Approaches to Stop Hypertension (DASH)-style diet with standard therapy in overweight or obese patients with PsA experiencing persistent symptoms. Preliminary results indicate that both dietary strategies were associated with significant, though modest, weight loss accompanied by clinical improvement, as measured by Disease Activity Index for Psoriatic Arthritis (DAPSA) scores. These clinical benefits were particularly pronounced in patients who achieved greater weight reduction. A key component of the trial was the integration of personalized support, including nutritional coaching and targeted adherence strategies, which contributed to the effectiveness and sustainability of the intervention.⁵ Overall, these findings support the integration of nutritional approaches in PsA management as a valuable complementary strategy, with the dual objective of modulating joint inflammation and reducing the burden of associated comorbidities (L. Eder, MD, PhD, unpublished data, 2024).

GLP-1RAs in PsD: dermatologist and rheumatologist perspectives

GLP-1RAs, approved for T2DM and obesity, have recently attracted interest among rheumatologists and dermatologists owing to their potential antiinflammatory and metabolic benefits.^17,18 Obesity and T2DM are frequent comorbidities in patients with PsD, contributing to increased disease incidence, poorer outcomes, and reduced treatment responses.^1-4 Weight loss is associated with clinical improvement in PsA and PsO, making GLP-1RAs an appealing therapeutic adjunct.^2,19 Although robust data in PsA are lacking, early signals suggest that GLP-1RAs may reduce inflammation and possibly improve symptoms. In a small prospective study including patients with inflammatory arthritis (PsA and RA), liraglutide use was associated with clinical improvement.²⁰ From a PsO standpoint, interest in GLP-1RAs has grown since Hogan et al reported improvement in PsO in 3 obese patients with T2DM treated with these agents.²¹ Since then, subsequent prospective cohort studies and randomized clinical trials have shown statistically significant improvements in the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI), further supporting GLP-1RA use for PsO.^22-25 No serious adverse events were reported.

GLP-1RAs are generally safe, with mild and transient gastrointestinal side effects. Importantly, they do not require specific monitoring, they may offer cardiovascular benefits, and there has been no demonstrated increase in overall cancer risk or mortality with GLP-1RAs.²⁶ In fact, multiple studies have demonstrated a survival benefit of GLP-1RAs.⁸

Mechanistically, research suggests GLP-1RAs modulate PsO-relevant immune pathways, including reduced interferon-γ production by invariant natural killer T cells, keratinocyte proliferation, macrophage migration, TNF production, and IL-17–producing dermal γδ T cells.^20,21,27,28

However, the extent to which these immunomodulatory effects contribute to clinical improvement in PsO, independent of weight loss, remains uncertain. Existing studies have small sample sizes, are of short durations, and lack adequate controls. Responses may vary by patient phenotype; studies thus far have mostly evaluated men, and conflicting results in 2 randomized controlled trials (RCTs) evaluating liraglutide for PsO (one showing improvement in patients with T2DM and the other showing no improvement in glucose-tolerant patients) suggest a decrease in obesity alone may not be sufficient for GLP-1RA–induced PsO improvement.^23,24 Most patients studied were naïve to systemic therapy, raising questions about generalizability.

Dermatologists and rheumatologists managing GLP-1RAs must also be aware of potential rare but serious adverse events, including pancreatitis, cholecystitis, aspiration risk under anesthesia, and the potential risk of medullary thyroid carcinoma, although a causal association in humans remains unproven.²⁶

In summary, select PsO and PsA patients with obesity and/or T2DM may benefit from GLP-1RAs. Their favorable safety profile and metabolic effects are promising, yet current data do not support their routine use for PsD. The expanding use of GLP-1RAs across multiple chronic conditions has prompted discussion regarding appropriate indications, equity of access, and the need for robust long-term evidence to support benefits beyond weight reduction.²⁹ Well-designed RCTs with longer follow-up are needed to define their therapeutic role. Until then, a cautious, case-by-case approach shared across specialties is warranted.

PRP survey and perspective on weight-loss drugs and lifestyle in PsD

The GRAPPA PRPs presented the results of a survey conducted among their network aimed at exploring perceptions and expectations regarding weight management, lifestyle modifications, and the potential role of GLP-1RAs in PsD. The survey was developed by a small group of PRPs with input and feedback from an expert in PsD and was completed in June 2025 by 11 of 13 members. The questionnaire, administered anonymously through the Qualtrics platform, required approximately 5 to 10 minutes to complete.

Nearly all respondents (> 99%) reported their PsD was manageable with current therapies. However, persistent challenges were noted, including treatment-related adverse events, lifestyle-driven fluctuations in well-being, and—in approximately one-third of participants—the presence of comorbidities such as obesity, T2DM, and cardiovascular disease. All PRPs acknowledged the importance of maintaining a healthy body weight as an integral component of PsD management.

Most participants (90.9%) reported independently attempting lifestyle changes related to diet and/or physical activity. Nevertheless, only 27% received specific recommendations from their treating clinicians. The most frequently reported barriers to sustained lifestyle modification were fatigue and lack of motivation, which were often perceived as interrelated factors; additional barriers included time constraints, pain, and limited access to healthy foods.

Regarding nutrition, many PRPs reported having reduced their intake of processed foods, sugar, and sodium, highlighting both the patients’ willingness to modify dietary habits and the diversity of dietary approaches adopted. These findings underscore the need for individualized nutritional strategies tailored to patient-specific preferences and needs. None of the respondents had prior experience with GLP-1RAs; however, 27.3% expressed interest in their potential use for weight management. Concerns were simultaneously raised about long-term safety, accessibility, cost, and the implications of lifelong therapy. More than half of the PRPs reported being unaware of whether they would have access from their health plans to GLP-1RAs if desired, highlighting the need for more information.

PRPs emphasized the need for greater engagement of healthcare professionals in discussions surrounding nutrition and physical activity. Although acknowledging limitations in clinical time and expertise, participants stressed the value of being directed toward appropriate resources and supportive services. Further, respondents highlighted the importance of advancing research on the role of lifestyle factors in PsD, including the effect of dietary modifications (eg, dairy or meat exclusion) and behavioral interventions, with the goal of generating systematic, evidence-based data to guide patient care.

This survey provides valuable insights into the lived experiences and unmet needs of PRPs regarding PsD management, underscoring the importance of a multidimensional approach that integrates pharmacologic treatment, lifestyle modification, and psychosocial support. The next steps planned include revising and expanding the survey to be conducted on a global scale, with a stronger focus on GLP-1RA therapies and nutrition.