Erin P. Westby, MD1; Charles Lynde, MD, FRCPC2-4; Gordon Sussman, MD, FRCPC, FACP, FAAAI4-6

1Dalhousie University, Halifax, NS, Canada
2Lynderm Research Inc., Markham, ON, Canada
3University Health Network, Toronto Western Hospital, Toronto, ON, Canada
4Department of Medicine, University of Toronto, Toronto, ON, Canada
5Gordon Sussman Clinical Research, Toronto, ON, Canada
6Division of Allergy and Clinical Immunology, St. Michael’s Hospital, Toronto, ON, Canada

Conflict of interest:
Erin Westby has no conflicts to report. Charles Lynde has been a speaker, principal investigator and consultant for Novartis and Pfizer, a speaker and consultant for Aralez, and a consultant for PediaPharm. Gordon Sussman is an advisor for Novartis and Aralez and gives funded lectures for them.

Abstract
Histamine is a key inflammatory player in the pathogenesis of urticaria, a mast-cell-driven disease characterized clinically by the development of wheals, angioedema, or both. Changes to the management of chronic spontaneous urticaria have recently been adopted due to increasing literature surrounding the efficacy and safety of up-dosing modern second-generation H1-antihistamines and the use of omalizamub, a biologic agent, as a third-line treatment. Given the prevalence of chronic urticaria and its impact on quality of life, this editorial aims to provide a summary of the proposed updated guidelines for the management of chronic urticaria as agreed upon at the 5th Consensus Conference on the Update and Revision of the EAACI/GA2LEN/EDF/WAO Guideline for Urticaria in Berlin in December 2016. The chronic urticaria treatment algorithm outlined here reflects the updates and revisions made by 43 international experts representing 40 societies from 25 countries. These guidelines have yet to be published and therefore will require approval by respective national and international boards before adoption.

Key Words:
chronic spontaneous urticaria, chronic idiopathic urticaria, urticaria, antihistamines, biologics, omalizumab, monoclonal, anti-IgE antibody, up-dosing

Introduction

Urticaria is a common, mast-cell-driven disease, characterized clinically by the development of wheals, angioedema, or both. Histamine and other inflammatory mediators, including leukotrienes and prostaglandins, are considered major players in the development of symptoms. Intermittent urticaria and angioedema lasting greater than 6 weeks is defined as chronic urticaria and differentiates it from acute urticaria. The prevalence of chronic urticaria in the general population has been estimated to range between 0.5-1%.1 Chronic urticaria has been shown to decrease quality of life and negatively impact performance at work and school. It has also been associated with increased levels of anxiety and depression, independently affecting quality of life.2,3 Although self-limiting, the disease course can last longer than 5 years in an estimated 10-25% of people affected.4 As such, current management aims to improve quality of life and reduce impairment through symptom relief. Urticaria guidelines have promoted changes in the classification, approach to diagnosis, and management of chronic urticaria. These evidenced based guidelines are updated every 4 years by a joint initiative of the European Academy of Allergy and Clinical immunology (EAACI) Dermatology Section, Global Allergy and Asthma European Network (GA2LEN), the European Dermatology Forum (EDF), the World Allergy Organization (WAO), and by the Canadian Society of Allergy and Clinical Immunology (CSACI). The most recently proposed guidelines were updated and presented at the URTICARIA 2016, GA2LEN Global Urticaria Forum: 5th Guideline Consensus Conference in Berlin in December 2016.5 These updates and revisions reflect the work and collaboration made by a group of 43 international experts representing 40 societies from 25 countries. This review will summarize the current proposed consensus guidelines for the treatment algorithm of chronic urticaria. These guidelines have yet to be published and will require approval by respective national and international boards before adoption.

Classification

Urticaria can be arbitrarily divided into an acute condition wherein wheals, angioedema or both last less than 6 weeks versus a chronic process wherein wheals, angioedema or both last greater than 6 weeks. Generally, acute urticaria may be associated with identifiable causes, most notably an acute viral infection or an allergic reaction to medications, insects or foods. Alternatively, chronic urticaria can be further subdivided into two groups based on whether an inducible cause can be identified; induced urticaria and chronic spontaneous urticaria.6-8

It should be noted that urticarial-related disease such as Schnitzler’s syndrome, Gleich’s syndrome, Well’s syndrome, bradykinin-mediated angioedema, cutaneous mastocytosis, and urticarial vasculitis are not considered subtypes of urticaria as they reflect distinctly different pathophysiology.

Diagnosis

A thorough history is the critical component of any initial patient evaluation, urticaria being no exception. Duration and frequency of intermittent symptoms will help establish chronicity of disease, whereas duration of individual urticarial lesions can help distinguish underlying pathogenesis, i.e. lasting greater than 24 hours would suggest vascular component rather than an immunoglobin E (IgE)-mediated phenomenon. When patients report identifiable triggers that would suggest chronic inducible urticaria, i.e., cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticarial, or aquagenic urticaria, specific provocation and threshold testing should be performed. If chronic spontaneous urticaria is suspected, initial blood work should be limited to complete blood count with differential and erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Omission of suspected drugs [e.g., nonsteroidal antiinflammatory drugs (NSAIDS)] should also be trialed. The American Joint Task Force on Practice Parameters (JTFPP) also include liver enzymes, renal function and thyroid-stimulating hormone (TSH) testing in their initial workup and recommends these laboratory investigations for all patients presenting with chronic spontaneous urticaria. Unless strongly suggested by history, extensive and costly screening programs for causes of urticaria are not recommended, which could include investigating for underlying infectious etiology (e.g., Helicobacter pylori), type I allergy, functional autoantibodies, thyroid hormones and autoantibodies, pseudoallergen-free diet for 3 weeks, tryptase, autologous serum skin test, and lesional skin biopsy (Table 1).9-12

Investigations
Recommended routine investigations
  • History and physical examination
  • CBC and differential
  • ESR or CRP
  • Omission of suspected drugs (e.g., NSAIDs)
  • Provocation and threshold test
  • Liver enzymes, TSH, renal function
  • Extended diagnostic tests
  • Only if indicated on history and physical

Extended diagnostic tests

  • Only if indicated on history and physical
Table 1: Step-wise approach to the diagnosis of chronic urticaria according to the updated and revised 2016 guidelines by a joint initiative of the EAACI Dermatology Section, GA2LEN, EDF, WAO, and CSACI.
CBC = complete blood count; ESR = erythrocyte sedimentation rate;
CRP = C-reactive protein; NSAIDs = nonsteroidal anti-inflammatory
drugs; TSH = thyroid-stimulating hormone

Management

Prevention of mast-cell degranulation through blockade of histamine on H1-receptors remains the mainstay of treatment for chronic urticaria. Modern second-generation non-impairing, non-sedating H1-antihistamines have been widely adopted as first-line treatment of chronic urticaria and have essentially replaced older first-generation antihistamines (Figure 1). They are effective and safe and do not possess the significant anticholinergic and sedating side effects that plague the first-generation antihistamines. Furthermore, current guidelines recommend against the use of first-generation H1-antihistamines in the treatment of chronic urticaria, especially in the pediatric and geriatric populations, given their side effect profile.6,7

If adequate control is not attained after 2-4 weeks or earlier if symptoms are intolerable, a trial of up to a fourfold increase in the standard therapeutic dose of modern second generation H1– antihistamine is suggested. This has been proven to be safe and effective and is preferred over alternative treatments as second-line treatment based on recommendations by the updated and revised international guidelines.5,6,13-15 First generation H1-antihistamines are not recommended, but can still be used as adjunct therapy. H2-antihistamines are not recommended as first-, second- or third-line therapy.6,8,15-17 Similarly, antidepressants with potent H1– and H2-antagonism, such as hydroxyzine or doxepin, are not recommended given their sedating and anticholinergic nature, as well as the multiple drug-drug interactions.18,19

The third-line treatment for resistant chronic urticaria, i.e., inadequate control after 2-4 weeks or earlier if symptoms are intolerable, includes the addition of omalizumab, an anti- IgE humanized monoclonal antibody (Figure 1).1,5,6 In large, randomized, double-blind, placebo-controlled trials, omalizumab has been demonstrated to be efficacious, safe, and well-tolerated. 20-24 Omalizumab has been shown to have few side effects and requires minimal ongoing monitoring. Omalizumab should be trialed for 6 months, unless symptoms are intolerable, before moving on to fourth-line therapy, cyclosporin A. Although trials using cyclosporin A have shown promising results when treating refractory chronic urticaria, continuous monitoring of blood pressure, renal function, serum drug levels, and other metabolic factors is important, in order to avert possible toxicity.25,26 It is important to note that leukotriene receptor antagonists are no longer in the treatment algorithm for chronic spontaneous urticaria.5

At any stage of the disease, a short course of an oral corticosteroid could be added for treating acute exacerbations. Long-term treatment with corticosteroids should be avoided (Figure 1).7,13,27

Use of other pharmacologic agents, such as sulfasalazine, hydroxychloroquine, colchicine, tacrolimus, mycophenolate mofetil, intravenous immunoglobulin, and dapsone have been used in the treatment for chronic urticaria with inconsistent results. These agents have limited utility because of their side effect profile, modest benefit seen in clinical trials, or lack of available data.6,27,28

Chronic Urticaria: Following Practice Guidelines - image
Figure 1. Step-wise approach to the management of chronic urticaria according to the updated and revised 2016 guidelines by a joint initiative of the EAACI Dermatology Section, GA2LEN, EDF, WAO, and CSACI.

Conclusion

National and international guidelines recommend avoidance of intensive and costly general screening for causes of urticaria, relying largely on history, physical examination, and appropriate follow-up. Recently updated and revised international guidelines suggest a step-wise approach to the management of chronic spontaneous urticaria. These proposed recommendations have yet to be published but represent a framework for further review by respective national and international boards before adoption. In sum, these guidelines suggest that first-line therapy includes second-generation non-impairing, non-sedatingH1-antihistamines. If no response by 2-4 weeks, up-dosing with second-generationH1-antihistamines, up to fourfold increase, has been widely adopted as a safe and efficacious second-line therapy when treatment is inadequate with standard therapeutic dosages. A large body of data has demonstrated that omalizumab, a biologic agent, is safe and effective in the treatment of H1– antihistamine refractory urticaria and should be considered as a third-line agent, with cyclosporin A reserved for fourth-line therapy.

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