An update on the use of antihistamines in managing chronic urticaria

Figures & data

Table 1. Summary of the properties of the first and second generation antihistamines [20,21].

Generation	Drug name	Standard adult daily dose (mg)	Elimination half-life (hours)	Time to reach maximum plasma concentration after a single dose (hours)	Time to action (hours)	Duration of action (hours)	Liver metabolization	Renal failure	Liver failure	Pregnancy considerations	Use in lactation*	Use in elderly	Clinically relevant drug interaction
fg-AH	Chlorpheniramine	24	27.9 ± 8.7	2.8 ± 0.8	3	24	+	Dose adjustment not needed-	Dose adjustment needed	Based on animal studies, the use is not expected to increase the risk of malformations. Human studies have reported associations with varied birth defects	Excretion in breast milk is not known. May cause drowsiness in newborn	Not recommended	Possible
fg-AH	Diphenhydramine	75–150	9.2 ± 2.5	1.7 ± 1.0	2	12	+	Dose adjustment not needed	Dose adjustment needed	Based on animal studies and available human data diphenhydramine is not expected to increase the risk of congenital anomalies	Excretion in breast milk is considered low. May cause drowsiness in newborn	Not recommended	Possible
fg-AH	Hydroxyzine	75–150	20 ± 4.1	2.1 ± 0.4	2	24	+	Dose adjustment not needed	Dose adjustment needed	Hydroxyzine showed adverse pregnancy effects in rodents. Limited published data during human pregnancy. Manufacturer contraindicates use in early pregnancy	Excretion in breast milk is not known. May cause drowsiness in newborn	Not recommended	Possible
sg-AH	Rupatadine	10	5.9	0.75	2	24	+	Dose adjustment needed	Dose adjustment needed	Based on animal data, therapy with rupatadine is not expected to increase the risk of congenital anomalies	Excretion in breast milk is not known	Be careful in liver function failure and polypharmacy	Possible
sg-AH	Fexofenadine	120–180	14.4	2.6	2	24	<8%	Dose adjustment needed	Dose adjustment not needed	Based on animal data and human data, fexofenaydne exposure during pregnancy is not expected to increase the risk of adverse outcomes	Excretion in breast milk is considered low	Safer to use	With p-glycoproteins
sg-AH	Loratadine	10	7.8 ± 4.2	1.2 ± 0.3	2	24	+	Dose adjustment needed	Dose adjustment needed	Based on animal data and human reports, loratadine is not expected to increase the risk of adverse pregnancy outcomes.	Excretion in breast milk is considered low	May have anticholinergic effects	Possible
sg-AH	Desloratadine	5	27	1–3	2	24	+	Dose adjustment needed	Dose adjustment needed	Based on animal and human data, the use during pregnancy is not expected to increase the risk of congenital anomalies	Excretion in breast milk is considered low	May have anticholinergic effects	Possible
sg-AH	Cetirizine	10	7–11	1.0 ± 0.5	1	24	<40%	Dose adjustment needed	Dose adjustment needed	Based on animal and human data, the use is not expected to increase the risk of adverse pregnancy outcomes	Excretion in breast milk is considered low	May cause sedation	Unlikely
sg-AH	Levocetirizine	5	7 ± 1.5	0.8 ± 0.5	1	24	<15%	Dose adjustment needed	Dose adjustment needed	Based on animal and reported human data, the use is not expected to increase the risk of adverse pregnancy outcomes	There is not enough data however since it is an enantiomer of cetirizine, excretion in breast milk is considered low	May cause sedation	Unlikely
sg-AH	Bilastine	20	14.5	1.2	2	24	Not metabolized in humans	Dose adjustment not needed	Dose adjustment not needed	Information is limited. Based on animal and human data, no increased risk of adverse pregnancy outcome expected	Excretion in breast milk is not known.	Safer to use	With p-glycoproteins
sg-AH	Ebastine	10–20	10.3 ± 19.3	2.6 ± 5.7	2	24	+	Dose adjustment needed	Dose adjustment needed	Information is limited. Animal studies do not indicate direct or indirect harmful effects on embryonal/fetal development, parturition or postnatal development	the amounts in milk are unlikely to affect a breastfed infant.	Be careful in liver failure and polypharmacy	Possible

*The percentage of drug concentration that penetrates into breast milk is typically categorized as follows: Low: Less than 1% of the maternal dose appearing in breast milk. Moderate: Between 1% to 10% of the maternal dose appearing in breast milk. High: Greater than 10% of the maternal dose appearing in breast milk.

Abbreviations: fg-AH, first-generation antihistamines; sg-AH, second-generation antihistamines.

Table 2. Characteristics of included studies concerning standard dose sg-AH in chronic urticaria.

Name of author, year, place of study	Type of study	Study participants and type of Urticaria	Interventions (n)	Study duration (weeks)	Study results	Remarks
(1) Shah et al., 2022, India [46]	Comparative, Three-Arm, Randomized Clinical Trial	18–60 years with a clinical history of CSU for at least 6 weeks during the last 3 months without an identifiable cause and urticaria activity score (UAS7) of ≥ 7.	Bilastine 20 mg OD (39) Fexofenadine 180 mg OD (35) Levocetirizine 5 mg OD (36)	2 weeks	At week 2, 23 patients achieved well-controlled urticaria in the bilastine group, whereas 18 and 17 patients achieved well-controlled urticaria in the fexofenadine and levocetirizine arms, respectively. There was no statistical difference between any of the groups at week 2. All drugs were safe and well tolerated.	Bilastine, Fexofenadine and Levocetirizine are effective, safe and well-tolerated at their standard doses.
(2) Sil et al., 2021, India [48]	Single-center, investigator-blind, randomized, active-controlled, parallel-group phase IV trial	Adult patients with CSU of either gender.	Bepotastine besilate 10 mg BD (30) Levocetirizine 5 mg OD (29)	6 weeks, fortnightly follow-up	UAS7 and TSS reduced significantly (p < 0.001) in both treatment groups from 1st follow-up visit (bepostatine) and 2nd follow-up visits (levocetirizine). At week 6, UAS7 (5.13 ± 8.21 vs 7.48 ± 8.96) and TSS (5.10 ± 4.06 vs 7.07 ± 4.48) were less with bepotastine than levocetirizine although not statistically significant. Day-time sedation significantly more with levocetirizine (p < 0.001).	Bepotastine is comparable to levocetirizine with respect to its effectiveness with an edge in terms of side-effect (day-time sedation)
(3) Fayaz et al., 2021, India [55]	Single-blind randomized, parallel-group trial	Patients with CIU, 18–65 years, having symptoms ≥3 days per week in the last 6 weeks.	Loratadine 10 mg OD (25) Rupatadine 10 mg OD (26)	6 weeks, follow-up every 2 weeks	Rupatadine is more efficacious than loratadine in the reduction of Total Leucocyte Count, Differential Count and Absolute Eosinophil Count, the key determinants of allergy. Rupatadine also produced better improvement in Total symptom Score, Dermatology Life Quality Index in patients with CIU.	Rupatadine is superior to Loratadine for treating CIU, based on efficacy and safety parameters.
(4) Podder et al., 2020, India [58]	Double-blind RCT	CSU patients aged 18–65 years with moderate-to-severe disease (UAS 17 > 16)	Bilastine 20 mg OD (31) Levocetirizine 5 mg OD (27)	6 weeks, follow-up every 2 weeks	Both drugs significantly improved UAS7, DLQI, and VAS at end-of-treatment (D42) compared to baseline (intra-group). All parameters showed greater improvement with bilastine, but only UAS7 reduction was significant (bilastine > levocetirizine, p = .03). Sedation was significantly less with bilastine (p = .04), while neither drug showed any serious adverse-effect.	Bilastine is a more effective and less-sedative therapy for CSU compared to levocetirizine, with similar effect on quality of life.
(5) Thi et al., 2019, Vietnam [49]	Open-label trial	Patients with chronic urticaria, aged >12 years	Levocetirizine 5 mg OD (52) Fexofenadine 180 mg OD (50)	2 weeks	TSS reduced significantly in both groups at 2 weeks, compared to baseline [7.4 vs 2.3 for levocetirizine group and 8.0 vs 2.6 for fexofenadine group (p < 0.05)]. No significant ADR reported in either group.	Levocetirizine and Fexofenadine are effective medications for CSU at their conventional dose, without any significant adverse reaction.
(6) Hide et al., Japan, 2019 [38]	Multi-center double-blind placebo controlled RCT	Patients with CIU, aged 12 to <65 years, total pruritus score (TPS) ≥ 2 for at least 3 consecutive days before drug administration	Rupatadine 10 mg OD (91) Placebo (94)	2 weeks	TPS reduced significantly in those receiving rupatadine 10 mg, compared to placebo (mean TPS difference −1.956, p < 0.001). No significant ADR was reported apart from somnolence in 20.9% patients (vs. 8.5% in placebo).	Rupatadine is safe and effective at a dose of 10 mg once daily, significantly better than placebo. It can be safely increased to 20 mg once daily, as necessary.
(7) Hide et al., Japan, 2017 [35]	Multi-center double-blind placebo controlled RCT	Patients with documented CSU aged 18–74 years	Bilastine 20 mg OD (101) Bilastine 10 mg (100) Placebo (103)	2 weeks	TSS reduced significantly in Bilastine 20 mg group, compared to placebo demonstrating its superiority (p < 0.001). Bilastine 10 mg also reduced TSS significantly vs. placebo (p < 0.001) Improvement started from day 1 and it was maintained, DLQI also improved with Bilastine treatment. Bilastine was found to be safe and tolerable.	Two-week treatment with bilastine (20 or 10 mg) once daily was significantly more effective and tolerable in Japanese patients with CSU (vs. placebo), demonstrating an early onset of action.
(8) Goyal et al., 2017, India [50]	Open-label comparative longitudinal study	Patients with documented CSU, aged 10–70 years	Ebastine 10 mg OD (50) Levocetirizine 5 mg OD (50)	4 weeks	50% and 70% patients achieved complete urticaria remission (UAS7 = 0) at end-of-treatment with Ebastine 10 mg OD and Levocetirizine 5 mg OD (p > 0.05) Levocetirizine 5 mg showed more side effects like dryness of mouth and sedation as compared to ebastine.	The effectiveness of Ebastine is comparable to levocetirizine at licensed dose for CSU. However, adverse effects are more frequent with levocetirizine.
(9) Dakhale et al., India, 2016 [62]	Double-blind RCT	Patients with CSU, aged 18–65 years, with history of urticarial wheals and/or angioedema for ≥3 days per week for 6 consecutive weeks without any obvious cause.	Rupatadine 10 mg OD (30) Olopatadine 10 mg OD (30)	6 weeks	In olopatadine group, there was significantly higher reduction in mean total symptom score [MTSS] (p = 0.01), number of wheals (p < 0.05), size of wheals (p < 0.05), intensity of erythema (p < 0.05) and change in eosinopil count (p = 0.015), compared to rupatadine. Adverse effects were less in the olopatadine group, vs rupatadine.	Olopatadine is a better choice in chronic spontaneous urticaria in comparison to rupatadine due to its better efficacy, safety and cost effectiveness profile.
(10) Dakhale et el, India, 2014 [56]	Double-blind RCT	Patients with CSU, aged 18–65 years, with history of urticarial wheals and/or angioedema for ≥3 days per week for 6 consecutive weeks without any obvious cause.	Cetirizine 10 mg OD (35) Rupatadine 10 mg OD (35)	6 weeks	Both drugs reduced MTSS (mean total symptom score), MNW (mean number of wheals), and pruritus significantly, but it was significantly more with rupatadine (p < 0.05). No drug reported any significant adverse effect.	Rupatadine is a more attractive therapeutic modality compared to cetirizine for the treatment of CSU.
(11) Mahawar et al., India, 2014 [59]	Open-label trial	Patients with documented CSU, 14–70 years, either gender.	Levocetirizine 5 mg OD (77) Olopatadine 5 mg BD (77)	6 weeks	Both drugs reduced UAS significantly (p < 0.05) at all visits and olopatadine reduced UAS more than levocetirizine at 2 weeks (p < 0.05). Each drug reduced DLQI score significantly. Levocetirizine reduced more DLQI than olopatadine, but the difference was not significant (p > 0.05). Olopatadine was associated with more side-effect profile, and most common side-effect was somnolence in both groups.	Levocetirizine is a marginally superior drug as compared with olopatadine for long-term treatment of CIU in Indian population.
(12) Sil et al., India, 2013 [63]	Accessor blind, parallel-group, active controlled phase IV trial	Adults (>18 years) suffering from chronic urticaria.	Olopatadine 5 mg BD (54) Levocetirizine 5 mg OD (51)	9 weeks (continuously for first 4 weeks and then on demand basis for last 5 weeks).	UAS and TSS values declined significantly with both drugs over the treatment period but the reduction was greater with olopatadine. Adverse event profiles were comparable with sedation being the commonest complaint.	Olopatadine is a safe and more effective alternative to levocetirizine in the treatment of CU.
(13) Maiti et al., India, 2011 [57]	Single-blind randomized parallel group trial	Patients aged 12–60 years suffering from CSU	Rupatadine 10 mg OD (35) Levocetirizine 5 mg OD (35)	4 weeks	In rupatadine group, there was 27.9% decrease (p = 0.027) in DC eosinophil, 35.6% decrease (p = 0.036) in AEC, 15.3% decrease (p = 0.024) in serum IgE, 28.2% decrease (p = 0.02) in Total Symptom Scoring, and 27.3% decrease (p = 0.006) in Aerius Quality of Life Questionnaire score. Global efficacy score of rupatadine was found to be significantly greater (p = 0.009) than levocetirizine. Adverse effects were more with levocetirizine.	Rupatadine is a better choice in CIU in comparison to levocetirizine being more effective and safe.
(14) Zuberbier et al., Germany, 2010 [47]	Multicentre, double-blind placebo controlled RCT	Male and female patients with documented history of moderate-to-severe CIU, having symptoms for at least 3 days per week for 6 weeks.	Bilastine 20 mg OD (173) Levocetirizine 5 mg OD (165) Placebo (184)	4 weeks	Bilastine significantly reduced patients’ mean reflective and instantaneous TSS from baseline to a greater degree than placebo (p < 0.001); from day 2 onwards of treatment. The DLQI, general discomfort, and sleep disruption were also improved significantly in bilastine-treated patients as compared to placebo-treated patients (p < 0.001 for all parameters). Comparison with levocetirizine indicated both treatments to be equally efficacious as well as equally safe and well tolerated.	Bilastine 20 mg is a novel effective and safe treatment option for the management of CU, comparable to levocetirizine.
(15) Anuradha et al., 2010, India [60]	Open-label trial	CIU patients aged between 12–60 years	Loratadine 10 mg OD (30) Levocetirizine 5 mg OD (30)	4 weeks	TSS reduction significantly more in Levocetrizine group (13.3%), compared to Loratadine group (4.8%), [p < 0.001] Minor ADRs noted in both groups [Loratadine (19%) > Levocetirizine (12%)- drowsiness, headache, gastric irritation, dry mouth. Drug discontinuation not needed.	Levocetirizine is superior to loratadine for CSU in terms of efficacy and safety.
(16) Potter et al., Germany and UK, 2009 [61]	Multi-center, double-blind RCT	Adult patients (>18 years) with documented CIU, having episodes at least 3 times per week for 6 consecutive weeks during 3 months prior to inclusion.	Levocetirizine 5 mg OD (438) Desloratadine 5 mg OD (448)	4 weeks	Levocetirizine led to a significantly greater decrease in pruritus severity than desloratadine after 4 weeks (p = 0.004) Additionally, levocetirizine decreased pruritus duration and the mean CIU composite scores to a significantly greater extent than desloratadine. Levocetirizine increased the patients’ global satisfaction after 4 weeks (p = 0.021), compared to desloratadine.	Levocetirizine 5 mg was significantly more efficacious than desloratadine 5 mg in the treatment of CIU symptoms.
(17) Ortonne et al., 2007, France [41]	Multi-center, placebo-controlled, double-blind RCT	Patients aged >18 years with active moderate-to-severe CIU	Desloratadine 5 mg OD (65) Placebo (77)	6 weeks	The mean score for the number of wheals was significantly lower in the desloratadine group than in the placebo group on days 14 and 42 (p < or = 0.016). Overall improvement in CIU (complete, marked, or moderate therapeutic response) was also greater at the end of the study in the desloratadine group compared with placebo (p < 0.001), which started as early as day 1 of treatment. Adverse effects were comparable between both groups.	Once-daily desloratadine 5 mg is well tolerated and superior to placebo in reducing pruritus and wheals associated with CIU. It provided rapid and sustained symptomatic relief.
(18) Gimenez-Arnau et al., 2007, Spain [39]	Multi-center, placebo-controlled, double-blind RCT	Male and female patients with minimum 6-week history of CIU, aged 12–65 years, having an active flare for at least 3 days/week.	Rupatadine 10 mg OD (110) Placebo (111)	4 weeks	A 57.5% (p < 0.005) significant MPS (mean pruritus score) reduction from baseline, was observed at week 4 with 10 mg rupatadine compared to placebo (44.9%). No significant adverse effects were reported with rupatadine.	Rupatadine 10 mg is a fast, long-acting, efficacious and safe treatment option for moderate-to-severe CIU, significantly better than placebo.
(19) Dubertret et al., 2007, France [40]	Randomised, double-blind, placebo-controlled, parallel-group, international, dose-ranging study	Male and female patients with documented CSU, aged 12–65 years, having symptoms at least 3 days per week over the last 6 weeks.	Rupatadine 10 mg OD (73) Placebo (69)	4 weeks	Rupatadine10 mg significantly reduced the mean pruritus score (MPS) from baseline by 1.52 (p < 0.05), compared to reduction of 1.14 with placebo, reflecting significant reductions in pruritus severity of 62.7% compared with 45.8% with placebo. Mean total symptom score (MTSS) reduced significantly with rupatadine 10 mg, compared to placebo (p < 0.05) over the 4-week period. Incidence of ADRs was comparable between rupatadine and placebo treated groups.	Rupatadine 10 mg is a fast-acting, efficacious and safe treatment for moderate-to-severe CIU, significantly better than placebo.
(20) Pons-Guirau et al., 2006, France [54]	Double-blind RCT	Patients aged 18–64 years, having CIU for at least 3 months	Loratadine 10 mg OD (77) Emedastine difumarate 2 mg BD (84)	4 weeks	The efficacy of the two drugs was similar in terms of mean change in total urticaria symptom score (– 5.57 ± 3.15 with emedastine vs. 5.67 ± 3.26 with loratadine), proportion of symptom-free patients (52.4% vs. 54.5%) after 4 weeks treatment. The most common adverse event was somnolence (7 with emedastine and 2 with loratadine).	Emedastine is well tolerated, and as effective as loratadine in the short-term treatment of chronic idiopathic urticaria.
(21) Kapp and Pichler, 2006, Germany [36]	Randomized, double-blind, placebo-controlled, parallel, multicenter study	Patients with moderate-to-severe CIU having episodes at least 3 times per week for a period of 6 weeks during the previous 3 months.	Levocetirizine 5 mg OD (81) Placebo (85)	4 weeks	Pruritus severity scores improved significantly with levocetirizne, compared to placebo (p < 0.001). The number and size of wheals were considerably reduced compared with placebo over 1 week and over the total treatment period (P  = 0.001). Levocetirizine significantly improved the QoL and work-productivity. No unexpected adverse events were reported.	Levocetirizine, 5 mg once daily, is an effective and safe treatment for CIU, significantly better than placebo.
(22) Nettis et al., 2006, Italy [37]	Randomized, double-blind, placebo-controlled study	Adult patients with CIU, >18 years age	Leocetirizine 5 mg OD (53) Placebo (53)	6 weeks	Levocetirizine was superior to placebo in reducing the mean total symptoms score as well as individual symptoms, the number of daily episodes and the number of weals, the overall severity of symptoms and the quality of life. The significant beneficial effects of levocetirizine lasted only during the active trial, while at follow-up there was a significant worsening of all the variables (week 7). No significant adverse effects reported.	Levocetirizine 5 mg once daily is an effective agent in patients with chronic idiopathic urticaria, significantly better than placebo. There is rapid onset of action but effect is limited to duration of treatment.
(23) Kaplan et al., 2005, U.S.A. [44]	Randomized, double-blind, parallel-group, placebo-controlled study	Male and female patients (>12 years) with CIU, with history of urticarial wheals at least 3 days per week for the 6 consecutive weeks before first visit.	Fexofenadine 180 mg OD (167) Placebo (92)	4 weeks	Mean number of wheals (MNW) and pruritus severity score improved significantly more with fexofenadine, compared to placebo (both p’s < 0.001). There were no significant differences in the frequency of treatment-emergent adverse events between the 2 treatment groups.	A once-daily dose of fexofenadine hydrochloride, 180 mg, offered effective, well-tolerated relief for the management of CIU, significantly better than placebo.
(24) Handa et al., 2004, India [64]	Double-blind RCT	Patients aged 17 to 65 years, with CIU (urticarial wheals for at least two days per week for six consecutive weeks before entry).	Cetirizine 10 mg OD (52) Fexofenadine 180 mg OD (45)	4 weeks, with follow-up at 2 weeks	The treatment response in both the groups at the end of treatment period was- symptom free [cetirizine 27(51.9%), fexofenadine 2(4.4%)], partial improvement [cetirizine 19(36.5%), fexofenadine 19(42.2%)], no improvement [cetirizine 6(11.5%), fexofenadine 24(53.3%)]. Adverse effects were comparable with both drugs.	Cetirizine seems to have therapeutic advantage over fexofenadine in the treatment of CIU.
(25) Yin et al., 2003, China [52]	Randomized, open-label, parallel comparative clinical trial	Adult patients (>18 years) with documented CIU.	Mizolastine 10 mg OD (32) Cetirizine 10 mg OD (32) Loratadine 10 mg OD (32)	4 weeks, with follow-up at 2 weeks	The efficiency rates of mizolastine, cetirizine and loratatine were 90.0%,85.3%,90.6% at14th day and 96.7%,94.2%,93.8% at 28th day, respectively. (p > 0.05) The recurrent rates of mizolastine, cetirizine and loratatine were 40.0%, 35.3% and 28.1% respectively. No obvious and notable adverse effects occurred with either drug.	All the three antihistamines (mizolastine, cetirizine and loratadine) have high clinical efficacy and safety in the treatment of chronic idiopathic urticaria.
(26) Monroe et al., 2003, U.S.A. [42]	Randomized, double-blind, placebo-controlled, parallel-group, multicenter trial	Patients aged 12 years or older, of either sex and any racial group, with documented CIU, having a flare for 3 weeks or more before screening, with urticarial lesions visible 3 days or more per week.	Desloratadine 5 mg OD (116) Placebo (110)	6 weeks	Compared with placebo, desloratadine significantly improved the total CIU symptom score as well as pruritus, the number of hives, and the size of the largest hive. Overall, global CIU status improved significantly with desloratadine; interference with sleep was reduced and the performance of daily activities improved. Adverse effects were comparable in both groups.	Desloratadine is a well-tolerated and effective treatment of CIU, significantly better than placebo.
(27) Hao et al., 2003, China [53]	Multiple-center, double-blind comparative clinical trial	Adult patients with documented diagnosis of CIU	Desloratadine 5 mg OD (106) Loratadine 10 mg OD (106)	4 weeks	The effective rates of desloratadine group and loratadine group were 23.81% and 32.08% at 7th day, 62.86% and 59.43% at 14th day after treatment and 88.78% and 83.02% by the end of treatment respectively. Adverse effects (mouth dryness, dizziness and headache etc.) were comparable in both groups.	Both desloratadine and loratadine are effective and safe treatment for CIU, statistically comparable.
(28) Ring et al., 2001, Germany [43]	Multicenter, randomized, double-blind, placebo-controlled study	Patients aged 12–79 years with CIU, having a moderate-to-severe flare at the time of recruitment.	Desloratadine 5 mg OD (95) Placebo (95)	6 weeks	Desloratadine was superior to placebo in controlling pruritus and total symptoms after the first dose and maintained this superiority to the end of the study. Measures of sleep, daily activity, therapeutic response, and global CIU status were also significantly better with desloratadine. No significant adverse effects were reported.	Desloratadine 5 mg daily is a safe and effective treatment for CIU with significant benefits over placebo. Onset of action is rapid within 24 hours.
(29) Nelson et al., 2000, U.S.A. [45]	Double-blind, randomized, placebo-controlled study	Chronic urticaria patients aged 12–65 years, with moderate-to-severe pruritus	Fexofenadine 60 mg BD (90) Placebo (79)	4 weeks	Fexofenadine was statistically superior to placebo for reducing pruritus and number of wheals (p < 0.01). Additionally, patients receiving fexofenadine experienced significantly less interference with sleep and daily activities than patients receiving placebo (p < or = .0014). No patient developed any treatment emergent adverse event.	Fexofenadine significantly reduced pruritus severity, number of wheals, and interference with sleep and normal daily activities in patients with chronic urticaria compared with placebo. Twice-daily doses of 60 mg or greater were most effective.
(30) Leynadiar et al., 2000, France [51]	Double-blind comparative trial	Adult patients suffering from CIU	Mizolastine 10 mg OD (26) Loratadine 10 mg OD (35)	4 weeks	The reduction in the number of episodes per week (5. 6 ± 16.3 and 6.4 ± 12.4 for mizolastine and loratadine, respectively) and the reduction in the symptom severity score, measured using a Visual Analogue Scale (VAS), were comparable (30.2 ± 39.0 mm and 30.5 ± 28.5 mm for mizolastine and loratadine, respectively). No notable adverse effects occurred.	Both Mizolastine and loratadine are comparable with respect to safety, efficacy and tolerability in CIU.

Abbreviations: CU; chronic urticaria, CIndU; chronic inducible urticaria, CSU; chronic spontaneous urticaria, CIU; chronic idiopathic urticaria, sg-AH; second-generation antihistamines, RCT; randomized controlled trials, MNW; mean number of wheals, MTSS; mean total symptom score, MPS; mean pruritus score, ADR; adverse drug reactions, UAS7; urticaria activity score 7, TSS; total symptom score, QoL; quality of life, AEC; absolute eosinophil count, DC; differential count, OD; once daily, BD; twice daily, DLQI; Dermatology Life Quality Index, VAS; visual analog scale.

Table 3. Recent evidence on response rates comparison between updosing or combinations of antihistamines.

Recent Evidence	Type of urticaria	Treatment groups	Response rates	Comparison on response rates	Comparison on side effects
Zhang et al. 2020 [66]	CSU	Standard dose sg-AH	35.5% (60/169)	/	/
		2-fold dose sg-AH vs. 2-fold combination sg-AH	18.3% (31/169) vs.14.8% (25/169)	No significant difference	No difference
		4-fold dose sg-AH vs. 4-fold combination sg-AH	1.8% (3/169) vs.3% (5/169)	No significant difference	No difference
		4-fold dose sg-AH + H2-antihistamine/leukotriene receptor antagonist vs. 4-fold combination sg-AH + H2-antihistamine/leukotriene receptor antagonist	6.5% (11/169) vs.6.5% (11/169)	No significant difference	No difference
Ornek et al. 2022 [9]	CU	Standard dose sg-AH	43.1% (283/657)	/	/
		4-fold dose sg-AH	29.4% (53/180)	/	/
		2-fold dose sg-AH vs. 2-fold combination sg-AH	46.3% (94/203) vs.35.8% (24/67)	No significant difference, updosing group demonstrated better outcomes than the combination group	No difference
		Updosing sg-AH (2-fold +4-fold) vs. 2-fold combination sg-AH vs. sg-AH +first-generation H1-antihistamine	38.3% (147/383) vs.35.8% (24/67) vs. 37.5% (6/16)	No significant difference	No difference
Kim et al. 2023 [67]	CU	4-fold dose sg-AH vs. 4-fold combination sg-AH	40% (10/25) vs.10.7% (3/28)	Updosing group demonstrated significantly (p = 0.03) better outcomes than the combination group	No difference

Abbreviations: CU, chronic urticaria; CSU, chronic spontaneous urticaria; sg-AH, second-generation antihistamines.

Table 4. Clinical and biochemical parameters predicting nonresponse or poor response to second generation antihistamines.

Clinical orbiochemical parameter	Publication	Details
High disease burden	Ulambayar, 2019 [76]	Higher UAS7 predicts poor response to sg-AH (p = 0.024)
	Curto-Barredo, 2018 [77]	Higher baseline UAS7 in sg-AH refractory patients (p = 0.035)
	Magen, 2011 [88]	Higher baseline UAS in sg-AH resistant cases (p < 0.001)
	Ornek, 2022 [9]	Lower baseline UCT scores in AH-refractory CSU patients (p < 0.001) Lower baseline UCT scores in AH-refractory CIndU patients (p < 0.001)
CRP	Kolkhir, 2018 [78]	CRP (≥5 mg/L) higher in sg-AH nonresponders (p < 0.001)
	De Montjoye, 2021 [79]	CRP levels higher in sg-AH nonresponders (p < 0.0001)
	Magen, 2011 [88]	Higher CRP levels in sg-AH -resistant cases (p < 0.001)
D-dimer	Asero, 2013 [84]	Elevated D-dimer levels more frequently observed in sg-AH-resistant cases (p < 0.001)
	De Montjoye, 2021 [79]	D-dimer levels higher in sg-AH nonresponders (p = 0.009)
	Kolkhir, 2017 [85]	D-dimer levels higher in nonresponders (p < 0.001)
Concomitant CSU-CIndU	Curto-Barredo, 2018 [77]	Higher sg-AH doses required and frequent treatment after 5 years observed in CSU with concomitant CIndU (p < 0.05)
	Magen, 2011 [88]	Concomitant CIndU more commonly observed in sg-AH-resistant group (p = 0.014)
	Ornek, 2022 [9]	CSU with accompanying CIndU patients were more refractory to AH as compared to isolated CIndU (p = 0.017)

Abbreviations: CIndU, chronic inducible urticaria; CRP, C-reactive protein; CSU, chronic spontaneous urticaria; sg-AH, second-generation antihistamines; UAS, Urticaria activity score; UCT, Urticaria control test.

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