In a recent review published in The Lancet, a group of authors explored emerging personalized treatment approaches for chronic urticaria (a persistent skin condition with recurring itchy wheals and swelling lasting over six weeks), emphasizing novel therapies and addressing the limitations of current management guidelines.
Study: Chronic urticaria: unmet needs, emerging drugs, and new perspectives on personalised treatment. Image Credit: onstockphoto/Shutterstock.com
Background
Chronic urticaria, lasting over six weeks, presents as wheals and angioedema due to skin mast cell activation. It is either spontaneous, with no specific triggers, or inducible, triggered by stimuli like cold or pressure.
This condition is often accompanied by autoimmune and psychiatric disorders, significantly affecting quality of life and imposing economic burdens. While spontaneous remission occurs in about 50% of cases within five years, many require long-term treatment.
Current guidelines recommend second-generation antihistamines, omalizumab, and ciclosporin. However, many patients remain uncontrolled, necessitating further research to develop more effective therapies targeting chronic urticaria's heterogeneous pathophysiology.
Classification and pathogenesis
Chronic urticaria is divided into spontaneous and inducible types. Nine forms of Chronic Inducible Urticaria (CIU) include symptomatic dermographism, cold urticaria, cholinergic urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, aquagenic urticaria, contact urticaria, and vibratory angioedema.
The pathogenesis involves the activation of skin mast cells and the subsequent release of histamine and other inflammatory mediators. This activation can be spontaneous or triggered by external stimuli, leading to the development of characteristic symptoms.
Clinical impact and remission
Chronic urticaria significantly affects patients' lives. It is associated with high economic costs due to medical expenses and loss of productivity. The condition also leads to psychological stress and diminished quality of life.
Approximately 50% of patients experience spontaneous remission within five years, but many require long-term treatment. The disease's chronic nature and impact on daily functioning necessitate effective management strategies.
Current management guidelines
Current international guidelines for managing urticaria, updated between 2020 and 2024, recommend a stepwise approach starting with second-generation Histamine H1 receptor antagonists (H1-antihistamines). If necessary, these antihistamines can be dosed up to four times the standard approved dose.
If symptoms persist, omalizumab, a monoclonal anti-immunoglobulin E (IgE) antibody, and ciclosporin, an immunosuppressive agent, are recommended.
However, variations exist among guidelines; for example, the United Kingdom (UK) and Australian-New Zealand guidelines suggest using montelukast before omalizumab. Despite these guidelines, many patients remain uncontrolled, indicating a need for new therapeutic approaches.
Unmet needs in chronic urticaria management
Despite existing treatments, many patients with chronic urticaria do not achieve adequate disease control. At least a quarter of patients do not respond to second-generation antihistamines, and a substantial number also do not react to omalizumab.
This lack of response is partly due to the heterogeneous nature of the disease, which involves various underlying mechanisms and distinct endotypes. Therefore, treatments that can modify the disease, prevent progression, and induce long-term remission are needed.
Autoimmune chronic spontaneous urticaria (CSU)
The pathogenesis of chronic spontaneous urticaria involves complex interactions between autoimmunity, complement, coagulation, and inflammation. Two emerging endotypes of CSU are autoimmune CSU, mediated by Immunoglobulin G (IgG) autoantibodies, and autoallergic CSU, mediated by IgE autoantibodies.
These autoantibodies activate mast cells, leading to disease symptoms. Autoimmune CSU is linked to high disease activity, autoimmune comorbidities, and poor response to standard treatments but shows a good response to ciclosporin.
Difficult-to-treat CIU
CIU's pathogenesis remains unclear and is often linked to specific neoallergen production in the skin. Identifying relevant triggers is crucial for management but can be challenging.
Omalizumab is used off-label for CIU, but its efficacy varies. Patients with comorbid CSU and CIU often experience worse disease control. Therefore, more effective treatments for CIU are needed.
Type 2 chronic inflammation
CSU is considered a type 2 chronic inflammatory disease, particularly in patients with T-helper 2 (Th2) (a subset of T-helper cells)-skewed cutaneous inflammation. Cytokines such as Interleukin (IL)-4, IL-5, IL-13, and IL-31 play significant roles in the disease's pathogenesis.
Type 2 chronic inflammatory diseases, including allergic rhinitis, atopic dermatitis, and asthma, are common comorbidities in chronic urticaria patients. Omalizumab, approved for several type 2 diseases, can benefit patients with these comorbidities.
Disease modification
There is a critical need for disease-modifying treatments that address the underlying mechanisms of chronic urticaria. Such therapies should aim to induce long-term remission or cure after withdrawal.
Currently, omalizumab and antihistamines are considered symptomatic treatments with symptom recurrence after discontinuation. Ciclosporin has shown potential for inducing long-term remission, but its adverse effects limit its use.
Emerging therapies
Several new therapies are in development, targeting specific mechanisms of chronic urticaria. These include:
Anti-IgE therapies
Biosimilars and new anti-IgE drugs like UB-221 (a monoclonal antibody targeting IgE) and YH35324 (a fusion protein targeting IgE) are being investigated. These therapies aim to neutralize IgE and reduce disease symptoms.
Bruton's Tyrosine Kinase (BTK) inhibitors
BTK inhibitors such as fenebrutinib, remibrutinib, and rilzabrutinib show promise in treating antihistamine-refractory CSU. These inhibitors target mast cell and basophil activation pathways.
Anti-cytokine therapies
Therapies targeting cytokines like IL-4, IL-5, IL-13, and IL-31 are being explored. Dupilumab, an IL-4Rα inhibitor, has shown efficacy in CSU and other type 2 diseases.
Other anti-cytokine therapies, such as reslizumab, benralizumab, mepolizumab, secukinumab, and tildrakizumab, are under investigation.
Mast cell depletion
Drugs targeting Tyrosine-protein kinase KIT (KIT), a receptor involved in mast cell proliferation, show potential for treating chronic urticaria.
Barzolvolimab and other similar drugs are being studied for their efficacy in reducing mast cell numbers and activity.
Conclusions
To summarize, chronic urticaria remains challenging to manage due to its heterogeneous nature and the variable response to current treatments.
The development of personalized therapies targeting specific disease mechanisms offers hope for better management and improved patient outcomes.
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