Real-Life Experience of Efficacy and Safety of Bilastine in the Refractory Cases of Chronic Spontaneous Urticaria and its Effect on the Quality of Life of Patients.

INTRODUCTION: Second-generation H1-antihistamines (SGAHs) are the mainstay of treatment of chronic spontaneous urticaria (CSU). Bilastine, newer non-sedating SGAHs, was recently introduced in India after the approval of the Drugs Controller General of India. There is a paucity of evidence about the long-term efficacy and safety of Bilastine in Indian patients. We undertook this study to find the long-term efficacy and tolerability of Bilastine in patients with CSU in India.
MATERIALS AND METHODS: This retrospective chart analysis was conducted by analyzing electronic medical records from May 1, 2019, to March 20, 2020, to identify patients of CSU who were prescribed Bilastine. Adult patients, with CSU >6 months were included, who had an unsatisfactory response as per Urticaria Activity Score 7 (UAS7) to previous antihistamine therapies, and who continued treatment for at least 6 months were included. Treatment effectiveness was determined by retrospectively reviewing their UAS7 scores from their medical records and evaluating their scores at weeks 4, 8, 12, 16, 20, and 24. Also, DLQI was assessed and compared at baseline and week 24. RESULT: Forty-nine patients were found to fulfill the criteria and included in the study. At the end of 24 weeks, 51% of patients (n = 25) achieved complete treatment response (UAS = 0), whereas 49% of patients (n = 24) were labeled as well-controlled urticaria (UAS<6). At 24 weeks, the mean UAS7 score (1.35 ± 1.61) was statistically significant compared to the baseline score (20.2 ± 5.73). The mean score of DLQI was also reduced to 1.63 ± 1.18 at 24 weeks from 8.39 ± 2.49 at baseline (P-value <0.001).
CONCLUSION: The study showed that in patients who had an inadequate response with commonly used antihistamines at a double dose or combined use, switching over to Bilastine resulted not only in relieving the symptoms of CSU but also improved the quality of life of the patients with CSU. Copyright:

Introduction

Chronic spontaneous urticaria (CSU) is a common skin disease characterized by pruritic, erythematous, and edematous wheals with daily or near-daily episodes, for >6 weeks as a result of known or unknown causes.[1] The exact prevalence of urticaria in India is not known. However, lifetime prevalence is reported as 7.8%–22.3%.[2]

Second-generation H1-antihistamines (SGAHs) are the mainstay of treatment since mast cell-derived histamine is the major mediator of CSU.[345] However, licensed doses of SGAHs are ineffective in completely relieving symptoms in many patients because histamine may reach very high concentrations in the skin, due to its poor diffusibility in the dermis.[67] In such patients, the European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) guidelines recommend increasing the dosage up to fourfold.[8] However, Japanese guidelines for diagnosis and treatment of urticaria recommend the combined use of two antihistamines or switch over to some other SGAH.[9]

However, it has been seen that only 78% of patients achieve a good outcome.[10] Although SGAHs have a much-reduced brain penetration compared to first-generation antihistamines, most may only be referred to as ‘minimally sedating’ rather than ‘non-sedating’. In one of the studies of patients’ perspective of effectiveness and side effects of H1-antihistamine up dosing in CSU, more than 20% of patients reported sedation as the most common side effect of SGAHs.[11]

Therefore, two major factors are important for CSU management. First, the freedom from unwanted side effects, especially sedation to let the up dosing occur safely; and second is strong clinical efficacy with a rapid onset and long duration of action.

Bilastine, a newer, non-sedating SGAH, has been approved for therapeutic use in patients with urticaria, with a recommended dose of 20 mg once daily in patients >12 years. Bilastine has been assessed in multiple clinical trials involving patients with chronic urticaria. The total symptom score (TSS), which is defined as, the sum of the scores for rashes and itching, was significantly improved at an early stage (days 1–3) in a group given bilastine 20 mg once daily compared to placebo.[12] Long-term treatment with bilastine 20 mg once daily for 52 weeks in Japanese patients with chronic urticaria, concluded bilastine to be safe and well-tolerated.[13]

Bilastine was recently introduced in India after the approval of the Drugs Controller General of India. There is a paucity of evidence about the long-term efficacy and safety of Bilastine in Indian patients. We undertook this study, to retrospectively analyze the long-term efficacy and tolerability of Bilastine in patients with CSU in India.

Materials and Methods

This retrospective chart analysis was conducted at Wizderm Speciality Skin and Hair Clinic in Kolkata. The electronic medical records were analyzed from May 1, 2019, to March 20, 2020, to identify patients who were prescribed Bilastine. The inclusion criteria for this study were given below:

The adult patients diagnosed with CSU for 6 months or more

All these patients with an unsatisfactory response as per UAS7 to previous antihistamine therapies, either on a double dose of the previous antihistamine or on the combined use of antihistamines at the licensed dose

All these patients switched over to Bilastine 40 mg/day and continued Bilastine for 6 months in varying doses of Bilastine depending on the response.

Patients who were under 18 years of age, who were pregnant or on lactation, who had CSU less than 6 months, or who discontinued or changed treatment in between the course were excluded from the study.

All the patients were started on Bilastine 40 mg/day since many of them were either on a double dose of previous antihistamines or combined use of antihistamines. According to clinical response, Bilastine dose was either increased gradually to 80 mg/day or decreased to 20 mg/day.

In addition, only those records were considered for analysis, whose assessments were done at regular intervals (i.e., on monthly basis) by using UAS7 scoring system and (Dermatology Life Quality Index) DLQI questionnaire.

The UAS assigns a score from 0 (no disease activity) to 3 (intense activity) for each of the two key urticaria symptoms, wheals, and pruritus. The sum of the scores represents disease severity on a scale from 0 (minimum) to 6 (maximum). UAS7 values were assigned to five score ranges (bands), reflecting urticaria disease activity, measured by the weekly UAS7 as shown in Table 1.

Table 1

UAS7 score and disease severity

UAS7 Score	Disease severity
0	Itch and hive free—indicative of no symptoms of CSU and considered a full treatment response
1-6	Well-controlled urticaria—indicates a good response to treatment
7-15	Mild urticaria—indicates also a lower response level
16-27	Moderate urticaria
28-42	Severe urticaria

The DLQI questionnaire is designed for use in many dermatological diseases and is self-explanatory. The DLQI is calculated by summing the score of each question resulting in a maximum of 30 and a minimum of 0. The higher the score, the more quality of life is impaired [Table 2].

Table 2

Grades of DLQI score

Score	Effect on patients’ life
0-1	no effect at all on patient’s life
2-5	small effect on patient’s life
6-10	moderate effect on patient’s life
11-20	very large effect on patient’s life
21-30	extremely large effect on patient’s life

Treatment effectiveness was determined by retrospectively reviewing their UAS7 scores from their medical records and evaluating their scores at weeks 4, 8, 12, 16, 20, and 24. Also, DLQI was assessed and compared at baseline and week 24. Then, these evaluations were compared with each other.

All characteristics were summarized descriptively. For continuous variables, the summary statistics of mean ± standard deviation (SD) were used. For categorical data, the number and percentage were used in the data summaries and diagrammatic presentation. The difference between the means of analysis variables between two-time points in the same group was tested by a paired t-test. The level of significance was set at P < 0.05. Data were analyzed using SPSS software (v. 23.0) and Microsoft office (2010).

Result

The patients that met inclusion criteria for this review consisted of 49 adult patients, among whom 30 (61.2%) were male and 19 (38.8%) were female patients. The mean age of the patients was 38.53 ± 14.5 years. The mean disease duration was 10.02 ± 6.78 months. Most of the patients were on the combined use of antihistamines at a licensed dose. All the demographics are depicted in Table 3.

Table 3

Baseline demographics

Attributes	Numbers
Patient characteristics
Number (n)	49
Male; n (%)	30 (61.2)
Female; n (%)	19 (38.8)
Mean age (years)	38.53±14.5
Mean Disease Duration (months)	10.02±6.78
Previous medication; n (%)
Patients on 2 drugs (Combined use)	36 (73.47)
Patients on 1 drug (Double dose or more)	13 (26.53)
Associated comorbidities; n (%)
Hypothyroidism	9 (18.37)
Diabetes	3 (6.12)
Hypertension	1 (2.04)
Mean baseline DLQI	8.39±2.49
Mean baseline UAS7	20.2±5.73

Efficacy

Based on UAS7, 84% of the patients were in moderate to severe urticaria at baseline [Table 4], whereas the mean UAS7 score was 20.2 ± 5.73. At the end of 4 weeks only, 2 patients (4%) achieved complete treatment response and 19 patients (39%) had well-controlled urticaria on Bilastine 40 mg/day. Moreover, the mean UAS7 score was reduced to 8.2 ± 5.1 (P value <0.001). A similar trend of improvement in the number of patients achieving full treatment response and change in mean UAS7 score was seen over 24 weeks.

Table 4

No. of patients in different types of CSU grade as per UAS7 & DLQI

	Baseline	Week 24
UAS7
Complete Treatment response (symptom free)	0	25
Well-controlled urticaria	0	24
Mild urticaria	8	0
Moderate urticaria	34	0
Severe urticaria	7	0
DLQI
no effect at all on patient’s life	0	28
small effect on patient’s life	6	21
moderate effect on patient’s life	33	0
very large effect on patient’s life	10	0

Figure 1 shows the patients’ overall improvement at each visit. As for overall improvement, as assessed by UAS7, complete response and well-controled response was observed in 42.8% (21/49) of patients at week 4, 71.4% (35/49) at week 8, 91.8% (45/49) at week 16 and 100% (49/49) at week 24.

Figure 1

Week wise categorization of patients who responded to Bilastine

At the end of 24 weeks, 51% of the patients (n = 25) achieved complete treatment response, whereas 49% of the patients (n = 24) were labeled as well-controlled urticaria [Figure 1]. The Mean UAS7 score also showed a declining trend over 24 weeks [Figure 2]. At 24 weeks, the mean UAS7 score was 1.35 ± 1.61 which was statistically significant compared to baseline [Figure 3].

Figure 2

Week wise change in mean UAS7 score

Figure 3

Change in mean score

As per the inclusion criteria, all the patients were started on Bilastine 40 mg/day at baseline. Although there was clinical improvement in many patients, nine patients required up-dosing of Bilastine to 60 mg/day at week 4. Some of the patients were further up dosed to Bilastine 80 mg/day at weeks 8 and 12. In addition, dose reduction trend was also seen in patients from 8 weeks onwards; whereas 11 patients (22.4%) at week 8, 27/49 (55.1%) at week 12, 35/49 (71.4%) at week 16, 40/49 (81.6%) at week 20 were shifted on Bilastine 20 mg/day. At the end of week 24, 43 patients (87.7%) were on Bilastine 20 mg/day and 6 patients were on Bilastine 40 mg/day [Figure 4]. Though all these 6 patients had well-controlled urticaria on Bilastine 40 mg/day, 5 patients were added cyclosporine and 1 patient was added omalizumab for better control.

Figure 4

Week wise Bilastine dosing

Discomfort caused by urticaria

The analysis of the DLQI for discomfort caused by urticaria [Table 2] showed that patients may be divided into five broad groups. Based on DLQI, quality of life was moderately to severely affected in 88% of the patients (n = 43) at baseline. At the end of 24 weeks, CSU had no effect on 57% of the patients whereas 43% of the patients had a small effect of CSU on their quality of life [Table 4]. The mean score of DLQI was also reduced to 1.63 ± 1.18 at 24 weeks from 8.39 ± 2.49 at baseline (P-value <0.001).

Safety assessment

Five patients (10.2%) complained of sedation but it was mild and did not require discontinuation of treatment. Overall Bilastine was well tolerated at all doses.

Discussion

We conducted this real-world retrospective study to evaluate the safety and efficacy of Bilastine in different doses for up to 24 weeks in patients with CSU. To the best of our knowledge, this is the first real-world study to evaluate the long-term safety and efficacy of 24 weeks Bilastine treatment in Indian patients with CSU. This real-world study thus assessed the response of switching over to Bilastine in Indian patients who showed inadequate response with other antihistamines.

Bilastine has been assessed for its efficacy in chronic urticaria in multiple clinical studies.[1213] However, there are very few studies that have assessed the effect of switching over to Bilastine in chronic urticaria refractory to other antihistamines at licensed dose. Moreover, there is no clinical study that has assessed the effect of Bilastine 40 mg per day in real-world settings.

Weller et al. in a real-life study[14] assessed the effects of Bilastine at 20, 40, and 80 mg daily for 2 weeks on the signs and symptoms of CSU in patients who had not responded sufficiently to licensed doses of other H1-antihistamines. This study concluded that up dosing to double the licensed dose of bilastine appeared to be sufficient for the majority of the patients with CSU. But in this study, every dose of Bilastine was studied for 2 weeks only, and on non-response to the previous dose, the Bilastine dose was up dosed as recommended by many guidelines.

Another prospective study conducted by Shigeki Inui et al. assessed the effect of bilastine in the patients with CSU refractory to other antihistamines like Fexofenadine, Levocetirizine, Cetirizine and concluded that Bilastine 20 mg per day when administered for 4 weeks, showed good to excellent treatment effects in 83.3% of the patients.[15] In both the studies, patients were prescribed Bilastine 20 mg per day in the initial period, and all the patients were followed up every 2 weeks. But in the real world, such kind of practice may not be possible every time. In fact, in one article by Kolkhir et al., it was seen that almost one-third of physicians either do not follow a guideline or deviate from it.[16]

Similarly, in our study, all the patients were started on Bilastine 40 mg per day since all the patients were either on a double dose of SGAHs or on the combined use of different antihistamines. In addition, all the patients were followed up every 4 weeks. At the end of 4 weeks only, 2 patients (4%) achieved complete treatment response and 19 patients (39%) had well-controled urticaria on Bilastine 40 mg/day. This suggests that up dosing to double the licensed dose of Bilastine appeared to be effective in patients of CSU as seen in Weller et al. study.[14] At the end of 8 weeks, though 11 patients required further up dosing but 11 patients were switched down to Bilastine 20 mg per day also. This trend of switching down to Bilastine 20 mg per day further continued till 24 weeks suggesting efficacy of Bilastine 20 mg in the patients with CSU as seen in other clinical studies.[1213] With respect to long-term efficacy in the patients with CSU, bilastine 20 mg once daily significantly improved UAS7 and quality-of-life scores as compared with the baseline scores.

Symptoms of CSU can irritate and affect the patient's quality of life, and the most frequently reported concern with the use of antihistaminic drugs is somnolence which leads to decreased patient satisfaction and non-compliance with the treatment, resulting in an inadequate response. Multiple clinical trials have shown that Bilastine 20 mg is effective not only in relieving symptoms but also improving the patients’ quality of life.[131718] In a study conducted by Zuberbier et al., out of 338 patients who received either bilastine 20 mg or levocetirizine 5 mg, somnolence was reported lesser in patients receiving bilastine (5.8%) as compared to levocetirizine (6.7%).[17] In our study, 10% of the patients experienced somnolence which may be due to less sample size. Additionally, there was a significant improvement in the DLQI with bilastine at week 24 compared to the baseline.

The overall treatment compliance rate in this study was 100% indicating that the compliance to long-term treatment with bilastine was very good. None of the patients experienced serious AE or discontinued the treatment. This suggests that in the long term, Bilastine is effective not only in compliance but also in the betterment of the quality of life.

To the best of our knowledge, the present study is the first real-world study in India, assessing the long-term effect of switching over to Bilastine in CSU refractory to other antihistamines. Though this study is a retrospective study, which is the limitation, yet the clinical response which was achieved with a switch over to Bilastine is noteworthy. However, larger observational studies are recommended to confirm these results.

In conclusion, this study showed that in patients who had an inadequate response with commonly used antihistamines at a double dose or combined use, switching over to bilastine at 40 mg/day resulted not only in relieving the symptoms of CSU but also improved the quality of life of the patients with CSU.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.