The efficacy of omalizumab treatment in chronic spontaneous urticaria is associated with basophil phenotypes

Abstract

Background: The mechanisms underlying disease pathogenesis in chronic spontaneous urticaria (CSU) and improvement with omalizumab are incompletely understood.

Objectives: This study sought to examine whether the rate of clinical remission is concordant with baseline basophil features or the rate of change of IgE-dependent functions of basophils and/or plasmacytoid dendritic cells during omalizumab therapy.

Methods: Adults (n = 18) with refractory CSU were treated with omalizumab 300 mg monthly for 90 days. Subjects recorded daily urticaria activity scores, and clinical assessments with blood sampling occurred at baseline and on days 1, 3, 6, 10, 20, 30, 60, and 90 following omalizumab. At baseline, subjects were categorized by basophil functional phenotypes, determined by in vitro histamine release (HR) responses to anti-IgE antibody, as CSU-responder (CSU-R) or CSU-non-responder (CSU-NR), as well as basopenic (B) or nonbasopenic (NB).

Results: CSU-R/NB subjects demonstrated the most rapid and complete symptom improvement. By day 6, CSU-R/NB and CSU-NR/NB had increased anti-IgE-mediated basophil HR relative to baseline, and these shifts did not correlate with symptom improvement. In contrast, CSU-NR/B basophil HR did not change during therapy. The kinetics of the decrease in surface IgE/FcεRI was similar in all 3 phenotypic groups and independent of the timing of the clinical response. Likewise, plasmacytoid dendritic cells' surface IgE/FcεRI decline and TLR9-induced IFN-α responses did not reflect clinical change.

Conclusions: Changes in basophil IgE-based HR, surface IgE, or FcεRI bear no relationship to the kinetics in the change in clinical symptoms. Baseline basophil count and basophil functional phenotype, as determined by HR, may be predictive of responsiveness to omalizumab.

Keywords: Basophil; FcεRI; IgE; basophil activation test; chronic spontaneous urticaria; histamine release; omalizumab; plasmacytoid dendritic cell.

Figure 1:

Study design. Depicted days indicate visits with laboratory studies. Black arrows indicate days of omalizumab dosing. Blue arrows indicate timing of skin biopsies. The second skin biopsy occurred between day 6 and 30 at the time of 50% symptom reduction relative to baseline UAS-7. If 50% symptom reduction was not achieved by day 30 then biopsy performed at day 30.

Figure 2.

Clinical response during treatment represented by daily UAS scores for subjects. Black arrows indicate days of omalizumab dosing. (A) Single parameter classification based on basopenic status: Blue line (n=9) – basopenics average, Black line (n=9) – non-basopenics average, Green dashed line (n=18) – Average. (B) Single parameter classification based on basophil histamine response: Black line (n=7) – responders average, Blue line (n=10) – non-responders average, Green line (n=17) – Average. (C) Daily UAS scores during treatment with omalizumab according to the dual parameter basophil categorization of basopenia and responder status. (D) Weekly UAS7 scores during treatment. Black arrows indicate days of omalizumab dosing. For both panels 2C and 2D, Black line (n=6) – CSU-R/NB average, Orange line (n=3) – CSU-NR/NB average, Blue line (n=7) – CSU-NR/B average, Green line (n=16) – Average.

Figure 3:

In vitro basophil histamine release in response to anti-IgE antibody stimulation at the indicated day of study. (A) Responder/Non-basopenics (CSU-R/NB), (n=6); (B) Non-responder/Non-basopenics (CSU-NR/NB), (n=3); (C) Non-responder/basopenics (CSU-NR/B) (n=7). The colored lines represent day of study.

Figure 4.

Omalizumab-induced reductions in basophil surface IgE (A) and FcεRI (B) were similar amongst basophil subsets. Inset figures represent change relative to baseline for the 3 categories (2-parameter categories). For both panels, Black line – CSU-R/NB average, Orange line – CSU-NR/NB average, Blue line – CSU-NR/B average, Green line – Average. Colored regions surrounding each line represent the SEM bands for the averages.

Figure 5:

Relationship between rates of reduction (T_1/2) in basophil surface IgE (A)or FcεRI (B) versus the rate of reduction (T_1/2) in clinical symptoms. Each dot represents one subject.

Figure 6:

TLR9-mediated secretion of IFN-α, in vitro, from isolated pDCs at baseline and at mid-study measurement. Grouped by dual parameter basophil classifications (A):CSU-R/NB (n=6, grey bar), CSU-NR/NB (n=3, blue bar), NR/B (n=6, orange bar). (B): CSU-R (n=6, grey bar), CSU-NR (n=9, blue bar). (C) FcεRI (D) surface IgE, and (E) percent BDCA2⁺ pDC by flow at baseline and mid-study timepoints.