Evidence for histamine release in chronic inducible urticaria – A systematic review

Abstract

BackgroundChronic inducible urticaria (CIndU) constitutes a group of nine different CIndUs in which pruritic wheals and/or angioedema occur after exposure to specific and definite triggers. Histamine released from activated and degranulating skin mast cells is held to play a key role in the pathogenesis of CIndU, but evidence to support this has, as of yet, not been reviewed systematically or in detail. We aim to characterize the role and relevance of histamine in CIndU.MethodsWe systematically searched 3 electronic databases (PubMed, Scopus, and Embase) for studies that reported increased serum or skin histamine concentration (direct evidence) or in vitro or ex vivo histamine release (indirect evidence) following trigger exposure.ResultsAn initial total of 3,882 articles was narrowed down to 107 relevant studies of which 52 were in cold urticaria, 19 in cholinergic urticaria, 14 in heat urticaria, 10 in contact urticaria, 7 each in solar urticaria and vibratory angioedema, 4 each in symptomatic dermographism and aquagenic urticaria, and 3 in delayed pressure urticaria. The results of our review support that histamine has a key pathogenic role in the pathogenesis of all CIndUs, but it is not the sole mediator as evidenced by the often poor relationship between the level of histamine and severity of symptoms and the variable clinical efficacy of H1-antihistamines.ConclusionsHistamine released from skin mast cells is a key driver of the development of signs and symptoms and a promising therapeutic target in CIndU.

A comparative analysis of chronic inducible urticaria in 423 patients: Clinical and laboratory features and comorbid conditions

“…The presence of systemic symptoms such as fatigue, nausea, dyspnea and arthralgia during the attack was more common in CSU plus CIndU. That is not surprising, since in CSU plus CIndU patients, the main diagnosis is CSU, which involves a significant cellular infiltrate when compared to CIndU (lack this feature) where the hives are a consequence of mast cell degranulation and release of histamine and last no more than 1 hour 25,26 . The lack of cellular infiltrate in CIndU can be an explanation for the lack of systemic complaints due to the lack of many cytokines and chemokines that would be released from the infiltrating cells into the circulation 27…”

“…That is not surprising, since in CSU plus CIndU patients, the main diagnosis is CSU, which involves a significant cellular infiltrate when compared to CIndU (lack this feature) where the hives are a consequence of mast cell degranulation and release of histamine and last no more than 1 hour. 25,26 The lack of cellular infiltrate in CIndU can be an explanation for the lack of systemic complaints due to the lack of many cytokines and chemokines that would be released from the infiltrating cells into the circulation. 27 The parameters which have been linked to severe and refractory disease 8 such as higher frequency of angioedema, systemic steroid use, need for emergency referrals and lower UCT scores were higher in CSU plus CIndU in our study.…”

Inhibition of interleukin‐1 with rilonacept is not effective in cold urticaria—Results of a randomized, placebo‐controlled study

“…The development of wheals and angioedema is thought to be driven by the activation and degranulation of cutaneous mast cells with subsequent release of various inflammatory mediators including histamine, leukotrienes and cytokines after cold exposure of the skin. 9 , 10 , 11 , 12 …”

“…The development of wheals and angioedema is thought to be driven by the activation and degranulation of cutaneous mast cells with subsequent release of various inflammatory mediators including histamine, leukotrienes and cytokines after cold exposure of the skin. [9][10][11][12] Current treatment strategies in ColdU comprise the avoidance of cold exposure and the use of H1 antihistamines. 13 Antihistamine treatment in ColdU patients significantly reduces cutaneous histamine release as well as levels of interleukin (IL)-6, a downstream effector of IL-1β, and IL-8 after cold exposure.…”

Anti‐KIT antibody, barzolvolimab, reduces skin mast cells and disease activity in chronic inducible urticaria

“…6,10 Although the pathophysiology of ColdU and SD is not fully understood, activation and degranulation of skin mast cells and their release of histamine are held to be involved in both of CIndUs in the development of signs and symptoms. [11][12][13] Mast cells (MCs) are powerful inflammatory tissue-resident immune cells implicated in numerous disorders spanning several disease areas, including allergy, inflammation, auto-immunity, fibrosis, and neurodegeneration. MCs are considered the main effectors in the pathogenesis of various inflammatory diseases including CU and systemic mastocytosis.…”