Novel therapies for chronic spontaneous urticaria (CSU) are reshaping care, expanding options when antihistamine up-dosing fails to work and minimizing the need for corticosteroids. Omalizumab, dupilumab, and remibrutinib have distinct mechanisms of action and response profiles in the treatment of CSU. However, therapeutic advances are outpacing our understanding of CSU pathogenesis, highlighting the persistent scientific gaps despite improvements in clinical outcomes.

We have recently had the US Food and Drug Administration (FDA) approvals of 2 additional treatments beyond omalizumab for CSU that is unresponsive to antihistamines: dupilumab and remibrutinib.

People may be familiar with dupilumab because it has indications for a variety of diseases. Using dupilumab for CSU makes sense because IL-4 and IL-13 are important in key pathophysiologic events leading to CSU and angioedema. The first major study of this drug in CSU compared dupilumab with placebo in omalizumab-naive and -unresponsive patients. Although dupilumab did work, the study was stopped early because it did not quite meet the end point for improvement in omalizumab-unresponsive patients—but it was close. This study and a recently published additional study in omalizumab-naive patients showed that dupilumab does work compared with placebo in patients with CSU. The onset of action may be a little slower, but the improvement in CSU continued to progress over the 24-week study period.

The other recent drug of interest is remibrutinib, a BTK inhibitor. We know that when you trigger a mast cell through its high-affinity IgE receptor, downstream of that signaling is BTK. If you block that pathway, you can prevent mast cell degranulation. In several CSU studies, remibrutinib showed a fairly rapid onset of action. Some patients actually got better within a few days to 1 week; over 12 or 24 weeks, there was a significant improvement in CSU compared with placebo.

So now that we have 3 additional treatment options for patients with CSU who are unresponsive to antihistamines, we really need to use shared decision making to determine which of these options would best fit a patient’s lifestyle and comfort level.

The recent additions to our armamentarium are the first major additions in a long time, and Dr Casale has provided a very good summary. Upon failing antihistamine up-dosing, the patient should move on to another type of drug. With omalizumab, some patients improve rapidly, but many patients will need a few injections; it is usually 2 to 3 months before they have an obvious response. It is not well understood why some patients respond faster and others respond only after a few months, but there is a wide range of response times among patients.

I think that remibrutinib is a great addition, with a high reported success rate, and it is oral, which facilitates treatment in many patients. We will see over time how it fits into the armamentarium and how providers use it. We currently have many more treatment options than we did previously.

In some respects, when you look at the details, our ability to treat CSU at this point may exceed our molecular understanding of the disease, which still has a ways to go. With other disorders (for example, hereditary angioedema), we understood the disease in great detail before we had therapies. However, with CSU, we now have a number of really successful therapies, but there is still a lot more work to do in terms of understanding the pathogenesis of the disease.

I have been treating patients with CSU long before we had the drugs that we have now, and it has been very hard to explain this disorder to patients. I emphasize to patients with CSU that they have an internal skin disease caused by an internal aberration of the immune system and that there is nothing outside precipitating it. I also emphasize that CSU primarily targets the skin. Even though, to this day, there are details of CSU pathogenesis that are still unclear, we have very excellent treatments for it.

Patients often get frustrated that we cannot explain the root cause of their CSU. We explain to them that we now have these great treatment choices: omalizumab, dupilumab, and remibrutinib. But still, patients want to know, “Why is this happening? Why am I having CSU? Why am I having it now?”

When I first started treating patients with CSU, they would often come from primary care with a referral to an allergist and an immunologist for food allergy testing because they were experiencing hives. I would explain to them that this was not due to a food allergy, since they were having hives in the middle of the night when they were not eating anything and/or when they first woke up in the morning when they had not yet eaten anything. They were having hives regardless of what they ate. I would explain that if a person has a food allergy, they experience symptoms such as generalized hives, shortness of breath, or wheezing within seconds or minutes of eating that specific food. Additionally, they may have vomiting, throat swelling, or a drop in blood pressure, and they may need epinephrine immediately. However, some patients were still not satisfied and would demand food allergy testing, and it would be a very difficult situation.

Since that time, I have changed my approach so that I am now able to explain to patients and help them understand that they do not need food allergy testing to treat their condition because CSU is unlike many other allergic conditions in which there is an identifiable trigger. With allergic rhinitis, for example, the patient comes in and describes their symptoms. We do skin testing and find that they are allergic to tree pollen, which explains their symptoms, and we then talk about treatment.

With CSU, although we now have much-improved therapies, we are still not able to tell patients specifically why they are having CSU, why they are having it now, or how long it is going to last, so giving them as much information as we can is key. It is a very delicate—and very important—conversation. I try to explain that this may be an autoallergic or autoimmune condition. It is not caused by something in the environment. It is happening inside of their bodies. CSU can be very debilitating and affects quality of life, but it is not life-threatening.