chronic spontaneous urticaria - Dermatologica Sinica

DERMATOLOGICA SINICA xxx (2017) 1e5

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ORIGINAL ARTICLE

Efficacy of omalizumab treatment for patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) in Taiwan Che-Wen Yang, Yung-Tsu Cho, Chia-Yu Chu* Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan

a r t i c l e i n f o

a b s t r a c t

Article history: Received: Jul 11, 2016 Revised: Mar 20, 2017 Accepted: Jun 2, 2017

Background/Objectives: Accumulating evidence has shown that omalizumab is an effective and safe treatment for chronic spontaneous urticaria (CSU), but there is little information regarding the use of omalizumab to treat CSU in Taiwan. Reports on clinical experiences with using omalizumab for CSU for more than 6 months are also lacking. Methods: A retrospective review of medical records of consecutive CSU patients receiving omalizumab treatment in the Urticaria Special Clinic of one tertiary referral center in Taiwan was conducted. We analyzed clinical features of the patients, treatment efficacy and safety, and also long-term outcomes after omalizumab treatment. An Urticaria Activity Score over 7 days (UAS7) was recorded at each visit. Results: A total of 17 CSU patients were identified (11 females and 6 males, age range: 21e83 years) with a baseline mean UAS7 of 29.8 ± 8.9 despite antihistamine treatment. All patients were treated with at least 3 doses of monthly subcutaneous injections of omalizumab. Fifteen patients achieved a UAS7 of 6 or less after 3 doses of monthly omalizumab injections. Seven of those 15 patients received an additional 1 to 3 doses and all ended up with a UAS7 of less than 2 at the 24-week follow-up. A sustained response to maintenance treatment after 24 weeks was observed in 5 patients with individual tailoring of treatment duration and dosing interval. Conclusion: Omalizumab is an effective and safe treatment for antihistamine refractory CSU. Maintenance therapy with individual tailoring of the treatment duration and interval is possible. Copyright © 2017, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Keywords: Chronic spontaneous urticaria Efficacy Maintenance treatment Omalizumab Safety

Introduction Chronic idiopathic urticaria (CIU), also known as chronic spontaneous urticaria (CSU), is a common disease characterized by the daily or almost daily spontaneous emergence of wheals, angioedema, or both for more than 6 weeks.1 Due to the intolerable itching and episodic attacks of disfiguring wheals, the impact of CSU on a patient's quality of life is profound and has been reported to be similar to that experienced by patients waiting for coronary artery bypass graft surgery.2 A nationwide cross-sectional observational study in Taiwan found that CSU causes severe psychological pressure and that most cases are not satisfactorily managed.3 Furthermore, a case-control study identified stress and insomnia as important factors for the development and worsening of CSU, * Corresponding author. Department of Dermatology, National Taiwan University Hospital and National Taiwan University College of Medicine, 15F, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan. Fax: þ886 2 23934177. E-mail address: [email protected] (C.-Y. Chu).

respectively.4 Different treatment options for this rather common dermatological disease (estimated prevalence: 0.5%e5%) have already been discussed by different guidelines and consensus reports in recent years.1,5 In the past, the pharmacological treatments of CSU mainly focused on the pathogenic role of mast cell activation. With their ability to block histamines while causing less drowsiness than other treatments, modern second generation H1antihistamines have become the standard first-line treatment for CSU.1,5,6 Options for second-line therapies include a trial of up to a four-fold dose of one non-sedating second generation H1 antihistamine or the addition of other antihistamines (second generation H1, first generation H1, or H2 antihistamines).1,5 However, it has been proposed that the pathogenic role of mast cells in CSU may not only involve the downstream degranulation of histamine and proinflammatory cytokines, but also the upstream activation process. The IgEeFcεRIemast cell axis and the presence of anti-IgE auto antibodies may increase mast cell activity without degranulation.7 In phase II and phase III trials, omalizumab, a humanized

http://dx.doi.org/10.1016/j.dsi.2017.05.003 1027-8117/Copyright © 2017, Taiwanese Dermatological Association. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/).

Please cite this article in press as: Yang C-W, et al., Efficacy of omalizumab treatment for patients with chronic idiopathic urticaria (CIU)/chronic spontaneous urticaria (CSU) in Taiwan, Dermatologica Sinica (2017), http://dx.doi.org/10.1016/j.dsi.2017.05.003

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C.-W. Yang et al. / Dermatologica Sinica xxx (2017) 1e5

monoclonal anti-IgE antibody, has been shown to be effective in the treatment of patients who remain symptomatic despite H1 antihistamine treatment, and omalizumab is also recommended as an add-on therapy to second generation H1 antihistamines.8e11 A 300 mg subcutaneous injection every 4 weeks for 12 or 24 weeks has been shown to have a more rapid onset of action and sustainable effectiveness in comparison to lower dosing regimens.11 Omalizumab has been licensed by the Taiwan Food and Drug Administration (TFDA) for the treatment of CSU patients with unsatisfactory responses to H1 antihistamines. Owing to the variations in clinical responses and economic considerations, the beneficial roles of personalized dosing intervals and continued treatment during extension periods have only been conceptualized in limited studies.12,13 Herein, we report our experiences with using omalizumab for the treatment of CSU patients at a tertiary referral center in Taiwan. Methods Patients We conducted a retrospective analysis of the effects of using omalizumab to treat CSU patients at the Urticaria Special Clinic of one tertiary referral center, National Taiwan University Hospital. The medical records of CSU patients who underwent omalizumab treatment between October 2013 and March 2016 were reviewed. Most of the patients were started on omalizumab therapy after exhibiting unsatisfactory responses to H1 antihistamines and persistent daily symptoms consisting of pruritus, wheals, or angioedema (Table 1). The severity of CSU for each patient was recorded using an Urticaria Activity Score over 7 days (UAS7) score at baseline and each follow-up visit. The total serum IgE levels were also documented. Omalizumab has been approved for the treatment of refractory CSU in Taiwan since December 2015. Before the approval, informed consent was obtained for any off-label use of the drug. For all the patients, three doses of 150 or 300 mg of omalizumab were injected subcutaneously every 4 weeks (i.e., at week 0, week 4, and week 8) while the patients continued receiving antihistamine therapy. After week 8, the number of and intervals between any additional injections were tailored according to the given patient's clinical response. Assessment Each patient was evaluated by the same dermatologist. The sum of the UAS7 at baseline and the UAS7 at the time before the administration of the next dose was recorded. The UAS is composed of a pruritus score on a scale of 0 (none) to 3 (severe) and the number of hives calculated on a scale of 0 (none), 1 (50 hives/24 h). Treatment responses were categorized as well-controlled disease (UAS7 6), complete response (UAS7 ¼ 0), or non-response (UAS7 > 6). Table 1 Patient's demographics (n ¼ 17). Age Female sex, no. (%) Body weight (kg) Time since diagnosis of CSU (years) Mean total IgE level (IU/mL) (range) Presence of angioedema, no (%) Mean no. of previous medications for CIU/CSU Previous use of corticosteroids, no. (%) Mean baseline UAS7 Mean UAS 7 at week 8 Mean UAS 7 at week 12

44.6 ± 20.5 11 (64.7) 60.1 ± 10.9 5.9 ± 6.4 272.6 (8.9e1510.0) 7 (41.2) 2 ± 0.9 4 (23.5) 29.8 ± 8.9 1.9 ± 4.0 1.5 ± 3.6

Statistical analyses Demographic data were analyzed by descriptive statistics. Measurement data for each group were shown in terms of mean ± SD. Statistical comparisons between the groups were made using the Student's t-test (Excel 2007, Microsoft Corp., Redmond, WA, USA). Statistical significance was defined as P < 0.05. Results Seventeen CSU patients with a UAS7 of more than 16 despite receiving different H1 antihistamines were identified. The demographic data of these patients are summarized in Table 1. The mean duration of CSU was 5.9 years (range: 2 months to 20 years). The treatment regimen and response are shown in Table 2. Four patients had been treated with different doses of systemic corticosteroids. The average baseline UAS7 was 29.8 ± 8.9. All the patients received 3 initial subcutaneous doses of 150 or 300 mg of omalizumab at an interval of every 4 weeks. For every patient, a significant reduction of UAS7 was found over time (Fig. 1). The clinical efficacy of the treatment in terms of the urticaria disease activity during the treatment period was demonstrated by increased proportions of well-controlled disease (UAS7 6) and complete response (UAS7 ¼ 0) (Fig. 2). At week 12, 88.2% patients had a well-controlled disease and 76.5% patients had achieved a complete response. Disease flare-ups while receiving omalizumab therapy were observed in 2 patients due to the patient's discontinuation of all baseline antihistamines. One of those patients (patient No. 6) then achieved well-controlled status by adding on levocetirizine and buclizine while continuing the omalizumab treatment and the other (patient No. 7) was lost to follow-up. The response parameters, including UAS7 at week 12 and the total number of injections, did not correlate with the IgE levels or the presence of angioedema (statistical data now shown). Individualized treatment duration, interval, and dose Five patients received omalizumab for maintenance therapy after 6 doses of omalizumab over 24 weeks and reached a UAS7 of 6 or less. Satisfactory maintenance effects were achieved by tailoring omalizumab treatment to each patient's individual condition. Of the 5 patients who received extended treatment of a duration ranging from 16 to 78 weeks beyond week 24, four obtained and maintained a complete response, while the fifth achieved the well-controlled disease status (Table 3). With regard to extended dosing interval, one patient maintained a complete response on 150 mg doses of omalizumab with dose intervals tapered from every 4 weeks to every 12 weeks; one patient had a well-controlled disease, and the remaining two patients had a complete response on 300 mg doses of omalizumab at intervals of 4e8 weeks. Among three patients received antihistamine only as maintenance treatment, one remained in complete remission and patient No. 5 and No. 17 experienced flares 8 and 9 weeks respectively after the end of omalizumab treatment. Safety During the treatment period, no severe adverse events such as death or anaphylactic shock were reported. Only one patient experienced nausea and another had an injection-site reaction presenting as a painful induration for 1 day after the first injection. Neither of those patients had a recurrence of similar side effects after the first injection.


No./Sexa/Age

Angioedemab

IgE (IU/ml)

Body weight

Dermogarphismb

Antihistamines (mg/day)

Other treatments (mg/day)b

Omalizumab dose (mg)

Total number of injections

Baseline UAS7c

UAS7 Week 8

UAS7 Week 12

Time to complete remission

1/F/83 2/M/48

Y N

68.2 86.7

51.6 65

N Y

N N

150 300

13 18

21 28

0 0

0 0

8 8

3/F/43 4/F/76

N Y

140 995

71 47

Y Y

Levocetirizine (5) Desoloratidine (5) Fexofenadine (180) Cyproheptadine (12) Levocetirizine (5) Levocetirizine (5)

150 300

3 9

40 42

14 0

12 0

NA 8

5/F/75

N

92

68.9

N

Levocetirizine (5)

150

7

35

3

0

12

6/M/32

N

76

74

Y

300

9

16

0

0

4

7/F/45

N

NA

61.9

Y

N

300

3

40

14

Lost to follow up

NA

8/M/63 9/F/51

N Y

1510 9.79

65 60

Y Y

5 9

28 35

0 6

0 2

4 24

N Y

8.87 261

45.7 45

N Y

300 300

5 6

16 35

0 0

0 6

8 8

12/F/27 13/M/22

Y N

87.3 524

55 72

Y N

N Prednisolone (20) Ketotifen (4) N Sulfasalazine (1000) Hydroxychloroquine (400) N N

300 300

10/F/61 11/F/31

300 300

4 3

42 28

0 0

0 0

4 4

14/F/26

N

188

48

N

N

300

3

16

0

0

4

15/M/30

N

32.4

79

N

N

300

3

28

0

0

8

16/M/24 17/F/21

Y Y

69.5 32

63 50

Y Y

Levocetirizine (10) Buclizine (50) Fexofenadine (120) Dexchlorpheniramine maleate (8) Desoloratidine (5) Levocetirizine (5) Cetirizine (10) Levocetirizine (10) Levocetirizine (20) Buclizine (50) Levocetirizine (5) Levocetirizine (5) Hydroxyzine (25) Levocetirizine (5) Fexofenadine (180) Desoloratidine (5) Chlopheniramine (12) Desoloratidine (5) Buclizine (50) Dexchlorpheniramine maleate (8)

Doxepine (25) Prednisolone (10) Oxazolam (30) Prednisolone (5) Doxepine (50) autologous whole blood injection N

N Prednisolone (10)

300 300

3 3

28 28

0 4

0 0

8 8

a b c



Table 2 Summary of clinical parameters and treatment response in 17 patients.

F ¼ female; M ¼ male Y ¼ yes; N ¼ no; NA ¼ non applicable UAS7 ¼ Urticaria Activity Score over 7 days.

3

4


Fig. 1 Mean changes of Urticaria Activity Score over 7 days (UAS7) at each follow up visit.

Fig. 2 Responder analysis. Proportion of patients responded at each time point in the first 3 months.

Table 3 Individualized dosing and treatment interval as maintenance therapy. ID

Extended dosing schedule

Total number of injections beyond the week 24

Mean UAS7a (range)

1

150 mg Q8W for 4 injections, Q12W for 3 injections 300 mg Q4W for 6 injection, Q8W for 3 injections, Q10W for 2 injections, Q12W for 1 injection 300 mg Q4W for 3 injections 300 mg Q4W for 1 injection, Q6W for 1 injection, Q8W for 1 injection 300 mg Q4W for 2 injections, Q8W for 2 injections

7

0

12

2.2 (0e6)

3 3

0 0

4

0

2

4 6

9 a

UAS7 ¼ Urticaria Activity Score over 7 days.

Discussion In this retrospective analysis, we confirmed that omalizumab can provide effective symptom relief in Taiwanese CSU patients, with 88.2% of the investigated patients having well-controlled disease at a week 12 follow-up. Among the 17 patients who completed three monthly injections with a documented UAS7 at week 12, well-controlled disease was achieved in 15 patients. The efficacy

of omalizumab in treating CSU has been proved by previous double-blinded, randomized controlled trials and meta-analysis9e11,14 and was proposed as a third line or alternative add-on treatment in different treatment guidelines.1,5,6 Using second generation H1 antihistamines with dose advancement is still the mainstay of treatment. The timing to start omalizumab in this retrospective study varied among patients, with three patients receiving updosing of the second generation antihistamines before the administration of omalizumab and the others taking combination of another second generation antihistamine, first generation antihistamines, H2 antihistamines or autologous whole blood injection. Such diversity reflects real world practice because most of the patients with CSU referred for treatment at our facility had been treated at local clinics or outside hospitals over a period of time. Because the strategy for dose escalation may take weeks,15 the most frequently encountered question is the effectiveness of antihistamine updosing in improving the symptoms of CSU. A recent published meta-analysis demonstrated the response rate to antihistamines updosing for prior nonresponders with CSU was 63.2%.16 Furthermore, dose escalation could improve the severity of pruritus but not wheal number. Due to the lack of accurate biological markers for predicting the responder to updosing of antihistamines, whether all patients should undergo a trial of four-fold updosing before being treated with omalizumab is worth further exploring. In terms of response to omalizumab treatment, there was also no ideal biomarker testing for patient selection. In accordance to previous observations, the response rates among subgroups with different IgE levels and the presence of angioedema showed no statistically significant differences.17,18 The current report also highlights the clinical practice of CSU management in real life. Previous phase III trials provided information regarding the treatment responses to and safety of 3 doses or 6 doses of omalizumab every 4 weeks compared with placebo, while also reporting that the disease activity relapsed at around 8 weeks after the discontinuation of omalizumab.9e11 For those wellcontrolled CSU patients who have received regular omalizumab treatment via 6 doses, the question of whether omalizumab should be used as a maintenance treatment is a frequently encountered clinical issue. The mechanisms of omalizumab in treating CSU are mainly attributed to the depletion of free form IgE, resulting in the downregulation of FcεRI and a reduction in mast cell activation.7 Furthermore, a pharmacokinetic study of patients with allergic asthma found that omalizumabeIgE binding at a longer duration can significantly decrease IgE production.19 The long-term efficacy and safety of omalizumab for the treatment of allergic asthma has already been established, but whether CSU patients could also benefit from long-term omalizumab treatment was previously unknown.20 Uysal et al. had, however, used an algorithm for treating CSU with omalizumab in an individualized dosing regimen, showing adequate treatment response.12 According to our observations, omalizumab was well-tolerated for a longer duration in 5 patients and was effective in maintaining their well-controlled condition. In addition, extended-interval omalizumab dosing did not lower the maintenance effect. With regard to the long-term control of CSU, the modification of the dosing interval according to a given patient's individual clinical response may be a cost-effective means of drug administration. It was previously estimated that a monthly amount of omalizumab in mg equaling 0.016 body weight in kg serum IgE concentration in IU/mL is necessary to neutralize a patient's free IgE sufficiently.19 Whether a dosage of omalizumab should be considered high or low should be determined in reference to its ability to neutralize free IgE in the blood or interstitial fluids at the times of administration



of omalizumab and during the intervals between omalizumab administrations.21 With a high-dosage regimen, free IgE is kept near 0 for the entire treatment period. In humans, IgE turns over with a relatively short half-life (2.4 days). In the approved protocols for omalizumab, which has a half-life of about 23 days, the antibody is administered in excess so that it will be of sufficient quantity to neutralize all the IgE present in the body at the time of the initial injection and all the IgE produced during the 4-week intervals between injections.21 Four of the 5 patients who received extended treatment had IgE levels below 100 IU/ml, and all of them had body weights of less than 70 kg. In previous phase III studies, the mean body weight and mean body mass index in the Asian subgroup were significantly lower than those of the non-Asian subpopulation,22 indicating that lower amounts of monthly omalizumab injections or prolonged injection intervals of every 6e12 weeks might be enough in some slim patients with low IgE levels. Based upon the above assumption, it is reasonable to conclude that we clinicians may want to taper the omalizumab dosage to 150 mg per month or continue with 300 mg standard doses while slowly prolonging the treatment intervals from every 4 weeks to every 12 weeks. In this regard, our observations of satisfactory long-term effects with continuing treatment can provide additional information for clinical practice. The main limitations of our study include the small number of patients included, a wide range of pretreatment disease duration, its retrospective design, and its single-center nature. Also, the study was limited by the lack of a control group or a standardized study protocol. Conclusion In this case series, we found that omalizumab was safe and efficacious for patients with CSU refractory to standard treatment in Taiwan. Individualized treatment durations and dosing intervals for long-term control can be a cost-effective option for those patients needing maintenance omalizumab treatment. Funding sources

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Conflict of interest 19.

The corresponding author is a clinical trial investigator of Novartis and has received travel support, consulting fees and payment for lectures from Novartis. The other authors declare that they have no financial or non-financial conflicts of interest related to the subject matter or materials discussed in this article. References 1. Chung W-H, Chu C-Y, Huang Y-H, Wang W-M, Yang C-H, Tsai T-F. Taiwanese Dermatological Association consensus for the definition, classification,

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