Lack of basophil CD203c-upregulating activity as an immunological marker to predict response to treatment with omalizumab in patients with symptomatic chronic urticaria

Chronic urticaria (CU) is defined as recurrent, transitory, pruritic-raised wheals present on most days of the week for more than 6 weeks. The pathogenesis of CU is unknown, but it is thought to be the result of autoimmunity, at least in some patients. Evidence supporting this comes from assays suggesting the presence of functional autoantibodies. IgG autoantibodies to IgE or to the high-affinity IgE receptor (FceRI) have been directly detected in approximately 40%-50% of patients with CU. Although of interest, identifying these antibodies is laborious and not fully validated; therefore, numerous surrogate assays have been developed. A positive autologous serum skin test (ASST) can be identified in 30%-67% of patients with CU and is an indirect reflection of autoantibodies. However, the ASST is positive in 37% of patients with non-CU, making it of less certain clinical relevance. Alternatively, the sera of 40%-50% of patients with CU can induce the release of histamine from the basophils of healthy subjects (basophil histamine-releasing assay, [HRA]). Limitations to this test are based on interlaboratory reproducibility and variation in healthy basophil donor characteristics; and as with the ASST, the HRA lacks diagnostic specificity for CU. More recently, flow cytometry has been used to evaluate the ability of serum of patients with CU to activate donor basophils as determined by the upregulation of CD203c (ectonucleotide pyrophosphatase and/or phosphodiesterase). In the validation studies for this assay, the upregulation of CD203c surface expression was evaluated on basophils obtained from a healthy atopic donor after exposure for 10 minutes to serum obtained from 32 patients with CU and 11 healthy controls. (See Yasnowsky et al for a more detailed description.) The data are expressed as the percentage of basophils expressing more CD203c than 99% of basophils incubated with buffer only. A result 5% or more is highly specific for CU as this result was never seen using serum obtained from healthy controls. Serum factors driving increased CD203c expression in this assay are unknown and as with the HRA are assumed to reflect autoantibodies; however, this has never been determined. Furthermore, factors driving histamine release from basophils may differ from those responsible for CD203c upregulation. Treating CU is challenging, as many patients are refractory to the standard pharmacological therapy. Omalizumab, a humanized anti-IgE monoclonal antibody, has been approved for the treatment of CU. During phase 3 trials, omalizumab was effective in 52% of patients with CU based on Urticaria Activity Score (UAS7) of less than 6, but only 34% had complete clinical response (UAS7 of 0). Given this modest response rate, the requirement to administer this agent for up to 3 months before recognizing treatment failure, and the expense associated with its use, the identification of biomarkers predicting responsiveness would prove valuable. In the omalizumab CU clinical trials, the HRA was positive in only 25%-30% of subjects and had no value in predicting therapeutic response. The greater specificity of the CD203c assay for CU suggests that it may have superior predictive value in determining omalizumab responsiveness. Therefore, we performed a retrospective chart review of 41 consecutive adult patients with antihistamine-refractory CU seen at the University of Virginia outpatient allergy clinic between 2011 and 2013 to investigate the use of the basophil CD203c assay as a biomarker of responsiveness to omalizumab in CU. This study was approved by the University of Virginia Health System Institutional Review Board (IRB-HSR #18100). Basophil CD203c-upregulating activity was obtained in all subjects before omalizumab administration (National Jewish Health Advance Diagnostic Laboratories, Denver, Colo). Clinical response was evaluated after a minimum of 3 months of treatment based on the patient’s and physician’s subjective determination. Fisher’s exact test was used to compare basophil CD203c-upregulating activity in responders and nonresponders (GraphPad Prism 6.0) and P < .05 was considered significant. Patients’ characteristics are summarized in Table I. CD203cupregulating activity was present in 18 of the 41 subjects (43.9%). Subjects were treated with omalizumab 300 mg SC q4weeks for at least 3 months. Omalizumab was effective in 29 of the 41 (71%) patients with CU overall, slightly higher than what has been reported in published studies. Of the 18 subjects demonstrating CD203c-upregulating activity, only 9 (50%) had clinical improvement with omalizumab (Figure 1). In contrast, of the 23 without CD203c-upregulating activity, 20 (87%) had a clinical response to omalizumab (P 1⁄4 .02, Fisher’s exact test). Thus, having a negative result predicts a much greater likelihood of responding to omalizumab with the odds ratio of a negative test being 6.7 (95% CI, 1.4-31). No correlation of efficacy was found with age, sex, or the presence of thyroid autoantibodies (not shown). Although not proven, basophil CD203c-upregulating activity is thought to reflect the presence of autoantibodies to IgE and/or FceRIa, suggesting that the presence of these autoantibodies unexpectedly predicted a lower likelihood of clinical response. Clearly, this observation needs to be repeated in a prospective fashion, but if confirmed in those studies, this holds promise as a clinically useful biomarker predicting response to treatment. The mechanism of action of omalizumab in CU is not known, and this understanding will ultimately be central to predicting