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Professor of Medicine
Division of Immunology, Rheumatology, and Allergy
Department of Internal Medicine
University of Cincinnati
Jonathan A. Bernstein, MD: consultant/advisor/speaker: AstraZeneca, Genentech, Novartis, Sanofi-Regeneron; research support: Allakos, AstraZeneca, Amgen, Celldex, Genentech, Sanofi-Regeneron, TLL.
Chronic spontaneous urticaria (CSU) is a prevalent condition that impacts up to 1% of the general population. CSU is defined as the presence of urticaria or angioedema for longer than 6 weeks with no known trigger. Approximately 40%-50% of patients have isolated chronic urticaria, 40% have chronic urticaria and angioedema, and 10%-20% have isolated angioedema. Typically, the hives do not last longer than 24 hours. Patients experience a significant physical and emotional burden from CSU, which affects leisure activities, work productivity, and interpersonal relationships. CSU can have a similar burden on patients as other common conditions, such as hypertension or depression—so it is not a trivial disease, and it must be managed accordingly.
The Importance of a Patient History
When a patient presents with chronic hives, it is necessary to understand their journey. Therefore, a thorough history and physical exam is imperative to identify potential triggers and previous treatments. It is also important to assess the impact on a patient’s quality of life and any limitations they experiences due to the presence of CSU.
The patient also needs to be questioned about any inducible factors, such as physical or neurologic triggers. There are different types of physical triggers, such as heat and/or cold, pressure, sunlight, and dermatographia. There are also certain other inducible forms, such as cholinergic or adrenergic urticaria, caused by overactivity of either the parasympathetic or sympathetic nervous system. Up to 25% of patients have chronic inducible urticaria, so it is important to rule this out as a diagnosis.
Limited Blood Tests Are Required
CSU is a clinical disease, so limited laboratory work-up is required given the low likelihood that it would identify an underlying cause. Nevertheless, some lab tests have been shown to be prognosticators of treatment response. A complete blood count (CBC) with differential may be useful to rule out an infection, and low eosinophils and basophils may have a role in determining treatment response. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are acute phase reactants, and an elevated CRP level may predict the patient will not respond well to antihistamines. A skin biopsy may be considered to see if these patients have traditional lymphocytes with perivascular eosinophils or predominant neutrophils which respond differently to medications. Patients with mixed eosinophil and neutrophil infiltrate are more likely to have chronic autoimmune urticaria.
Assess Severity of Urticaria
Once a CSU diagnosis is confirmed, the severity of the hives should be determined. This is accomplished by using validated patient-reported outcome measures such as the Urticaria Activity Score-7, which is a compilation of quantifying hives and itching over a 7-day period found to correlate well with CSU severity. The Urticaria Control Test is another tool that measures not only control, but also how often patients are having hives and how the hives have impacted their lives over the previous 4 weeks. I think that quantifying the disease with validated patient reported outcomes will help the healthcare professional get a better perspective on the impact of hives on the patient’s quality of life and provide guidance on appropriate treatment.
Guideline-Recommended Treatment Options
The first-line treatment for CSU is non-sedating second-generation antihistamines at 1 to 4 times the recommended dose. If a patient fails first-line treatment, they should be referred to an urticaria specialist who is experienced in managing complex cases. Additional lab tests can be drawn, such as immunoglobulin E (IgE) levels or a basophil activation test, which may indicate a poor response to other therapies.
Nevertheless, I would recommend omalizumab, a monoclonal antibody that blocks IgE, in most patients who fail high-dose antihistamines. If a patient fails to respond to the initial dose of omalizumab after 4-6 months, the current guidelines recommend increasing the dosing frequency to every 2 weeks, and in some situations, doubling the dose as well. However, this latter recommendation can be difficult to get approved by insurance companies. Therefore, if a patient fails omalizumab, guidelines recommend using cyclosporine, which is an immunosuppressant agent that's been effective for the treatment of hives in some clinical trials. Although it is not approved by the FDA, there's strong evidence to support its use in patients that do not respond to omalizumab. Of course, there's toxicity involved, and one does need to monitor blood pressure, kidney and hepatic function, lipids, and other related adverse effects.
Emerging Therapies for CSU
There are several medications currently being evaluated for the treatment of CSU. Dupilumab, an anti-interleukin-4 alpha (IL-4α) monoclonal antibody, is approved for asthma, nasal polyps, atopic dermatitis, and eosinophilic esophagitis. It is currently in phase III studies for CSU. Benralizumab, an IL-5 receptor antagonist, is approved for asthma and nasal polyps, and it is currently in phase IIb studies in CSU. Tezepelumab, a soluble thymic stromal lymphopoietin (TSLP) antagonist approved for asthma, just completed enrollment for a study in patients with CSU and we are waiting for results. Barzolvolimab, a C-kit inhibitor, is being developed and just entered phase III trials. Janus kinase (JAK) and Bruton’s tyrosine kinase (BTK) inhibitors are additional therapies that are in clinical trials to see if they can fill gaps in treatment. It is exciting to have a multitude of medications currently in the pipeline for patients with CSU as these can potentially lead to improved treatment options and improved quality of life in patients not responsive to currently available therapies.
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