Biomarkers for chronic spontaneous urticaria (CSU) can assist providers with therapeutic decision making, as they may help predict response to available therapies such as antihistamines, omalizumab, and cyclosporine. The availability of new biomarkers may also help guide treatment with emerging therapies such as BTK inhibitors.

There has been a paradigm shift in the management of CSU wherein we now know that certain tests for biomarkers can predict treatment response. For instance, patients with a high C-reactive protein and D-dimer levels may not respond well to antihistamines. Similarly, patients with a low total IgE (<40 IU/mL), high IgG anti-TPO antibodies, and a low eosinophil or basophil count may not be good candidates for the monoclonal antibody omalizumab, which binds to IgE in peripheral blood and causes the downregulation of IgE receptors on mast cells and basophils. Patients with a Chronic Urticaria Index (a surrogate marker for measuring IgG autoantibodies against IgE receptors on mast cells) of greater than or equal to 10 might respond better to cyclosporine. Thus, we are starting to understand that biomarkers can help with navigating the therapeutic algorithms for CSU.

Then again, it really depends on how the patient presents. If they present de novo with new-onset hives for 6 to 8 weeks and are only using second-generation antihistamines as needed, we typically do not order many blood tests to gauge treatment activity. Obtaining a complete blood count with differential, a C-reactive protein, IgG anti-TPO, and total IgE can help guide initial treatment by providing useful information on the patient’s endotype. Of course, every patient with CSU should be treated with up to 4 times the starting dose of a second-generation antihistamine to see whether they respond prior to using advanced therapeutics. If they are unresponsive, then there is a fork in the road to determine the next treatment steps based on biomarkers, which can help decide whether treatment with omalizumab or cyclosporine would be most appropriate, recognizing that cyclosporine is associated with more toxicity but works better in patients with autoimmune urticaria.

The usefulness of biomarkers as prognosticators for selecting CSU treatments evolved because of studies conducted to better understand responders and nonresponders to omalizumab. However, the known biomarkers still require further validation before they can be reliably incorporated into guidelines, and the ones that are currently identified for omalizumab do not necessarily apply to newer therapies that are currently in development, such as BTK inhibitors.

In preliminary studies of BTK inhibitors, there was a broad response to BTK inhibitor therapy, regardless of whether the patients had previously responded or did not respond to omalizumab. BTK inhibitors probably work on critical signaling pathways that affect mast cell activation. If you can identify and block these critical pathways, you may be able to stabilize mast cells and prevent bioactive mediator and cytokine release. As more data become available regarding these novel therapies, our understanding of the pathogenesis of CSU will improve, along with the utility of specific biomarkers for predicting treatment response.