Consensus on the diagnostic and therapeutic management of chronic spontaneous urticaria in adults - Brazilian Society of Dermatology*



# Introduction
Urticaria is characterized by the rapid onset of hives (edema in superficial dermis), which may be accompanied by angioedema

## Classification 5
Chronic urticaria (CU) is subdivided into two types: "chronic spontaneous urticaria" (CSU, which is represented by urticaria with hives and/or angioedema of spontaneous onset, with an evolution of over 6 weeks, due to a known cause, such as autoreactivity, resulting from mast cells that are activated by autoantibodies, or unknown causes) and "induced urticarias" (symptomatic dermographism, cold urticaria, delayed pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, and aquagenic urticaria).
In this classification, conditions or diseases that may manifest with urticaria or angioedema, such as urticarial vasculitis, urticaria pigmentosa, autoinflammatory syndromes (in general, periodic syndromes cryopyrin-associated or Schnitzler syndrome), exercise-induced anaphylaxis, Gleich syndrome (episodic angioedema with eosinophilia), Wells syndrome (eosinophilic cellulitis), bullous pemphigoid prior to bullous lesions, angioedema mediated by non-mast cell mediators (in general, bradykinin-mediated angioedema), and other similar diseases, are not considered urticaria subtypes due to their different pathophysiological mechanisms. 5 DIAGNOSTIC APPROACH TO CHRONIC URTICARIA [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] The diagnostic approach was recommended to meet three main objectives: (i) to exclude differential diagnoses, (ii) to assess di- screening for infectious agents (e.g., Helicobacter pylori); 3. thyroid diseases (thyroid hormones and autoantibodies); 4. allergy (intradermal tests and tests to exclude allergens, in general, restriction diet); 5. presence of associated induced-urticaria; 6. associated systemic disease (e.g., serum tryptase levels); and 7. others (e.g., histopathology of skin lesion). [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] The frequency and relevance of infections vary considerably between patient groups and different areas. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Exclusion of malignancies with examinations is indicated only if the patient's history impli-cates this possibility (in general, sudden and relevant weight loss). [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Plasma D-dimer levels are significantly higher in patients with active CSU and decrease according to the clinical response to treatment with omalizumab. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] The recommendation on measuring D-dimer levels in all patients with CSU is still debated. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] CSU activity may be evaluated using a simple unified validated system, the UAS7 score. 4,5 UAS7 is based on the evaluation of key properties of urticaria, its signs (hives), and its symptoms (pruritus), which are documented by the patient. 5 UAS7 consists of self-assessment over a 24-hour period once a day for several days, with summing the daily scores over 7 days. Maximum score each for daily hives and symptom intensity is 3, yielding a daily total score of between 0 and 6 and a weekly score of between 0 and 42 (Chart 1 and [fig_ref] FIgure 1: Urticaria activity score for seven consecutive days [/fig_ref]. UAS7 should be performed in the week prior to medical consultation.

## Evaluation of impact of csu activity and its control
It is a valuable tool for clinical evaluation of CSU .
The urticaria control test (UCT), in addition to UAS7, has become important in assessing the impact of the disease on quality Severe (>50 hives/24 hours or large confluent areas of hives) Intense *Sum of scores (hives + pruritus) = (0-6). of life and disease control, both in clinical practice and in research protocols. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] UCT was developed and validated to determine the level of disease control for all forms of urticaria (CSU and induced urticaria), because UAS does not evaluate angioedema or induced urticarias. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] UCT is composed of only four items, defining the limit between "well-controlled disease" and "poorly controlled disease;" thus, it is usable in clinical practice, with a cutoff point for "well--controlled disease" ranging from 12 and 16. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] The score varies from 0 to 16 and higher values reflect better disease control. It is an instrument that helps guide therapeutic decisions. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] UCT is under validation in Brazil by the Department of Allergy and Immunology of UFRJ, and the Portuguese version is described in chart 2. In order to eliminate an underlying cause, an accurate diagnosis is necessary. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] The identification of a cause for CU, however, is difficult in most cases; for example, with infections, which may be a cause or an aggravating factor or have no relation to CU. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] The only definitive proof of the causal nature of a suspected or triggering agent is the remission of symptoms following its removal and their recurrence following re-exposure in a double-blind challenge. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] In practice, this approach is often not feasible. Spontaneous remission of urticaria may occur over time. Urticaria may go into remission with the elimination of a suspected cause or triggering factor coincidentally, without any cause-effect relationship. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Pharmacological treatment of CSU has, as main goal, to relieve symptoms by reducing the effects of mast cell mediators, such as histamine and platelet-activating factor (PAF) and others, on target organs and tissues. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Many symptoms of urticaria are mediated primarily by the actions of histamine on H1 receptors on endothelial cells (resulting in hives) and sensory nerves (neurogenic erythema and pruritus). [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Thus, continuous treatment with antihistamines is fundamental in the treatment of urticaria; safety data are available for continuous use over several years. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Other mast cell mediators (PAF, leukotrienes, and cytokines) may be involved, and a pronounced cellular infiltrate, including basophils, lymphocytes, and eosinophils, can be seen in the lesions. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] These patients may respond completely to a brief course of corticosteroids and be relatively refractory to antihistamines. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] First-generation antihistamines have prominent anticholinergic effects and sedative actions on the central nervous system (CNS) and have many interactions with alcohol and drugs that affect the CNS, such as analgesics, hypnotics, sedatives, and mood--altering substances. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] They can interfere with rapid eye movement sleep (REM sleep) and impact learning and cognitive performance. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Interference with the CNS is observed especially in multiple concurrent tasks and the performance of complex sensorimotor tasks, such as driving vehicles, [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Although antihistamines achieve CSU control when used at up to 4-fold the licensed doses, in many patients with CSU, alternative treatments may be required. Before changing the treatment to alternative therapies (adjuvants), it is recommended to wait 1-4 weeks to achieve complete effectiveness of the drugs that are in use. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Because the severity of urticaria may vary and because spontaneous remission may occur over time, therapeutic re-evaluation of the need for continued treatment or a separate or adjunctive treatment is also recommended every 3 to 6 months. 5

## Management of patients with

## Third-line pharmacological treatment:
In recent years, the use of biological agents for urticaria, particularly omalizumab, has become more prominent as a third-line agent in chronic urticaria that is refractory to initial approaches (first-and second-lines of treatment). [bib_ref] Treatment of refractory chronic urticaria: current and future therapeutic options, Asero [/bib_ref] thus, the decision to discontinue treatment should be individualized.
The proposed mechanism of action for this drug is based on the finding that when there are high circulating IgE levels in the blood, mast cells and basophils express higher amounts of FcRI receptors on their membranes, becoming vulnerable to binding with anti-FcRI IgG autoantibodies. Doses of omalizumab in CSU independent of serum IgE levels. The approved doses, and the treatment duration may vary by country. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] In Brazil, omalizumab was approved for CSU in children aged over 12 years, at 300 mg subcutaneously every 4 weeks for 6 consecutive months.

## Treatment of exacerbations
Oral corticosteroids, particularly prednisone at doses of 20-50mg per day, may be necessary for short periods of use (7 days, maximum 10 days) for significant exacerbations of chronic urticaria that does not respond completely to antihistamines or for sporadic episodes of exacerbation. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Prolonged use should be avoided due to the side effects and development of comorbidities. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Their use should be avoided for more than 7 days each month. There is a strong recommendation for only using systemic corticosteroids under specialist supervision in the treatment of CSU. 5

## Fourth-line pharmacological treatments
Despite the absence of strong published scientific evidence, all fourth-line drugs may be valuable for patients in certain cases of refractoriness in the earlier stages, in the appropriate clinical settings. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] In patients with severe disease and persistent progression, with treatment failure to previous measures, cyclosporine therapy Adaptaded from is an option to refractory CSU. Cyclosporine acts by inhibiting IL-2 production in lymphocytes. In urticaria, it is believed that an additional mechanism of action is its reduction of immunoglobulin production and reduction of the high-affinity IgE receptor. It has been studied in cohorts and placebo-controlled studies at doses of 1 to 5mg/kg/day. The effective dose in chronic urticaria appears to be 3 mg/kg/day for periods of 8 to 16 weeks, yielding success rates of 64% to 95%. [bib_ref] Treatment with omalizumab or cyclosporine for resistant chronic spontaneous urticaria, Koski [/bib_ref] [bib_ref] Cyclosporine for Chronic Spontaneous Urticaria: A Meta-Analysis and Systematic Review, Kulthanan [/bib_ref] It is important to emphasize that before use, patients should perform blood pressure measures and evaluate renal function, magnesium, uric acid, and potassium; these tests should be repeated periodically. [bib_ref] Treatment with omalizumab or cyclosporine for resistant chronic spontaneous urticaria, Koski [/bib_ref] Side effects appear to be dose-dependent and occur in more than half of all patients who are treated with moderate doses (4 to 5mg/kg/day). 21

## Other treatments
Other non-licensed medications should be used in patients in whom previous steps of treatment failed. They have a low level of recommendation and have only been presented in case reports and studies of small series. 5 a) Anti-inflammatory drugs: dapsone, colchicine, and montelukast are medications that present clinical studies with low scientific evidence. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] [bib_ref] Urticaria unresponsive to antihistaminic treatment: an open study of therapeutic options based..., Criado [/bib_ref] [bib_ref] Double-blind placebocontrolled trial of dapsone in antihistamine refractory chronic idiopathic urticaria, Morgan [/bib_ref] [bib_ref] Treatment of chronic urticaria with colchicine, Pho [/bib_ref] Montelukast showed good response in 20% to 50% of patients who did not responded to therapy with antihistamines alone. [bib_ref] Chronic urticaria: a role for newer immunomodulatory drugs?, Tedeschi [/bib_ref] Reeves et al. [bib_ref] Impact of hydroxychloroquine therapy on chronic urticaria: chronic autoimmune urticaria study and..., Reeves [/bib_ref] studied 18 CU patients who had been treated with hydroxychloroquine for 12 weeks, noting disease control and improved quality of life. This drug is relatively safe, but the possibility of retinopathy should be monitored.

## B)
Other Immunosuppressants -Methotrexate has been used at a mean weekly dose of 15 mg. [bib_ref] Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria, Sagi [/bib_ref] This drug has anti-inflammatory and immunomodulatory properties, and its mechanism of action comprises an increase in adenosines, apoptosis of CD4 lymphocytes, and inhibition of neutrophil chemotaxis. [bib_ref] Evidence for methotrexate as a useful treatment for steroid-dependent chronic urticaria, Sagi [/bib_ref] [bib_ref] Methotrexate: a useful steroid-sparing agent in recalcitrant chronic urticaria, Perez [/bib_ref] -Other oral drugs, with immunomodulatory and immunossupressive effects, such as sulfasalazine, mycophenolate mofetil, azathioprine, cyclophosphamide, and tacrolimus. are available for use in CSU. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] There are no controlled studies, with relevant number of patients and efficacy; they mau be used as alternatives on failure with conventional therapy. 5 c) Other Immunobiologicals: -Anti-tumor necrosis factor (TNF) medications are indicated in CU due to increased production of TNF, implicated in the pathogenesis of the disease. Etanercept, infliximab, and adalimumab have been used in case reports and small series for various types of urticaria. [bib_ref] Biologics in chronic urticaria, Ferrer [/bib_ref] -Interleukin 1 antagonists (anti-IL-1: canakinumab, anakinra), although formally indicated for autoimmune diseases, have been used in urticaria due to inflammatory cytokine production in the disease. [bib_ref] Biologics in chronic urticaria, Ferrer [/bib_ref] Canakinumab is under investigation in a placebo-controlled study, but the results have not been made available. [bib_ref] Biologics in chronic urticaria, Ferrer [/bib_ref] -Rituximab (anti-CD20) is a chimeric monoclonal antibody against CD20, expressed on B cells, that decreases autoantibody production. The recommended dose is 375mg/m 2 . There are few case reports using this drug. [bib_ref] Biologics in chronic urticaria, Ferrer [/bib_ref] -Intravenous immunoglobulin (IVIg) is an IgG purified polyclonal preparation derived from the plasma of several donors.
In urticaria, IVIg has an immunomodulatory effect decreasing IgG anti-FcRII and IgG anti-IgE. [bib_ref] Biologics in chronic urticaria, Ferrer [/bib_ref] 

## Second-line of treatment
As second-line of treatment up-dosing (up to 4-fold) of second-generation antihistamines is indicated; furthermore, add other sgAH, H2-antagonists, anti-leukotriene (montelukast) or first-generation antihistamines at bedtime.

## Third-line treatment
If there is no control with the previous steps, hydroxyzine or doxepin are indicated, as third-line treatment.

## Fourth-line treatment
As fourth-line of treatment, omalizumab or cyclosporine are indicated, as well as, other anti-inflammatory drugs, immunossupressants ou immunobiological drugs (dapsone, sulfasalazine, hydroxychloroquine, coclchicine, tacrolimus, mycophenolate mofetil, sirolimus, cyclophosphamide, methotrexate, IVIg, anti-TNF, anti-IL-1 receptor and anti-CD20. 31 [fig_ref] FIgure 3: Differences between the Internacional and US Guidelines in CSUAdapted from [/fig_ref] shows the differences between the Internacional and US Guidelines in CSU. 32

## Pregnancy and lactation
Regarding treatment during gestation, to date, there are no reports of congenital defects in women who have used second-generation anti-H1 antihistamines during pregnancy. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] However, few studies are available regarding the use of cetirizine, [bib_ref] The safety of cetirizine during pregnancy. A prospective observational cohort study, Weber-Schoendorfer [/bib_ref] and a large meta-analysis has examined the use of loratadine. [bib_ref] Risk of hypospadias in offspring of women using loratadine during pregnancy: a..., Schwarz [/bib_ref] Loratadine is metabolized in the liver, whereas desloratadine is not. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Due to safety profile, the preferred second-generation anti-histamines in pregnacy are loratadine, (with possible extrapolation to desloratadine) and cetirizine (with possible extrapolation to levocetirizine). 5 All anti-H1 antihistamines are excreted in human milk at low concentrations. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] First-generation anti-H1s should be avoided during breastfeeding. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] Omalizumab use in pregnancy has shown no evidence of maternal or fetal harm. [bib_ref] The EAACI/GA(2)LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria, Zuberbier [/bib_ref] For the evaluation of CSU activity, 62% of participants indicated the use of the UAS-7 form but noted inadequate comprehension and completion by many patients with CSU.

# Conclusions

## Other adjuvant drugs are available for off-label use in
Brazil; thus, they may be useful and necessary for refractory cases of CSU, with strict clinical and laboratory monitoring and information of the possible benefits and risks when using them.q
[fig] FIgure 1: Urticaria activity score for seven consecutive days (UAS7) [/fig]
[fig] URTICARIA 5: Three basic considerations are proposed in the treatment of these patients: a)The goal is to treat urticaria until it enters remission b)The therapeutic approach involves several aspects, such as: should follow the basic principles of treating as much as necessary and as little as possible; e.g., advancing in steps or retroactively in stages in the therapeutic escalation according to the course of disease. [/fig]
[fig] FIgure 2: Treatment scheme proposed by the 2018 International Urticaria Guideline [/fig]
[fig] First: -line treatment The US Guideline for CSU, published in 2014, indicates use of second-generation anti-histamines (sgAH) at licensed doses as first-line of treatment. [/fig]
[fig] FIgure 3: Differences between the Internacional and US Guidelines in CSUAdapted from: Zuberbier, et al, 2018. 32 [/fig]
[table] table 1: Treatment of chronic spontaneous urticaria (CSU): Brazilian Society of Dermatology 2018 Most requested laboratory tests Blood count, ESR, CRP, free T4, TSH 50% Stool Parasitologic Examination, thyroid autoantibodies, D-dimer, hepatitis serologies, ANA, complement, IgE, hepatic enzymes <50% Indicates histopathological examination if urticaria vasculitis is suspected? SCU: spontaneous chronic urticaria; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; TSH: thyroid stimulating hormone; ANA: antinuclear antibody; IgE: immunoglobulin E; AH: antihistamines; *8/16 of specialists use a combination of treatment protocols. preservatives should be avoided; 75% questioned patients about perimenstrual aggravation (autoimmune progesterone dermatitis in the differential diagnosis); 13% inquired about the possibility of infestation by Toxocara canis (toxocariasis) due to the presence of domestic animals; and 94% considered the association with other general symptoms, such as fever and arthralgia. [/table]