**4. Proper duration of omalizumab treatment**

As shown in all phase III trials, cessation of omalizumab resulted in an increase in weekly itch and wheal scores and returning to placebo levels within 16 weeks [9–11]. These results indicate that omalizumab is effective in controlling symptoms, but they do not provide evidence that omalizumab induces remission from CSU. Therefore, longer durations of treatment may be required for some patients. Omalizumab shows very good safety efficacious at therapeutic durations of more than 1 year [23, 24]. As soon as patients achieved complete control, antihistamines can be tapered off [4].

Several strategies have been proposed for weaning including reduction monthly doses or lengthening the time between doses [28]. A patient-tailored tapering protocol on the basis of a patient's UAS7 scores while on omalizumab treatment is needed. Increase the injection interval by 1-week intervals can be recommended when the patient achieved a complete response to omalizumab after 6 months of treatment [29]. If a patient can tolerate every 8-week injections over a 4-month period without increased activity, these patients can often have omalizumab discontinued. Fortunately, most of patients who have experienced relapsed urticaria after stopping omalizumab treatment, respond well to retreatment of omalizumab with previously effective dose and interval [30, 31].

### **5. Predictors of the response to omalizumab treatment**

In patients with CU, omalizumab is not a disease-modifying or curative treatment. The treatment response to omalizumab in patients with CU is classified according to the onset and extent of the response. Fast or early response is defined when the onset of therapeutic response to omalizumab in CU patients starts within the first 4 weeks. On the other hand, the response appearing gradually by weeks 12–16 weeks is defined as slow or late response. The extent of therapeutic response to omalizumab is based on the UAS7. Complete response includes the patients

who achieve UAS7 = 0, no itch and wheal or UAS7 ≤ 6, well-controlled urticaria or have a significant improvement in UAS7 reduction from baseline (> 90%). Partial response is defined as UAS7 reduction between 30% and 90%. No response means that UAS7 reduction is less than 30% from baseline or the exacerbation of itchy wheals during omalizumab treatment [32, 33].

Around 70% of patients with CSU who benefit from omalizumab respond within the first week of treatment. From the results of 3 pivotal phase III trials, at week 4, well-controlled urticaria (UAS7 ≤ 6) was reported by 2 ~ 5%, 12 ~ 15%, 21 ~ 28%, and 37 ~ 51% of patients receiving placebo, 75, 150, 300 mg of omalizumab, respectively. And early response is linked to type I autoimmunity or IgE autoantibodies, such as IgE to thyroid persoxidase [13]. The proportion of wellcontrolled urticaria and complete responders during the 12-week of active treatment increased continuously. With continuous dosing of omalizumab 300 mg from 12 weeks to 24 weeks in ASTERIA I [9] and GLACIAL, [11] around a half of patients who did not respond at week 12 achieved complete response at week 24. The median time to complete response was also dependent on the dose of omalizumab. It was noted between 8 and 10 weeks for 300 mg of omalizumab, whereas fewer than 50% of patients in the 75 mg or 150 mg of omalizumab groups achieved complete response within the 12-week of treatment. However, around 40 ~ 50% of patients had partly or uncontrolled urticaria even with an active treatment of omalizumab for 24 weeks. Thus, before determining non-responders to omalizumab treatment and considering other therapeutics, use of omalizumab for at least 6 months is needed.

There are no markers to predict when their CSU will go into remission. Despite older and higher disease activity at onset, being female, and hypersensitivity to nonsteroidal anti-inflammatory drugs, comorbid CIndU, presence of angioedema, and thyroid disease were all reported to be associated with longer urticaria duration in CSU patients, [29] however, none on these markers guides to decide when to discontinue omalizumab.

Lower levels of serum total IgE at baseline (< 40 IU/mL) and decreased ratio of IgE levels at 4 weeks by baseline levels (<2.0) have been associated with higher risk of non-responder to omalizumab treatment in CSU patients [34]. Positive response to diagnostic tests for type IIb autoimmunity including basophil histamine releasibility assay, autologous serum skin test, and anti-FcεRI autoantibody in the sera from CSU patients are regarded as indicators for slow or poor response to omalizumab [34, 35].

Studies evaluating the efficacy of up-dosing of omalizumab to 450 mg or 600 mg in a month revealed a comparable benefit for CSU patients with partial or non-response to 300 mg of omalizumab [26, 27, 36]. There also reports that shortening the injection interval can lead to complete response inpatients with partial or no response to omalizumab 300 mg every 4 weeks. The most recent guidelines recommend cyclosporine add-on as a fourth-line treatment in CSU patients whose urticaria is not controlled with omalizumab treatment [3, 4, 37].

### **6. Omalizumab treatment for chronic inducible urticaria**

As chronic inducible urticaria (CIndU), induced by common physical stimuli including exposure to cold or heat, skin friction or pressure, sunlight, and exercise, with longer duration, difficult to avoid the offending trigger, CIndU affects severely patients' quality of life. A recent study reported that up to 76% of CSU patients were found to have a concurrent CIndU and these patients have more severe

#### *The Use of Omalizumab in Chronic Urticaria: Available Data and Future Aspects of Anti-IgE… DOI: http://dx.doi.org/10.5772/intechopen.97226*

urticaria [38]. While omalizumab has been used to successfully treat CSU on the basis of strong evidence from randomized controlled trials, real-life studies, and meta-analyses, omalizumab is not yet licensed for CIndU.

A meta-analysis reported recently that omalizumab has substantial benefits in patients with various CIndUs [16]. Variation of omalizumab use was seen between the CIndU subtypes, with the strongest evidence available in patients with symptomatic dermographism (complete or partial response in 38/54 patients), cold urticaria (complete/partial response in 41/51 patients), and solar urticaria (complete/partial response in 28/36 patients). Little or no evidence was available on vibratory, aquagenic and contact urticaria.

A randomized, placebo-controlled trial involving 55 patients with symptomatic dermographism revealed that significant improvement in critical friction thresholds after 10 weeks of treatment with omalizumab 150 mg and 300 mg, compared with the placebo group [39]. No significant difference in efficacy was observed between omalizumab 150 mg and 300 mg groups. After 10 weeks of treatment, 6 (33%) of 18 receiving 150 mg of omalizumab and 8 (42%) of 19 patients receiving 300 mg of omalizumab did not respond at all compared with 15 (83%) of 18 in the placebo group. A retrospective observational study showed 86% of patients achieved a complete response [32].

Cold urticaria is the second most prevalent physical urticaria. A randomized, placebo-controlled trial including 31 patients with cold urticaria demonstrated significant clinical superiority of omalizumab versus placebo [40]. Mean changes in critical temperature threshold after 10 weeks of treatment were significantly higher in the omalizumab 150 mg and 300 mg groups compared with the placebo group. Improvements were seen by week 4. No significant dose-dependent response between the omalizumab 150 mg and 300 mg groups. After 10 weeks of treatment, 10% of 10 patients receiving omalizumab 150 mg and 22% of 9 patietns receiving 300 mg of omalizumab were non-responders compared with 75% of 12 patients in the placebo group.

Due to a longer symptomatic episode and a subtype of frequently accompanied in patients with CSU, delayed pressure urticaria was reported to result in a significant impairment of quality of life than other types of CIndU [41]. Furthermore, it is difficult to control delayed pressure urticatia with up-dosing of antihistamine treatment [16]. In a meta-analysis that found 11 publications of omalizumab treatment for patients with delayed pressure urticaria, favorable results were obtained [16]. Starting with 150 mg of omalizumab, 60% ~ 88% of patients with delayed pressure urticatia achieved complete control within 2 days.

There is sparse data on the efficacy of omalizumab for patients with cholinergic urticaria. Among retrospective analyses, one from the Germany [32] reported 62% of complete response and 25% of no response assessed by provocation test, whereas another study reported from Korean populations [42] showed relatively lower complete responders (4.8%, 1 of 21 patients).

Taken together, although evidence of the efficacy of omalizumab in CIndU has been accumulating, more data from randomized controlled trials are needed to establish the dose, injection interval, and treatment duration according to the type of CIndU. To date, while many studies proved a lower dose of 150 mg was enough to reach a good response, however as like in CSU patients, increasing dose of omalizumab in some patients with CIndU had better response. Most of studies found that CIndU patients achieved complete symptom control after the first injection of omalizumab, however, once discontinued, all patients got worse within 8 weeks after the last injection to need retreatment of omalizumab because antihistamines did not work for these patients [16].
