When you reflect on the treatment of hives, we really did not have many treatment options beyond second-generation nonsedating H₁ antihistamines until the development of omalizumab, which has made a significant impact on the treatment of many patients with CSU. More recently, with the FDA approval of dupilumab for CSU, we now have a second biologic option. Although not dependent on blood IgE levels like omalizumab is, dupilumab was not shown to be necessarily more effective than omalizumab.

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The recent FDA approval of the small-molecule BTK inhibitor remibrutinib has further increased the CSU treatment armamentarium. Anti–c-KIT monoclonal antibodies such as barzolvolimab and briquilimab are also advancing in clinical trials, demonstrating good clinical efficacy but having more side effects. I am really excited about novel therapies targeting non–IgE-mediated pathways, such as MRGPRX2 inhibitors, which are also showing promise. Other agents in early-phase clinical trials, such as JAK inhibitors and IgE fusion molecules, also look promising but have a way to go before they are FDA approved.

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With all these therapeutic options, we will need to identify the patient profile of those who are most likely to benefit from 1 or all of the newer agents while weighing the benefits and risks of each therapy, taking into consideration our patients’ CSU severity and their preferences and values. Overall, I think that the future is really bright for CSU treatment options. We took a previously elusive, difficult-to-manage condition and, through scientific advancements elucidating the pathogenesis of CSU, developed several effective novel therapies that allow the achievement of complete CSU control in many of our H₁ antihistamine–unresponsive patients.

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I want to acknowledge the American Academy of Allergy, Asthma & Immunology (AAAAI)/American College of Allergy, Asthma & Immunology (ACAAI) Joint Task Force on Practice Parameters, which is in the final stages of developing an updated CSU guideline that is expected to be made public later in 2025 or in early 2026. This evidence-based guideline synthesizes all the available data on CSU treatments to generate recommendations that will help the clinician manage this often challenging condition more effectively.

The BTK inhibitor remibrutinib is the latest agent to be FDA approved for CSU. Remibrutinib works in at least 2 ways in patients with CSU. We know the importance of IgE signaling in inducing mast cell degranulation, whether it is triggered by an allergen or an autoantibody. BTK is one of the important transcription factors in that signaling pathway, so blocking it inhibits mast cell degranulation. However, we also know that there are a number of autoantibodies involved in CSU, and BTK affects both B cells and the production of these autoantibodies.

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An advantage of using BTK inhibitors may be that they appear to work more quickly than other drugs, although there are no head-to-head trials looking at this. In the phase 3 REMIX-1 and REMIX-2 trials, remibrutinib demonstrated very good effects and good tolerability. Many patients had a fairly rapid reduction of urticaria and angioedema signs and symptoms within 2 weeks. Also, this is an oral drug, which is an advantage for people who do not like injections, but you have to take it twice a day.

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With respect to blocking multiple pathways in CSU, there is a trend toward developing bsAbs such as tezepelumab, which blocks TSLP, an upstream alarmin. So, you potentially have a molecule that would inhibit the overall T2 inflammatory pathways and, hopefully, cause mast cells to die.

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Another way in which we might turn off or silence mast cells is by targeting the c-KIT pathway and a mast cell anchor protein. This provides a more mast cell–specific mechanism of action, avoiding some off-target effects of inhibiting the c-KIT pathway. I think that, with all these agents, we are getting new strategies for treating CSU and other mast cell–driven diseases.

I am really excited about these new agents, and, of course, we have more coming. To me, it is always a good sign that review articles are able to highlight not only a better understanding of pathophysiology through a complex figure but also that many of these pathways have acronyms for investigational drugs targeting different cells and factors included. These figures go beyond the mast cell, and, certainly, it is not just about histamine. I am really excited that we do have a pipeline and are likely soon going to have several new options in our therapeutic “war chest.” More options also mean more confidence for practitioners who may not have had CSU in their crosshairs, which means more access for patients.

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Furthermore, I do not believe that a single agent is going to be the “silver bullet” for all patients with CSU. Historically, we were focused on the high-affinity IgE-mediated receptors, but the mast cell is littered with other cell surface receptors. There are a lot of ways to “skin” a mast cell, and I think that there is going to be a lot of utility in considering combination therapies. I just do not see how you could knock everything out with 1 blow. The use of dual-action biologics, which are already coming out for atopic dermatitis (and we will also see them soon for psoriasis), may be a way to hit multiple pathways with a single agent, although, for now, combination therapy is “king/queen.”

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The fact that we can even consider these approaches right now is incredibly impactful. If you had asked me about this 5 years ago, I would have laughed. What innovation? What am I excited about? There was not a whole lot, at least not that we were aware of. This is really an exciting time.