Chronic Urticaria: Following Practice Guidelines (Family Practice)

Erin P. Westby MD¹, Charles Lynde MD, FRCPC^2-4, Gordon L. Sussman MD, FRCPC, FACP, FAAAAI^4-6

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

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. It has also been associated with increased levels of anxiety and depression.^2,3 Although self-limiting, the disease course can last longer than 5 years in an estimated 10-25% of people affected.⁴

Urticaria 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: 5^th Guideline Consensus Conference in Berlin in December 2016.⁵ These updates reflect the collaboration made by a group of 44 international experts, representing 42 societies from 25 countries. This review will summarize the current consensus guidelines for the treatment algorithm of chronic urticaria.

Classification

• Urticaria can be arbitrarily divided into an acute condition wherein wheals, angioedema or both last less than 6 weeks versus a chronic process.
• Generally, acute urticaria may be associated with identifiable causes, most notably an acute viral infection or an allergic reaction to medications, insects or foods.
• 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

Diagnosis

• 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 urticaria, or aquagenic urticaria, specific provocation and threshold testing should be performed.
• Omission of suspected drugs [e.g., nonsteroidal anti-inflammatory drugs (NSAIDS)] should be trialed.
• 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).
• 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

Table 1. Step-wise approach to the diagnosis of chronic urticaria
according to the updated and revised 2017 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 such as bilastine (BLEXTEN^®) have been widely adopted as first-line treatment of chronic urticaria (Figure 1). They are effective and safe and do not possess the significant anticholinergic and sedating side effects.
• 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
• A trial of up to a fourfold increase in the standard therapeutic dose of modern second-generation H₁– antihistamine is suggested if adequate control of urticaria is not attained after 2-4 weeks or earlier if symptoms are intolerable.^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
• 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
• 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
• The third-line treatment for resistant chronic urticaria includes the addition of omalizumab, an anti- IgE humanized monoclonal antibody (Figure 1).^1,5,6,20-24 Omalizumab has been shown to have few side effects and requires minimal ongoing monitoring. Omalizumab should be trialed for 6 months 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
• 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 limited utility because of their side effect profile, modest benefit seen in clinical trials, or lack of available data.^6,27,28

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.
• In summary, these guidelines suggest that first-line therapy should be second-generation non-impairing, non-sedating H₁-antihistamines such as bilastine (BLEXTEN^®).
• If no response by 2-4 weeks, up-dosing with second-generation H₁-antihistamines, up to fourfold increase, has been widely adopted.
• 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.
• Cyclosporin A is reserved for fourth-line therapy.