Chronic spontaneous urticaria (CSU) remains a misunderstood and frequently mismanaged inflammatory skin disease, often referred out of dermatology to allergy despite its primary cutaneous manifestations. This autoimmune-driven condition affects up to 20% of individuals globally at some point in their lives.1 Recent perspectives emphasize the need to reframe how to analyze urticaria by re-centering dermatology as an essential, equipped, and accountable discipline in CSU management.

Rethinking Diagnostic Anchors

Dermatologists must look past outdated textbook narratives that often misrepresent wheals as primary lesions. Instead, practitioners should pay attention to the heterogenous manifestation and transient nature of wheals, the defining diagnostic criteria for all types of urticaria. Individual wheals that appear and resolve within 24 hours are hallmarks of urticaria, whereas angioedema, another manifestation of urticaria, can last up to 72 hours and represents a greater degree of tissue edema. Anchoring the diagnosis in timing and morphology, not fixed appearance, is foundational for improved diagnostic sensitivity and accuracy. Understanding CSU requires a dynamic view of how lesions evolve and resolve over time.

CSU Is Spontaneous

A major point of confusion in CSU management is the persistent (and often patient-driven) search for external triggers or “causes” of CSU. By definition, CSU is spontaneous and lacks an identifiable external cause. Unlike inducible forms strongly associated with an external stimulus, CSU stems from internal autoimmune dysregulation.2 There is no external allergen and no exogenous cause to eliminate.

This redefinition is critical. It requires both providers and patients to shift expectations away from uncovering an external cause or external trigger towards long-term symptom management and/or immune modulation. Factors like stress, medications, or pregnancy may modulate disease activity, but these factors are not the primary factors driving disease.

CSU Is Chronic, and Often Autoimmune

Some studies show that as many as 50% of CSU patients have persistent disease 10 years post diagnosis.3 This highlights the need for continued treatment and monitoring of patients with chronic urticaria. Importantly, CSU appears to share overlapping immunologic architecture with other autoimmune diseases. Women are affected twice as often as men,1 and patients with CSU frequently exhibit comorbid autoimmune conditions like autoimmune thyroid disease, despite low rates of lab-confirmed pathology.

Understanding CSU as an autoimmune condition offers a unifying framework for patient education and provider decision-making, where skin often serves as both a barrier and a biomarker of systemic immune health.

The Role of Mast Cells and the IgE Axis

Mast cells, not T-cells, play a central role in CSU pathogenesis. These cells, which often reside in the perivascular dermis, become activated via IgE-dependent and IgE-independent pathways. While IgE autoantibodies often drive mast cell activation, other autoantibodies, including IgG and IgA, can also crosslink IgE antibodies or bind directly to high affinity IgE receptors on mast cells leading to the activation and degranulation of mast cells. In this way, both IgE and non-IgE autoantibodies play a role in driving the clinical manifestation of both wheals and angioedema in patients with CSU.

This dual mechanism helps explain why targeted therapies like omalizumab work for a subset of patients, whereas other, newer emerging therapies that target Th2 inflammation or downstream signalling pathways in mast cells like BTK (Bruton’s Tyrosine Kinase) may be beneficial in a larger subset of CSU patients.

Treatment Hierarchy: From Antihistamines to Biologics

CSU treatment begins with second-generation H1 antihistamines, but as many as 50% of patients do not respond, even at fourfold dosing. The International Guidelines for Urticaria called for therapeutic escalation to biologic therapy when this occurs, particularly Omalizumab, which boasts a 76% overall response rate in real-world CSU studies.4

Dermatologists should not hesitate to use omalizumab given its strong efficacy and excellent safety profile, especially in contrast to systemic immunosuppressants like oral steroids, cyclosporine, or methotrexate. Importantly, concerns about anaphylaxis have been significantly reduced: a recent meta-analysis found that anaphylaxis occurred in only ~0.1-0.2% of cases and notably, none of those occurred in CSU-treated patients.4 In fact, most anaphylaxis episodes were linked to unrelated causes, such as bee stings, rather than medication dosing. These data reinforce omalizumab’s position as one of the safest and most effective treatments available for CSU.

Additionally, new agents are expanding therapeutic horizons:

• Dupilumab, an IL-4/IL-13 inhibitor, recently gained FDA approval for CSU. It is familiar to dermatologists due to its role in atopic dermatitis and prurigo nodularis and has shown strong efficacy in reducing both itch and wheals, especially in biologic-naïve patients. The well-known safety profile of dupilumab and lack of lab monitoring requirements or black box warnings is also reassuring to both patients and providers.

• Remibrutinib, a twice daily oral BTK inhibitor, represents a promising fast-acting alternative for patients who may prefer to take pills to an injection. In clinical trials, over 50% of patients achieved control by week two, and up to 40–50% were clear of hives and angioedema within 6–12 months (Zuberbier et al.). The long-term safety data for remibrutinib is still being collected, and FDA-approval for this medication is anticipated some time in 2025.

Importantly, both novel medications work regardless of a patient’s baseline IgE level, a fact that further supports the autoimmune—not allergen-based—understanding of CSU.