Improvement of Chronic Spontaneous Urticaria After Glucagon-Like Peptide 1 Receptor Agonist Therapy: Report of Two Cases.

We report two cases of chronic spontaneous urticaria (CSU) refractory to high doses of second-generation non-sedating H 1 -antihistamines but which cleared within 3 weeks after introduction of glucagon-like peptide 1 receptor agonists (GLP-1RA) for metabolic reasons. Response of CSU to GLP-1RA observed in two patients may indicate systemic immunometabolic or local immunological effects of this therapy as has been suggested for other autoinflammatory and autoimmune diseases. Rapid response of CSU to GLP-1RA may suggest a direct effect of the drug on mast cell degranulation or other factors that change immediately after the change of diet such as the inflammasome. To confirm the hypothesis of the beneficial effect of GLP-1RA on CSU larger observational and prospective studies are indispensable.

A 44-year-old woman with CSU since March 2020 reported persistent daily wheals despite long-term H1AH, with fexofenadine 720 mg per day between March and June 2024 (UAS7 16–18 at that time). She also had deep endometriosis requiring intestinal resection followed by dienogest therapy. She reported no personal and familial history of atopy. Her IgE was low. She had no history of thyroiditis and her anti-TPO antibodies were within normal range, as were the basophils and eosinophils counts and CRP. Fasting glucose and HbA1c and lipid panel were within normal range as was the blood pressure. She was prescreened for a clinical trial with barzolvolimab. Meanwhile, in mid-June 2024, she began tirzepatide 2.5 mg weekly subcutaneously, titrated to 7.5 mg after 3 weeks, to facilitate weight reduction (baseline 85 kg, BMI 28) prescribed by her family doctor. Within 3 weeks, she noted a marked decrease in urticarial activity, accompanied by a weight loss of 7.5 kg after 2 months. No new wheals occurred while reducing fexofenadine to 180 mg daily. The remission persisted during 18-month follow-up on tirzepatide 7.5 mg/week (UAS7 0 to 2). No side effects were observed and reported by patient.

The rapid improvement seen in two patients with long-lasting history of CSU refractory to high-dose H1AH after introduction of GLP-1RA inhibitors may be coincidental. However the broad spectrum of changes that are induced by this group of drugs in immunometabolism, gut and gut microbiome biology, and the possible direct effect on mast cell degranulation should encourage further observations and studies in this field.

First-line treatment of CSU with H 1 -antihistamines often requires dose titration up to four times the standard dose, as recommended in guidelines [ 11 ]. However, the evidence supporting both the efficacy and safety of high-dose H1AH remains limited. Since the introduction of omalizumab as the first anti-IgE biologic, a new era of targeted CSU therapies has begun, including agents modulating interleukin (IL)-4/IL-13, KIT, and Bruton’s tyrosine kinase pathways [ 12 ]. Nevertheless, a considerable proportion of patients remain symptomatic despite H1AH and omalizumab, highlighting the need for alternative treatment approaches. GLP-1RA are associated with several adverse reactions mainly gastrointestinal ones [ 13 ], the great majority of which are mild in nature. However serious adverse effect include acute pancreatitis and cholecystitis. The most common adverse effect related to skin are site injection reactions, effluvium, and allergic reactions including acute urticaria and angioedema [ 5 ]. Both patients described herein achieved rapid remission of long-standing, antihistamine-refractory CSU shortly after starting GLP-1RA therapy (semaglutide or tirzepatide), initially prescribed for metabolic indications. As a result, initiation of systemic biologic therapy with barzolvolimab was no longer required. Although spontaneous remission cannot be entirely excluded, the rapid and sustained improvement strongly supports a possible immunometabolic mechanism. Dietary modification may also influence CSU activity in selected individuals [ 14 ] (Fig.  1 ). Weight loss may reduce inflammatory status related to excessive fat tissue activity (Fig.  1 a). In our patients the dynamics of the CSU improvement went along with the weight loss within the first weeks of treatment. However both patients were losing weight gradually within 2–3 months (approximately 1 kg weekly). This indicates that probably not just the total adipose tissue weight but other mechanisms were important for the reduction of inflammatory burden in these patients. Fig. 1 Hypothetical mechanisms that could be responsible for resolution of chronic spontaneous urticaria (CSU) after glucagon-like peptide 1 receptor agonists (GLP-1RA). (1) Indirect influence of GLP-1RA on immune system: (1a) In patients with obesity adipose tissue is responsible for the state of chronic systemic low-grade inflammation mediated by proinflammatory cytokines (TNFα, IL-6, IL-1α). (1b) GLP-1RA reduce gut inflammation by improving gut barrier integrity, modulating the gut microbiome, and influencing gut immune cells. Changing the gut barrier and immunity together with modified diet provoked by GLP-1RA drugs may change the intestinal uptake of allergens and pseudoallergens (2). This may be important for some patients as diet may improve CSU in a subgroup of patients. (3) GLP-1RA is present on several immune cell types such as eosinophils, neutrophils, regulatory T cells, macrophages. Expression on mast cells was shown in rodents but data from humans are conflicting. This may lead to direct impact of GLP-1RA on mast cell function. (4) CSU is not primarily a Th2/ILC2 disease but in some patients there are Th2 comorbidities and elevation of Th2 cytokines. GLP-1RA modulate Th2 response in asthma but it was never shown for the skin and circulating Th2 cytokines Hypothetical mechanisms that could be responsible for resolution of chronic spontaneous urticaria (CSU) after glucagon-like peptide 1 receptor agonists (GLP-1RA). (1) Indirect influence of GLP-1RA on immune system: (1a) In patients with obesity adipose tissue is responsible for the state of chronic systemic low-grade inflammation mediated by proinflammatory cytokines (TNFα, IL-6, IL-1α). (1b) GLP-1RA reduce gut inflammation by improving gut barrier integrity, modulating the gut microbiome, and influencing gut immune cells. Changing the gut barrier and immunity together with modified diet provoked by GLP-1RA drugs may change the intestinal uptake of allergens and pseudoallergens (2). This may be important for some patients as diet may improve CSU in a subgroup of patients. (3) GLP-1RA is present on several immune cell types such as eosinophils, neutrophils, regulatory T cells, macrophages. Expression on mast cells was shown in rodents but data from humans are conflicting. This may lead to direct impact of GLP-1RA on mast cell function. (4) CSU is not primarily a Th2/ILC2 disease but in some patients there are Th2 comorbidities and elevation of Th2 cytokines. GLP-1RA modulate Th2 response in asthma but it was never shown for the skin and circulating Th2 cytokines CSU has a heterogenous nature but two distinct endotypes may be distinguished upon basic tests. So-called autoallergic CSU with IgE autoantibodies to self-antigen is driven by autoimmunity type I (CSU aiTI). The second subtype is autoimmunity type IIb CSU (CSU aiTIIb) with mast cell-directed activating autoantibodies being responsible for their degranulation. The results of the basic tests such as CRP, eosinophil and basophil levels, total IgE and anti-TPO antibodies may help to distinguish between these two variants. Case 1 has Hashimoto’s thyroiditis, with high levels of anti-TPO antibodies and low IgE which suggest CSU aiTIIb. Additionally the patient has a history of angioedema. Both factors are predictors of the poor response to H1AH and even to omalizumab. Therefore, the rapid remission after GLP-1RA is surprising. Case 2 does not follow any of the two endotypes but responded to the treatment in the same time frame. This may suggest that the response is related to some direct influence on the mast cell degranulation process or other cofactors that modify mast cell degranulation threshold. One cannot exclude the influence of the calory restriction on the inflammasome that may influence the activation of mast cells [ 15 ]. GLP-1RA were shown to modify gut microbiota and this could also be one of the possible mechanisms behind their impact on inflammatory diseases [ 16 ] (Fig.  1 ). GLP1RA inhibit NF-κB signaling, reduce IL-6 and tumor necrosis factor alpha (TNFα), and promote M2 macrophage polarization [ 4 , 17 ]. CSU cannot be regarded as a typical Th2 disease but there are a subgroup of patients with Th2-related comorbidities and increased levels of circulating Th2 cytokines. In animal models of asthma, GLP-1RA suppress IL-33 release, limit ILC2 proliferation, and decrease IL-5 and IL-13 production, indicating downregulation of Th2-driven inflammation [ 7 ]. In stimulated human eosinophils GLP-1RA reduced production of IL-4 and IL-13 (Fig.  1 ). Our patients did not exhibit any signs of atopy nor elevated total IgE, eosinophils, and basophil counts. Dupilumab that acts on the Th2 pathway improves CSU gradually. Thus for our cases Th2 response inhibition is not likely to be responsible for the rapid improvement observed in our patients. Recently, first clinical observations have emerged suggesting that GLP-1RAs may improve inflammatory skin diseases, including psoriasis [ 18 ], hidradenitis suppurativa [ 19 ], and atopic dermatitis [ 20 ], but the pathophysiologic pathways behind these observations remain speculative. Moreover, GLP-1 receptors have been identified on several immune cells including ILC2 cells, regulatory T cells, eosinophils, neutrophils, and macrophages. They were also found on mast cells in rodents. A recent study demonstrated their potential benefit in patients with mast cell activation syndrome (MCAS) [ 21 ]. This further supports the concept that GLP-1 signaling may influence mast cell-driven diseases, including CSU. Thus dual immunometabolic action of GLP-1RA may therefore be relevant to both the pathogenesis and control of CSU.

Chronic spontaneous urticaria (CSU) is characterized by mast cell degranulation leading to the recurrent appearance of wheals lasting for more than 6 weeks. CSU remains refractory in a subset of patients despite standard treatment with second-generation non-sedating H 1 -antihistamines (H1AH), even after dose escalation up to four times the standard dose. The introduction of the first anti-IgE monoclonal antibody, omalizumab, revolutionized CSU management; however, there remains an unmet need for new treatment options, as adequate symptom control is achieved in only 52–60% of patients, and complete remission in 36–44% [ 1 ]. GLP-1 receptor agonists (GLP-1RAs) are well established for glycemic control and weight reduction in patients with type 2 diabetes mellitus (T2DM) and/or obesity and have demonstrated cardiovascular benefit [ 2 ]. Prescription of GLP-1RAs has markedly increased in the past decade [ 3 ]. Emerging evidence suggests beneficial effects of GLP-1RAs on inflammatory diseases, including cutaneous disorders [ 4 , 5 ]. Initial reports indicated improvement in psoriasis and hidradenitis suppurativa—autoinflammatory dermatoses commonly associated with obesity and metabolic syndrome. Other anecdotal reports on acanthosis nigricans and Hailey–Hailey disease, may also reflect overlapping metabolic and inflammatory pathways influenced by GLP-1RAs [ 6 ]. Similar overlaps may exist in atopic dermatitis, but additional Th2-mediated immune mechanisms could be involved, as in asthma [ 7 , 8 ]. CSU is frequently associated with autoimmune comorbidities but coexistence with metabolic diseases is less evident. Few studies have shown a higher prevalence of obesity among patients with CSU compared to healthy controls, although the association with metabolic syndrome remains debated [ 9 ]. Recent data indicate that women with CSU present with more comorbidities than men, including asthma, thyroid disease, obesity, autoimmune conditions, gastrointestinal disorders, and depression [ 10 ]. We report two female patients with long-standing CSU who experienced rapid and sustained remission after initiation of GLP-1RA therapy (semaglutide or tirzepatide), prescribed primarily for metabolic indications. Both cases suggest a potential immunometabolic link between GLP-1 signaling and mast cell activation, highlighting a new therapeutic perspective for antihistamine-resistant CSU.