<p>Many patients with chronic spontaneous urticaria (CSU) have disease that is refractory to first-line therapy with high-dose, second-generation H1 antihistamines. Our featured experts share their perspectives on treating patients who are refractory to antihistamines and later lines of therapy.</p>

Patients sometimes present to us after having tried high-dose, second-generation H1 antihistamines. When this happens, I first want to make sure that these patients actually have hives, because sometimes individuals with itchy rashes think or have been told that they have hives when they actually do not. There are urticaria mimickers, and urticaria can be the primary disease or a secondary disorder. A number of conditions may present as hives, such as systemic mastocytosis and other mast cell disorders. Underlying conditions need to be ruled out to provide the patient with the proper diagnosis and treatment recommendations.

 

Once I have established that the patient has CSU, I follow the CSU guidelines to ensure that second-generation H1 antihistamine therapy has been maximized before moving on to the next step. Sometimes, people have taken these medications as needed and do not take them regularly, or they are not taking the right dose. I typically start these patients on high-dose, second-generation H1 antihistamines for at least 2 weeks to see if they are still unresponsive. I use patient-reported outcome measures, such as the Urticaria Control Test and the Urticaria Activity Score, to help objectively quantify the patient’s disease severity, disease control, and response to treatment.

 

I may order a few tests, such as a complete blood count with differential, anti–thyroid peroxidase, C-reactive protein, and total IgE. I sometimes use these biomarkers, even though they are not validated, to predict treatment response, as I like to be able to give patients some expectations of treatment outcomes. Their clinical presentation can also help to determine the severity of their hives and whether a protracted course of disease is a concern. For example, baseline angioedema is a marker of disease severity, and the presence of inducible hives such as dermatographism, cold-induced hives, or heat-induced hives is an indicator of a more protracted course of disease.

 

After treatment with high-dose, second-generation H1 antihistamine therapy, we have to make decisions about the next level of treatment. Omalizumab and cyclosporine are currently available. It is critical for us to really involve the patient and understand their preferences and values for management. It is not one-size-fits-all. There is certainly an unmet need for new therapies to treat patients who do not have a complete response to high-dose, second-generation H1 antihistamines.

I agree with what Dr Bernstein has outlined, and I order most of the tests that he alluded to. In addition, I routinely order thyroid function tests even though this is not recommended in the guidelines because I have seen enough patients with symptomatic Hashimoto’s thyroiditis who needed thyroid hormone replacement therapy. Antithyroglobulin antibodies and antithyroid microsomal antibodies are also sufficiently common enough for me to test for them. The most important thing is to not order too many tests in the search of causes.

 

The guidelines say to prescribe your favorite second-generation H1 antihistamine at the standard dose for patients with severe CSU, just like you would prescribe it for most patients with allergic rhinitis. If that does not work, you can increase the dose up to fourfold. However, instead, I would start with the fourfold dose, and if the patient’s symptoms are relieved, then I would back off and find the minimum dose that works for that patient.

 

If this antihistamine regimen fails, I think that omalizumab is the next-best choice. Cyclosporine may be just about as effective on a percentage basis, but it is associated with more side effects and requires the patient’s blood pressure and renal function to be monitored, which you do not have to do with omalizumab. I agree with the guidelines that cyclosporine be used when omalizumab does not work. There are a few options for someone who fails everything. For example, I would use dupilumab before steroids and would think about dapsone, although it can cause aplastic anemia. I would not use colchicine.

Let me jump in and add to what my colleagues have said. First, it is very important to make sure patients know that CSU is a disease unto itself, and they do not have to have another condition, such as cancer or allergies to detergents or anything else, to have CSU. Based on that, I order very few tests, as Dr Bernstein and Dr Kaplan do, because tests are not helpful in most cases. Second, I think that we really need to assess patients’ quality of life. Are they able to do what they want, or are they restricting their activities because of their urticaria? Finally, I like to ask patients about their goals for therapy. I think that it is important to tell patients that CSU can last for years and that there will naturally be times when it is better and times when it is worse.

 

As far as initial therapy goes, I have not really found anything other than second-generation H1 antihistamines that is successful. I basically do what my colleagues do and put patients on high-dose, second-generation H1 antihistamines with the understanding that we will not have to wait longer than 2 or 3 weeks to find out if they are getting better. The next step, for me, would be omalizumab. I might measure IgE levels to help me counsel the patient about how they might respond to omalizumab and if they might not respond immediately.

 

In patients who do not respond to omalizumab, I tend to use tacrolimus instead of cyclosporine because it has a slightly better safety profile in my experience, but otherwise, I am fully on board with what my colleagues have said. If patients do not respond to tacrolimus or cyclosporine, I start looking at drugs that are US Food and Drug Administration (FDA) approved for other indications that I think might work, such as JAK inhibitors, BTK inhibitors, and interleukin inhibitors, with the latter 2 currently being evaluated in phase 3 trials for CSU.