Recent updates in urticaria | Medicina Clínica

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Giménez-Arnau, Nerea Manzanares, Indrashis Podder" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Ana M." "apellidos" => "Giménez-Arnau" "email" => array:2 [ 0 => "anamariagimenezarnau@gmail.com" 1 => "22505aga@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Nerea" "apellidos" => "Manzanares" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Indrashis" "apellidos" => "Podder" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:2 [ 0 => array:3 [ "entidad" => "Department of Dermatology, Hospital del Mar-IMIM, Universitat Pompeu Fabra de Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Dermatology, College of Medicine and Sagore Dutta Hospital, Kolkata 700058, West Bengal, India" "etiqueta" => "b" "identificador" => "aff0010" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Actualización en urticaria" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:2 [ 0 => array:1 [ "imagen" => "gr2a.jpeg" ] 1 => array:1 [ "imagen" => "gr2b.jpeg" ] ] "descripcion" => array:1 [ "en" => "(a) Schematic diagram showing diagnostic approach for urticaria and (b) schematic diagram showing treatment of urticaria." ] ] ] "textoCompleto" => "IntroductionUrticaria is a common dermatological disorder characterized by sudden and unpredictable pruritic wheals, angioedema or both. A wheal indicates a transient or evanescent erythematous well-circumscribed swelling of variable shape and size, disappearing within 24h. Angioedema refers to erythematous or skin-colored deep swelling preferentially involving areas with loose skin, e.g. eyelids, lips, genitalia and tongue, more burning than pruritic, with slower resolution than wheals, approximately 72–96h.<a class="elsevierStyleCrossRef" href="#bib0225">1</a>The global lifetime prevalence of all types of urticaria is approximately 3%–22%, which been increasing over the years.<a class="elsevierStyleCrossRef" href="#bib0230">2</a> The prevalence is heterogeneous across the world – higher in Latin America and Asia, and lower in North America.<a class="elsevierStyleCrossRef" href="#bib0235">3</a> This geographic variability is poorly explained, and more global studies are needed.Classification and epidemiologyUrticaria can be classified according to (a) duration and (b) presence or absence of definite triggers.Based on symptom duration, two types exist – acute and chronic urticaria. Acute urticaria refers to symptom duration 6 weeks or less, while persistent symptoms >6 weeks indicate chronic urticaria (CU). In CU symptoms can occur daily or almost daily, or recur intermittently following variable periods of remission.<a class="elsevierStyleCrossRef" href="#bib0225">1</a>Based on triggering factors, urticaria can be spontaneous or inducible, indicating their absence or presence respectively. Acute urticaria is mostly spontaneous, however some factors may aggravate it in selected patients, e.g. infections, drugs and foods.<a class="elsevierStyleCrossRef" href="#bib0240">4</a> CU can be spontaneous or induced. In chronic spontaneous urticaria (CSU) itchy wheals and/or angioedema develop unpredictably without any specific trigger (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>a). The cause of CSU may be known (type I or type IIb autoimmunity) or unknown. In contrast, specific triggers are a prerequisite for chronic inducible urticaria (CIndU), and they range from physical to non-physical stimuli such as symptomatic dermographism (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>b), pressure, vibration, internal or external thermal variation (cholinergic stimulation, heat or cold), sunlight, water and contact with certain substances. The CIndUs can be confirmed by provocation and threshold tests, based on suspected triggers. Notably, some CSU patients may experience symptomatic exacerbation by certain triggers, but they are not specific as symptoms can occur in their absence (spontaneously) and triggers do not always cause symptoms.<a class="elsevierStyleCrossRef" href="#bib0225">1</a> Interestingly, some patients may present with more than one urticaria sub-type, e.g. concomitant CSU and CIndU, and cold-induced cholinergic urticaria.<a class="elsevierStyleCrossRef" href="#bib0245">5</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>A recent systematic review has reported the overall life-time prevalence of acute and chronic urticaria as 3%–22%, 4.4%, respectively. The point-prevalence is variable, ranging from 1.5% (USA and Europe) to 4% (Asia and Latin America).<a class="elsevierStyleCrossRef" href="#bib0230">2</a> Acute urticaria is predominant in children <5 years, while CU frequently affects middle-aged women.<a class="elsevierStyleCrossRef" href="#bib0250">6</a> CSU is most common variant of CU, encompassing 60%–90% cases. Among the CIndUs, symptomatic dermographism iscommonest, followed by CholU and ColdU.<a class="elsevierStyleCrossRef" href="#bib0240">4</a> Notably, CU prevalence has been increasing in children (about 1%) and is more common than previously thought.<a class="elsevierStyleCrossRef" href="#bib0235">3</a> Interestingly, urticaria improved during pregnancy in 51% patients, while it worsened and remained unchanged in 29% and 20% patients respectively.<a class="elsevierStyleCrossRef" href="#bib0255">7</a> Maximal CU exacerbation was reported during third trimester (27.6%) followed by first trimester (22.8%). Untreated CU, CIndU, absence of angioedema, history of worsening during previous pregnancy and stress are risk-factors for CU worsening during pregnancy.<a class="elsevierStyleCrossRef" href="#bib0255">7</a>Despite being non-lethal, CU considerably impairs the patients’ quality of life and poses a significant burden for society. Concomitant angioedema and/or inducible urticaria are significant risk-factors for worsening HRQoL (health related quality of life). Several life-quality aspects are affected such as sleep disorders; sexual dysfunction; limitations on daily life, work and sports activities; interactions within the family and society; and patients’ performance at school and work (6% absenteeism and 25% presentism). Additional psychiatric co-morbidities such as depression and anxiety have been reported in ∼30% CSU patients.<a class="elsevierStyleCrossRef" href="#bib0260">8</a> Children with CU also increase their parental stress and adversely affect their quality of lives.<a class="elsevierStyleCrossRef" href="#bib0265">9</a>PathogenesisUrticaria is primarily mediated by dermal and subcutaneous skin mast cells (MCs), along with perivascular (around small skin venules) and perineural heterogeneous cellular infiltrate comprising CD4 T-lymphocytes (Th2>Th1/Th17), neutrophils, eosinophils, basophils, and monocytes.<a class="elsevierStyleCrossRef" href="#bib0270">10</a> Activated MCs degranulate to release several pre-formed and newly synthesized mediators such as histamine (most important), platelet activating factor (PAF) and diverse cytokines viz. IL-6, IL-5 and IL-13.<a class="elsevierStyleCrossRef" href="#bib0225">1</a> These mediators promote vasodilatation, increase vascular permeability, stimulate sensory nerves, activate the coagulation cascade (factor Xa and IIa [thrombin]) and complement system (C3a and C5a), and recruit other inflammatory cells like basophils, eosinophils and T-cells. Additionally, endothelial cytokines, e.g. VEGF promote the dermal chemotaxis of mast cells and participate in pathogenesis.<a class="elsevierStyleCrossRefs" href="#bib0235">3,10</a> All these factors engage in a bi-directional cross-talk collectively resulting in urticarial lesions.<a class="elsevierStyleCrossRef" href="#bib0235">3</a> The pathogenesis of different urticaria subtypes is briefly discussed below.Acute urticariaAcute urticaria may develop spontaneously, or as a presenting feature of anaphylaxis. In both cases, immediate type I hypersensitivity reaction to exo-allergens such as foods, drugs or other allergens is incrimated. These exo-allergens bind to IgE-FceR1 complex on MCs and basophils resulting in their degranulation and subsequent symptoms.<a class="elsevierStyleCrossRef" href="#bib0240">4</a> NSAID induced urticaria may involve T-cells and increased levels of cysteinyl leukotrienes.<a class="elsevierStyleCrossRef" href="#bib0240">4</a> Acute contact urticaria may develop following direct contact with urticariogenic substances, with or without prior sensitization, e.g. stinging nettles.<a class="elsevierStyleCrossRef" href="#bib0275">11</a>Chronic spontaneous urticariaRecently, two autoimmune pathways have been identified to trigger MC degranulation in CSU, the basis for endotypic classification. Currently, two endotypes have been characterized – Type I autoimmunity/autoallergy (auto-allergens such as TPO, IL-24, TG and tissue factor cross-link IgE autoantibodies on MCs and basophils) and Type IIb autoimmunity (IgG autoantibodies against FceR1>IgE).<a class="elsevierStyleCrossRefs" href="#bib0235">3,4</a> Recently, anti-FceR1 IgM and IgA autoantibodies have been detected in type IIb endotype.<a class="elsevierStyleCrossRef" href="#bib0280">12</a> Type IIb endotype is associated with longer disease duration, higher disease activity and higher prevalence of autoimmune comorbidities. These patients have more frequent basopenia, eosinopenia, higher CRP, positive ASST and positive BAT. Although Omalizumab improves both endotypes, type I endotype (high baseline IgE) is a marker for more favorable and faster response. Type IIb autoimmune CSU patients are more-often slow – or non-responders to Omalizumab, and Cyclosporine seems more effective.<a class="elsevierStyleCrossRef" href="#bib0285">13</a> The recent PURIST study detected true type IIb autoimmunity in only 8% patients – triple positive for IgG-anti FceR1/IgE, BAT and ASST, and proposed high IgG-anti-TPO/IgE ratio as the most suitable surrogate marker for type IIb endotype.<a class="elsevierStyleCrossRef" href="#bib0290">14</a> However, these two endotypes may co-exist in some patients as evidenced by detection of auto-IgE followed by auto-IgG antibodies along the disease course.<a class="elsevierStyleCrossRef" href="#bib0295">15</a>Recently researchers are exploring additional CSU endotypes based on their pathogenesis involving coagulation factors, MAS-related G protein coupled receptor X2 (MRGPRX2), alarmins and other signals.<a class="elsevierStyleCrossRefs" href="#bib0300">16–18</a> More work is needed to characterize these endotypes and elucidate their roles in disease pathogenesis. The role of infections is CSU is controversial. Viral infections such as HHV-6 and COVID-19 have been linked with acute exacerbations without any causal association.<a class="elsevierStyleCrossRefs" href="#bib0315">19,20</a> A recent meta-analysis has failed to demonstrate significant benefit with Helicobacter pylori eradication in majority CSU patients.<a class="elsevierStyleCrossRef" href="#bib0325">21</a> However, parasitic sensitization and infestation are significantly higher in CSU patients compared to healthy controls.<a class="elsevierStyleCrossRef" href="#bib0330">22</a>Chronic inducible urticariaThe pathogenesis of CIndU is unclear and scattered information is available regarding its subtypes. IgE-mediated mast cell activation (autoallergy) is implicated in symptomatic dermographism, ColdU, CholU and SolU and the proposed autoallergens include cold-induced activation of an epidermal protein (ColdU), chromophores stimulated by solar radiation (SolU) or sweat antigen leaked into dermis (CholU).<a class="elsevierStyleCrossRefs" href="#bib0335">23–25</a> Another proposed mechanism in CholU is the reduced expression of cholinergic receptor M3 in eccrine sweat glands and subsequent accumulation of acetylcholine, a mast cell degranulator.<a class="elsevierStyleCrossRef" href="#bib0345">25</a> Hereditary vibratory angioedema may have an autosomal dominant gain-of-function mutation of the ADGRE2 gene, thus making mast cells susceptible to vibration mediated degranulation.<a class="elsevierStyleCrossRef" href="#bib0350">26</a> Delayed pressure urticaria may have a non-immunologic pathogenesis, suggested by dense dermal leucocytic infiltration and pro-inflammatory mediators such as IL-1, IL-6, IL-3 and TNF-α.<a class="elsevierStyleCrossRef" href="#bib0355">27</a> Contact urticaria may either be immunologic (IgE or T-cell mediated) or non-immunologic.<a class="elsevierStyleCrossRef" href="#bib0360">28</a>Clinical approachUrticaria is essentially a clinical diagnosis presenting with itchy wheals and/or angioedema. Thus, detailed history and physical examination are indispensable. A step-wise algorithmic diagnostic approach is suggested (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>a).<elsevierMultimedia ident="fig0010"></elsevierMultimedia>In patients presenting with isolated angioedema, ruling out causative drugs, e.g. ACEIs, gliptins, etc. is the first step by eliciting drug history. Absence of drug history but positive family history should hint toward hereditary angioedema, which must be ruled out with further detailed investigations.In patients presenting with wheals±angioedema, one needs to enquire about concomitant fever/recurrent febrile episodes and/or joint pain or malaise to rule out autoinflammatory conditions. If there is no indication of autoinflammatory disease, one must enquire about the disease duration and average wheal duration. Urticaria can be classified acute or chronic based on disease duration <6 weeks or >6 weeks respectively. If the average wheal duration is >24h, urticarial vasculitis must be considered, and a skin biopsy is necessary for diagnostic confirmation. In patients with CU, one must enquire whether they can produce the wheals themselves or they occur on their own – to identify chronic inducible urticaria (CIndU) and chronic spontaneous urticaria (CSU), respectively.Recently, Turk et al.<a class="elsevierStyleCrossRef" href="#bib0365">29</a> have identified several phenotypic subgroups of CU patients, based on disease characteristics, underlying immunology and concomitant comorbidities. Four such phenotypic subgroups have been identified – Cluster 1 (‘CIndU only’ cluster characterized by highest age, shortest duration and lowest serum IgE), Cluster 2 (‘high IgE’ cluster – highest IgE, highest frequency of atopic comorbidities and lowest ANA and anti-TPO IgG positivity), Cluster 3 (‘autoimmune cluster’ – highest angioedema, second-lowest IgE and highest ANA and anti-TPO IgG positivity) and Cluster 4 (‘high comorbidity’ cluster – highest frequency of non-atopic comorbidities such as hypertension, diabetes mellitus and hypothyroidism). The phenotypic categorization of CU patients may facilitate better characterization of underlying patho-mechanisms and enable a targeted patient-oriented management.Role of biomarkersAnother emerging area of research is the use of several biomarkers to define disease characteristics such as activity or severity and disease course (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). An idea about these disease characteristics would help physicians counsel their patients appropriately in the early stages of their disease, eventually improving the physician-patient relationship and patient compliance to treatment. Additionally, some biomarkers are being investigated to predict the therapeutic response prior to initiation of actual therapy (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>). This would help in identifying patient subtypes based on these biomarkers, and provide targeted therapy to achieve maximum benefits with minimum adverse-effects.<a class="elsevierStyleCrossRefs" href="#bib0285">13,30–32</a><elsevierMultimedia ident="tbl0005"></elsevierMultimedia>Diagnostic work-upAlthough urticaria is primarily a distinct clinical diagnosis, detailed work-up is recommended in some cases, as discussed below.Acute urticariaNo laboratory investigations are recommended in acute urticaria due to its self-limited course. However, investigations may be needed if suggested by patient history, e.g. acute urticaria as a manifestation of food allergy (symptoms developing rapidly within 30min to 1h) or drug hypersensitivity especially due to NSAIDs. In such cases, allergy tests and patient education are needed to prevent re-exposure to causative agents.<a class="elsevierStyleCrossRef" href="#bib0225">1</a>Chronic spontaneous urticariaThe current guideline recommends the 7C approach for all CSU patients, which reflect the 7 aims.<a class="elsevierStyleCrossRef" href="#bib0225">1</a> The 7 Cs include confirming the diagnosis and ruling out differentials, exploring the cause by assessing endotype, identifying potential triggers or aggravators as co-factors, checking for co-morbidities, e.g. autoimmunity, CIndU and mental health disorders, exploring the consequences of disease, e.g. sleep disturbances, sexual health and disease burden, evaluating the disease components such as biomarkers of disease course and treatment response, and monitoring the disease course, i.e. CSU activity, control and impact. All CSU patients must undergo a detailed clinical history, physical examination, evaluation of disease activity, impact and control, and some laboratory tests. Clinical history also involves the review of patient photographs, as wheals are transient and may not be present during consultation. The laboratory tests may be categorized as basic/routine tests (to be performed on all patients) and some special tests which form a part of extended diagnostic program in special situations when suggested by history, e.g. ruling out differentials and identifying the disease endotype. <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> highlights the diagnostic work-up recommended in CSU patients.<elsevierMultimedia ident="tbl0010"></elsevierMultimedia>Chronic inducible urticariaMultiple provocation tests are available to confirm the various types of chronic inducible urticaria, e.g. cold provocation and threshold test (cold urticaria), pressure test (delayed pressure urticaria), using a pen or dermographometer to check the threshold for symptomatic dermographism, heat provocation tests (heat urticaria), threshold determination using UV and visible light (solar urticaria), treadmill or bicycle test (cholinergic urticaria), provocation testing (contact urticaria) and vortex (vibratory angioedema). Routine and extended diagnostic tests can be performed when necessary, as directed by history and examination.<a class="elsevierStyleCrossRefs" href="#bib0225">1,4</a>Role of Patient reported outcome measures (PROMs)The recent EAACI/GA(2) LEN/EuroGuiDerm/APAAACI guideline recommends the use of validated patient reported outcome measures (PROMs) to monitor disease activity, control and impact.<a class="elsevierStyleCrossRef" href="#bib0225">1</a> The assessment should be done at baseline and every follow-up visit to evaluate their therapeutic response. This would enable therapeutic modification based on patient response to achieve optimum treatment outcome. Some of the important PROMs and their utility are briefly discussed below.Assessment of disease activityThe Urticaria activity score 7 (UAS7) is the gold-standard for assessing disease activity in CU. It is a prospective 2-item self-evaluation questionnaire grading wheal and itch intensity over 7 days. Both wheal and itch are graded from 0 to 3, indicating minimum to maximum intensity respectively, and the scores are added for each day. The final UAS7 score is obtained by adding the daily scores for 7 consecutive days, ranging from 0 to 42. The disease activity is graded as – 0=no activity, <6=well controlled, 7–15=mild disease, 16–27=moderate disease and 28–42=severe disease. The grading is patient-documented, making this score especially valuable. The scoring helps to assess disease activity, therapeutic response and also facilitates comparison of study results from different centers. For patients developing angioedema, a similar Angioedema activity score (AAS) is available. Modified versions of the UAS are also available for inducible urticarias such as Cholinergic Urticaria Activity Score (CholUAS) and Cold Urticaria Activity Score (ColdUAS), but they are not yet validated.<a class="elsevierStyleCrossRefs" href="#bib0225">1,4</a>Assessment of disease controlThe disease control can be assessed by the validated Urticaria Control Test (UCT), both in CSU and CIndu. It is a retrospective questionnaire with a 4-week recall period. It consists of 4 questions each being graded from 0 to 4 in a Likert scale, thus obtaining the total score from 0 (minimum) to 16 (maximum) indicating worst and best controls respectively. The cut-off value is 12, UCT<12 indicates “poorly controlled” while UCT≥12 indicates “well-controlled” urticaria and complete control is indicated by UCT=16 (final goal of treatment in CU). Similarly, there is Angioedema control test (AECT) with two versions – one with a recall period of 4-weeks and another with recall period of 3-months; the cut-off value for well-controlled disease is 10.<a class="elsevierStyleCrossRef" href="#bib0225">1</a>Assessment of disease impactIt is important to assess the impact of disease on quality of life both in clinical practice and trials and it also affects the overall treatment outcome. The Chronic Urticaria-Quality of life (CU-Q2oL) questionnaire should be used for this purpose. For patients presenting with wheals, additional AE-QoL must be used.<a class="elsevierStyleCrossRef" href="#bib0225">1</a>All these PROMs are easy to use, score and interpret, and must be administered to all CSU patients for optimum management. These questionnaires are available in multiple languages to suit patients from various backgrounds.Differential diagnosesSeveral clinical conditions may present with wheals and/or angioedema, which form the differential diagnoses for urticaria. <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> enumerates some of the common differential diagnoses and their differentiating features.<elsevierMultimedia ident="tbl0015"></elsevierMultimedia>TreatmentUrticaria is a morbid condition, adversely affecting the patient's quality of life, and most cases of CU last for about 1–4 years. CIndUs have a longer duration, approximately ranging from 5 to 12 years. Relapses are also common, reported in about 6–31% CSU patients.<a class="elsevierStyleCrossRef" href="#bib0385">33</a> So, we should treat urticarias effectively to improve the patients’ quality of life, reduce their societal burden and reduce the disease comorbidities. We have categorized the therapeutic options under two heads – general/non-pharmacologic measures and specific/pharmacologic measures. Specific measures have been further subdivided into current treatment recommendations and emerging and investigational therapies. This section is intended to appraise readers about the currently available treatment options, and also make them aware about emerging therapeutic strategies for recalcitrant patients.General/non-pharmacologic measuresElimination of exogenous triggers, e.g. NSAIDs and cross-reacting agents constitute the most important general/non-pharmacologic measure for both acute and chronic urticarias, when suggested by history and intermittent course. One must also address other inciting factors such as infections, stress or any underlying condition such as malignancy, to achieve disease remission.<a class="elsevierStyleCrossRef" href="#bib0390">34</a> CIndUs, by definition, are triggered by specific factors, which must be eliminated/reduced to achieve resolution, but the avoidance may be difficult for patients and worsen their quality of life, e.g. avoiding hot temperatures in cholinergic urticarias.<a class="elsevierStyleCrossRef" href="#bib0240">4</a> So, these patients must be counseled adequately to minimize such triggers. Notably, urticaria does not improve in a subset of patients despite addressing their triggering/associated factors, e.g. H.pylori eradication in CSU and limited role of thyroid medications even in CSU patients with concomitant thyroid disorders.<a class="elsevierStyleCrossRefs" href="#bib0325">21,35</a> Thus, it is not recommended to perform the extended diagnostic tests in all CU patients, unless clinically indicated.Specific/pharmacologic measuresSeveral therapeutic options are being currently utilized for treating urticaria, while newer options are being investigated for inadequate responders to conventional therapy. The current and investigational therapies are briefly discussed below.Current treatment recommendationsAll current treatment guidelines recommend a 3-step algorithmic approach, where we start with the 1st step and gradually progress to the 2nd and 3rd steps if patients fail to respond to the preceding step in a timely and effective manner (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>b). These guidelines are applicable to both CSU and CIndU, and also in special populations including children, elderly (dose adjusted for weight) and pregnancy.First-stepAll guidelines recommend 2nd generation antihistamines (sgAHs) in standard-doses which may be up-dosed up to 4-times their standard dose, as the 1st line therapy.<a class="elsevierStyleCrossRefs" href="#bib0225">1,36</a> Almost all 2nd generation antihistamines have proven their safety and efficacy even when up-dosed to 4-times their standard does, such as cetirizine, levocetirizine, loratadine, desloratadine, fexofenadine, ebastine, rupatadine and bilastine.<a class="elsevierStyleCrossRef" href="#bib0405">37</a> A recent meta-analysis has reported higher risk of somnolence with up-dosed sgAHs, compared to their standard doses.<a class="elsevierStyleCrossRef" href="#bib0410">38</a> These drugs are affordable and act as inverse agonists blocking the effect of histamine via H1 receptors. The use of first-generation antihistamines is strongly discouraged by all guidelines, as they have multiple anti-cholinergic adverse-effects and drug interactions. The widely accepted EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline does not recommend additional montelukast or switching to another sgAH in non-responders, however these measures are considered by the British guideline for inadequate responders, before moving to the 2nd step.<a class="elsevierStyleCrossRef" href="#bib0400">36</a>Acute urticarias usually resolve with sgAHs alone and many cases are self-resolving, but almost 60% CU patients do not respond adequately to up-dosed sgAHs even after 2–4 weeks.<a class="elsevierStyleCrossRef" href="#bib0405">37</a> In such patients one must initiate the 2nd-step of guideline.Second-stepThe second step involves add-on Omalizumab (humanized monoclonal anti-IgE Ab) in standard dose (300mg SC q4weeks), which may be up-dosed to 600mg q4weeks if needed.<a class="elsevierStyleCrossRefs" href="#bib0225">1,36</a> This molecule binds free IgE and reduces its serum level, subsequently downregulating the high affinity FceR1 receptors on basophils and mast cells. Reduced FceR1 expression further lowers the chance of activation by IgE and IgG antibodies, thus restricting histamine release and improving urticarial symptoms.<a class="elsevierStyleCrossRef" href="#bib0240">4</a> Omalizumab is approved in all CSU patients aged ≥12 years, and it also improves the patient's quality of life in real-life settings.<a class="elsevierStyleCrossRef" href="#bib0415">39</a> Omalizumab is extremely safe, without any serious adverse events, however its use remains guarded during pregnancy and lactation.<a class="elsevierStyleCrossRef" href="#bib0420">40</a> CSU patients with type 1 autoimmunity or autoallergy, i.e. high IgE/anti-TPO IgG ratio, show a more favorable and rapid response with omalizumab, while those with type IIb autoimmunity are more likely slow-responders, partial responders or non-responders to omalizumab.Third stepThe third and final step constitutes cyclosporine (PO, 3–5mg/kg/day, add-on to sgAHs) in patients remaining uncontrolled after 6 months therapy with omalizumab. It is a T-cell immune-suppressor which blocks the release of Th2 cytokines, thereby halting the activation of effector mast cells and basophils in CU. A recent meta-analysis has established its efficacy in almost 75% CSU patients, however its long-term use needs careful monitoring to reduce the risks of severe adverse effects including renal impairment, hypertension and dyslipidemias.<a class="elsevierStyleCrossRef" href="#bib0425">41</a> The British guidelines have placed cyclosporine in the second step along with omalizumab, and have recommended multiple agents such as H2 antihistamines, azathioprine, dapsone, doxepin, hydroxychloroquine, IVIg, methotrexate, mycophenolate mofetil, NB-UVB, sulfasalazine, tacrolimus or tranexamic acid (isolated angioedema without wheals) as third line therapy for refractory cases.<a class="elsevierStyleCrossRef" href="#bib0400">36</a> However, the evidence regarding these agents is variable and there is lack of comparative controlled trials, so they are not recommended by the EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline.<a class="elsevierStyleCrossRef" href="#bib0225">1</a> Cyclosporine shows better results in type IIb autoimmune CSU.<a class="elsevierStyleCrossRef" href="#bib0240">4</a>Treatment monitoring and goalsThe current EAACI/GA(2)LEN/EuroGuiDerm/APAAACI guideline recommends assessment of urticaria control to monitor treatment status, and decide whether upgrade or downgrade of treatment is needed. Urticaria control can be assessed by a simple 4-item questionnaire, the urticaria control test (UCT). The total score ranges from 0 to 16, 0 and 16 indicating worst and best disease control respectively. The cut-off value is 12. If UCT<12, the disease is poorly controlled, so up-dosing is needed, while if the UCT is 12–15, then the current treatment regimen may be maintained, while UCT=16 indicates complete cure.<a class="elsevierStyleCrossRef" href="#bib0225">1</a>The current treatment goal in CSU is complete disease control, indicated by an urticaria activity score 7 (UAS7=0) and urticaria control test (UCT=16).<a class="elsevierStyleCrossRef" href="#bib0225">1</a>As discussed previously, several biomarkers have been studied to predict the therapeutic response of CSU to H1-antihistamines, omalizumab and cyclosporine, even before initiation of actual treatment. Inadequate responders to omalizumab may be grouped under 3 heads – partial responders, slow responders and non-responders. This would subsequently help physicians in foretelling the disease prognosis and initiate appropriate targeted therapy, subsequently improving the physician-patient relationship. <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> highlights the important biomarkers in CSU and their association with disease characteristics.<a class="elsevierStyleCrossRefs" href="#bib0370">30,32,42</a>Emerging and investigational therapiesThe currently available treatments fail to achieve complete disease control in all patients, so newer treatment options are being explored for recalcitrant patients. These treatment options are targeted against newer mediators and receptors, beyond mast-cells and IgE, which are being unraveled by recent research (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>). These agents are in different phases of development and may herald a brighter and better future for all urticaria patients.<elsevierMultimedia ident="tbl0020"></elsevierMultimedia>Systemic comorbiditiesAlthough urticaria is a relatively benign condition, recently several systemic comorbidities have been reported in long-standing cases. These comorbidities involve multiple systems and have a variable occurrence. It is now known that patients with type IIb autoimmunity are more prone to develop long standing disease and such systemic comorbidities.<a class="elsevierStyleCrossRef" href="#bib0285">13</a> So, it is imperative to diagnose urticaria correctly, and initiate early and appropriate treatment early to reduce such comorbidities. Patients at higher risk should be screened regularly for systemic comorbidities, even at nascent stage, for early detection and management. The most important systemic comorbidities include autoimmune, atopic and psychiatric disorders.<a class="elsevierStyleCrossRefs" href="#bib0435">43,44</a> However, it is unclear whether these co-morbidities develop after urticaria onset, i.e. causally related or simply coexist independently.ConclusionUrticaria is a relatively common dermatosis, which can be acute (<6 weeks duration) or chronic (>6 weeks). Chronic urticaria can either be spontaneous or inducible, based on the absence or presence of specific triggering factors, and both subtypes may co-exist. It is primarily a mast cell mediated histaminergic disorder, however, newer research has highlighted the role of heterogeneous inflammatory cells, e.g. eosinophils and lymphocytes and their mediators, e.g. platelet activating factor. Acute urticaria is a type 1 hypersensitivity reaction to exo-allergens such as food and drug and may occur spontaneously or as a manifestation of anaphylaxis. In contrast, chronic urticaria occurs as a result of autoimmunity against endogenous substances, and role of external agents is negligible. Recently two pathways have been described which may trigger the activation and degranulation of mast cells in CSU and form the basis of an endotypic classification – type 1 autoimmunity/autoallergy and type IIb autoimmunity involving IgE and IgG autoantibodies respectively. Further work is needed to characterize these endotypes, search for newer ones and decipher the mechanisms of inducible urticarias. Although urticaria is primarily a clinical diagnosis, recent recommendations involve the use of PROMs in chronic urticaria to assess disease activity, control and impact, which reflects the societal burden of this chronic disorder. The other indications of investigations in chronic urticaria including ruling out differential diagnoses, screening patients for systemic co-morbidities and confirming inducible urticarias (threshold tests). Currently, 2nd generation H1-antihistamines, omalizumab and cyclosporine are approved for a step-wise algorithmic treatment approach, but almost 1 in 3 patients remain uncontrolled. Several newer therapeutic strategies are being currently investigated aimed at inhibiting signals blocking mast cell activation, blocking intracellular effector pathways, silencing and depleting mast cells, and targeting other inflammatory cells, their mediators and receptors. Complete disease control remains the ultimate goal along with improved quality of life. The current review will appraise urticaria treating physicians about recent developments in this field, including novel treatment strategies, to ensure best care for their patients.Data availability statementFurther data, if necessary, would be available from corresponding author upon reasonable request.Author's contributionAll authors contributed equally to this manuscript.Ethical considerationThis manuscript is a review. No patients are included. No informed consent is required.FundingNo funding sources.Conflicts of interestAna Maria Gimenez-Arnau – Medical Advisor for Uriach Pharma/Neucor, Genentech, Novartis, FAES, GSK, Sanofi–Regeneron, Amgen, Thermo Fisher Scientific, Almirall, Celldex, Leo Pharma Research Grants supported by Uriach Pharma, Novartis, Grants from Instituto Carlos III – FEDER Educational activities for Uriach Pharma, Novartis, Genentech, Menarini, LEO-PHARMA, GSK, MSD, Almirall, Sanofi, Avene. Nerea Manzanares and Indrashis Podder have no conflicts of interest to declare." "textoCompletoSecciones" => array:1 [ "secciones" => array:19 [ 0 => array:3 [ "identificador" => "xres2007985" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1720490" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2007986" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1720491" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Classification and epidemiology" ] 6 => array:3 [ "identificador" => "sec0015" "titulo" => "Pathogenesis" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Acute urticaria" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Chronic spontaneous urticaria" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Chronic inducible urticaria" ] ] ] 7 => array:3 [ "identificador" => "sec0035" "titulo" => "Clinical approach" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0040" "titulo" => "Role of biomarkers" ] ] ] 8 => array:3 [ "identificador" => "sec0045" "titulo" => "Diagnostic work-up" "secciones" => array:7 [ 0 => array:2 [ "identificador" => "sec0050" "titulo" => "Acute urticaria" ] 1 => array:2 [ "identificador" => "sec0055" "titulo" => "Chronic spontaneous urticaria" ] 2 => array:2 [ "identificador" => "sec0060" "titulo" => "Chronic inducible urticaria" ] 3 => array:2 [ "identificador" => "sec0065" "titulo" => "Role of Patient reported outcome measures (PROMs)" ] 4 => array:2 [ "identificador" => "sec0070" "titulo" => "Assessment of disease activity" ] 5 => array:2 [ "identificador" => "sec0075" "titulo" => "Assessment of disease control" ] 6 => array:2 [ "identificador" => "sec0080" "titulo" => "Assessment of disease impact" ] ] ] 9 => array:2 [ "identificador" => "sec0085" "titulo" => "Differential diagnoses" ] 10 => array:3 [ "identificador" => "sec0090" "titulo" => "Treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "sec0095" "titulo" => "General/non-pharmacologic measures" ] 1 => array:2 [ "identificador" => "sec0100" "titulo" => "Specific/pharmacologic measures" ] 2 => array:3 [ "identificador" => "sec0105" "titulo" => "Current treatment recommendations" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0110" "titulo" => "First-step" ] 1 => array:2 [ "identificador" => "sec0115" "titulo" => "Second-step" ] 2 => array:2 [ "identificador" => "sec0120" "titulo" => "Third step" ] ] ] 3 => array:2 [ "identificador" => "sec0125" "titulo" => "Treatment monitoring and goals" ] 4 => array:2 [ "identificador" => "sec0130" "titulo" => "Emerging and investigational therapies" ] ] ] 11 => array:2 [ "identificador" => "sec0135" "titulo" => "Systemic comorbidities" ] 12 => array:2 [ "identificador" => "sec0140" "titulo" => "Conclusion" ] 13 => array:2 [ "identificador" => "sec0145" "titulo" => "Data availability statement" ] 14 => array:2 [ "identificador" => "sec0150" "titulo" => "Author's contribution" ] 15 => array:2 [ "identificador" => "sec0155" "titulo" => "Ethical consideration" ] 16 => array:2 [ "identificador" => "sec0160" "titulo" => "Funding" ] 17 => array:2 [ "identificador" => "sec0165" "titulo" => "Conflicts of interest" ] 18 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-03-26" "fechaAceptado" => "2023-06-23" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1720490" "palabras" => array:6 [ 0 => "Urticaria" 1 => "Acute" 2 => "Chronic" 3 => "Pathogenesis" 4 => "Diagnosis" 5 => "Treatment" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1720491" "palabras" => array:6 [ 0 => "Urticaria" 1 => "Aguda" 2 => "Crónica" 3 => "Patogenia" 4 => "Diagnóstico" 5 => "Tratamiento" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Urticaria is a skin-condition characterized by sudden-onset pruritic wheals with/without angioedema. Urticaria can be acute or chronic. Chronic urticaria may be spontaneous or inducible, based on absence/presence of specific triggers. Chronic spontaneous urticaria is most frequent (∼80%). Urticaria is primarily a mast-cell mediated histaminergic-disorder. Recently, other inflammatory cells and pro-inflammatory cytokines have been implicated. Deeper understanding has unmasked two endotypes – IgE-mediated type I autoimmunity/autoallergy and IgG-mediated type IIb autoimmunity. Current treatment recommendation involving second-generation H1-antihistamines, omalizumab and cyclosporine is effective in 60–80% patients. So, newer treatment options are being explored based on emerging targets. Despite being non-lethal, urticaria considerably impairs patient's quality-of-life and may be associated with extra-cutaneous comorbidities. Several “patient reported outcome measures” have been proposed to evaluate disease-activity, impact and control, for effective treatment modulation till complete disease control. This review discusses the current understanding about urticaria and its future directions, to facilitate optimum evidenced-based care." ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "La urticaria es una afección de la piel caracterizada por ronchas pruriginosas de aparición repentina con o sin angioedema. La urticaria puede ser aguda o crónica. La urticaria crónica puede ser espontánea o inducible, según la ausencia/presencia de desencadenantes específicos. La urticaria crónica espontánea es la más frecuente (∼80%). La urticaria es principalmente un trastorno histaminérgico mediado por mastocitos. Recientemente se han implicado otras células inflamatorias y citocinas proinflamatorias. Una comprensión más profunda ha desenmascarado dos endotipos: autoinmunidad/autoalergia tipo I mediada por IgE y autoinmunidad tipo IIb mediada por IgG. La recomendación de tratamiento actual que incluye antihistamínicos H1 de segunda generación, omalizumab y ciclosporina es eficaz en 60-80% de los pacientes. Por lo tanto, se están explorando opciones de tratamiento más nuevas en función de objetivos emergentes. A pesar de no ser letal, la urticaria deteriora considerablemente la calidad de vida del paciente y puede estar asociada con comorbilidades extracutáneas. Se han propuesto varias «medidas de resultado informadas por el paciente» para evaluar la actividad, el impacto y el control de la enfermedad, para la modulación efectiva del tratamiento hasta el control completo de la enfermedad. Esta revisión analiza la comprensión actual sobre la urticaria y sus direcciones futuras, para facilitar una atención óptima basada en evidencia." ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 682 "Ancho" => 1207 "Tamanyo" => 87372 ] ] "descripcion" => array:1 [ "en" => "(a) Extensive chronic spontaneous urticaria and (b) symptomatic dermographism on the back." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:2 [ 0 => array:1 [ "imagen" => "gr2a.jpeg" ] 1 => array:1 [ "imagen" => "gr2b.jpeg" ] ] "descripcion" => array:1 [ "en" => "(a) Schematic diagram showing diagnostic approach for urticaria and (b) schematic diagram showing treatment of urticaria." ] ] 2 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "sgAH: second generation anti-histamines; ASST: autologous serum skin test; CRP: C-reactive protein; IL: interleukin; PAF-AH: platelet activating factor-acetylhydrolase; PAF: platelet activating factor; BHRA: basophil histamine release assay; TPO: thyroidperoxidase." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n \t\t\t\t\ttable-head\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col">Disease characteristic indicated \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " colspan="2" align="center" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name of biomarker</th></tr><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black"> \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Serological \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="6" align="left" valign="middle">Increased CSU activity or severity</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Older age of disease onset \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Elevated CRP, mean platelet volume, D-dimer, anti-thyroid antibodies, IL-6, IL-17 and IL-18. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Female gender \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Basopenia, Eosinopenia, low serum vitamin D \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Longer duration of disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Positive basophil activation test (BAT) (increased expression of CD63 and CD203) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Presence of angioedema, concomitant CIndU, NSAID hypersensitivity \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Inadequate response to sgAHs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Positive ASST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Prolonged disease course \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Elevated levels of anti-thyroid antibodies, Positive BAT and higher CD63 expression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Shorter disease duration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Elevated serum CRP level. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle">Poor/inadequate response to second-generation anti-histamines</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• More severe disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Elevated CRP and D-dimer levels. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Positive ASST \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Lower PAF-AH/PAF ratio \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="middle">Good responders to omalizumab</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">–</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• High baseline serum total IgE level (T1aiCSU) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Week-4IgE/baseline IgE ratio >2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• ↑FceR1 expression on basophils \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Slow/non-responders to omalizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Positive BAT/BHRA indicating T2aiCSU \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " colspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t"></td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="middle">Good responders to cyclosporine</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">–</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Patients with T2aiCSU indicated by high serum anti-TPO IgG, low total IgE, positive ASST and positive BAT/BHRA. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Low serum D-dimer level \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3334302.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Emerging biomarkers in chronic spontaneous urticaria and their interpretation." ] ] 3 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "leyenda" => "CIndU: chronic inducible urticaria; ESR: erythrocyte sedimentation rate; CRP: C-reactive protein; ANA: anti-nuclear antigen; RA: rheumatoid arthritis; TPO: thyroid peroxidase; PROM: patient reported outcome measures; UAS7: urticaria activity score 7; CU2QoL: chronic urticaria quality of life; UCT: urticaria control test." "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Aims-7Cs \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Physical examination (all patients) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Basic tests (all patients) \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Extended diagnostic tests (selected patients if necessary after basic tests) \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Confirm and rule out differentials \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Presence of characteristic itchy wheals±angioedema. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Differential blood count, ESR or CRP.• Total serum IgE and IgG-anti-TPO (high or low IgE/TPO ratio indicates type 1 or type 2 autoimmune pathogenesis respectively). \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Skin biopsy (to rule out differentials, e.g. urticarial vasculitis) provocation tests for CIndUs, basophil activation tests, thyroid hormones, serum tryptase (for severe systemic disease), H. pylori evaluation, allergy tests, e.g. elimination diets – may be performed when necessary in select patients. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cause \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autologous serum skin test (ASST), basophil activation test (BAT), thyroid hormone level, ANA, RA factor may be done in patients with type IIb autoimmunity. Raised CRP, basopenia and eosinopenia are more frequent in type II endotype. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Co-factors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Identify potential triggers and aggravators that can modify disease activity – drugs, food/pseudo-allergens, stress and infection. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Drug provocation tests (e.g. NSAID induced/exacerbated disease), elimination diets for 3–4 weeks.Food induced CSU is extremely rare, however pseudo-allergens act as a trigger in some patients by a non-immunologic mechanism (non-IgE). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Comorbidities \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">To check for CIndUs, autoimmunity and mental health. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Provocation tests to confirm CIndUs, other tests to confirm autoimmunity [as stated above] \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Consequences \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Identify associated problems such as sleep disturbances, sexual health and societal burden due to disease. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Components \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Assess potential biomarkers for therapeutic response, e.g. raised d-dimer is a marker for antihistamine unresponsiveness, type I autoimmunity (high IgE/TPO) is a marker for faster and better omalizumab response while type IIb autoimmunity (high TPO, low IgE, ASST+, BAT+, high CRP, basopenia, eosinopenia) is a marker for poor response to omalizumab and more favorable response with cyclosporine. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Course \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evaluate and monitor disease activity, impact and control by PROM questionnaires.Activity – UAS7Impact – CU2QoLControl – UCT \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">– \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3334300.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Diagnostic work-up recommended in chronic spontaneous urticaria patients." ] ] 4 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name of condition \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Differentiating features from urticaria \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Urticarial vasculitis</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Wheals persist for >24h, while in urticaria they last <24h \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Skin biopsy shows fibrinolytic degeneration of vessel walls, extravasated blood cells \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="2" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cell disorders like maculopapular cutaneous mastocytosis (urticaria pigmentosa), indolent systemic mastocytosis with skin involvement and mast cell activation syndrome (MCAS)</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Urticaria pigmentosa usually occurs in young children, wheals heal with residual pigmentation, Darier's sign positive \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Serum tryptase level may be elevated, other features of systemic mastocytosis may be present in indolent systemic mastocytosis and MCAS \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " rowspan="3" align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hereditary angioedema/drug-induced angioedema</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Positive family history, low complement levels (C3, C4, CH50), quantitative and/or qualitative deficiency of C1-esterase inhibitor \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• The principal mediator is bradykinin (vs. histamine in urticaria) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Offending drug history is present, e.g. ACEIs, gliptins, etc. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Autoinflammatory syndromes (cryopyrin associated periodic syndromes [CAPS], familial cold autoinflammatory syndrome [FCAS], Muckle-Wells syndrome [MWS] and Neonatal onset multisystem inflammatory disorder [NOMID] \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Recurrent fever episodes, arthralgia or arthritis, fatigue, headache, very high ESR or CRP on routine hematology, amyloidosis [MWS], raised serum ferritin→Still's disease. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Schnitzler's syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Recurrent fever, joint pain, muscle pain, lymphadenopathy and monoclonal gammopathy. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Adult onset Still's disease \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Raised serum ferritin, echocardiographic changes suggesting cardiologic involvement \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Gleich's syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Recurrent episodic angioedema with eosinophlia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Well's syndrome \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Granulomatous dermatitis with eosinophilia \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bullous pemphigoid (pre-bullous stage) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Long standing disease especially in the elderly, characteristic skin biopsy and DIF findings \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3334299.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Common and important differential diagnoses of urticaria and their identifying features." ] ] 5 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:2 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Class of drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of action \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name of drug \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Remarks \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Current status \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Inhibitors of mast cell activation by blocking ligands and/or receptors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reducing serum IgE concentration by binding free IgE and subsequently down regulating FceR1 receptors on mast cells and basophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Ligelizumab• UB-221 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">These molecules have a higher affinity for IgE and FceR1 receptors – so block them more effectively (vs. omalizumab) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ligelizumab trial stopped in phase 3, as it failed to show significant benefit over omalizumab.UB-221 – Undergoing phase 1 trials \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blockers of MRGPRX2 receptor on mast cells, and its agonists, e.g. substance P \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Aprepitant• Tradipitant• Serlopitant• Orvepitant \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Block substance P mediated activation of MRGPRX2 receptors (expressed preferentially by skin mast cells) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Preclinical \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blockers of CRTh2 or PGD2 receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• AZD1981 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocks PGD2 mediated activation of mast cells and basophils \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2 trial completed, but primary objective not achieved. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Complement C5a receptor blocker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Eculizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocks C5a mediated activation and degranulation of skin mast cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Proof of concept \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Interferes with intracellular signaling pathways, thus blocking the degranulation of mast cells, even if activated \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bruton's tyrosine kinase inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Fenebrutinib, Remibrutinib and Rilzabrutinib \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral drugs \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2–3 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Spleen tyrosine kinase inhibitor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• GSK2646264 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Topical medication \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cell silencers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-Siglec-8 monoclonal antibody (humanized, non-fucosylated IgG1) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Lirentelimab/AK002 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Engage/occupy inhibitory receptors on mast cells (Siglec-8), thus making them dormant and preventing their activation by triggers. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 2 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mast cell depletors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blockers of KIT receptor (CD117) on mast cells \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Barzolvolimab (CDX-0159) \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Stem cell factor (SCF) is needed for the survival, differentiation, proliferation and activation of mast cells, which act via CD117. These drugs block the action of SCF and deplete mast cells.Not specific for skin mast cells, so can deplete other tissue mast cells like brain, lung resulting in systemic complications. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Phase 1 \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-5 blockers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Anti-IL-5 monoclonal antibody \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Mepolizumab and Reslizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Block the IL-5 mediated recruitment and activation of eosinophils and mast cells, which are important effector cells for urticaria These drugs are currently approved for recalcitrant eosinophilic asthma. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Mepolizumab and Reslizumab→Not yet approved, pilot study underway for CSU and cold urticaria.Benralizumab→Phase 2b dose determining trial – ARROYO is currently underway. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Monoclonal antibody blocking the IL-5 receptor \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Benralizumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-4/IL-13 blocker \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-4 and IL-13 are important Th2 cytokines involved in the pathogenesis of urticaria.IL-4 mediates Ig class switching to IgE. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Dupilumab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Currently approved for recalcitrant cases of moderate to severe atopic dermatitis, bronchial asthma and chronic rhinosinusitis with polyposis \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">RCTs being conducted in CSU and CIndU. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blockers/inhibitors of type 1 cytokines, e.g. TNF-α and IL-1 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">TNF-α inhibitors \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Adalimumab, Etanercept, Infliximab \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Type 1 cytokines are involved in a subset of patients with autoinflammatory syndromes. Cautious use is warranted as they may reactivate latent infections such as tuberculosis and hepatitis. There are also reports of demyelinating disorders and lymphomas \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">No robust evidence, only sporadic reports suggest its beneficial role in a subset of patients. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">IL-1 blockers \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Canakinumab, rilonacept, anakinra \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="" valign="\n \t\t\t\t\ttop\n \t\t\t\t"> \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Antifibrinolytic \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Block the fibrin degeneration \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">• Tranexamic acid \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Blocks the action of extrinsic coagulation pathway in CSU pathogenesis. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Role is not completely clear, sporadic reports exist. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] "imagenFichero" => array:1 [ 0 => "xTab3334301.png" ] ] ] ] "descripcion" => array:1 [ "en" => "Newer and emerging treatment options for recalcitrant urticaria<a class="elsevierStyleCrossRefs" href="#bib0240">4,13</a>." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:44 [ 0 => array:3 [ "identificador" => "bib0225" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The international EAACI/GA2LEN/EuroGuiDerm/APAAACI guideline for the definition, classification, diagnosis, and management of urticaria" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "T. 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Recent updates in urticaria

Actualización en urticaria

Ana M. Giménez-Arnaua,

Corresponding author

anamariagimenezarnau@gmail.com
22505aga@gmail.com

Corresponding author.

, Nerea Manzanaresa, Indrashis Podderb

a Department of Dermatology, Hospital del Mar-IMIM, Universitat Pompeu Fabra de Barcelona, Spain

b Department of Dermatology, College of Medicine and Sagore Dutta Hospital, Kolkata 700058, West Bengal, India

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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Urticaria is a common dermatological disorder characterized by sudden and unpredictable pruritic wheals&#44; angioedema or both&#46; A wheal indicates a transient or evanescent erythematous well-circumscribed swelling of variable shape and size&#44; disappearing within 24<span class="elsevierStyleHsp" style=""></span>h&#46; Angioedema refers to erythematous or skin-colored deep swelling preferentially involving areas with loose skin&#44; e&#46;g&#46; eyelids&#44; lips&#44; genitalia and tongue&#44; more burning than pruritic&#44; with slower resolution than wheals&#44; approximately 72&#8211;96<span class="elsevierStyleHsp" style=""></span>h&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The global lifetime prevalence of all types of urticaria is approximately 3&#37;&#8211;22&#37;&#44; which been increasing over the years&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">2</span></a> The prevalence is heterogeneous across the world &#8211; higher in Latin America and Asia&#44; and lower in North America&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">3</span></a> This geographic variability is poorly explained&#44; and more global studies are needed&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Classification and epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Urticaria can be classified according to &#40;a&#41; duration and &#40;b&#41; presence or absence of definite triggers&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">Based on symptom duration&#44; two types exist &#8211; acute and chronic urticaria&#46; Acute urticaria refers to symptom duration 6 weeks or less&#44; while persistent symptoms &#62;6 weeks indicate chronic urticaria &#40;CU&#41;&#46; In CU symptoms can occur daily or almost daily&#44; or recur intermittently following variable periods of remission&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Based on triggering factors&#44; urticaria can be spontaneous or inducible&#44; indicating their absence or presence respectively&#46; Acute urticaria is mostly spontaneous&#44; however some factors may aggravate it in selected patients&#44; e&#46;g&#46; infections&#44; drugs and foods&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> CU can be spontaneous or induced&#46; In chronic spontaneous urticaria &#40;CSU&#41; itchy wheals and&#47;or angioedema develop unpredictably without any specific trigger &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>a&#41;&#46; The cause of CSU may be known &#40;type I or type IIb autoimmunity&#41; or unknown&#46; In contrast&#44; specific triggers are a prerequisite for chronic inducible urticaria &#40;CIndU&#41;&#44; and they range from physical to non-physical stimuli such as symptomatic dermographism &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>b&#41;&#44; pressure&#44; vibration&#44; internal or external thermal variation &#40;cholinergic stimulation&#44; heat or cold&#41;&#44; sunlight&#44; water and contact with certain substances&#46; The CIndUs can be confirmed by provocation and threshold tests&#44; based on suspected triggers&#46; Notably&#44; some CSU patients may experience symptomatic exacerbation by certain triggers&#44; but they are not specific as symptoms can occur in their absence &#40;spontaneously&#41; and triggers do not always cause symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a> Interestingly&#44; some patients may present with more than one urticaria sub-type&#44; e&#46;g&#46; concomitant CSU and CIndU&#44; and cold-induced cholinergic urticaria&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0030" class="elsevierStylePara elsevierViewall">A recent systematic review has reported the overall life-time prevalence of acute and chronic urticaria as 3&#37;&#8211;22&#37;&#44; 4&#46;4&#37;&#44; respectively&#46; The point-prevalence is variable&#44; ranging from 1&#46;5&#37; &#40;USA and Europe&#41; to 4&#37; &#40;Asia and Latin America&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">2</span></a> Acute urticaria is predominant in children &#60;5 years&#44; while CU frequently affects middle-aged women&#46;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">6</span></a> CSU is most common variant of CU&#44; encompassing 60&#37;&#8211;90&#37; cases&#46; Among the CIndUs&#44; symptomatic dermographism iscommonest&#44; followed by CholU and ColdU&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> Notably&#44; CU prevalence has been increasing in children &#40;about 1&#37;&#41; and is more common than previously thought&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">3</span></a> Interestingly&#44; urticaria improved during pregnancy in 51&#37; patients&#44; while it worsened and remained unchanged in 29&#37; and 20&#37; patients respectively&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">7</span></a> Maximal CU exacerbation was reported during third trimester &#40;27&#46;6&#37;&#41; followed by first trimester &#40;22&#46;8&#37;&#41;&#46; Untreated CU&#44; CIndU&#44; absence of angioedema&#44; history of worsening during previous pregnancy and stress are risk-factors for CU worsening during pregnancy&#46;<a class="elsevierStyleCrossRef" href="#bib0255"><span class="elsevierStyleSup">7</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Despite being non-lethal&#44; CU considerably impairs the patients&#8217; quality of life and poses a significant burden for society&#46; Concomitant angioedema and&#47;or inducible urticaria are significant risk-factors for worsening HRQoL &#40;health related quality of life&#41;&#46; Several life-quality aspects are affected such as sleep disorders&#59; sexual dysfunction&#59; limitations on daily life&#44; work and sports activities&#59; interactions within the family and society&#59; and patients&#8217; performance at school and work &#40;6&#37; absenteeism and 25&#37; presentism&#41;&#46; Additional psychiatric co-morbidities such as depression and anxiety have been reported in &#8764;30&#37; CSU patients&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">8</span></a> Children with CU also increase their parental stress and adversely affect their quality of lives&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">9</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis</span><p id="par0040" class="elsevierStylePara elsevierViewall">Urticaria is primarily mediated by dermal and subcutaneous skin mast cells &#40;MCs&#41;&#44; along with perivascular &#40;around small skin venules&#41; and perineural heterogeneous cellular infiltrate comprising CD4 T-lymphocytes &#40;Th2<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>Th1&#47;Th17&#41;&#44; neutrophils&#44; eosinophils&#44; basophils&#44; and monocytes&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">10</span></a> Activated MCs degranulate to release several pre-formed and newly synthesized mediators such as histamine &#40;most important&#41;&#44; platelet activating factor &#40;PAF&#41; and diverse cytokines viz&#46; IL-6&#44; IL-5 and IL-13&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a> These mediators promote vasodilatation&#44; increase vascular permeability&#44; stimulate sensory nerves&#44; activate the coagulation cascade &#40;factor Xa and IIa &#91;thrombin&#93;&#41; and complement system &#40;C3a and C5a&#41;&#44; and recruit other inflammatory cells like basophils&#44; eosinophils and T-cells&#46; Additionally&#44; endothelial cytokines&#44; e&#46;g&#46; VEGF promote the dermal chemotaxis of mast cells and participate in pathogenesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">3&#44;10</span></a> All these factors engage in a bi-directional cross-talk collectively resulting in urticarial lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">3</span></a> The pathogenesis of different urticaria subtypes is briefly discussed below&#46;</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Acute urticaria</span><p id="par0045" class="elsevierStylePara elsevierViewall">Acute urticaria may develop spontaneously&#44; or as a presenting feature of anaphylaxis&#46; In both cases&#44; immediate type I hypersensitivity reaction to exo-allergens such as foods&#44; drugs or other allergens is incrimated&#46; These exo-allergens bind to IgE-FceR1 complex on MCs and basophils resulting in their degranulation and subsequent symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> NSAID induced urticaria may involve T-cells and increased levels of cysteinyl leukotrienes&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> Acute contact urticaria may develop following direct contact with urticariogenic substances&#44; with or without prior sensitization&#44; e&#46;g&#46; stinging nettles&#46;<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Chronic spontaneous urticaria</span><p id="par0050" class="elsevierStylePara elsevierViewall">Recently&#44; two autoimmune pathways have been identified to trigger MC degranulation in CSU&#44; the basis for endotypic classification&#46; Currently&#44; two endotypes have been characterized &#8211; Type I autoimmunity&#47;autoallergy &#40;auto-allergens such as TPO&#44; IL-24&#44; TG and tissue factor cross-link IgE autoantibodies on MCs and basophils&#41; and Type IIb autoimmunity &#40;IgG autoantibodies against FceR1<span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>IgE&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0235"><span class="elsevierStyleSup">3&#44;4</span></a> Recently&#44; anti-FceR1 IgM and IgA autoantibodies have been detected in type IIb endotype&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">12</span></a> Type IIb endotype is associated with longer disease duration&#44; higher disease activity and higher prevalence of autoimmune comorbidities&#46; These patients have more frequent basopenia&#44; eosinopenia&#44; higher CRP&#44; positive ASST and positive BAT&#46; Although Omalizumab improves both endotypes&#44; type I endotype &#40;high baseline IgE&#41; is a marker for more favorable and faster response&#46; Type IIb autoimmune CSU patients are more-often slow &#8211; or non-responders to Omalizumab&#44; and Cyclosporine seems more effective&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">13</span></a> The recent PURIST study detected true type IIb autoimmunity in only 8&#37; patients &#8211; triple positive for IgG-anti FceR1&#47;IgE&#44; BAT and ASST&#44; and proposed high IgG-anti-TPO&#47;IgE ratio as the most suitable surrogate marker for type IIb endotype&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">14</span></a> However&#44; these two endotypes may co-exist in some patients as evidenced by detection of auto-IgE followed by auto-IgG antibodies along the disease course&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">15</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Recently researchers are exploring additional CSU endotypes based on their pathogenesis involving coagulation factors&#44; MAS-related G protein coupled receptor X2 &#40;MRGPRX2&#41;&#44; alarmins and other signals&#46;<a class="elsevierStyleCrossRefs" href="#bib0300"><span class="elsevierStyleSup">16&#8211;18</span></a> More work is needed to characterize these endotypes and elucidate their roles in disease pathogenesis&#46; The role of infections is CSU is controversial&#46; Viral infections such as HHV-6 and COVID-19 have been linked with acute exacerbations without any causal association&#46;<a class="elsevierStyleCrossRefs" href="#bib0315"><span class="elsevierStyleSup">19&#44;20</span></a> A recent meta-analysis has failed to demonstrate significant benefit with <span class="elsevierStyleItalic">Helicobacter pylori</span> eradication in majority CSU patients&#46;<a class="elsevierStyleCrossRef" href="#bib0325"><span class="elsevierStyleSup">21</span></a> However&#44; parasitic sensitization and infestation are significantly higher in CSU patients compared to healthy controls&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Chronic inducible urticaria</span><p id="par0060" class="elsevierStylePara elsevierViewall">The pathogenesis of CIndU is unclear and scattered information is available regarding its subtypes&#46; IgE-mediated mast cell activation &#40;autoallergy&#41; is implicated in symptomatic dermographism&#44; ColdU&#44; CholU and SolU and the proposed autoallergens include cold-induced activation of an epidermal protein &#40;ColdU&#41;&#44; chromophores stimulated by solar radiation &#40;SolU&#41; or sweat antigen leaked into dermis &#40;CholU&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0335"><span class="elsevierStyleSup">23&#8211;25</span></a> Another proposed mechanism in CholU is the reduced expression of cholinergic receptor M3 in eccrine sweat glands and subsequent accumulation of acetylcholine&#44; a mast cell degranulator&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">25</span></a> Hereditary vibratory angioedema may have an autosomal dominant gain-of-function mutation of the ADGRE2 gene&#44; thus making mast cells susceptible to vibration mediated degranulation&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">26</span></a> Delayed pressure urticaria may have a non-immunologic pathogenesis&#44; suggested by dense dermal leucocytic infiltration and pro-inflammatory mediators such as IL-1&#44; IL-6&#44; IL-3 and TNF-&#945;&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">27</span></a> Contact urticaria may either be immunologic &#40;IgE or T-cell mediated&#41; or non-immunologic&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">28</span></a></p></span></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Clinical approach</span><p id="par0065" class="elsevierStylePara elsevierViewall">Urticaria is essentially a clinical diagnosis presenting with itchy wheals and&#47;or angioedema&#46; Thus&#44; detailed history and physical examination are indispensable&#46; A step-wise algorithmic diagnostic approach is suggested &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>a&#41;&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0070" class="elsevierStylePara elsevierViewall">In patients presenting with isolated angioedema&#44; ruling out causative drugs&#44; e&#46;g&#46; ACEIs&#44; gliptins&#44; etc&#46; is the first step by eliciting drug history&#46; Absence of drug history but positive family history should hint toward hereditary angioedema&#44; which must be ruled out with further detailed investigations&#46;</p><p id="par0075" class="elsevierStylePara elsevierViewall">In patients presenting with wheals<span class="elsevierStyleHsp" style=""></span>&#177;angioedema&#44; one needs to enquire about concomitant fever&#47;recurrent febrile episodes and&#47;or joint pain or malaise to rule out autoinflammatory conditions&#46; If there is no indication of autoinflammatory disease&#44; one must enquire about the disease duration and average wheal duration&#46; Urticaria can be classified acute or chronic based on disease duration &#60;6 weeks or &#62;6 weeks respectively&#46; If the average wheal duration is &#62;24<span class="elsevierStyleHsp" style=""></span>h&#44; urticarial vasculitis must be considered&#44; and a skin biopsy is necessary for diagnostic confirmation&#46; In patients with CU&#44; one must enquire whether they can produce the wheals themselves or they occur on their own &#8211; to identify chronic inducible urticaria &#40;CIndU&#41; and chronic spontaneous urticaria &#40;CSU&#41;&#44; respectively&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Recently&#44; Turk et al&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">29</span></a> have identified several phenotypic subgroups of CU patients&#44; based on disease characteristics&#44; underlying immunology and concomitant comorbidities&#46; Four such phenotypic subgroups have been identified &#8211; Cluster 1 &#40;&#8216;CIndU only&#8217; cluster characterized by highest age&#44; shortest duration and lowest serum IgE&#41;&#44; Cluster 2 &#40;&#8216;high IgE&#8217; cluster &#8211; highest IgE&#44; highest frequency of atopic comorbidities and lowest ANA and anti-TPO IgG positivity&#41;&#44; Cluster 3 &#40;&#8216;autoimmune cluster&#8217; &#8211; highest angioedema&#44; second-lowest IgE and highest ANA and anti-TPO IgG positivity&#41; and Cluster 4 &#40;&#8216;high comorbidity&#8217; cluster &#8211; highest frequency of non-atopic comorbidities such as hypertension&#44; diabetes mellitus and hypothyroidism&#41;&#46; The phenotypic categorization of CU patients may facilitate better characterization of underlying patho-mechanisms and enable a targeted patient-oriented management&#46;</p><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Role of biomarkers</span><p id="par0085" class="elsevierStylePara elsevierViewall">Another emerging area of research is the use of several biomarkers to define disease characteristics such as activity or severity and disease course &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; An idea about these disease characteristics would help physicians counsel their patients appropriately in the early stages of their disease&#44; eventually improving the physician-patient relationship and patient compliance to treatment&#46; Additionally&#44; some biomarkers are being investigated to predict the therapeutic response prior to initiation of actual therapy &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46; This would help in identifying patient subtypes based on these biomarkers&#44; and provide targeted therapy to achieve maximum benefits with minimum adverse-effects&#46;<a class="elsevierStyleCrossRefs" href="#bib0285"><span class="elsevierStyleSup">13&#44;30&#8211;32</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia></span></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Diagnostic work-up</span><p id="par0090" class="elsevierStylePara elsevierViewall">Although urticaria is primarily a distinct clinical diagnosis&#44; detailed work-up is recommended in some cases&#44; as discussed below&#46;</p><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Acute urticaria</span><p id="par0095" class="elsevierStylePara elsevierViewall">No laboratory investigations are recommended in acute urticaria due to its self-limited course&#46; However&#44; investigations may be needed if suggested by patient history&#44; e&#46;g&#46; acute urticaria as a manifestation of food allergy &#40;symptoms developing rapidly within 30<span class="elsevierStyleHsp" style=""></span>min to 1<span class="elsevierStyleHsp" style=""></span>h&#41; or drug hypersensitivity especially due to NSAIDs&#46; In such cases&#44; allergy tests and patient education are needed to prevent re-exposure to causative agents&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Chronic spontaneous urticaria</span><p id="par0100" class="elsevierStylePara elsevierViewall">The current guideline recommends the 7C approach for all CSU patients&#44; which reflect the 7 aims&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a> The 7 Cs include confirming the diagnosis and ruling out differentials&#44; exploring the cause by assessing endotype&#44; identifying potential triggers or aggravators as co-factors&#44; checking for co-morbidities&#44; e&#46;g&#46; autoimmunity&#44; CIndU and mental health disorders&#44; exploring the consequences of disease&#44; e&#46;g&#46; sleep disturbances&#44; sexual health and disease burden&#44; evaluating the disease components such as biomarkers of disease course and treatment response&#44; and monitoring the disease course&#44; i&#46;e&#46; CSU activity&#44; control and impact&#46; All CSU patients must undergo a detailed clinical history&#44; physical examination&#44; evaluation of disease activity&#44; impact and control&#44; and some laboratory tests&#46; Clinical history also involves the review of patient photographs&#44; as wheals are transient and may not be present during consultation&#46; The laboratory tests may be categorized as basic&#47;routine tests &#40;to be performed on all patients&#41; and some special tests which form a part of extended diagnostic program in special situations when suggested by history&#44; e&#46;g&#46; ruling out differentials and identifying the disease endotype&#46; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a> highlights the diagnostic work-up recommended in CSU patients&#46;</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Chronic inducible urticaria</span><p id="par0105" class="elsevierStylePara elsevierViewall">Multiple provocation tests are available to confirm the various types of chronic inducible urticaria&#44; e&#46;g&#46; cold provocation and threshold test &#40;cold urticaria&#41;&#44; pressure test &#40;delayed pressure urticaria&#41;&#44; using a pen or dermographometer to check the threshold for symptomatic dermographism&#44; heat provocation tests &#40;heat urticaria&#41;&#44; threshold determination using UV and visible light &#40;solar urticaria&#41;&#44; treadmill or bicycle test &#40;cholinergic urticaria&#41;&#44; provocation testing &#40;contact urticaria&#41; and vortex &#40;vibratory angioedema&#41;&#46; Routine and extended diagnostic tests can be performed when necessary&#44; as directed by history and examination&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">1&#44;4</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Role of Patient reported outcome measures &#40;PROMs&#41;</span><p id="par0110" class="elsevierStylePara elsevierViewall">The recent EAACI&#47;GA&#40;2&#41; LEN&#47;EuroGuiDerm&#47;APAAACI guideline recommends the use of validated patient reported outcome measures &#40;PROMs&#41; to monitor disease activity&#44; control and impact&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a> The assessment should be done at baseline and every follow-up visit to evaluate their therapeutic response&#46; This would enable therapeutic modification based on patient response to achieve optimum treatment outcome&#46; Some of the important PROMs and their utility are briefly discussed below&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Assessment of disease activity</span><p id="par0115" class="elsevierStylePara elsevierViewall">The Urticaria activity score 7 &#40;UAS7&#41; is the gold-standard for assessing disease activity in CU&#46; It is a prospective 2-item self-evaluation questionnaire grading wheal and itch intensity over 7 days&#46; Both wheal and itch are graded from 0 to 3&#44; indicating minimum to maximum intensity respectively&#44; and the scores are added for each day&#46; The final UAS7 score is obtained by adding the daily scores for 7 consecutive days&#44; ranging from 0 to 42&#46; The disease activity is graded as &#8211; 0<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>no activity&#44; &#60;6<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>well controlled&#44; 7&#8211;15<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>mild disease&#44; 16&#8211;27<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>moderate disease and 28&#8211;42<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>severe disease&#46; The grading is patient-documented&#44; making this score especially valuable&#46; The scoring helps to assess disease activity&#44; therapeutic response and also facilitates comparison of study results from different centers&#46; For patients developing angioedema&#44; a similar Angioedema activity score &#40;AAS&#41; is available&#46; Modified versions of the UAS are also available for inducible urticarias such as Cholinergic Urticaria Activity Score &#40;CholUAS&#41; and Cold Urticaria Activity Score &#40;ColdUAS&#41;&#44; but they are not yet validated&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">1&#44;4</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Assessment of disease control</span><p id="par0120" class="elsevierStylePara elsevierViewall">The disease control can be assessed by the validated Urticaria Control Test &#40;UCT&#41;&#44; both in CSU and CIndu&#46; It is a retrospective questionnaire with a 4-week recall period&#46; It consists of 4 questions each being graded from 0 to 4 in a Likert scale&#44; thus obtaining the total score from 0 &#40;minimum&#41; to 16 &#40;maximum&#41; indicating worst and best controls respectively&#46; The cut-off value is 12&#44; UCT<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>12 indicates &#8220;poorly controlled&#8221; while UCT<span class="elsevierStyleHsp" style=""></span>&#8805;<span class="elsevierStyleHsp" style=""></span>12 indicates &#8220;well-controlled&#8221; urticaria and complete control is indicated by UCT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16 &#40;final goal of treatment in CU&#41;&#46; Similarly&#44; there is Angioedema control test &#40;AECT&#41; with two versions &#8211; one with a recall period of 4-weeks and another with recall period of 3-months&#59; the cut-off value for well-controlled disease is 10&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Assessment of disease impact</span><p id="par0125" class="elsevierStylePara elsevierViewall">It is important to assess the impact of disease on quality of life both in clinical practice and trials and it also affects the overall treatment outcome&#46; The Chronic Urticaria-Quality of life &#40;CU-Q2oL&#41; questionnaire should be used for this purpose&#46; For patients presenting with wheals&#44; additional AE-QoL must be used&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p><p id="par0130" class="elsevierStylePara elsevierViewall">All these PROMs are easy to use&#44; score and interpret&#44; and must be administered to all CSU patients for optimum management&#46; These questionnaires are available in multiple languages to suit patients from various backgrounds&#46;</p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Differential diagnoses</span><p id="par0135" class="elsevierStylePara elsevierViewall">Several clinical conditions may present with wheals and&#47;or angioedema&#44; which form the differential diagnoses for urticaria&#46; <a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a> enumerates some of the common differential diagnoses and their differentiating features&#46;</p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Treatment</span><p id="par0140" class="elsevierStylePara elsevierViewall">Urticaria is a morbid condition&#44; adversely affecting the patient&#39;s quality of life&#44; and most cases of CU last for about 1&#8211;4 years&#46; CIndUs have a longer duration&#44; approximately ranging from 5 to 12 years&#46; Relapses are also common&#44; reported in about 6&#8211;31&#37; CSU patients&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">33</span></a> So&#44; we should treat urticarias effectively to improve the patients&#8217; quality of life&#44; reduce their societal burden and reduce the disease comorbidities&#46; We have categorized the therapeutic options under two heads &#8211; general&#47;non-pharmacologic measures and specific&#47;pharmacologic measures&#46; Specific measures have been further subdivided into current treatment recommendations and emerging and investigational therapies&#46; This section is intended to appraise readers about the currently available treatment options&#44; and also make them aware about emerging therapeutic strategies for recalcitrant patients&#46;</p><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">General&#47;non-pharmacologic measures</span><p id="par0145" class="elsevierStylePara elsevierViewall">Elimination of exogenous triggers&#44; e&#46;g&#46; NSAIDs and cross-reacting agents constitute the most important general&#47;non-pharmacologic measure for both acute and chronic urticarias&#44; when suggested by history and intermittent course&#46; One must also address other inciting factors such as infections&#44; stress or any underlying condition such as malignancy&#44; to achieve disease remission&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">34</span></a> CIndUs&#44; by definition&#44; are triggered by specific factors&#44; which must be eliminated&#47;reduced to achieve resolution&#44; but the avoidance may be difficult for patients and worsen their quality of life&#44; e&#46;g&#46; avoiding hot temperatures in cholinergic urticarias&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> So&#44; these patients must be counseled adequately to minimize such triggers&#46; Notably&#44; urticaria does not improve in a subset of patients despite addressing their triggering&#47;associated factors&#44; e&#46;g&#46; <span class="elsevierStyleItalic">H&#46;pylori</span> eradication in CSU and limited role of thyroid medications even in CSU patients with concomitant thyroid disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0325"><span class="elsevierStyleSup">21&#44;35</span></a> Thus&#44; it is not recommended to perform the extended diagnostic tests in all CU patients&#44; unless clinically indicated&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Specific&#47;pharmacologic measures</span><p id="par0150" class="elsevierStylePara elsevierViewall">Several therapeutic options are being currently utilized for treating urticaria&#44; while newer options are being investigated for inadequate responders to conventional therapy&#46; The current and investigational therapies are briefly discussed below&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Current treatment recommendations</span><p id="par0155" class="elsevierStylePara elsevierViewall">All current treatment guidelines recommend a 3-step algorithmic approach&#44; where we start with the 1st step and gradually progress to the 2nd and 3rd steps if patients fail to respond to the preceding step in a timely and effective manner &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>b&#41;&#46; These guidelines are applicable to both CSU and CIndU&#44; and also in special populations including children&#44; elderly &#40;dose adjusted for weight&#41; and pregnancy&#46;</p><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">First-step</span><p id="par0160" class="elsevierStylePara elsevierViewall">All guidelines recommend 2nd generation antihistamines &#40;sgAHs&#41; in standard-doses which may be up-dosed up to 4-times their standard dose&#44; as the 1st line therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">1&#44;36</span></a> Almost all 2nd generation antihistamines have proven their safety and efficacy even when up-dosed to 4-times their standard does&#44; such as cetirizine&#44; levocetirizine&#44; loratadine&#44; desloratadine&#44; fexofenadine&#44; ebastine&#44; rupatadine and bilastine&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">37</span></a> A recent meta-analysis has reported higher risk of somnolence with up-dosed sgAHs&#44; compared to their standard doses&#46;<a class="elsevierStyleCrossRef" href="#bib0410"><span class="elsevierStyleSup">38</span></a> These drugs are affordable and act as inverse agonists blocking the effect of histamine via H1 receptors&#46; The use of first-generation antihistamines is strongly discouraged by all guidelines&#44; as they have multiple anti-cholinergic adverse-effects and drug interactions&#46; The widely accepted EAACI&#47;GA&#40;2&#41;LEN&#47;EuroGuiDerm&#47;APAAACI guideline does not recommend additional montelukast or switching to another sgAH in non-responders&#44; however these measures are considered by the British guideline for inadequate responders&#44; before moving to the 2nd step&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">36</span></a></p><p id="par0165" class="elsevierStylePara elsevierViewall">Acute urticarias usually resolve with sgAHs alone and many cases are self-resolving&#44; but almost 60&#37; CU patients do not respond adequately to up-dosed sgAHs even after 2&#8211;4 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0405"><span class="elsevierStyleSup">37</span></a> In such patients one must initiate the 2nd-step of guideline&#46;</p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Second-step</span><p id="par0170" class="elsevierStylePara elsevierViewall">The second step involves add-on Omalizumab &#40;humanized monoclonal anti-IgE Ab&#41; in standard dose &#40;300<span class="elsevierStyleHsp" style=""></span>mg SC q4weeks&#41;&#44; which may be up-dosed to 600<span class="elsevierStyleHsp" style=""></span>mg q4weeks if needed&#46;<a class="elsevierStyleCrossRefs" href="#bib0225"><span class="elsevierStyleSup">1&#44;36</span></a> This molecule binds free IgE and reduces its serum level&#44; subsequently downregulating the high affinity FceR1 receptors on basophils and mast cells&#46; Reduced FceR1 expression further lowers the chance of activation by IgE and IgG antibodies&#44; thus restricting histamine release and improving urticarial symptoms&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a> Omalizumab is approved in all CSU patients aged &#8805;12 years&#44; and it also improves the patient&#39;s quality of life in real-life settings&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">39</span></a> Omalizumab is extremely safe&#44; without any serious adverse events&#44; however its use remains guarded during pregnancy and lactation&#46;<a class="elsevierStyleCrossRef" href="#bib0420"><span class="elsevierStyleSup">40</span></a> CSU patients with type 1 autoimmunity or autoallergy&#44; i&#46;e&#46; high IgE&#47;anti-TPO IgG ratio&#44; show a more favorable and rapid response with omalizumab&#44; while those with type IIb autoimmunity are more likely slow-responders&#44; partial responders or non-responders to omalizumab&#46;</p></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Third step</span><p id="par0175" class="elsevierStylePara elsevierViewall">The third and final step constitutes cyclosporine &#40;PO&#44; 3&#8211;5<span class="elsevierStyleHsp" style=""></span>mg&#47;kg&#47;day&#44; add-on to sgAHs&#41; in patients remaining uncontrolled after 6 months therapy with omalizumab&#46; It is a T-cell immune-suppressor which blocks the release of Th2 cytokines&#44; thereby halting the activation of effector mast cells and basophils in CU&#46; A recent meta-analysis has established its efficacy in almost 75&#37; CSU patients&#44; however its long-term use needs careful monitoring to reduce the risks of severe adverse effects including renal impairment&#44; hypertension and dyslipidemias&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">41</span></a> The British guidelines have placed cyclosporine in the second step along with omalizumab&#44; and have recommended multiple agents such as H2 antihistamines&#44; azathioprine&#44; dapsone&#44; doxepin&#44; hydroxychloroquine&#44; IVIg&#44; methotrexate&#44; mycophenolate mofetil&#44; NB-UVB&#44; sulfasalazine&#44; tacrolimus or tranexamic acid &#40;isolated angioedema without wheals&#41; as third line therapy for refractory cases&#46;<a class="elsevierStyleCrossRef" href="#bib0400"><span class="elsevierStyleSup">36</span></a> However&#44; the evidence regarding these agents is variable and there is lack of comparative controlled trials&#44; so they are not recommended by the EAACI&#47;GA&#40;2&#41;LEN&#47;EuroGuiDerm&#47;APAAACI guideline&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a> Cyclosporine shows better results in type IIb autoimmune CSU&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">4</span></a></p></span></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Treatment monitoring and goals</span><p id="par0180" class="elsevierStylePara elsevierViewall">The current EAACI&#47;GA&#40;2&#41;LEN&#47;EuroGuiDerm&#47;APAAACI guideline recommends assessment of urticaria control to monitor treatment status&#44; and decide whether upgrade or downgrade of treatment is needed&#46; Urticaria control can be assessed by a simple 4-item questionnaire&#44; the urticaria control test &#40;UCT&#41;&#46; The total score ranges from 0 to 16&#44; 0 and 16 indicating worst and best disease control respectively&#46; The cut-off value is 12&#46; If UCT<span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>12&#44; the disease is poorly controlled&#44; so up-dosing is needed&#44; while if the UCT is 12&#8211;15&#44; then the current treatment regimen may be maintained&#44; while UCT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16 indicates complete cure&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The current treatment goal in CSU is complete disease control&#44; indicated by an urticaria activity score 7 &#40;UAS7<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#41; and urticaria control test &#40;UCT<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>16&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">1</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">As discussed previously&#44; several biomarkers have been studied to predict the therapeutic response of CSU to H1-antihistamines&#44; omalizumab and cyclosporine&#44; even before initiation of actual treatment&#46; Inadequate responders to omalizumab may be grouped under 3 heads &#8211; partial responders&#44; slow responders and non-responders&#46; This would subsequently help physicians in foretelling the disease prognosis and initiate appropriate targeted therapy&#44; subsequently improving the physician-patient relationship&#46; <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a> highlights the important biomarkers in CSU and their association with disease characteristics&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">30&#44;32&#44;42</span></a></p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Emerging and investigational therapies</span><p id="par0195" class="elsevierStylePara elsevierViewall">The currently available treatments fail to achieve complete disease control in all patients&#44; so newer treatment options are being explored for recalcitrant patients&#46; These treatment options are targeted against newer mediators and receptors&#44; beyond mast-cells and IgE&#44; which are being unraveled by recent research &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;&#46; These agents are in different phases of development and may herald a brighter and better future for all urticaria patients&#46;</p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia></span></span><span id="sec0135" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0155">Systemic comorbidities</span><p id="par0200" class="elsevierStylePara elsevierViewall">Although urticaria is a relatively benign condition&#44; recently several systemic comorbidities have been reported in long-standing cases&#46; These comorbidities involve multiple systems and have a variable occurrence&#46; It is now known that patients with type IIb autoimmunity are more prone to develop long standing disease and such systemic comorbidities&#46;<a class="elsevierStyleCrossRef" href="#bib0285"><span class="elsevierStyleSup">13</span></a> So&#44; it is imperative to diagnose urticaria correctly&#44; and initiate early and appropriate treatment early to reduce such comorbidities&#46; Patients at higher risk should be screened regularly for systemic comorbidities&#44; even at nascent stage&#44; for early detection and management&#46; The most important systemic comorbidities include autoimmune&#44; atopic and psychiatric disorders&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">43&#44;44</span></a> However&#44; it is unclear whether these co-morbidities develop after urticaria onset&#44; i&#46;e&#46; causally related or simply coexist independently&#46;</p></span><span id="sec0140" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0160">Conclusion</span><p id="par0205" class="elsevierStylePara elsevierViewall">Urticaria is a relatively common dermatosis&#44; which can be acute &#40;&#60;6 weeks duration&#41; or chronic &#40;&#62;6 weeks&#41;&#46; Chronic urticaria can either be spontaneous or inducible&#44; based on the absence or presence of specific triggering factors&#44; and both subtypes may co-exist&#46; It is primarily a mast cell mediated histaminergic disorder&#44; however&#44; newer research has highlighted the role of heterogeneous inflammatory cells&#44; e&#46;g&#46; eosinophils and lymphocytes and their mediators&#44; e&#46;g&#46; platelet activating factor&#46; Acute urticaria is a type 1 hypersensitivity reaction to exo-allergens such as food and drug and may occur spontaneously or as a manifestation of anaphylaxis&#46; In contrast&#44; chronic urticaria occurs as a result of autoimmunity against endogenous substances&#44; and role of external agents is negligible&#46; Recently two pathways have been described which may trigger the activation and degranulation of mast cells in CSU and form the basis of an endotypic classification &#8211; type 1 autoimmunity&#47;autoallergy and type IIb autoimmunity involving IgE and IgG autoantibodies respectively&#46; Further work is needed to characterize these endotypes&#44; search for newer ones and decipher the mechanisms of inducible urticarias&#46; Although urticaria is primarily a clinical diagnosis&#44; recent recommendations involve the use of PROMs in chronic urticaria to assess disease activity&#44; control and impact&#44; which reflects the societal burden of this chronic disorder&#46; The other indications of investigations in chronic urticaria including ruling out differential diagnoses&#44; screening patients for systemic co-morbidities and confirming inducible urticarias &#40;threshold tests&#41;&#46; Currently&#44; 2nd generation H1-antihistamines&#44; omalizumab and cyclosporine are approved for a step-wise algorithmic treatment approach&#44; but almost 1 in 3 patients remain uncontrolled&#46; Several newer therapeutic strategies are being currently investigated aimed at inhibiting signals blocking mast cell activation&#44; blocking intracellular effector pathways&#44; silencing and depleting mast cells&#44; and targeting other inflammatory cells&#44; their mediators and receptors&#46; Complete disease control remains the ultimate goal along with improved quality of life&#46; The current review will appraise urticaria treating physicians about recent developments in this field&#44; including novel treatment strategies&#44; to ensure best care for their patients&#46;</p></span><span id="sec0145" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0165">Data availability statement</span><p id="par0210" class="elsevierStylePara elsevierViewall">Further data&#44; if necessary&#44; would be available from corresponding author upon reasonable request&#46;</p></span><span id="sec0150" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0170">Author&#39;s contribution</span><p id="par0215" class="elsevierStylePara elsevierViewall">All authors contributed equally to this manuscript&#46;</p></span><span id="sec0155" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0175">Ethical consideration</span><p id="par0220" class="elsevierStylePara elsevierViewall">This manuscript is a review&#46; No patients are included&#46; No informed consent is required&#46;</p></span><span id="sec0160" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0180">Funding</span><p id="par0225" class="elsevierStylePara elsevierViewall">No funding sources&#46;</p></span><span id="sec0165" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0185">Conflicts of interest</span><p id="par0230" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleBold">Ana Maria Gimenez-Arnau</span> &#8211; Medical Advisor for Uriach Pharma&#47;Neucor&#44; Genentech&#44; Novartis&#44; FAES&#44; GSK&#44; Sanofi&#8211;Regeneron&#44; Amgen&#44; Thermo Fisher Scientific&#44; Almirall&#44; Celldex&#44; Leo Pharma Research Grants supported by <span class="elsevierStyleGrantSponsor" id="gs1">Uriach Pharma</span>&#44; <span class="elsevierStyleGrantSponsor" id="gs2">Novartis</span>&#44; Grants from <span class="elsevierStyleGrantSponsor" id="gs3">Instituto Carlos III</span> &#8211; FEDER Educational activities for Uriach Pharma&#44; Novartis&#44; Genentech&#44; Menarini&#44; LEO-PHARMA&#44; GSK&#44; MSD&#44; Almirall&#44; Sanofi&#44; Avene&#46; <span class="elsevierStyleBold">Nerea Manzanares</span> and <span class="elsevierStyleBold">Indrashis Podder</span> have no conflicts of interest to declare&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Urticaria is a skin-condition characterized by sudden-onset pruritic wheals with&#47;without angioedema&#46; Urticaria can be acute or chronic&#46; Chronic urticaria may be spontaneous or inducible&#44; based on absence&#47;presence of specific triggers&#46; Chronic spontaneous urticaria is most frequent &#40;&#8764;80&#37;&#41;&#46; Urticaria is primarily a mast-cell mediated histaminergic-disorder&#46; Recently&#44; other inflammatory cells and pro-inflammatory cytokines have been implicated&#46; Deeper understanding has unmasked two endotypes &#8211; IgE-mediated type I autoimmunity&#47;autoallergy and IgG-mediated type IIb autoimmunity&#46; Current treatment recommendation involving second-generation H1-antihistamines&#44; omalizumab and cyclosporine is effective in 60&#8211;80&#37; patients&#46; So&#44; newer treatment options are being explored based on emerging targets&#46; Despite being non-lethal&#44; urticaria considerably impairs patient&#39;s quality-of-life and may be associated with extra-cutaneous comorbidities&#46; Several &#8220;patient reported outcome measures&#8221; have been proposed to evaluate disease-activity&#44; impact and control&#44; for effective treatment modulation till complete disease control&#46; This review discusses the current understanding about urticaria and its future directions&#44; to facilitate optimum evidenced-based care&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">La urticaria es una afecci&#243;n de la piel caracterizada por ronchas pruriginosas de aparici&#243;n repentina con o sin angioedema&#46; La urticaria puede ser aguda o cr&#243;nica&#46; La urticaria cr&#243;nica puede ser espont&#225;nea o inducible&#44; seg&#250;n la ausencia&#47;presencia de desencadenantes espec&#237;ficos&#46; La urticaria cr&#243;nica espont&#225;nea es la m&#225;s frecuente &#40;&#8764;80&#37;&#41;&#46; La urticaria es principalmente un trastorno histamin&#233;rgico mediado por mastocitos&#46; Recientemente se han implicado otras c&#233;lulas inflamatorias y citocinas proinflamatorias&#46; Una comprensi&#243;n m&#225;s profunda ha desenmascarado dos endotipos&#58; autoinmunidad&#47;autoalergia tipo I mediada por IgE y autoinmunidad tipo IIb mediada por IgG&#46; La recomendaci&#243;n de tratamiento actual que incluye antihistam&#237;nicos H1 de segunda generaci&#243;n&#44; omalizumab y ciclosporina es eficaz en 60-80&#37; de los pacientes&#46; Por lo tanto&#44; se est&#225;n explorando opciones de tratamiento m&#225;s nuevas en funci&#243;n de objetivos emergentes&#46; A pesar de no ser letal&#44; la urticaria deteriora considerablemente la calidad de vida del paciente y puede estar asociada con comorbilidades extracut&#225;neas&#46; Se han propuesto varias &#171;medidas de resultado informadas por el paciente&#187; para evaluar la actividad&#44; el impacto y el control de la enfermedad&#44; para la modulaci&#243;n efectiva del tratamiento hasta el control completo de la enfermedad&#46; Esta revisi&#243;n analiza la comprensi&#243;n actual sobre la urticaria y sus direcciones futuras&#44; para facilitar una atenci&#243;n &#243;ptima basada en evidencia&#46;</p></span>"
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          "leyenda" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">sgAH&#58; second generation anti-histamines&#59; ASST&#58; autologous serum skin test&#59; CRP&#58; C-reactive protein&#59; IL&#58; interleukin&#59; PAF-AH&#58; platelet activating factor-acetylhydrolase&#59; PAF&#58; platelet activating factor&#59; BHRA&#58; basophil histamine release assay&#59; TPO&#58; thyroidperoxidase&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td-with-role" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col">Disease characteristic indicated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " colspan="2" align="center" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name of biomarker</th></tr><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Serological&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="6" align="left" valign="middle">Increased CSU activity or severity</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Older age of disease onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Elevated CRP&#44; mean platelet volume&#44; D-dimer&#44; anti-thyroid antibodies&#44; IL-6&#44; IL-17 and IL-18&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Female gender&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Basopenia&#44; Eosinopenia&#44; low serum vitamin D&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Longer duration of disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Positive basophil activation test &#40;BAT&#41; &#40;increased expression of CD63 and CD203&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Presence of angioedema&#44; concomitant CIndU&#44; NSAID hypersensitivity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Inadequate response to sgAHs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Positive ASST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Prolonged disease course&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Elevated levels of anti-thyroid antibodies&#44; Positive BAT and higher CD63 expression&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Shorter disease duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Elevated serum CRP level&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="middle">Poor&#47;inadequate response to second-generation anti-histamines</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; More severe disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Elevated CRP and D-dimer levels&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Positive ASST&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Lower PAF-AH&#47;PAF ratio&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="middle">Good responders to omalizumab</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; High baseline serum total IgE level &#40;T1aiCSU&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Week-4IgE&#47;baseline IgE ratio &#62;2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; &#8593;FceR1 expression on basophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Slow&#47;non-responders to omalizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Positive BAT&#47;BHRA indicating T2aiCSU&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " colspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleVsp" style="height:0.5px"></span></td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="middle">Good responders to cyclosporine</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Patients with T2aiCSU indicated by high serum anti-TPO IgG&#44; low total IgE&#44; positive ASST and positive BAT&#47;BHRA&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Low serum D-dimer level&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Emerging biomarkers in chronic spontaneous urticaria and their interpretation&#46;</p>"
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        "identificador" => "tbl0010"
        "etiqueta" => "Table 2"
        "tipo" => "MULTIMEDIATABLA"
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          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">CIndU&#58; chronic inducible urticaria&#59; ESR&#58; erythrocyte sedimentation rate&#59; CRP&#58; C-reactive protein&#59; ANA&#58; anti-nuclear antigen&#59; RA&#58; rheumatoid arthritis&#59; TPO&#58; thyroid peroxidase&#59; PROM&#58; patient reported outcome measures&#59; UAS7&#58; urticaria activity score 7&#59; CU2QoL&#58; chronic urticaria quality of life&#59; UCT&#58; urticaria control test&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Aims-7Cs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Physical examination &#40;<span class="elsevierStyleItalic">all patients</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Basic tests &#40;<span class="elsevierStyleItalic">all patients</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Extended diagnostic tests &#40;<span class="elsevierStyleItalic">selected patients if necessary after basic tests</span>&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Confirm and rule out differentials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Presence of characteristic itchy wheals<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>angioedema&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Differential blood count&#44; ESR or CRP&#46;&#8226; Total serum IgE and IgG-anti-TPO &#40;high or low IgE&#47;TPO ratio indicates type 1 or type 2 autoimmune pathogenesis respectively&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Skin biopsy &#40;to rule out differentials&#44; e&#46;g&#46; urticarial vasculitis&#41; provocation tests for CIndUs&#44; basophil activation tests&#44; thyroid hormones&#44; serum tryptase &#40;for severe systemic disease&#41;&#44; <span class="elsevierStyleItalic">H&#46; pylori</span> evaluation&#44; allergy tests&#44; e&#46;g&#46; elimination diets &#8211; may be performed when necessary in select patients&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cause&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autologous serum skin test &#40;ASST&#41;&#44; basophil activation test &#40;BAT&#41;&#44; thyroid hormone level&#44; ANA&#44; RA factor may be done in patients with type IIb autoimmunity&#46; Raised CRP&#44; basopenia and eosinopenia are more frequent in type II endotype&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Co-factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Identify potential triggers and aggravators that can modify disease activity &#8211; drugs&#44; food&#47;pseudo-allergens&#44; stress and infection&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Drug provocation tests &#40;e&#46;g&#46; NSAID induced&#47;exacerbated disease&#41;&#44; elimination diets for 3&#8211;4 weeks&#46;Food induced CSU is extremely rare&#44; however pseudo-allergens act as a trigger in some patients by a non-immunologic mechanism &#40;non-IgE&#41;&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Comorbidities&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">To check for CIndUs&#44; autoimmunity and mental health&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Provocation tests to confirm CIndUs&#44; other tests to confirm autoimmunity &#91;as stated above&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Consequences&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Identify associated problems such as sleep disturbances&#44; sexual health and societal burden due to disease&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Components&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Assess potential biomarkers for therapeutic response&#44; e&#46;g&#46; raised d-dimer is a marker for antihistamine unresponsiveness&#44; type I autoimmunity &#40;high IgE&#47;TPO&#41; is a marker for faster and better omalizumab response while type IIb autoimmunity &#40;high TPO&#44; low IgE&#44; ASST&#43;&#44; BAT&#43;&#44; high CRP&#44; basopenia&#44; eosinopenia&#41; is a marker for poor response to omalizumab and more favorable response with cyclosporine&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Course&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Evaluate and monitor disease activity&#44; impact and control by PROM questionnaires&#46;Activity &#8211; UAS7Impact &#8211; CU2QoLControl &#8211; UCT&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8211;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Diagnostic work-up recommended in chronic spontaneous urticaria patients&#46;</p>"
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      4 => array:8 [
        "identificador" => "tbl0015"
        "etiqueta" => "Table 3"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
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          0 => array:3 [
            "identificador" => "at3"
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        "tabla" => array:1 [
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name of condition&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Differentiating features from urticaria&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Urticarial vasculitis</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Wheals persist for &#62;24<span class="elsevierStyleHsp" style=""></span>h&#44; while in urticaria they last &#60;24<span class="elsevierStyleHsp" style=""></span>h&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Skin biopsy shows fibrinolytic degeneration of vessel walls&#44; extravasated blood cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="2" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cell disorders like maculopapular cutaneous mastocytosis &#40;urticaria pigmentosa&#41;&#44; indolent systemic mastocytosis with skin involvement and mast cell activation syndrome &#40;MCAS&#41;</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Urticaria pigmentosa usually occurs in young children&#44; wheals heal with residual pigmentation&#44; Darier&#39;s sign positive&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Serum tryptase level may be elevated&#44; other features of systemic mastocytosis may be present in indolent systemic mastocytosis and MCAS&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " rowspan="3" align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Hereditary angioedema&#47;drug-induced angioedema</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Positive family history&#44; low complement levels &#40;C3&#44; C4&#44; CH50&#41;&#44; quantitative and&#47;or qualitative deficiency of C1-esterase inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; The principal mediator is bradykinin &#40;vs&#46; histamine in urticaria&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Offending drug history is present&#44; e&#46;g&#46; ACEIs&#44; gliptins&#44; etc&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Autoinflammatory syndromes &#40;cryopyrin associated periodic syndromes &#91;CAPS&#93;&#44; familial cold autoinflammatory syndrome &#91;FCAS&#93;&#44; Muckle-Wells syndrome &#91;MWS&#93; and Neonatal onset multisystem inflammatory disorder &#91;NOMID&#93;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Recurrent fever episodes&#44; arthralgia or arthritis&#44; fatigue&#44; headache&#44; very high ESR or CRP on routine hematology&#44; amyloidosis &#91;MWS&#93;&#44; raised serum ferritin<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>Still&#39;s disease&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Schnitzler&#39;s syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Recurrent fever&#44; joint pain&#44; muscle pain&#44; lymphadenopathy and monoclonal gammopathy&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Adult onset Still&#39;s disease&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Raised serum ferritin&#44; echocardiographic changes suggesting cardiologic involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Gleich&#39;s syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Recurrent episodic angioedema with eosinophlia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Well&#39;s syndrome&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Granulomatous dermatitis with eosinophilia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bullous pemphigoid &#40;pre-bullous stage&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Long standing disease especially in the elderly&#44; characteristic skin biopsy and DIF findings&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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        "descripcion" => array:1 [
          "en" => "<p id="spar0045" class="elsevierStyleSimplePara elsevierViewall">Common and important differential diagnoses of urticaria and their identifying features&#46;</p>"
        ]
      ]
      5 => array:8 [
        "identificador" => "tbl0020"
        "etiqueta" => "Table 4"
        "tipo" => "MULTIMEDIATABLA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at4"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:1 [
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Class of drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Mechanism of action&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Name of drug&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Remarks&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Current status&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Inhibitors of mast cell activation by blocking ligands and&#47;or receptors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Reducing serum IgE concentration by binding free IgE and subsequently down regulating FceR1 receptors on mast cells and basophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Ligelizumab&#8226; UB-221&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">These molecules have a higher affinity for IgE and FceR1 receptors &#8211; so block them more effectively &#40;vs&#46; omalizumab&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ligelizumab trial stopped in phase 3&#44; as it failed to show significant benefit over omalizumab&#46;UB-221 &#8211; Undergoing phase 1 trials&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blockers of MRGPRX2 receptor on mast cells&#44; and its agonists&#44; e&#46;g&#46; substance P&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Aprepitant&#8226; Tradipitant&#8226; Serlopitant&#8226; Orvepitant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Block substance P mediated activation of MRGPRX2 receptors &#40;expressed preferentially by skin mast cells&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Preclinical&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blockers of CRTh2 or PGD2 receptor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; AZD1981&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blocks PGD2 mediated activation of mast cells and basophils&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2 trial completed&#44; but primary objective not achieved&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Complement C5a receptor blocker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Eculizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blocks C5a mediated activation and degranulation of skin mast cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Proof of concept&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Interferes with intracellular signaling pathways&#44; thus blocking the degranulation of mast cells&#44; even if activated&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Bruton&#39;s tyrosine kinase inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Fenebrutinib&#44; Remibrutinib and Rilzabrutinib&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Oral drugs&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2&#8211;3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Spleen tyrosine kinase inhibitor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; GSK2646264&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Topical medication&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cell silencers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-Siglec-8 monoclonal antibody &#40;humanized&#44; non-fucosylated IgG1&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Lirentelimab&#47;AK002&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Engage&#47;occupy inhibitory receptors on mast cells &#40;Siglec-8&#41;&#44; thus making them dormant and preventing their activation by triggers&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mast cell depletors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blockers of KIT receptor &#40;CD117&#41; on mast cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Barzolvolimab &#40;CDX-0159&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stem cell factor &#40;SCF&#41; is needed for the survival&#44; differentiation&#44; proliferation and activation of mast cells&#44; which act via CD117&#46; These drugs block the action of SCF and deplete mast cells&#46;Not specific for skin mast cells&#44; so can deplete other tissue mast cells like brain&#44; lung resulting in systemic complications&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Phase 1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-5 blockers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Anti-IL-5 monoclonal antibody&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Mepolizumab and Reslizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Block the IL-5 mediated recruitment and activation of eosinophils and mast cells&#44; which are important effector cells for urticaria These drugs are currently approved for recalcitrant eosinophilic asthma&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mepolizumab and Reslizumab<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>Not yet approved&#44; pilot study underway for CSU and cold urticaria&#46;Benralizumab<span class="elsevierStyleHsp" style=""></span>&#8594;<span class="elsevierStyleHsp" style=""></span>Phase 2b dose determining trial &#8211; ARROYO is currently underway&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monoclonal antibody blocking the IL-5 receptor&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Benralizumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-4&#47;IL-13 blocker&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-4 and IL-13 are important Th2 cytokines involved in the pathogenesis of urticaria&#46;IL-4 mediates Ig class switching to IgE&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Dupilumab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Currently approved for recalcitrant cases of moderate to severe atopic dermatitis&#44; bronchial asthma and chronic rhinosinusitis with polyposis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">RCTs being conducted in CSU and CIndU&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blockers&#47;inhibitors of type 1 cytokines&#44; e&#46;g&#46; TNF-&#945; and IL-1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">TNF-&#945; inhibitors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Adalimumab&#44; Etanercept&#44; Infliximab&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Type 1 cytokines are involved in a subset of patients with autoinflammatory syndromes&#46; Cautious use is warranted as they may reactivate latent infections such as tuberculosis and hepatitis&#46; There are also reports of demyelinating disorders and lymphomas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No robust evidence&#44; only sporadic reports suggest its beneficial role in a subset of patients&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">IL-1 blockers&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Canakinumab&#44; rilonacept&#44; anakinra&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Antifibrinolytic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Block the fibrin degeneration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#8226; Tranexamic acid&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Blocks the action of extrinsic coagulation pathway in CSU pathogenesis&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Role is not completely clear&#44; sporadic reports exist&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
              ]
              "imagenFichero" => array:1 [
                0 => "xTab3334301.png"
              ]
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        "descripcion" => array:1 [
          "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Newer and emerging treatment options for recalcitrant urticaria<a class="elsevierStyleCrossRefs" href="#bib0240"><span class="elsevierStyleSup">4&#44;13</span></a>&#46;</p>"
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0015"
          "bibliografiaReferencia" => array:44 [
            0 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The international EAACI&#47;GA<span class="elsevierStyleSup">2</span>LEN&#47;EuroGuiDerm&#47;APAAACI guideline for the definition&#44; classification&#44; diagnosis&#44; and management of urticaria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Zuberbier"
                            1 => "A&#46;H&#46; Abdul Latiff"
                            2 => "M&#46; Abuzakouk"
                            3 => "S&#46; Aquilina"
                            4 => "R&#46; Asero"
                            5 => "D&#46; Baker"
                          ]
                        ]
                      ]
                    ]
                  ]
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