Dr Gil Yosipovitch: Biologics Have Changed the World of CSU Care

Gil Yosipovitch, MD

The major issue with antihistamines to treat chronic spontaneous urticaria is the lack of efficacy, said Gil Yosipovitch, MD, Stiefel Chair in Medical Dermatology and professor, Dr Phillip Frost Department of Dermatology and Cutaneous Surgery, Miller School of Medicine, University of Miami.

Since many patients don’t respond to even high doses of antihistamines, biologics have been a huge improvement for patients. However, Yosipovitch noted that payers do require patients try antihistamines first, which can be very disappointing.

In an interview with The American Journal of Managed Care® (AJMC®), he also discussed the use of omalizumab, treatment considerations with omalizumab, and the need for updated guidelines for CSU.

AJMC:Which therapies, including antihistamines, do you typically use in the first line for patients with CSU? And what is your approach to switching?

Yosipovitch: Based on the guidelines, cetirizine is my number one. I use it in a dose of up to 4 tablets a day for chronic spontaneous urticaria. I've tried many of the antihistamines, including levocetirizine, which is supposed to be more effective. I didn't see differences between cetirizine and levocetirizine. But I've tried all of them. I've tried the sedating antihistamines, especially when patients would tell me that at nighttime they can't sleep. My favorite has been hydroxyzine, and I would go up to doses of almost 75 milligrams at nighttime or divided doses during daytime. I’m less likely to use doxepin and other non-sedating antihistamine like fexofenadine.

Overall, I have to admit that I never saw something that kind of struck me that if one antihistamine, like cetirizine, didn't work, the others were amazingly impressive. In terms of the patient population with CSU, there's no big difference of using one antihistamine versus another.

AJMC:If patients aren't responding well to antihistamines, which therapies do you consider next? When do you consider using biologics and what patient considerations do you take into account that drive your decision to go to the next therapy?

Yosipovitch: The lack of efficacy is the major issue. If I don't see any improvement with antihistamines after 3 months [I consider biologics]. And I usually tell them nowadays in the first visit that I would opt to start using omalizumab as fast as I can. Remember, some of these patients come to me with a long history of chronic spontaneous urticaria, and some of them already have been on over-the-counter antihistamines, and they didn't respond. I tend to immediately go to the best available drug: omalizumab, which is an anti-IgE antibody.

The payers are very difficult, but in some patients, I would give cyclosporine or methotrexate, but I try to avoid that, because I think omalizumab is a better choice.

AJMC: Are payers requiring different drug classes besides antihistamines before you can use biologics? How many antihistamines are payers requiring before they'll approve coverage for omalizumab?

Yosipovitch: Usually, the one is enough for them, but they want to see higher doses—not just twice a day or once or day. They want to see up to 4 times a day. I have seen that they also require H2 blockers, which I have to admit that I don't see any scientific basis to support the use of them except in patients who have some gastric irritation because there's no data to support that. It's only based on anecdotal reports. The same applies, unfortunately, that payers want us to use leukotriene inhibitors. There's, again, very minimal data to support that. I would say that there are only anecdotal reports showing that they did something for CSU. Unfortunately, sometimes I'm mandated to show use of that. But in terms of the science and my understanding of the disease process, it's a waste of my energy and it's a bit disappointing for me that patients still sometimes deal with drugs that I don't believe work.

AJMC: Are you seeing a big gap in treatment efficacy between antihistamines and biologics?

Yosipovitch: I do believe that biologics have changed the world of CSU, because many of the patients—I would say the majority of the patients—don't respond to just very high doses of antihistamine. So, there is a significant number of patients who need drugs like omalizumab.

AJMC: Some of these patients receiving omalizumab are still symptomatic with CSU while on the required dose. What do you believe accounts for this high number of patients who are not responding adequately?

Yosipovitch: It has become very clear to us in the last couple of years that not all the CSU pathophysiologies are related to IgE antibodies and to autoallergen. There's what we call type IIB autoimmunity of the mast cells that involves IgG against epsilon receptor, anti–thyroid peroxidase (TPO) receptors, anti-TPO antibodies, and other autoimmune factors and antibodies. Therefore, omalizumab unfortunately is not so effective for these patients who have other autoantibodies. Although, it does help in some cases, it requires a longer period of treatment, and there are also failures. So, that's why omalizumab cannot cover all types of CSU.

I don't believe a blood test is really important in the diagnosis of CSU, but I do believe that IgE levels help me better understand how to continue treatment of patients who I predict will most probably fail or, less likely, will respond to omalizumab, due to the fact that patients with low IgE levels with CSU will not respond well to omalizumab. That kind of directs me to think about other treatments.

AJMC: There are some additional treatment considerations with omalizumab. Patients have to come in for the first 3 doses because it's a biologic, and can you just explain that burden?

Yosipovitch: This has a significant impact on dermatologists. Dermatologists are not used to keep patients an hour waiting and administering an injection in house. That's why a lot of dermatologists would avoid using omalizumab. Until 2 or 3 years ago in the US, it was actually mandated that the patients would have to be given the drug in a doctor's office. That's why a lot of dermatologists refuse to use this drug.

I do believe that even the first 3 visits is causing a lot of concerns among dermatologists who don't want to deal with this. They're not built to deal with patients waiting an hour and being monitored to see whether they develop anaphylaxis. I have to mention, the risk of anaphylaxis is extremely rare in these patients, but due to that warning and this indication of administering the first injection deters doctors from giving this drug.

AJMC: The CSU guidelines have not been updated since 2014. What are the key updates that are needed in the newest version of the guidelines?

Yosipovitch: There are new drugs very close to being approved. One of them on the market already with an off-label use, but being tested in phase 3 trials, is dupilumab, which is an IL-4 receptor inhibitor. Type 2 cytokines have a significant impact on CSU, so the fact that this drug is already available, it could be added to the treatment regimen in patients who failed omalizumab. If the drug is approved later on in the US market, clearly it may change its positioning in the guidelines.

In addition, there are Bruton kinase inhibitors, like remibrutinib, which should be submitted for approval later in 2024. This will be another important additional treatment in our drug armamentarium for CSU. I think that the question would be whether it would be a first-line drug after antihistamines rather than omalizumab, because it has an effect beyond just IgE antibody, auto-immune, or auto-antigen antibody, because it targets more comprehensive antibodies due to the fact that it targets B cells. And it's an oral medication, and I do believe that we have a large patient population that would prefer to have oral medication, like we have with oral antihistamines. I think another advantage of having an oral medication is since CSU is not consistent, meaning the symptoms wax and wane, and patients may have multiple lesions one day and maybe none another day, the patient may be able to use it on and off. Although I don't think it would be stated by the drug company or the manufacturer as an on and off treatment on and off.