TABLE 2.

Studies concerning up-dosing of second-generation antihistamines (sgAH) in uncontrolled chronic spontaneous urticaria (CSU)

AUTHOR, YEAR	TYPE OF STUDY	NUMBER OF UNCONTROLLED CSU PATIENTS	STUDY OUTCOME		LEVEL OF EVIDENCE
			EFFECTIVENESS	SAFETY	SORT	OCEBM
Cetirizine
Kameyoshi et al, 200710	Open-label randomized, parallel-group trial	21	Doubled dose of cetirizine (20 mg daily) is more effective than licensed dose (10 mg daily) in uncontrolled patients, as evidenced by lower UAS score.	Minimal adverse effects reported, only 9.5% complained of increased drowsiness on double-dose.	II	2
Asero R, 200711	Open-label longitudinal, single group	22	Only 1 patient (4.9%) demonstrated clinical benefit with up-dosed cetirizine (30 mg daily) after 2 weeks, Urticaria severity was assessed by visual analogue scale.	Tiredness and somnolence reported by 59% patients on higher dose, No other ADR reported.	II	3
Guillen-Aguinaga et al, 201612	Systematic review and meta-analysis	20-418	Cetirizine up-dosing was effective in 53.8% (95% CI 33.3-79.2) non-responsive CSU patients. Up-dosing significantly improved pruritus, but not wheal number.	No dose-dependent increase of ADRs.	I	1
Iriarte et al, 20203	Systematic review	20-439	Cetirizine showed increased effectiveness on up-dosing	No dose-dependent increase of ADRs.	I	1
Fexofenadine
Godse et al, 201013	Non-randomized, dose escalating, single group longitudinal trial	37	70% remained unresponsive to conventional dose but 97% became asymptomatic on up-dosing (up to 3 times or 540 mg daily). UAS7 score was used to assess effectiveness.	No significant ADR. Headache reported in 2 patients with higher dose; mild sedation in 1 patient with 540mg dose.	II	3
Magen et al, 201214	Non-randomized, non-controlled clinical trial	67	UAS7 score improved significantly in 68.7% patients on standard dose (180 mg daily), while 31.3% had no significant improvement on 4-times updosing. Up-dosed fexofenadine significantly reduced autologous serum induced wheal size, compared to standard dose.	NA	II	3
Tanizaki et al, 201315	Open-label, longitudinal, non-randomized, single group	20	Significant reduction in pruritus severity and histamine-induced flare and itch noted with 240 mg daily, compared to 120 mg daily.	No dose-dependent increased of ADR	II	3
Guillen-Aguinaga et al, 201612	Systematic review and meta-analysis	15 publications following PRISMA guidelines	Among all sgAHs fexofenadine up-dosing has highest proportion of responders in 83.07% uncontrolled patients. Up-dosing significantly improved pruritus, but not wheal number.	No dose-dependent increase of ADRs.	I	1
Iriarte et al, 20203	Systematic review	20-439	Fexofenadine up-dosing (up to 2 times) produced dose-dependent significant response and controlled CSU in majority patients	No dose-dependent increase of ADRs.	I	1
Levocetirizine
Godse K, 201016	Non-randomized, open label, dose-escalating trial	20	60% (12/20), 75% (6/8) and 100% (2/2) patients became asymptomatic (UAS7=0) with 5 mg, 10 mg and 20 mg daily levocetirizine respectively.	1 patient complained of mild sedation with 10 mg and 20 mg levocetirizine each. No significant ADR noted.	II	3
Staevska et al, 201017	Randomized, double-arm (levocetirizine vs desloratadine).	40	22.5% (9/40) patients became symptom free with 5 mg, 25.8% (8/31) with 10mg and 21.7% (5/23) with 20 mg daily dose. 18 patients (45%) remained non-responsive to up-dosed levocetirizine. Increased dose also improved quality of life.	No dose-related increase in ADR (sedation) reported.	I	2
Sharma et al, 201718	Open-label longitudinal/ cohort, single arm	113	18.6% became asymptomatic with 5 mg, proportion increased to more than twofold and threefold on doubling and quadrupling the standard dose respectively. Almost 30% unresponsive to four-times up-dosed levocetirizine	No notable ADR, no dose-related increase	II	3
Guillen-Aguinaga et al, 201612	Systematic review and meta-analysis	20-418	Levocetirizine up-dosing was effective in 55.26% (95% CI 39.82-73.19) non-responsive CSU patients. Up-dosing significantly improved pruritus, but not wheal number.	No dose-dependent increase of ADRs.	I	1
Iriarte et al, 20203	Systematic review	20-439	Levocetirizine showed increased effectiveness on up-dosing	No dose-dependent increase of ADRs.	I	1
Desloratadine
Staevska et al, 201017	Randomized, double-arm, cross-over (levocetirizine vs. desloratadine)	40	10% (4/40) patients became symptom free with 5 mg, 19.4% (7/36) with 10mg and 3.4% (1/29) with 20 mg daily dose. 28 patients (70%) remained non-responsive to up-dosed desloratadine. Increased dose also improved quality of life. 7/28 non-responders (25%) responded to 20 mg levocetirizine.	No dose-related increase in ADR (sedation) reported. One patient developed palpitation on 20 mg dose, without any ECG change.	I	2
Ebastine
Godse K, 201119	Non-randomized, dose escalating, single group longitudinal trial	30	33% remained uncontrolled with standard dose, but 100% patients responded on up-dosing (up to 4 times or 40 mg daily). UAS7 score was used to assess effectiveness.	No significant ADR. 1 patient reported mild sedation on 40 mg dose.	II	3
Bilastine
Audicana et al, 200720	Double-blind, randomized, placebo-controlled dose-ranging trial	222	Bilastine (10,20,30 mg) significantly better than placebo for disease control (reduced wheal number and itching). No significant difference between 10, 20 and 30 mg doses.	No ADR reported	I	2
Weller et al, 201821	Open-label, non-controlled, longitudinal trial	31	Uncontrolled patients received bilastine in escalating doses (20, 40 and 80 mg) at 2-week intervals, if UAS7 >3 with preceding lower dose. Six patients (19%) gained complete (UAS7 ≤ 3) relief with bilastine 20 mg and a further 3(10%) bilastine 40 mg. Seven patients (23%) gained complete relief from itching with bilastine 20 mg and a further 3 (10%) with 40 mg. Urticaria became well-controlled (UAS7<6) in 26%, 6% and 3% patients with 20, 40 and 80 mg respectively.	No significant ADR reported.	II	3
Iriarte et al, 20203	Systematic review	20-439	Bilastine showed increased effectiveness on up-dosing	No dose-dependent increase of ADRs.	I	1