Leukotriene Receptor Antagonists as Add-On Therapy to Antihistamines for Urticaria: Systematic Review and Meta-Analysis of Randomized Clinical Trials

As part of the American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma & Immunology Joint Task Force on Practice Parameters urticaria guidelines, the authors sought to identify the benefits and risks of adding any leukotriene receptor antagonist (LTRA) to antihistamines for the treatment of urticaria.Online database and registry searches were done for randomized controlled trials (RCTs) in any language for LTRAs plus H1 antihistamines (AH). A systematic review and meta-analysis used Cochrane and Grades of Recommendation Assessment, Development, and Evaluation (GRADE) guidance. Prioritized outcomes were as follows: urticaria activity over 7 days (UAS7, a combination of itch and wheal severity), itch and wheal severity considered separately, sleep disturbance, dermatology health-related quality of life (QoL), and any adverse event.Initial searches identified 3847 unique citations, but after screening and eliminating those that did not meet the strict review criteria, 34 studies were included in the analysis. Of those, 6 were limited to children, 21 to adults, 6 included both, and 1 did not report ages. All but 1 evaluated montelukast. UAS7 score (range 0–42, lower better) was reported in 28 (82%) of the studies (n = 2579 patients). The addition of LTRA to AH probably modestly reduced urticaria activity (mean difference [MD] −5.04, GRADE: moderate certainty). However, the minimally important difference (MID) of the UAS7 is −9.9 to −10.5. Itch and wheal severity using a 3-point numeric rating scale (range 0–3, lower better) was assessed in 8 (27%) studies (n = 542). The addition of LTRA to AH probably modestly reduced both: the MD improvement was −0.25 for each (moderate certainty, MID estimated to be −1.0). Also using a 3-point scale in 2 RCTs, there was little or no effect on sleep disturbance with the addition of LTRA (MD = 0.0, low certainty). Four RCTs (n = 430) using the Dermatology Life Quality of Life Index (range 0-30, lower better, MID = −4.0) found an MD of −3.51 (low certainty), indicating that LTRAs may improve QoL. The addition of LTRA to AH had little or no effect on adverse event frequency as evaluated in 19 (56%, n = 1884) RCTs (relative risk = 0.80). No study reported neuropsychiatric adverse events.In this systematic review and meta-analysis, the addition of LTRA to AH for treatment of urticaria probably improves UAS7 score and itch and wheal severity, and may improve QoL, but the effects fell below the MID thresholds. The authors’ estimates are that the chance of improvement with the addition of LTRA in UAS7 is only 12%.Montelukast only has Food and Drug Administration approval for asthma (1998) and allergic rhinitis (2003). Shortly after 2003, it seemed to me that some clinicians were prescribing it for virtually anything remotely related to allergic conditions (including urticaria) without any data to support its use. To their credit, as the medication failed to help in those cases, the practice abated. This study confirms that montelukast can provide relief of urticaria, but the measured improvements are rarely clinically relevant (less than the MID). Most of the 34 studies reviewed were published before the first time an urticaria practice parameter recommended off-label use of second-generation antihistamines to as much as 4-fold the recommended dose (J Allergy Clin Immunol. 2014;133(5):1270-1277). The addition of an LTRA to high-dose antihistamines might show an even less favorable response to the added medication. The data in this study do not preclude the option of off-label trials of add-on medications. However, they do require that the prescriber assesses how the patient feels, not just whether there are fewer hives or less itch. I do not recommend the practice unless all else fails. If high-dose antihistamines do not provide adequate relief of urticaria, omalizumab is the preferred next step for eligible patients.