Total IgE as a Marker for Chronic Spontaneous Urticaria.

OBJECTIVE: Immunoglobulin E (IgE) and its receptor, FcɛRI, importantly contribute to the pathophysiology of chronic spontaneous urticaria (CSU). Recent findings point to a possible role of total IgE as a marker of CSU disease activity, endotypes, and responses to treatment. The evidence in support of total IgE included in the diagnostic workup of patients with CSU has not yet been reviewed.
METHODS: Publications were searched via PubMed. The search terms used were "chronic urticaria" and "total IgE." Studies were screened by titles and abstracts, and 141 were used in the review.
RESULTS: CSU patients frequently had elevated total IgE serum levels (up to 50%), but normal or very low total IgE levels also occurred. High total IgE may represent high disease activity, longer disease duration, high chance of responding to omalizumab treatment, quick relapse after stopping omalizumab, and lower chance of responding to cyclosporine. Low IgE, in contrast, may suggest Type IIb autoimmune CSU, poor response to treatment with omalizumab and a better chance to benefits from cyclosporine treatment. Furthermore, IgE in different CSU cohorts may have different physicochemical properties that could explain differences in treatment responses to IgE-directed therapies.
CONCLUSION: The results of our review suggest that total IgE is a valuable marker for CSU, and we recommend its assessment in the routine diagnostic workup of CSU patients.

INTRODUCTION

Chronic urticaria is a frequent disease with a broad spectrum of different clinical presentations.12 Chronic spontaneous urticaria (CSU), where recurrent itchy wheals and flare skin reactions occur spontaneously, i.e. without definite triggers, is the most common form of chronic urticaria. CSU Patients suffer from recurrent wheals, with or without angioedema, mostly with high quality of life impairment, insufficient control over their disease, and long disease duration.3

Skin mast cells are the key effector cells in the pathophysiology of CSU.4 Their activation, degranulation and release of mediators, including histamine, drive the clinical manifestation of CSU, the development of itchy wheals, angioedema or both. In many CSU patients, immunoglobulin E (IgE) and its high affinity receptor, FcɛRI, are involved in the activation and degranulation of mast cells, and the current urticaria guideline treatment algorithm recommends the use of omalizumab, an anti-IgE antibody, when the treatment with a second-generation antihistamine is not effective.3 Anti-IgE treatment, with omalizumab and ligelizumab, markedly reduces disease activity in many patients with CSU refractory to antihistamine therapy.5

Beyond its key role in the pathogenesis of CSU and as a target of treatment, IgE in CSU has been reported 1) to be elevated, 2) to reflect disease activity, 3) to be linked to disease endotypes, 4) to be biologically and functionally different, and 5) to predict the course of the disease and the response to treatment. In this review, we evaluate the role and relevance of total serum IgE as a diagnostic marker for CSU and discuss the rationale and value of measuring total serum IgE in the routine diagnostic workup of CSU patients.

ARE TOTAL SERUM IgE LEVELS ELEVATED IN CSU?

IgE levels of < 100 or >100 IU/mL are often considered normal or elevated, respectively.6 However, it is well documented that mean IgE levels are different between men and women, between children and adults, and among populations of different genetic background and exposure to environmental factors.78910 In CSU, elevated total IgE levels were first reported more than 40 years ago.11 More recent publications have demonstrated higher than normal total IgE levels in about half of CSU patients, varying from 18% to 82% in different studies using different tests and cutoff levels (Supplementary Table S1).

The median or mean total IgE levels were reported to be between 100 and 300 IU/mL in most studies in CSU (20 of 32, 63%). Case control studies indicate that total IgE levels are higher in CSU patients as compared with healthy individuals.1213141516 On the other hand, total IgE levels in patients with CSU are not so high as in patients with allergies or atopic diseases. In atopic dermatitis, for example, IgE levels often reach 1,000 IU/mL or more.17 Mean IgE values in CSU patients vary from 66 to 1,037 IU/mL (Supplementary Table S1), regardless of whether comorbid atopic dermatitis was excluded.1819 The highest levels of IgE were found in atopic patients with CSU,20 CSU with concomitant gastroesophageal reflux disorder,21 and CSU patients with high interleukin (IL)-33 serum levels,22 indicating that atopic status and concomitant disorders may influence serum total IgE levels of CSU patients.

In our patient cohort with CSU, total IgE levels average 89 IU/ml (Fig. 1), with about 50% of patients showing serum total IgE levels > 100 IU/mL. Of note, our patients with CSU display a wide range of total IgE-low (< 30 IU/mL) levels in 25% of patients and very low levels (< 2 IU/mL) in 10% of patients. Several other studies reported subpopulations of CSU patients with low or very low levels of total IgE.2324252627 Taken together, CSU comes with both elevated or low total IgE, the former being more common.

Fig. 1

Comparison of total serum IgE levels between 926 CSU patients and 36 healthy controls as measured by ImmunoCap Method (own data). Depicted are median (50%, prominent line), 25% and 75% percentile (dark shaded) as well as 10% and 90% percentile (light shaded) and extreme values (white shaded).

IgE, immunoglobulin E; CSU, chronic spontaneous urticaria.

IS CSU DIFFERENT AMONG PATIENTS WITH ELEVATED, NORMAL OR LOW LEVELS OF IgE?

Very few studies have compared CSU patients with different levels of IgE for differences in the clinical characteristics of their disease. Straesser et al. 23 reported that CSU patients with low total IgE levels are younger, 34 years old when total IgE is < 15 IU/mL, than patients with normal or higher total IgE levels, 44 and 53 years old, respectively; howeer, these differences did not reach significance. Kessel et al. 14 reported significantly higher rates of elevated IgE levels in patients who had their CSU for more than 25 months compared with those with shorter disease duration (40% [27/68] vs. 23% [31/132]). In 2 studies, serum total IgE levels correlated with CSU disease severity,1428 but not 1 study.29

Further studies are needed. Importantly, they should compare patients with high and normal IgE levels as well as those with low and normal IgE levels, as correlation analyses across all patients may fail to detect how IgE levels are linked to clinical features of CSU.

ARE TOTAL IgE LEVELS LINKED TO DIFFERENCES IN LABORATORY MARKERS FOR CSU?

Basopenia and eosinopenia, markers for high CSU disease activity, are found in up to 14% and 10% of CSU patients, respectively.303132 While there are no studies on the link between total IgE and basopenia, a recent report showed a weak, but highly significant, positive correlation between total IgE levels and eosinophil numbers (r = 0.275, P < 0.01).32

Previous studies reported significant positive correlations between serum total IgE and basophil FcɛRI expression levels.1833

Elevated levels of D-Dimer and CRP, also markers of high inflammatory activity in CSU, were reported not to be linked to total IgE. IgE levels and rates of elevated IgE levels were similar in CSU patients with elevated and normal D-Dimer levels2934 and in patients with elevated and normal CRP.293536

THE ROLE OF IgE IN THE PATHOGENESIS OF CSU

Our current understanding of the underlying pathophysiology of CSU suggests that there are at least 2 endotypes of CSU.373839 In Type I autoimmune CSU (TIaiCSU; also referred to as autoallergic CSU) autoreactive IgE antibodies directed against autoantigens are thought to degranulate skin mast cells via the classical activation of the high affinity IgE receptor FcɛRIα.40 In Type IIb autoimmune CSU (TIIbaiCSU), mast cell degranulation is caused by IgG and/or IgM autoantibodies directed against FcɛRIα or FcɛRIα-bound IgE (Fig. 2A and B).41 IgE, therefore, plays a key role in the pathogenesis of CSU and is an important driver of mast cell degranulation. Other mast cell-activating and -priming signals and mechanisms that are held to contribute to the pathogenesis of CSU include IgE stacking (Fig. 2C) and aggregation, alarmins, ligands of MRGPRX2, activated complement components as well as cytokines, but their roles are less well defined and understood.

Fig. 2

IgE can exert MC activation via different mechanisms in CSU. (A) IgE bound to the high-affinity receptor subunit alpha on the surface of MC can detect (auto-)allergens and by recognition of 2 IgE molecules in close proximity downstream signal transduction is exerted, leading to MC degranulation and subsequent mediator production (type I CSU). (B) In CSU the occurrence of IgG autoantibodies directed against IgE (left) or against the high affinity receptor subunit alpha (right) can result in high affinity receptor cross-linking and MC activation (type IIb CSU). (C) Further alternative mechanisms could also lead to MC activation, e.g. unspecific IgE antibody stacking has been shown to lead to mediator production and release.

IgE, immunoglobulin E; MC, mast cell; CSU, chronic spontaneous urticaria.

THE ROLE OF IgE IN TIaiCSU

Patients with TIaiCSU are thought to have autoreactive IgE antibodies to self-antigens such as thyroid peroxidase (TPO),424344 tissue factor (TF), thyroglobulin (TG),45 double stranded DNA (dsDNA),46 and IL-24.40 The rate of TIaiCSU patients has not been established because commercially available and standardized and validated assays are not yet available. Different studies show different rates of patients with IgE to individual autoallergens, ranging, for TPO for example, from 8%47 to 54%,42 possibly depending on the used ELISA detection method. As of now, more than 200 autoallergens have been reported to be targets of IgE in CSU patients40 and most of the IgE of CSU patients have autoreactive IgE,48 very different from the IgE in healthy controls, where less than 1% of all IgE binds to autoantigens.

Is the presence of auto-IgE in patients with TIaiCSU linked to elevated serum total IgE levels? Three studies showed that this is indeed the case reporting significantly higher total IgE levels in patients with IgE to TPO compared to those without,434447 but a study did not.42

THE ROLE OF IgE IN TIIbaiCSU

Antigen-IgE interactions are not involved in the degranulation of mast cells that drive the development of wheals and angioedema in TIIbaiCSU. In TIIbaiCSU, mast cell degranulation is due to IgG or IgM autoantibodies to the high-affinity IgE receptor FcεRIα,4950 or IgE bound to it.51 The ability of these autoantibodies to degranulate mast cells is linked to the expression levels of its targets, FcεRIα and IgE, on the surface of mast cells.52 Total IgE levels are known to regulate FcεRI and FcεRI-bound IgE expression levels, with low and high IgE levels linked to low/high FcεRI and bound IgE expression levels, respectively. Also, IgE bound to FcεRI can inhibit the activation of mast cells by autoantibodies directed to FcεRI.53 Accordingly, total IgE levels could modulate TIIbaiCSU disease activity.

TIIbaiCSU is identified by the combination of positive results of autologous serum skin testing, basophil testing, and tests for FceRI/IgE autoantibodies.54 Also, in the only study that used all the 3 tests in CSU patients, less than 10% had TIIbaiCSU, but many tested patients were positive for one or 2 markers.38 In this study, patients with TIIbaiCSU had markedly lower total IgE levels, 22 IU/mL, as compared with 102 IU/mL in non-TIIbaiCSU patients (P < 0.001).38 TIIbaiCSU patients also had a higher rate of low total IgE (< 40 IU/mL), 86%, than non-TIIbaiCSU patients (26%, P < 0.01).38

In support of these findings, most studies on total IgE in ASST-positive CSU patients also reported to be lower levels,203855 but one study each found similar36 and higher levels.14 Also, Baioumy et al.13 reported lower total IgE levels in CSU patients with IgG to FcεRIα, although the difference in CSU patients without these autoantibodies was not significant. Why total IgE levels are reduced in patients with TIIbaiCSU is currently unknown.

Taken together, TIaiCSU is thought to be linked to normal/high total IgE levels, and there is strong evidence that TIIbaiCSU is linked to low and very low total IgE levels. Are these 2 endotypes also linked to differences in the biological and functional properties of IgE?

DIFFERENCES IN THE BIOLOGY AND FUNCTION OF IgE BETWEEN TIaiCSU AND TIIbaiCSU

In a recent study, CSU patients had more lipophilic IgE than healthy controls, and IgE lipophilicity correlated with autoreactivity (r = 0.8; P < 0.0001).48 It is currently unclear why IgE in patients with TIaiCSU is more lipophilic; however, glycosylation patterns may be involved. IgE is heavily glycosylated (Supplementary Fig. S1),56 and recent publications showed that modifications of the glycosylation pattern affect IgE-receptor binding and allergenic pathogenicity.5758 The glycosylation of IgE is thought to be important for its 3-dimensional folding and bending and its lipophilicity (Supplementary Fig. S1B).56 Higher lipophilicity may promote IgE aggregation and stacking, as is seen with highly cytokinergic IgE,59 which can crosslink FcɛRI without antigen binding, initiate cytokine production in mast cells (MCs) (Fig. 2C),60 and shows polyreactivity to various self-antigens (β-galactosidase, dsDNA, TG, ssDNA and histamine releasing factor) that induce MC degranulation.616263

The IgE in CSU patients with low levels often fails to increase upon treatment with omalizumab. Omalizumab usually results in a rapid and sustained increase in total IgE due to the prolongation of the half-life of IgE after binding to omalizumab. In a recent study, 60 of 63 (95%) CSU patients with IgE higher than 43 IU/mL, but only 17 of 33 (52%) patients with low IgE (≤ 43 IU/mL), increased their IgE level by at least 100% during the first 4 weeks of omalizumab treatment.27 Failure to double IgE levels by week 4 predicted non-response to treatment. This indicates that the IgE in patients with TIIbaiCSU is not only often low but also functionally different in regard to its binding to omalizumab, and that this difference is linked to impaired treatment responses. Further studies need to clarify, in detail, how IgE in patients with TIaiCSU and TIIbaiCSU differs from IgE in healthy individuals.

IS TOTAL IgE A MARKER AND PREDICTOR FOR THE RESPONSE OF CSU PATIENTS TO THERAPY?

A second-generation antihistamine (sgAH) at a standard dose is the first-line treatment of CSU. Updosing can improve the response to sgAH treatment in some patients.64 If this fails, omalizumab treatment is needed and recommended, with ciclosporin as a fourth-line fall back option.

Total IgE levels were similar in responders and non-responders to sgAH treatment in 4 CSU studies with at least 95 patients each.20656667 In contrast, most studies on total IgE and omalizumab treatment showed that low IgE levels predict non-response in patients with CSU (Supplementary Table S2). For example, Straesser et al.23 reported that 48% of patients with low total IgE (≤15 IU/mL), but more than 85% of those with IgE levels higher than 15 IU/mL, benefitted from omalizumab treatment.23 In another study, low IgE levels (≤ 43 IU/mL) were linked to benefit in 66% of treated patients as compared with 95% in those with higher IgE levels.27 Weller and colleagues26 reported low IgE levels in 40% of CSU patients who showed no response to omalizumab treatment, as compared with 27% and 3% of patients with normal and complete response, respectively.

Total IgE does not appear to be linked to the onset time of treatment responses to omalizumab in CSU patients. A large-scale retrospective study found no difference in total IgE levels between early complete, late complete and late partial responders to omalizumab.68 Another more recent and smaller study reported a tendency to higher IgE in early responders.69 In contrast, high elevated IgE levels in 1 study were linked to a shorter time to relapse in CSU patients who stopped treatment.70 However, 2 subsequent studies failed to confirm this.6869

Two smaller studies reported that IgE levels are also linked to the outcome of cyclosporine treatment. In 1 study, serum IgE levels were significantly lower in cyclosporine responders vs. non-responders and were negatively correlated with the benefit of treatment.71 The other study showed that patients with high IgE levels had lower rates of response than those with low IgE.72

Taken together, serum total IgE levels can help predict the outcome of omalizumab and cyclosporine treatment. There is strong evidence that low levels are linked to poor response to omalizumab but good response to cyclosporine, whereas some reports point towards a connection of normal and high IgE levels and good response to omalizumab and maybe a poor response to cyclosporine (Supplementary Table S2).

DO IgE LEVELS CHANGE IN RESPONSE TO TREATMENT OR SPONTANEOUS REMISSION OF CSU?

In CSU, changes in total IgE levels, as of yet, have only been studied in patients treated with omalizumab, quilizumab, or acupuncture. Omalizumab leads to an increase in total IgE in most CSU patients (Supplementary Table S3). Patients with low IgE before treatment, in 1 study, showed lower rates of elevated total IgE in week 4 of omalizumab treatment, and this was linked to non-response.27 In a proof-of-concept study, quilizumab, which targets the M1-prime segment of membrane-expressed IgE, reduced median serum total IgE level by 30%, but did not result in clinically meaningful improvements.73 One small acupuncture study in CSU reported significant drops in total IgE levels of about 40%,74 but did not report the clinical effects of treatment. As of now, there is no study on the change of total IgE levels after spontaneous remission of CSU (supplementary Table S3).

Autoallergen-specific IgE, i.e., IgE-anti-TPO, was reported to be increased in CSU patients who experience symptom exacerbation.44 Serum IgE-anti-IL-24 levels, but not IgG-anti-IL-24 serum levels, were significantly decreased in responders, but not in non-responders to autologous serum therapy.7576

DISCUSSION AND SUMMARY: VALUE OF MEASURING TOTAL IgE IN CSU

High total IgE levels may point to high disease activity, longer disease duration, TIaiCSU, a high chance to respond to omalizumab treatment, a quick relapse after stopping omalizumab, and a lower chance of responding to cyclosporine. Low IgE, in turn, may point to TIIbaiCSU, a reduced chance to respond to omalizumab and a better chance to benefit from cyclosporine treatment. This makes total IgE a valuable marker, and we recommend including its assessment in the routine diagnostic work up of patients with CSU.

Does the knowledge of a patient's total IgE level help decide which treatment is best? At present, it does not. Total IgE does not appear to predict the response to first- and second-line treatment, a standard and higher than standard-dose antihistamine, respectively. Omalizumab is the best treatment option for patients who fail to respond to antihistamine treatment, regardless of their total IgE levels. However, low total IgE, especially in combination with elevated IgG-anti-TPO38 should have us suspect that a patient has TIIbaiCSU and should, therefore, be monitored closely.

CONCLUSIONS

Taken together, there is strong circumstantial evidence that total IgE is currently one of the best generally available surrogate markers for the discrimination of TIaiCSU and TIIbaiCSU. However, many questions remain to be answered. These include, but are not limited to: What exactly are the clinical differences in CSU patients at different total IgE serum levels? Why is total IgE reduced in TIIbaiCSU? Does total IgE, in patients with low and high levels, return to normal after CSU remission occurs? Are normal and high levels of total IgE a marker of response to omalizumab and cyclosporine? What is an optimal cutoff value for low total IgE? Further studies are needed to address these questions, and, answering them will help advance our understanding of CSU and improve its treatment.