Biologics have greatly improved treatment outcomes for patients with chronic spontaneous urticaria (CSU) who are refractory to second-generation H1 antihistamines, as they previously had few treatment options. Our featured experts discuss how they use biologic therapy in patients with CSU and how they treat biologic-refractory individuals.

Omalizumab is a very good drug for CSU, and approximately 70% to 75% of patients experience significant improvement with this treatment. Although it may take up to 24 weeks for a response to occur, some patients respond to omalizumab within 1 week. This is surprising because it can take time for the drug to bind free IgE and for the high-affinity IgE receptor on mast cells and basophils to decrease. Rapid responders may have IgE autoantibodies against thyroid peroxidase or other autoantigens.

If a patient does not respond at all after 6 months of omalizumab therapy, what should you do? Do you increase the dose of omalizumab or add cyclosporine or tacrolimus? Or do you stop omalizumab and switch to cyclosporine or tacrolimus? Right now, the literature is inconclusive, but the international guidelines state that if omalizumab does not work at 300 mg, you can try updosing to up to 600 mg every 2 weeks. However, if a patient does not respond to omalizumab at the standard dose, I personally do not think that it makes sense to updose. At that point, I would switch to cyclosporine or tacrolimus. If they do not respond to cyclosporine or tacrolimus, I start considering drugs with US Food and Drug Administration (FDA) approval for other indications that I think might work for CSU, because we do not want to use corticosteroids. These drugs include JAK inhibitors, BTK inhibitors, and interleukin inhibitors, with the latter 2 currently being evaluated in phase 3 trials for CSU.

Phase 3 data with the IL-4 receptor inhibitor dupilumab in CSU show that there appears to be a sustained effect after stopping the drug. This does not occur with omalizumab, although it has a slow onset, which could be problematic.

Like Dr Casale, if a patient does not respond to the standard dose of omalizumab, I do not increase the dose. However, if a patient partially responds and tells me that the omalizumab seems to wear off after 3 weeks, I instruct them to take it every 2 weeks to see if that helps. Anecdotally, it works in a subset of patients, but we try to be judicious and set expectations. It is sometimes not easy to get approved, and it requires prior authorizations and a lot of legwork.

Case studies have reported that some patients with omalizumab-refractory CSU respond beautifully to drugs that help reduce antibody titers, such as rituximab or cyclophosphamide. I have had very good success with cyclosporine but have used tacrolimus in some cases, as it may be associated with fewer side effects. I think that, as long as patients are monitored, these medications are well tolerated, are generally safe, and can be used.

The good thing about these agents is that responses occur fairly quickly, within the first month. I often do not think it necessary to keep patients on these drugs longer than 6 months. We can usually get their CSU controlled and then step down treatment and see how they do. If patients are unresponsive to high-dose, second-generation H1 antihistamines, omalizumab, or cyclosporine, I often recommend participation in clinical trials investigating novel therapies that might treat CSU through a different mechanistic pathway.

Although I do not currently use JAK inhibitors for CSU, JAK inhibitors have worked wonderfully in some patients to a similar extent to how they have been reported to work in patients with atopic dermatitis. When some patients read about the side-effect profiles of some of the drugs, they become concerned. Looking at alternative therapies can be challenging, but I have used a lot of the alternative therapies that are listed in the international guidelines and were more popular before omalizumab became an option.

For years, the biggest problem in urticaria was that we were using drugs that did not work, and we were overusing steroids. Now we have really good drugs that we can use. Controlling the disease without curing it is a tremendous step forward.

If a patient has a partial response to omalizumab, by 16 weeks, I would up the dose. If a patient does not respond to omalizumab by 16 weeks, my approach is to stop it and use cyclosporine instead. Right now, 6 months of cyclosporine therapy is good if you follow the patient carefully, and you can probably go 1 year, or 1.5 years at most. However, a small number of patients are refractory to everything. I have switched between omalizumab, cyclosporine, and tacrolimus and have seen an effect, with some patients being a little more responsive to one of the agents than to the others.

I have also combined omalizumab and cyclosporine a few times in patients who were not responding well to either drug. In these rare cases, I have added a lower-than-normal dose of cyclosporine to omalizumab. Although anecdotal, a small number of patients have responded to this combination.

Dupilumab is another biologic that is being studied in patients with CSU and that affects Th2-driven inflammation. I am not particularly impressed with the dupilumab data, even though it may receive FDA approval. There is hope that it works in patients who fail to respond to omalizumab, and it is reasonable to try it in a patient who does not respond to the other drugs that we have talked about.