Positive basophil histamine release assay predicts insufficient response to standard‐dosed omalizumab in patients with chronic spontaneous urticaria

Abstract

Two types of autoimmunity are thought to be involved in the pathogenesis of chronic spontaneous urticaria (CSU): type I, with IgE autoantibodies against autoallergens; type IIb, with IgG autoantibodies, but also IgM and/or IgA1 against the IgE receptor (FcεRI) or IgE.2 Recent studies suggest that CSU patients can exhibit both types simultaneously.3 Patients with type IIb autoimmunity are more likely to exhibit co-existence of mixed autoimmunity compared with type I CSU patients.4 Type IIb autoimmune CSU constitutes a relatively small subgroup of patients that cannot be identified exclusively by routine clinical parameters.5 However, a positive basophil histamine release assay (BHRA; formerly known as HR-urticaria test) may aid identification of type IIb CSU patients, who have been shown to have a higher disease severity, poorer prognosis and be more refractory to second-generation antihistamines and omalizumab.2, 6 There are no routinely available diagnostic tests for type I CSU. Omalizumab, a humanized recombinant monoclonal anti-IgE, is recommended as second-line treatment with 300 mg applied subcutaneously every 4 weeks.7 Off-label up-dosing can benefit patients with insufficient response. To further characterize subgroups of CSU patients and to investigate the use of BHRA as a predictor of treatment response to omalizumab, we examined consecutive, newly referred, adult patients with CSU from a Urticaria Center of Reference and Excellence (UCARE)8 at a dermatological university hospital department (Bispebjerg Hospital, Copenhagen, Denmark). Information on demographics, clinical characteristics, comorbidities, patient-reported outcomes, as well as treatment regimen and duration of omalizumab, was collected via interview and clinical examination (see Tables S1 and S2 for a full list of variables assessed). BHRA was regarded positive when basophil activation was >16.5%.9 Data were analysed using IBM SPSS statistics version 25 (SPSS, Inc.). Continuous data were presented as means with standard deviations (SD) and medians with ranges and categorical data as numbers with percentages. Associations between patient-specific factors and BHRA positivity were assessed with t-test and Chi-square test. Associations between patient-specific factors and BHRA test value were evaluated with Spearman's rank correlation. Receiver operating characteristics (ROC) analysis of biomarkers was performed to calculate area under the curve (AUC) value, sensitivity, specificity, positive- and negative predictive values for BHRA positivity. Kaplan Meier and Cox proportional regression analysis was conducted to estimate drug survival of omalizumab related to BHRA positivity. All tests were considered statistically significant at p-value <.05. A total of 385 patients (279 women, 106 men) with a mean age of 40.5 years (range 18–91 years) were included. Of these, 53 (13.8%) had a positive BHRA; 16.1% in women and 7.5% in men. Restricting the comparison to only include pure CSU (excluding 72 patients with concomitant chronic inducible urticaria, CIndU) showed a prevalence of BHRA positivity of 16.0%; 18.3% in women and 9.6% in men. The median BHRA value among BHRA-positive patients was 46.1% (SD = 20.5, range 17%–84%). Out of the 385 patients, 226 patients (58.7%; including 17 patients with detailed treatment data missing) were treated with omalizumab. Among the remaining 209 patients, the fraction of patients with omalizumab discontinuation due to inadequate effect, dose escalation beyond 300 mg every 4 weeks and/or shortening of intervals to less than 4 weeks between injections, within the first 12 months of treatment, was 56.3% (18 out of 32) in the BHRA-positive group and 26.0% (46 out of 177) in the BHRA-negative group, hazard ratio (HR) = 2.61 (1.54–4.40), p = .0003 (Figure 1). The result remained statistically significant after adjustment for sex, angioedema, thyroid disease, CIndU, baseline urticaria activity score in the past 7 days (UAS7) and history of oral corticosteroid use, HR = 2.94 (1.56–5.55), p = .0009. Changing the cut-off value for a positive BHRA from 16.5% to 10%, 30% and 40%, respectively, yielded an adjusted HR = 2.15 (1.30–3.55), p = .003; HR = 3.21 (1.61–6.38), p = .001; HR = 3.38 (1.64–6.99), p = .001. An eosinophil number <0.05 × 109/L was the only other parameter found to significantly predict non-response to licensed-dosed omalizumab, HR = 3.37 (1.93–5.88), p < .001, whereas a basophil number <0.01 × 109/L was borderline significant, HR = 1.68 (0.96–2.92), p = .067. However, not all patients from the full group underwent omalizumab treatment, including 21 BHRA-positive patients, which could have affected the representativeness of the results. Our study confirms previous associations between BHRA positivity and female sex, angioedema, thyroid disease, absence of CIndU, higher UAS7 score, particularly wheal subscore, history of oral corticosteroid use, lower total IgE, lower basophil and eosinophil number, higher CRP, neutrophil number, eosinophil/basophil ratio, TSH and IgG-anti-TPO.5, 6 Of these factors, only IgG-anti-TPO levels were also significantly correlated with the BHRA value (r = .69, p = .019). Receiver operating characteristics analysis showed that the highest diagnostic values for identifying CSU patients with a positive BHRA were observed for basophil number, total IgE and IgG-anti-TPO, with AUC values of 0.87 (95% CI 0.81–0.92), 0.75 (0.68–0.83) and 0.74 (0.56–0.92), meaning that more than three out of four patients with a positive BHRA exhibit higher values of these biomarkers (except for IgE and basophil number, where values were lower) than BHRA-negative patients. We conclude that BHRA positivity, indicative of type IIb autoimmune CSU, occurs in approximately one out of seven patients and that BHRA positivity may be used as a predictor of poorer response to omalizumab, indicating the need for off-label use (e.g. in the form of up-dosing) in these patients. Furthermore, in patients with BHRA positivity, a high prevalence of angioedema and thyroid disease was seen. This suggests that BHRA-positive patients may represent a distinct endotype of CSU. Additional information is available in the following repository: https://zenodo.org/record/8077576. All authors contributed to the study by critical reviewing of the manuscript. KB, A-HRJ, JAS, DGZ, MNG, PSS, CV, MM, AW and SFT were involved in designing the study. A-HRJ, JAS, DGZ, MNG and SFT performed patient enrolment and clinical assessment. KB, A-HRJ, JAS, DGZ, MNG, PSS and SFT performed data acquisition. KB, A-HRJ and SFT performed data analysis. All authors have approved the final version of the manuscript. Katrine Baumann was supported by the BRIDGE—Translational Excellence Programme (bridge.ku.dk) at the Faculty of Health and Medical Sciences, University of Copenhagen, funded by the Novo Nordisk Foundation. Grant agreement no. NNF20SA0064340 (2021 fellows). This study benefitted from the GA2LEN network of Urticaria Centers of Reference and Excellence (UCAREs, https://ga2len-ucare.com/). Katrine Baumann and Per Stahl Skov are part-time employees of RefLab ApS. The other authors have no conflicts of interest in relation to this study. Outside of it, Marcus Maurer is or recently was a speaker and/or advisor for and/or has received research funding from Allakos, Amgen, Aralez, ArgenX, AstraZeneca, Celldex, Centogene, CSL Behring, FAES, Genentech, GIInnovation, GSK, Innate Pharma, Kyowa Kirin, Leo Pharma, Lilly, Menarini, Moxie, Novartis, Pfizer, Roche, Sanofi/Regeneron, Third Harmonic Bio, UCB and Uriach. This study was conducted in accordance with the Declaration of Helsinki and informed consent was obtained from all participants. The protocol was waivered from ethical approval since it was purely observational. According to Danish law, purely observational studies need no approval from a scientific ethics committee. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. Tables S1–S2. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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